Brain and Behavior

BRAIN AND BEHAVIOR

JILL GROSE-FIFER, PH.D.

Brain and Behavior Copyright © 2024 by Jill Grose-Fifer is licensed under a Creative Commons
Attribution-NonCommercial-ShareAlike 4.0 International License, except where otherwise noted.
CONTENTS

Front Matter 1

Chapter 1: Introduction to Biological Psychology

1.1: Introduction 5
Michael J. Hove and Steven A. Martinez
1.2: The Field of Biological Psychology 9
Michael J. Hove and Steven A. Martinez
1.3: The Scientific Approach to Understand Brain and Behavior 13
Michael J. Hove and Steven A. Martinez
1.4: Payoffs of Biological Psychology 17
Michael J. Hove and Steven A. Martinez
1.5: Research with Animals 22
Michael J. Hove and Steven A. Martinez
1.6: Diversity in Biological Psychology 24
Michael J. Hove and Steven A. Martinez
1.7: Biological Psychology Myths 26
Austin Lim, Ph.D.
1.8: References 32

References 32
Chapter 2: Neurons

2.1: Introduction 37
Jill Grose-Fifer, Ph.D.; Michael J. Hove; and Steven A. Martinez
2.2: The Structure of the Neuron 41
Michael J. Hove and Steven A. Martinez

Basic Nomenclature 41
2.3: Types of Cells in the Brain 44
2.4: Communication Within and Between Neurons 48

Resting Membrane Potential 48

Action Potential 52

The Change in Membrane Potential During an Action Potential 55

2.5: Discussion Questions and Resources 60
2.6: References 63

References 63

Chapter 3: The Brain and Nervous System

3.1: Introduction 67
Michael J. Hove and Steven A. Martinez
3.2: Visualizing and Navigating the Human Brain 68
Michael J. Hove and Steven A. Martinez
3.3: The Nervous System 70
Michael J. Hove and Steven A. Martinez
3.4: The Peripheral Nervous System 73
Michael J. Hove and Steven A. Martinez

The Autonomic Nervous System 74

The Somatic Nervous System 76

3.5: The Central Nervous System 82
Michael J. Hove and Steven A. Martinez
3.6: The Brain 85
Michael J. Hove and Steven A. Martinez

Cerebral Cortex 86

Frontal Lobe 91

Temporal Lobe 94

Parietal Lobe 96

Occipital Lobe 99

Insula 99

Limbic System 100

Basal Ganglia 103

Thalamus 105

Hypothalamus 107

Cerebellum 108

Brainstem 109
3.7: Non-Neuronal Structures in the Central Nervous System 111
Michael J. Hove and Steven A. Martinez

Ventricular System and Cerebrospinal Fluid 111

Vasculature 113
3.8: Conclusion 116
3.9: Discussion Questions and Resources 117
3.10: References 119

Parts of this chapter were adapted from: 119

The Brain and Nervous System References 120

Chapter 4: Research Methods in Biological

Psychology

4.1: Introduction 125

4.2: Historical Methods – Studies of Brain Damage in Humans 126
4.3: Invasive Physiological Research Methods 131
4.4: Tools of Cognitive Neuroscience – EEG and MEG 136
4.5: Tools of Cognitive Neuroscience – Brain imaging, PET and 140
MRI

Magnetic Resonance Imaging 141

4.6: Techniques that Modulate Brain Activity 148
4.7: References 152

Parts of this chapter were adapted from: 152

References 152

Chapter 5: Development of the Brain and Nervous

System

5.1: Introduction 157

Jill Grose-Fifer, Ph.D.; Michael J. Hove; and Steven A. Martinez
5.2 Human Genetics, Evolution, and Epigenetics 158

Genetic Variation 158

Theories of Evolution 161

Gene-Environment Interactions 162

5.3 Nature-Nurture and Twin Studies 165
Jill Grose-Fifer, Ph.D.

Nature-Nurture and Twin Studies 165

What Have We Learned About Nature–Nurture? 171

5.4: Early formation of the structures of the brain 177

Neural Tube 177

Primary Vesicles 179

Secondary Vesicles 179

5.5: Stages of Neuronal Development 181

Adult Neurogenesis 187

5.6: Sensitive and Critical Periods of Development 188

Sensitive Periods of Development 188

Critical Periods of Development 190

Adolescence as a sensitive period of development 191

5.7: Characterizing brain development from infancy through 193
young adulthood
5.8: Conclusion 195
5.9: Discussion Questions and Resources 196
5.10: References 198

Parts of this chapter were adapted from: 198

References 198
Chapter 6. Hearing and the Vestibular System

Chapter 6.1: Introduction to Sensation and Perception 207

Jill Grose-Fifer, Ph.D.

Sensation 207

Perception 207
Chapter 6.2: Perceiving sound: our sense of hearing 209
Dr Eleanor J. Dommett
Chapter 6.3: Vestibular System 244
Austin Lim, Ph.D.

Chapter 7: Vision

Chapter 7: Lighting the world: our sense of vision 251

Dr Eleanor J. Dommett

Chapter 8: Circadian Rhythms and Sleep

Chapter 8:1 Introduction 283

Austin Lim, Ph.D.; Ben Marcus, PhD (editor); and Dana
Simmons, PhD (editor)
8.2: Phases of sleep 286
8.3: Why do we sleep? 291
8.4: The circadian rhythm 299
8.5: Neurochemical signals 306
8.6: Brain structures involved in sleep 312
8.7: Sleep disorders 317
Chapter 9: Learning and Memory

9.1: Introduction to Learning and Memory 327

Austin Lim, Ph.D.; David Graykowski; and Alexandrina Guran,
PhD (Editor)
9.2: Patient HM 329
9.3: Neural Structures Involved in Memory and Learning 340
9.4: Cellular Mechanisms of Learning 355
9.5: Molecular Mechanisms of Learning 366
9.6: Disorders of memory 375

Chapter 10: Lateralization and Language

10.1: Introduction 387

Austin Lim, Ph.D. and Alexandrina Guran, PhD (Editor)
10.1: Lateralization 388
10.2 Language 393

Chapter 11: Emotion and Affective Neuroscience

11.1: Affective Neuroscience: What is it? 409

11.2 Theories of Emotion 412
Austin Lim, Ph.D. and Helena Ledmyr, PhD, INCF (Editor)
11.3: Basic Emotions and Brain Circuitry 418

“Liking”: The neural circuits of pleasure and enjoyment 428

Love: The neural systems of care and attachment 428

11.4 Physiology of stress 435
Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper; William
Jenkins; Arlene Lacombe; Marilyn Lovett; and Marion
Perlmutter

The Physiological Basis of Stress 440

Summary 442
11.5 Stress and Illness 444
Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper; William
Jenkins; Arlene Lacombe; Marilyn Lovett; and Marion
Perlmutter

Psychophysiological Disorders 444

Stress and the Immune System 446

Cardiovascular Disorders 451

Are You Type A or Type B? 453

Depression and the Heart 457

Asthma 460

Tension Headaches 462

Summary 463
11.6 Regulation of Stress 464
Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper; William
Jenkins; Arlene Lacombe; Marilyn Lovett; and Marion
Perlmutter

Coping Styles 464

Control and Stress 465

Social Support 469

Stress Reduction Techniques 473

Summary 475
11.7: References 476
Chapter 12: Brain Damage, Neurodegeneration, and
Neurological Diseases

12.1: Introduction 501

12.2: Stroke 503
12.3: Brain Tumors 508
12.4: Traumatic Brain Injury 511

How TBI affects the brain 511

Diagnosing and Treating TBIs 515

Chronic Traumatic Encephalopathy (CTE) 516

Causes of TBI 518

Traumatic Brain Injury from Intimate Partner Violence – By 519

Prof. Eve Valera
12.5: Neurological and Neurodegenerative Disorders 523
12.6: Alzheimer's Disease 524
12.7: Parkinson’s Disease 529
12.8: Multiple Sclerosis 534
12.9: References 539

Parts of this chapter were adapted from: 539

References 540

Chapter 13: Psychopharmacology

13.1: Introduction 547

13.2: Pharmacokinetics: What Is It and Why Is It Important? 552

Drug Administration 552

Drug Metabolism 554

13.3: Recent Issues Related to Psychotropic Drugs and 556
Metabolism

Grapefruit Juice and Metabolism 556

Individualized Therapy, Metabolic Differences, and Potential 557

Prescribing Approaches for the Future
13.4: Other Controversial Issues 559

Juveniles and Psychopharmacology 559

The Elderly and Psychopharmacology 561

13.5: How Drugs Affect Neurotransmitters 563

Alcohol 563

Caffeine 564

Cannabis 565

Opiates (heroin, morphine, etc.) 567

13.6: Discussion Questions and Resources 569
13.7: Addiction 571
13.8: References 598

References 598

Chapter 14: Biopsychology of Psychological

Disorders

14.1: Biopsychology of Psychological Disorders Overview 605

What are Psychological Disorders? 605

The American Psychiatric Association (APA) Definition of a 606

Psychological Disorder

Understanding the Classification Systems of Psychological 607

Disorders
14.2: Anxiety Disorders 610

Neural mechanisms underlying anxiety disorders 611

14.3: Post-Traumatic Stress Disorder 615

Neural mechanisms underlying post-traumatic stress disorder 615

14.4: Obsessive-Compulsive and Related Disorders 618

Body Dysmorphic Disorder 621

Hoarding Disorder 622

Neural and genetic mechanisms underlying obsessive- 623

compulsive and related disorders
14.5: Mood Disorders 626

Neural mechanisms underlying depression 627

Neural mechanisms underlying bipolar disorders 628

14.6: Schizophrenia 633

Neural mechanisms underlying schizophrenia 634

14.7: Conclusion 639
14.8: Discussion Questions and Resources 641
14.9: References 642

Parts of this chapter were adapted from: 642

References for Psychological Disorders 643

Chapter 15: Hormones and Behavior

15.1: Introduction 657

15.2: Sex Differences 666
15.4: Aggressive Behaviors 674
15.5: Parental Behaviors 677
15.5: Discussion Questions and Resources 680
15.6: References 683

Adapted from: 683

References 683
 FRONT MATTER | 1

FRONT MATTER

This open educational resource has been remixed and edited by Dr. Jill Grose-
Fifer from multiple sources for students in a Brain and Behavior course at John
Jay College. Creative Commons Attribution-NonCommercial-ShareAlike 4.0
International License.
Materials came from:
Lim, A. (2021). Open Neuroscience Initiative https://www.austinlim.com/open-
neuroscience-initiative. To my knowledge, Austin Lim, provided the first OER on
Biological Psychology. I am very grateful for his leadership in paving the
way for others (including myself ) to create free resources for our students.
Creative Commons Attribution-NonCommercial 4.0 International License.
Grose-Fifer et al., (2023). Introduction to psychology: A critical approach. CUNY.
https://pressbooks.cuny.edu/jjcpsy101/. Creative Commons Attribution-
NonCommercial-ShareAlike 4.0 International License.
Hall, C. (Ed). (2023). Introduction to biological psychology. University of Sussex.
https://doi.org/10.20919/ZDGF9829 Creative Commons Attribution-
NonCommercial 4.0 International License.
Much of the material in this book comes from:
Hove, M. J., & Martinez, S. A. (2024). Biological psychology. ROTEL (Remixing
Open Textbooks with an Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/. Creative Commons Attribution-NonCommercial-
ShareAlike 4.0 International License

Cover: Jill Grose-Fifer and Dall-E

2 | FRONT MATTER
 CHAPTER 1: INTRODUCTION TO BIOLOGICAL PSYCHOLOGY | 3

CHAPTER 1:
INTRODUCTION TO
BIOLOGICAL
PSYCHOLOGY

Learning Objectives

• Learn how the field of biological psychology is defined and

identify some of the major branches in the field
• Understand the scientific method that is used to study the brain
and behavior
• Know experimental and research terms, such as hypothesis,
theory, independent variable, dependent variable, random
assignment, replication
• Differentiate basic and applied research
• Learn about the payoffs of biological psychology, such as healing
the brain and guiding artificial intelligence
• Understand and think about how and why research in
biopsychology is performed on animals and the ethical principles
that guides animal research
• Recognize the value of diversity in the field of biological
psychology
• Get an overview of the contents of book
4 | CHAPTER 1: INTRODUCTION TO BIOLOGICAL PSYCHOLOGY

Modules 1.1 to 1.6 of chapter are adapted from Hove, M. J., &
Martinez, S. A. (2024). Biological Psychology. ROTEL (Remixing Open
Textbooks with an Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/

and

Module 1.7 from Lim, A. (2021). Open Neuroscience Initiative.

https://www.austinlim.com/open-neuroscience-initiative
 1.1: INTRODUCTION | 5

1.1: INTRODUCTION
Michael J. Hove and Steven A. Martinez

As you start reading, take a couple of deep breaths. Breathing typically happens
automatically and without your awareness, but you can easily control your body
to take a deep breath. Now point your attention to your expanding chest, the
feeling of air flowing past your lips, and the sound of your deep breath. After
a few mindful breaths, you might feel more “in your body” or relaxed. After a
few months of regularly attending to your breath (as is done in many meditation
practices), you might notice increased attentional control, emotion regulation, and
self-awareness, and actually change the physical structure of your brain (Tang et al.,
2015).
This is all kind of strange and leads to questions such as:

• How can some bodily functions be maintained automatically without

awareness, but can also be controlled under your volition?
• Why are we typically unaware of sensations that are constant, but we can
direct our attention to consciously perceive them?
• Why do we even have subjective experience? (or from an evolutionary
perspective, did having subjective experience help humans survive and pass
on their genes?)
• Who, what, and where is the “self” who experienced this? (There are no little
characters pulling levers in your head like in the Disney movie Inside Out.)
• How can awareness of a few deep breaths change your emotional state?
• How can regularly performing an activity change the structure of your
brain?

The answers to all these questions relate to the brain. Experience, awareness, and
the feeling of self, and in fact all of our thoughts, perceptions, movements, and
emotions, emerge from the patterns of electrochemical signals zipping along the 86
billion neurons in your brain. The human brain is the most complex object that
we know of in the universe; each neuron is as complex as a major city and connects
 6 | 1.1: INTRODUCTION
with thousands of other neurons, resulting in 300 million neuronal connections
in a single cubic millimeter of brain (that’s the size of the tip of a ballpoint pen!)
(Eagleman & Downar, 2016; Lichtman, n.d.). Scaling that up, the entire
brain–about 1200 cubic centimeters and weighing around 3 pounds–contains
about 60 trillion synaptic connections and essentially infinite possible patterns of
activation. These patterns of brain activation make you, you.1
We are still learning about the brain and many big mysteries remain, but
scientists do know an astounding amount about how the brain works. In the
past decades, researchers have made tremendous progress in understanding the
molecular and chemical processes in the brain, how neurons communicate with
each other, the function of different brain areas and networks, how drugs and
hormones affect brain function, how genes and environment shape brain and
behavior, how the brain develops and changes over time, and ways things can go
wrong in the brain due to damage, disease, or psychological disorders. We’ll explore
these topics and more in this book on Biological Psychology.

1. The nature of the self and what makes you "you" is a deep and nuanced scientific, philosophical, and
even spiritual question. Understanding the nature of the "true self" is a primary goal of many spiritual
traditions (Singer, 2007). For an excellent scientific treatment of the nature of the self, including the
brain, bodily, social, and environmental underpinnings of selfhood, see the book "Who You Are: The
Science of Connectedness" by Michael Spivey (2020).
 1.1: INTRODUCTION | 7

Figure 1.1a. Why we are the way we are: networks of axonal nerve fibers
in the brain as measured by Magnetic Resonance Imaging (MRI),
specifically diffusion tensor imaging. CREDIT: Axonal nerve fibers ©
Wikipedia is licensed under a CC BY (Attribution) license
8 | 1.1: INTRODUCTION

Figure 1.1b. A graphical depiction of the vast interconnectedness of

large-scale brain regions. Nodes are depicted as white squares and
interconnections between nodes (i.e., brain regions) are depicted in
red-blue lines overlaid on a grayscale image of the brain. CREDIT:
Interconnectedness of large-scale brain regions. © Wikipedia is licensed under a
CC BY (Attribution) license
 1.2: THE FIELD OF BIOLOGICAL PSYCHOLOGY | 9

1.2: THE FIELD OF BIOLOGICAL

PSYCHOLOGY
Michael J. Hove and Steven A. Martinez

What is Biological Psychology? Biological psychology is the scientific study

that links brain and behavior. Biological psychology, or biopsychology or biopsych
for short, is related to neighboring disciplines including psycho-biology and
behavioral neuroscience (Pinel & Barnes, 2017). The distinction is subtle, but
we use the term biological psychology here because it emphasizes the centrality
of psychology (i.e., the science of mental processes and behavior). Our goal is to
understand the biological bases of psychology, rather than psychological aspects of
biology or neuroscience. Thus, biological psychology investigates how biological
factors like the brain, nervous system, hormones, and genes influence our
cognition, emotions, motivations, memories, and actions. Biological psychology
is not only a scientific discipline, it is also a viewpoint that emphasizes that brain
mechanisms underlie all of our thoughts and actions and that these brain
mechanisms have evolved over an incredibly long time from our ancient ancestors
who survived and reproduced (Kalat, 2019).
The History of Biological Psychology. Thinkers have long mused about the
nature of human behavior and experience, but the scientific discipline of biological
psychology has roots in physiology, philosophy, and the early psychologists who
adopted empiricism in the 19th century (Garrett, 2015). Wilhem Wundt,
considered the founder of experimental psychology, started the first psychology
laboratory in the 1870s in Leipzig, Germany, where his research emphasized
systematic observation to understand consciousness and mental processes. In The
Principles of Psychology (1890), William James argued that the scientific study of
psychology should be grounded in an understanding of biology (Walinga, 2019).
Although we can’t pin down the exact start of the field of biological psychology,
the publication of Donald Hebb’s groundbreaking book The Organization of
Behavior in 1949 marked a defining moment. Hebb proposed the first brain-based
account of how psychological phenomena like perception, thought, and memory
10 | 1.2: THE FIELD OF BIOLOGICAL PSYCHOLOGY
could emerge from brain activity, and thereby challenged the prevailing view that
psychological phenomena were too complex to originate from brain processes
(Pinel & Barnes, 2017).
Divisions of Biological Psychology. Nowadays, biological psychology is a
broad and diverse field that consists of many different approaches to studying
links between the brain and behavior. Here are some major branches of biological
psychology:

• Psychopharmacology examines how drugs and other substances affect the

brain and behavior, as well as how they can be used to treat psychological
disorders.
• Neuropsychology investigates the relationship between brain function and
behavior, focusing on how brain damage or dysfunction can impact
cognitive processes and psychological functioning especially in human
patients.
• Psychophysiology: studies of the relation between physical functions of
organisms (physiology) and psychological processes. Common physiological
measures include electroencephalogram (EEG), heart rate, and pupil
dilation.
• Psychoneuroimmunology examines the relationships between the nervous
system, immune system and hormones, and behavior.
Psychoneuroimmunologists often study the impact of stress and stress
hormones on illness susceptibility and recovery.
• Evolutionary psychology explores how evolutionary processes, like natural
selection, have adaptively shaped human traits and behaviors.
• Behavioral genetics analyzes how genetic factors contribute to individual
differences in behavior, cognition, personality, etc. and how genetic factors
interact with environmental influences.
• Cognitive neuroscience studies the neural basis of human cognitive
processes, including perception, attention, memory, language, and decision-
making. It often uses tools like functional brain imaging.
• Comparative psychology examines the behavior and mental processes of
nonhuman animals to gain insights into the evolutionary and environmental
factors that shape animal and human behavior and mental processes.
 1.2: THE FIELD OF BIOLOGICAL PSYCHOLOGY | 11
Biological psychology can be parsed into more subfields, the subfields overlap, and
researchers often work in more than one of these areas. But this list shows the
breadth of approaches used to study links between the brain and behavior.
Biological psychology is highly interdisciplinary and researchers may have
trained in psychology, neuroscience, biology, computer science, medicine,
philosophy, engineering, etc. Each discipline contributes a different perspective
and approach to understanding the brain and its functions, but also poses new
questions and problems that require collaboration and integration. Understanding
and integrating knowledge from various subfields can be challenging for both
students and researchers, but that integration provides a richer understanding
of brain structure and function and often leads to breakthroughs that propel
scientific progress.

Figure 1.2. Pyramidal neurons in the mouse cerebral cortex expressing

green fluorescent protein. The red staining indicates GABAergic
interneurons. CREDIT: Pyramidal neurons © Wikipedia is licensed under a CC
BY (Attribution) license
12 | 1.2: THE FIELD OF BIOLOGICAL PSYCHOLOGY
 1.3: THE SCIENTIFIC APPROACH TO UNDERSTAND BRAIN AND

1.3: THE SCIENTIFIC APPROACH

TO UNDERSTAND BRAIN AND
BEHAVIOR
Michael J. Hove and Steven A. Martinez

Biological psychology uses many techniques to observe, measure, and manipulate

the brain, but researchers across all fields use the same underlying
approach–science and the scientific method. The scientific method is a systematic
way of gathering and testing evidence based on observation and experimentation.
The scientific process usually starts with an observation or question that one
wants to understand. A researcher proposes a tentative explanation, called a
hypothesis, to explain the phenomenon. A valid hypothesis must be testable.
It should also be falsifiable, meaning that experimental results can disprove it.
Importantly, science does not claim to “prove” anything because scientific
understandings are always subject to modification with further information. This
step–openness to disproving ideas–is what distinguishes sciences from non-
sciences. The presence of the supernatural, for instance, is neither testable nor
falsifiable. A hypothesis should also fit into the context of a scientific theory,
which is a broad explanation or group of explanations for some aspect of the
natural world that is consistently supported by evidence over time. A theory is the
best understanding we have of that part of the natural world.
The researcher then tests the validity of the hypothesis by making observations
or carrying out an experiment. An experiment will have one or more variables and
one or more controls. A variable is any part of the experiment that can vary or
change during the experiment; an independent variable is manipulated by the
researcher, and a dependent variable is the outcome variable that is measured.
The control group contains every feature of the experimental group except it is not
given the manipulation from the researcher’s hypothesis. Therefore, if results from
the experimental group differ from the control group, that difference must be due
to the hypothesized manipulation, rather than some outside factor.
14 | 1.3: THE SCIENTIFIC APPROACH TO UNDERSTAND BRAIN AND
For example, if a researcher hypothesizes that a certain drug decreases appetite,
they could perform an experiment with the independent (manipulated) variable
“drug or no-drug,” and the dependent (measured) variable “amount of food
eaten.” The researcher would randomly assign some participants to the
experimental group who gets the drug, and other participants to the control group
who gets a placebo pill that looks like the drug. Through random assignment and
a proper control condition, only the drug would differ between the experimental
and control groups. If the experimental (drug) group eats less than the control
(placebo) group, then one could conclude that the hypothesis is supported.
Conversely, the research could lead to rejecting the hypothesis if not supported by
the experimental data.
After analyzing their data, researchers communicate their results and
conclusions in publications or presentations so that others can critique, replicate,
or build on the results. In addition to publishing a report, researchers now
regularly publish their datasets, so that others can re-analyze the data to ensure
quality and maybe find something new without having to collect new data. Results
from one study inform future studies and guide refinement of the hypothesis (see
Figure 1.3). Sometimes an experiment leads to conclusions that favor a change in
approach or inspires entirely new scientific questions. Many times, science does
not operate in a linear fashion. Instead, scientists continually draw inferences and
make generalizations, finding patterns as their research proceeds.
Science and the scientific method are the best way to understand and study the
brain because they provide us with rigorous, objective, and verifiable knowledge
that can help us improve our health, education, and well-being.
1.3: THE SCIENTIFIC APPROACH TO UNDERSTAND BRAIN AND
16 | 1.3: THE SCIENTIFIC APPROACH TO UNDERSTAND BRAIN AND
Figure 1.3. The scientific method consists of a series of well-defined
steps. If a hypothesis is not supported by experimental data, one can
propose a new hypothesis. The scientific method is an ongoing,
iterative process, wherein the results from one study will inform and
guide the process for a future hypothesis or study. CREDIT: The scientific
method © OpenStax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Basic and Applied Research. Across the various subfields of biological

psychology, research can be categorized as basic or applied. Basic research, also
known as pure research, is driven by scientific curiosity or an interest in
understanding the mechanisms of brain function and brain-behavior
relationships. It seeks to answer fundamental questions about how the brain works
and explores the biological basis of behavior, emotions, and cognitive processes,
by examining genetics, neurotransmission, brain circuitry, and other physiological
processes. On the other hand, applied research in biological psychology takes
findings from basic research and uses them to solve real-world issues. Examples of
applied research include developing therapeutic interventions for mental disorders,
devising strategies to optimize learning and memory, or creating neurofeedback
methods for stress reduction. While the two types of research may seem distinct,
they are interdependent. Basic research lays the groundwork for the applications
that emerge from applied research, and applied research often raises new questions
that drive basic research. In public and political debates, people sometimes argue
for cutting funding of basic science because they contend it has no practical value.
However basic science works in synergy with applied science–together they are
both essential to the development of biological psychology and science more
broadly.
Text Attributions
This section contains material adapted from:
Clark, M. A., Douglas, M., & Choi, J. (2018). 1.1 The Science of Biology. In
Biology 2e. OpenStax. Access for free at https://openstax.org/books/biology-2e/
pages/1-1-the-science-of-biology License: CC BY 4.0 DEED.
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 1.1 What Is
Psychology? In Psychology 2e.OpenStax. Access for free at https://openstax.org/
books/psychology-2e/pages/1-1-what-is-psychology License: CC BY 4.0 DEED.
 1.4: PAYOFFS OF BIOLOGICAL PSYCHOLOGY | 17

1.4: PAYOFFS OF BIOLOGICAL

PSYCHOLOGY
Michael J. Hove and Steven A. Martinez

Biological psychology and related neuroscience fields are extremely active areas
of research. Billions of dollars are invested annually and tens of thousands of
researchers are studying the brain and behavior. The vast undertaking to
understand the brain will help unravel the mysteries of human nature and our
human experience. In addition, research on the brain has impactful applications–it
helps to heal brain damage and psychological disorders and guides the
development of artificial intelligence and brain-compatible social policies
(Eagleman & Downar, 2016).
Healing the brain. Brain damage and psychological disorders affect tens of
millions of people each year. Treatment and care of afflicted patients benefits
greatly from basic brain science. Research on cellular and molecular mechanisms
of the brain can lead to the development of new drugs, and ways to regrow neurons
and increase neural plasticity. Researchers have developed mind-boggling new
technology like transcranial magnetic stimulation that stimulates the brain with
magnetic pulses and can treat depression, or deep brain stimulation that uses brain
implants to treat diseases like Parkinson’s. Brain-computer interfaces that pick up
brain signals, analyze them, and translate them into commands for an external
device like a wheelchair or robotic arm can help people regain movement who have
neuromuscular disorders including amyotrophic lateral sclerosis (ALS), spinal cord
injury, or stroke (Figure 1.4).
18 | 1.4: PAYOFFS OF BIOLOGICAL PSYCHOLOGY

Figure 1.4. Components of a typical system for Brain-Computer Interface

that picks up brain signals, analyzes them, and translates them into
commands to an external output device like a wheelchair or robotic arm.
CREDIT: BCI System © MDPI is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Guiding Artificial Intelligence. Neuroscience is closely intertwined with artificial

intelligence (AI). Understanding biological brains is important for building
artificial brains and neuroscience has inspired the design of AI systems (Hassabis
et al., 2017). Similar to neurons in the human brain, artificial neural networks
have many interconnected units that work in parallel. Neuroscience provided early
guidance for AI-system architecture (e.g., units organized in many layers) and
algorithms (e.g., a “backpropagation algorithm” that adjusts the connections
between units across multiple layers to enable learning). Another example of
neuroscience-inspired AI is in attention—until recently artificial neural networks
processed an entire image or video frame with equal priority given to all pixels.
Conversely, humans focus on one very small aspect at a time and strategically shift
 1.4: PAYOFFS OF BIOLOGICAL PSYCHOLOGY | 19
our “spotlight of attention.” By incorporating a biologically-inspired approach
with prioritized focus, AI-image processing has improved performance and
efficiency (Hassabis et al., 2017).
AI has recently made dramatic advances thanks to breakthroughs in “deep
learning” and “reinforcement learning” methods (wherein learning is optimized
by reinforcing or rewarding when desired outcomes occur). By incorporating
principles from neuroscience, AI researchers have been able to improve the
efficiency and accuracy of AI algorithms, resulting in significant advances in areas
like computer vision, decision-making, and natural language processing. Those AI
assistants you might have used, like ChatGPT and LLaMa for text generation or
Stable Diffusion and DALL-E for image generation, built on principles discovered
in brain science. Finally, advances in AI that were inspired by neuroscience are
now being applied back to neuroscience as tools to understand the brain. For
example, AI and deep learning can be used to analyze neuroimaging data, build
computational models to simulate and study the brain, and identify and predict
the trajectory of psychological disorders or diseases like Alzheimer’s (Kreigeskorte
& Douglas, 2018; Colliot, 2023).
20 | 1.4: PAYOFFS OF BIOLOGICAL PSYCHOLOGY

Figure 1.5. AI-generated image from DALL-E 3 using the prompt

“Artificial Intelligence computer system inspired by neurons and brains.”
DALL-E 3 © DALL-E 3 is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Brain-compatible social policies. As outlined by Eagleman and Downar (2016),

brain science can also have payoffs in guiding brain-compatible social policies.
For example, psychology and neuroscience research has implications for how to
view and address drug addiction. As brain science learns more about
psychopharmacology and the brain mechanisms underlying addiction, it has
become increasingly clear that addiction is driven by biological processes in the
brain. As a result, policies that attack only drug supply are typically
unsuccessful—if one point of supply is busted, another will pop up soon because
the demand remains. Instead, policies should focus on attacking the demand for
 1.4: PAYOFFS OF BIOLOGICAL PSYCHOLOGY | 21
drugs—treatments that are rooted in interrupting the brain circuits that drive
addiction will be more effective than an incarceration-focused approach.
Finally, a large portion of the prison population in the U.S. is mentally ill. The
prevalence of serious mental illness in jail inmates is around 15% for men and
31% for women (Steadman et al., 2009). Jails and prisons have become mental
health care facilities. For example, the Rikers Island prison is New York’s largest
mental institution (Ransom & Harris, 2023), and more mentally ill persons are
in jails and prisons than are in hospitals (Torrey et al., 2010). Brain science clearly
demonstrates that psychological disorders are rooted in the brain, so one must ask
whether policies that support and treat those with mental-health problems might
keep them from committing crimes, and whether a treatment-approach could be
more humane and cost-effective (Eagleman & Downar, 2016).

Text Attributions
This section contains material adapted from:
Stangor, C., Walinga, J. & Cummings, J. A. (2019). 3.1 Psychologists Use the
Scientific Method to Guide Their Research. In Introduction to Psychology.
University of Saskatchewan. https://openpress.usask.ca/
introductiontopsychology/chapter/psychologists-use-the-scientific-method-to-
guide-their-research/ Licence: CC BY-NC-SA 4.0 DEED
22 | 1.5: RESEARCH WITH ANIMALS

1.5: RESEARCH WITH ANIMALS

Michael J. Hove and Steven A. Martinez

To understand the human brain and human psychology, ideally we would only
study humans. But some research cannot be conducted with humans, so
researchers in biological psychology also perform research with animals. Most
psychological research using animals is now conducted with rats, mice, and birds,
as the use of other animals such as non-human primates is declining (National
Research Council, 2011; Thomas & Blackman, 1992). Like research with humans,
all research plans with animals must be reviewed by ethics boards to ensure that it
meets important ethical principles such as:

• Use animals in research only if there is a reasonable expectation that the

research will provide some benefit such as increasing understanding of the
structures and processes underlying behavior or benefiting the health and
welfare of humans or other animals.
• Use a procedure that subjects animals to pain or stress only if an alternative
procedure is not available and the research goals are justified by its
prospective scientific, educational, or applied value.
• Make every effort to minimize discomfort, illness, and pain of the animals.

People naturally disagree about the practice of using animals in research. Although
many people accept the value of such research (Plous, 1996), a minority of people,
including some animal-rights activists, believe that it is ethically wrong to conduct
research on animals because animals are living creatures just as humans are, so no
harm should be done to them.
Most scientists, however, argue that such beliefs ignore the benefits that can
come from animal research (Stangor et al., 2019). For instance, drugs to prevent or
treat polio, diabetes, smallpox, cancer, or Alzheimer’s disease may first be tested on
animals, and surgery that can save human lives may first be practiced on animals.
Research on animals has also led to a better understanding of the physiological
causes of depression, phobias, and stress, among other illnesses. Many scientists
 1.5: RESEARCH WITH ANIMALS | 23
believe that because there are many possible benefits from animal research, such
research should continue as long as the animals are treated humanely and ethical
principles mentioned above are met. The animal-research debate is active and
ongoing, and need not be characterized as a simple dichotomy between “Yes,
always” or “No, never.” The efforts by animal-rights groups have led to better
treatment and conditions for lab animals.

Text Attributions
This section contains material adapted from:
Stangor, C., Walinga, J. & Cummings, J. A. (2019). 3.1 Psychologists Use the
Scientific Method to Guide Their Research. In Introduction to Psychology.
University of Saskatchewan. https://openpress.usask.ca/
introductiontopsychology/chapter/psychologists-use-the-scientific-method-to-
guide-their-research/ Licence: CC BY-NC-SA 4.0 DEED
24 | 1.6: DIVERSITY IN BIOLOGICAL PSYCHOLOGY

1.6: DIVERSITY IN BIOLOGICAL

PSYCHOLOGY
Michael J. Hove and Steven A. Martinez

While biological psychology is diverse in the approaches to study the brain,

historically the people involved in the research have not been especially diverse.
Most of the early research was done by men of European descent due to social
and cultural factors, systemic barriers, as well as unconscious biases. The field has
been getting more diverse in the last decades and many leading labs are headed
by women and historically underrepresented minorities. Diversity both across and
within labs contributes to better quality science. If everyone has the same
background and viewpoint, innovation lags because novel ideas are generated less
often and new ideas may be derided and viewed as dissenting. Unique perspectives
advance science, and research shows that more diverse groups outperform less
diverse groups in many settings (Page, 2008). Diversity in science can be increased
with policies and programs that address bias, harassment, mentorship, work-life
balance, and educational and training opportunities, so that all have equal
opportunity to succeed (Greider et al., 2019; National Academies of Sciences,
Engineers, and Medicine, 2023).
Another area lacking diversity in biological psychology is in the research
subjects. The vast majority of research subjects in psychology studies (96% by
one estimate) are from Western, educated, industrialized, rich, and democratic
(“WEIRD”) societies. These WEIRD subjects represent a very narrow slice of
humankind, and research findings from them don’t necessarily generalize to other
populations or serve the goal of understanding human psychology (Henrich et al.,
2008).
Likewise, most participants in mental health studies, such as those looking at
genetic risk in psychiatric disorders, have been of European ancestry; thus it is
unclear how those studies will benefit people of differing ethnicities who might
have different mental health needs and respond differently to treatments (Gordon,
2018). Research on diverse populations is especially important considering the
 1.6: DIVERSITY IN BIOLOGICAL PSYCHOLOGY | 25
long-standing disparities in mental health care–individuals from racial and ethnic
minority groups, those with lower socioeconomic status, and residents of rural
areas, are more likely to receive lower quality mental health care (Agency for
Healthcare Research and Quality, 2016). Funding agencies, including the National
Institute of Mental Health (NIMH), are increasingly paying attention to the
importance of including people from diverse backgrounds when developing
funding mechanisms and reviewing grant proposals, which ultimately shapes the
direction of the science.
In sum, the field of biological psychology benefits from researchers and
participants with different backgrounds to enrich the quality and creativity of the
science, and make the findings and field more relevant and applicable for all.
26 | 1.7: BIOLOGICAL PSYCHOLOGY MYTHS

1.7: BIOLOGICAL PSYCHOLOGY

MYTHS
Austin Lim, Ph.D.

This module is adapted from:

Lim, A. (2021). What neuroscience is not. In Open Neuroscience.

Access for free at https://static1.squarespace.com/static/
56555dbee4b0f0c1a002808a/t/60ca0e87af05e35f06d05b56/
1623854731347/Open+Neuroscience+Initiative+-+Chapter+1+-
+Introduction.pdf

As complex as the brain is, naturally misconceptions make their way into
popular culture. It’s valuable to address these myths about neuroscience and
explain the evidence that refutes these statements .
 1.7: BIOLOGICAL PSYCHOLOGY MYTHS | 27

“We only use 10% of our brain.”

This wildly-inaccurate statistic has been the foundation for several fictional
movies, TV shows, and books. The truth is that we use every part of the brain, and
most of our brain is active most of the time – just not at the same time. Neurologist
V.S. Ramachandran uses a great analogy to describe the fallacy of this myth: does a
traffic light only use 33% of its lights?

Figure 1.6 A fully-functioning brain uses nearly 100% of the component

parts, but at precisely controlled times, like a traffic light. CREDIT:
https://pixabay.com/photos/light-red-stop-street-427961/

A properly functioning traffic light will use all three lights at very precise times.
The activity of the brain is closely regulated by multiple mechanisms which
prevent unusual electrical activity. In fact, if too many cells were active at the wrong
28 | 1.7: BIOLOGICAL PSYCHOLOGY MYTHS
times, just like a traffic light showing both green and red, chaos ensues – one cause
of seizures is excessive neural activity.

“Forming memories causes new neurons to

be born.”

Another misconception is the idea that each new cell in

our brain represents a new memory. While we are far from understanding the
process of exactly how memories are formed in the brain, we do have a few clues.
Most likely, memories are stored at the sites of close contact between neurons,
called synapses. Changes in in ways neurons connect and communicate with one
another is likely the mechanism behind how memories are formed and stored,
rather than the creation of new neurons.
Even though the process of cell reproduction is halted in the majority of adult
neurons, we are still capable of new neuronal growth, a process called
neurogenesis. A few brain areas in particular, like the hippocampus (used in
learning and memory functions) and the olfactory epithelium (used for smelling),
do exhibit frequent birth and death of new neurons.
 1.7: BIOLOGICAL PSYCHOLOGY MYTHS | 29

Figure 1.7 The weight of the brain does not increase much beyond the
teen years, but we continue to learn throughout the rest of our lives.
CREDIT: https://commons.wikimedia.org/wiki/File:Brain_weight_age.gif Modified
by Austin Lim.

“The brain cannot repair itself.”

If neurons aren’t being replaced in adulthood, then how do people spontaneously
recover from neurological injuries like a stroke?
One of the most amazing features of the brain is the phenomenon of plasticity,
the ability to change over time. Even if critical brain areas are damaged, it is
theorized that the brain learns how to “rewire itself,” essentially figuring out how
to carry out these functions without using the damaged connections.
Unfortunately, there are some conditions that are neurodegenerative, meaning
30 | 1.7: BIOLOGICAL PSYCHOLOGY MYTHS
that their symptoms get progressively worse over time. Many of these disorders,
like Parkinson’s disease and Alzheimer’s disease, currently don’t have any simple
cures or treatments that don’t carry risks and side effects. For people with these
conditions, there isn’t strong evidence that the brain can recover from the
destruction from these diseases.
Fascinatingly, we do have one strange quirk about signaling between the brain
and the rest of the body: signaling pathways from the left brain crosses over to
communicate with the right half of the body, and vice versa. This contralateral
organization is an unintended consequence o f evolution, and is one of the major
distinguishing features of the vertebrate brain.

Figure 1.8 The vertebrate nervous system likely twists in development,

resulting in a contralateral organization. CREDIT: https://en.wikipedia.org/
wiki/Contralateral_brain#/media/File:AxialTwistDevelopment.png
 1.7: BIOLOGICAL PSYCHOLOGY MYTHS | 31

“If you are analytical, you are

left brain dominant, but if you are creative,
you are right brain dominant.”
A common misconception is that the two hemispheres of the brain are responsible
for wildly different functions. The truth is that nearly every function that the
left half of the brain can do, the right half can do just as well, and vice versa.
Sensory information, voluntary control of the muscles, memories, and many other
behaviors can be performed equally well by both the left and right halves of the
brain.
A major exception to the “left vs. right” component is the processing and
production of language. For some reason unknown to scientists, these functions
are heavily lateralized in the left hemisphere for most people.
32 | 1.8: REFERENCES

1.8: REFERENCES

Parts of this chapter were adapted from:

Clark, M. A., Douglas, M., & Choi, J. (2018). 1.1 The Science of Biology. In
Biology (2nd ed.). OpenStax. Access for free at https://openstax.org/books/
biology-2e/pages/1-1-the-science-of-biology
Lim, A. (2021). What neuroscience is not. In Open Neuroscience. Access for free
at https://static1.squarespace.com/static/56555dbee4b0f0c1a002808a/t/
60ca0e87af05e35f06d05b56/1623854731347/
Open+Neuroscience+Initiative+-+Chapter+1+-+Introduction.pdf
Hove, M. J., & Martinez, S. A. (2024). Biological psychology. ROTEL
(Remixing Open Textbooks with an Equity Lens) Project.
https://rotel.pressbooks.pub/biologicalpsychology/.
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 1.1 What Is Psychology?
In Psychology 2e. OpenStax. Access for free at https://openstax.org/books/
psychology-2e/pages/1-1-what-is-psychology
Stangor, C., Walinga, J. & Cummings, J. A. (2019). 3.1 Psychologists Use the
Scientific Method to Guide Their Research. In Introduction to Psychology.
University of Saskatchewan. https://openpress.usask.ca/
introductiontopsychology/chapter/psychologists-use-the-scientific-method-to-
guide-their-research/

References
Colliot, O. (Ed.). (2023). Machine Learning for Brain Disorders. Springer.
https://link.springer.com/book/10.1007/978-1-0716-3195-9
Eagleman, D., & Downar, J. (2016). Brain and behavior: A cognitive neuroscience
perspective. Oxford University Press.
Garrett, B. (2015). Brain and behavior: An introduction to biological psychology (4th
ed.). Sage Publications, Inc.
Gordon, J. (2018). Mental Health Research—Diversity Matters.
 1.8: REFERENCES | 33
https://www.nimh.nih.gov/about/director/messages/2018/mental-health-
research-diversity-matters
Greider, C. W., Sheltzer, J. M., Cantalupo, N. C., Copeland, W. B., Dasgupta, N.,
Hopkins, N., … & Wong, J. Y. (2019). Increasing gender diversity in the STEM
research workforce. Science, 366(6466), 692-695.
Harmon-Jones, E. & Harmon-Jones, C. (2023). Affective neuroscience. In R.
Biswas-Diener & E. Diener (Eds), Noba textbook series: Psychology.
Champaign, IL: DEF publishers. Retrieved from http://noba.to/qnv3erb9
Hassabis, D., Kumaran, D., Summerfield, C., & Botvinick, M. (2017).
Neuroscience-inspired artificial intelligence. Neuron, 95(2), 245-258.
Henrich, J., Heine, S. J., & Norenzayan, A. (2010). Most people are not WEIRD.
Nature, 466(7302), 29-29.
Kriegeskorte, N., & Douglas, P. K. (2018). Cognitive computational neuroscience.
Nature Neuroscience, 21(9), 1148-1160.
Lichtman, J., Pfister, H., & Reid, C. (n.d.). Connections in the Brain. Retrieved
July 7, 2023. https://www.rc.fas.harvard.edu/case-studies/connections-in-the-
brain/
National Academies of Sciences, Engineering, and Medicine. 2023. Advancing
Antiracism, Diversity, Equity, and Inclusion in STEMM Organizations: Beyond
Broadening Participation. Washington, DC: The National Academies Press.
Online Access: https://nap.nationalacademies.org/read/26803
National Research Council. (2011). Chimpanzees in biomedical and behavioral
research: Assessing the necessity. The National Academies Press.
Nelson, R. J. (2023). Hormones & behavior. In R. Biswas-Diener & E. Diener
(Eds), Noba textbook series: Psychology. Champaign, IL: DEF publishers.
Retrieved from http://noba.to/c6gvwu9m
Page, S. (2008). The difference: How the power of diversity creates better groups,
firms, schools, and societies-new edition. Princeton University Press.
Pinel, J. P., & Barnes, S. (2017). Biopsychology (11th ed.) Pearson.
Plous, S. (1996). Attitudes toward the use of animals in psychological research and
education. Psychological Science, 7, 352–358.
Ransom, J. & Harris, A. J. (2023, December 23). How Rikers Island Became New
York’s Largest Mental Institution. New York Times. https://www.nytimes.com/
2023/12/29/nyregion/nyc-rikers-homeless-mental-illness.html
34 | 1.8: REFERENCES
Singer, M. (2007). The untethered soul: The journey beyond yourself. New
Harbinger Publications.
Spivey, M. J. (2020). Who you are: The science of connectedness. MIT Press.
Steadman, H. J., Osher, F. C., Robbins, P. C., Case, B., & Samuels, S. (2009).
Prevalence of serious mental illness among jail inmates. Psychiatric Services,
60(6), 761-765.
Tang, Y. Y., Hölzel, B. K., & Posner, M. I. (2015). The neuroscience of mindfulness
meditation. Nature Reviews Neuroscience, 16(4), 213-225.
Thomas, G., & Blackman, D. (1992). The future of animal studies in psychology.
American Psychologist, 47, 1678.
Torrey, E. F., Kennard, A. D., Eslinger, D., Lamb, R., & Pavle, J. (2010). More
mentally ill persons are in jails and prisons than hospitals: A survey of the states.
Arlington, VA: Treatment Advocacy Center, 1-18.
Walinga, J. (2019). 2.1 Biological Psychology. In J. A. Cummings & L. Sanders
(Eds). Introduction to Psychology. University of Saskatchewan Open Press.
https://openpress.usask.ca/introductiontopsychology/chapter/biological-
psychology-structuralism-and-functionalism/
Yeung, A. W. K., Goto, T. K., & Leung, W. K. (2017). The changing landscape
of neuroscience research, 2006–2015: A bibliometric study. Frontiers in
Neuroscience, 11, 120.
 CHAPTER 2: NEURONS | 35

CHAPTER 2: NEURONS

This chapter is adapted from Hove, M. J., & Martinez, S. A. (2024).

Biological Psychology. ROTEL (Remixing Open Textbooks with an
Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/

They adapted their chapter from:

Furtak, S. (2021). Neurons. In R. Biswas-Diener & E. Diener (Eds),

Noba textbook series: Psychology. Champaign, IL: DEF publishers.
Retrieved from http://noba.to/s678why4 License: CC BY-NC-SA 4.0
DEED

This chapter relating to the biological basis of behavior provides an overview of the
basic structure of neurons and their means of communication. Neurons, cells in
the central nervous system, receive information about the world around us from
our sensory systems (vision, audition, olfaction, gustation, and somatosensation);
in turn, they process that information and plan and execute appropriate responses,
including attending to a stimulus, learning new information, speaking, eating,
mating, and evaluating potential threats. The goal of this chapter is to become
familiar with the anatomical structure of neurons and to understand how neurons
communicate by electrochemical signals to process sensory information and
produce complex behaviors. A basic knowledge of the structure and function of
neurons is a necessary foundation as you move forward in the field of psychology.

Learning Objectives
36 | CHAPTER 2: NEURONS

• Differentiate the functional roles of the two main cell classes in

the brain—neurons and glia.
• Describe how the forces of diffusion and electrostatic pressure
work collectively to facilitate electrochemical communication.
• Define resting membrane potential, excitatory postsynaptic
potentials, inhibitory postsynaptic potentials, and action
potentials.
• Explain features of axonal and synaptic communication in
neurons.
 2.1: INTRODUCTION | 37

2.1: INTRODUCTION
Jill Grose-Fifer, Ph.D.; Michael J. Hove; and Steven A.
Martinez

Imagine trying to string words together into a meaningful sentence without

knowing the meaning of each word or its function (i.e., Is it a verb, a noun, or an
adjective?). In a similar fashion, to appreciate how groups of cells work together
in a meaningful way in the brain, we must first understand how individual cells in
the brain function. Much like words, brain cells, called neurons, have an underlying
structure that provides the foundation for their functional purpose. Have you ever
seen a neuron? Did you know that the basic structure of a neuron is the same
whether it is from the brain of a rat or a human? How do the billions of neurons
in our brain allow us to do all the things we enjoy, such as chatting with a friend,
cheering on our favorite sports team, or laughing?
38 | 2.1: INTRODUCTION

Figure 2.1. Three drawings by Santiago Ramón y Cajal, taken from

“Comparative study of the sensory areas of the human cortex”, pages
314, 361, and 363. Left: Nissl-stained visual cortex of a human adult.
Middle: Nissl-stained motor cortex of a human adult. Right:
Golgi-stained cortex of a 1 1/2 month old infant. CREDIT: Cajal cortex
drawings © Santiago Ramón via wikimedia is licensed under a Public Domain
license

Our journey in answering these questions begins more than 100 years ago with
a scientist named Santiago Ramón y Cajal. Cajal (1911) boldly concluded that
discrete individual neurons are the structural and functional units of the nervous
 2.1: INTRODUCTION | 39
system. He based his conclusion on the numerous drawings he made of Golgi-
stained tissue, a stain named after the scientist who discovered it, Camillo Golgi.
Scientists use several types of stains to visualize cells. Each stain works in a unique
way, which causes them to look different when viewed under a microscope. For
example, a very common Nissl stain labels only the main part of the cell (i.e., the
cell body; see left and middle panels of Figure 2.1). In contrast, a Golgi stain fills
the cell body and all the processes that extend from it (see right panel of Figure 2.1).
A more notable characteristic of a Golgi stain is that it only stains approximately
1–2% of neurons (Pasternak & Woolsey, 1975; Smit & Colon, 1969), permitting
the observer to distinguish one cell from another. These qualities allowed Cajal to
examine the full anatomical structure of individual neurons for the first time. This
significantly enhanced the appreciation of the intricate networks their processes
form. Based on his observation of Golgi-stained tissue, Cajal suggested neurons
were distinct individual units rather than continuous structures. This was opposed
to the dominant theory at the time proposed by Joseph von Gerlach, which stated
that the nervous system was composed of a network of long continuous fibers,
like telegraph wires (for review see Lopez-Munoz et al., 2006). Camillo Golgi
himself had been an avid supporter of Gerlach’s theory. Despite their scientific
disagreement, Cajal and Camillo Golgi shared the Nobel Prize for Medicine in
1906 for their combined contribution to our understanding of neurons. This
seminal work paved the way for our current understanding of the basic structure of
the nervous system described in this chapter (for reviews see: De Carlos & Borrell,
2007; Grant, 2007).

This chapter first introduces some basic terminology and the anatomy of neurons
in the section called “The Structure of the Neuron.” The remainder of the chapter
focuses on the electrochemical signals through which neurons communicate.
While the electrochemical process might sound intimidating, it is broken down
into manageable sections. The first subsection, “Resting Membrane Potential,”
describes what occurs in a neuron at rest, when it is theoretically not receiving
or sending signals. Building upon this, we examine the electrical conductance
that occurs within a single neuron when it receives signals. Finally, the chapter
concludes with a description of the electrical conductance, which results in
communication between neurons through a release of chemicals. At the end of the
40 | 2.1: INTRODUCTION
chapter, you should have a broad understanding of how neurons send and receive
information by electrical and chemical signals.
A note of encouragement: This chapter introduces a vast amount of
terminology that at times may feel overwhelming. Do not get discouraged or
bogged down in the details. Utilize the book’s glossary, which contains all terms
in bold typing. On your first read of this chapter, try focusing on the broader
concepts and functional aspects of the terms instead of trying to commit all the
terminology to memory. I suggest reading this chapter at least twice, once prior to
and once after the course lecture on this material. Repetition is the best way to gain
clarity and commit to memory the challenging concepts and detailed vocabulary
presented here.
 2.2: THE STRUCTURE OF THE NEURON | 41

2.2: THE STRUCTURE OF THE

NEURON
Michael J. Hove and Steven A. Martinez

Basic Nomenclature
There are approximately 86 billion neurons in the human brain (Herculano-
Houzel, 2009). Each neuron has three main components: dendrites, the soma,
and the axon (see Figure 2). Dendrites are processes that extend outward from
the soma, or cell body of a neuron, and typically branch several times. Dendrites
receive information from thousands of other neurons and are the main source of
input of the neuron. The nucleus, which is located within the soma, contains
genetic information, directs protein synthesis, and supplies the energy and the
resources the neuron needs to function. The main source of output of the neuron
is the axon. The axon extends away from the soma and carries an important signal
called an action potential to another neuron. The place at which the axon of one
neuron approaches the dendrite of another neuron is a synapse (Figures 2–3).
Typically, the axon of a neuron is covered with an insulating substance called a
myelin sheath that allows the signal of one neuron to travel rapidly to another
neuron.
42 | 2.2: THE STRUCTURE OF THE NEURON

Figure 2.2. Basic structure of a neuron. CREDIT: Basic structure of neuron ©

Noba is licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike)
license

The axon splits many times so that it can communicate, or synapse, with several
other neurons (see Figure 2.2). At the end of the axon is a terminal button,
which forms synapses with spines, or protrusions, on the dendrites of neurons.
Synapses form between the presynaptic terminal button (neuron sending the
signal) and the postsynaptic membrane, which is the neuron receiving the signal).
(see Figure 3). Here we will focus specifically on synapses between the terminal
button of an axon and a dendritic spine; however, synapses can also form between
the terminal button of an axon and the soma or the axon of another neuron.
A very small space called a synaptic gap, approximately 5 nm (nanometers),
exists between the presynaptic terminal button and the postsynaptic dendritic
spine. To give you a better idea of the size, the thickness of a dime is 1.35 mm
(millimeters) or 1,350,000 nm. In the presynaptic terminal button, there are
synaptic vesicles that package together groups of chemicals called
neurotransmitters (see Figure 2.3). Neurotransmitters are released from the
presynaptic terminal button, travel across the synaptic gap, and activate ion
channels on the postsynaptic spine by binding to receptor sites. We will discuss the
role of receptors in more detail later in the chapter.
 2.2: THE STRUCTURE OF THE NEURON | 43

Figure 2.3. Characteristics of a synapse. CREDIT: synapse © Noba is licensed

under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license
44 | 2.3: TYPES OF CELLS IN THE BRAIN

2.3: TYPES OF CELLS IN THE

BRAIN

Not all neurons are created equal. Sensory neurons help us receive information
about the world around us. Motor neurons allow us to initiate movement and
behavior, ultimately allowing us to interact with the world around us. Interneurons
process sensory input from our environment into meaningful representations,
plan behavioral responses, and connect to the motor neurons to execute these
behavioral plans.
The main categories of neurons are defined by their specific structure. The
structures support their unique functions. Unipolar neurons are structured in a
way that is ideal for relaying information forward, so they have one neurite (axon)
and no dendrites (Figure 2.4). They are involved in transmission of physiological
information from the body’s periphery such as communicating body temperature
through the spinal cord up to the brain. Bipolar neurons are involved in sensory
perception such as perception of light in the retina of the eye. They have one
axon and one dendrite which help acquire and pass sensory information to various
centers in the brain. Finally, multipolar neurons are the most common and they
communicate sensory and motor information in the brain. Multipolar neurons
have one axon and many dendrites which allows them to communicate with other
neurons. One of the most prominent neurons is a pyramidal neuron, which falls
under the multipolar category. It gets its name from the triangular or pyramidal
shape of its soma (for examples see, Furtak et al., 2007).
 2.3: TYPES OF CELLS IN THE BRAIN | 45

Figure 2.4. Types of Neurons: Neurons are broadly divided into a few
main types based on the number and placement of axons: (1) unipolar,
(2) bipolar, (3) multipolar, and (4) pseudounipolar. CREDIT: types of
neurons © Libre Texts Biology is licensed under a CC BY-SA (Attribution
ShareAlike) license

In addition to neurons, non-neuronal cells in the nervous system called glia or

neuroglia provide support and play essential roles in the functioning of neurons.
Glial cells have several functions, just a few of which we will discuss here. One type
of glial cell, called oligodendroglia, forms the myelin sheaths that insulate axons
(Simons & Trotter, 2007; see Figures 2.5). In the central nervous system (CNS),
oligodendroglia wrap their dendritic processes around the axons of neurons many
times to form the myelin sheath. One cell will form the myelin sheath on several
axons. In the peripheral nervous system (PNS), Schwann cells, another type of glial
cell, form the myelin sheath for neurons. One cell will wrap around a singular axon
in the PNS. Other types of glial cells, such as microglia and astrocytes, digest debris
of dead neurons, carry nutritional support from blood vessels to the neurons,
and help to regulate the ionic composition of the extracellular fluid. While glial
cells play a vital role in neuronal support, they do not carry electrical signals or
participate in the communication between cells as neurons do.
46 | 2.3: TYPES OF CELLS IN THE BRAIN

Figure 2.5. An oligodendrocyte myelinating several axons in the central

nervous system. CREDIT: Oligodendrocyte © Wikimedia is licensed under a CC
BY-SA (Attribution ShareAlike) license
 2.3: TYPES OF CELLS IN THE BRAIN | 47

Figure 2.6. The peripheral nervous system (PNS) has myelinating

Schwann cells. CREDIT: Glial Cells of the PNS © Wikimedia is licensed under a
CC BY-SA (Attribution ShareAlike) license
48 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS

2.4: COMMUNICATION WITHIN

AND BETWEEN NEURONS

Thus far, we have described the main characteristics of neurons, including how
their processes come in close contact with one another to form synapses. In this
section, we consider the conduction of communication within a neuron and how
this signal is transmitted to the next neuron. There are two stages of this
electrochemical action in neurons. The first stage is the electrical conduction of
dendritic input to the initiation of an action potential within a neuron. The
second stage is a chemical transmission across the synaptic gap between the
presynaptic neuron and the postsynaptic neuron of the synapse. To understand
these processes, we first need to consider what occurs within a neuron when it is at
a steady state, called resting membrane potential.

Resting Membrane Potential

The intracellular (inside the cell) fluid and extracellular (outside the cell) fluid of
neurons is composed of a combination of ions (electrically charged molecules;
Figure 2.7). Cations are positively charged ions, and anions are negatively charged
ions. The composition of intracellular and extracellular fluid is similar to salt water,
containing sodium (Na+), potassium (K+), chloride (Cl–), and anions (A–).
The cell membrane, which is composed of a lipid bilayer of fat molecules,
separates the cell from the surrounding extracellular fluid. There are proteins that
span the membrane, forming ion channels that allow particular ions to pass
between the intracellular and extracellular fluid (Figure 2.7). These ions are in
different concentrations inside the cell relative to outside the cell, and the ions
have different electrical charges. Due to this difference in concentration and charge,
two forces act to maintain a steady state when the cell is at rest: diffusion and
electrostatic pressure. Diffusion is the force on molecules to move from areas of
high concentration to areas of low concentration. Electrostatic pressure is the
 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 49
force on two ions with similar charge to repel each other and the force of two
ions with opposite charge to attract one another. Remember the saying “opposites
attract”?
50 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS

Figure 2.7. Representation of ion concentrations inside (intracellular)

and outside (extracellular) a neuron in the unmyelinated segment of
the axon. CREDIT:Unmylenated segment of the axon © Noba is licensed
under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

There is a membrane potential at which the force of diffusion is equal and

 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 51
opposite to the force of electrostatic pressure. This voltage, called the equilibrium
potential, is the voltage at which no ions flow. Since there are several ions that
can permeate the cell’s membrane, the baseline electrical charge inside the cell
compared with outside the cell, referred to as resting membrane potential, is
based on the collective drive of force on several ions. Relative to the extracellular
fluid, the membrane potential of a neuron at rest is negatively charged at
approximately -70 millivolts (mV). These are very small voltages compared with the
voltages of batteries and electrical outlets that are measured in volts not millivolts,
and range from 1.5 to 240 volts.
Let us see how these two forces, diffusion and electrostatic pressure, act on the
four groups of ions mentioned above.

1. Anions (A-): Anions are highly concentrated inside the cell and contribute
to the negative charge of the resting membrane potential. Diffusion and
electrostatic pressure are not forces that determine A– concentration because
Anions are impermeable to the cell membrane. There are no ion channels
that allow for A– to move between the intracellular and extracellular fluid.
2. Potassium (K+): The cell membrane is very permeable to potassium at rest,
but potassium remains in high concentrations inside the cell. Diffusion
pushes K+ outside the cell because it is in high concentration inside the cell.
However, electrostatic pressure pushes K+ inside the cell because the positive
charge of K+ is attracted to the negative charge inside the cell. In
combination, these forces oppose one another with respect to K+.
3. Chloride (Cl-): The cell membrane is also very permeable to chloride at rest,
but chloride remains in high concentration outside the cell. Diffusion
pushes Cl– inside the cell because it is in high concentration outside the cell.
However, electrostatic pressure pushes Cl- outside the cell because the
negative charge of Cl– is attracted to the positive charge outside the cell.
These forces on Cl- oppose one another.
4. Sodium (Na+): The cell membrane is not very permeable to sodium at rest.
Diffusion pushes Na+ inside the cell because it is in high concentration
outside the cell. Electrostatic pressure also pushes Na+ inside the cell because
the positive charge of Na+ is attracted to the negative charge inside the cell.
Both of these forces push Na+ inside the cell; however, Na+ cannot
permeate the cell membrane and remains in high concentration outside the
52 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS
cell. The small amounts of Na+ inside the cell are removed by a sodium-
potassium pump, which uses the neuron’s energy (adenosine triphosphate,
ATP) to pump 3 Na+ ions out of the cell in exchange for bringing 2 K+ ions
inside the cell.

Action Potential
Now that we have considered what occurs in a neuron at rest, let us consider what
changes occur to the resting membrane potential when a neuron receives input
from the presynaptic terminal button of another neuron. Our understanding of
the electrical signals or potentials that occur within a neuron results from the
seminal work of Hodgkin and Huxley that began in the 1930s at a well-known
marine biology lab in Woods Hole, MA. Their work, for which they won the
Nobel Prize in Medicine in 1963, resulted in the general model of electrochemical
transduction described here (Hodgkin & Huxley, 1952). Hodgkin and Huxley
studied a very large axon in the squid, a common species for that region of the
United States. The giant axon of the squid is roughly 100 times larger than that
of axons in the mammalian brain, making it much easier to see and work with.
Activation of the giant axon is responsible for a withdrawal response the squid uses
when escaping from a predator. The large axon size is no mistake in nature’s design;
it allows for very rapid transmission of an electrical signal, enabling the squid a
swift escape from its predators.
While studying this species, Hodgkin and Huxley noticed that if they applied
an electrical stimulus to the axon, a large, transient electrical current conducted
down the axon. This transient electrical current is known as an action potential
(Figure 2.8). An action potential is an all-or-nothing response that occurs when
there is a change in the charge or potential of the cell from its resting membrane
potential (-70 mV) in a more positive direction, which is a depolarization (Figure
2.8). What is meant by an all-or-nothing response? This all-or-nothing concept
parallels the binary code used in computers, where there are only two possibilities,
0 or 1. There is no halfway or in-between these possible values; for example, 0.5
does not exist in binary code. There are only two possibilities, either the value of
0 or the value of 1. The action potential is the same in this respect. There is no
halfway; it occurs, or it does not occur. There is a specific membrane potential that
 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 53
the neuron must reach to initiate an action potential. This membrane potential,
called the threshold of excitation, is typically around -50 mV. If the threshold of
excitation is reached, then an action potential is triggered.

Figure 2.8. Changes in membrane potentials of neurons.

CREDIT:Changes in membrane of neurons © Noba is licensed under a CC
BY-NC-SA (Attribution NonCommercial ShareAlike) license

How is an action potential initiated? At any one time, each neuron may receive
hundreds of inputs from the cells that synapse with it. These inputs can cause
several types of fluctuations in the neuron’s membrane potentials (Figure 8):

1. excitatory postsynaptic potentials (EPSPs): a depolarizing current that

causes the membrane potential to become more positive and closer to the
threshold of excitation
2. inhibitory postsynaptic potentials (IPSPs): a hyperpolarizing current that
54 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS
causes the membrane potential to become more negative and further away
from the threshold of excitation

These postsynaptic potentials, EPSPs and IPSPs, summate or add together in time
and space. The (inhibitory) IPSPs make the membrane potential more negative,
but how much so depends on their strength. The (excitatory) EPSPs make the
membrane potential more positive; again, how much more positive depends on
their strength. If you have two small EPSPs at the same time and same synapse,
then the result will be a large EPSP. If you have a small EPSP and a small IPSP at
the same time and same synapse, then they will cancel each other out. Unlike the
action potential, which is an all-or-nothing response, IPSPs and EPSPs are smaller
and graded potentials, varying in strength. The change in voltage during an action
potential is approximately 100 mV. In comparison, EPSPs and IPSPs are changes
in voltage between 0.1 to 40 mV. They can be different strengths, or gradients, and
they are measured by how far the membrane potentials diverge from the resting
membrane potential.
I know the concept of summation can be confusing. As a child, I used to play
a game in elementary school with a very large parachute where you would try to
knock balls out of the center of the parachute. This game illustrates the properties
of summation rather well. In this game, a group of children next to one another
would work in unison to produce waves in the parachute in order to cause a wave
large enough to knock the ball out of the parachute. The children would initiate
the waves at the same time and in the same direction. The additive result was a
larger wave in the parachute, and the balls would bounce out of the parachute.
However, if the waves they initiated occurred in the opposite direction or with
the wrong timing, the waves would cancel each other out, and the balls would
remain in the center of the parachute. EPSPs or IPSPs in a neuron work in the same
fashion as the properties of the waves in the parachute; they either add or cancel
each other out. If you have two EPSPs, then they sum together and become a larger
depolarization. Similarly, if two IPSPs come into the cell at the same time, they
will sum and become a larger hyperpolarization in membrane potential. However,
if two inputs were opposing one another, moving the potential in opposite
directions, such as an EPSP and an IPSP, their sum would cancel each other out.
At any moment, each cell is receiving mixed messages, both EPSPs and IPSPs. If
the summation of EPSPs is strong enough to depolarize the membrane potential
 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 55
to reach the threshold of excitation, then it initiates an action potential. The action
potential then travels down the axon, away from the soma, until it reaches the ends
of the axon (the terminal button). In the terminal button, the action potential
triggers the release of neurotransmitters from the presynaptic terminal button into
the synaptic gap. These neurotransmitters, in turn, cause EPSPs and IPSPs in the
postsynaptic dendritic spines of the next cell (Figure 2.9). The neurotransmitter
released from the presynaptic terminal button binds with ionotropic receptors
in a lock-and-key fashion on the postsynaptic dendritic spine. Ionotropic receptors
are receptors on ion channels that open, allowing some ions to enter or exit the
cell, depending upon the presence of a particular neurotransmitter. The type of
neurotransmitter and the permeability of the ion channel it activates will
determine if an EPSP or IPSP occurs in the dendrite of the postsynaptic cell. These
EPSPs and IPSPs summate in the same fashion described above and the entire
process occurs again in another cell.

The Change in Membrane Potential

During an Action Potential
We discussed previously which ions are involved in maintaining the resting
membrane potential. Not surprisingly, some of these same ions are involved in the
action potential. When the cell becomes depolarized (more positively charged) and
reaches the threshold of excitation, this causes a voltage-dependent Na+ channel
to open. A voltage-dependent ion channel is a channel that opens, allowing some
ions to enter or exit the cell, depending upon when the cell reaches a particular
membrane potential. When the cell is at resting membrane potential, these voltage-
dependent Na+ channels are closed. As we learned earlier, both diffusion and
electrostatic pressure are pushing Na+ inside the cells. However, Na+ cannot
permeate the membrane when the cell is at rest. Now that these channels are
open, Na+ rushes inside the cell, causing the cell to become very positively charged
relative to the outside of the cell. This is responsible for the rising or depolarizing
phase of the action potential (Figure 2.8). The inside of the cell becomes very
positively charged, +40mV. At this point, the Na+ channels close and become
refractory. This means the Na+ channels cannot reopen again until after the cell
56 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS
returns to the resting membrane potential. Thus, a new action potential cannot
occur during the refractory period. The refractory period also ensures the action
potential can only move in one direction down the axon, away from the soma. As
the cell becomes more depolarized, a second type of voltage-dependent channel
opens; this channel is permeable to K+. With the cell very positive relative to the
outside of the cell (depolarized) and the high concentration of K+ within the cell,
both the force of diffusion and the force of electrostatic pressure drive K+ outside
of the cell. The movement of K+ out of the cell causes the cell potential to return
back to the resting membrane potential, the falling or hyperpolarizing phase of the
action potential (Figure 2.8). A short hyperpolarization occurs partially due to the
gradual closing of the K+ channels. With the Na+ closed, electrostatic pressure
continues to push K+ out of the cell. In addition, the sodium-potassium pump is
pushing Na+ out of the cell. The cell returns to the resting membrane potential,
and the excess extracellular K+ diffuses away. This exchange of Na+ and K+ ions
happens very rapidly, in less than 1 millisecond. The action potential occurs in a
wave-like motion down the axon until it reaches the terminal button. Only the ion
channels in very close proximity to the action potential are affected.
 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 57

Figure 2.9. Summary of the electrochemical communication within

and between neurons. CREDIT:Electrochemical communication © Noba is
licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike)
license

Earlier you learned that axons are often covered in myelin. Let us consider how
myelin speeds up the process of the action potential. There are gaps in the myelin
sheaths called nodes of Ranvier. The myelin insulates the axon and does not allow
any fluid to exist between the myelin and cell membrane. Under the myelin, when
the Na+ and K+ channels open, no ions flow between the intracellular and
extracellular fluid. This saves the cell from having to expend the energy necessary
to rectify or regain the resting membrane potential. (Remember, the pumps need
ATP to run.) Under the myelin, the action potential degrades some, but still has
a large enough potential to trigger a new action potential at the next node of
Ranvier. Thus, the action potential jumps from node to node (Figure 2.10); this
process is known as saltatory conduction (Saltus means “jump” in Latin).
58 | 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS

Figure 2.10. Action potential propagation in myelinated neurons (right)

is faster than in unmyelinated neurons (left) because of saltatory
conduction. CREDIT:Saltatory Conduction © Wikipedia is licensed under a CC
BY (Attribution) license

In the presynaptic terminal button, the action potential triggers the release of
neurotransmitters. Neurotransmitters cross the synaptic gap and open subtypes
of receptors in a lock-and-key fashion (see Figure 2.9). Depending on the type
of neurotransmitter, an EPSP or IPSP occurs in the dendrite of the postsynaptic
cell. Neurotransmitters that open Na+ or calcium (Ca+) channels cause an EPSP;
an example is the NMDA receptors, which are activated by glutamate (the main
excitatory neurotransmitter in the brain). In contrast, neurotransmitters that open
Cl- or K+ channels cause an IPSP; an example is gamma-aminobutyric acid
(GABA) receptors, which are activated by GABA, the main inhibitory
 2.4: COMMUNICATION WITHIN AND BETWEEN NEURONS | 59
neurotransmitter in the brain. Once the EPSPs and IPSPs occur in the
postsynaptic site, the process of communication within and between neurons
cycles on (Figure 2.9). A neurotransmitter that does not bind to receptors is broken
down and inactivated by enzymes or glial cells, or it is taken back into the
presynaptic terminal button in a process called reuptake, which will be discussed
further in the chapter on psychopharmacology.
60 | 2.5: DISCUSSION QUESTIONS AND RESOURCES

2.5: DISCUSSION QUESTIONS

AND RESOURCES

Discussion Questions

1. What structures of a neuron are the main input and output of

that neuron?
2. What does the statement mean that communication within and
between cells is an electrochemical process?
3. How does myelin increase speed and efficiency of the action
potential?
4. How does diffusion and electrostatic pressure contribute to the
resting membrane potential and the action potential?
5. Describe the cycle of communication within and between
neurons.

Outside Resources

Video Series: Neurobiology/Biopsychology – Tutorial animations of

action potentials, resting membrane potentials, and synaptic
transmission.

http://www.sumanasinc.com/webcontent/animations/
neurobiology.html
 2.5: DISCUSSION QUESTIONS AND RESOURCES | 61

Video: An animation and an explanation of an action potential

https://youtu.be/OZG8M_ldA1M

Video: What’s so special about the human brain? Suzana

Herculano-Houzel

https://www.youtube.com/
watch?v=_7_XH1CBzGw&ab_channel=TED

Video: An animation of neurotransmitter actions at the synapse

http://www.youtube.com/watch?v=90cj4NX87Yk

Video: An interactive animation that allows students to observe the

results of manipulations to excitatory and inhibitory post-synaptic
potentials. Also includes animations and explanations of
transmission and neural circuits.

https://apps.childrenshospital.org/clinical/animation/neuron/

Video: Another animation of an action potential

http://www.youtube.com/watch?v=-
SHBnExxub8&list=PL968773A54EF13D21

Video: Another animation of neurotransmitter actions at the

synapse

http://www.youtube.com/
watch?v=LT3VKAr4roo&list=PL968773A54EF13D21

Video: Domino Action Potential: This hands-on activity helps

students grasp the complex process of the action potential, as well
as become familiar with the characteristics of transmission (e.g., all-
or-none response, refractory period).

https://www.youtube.com/watch?v=xzvZ11EutBY

Video: For perspective on techniques in neuroscience to look inside

the brain

https://www.youtube.com/watch?v=s4smjT1qwZU
62 | 2.5: DISCUSSION QUESTIONS AND RESOURCES

Video: The Behaving Brain is the third program in the

DISCOVERING PSYCHOLOGY series. This program looks at the
structure and composition of the human brain: how neurons
function, how information is collected and transmitted, and how
chemical reactions relate to thought and behavior.

http://www.learner.org/series/discoveringpsychology/03/
e03expand.html

Video: You can grow new brain cells. Here’s how. -Can we, as
adults, grow new neurons? Neuroscientist Sandrine Thuret says that
we can, and she offers research and practical advice on how we can
help our brains better perform neurogenesis—improving mood,
increasing memory formation and preventing the decline associated
with aging along the way.

https://www.youtube.com/watch?v=B_tjKYvEziI

Web: For more information on the Nobel Prize shared by Ramón y

Cajal and Golgi

http://www.nobelprize.org/nobel_prizes/medicine/laureates/
1906/
 2.6: REFERENCES | 63

2.6: REFERENCES

Hove, M. J., & Martinez, S. A. (2024). Biological psychology. ROTEL (Remixing

Open Textbooks with an Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/. Adapted this chapter from:
Furtak, S. (2021). Neurons. In R. Biswas-Diener & E. Diener (Eds), Noba
textbook series: Psychology. Champaign, IL: DEF publishers. Retrieved from
http://noba.to/s678why4 License: CC BY-NC-SA 4.0 DEED

References
De Carlos, J. A., & Borrell, J. (2007). A historical reflection of the contributions of
Cajal and Golgi to the foundations of neuroscience. Brain Res Rev, 55(1), 8-16.
doi: 10.1016/j.brainresrev.2007.03.010
Furtak, S. C., Moyer, J. R., Jr., & Brown, T. H. (2007). Morphology and ontogeny
of rat perirhinal cortical neurons. J Comp Neurol, 505(5), 493-510. doi:
10.1002/cne.21516
Grant, G. (2007). How the 1906 Nobel Prize in Physiology or Medicine was
shared between Golgi and Cajal. Brain Res Rev, 55(2), 490-498. doi: 10.1016/
j.brainresrev.2006.11.004
Herculano-Houzel, S. (2009). The human brain in numbers: a linearly scaled-up
primate brain. Frontiers in Human Neuroscience, 31.
Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane
current and its application to conduction and excitation in nerves. J Physiol,
117(4), 500-544.
Lopez-Munoz, F., Boya, J., & Alamo, C. (2006). Neuron theory, the cornerstone
of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramon
y Cajal. Brain Res Bull, 70 (4-6), 391-405. doi: 10.1016/
j.brainresbull.2006.07.010
Pasternak, J. F., & Woolsey, T. A. (1975). On the “selectivity” of the Golgi-Cox
method. J Comp Neurol, 160(3), 307-312. doi: 10.1002/cne.901600304
64 | 2.6: REFERENCES
Ramón y Cajal, S. (1911). Histology of the nervous system of man and vertebrates.
New York, NY: Oxford University Press.
Simons, M., & Trotter, J. (2007). Wrapping it up: the cell biology of myelination.
Curr Opin Neurobiol, 17(5), 533-540. doi: 10.1016/j.conb.2007.08.003
Smit, G. J., & Colon, E. J. (1969). Quantitative analysis of the cerebral cortex. I.
Aselectivity of the Golgi-Cox staining technique. Brain Res, 13(3), 485-510.
 CHAPTER 3: THE BRAIN AND NERVOUS SYSTEM | 65

CHAPTER 3: THE BRAIN

AND NERVOUS SYSTEM

The Brain and Nervous System Learning Objectives

• Learn about the central and peripheral nervous systems and their
subdivisions including the sympathetic and parasympathetic
nervous systems
• Know terms to describe locations in the brain such as anterior,
posterior, inferior, superior, dorsal, ventral, medial, and lateral
• Know the coronal, sagittal, and horizontal anatomical planes used
to visualize the brain in two dimensions
• Describe the basic functions of the brainstem, cerebellum,
thalamus, hypothalamus, and cerebral hemispheres
• Understand the differences between gray matter and white
matter
• Learn about the four lobes of the cerebral cortex: occipital,
temporal, parietal, and frontal lobes.
• Learn about the roles of major subcortical structures including the
basal ganglia, hippocampus, amygdala, thalamus, and
hypothalamus
• Understand important non-neuronal structures, including the
meninges that surround and protect the brain, the ventricles that
contain cerebrospinal fluid, and the vasculature that supplies
blood throughout the brain
66 | CHAPTER 3: THE BRAIN AND NERVOUS SYSTEM

This chapter is adapted from Hove, M. J., & Martinez, S. A. (2024).

Biological Psychology. ROTEL (Remixing Open Textbooks with an
Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/
 3.1: INTRODUCTION | 67

3.1: INTRODUCTION
Michael J. Hove and Steven A. Martinez

In this chapter we focus on the structures of the brain and nervous system.
Understanding the biological structures of the nervous system is vital to
understanding psychology, for the various brain structures play specific roles in
psychological processes. Throughout this book, we refer to many brain structures
and describe their role in emotion, cognition, perception, neurological diseases,
and psychological disorders.
An introduction to the biological aspects of psychology can be very interesting,
but also frustrating for new students of psychology. This is largely because there is
so much new information and vocabulary associated with parts of the brain and
nervous system. We encourage you not to get bogged down in difficult vocabulary.
Instead, on a first reading, pay particular attention to the broader concepts. Then,
once familiar with the topic, pass back through with attention to learning the
vocabulary. With the help of the figures and some studying, you can master the
terminology of the nervous system.

Text Attributions
This section contains material adapted from:
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener
& E. Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/4hzf8xv6 License: CC BY-NC-SA 4.0
DEED
68 | 3.2: VISUALIZING AND NAVIGATING THE HUMAN BRAIN

3.2: VISUALIZING AND

NAVIGATING THE HUMAN
BRAIN
Michael J. Hove and Steven A. Martinez

Before diving into the organization of the nervous system and introducing brain
structures, we present some important anatomical terms for visualizing and
navigating the brain. The brain is a three-dimensional (3-D) structure that can
be visualized in two-dimensional (2-D) slices. There are three standard anatomical
planes for visualizing the brain: 1) the coronal or frontal plane; 2) the sagittal plane;
and 3) the horizontal or axial plane (Figure 3.1). The coronal or frontal plane is a
vertical plane and splits the brain into front and back sections. The sagittal plane
is a vertical plane which splits the brain into left and right sections. The horizontal
or axial plane is a horizontal plane which splits the brain into upper and lower
sections.
 3.2: VISUALIZING AND NAVIGATING THE HUMAN BRAIN | 69

Figure 3.1: Slices of the human brain. Three possible 2-D cuts through
the brain: a coronal or frontal slice (top image), a sagittal slice (middle),
and a horizontal slice (bottom), which is also known as a transverse or
axial slice. CREDIT: Slices of the human brain © Wikimedia is licensed under a
CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Conventional terms describe locations and directions in the brain and are helpful
for navigating around the brain. Anterior means toward the front of the brain;
Posterior means toward the back of the brain. Rostral means toward the front or
the “beak”; Caudal means toward the tail end. Superior means toward the top;
Inferior means toward the bottom. Dorsal means toward the top or back (think
dorsal fin); and ventral means toward the belly. Medial means toward the middle;
and Lateral toward the side. Contralateral means on the opposite (left/right) side;
Ipsilateral means on the same side. You’ll hear these terms a lot as you learn about
the brain.
70 | 3.3: THE NERVOUS SYSTEM

3.3: THE NERVOUS SYSTEM

Michael J. Hove and Steven A. Martinez

The nervous system can be thought of as the body’s command center and
communication network; it processes information, relays sensory input, and
coordinates actions by transmitting signals to and from other body parts (Ahmad,
2023). The nervous system is divided into the central nervous system (CNS) and
the peripheral nervous system (PNS) (Figure 3.2). The central nervous system
consists of the brain and spinal cord. The peripheral nervous system consists of
nerves outside the brain and spinal cord and forms the communication network
between the CNS and other body parts. The PNS has several subdivisions that we
explore in more detail in the following section.
 3.3: THE NERVOUS SYSTEM | 71

Figure 3.2. The human nervous system. The Central Nervous System
(CNS), shown in yellow, is made up of the brain and spinal cord. The
Peripheral Nervous System (PNS), shown in blue, is made up of nerves
that connect the brain and spinal cord to the rest of the body. CREDIT:
Nervous system diagram © Wikipedia is licensed under a CC0 (Creative
Commons Zero) license

Text Attributions
This section contains material adapted from:
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener
72 | 3.3: THE NERVOUS SYSTEM
& E. Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/4hzf8xv6 License: CC BY-NC-SA 4.0
DEED
 3.4: THE PERIPHERAL NERVOUS SYSTEM | 73

3.4: THE PERIPHERAL NERVOUS

SYSTEM
Michael J. Hove and Steven A. Martinez

The peripheral nervous system (PNS) connects the central nervous system with
the rest of the body. It serves as a communication relay between the CNS and
muscles, organs, and glands. The peripheral nervous system includes nerves that
are connected to the brain (cranial nerves) and the spinal cord (spinal nerves).
Unlike the CNS, the PNS is not protected by the bone of the skull and spine. Nor
does it have a barrier between itself and the blood (like the blood-brain barrier),
leaving it exposed to toxins and mechanical injuries .
The PNS can be divided into the autonomic nervous system, which controls
bodily functions without conscious control, and the somatic nervous system,
which transmits sensory information from the skin, muscles, and sensory organs
to the CNS and also sends motor commands from the CNS to the muscles (Figure
3.3).
74 | 3.4: THE PERIPHERAL NERVOUS SYSTEM

Figure 3.3: Components of the peripheral nervous system. Peripheral

nervous system © Noba is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

The Autonomic Nervous System

The autonomic nervous system serves as the relay between the CNS and the
internal organs. It controls the lungs, the heart, smooth muscle, and exocrine and
endocrine glands. The autonomic nervous system controls these organs largely
without conscious control. It can continuously monitor the conditions of these
different systems and implement changes as needed. There are two divisions of
the autonomic nervous system that often have opposing effects: the sympathetic
nervous system and the parasympathetic nervous system.
The Sympathetic Nervous System. The sympathetic nervous system is
responsible for the “fight or flight” response that occurs when an animal
encounters a dangerous situation. One way to remember this is to think of the
surprise a person feels when encountering a snake (“snake” and “sympathetic”
both begin with “s”). Examples of functions controlled by the sympathetic nervous
system include an accelerated heart rate and inhibited digestion. These functions
help prepare an organism’s body for the physical strain required to escape a
potentially dangerous situation or to fend off a predator.
The Parasympathetic Nervous System. While the sympathetic nervous
 3.4: THE PERIPHERAL NERVOUS SYSTEM | 75
system is activated in stressful situations, the parasympathetic nervous system
allows an animal to “rest and digest.” One way to remember this is to think
that during a restful situation like a picnic, the parasympathetic nervous system
is in control (“picnic” and “parasympathetic” both start with “p”). The
parasympathetic nervous system resets organ function after the sympathetic
nervous system is activated (the common adrenaline dump you feel after a ‘fight-
or-flight’ event). Thus the sympathetic and parasympathetic nervous systems work
in a push–pull manner (Figure 4). Examples of functions controlled by the
parasympathetic nervous system include slowing of heart rate, lowered blood
pressure, and stimulation of digestion.
76 | 3.4: THE PERIPHERAL NERVOUS SYSTEM

Figure 3.4. The sympathetic and parasympathetic nervous systems

often have opposing effects on target organs. CREDIT:The sympathetic and
parasympathetic nervous systems © OpenStax is licensed under a CC BY-NC-SA
(Attribution NonCommercial ShareAlike) license

The Somatic Nervous System

The somatic nervous system deals with interactions with the external environment,
including sensing the outside world via sensory neurons and sending commands
via motor neurons to skeletal muscles. Many behaviors associated with the somatic
nervous system are voluntary and are initiated by complex decision making
processes in the brain. You hear a voice call your name, you interpret the speech,
and turn your head towards the sound.
 3.4: THE PERIPHERAL NERVOUS SYSTEM | 77
The somatic nervous system is made up of cranial and spinal nerves and
contains both sensory and motor neurons. Sensory neurons transmit sensory
information from the skin, skeletal muscle, and sensory organs to the CNS. Motor
neurons transmit messages about desired movement from the CNS to skeletal
muscles to make them contract. Without a somatic nervous system, an animal
would be unable to process any information about its environment (what it sees,
feels, hears, etc.) and could not control motor movements.
Cranial nerves. Humans have 12 cranial nerves; these nerves emerge from the
skull (cranium), as opposed to the spinal nerves, which emerge from the vertebral
column. Each cranial nerve is accorded a name, as shown in Figure 5. Some
cranial nerves transmit only sensory information. For example, the olfactory nerve
transmits information about smells from the nose to olfactory regions in the brain.
Other cranial nerves transmit almost solely motor information. For example, the
oculomotor nerve controls the opening and closing of the eyelid and some eye
movements. Other cranial nerves contain a mix of sensory and motor fibers. For
example, the glossopharyngeal nerve has a role in both taste (sensory) and
swallowing (motor).
78 | 3.4: THE PERIPHERAL NERVOUS SYSTEM

Figure 3.5. Inferior view (from below) of the human brain showing the
cranial nerves in orange. The human brain contains 12 cranial nerves
that receive sensory input and control motor output for the head and
neck. CREDIT:12 cranial nerves © OpenStax is licensed under a CC BY-NC-SA
(Attribution NonCommercial ShareAlike) license

Spinal nerves. Spinal nerves transmit sensory and motor information between
the spinal cord and the rest of the body. Each of the 31 spinal nerves (in humans)
contains both sensory and motor axons. The sensory neuron cell bodies are
grouped in structures called dorsal root ganglia (Figure 6) (dorsal = toward back).
Each sensory neuron projects from a sensory receptor in skin, muscle, or sensory
organs to a synapse with a neuron in the dorsal spinal cord. Motor neurons have
cell bodies in the ventral gray matter of the spinal cord that project to muscle
through the ventral root (ventral = toward belly). These neurons are usually
stimulated by interneurons within the spinal cord but are sometimes directly
stimulated by sensory neurons (as in a reflex arc). Each spinal nerve corresponds
to different body regions–for example, spinal nerves that exit near the top of the
spine correspond to the shoulders and arms, whereas spinal nerves that exit near
the bottom of the spine correspond to legs and feet (see Figure 7).
 3.4: THE PERIPHERAL NERVOUS SYSTEM | 79

Figure 3.6. Spinal nerves contain both sensory and motor axons. The
somas (cell bodies) of sensory neurons are located in dorsal root
ganglia. The somas of motor neurons are found in the ventral portion of
the gray matter of the spinal cord. CREDIT: Spinal nerves © OpenStax is
licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license
80 | 3.4: THE PERIPHERAL NERVOUS SYSTEM

Figure 3.7. Spinal nerves exit the spinal cord through notches in the
vertebrae. This figure illustrates the spinal cord segments in the
vertebral column (cervical, thoracic, lumbar, sacral), and how each spinal
nerve relates to different regions of the body. CREDIT:Spinal cord segments
in the vertebral column © Wikipedia is licensed under a CC0 (Creative Commons
Zero) license

Text Attributions
This section contains material adapted from:
The Nervous System in General Biology (Boundless). https://bio.libretexts.org/
Bookshelves/Introductory_and_General_Biology/
Book%3A_General_Biology_(Boundless)/35%3A_The_Nervous_System/
35.09%3A__The_Nervous_System License: CC BY SA 4.0
 3.4: THE PERIPHERAL NERVOUS SYSTEM | 81
Clark, M.A., Douglas, M. & Choi, J. (2023). 34.5 The Peripheral Nervous
System. In Biology 2e. OpenStax. Access for free at https://openstax.org/books/
biology-2e/pages/35-4-the-peripheral-nervous-system License: CC BY 4.0 DEED.
Hall, C. N. (2023). 2 Exploring the brain: A tour of the structures of the
nervous system. In Introduction to Biological Psychology. University of Sussex
Library. Access for free at https://openpress.sussex.ac.uk/
introductiontobiologicalpsychology/chapter/exploring-the-brain-a-tour-of-the-
structures-and-cells-of-the-nervous-system/ License: CC BY-NC 4.0 DEED
82 | 3.5: THE CENTRAL NERVOUS SYSTEM

3.5: THE CENTRAL NERVOUS

SYSTEM
Michael J. Hove and Steven A. Martinez

The central nervous system is made up of the brain and spinal cord. The brain
and spinal cord are enclosed in three layers of protective coverings called meninges
(from the Greek word for membrane) (Figure 3.8). The outermost layer is the
dura mater (Latin for “hard mother”)—a thick layer that protects the brain and
spinal cord and contains large blood vessels. The middle layer is the web-like
arachnoid mater. The innermost layer is the pia mater (Latin for “soft mother”),
which directly contacts and covers the brain and spinal cord like plastic wrap. The
space between the arachnoid and pia maters, the subarachnoid space, is filled with
cerebrospinal fluid (CSF), a fluid that helps cushion and protect the brain and
spinal cord. We discuss cerebrospinal fluid in more detail in the next section on The
Brain.
 3.5: THE CENTRAL NERVOUS SYSTEM | 83

Figure 3.8. The cerebral cortex is covered by three layers of meninges:

the dura, arachnoid, and pia maters (Credit: modification of work by
Gray’s Anatomy). CREDIT: The cerebral cortex © OpenStax is licensed under
a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

The Spinal Cord

The spinal cord is the major bundle of nervous tissues that extends from the
brainstem down the backbone to the lumbar region of the spine. The spinal cord
transmits information from the skin, muscles, and internal organs to the brain,
and vice versa. Information that travels from the bodily periphery toward the brain
(or deeper centrally within the brain) is called an afferent signal. Information that
travels away from the brain, such as a motor command to a muscle, is called an
efferent signal.
In addition to sending information to and from the brain, the spinal cord
controls some simple reflexive movements like removing your hand from a hot
object and the knee reflex. These reflexive movements are very fast because the
sensory signal is processed and the motor command is initiated directly in the
84 | 3.5: THE CENTRAL NERVOUS SYSTEM
spinal cord. Processing in the spinal cord avoids the time-consuming signal
transmission to and from the brain, saves hundreds of milliseconds, and helps to
protect our tissue from damage.
The spinal cord also houses central pattern generators that control some simple
rhythmic movements such as walking. Experiments with cats have shown that
even after severing the spinal cord (thereby cutting off motor commands from the
brain), cats can still produce relatively normal walking on a treadmill (Duysens &
Van de Crommert, 1998).
The spinal cord is protected by the bony vertebrae in the backbone and
cushioned by cerebrospinal fluid. However spinal cord injuries still can occur and
are very serious. In the United States, around 10,000 spinal cord injuries occur
each year. Because the spinal cord is the information superhighway connecting the
brain with the body, damage to the spinal cord can lead to paralysis. The extent
of the paralysis depends on the location of the injury along the spinal cord and
whether the spinal cord was completely severed. For example, if the spinal cord is
damaged at the level of the neck, it can cause paralysis from the neck down, whereas
damage further down the spinal column may limit paralysis to the legs. Spinal cord
injuries are notoriously difficult to treat because spinal nerves do not regenerate,
although ongoing research suggests that stem-cell transplants may be able to act as
a bridge to reconnect severed nerves.

Text Attributions
This section contains material adapted from:
Clark, M.A., Douglas, M. & Choi, J. (2023). 35.3 The Central Nervous System.
In Biology 2e. OpenStax. Access for free at https://openstax.org/books/biology-2e/
pages/35-3-the-central-nervous-system License: CC BY 4.0 DEED.
 3.6: THE BRAIN | 85

3.6: THE BRAIN

Michael J. Hove and Steven A. Martinez

The brain is the most complex part of the human body, consisting of 86 billion
neurons, each of which may connect with 1000s of other neurons. It is the center
of higher-order processes like planning, memory, problem solving, and
consciousness, and coordinates voluntary and involuntary movements and bodily
functions. This section provides an introductory overview of the brain and some
basic neuroanatomy.
The mammalian brain can be subdivided in many ways, resulting in some
inconsistent and ambiguous naming conventions over the history of
neuroanatomy (Swanson, 2000). One way to think about brain organization
reflects brain development in the embryo. The human nervous system starts as a
simple neural tube, and 3-4 weeks after conception, the tube expands into three
primary vesicles—the forebrain, midbrain, and hindbrain. After a few more weeks,
these primary vesicles give rise to secondary vesicles that eventually develop into
the components of the adult nervous system (more detail on brain development
in Chapter 7). As seen in Figure 3.9, the forebrain vesicle develops into a) the
cerebrum, which includes the cerebral cortex (frontal, temporal, parietal, and
occipital lobes) and underlying subcortical structures (e.g., the hippocampus,
amygdala, and basal ganglia), and b) the diencephalon, which includes the
thalamus and hypothalamus. The midbrain primary vesicle develops into part
of the brainstem, including the superior and inferior colliculi. The hindbrain
develops into the cerebellum and other brainstem regions including the pons and
medulla oblongata. We introduce these brain structures in the section below.
86 | 3.6: THE BRAIN

Figure 3.9: The central nervous system and its various major
subdivisions. CREDIT: Central nervous system subdivisions © Steven Martinez
is licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Cerebral Cortex
The cerebral cortex is a thin sheet of neurons that makes up the outermost layer
of the cerebral hemispheres. The term cortex, derived from the Latin for “bark,”
refers to a thin sheet of neurons; in contrast, the term nucleus(plural: nuclei) in
neuroanatomy refers to a cluster of neurons. The cerebral cortex is made up of
gray matter, a type of tissue named for its color that consists largely of neuronal
cell bodies and short-range connections. Conversely, white matter tissue consists
largely of axons covered in myelin, a fatty white substance that insulates axons to
speed the transmission of neural signals. White-matter fiber tracts underlie the gray
matter of the cerebral cortex and send signals to more distant brain regions (Figure
3.10).
 3.6: THE BRAIN | 87

Figure 3.10. Coronal tissue slice from the brain of a macaque monkey.
The gray matter of the cerebral cortex is the outer layer depicted in dark
violet. The underlying white matter fiber tracts are shown in lighter
color. CREDIT: Brain maps © Wikipedia is licensed under a CC0 (Creative
Commons Zero) license

The cerebral cortex ‘bark’ is only 2-4 mm across, but most cortex consists of 6
layers. Each layer has characteristic cell types and connectivity—the innermost
layers 5 and 6 send signals out of cortex, layer 4 receives input from the thalamus,
layers 2 and 3 project to nearby regions within cortex, and layer 1 has very few cell
bodies and mostly contains the tips of dendrites and axons (Hall, 2023).
The thin cortex has a surprisingly large surface area—the human cortex is about
1800 cm2, making the cortex in each hemisphere about the size of medium thin-
crust pizza (minus the sauce, cheese, and toppings) (Van Essen et al., 2018) (Figure
3.11). This large surface area fits into the small volume of the cranium, because the
human cortex is extensively folded (most other animals including small mammals
have smooth cortex). Folding maximizes the surface-to-volume ratio, and improves
packaging and communication efficiency (Shipp, 2007).
88 | 3.6: THE BRAIN

Figure 3.11. The thin outermost layer of each cerebral hemisphere, the
cerebral cortex, is about the size of a medium thin-crust pizza–minus the
sauce, cheese, and toppings. CREDIT: Pizza brain © AI Generated is licensed
under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

The folding of the cortex also gives the brain its bumpy appearance. The bumps are
called gyri (singular: gyrus) and the valleys between gyri are called sulci (singular:
sulcus). Larger and deeper sulci are called fissures. Major gyri, sulci, and fissures
are used as landmarks to separate the cortex into its major regions, including the
frontal, temporal, parietal, and occipital lobes (Figure 3.12). The central sulcus
marks the border between the frontal and parietal lobes. The lateral sulcus (also
called the Sylvian fissure), separates the temporal lobe from the frontal and parietal
 3.6: THE BRAIN | 89
lobes. The occipital lobe has no obvious anatomical border on the outer surface
of the brain. However, from the medial (inner) surface, an obvious landmark, the
parieto-occipital sulcus, separates the parietal and occipital lobes.

Figure 3.12: The lobes of the brain and the major sulci that mark the
borders. The central sulcus separates the frontal and parietal lobes. The
lateral sulcus marks the upper border of the temporal lobe. And the
parieto-occipital sulcus (which is more clearly seen on the medial
surface) separates the parietal and occipital lobes. CREDIT:Lobes of the
Cerebral Cortex © OpenStax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Another prominent landmark, the longitudinal fissure, runs down the brain’s
midline and separates the left and right cerebral hemispheres. The two cerebral
hemispheres are connected to each other via the corpus callosum, a large white
matter tract that passes information between hemispheres. The left and right
hemispheres are structurally symmetrical and often have overlapping and
 90 | 3.6: THE BRAIN
redundant functions, but there is some lateralization of function, where some
brain functions are processed more in one hemisphere than the other. For example,
touch signals and motor commands for each side of the body are processed in the
contralateral (opposite) side of the brain, and language for most people is processed
more in the left hemisphere.
Finally, smaller subregions of the cerebral cortex are associated with particular
functions, a concept known as localization of function. In the early 1900s,
a German neuroscientist named Korbinian Brodmann extensively studied the
microscopic anatomy, or cytoarchitecture, of the cerebral cortex and divided the
cortex into 52 separate regions based on the microscopic tissue structure. These
“Brodmann areas” are still used today to describe anatomical regions within the
cortex (Figure 3.13). Brodmann’s anatomical work aligns well with the particular
functions within the cortex. For example, Brodmann area 4 (as defined based on
the microscopic tissue structure) aligns with the primary motor cortex that sends
motor commands to the spinal cord.1

1. This section contains material adapted from: Betts, J. G. et al. (2022). 13.2 The Central Nervous
System. In Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/
anatomy-and-physiology-2e/pages/13-2-the-central-nervous-system License: CC BY 4.0 DEED.
- Hall, C. N. (2023). 2 Exploring the brain: A tour of the structures of the nervous system. In
Introduction to Biological Psychology. University of Sussex Library. Access for free at
https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/chapter/exploring-the-brain-a-
tour-of-the-structures-and-cells-of-the-nervous-system/ License: CC BY-NC 4.0 DEED
 3.6: THE BRAIN | 91

Figure 3.13. Brodmann’s maps from 1909 that he built based on the
cytoarchitecture or microscopic tissue structure and organization.
Several important Brodmann areas are shown on the brain’s lateral
surface (left) and the medial surface (right). CREDIT:Brodmann’s Areas of
the Cerebral Cortex © OpenStax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Frontal Lobe
The frontal lobe, located in the front of the brain (where else?), is involved in
planning and implementing movement, as well as higher-order cognitive processes
such as attention, language, reasoning, problem solving, and abstract thought.
The frontal lobe is made up of subregions that perform specialized functions. At
the back of the frontal lobe is the precentral gyrus (the gyrus or bump directly
pre- or anterior to the central sulcus); this region is the primary motor cortex,
which contains neurons that send commands to the spinal cord to move skeletal
muscles. Areas within the primary motor cortex map to different muscle groups
in an ordered manner (Figure 3.14). Body parts that require especially fine motor
control, like the fingers, lips, and tongue, occupy more “neural real estate” on
the motor cortex than, say, the shoulder or trunk. Anterior to the primary motor
cortex are other areas associated with movement, including the premotor area
92 | 3.6: THE BRAIN
(involved in movement planning) and the frontal eye fields (involved in eliciting eye
movements and visual attention).

Figure 3.14. The primary motor cortex on the precentral gyrus is directly
anterior to the central sulcus. It is organized so certain areas of the
motor strip send signals to specific body parts like the tongue or
fingers. CREDIT: Central sulcus © Noba is licensed under a CC BY-NC-SA
(Attribution NonCommercial ShareAlike) license

Anterior to the motor and premotor cortex is the prefrontal cortex (PFC), which
is involved in many cognitive and executive functions (Figure 3.15). In the inferior
prefrontal cortex (usually left lateralized) lies Broca’s area (Figure 3.16), a region
involved in language production. Broca’s area is named after a French physician,
Paul Broca, who in 1861, documented that damage here impaired speech
production. Other major subregions of the prefrontal cortex include the
dorsolateral PFC (dorsal=upper, lateral=outer) involved in working memory,
planning, inhibiting responses, and cognitive flexibility, and the orbitofrontal
cortex at the very front (by the orbits of the eye), which is involved in complex
decision making, encoding value, emotion, sociality, and predicting the
consequences of our actions (Rudebeck & Rich, 2018).
In general, more anterior regions in the brain and within the frontal lobe are
roughly associated with ‘higher’ cognitive function, such as rule learning at higher
levels of abstraction. High-level abstract thought, executive function (such as
maintaining goal-directed behavior), language, and navigating complex social
 3.6: THE BRAIN | 93
contexts are crucial for what we consider “human” cognition. Indeed, the
corresponding prefrontal regions are disproportionately large in humans and have
expanded or reorganized in humans compared to other species, especially
compared to species more distant on the evolutionary tree (Van Essen et al., 2018)
Humans with frontal lobe damage can have a variety of impairments depending
on the location and extent of the damage. These impairments include changes
in personality, cognition, learning, decision making, risk assessment, behavioral
inhibition, and social function.2

2. This section contains material adapted from: Biswas-Diener, R. (2023). The brain and nervous system.
In R. Biswas-Diener & E. Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/4hzf8xv6 License: CC BY-NC-SA 4.0 DEED -
Betts, J. G. et al. (2022). 13.2 The Central Nervous System. In Anatomy and Physiology 2e. OpenStax.
Access for free at https://openstax.org/books/anatomy-and-physiology-2e/pages/13-2-the-central-
nervous-system License: CC BY 4.0 DEED. - Clark, M.A., Douglas, M. & Choi, J. (2023). 35.3
The Central Nervous System. In Biology 2e. OpenStax. Access for free at https://openstax.org/books/
biology-2e/pages/35-3-the-central-nervous-system License: CC BY 4.0 DEED.
94 | 3.6: THE BRAIN

Figure 3.15. Prefrontal cortex in blue-ish colors. Subregions include:

Broca’s area marked by its Brodmann areas (BA) numbers 44 and 45; the
dorsolateral prefrontal cortex [BA 9 and 46], and the orbitofrontal
cortex [BA 10 and 11]. CREDIT: Prefrontal cortex © Wikipedia is licensed under
a CC BY-SA (Attribution ShareAlike) license

Temporal Lobe
The temporal lobe is located in the lateral portion of each hemisphere under
the temples (hence “temporal”). It is involved in processing auditory information,
understanding language, recognizing visual objects, and memory. The auditory
cortex, the main area responsible for processing auditory information, is located in
the superior temporal lobe. In the posterior part of the superior temporal lobe lies
Wernicke’s area, a region involved in language comprehension; Wernicke’s area
connects to the frontal Broca’s area (involved in language production) through the
arcuate fasciculus, a white-matter fiber tract (Figure 3.16).
In addition to processing sound and language, the temporal lobe is also critical
for visual object recognition and memory. The ventral (bottom) surface of the
temporal lobe receives visual signals from the visual cortex and contains subregions
 3.6: THE BRAIN | 95
that are highly specialized to perceive and recognize faces (the fusiform face area)
and places and scenes (the parahippocampal place area). Damage to these regions,
from a stroke for example, can impair very specific abilities; lesions to the inferior
temporal lobe may lead to prosopagnosia, the inability to recognize and identify
faces (Kanwisher & Yovel, 2008). Finally, the medial temporal lobes are important
for encoding long-term memory.3

3. This section contains material adapted from: Ahmad, A. (2024). The nervous system. In R. Biswas-
Diener & E. Diener (Eds), Noba textbook series: Psychology. Retrieved from http://noba.to/
wnf72q34 License: CC BY NC SA 4.0 DEED. - Spielman, R. M., Jenkins, W. J., & Lovett, M.
D. (2020). 3.4 The Brain and Spinal Cord. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/3-4-the-brain-and-spinal-cord License: CC BY 4.0
DEED.
96 | 3.6: THE BRAIN

Figure 3.16. Broca’s area in the left frontal gyrus; Wernicke’s area in the
superior temporal gyrus; and the arcuate fasciculus, a white matter tract
that connects the caudal temporal cortex with the inferior frontal lobe.
CREDIT: Wernickes area © Noba is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Parietal Lobe
The parietal lobe, located above the temporal lobe and behind the frontal lobe,
processes touch, bodily and spatial maps, and integrates senses. The postcentral
gyrus (directly behind the central sulcus) houses the primary somatosensory
cortex (S1). This region processes the tactile senses, including touch, pressure,
pain, itch, and vibration, as well as more general bodily senses of proprioception
(body position) and kinesthesia (movement sense). The somatosensory cortex is
organized topographically, meaning that adjacent parts of the skin are represented
 3.6: THE BRAIN | 97
by adjacent areas of the somatosensory cortex. HIghly sensitive body parts have
more nerve receptors on the skin and occupy larger regions of the cortex than less
sensitive areas. For example as seen in Figure 3.17, the highly sensitive fingers and
lips occupy much more somatosensory cortex than the leg and trunk.

Figure 3.17. A coronal brain slice showing the somatosensory cortex and
its topographic organization. More sensitive body parts, like the face
and hands, are processed by larger regions of the somatosensory
cortex, compared to less sensitive regions like the leg and trunk.
CREDIT:Sensory Homunculus © Wikipedia is licensed under a CC BY-SA
(Attribution ShareAlike) license

While the anterior parietal cortex processes body senses, the posterior parietal
cortex is an “associative” region, meaning that it is neither strictly sensory nor
 98 | 3.6: THE BRAIN
motor. Rather it combines inputs from touch, proprioception, vision, and
audition, as well as from motor and prefrontal regions (Whitlock, 2017). This
integrative aspect makes it important for making spatial maps to guide attention
and movement. In order to grasp an object, that object’s location must be
translated from its retinotopic coordinates (i. e., where it lands on the retina) into
coordinates in space; this translation depends on the direction the eyes and head are
pointed. Parietal maps of the locations of body parts and objects in space are critical
for planning and executing movements to manipulate objects. These spatial maps
output to frontal motor regions for planning body movement and to the frontal
eye fields for directing eye movements and attention.
Damage to the posterior parietal lobe can impair visually guided reaching
movements and spatial perception (Karnath, 1997). In light of its role in attention
and awareness, damage here can also lead to a condition called hemispatial
neglect, wherein a patient loses awareness of one side of space—for example, a
stroke in the right posterior parietal lobe can lead to the inability to perceive the left
visual field, causing the patient to act as if the left side of space doesn’t exist (they
might ignore food on the left side of their plate, or when asked to copy a picture,
they might only draw the right half). Ultimately, the parietal lobe is critical for
processing and integrating sensory information and transmitting this information
to brain areas that control attention and movement.4

4. This section contains material adapted from: Betts, J. G. et al. (2022). 13.2 The Central Nervous
System. In Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/
anatomy-and-physiology-2e/pages/13-2-the-central-nervous-system License: CC BY 4.0 DEED.
- Hall, C. N. (2023). 2.1: Exploring the brain: A tour of the structures of the nervous system. In
Introduction to Biological Psychology. University of Sussex Library. Access for free at
https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/chapter/exploring-the-brain-a-
tour-of-the-structures-and-cells-of-the-nervous-system/ License: CC BY-NC 4.0 DEED -
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 3.4 The Brain and Spinal Cord. In
Psychology 2e.OpenStax. Access for free at https://openstax.org/books/psychology-2e/pages/3-4-the-
brain-and-spinal-cord License: CC BY 4.0 DEED.
 3.6: THE BRAIN | 99

Occipital Lobe
The occipital lobe, located at the back of the brain, contains the visual cortex
that processes visual information. Visual input from the eyes travels along the optic
nerves to the lateral geniculate nucleus (LGN) in the thalamus, and continues
on to the visual cortex. Visual input enters the cortex at most posterior portion
of the occipital lobe—the primary visual cortex (V1). V1 (and other regions in
the visual system) is organized retinotopically, meaning that adjacent regions of
the retina (and visual field) are represented by adjacent parts of visual cortex.
From V1, visual signals are sent to different brain regions (in the visual cortex and
beyond) that specialize in processing different image features such as color, edges,
orientation, texture, and movement. Visual regions are highly interconnected and
recurrent, sending feedforward signals “up” the processing hierarchy, as well as
feedback signals “back down” the processing chain (Van Essen et al., 1992). There
are two main visual processing pathways—the lower ventral or “what” pathway
proceeds to the inferior temporal lobe for object recognition, and the upper dorsal
or “where” pathway proceeds to parietal regions for mapping object location,
especially for eye or hand movements.5

Insula
The insula is part of the cerebral cortex tucked deep into the lateral sulcus. It
lies underneath parts of the frontal, temporal, and parietal lobes (Figure 3.18).
It is sometimes called the insular lobe, a fifth lobe of the cerebral cortex, but it
remains less understood than the four cortical lobes visible on the brain’s surface.
The insula has been implicated in a dizzying array of functions, including sensory
processing (e.g., taste and interoceptive processing of bodily states like hunger,

5. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
3.4 The Brain and Spinal Cord. In Psychology 2e.OpenStax. Access for free at https://openstax.org/
books/psychology-2e/pages/3-4-the-brain-and-spinal-cord License: CC BY 4.0 DEED.
100 | 3.6: THE BRAIN
pain, and arousal), representing emotions, motor control, self-awareness, empathy,
risk prediction, cognitive functioning, consciousness, etc. (Gogolla, 2017). The
insula’s involvement in so many functions and its heavy structural connectivity to
other brain regions indicates its importance as a hub that links large-scale brain
systems. The insula is thought to be involved in many psychological and
neurological conditions including anxiety and depressive disorders, emotion
dysregulation, autism spectrum disorders, and addiction. While the insula is
considered one of the least understood cortical structures of the brain and many
open questions remain, a surge of recent research interest is making headway
(Gogolla, 2017; Kortz & Lillehei, 2023).

Figure 3.18. Anatomical illustration of the right insula from the 1908
edition of Sobotta’s Anatomy Atlas. The insula is exposed here by
removing portions of the overlying frontal, parietal, and temporal
regions (these overlying areas are termed the “operculum”). CREDIT:
Right Insula from the 1908 © Wikipedia is licensed under a CC BY-SA
(Attribution ShareAlike) license

Limbic System
The limbic system is a collection of highly specialized neural structures, both
 3.6: THE BRAIN | 101
subcortical and cortical, that sit at the top of the brainstem (Figure 3.19). The
limbic system was originally defined by Paul Broca (1880) as a series of structures
near the border between the brainstem and the cerebral hemispheres (“limbus”
is Latin for border). The limbic system is involved in many functions including
memory, emotion, behavior, motivation, and olfaction. Given advances in
neuroscience, the definition of which structures are included in the limbic system
has gone through many iterations (Torrico & Abdijadid, 2019). Major
components of the limbic system include the hippocampus, the amygdala, and
the cingulate cortex.

Figure 3.19: A midsagittal plane showing the interior of the brain and
the locations of several limbic-system structures, including the
hippocampus, amygdala, and cingulate cortex. CREDIT: Limbic system ©
Wikimedia is licensed under a CC BY-NC-SA (Attribution NonCommercial
ShareAlike) license

Hippocampus. The hippocampus is a seahorse shaped structure involved in

memory, learning, and spatial processing (Figures 19 and 20). The hippocampus
is richly connected to many cortical and subcortical regions. During learning,
the connection strengths of hippocampal neurons change, and those changes are
thought to be important for particular aspects of memory, particularly the ability
102 | 3.6: THE BRAIN
to remember more of an event or stimulus when exposed to only part of it (pattern
completion), and to remember events or stimuli as distinct from each other
(pattern separation). Damage to the hippocampus produces memory deficits.
Hippocampus damage occurs early in Alzheimer’s disease, and extensive damage
can lead to anterograde amnesia (the inability to form new memories). The
hippocampus is also important for spatial navigation. As discovered in rats and
mice, many neurons in the hippocampus respond as “place cells,” meaning that
they fire bursts of action potentials when the animal passes through a specific place
in its environment.

Figure 3.20. Location of the hippocampus in red. CREDIT: Hippocampus 3D

© Wikipedia is licensed under a CC BY-SA (Attribution ShareAlike) license
 3.6: THE BRAIN | 103
Amygdala. The amygdala, named for its almond shape, sits adjacent to the
hippocampus beneath the cerebral cortex (Figure 3.19). It is important for
processing of emotions, including generating emotional responses (e.g., fear,
anxiety, aggression) and emotional learning (e.g., fear conditioning).
The amygdala receives inputs from wide regions of sensory and prefrontal
cortex, the hippocampus, and visceral information from the brainstem, enabling
it to integrate information about the situation, the bodily state, memory, and
contextual information. The amygdala sends output signals to many regions
throughout the brain, including the frontal lobes, hippocampus, basal ganglia,
thalamus, and hypothalamus. This connectivity allows it to produce emotional
responses appropriate to a given situation; for example, when a stimulus appears
that is associated with punishment, a fear response can be produced by altering
hormone release via the hypothalamus, triggering freezing behaviors, and
activating the sympathetic nervous system via the brainstem. People with amygdala
damage can display reduced emotional behavior or “flat affect”, and show reduced
learning about emotional or frightening stimuli or situations.6

Basal Ganglia
The basal ganglia (Figure 3.21) are a group of subcortical nuclei (i.e., clusters
of cell bodies that lie below the cerebral cortex) that are especially critical for
regulating and selecting voluntary movement. In particular, the basal ganglia are
traditionally defined as the caudate nucleus, putamen, and globus pallidus, but
are known to rely on engagement with related nuclei, such as the subthalamic

6. This section contains material adapted from: Hall, C. N. (2023). 2 Exploring the brain: A tour of the
structures of the nervous system. In Introduction to Biological Psychology. University of Sussex
Library. Access for free at https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/
chapter/exploring-the-brain-a-tour-of-the-structures-and-cells-of-the-nervous-system/ License: CC
BY-NC 4.0 DEED
 104 | 3.6: THE BRAIN
nucleus and substantia nigra, in order to initiate voluntary movement (Lanciego
et al., 2012).
Information flows from widespread areas of the cerebral cortex, through the
basal ganglia and thalamus, and back to the cerebral cortex. These cortico-basal
ganglia-thalamo-cortical loops are important for selecting motor actions, starting
and stopping behaviors, and for aspects of motivated behavior (e.g., selecting
actions based on whether they are likely to result in something good or bad
happening to the individual). The loops include excitatory and inhibitory
pathways, the balance of which is important for initiating or inhibiting motor
outputs. Disruptions to this circuitry can cause an imbalance between these
excitatory and inhibitory effects, as is seen in a number of neurological conditions
including Parkinson’s disease and Huntington’s disease, as well as schizophrenia,
Tourette’s syndrome, obsessive-compulsive disorder, and addiction.7

7. This section contains material adapted from: Hall, C. N. (2023). 2.1: Exploring the brain- a tour of the
structures of the nervous system. In Introduction to Biological Psychology. University of Sussex
Library. https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/chapter/exploring-the-
brain-a-tour-of-the-structures-and-cells-of-the-nervous-system/ License: CC BY-NC 4.0 DEED
 3.6: THE BRAIN | 105

Figure 3.21: Basal Ganglia and related structures. CREDIT:Basal Ganglia and
related structures © Wikimedia is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Thalamus
The thalamus is an information hub that relays information from and to
widespread brain areas (Figure 3.22A). Nerve fibers project from the thalamus
to the cerebral cortex in all directions, allowing it to act as an information hub.
The thalamus is organized into specialized regions or nuclei that process specific
modalities. All sensory systems, except smell, have a thalamic nucleus that receives
sensory signals and sends them on to their corresponding primary cortical areas.
For example, the lateral geniculate nucleus of the thalamus receives visual
information from the eye via the optic nerve and sends projections to primary
visual cortex (Figure 3.22B); the medial geniculate nucleus receives auditory
information from the ear via the inferior colliculus and projects to auditory cortex.
Rather than simply relaying information in one direction, however, a key feature
of thalamic processing is that nuclei also receive descending information from the
cortex, forming circuits termed thalamocortical loops.
Thalamocortical loops are not limited to sensory processing, but also play
 106 | 3.6: THE BRAIN
important roles in memory, attention, motor control, and decision making. These
loops demonstrate that the ‘input-computation-output’ function of the nervous
system is not simply in one direction—instead, outputs from a given region often
feed back to structures that provide inputs to that region, as well as sending
outputs to ‘upstream’ brain areas. Finally, because of its role as informational/
sensory hub, the thalamus plays a role in transitioning between sleep and
wakefulness, as well as modulating alertness and attention (Portas et al., 1998).8

Figure 3.22A. Location of the thalamus in red. Thalamus

animation © Wikipedia is licensed under a CC BY-SA (Attribution
ShareAlike) license

8. This section contains material adapted from: Hall, C. N. (2023). 2 Exploring the brain: A tour of the
structures of the nervous system. In Introduction to Biological Psychology. University of Sussex
Library. Access for free at https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/
chapter/exploring-the-brain-a-tour-of-the-structures-and-cells-of-the-nervous-system/ License: CC
BY-NC 4.0 DEED
 3.6: THE BRAIN | 107

Figure 3.22B. Visual pathway from the eyes through the thalamus to the
visual cortex. Visual information is sent from the retinas at the back of
the eyeballs, along the optic nerve to the lateral geniculate nucleus
(LGN) of the thalamus, then to the primary visual cortex. Blue color
represents the path of information from the left visual field; red from
the right visual field. CREDIT: Visual System © Wikipedia is licensed under a
CC BY-SA (Attribution ShareAlike) license

Hypothalamus
The hypothalamus is located below the thalamus (hence its name) and is
primarily responsible for regulating endocrine hormones in conjunction with the
pituitary gland that extends from the hypothalamus (Figure 3.17). Endocrine
 108 | 3.6: THE BRAIN
hormones are known to be important for controlling mood, development, growth,
and reproduction. Given its central location in the brain, the hypothalamus has
connections to the brainstem, cerebral cortex, hippocampus, amygdala, and
thalamus (Bear et al., 2018). As a result, the hypothalamus, both by trafficking
sensory and motor information and secreting endocrine hormones across different
brain regions, is well-positioned to regulate drives and motivations.

Cerebellum
The cerebellum (Latin for “little brain”) is the distinctive structure at the back of
the brain (Beck & Tapia, 2023). In Figure 3.23, you can see the cerebellar white
matter (arbor vitae) and the cerebellum’s tightly folded surface. The cerebellum
is critical for coordinated movement and posture. It does not initiate motor
commands, but contributes to movement precision, timing, and fine-tuning
(based on sensory feedback), as well as motor learning. In addition to the
cerebellum’s long established role in motor control, neuroimaging studies have
implicated it in many cognitive functions, including language and attention. It is
perhaps not surprising that the cerebellum’s influence extends beyond movement,
given that it contains ~80% of the brain’s neurons (most of its neurons are tiny
and densely packed granule cells, van Essen et al., 2018) and the majority of the
cerebellum maps to cerebral brain networks involved in cognition (Buckner,
2013).9

9. This section contains material adapted from: Beck, D. & Tapia, E. (2024). The brain. In R. Biswas-
Diener & E. Diener (Eds), Noba textbook series: Psychology. Access for free at http://noba.to/
jx7268sd License: CC BY-NC-SA 4.0 DEED
 3.6: THE BRAIN | 109

Figure 3.23. Image shows the location of the cerebellum at the bottom
of the brain. Illustrated in white on the medial view are the cerebellar
white matter tracts, the arbor vitae (their name stems from their
branching, tree-like structure). On the lateral view, you can see the
cerebellum’s tightly folded surface. CREDIT: Arbor vitae animation ©
Wikipedia is licensed under a CC BY-SA (Attribution ShareAlike) license

Brainstem
The brainstem (or brain stem) is sometimes referred to as the “trunk” of the brain
(Beck & Tapia, 2023). It contains many white matter tracts carrying information
to and from the spinal cord, cranial nerves, and the rest of the brain. The brainstem
is responsible for many of the neural functions that keep us alive, including
regulating breathing, heart rate, and digestion. In keeping with its function, if a
patient sustains severe damage to the brainstem they will often require life-support
machines to keep them alive. The brainstem can be divided into multiple sections
in descending order: midbrain, pons, and medulla oblongata (Figure 3.24). At the
top of the brainstem is the midbrain, which houses dopamine-producing cells,
regulates movement, and includes the superior and inferior colliculi, which process
and relay visual and auditory information, respectively. Below the midbrain lies the
pons which processes and relays sensory and motor information. By employing the
cranial nerves, the pons is able to serve as a bridge that connects the cerebral cortex
with the medulla and exchange information back and forth between the brain
and the spinal cord. The lowest portion of the brainstem, the medulla oblongata,
processes breathing, digestion, heart and blood vessel function, swallowing, and
sneezing. Collectively, these regions are involved in body regulation, the
sleep–wake cycle, and sensory and motor function.10

10. This section contains material adapted from: Beck, D. & Tapia, E. (2024). The brain. In R. Biswas-
Diener & E. Diener (Eds), Noba textbook series: Psychology. Access for free at http://noba.to/
jx7268sd License: CC BY-NC-SA 4.0 DEED
110 | 3.6: THE BRAIN

Figure 3.24. Brainstem and its component substructures, in descending

order: the midbrain, pons, and medulla. CREDIT: Brainstem substructures ©
Wikimedia is licensed under a CC BY-NC-SA (Attribution NonCommercial
ShareAlike) license
 3.7: NON-NEURONAL STRUCTURES IN THE CENTRAL NERVOUS

3.7: NON-NEURONAL
STRUCTURES IN THE CENTRAL
NERVOUS SYSTEM
Michael J. Hove and Steven A. Martinez

Ventricular System and Cerebrospinal

Fluid
The cerebral ventricular system is a set of interconnected cavities known as
cerebral ventricles that produce and transport cerebrospinal fluid (CSF) (Shenoy
& Lui, 2022). This ventricular system is made up of 4 main ventricles—2 lateral
ventricles, the third ventricle, the fourth ventricle, and the cerebral aqueduct
(Figure 3.25). CSF is produced in the ventricles by a tissue called choroid plexus.
It drains through sinuses around the brain and through lymphatic vessels. CSF
fills the subarachnoid space around the brain, so the brain is suspended in CSF.
CSF thus acts as a shock absorber to cushion and protect the brain. Additionally,
being suspended in CSF reduces the effective weight of the brain from around
1500 grams to around 50 grams (Wright et al., 2012). Without CSF, the brain’s
own weight would cut off blood supply and kill neurons especially in the lower
sections of the brain. Finally, CSF circulates nutrients throughout the brain and
helps clear waste products away from the brain.
112 | 3.7: NON-NEURONAL STRUCTURES IN THE CENTRAL NERVOUS

Figure 3.25: A) The cerebral ventricular system showing the 4 major

ventricles. CREDIT: CSF System © Wikipedia is licensed under a CC BY
(Attribution) license
 3.7: NON-NEURONAL STRUCTURES IN THE CENTRAL NERVOUS

Figure 3.25: B) Rotating 3D rendering of the ventricles. CREDIT: Human

ventricular system animation © Wikipedia is licensed under a CC BY (Attribution)
license

Vasculature
The brain is an energetically demanding organ. It is only 2% of the body’s mass,
but uses 20% of its energy when the body is resting (i.e., when muscles are not
active). It relies on a constant supply of oxygen and glucose in the blood to sustain
neurons—a disruption of blood flow to the brain leads to a loss of consciousness
within 10 seconds. To deliver a constant flow of oxygenated blood, the brain
has a complex and tightly regulated vasculature that directs blood to the most
active brain regions. Four arteries feed the brain with oxygenated blood, forming
114 | 3.7: NON-NEURONAL STRUCTURES IN THE CENTRAL NERVOUS
a circle—the circle of Willis. Several large arteries branch off the circle of Willis to
perfuse different regions of the brain. Branches of these major arteries form smaller
and smaller arteries and arterioles that pass through the subarachnoid space before
diving into the brain, and branch yet further to form a dense capillary network
(Figure 3.26).
A mind-blowing 1 to 2 meters of capillaries exist in every cubic millimeter of
brain tissue. These capillaries are less than 10 microns in diameter, though, so
they only take up about 2% of the brain volume. This means that, in cerebral
cortex, each neuron is only around 10-20 microns from its nearest capillary. This
dense vascular network can therefore supply oxygen and glucose very close to active
neurons.
The blood supply is finely adjusted according to the needs of each brain region.
Active neurons produce molecules that dilate smooth muscle cells and pericytes on
local arterioles and capillaries, increasing blood flow to these regions of increased
activity. In fact this increase in blood flow usually supplies more oxygen than is
needed, so that blood oxygen levels increase in active brain regions. This increase
in blood oxygen gives rise to the BOLD (blood oxygen level dependent) signal
that can be detected using magnetic resonance imaging and is often used as a
surrogate for neuronal activity in experiments studying the function of different
brain regions (see Chapter 4–Research Methods).
 3.7: NON-NEURONAL STRUCTURES IN THE CENTRAL NERVOUS

Figure 3.26. A cast of the brain’s vasculature. CREDIT:

brainVesselsCorosionCast-768×486 © Hall, C. N. (2023). 2.1: Exploring the brain-
a tour of the structures of the nervous system. In Introduction to Biological
Psychology. University of Sussex Library. is licensed under a CC BY-NC-SA
(Attribution NonCommercial ShareAlike) license

Text Attributions
This section contains material adapted from:
Hall, C. N. (2023). 2.1: Exploring the brain- a tour of the structures of the
nervous system. In Introduction to Biological Psychology. University of Sussex
Library. https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/
chapter/exploring-the-brain-a-tour-of-the-structures-and-cells-of-the-nervous-
system/ License: CC BY-NC 4.0 DEED
116 | 3.8: CONCLUSION

3.8: CONCLUSION

Understanding the brain and nervous system has been a long journey of inquiry,
spanning hundreds of years of meticulous studies in the fields of anatomy,
neurology, neuroscience, philosophy, evolution, biology, cognitive sciences, and
psychology (Ahmad, 2023). The journey continues with new discoveries about the
brain emerging every day. A good foundational understanding of brain structure
is critical for understanding brain function and the biological bases of psychology.
Future research linking brain function to complex mental processes and behavior
will help us better understand human psychology and ultimately improve well-
being.
 3.9: DISCUSSION QUESTIONS AND RESOURCES | 117

3.9: DISCUSSION QUESTIONS

AND RESOURCES

Discussion Questions

1. In what ways does the segmentation of the brain into the

brainstem, cerebellum, thalamus, hypothalamus, and cerebral
hemispheres provide a natural division?
2. Compare and contrast the peripheral nervous system and central
nervous system.
3. What are the similarities and differences between the somatic
and autonomic nervous systems?
4. Describe the basic functions of the four cerebral lobes: occipital,
temporal, parietal, and frontal.
5. What is the difference between gray and white matter?
6. Describe the basic functions of the major subcortical structures:
basal ganglia, hippocampus, amygdala, thalamus, and
hypothalamus

Outside Resources

Video: Pt. 1 video on the anatomy of the nervous system

Video: Pt. 2 video on the anatomy of the nervous system

118 | 3.9: DISCUSSION QUESTIONS AND RESOURCES

Video: To look at functions of the brain and neurons

Web: Atlas of the Human Brain: interactive demos and brain

sections

The Human Brain · Atlas of the Human Brain

Web: 3D interactive brain website and its associated free app:

https://www.brainfacts.org/3d-brain
 3.10: REFERENCES | 119

3.10: REFERENCES

Parts of this chapter were adapted

from:
Ahmad, A. (2023). The nervous system. In R. Biswas-Diener & E. Diener (Eds),
Noba textbook series: Psychology. Champaign, IL: DEF publishers.
http://noba.to/wnf72q34
Beck, D. & Tapia, E. (2023). The Brain. In R. Biswas-Diener & E. Diener (Eds),
Noba textbook series: Psychology. Champaign, IL: DEF publishers.
http://noba.to/jx7268sd
Betts, J. G. et al. (2022). Anatomy and Physiology 2e. OpenStax.
https://openstax.org/details/books/anatomy-and-physiology-2e
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener & E.
Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF publishers.
http://noba.to/4hzf8xv6
Clark, M.A., Douglas, M. & Choi, J. (2023). Biology 2e. OpenStax.
https://openstax.org/books/biology-2e
Hall, C. N. (2023). Introduction to Biological Psychology. University of Sussex
Library. https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/
The Nervous System. (2023, October 31). In General Biology. Boundless (now
LumenLearning). https://bio.libretexts.org/@go/page/13875
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). Psychology 2e. OpenStax.
Access for free at https://openstax.org/books/psychology-2e/pages/1-1-what-is-
psychology
120 | 3.10: REFERENCES

The Brain and Nervous System

References
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Broca. Science, 1(8), 93. http://www.jstor.org/stable/2900242
Bear, M. H., Reddy, V., & Bollu, P. C. (2018). Neuroanatomy, hypothalamus.
In: StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/
NBK525993/ Buckner, R. L. (2013). The cerebellum and cognitive function:
25 years of insight from anatomy and neuroimaging. Neuron, 80(3), 807-815.
Duysens, J., & Van de Crommert, H. W. (1998). Neural control of locomotion:
The central pattern generator from cats to humans. Gait & Posture, 7(2),
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Gogolla, N. (2017). The insular cortex. Current Biology, 27(12), R580-R586.
Hall, C. N. (2023). Introduction to Biological Psychology. University of Sussex
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Kanwisher, N. & Yovel, G. (2006). The fusiform face area: a cortical region
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Karnath, H. O. (1997). Spatial orientation and the representation of space with
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Series B: Biological Sciences, 352(1360), 1411-1419.
Kortz, M.W., & Lillehei, K. O. (2023). Insular Cortex. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing.
Lanciego, J. L., Luquin, N., & Obeso, J. A. (2012). Functional neuroanatomy of
the basal ganglia. Cold Spring Harbor Perspectives in Medicine, 2(12), a009621.
Portas, C. M., Rees, G., Howseman, A. M., Josephs, O., Turner, R., & Frith, C. D.
(1998). A specific role for the thalamus in mediating the interaction of attention
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Rudebeck, P. H., & Rich, E. L. (2018). Orbitofrontal cortex. Current Biology,
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Shenoy, S. S., & Lui, F. (2022). Neuroanatomy, ventricular system. In StatPearls
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Swanson, L. (2000). What is the brain? Trends in Neurosciences, 23, 519–527.
Torrico, T. J., & Abdijadid, S. (2019). Neuroanatomy, limbic system.
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Van Essen, D. C., Donahue, C. J., & Glasser, M. F. (2018). Development and
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122 | 3.10: REFERENCES
CHAPTER 4: RESEARCH METHODS IN BIOLOGICAL PSYCHOLOGY | 123

CHAPTER 4: RESEARCH
METHODS IN BIOLOGICAL
PSYCHOLOGY

Learning Objectives

• Review how cases of brain damage provided early insight into the
localization of brain function
• Examine invasive research methods used in animals, such as brain
lesions, implanted recording devices, and genetic manipulations
• Understand advantages and disadvantages of various cognitive
neuroscience methods used in humans such as EEG, TMS, PET,
and MRI
• Examine how brain stimulation can provide causal evidence for
how brain function drives thought and behavior

This chapter is adapted from Hove, M. J., & Martinez, S. A. (2024).

Biological Psychology. ROTEL (Remixing Open Textbooks with an
Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/
124 | CHAPTER 4: RESEARCH METHODS IN BIOLOGICAL PSYCHOLOGY
 4.1: INTRODUCTION | 125

4.1: INTRODUCTION

Biological psychology is a broad and diverse field that consists of many different
approaches including neuroscience, neuropsychology, cognitive neuroscience,
behavioral genetics, and psychopharmacology. With so many different approaches,
it is not surprising that the research methods used in biological psychology are
also broad and diverse. Techniques range from low-level approaches like recording
activity of a single neuron and dissecting animal brains to high-level cognitive
testing and brain imaging in humans. We’ve learned about brain function from
case studies of brain damage and by using technical marvels such as high-resolution
brain imaging and optogenetics (in which cells in animal brains are genetically
manipulated so they can be controlled by specific wavelengths of light while the
animal is awake!).
Each different technique in biological psychology has strengths and limitations
and can be used to answer distinct types of questions. When establishing the
specific function of a particular brain area, the strongest evidence comes from
converging evidence, whereby multiple studies using different methods report
similar or converging findings (Beck & Tapia, 2023). In this chapter, we cover some
of the major research methods in the field of biopsychology and how the methods
converge to help us understand how the three pound human brain gives rise to our
thoughts, actions, perceptions, feelings, and emotions.
126 | 4.2: HISTORICAL METHODS – STUDIES OF BRAIN DAMAGE IN

4.2: HISTORICAL METHODS –

STUDIES OF BRAIN DAMAGE IN
HUMANS

Some early influential examples showing links between brain and behavior come
from cases of brain damage. Prominent examples from the 19th century include
Phineas Gage and the patients of physicians like Paul Broca and Carl Wernicke.
In the mid-1800s, the railroad worker Phineas Gage was responsible for placing
explosive charges to blast through rock for railroad tracks. Using a 1-meter long
tamping iron, he would tamp down the charges, but on one September afternoon,
a spark set off the explosive prematurely. The tamping iron shot through the air
like a rocket, entering the side of Gage’s face, passing behind his left eye, exiting
the top of his head, and landing 80 feet away (see Figure 4.1). Amazingly, he
survived the accident and even was able to talk and walk away from it. Although
he lost a portion of his left frontal lobe, he lived for another 12 years without
apparent impairment in speech, motor abilities, memory, or intelligence (Damasio
et al., 1994). However, what’s fascinating about this incident from a biopsych
perspective is that Gage’s personality changed drastically as a result of the accident
(Infantolino & Miller, 2023). Prior to the accident Gage had been responsible and
socially well-adapted, but afterward, he became irreverent, vulgar, impulsive, did
not follow social conventions, and had difficulty executing plans.
 4.2: HISTORICAL METHODS – STUDIES OF BRAIN DAMAGE IN

Figure 4.1: A computerized tomography (CT) image reconstruction of the

path of the tamping rod that entered Phineas Gage’s mouth and blasted
through his skull and left frontal lobe. The bright colors represent White
Matter fiber pathways that were likely intersected by the rod (Van Horn
et al. 2012). CREDIT: Simulated Damage of Phineas Gage © Wikimedia is
licensed under a CC BY-SA (Attribution ShareAlike) license

In another example from the 1800s, the French physician Paul Broca found that
some patients who were unable to produce speech had brain damage to their left
inferior frontal cortex. One of Broca’s patients was referred to as “Tan” because his
speech production was limited to the single repetition of the syllable “Tan.” After
Tan’s death, Broca discovered a major lesion on the surface of Tan’s left frontal lobe
(see Figure 4.2). Another patient of Broca’s was also severely aphasic (i.e., couldn’t
produce fluent speech) and had brain damage to the same portion of his left frontal
lobe. This led Broca to surmise that speech production was localized to this region
of the left inferior frontal lobe.
Around the same time, the German physician Carl Wernicke discovered that
damage to a different brain region—the left superior temporal lobe—was
associated with impaired speech comprehension. So together, this “double
dissociation” showed that brain damage to specific locations can be associated with
128 | 4.2: HISTORICAL METHODS – STUDIES OF BRAIN DAMAGE IN
specific types of behavioral impairments (Figure 4.3). (Here is a memory gem for
distinguishing Broca’s and Wernicke’s brain areas: use the first three letters of each
word: BROca’s area = speech PROduction = FROntal; and WERnicke’s area =
speech PERception).
 4.2: HISTORICAL METHODS – STUDIES OF BRAIN DAMAGE IN

Figure 4.2. The brain of Broca’s patient, “Tan,” preserved in a jar in a

museum in Paris. The arrow points to the damaged left inferior frontal
lobe (associated with impaired speech production). CREDIT: The brain of
Broca’s patient © Wikimedia adapted by https://commons.wikimedia.org/ is
licensed under a CC BY-SA (Attribution ShareAlike) license
130 | 4.2: HISTORICAL METHODS – STUDIES OF BRAIN DAMAGE IN

Figure 4.3. Broca’s area for Speech Production is located in the left
frontal lobe. Wernicke’s area for Speech Perception is located in the left
temporal lobe. CREDIT: Broca’s Brain Left Side View © Wikimedia is licensed
under a Public Domain license

These and countless other examples show that brain damage can lead to behavioral
and cognitive impairments. Such cases demonstrate localization of
function—that certain brain regions perform specific functions (like the previous
examples of impulse control, speech production, and perception). However,
studies with human brain damage are a limited tool for understanding the brain.
For example, when a patient suffers brain damage from force, trauma, a tumor,
stroke, or a neurosyphilitic lesion (like Broca’s patient Tan), that brain damage is
a) unique to that patient making it difficult to extrapolate or generalize to others’
brains, and b) rarely confined to just one brain area thus making it difficult to
isolate the roles of specific brain structures. Creating controlled and localized
damage to human brains in laboratory experiments is clearly not possible, so
researchers have resorted to creating carefully controlled brain damage or lesions in
laboratory animals, such as mice and rats.
 4.3: INVASIVE PHYSIOLOGICAL RESEARCH METHODS | 131

4.3: INVASIVE PHYSIOLOGICAL

RESEARCH METHODS

Invasive techniques, such as lesioning brain regions or implanting recording

electrodes in the brain, are commonly used in biological psychology research with
non-human animals. For the experimental procedure, the animal undergoes
surgery using a stereotaxic unit that allows precise positioning in the brain (see
Figure 4.4). The stereotaxic unit has two main parts: a head holder to immobilize
the head, and an electrode holder, which holds the device to be inserted. After
the animal is anesthetized, its head is immobilized in the head holder. To locate
target positions in the brain, researchers use a stereotaxic atlas (like a road atlas,
but showing exact locations of brain regions instead of roads and cities). Then the
researcher drills a small hole and performs the surgery. In some studies, researchers
will lesion or remove a part of the brain; this is called ablation. The surgeon may
use a surgical knife, a current-passing electrode, or an aspirating (suction) pipette.
After the target region is carefully removed or inactivated, the behavior of the
animal is tested to determine the function of the lesioned structure. For example,
researchers may remove (sub)components of the amygdala or hypothalamus and
test how behavior changes. Studies will often include a control condition, in which
control animals receive a sham lesion, wherein they undergo a similar surgical
procedure but don’t receive a lesion. This control condition allows researchers to
more confidently interpret that the change in behavior stems from the lesioned
brain area, rather than the handling, anesthesia, or other ancillary procedures.
In other words, the direct manipulation of the brain, coupled with the control
condition, allows researchers to make causal claims (something that cannot be
done with other correlational research methods). After the animal’s death, its brain
is often cut into thin slices, prepared with a staining procedure to allow a clear view
of some part of the neuronal structure, then examined with a microscope to verify
the extent and precise location of the lesions.
As an alternative to permanent lesions through ablation, researchers can
temporarily lesion brain regions, for example, by cooling down or injecting an
132 | 4.3: INVASIVE PHYSIOLOGICAL RESEARCH METHODS
anesthetic into the target brain tissue. Additionally, electrical stimulation from
implanted electrodes can be used to temporarily inactivate or activate targeted
brain regions.
 4.3: INVASIVE PHYSIOLOGICAL RESEARCH METHODS | 133

Figure 4.4. A stereotaxic device used to perform surgeries on rodents.

This unit would immobilize an anesthetized rat and allow precise
placement of electrodes in the brain. CREDIT:
YW066573L_Stereotaxic-unit-Chicago-United-States-1980-1999 © Look and
Learn is licensed under a CC0 (Creative Commons Zero) license
134 | 4.3: INVASIVE PHYSIOLOGICAL RESEARCH METHODS

Figure 4.5. A lab rat with a brain implant that was used to record
neuronal activity while the rat performed a particular task (vibration
discrimination in this case). In this picture, a scientist feeds the rat apple
juice through a pipette. CREDIT: Laboratory Rat © Wikimedia is licensed
under a CC BY-SA (Attribution ShareAlike) license

In addition to manipulating brain function by damaging or stimulating brain

regions, researchers learn about brain function by implanting recording devices
directly in animal brains to ‘listen in’ on brain activity. The animal undergoes
a stereotaxic surgery wherein a recording device or electrode is inserted into a
target area then fixed into position on the skull (see Figure 4.5). Different types
of invasive electrophysiological recording include: intracellular unit recording,
wherein a microelectrode is inserted into a single neuron to measure its electrical
activity; extracellular recordings that pick up the firing of one nearby neuron
(single unit recording) or several adjacent neurons (multiunit recording); and
invasive electroencephalography (EEG), wherein a large electrode picks up the
electrical brain activity of a large swath of nearby neurons. These electrodes can
pick up neural activity while the animal is performing some task and provide
insight into links between neural activity and behavior.
Directly recording from within human brains for research is uncommon
 4.3: INVASIVE PHYSIOLOGICAL RESEARCH METHODS | 135
because it’s not justifiable to invasively cut open the skull solely for research.
However, some patients who are already undergoing surgery for medical
procedures, such as treatments of Parkinson’s disease or epilepsy, might have
electrodes placed directly on or in their brains. They occasionally participate in
research. Such intracranial (meaning within the skull) electroencephalography
(iEEG) or Electrocorticography (ECoG) is a valuable research tool because these
direct recordings offer especially clear and precise signals from the brain. However,
these patients are rare, and the placement of electrodes is determined by the
neurosurgeon and medical needs rather than the research question.
136 | 4.4: TOOLS OF COGNITIVE NEUROSCIENCE – EEG AND MEG

4.4: TOOLS OF COGNITIVE

NEUROSCIENCE – EEG AND
MEG

Advances in technology have led to ever more sophisticated brain recording

techniques. Just as X-ray technology allows us to peer inside the body,
neuroimaging techniques allow us to view the working brain (Raichle,1994).
Many noninvasive techniques for studying human brain function are used in the
field of biopsychology and each technique has advantages and disadvantages. It is
important to recognize that each method allows us to “see’” brain activity through
a different lens. As a result, it is important to understand how each technique
works. It is fascinating to think about how our understanding of the brain is
intimately related to the available technologies. As new technologies and
techniques are developed, we will be able to develop an even deeper understanding
of brain function (Biswas-Diener, 2023).
Electroencephalography (EEG) measures the electrical activity of the brain
and has been used for a century (e.g., Berger, 1929). When large populations of
neurons are active, they create a small electrical voltage that passes through the skull
and scalp. Electrodes placed on the participant’s head pick up the voltages, which
are amplified and recorded. Researchers can record the voltages from brain activity
as the participant performs a task.
Because the small voltages are distorted as they pass through brain tissue, skin,
and bone, researchers only have a rough idea where in the brain a signal was
generated. This uncertainty is especially the case for signals coming from deep
within the brain (even if the researchers have the person’s structural brain scan,
high-density electrode coverage from a cap with 256 electrodes, and sophisticated
localization analysis algorithms). Thus, EEG’s spatial resolution of where
something occurs in the brain is rather low. Conversely, EEG’s temporal
resolution is excellent and indicates when something happens in the brain to
the millisecond. With the excellent temporal resolution, EEG is well suited for
 4.4: TOOLS OF COGNITIVE NEUROSCIENCE – EEG AND MEG | 137
examining the brain’s response to a stimulus event, or the event-related potentials
(ERP). In a typical ERP experiment, researchers might play a visual or auditory
event like a word, then measure the corresponding voltage changes that unfold
in the brain over the next few hundred milliseconds. The amplitude, timing, and
topography (position) of the EEG signal capture the underlying neural/mental
processes.
The high temporal resolution and continuous recording of EEG allows it to
capture different frequency brain waves, such as theta waves (oscillating at 4-7
Hertz (Hz), i.e. cycles per second), alpha waves (at 8-13 Hz), and beta waves (at
14-30 Hz). Brain oscillations reflect the summed activity of millions of neurons.
They capture attentional or conscious states and play a role in how specific
information is encoded and how attention is modulated in the brain (da Silva,
2013). In addition to the research uses noted above, EEG is also particularly
important in clinical diagnosis, specifically with respect to diagnosing epilepsy as
well as seizure and sleep disorders.

Figure 4.6. Participant wearing an EEG cap that uses electrodes to pick
up voltages on the scalp. CREDIT: EEG Recording Cap © Wikimedia is licensed
under a CC BY-SA (Attribution ShareAlike) license
138 | 4.4: TOOLS OF COGNITIVE NEUROSCIENCE – EEG AND MEG

Figure4.7. An EEG readout of voltages at 16 electrode sites. Each row is

one electrode; the voltage of each electrode is mapped on the vertical
axis; and time is mapped on the horizontal axis with each vertical line
marking 1 second. This particular EEG readout is showing characteristic
3 Hz spike and wave discharges in a child with epilepsy (notice the 3
peaks occurring every second). CREDIT: Spike Waves © Wikimedia is
licensed under a CC BY-SA (Attribution ShareAlike) license

Magnetoencephalography (MEG) is similar to EEG, but instead of electrical

signals, MEG picks up the weak magnetic fields generated by the flow of electrical
charge associated with neural activity. Because the magnetic fields generated by
brain activity are so small, special rooms are needed that shield out magnetic
fields in the environment so that the MEG sensors pick up magnetic fields from
neural activity without environmental contamination. Similar to EEG, MEG also
 4.4: TOOLS OF COGNITIVE NEUROSCIENCE – EEG AND MEG | 139
has excellent (millisecond) temporal resolution. The spatial resolution of MEG
is far better than that of EEG because magnetic fields are able to pass relatively
unchanged through hard and soft tissue and therefore are not distorted by skull
and scalp. In spite of MEG’s excellent spatial and temporal resolution, it is used
much less widely than EEG because the MEG apparatus is much more expensive
and unwieldy than that for EEG.

Text Attributions
This section contains material adapted from:
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener
& E. Diener (Eds), Noba textbook series: Psychology. Access for free at
http://noba.to/4hzf8xv6 License: CC BY-NC-SA 4.0 DEED
140 | 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET

4.5: TOOLS OF COGNITIVE

NEUROSCIENCE – BRAIN
IMAGING, PET AND MRI

Many imaging technologies can capture detailed inner images of the brain. In the
1970s, the development of computerized tomography (CT) scans allowed non-
invasive imaging of the living brain using X-rays. CT scans are rarely used today
for purely research purposes due to the radiation exposure and relatively low image
resolution.
Positron Emission Tomography (PET) scans are a powerful way to image
brain activation (as opposed to brain structure). The PET scanner detects a
radioactive substance that is injected into the bloodstream of the participant just
before or while they perform a task (e.g., adding numbers). Because active neuron
populations require metabolites, more blood flows into active regions bringing
with it more radioactive substances. PET scanners detect the injected radioactive
substance in specific brain regions, allowing researchers to infer that those areas
were active during the task. PET scans are not common in biopsych research
because they require the ability to work with radioactive materials and expose
subjects to low-levels of radiation. However, PET is a powerful tool that provides
the unique capability of identifying the distribution of particular molecules, like
neurotransmitters or receptors, in the brain.
 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET AND

Figure 4.8. This is a transaxial slice of the brain taken with positron
emission tomography (PET). Red areas show more accumulated tracer
substance and blue areas show where little to no tracer has
accumulated. CREDIT; PET Image © Wikimedia is licensed under a Public
Domain license

Magnetic Resonance Imaging

The most commonly used brain-imaging modality today is Magnetic Resonance
Imaging (MRI). Different types of scans from the same MRI machine can give
high resolution images of brain structure (structural MRI or sMRI) and brain
function (functional MRI or fMRI). MRI scanners may be expensive, noisy, and
claustrophobic to some, but they are harmless and painless and are powerful and
prevalent tools for illuminating brain structure and function.
MR scanners use a strong magnetic field that is around 60,000 times stronger
than the earth’s magnetic field. As a person lies very still in the scanner, the
142 | 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET
magnetic field forces protons in their body to align. Pulsations of low-energy
radio frequencies cause the protons to change their spin. As the radiofrequency is
turned off, these protons return to their aligned state and give off energy that is
detected by MRI sensors. The timing and amount of energy released as the protons
realign with the magnetic field differs based on the type of tissue, and can clearly
depict differences between the brain’s white matter, gray matter, cerebrospinal
fluid, bone, blood, blood vessels, etc.
 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET AND

Figure 4.9. MRI scanner with subject laying down in the scanner bore.
CREDIT: MRI Scanner © Mart Production via. Pexels is licensed under a CC0
(Creative Commons Zero) license
144 | 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET
Structural magnetic resonance imaging (sMRI) creates detailed images of
brain structure with millimeter resolution. The high-resolution 3D images might
show the brain’s gray matter and white matter in voxels (i.e. like 3D pixels) that
are 1mm x 1mm x 1mm cubes. Researchers may use the image to compare the size
of structures in different groups of people (for example, Are areas associated with
pleasure smaller in individuals with depression or are areas for controlling fingers
larger in string musicians than vocalists or trombonists?). These structural images
can also be used to increase the accuracy of locations as measured with functional
magnetic resonance imaging (fMRI).
Diffusion Tensor Imaging (DTI) is a variant of structural Magnetic
Resonance Imaging that focuses on myelinated axon pathways in the brain. DTI
imaging is highly sensitive to the movement of water molecules in the brain.
Because water moves differently along myelinated axons in the brain, DTI can map
out the large white matter tracts, that, like superhighways, connect distant brain
regions (e.g., the corpus callosum, a white matter fiber tract that connects right and
left cerebral hemispheres, or the arcuate fasciculus, a bundle of axons that connects
Broca’s area and Wernicke’s area, see Figure 4.10). DTI can be used to look at
white matter integrity in diseases such as Multiple Sclerosis or the brain plasticity
after learning a new skill like juggling.
 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET AND

Figure 4.10. DTI image showing the white matter tracts, including the
arcuate fasciculus, a bundle of axons that connects Broca’s area and
Wernicke’s area. CREDIT: Arcuate Fasciculus © Wikimedia is licensed under a
CC BY-SA (Attribution ShareAlike) license

Functional MRI (fMRI) uses the same MR scanners, but instead of capturing
a high-resolution snapshot of brain structure, it measures brain “function” or
activation while a subject performs some task. As a brain region becomes more
active, it uses oxygen and causes an inflow of oxygenated blood to that region
over the following few seconds. fMRI measures the change in the concentration
of oxygenated hemoglobin, which is known as the blood-oxygen-level-dependent
(BOLD) signal. From the BOLD signal, researchers infer neuronal activation in
that brain region (note that fMRI does not directly measure the neuronal activity).
Because cerebral blood flow is coupled with neural activation, researchers can map
brain activation while people in the scanner perform tasks like reading, speaking,
146 | 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET
viewing images of faces or places, recalling memories, etc. In this way, fMRI
provides evidence of localization of function and which areas are active during
specific tasks. fMRI has high spatial resolution and the activation maps in a
typical fMRI study consist of cubic voxels that are a few mm on each side.
However, the temporal resolution of fMRI is quite poor and it typically takes a
snapshot of brain activation averaged over a 2 or 3 second window.
In addition to measuring BOLD responses while subjects perform some task,
fMRI can measure subjects’ brain activation over many minutes while they
perform no task (so-called “resting state scans” wherein they might lay in the brain
scanner for 10 minutes while instructed “don’t do anything in particular”). Such
recordings have shown surprisingly correlated spontaneous fluctuations of brain
regions that can be far apart from each other in the brain. Regions with highly
correlated activation work together in the same large-scale distributed network.
The brain has several large-scale networks including sensorimotor, attention,
control, default mode, and limbic networks.

Figure 4.11. Researcher checking MRI images. On the monitor on the

right, activations are overlaid on brain structure; typically “hotter”
colors (reds and oranges) denote more brain activation than a baseline,
and “cooler” colors (blues and greens) denote less brain activation than
baseline. CREDIT: Researcher Test © Wikimedia is licensed under a CC BY-SA
(Attribution ShareAlike) license

While fMRI is popular and powerful and people find the pretty images
convincing, they are correlational and don’t fully explain the causal role of specific
 4.5: TOOLS OF COGNITIVE NEUROSCIENCE – BRAIN IMAGING, PET AND
brain regions in determining mental processes. This is an important example of
why it is essential to rely upon converging evidence—as an example, correlational
fMRI data coupled with causal experimental data from lab animals. Also to address
some of the limits of correlational research, researchers are developing techniques
that can directly modulate brain activity.
148 | 4.6: TECHNIQUES THAT MODULATE BRAIN ACTIVITY

4.6: TECHNIQUES THAT

MODULATE BRAIN ACTIVITY

Neuroimaging studies focus on correlations between brain activity and behavior

and can’t establish a causal role of a brain region in determining behavior. In
order to establish a causal rather than correlational relationship, we need to alter
brain function and observe subsequent change in behavior. Lesions are one way
to alter the brain and can reveal a casual relationship (e.g., when losing a brain
region leads to loss of function, that brain area is necessary or involved in the
function). However, invasive lesions can only be introduced in animals, which
differ from humans in key ways. Lesions in human brains can only be studied in
patient populations; that is, after a patient experiences brain damage from a stroke
or other injury. New technologies have been developed that allow researchers to
temporarily and non-invasively alter brain function in humans.
Transcranial magnetic stimulation (TMS) is a form of brain stimulation
that uses magnets to alter brain activity. Researchers place a magnetic coil over the
scalp and apply a magnetic current that stimulates the neurons below the magnetic
coil (Figure 4.12). Depending on the type and rate of magnetic pulses, TMS can
be used to temporarily “turn off” or “turn on” the brain area under the coil. In
research domains, researchers might temporarily “turn off” or “turn on” parts of
the frontal lobe and look at subsequent feelings of craving or emotion processing.
TMS is also used in clinical or medical settings, and has been shown to be an
effective treatment for some people with depression (Perera et al., 2016).
 4.6: TECHNIQUES THAT MODULATE BRAIN ACTIVITY | 149

Figure 4.12. A transcranial magnetic stimulation (TMS) coil positioned

over a person’s scalp. CREDIT: Transcranial Magnetic Stimulation (TMS) ©
Wikimedia is licensed under a CC BY-SA (Attribution ShareAlike) license

Transcranial direct current stimulation (tDCS) is similar to TMS except that

it uses electrical current directly (rather than inducing it with magnetic pulses) via
small electrodes on the skull (Beck & Tapia, 2023). A brain area is stimulated by a
low current (equivalent to an AA battery) for an extended period of time. When
used in combination with cognitive training, tDCS has been shown to improve
performance of many cognitive functions such as mathematical ability, memory,
attention, and coordination (e.g., Brasil-Neto, 2012; Feng et al., 2013; Kuo &
Nitsche, 2012).
Gene Knockout is a genetic technique used in animals, wherein researchers
remove or inactivate a specific gene. This allows researchers to study the function
of that specific gene in a living organism and its effects on the phenotype. Gene
knockout is considered a “loss-of-function mutation” (what function is lost after
knocking out a specific gene?). Gene knockouts are used in many organisms
including fruit flies, zebrafish, and mice. Studies with “knockout mice” have been
extremely valuable in understanding the role of genes in brain development,
150 | 4.6: TECHNIQUES THAT MODULATE BRAIN ACTIVITY
neurological disease, cancer, immune disorders, and even the genes involved in bad
breath (Pol et al., 2018). Gene Knock-in is a related technique, but instead of
removing a gene, knock-in inserts a gene. Gene knock-in is considered a “gain-of-
function mutation” (what function is gained after inserting this gene?).
Brainbow is another innovative transgenic technique (transgenic means
transferring genes from one organism to another) that inserts genetic material to
label individual neurons with distinct colors and produces detailed neural maps.
In brainbow, green fluorescent protein, a protein found in jellyfish and corals that
exhibits bright green fluorescence, is mutated to produce different colors; these
different color fluorescent proteins are inserted into individual neurons in different
ratios to flag each neuron with a unique color (see Figure 4.13). Brainbow has
enabled the simultaneous mapping of hundreds of neurons and allows scientists
to trace the intricate connections between neurons. Thus, brainbow has been
groundbreaking for the field of neural connectomics, which studies how neural
networks are organized. The brainbow technique provides beautiful images of
neurons and highlights biopsych research at the molecular and cellular level.

Figure 4.13. Three brainbows of mouse neurons from Lichtman et al.

(2008). a) a motor nerve innervating ear muscle. b) An axon tract in the
brainstem. c) The hippocampal dentate gyrus. CREDIT: Brainbow
(Lichtman_2008) © Wikimedia is licensed under a CC BY-SA (Attribution
ShareAlike) license

Optogenetics is an especially exciting technique to change brain activity in non-

human animals (Deisseroth, 2011). Optogenetics uses light to control specific
populations of neurons in living animals. For the neurons to be sensitive to light,
researchers genetically insert light-sensitive proteins (taken from algae) into a
 4.6: TECHNIQUES THAT MODULATE BRAIN ACTIVITY | 151
specific type of neuron. After inserting tiny optical fibers into the animal’s brain,
researchers can turn on the light to excite or inhibit these specific cells. Scientists
have used the ability to control the activity of a genetically defined set of neurons
to understand their contribution to learning, memory, decision making, addiction,
movement, and many other active research areas.
In sum, the various research techniques used in biological psychology each
have their own strengths and weaknesses in terms of spatial resolution, temporal
resolution, ease-of-use, invasiveness, cost, precision, etc. Using the different tools
in a complementary manner provides converging evidence for understanding how
the brain works.

Text Attributions
This section contains material adapted from:
Beck, D. & Tapia, E. (2023). The brain. In R. Biswas-Diener & E. Diener (Eds),
Noba textbook series: Psychology. Access for free at http://noba.to/jx7268sd License:
CC BY-NC-SA 4.0 DEED
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener
& E. Diener (Eds), Noba textbook series: Psychology. Access for free at
http://noba.to/4hzf8xv6 License: CC BY-NC-SA 4.0 DEED
152 | 4.7: REFERENCES

4.7: REFERENCES

Parts of this chapter were adapted

from:
Beck, D. & Tapia, E. (2023). The brain. In R. Biswas-Diener & E. Diener (Eds),
Noba textbook series: Psychology. Champaign, IL: DEF publishers. Retrieved
from http://noba.to/jx7268sd
Biswas-Diener, R. (2023). The brain and nervous system. In R. Biswas-Diener
& E. Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/4hzf8xv6

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& E. Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/4hzf8xv6
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Pol, A., Renkema, G. H., Tangerman, A., Winkel, E. G., Engelke, U. F., de
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154 | 4.7: REFERENCES
 CHAPTER 5: DEVELOPMENT OF THE BRAIN AND NERVOUS

CHAPTER 5:
DEVELOPMENT OF THE
BRAIN AND NERVOUS
SYSTEM

Learning Objectives

• Describe how genetics can influence our appearance, mind, and

behavior
• Describe how evolution plays a role in shaping our behaviors over
time
• Understand what epigenetics is and how epigenetic mechanisms
can alter gene expression and impact physical and mental health
• Describe the different stages of neuronal development
• Relate the embryonic stage of nervous system development to
the adult structures of the central nervous system
• Understand sensitive and critical periods of development
• Relate the trade-off between neuroplasticity and neural efficiency
to brain development

This chapter was adapted from: Hove, M. J., & Martinez, S. A. (2024).
156 | CHAPTER 5: DEVELOPMENT OF THE BRAIN AND NERVOUS

Biological psychology. ROTEL (Remixing Open Textbooks with an

Equity Lens) Project. https://rotel.pressbooks.pub/
biologicalpsychology/.

and

Grose-Fifer, J., Spielman, R., Dumper, K., Jenkins, W., Lacombe, A.,
Lovett, M. & Perlmutter, M. (2023). Introduction to Psychology (A
critical approach). CUNY. https://pressbooks.cuny.edu/jjcpsy101/.
Creative Commons Attribution-NonCommercial-ShareAlike 4.0
International License.
 5.1: INTRODUCTION | 157

5.1: INTRODUCTION
Jill Grose-Fifer, Ph.D.; Michael J. Hove; and Steven A.
Martinez

The development of the nervous system is a complex and intricately coordinated

process spanning multiple stages, from the early embryonic stages through
childhood, adolescence, and adulthood. During early developmental stages, the
brain becomes able to dynamically transfer information across billions of
interconnected neurons, and coordinate and control mental and bodily functions,
including perception, cognition, and movement.
Psychologists study genetics in order to better understand the biological factors
that contribute to certain behaviors, thoughts, and feelings. Our genes provide a
“blue-print” for making the proteins that are the building blocks of our bodies,
including our nervous system. Understanding genetics helps us to answer
questions like: How are genetic diseases passed through family lines? Are there
genetic components to psychological disorders such as depression or
schizophrenia?
In this chapter, we first take a look at how we inherit our genes and how they can
affect our appearance, our minds and behavior. We then cover the stages of nervous
system and brain development in humans. We examine prenatal and postnatal
stages of development from embryo through old age. We will also cover different
stages of neuronal development, including neuron growth, migration, and death,
as well as adult neurogenesis. Lastly, we will examine neuroplasticity—the brain’s
ability to reorganize in response to intrinsic or extrinsic experiences—and how
neuroplasticity is strongest during sensitive and critical periods of development.
Learning how the nervous system develops and changes across the lifespan provides
a more complete understanding of the brain.
158 | 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS

5.2 HUMAN GENETICS,

EVOLUTION, AND EPIGENETICS

Genetic Variation
After a sperm fertilizes an egg, it forms a zygote. The egg and the sperm each
contain 23 chromosomes, and so the zygote has 23 pairs of chromosomes.
Therefore, each child inherits half of their genetic information from each
biological parent. Chromosomes are long strings of genetic material known as
deoxyribonucleic acid (DNA). Each chromosome contains multiple genes, which
are formed by specific sequences of DNA (Figure 5.1a). A single gene often has
multiple variations, which we refer to as alleles. So, if there was a specific gene that
coded for hair color, different alleles of that gene will determine the hair color of
an individual. Thus, scientists investigate how our genotypes (or genetic makeup)
determine our phenotypes, such as hair color, eye color, skin color, whether we
have a cleft chin, or other psychological traits (see Figure 5.1b).
Most traits are controlled by multiple genes (i.e., they are polygenic), but there
are a few traits that are controlled by one single gene, such as having wet or dry
earwax in humans or the length of fur in a cat (McDonald, 2013). We inherit one
“earwax” allele from each parent and there two possible variants of the allele – the
dominant form (B) and the recessive form (b). When someone has two copies of
the same allele, they are said to be homozygous for that allele (BB or bb). When
someone has a mixture of alleles for a given gene, they are said to be heterozygous
(Bb). Having wet earwax is a dominant trait (B), so if we have that dominant allele
in our genotype we will have wet earwax, regardless of the other allele we inherit
(BB or Bb). Having dry earwax is a recessive trait, which means that we will only
have dry earwax if we are homozygous for that recessive allele (bb).
 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS | 159

Figure 5.1. (a) Genotype refers to the genetic makeup of an individual

based on the genetic material (DNA) inherited from one’s biological
parents. (b) Phenotype describes an individual’s observable
characteristics, such as hair color, skin color, height, and build. CREDIT:
Psychology 2e Open Stax

If you AND your partner both have wet earwax, you might be thinking that it is
inevitable that your offspring will have wet earwax too. But, actually it’s not that
simple. It depends on the specific alleles that you and your partner carry. If one of
you is homozygous (BB), then all your offspring will have wet earwax. It gets a little
more complicated, however, if you and your partner are both heterozygous for this
gene (Bb). If we use a Punnett square to look at the four possible combinations
of genes (Figure 5.2), we see there is a 75% chance your offspring will have wet
earwax and a 25% chance they will have dry ear wax (Figure 5.2). We recognize that
earwax is rather a strange trait to talk about, but we did not want to perpetuate the
common myth that traits such as eye color, cleft chins, presence of earlobes, and
tongue rolling are determined by a single gene. These traits are polygenic and occur
on a continuum.
160 | 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS

Figure 5.2. A Punnett square is a tool used to predict how genes will
interact in the production of offspring. The capital B represents the
dominant allele, and the lowercase b represents the recessive allele. In
the example of the type of earwax, where B is wet (dominant allele),
wherever a pair contains the dominant allele, B, there is a wet ear wax
phenotype. You will have a dry earwax phenotype only when there are
two copies of the recessive allele, bb. CREDIT: Psychology 2e openstax.org

Some genetic disorders come from inheriting two recessive alleles. For example,
phenylketonuria (PKU) is a metabolic condition where individuals lack an enzyme
that normally converts harmful amino acids in foods into harmless byproducts. If
this condition goes untreated, people with PKU can experience significant deficits
in cognitive function, seizures, and an increased risk of various psychiatric
disorders. Because PKU is a recessive trait, each parent must have at least one copy
of the recessive allele in order to produce a child with the condition.
 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS | 161
Where do genes that contribute to diseases like PKU come from? It has been
shown that PKU is due to a gene mutation. This is where the DNA sequencing
in a specific gene is slightly altered. Gene mutations can arise spontaneously but
once present, it can be passed down to future generations. While many mutations
can be harmful or lethal, once in a while, a mutation benefits an individual by
giving that person an advantage over those who do not have the mutation. Recent
research shows that people who have long lives despite an unhealthy lifestyle,
may be benefiting from gene mutations that protect from heart disease and high
cholesterol (Williams, 2016).

Theories of Evolution
Theories of evolution aim to explain how genetic variation among a population
changes over time. Charles Darwin, an English biologist, proposed an influential
evolutionary theory called the theory of natural selection of evolution. He
suggested that the individuals within a species that were best suited to their
particular environments were more likely to survive and reproduce and pass on
their genes to future generations. This is often referred to as the survival of the
th
fittest. Let’s consider the story of the peppered moth in the UK. In the early 19
century, these moths were predominantly light in color, which provided them with
good camouflage from predatory birds. However, during the industrial revolution,
the trees in and around large cities became covered in black soot and the light
colored moths were virtually eradicated because they were eaten by birds. However,
there were also some rarer, dark-colored moths that were now much harder to see
when they landed on the trees. Thus, they were more likely to thrive and mate,
and pass their dark coloring genes to their offspring. So, over time, there were more
and more dark colored peppered moths. Darwin assumed that each successive
generation would evolve to be better adapted for the environment. We certainly
see evidence for evolution through natural selection among multiple species.
However, scientists now acknowledge that evolution simply means changes in
genetic variations, and not necessarily improvements. Darwin’s studies focused on
plants and animals, but modern-day scientists have found genetic linkages to a
number of behavioral characteristics, ranging from basic personality traits to sexual
orientation to spirituality (for examples, see Mustanski et al., 2005; Comings et al.,
162 | 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS
2000). Genes are also associated with temperament and a number of psychological
disorders, such as depression and schizophrenia.
Darwin’s theories on evolution took the world by storm, because it was in
direct opposition to the popular religious doctrine of the time. Most believed
that people were created by God. However, Darwin believed that humans evolved
from other species, Unfortunately, like many other White men of his time, Darwin
mistakenly believed that race was genetically determined and Anglo-Europeans
were “genetically superior” to people of color. Darwin’s theory of natural selection
was abused by eugenicists to provide a “scientific rationale” for racism, sexism, and
xenophobia. We now know that race is a social, not a biological construct. There is
actually more genetic variation within a given racial category than there is between
racial categories, so two white people typically share more genetic overlap with a
person of color, than they do with each other.
Modern biology acknowledges that most human characteristics are controlled
by multiple genes. Each of us represents a unique interaction between our genetic
makeup and our environment. For example, intelligence is a complex construct
that has a polygenetic component to it, but it is also highly dependent on
education, nutrition, and other environmental factors, such as stress. People have
questioned whether evolution through natural selection still applies to humans
in our modern world given the advances in modern medicine. However, humans
have not stopped evolving. Evolution does not necessarily result in improvements;
evolution simply means that there are changes in genetic variation over time.

Gene-Environment Interactions
Environmental factors can turn some genes on and others off, we call these
epigenetic changes. Epigenetics helps to explain why two identical twins (who
have identical genes) show an incredible amount of variability in their phenotypes.
For example, one twin could develop a mental illness such as schizophrenia, while
the other never does. Their unique environmental interactions determine how
their genetic information is expressed, which in turn gives rise to different
phenotypes for various traits. Tienari and colleagues found that among adoptees
whose biological mothers had schizophrenia, those who were raised in a disturbed
family environment were about 6 times more likely to develop schizophrenia (or
 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS | 163
related disorder) than those raised in a healthy environment. Adoptees with a
biological mother who had schizophrenia and who raised in a disturbed
environment were also much more likely to develop schizophrenia than
participants with no biological family history of schizophrenia, regardless of type
of childhood environment (Tienari et al., 2004). This research highlights that both
genetic vulnerability and environmental stress are necessary for schizophrenia to
develop, and that genes alone do not tell the full tale (Figure 5.3).

Link to Learning

Watch this video about the epigenetics of twin studies to learn

more.

We also know that the genes can influence the environment, which in turn can
amplify the effects of any genetic predispositions we have, this is often referred to
as the multiplier effect. For example, imagine a child who, due to their genes, is
naturally agile and athletic. Their parents notice this at an early age and they set up
a mini-basketball court and teach their child how to dribble and shoot. The child is
encouraged by their enthusiasm and likes to practice. The parents sign their child
up for basketball camp and a local team. Thus, the child’s genes have influenced
their environment. As a consequence, the child is likely to be a better player than
other children.
164 | 5.2 HUMAN GENETICS, EVOLUTION, AND EPIGENETICS

Figure 5.3. Nature and nurture work together like complex pieces of a
human puzzle. The interaction of our environment and genes makes us
the individuals we are. CREDIT: Psychology 2e openstax.org

Text Attribution:
Materials in this section came from:
Grose-Fifer, J., Spielman,R., Dumper,K., Jenkins, W., Lacombe, A., Lovett,
M. & Perlmutter, M. (2023). Introduction to Psychology (A critical approach).
CUNY. https://pressbooks.cuny.edu/jjcpsy101/. Creative Commons Attribution-
NonCommercial-ShareAlike 4.0 International
License.https://pressbooks.cuny.edu/jjcpsy101/
 5.3 NATURE-NURTURE AND TWIN STUDIES | 165

5.3 NATURE-NURTURE AND

TWIN STUDIES
Jill Grose-Fifer, Ph.D.

Nature-Nurture and Twin Studies

People have a deep intuition about what has been called the “nature–nurture
question” (Turkheimer, 2023). Some aspects of our behavior feel as though they
originate in our genetic makeup, while others feel like the result of our upbringing
or our own hard work. The scientific field of behavioral genetics attempts to
study these differences empirically, either by examining similarities among family
members with different degrees of genetic relatedness or, more recently, by
studying differences in the DNA of people with different behavioral traits. The
scientific methods that have been developed are ingenious but often inconclusive.
Many of the difficulties encountered in the empirical science of behavioral genetics
turn out to be conceptual, and our intuitions about nature and nurture get more
complicated the harder we think about them. In the end, it is an oversimplification
to ask how “genetic” some particular behavior is. Genes and environments always
combine to produce behavior, and the real science is in the discovery of how they
combine for a given behavior.
It may seem obvious that we are born with certain characteristics while others
are acquired, yet in the history of psychology, the “nature–nurture debate” has
caused much controversy and offense: We are so concerned with nature–nurture
because our very sense of moral character seems to depend on it. While we may
admire the athletic skills of a great basketball player, we think of his height as
simply a gift, a payoff in the “genetic lottery.” For the same reason, no one blames a
short person for his height or someone’s congenital disability on poor decisions. To
state the obvious, it’s “not their fault.” But we do praise the concert violinist (and
perhaps her parents and teachers as well) for her dedication, just as we condemn
cheaters, slackers, and bullies for their bad behavior.
166 | 5.3 NATURE-NURTURE AND TWIN STUDIES
The problem is that most human characteristics aren’t usually as clear-cut as
height or instrument mastery, affirming our nature–nurture expectations strongly
one way or the other. In fact, even the great violinist might have some inborn
qualities— pitch perception talent or long, nimble fingers—that support and
reward her hard work. And the basketball player might have eaten a diet while
growing up that promoted his genetic tendency to be tall. When we think about
our own qualities, they seem under our control in some respects yet beyond our
control in others. And often, the traits that don’t seem to have an obvious cause
are the ones that concern us the most and are far more personally significant. What
about how much we drink or worry? What about our honesty, or religiosity, or
sexual orientation? They all come from that uncertain zone, neither fixed by nature
nor totally under our own control.

Figure 5.4 Researchers have learned a great deal about the

nature-nurture dynamic by working with animals. But of course, many
of the techniques used to study animals cannot be applied to people.
Separating these two influences in human subjects is a greater research
challenge. CREDIT: Puppies © Flickr is licensed under a CC BY-NC (Attribution
NonCommercial) license
 5.3 NATURE-NURTURE AND TWIN STUDIES | 167
One major problem with answering nature-nurture questions about people is how
to set up an experiment. In nonhuman animals, relatively straightforward
experiments can tackle nature–nurture questions. Say, for example, you are
interested in aggressiveness in dogs. You want to test for the more important
determinant of aggression: being born to aggressive dogs or being raised by them.
You could mate two aggressive dogs—angry Chihuahuas—together, and mate two
nonaggressive dogs—happy beagles—together, then switch half the puppies from
each litter between the different sets of parents to raise. You would then have
puppies born to aggressive parents (the Chihuahuas) but being raised by
nonaggressive parents (the Beagles), and vice versa. The big questions are: Would
the Chihuahua parents raise aggressive beagle puppies? Would the beagle parents
raise nonaggressive Chihuahua puppies? Would the puppies’ nature win out,
regardless of who raised them? Or… would the result be a combination of nature
and nurture? Much of the most significant nature–nurture research has been
done in this way (Scott & Fuller, 1998), and animal breeders have been doing it
successfully for thousands of years. In fact, it is fairly easy to breed animals for
behavioral traits.
With people, however, we can’t assign babies to parents at random, or select
parents with certain behavioral characteristics to mate, merely in the interest of
science (though history does include horrific examples of such practices in
misguided attempts at “eugenics,” the shaping of human characteristics through
intentional breeding). In typical human families, children’s biological parents raise
them, so it is very difficult to know whether children act like their parents due
to genetic (nature) or environmental (nurture) reasons. Nevertheless, despite our
restrictions on setting up human-based experiments, we do see real-world examples
of nature-nurture at work in the human sphere—though they only provide partial
answers to our many questions.
The science of how genes and environments work together to influence
behavior is called behavioral genetics. The easiest opportunity we have to observe
this is the adoption study. When children are put up for adoption, the parents
who give birth to them are no longer the parents who raise them. This setup isn’t
quite the same as the experiments with dogs (children aren’t assigned to random
adoptive parents in order to suit the particular interests of a scientist), but adoption
still tells us some interesting things. For instance, if the biological child of tall
parents were adopted into a family of short people, do you suppose the child’s
168 | 5.3 NATURE-NURTURE AND TWIN STUDIES
growth would be affected? What about the biological child of a Spanish-speaking
family adopted at birth into an English-speaking family? What language would
you expect the child to speak? And what might these outcomes tell you about the
difference between height and language in terms of nature-nurture?

Figure 5.5. Studies focused on twins have led to important insights

about the biological origins of many personality characteristics. CREDIT:
Twin babies © Noba is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license
 5.3 NATURE-NURTURE AND TWIN STUDIES | 169
Another option for observing nature-nurture in humans involves twin studies.
There are two types of twins: monozygotic (MZ) and dizygotic (DZ).
Monozygotic twins, also called “identical” twins, result from a single zygote
(fertilized egg) and have the same DNA. They are essentially clones. Dizygotic
twins, also known as “fraternal” twins, develop from two zygotes and share 50% of
their DNA. Fraternal twins are ordinary siblings who happen to have been born at
the same time. To analyze nature–nurture using twins, we compare the similarity
of MZ and DZ pairs. Sticking with the features of height and spoken language,
let’s take a look at how nature and nurture apply: Identical twins, unsurprisingly,
are almost perfectly similar in height. The heights of fraternal twins, however,
are like any other sibling pairs: more similar to each other than to people from
other families, but hardly identical. This contrast between twin types gives us a
clue about the role genetics plays in determining height. Now consider spoken
language. If one identical twin speaks Spanish at home, the co-twin with whom
she is raised almost certainly does too. But the same would be true for a pair of
fraternal twins raised together. In terms of spoken language, fraternal twins are just
as similar as identical twins, so it appears that the genetic match of identical twins
doesn’t make much difference.
Twin and adoption studies are two instances of a much broader class of methods
for observing nature-nurture called quantitative genetics, the scientific discipline
in which similarities among individuals are analyzed based on how biologically
related they are. We can do these studies with siblings and half-siblings, cousins,
and twins who have been separated at birth and raised separately (Bouchard et al.,
1990; such twins are very rare and play a smaller role than is commonly believed
in the science of nature–nurture), or with entire extended families (see Plomin
et al., 2012, for a complete introduction to research methods relevant to
nature–nurture).
For better or for worse, contentions about nature–nurture have intensified
because quantitative genetics produces a number called a heritability coefficient,
varying from 0 to 1, that is meant to provide a single measure of genetics’ influence
on a trait. In a general way, a heritability coefficient measures how strongly
differences among individuals are related to differences in their genes. But beware.
Heritability coefficients, although simple to compute, are deceptively difficult to
interpret. Nevertheless, numbers that provide simple answers to complicated
questions tend to have a strong influence on the human imagination, and a great
170 | 5.3 NATURE-NURTURE AND TWIN STUDIES
deal of time has been spent discussing whether the heritability of intelligence or
personality or depression is equal to one number or another.

Figure 5.6. Quantitative genetics uses statistical methods to study the

effects that both heredity and environment have on test subjects. These
methods have provided us with the heritability coefficient which
measures how strongly differences among individuals for a trait are
related to differences among their genes. CREDIT: Viral DNA © Flickr is
licensed under a Public Domain license

One reason nature–nurture continues to fascinate us is that we live in an era of

great scientific discovery in genetics. DNA was discovered by Watson and Crick
in the 1950s; the human genome–about 3 billion base pairs long–was completely
sequenced at the turn of the 21st century, and we are now on the verge of being
 5.3 NATURE-NURTURE AND TWIN STUDIES | 171
able to obtain the specific DNA sequence of anyone at a relatively low cost (the
cost of sequencing a human genome has fallen from around $10 million in 2007
to well below $1000 today; National Human Genome Research Institute, 2021).
Every day, it seems, new discoveries are made, and new possibilities are proposed.
No one knows what this new genetic knowledge will mean for the study of
nature–nurture, but as we will see in the next section, answers to nature–nurture
questions have turned out to be far more difficult and mysterious than anyone
imagined.

What Have We Learned About

Nature–Nurture?
It would be satisfying to be able to say that nature–nurture studies have given
us conclusive and complete evidence about where traits come from, with some
traits clearly resulting from genetics and others almost entirely from environmental
factors such as childrearing practices and personal will, but that is not the case.
Instead, everything has turned out to have some footing in genetics. The more
genetically related people are, the more similar they are—for everything: height,
weight, intelligence, personality, mental illness, etc. Sure, it seems like common
sense that some traits have a genetic bias. For example, adopted children resemble
their biological parents even if they have never met them, and identical twins
are more similar to each other than are fraternal twins. However, while certain
psychological traits, such as personality or mental illness (e.g., schizophrenia), seem
reasonably influenced by genetics, it turns out that the same is true for political
attitudes, how much television people watch (Plomin et al., 1990), and whether
or not they get divorced (McGue & Lykken, 1992). The message is clear: You
can’t leave genes out of the equation. But keep in mind, no behavioral traits are
completely inherited, so you can’t leave the environment out altogether, either.
172 | 5.3 NATURE-NURTURE AND TWIN STUDIES

Figure 5.7. Research over the last half-century has revealed how central
genetics are to behavior. The more genetically related people are, the
more similar they are, not just physically but also in terms of personality
and behavior. CREDIT: Like father like son © Flickr is licensed under a Public
Domain license

Trying to untangle the various ways nature-nurture influences human behavior can
be messy, and often common-sense notions can get in the way of good science. One
very significant contribution of behavioral genetics that has changed psychology
for good can be very helpful to keep in mind: When your subjects are biologically
related, no matter how clearly a situation may seem to point to environmental
influence, it is never safe to interpret behavior as wholly the result of nurture
without further evidence. For example, when presented with data showing that
children whose mothers read to them often are likely to have better reading scores
 5.3 NATURE-NURTURE AND TWIN STUDIES | 173
in third grade, it is tempting to conclude that reading to your kids is important to
success in school; this may well be true, but the study as described is inconclusive
because there are genetic as well as environmental pathways between the parenting
practices of mothers and the abilities of their children. This is a case where
“correlation does not imply causation.” To establish that reading aloud causes
success, a scientist can either study the problem in adoptive families (in which the
genetic pathway is absent) or by conducting an experiment that randomly assigns
children to oral reading conditions.
An issue with the heritability coefficient is that it divides traits’ determinants
into two portions—genes and environment—which are then calculated together
for the total variability. This is a little like asking how much of the experience
of a symphony comes from the horns and how much from the strings; the ways
instruments or genes integrate is more complex than that.
As noted in the previous section, the heritability coefficient does not capture
the complexity of the nature-nurture relationship. Instead, for many traits, genetic
differences affect behavior under some environmental circumstances but not
others—a phenomenon called gene-environment interaction, or G x E. In one
well-known example, Caspi et al. (2002) found that among maltreated children,
those who carried a particular allele of the MAOA gene showed a predisposition to
violence and antisocial behavior, while those with other alleles did not. However,
in children who had not been maltreated, the gene had no effect. In another
example of gene-environment interaction, adoptees whose biological mothers had
schizophrenia and who had been raised in a disturbed family environment were
much more likely to develop schizophrenia than were any of the other groups in
the study (Tienari et al., 2004):

• Of adoptees whose biological mothers had schizophrenia (high genetic risk)

and who were raised in disturbed family environments, 36.8% were likely to
develop schizophrenia.
• Of adoptees whose biological mothers had schizophrenia (high genetic risk)
and who were raised in healthy family environments, 5.8% were likely to
develop schizophrenia.
• Of adoptees with a low genetic risk (whose mothers did not have
schizophrenia) and who were raised in disturbed family environments, 5.3%
were likely to develop schizophrenia.
174 | 5.3 NATURE-NURTURE AND TWIN STUDIES
• Of adoptees with a low genetic risk (whose mothers did not have
schizophrenia) and who were raised in healthy family environments, 4.8%
were likely to develop schizophrenia.

The study shows that adoptees with high genetic risk were most likely to develop
schizophrenia if they were raised in disturbed home environments. This research
suggests genetic vulnerability and environmental stress both contribute to
developing schizophrenia and that genes (or environment) alone do not tell the
full tale (Spielman et al., 2020). Making matters even more complicated are recent
studies of what is known as epigenetics (covered in the next section), a process in
which genes can be turned “on” or “off” in response to environmental events, and
those epigenetic changes transmitted to children.

Figure 5.8. The answer to the nature–nurture question has not turned
out to be as straightforward as we would like. The many questions we
can ask about the relationships among genes, environments, and human
traits may have many different answers, and the answer to one tells us
little about the answers to the others. CREDIT: Mother and son © Flickr is
licensed under a Public Domain license
 5.3 NATURE-NURTURE AND TWIN STUDIES | 175
Some common questions about nature–nurture are: how susceptible is a trait to
change, how malleable is it, and do we “have a choice” about it? These questions
are much more complex than they may seem at first glance. For example,
phenylketonuria is an inborn error of metabolism caused by a single gene; it
prevents the body from metabolizing phenylalanine. Untreated, it causes
intellectual disability and death. However, it can be treated effectively by a
straightforward environmental intervention: avoiding foods containing
phenylalanine. Height seems like a trait firmly rooted in our nature and
unchangeable, but the average height of many populations in Asia and Europe
has increased significantly in the past 100 years, due to changes in diet and the
alleviation of poverty.
With the Human Genome Project and DNA sequencing, it was believed that
we would be easily able to link specific genes with specific behaviors. That has not
happened. A few rare genes have been found to have significant (almost always
negative) effects, such as the single gene that causes Huntington’s disease or the
Apolipoprotein gene that causes early-onset dementia in a small percentage of
Alzheimer’s cases. Aside from these rare genes of great effect, however, the genetic
impact on behavior is broken up over many genes, each with very small effects. For
most behavioral traits, the effects are so small and distributed across so many genes
that we have not been able to catalog them in a meaningful way. In fact, the same
is true of environmental effects. We know that extreme environmental hardship
causes catastrophic effects for many behavioral outcomes, but fortunately, extreme
environmental hardship is very rare. Within the normal range of environmental
events, those responsible for differences (e.g., why some children in a suburban
third-grade classroom perform better than others) are much more difficult to
grasp.
Finding clear-cut solutions to nature–nurture problems is difficult. With
nature-nurture, what at first seems straightforward and possible to index with
a single number becomes more and more complicated the closer we look. The
many questions we can ask about the intersection among genes, environments,
and human traits—how sensitive are traits to environmental change, are parents
or culture more relevant; how sensitive are traits to differences in genes, and how
much do the relevant genes vary in a particular population, does the trait involve a
single gene or many genes, and is the trait more easily described in genetic or more
complex behavioral terms?—may have different answers, and the answer to one
176 | 5.3 NATURE-NURTURE AND TWIN STUDIES
tells us little about the answers to the others. Overall, we should continue studying
and thinking about nature and nature or genes and the environment without being
tempted to oversimplify these complex relationships.
 5.4: EARLY FORMATION OF THE STRUCTURES OF THE BRAIN | 177

5.4: EARLY FORMATION OF THE

STRUCTURES OF THE BRAIN

The embryo is initially formed through fertilization, which occurs when a sperm
cell and an egg cell unite into a single cell. This fertilized egg cell, or zygote, starts
dividing through the process of mitosis to generate the cells that make up an entire
organism. Sixteen days after fertilization, the developing embryo’s cells belong to
one of three layers that form into the different tissues in the body (Betts et al.,
2022). The endoderm, or inner tissue, is responsible for generating the lining
tissues of various spaces within the body, such as the mucosae of the digestive
and respiratory systems. The mesoderm, or middle tissue, gives rise to most of
the muscle and connective tissues. Finally the ectoderm, or outer tissue, develops
into the body’s outer layer of skin, hair, nails, as well as the nervous system. It is
probably easy to see that the outer tissue of the embryo becomes the outer covering
of the body, but how is it responsible for the nervous system?1

Neural Tube
Two weeks into embryonic development, the human nervous system begins to
form. As the embryo develops, a portion of the ectoderm differentiates into a
specialized region of neuroectoderm, which is the precursor for the tissue of the
nervous system (Betts et al., 2022). Cells in this region form a neural plate that
begins to fold inward to form a neural groove that is lined on each side by a neural

1. This section contains material adapted from: Betts et al., (2022). 13.1 The Embryologic Perspective. In
Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/psychology-2e/
pages/15-4-anxiety-disorders License: CC BY 4.0 DEED.
 178 | 5.4: EARLY FORMATION OF THE STRUCTURES OF THE BRAIN
fold. These two neural folds eventually fuse together to form the neural tube
(Figure 5.9) and set up the development of the brain and spinal cord. Cells from
the neural folds then separate from the ectoderm to form a cluster of cells referred
to as the neural crest, which runs lateral to the neural tube. These neural crest
cells migrate away from the nascent central nervous system (CNS) that will form
along the neural groove and develop into several parts of the peripheral nervous
system (PNS) including the enteric nervous system that governs the function of
the gastrointestinal tract.

Figure 5.9: During the embryonic stage of development, the

neuroectoderm folds inward to form the neural groove. As the two sides
of the neural groove fuse together, they form the neural tube. The
anterior end of the neural tube will develop into the brain, and the
posterior portion will develop into the spinal cord. CREDIT: nervous
system © Openstax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

During the third week of embryonic development, the anterior end of the neural
tube begins developing into the brain, and the posterior portion begins developing
into the spinal cord. This basic arrangement of tissue in the nervous system gives
rise to more complex structures by the fourth week of development.2

2. This section contains material adapted from: Betts et al., (2022). 13.1 The Embryologic Perspective. In
Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/psychology-2e/
pages/15-4-anxiety-disorders License: CC BY 4.0 DEED.
 5.4: EARLY FORMATION OF THE STRUCTURES OF THE BRAIN | 179

Primary Vesicles
As the anterior end of the neural tube starts to develop into the brain, it generates
three primary vesicles: the forebrain (prosencephalon), the midbrain
(mesencephalon), and the hindbrain (rhombencephalon) (Betts et al., 2022).
The forebrain is the upper-most vesicle, the midbrain is the next vesicle, and the
hindbrain is the lowest vesicle. One way of thinking about how the brain is
arranged is to use these three regions—forebrain, midbrain, and hindbrain (Figure
5.10).3

Figure 5.10: During the embryonic stage of development, the neural

tube evolves into three primary vesicles. These three primary vesicles
then give rise to five secondary vesicles. CREDIT: Embryonic stages of
development © Openstax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Secondary Vesicles
By week 5, the three primary vesicles differentiate further into five secondary

3. This section contains material adapted from: Betts et al., (2022). 13.1 The Embryologic Perspective. In
Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/psychology-2e/
pages/15-4-anxiety-disorders License: CC BY 4.0 DEED.
 180 | 5.4: EARLY FORMATION OF THE STRUCTURES OF THE BRAIN
vesicles (Betts et al., 2022) (Figure 5.10). The forebrain enlarges into two new
vesicles called the telencephalon and the diencephalon. The telencephalon will
become the cerebrum—the largest part of the adult brain which contains the
lobes of the cerebral cortex, hippocampus, and basal ganglia. The diencephalon
will give rise to several structures including the thalamus (the central relay hub
for sensory signals) and hypothalamus (involved in homeostasis and regulating
functions including hunger, sleep, and mood).
A third secondary vesicle, the mesencephalon or midbrain, is composed of the
tectum, the cerebral aqueduct, the tegmentum, and the cerebral peduncles.
The midbrain is an established region of the brain at the primary vesicle stage and
does not further differentiate into finer divisions. The rest of the brain develops
around the midbrain, which is involved in many functions including head and eye
movements, motivation, and reward.
The hindbrain develops into the final secondary vesicles, the metencephalon
and myelencephalon. The metencephalon gives rise to the pons and cerebellum.
The cerebellum accounts for about 10 percent of the mass of the brain and is an
important structure for coordinated movement, posture, as well as cognition. The
cerebellum connects to the rest of the brain via the pons, because the pons and
cerebellum develop out of the same vesicle. Finally, the myelencephalon gives rise
to the adult structure known as the medulla oblongata (involved in breathing,
digestion, heart rate, blood pressure, etc.). The structures that arise from the
midbrain and hindbrain, except for the cerebellum, are collectively considered the
brain stem, which specifically includes the midbrain, pons, and medulla.
We first learned about the above structures in Chapter 3: The Brain and
Nervous System. In order to understand the outcome of fetal brain development,
it may be helpful to return to Chapter 3 to review details of these structures in the
adult brain.4

4. This section contains material adapted from: Betts et al., (2022). 13.1 The Embryologic Perspective. In
Anatomy and Physiology 2e. OpenStax. Access for free at https://openstax.org/books/psychology-2e/
pages/15-4-anxiety-disorders License: CC BY 4.0 DEED.
 5.5: STAGES OF NEURONAL DEVELOPMENT | 181

5.5: STAGES OF NEURONAL

DEVELOPMENT

As discussed in previous chapters, the brain is made up of neurons and

glial cells. Neurons, also called nerve cells, are electrically excitable cells
that transmit signals called action potentials to other neurons and are
considered the fundamental units of the brain and nervous system
(Ludwig et al., 2022). Neurons communicate information about
sensations and movements, and process information within the brain.
Glial cells, or neuroglia or simply glia, are the other type of cells found in
the nervous system. Glial cells are considered supporting cells, and help
neurons complete their function for communication. We discuss six main
types of glial cells. Four of them are found in the CNS and two are found in
the PNS. Figure 5.11 provides a visualization of the different types of glial
cells and Table 5.1 defines their common characteristics and functions.
182 | 5.5: STAGES OF NEURONAL DEVELOPMENT

Figure 5.11: Visualizing the different glial cell types. CREDIT:

Blausen_0870_TypesofNeuroglia © Wikiversity.org is licensed under a CC BY
(Attribution) license

Glial Cell Types By Location and Function

Table 5.1: Different types of glial cells and their basic functions
[Table adapted from: Anatomy and Physiology 2e: 12.2 Nervous
Tissue] CC BY 4.0.

CNS Glia PNS Glia Function

Astrocyte Satelite cell Support

Insulation,
Oligodendrocyte Schwann cell
myelination

Maintenance of
Microglia –
neural networks

Creating
Ependymal cell –
cerebrospinal fluid
 5.5: STAGES OF NEURONAL DEVELOPMENT | 183
Neuronal Proliferation
Neuronal development includes several stages. Once the neural tube has closed,
the first stage of neuron growth, known as neural proliferation, begins to occur
in the ventricular zone of the neural tube. Roughly four weeks into embryonic
development, neurogenesis begins, such that cells of the neural tube begin to
increase significantly in number (i.e., proliferate). The cells produced during neural
proliferation will eventually develop into neurons that integrate into the neural
circuitry that give rise to the central nervous system (brain and spinal cord). The
vast majority of neurons in the human telencephalon (i.e., cortex, hippocampus,
basal ganglia, etc.) are generated before birth. Extensive neurogenesis does occur
after birth in other regions of the brain (e.g., cerebellum). But all in all, the bulk
of neurogenesis (i.e., the 86 billion neurons) in the CNS occurs between 4th
week post-conception to 18 months after birth—this means that about 4.6 million
neurons are generated every hour during this early developmental period (Silbereis
et al., 2016).
During neural proliferation, the cells being formed are neural stem cells. There
are two basic types of stem cells, pluripotent and totipotent cells. Pluripotent cells
can give rise to all of the cell types that make up the body, whereas multipotent
cells are more limited than pluripotent cells. Given that pluripotent stem cells can
give rise to all cell types that make up the body, scientists have begun focusing on
how pluripotent cells can be used in regenerative cell-based treatment strategies to
counter a wide-range of diseases including diabetes, spinal cord injury, and heart
disease. In regard to CNS development, neural stem cells are a special type of
pluripotent cell, in that they only generate radial glial cells, which eventually give
rise to the neurons and glial cells of the central nervous system. In summary, neural
proliferation is the process by which billions of cells are generated, and certain cell
types (i.e., neural stem cells), have the capability of differentiating into the neurons
and glial cells that will develop into the central nervous system.

Neuronal Migration
Newly formed neurons may remain where they are and continue to divide, or
may migrate to other parts of the nervous system. Neuronal migration refers to
184 | 5.5: STAGES OF NEURONAL DEVELOPMENT
the process by which neurons travel from their original location to a new target
location. For neurons of the central nervous system, neural migration remains
within the confines of the neural tube, whereas for neurons of the peripheral
nervous system, neural migration may take place across different neural regions
(Purves et al., 2001). During the migration period, neurons remain immature,
and still lack fundamental neuronal characteristics such as axons and dendrites.
Ultimately, neuronal migration is supported by sophisticated molecular and
cellular signaling that results in pulling and pushing the immature neuron to its
appropriate target location.
In general, migration tends to follow an inside-out pattern, where neurons travel
from the inside of the neural tube, also known as the ventricular zone, outwards
toward their target location. This migration can be classified into two modes: 1)
radial migration, and 2) tangential migration. Radial migration, long seen as
the primary mode of neuronal movement in the cortex, occurs when neurons are
guided by radial glial cells to migrate toward the surface of the brain following the
radial pattern of the neural tube and ultimately establish the layered organization
of the neocortex (Marin et al., 2003; Wong, 2002). The second mode of neuronal
movement, tangential migration, occurs when neurons move to the surface of the
central nervous system (or orthogonal to the direction of radial migration). Of
note, these two migration methods are not mutually exclusive, as some neurons
may alternate from radial to tangential movement along the course of their
migration to their target location (Marin et al., 2010).
Additionally, the mechanisms of migration are interesting. One method, called
somal translocation, involves an extension that reaches out from the soma of the
immature neuron to lead it on its journey to its target location. Both radial and
tangential migration can occur through somal translocation. A second method
is called glial-mediated migration. This involves the immature neuron “hopping
onto” an extended glial cell. This immature neuron “pulls” itself up the glial cell to
its target location. Radial migration occurs according to glial-mediated migration.
By the end of migration, neurons are aligned in such a manner that enables
them to acquire specific functions, interact with other neurons, and eventually
give rise to neural circuits that make up the human nervous system; a process
known as aggregation. Aggregation is thought to be supported by cell-adhesion
molecules, which are located on the surfaces of cells. Cell-adhesion molecules
are able to recognize identical or different cell types and subsequently adhere to
 5.5: STAGES OF NEURONAL DEVELOPMENT | 185
molecules on other cells (Jaffe et al., 1990; Takeichi, 1988). Gap junctions are
also thought to support migration and aggregation processes. Gap junctions are
clusters of communication channels between neighboring cells that link the
cytoplasm of two cells and facilitate the exchange of ions and metabolites such
as glucose, which subsequently promotes biochemical coupling between the two
cells (Mese et al., 2007). Ultimately, through supportive mechanisms such as cell-
adhesion molecules and gap junctions, neurons are able to interact and coalesce to
give rise to the neural circuitry that makes up the human nervous system.

Neuronal Differentiation
After reaching their target location, the immature neurons begin differentiation
— acquiring distinct neuronal characteristics, such as dendrites and axons, which
allow neurons to communicate with other neurons via synapses.

Synaptogenesis
Ultimately, synaptogenesis — the ability for neurons to communicate with one
another leads to the establishment of functional neural circuits that make up the
adult nervous system. In fact, if neurons do not synapse with other cells during
development they will die as they are simply not needed. Neuronal cell death,
which refers to the elimination of neurons in the nervous system, occurs
extensively during development and is actually helpful for supporting brain
development. This type of neuron death is called Apoptosis it refers to active,
programmed cell death to maintain appropriate development (Khalid &
Azimpouran 2023). One example of apoptosis can be seen after neuronal
proliferation, when excess neurons and immature neurons must be selectively
eliminated in order to enable adequate neuronal connectivity and support the
maturation of functional networks (Hollville et al., 2019).
Early research showed a pattern in synapse formation during brain development
such that there is first a rapid overproduction of synapses, followed by a
programmed elimination of non-functional synapses, which eventually brings the
overall number of synapses down to adult levels (Huttenlocher, 1979;
Huttenlocher & Dabholkar, 1997; Shonkoff & Phillips, 2000). This synapse-
186 | 5.5: STAGES OF NEURONAL DEVELOPMENT
formation pattern emerges at different timescales for different brain
networks—synapse formation related to sensory processes peaks first, followed
by language-related processes, and finally higher-order cognitive functions (Figure
5.12). Relevant to neural efficiency, one hypothesis proposes that excess synapses
during adolescence in frontal lobe regions, such as the prefrontal cortex, may
render information processing less efficient in those brain regions (Blakemore,
2012). In other words, during adolescence the brain may require many synapses
to carry out cognitive processes. However, as these neuronal connections and
functional networks become refined throughout development, the brain may
require fewer synapses to carry out the same cognitive processes. In this way, the
brain is hypothesized to shift toward prioritizing the most efficient synapses, which
may ultimately lead to more efficient cognitive processing.Synapses are constantly
being rewired throughout our lives as we learn new things — the function of the
brain to change with experience is called neuroplasticity.

Figure 5.12. The number of new synapses related to sensory function,

language skills, and higher-order cognition across development.
Synapse formation related to sensory functioning is thought to peak
first, followed by language skills, and lastly higher-order cognitive
functions. CREDIT: Syanpse Formation Across Development © National Library
of Medicine is licensed under a CC BY-NC-SA (Attribution NonCommercial
ShareAlike) license
 5.5: STAGES OF NEURONAL DEVELOPMENT | 187

Adult Neurogenesis
Until about 25 years ago, the prevailing view was that new neurons could not be
generated in the human brain after birth. However, a landmark research study
showed that regions of the adult brain, such as the hippocampus, are able to
generate new neurons throughout adulthood (Eriksson et al., 1997). The
generation of new neurons in the adult brain is referred to as adult neurogenesis.
However, adult neurogenesis does not appear to take place in all parts of the
brain. Neurogenesis has been most consistently observed in two regions: 1) the
subventricular zone of the lateral ventricles and; 2) the subgranular zone in the
dentate gyrus of the hippocampus (Ribeiro & Xapelli 2021). Additionally, of the
neurons that are generated during adulthood, many neurons do not survive and as
a result, cannot integrate into existing neural circuits. While multiple studies have
demonstrated evidence of adult neurogenesis, the topic remains fairly controversial
in the field. Some studies suggest that 700 new neurons are generated in the adult
hippocampus every day, while other studies suggest that adult hippocampal
neurogenesis is undetectable or may not exist at all (Sorrel et al., 2018; Spalding
et al., 2013). Nonetheless, given the potential clinical implications of new neurons
throughout adulthood, and their potential for possibly preserving cognitive
function, future research will continue exploring the mechanisms that support
neurogenesis especially in adulthood.
188 | 5.6: SENSITIVE AND CRITICAL PERIODS OF DEVELOPMENT

5.6: SENSITIVE AND CRITICAL

PERIODS OF DEVELOPMENT

Life experiences impact brain development and subsequent behavior. Sensitive and
critical periods are developmental periods that are especially pertinent in shaping
neural and behavioral outcomes. Sensitive periods refer to the developmental
time windows during which experiences have an especially strong impact on brain
organization. Of note, while similar experiences can still affect the brain outside
of these sensitive periods, the consequences for brain reorganization will not be
as strong. Critical periods refer to the limited time windows during which
experiences, or lack thereof, have lasting effects on brain function and behavior
(Knudsen, 2004). Indeed, disruptions during critical periods due to atypical
experiences or adversity may lead to irreversible changes to brain structure. While
sensitive and critical periods both share heightened neuroplasticity, sensitive
periods are a broad time window during which experience may shape neural
circuitry, whereas critical periods are a special class of sensitive periods that result
in potentially irreversible changes in brain function (Knudsen, 2004).

Sensitive Periods of Development

Early childhood is a time that the brain is especially malleable and adaptive to
environmental inputs. Early life experiences have a profound impact on how brain
networks are organized and develop. For example, language acquisition occurs
during early childhood. Research shows a close relationship between the age of
exposure to a language and proficiency in that language—peak proficiency is far
more likely for those who were exposed to that language in early childhood
(Newport et al., 2001). This is especially pertinent for learning a second language.
A seminal study examined second language acquisition in native Chinese or
Korean speakers who moved to the United States and learned English at different
ages (Johnson & Newport, 1989). Results indicated that children who began
 5.6: SENSITIVE AND CRITICAL PERIODS OF DEVELOPMENT | 189
learning the second language (English) before age 7 were able to reach proficiency
akin to native English speakers; children arriving between age 7 and puberty were
less proficient; and after puberty an individual’s second language proficiency is
likely to remain low (Figure 5.13). These findings support a brain maturation
account, such that language-learning ability gradually declines and ultimately
flattens as the brain matures. Importantly, this is not to say that learning a second
language is impossible after brain maturation; but lower neuroplasticity after this
sensitive period contributes to slower second language learning. The fact that
second languages are still able to be learned throughout the lifespan, albeit at
a slower rate, further exemplifies how age-related differences in second language
learning reflect a sensitive, rather than critical, period in development. In summary,
children may be better equipped to learn a second language during this sensitive
period due to the heightened brain malleability.
190 | 5.6: SENSITIVE AND CRITICAL PERIODS OF DEVELOPMENT

Figure 5.13: The relationship between age of learning a second

language and total correct responses on an assessment of grammar
for a second language [Image adapted from: Johnson, J. S., &
Newport, E. L. (1989). Critical period effects in second language
learning: The influence of maturational state on the acquisition of
English as a second language. Cognitive Psychology, 21(1), 60-99.]
CREDIT: Grammar Score vs Age © National Library of Medicine is licensed
under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Critical Periods of Development

Critical periods of development, during which exposure to environmental input
causes irreversible changes to brain function and structure also occur during early
childhood. Critical periods can be exemplified in sensory development and first
language learning. Past experiments with animals have shown that sensory
deprivation during infancy (e.g., an animal is deprived of sight or sound) can have
lasting and irreversible consequences on their brain development (Hubel & Wiesel,
1970). For instance, in research with animals, visual deprivation to one eye during
 5.6: SENSITIVE AND CRITICAL PERIODS OF DEVELOPMENT | 191
a critical period causes lasting vision loss due to decreased cortical neuron spiking
responses to the deprived eye (Gordon & Stryker, 1996). In response to visual
deprivation to one eye during a critical period, the brain reorganizes and prioritizes
visual input from the non-deprived eye.
The brain’s adaptive nature can also be seen in individuals who are born blind
or deaf and as a result may rely on other sensory systems. For example, in humans,
the occipital cortex is typically involved in visual perception. In individuals with
early blindness (who become blind during the first few years of life), the occipital
cortex shifts from processing visual input to processing other sensory-related
information, such as tactile and auditory sensations (Voss, 2013). This adaptive
process is known as cross-modal plasticity. Recent research indicates that cross-
modal plasticity may persist even after sensory functioning (i.e., vision) is restored,
which may suggest that the manner in which the brain reorganizes itself during a
critical period could persist throughout adulthood (Mowad et al., 2020).
Critical periods of development have also been discussed for first language
acquisition. In the early 1970s, the tragic story of Genie, an adolescent girl who
for most of her childhood experienced severe isolation and neglect, caught the
world by storm. Upon encountering Genie, it was determined that she was unable
to verbally communicate through language. A research team began working with
Genie to study her linguistic development and ultimately concluded that, while
Genie showed initial progress in learning speech production and grammatical
structure, her language proficiency remained atypical and severely impaired
(Curtiss, 1974). A more recent study assessed children who did not receive the
required language input during the first year of life, due to either isolation or
hearing difficulties, and found that those children later showed severe language
syntax impairments (Friedmann & Rusou, 2015). In sum, the absence of key
environmental inputs, especially during critical periods in early childhood, may be
particularly detrimental to subsequent brain development.

Adolescence as a sensitive period of

development
Adolescence, the phase of life between childhood and adulthood, which is
192 | 5.6: SENSITIVE AND CRITICAL PERIODS OF DEVELOPMENT
generally considered ages 10-24 years, is marked by significant brain and behavioral
changes. As a result of the ubiquitous social, cognitive, and emotional changes
during adolescence, this stage of development is now widely considered to be a
sensitive period of development.
How does brain development during adolescence shape behavior? Substantial
neuroimaging research has shown that the frontal lobes, which include regions
of the brain involved in executive function, such as the prefrontal cortex, are
late-developing and undergo significant maturation that continues well into
adolescence (Fuster et al., 2002; Casey et al., 1997; Giedd, 2004). Parallel to these
brain development findings, prior work also suggests that adolescence is marked
by increased sensation-seeking and risk-taking behaviors (Spear, 2000).
Neuroscientists have since suggested that the increase in risk-taking during
adolescence may emerge as a result of delayed development of self-regulatory
capabilities, which may arise as the product of an interaction between heightened
sensation-seeking and an immature executive function system that is not yet able
to modulate reward-seeking impulses (Steinberg et al., 2004).
 5.7: CHARACTERIZING BRAIN DEVELOPMENT FROM INFANCY THROUGH

5.7: CHARACTERIZING BRAIN

DEVELOPMENT FROM INFANCY
THROUGH YOUNG ADULTHOOD

Exposure to adversity, especially early in childhood, is known to have long-lasting

consequences on brain development and subsequent behavioral outcomes. For
instance, research has shown that experiencing poverty during early childhood is
associated with lower academic performance, educational attainment, and adult
earnings (Duncan et al., 1998, 2010). Relatedly, children whose families have
higher family income tend to be associated with higher language, memory, social-
emotional processing, and self-regulation skills (Noble et al., 2005, 2007). In terms
of shaping the brain, higher family income has been associated with expanded
surface area in brain regions involved in language and executive functioning (Noble
et al., 2015). Ultimately, while it’s clear that poverty is closely associated with
negative effects on the brain and behavior, much remains unknown about how
these effects on neural development emerge over time. One landmark study, the
Baby’s First Years project, is carrying out the first randomized control trial of
poverty reduction in early childhood and assessing how poverty reduction
influences children’s brain development over time (Noble et al., 2021). As part
of the study, 1,000 diverse low-income mothers in four metropolitan areas in the
United States were randomly assigned to receive either a large ($333) or nominal
($20) monthly cash gift. By measuring infants’ electrical brain activity one year
into the poverty-reduction intervention, the researchers showed that infants whose
mothers were randomized at the time of birth to receive a large monthly cash gift
showed greater electrical brain activity in regions associated with better language,
cognitive, and social-emotional outcomes in later childhood. Ultimately, brain
development during early childhood is responsive to their lived experiences, and
as such, scientists are beginning to further explore how exposure to adversity may
influence brain organization and how this may be associated with behavioral
outcomes.
194 | 5.7: CHARACTERIZING BRAIN DEVELOPMENT FROM INFANCY
Given the extensive array of social, emotional, and cognitive changes that take
place during adolescence, the Adolescent Brain Cognitive Development (ABCD)
study was launched as the largest long-term study of brain development and child
health in the United States. Twenty-one research sites across the country are
following over 11,000 children for ten years, beginning at age nine and continuing
through adolescence into early adulthood and tracking their biological and
behavioral development (Luciana et al., 2018). By conducting assessments on
brain structure and function, neurocognition, physical and mental health, social
and emotional function, and culture and environment, the ABCD study will
provide a comprehensive window into how this sensitive period of development
unfolds in the brain and how that may lead to differences in behavior from
childhood through young adulthood. The rich data from this massive ABCD
study will provide key insights into understanding important topics, such as links
between family environment, children’s behavior problems, and brain structure
(Gong et al., 2021), effects of cannabis use on psychopathology (Paul et al., 2021),
and links between screen time, academic performance, and mental health (Paulich
et al., 2021).
 5.8: CONCLUSION | 195

5.8: CONCLUSION

This chapter aimed to provide an overview of the development of the human

nervous system and the brain, including how it is influenced by genetics,
epigenetics, and evolution. The different stages of nervous system and brain
development are key for understanding how brain functions and behaviors emerge
across the lifespan. Also, recognizing how neural networks emerge, as well as the
extent of their malleability across the lifespan, is important for creating
interventions to preserve cognitive function. Coordinated efforts to characterize
brain development are already underway and will advance our understanding of
how individual differences in brain function and behavior may emerge across the
lifespan.
196 | 5.9: DISCUSSION QUESTIONS AND RESOURCES

5.9: DISCUSSION QUESTIONS

AND RESOURCES

Discussion Questions

1. Describe how environment affects whether genes are expressed

2. Describe how scientists can study the influence of genes
3. Describe neural stages of development from neuron growth to
neuron death.
4. In what ways does the embryonic stage of development set the
stage for the development of adult structures of the nervous
system?
5. Compare and contrast sensitive and critical periods of
development.
6. In what ways does the trade-off between neuroplasticity and
neural efficiency shape brain function and behavior?

Outside Resources

Video: Neural Stem Cells

Video: Joan Stiles Lecture: The Developing Brain

Video: 2 minute walk-through on Early Neural Development

 5.9: DISCUSSION QUESTIONS AND RESOURCES | 197

Web: Build Your Network – An interactive module demonstrating

how neurons transfer information
198 | 5.10: REFERENCES

5.10: REFERENCES

Parts of this chapter were adapted

from:
Betts, J. G., Young, K. A., Wise, J. A., Johnson, E., Poe, B., Kruse, D. H., Korol,
O., Jonhson, J. E., Womble, M., & DeSaix, P. (2022). 13.1 The Embryologic
Perspective. In Anatomy and Physiology 2e. OpenStax. Access for free at
https://openstax.org/books/anatomy-and-physiology-2e/pages/13-1-the-
embryologic-perspective
Clark, M. A., Douglas, M., & Choi, J. (2018). 35.2 How Neurons
Communicate. In Biology 2e. OpenStax. Access for free at https://openstax.org/
books/biology-2e/pages/35-2-how-neurons-communicate
Duboc, B. (2002). The Brain from Top to Bottom (n.d.). Access for free at
https://thebrain.mcgill.ca/
Grose-Fifer, J., Spielman, R.M., Dumper, K., Jenkins, W., Lacombe, A.,
Lovett. M., & Perlmutter, M. (2023). Introduction to Psychology (A critical
approach). https://pressbooks.cuny.edu/jjcpsy101/

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(1994). Immunocytochemical analysis of tumor necrosis factor and its receptors
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 CHAPTER 6. HEARING AND THE VESTIBULAR SYSTEM | 205

CHAPTER 6. HEARING
AND THE VESTIBULAR
SYSTEM
Chapters 6 and 7 review sensation and perception from the perspective of hearing
and the vestibular system (Chapter 6) and vision (Chapter 7).

This chapter is adapted from:

Dommett, E. (2023). Perceiving sound: our sense of hearing. In Hall,

C. (Ed). Introduction to biological psychology. University of Sussex.
https://doi.org/10.20919/ZDGF9829 Creative Commons Attribution-
NonCommercial 4.0 International License.

Illustrations are by Dr. Eliza Wolfson

206 | CHAPTER 6. HEARING AND THE VESTIBULAR SYSTEM
 CHAPTER 6.1: INTRODUCTION TO SENSATION AND PERCEPTION | 207

CHAPTER 6.1: INTRODUCTION

TO SENSATION AND
PERCEPTION
Jill Grose-Fifer, Ph.D.

Sensation
What does it mean to sense something? Our sense organs (like our ears and eyes)
contain sensory receptors, which are specialized neurons that respond to specific
types of information in our physical world. They convert or transduce the external
information into neural energy and then send this to the brain. These biological
processes collectively are known as sensation. For example, light causes chemical
changes in cells that line the back of the eye. These cells relay messages to the
central nervous system. Because information from the world around us stimulates
our senses, we refer to various types of sensory information as stimuli (singular:
stimulus).
You probably know about our five major senses: vision, hearing (audition), smell
(olfaction), taste (gustation), and touch (somatosensation). However, we also have
sensory systems that provide information about balance (vestibular sense), body
position (proprioception), body movement (kinesthesia), pain (nociception), and
temperature (thermoception). In this book, we are focusing on hearing and vision.

Perception
Our sensory receptors are constantly collecting information from the
environment. However, our interactions with the world are affected by how we
interpret that information. Perception refers to the way sensory information is
interpreted and consciously experienced. In some cases our brains may receive a
message, but we are not consciously aware of it. Over the years there has been a
208 | CHAPTER 6.1: INTRODUCTION TO SENSATION AND PERCEPTION
great deal of speculation about the use of subliminal messages in advertising, rock
music, and self-help audio programs. Research shows that in laboratory settings,
people can process and respond to information outside of awareness. But this does
not mean that we obey these messages like zombies; in fact, subliminal messages
have little effect on behavior outside the laboratory (Kunst-Wilson & Zajonc,
1980; Rensink, 2004; Nelson, 2008; Radel et al., 2009; Loersch et al., 2013).
Importantly, our perceptions are also shaped by our previous experiences and so
influences like culture can affect how we interpret the physical world around us.
 PERCEIVING SOUND | 209

CHAPTER 6.2: PERCEIVING

SOUND: OUR SENSE OF
HEARING
Dr Eleanor J. Dommett

I always say deafness is a silent disability: you can’t see it, and it’s not life-
threatening, so it has to touch your life in some way in order for it to be on your
radar.
Rachel Shenton, Actress and Activist

Rachel Shenton, quoted above, is an actress who starred in, created and co-
produced The Silent Child (2017), an award-winning film based on her own
experiences as the child of a parent who became deaf after chemotherapy. The
quote illustrates the challenge of deafness, which in turn demonstrates our reliance
on hearing. As you will see in this section, hearing is critical for safely navigating
the world and communicating with others. Consequently, hearing loss can have a
devastating impact on individuals. To understand the importance of hearing and
how the brain processes sound, we begin with the sound stimulus itself.

Making waves: the sound signal

The stimulus that is detected by our auditory system is a sound wave – a
longitudinal wave produced from fluctuations in air pressure by vibration of
objects. The vibration creates regions where the air particles are closer together
(compressions) and regions where they are further apart (rarefractions) as the wave
moves away from the source (Figure 6.1).
210 | PERCEIVING SOUND

Fig 6.1. Sound waves created by vibration of an object. CREDIT: Wolfson

https://doi.org/10.20919/ZDGF9829

The nature of the sound signal is such that the source of the sound is not in direct
physical contact with our bodies. This is different from the bodily senses described
in the first two sections because in the senses of touch and pain the stimulus
contacts the body directly. Because of this difference touch and pain are referred
to as proximal senses. By contrast, in hearing, the signal originates from a source
not in direct contact with the body and is transmitted through the air. This makes
hearing a distal, rather than proximal, sense.
The characteristics of the sound wave are important for our perception of
sound. Three key characteristics are shown in Figure 6.2: frequency, amplitude and
phase.
 PERCEIVING SOUND | 211

Fig 6.2 Key characteristics of sound are a) frequency, b) amplitude and c)

phrase. CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

The frequency is the time it takes for one full cycle of the wave to repeat, and
is measured in Hertz (Hz). One Hertz is simply one cycle per second. Humans
can hear sounds with a frequency of 20 – 20000Hz (20 KHz). Examples of low
frequency sounds, which are generally considered to be under 500 Hz, include
the sounds of waves and elephants! In contrast, higher frequency sounds include
the sound of whistling and nails on a chalk board. Amplitude is the amount of
fluctuation in air pressure that is produced by the wave. The amplitude of a wave
is measured in pascals (Pa), the unit of pressure. However, in most cases when
considering the auditory system, this is converted into intensity and intensities are
discussed in relative terms using the unit of the decibel (dB). Using this unit the
range of intensities humans can typically hear are 0-140 dB. Above this level can
be very harmful to our auditory system. Although you may see sound intensity
expressed in dB, another expression is also commonly used. Where the intensity
of sound is expressed with reference to a standard intensity (the lowest intensity
212 | PERCEIVING SOUND
a young person can hear a sound of 1000 Hz), it is written as dB SPL. The
SPL stands for sound pressure level. Normal conversation is typically at a level of
around 60 dB SPL.
Unlike frequency and amplitude, phase is a relative characteristic because it
describes the relationship between different waves. They can be said to be in phase,
meaning they have peaks at the same time or out of phase, meaning that they are at
different stages in their cycle at anyone point in time.
The three characteristics above and the diagrams shown indicate a certain
simplicity about sound signals. However, the waves shown here are pure waves, the
sort you might expect from a tuning fork that emits a sound at a single frequency.
These are quite different to the sound waves produced by more natural sources,
which will often contain multiple different frequencies all combined together
giving a less smooth appearance (Figure 6.3).

Fig 6.3. Examples of sound waves produced by the clarinet and clarinet.
CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

In addition, it is rare that only a single sound is present in our environment, and
sound sources also move around! This can make sound detection and perception
a very complex process and to understand how this happens we have to start with
the ear.
 PERCEIVING SOUND | 213
Sound detection: the structure of the ear
The human ear is often the focus of ridicule but it is a highly specialised structure.
The ear can be divided into three different parts which perform distinct functions:

• The outer ear which is responsible for gathering sound and funnelling it
inwards, but also has some protective features
• The middle ear which helps prepare the signal for receipt in the inner ear and
serves a protective function
• The inner ear which contains the sensory receptor cells for hearing, called
hair cells. It is in the inner ear that transduction takes place.

Figure 6.4 shows the structure of the ear divided into these three sections.

Fig 6.4. The human ear can be divided into the outer, middle and inner
ear, each of which has a distinct function in our auditory system. CREDIT:
Wolfson https://doi.org/10.20919/ZDGF9829

Although transduction happens in the inner ear, the outer and middle ear have
key functions and so it is important that we briefly consider these.
The outer ear consists of the pinna (or auricle), which is the visible part that
214 | PERCEIVING SOUND
sticks out of the side of our heads. In most species the pinna can move but in
humans they are static. The key function of the outer ear is in funnelling sound
inwards, but the ridges of the pinna (the lumps and bumps you can feel in the ear)
also play a role in helping us localise sound sources. Additional to this and often
overlooked is the protective function of the outer ear. Ear wax found in the outer
ear provides a water-resistant coating which is antibacterial and antifungal, creating
an acidic environment hostile to pathogens. There are also tiny hairs in the outer
ear, preventing entry of small particles or insects.
The middle ear sits behind the tympanic membrane (or ear drum) which divides
the outer and middle ear. The middle ear is an air-filled chamber containing three
tiny bones, called the ossicles. These bones are connected in such away that they
create a lever between the tympanic membrane and the cochlea of the inner ear,
which is necessary because the the cochlear is fluid-filled.

Spend a moment thinking about the last time you went swimming or
even put your head under the water in a bath. What happens to the
sounds you could hear beforehand?

The sounds get much quieter, and will likely be muffled, if at all audible,
when your ear is filled with water.

Hopefully you will have noted that when your ear contains water from a pool
or the bath, sound becomes very hard to hear. This is because the particles in the
water are harder to displace than particles in air, which results in most of the sound
being reflected back off the surface of the water. In fact only around 0.01% of
sound is transmitted into water from the air, which explains why it is hard to hear
underwater.
Because the inner ear is fluid-filled, this gives rise to a similar issue as hearing
under water because the sound wave must move from the air-filled middle ear
 PERCEIVING SOUND | 215
to the fluid-filler inner ear. To achieve this without loss of signal, the signal is
amplified in the middle ear, by the lever actions of the ossicles, along with changes
in the area of the bones contacting the tympanic membrane and cochlea, both of
which result in a 20-fold increase in pressure changes as the sound wave enters the
cochlea.
As with the outer ear, the middle ear also has a protective function in the form of
the middle ear reflex. This reflex is triggered by sounds over 70 dB SPL and involves
muscles in the middle ear locking the position of the ossicles.

What would happen if the ossicles could not move?

The signal could not be transmitted from the outer ear to the inner ear.

Fig 6.5a. Diagrammatic representation of the three scalae of the cochlea

(uncoiled). CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

We now turn our attention to the inner ear and, specifically, the cochlea, which
is the structure important for hearing (other parts of the inner ear form part of
216 | PERCEIVING SOUND
the vestibular system which is important for balance). The cochlea consists of a
tiny tube, curled up like a snail. A small window into the cochlea, called the oval
window (Figure 6.5a), is the point at which the sound wave enters the inner ear, via
the actions of the ossicles.
The tube of the cochlea is separated into three different chambers by
membranes. The key chamber to consider here is the scala media which sits
between the basilar membrane and Reissner’s membrane, and contains the
organ of corti (Figures 6.5 b, c).

Fig 6.5b. The cross-sectional structure of the cochlea, CREDIT: Wolfson

https://doi.org/10.20919/ZDGF9829
 PERCEIVING SOUND | 217

Fig 4.65c. The cross-sectional structure of the organ of Corti. CREDIT:

Wolfson https://doi.org/10.20919/ZDGF9829

The cells critical for transduction of sound are the inner hair cells which can be
seen in Figure 6.5c.
These cells are referred to as hair cells because they contain hair-like stereocillia
protruding from one end. The end from which the stereocillia protrude is referred
to as the apical end. They project into a fluid called endolymph, whilst the other
end of the cell, the basal end, sits in perilymph. The endolymph contains a very
high concentration of potassium ions.

How does this differ from typical extracellular space?

Normally potassium is at a low concentration outside the cell and a

higher concentration inside, so this is the opposite to what is normally
found.
218 | PERCEIVING SOUND

When a sound wave is transmitted to the cochlea, it causes the movement of

fluid in the chambers which in turn moves the basilar membrane upon which
the inner hair cells sit. This movement causes their stereocilia to bend. When
they bend, mechano-sensitive ion channels in the tips open and potassium floods
into the hair cell causing depolarization (Figure 6.6). This is the auditory receptor
potential.

Spend a moment looking at Figure 6.6. What typical neuronal features

can you see? How are these cells different from neurons?

There are calcium gated channels and synaptic vesicles but there is no
axon.
 PERCEIVING SOUND | 219

Fig 6.6. The inner hair cell responsible for transduction of sound
waves. CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

You should have noted that the inner hair cells only have some of the typical
structural components of neurons. This is because, unlike the sensory receptor
cells for the somatosensory system, these are not modified neurons and they cannot
produce action potentials. Instead, when sound is detected, the receptor potential
220 | PERCEIVING SOUND
results in the release of glutamate from the basal end of the hair cell where it
synapses with neurons that form the cochlear nerve to the brain. If sufficient
glutamate binds to the AMPA receptors on these neurons, an action potential will
be produced and the sound signal will travel to the brain.

Auditory pathways: what goes up must

come down
The cochlear nerve leaves the cochlea and enters the brain at the level of the
brainstem, synapsing with neurons in the cochlear nuclear complex before
travelling via the trapezoid body to the superior olive, also located in the brainstem.
This is the first structure in the pathway to receive information from both ears.
Prior to this in the cochlear nuclear complex, information is only received from
the ipsilateral ear. After leaving the superior olive, the auditory pathway continues
in the lateral leminiscus to the inferior colliculus in the midbrain before travelling
to the medial geniculate nucleus of the thalamus. From the thalamus, as with the
other senses you have learnt about, the signal is sent onto the cortex. In this case,
the primary auditory cortex in the temporal lobe. This complex ascending pathway
is illustrated in Figure 6.7.
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Fig 6.7. The ascending pathway from the cochlea to the cortex. CREDIT:
Wolfson https://doi.org/10.20919/ZDGF9829

You will learn about the types of processing that occurs at different stages of this
pathway shortly but it is also important to recognise that the primary auditory
cortex is not the end of the road for sound processing.

Where did touch and pain information go after the primary

somatosensory cortex?

In both cases, information was sent onto other cortical regions,

including secondary sensory areas and areas of the frontal cortex.
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As with touch and pain information, auditory information from the primary
sensory cortex, in this case the primary auditory cortex, is carried to other cortical
areas for further processing. Information from the primary auditory cortex divides
into two separate pathways or streams: the ventral ‘what’ pathway and the dorsal
‘where’ pathway.
The ventral pathway travels down and forward and includes the superior
temporal region and the ventrolateral prefrontal cortex. It is considered critical
for auditory object recognition, hence the ‘what’ name (Bizley & Cohen, 2013).
There is not yet a clear consensus on the exact role in recognition that the different
structures in the pathway play, but it is known that activity in this pathway may be
modulated by emotion (Kryklywy, Macpherson, Greening, & Mitchell, 2013).
In contrast to the ventral pathway the dorsal pathway travels up and forward,
going into the posterodorsal cortex in the parietal lobe and forwards into the dorsal
lateral prefrontal cortex (Figure 6.8). This pathway is critical for identifying the
location of sound, as suggested by the ‘where’ name. As with the ventral pathway,
the exact role of individual structure is not clear but it too can be modulated by
other functions. Researchers have found that whilst it is not impacted by emotion
(Kryklywy et al., 2013) it is, perhaps unsurprisingly, modulated by spatial attention
(Tata & Ward, 2005).
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Fig 6.8. The dorsal and ventral streams of auditory information. CREDIT:
Wolfson https://doi.org/10.20919/ZDGF9829

Recall that when discussing pain pathways you learnt about a pathway which
extends from higher regions of the brain to lower regions – a descending pathway.
This type of pathway also exists in hearing. The auditory cortex sends projections
down to the medial geniculate nucleus, inferior colliculus, superior olive and
cochlear nuclear complex, meaning every structure in the ascending pathway
receives descending input. Additionally, there are connections from the superior
olive directly onto the inner and outer hair cells. These descending connections
have been linked to several different functions including protection from loud
noises, learning about relevant auditory stimuli, altering responses in accordance
with the sleep/wake cycle and the effects of attention (Terreros & Delano, 2015).
224 | PERCEIVING SOUND
Perceiving sound: from the wave to
meaning
In order to create an accurate perception of sound information we need to extract
key information from the sound signal. In the section on the sound signal we
identified three key features of sound: frequency, intensity and phase. In this
section we will consider these as you learn about how key features of sound are
perceived, beginning with frequency.
The frequency of a sound is thought to be coded by the auditory system in two
different ways, both of which begin in the cochlea. The first method of coding
is termed a place code because this coding method relies on stimuli of different
frequencies being detected in different places within the cochlea. Therefore, if the
brain can tell where in the cochlea the sound was detected, the frequency can be
deduced. Figure 6.9 shows how different frequencies can be mapped within the
cochlea according to this method. At the basal end of the cochlea sounds with a
higher frequency are represented whilst at the apical end, low frequency sounds are
detected. The difference in location arises because the different sound frequencies
cause different displacement of the basilar membrane. Consequently, the peak of
the displacement along the length of the membrane differs according to frequency,
and only hair cells at this location will produce a receptor potential. Each hair cell
is said to have a characteristic frequency to which it will respond.
 PERCEIVING SOUND | 225

Fig 6.9 (a). A schematic diagram of how different frequencies are

located along the length of the cochlea. (b) Distinct displacement
patterns for signals of different frequencies. CREDIT: Wolfson
https://doi.org/10.20919/ZDGF9829
226 | PERCEIVING SOUND

Fig 6.10. Temporal code assumes a direct relationship

between stimulus intensity and firing of action
potentials in the cochlear nerve. The neural response
phase, locked to every cycle of the sound wave, is
shown in the upper trace (A) and the frequency of the
stimulus sound waveform (in ms) in the lower trace (B).
CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

Although there is some support for a place code of frequency information, there
 PERCEIVING SOUND | 227
is also evidence from studies in humans that we might be able to detect smaller
changes in sound frequency that would be possible from place coding alone.
This led researchers to consider other possible explanations and to the proposal
of a temporal code. This proposal is based on research which shows a relationship
between the frequency of the incoming sound wave and the firing of action
potentials in the cochlear nerve (Wever & Bray, 1930), which is illustrated in Figure
6.10. Thus when an action potential occurs, it provides information about the
frequency of the sound.

Recall that we can hear sounds of up to 20,000 Hz or 20 KHz. How does

this compare to the firing rate of neurons?

This is much higher than the firing rate of neurons. Typical neurons are
thought to be able to fire at up to 1000 Hz.

Given the constraints of firing rate, it is not possible for temporal code to account
for the range of frequencies that we can perceive. Wever and Bray (1930) proposed
that groups of neurons could work together to account for higher frequencies, as
illustrated in Figure 6.11.
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Fig 6.11. Wever and Bray suggested the volley principle where neurons
work together to create an output which mimics the stimulus
frequency. CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

The two coding mechanisms are not mutually exclusive and researchers now
believe that temporal code may operate at very low frequencies (< 50 Hz) and
place code may operate at higher frequencies (> 3000 Hz) with all intermediate
frequencies being coded for my both mechanisms. Irrespective of which coding
method is used for frequency in the cochlea, once encoded, this information is
preserved throughout the auditory pathway.
Sound frequency can be considered an objective characteristic of the wave but
the perceptual quality it most closely relates to is pitch. This means that typically
sounds of high frequency are perceived as having a high pitch.
The second key characteristic of sound to consider is intensity. As with
frequency, intensity information is believed to be coded initially in the cochlea
and then transmitted up the ascending pathway. Also in line with the coding
of frequency, there are two suggested mechanisms for coding intensity. The first
method suggests that intensity can be encoded according to firing rate in the
 PERCEIVING SOUND | 229
auditory nerve. To understand this it is important to remember the relationship
between stimulus and receptor potential which was first described in the section
on touch. You should recall that the larger the stimulus, the bigger the receptor
potential. In the case of sound, the more intense the stimulus, the larger the
receptor potential will be, because the ion channels will be held open longer with
a larger amplitude sound wave. This means that more potassium can flood into
the hair cell causing greater depolarisation and subsequently greater release of
glutamate. The more glutamate that is released, the greater the amount that is likely
to bind to the post-synaptic neuron forming the auditory nerve. Given action
potentials are all-or-none, the action potentials stay the same size but the frequency
of them is increased.
The second method of encoding intensity is thought to be the number of
neurons firing. Recall from Figure 6.5b that sound waves will result in a specific
position of maximal displacement of the basilar membrane, and so typically only
activate hair cells with the corresponding frequency which in turn signal to specific
neurons in the cochlear nerve. However, it is suggested that as a sound signal
becomes more intense there will be sufficient displacement to activate hair cells
either side of the characteristic frequency, albeit to a lesser extent, and therefore
more neurons within the cochlear nerve may produce action potentials.
You may have noticed that the methods for coding frequency and intensity here
overlap.

Considering the mechanisms described, how would you know whether

an increased firing rate in the cochlear nerve is caused by a higher
frequency or a greater intensity of a sound?

The short answer is that the signal will be ambiguous and you may not
know straight away.
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The overlapping coding mechanism can make it difficult to achieve accurate
perception; indeed we know that perception of loudness, the perceptual experience
that most closely correlates with sound intensity, is impacted significantly by the
frequency of sound. It is likely that the combination of multiple coding
mechanisms supports our perception because of this. Furthermore, small head
movements can be made which can impact on intensity of sound and therefore
inform our perception of both frequency and intensity when the signal is
ambiguous.
This leads us nicely onto the coding of sound location, which requires
information from both ears to be considered together. For that reason sound
localisation coding cannot take place in the cochlea and so happens in the
ascending auditory pathway.

Which is the first structure in the pathway to receive auditory signals

from both ears?

It is the superior olive in the brainstem.

The superior olive can be divided into the medial and lateral superior olive
and each is thought to use a distinct mechanism for coding location of sound.
Neurons within the medial superior olive receive excitatory inputs from both
cochlear nuclear complexes (i.e., the one of the right and left), which allows them
to act as coincidence detectors. To explain this a little more it is helpful to think
about possible positions of sound sources relative to your head. Figure 6.12 shows
the two horizontal planes of sound: left to right and back to front.
 PERCEIVING SOUND | 231

Fig 6.12. Examples of sound sources relative to the head. CREDIT: Wolfson
https://doi.org/10.20919/ZDGF9829

We will ignore stimuli falling exactly behind or exactly in front for a moment
and focus on those to the left or right. Sound waves travel at a speed of 348 m/s
-1
(which you may also see written as ms ) and a sound travelling from one side of the
body will reach the ear on that side ahead of the other side. The average distance
between the ears is 20cm so this means that sound waves coming directly from,
for example, the right side, will hit the right ear 0.6 ms before they reach the left
ear and vice versa if sound was coming from the left. Shorter delays between the
sounds arriving at the left and right ear are experienced for sounds coming from less
extreme right or left positions. This time delay means that neurons in the cochlear
nerve closest to the sound source will fire first. This head start is maintained in the
cochlear nuclear complex. Neurons in the medial superior olive are thought to be
arranged such that they can detect specific time delays and thus code the origin of
the sound. Figure 6.13 illustrates how this is possible. If a sound is coming from the
left side, the signal from the left cochlear nuclear complex will reach the superior
232 | PERCEIVING SOUND
olive first and likely get all the way along to neuron C before the signal from the
right cochlear nuclear complex combines with it, maximally exciting the neuron.

Fig 6.13. Delay lines and coincident detectors in the medial superior
olive. Each of the three neurons shown (A, B, C) will fire most strongly
when a signal from both ears reaches it at the same time. This will
happen for neuron C when the sound wave is coming from the left, as
the signal from the left cochlear nucleus has time to travel further (past
neurons A and B) before the signal from the right cochlear nucleus
arrives. CREDIT: Wolfson https://doi.org/10.20919/ZDGF9829

Using Figure 6.13, what would happen if the sound was from exactly in
front or behind?
 PERCEIVING SOUND | 233

The input from the two cochlear nuclear complexes would likely
combine on neuron B. Neuron B is therefore, in effect, a coincidence
detector for no time delay between signals coming from the two ears.
The brain can therefore deduce that the sound location is not to the left
or the right – but it can’t tell from these signals if the sound is in front of
or behind the person.

This method, termed interaural (between the ears) time delay, is thought to be
effective for lower frequencies, but for higher frequencies another method can
be used by the lateral superior olive. Neurons in this area are thought to receive
excitatory inputs from the ipsilateral cochlear nuclear complex and inhibitory
inputs from the contralateral complex. These neurons detect the interaural
intensity difference, that is the reduction in intensity caused by the sound travelling
across the head. Importantly the drop of intensity as sound moves around the
head is greater for higher frequency sounds. The detection of interaural time and
intensity differences are therefore complementary, favouring low and high
frequency sounds, respectively.
The two mechanisms outlined for perceiving location here are bottom-up
methods. They rely completely on the data we receive, but there are additional cues
to localisation. For example, high frequency components of a sound diminish more
than low frequency components when something is further away, so the relative
amount of low and high frequencies can tell us something about the sound’s
location.

What would we need to know to make use of this cue?

We would need to know what properties (the intensity of different

234 | PERCEIVING SOUND

frequencies) to expect in the sound to work out if they are altered due
to distance. Use of this cue therefore requires us to have some prior
experience of the sound.

By combining all the information about frequency, intensity and localisation we

are able to create a percept of the auditory world. However, before we move on it
is important to note that whilst much of the auditory coding appears to take place
in lower areas of the auditory system, this information is preserved and processed
throughout the cortex. More importantly, it is also combined with top-down input
and several structures will co-operate to create a perception of complex stimuli
such as music, including areas of the brain involved in memory and emotion
(Warren, 2008).

Hearing loss: causes, impact and treatment

As indicated in the opening quote to this section, hearing loss can be a difficult and
debilitating experience. There are several different types of hearing loss and each
comes with a different prognosis. To begin with it is helpful to categorise types of
hearing loss according to the location of the impairment:

• Conductive hearing loss occurs when the impairment is within the outer or
middle ear, that is, the conduction of sound to the cochlea is interrupted.
• Cochlear hearing loss occurs when there is damage to the cochlea itself.
• Retrocochlear hearing loss occurs when the damage is to the cochlear nerve
of areas of the brain which process sound. The latter two categories are often
considered collectively under the classification of sensorineural hearing loss.

The effects of hearing loss are typically considered in terms of hearing threshold
and hearing discrimination. Threshold refers to the quietest sound that someone
is able to hear in a controlled environment, whilst discrimination refers to their
 PERCEIVING SOUND | 235
ability to concentrate on a sound in a noisy environment. This means that we can
also categorise hearing loss by the extent of the impairment as indicated in Table
6.1.

Hearing Loss Classification Hearing level (dB HL) Impairment

Mild 20-39 Following speech is difficult esp. in noisy env

Moderate 40-69 Difficulty following speech without hearing

Severe 70-89 Usually need to lip read or use sign language

Profound 90-120 Usually need to lip read or use sign language

Table 6.1. Different classes of hearing loss

You should have spotted that the unit given in Table 6.1 is not the typical dB or
dB SPL. This is a specific type of unit, dB HL or hearing level, used for hearing loss
(see Box: Measuring hearing loss, below).

Measuring hearing loss

If someone is suspected of having hearing loss they will typically

undergo tests at a hearing clinic to establish the presence and extent of
hearing loss. This can be done with an instrument called an audiometer,
which produces sounds at different frequencies that are played to the
person through through headphones (Figure 6.14).
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Fig 6.14. A hearing test being conducted with an audiometer. CREDIT: Wolfson
https://doi.org/10.20919/ZDGF9829

The threshold set for the tests is that of a healthy young listener and
this is considered to be 0 dB. If someone has a hearing impairment they
are unlikely to be able to hear the sound at this threshold and the
intensity will have to be increased for them to hear it, which they can
indicate by pressing a button. The amount by which is it increased is the
dB HL level. For example, if someone must have the sound raised by 45
dB in order to detect the sound they will have moderate hearing loss
because the value of 45 dB HL falls into that category (Table 6.1).

Conductive hearing loss typically impacts only on hearing threshold such that the
threshold becomes higher, i.e., the quietest sound that someone can hear is louder
than the sound someone without hearing loss can hear. Although conductive
hearing loss can be caused by changes within any structure of the outer and middle
 PERCEIVING SOUND | 237
ear, the most common occurrence is due to a build up of fluid in the middle
ear, giving rise to a condition called otitis media with effusion, or glue ear. This
condition is one of the most common illnesses found in children and the most
common cause of hearing loss within this age group (Hall, Maw, Midgley, Golding,
& Steer, 2014).

Why would fluid in the middle ear be problematic?

This is normally an air filled structure, and the presence of fluid would
result in much of the sound being reflected back from the middle ear
and so the signal will not reach the inner ear for transduction.

Glue ear typically arises in just one ear, but can occur in both. It generally only
causes mild hearing loss. It is thought to be more common in children than adults
because the fluid build-up arises due to the eustachian tube not draining properly.
This tube connects the ear to the throat and normally drains the moisture from the
air in the middle ear. In young children its function can be impacted adversely by
the growth of adenoid tissue, which blocks the throat end of the tube meaning it
cannot drain and fluid gradually builds up. However, several risk factors for glue
ear have been identified.
These include iron deficiency (Akcan et al., 2019), allergies, specifically to dust
mites (Norhafizah, Salina, & Goh, 2020), and exposure to second hand smoke as
well as shorter duration of breast feeding (Kırıs et al., 2012; Owen et al., 1993).
Social risk factors have also been identified including living in a larger family
(Norhafizah et al., 2020), being part of a lower socioeconomic group (Kırıs et al.,
2012) and longer hours spent in group childcare (Owen et al., 1993).
The risk factors of glue ear are possibly less important than the potential
consequences of the condition. It can result in pain and disturbed sleep which
can in turn create behavioural problems, but the largest area of concern is on
educational outcomes, due to delays in language development and social isolation
238 | PERCEIVING SOUND
as children struggle to interact with their peers. Studies have demonstrated poorer
educational outcomes for children who experience chronic glue ear (Hall et al.,
2014; Hill, Hall, Williams, & Emond, 2019) but it is likely that they can catch up
over time, meaning any long lasting impact is minimal.
Despite the potential for disruption to educational outcomes, the first line of
treatment for glue ear is simply to watch and wait and treat any concurrent
infections. If the condition does not improve in a few months, grommets may be
used. These are tiny plastic inserts put into the tympanic membrane to allow the
fluid to drain. This minor surgery is not without risk because it can cause scarring
of the membrane which may impact on its elasticity.
Whilst glue ear is the most common form of conductive hearing loss, the most
common form of sensorineural hearing loss is Noise Induced Hearing Loss
(NIHL). This type of hearing loss is caused by exposure to high intensity noises,
from a range of contexts (e.g., industrial, military and recreational) and normally
comes on over a period of time so gets greater with age, as hair cells are damaged
or die. It is thought to affect around 5% of the population and typically results
in bilateral hearing loss that affects both the hearing threshold and discrimination.
Severity can vary and its impact is frequency dependent with the biggest loss of
sensitivity at higher frequencies (~4000 Hz) that coincide with many of the every
day sounds we hear, including speech.
At present there is no treatment for NIHL and instead it is recommended that
preventative measures should be taken, for example through the use of personal
protective equipment (PPE).

What challenges can you see to this approach [using PPE]?

This assumes that PPE is readily available, which it may not be. For
example, in the case of military noises, civilians in war zones are unlikely
to be able to access PPE. It also assumes that PPE can be worn without
impact. A musician is likely to need to hear the sounds being produced
 PERCEIVING SOUND | 239

and so although use of some form of PPE may be possible, doing so

may not be practical.

The impact of NIHL on an individual is substantial. For example research has

demonstrated that the extent of hearing loss in adults is correlated with measures
of social isolation, distress and even suicide ideation (Akram, Nawaz, Rafi, &
Akram, 2018). Other studies indicate NIHL can result in frustration, anxiety,
stress, resentment, depression, and fatigue (Canton & Williams, 2012). There are
also reported effects on employment with negative effects on employment
opportunities and productivity (Canton & Williams, 2012; Neitzel, Swinburn,
Hammer, & Eisenberg, 2017). Additionally, given NIHL will typically occur in
older people, it may be harder to diagnose because they mistake it for a natural
decline in hearing that occurs as people get older, meaning they may not recognise
the need for preventive action if it is possible, or the need to seek help.

Summarizing hearing

Key Takeaways

• Our sense of hearing relies on the detection of a longitudinal

wave created by vibration of objects in air. These waves typically
vary in frequency, amplitude and phase
• The three-part structure of the ear allows us to funnel sounds
inwards and amplify the signal before it reaches the fluid-filled
cochlea of the inner ear where transduction takes place
• Transduction occurs in specialized hair cells which contain
240 | PERCEIVING SOUND

mechano-sensitive channels that open in response to vibration

caused by sound waves. This results in an influx of potassium
producing a receptor potential
• Unlike the somatosensory system, the hair cell is not a modified
neuron and therefore cannot itself produce an action potential.
Instead, an action potential is produced in neurons of the cochlear
nerve, when the hair cell releases glutamate which binds to
AMPA receptors on these neurons. From here the signal can
travel to the brain
• The ascending auditory pathway is complex, traveling through
two brainstem nuclei (cochlear nuclear complex and superior
olive) before ascending to the midbrain inferior colliculus, the
medial geniculate nucleus of the thalamus and then the primary
auditory cortex. From here it travels in dorsal and ventral
pathways to the prefrontal cortex, to determine where and what
the sound is, respectively
• There are also descending pathways from the primary auditory
cortex which can influence all structures in the ascending
pathway
• Key features are extracted from the sound wave beginning in the
cochlea. There are two proposed coding mechanisms for
frequency extraction: place coding and temporal coding. Place
coding uses position-specific transduction in the cochlea whilst
temporal coding locks transduction and subsequent cochlea nerve
firing to the frequency of the incoming sound wave. Once coded
in the cochlea this information is retained throughout the
auditory pathway
• Intensity coding is thought to occur either through the firing rate
of the cochlea nerve or the number of neurons firing.
• Location coding requires input from both ears and therefore first
occurs outside the cochlea at the level of the superior olive. Two
mechanisms are proposed: interaural time delays and interaural
intensity differences
 PERCEIVING SOUND | 241

• Hearing loss can be categorized according to where in the

auditory system the impairment occurs. Conductive hearing loss
arises when damage occurs to the outer or middle ear and
sensorineural hearing loss arises when damage is in the cochlea
or beyond
• Different types of hearing loss impact hearing threshold and
hearing discrimination differently. The extent of hearing loss can
vary as can the availability of treatments
• Hearing loss is associated with a range of risk factors and can
have a significant impact on the individual including their social
contact with others, occupational status and, in children,
academic development.

References
Akcan, F. A., Dündar, Y., Bayram Akcan, H., Cebeci, D., Sungur, M. A., & Ünlü,
İ. (2019). The association between iron deficiency and otitis media with effusion.
The Journal of International Advanced Otology, 15(1), 18-21. https://doi.org/
10.5152/iao.2018.5394
Akram, B., Nawaz, J., Rafi, Z., & Akram, A. (2018). Social exclusion, mental
health and suicidal ideation among adults with hearing loss: Protective and
risk factors. Journal of the Medical Association Pakistan, 68(3), 388-393.
https://jpma.org.pk/article-details/8601?article_id=8601
Bizley, J. K., & Cohen, Y. E. (2013). The what, where and how of auditory-object
perception. Nature Reviews Neuroscience, 14(10), 693-707. https://dx.doi.org/
10.1038/nrn3565
Canton, K., & Williams, W. (2012). The consequences of noise-induced hearing
loss on dairy farm communities in New Zealand. J Agromedicine, 17(4),
354-363. https://dx.doi.org/10.1080/1059924x.2012.713840
Hall, A. J., Maw, R., Midgley, E., Golding, J., & Steer, C. (2014). Glue ear, hearing
242 | PERCEIVING SOUND
loss and IQ: an association moderated by the child’s home environment. PloS
One, 9(2), e87021. https://doi.org/10.1371/journal.pone.0087021
Hill, M., Hall, A., Williams, C., & Emond, A. M. (2019). Impact of co-occurring
hearing and visual difficulties in childhood on educational outcomes: a
longitudinal cohort study. BMJ Paediatrics Open, 3(1), e000389.
http://dx.doi.org/10.1136/bmjpo-2018-000389
Kırıs, M., Muderris, T., Kara, T., Bercin, S., Cankaya, H., & Sevil, E. (2012).
Prevalence and risk factors of otitis media with effusion in school children
in Eastern Anatolia. Int J Pediatr Otorhinolaryngol, 76(7), 1030-1035.
https://dx.doi.org/10.1016/j.ijporl.2012.03.027
Kryklywy, J. H., Macpherson, E. A., Greening, S. G., & Mitchell, D. G. (2013).
Emotion modulates activity in the ‘what’ but not ‘where’ auditory processing
pathway. Neuroimage, 82, 295-305. https://dx.doi.org/10.1016/
j.neuroimage.2013.05.051
Neitzel, R. L., Swinburn, T. K., Hammer, M. S., & Eisenberg, D. (2017).
Economic Impact of Hearing Loss and Reduction of Noise-Induced Hearing
Loss in the United States. Journal of Speech, Language, and Hearing Research,
60(1), 182-189. https://dx.doi.org/10.1044/2016_jslhr-h-15-0365
Norhafizah, S., Salina, H., & Goh, B. S. (2020). Prevalence of allergic rhinitis
in children with otitis media with effusion. European Annals of Allergy and
Clinical Immunology, 52(3), 121-130. https://dx.doi.org/10.23822/
EurAnnACI.1764-1489.119
Owen, M. J., Baldwin, C. D., Swank, P. R., Pannu, A. K., Johnson, D. L., &
Howie, V. M. (1993). Relation of infant feeding practices, cigarette smoke
exposure, and group child care to the onset and duration of otitis media with
effusion in the first two years of life. The Journal of Pediatrics, 123(5), 702-711.
https://dx.doi.org/10.1016/s0022-3476(05)80843-1
Tata, M. S., & Ward, L. M. (2005). Spatial attention modulates activity in a
posterior “where” auditory pathway. Neuropsychologia, 43(4), 509-516.
https://dx.doi.org/10.1016/j.neuropsychologia.2004.07.019
Terreros, G., & Delano, P. H. (2015). Corticofugal modulation of peripheral
auditory responses. Frontiers in Systems Neuroscience, 9, 134. https://dx.doi.org/
10.3389/fnsys.2015.00134
Warren, J. (2008). How does the brain process music? Clinical Medicine, 8(1),
32-36. https://doi.org/10.7861/clinmedicine.8-1-32
 PERCEIVING SOUND | 243
Wever, E. G., & Bray, C. W. (1930). The nature of acoustic response: The relation
between sound frequency and frequency of impulses in the auditory nerve.
Journal of Experimental Psychology, 13(5), 373. https://doi.org/10.1037/
h0075820
244 | CHAPTER 6.3: VESTIBULAR SYSTEM

CHAPTER 6.3: VESTIBULAR

SYSTEM
Austin Lim, Ph.D.

Material in this module comes from: Lim, A. (2021). Open

Neuroscience Initiative https://www.austinlim.com/open-
neuroscience-initiative.

When we tilt our head to the side, or look up and down, that movement
information is conveyed to our brain using the vestibular system. The vestibular
system is a sort of three- dimensional compass that can detect head movement,
and that information helps us figure out how our head is oriented and how to
balance ourselves in changing conditions. The vestibular system is made up of two
structures that are intimately tied in with the anatomical features of the inner ear.

The Otolith Organs

Next to the cochlea and within the vestibular labyrinth are two membranous
sacs, the saccule and the utricle. Collectively, these structures are responsible
for determining changes in inertia. The saccule is more sensitive to vertical
movements, like when you are standing in a moving elevator. The utricle is more
responsive to horizontal movements, such as when driving around a corner too
quickly.
 CHAPTER 6.3: VESTIBULAR SYSTEM | 245

Figure 6.13 Anatomy of the vestibular system.

Within the saccule and utricle are otoliths, are a series of small calcium
carbonate crystals (the prefix oto– meaning “ear”, and the suffix-lith meaning
“rock”) embedded in a 50 uM thick gelatinous membrane. Also embedded within
this membrane are the stereocilia of a different population of hair cells. These
otolith hair cells are biologically similar to the hair cells found in the cochlea:
deflection of the stereocilia allows for K+ in the surrounding endolymph to enter
the cells through mechanically-gated ion channels. The main difference is the
nature of the stimulus that cause the sterocilia to bend. In the cochlea, vibrations
in the surrounding tissue cause hair cell movement. In the saccule and utricle,
however, it is a shifting of the physical weight of the otoconia that result in hair cell
movement.
The information encoded by the hair cells is passed into the brain via a branch of
the vestibulocochlear nerve (CN VIII). These axons send projections to several
brain areas, notably the cerebellum, which is a structure critically important for
balance. CN VIII also projects into the reticular formation of the brain stem, the
spinal cord, and the thalamus.

The Semicircular Canals

The semicircular canals are the structures that are responsible for detecting head
rotation. Anatomically, they are a series of three arch-shaped membranous tubes
246 | CHAPTER 6.3: VESTIBULAR SYSTEM
within the vestibular labyrinth, each one oriented at a right angle to each other.
Because of this shape, the semicircular canals sense and convey information about
any direction of head movement: roll, pitch, and yaw.
These semicircular canals are filled with endolymph, the same potassium-rich
solution that is in the cochlea that is important for auditory sensation. At the end
of each of the three canals is a small swelling called the ampulla. Contained in
the ampulla is a gelatinous membrane called the cupula. Here, hair cells extend
stereocilia, as well as one cellular protrusion called a kinocilium, into the cupula.
When we tilt our head, the endolymph in the semicircular canals flows in the
ampulla, which physically displaces the cilia. As in the auditory system, these hair
cells have mechanically-gated ion channels which work on a “push-pull” system:
when the stereocilia are deflected in one direction, the hair cells depolarize, while
deflection in the opposite direction causes hyperpolarization.

Vestibular reflexes
Many axons from the pontine vestibular areas send projections into the
cerebellum, and these signals are important for reflexes related to balance. For
example, imagine you are standing facing forward on a crowded bus when it stops
abruptly. The sudden change in inertia causes your body to reflexively pushing
your toes into the ground, preventing your body from toppling forward. This
behavior is driven by neural signaling in the vestibular organs and their
communication with the cerebellum.
A similar postural reflex that depends on vestibular inputs is the righting
reflex. This is a behavior that develops early in several animals from humans to
Drosophila, and allows the animal to correct their body position if they are in an
abnormal orientation (imagine a baby who can get back to crawling on all fours
after they have fallen on their side). Generally, this reflex is learned during the
first few weeks of life. Knowing up from down depends on the afferent vestibular
signals, however performance of the motor task also requires integration of visual
and somatosensory inputs.
A more subtle reflex is the vestibulo- ocular reflex (VOR), which is observed
as our eyes stay fixated on a target while our head moves. This allows our vision to
stay focused, even as the head is moving. For example, after rotating your head to
 CHAPTER 6.3: VESTIBULAR SYSTEM | 247
the right, the eyes reflexively move to the left, which allows for the visual field to be
stabilized briefly. It can be observed as a physician performs a diagnostic assessment
called the rapid head impulse test, where they move your head quickly side to side
(as if you were shaking your head “no”) while watching your gaze.
This response is driven through a series of three synapses. The first synapse is
formed between the axonal projections from neurons of the vestibular system, and
neurons of the vestibular brainstem nuclei. From here, these neurons send axonal
projections to the contralateral hemisphere (that is to say, their axons decussate)
and form synaptic connections with two populations of neurons in the
contralateral pons. One set of motor neurons excite the extraocular muscle
opposite of the eye movement: a right head turn will trigger excitation of the lateral
rectus of the left eyeball, which pulls the left eyeball in the temporal direction (left).
The other population are interneurons that eventually excite the medial rectus of
the right eyeball, the extraocular muscle that pulls the right eyeball in the nasal
direction (left, again). Simultaneously, there are inhibitory circuits that act at the
opposite muscles to inhibit the eye from moving in the same direction as the head
turn. Operating on the span of about 10 ms, the VOR is one of the fastest reflexes
in the body.

Figure 6.14 Neural circuitry underlying the vestibulo- ocular reflex (VOR)
248 | CHAPTER 6.3: VESTIBULAR SYSTEM
originates at the semicircular canals that detect head movement and ends with
compensatory extraocular muscle activation. CREDIT: Lim, 2021. Open
Neuroscience Initiative.

Clinical connection: Vertigo

Vertigo is the sensation of spinning or movement while standing still. Vertigo often
leads to dizziness, imbalance, ear pain, nausea, or vomiting. It can indirectly lead to
injuries, especially as a person stands up or if they experience vertigo while driving.
A symptom rather than a disease itself, an estimated 7% of people experience
vertigo in their lifetimes, affecting women about 3 times as often as men.
There are a variety of conditions that could cause a person to experience vertigo.
Benign paroxysmal positional vertigo can come and go spontaneously, and
is generally not a sign of an underlying health condition. People with Meniere’s
disease, a chronic condition diagnosed in early adulthood, often experience vertigo
along with other ear-related symptoms such as tinnitus or hearing loss. Bacterial
or viral infections can cause inflammation of the inner ear, resulting in abnormal
vestibular signaling. Excessive alcohol intoxication decreases the density of the
endolymph and potentiates inhibitory signaling, resulting in exaggerated motor
responses following head movement. Severe head trauma that damages the inner
ear may also cause vertigo.
 CHAPTER 7: VISION | 249

CHAPTER 7: VISION
VISION
250 | CHAPTER 7: VISION
 VISION | 251

CHAPTER 7: LIGHTING THE

WORLD: OUR SENSE OF VISION
Dr Eleanor J. Dommett

Materials in this chapter come from:

Dommett, E. (2023). Lighting the world: our sense of vision. In C.

Hall (Ed). Introduction to biological psychology. University of
Sussex. https://doi.org/10.20919/ZDGF9829

Just by seeing is believing, I don’t need to question why.

Sung by Elvis Presley. Lyrics by Red West & Glen Spreen

The song lyric above from ‘Seeing is Believing’, made famous by Elvis Presley,
encapsulates the power we give our sense of vision. This lyric is one of many
examples in our language which indicates how important we consider vision to
be. For example, phrases such as ‘I see’, intended to mean that we understand,
or ‘A picture paints a thousand words,’ rely on the metaphor of vision. Similarly,
in business and industry, organisations typically have vision statements, which
outline what they want to achieve. All these phrases point to the importance of
vision in our everyday lives. In keeping with our approach to the other senses, we
will now begin our journey to understanding vision, with the signal that reaches
our senses – the visual stimulus.

Light: the wave and the particle

The signal detected by the visual system is light that is either reflected from a
252 | VISION
surface or emitted from a source, such as a light bulb or natural sources of light
like the sun. We can detect light ranging in intensity or luminance, measured in
-2 -6 8 -2
candela per metre squared (cd m ), from 10 to 10 cd m . To give some context
to this, this incorporates everything from a dimly lit night sky to the sun. A typical
computer screen, like the one you may be reading from now, has a luminance
-2
of 50-300 cd m . The light we can detect is just a small part of electromagnetic
spectrum (Figure 7.1).

Fig 7.1 The electromagnetic spectrum includes visible light which can be
detected by our visual system. CREDIT: Wolfson. https://doi.org/10.20919/
ZDGF9829

This electromagnetic spectrum includes other signals you may be familiar with,
such as radio waves, X-rays and microwaves, but the visible light spectrum spans
the wavelengths of 380-780 nm, which corresponds to a frequency range of 7.9 x
14 14
10 – 3.8 x 10 Hz (790000000000000 – 380000000000000 Hz), what we see
as the colours from violet to red.

Looking at Figure 7.1, which wavelength and frequency is associated

with violet?
 VISION | 253

Violet is at the end of the visible light spectrum with a wavelength of

14
380nm and a frequency of 7.9 x 10 Hz.

Waves in this spectrum are transverse waves and consist of simultaneous

variations in electrical and magnetic fields at right angles to each other (Figure 7.2).
Unlike the sound waves you learnt about for hearing, electromagnetic waves do not
require a medium to be transmitted, so light can travel through a vacuum.

Fig 7.2. The electromagnetic wave consists of fluctuating and

perpendicular electrical and magnetic fields. CREDIT: Wolfson.
https://doi.org/10.20919/ZDGF9829

The perceptive amongst you will have spotted that the title to this section indicates
that light is not just a wave, but also a particle. This subheading hints at a fierce
scientific debate between some of the most famous scientists in history – a Who’s
Who of the Royal Society. Isaac Newton believed that light was made up of
particles, referred to as photons, whilst his rival Robert Hooke believed light was a
wave. Over time, experiments and calculations by James Clerk Maxwell appeared
to prove Hooke right, and the once-fierce debate was calmed.
However, the discovery of the photoelectric effect (see Box: The photoelectric
effect, below) reignited this debate and drew the attention of Albert Einstein. He
proposed a new theory: that light was not made of waves or particles, but both –
light was made of wave packets or photons. This idea was elaborated on to show
that some experimental findings are best explained when we conceive light as a
254 | VISION
wave, whilst others work best when it is described as a particle, and others still can
work with either explanation. It was this work that led to Einstein’s Nobel Prize in
physics.

The Photoelectric Effect

The photoelectric effect refers

to the emission of electrons from
a material when an
electromagnetic radiation hits
that material. It is best
demonstrated when the material
is a metal. When an
electromagnetic radiation hits a
metal, the energy within it can
transfer to the electrons within
the metal, and if that energy
exceeds the binding energy (the
energy keeping the electron in
the metal), the electrons can be

Fig 7.3. A gold-leaf electroscope which

ejected from the substance.
can be used to demonstrate the Critically though this will not
photoelectric effect
happen with just any radiation, it
only happens with very high
energy sources. The energy within electromagnetic spectrum is related
to its frequency and wavelength, such that the waves with the highest
frequency, and therefore lowest wavelength, have the most energy.
This means light at the violet end of the visible spectrum has more
energy than light at the red end. The effect can be demonstrated using
an electroscope (Figure 7.3). In this gold-leaf electroscope, the two gold
leaves hanging down are separated when negatively charged but, if
 VISION | 255

high energy photons are delivered to the plate above, causing the loss
of electrons, the leaves fall back together. The fact that this effect only
worked for some wavelengths of light was critical in understanding
light as both a wave and a particle.

Now that we have examined the nature of the signal in vision, it is helpful to look
at how that signal can be detected. From this it might be expected that the next
section will focus on transduction, but in the visual system there is quite a lot to do
before we reach the sensory receptor cells for transduction, so we start by looking
at the structure of the eye.

From light source to retina: bringing the

world into focus
The sense organ of the visual system is the eye and, just like the ear, it is made up of
several different parts, all of which play a critical role in ensuring we have accurate
vision (Figure 7.4).
256 | VISION

Figure 7.4. The structure of the eye, CREDIT: Wolfson. https://doi.org/10.20919/

ZDGF9829

Figure 7.4 shows that there are several structures which the light must pass through
before it gets to the retina, where the sensory receptor cells, referred to as
photoreceptors, are located. These structures have a dioptric effect and are referred
to as the dioptric apparatus, which simply means that they are involved in
refracting or bending the light to a focal point. Despite there being several
structures involved, the refractive power in the eye comes almost entirely from the
cornea and the lens. The cornea has a fixed refractive power, but the lens can alter
its power by becoming fatter or flatter. When the ciliary muscles contract the lens
becomes rounder, increasing its refractive power and the ability to bend the light
waves. This allows sources at different distances from the eye to be brought into
focus, which means that the light waves are brought to a focal point on the surface
of the retina (Figure 7.5).
 VISION | 257

Fig 7.5. The first stage of successful vision is for the light waves to reach
a focal point on the surface of the retina. CREDIT: Wolfson. https://doi.org/
10.20919/ZDGF9829

Despite this process appearing quite simple in comparison to much of what you
have learnt in this chapter about the senses, refractive errors are extremely
common. There are different types of refractive errors, but you are mostly likely to
have heard of:

• Myopia or short-sightedness which makes distant objects look blurry

• Hyperopia or long-sightedness which makes nearby objects look blurry
• Presbyopia which makes it hard for middle-aged and older adults to see
things up close

Collectively these conditions are thought to impact 2.2 billion people worldwide
(World Health Organisation, 2018), with 800 million people with an impairment
that could be addressed with glasses or contact lenses (World Health Organisation,
2021). To correct for these refractive errors requires lenses to be produced that can
258 | VISION
increase (hyperopia) or decrease (myopia) the overall refraction of light (see Box:
Refractive errors, below ).

Refractive errors and corrective lenses

Myopia and hyperopia are two of the most common refractive errors.
Myopia arises when the refractive power of the eye is too great and the
focal point occurs before the retina (Figure 7.6), whilst hyperopia occurs
when the refractive power of the eye is too low, and the image has
therefore not been focused by the time it reaches the retina – it would
effectively have a focal point behind the retina (Figure 7.6). To address
this, lenses need to be placed in front of the eye in the form of glasses
or contact lenses. For myopia, the lens counters the normal refractive
power of the eye (Figure 7.6) whilst for hyperopia it bends the light in
the same direction as the eye (Figure 7.6).
 VISION | 259

Fig 7.6. The focal point falls in front of the retina in myopia (a) and
behind it in hyperopia (c). To correct for this diverging (b) and
converging (d) lenses are needed. CREDIT: Wolfson. https://doi.org/10.20919/
ZDGF9829

Presbyopia typically arises with age and is caused by the gradual

hardening of the lens in the eye. As it hardens, flexibility is lost which
means that it is difficult to focus. The solution is bifocal or varifocal
lenses which have different refractive powers at different positions of
the lens.

Assuming that the light waves can be brought to a focal point on the retina, the
visual system can produce an unblurred image. As stated above, the retina contains
the photoreceptors that form the sensory receptor cell of the visual system.
However, it also contains many other types of cells in quite a complex layered
structure (Figure 7.7).
260 | VISION

Fig 7.7. The layered cellular structure of the retina. CREDIT: Wolfson.
https://doi.org/10.20919/ZDGF9829

If you examine Figure 7.7 you will see that the photoreceptors form the deepest
layer of the retina, that is, the one furthest from the light source. You should also
spot that there are two different types of photoreceptors: rods and cones. These
two different types of photoreceptors allow the visual system to operate over a wide
range of luminance and wavelength conditions.
Rods outnumber cones by around 20:1 and they are found predominantly in
the peripheral area of the retina rather than the fovea or central point of the retina.
They are much more sensitive to light than cones, meaning they are suitable for
scotopic vision – that is night vision or vision in dimly lit environments. They
also provide lower acuity visual information because they are connected in groups
rather than singularly to the next type of cell in the retina. This means that the
brain cannot be sure exactly which of a small number of rods a signal originated
from. There is only one type of rod in the human eye, and it is most sensitive to
light with a wavelength of 498 nm.
 VISION | 261

Look back at Figure 7.1. What color does a wavelength of 498 nm

correspond to?

This corresponds to a green-blue colour.

In contrast to rods, cones are found in a much greater number within the fovea
and provide us with high acuity vision due to one-to-one connections with other
cells creating very small receptive fields. They are less sensitive than rods and so best
suited to photopic or day vision. There are, however, three different types of cones,
each with different spectral sensitivities (Figure 7.8).

Fig 7.8. The spectral sensitivities of short (S), medium (M) and long (L)
wave human cone cells. CREDIT: Wolfson. https://doi.org/10.20919/ZDGF9829

Although the cones are often referred to as short (S), medium (M) and long wave
cones (L), indicative of their wavelength sensitivity, they are sometimes called blue,
262 | VISION
green and red cones, corresponding to the colours we perceive of the wavelengths
that optimally activate them.

Looking at Figure 7.8, what cone would you expect to react if a light
with a wavelength of 540 nm was to be detected by the retina?

You would expect to see that the red and the green cone would react
because this is within their spectral sensitivity.

In the question above, we asked you about photoreceptors reacting, which leads on
to the next stage of our journey through the visual system to look at this process in
detail as we turn our attention to transduction.

Photoreceptors and visual transduction

To understand transduction it is helpful to look at the structure of the
photoreceptors in a little more detail (Figure 7.9).
 VISION | 263

Fig 7.9. The structure of rods and cones. CREDIT: Wolfson. https://doi.org/
10.20919/ZDGF9829

Both rods and cones contain an outer segment which includes a photosensitive
pigment which can be broken down by light. The pigment in rods, which is
referred to rhodopsin, contains a protein – opsin – attached to a molecule called
11-cis-retinal. The pigment in cones is generally referred to as iodopsin and still
consists of opsin and 11-cis-retinal but these are three slightly different opsin
molecules that have different spectral sensitivies. The process of phototransduction
is similar for all rods and cones. It is described below in detail for rods, referring to
rhodopsin rather than the different cone opsins, though the process is analogous in
cones.
The process of visual transduction (or phototransduction) is more complex
than the process for touch, pain or hearing so we will need to break this down into
a series of steps, but it is also helpful to have an oversight (no pun intended) from
the start (Figure 7.10).
264 | VISION

Fig 7.10. The process of transduction in the visual system. R = rhodopsin,

R* = activated rhodopsin, G = transducin, G* = activated transducin, PDE
= phosphodiesterase, GC – Guanylyl cyclase. CREDIT: Wolfson.
https://doi.org/10.20919/ZDGF9829

The first stage of transduction happens when the energy from a photon of light
reaching the retina is absorbed by rhodopsin. The absorption of energy forces the
11-cis-retinal to undergo a transformational change and become all-trans-retinal –
this ‘activates’ rhodopsin.
In the second stage, the newly-activated rhodopsin interacts with a G-protein
called transducin. We briefly met G-proteins in the “Neurotransmission” chapter.
Like rhodopsin, metabotropic neurotransmitter receptors are G-protein coupled
receptors (GPCRs). G-proteins are a group of proteins which are involved in
transmitting signals from outside of a cell to inside it and are so-called as they bind
guanine nucleotides. In phototransduction, activation of the G protein transducin
by rhodopsin transmits information about the light from outside the
photoreceptor to inside it, while in neurotransmission, ligand binding to the
receptor activates the G protein to transmit information about neurotransmitter
presence at the synapse. In each case the activated G protein releases guanosine
diphosphate (GDP) bound to it and instead binds a guanosine triphosphate
(GTP) molecule.
In the third stage of transduction, GTP binding to the G protein, transducin,
results in the β and γ subunits of transducin dissociating from the α subunit and
bound GTP molecule. In the fourth stage, the α subunit and bound GTP interact
with a second protein called phosphodiesterase (PDE) which in turn becomes
activated.
 VISION | 265

What would you expect to happen at some point during transduction if

a receptor potential is to be produced?

You would need to see ions channels open or close to allow a change in
ions moving across the membrane, carrying the charge that makes up
the receptor potential.

The final step sees activated PDE breakdown a molecule called cyclic guanosine
monophosphate (cGMP). cGMP is produced by guanylyl cyclase and opens
cGMP-gated ion channels in the cell’s membrane that allow sodium and calcium
ions to enter the cell. Thus when cGMP is broken down by PDE, these ion
channels close and no more calcium or sodium can enter the cell. This might
not be quite what you expected to happen because in the previous senses we
have looked at, transduction involves channels opening and positively charged
ions coming into the cell, depolarising the cell. However in light detection, the
reverse occurs: light detection causes cessation of a depolarising current and a
hyperpolarisation of the membrane. The current that flows when no photons of
light are being absorbed is called the ‘dark current’. One suggested reason that the
visual system operates in this way is to minimise background noise. To explain this
further, when there is a dark current, there is a steady flow of sodium into the cell
in the absence of light. This means that any minor fluctuations in sodium channel
openings will not impact the cell very much – the noise will effectively be ignored.
It is only when a large number of channels close in the light that the cell membrane
potential will be affected, giving rise to a clear signal.
In any event, the decrease in intracellular calcium that occurs because of
channels closing when light hits the retina results in a reduction in the release of
glutamate from the photoreceptor. This in turn impacts on the production of
action potentials in the bipolar cells that synapse with the rods and cones. There
are broadly two types of bipolar cells – ON cells and OFF cells. OFF bipolar
cells respond to the decrease in glutamate release during light stimulation with a
266 | VISION
decrease in action potential firing, i.e. a decrease in glutamate causes a decrease in
excitation and reduced firing. However, ON bipolar cells respond to the decrease
of glutamate during light stimulation with an increase in action potential firing.
Glutamate is usually excitatory, so how can a decrease in glutamate during light
cause an increase in bipolar cell firing? This happens because instead of expressing
ionotropic AMPA glutamate receptors, ON cells express a specific metabotropic
glutamate receptor, mGluR6. When mGluR6 is activated, its G-protein subunits
close a non-specific cation (positive ion) channel, hyperpolarising the cell. When
glutamate release is reduced, mGluR6 is inactive, allowing the cation channel to
open, and sodium ions to enter the bipolar cell, depolarising it and causing action
potentials to fire. Bipolar cells in turn connect to the retinal ganglion cells, whose
axons form the optic nerve and transmit action potentials from the eye to the brain.

Visual pathways: to the visual cortex and

beyond
The axons of the retinal ganglion cells form the optic nerve and leave the eye
through the blind spot. From the optic nerve, two routes that can be taken, a
cortical and a subcortical route. The cortical route is the pathway that is responsible
for much of our higher processing of visual information and has been the focus of
a large amount of research and, as such, it is a logical starting point. Figure 7.11
shows the route that visual information typically takes from the eye to the primary
visual cortex, located in the occipital lobe. In contrast to the pathway from the ear
to the primary auditory cortex this pathway looks quite simple, but information is
very carefully sorted throughout the pathway.
 VISION | 267

Fig 7.11. The route visual information takes from the eye to the visual
cortex. CREDIT: Wolfson. https://doi.org/10.20919/ZDGF9829

Starting from the eye, information leaves via the optic nerve. The optic nerves from
both eyes meet at the optic chiasm which can be seen on the underside of the brain
(Figure 7.11). At this point information is arranged such that signals from the left
visual field of both eyes continues its pathway via the right side of the brain, whilst
information from the right visual field of both eyes travels onwards in the left side
of the brain. The first stop in the brain is the lateral geniculate nucleus (LGN)
which is part of the thalamus. Each LGN is divided into six layers. Three of these
layers receive information from one eye and three receive it from the other. These
layers are said to be retinotopically mapped, which means that adjacent neurons
will receive information about adjacent regions in the visual field.
From the LGN, information travels, via the optic radiation, to the primary
visual cortex (V1), sometimes also referred to as the striate cortex because of its
striped appearance. As we learnt in an earlier chapter (Exploring the brain), the
cortex consists of a series of layers from the outside of the brain to the inside. The
268 | VISION
most dorsal or outer layer is labelled Layer I and the deepest or innermost layer is
layer VI. Information from the LGN enters the primary visual cortex in layer IV
where different layers of the LGN enter different subsections of layer IV (Figure
7.12).

Fig 7.12. The input from the LGN into the primary visual cortex. CREDIT:
Wolfson. https://doi.org/10.20919/ZDGF9829

There will be many thousands of cortical neurons receiving information from

each small region of the retina and these cells are organised into columns which
respond to specific stimulus features such as orientation. This means that cells in
one orientation column preferentially respond to a specific orientation (e.g. lines
at 45° clockwise from the vertical) whilst those in the next column will respond
to a slightly different orientation. Across all columns, all orientations can be
represented. Primary visual cortex can also be divided into columns that respond
preferentially to one eye or the other – these are termed ‘ocular dominance
columns’. Theoretically, the cortex can be split into ‘hypercolumns’ each of which
 VISION | 269
contains representations from both ocular dominance columns and all
orientations for each part of the visual field, though these do not map as neatly
onto the cortical surface as was once theorised (Bartfeld and Grinvald, 1992).
However, despite the exquisite organisation of the primary visual cortex,
information does not stop at this point. In fact visual information travels to many
different cortical regions – with 30 identified so far.

Can you recollect how auditory information was divided after the
primary auditory cortex?

It was divided into a dorsal and ventral pathway.

Visual information can also be divided into a dorsal and ventral pathway. The
ventral pathway, which includes V1, V2, V4, and further regions in inferior
temporal areas, is thought to be responsible for object identity i.e., a ‘what’
pathway. The dorsal stream, which includes V1, V2, V3, V5, supports detection
of location and visually-controlled movements (e.g., reaching for an object), i.e., a
‘where’ pathway (Figure 7.13).

Fig 7.13. The dorsal and ventral streams of the visual system. CREDIT:
Wolfson. https://doi.org/10.20919/ZDGF9829
270 | VISION
We mentioned that there is also a subcortical pathway that visual information can
take through the brain. In fact there are several different subcortical structures that
receive visual information but one of the main ones is a structure call the superior
colliculus. This name may sound familiar because you have already learnt about
the inferior colliculus in your exploration of hearing. The superior colliculus sits
just above the inferior colliculus, on the surface of the midbrain. Although often
overlooked when describing visual processing, the superior colliculus is thought to
be involved in localisation and motion coding. It has also been implicated in an
interesting phenomenon termed Blindsight (see Box below, Blindsight: I am blind
and yet I see).

Blindsight: I am blind and yet I see

Blindsight was first described in the 1970s by researchers who had

identified residual visual functioning in individuals who were deemed to
be clinically blind due to damage to the visual cortex (Pöppel, Held, &
Frost, 1973; L Weiskrantz & Warrington, 1974). These individuals
reported being unable to see, but could detect, localize or discriminate
stimuli that they were unaware of more reliably than if they were just
guessing. Later work allowed a further distinction to be made into
blindsight Type 1, where the individual could guess certain features of
the stimulus e.g., type of motion, without any conscious awareness of
it, and Type 2 where individuals could detect a change in the visual field
but cannot describe the type of change (L. Weiskrantz, 1997).

Several explanations have been proposed for this interesting

phenomenon:

• Areas other than primary visual cortex underlie the responses,

including the superior colliculus, which has been shown to
provide quick crude responses to visual stimuli.
 VISION | 271

• Whilst much of the primary visual cortex is destroyed in people

with blindsight, small pockets of functionality remain, and this
explains the residual abilities.
• The LGN is capable for detecting key visual information and
passing this directly to other cortical areas which could explain
the phenomenon.

Research continues into blindsight and the role of several brain

structures in visual processing, but the existence of this phenomenon
has demonstrated that subcortical pathways and structures outside the
primary visual cortex can still play a significant role in visual processing.

We have now discussed transduction and pathways for vision but not said much
about specific features of the visual scene are detected. As you will probably have
guessed this is an extremely complicated process and so we will focus just on three
components of the visual scene in the next section: color, motion and depth.

Perceiving the world: color, motion and

depth
Color processing is critical to our perception of the world, and you learnt earlier
in this section that we have three types of cones with distinct but overlapping
spectral sensitivities. These three types of cones in the retina are the start of our
colour perception journey. The presence of three types of cones is referred to as
trichromacy. The development of trichromacy is thought to offer an evolutionary
advantage because it can help identify suitable foods and better discriminate their
ripeness. For example, the ability to differentiate red-green is thought to be
important as reddish colors in fruits are indicative of higher energy or greater
protein content. Work with humans suggest color remains important in food
preferences (Foroni et al., 2016).
The output from the three types of cones is thought to be translated into an
opponent color system in the retinal ganglion cells which can then give rise to
272 | VISION
specific channels of information in the visual system, referred to as the opponent
processing theory of color processing (Figure 7.14):

• A red-green channel which receives opposing inputs from red and green
channels.
• A luminance channel which receives matching inputs from red and green
channels.
• A blue- yellow channel which receives excitatory input from blue channels
and inhibitory input from the luminance channel (which in turn is created
from excitation from red and green cones).

Fig 7.14. Opponent processing channels in the visual system. CREDIT:

Wolfson. https://doi.org/10.20919/ZDGF9829

Cells that respond in line with this theory have been found in the LGN and the
primary visual cortex. Further along in the ventral pathway, V4 has been found to
contain neurons which respond to a range of colours i.e., not just red, green, blue
and yellow (Zeki, 1980). This area receives input from V2 and sends information
 VISION | 273
onwards to V8. The latter of which appears to combine color information with
memory information (Zeki & Marini, 1998).

Imagine looking out of your window on a bright morning to the leaves

on the trees outside in the sunshine. Now consider looking out a few
hours later when the weather has become dull and overcast. Do you
perceive that the leaves have changed color?

Hopefully you answered ‘No’ this question because you know that the
leaves have not changed color. But how do you know this?

The fact that we can perceive color as unchanging despite overall changes in
luminance is because of a phenomenon called color constancy. The brain
compensates for differences in luminance by taking into account the average color
across the visual scene.
We mentioned previously that some cells in V1 respond to specific orientations
of stimuli. In addition to these cells, other cells in V1 have been found to respond
to specific movement of stimuli indicating that motion detection begins early in
cortical processing. However, it is V5, also known as MT (for medial temporal
area), and the adjacent region V5a or medial superior temporal area, that are
thought to be critical in motion detection. V5 region receives input from V1
but also from the superior colliculus which is involved in visual reflexes that are
important for motion. Information from V5 is then sent onwards to V5a which
has been found to have neurons that respond to specific motion patterns including
spiral motion (Vaina, 1998).
Before we move on to the final subsection on visual impairment, we will look
briefly at depth perception. The image created on the retina is two dimensional
and yet we can perceive a three-dimensional world. This is possible because we use
specific depth cues. Spend a moment looking at the visual scene in Figure 7.15.
274 | VISION

Fig 7.15. Chatsworth House in Derbyshire, England

The image shown in Figure 7.15 is complex, with multiple components including
the house, fountain cascade, trees and the landscape beyond the house leading
to the horizon. But how do we know how all the components fit together? For
example, how do we know which trees are in front of the house and which are
behind it or whether the trees in the distance are far away or just small? We can
interpret the scene using depth cues including:

• Interposition: Objects which obscure other objects are closer to the viewer
than the ones they obscure.
• Linear perspective: Parallel lines will converge as they move further away.
This is illustrated with the sides of the fountain cascade in the image.
• Size constancy: Objects which appear smaller are likely be further away so
trees in the distance will be smaller than those nearby because they are in the
distance rather than because they differ in size.
• Height in the field: The horizon tends to appear towards the middle of the
image with objects below the horizon nearer to the observer than the
 VISION | 275
horizon and those close to the bottom of the image the nearest to the viewer.

We also obtain visual cues by comparing the images we have from the left and right
eye – these are binocular cues. For example, when our left and right eye receive
slightly different images, referred to as binocular disparity, this can alter our depth
perception. It is through compiling cues like this, along with discrete information
about color, orientation and motion, that we can create a perception of the world
around us.

Blindness: causes, impact and treatment

Globally, the main causes of visual impairment are uncorrected refractive errors
(myopia etc.), as discussed above. However, these do not typically result in
blindness. The leading cause of blindness is cataracts which accounts for 51% of
blindness worldwide (Pascolini & Mariotti, 2012). Cataracts occur when the lens
of the eye develops cloudy patches, losing the transparency which is critical for
transmitting light. Individuals may experience cataracts in one or both eyes. As
the lens becomes cloudy, light cannot reach the retina. The National Institute for
Health Care and Excellence (NICE, 2022) have identified several risk factors for
cataracts including:

• Ageing – most cataracts occur in people over 60 years of age

• Eye disease – in this case the cataracts can occur because of other conditions
• Trauma – the cataracts arise due to injury to the eye
• Systemic disease – the cataracts arise because of other conditions, for
example, diabetes

Aside from a decline in visual abilities to the point of blindness, cataracts have been
associated with wider impact on health. In age-related cataracts the presence of
cataracts is related to cognitive decline and increased depression (Pellegrini et al.,
2020).
At the time of writing the only proven effective treatment for cataracts is surgery
to replace the lens of the eye with a synthetic lens. These lenses cannot adjust like
the natural lens so glasses will typically need to be worn after the surgery. The
276 | VISION
surgery is short (around 30 mins) and carried out under a local anesthetic with a
2-6 week recovery period. These operations are considered routine in countries like
the UK, but in low- and middle-income countries, eye care is often inaccessible,
and cataracts can cause blindness.
After cataracts, the next leading cause of blindness is glaucoma, accounting for
8% of cases; followed by age-related macular degeneration (AMD), accounting for
5% of cases (Pascolini & Mariotti, 2012). Glaucoma refers to a build-up of pressure
within the eye that can lead to damage to the optic nerve. This build-up happens
because the fluid in the eye cannot drain properly, and it typically happens over
time. As with cataracts, the condition is more common in older people. Several
treatment options exist for glaucoma including use of eye drops, laser treatment
and surgery, all aiming to reduce the intraocular pressure, but damage may be
irreversible. Perhaps unsurprisingly, this condition is also associated with poorer
quality of life (Quaranta et al., 2016).
For both cataracts and glaucoma, the site of damage is not specifically the retina
and the photoreceptors. However, AMD does result from damage to the retina.
In this case, the macular region of the retina deteriorates causing blurred central
vision, although peripheral vision is intact, meaning it only causes complete
blindness in a small percentage of people. As indicated by the name, this is an age-
related condition such that older people are more likely to develop it, but other
risk factors include smoking and exposure to sunlight. Whilst the remaining vision
might suggest less impact on individuals than other types of visual impairment, it
is still associated with reduced quality of life, anxiety and depression (Fernández-
Vigo et al., 2021).
There are two types of age-related macular degeneration: dry and wet. Dry
AMD occurs because of a failure to remove cellular waste products from the retina.
These products build up causing deterioration of blood vessels and cell death of
the rods and cones. This type of AMD accounts for around 90% of the AMD cases
and there is no treatment for this type of AMD. Wet AMD arises in around 10%
of people with AMD as a progression from dry AMD. Here new blood vessels
form in the eye, but they are weak and prone to leaking. This type of AMD
can be treated with regular injections into the eye to reduce the growth of new
blood vessels. An alternative to injections, or to be used alongside the injections, is
Photodynamic Therapy (PDT) where a laser is directed to the back of the eye to
destroy the abnormal blood vessels there.
 VISION | 277

Key Takeaways: Summarizing Vision

• Our sense of vision uses light as a sensory stimulus. Visible light is

part of the electromagnetic spectrum and can be conceptualized
as both a wave and a particle
• Light emitted from objects or reflected off them enters the eye
through the dioptric apparatus where it is bent to a focal point on
the retina at the back of the eye. Most of the refractive power
comes from the cornea, but the lens provides an adjustable
amount of power
• Refractive errors such as myopia can arise when the dioptric
apparatus is too weak or powerful, causing the focal point to be
in front of, or behind, the retina. Although refractive errors are a
leading cause of visual impairment worldwide, they do not
typically result in blindness
• Visual transduction occurs in the photoreceptors at the back of
the retina of which there are two classes: rods and cones. Rods
outnumber cones overall and are more sensitive, providing vision
in scotopic conditions, but provide lower acuity and are found
predominantly in the peripheral retinal areas. In contrast, cones
are largely found in the fovea, and are specialized for high acuity,
photopic vision. There are three types of cones, each with
differing spectral sensitivity, giving rise to our colour perception
• The process of visual transduction begins with activation of
photosensitive pigment in the photoreceptors. After this a series
steps involving G-proteins results in the closure of ion channels
and therefore a reduction of calcium entering the cell. This results
in reduced glutamate release. Unlike the other senses, the
presence of a stimulus results in hyperpolarization of the receptor
• Retinal ganglion cells carry information away from the retina in
278 | VISION

the optic nerve to the lateral geniculate nucleus and onto the
primary visual cortex. Information is arranged according to the
eye and visual field and retinotopically mapped. After leaving the
primary visual cortex over 30 cortical regions will receive visual
input, including those forming the dorsal and ventral stream.
Subcortical pathways also exist, most notably the pathway from
the retina to the superior colliculus
• Specific features of the visual scene are identified by specific
neural processes. For example, colour is believed to arise through
opponent processing creating red-green, blue-yellow and
luminance channels in the ventral pathway. Motion sensitive cells
have been found in the dorsal pathway
• Different components of a visual scene can be combined and use
of specific cues e.g., linear perspective can be used to create a 3D
perception from the 2D image on the retina
• Leading causes of blindness are age related and include cataracts,
glaucoma and age-related macular degeneration. In all cases the
condition can have a significant impact on quality of life and result
in distress. Treatments exist for most of these conditions but
access to those treatments varies widely across the world.

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pinwheels, cytochrome oxidase blobs, and ocular-dominance columns in
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121.9.1669
 CHAPTER 8: CIRCADIAN RHYTHMS AND SLEEP | 281

CHAPTER 8: CIRCADIAN
RHYTHMS AND SLEEP

Materials for this chapter came from:

Lim, A. (2021). Open Neuroscience Initiative

https://www.austinlim.com/open-neuroscience-initiative
282 | CHAPTER 8: CIRCADIAN RHYTHMS AND SLEEP
 CHAPTER 8:1 INTRODUCTION | 283

CHAPTER 8:1 INTRODUCTION

Austin Lim, Ph.D.; Ben Marcus, PhD (editor); and Dana
Simmons, PhD (editor)

Sleep is such an important part of our lives that a lack of it strongly correlates
with negative outcomes on nearly every measure of health. People who sleep less
than approximately 7 hours a night are at a greater risk for heart disease, stroke,
asthma, arthritis, depression, and diabetes. Nearly 20% of all car crashes, both
fatal and nonfatal, are attributed to drowsy driving. The cancer research branch
of the World Health Organization has determined that disruption of regular sleep
is “probably carcinogenic to humans,” putting it in the same risk category as
the infectious agents malaria and human papillomavirus (HPV), as well as the
biochemical weapon mustard gas. Sexual health is affected by sleep deprivation as
well, as men with the worst sleeping habits have significantly lower sperm counts,
decreased circulating testosterone, and even testicular shrinkage.
Despite all that we know about the benefits of sleep, sleep is often the first
time commitment to get cut, often getting squeezed as people stay awake later
while waking up sooner. Consider that the CDC estimates that more than a third
of American adults fail to get enough sleep each night. Almost 70% of college
students fail to get the recommended amount of nightly sleep, and half of all
college students report experiencing daytime sleepiness as a result.
The current medical recommendation is 7-9 hours of sleep each night. But
why is sleep so important? It is possible to study sleep using a combination of
techniques; the output of sleep studies are visualized on a polysomnogram (pahl-
e-SOM-nuh-gram; somn- is the prefix referring to sleep). Several physiological
measures are taken in a polysomnogram, including heart rate, blood pressure and
oxygenation level, respiratory depth and pattern, muscle activity, eye movement,
and one of major interest to neuroscientists, brain wave activity. While everyone
knows what sleep is, it is useful to try to more precisely define sleep as a biological
function. Sleep is characterized by the following:
284 | CHAPTER 8:1 INTRODUCTION
A decrease in physical activity
This is not to say that people do not completely cease all movement during sleep.
It is very common to readjust posture many times in the middle of the night. Some
people may grind their teeth together or talk in their sleep, sometimes carrying
on full conversations by themselves! About 15% of people have experienced
somnambulism, or sleepwalking: full on wake-like behaviors such as navigating
down a flight of stairs or preparing a sandwich, performed entirely in the absence of
conscious awareness. Despite these rare occurrences of physical activity, the average
movement of the person over a night’s rest is still less than their average activity
when awake.
 CHAPTER 8:1 INTRODUCTION | 285
Figure 8.1 Sleep is usually characterized by a decrease in physical activity, but
some people experience somnambulism. CREDIT: Delacroix, Eugene. Lady
Macbeth Sleepwalking. 1849-1850.

A decoupling from external inputs

When we sleep, our conscious brains are “distanced” from the outside
world. Sleep causes a heightened threshold for detection of stimuli, so we do
not receive the same magnitude of inputs from our sensory systems as when
we’re awake. This is why someone else might have to talk loudly or even shake
you physically to wake you up.

Changes in brain wave activity

Sleep was once thought to be a period of time characterized by low
brain activity. After all, the person looks like they are not moving. Shouldn’t
brain activity be reflective of that decreased state of activity? With the
advancement of EEG technology in 1924, and the rise of sleep laboratories in
the 1970s, scientists who studied brain activity noticed that, at different times
throughout the night, the brain of a sleeping person was very similar in activity
to the brain of an awake person!
286 | 8.2: PHASES OF SLEEP

8.2: PHASES OF SLEEP

Each night when we go to sleep, our brains undergo a very stereotyped pattern of
activity changes. At times, neurons in the cortex exhibit synchronized patterns of
firing. And at other times, cortical activity looks very similar to an awake brain.
We can divide sleep roughly into two different phases depending on one of
the first physiological measures that sleep scientists studied: eye movement. A
study published in 1953 used a device to detect eye movement while a person
was asleep. Interestingly, they noticed that at some points in the night, usually
first occurring around three hours after falling asleep, the patient’s eyes would
dart rapidly and jerkily back and forth, a pattern of activity that the University
of Chicago researchers called rapid eye movement (REM). This first period of
REM activity lasted for about 20 minutes, after which the eyes would stop moving
again. This activity pattern repeated every hour or two for the rest of the night.
They used eye movement to separate sleep into two phases: REM sleep, and
non- REM sleep (NREM sleep.) In addition to eye movement, they observed
and measured other physiological behaviors. Respiration rate and heart rate both
increased during the REM phase of sleep and dipped during NREM sleep. They
also (rudely) woke up patients throughout the two phases of sleep, and found
that patients were more likely to recall dreams with visual imagery if their REM
sleep was interrupted. Those woken during NREM sleep were less likely to recall
dreams, hinting that dreaming is more likely to happen during REM sleep.
While eye movement could differentiate between two phases of sleep, another
common diagnostic technique, electroencephalography (EEG – see Figure
8.2), could further subdivide NREM sleep. EEG measures electrical activity at
the scalp, detecting the firing of large numbers of cortical neurons. Using EEG,
scientists discovered three distinct NREM phases based on neuron activity
patterns: NREM1, NREM2, and NREM3 sleep (see Figure 8.3). Currently,
readings collected via EEG are considered to be the gold standard for measuring the
stages of sleep.
 8.2: PHASES OF SLEEP | 287

Figure 8.2 In an EEG, electrodes are placed on the head that can detect
and record neuronal activity of the cortex. CREDIT:
https://commons.wikimedia.org/wiki/File:EEG_recording.jpg
288 | 8.2: PHASES OF SLEEP

Figure 8.3 Throughout the night, the EEG shows that the brain cycles
through different patterns of activity. CREDIT: Psychology 2e Openstax.org

But before we describe EEG traces while asleep, we should describe the
EEG of a person who is awake. Usually, the awake EEG is dominated by high-
frequency waves, falling in the beta band range of frequencies: between 13 and
30 Hz. The proportion of neurons firing at the beta frequency increases with
attention and mental activity: When a person is concentrating on a task, such
as reading a textbook, the beta wave frequency dominates.
NREM1 is the earliest stage of sleep. It’s also described as relaxed
wakefulness, drowsiness, or light sleep. During NREM1, a person’s muscles are
still somewhat active, their eyelids may open and close every so often, and they
may still respond to questions. In NREM1 sleep, the beta frequency amplitude
decrease as the slower frequency alpha waves (8-13 Hz) increase in amplitude.
Late in NREM1, theta waves (4-8 Hz) become more prevalent. Basically, the
 8.2: PHASES OF SLEEP | 289
deeper into NREM1 sleep a person becomes, more waves with lower and lower
frequencies start to emerge.
During NREM2 sleep, theta waves predominate. In a healthy adult, about
50% of a night’s sleep is spent in NREM2. NREM2 is characterized by the
appearance of two patterns of activity that interrupt theta activity. K-
complexes are large amplitude events that are observed about every minute.
These are the largest amplitude events in a healthy human EEG. Following a K-
complex you may see a sleep spindle, a high-frequency burst of rapid neural
activity in the low beta range that lasts for about a second. It is unknown exactly
what the function of these sleep spindles are, but some research suggests they
may be involved in memory processes or to minimize perception of outside
noises, which can help a person stay asleep even in the face of disruptive stimuli.
NREM3 is also called deep sleep. At this phase of the night, a person’s
physiological activity drops to its lowest point of the night: heart rate,
respiration, blood pressure, and metabolism all reach minimum during
NREM3. In this stage of sleep, many of the cortical neurons fire in
synchronicity with one another, and the subsequent change in potentials cause
large amplitude deflections in the EEG, at the low- frequency delta band (1 –
4Hz). Because the delta frequency is much slower than frequencies detected in
lighter stages of sleep or wake, NREM 3 is also called slow wave sleep.
The EEG trace of a person in REM sleep is quite the opposite of what is seen
in deep sleep. Instead of large amplitude events at a low frequency, the REM
brain has a lot of low amplitude events at a high frequency. In fact, the brain
in REM sleep has a pattern of activity that is more similar to a person who is
awake than asleep! Because of this asynchronous firing activity, REM sleep is
sometimes also called paradoxical sleep.
To illustrate the stages of sleep that a person experiences each night, we can
use a hypnogram (see Figure 8.4). These charts to plot time on the x-axis, and
stage of sleep on the y-axis. Awake is represented at the top, and deep sleep is
at the bottom. For an average night’s rest, neural activity will fluctuate through
the four phases relatively predictably. When a person first falls asleep, they will
move from NREM1 down through NREM2 then NREM3, before coming
back out of deep sleep progressively back to NREM1. After NREM1, they
may enter REM sleep before transitioning back through the stages to NREM3
again. This cycle of activity repeats roughly every one and a half hours.
290 | 8.2: PHASES OF SLEEP
People spend a larger percentage of each cycle in deep sleep and very little
time in REM sleep early in the night. On the other hand, in the last few cycles
before waking up from a full night’s rest, people spend a larger percentage of of
each cycle in REM sleep, and almost no time in deep sleep.

Figure 8.4. A hypnogram can be used to visualize the time spent in each
phase of sleep during the night. CREDIT: Psychology 2e Openstax.org
 8.3: WHY DO WE SLEEP? | 291

8.3: WHY DO WE SLEEP?

All organisms that we know of experience some type of sleep. But we still haven’t
figured out exactly why animals sleep. Here, we will discuss three theories that
have been proposed to explain sleep. None of these theories alone fully explains
the complex phenomenon of sleep, and they are not mutually exclusive. The most
likely reason we sleep is probably some combination of the following three
theories.

Case study: Peter Tripp

In 1959, New York City radio DJ Peter Tripp ran a publicity stunt to
raise money for the charity March of Dimes: he stayed awake for 201
hours. Sitting inside a glass booth in the middle of Times Square,
Peter played music and broadcasted his experiences across the
airwaves. The first night of sleep deprivation wasn’t awful, but the
next seven consecutive days and nights were a real challenge, for
both Tripp and the doctors who kept an eye on him.

Just a few days in, Peter began experiencing severe psychological

side effects. Tripp developed intense paranoia: He mistook his
psychiatrist, who was wearing all black, for being the undertaker
here to collect Peter’s body for a funeral. Tripp even began
hallucinating, seeing spiders and rodents in his clothes – prompting
him to strip naked and run into the street screaming. Some believe
the long-term sleep deprivation severely affected his brain beyond
this temporary psychosis. After the experiment, Tripp was involved
in a huge commercial bribery scandal, lost his job, and got divorced
(Of course, life has many variables, so we’ll never be completely sure
292 | 8.3: WHY DO WE SLEEP?

of the precise effect long-term sleep deprivation may have had on

his relationships and decisions.) Today, the Guinness Book of World
Records no longer allows people to compete for the prolonged-
wakefulness record due to health concerns.

Recuperation Theory
The recuperation theory of sleep is centered around the idea that being awake is
stressful and exerts a physically demanding toll on the body. The body therefore
needs a period of time when energy usage decreases and the body’s natural repair
systems can work without disruption. Sleep is how the body “wipes the slate clean”
and resets.
Evidence for the recuperation theory comes from experiments tailored around
the idea of looking at what happens when a person doesn’t get sufficient sleep.
As anyone who has ever pulled an all-nighter can attest, a single night of sleep
deprivation often leads to significant psychological changes, including anxiety,
irritability, and mood swings. Staying awake even longer than 24 hours can cause
more severe changes in mind state, such as temporary psychosis, hallucinations, or
delusions.
The recuperation theory is supported by several pieces of evidence, three of
which we will discuss.

1. Enhanced metabolic cleaning during sleep. When you’re awake, your

cells produce several biological waste products during cellular respiration.
These chemical byproducts can be potentially toxic to the body when they
accumulate. The glymphatic system, a sort of cellular rinse that floods the
extracellular space with CSF, clears these cellular waste byproducts when
they accumulate in the brain. When we sleep, the extracellular space expands
by about 60%, which increases the ability for CSF to penetrate deeper into
the brain tissue. One byproduct of interest is the molecule beta-amyloid, a
protein that exists in the healthy brain. But, accumulations of beta-amyloid
 8.3: WHY DO WE SLEEP? | 293
are found at high levels in the post-mortem analysis of brains from patients
with Alzheimer’s disease. During sleep, the glymphatic system’s “rinsing”
activity washes away beta-amyloid from the interstitial space and degrades
the protein.

WAKE SLEEP
294 | 8.3: WHY DO WE SLEEP?
Figure 8.5 During sleep, the glymphatic system increases flow of CSF
(green waves) that are able to wash out the amyloid-beta protein (black dots)
from the interstitial space. Modified from https://commons.wikimedia.org/
wiki/File:Video_schematic_of_glymphatic_flow.ogv

2. Immune system function improved with sleep. Sleeping more

enhances your ability to fight pathogens. Sleeping for fewer than 6 hours per
night increases the likelihood of catching a variety of transmissible illnesses,
such as cold, flu, or gastroenteritis. Sleep increases the effectiveness of
vaccines, and each hour of sleep over 6 hours increases said effectiveness by
about 50%.

3. Increased production of growth hormone during deep sleep.Most

cells of the body are turned over regularly as cells die and get replaced. One
of the signaling molecules that encourages the replacement process is
growth hormone (GH), which enhances cellular repair, muscle and bone
growth and protein synthesis. Normally, throughout a 24-hour day, GH is
produced and released throughout the body by the hypothalamus. The
largest wave of GH production occurs early in sleep, during NREM 3 sleep.
During this huge burst of GH release, a person’s circulating plasma GH
concentration may be 10 times higher than at baseline.

While the support for the recuperation theory is generally true for almost all
people, there are about 1% of people who seemingly gain the restorative benefits of
sleep, even with fewer than 6 hours of sleep each night. They may wake up at 4:30
in the morning feeling completely refreshed. And yet, despite getting so little sleep,
these short sleepers have similar health outcomes with respect to body mass index
and psychiatric measures such as depression and overall optimism. Something
about the circadian rhythms of these short sleepers allows them to “maximize”
their sleep efficiency. Many have very short sleep latencies, meaning they fall asleep
within minutes after lying down – as quickly as someone with narcolepsy. They
also spend a larger percentage of their night in deep sleep and REM sleep while
minimizing NREM1 and NREM2.
 8.3: WHY DO WE SLEEP? | 295

Figure 8.6 Growth hormone levels peak early in the night during deep sleep.

Evolutionary Adaptation Theory

The evolutionary adaptation theory is the idea that animal sleep patterns are
different across species for reasons that most efficiently benefit each animal. Over
millions of years of evolution, individuals with the most ideal sleep patterns have
an advantage, and their sleep habits will be selected for in the following generation.
For example, consider humans. As an animal highly dependent on light and the
visual system for navigation and accurate performance of tasks, the dark is a very
dangerous time to be active. The risks of wandering off a cliff, running head-first
into a tree while escaping a predator, or eating a wrong-colored poisonous berry
would all be elevated in the dark. We benefit from behaviors that minimize those
risks, such as inactivity until the sun rises. During this inactive period, sleeping
decreases our metabolism and our body’s need for energy.
296 | 8.3: WHY DO WE SLEEP?

Figure 8.7 In a traveling pod of dolphins, the animals on the edges sleep with
half of their brain in order to remain a vigilant lookout. https://pixabay.com/
photos/dolphins-fish-mammals-delphinidae-380034/
Humans are just one animal that has an evolutionary fine-tuned sleep pattern.
If you look across the animal kingdom, you’ll find all varieties of sleep behaviors
that are best fitted to the needs of the individual species. In the wild, for example,
dolphins are generally prey. They evolved with the ability to put one half of their
brain to “sleep” at a time, allowing the “awake” half to keep an eye out for potential
predators. Small prey animals, like squirrels, are faced with the threat of being
attacked at night. For them, remaining very still, quiet, and hidden improves their
survival. Tigers, the top alpha predators in any ecological niche, have almost no
predators to hide from, allowing them the luxury of sleeping up to 20 hours a day.
This evolutionary adaptation theory argument has a major weakness, however.
In almost all animals, sleep represents a period of time when an organism’s ability
to use their sensory organs to detect the hallmark signs of an approaching predator,
like the flurry of feathers from a hungry owl or the soft padding of a wolf footsteps,
decreases drastically. For an animal that can’t hide very effectively, sleep represents
a period of vulnerability, as they would be unable to sense incoming threats.
 8.3: WHY DO WE SLEEP? | 297

Figure 8.8 Alpha predators have no fear of being attacked, and are given
the luxury to sleep for prolonged periods of time. https://pixabay.com/photos/
tiger-big-cat-majestic-noble-zoo-3383616/

Brain Plasticity Theory

The brain plasticity theory suggests that the brain needs some period of time for
critical changes to occur. During sleep, circuits in the brain undergo consolidation
processes that are important for memory formation. For example, academic
performance and examination grades worsen as a person’s nightly sleep decreases.
Both the REM and NREM3 phases of sleep are important for different types of
memories, and studies suggest that declarative memory (information about
facts), benefits more from slow-wave sleep while procedural memory, the
learning of motor skills, is enhanced by REM sleep. Although the exact
mechanisms about how sleep improves memory are unknown, we theorize that
brain activity during sleep helps move memories held in “temporary” areas into
areas of stable, long-term storage.

The evidence in support of this theory starts with looking at the brains of
newborns. When you were first born, during those first few weeks of life, you
slept close to nearly 70% of the day, almost 17 hours! At this point in your life,
your brain starts to experience all sorts of new sensations: your eyes detect visible
light for the first time, the skin feels the air blow past it, and the ears sense new
frequencies and combinations of sound waves. As a result of these stimuli,
298 | 8.3: WHY DO WE SLEEP?
scientists hypothesize that your brain undergoes as many learning events as rapidly
as possible. This rapid learning helps you remember what you learned each day so
you can respond to your environment as you grow up.

Figure 8.9 According to the brain plasticity theory of sleep, newborns spend
most of their day sleeping in order for their brains to adapt to all the new
senses they are experiencing. https://pixabay.com/photos/father-baby-portrait-
infant-22194/
 8.4: THE CIRCADIAN RHYTHM | 299

8.4: THE CIRCADIAN RHYTHM

Almost every living organism that we know of on Earth exhibits some sort of
cyclic pattern of activity that closely matches the rising and setting of the sun.
The discovery of 24 hour patterns of behaviors began in 1729 with the French
scientist Jean-Jacque d’Ortous de Mairan, who documented the movement of
the Mimosa pudica plant. This unique organism was chosen since the plant
exhibits heliotropism, light-seeking movements. In particular, this plant
opened up the leaves in the daytime to capture sunlight, then closed at night,
minimizing predation. When the plants were put into a dark room with no
exposure to sunlight, to his surprise they still opened and closed their leaves
in time with the clock. Mairan concluded that the plant did not change its
behavior in response to light, but rather in response to some internal 24-hour
clock. His work laid the foundations for future chronobiologists, scientists
who study day- night dependent periodic phenomena in living beings.
300 | 8.4: THE CIRCADIAN RHYTHM

Figure 8.10 The leaves of the Mimosa pudica plant open and close their
leaves in time with the 24-hour cycle of sun rising and setting, even in
complete darkness. CREDIT: Brucewinter [CC BY-SA 4.0
(https://creativecommons.org/licenses/by-sa/4.0)] Pancrat [CC BY-SA 3.0
(https://creativecommons.org/licenses/by-sa/3.0)]

Any behavior or physiological measure that intrinsically cycles on a 24-hour

pattern is said to be a circadian rhythm. The word circadian comes from the
Latin words circa- meaning “around”, and diem meaning “day”. Compare this
with an ultradian rhythm, any cycle that is faster than 24 hours, such as the cycling
between deep sleep and REM sleep every 90 minutes. Alternatively, compare with
infradian rhythms, patterns that are longer than 24 hours, like the 4-week-long
human menstrual cycle.Although we mostly think of the circadian rhythm in the
context of sleep and wake, many other physiological measures fluctuate reliably
throughout the day. Blood pressure peaks at 11 AM, making the morning the time
with the highest risk for cardiac events. Body temperature dips late in the evening,
putting the body into a low-energy state that helps promote sleep. Withdrawal
 8.4: THE CIRCADIAN RHYTHM | 301
reflexes peak around midnight, hunger-driving hormone production rises before
lunch and dinner, attention is usually highest in the morning – all manner of
behaviors that rise and fall depending on the time of day can be said to be a part of
a circadian rhythm.
Bizarrely, even organisms with a life span shorter than a full day still exhibit 24
hour cycling patterns of circadian rhythm-like behaviors. Cyanobacteria, or blue-
green algae, are capable of a process called nitrogen fixation, where they convert
atmospheric nitrogen into organic compounds like amino acids. These organisms
are capable of asexual reproduction every 6 hours or so, but they still have nitrogen
fixation patterns that align with daily patterns of light and dark.
Circadian rhythms on a behavioral level
Luckily, a person’s circadian rhythm is not permanent. Anyone who has traveled
overseas to a different time zone for more than a few days has experienced that
uncomfortable sensation called jet lag, where a person experiences psychological
symptoms such as difficulty concentrating and mood swings, and physical
symptoms like daytime fatigue, insomnia, and gastrointestinal distress (nausea,
constipation, or diarrhea). Jet lag happens when there’s a mismatch between the
internal environment and the signals that the brain receives from the outside
world. If you flew east from Chicago to Cairo, for example, your circadian clock
will be off by 7 hours. When your internal “Chicago” clock is telling you to start
getting sleepy around 11 PM, the sun will be rising in Cairo, as the locals are
starting to wake up. You may be eating when you’re not hungry or laying down in
bed when you’re not sleepy, and this mismatch contributes to jet lag.
However, with a few days of adjustment, you will be able to overcome jet lag.
You will start sleeping as the sun sets, you will get hungry at the same time as the
Egyptians, and your physiological measures will start to align with your time zone.
This adjustment is only possible because our circadian rhythms are entrainable,
meaning they are able to change and fit the surroundings.
302 | 8.4: THE CIRCADIAN RHYTHM

Figure 8.11 Traveling to a part of the world where day and night misalign with
your internal circadian rhythm can cause jet lag. Image by Arek Socha from
Pixabay
Our circadian rhythms entrain in response to zeitgebers, the German word
for “time givers”: environmental cues, such as increased light exposure when the
sun comes up, or social cues, such as increased sensory input from heightened
activity of the people around you. A rise in the neurohormone melatonin is an
important signal that contributes to helping the brain entrain, which is why taking
a melatonin supplement late at night when in a new time zone may help someone
get over jet lag more quickly. If sunlight is a trigger that helps a person entrain
their circadian rhythm to new environments, what would happen if a person
is completely isolated from sunlight? In other words, what does a free-running
circadian rhythm look like? One of the early documented case studies addressing
this curiosity was conducted by a French cave explorer named Michel Siffre. In
1972, Siffre (voluntarily) spent six months deep in a Texan cave to evaluate what
would happen to a person completely isolated from zeitgebers. At the end of the
experiment, he found his circadian cycle was much longer than 24 hours, and very
unpredictable – some of his so-called days would consist of being awake for 36
hours and asleep for 12. A more rigorous scientific study, conducted in a group
of people living in an underground bunker with unchanging lighting conditions
for several days estimates the typical free-running circadian cycle to be close to 26
 8.4: THE CIRCADIAN RHYTHM | 303
hours. In other words, a person absent from external cues begin to fall asleep and
awaken 2 hours later each day.
Free-running circadian disruption is a potential issue for scientists aboard the
International Space Station, who experience about 16 sunsets and sunrises per
day, since the orbiting space vessel completes one trip around the earth every 90
minutes. In order to minimize the negative effects of jet lag on the researchers
aboard, NASA has the inside of the vessel set to an artificial 24-hour cycle. Bright
blue LEDs illuminate the cockpit in the “daytime,” while dim, red-shifted
wavelengths are used in the evening to induce sleepiness.

Figure 8.12 The free-running circadian rhythm is slightly longer than 24

hours. In conditions with unusual light conditions, such as aboard the
International Space Station’s research laboratory, “night-time” is
mimicked every 24 hours. CREDIT: https://commons.wikimedia.org/wiki/
File:ISS-47_The_International_Space_Station%27s_Destiny_Laboratory_
at_%27night%27.jpg

Circadian rhythms on a molecular level

The circadian cycle functions on the molecular scale at the level of cellular
transcription. In the mid 1980s, the gene period was discovered in the genome
of the fruit fly, Drosophila melanogaster. Normal fruit flies are no exception to
304 | 8.4: THE CIRCADIAN RHYTHM
24-hour cycles of behavior, as they generally exhibit periods of wakefulness that are
paralleled by the rising and setting of the sun. But, if this period gene was mutated,
there was an unusual change in the sleeping habits of the flies. Some of them slept
on a 29-hour cycle, some had a shorter rhythm at 19 hours, and some had no
predictable sleep-wake pattern whatsoever.
Later, it was discovered that another gene was related to the cycle of sleep and
wake, called timeless. This gene codes for a protein called TIM, which interacts
closely with the protein coded by period, the protein PER. When PER and TIM
interact with each other, they form a dimer (a pair of molecules) with the ability
to enter into the nucleus, bind to a specific sequence on the genome, and prevent
further transcription of both PER and TIM. Therefore, the paired proteins
function as a negative feedback regulatory system.

Figure 8.13. The molecular basis for the circadian cycle depends on
transcriptional repressors. CREDIT: PranjalAgr [CC BY-SA 4.0
(https://creativecommons.org/licenses/by-sa/4.0)]

The TIM protein, however, is degraded by light, so during the daytime, the
concentration of TIM in the cell is very low. As a result, the PER protein is
left by itself, where it can no longer repress transcription. The cells, without the
active repression of transcription, then proceed to create more protein. Once night
 8.4: THE CIRCADIAN RHYTHM | 305
falls, light no longer breaks down TIM, and TIM begins to accumulate again,
forming the dimer with PER, which prevents further protein transcription. The
cycle repeats itself the next morning. Since behavior can be driven or modified
based on protein levels, the capacity for an organism to change transcriptional
activity on a 24-hour cycle suggests that genetic level changes can possibly influence
the activity of the whole organism. These gene transcription-level changes were
discovered in Drosophila in 1990, and three scientists, Hall, Rosbash, and Young,
were recently awarded the 2017 Nobel Prize in Physiology or Medicine.
306 | 8.5: NEUROCHEMICAL SIGNALS

8.5: NEUROCHEMICAL SIGNALS

Many of the neurotransmitters that the brain uses for signaling are capable of
modifying some aspects of sleep. For example:

• Glutamatergic signaling is heightened during the awake state, and many

glutamatergic neurons increase their activity during REM sleep.
• Drugs that increase the action of GABA by acting as positive allosteric
modulators are used as sedatives and sleep aids.
• Norepinephrine, acting through increasing activity of the sympathetic
nervous system, enhances alertness.

Be aware that many neurotransmitters can affect sleep behavior. However, we

are only going to describe the function and actions of three sleep-related
neurochemicals.

Adenosine
Adenosine is a molecule that has a variety of functions in the body. In addition to
being one of the four main building blocks of DNA (the “A” of the A:T G:C base
pairing combinations), it acts as a signaling molecule in the body that is involved in
inflammation, the immune response, and modulation of heart rate.
It is also used as part of the molecule that stores cellular energy: ATP, or
adenosine triphosphate. Each molecule ofATP has phosphate bonds that release
tremendous energy when the bonds get hydrolyzed (broken apart). Vesicles, in
addition to containing neurotransmitters, have many molecules of ATP.
Throughout the day, as the body uses up cellular energy, there is anincrease of
adenosine as a result. Therefore, as our energy consumption increases, so do
adenosine levels, thus signaling to the brain that we are sleepy.
If you are able to chemically block the action of adenosine, you can stave off
sleepiness, increasing alertness and ability to focus. Odds are good that you have
 8.5: NEUROCHEMICAL SIGNALS | 307
used a psychostimulant to block adenosine signaling this morning, or are drinking
some right now. Caffeine, for example, is an adenosine receptor antagonist, and
is the world’s most popular unregulated psychostimulant drug. Other common
adenosine receptor antagonists include theobromine and theophylline, both of
which can be found in tea and chocolate. They are chemically very similar to
caffeine and adenine, part of the chemical structure of adenosine.

Figure 8.14 Caffeine acts as an antagonist for adenosine signaling.

CREDITS: https://pixabay.com/photos/asleep-sleep-bored-tired-nap-3126444/
https://pixabay.com/photos/crazy-fun-person- happy-girl-funny-2840240/
308 | 8.5: NEUROCHEMICAL SIGNALS
Melatonin
Melatonin is an endogenous hormone that helps the brain regulate the sleep-
wake cycle. Melatonin is produced by a single gland in the brain called the pineal
gland, so named for its pinecone-like shape. Specialized cells in the pineal gland
convert the amino acid tryptophan into melatonin, which is then secreted into the
bloodstream. Increased melatonin levels helps to signal the body to prepare for
sleep.
The production of melatonin is heavily dependent on exposure to sunlight.
While some of the cells in the retina are responsible for passing specific visual
information into the brain, other cells (such as the photosensitive retinal ganglion
cells) communicate whether or not it is daytime. These cells send their axonal
projections separately from the optic nerve that sends most visual information.
Rather, they project through a pathway called the retinohypothalamic tract
(RHT), synapsing on a clump of cells in the hypothalamus called the
suprachiasmatic nucleus (SCN). In turn, these cells of the SCN send inhibitory
projections to the pineal gland. In the day time, the SCN tonically inhibits activity
of the pineal gland, resulting in low production of melatonin. But when daylight
starts to decrease, the RHT sends a weaker excitatory signal onto the SCN, which
allows increased pineal gland activity.
 8.5: NEUROCHEMICAL SIGNALS | 309

Figure 8.15 Exposure to light sends information via the

retinohypothalamic tract and signals to the suprachiasmatic nucleus
(orange structure) of the hypothalamus, which inhibits pineal gland
(purple structure) production of melatonin. CREDIT: Davide Gnocchi,
Matteo Pedrelli, Eva Hurt-Camejo, and Paolo Parini [CC BY 4.0
(https://creativecommons.org/ licenses/by/4.0)]
310 | 8.5: NEUROCHEMICAL SIGNALS

Figure 8.16 Exponential decay of caffeine given a half life

of 5 hours CREDIT: Lim (2021)

Half-life
Exogenous substances that enter the body usually get degraded
over time through natural enzymatic processes. The half-life, also
written as t1/2, is the time that it takes for the concentration of the
substance to be degraded to one half of what it originally was.

The half-life of caffeine is about 5 hours. This implies that if you

drink a full cup of coffee at 2 PM and plan on going to bed at
midnight, the caffeine in your bloodstream is similar as if you just
chugged a quarter of a cup of coffee before trying to sleep.

Light exposure is the main environmental influence that decreases melatonin levels.
But, not all wavelengths of light are equally potent at dampening melatonin
production. The shorter wavelengths of light, down in the violet-blue range, are
much more efficient at activating the RHT compared to longer, yellow-red
wavelengths. Increased RHT activation leads to decreased melatonin production,
 8.5: NEUROCHEMICAL SIGNALS | 311
which can delay the onset of sleep. Fluorescent or LED lighting and digital devices,
such as computer screens and cell phone screens, use blue wavelengths of light.
Therefore, the best advice to optimize your sleep habits is to eliminate exposure to
all digital devices about one hour before your intended bed time.

Figure 8.17 Production of melatonin is most strongly suppressed by

blue wavelengths of light, which are emitted by the LEDs that backlight
digital devices like computer or cellphone screens. CREDIT: By Lamiot –
Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/
index.php?curid=36046024 Kipala [CC BY-SA 4.0 (https://creativecommons.org/
licenses/by-sa/4.0)]

Histamine
Histamine is a small signaling molecule that has a variety of functions. In the
body, histamine mediates the sensation of itch, participates in the inflammatory
response, and activates the immune system. In the brain, histamine is a
neurotransmitter that acts as a pro- wakefulness signal (the opposite of adenosine
and melatonin, which both increase drowsiness.) Most people understand the
role of histamine in the context of allergies. Seasonal allergy sufferers often take a
histamine antagonist (antihistamine) to decrease the severity of allergen exposure.
Many antihistamines warn against operating heavy machinery while taking these
drugs, since drowsiness is one of the major side effects. Newer generations of
antihistamines are more effective at minimizing drowsiness, so they often advertise
“non-drowsy” on the packaging.
312 | 8.6: BRAIN STRUCTURES INVOLVED IN SLEEP

8.6: BRAIN STRUCTURES

INVOLVED IN SLEEP

When scientists use an EEG to measure electrical activity, they look at the activity
of neurons in the cortex, the outermost layer of brain cells. However, sleep and
wake behaviors are driven by the action of cells that lie buried deep within the
phylogenetically older areas of the brain. The signals that originate here
communicate broadly throughout the rest of the brain, and these signals are the
ones that cause us to sleep or wake. It is not just a single part of the brain that
controls sleep behavior, but most likely a network of communication activity
between different areas. Here, we will only address a few of the brain areas that are
heavily involved with sleep.

Hypothalamus

Early studies on the role of the hypothalamus in sleep began with Viennese
neurologist, Constantin von Economo. He described a series of patients with a
disease called encephalitis lethargica in 1917. In his observations, patients
presented with one of two sets of symptoms. Some had progressive lethargy,
starting with drowsiness, moving to extended sleeping periods, worsening to coma.
On the complete opposite end of the spectrum, some patients had severe insomnia
– a clinically
significant difficulty with falling asleep. When von Economo performed the
autopsy on the patients, he found very specific injuries in the hypothalamus that
correlated with symptoms. Among those with persistent sleepiness, the posterior
hypothalamus was severely damaged. Von Economo concluded therefore that the
posterior hypothalamus contained structures that are needed for maintenance of
wakefulness in the healthy individual. In the patients with insomnia as their main
symptom, their anterior hypothalamus was injured, leading von Economo to
conclude that this area was important for promoting sleep.
Von Economo’s findings represented a shift in the way scientists thought of
 8.6: BRAIN STRUCTURES INVOLVED IN SLEEP | 313
sleep. Most researchers believed that sleep was brought on simply by an overall
decrease in brain activity. However, his discovery of hypothalamic localization of a
“sleep center” demonstrated that for normal sleep to happen, certain areas in the
anterior hypothalamus actually need to increase their activity.
The hypothalamus can be subdivided further into populations of neurons that
have previously been addressed in some context. The suprachiasmatic nucleus
(SCN), the neurons that receive light information via the retinohypothalamic tract
and help regulate melatonin release, is part of the hypothalamus. Elsewhere in
the hypothalamus is the tuberomammillary nucleus, the major site of neuronal
production of the wakefulness signal histamine. The lateral hypothalamus has
neurons that produce the pro-wakefulness signaling molecule orexin (sometimes
also called hypocretin), and these neurons are lost in people with severe
narcolepsy.

Clinical connection: Encephalitis lethargica

314 | 8.6: BRAIN STRUCTURES INVOLVED IN SLEEP

Figure 8.18 Hypothalamus damage was found in people who

experienced encephalitis lethargica (sleeping sickness). CREDIT: Life
Science Databases(LSDB). [CC BY-SA 2.1 jp (https://creativecommons.org/
licenses/ by-sa/2.1/jp/deed.en)]

In the midst of World War I, a strange disease of unknown origin

called encephalitis lethargica ravaged the globe. A worldwide
pandemic, an estimated five million people were affected. About half
of the patients died from early stage symptoms, and those who
survived often failed to recover fully.

Encephalitis lethargica was also called “sleeping sickness” because of

the symptoms that patients experienced: a lack of energy, extreme
muscle weakness, and loss of all desires. Neurologist Oliver Sacks
described these patients as being “insubstantial as ghosts, and as
passive as zombies.”

Today, cases of encephalitis lethargica are extremely rare. The cause

of the disease was never figured out, but one theory suggests that
 8.6: BRAIN STRUCTURES INVOLVED IN SLEEP | 315

malfunctions in the immune system are related to the onset of the

disease, since a major outbreak appeared in the wake of the Spanish
flu pandemic of 1918.

Reticular formation

The reticular formation is found in the brainstem. Like a large net of

interconnected clumps of neurons, it is difficult to anatomically classify the
structures of the reticular formation, since they do not have a clearly defined
border or boundary. Activity of these neurons contribute to a variety of behavioral
states, such as alertness and consciousness. The reticular formation is vulnerable to
ischemia, lesions, or physical trauma. Often, severe injuries may result in a loss of
consciousness or coma.
Information flow through the reticular formation passes in the upwards
(towards the cortex) and downwards (towards the body) directions. The upward
pathway, also called the ascending reticular activating system (ARAS), receives
inputs from all the sensory systems before sending wide projections all across the
cortex. (For your curiosity, the downward pathway is the reticulospinal tract that
is involved with motor control of the skeletal muscles, and is not strongly involved
with sleep behaviors.)
316 | 8.6: BRAIN STRUCTURES INVOLVED IN SLEEP

Figure 8.19 The reticular formation in the brain stem is a series of

interconnected neurons that control some functions of consciousness.
CREDIT: https://commons.wikimedia.org/wiki/File:Reticular_formation.svg
modified by Austin Lim
 8.7: SLEEP DISORDERS | 317

8.7: SLEEP DISORDERS

Insomnia
Almost everyone has experienced difficulty sleeping at some point in their lives,
often as a result of stress or anxiety. For example, it might be difficult to fall asleep
the night before a big interview, or you may wake periodically in the hours before
an important early morning flight. There is no strict definition for insomnia.
The major clinical symptoms are self-reported measures, such as a dissatisfaction
with nightly sleep or a change in daytime behavior, such as sleepiness, difficulty
concentrating, or altered mood states. The lack of clear diagnostic criteria makes
estimating prevalence difficult, but some guesses put the number of people with
insomnia close to one third of the US population.
Common triggers for insomnia include heightened anxiety, stress, or advanced
age. It may also be downstream of other diseases, such as Parkinson’s disease,
diabetes, depression, or chronic pain conditions. Lifestyle can also be a major
risk factor for insomnia, as jet lag and working late-night shifts can disrupt sleep
patterns.
We can describe insomnia as acting at two stages. Onset insomnia is defined as a
difficulty with initially falling asleep. People with onset insomnia will frequently lie
in bed for a long time before finally drifting off. Maintenance insomnia, however,
is a difficulty with remaining asleep. People with maintenance insomnia experience
many waking events throughout the middle of the night, or they may wake up very
early in the morning and be unable to get back to sleep. The two are not exclusive,
and people may experience both forms of insomnia in a single night.
The most effective treatments for insomnia begin at the level of behavioral
changes. Improving sleep habits, such as minimizing arousal states before bedtime,
developing a reliable pattern of sleep-wake timing, eliminating caffeine intake in
the afternoon and evening, and increasing daytime physical activity can decrease
insomnia. Prescription medications are less preferred for insomnia treatment, since
these drugs are more effective at inducing unconsciousness rather than biological
318 | 8.7: SLEEP DISORDERS
sleep. These drugs can also have adverse psychological side effects such as mood
swings and depression, and those adverse effects may be more severe than insomnia
itself. Prolonged use of prescription sleep medications can lead to a “rebound
effect,” causing a person to experience even worse insomnia when they are unable
to get sleep drugs. This is called iatrogenic insomnia, and can lead to a cycle of
dependence.

Clinical connection: Fatal familial insomnia

While many cases of sleeplessness last a day or two, and some
cases are clinically significant and treatable with behavioral changes,
a very small fraction of cases of insomnia are incurable and deadly. In
people with fatal familial insomnia (FFI), they experience severe
insomnia. Some patients stay awake for up to six months at a time.
As a result of either the disease or the sleep deprivation, they
experience altered mood states, hallucinations, dementia, and
eventually death, usually within two years after a diagnosis is made.

The cause of FFI is unknown. There is a strong genetic component

associated with it, as it appears frequently within certain family
trees. But, there have also been a few cases of sporadic FFI, people
with no apparent family members with the disease. One observation
in common among people with FFI is significant damage to the
thalamus, as a result of misshapen proteins called prions, a similar
disease-causing agent that is responsible for mad cow disease.

Sleep apnea
Sleep apnea is characterized by nightly sleep that is frequently interrupted by the
inability to breathe (a- meaning none, and pneu referring to wind, air, or breath,
 8.7: SLEEP DISORDERS | 319
as in pneumonia or pneumatic pump). In turn, this lowers blood oxygen levels,
causing the brain to wake the person in panic. Each wake event may only last
a few seconds, but these disruptions are significant enough to prevent a person
from getting the appropriate amount of restorative deep sleep. A person with
sleep apnea may wake 30 times an hour, despite having no recollection of waking.
The immediate result of sleep apnea is excessive daytime sleepiness, but over long
periods of time, sleep apnea contributes to the development of heart disease and an
increased risk for stroke.
There are two forms of sleep apnea, both of which may be seen in a person
with this sleep disorder. Obstructive sleep apnea is the more common of the
two. This happens when soft tissue in the back of the throat temporarily collapses,
which can decrease or completely block airflow into the lungs. On the other hand,
central sleep apnea is mediated by some biological change in the brain that
results in a decrease in involuntary breathing patterns at night, possibly due to
some damage in the respiratory centers of the brain. There are several risk factors
that contribute to sleep apnea, which are often a combination of genetic and
environmental influences. Obesity is a major risk factor, resulting in increased soft
tissue mass around the neck and torso, which can increase the likelihood of airway
blockage. Advanced age contributes to sleep apnea, as the muscles that keep the
airway open weaken and lose tone over time. Exposure to chemical irritants, such
as cigarette smoke, contribute to inflammation and increased water retention in the
soft tissue, both of which can decrease the size of the airway.
Sleep apnea is most often treated with a portable machine called a continuous
positive airway pressure device, or a CPAP device. These machines are basically
air pumps that connect to a mask that is worn over the nose and mouth. When
used correctly, the CPAP forcibly pushes air into the person’s respiratory system,
acting as an external lung. However, the CPAP can be loud and bulky, and the
mask must be airtight for the treatment to be effective, making the treatment
very uncomfortable. Because of this, CPAPs can cause more difficulty with sleep
compared to sleep apnea itself, so they often have a low compliance rate.
320 | 8.7: SLEEP DISORDERS
 8.7: SLEEP DISORDERS | 321
Figure 8.20 Sleep apnea is a blockage of the airway during sleep,
causing patients to wake in the middle of the night (top). It can be
treated by wearing a CPAP device (bottom). CREDITS:
https://commons.wikimedia.org/wiki/
File:Obstruction_ventilation_apn%C3%A9e_sommeil.svg https://commons.
wikimedia.org/wiki/File:CPAP.png?wprov=srpw1_26

Narcolepsy
Unlike the previous two sleep disorders, which result in a deficit of sleep,
narcolepsy can be thought of as an “excess” of sleep. More accurately, narcolepsy is
inappropriate sleep, and it manifests as frequent sleep attacks throughout the day,
each event lasting for seconds or minutes at a time. An estimated 1 in 2000 people
experience narcolepsy.
One of the life-threatening symptoms that appears in narcolepsy is cataplexy,
which is the sudden weakening of muscle tone that accompanies a sleep attack. A
cataplectic attack may cause someone to physically fall over during a narcoleptic
incident. Cataplexy often happens during high emotional states, such as
excitement. As with other sleep disorders, changes in lifestyle can improve the
course of narcolepsy. Introducing short daily naps can be helpful, as can general
good sleep habits (minimal digital device usage before sleep, going to bed and
waking up at the same time everyday and engaging in physical activity regularly but
not too close to bedtime). Drugs such as amphetamines (Modafinil) can be used in
the daytime to stimulate activity in the CNS, and can be prescribed to treat severe
cases of narcolepsy. Some antidepressant drugs can be used to treat cataplexy.
The exact cause of narcolepsy has not yet been identified. However, there are
many clues that point to a dysregulation of the signaling molecule orexin
produced by cells in the lateral hypothalamus. These neurons die off in people
with narcolepsy, but the cause of why the neurons die is unknown. Also, having
a genetic predisposition to narcolepsy does not guarantee that a person will
experience the symptoms, indicating that there is some combination of genetic and
environmental factors that lead to narcolepsy.
322 | 8.7: SLEEP DISORDERS

Clinical connection: REM sleep behavior disorder.

One very rare parasomnia (sleep disorder) called REM sleep behavior
disorder (RBD) can cause people to carry out complex, highly
coordinated motor actions while they are sleeping, sometimes acting
out their dreams as if they were reality. People with RBD are at risk
of injuring themselves or others.Their sleep actions may be in
response to a violent nightmare, causing them to jump out of bed,
kick or punch the air, run through the house, or throw things.
Perhaps, one of the most shocking instances of parasomnia-induced
sleepwalking was the 1987 case of Kenneth James Parks, a Canadian
man who, in his sleep, drove 23 km to the house of his in-laws and
stabbed both of them with a kitchen knife. After his arrest, scientists
discovered that his brain activity was highly abnormal during sleep.
As a result of the medical examination, the Supreme Court of Canada
acquitted him of murder in 1992.

Restless legs syndrome

A person with restless legs syndrome (RLS) experiences frequent
unusual sensations in their limbs, such as a tingling or buzzing. Because these
uncomfortable sensations disappear with movement, people with RLS often
want to move their legs around. Technically, RLS is not exclusively a sleep
disorder, since patients experience similar symptoms when they are simply at
rest, while sitting and watching TV or studying. But, the sensation happens
frequently as a person is lying down in bed, thus delaying the onset of sleep.
RLS is likely underdiagnosed, since it is a disease that exists on a spectrum.
Those who are minimally affected probably do not experience significant
changes in sleep. Estimates of prevalence of RLS range from 2.5% to 15%. Major
 8.7: SLEEP DISORDERS | 323
risk factors for RLS are iron deficiency and dopamine dysregulation. The exact
pathogenesis is unknown, but it does have some genetic component

Periodic limb movement disorder

Periodic limb movement disorder (PLMD) is a motor disorder that causes abrupt
limb movement such as kicking, flexing, or jerking. Usually, the limb movement
is in the legs, but arm movement can also be seen. Since motor activity is actively
suppressed during REM sleep, limb movement is most often seen in the first half
of sleep when NREM sleep dominates the sleep cycle. Each series of limb activity
repeats at about a 30 second interval. PLMD is different from RLS, since PLMD
results in involuntary movements that a person may not be aware of, while RLS
related-movement is voluntary. As a movement disorder, the course of PLMD can
be modified by dopaminergic drugs. Alternatively, sedatives can help minimize
nighttime movement.

Figure 8.21 Polysomnogram showing repeated muscle activity in both

left and right legs (bottom two traces) during sleep. CREDIT:
https://commons.wikimedia.org/wiki/File:PLMD_Polysomnogram.png
324 | 8.7: SLEEP DISORDERS
 CHAPTER 9: LEARNING AND MEMORY | 325

CHAPTER 9: LEARNING
AND MEMORY

Material in this chapter has been remixed and edited by Jill Grose-
Fifer. Ph.D, (John Jay College, CUNY).

Much of the material comes from Chapter 13 on Learning and

Memory from the Open Neuroscience Initiative
https://www.austinlim.com/open-neuroscience-initiative The orginal
material was written by Austin Lim, PhD (DePaul University) and
David Graykowski (DePaul University) Editor: Alexandrina Guran,
PhD (Universität Wien).
326 | CHAPTER 9: LEARNING AND MEMORY
 9.1: INTRODUCTION TO LEARNING AND MEMORY | 327

9.1: INTRODUCTION TO
LEARNING AND MEMORY
Austin Lim, Ph.D.; David Graykowski; and Alexandrina
Guran, PhD (Editor)

Figure 9.1. Do you remember your 6th birthday?

CREDIT: https://pixabay.com/photos/
handmade-birthday-cake-dessert-3989069/

Think back to your favorite birthday party. Which of your friends were there?
What did you do, where did you go, and did you have cake? Did you get gifts?
The ability to perform this task depends on our ability to create and recall
memories. According to our current understanding of the neuroscience of
learning, the underlying biology of a memory mainly consists of subtle changes
among synapses distributed across several brain areas. Our ability to learn new
facts, recount the events of last week, or to perform new motor skills is the result of
learning-induced neural plasticity. In this chapter, we will consider different aspects
of learning and memory, starting from the behavioral level down to the molecular
328 | 9.1: INTRODUCTION TO LEARNING AND MEMORY
changes responsible for memory formation, as well as some disorders that disrupt
healthy memory processes.
 9.2: PATIENT HM | 329

9.2: PATIENT HM

Patient HM
One of the most influential case
studies in the neuroscience of memory
is the story of Henry Molaison who
died in 2008 at age 82 of respiratory
failure. He was known as Patient
HM. HM was born in 1926 in a small
Connecticut town. He had a mostly
regular childhood: taking family road
trips, riding bicycles, and learning
Figure 9.2 Patient HM at 27 years
about American presidents in school.
old. Credit: https://en.wikipedia.org/
wiki/File:Henry_Gustav_1.jpg In his childhood, HM began having
mild seizures, probably the result of a
head injury when he was knocked down by a bike when he was seven years old. In
his teenage years, he started having tonic-clonic seizures, the most severe form of
seizures that produces a loss of consciousness and convulsions (extreme muscle
contraction or extension). In his early adulthood, he was having a tonic-clonic
seizure monthly and several minor seizures daily, preventing him from working a
normal job or living a normal life – despite taking a cocktail of anti-epileptic
medications.
Neurosurgeon William Scoville proposed a “frankly experimental operation” to
treat HM. It was known that most epilepsy originates in patches of neurons of
the medial temporal lobe (MTL), and HM’s epilepsy was typical in this respect.
Scoville decided to surgically resect the MTL. In 1953, Scoville removed about
8 cm of the MTL bilaterally, including part of the amygdala, and notably the
hippocampus, the seahorse-shaped structure of the brain.
330 | 9.2: PATIENT HM

Figure 9.3. The location of the hippocampus in the medial temporal lobe
(top). A dissected hippocampus and fornix (bottom left) looks like a
seahorse (bottom right). Credit: https://commons.wikimedia.org/wiki/
File:Hippolobes.gifhttps://commons.wikimedia.org/wiki/
File:Hippocampus_and_seahorse_cropped.JPG

The surgery succeeded at its primary goal: HM’s seizures were less frequent and less
severe. However, HM was left with a highly unusual and life-altering side effect: He
was unable to create new discrete memories, a memory deficit called anterograde
 9.2: PATIENT HM | 331
amnesia. For example, he could not remember what he had eaten for lunch just
minutes after finishing the last bite. Despite being an avid fan of watching the
news, HM couldn’t remember the names or the faces of different celebrities or
public figures. It was as if he was permanently living in the present. (In contrast,
retrograde amnesia affects the ability to successfully retrieve memory from one’s
past.) However, despite his pervasive memory deficits, HM did not display any
deficits in intelligence. His language and speech were unaffected, and word recall
was excellent, as he loved completing crossword puzzles and often did so
successfully late in life, with only the occasional spelling errors. He could learn to
acquire some new skills, such as keeping a pen still on a moving circular platform,
or a tapping task (these skills are a different form of memory called procedural
memory; see below). He was also capable of recalling things from his early
childhood, such as geography facts he had learned in elementary school.

Types of memories
The fact that HM’s MTL surgery disrupted some types of memories (e.g., memory
for facts) while others were still intact (e.g., motor skills) inspired
neuropsychiatrists to try to define the different forms of memory. Much of the
research was led by Dr. Brenda Milner, who carried out several behavioral tests on
HM to figure out what types of memories are dependent on the intact MTL and
which ones can function without MTL.
The most profound deficit was HM’s inability to create new declarative
memories. Declarative memories, also called explicit memories, are the pieces
of information that can be consciously declared or stated explicitly. Declarative
memories are thought of as a “knowing what”. Declarative memories can be
further subdivided into semantic memory and episodic memories.
Semantic memories are pieces of factual information. Some examples include:

• “Jupiter is the largest planet of our solar system.”

• “Rosalind Franklin discovered the double- helix structure of a DNA
molecule.”
• “The actor Keanu Reeves played the protagonist of the movie The Matrix.”
332 | 9.2: PATIENT HM
An episodic memory, sometimes also called an autobiographical memory, is the
recollection of a discrete moment in a person’s life. It can be thought of as “mental-
time travel” – when we think back to specific events or episodes in our lives. The
following memories are examples of episodic memories:

• “When I got home, I put my wallet and phone on the table.”

• “I ordered a pepperoni pizza last night.”
• “In 2019, I went to see my favorite musicians perform live.”

Several tests concluded that HM had lost his ability to create new semantic
memories. In one such study, HM was asked to determine if a word was made
up or real. He was shown common words that he had learned as a child, such
as “shepherd” or “butcher.” On these words, he performed as well as the control
group. When he was shown words that were made up, such as “phlage” or
“thweise”, he likewise performed as well as the controls. However, when shown
words that were added into the dictionary after his 1953-surgery, such as “granola”
or “jacuzzi,” he scored about 50% correct – consistent with guessing at random, as
if he never acquired the meaning of these words.
HM was also unable to create new autobiographical memories. When asked
to recall one of his birthday celebrations as an adult, he wasn’t able to give any
significant details about the event. Instead, his answers were often vague and
generic.
One interesting observation was that HM’s memory about details from his
childhood were still intact. The inability to recall memories from the past, in
this case, from before HM´s surgery, is called retrograde amnesia. Patient HM’s
retrograde amnesia was temporally graded, meaning that the farther back in time
he went, the more complete his memories were. Many of his memories for the two
years before his surgery were completely lost, but memories from his youth and
teenage years were just as accurate as in healthy individuals (there is contention
about this observation, because HM was taking several anti-epileptic drugs, which
may have impacted memory formation.) From this observation, memory
researchers concluded that the MTL functions as short-term storage site for
memories, but after some years, those memories get relocated to other brain areas
outside of the MTL. Currently, the scientific evidence suggests that memories are
distributed across several networks of cortical and subcortical brain areas.
 9.2: PATIENT HM | 333

Figure 9.4. In anterograde amnesia, a person is unable to create new

memories following a lesion (top). In temporally-graded retrograde
amnesia, older memories are better retained while recent memories are
more likely lost. Credit: https://www.austinlim.com/
open-neuroscience-initiative

While HM lost the ability to create new explicit memories, he was still able to
maintain a different class of memories, called implicit memories. They are
unconscious memories, that are recalled without conscious effort. One class of
implicit memories are procedural memories where we carry out series of actions
without conscious thought. Procedural memories include brushing your teeth or
riding a bike. People commonly call these “muscle memories”, even though the
muscles do not store any actual memory — it is you brain that tells your muscles
what to do! Another example of procedural memories involve the priming effect —
where our recent experiences affect our thought processes without our conscious
334 | 9.2: PATIENT HM
awareness. For example, if a person recently eats a banana, and then answers a
fill-in-the-blank puzzle — “b _ _ _ _ _” . They are more likely to answer with
“banana”, whereas other people might guess “bubble” or “booger”).

Figure 9.5. Summary diagram of major types of long-term memory.

Credit: Modified from http://open.lib.umn.edu/intropsyc/

The original test of implicit memory conducted by Dr. Brenda Milner was called
a procedural memory test called the mirror tracing task. In this test, the patient
is told to draw a third star in between the two stars as quickly as possible without
making any mistakes. The challenge is that the tracing is to be done while watching
their hand and the star in their reflection in a mirror. Because of these unusual
circumstances, completing this task is difficult. But over multiple days of practice,
people become better at this mirror tracing task, completing it faster with fewer
errors. Improvement on this task indicates that a person is learning or gaining some
memory about how to better perform the task.
 9.2: PATIENT HM | 335

Figure 9.6. Patient HM performed poorly on the mirror tracing task (top), but
improved at the task over time despite having no memory of performing the
task (bottom). Credit: https://pixabay.com/vectors/
pencil-sharp-school-supplies-153561/

After practicing this mirror tracing task, HM was able to finish drawing the star
about ten times faster than when he first began. He improved his performance
within each day’s worth of training, and he also improved day-to-day. There is
evidence that he maintained these skills up to one year later, despite not having
regular training on this task. Surprisingly, each day Milner examined HM, she
would need to reintroduce herself since he forgot who she was. She also had to
re-explain what HM was supposed to do in the mirror tracing task. Hence, while
HM was unable to form declarative memory about the experiment or the people
involved, learning of the procedural memories and motor actions involved in this
task remained intact.
Another type of implicit memory is an associative memory. Associative
memories are the types of information that we learn through traditional classical
conditioning. For example, you may recall learning about the classic Nobel prize-
336 | 9.2: PATIENT HM
winning experiment in physiology conducted by Ivan Pavlov in the late 1800s.
Pavlov accidentally discovered how animals learn. Pavlov was measuring the
amount of saliva that dogs produced in response to various foods. However, over
time, he also noticed that the dogs began to salivate not only at the taste of the
food, but also at the sight of food or the food bowl, and even at the sound of the
laboratory assistants’ footsteps (Pavlov, 1927). Salivating to food in the mouth is an
automatic reflex, so no learning is involved. However, dogs do not naturally salivate
at the sight of an empty bowl or the sound of footsteps—they had learned to make
the associations. Let’s review the terminology that describes classical conditioning.
The presentation of food causes a dog to salivate, a naturally happening behavior,
which is called the unconditioned response (UR). The stimulus that produces
the response is called the unconditioned stimulus (US). We can train a dog to
salivate to a neutral stimulus– like the sound of a bell. Before training, the dog
might look towards the bell and listen to it — but it’s not going to make them
drool. The training is simple — we ring the bell each time before we feed the dog.
At first, the bell has little effect, but when repeatedly paired with the food, the dog
learns that the bell signals that food is coming and starts to salivate to the sound of
the bell alone, this is called the conditioned response (CR). The bell has become
a conditioned stimulus (CS).
9.2: PATIENT HM | 337
338 | 9.2: PATIENT HM
Figure 9.7. A conditioned response after exposure to a conditioned
stimulus, such as in classical conditioning, is an example of an
associative memory, one type of implicit memory. Credit:
https://commons.wikimedia.org/wiki/File:Classical_Conditioning_Diagram.png
modified by Austin Lim

Short-term/Working Memory
HM also had his working memory tested by the psychologists that worked with
him. Working memory was traditionally called short-term memory, unlike long-
term memory, it involves storing information temporarily. Working memory
describes whatever we are thinking about in a given moment—in other words,
what our minds are working on. As you can see in the model in Figure 9.8
information can enter working memory either from long-term memory (LTM) ,
i.e., what we already know) or from sensory memory (what is happening in our
environment at a given moment).

Figure 9.8. According to the Atkinson-Shiffrin model of memory,

information passes through three distinct stages in order for it to be
stored in long-term memory. Credit: Modified from http://open.lib.umn.edu/
intropsyc/

Unlike long-term memory, working memory is very limited in how much it can
hold and for how long. Most people can only hold about 7 +/- 2 pieces of
information for about 30 seconds (unless they repeat it to themselves). After he
 9.2: PATIENT HM | 339
recovered from his surgery, HM was able to perform as well as age-matched
controls on working memory tasks.
For example, one test of working memory is the digit span test, where a
person is given a series of numbers to remember, then they are asked to repeat
the numbers in reverse order. After successfully completing this task, a different
series of numbers, this time one digit longer, is presented to the patient until they
first start making errors in recall. A related task is called the Corsi block tapping
test, where an experimenter sets up several blocks on a table. The experimenter
then taps a series of blocks in a specific order, then the subject is asked to tap
the same pattern on the blocks, but in reverse order. As with the digit-span test,
the experimenter then makes the number of blocks they tap longer until the
participant make mistakes in the tapping.

Figure 9.9. The digit span test (top) and the Corsi block tapping test
(bottom) are measures of working memory. Credit:
https://www.austinlim.com/open-neuroscience-initiative
340 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING

9.3: NEURAL STRUCTURES

INVOLVED IN MEMORY AND
LEARNING

In the previous section, we saw the effects that removing the hippocampus and
other parts of the medial temporal lobe had on HM’s memory. In this section,
we look a little more deeply at the function and anatomy of structures that are
important for memory.
 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 341
The Hippocampus (HPC)

Figure 9. 10. The circuitry of the hippocampus as illustrated by Ramon y

Cajal (top) and as a schematic diagram (bottom). Structures are labeled
in red and communication pathways are in black. Credit:
https://commons.wikimedia.org/wiki/File:CajalHippocampus.jpeg modified by
Austin Lim

The hippocampus (HPC), meaning “seahorse” in Greek, was named based on

its morphology. The HPC is located along the ventral and medial surface of the
brain. The HPC is one of the critical structures of the limbic system, a series of
subcortical brain structures that are involved in several different complex behaviors,
such as emotions and memory. The limbic system is an evolutionarily ancient brain
network.
The synaptic connectivity of the hippocampus is very well characterized.
342 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING
Hippocampal synaptic connectivity was first described by Ramon y Cajal, and is
made up of three main synaptic connections; sometimes called the trisynaptic
circuit. First, the axonal outputs of layers 2 and 3 from the entorhinal cortex
make up the inputs into the HPC. This white matter signaling tract is called
the perforant pathway, and they synapse onto the granule cells of the dentate
gyrus. These neurons send axons, called mossy fibers, to the pyramidal cells of the
Cornu ammonis (CA) 3 region of the HPC. The axonal projections from here,
called Schaffer collaterals, project into CA1, which are the neurons that make
up the output of the hippocampus. These outputs project out to layer 5 and 6
of entorhinal cortex. While the three main neuronal projections are glutamatergic,
the trisynaptic circuit is modulated by GABA, acetylcholine, norepinephrine, and
serotonin.
The HPC is involved in spatial memories, memories involved in navigation of
our surroundings and the creation of a mental map of our world. Spatial memories
are developed when we enter a new building for the first time, and we search for a
new classroom. We also use our spatial memory whenever we are walking around
campus, making our way from one building to another, thinking about the streets
you’d need to cross or the buildings you can cut through. While the volume of the
hippocampus is not a reliable indicator of the strength of a healthy person’s spatial
memory, injury to the hippocampus causes deficits in spatial memory.
One spatial memory test that is regularly used in rodents is called the Morris
water maze. In this test, a shallow pool is filled with an opaque liquid, making
it difficult to see through. Hidden somewhere in this pool is a clear plexiglass
platform, and there are different environmental cues (such as different colored
shapes) surrounding the pool that can be seen from the surface of the water. The
water is deep enough that when a rodent is put into the water maze, they have
to swim to stay afloat. The rodents swim around aimlessly until they find the
platform, the time it takes for this to happen is recorded, and the trial ends. Over
time, the animals learn that the platform is located near certain navigational cues,
and on future trials, the animals spend more time near those cues, and the latency
to find the platform decreases. When the HPC is surgically removed from rodents
or inactivated, they perform poorly in the Morris water maze.
Another non-human behavioral test used to assess the capacity for learning
navigational cues is the radial arm maze. In this test, a rodent is placed on a
circular platform. Extending from this platform are eight or more “arms”, at the
 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 343
end of each is a small dish. In one of the dishes is a morsel of food (“rewarded
arm”), while the other dishes contain nothing (“non-rewarded arms”). The maze is
designed so that the food cannot be seen from the end of each arm, so the animal
must return to the starting platform before exploring another arm. The number
of entries into a non-rewarded arms is counted as an error. Over time, the animals
make fewer errors as they learn which arm is rewarded and which ones are not.
Alzheimer’s disease model organisms perform poorly on this task.
344 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING

Figure 9.11. The Morris water maze (top) and the radial arm maze
(bottom) are behavioral tests to assess spatial memory. Credit:
https://commons.wikimedia.org/wiki/File:MorrisWaterMaze.svg
modified by Austin Lim https://commons.wikimedia.org/wiki/
 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 345
File:Simple_Radial_Maze.JPG

Based on the deficits seen in Patient HM and other experimental manipulations

of the HPC, we conclude that the HPC is strongly implicated in the process
of declarative memories and spatial navigation. Since some of HM’s memory
functions were still intact, such as procedural memories and working memory, it is
believed that these functions are independent of HPC function.

The Amygdala
The amygdala is another limbic system structure found in the medial temporal
lobe adjacent to the HPC that is important for experiencing emotion and
emotional memories. The word amygdala comes from the Greek word meaning
“almond,” which roughly describes its shape. While the amygdala is often spoken
of as a single structure, it is more accurately divided into several subnuclei, each
with different cell populations and functions. One broad division distinguishes
the basolateral amygdala (BLA) versus the central nucleus of amygdala (CeA): The
BLA contributes to both fear memories and reward processing, while the CeA
contributes more to the physiological response in emotions as well the perception
of emotion.

Figure 9.12. The amygdala are temporal lobe structures that contribute
to the salience of emotional stimuli. Credit: https://commons.wikimedia.org/
wiki/File:Amygdala.png
346 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING
The amygdala is strongly involved with the formation and storage of emotional
memories, memories or associations that have a strong emotional connection. Both
positive and negative emotional states activate the amygdala. For example, a whiff
of grandmother’s cooking may cause you to reminisce back to a fun childhood
summer. Alternatively, the smell of vomit may elicit the unpleasant emotions and
nausea associated with a nasty food poisoning incident.
One non-human test of emotional memory is the foot-shock paradigm, a form
of classical conditioning called fear conditioning. This test involves putting a
rodent into a chamber with floors made of metal rods, which are connected to
an electric current generator. The metal rods can deliver a non- lethal but painful
electric shock to the rodent’s foot. In this learning paradigm, a combination of
sound and light cues is presented to the animal. Shortly after, the painful foot
shock is delivered. If the animal learns that the cues are associated with the negative
painful memory, they exhibit freezing after exposure to the cues. Amygdala lesions
prevent the animal from freezing, while hippocampal lesions have no effect on
this emotional learning. Changing cellular signaling in the amygdala alters the
learning of fear conditioning. The foot-shock paradigm is often used as a non-
human model of post-traumatic stress disorder.
9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 347
Figure 9.13.
In the fear
conditionin
g paradigm,
a rodent is
put into a
room with
medal rods
as the floor
(left). Then,
a sound
tone is
repeatedly
paired with
a foot shock
(middle).
When the
sound is
played
again, the
rodent may
exhibit
freezing
behavior
(right).
Credit:
https://comm
ons.wikimedi
a.org/wiki/
File:202003_
Model_anima
l_mouse_mo
no.svg
https://pixaba
y.com/
vectors/
sound-audio-
music-icon-st
udio-2935370
/

Inferotemporal cortex (IT)

Structures of the inferotemporalcortex (IT) are part of the ventral stream of
visual perception (chapter 6). The IT stores some components of visual memory.
348 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING
We use these functions when we see a classmate outside the classroom and
recognize them from our Introduction to Neuroscience class, or when we see a
parody of a famous painting and recognize the similarities to the original work. A
simple behavioral task to assess visual memory would start by viewing a series of
abstract shapes, and when a shape appears that you have already seen, you push
on a button. The human capacity for visual memory is massive: After viewing
10,000 images for a few seconds apiece, people were able to identify a previously
seen image successfully about 83% of the time.

Figure 9.14. The inferotemporal cortex (purple area) is one of the

signaling pathways important for visual memories. Credit:
https://commons.wikimedia.org/wiki/File:Ventral-dorsal_streams.svg modified by
Austin Lim

A bit more specifically, one part of the IT is the fusiform gyrus, which has
been previously described in the context of facial recognition. People with
prosopagnosia, a visual perceptual disorder affecting the fusiform gyrus, can
perceive the different parts of a person’s face, but have a difficult time putting the
whole picture together and matching those features to a specific person. For facial
recognition to be accurate, there must be some memory that allows for a person to
9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 349
match those facial features with someone they have seen before, which is a memory
related process.
The parahippocampal place area (PPA), also found in IT, contributes to
visual memories associated with locations and environmental scenes. Imaging
studies have demonstrated that activity of the PPA increases specifically when
people view place-related images, including scenic landscapes like mountains, man-
made structures like campus buildings, or the interiors of rooms, both furnished
and completely empty. To serve as control stimuli, viewing faces or objects does not
increase the activity of the PPA.
350 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING
Figure 9.15.
The
inferotemp
oral cortex
(left,
sagittal
view) is
part of the
ventral
stream of
visual
perception,
and is likely
one site of
visual
information
storage.
Within the
IT is the
fusiform
gyrus
(middle),
which is
specifically
activated
strongly in
imaging
studies
when a
person is
shown with
a facial
stimulus
(right).
Credit:
https://comm
ons.wikimedi
a.org/wiki/
File:Gray727_
fusiform_gyr
us.png
modified by
Austin Lim;
https://comm
ons.wikimedi
a.org/wiki/
File:Fusiform
 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 351
_face_area_f
ace_recogniti
on.jpg;
https://pixaba
y.com/
photos/
man-water-
wet-male-fac
e-swimming-
984504/
modified by
Austin Lim

Prefrontal Cortex (PFC)

As part of the frontal lobe, the PFC is involved in high order decision making
and personality. In the context of memory, neural circuits in PFC are important
for short-term and working memory. Patients with injuries to their prefrontal
cortex after stroke, tumors or aneurysm, performed worse on a variety of working
memory tasks such as the digit span test. Additionally, people with frontotemporal
dementia, a neurodegenerative disorder characterized by a degradation of the
frontal lobe, often have difficulty with working memory.
The PFC also has strong projections with the hippocampus, and these circuits
are likely also involved in the formation of hippocampal- dependent memories.

Striatum
The striatum is a structure of the basal ganglia, a series of brain structures that
contribute to behaviors, such as motor activity and procedural memories. The
dorsal striatum likely stores memories involved in habits. Habitual behaviors help
us preserve cognitive bandwidth, reducing the “mental energy” that is used during
repetitive task performance. The downside of habits is that reliance on habitual
responding can limit behavioral flexibility, and cause a person to act in a
suboptimal manner, perhaps behaving in a way that led to a positive outcome in
a previous set of circumstances without incorporating and evaluating the present
circumstances.
352 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING
Habitual actions are likely related to a variety of neuropsychiatric disorders.
Obsessive compulsive disorder (OCD), for example, is characterized by the
presence of recurring, intrusive thoughts, which can lead to repetitive actions.
Commonly observed is the thought that one’s hands are unclean, which leads
to repeated handwashing. A rodent behavioral test of habitual activity is the
observation of self-grooming, a natural and healthy series of stereotyped actions
that consists of licking the paws and moving them through the fur of the nose,
caudally down the body. Mouse models of OCD show excessive self-grooming to
the point where they pull their fur out and paw their skin to the point of injury.
Drug addiction also involves the striatum. Compulsive drug use is often associated
with a series of habitual motor actions that happen before a person experiences
the drug effect. For example, in tobacco use disorder, people will perform an
orchestrated series of actions, including opening a pack of cigarettes, flicking the
lighter, withdrawing the cigarette and taking a deep inhalation. Some of these
behaviors are likely stored across striatal circuit. The ventral part of the striatum
is involved in operant conditioning, where we learn to repeat behaviors associated
with pleasurable consequences and to avoid those with negative consequences.
9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING | 353
Figure 9.16.
Several
subcortical
brain areas
make up
the basal
ganglia. The
areas
labeled here
are
particularly
important
for habitual
actions and
procedural
memories.
Credit:
https://comm
ons.wikimedi
a.org/wiki/
File:The_stru
ctures_of_th
e_basal_gan
glia.png

Hypermnesia

Solomon Shereshevsky was one of a handful of rare, clinically

documented cases of hypermnesia, the capacity to recall nearly any
memory with perfect precision, even after several years.
Remarkably, he could “easily remember any number of words and
digits, equally easily he memorizes whole pages from books on any
subject and in any language and for a quite long time at that.
Shereshevsky can accurately quote anything he was told ten or
twelve years ago.” He received recognition in 1968 when his
psychologist, A. R. Luria published a case study in “The Mind of a
Mnemonist.”Today, we would describe Shereshevsky as being
autistic with strong multimodal synesthesia. Also of note, he had
354 | 9.3: NEURAL STRUCTURES INVOLVED IN MEMORY AND LEARNING

significant deficits in executive function, difficulty with recognizing

faces, and could not interpret abstract ideas.

Cerebellum
The cerebellum is the phylogenetically ancient structure found posterior and
ventral to the cerebrum, and functions generally to help with motor functions.
The cerebellum is involved in procedural memories, particularly the performance
of motor abilities. Learning new motor skills likely requires changes in the circuit
strength of cerebellar neurons.
This list of brain structures involved in memory is certainly not exclusive. For
example, the orbitofrontal cortex plays a role in positive emotional memories, and
sensory cortices are important for the memories related to the specific stimuli that
are processed in those areas. A single memory is likely stored in a neural network
that involves several brain areas, much like a mosaic.
 9.4: CELLULAR MECHANISMS OF LEARNING | 355

9.4: CELLULAR MECHANISMS OF

LEARNING

In the late 1800s, around the time when Golgi and Ramon y Cajal were engaged in
intense debate about the organization of the nervous system, many neuroscientists
came to a strange observation: the weight of the brain increases dramatically over
the first 10 years of life, but not much more after that. Even though we learn lots
of new facts and make lots of new memories in adulthood, the brain itself doesn’t
grow in size. So how is it possible to store new knowledge if the brain is not making
many new neurons?
Most likely, new pieces of information are held in the connections between
cells, not just in the cells themselves. If our estimate of 150 trillion synapses per
adult brain is correct, then it is possible that we could store all the knowledge and
memories that we collect over our lifetime through some combination of activity
across certain connections.
The activity at the cellular level is believed to take place on at least three different
levels enabling us to build, store, and retrieve memories.

1. Encoding refers to the ability for brain circuits to store some piece of
information. In real life, you are presented with countless stimuli
simultaneously. Imagine walking down a busy street, and think of the
number of different sights, smells, and tactile stimuli you experience. Storing
memories is an energetically costly process, and we are limited in the fact that
all of our sensory inputs cannot possibly get encoded. Instead, evolution has
preferred to encode stimuli that are most salient pieces of information, such
as perceptual cues associated with predators. Alternatively, information that
we pay strong attention to can get encoded more strongly, like when we
repeat a phone number to ourselves until we have a chance to write it down.
It is also easier to encode novel information that “builds” on previous bits of
knowledge, or information that is closely related to other well-established
information, which is why analogies are such an effective way to learn new
356 | 9.4: CELLULAR MECHANISMS OF LEARNING
facts.
2. The process that enables memory storing is called consolidation, which
makes the memory more permanent. In 1949, psychologist, Donald O.
Hebb, offered an explanation for how changes in synapses could possibly
lead to a phenomenon as complex as learning. His theory can be summed up
in the phrase:“Cells that fire together, wire together.”In Hebb’s
framework, repeated activity at a synapse within a circuit of neurons acts as a
reinforcer signal that strengthens this synapse for future communication,
making the next incoming signal more robust. A cellular process called
reverberation is thought to be the mechanism that allows for consolidation.
Reverberation is the process by which networks of neurons fire repeatedly.
Each time that circuit is activated, the strength of the network is increased,
meaning that it becomes easier for that circuit to be activated in the future.
Hebb also implies the inverse is true: when cells do not fire together, they
weaken their connection (“use it or lose it”). A lifetime of memories can be
stored across a wide distribution of neurons, by fine tuning synaptic
connections, strengthening some and weakening others.

I
 9.4: CELLULAR MECHANISMS OF LEARNING | 357

Figure 9.17. A reverberating ciruit (purple) is a

series of neurons that are activated repeatedly
with the activity of a positive feedback circuit.
Credit: Open Neuroscience Initiative

Throughout the process of consolidation, memory traces are thought to become

more represented in the neocortex and less dependent on the subcortical structures
like the hippocampusor amygdala. Recall Patient HM’s temporally graded
retrograde amnesia, where he had lost declarative memories in the two years leading
up to this surgery, and yet his memories from the long past were maintained. This
finding suggests that some aspects of declarative memory consolidation depends
at least partially on medial temporal lobe and HPC for a period of time, maybe
up to two years, before those memories get stored in the cortex more permanently.
However, we cannot conclude how long consolidation takes in healthy humans
based on findings from HM, who had pervasive and frequent seizures, which
might have negatively impacted memory consolidation before the surgery.
Consolidation seems to occur predominantly during sleep. Studies suggest that
declarative memory is particularly enhanced during non-REM sleep, while
procedural memory is enhanced during REM sleep. Studies investigating sleep
consolidation are often done by letting participants learn or perform behavioral
358 | 9.4: CELLULAR MECHANISMS OF LEARNING
tasks, after which they are deprived of a specific phase of sleep. To wake participants
at the right moment, researchers commonly use EEG signatures, which are unique
for different phases of sleep: sleep deprivation early in the night denies non-REM
slow wave sleep, while late-sleep deprivation decreases time spent in REM sleep.
Some speculate that the visual images we sometimes experience during dreaming
are a consequence of consolidation processes, but it is inconclusive as to what role
dreaming plays in memory formation.

Long-term memory can be tested in a variety of ways. You could be asked to

memorize a list of 50 words and then to write down or say as many as you can
remember, this kind of test is called free-recall. However, if you were prompted
with some of the categories of the words, e.g., animals or spices. You would likely
perform much better at retrieving those memories in this cued-recall test.
Multiple choice tests are a form of cued-recall test.
Retrieval is not a passive function. When a memory is retrieved, it is
reconsolidated, which is an act similar to replaying the activity of the circuit.
During this reconsolidation, it is possible that some aspects of the memory are
emphasized, while others are lost. This is one reason why we often experience
false memories. A dysregulation of this reconsolidation process may lead to the
symptoms seen in post-traumatic stress disorder, where the negative emotional
components of a traumatic memory are exaggerated rather than being blunted.

Special populations of neurons

An individual memory is likely distributed widely across several different parts of
the brain. However, there are a few special populations of neurons mainly in the
MTL that contribute to highly specific types of memories.

Place cells
Place cells are a special population of pyramidal cells of the hippocampus. These
neurons increase their firing activity when the animal is in a particular location
in an environment, indicating that they contribute strongly to location and
navigational memory. There is no apparent topographical arrangement of these
 9.4: CELLULAR MECHANISMS OF LEARNING | 359
place cells, meaning that adjacent areas of an environment do not necessarily
activate adjacent hippocampal place cells. The place cells, when firing at the right
times, help the animal create a spatial map of their surroundings.
360 | 9.4: CELLULAR MECHANISMS OF LEARNING
Grid cells

Figure 9.18. A rat is tracked (left, gray) as they move through an open
field. Individual grid neurons spike when the rat passes through
particular areas of the open field (left, red). Heat map (right) showing
high neuronal activity in warm colors (red and yellow) with low activity
in cool colors (blue). Credit: 13.16 https://commons.wikimedia.org/wiki/
File:Examples_of_Grid_Cells_with_Different_Grid_Spacing_and_Field_Size.jpg
 9.4: CELLULAR MECHANISMS OF LEARNING | 361
Grid cells are located in the entorrhinal cortex, the main input structure to the
HPC. Closely related to the place cells described above, grid cells increase their
firing properties periodically when an animal is at an intersection of a “grid” in a
wide-open, previously-explored environment. The grid itself is roughly hexagonal,
and spans the whole environment an animal is in. The overlap of multiple grids
gives the animal an idea of the surroundings. The scientific description of grid cells
earned three scientists a Nobel Prize in Physiology or Medicine in 2014.
362 | 9.4: CELLULAR MECHANISMS OF LEARNING
Jennifer Aniston neurons
9.4: CELLULAR MECHANISMS OF LEARNING | 363
Figure 9.19.
Concept
cells change
their firing
pattern in
response to
the
presentatio
n of highly
specific
stimuli,
such as the
character
Luke
Skywalker
(portrayed
by actor
Mark
Hamill;
images 1, 3,
and 5).
Visually
similar but
conceptuall
y different
stimuli
(male
brunette
actors
appearing
in film), like
pictures of
Leonardo
diCaprio
(image 2) or
Keanu
Reeves
(image 4),
fail to
induce
changes in
firing.
However,
visually
distinct but
conceptuall
y-related
364 | 9.4: CELLULAR MECHANISMS OF LEARNING
stimuli, like
the picture
of Yoda (a
related
character
from the
same series
of films;
image 6)
may also
drive the
concept
cells to fire.
Credit:16
https://comm
ons.wikimedi
a.org/wiki/
File:Mark_Ha
mill_(right)_a
nd_me_(left)
_(210269249)
.jpg
https://comm
ons.wikimedi
a.org/wiki/
File:Mark_Ha
mill_(1980).jp
g
https://comm
ons.wikimedi
a.org/wiki/
File:Star_War
s_
characters_at
_Madame_Tu
ssaud.jpg
https://comm
ons.wikimedi
a.org/wiki/
File:Retrato_
del_Maestro_
Yoda.jpg
https://comm
ons.wikimedi
a.org/wiki/
File:Leonardo
_DiCaprio_20
 9.4: CELLULAR MECHANISMS OF LEARNING | 365
14.jpg
https://comm
ons.wikimedi
a.org/wiki/
File:Keanu_R
eeves_2014.j
pg

The “Jennifer Aniston” neurons, also called concept cells, are a series of cortical
neurons in the temporal lobe that increase their firing exclusively in response
to highly-specific stimuli, such as the idea of Jennifer Aniston, Halle Berry, or
the Tower of Pisa (based on a person’s experience). These concept cells respond
to much more than just pictures: for example, a Luke Skywalker neuron that
responded to a picture of young Mark Hamill (the actor who played Luke
Skywalker) will also respond to text that reads “LUKE SKYWALKER” and the
sound of a person saying “Luke Skywalker”. Although this particular neuron
probably won’t fire in response to pictures of athlete Manu Ginobili or actress
Marilyn Monroe, the neuron might fire in response to pictures of Yoda or Darth
Vader, indicating that the neuron may encode an even broader concept, such as
“Star Wars characters” or “Jedi”, or is a part of a network that encodes concepts
related to the Star Wars franchise.
366 | 9.5: MOLECULAR MECHANISMS OF LEARNING

9.5: MOLECULAR MECHANISMS

OF LEARNING

Zooming in beyond the level of anatomy, the substrates of learning can be found
at the level of synapses. Synapses change in a phenomenon called plasticity. The
word “plasticity” refers to a change in synaptic strength, which may be an increase
or a decrease. This change may persist for minutes, hours, days, or in some cases,
even a whole lifetime. When synaptic strength is increased and remains elevated,
we call this long- term potentiation (LTP). A prolonged weakness of a synapse
is called long-term depression (LTD). In our current limited understanding of
plasticity, both phenomena are important for a healthy brain, and neither one is
always good or always bad.
It is also important to clarify that both excitatory synapses and inhibitory
synapses can be subject to either LTP or LTD.

Long-term potentiation
In 1973, Bliss and Lomo were the first to publish evidence of plasticity using
electrophysiology. The experiment began at the hippocampal connections of an
anesthetized rabbit. They put a stimulating electrode among the axons of the
perforant pathway, at the entrance to the hippocampus. A second electrode,
capable of detecting electrical charges in brain tissue, was placed among the cells
of the dentate gyrus, the area where those axons release neurotransmitter. By
stimulating the perforant pathway, Bliss and Lomo could record how neurons
of the dentate gyrus respond. A single pulse caused the neurons to depolarize,
a measurable observation called a field excitatory post-synaptic potential
(fEPSP). The more neurons that depolarize, the larger the fEPSP would be.
Instead of simply giving a single electrical stimulation, however, Bliss and Lomo
were interested in testing Hebb’s theory about plasticity. If “cells that fire together,
wire together,” then perhaps they could experimentally drive those cells to fire
in a pattern that would induce a rewiring of the connections, resulting in LTP.
 9.5: MOLECULAR MECHANISMS OF LEARNING | 367
The duo delivered a very intense electrical stimulation, zapping the axons at 100
stimulations a second (100 Hz) for 3 seconds. This high frequency stimulation
(HFS) led to an enhancement of the amplitude of the fEPSP in response to a
single stimulus – this demonstrated that LTP was a measurable phenomenon. In a
different experimental setup, this LTP was shown to persist up to one year later! In
humans, we theorize that some synaptic connections may remain potentiated for
our entire lifetime, however investigating this is in humans is ethically constrained.
Long-lasting changes in synaptic strength, such as the LTP that Bliss and Lomo
demonstrated, are made possible through a series of molecular and cellular level
changes. One form of LTP results from a change in the types of glutamatergic
receptors. Of the three classes of ionotropic glutamate receptors, two are important
for this form of LTP: the AMPA and the NMDA receptors. The AMPA receptors
are the glutamate receptors that we generally imagine as contributing to excitation
(more information in section 5.4). When a molecule of glutamate binds to the
active site of this receptor, the ligand-gated ion channel changes and allows cations,
mostly Na+, to cross the cell membrane, leading to depolarization.

Figure 9.20. Schematic of the recording configuration of Bliss and

Lomo’s experiments (left) demonstrating that high frequency activation
of the Schaffer collaterals while recording the field EPSP in the CA1
region leads to long term potentiation (right). Credit: 16
https://commons.wikimedia.org/wiki/File:LTP_exemplar.jpg modified by Austin
Lim

The NMDA receptors are somewhat more complex. NMDA receptors are like the
ionotropic AMPA receptors because they are permeable to cations and therefore
excitatory, but they have a few specific functional differences. For one, their
368 | 9.5: MOLECULAR MECHANISMS OF LEARNING
molecular pore has space for a magnesium ion (Mg2+) to sit in the middle of
the ion channel. Mg2+, like the other ions that we have discussed (chapter 4.2),
responds similarly to the forces of the electrochemical gradient. Mg2+ is more
highly concentrated outside the cell compared to the inside, and it has two positive
charges, so these ions are drawn to the interior of the cell. But, the pore of the
NMDA receptor is not large enough to allow the bulky Mg2+ ion to actually cross
into or out of the cell membrane. Instead, it stays stuck inside the ion channel.
Mg2+ physically takes up so much space that it occludes the movement of other
ions across the cell membrane, basically blocking passage of ions through the
NMDA receptor.
The other relevant feature of the NMDA receptor is that it is permeable to
the Ca2+ ion. Increases in intracellular Ca2+ postsynaptically is the crucial trigger
that leads to the cellular expression of LTP. Ca2+ ions activate an enzyme called
calcium / calmodulin-dependent protein kinase II (CaMKII). CaMKII itself
has many molecular targets. As a kinase, it’s main molecular action is to
phosphorylate proteins. When CaMKII becomes activated, it phosphorylates
amino acid residues on the AMPA receptor, which enhances their current passing
properties, thereby increasing their response with glutamate present. Secondly,
CaMKII also contributes to cellular mechanisms which result in increased
trafficking of AMPA receptors to the cell surface. Thirdly, CaMKII interacts with
the transcription factor cAMP response element-binding protein (CREB),
which can then move into the nucleus and instruct the nucleus to synthesize more
of the mRNA that leads to increased synthesis of the AMPA receptors. Taken
together, increases in intracellular Ca2+ postsynaptically leads to an enhancement
of a signal that persists over the time course of hours: The definition of LTP.
9.5: MOLECULAR MECHANISMS OF LEARNING | 369
Figure 9.21.
Molecular
mechanisms
explaining
postsynapti
c LTP. At no
stimulation,
glutamate
(pink) does
not strongly
activate the
AMPA
receptors
(purple;
left). A
single
presynaptic
depolarizati
on causes
some
glutamate
to be
released,
which
activates
AMPA
receptors,
causing
postsynapti
c
depolarizati
on (middle).
At high
frequency
stimulation,
significant
glutamate
release
activates
AMPA
receptors,
strongly
depolarizin
g the
postsynapti
c cell, which
causes the
370 | 9.5: MOLECULAR MECHANISMS OF LEARNING
Mg2+ ion to
leave from
the NMDA
receptor
(green).
Ca2+ enters
through the
NMDA
receptor,
and can
trigger long
term
changes in
the
molecular
components
of the
neuron
(right).
Credit:16
https://comm
ons.wikimedi
a.org/wiki/
File:Potential
_mechanisms
_of_LTP_in_s
pinal_dorsal_
horn_in_vivo.
jpg modified
by Austin Lim

But, these NMDA receptors are not activated by glutamate alone. Because of
themolecular properties of the NMDA receptors, they need two conditions to
be fulfilled before these receptors get activated and Ca2+ moves into the cell
membrane:

1. A ligand like glutamate must activate the receptor. As with other receptors,
there is no activation in the absence of an agonist.
2. The postsynaptic cell must also be depolarized. When the cell is at positive
potentials, the electrical gradient causes the bulky Mg2+ ion that is stuck in
the pore to be repelled by the cell’s interior, which then frees the ion channel
for movement of cations across the cell membrane.
 9.5: MOLECULAR MECHANISMS OF LEARNING | 371
Because both conditions must be met before Ca2+ can trigger plasticity through
CaMKII activation, the NMDA receptor can be described as a coincidence
detector. These properties can help explain why LTP was only observed after Bliss
and Lomo activated the hippocampal slices robustly with their high frequency
stimulus paradigm. Strong activation depolarized the axonal fibers, which caused a
significant amount of glutamate to be released, activating many of the postsynaptic
AMPA receptors. This strong activation caused the postsynaptic neurons to
depolarize, which expels the Mg2+ ion out of the NMDA receptor. At this stage,
both conditions are fulfilled, and Ca2+ enters into the postsynaptic cell, which
activates CaMKII, triggering LTP.
Some glutamatergic connections between neurons contain only NMDA
receptors but no AMPA receptors. Because these postsynaptic cells do not
depolarize in response to glutamate release, and no current passes through the
NMDA receptor due to the Mg2+ block, these synapses do not change their
activity even with glutamate release. These synapses are called silent synapses.
As we grow, the number of silent synapses decreases, another aspect of brain
development.

Long-term depression
Around the same tine that LTP was being characterized in the rabbit
hippocampus, its cellular opposite, long-term depression (LTD), was also being
demonstrated in a different experimental preparation. Through the 60s,
psychiatrist Eric Kandel and his colleagues worked with the marine mollusk
Aplysia californica. With a nervous system of only 20,000 cells, Aplysia is orders
of magnitude simpler than the other model organisms used at the time.
Additionally, some Aplysia neurons are huge, up to a millimeter in diameter,
which took away the need for highly precise equipment.
Aplysia also has a relatively simple anatomy. It breathes using a half-circle of
delicate tissue called the gill, which is guarded by the mantle shelf. They also have
an organ called the siphon, a small tube that is used for moving water through the
animal. Kandel and his colleagues began their exploration of memory by studying
the gill-withdrawal reflex, a defensive motor response behavior. When a
stimulus, such as a hungry predator (or an experimenter’s paintbrush), grazed the
372 | 9.5: MOLECULAR MECHANISMS OF LEARNING
siphon, the Aplysia would reflexively withdraw their gill, as if to protect this vital
organ by shrinking away from the threat. However, after repeated brush strokes to
the siphon, the sea slugs figured out that the stimulus was completely innocuous,
and decreased the strength of gill withdrawal. Kandel and his team suggested that
this change in behavior (habituation) was a form of learning.

Figure 9.22. Aplysia californica was the model organism first

used to demonstrate the neuronal level changes that underlie
the habituation behavior. Credit: 16
https://commons.wikimedia.org/wiki/File:Aplysia_californica.jpg

Kandel discovered evidence of habituation, the suppression of a normal reflex

behavior that is dependent on LTD. To further explore the cellular and molecular
level changes behind this LTD, they conducted electrophysiological experiments
on Aplysia. The gill-withdrawal reflex circuit relies heavily on two different
populations of neurons: the sensory neurons that receive somatosensory
information from the skin of the siphon, and the motor neurons that control the
muscles of the gill. By using two different tiny glass pipettes, they could impale
these neurons, inducing action potential firing in the sensory neuron, and observe
changes in membrane potential of the motor neurons (a depolarization of the
membrane of a single neuron is called an excitatory post- synaptic potential,
or EPSP). When the sensory neuron was activated, they observed an EPSP in
response, since an action potential caused release of glutamate that activates post-
 9.5: MOLECULAR MECHANISMS OF LEARNING | 373
synaptic receptors on the motor neuron. However, after the reflex had been
habituated, the same sensory neuron activation caused a much smaller EPSP in the
motor neuron.
The group went about seeing if they could modify this habituated response,
curious if a stored memory can be modified by stimuli from the outside world.
When they paired the mild siphon touch with a painful electric shock to the tail,
the Aplysia began responding with a strong motor reaction, withdrawing the gill
very intensely, indicating that the inhibited response disappeared. They called this
observation sensitization. In electrophysiological studies, they observed that the
EPSP at the motor neuron was much larger following the tail shock.
On a molecular level, presentation of sensitization is downstream of the action
of a third population of neurons, interneurons that synapse onto the motor
neurons. The noxious stimulus triggers these interneurons to release the
neurotransmitter serotonin, which activates the excitatory signaling molecule
cAMP found at the terminals of the motor neurons, thus increasing release
probability and strengthening the gill withdrawal reflex.
374 | 9.5: MOLECULAR MECHANISMS OF LEARNING
Figure 9.23.
Habituation
of the gill
withdrawal
reflex was
modeled by
Kandel
using
Aplysia.
Repeated
brush
strokes to
the siphon
caused
cellular
level
changes
that led to
decreased
gill
withdrawal.
Credit:
https://comm
ons.wikimedi
a.org/wiki/
File:Habituati
on.png
 9.6: DISORDERS OF MEMORY | 375

9.6: DISORDERS OF MEMORY

Alzheimer’s disease
In 1907, Dr. Alois Alzheimer described one of his patients, a 50-year old woman
named Auguste Deter, whose symptoms included profound cognitive
impairment, memory deficits, and delusions. After Deter’s death, post-mortem
analysis of her brain revealed anomalies: degenerating neurons that contained
atypical tangles and deposits scattered between cells. These reports were the first
of a disease we now call Alzheimer’s disease (AD). It is an irreversible, slowly
progressing neurodegenerative condition that leads to deficits in thinking,
behavior, and memory loss. Specifically, declarative memory is the first form of
memory loss observed in AD patients. As the disease progresses, procedural
memory loss becomes more apparent.
AD is a devastating disease that accounts for 60-80% of all cases of dementia
and is the sixth leading cause of death in the United States. As for prevalence,
approximately 10% of people older than 65 and nearly a third older of people older
than 85 has AD.
AD is divided into two categories, familial and sporadic. Familial AD is
diagnosed when a person is in their 50s or 60s, and is strongly influenced by
genetic risk factors. This form of AD only makes up about 10% of cases. Sporadic
AD is by far more common than familial AD, and is believed to be caused by
a combination of old age and environmental factors in addition to genetic risk
factors.
Several genetic risk factors are linked to AD risk. Apolipoprotein epsilon4
(ApoE4) is the greatest genetic risk factor identified, where individuals who are
homozygous for the e4 polymorphism have a 12-times higher risk of developing
AD than people with the more common e3 variant. Additionally, mutations in
genes like amyloid-precursor protein (APP), presenilin-1 (PSEN1) presenilin-2
(PSEN2), and triggering receptors expressed on myeloid cells2 (TREM2) are all
associated with higher risk of developing AD.
376 | 9.6: DISORDERS OF MEMORY
Figure 9.24.
Gross
anatomical
changes
observed in
the brain of
a patient
with
Alzheimer’s
disease
(right)
compared
to healthy
brain (left).
Credit:
https://com
mons.wikim
edia.org/
wiki/
File:Alzheim
er%27s_dis
ease_brain_
comparison.
jpg

To this day, only post-mortem analysis can conclusively diagnose someone with
AD. As expected, this raises many issues in terms of treating these patients.
Currently, physicians diagnose a patient with AD based on the symptoms they
presented with. However, new techniques to make more accurate diagnoses are
emerging, including identifying the presence of biomarkers from blood samples,
certain functional characteristics as observed in PET or fMRI imaging, and
possibly even through eye exams!
An early hypothesis proposed to explain the neuronal loss and memory deficits
observed in AD is centered around changes in the signaling of acetylcholine. Early
post-mortem analyses discovered that people with AD have profound atrophy of
the basal forebrain, an area which contains a large density of cholinergic neurons.
The cholinergic hypothesis suggests that it is this loss of cholinergic neurons
and the loss of acetylcholine signaling that is the main pathological driver of AD.
The theory is supported by the idea that acetylcholine plays an important role in
learning and memory. Three of the four FDA approved drugs for AD are
 9.6: DISORDERS OF MEMORY | 377
acetylcholinesterase (AChE) inhibitors, drugs that act to increase levels of
acetylcholine. Unfortunately, these compounds show only short-term benefits for
cognitive function, and these therapeutic effects subside over time.

Pathologically, AD is characterized by the extracellular accumulation of amyloid-

beta plaques (Aβ) and intracellular hyperphosphorylated neurofibrillary tau-
tangles (NFT). The amyloid cascade hypothesis, originally proposed in 1992,
has become the leading theory in the field describing how AD develops. The
hypothesis suggests that the main driving factor of AD is the deposition of Aβ
in the brain, and this in turn leads to neurodegeneration via cell death, abnormal
protein buildup, and neuroinflammation. Aβ is produced from the cleavage of
amyloid-precursor protein (APP), an integral membrane protein expressed by
neurons. A class of secretase enzymes are responsible for the degradation of APP.
When the alpha and gamma secretases degrade APP, the resulting Aβ protein is
likely to clump together in unpredictable ways, leading to the formation of Aβ
plaques (pronounced “A beta”). These plaques can cause neuronal death and lead
to the cognitive deficits observed in AD patients. Two major genetic risk factors
for AD, presenilin 1 and 2, are mutations of the gamma secretase that leads to
increased APP cleavage.

Figure 9.25. Amyloid precursor protein is processed by a secretase

enzyme, resulting in beta amyoid, which may accumulate and form
plaques in the extracellular space. Credit: https://commons.wikimedia.org/
wiki/File:Amyloid-plaque_formation-big.jpg modified by Austin Lim

Therapies are being developed to target and control the Aβ protein to mitigate
AD symptoms. Recently an antibody-based drug has been approved by the FDA.
This groundbreaking drug is unique from those traditionally prescribed because it
directly targets Aβ.
However, the amyloid-cascade hypothesis does not tell the whole story. For one,
there are patients who carry a heavy Aβ load but present no clinical symptoms
378 | 9.6: DISORDERS OF MEMORY
ofAD. More so, in mouse models with APP mutations, they develop significant
Aβ plaques, but have no accumulation of tau (see below) and no significant
neurodegeneration. Additionally, there have been several drugs targeting Aβ that
have failed in human trials.
While these amyloid plaques seem to be the primary driving factor of AD,
hyperphosphorylated tau and neurofibrillary tangles (NFTs) are also
potential culprits in disease progression. NFTs are an intracellular pathological
marker of AD and correlate strongly with cognitive deficits in AD. Tau protein is
the major microtubule-associate protein (MAP) of mature neurons, and helps to
function to maintain cellular morphology. Excess phosphorylation of this protein
causes tau to accumulate inside the cell, leading to neuronal dysfunction and cell
death. The presence of Aβ increases the levels of the tau, and vice versa, adding
to the complexity and difficulty of treating AD. Tau pathology is also observed
in other neurodegenerative diseases such as frontotemporal lobe dementia and
Parkinson’s disease.
Although most discussion of AD revolves around plaques and tangles, it is
well known that a host of pathological markers are also seen in AD, including
neuroinflammation, oxidative stress, blood-brain barrier dysfunction, heavy metal
dysregulation, mitochondrial impairment, and many more.
 9.6: DISORDERS OF MEMORY | 379

Figure 9. 26. Tau protein is used in stabilization of microtubules. Credit:

https://commons.wikimedia.org/wiki/File:Amyloid-plaque_formation-big.jpg
modified by Austin Lim

Korsakoff’s syndrome
Korsakoff’s syndrome is a disorder resulting from a severe deficiency of thiamine,
an essential vitamin that functions in metabolic processes. Dietary thiamine is
found in whole grains, legumes such as beans and peas, as well as some meats and
fishes. Healthy people with a well-balanced diet get sufficient thiamine, however
gastrointestinal illnesses can cause an inability to absorb thiamine properly.
Chronic alcohol misuse also impairs the body’s ability to take up thiamine, and is
the most common cause of Korsakoff’s syndrome.
People with Korsakoff’s syndrome experience both retrograde and anterograde
amnesia, as well as severely impaired short-term memory. The patients may
experience a very strange behavior called confabulation, which is the fabrication
of false memories ranging from subtle to wildly fantastical. People who confabulate
do not consciously recognize that their statements are untrue, and are not
intentionally trying to deceive others, which is why it is sometimes called “honest
380 | 9.6: DISORDERS OF MEMORY
lying”. Generally, confabulation only happens as a person is trying to recall recent
autobiographical memories, while their semantic and procedural memories are
less susceptible to confabulation. Scientists suggest that people confabulate as a
compensatory mechanism to
make up for their retrograde amnesia. Destruction of both neurons and glia are
seen in the brains of people with Korsakoff’s syndrome. As a result of this cell
loss, there is often shrinkage of the cortex, thalamus, the hippocampus, cerebellum,
and the mammillary bodies, paired structures located at the ventral surface of the
brain close to the brain stem, themselves part of the limbic system.
Korsakoff’s syndrome can be treated by giving thiamine supplements and
eliminating alcohol consumption. If treated within days after the onset of brain
damage, people are expected to make a complete recovery. However, one of the
major challenges is making a proper diagnosis, since the symptoms of Korsakoff’s
syndrome present similarly to other disorders.
 9.6: DISORDERS OF MEMORY | 381
Figure 9.27.
On a
delayed-res
ponse task,
a measure
of short
term
memory,
patients
with
Korsakoff’s
perform
significantly
worse than
either a
control
population
or a similar
group of
alcoholics.
Credit:
https://upload
.wikimedia.or
g/wikipedia/
commons/a/
a8/
Alcohol-induc
ed_brain_da
mage_%28IA
_
alcoholinduce
dbr00hunt%
29.pdf
modified by
Austin Lim

Traumatic brain injury

A sudden blow to the head is likely to produce a traumatic brain injury (TBI).
TBIs are the most common form of brain damage in younger people, with about
2.88 million Americans in 2014 with a TBI-related emergency department visit,
hospitalization, or death. TBI most frequently results from automobile accidents,
falls, high-contact sports, and due to occupational hazards such as in construction
382 | 9.6: DISORDERS OF MEMORY
or military deployment, among many others. A concussion is a mild form of
a TBI. Some of the common symptoms that people experience shortly after
experiencing a TBI include double-vision, headache, dizziness, nausea and
vomiting, and loss of consciousness, which are common symptoms in concussions
as well.
Usually in a traumatic brain injury, there are two simultaneous insults: the coup,
which is the injury when the brain hits the inside of the skull closest to the external
force. Shortly after, the contrecoup happens, which is the injury when the brain
recoils backwards and hits the interior surface of the skull opposite of the cause of
the insult. Following these injuries, there is a widespread inflammatory response
that changes cellular activity in numerous complex ways, such as microglial
activation, axonal stretching, and elevated levels of immune signaling molecules.
People with repeat head injuries may also experience some memory loss. It is
suggested that the damage to the brain creates an abnormal cellular environment
that interferes with the reverberation processes that are normally important for
solidifying memories. Additionally, TBI decreases hippocampal neurogenesis,
which is likely to impair the formation of declarative memories. One of the biggest
difficulties is that TBI is very different from case to case, making development of
new therapeutic strategies challenging. Currently, the best treatment for TBI is
rest. There is still debate about the types of medications that can help best improve
outcomes, psychostimulants and antidepressants being the most common classes
of drugs used in TBI.
 9.6: DISORDERS OF MEMORY | 383

Figure 9.28. TBI is often characterized by a pair of injuries, the coup and
the contrecoup injury. Credit: https://commons.wikimedia.org/wiki/
File:Contrecoup.svg
384 | 9.6: DISORDERS OF MEMORY
 CHAPTER 10: LATERALIZATION AND LANGUAGE | 385

CHAPTER 10:
LATERALIZATION AND
LANGUAGE

Material in this chapter has been remixed and edited by Jill Grose-
Fifer. Ph.D, (John Jay College, CUNY). Much of the material comes
from Chapter 14 Lateralization and Language from the Open
Neuroscience Initiative https://www.austinlim.com/open-
neuroscience-initiative The original material was written by Austin
Lim, PhD (DePaul University) Editor: Sandra Virtue, PhD (DePaul
University)
386 | CHAPTER 10: LATERALIZATION AND LANGUAGE
 10.1: INTRODUCTION | 387

10.1: INTRODUCTION
Austin Lim, Ph.D. and Alexandrina Guran, PhD (Editor)

A common misconception among non-scientists, popularized by the media and

online quizzes, is that analytic people are “left brained” while the creatives among
us are “right brained” (Chapter 1). Modern studies have concluded repeatedly that
correlating brain function with behavior on this broad level is not this simple. Both
hemispheres of the brain are capable of carrying out the same essential functions:
processing sensory and perception information, motor communication to the
body, and the storage and retrieval of memory.
However, there are some features that are slightly more focused in one
hemisphere than the other. We describe these features as being lateralized. Many
different functions have a slight preference in lateralization: for example, the right
hemisphere seems slightly better at making judgments about the duration of visible
stimuli or processing of low-frequency musical stimuli. Keep in mind, the left
hemisphere can also perform these functions, just not quite as well as the right can.
One heavily-lateralized function is language: for most people, the production
and comprehension of language is dominated by structures in the left hemisphere
of the brain. This chapter will focus primarily on language.
388 | 10.1: LATERALIZATION

10.1: LATERALIZATION

Almost all mammals are bilaterally symmetrical, with a left half that is more or less
a mirror image of the right half. The internal organs, however, often tell a different
story. We have a single stomach, liver, and heart, none of which are symmetrical.
Even paired organs like the lungs or kidneys, are slightly asymmetrical. The brain
can most accurately be thought of as a pair of intimately-connected organs with
subtle differences in function.
Typically, information from one half of body is sent to the opposite side of the
brain and each side of the brain controls the opposite side of the body. However,
our eyes and ears have a more complicated pattern of information transfer. Most
of the crossing of the information occurs in the brain stem, in or close to the
pons (which means bridge). However, this doesn’t mean that that information
stays only in the separate hemispheres. The brain’s two hemispheres are connected
by white matter tracts that allow the two halves to communicate. Information
received by the right hemisphere is quickly shared with the left and vice versa. The
largest interhemispheric white matter tract is the corpus callosum, which is made
up of 200-250 million axons. If you held a human brain and separated the two
hemispheres dorsally along the longitudinal fissure, you would be able to see the
fibers of the corpus callosum holding the two halves together. The corpus callosum
is about 10 cm (~4 inches) long from anterior to posterior, and the middle part of
the structure forms the dorsal-most roof of the lateral ventricles.
In addition to the corpus callosum, there are a handful of other white matter
tracts that allow the hemispheres to communicate. The much-smaller anterior
commissure is a tenth of the thickness of the corpus callosum, connects the
two temporal lobes, and conveys important limbic information such as memory
and emotion. The hippocampal commissure is one of the outputs of the
hippocampus that connects the structures in the left and right hemispheres. These
small white matter tracts are often used as points of reference in imaging studies or
surgical dissection.
In the 1950s, a pair of researchers, Drs. Ronald Myers and Roger Sperry, were
very curious about these pathways of communication between the two
 10.1: LATERALIZATION | 389
hemispheres. They wanted to understand how information from one visual field
gets conveyed into the opposite hemisphere of the brain. To answer the question
of interhemispheric transfer, they conducted a series of experiments in cats
and monkeys. As you may remember from Chapter 7, the anatomy of the visual
pathways is a a little unusual. Information from each eye is sent to each hemisphere
in a very specific way. 50% of the information from each eye crosses to the other
side of the brain, so that information about the right visual field from each eye is
sent to the left hemisphere and information from the left visual field is sent to the
right hemisphere. Sperry and Myers found that when they cut the optic chiasm,
which is at the crossing point of the visual pathways – information from each
eye was no longer sent to the opposite hemisphere. However, information could
still be shared across the hemispheres via the corpus callosum. Cutting both the
optic chiasm and the corpus callosum, however, meant that if an animal learned
a task with one eye covered, e.g., if the right eye was covered they were unable to
demonstrate a similar level of learning when the eye patch was switched to the
other eye.
Myers and Sperry then extended their research to humans. Sometimes, cutting
the corpus callosum or commissurotomy is suggested for younger patients with
drug-resistant epilepsy. Grand mal seizures are often characterized by uncontrolled
electrical activity in one hemisphere, which then crosses the corpus callosum to
the other hemisphere before “bouncing back” to the original hemisphere. During
the procedure, the surgeon cuts the corpus callosum, and in doing so, keeps the
atypical electrical activity isolated in one hemisphere. Patients have significantly
fewer and less severe seizures following recovery from the operation.
People who have had this surgery are sometimes called split-brain patients, a
population of patients who were extensively studied by Dr. Michael Gazzaniga..
Overwhelmingly, split-brain patients are healthy with no significant changes in
intelligence and no dramatic changes in personality. However, some of them do
experience deficits in memory and concentration.
Among split-brain patients, very unique behavioral and cognitive deficits can
be observed under specific experimental circumstances. In a lab setting, we can
also use a technique known as hemi-field presentation that capitalizes on the
anatomical arrangement of the visual pathways to present information to each
hemisphere of the brain separately (Figure 10.1). If we stare at a center spot on a
computer screen – information to the right of the spot (i.e., the right visual field of
390 | 10.1: LATERALIZATION
each eye) goes to the left side of the brain and information on the left of the spot
(left visual field) goes to the right side of the brain (Figure 10.1). In typical healthy
brains, this information is quickly shared across the corpus callosum, but in a
split-brain patient, the information stays within each hemisphere. Thus, split brain
patients provide scientists with a way to study the function of each hemisphere
separately. Myers and Sperry’s human studies noted an interesting difference in
the ability of split-brain patients to respond verbally. When the stimulus was sent
into the left hemisphere, either using a visual stimulus in the right visual field or
an object placed in the right hand, the patients were able to verbalize what they
either saw or felt. But, when the stimulus was represented in the right hemisphere,
they couldn’t. For example, as in Figure 10.1, if a split brain person looks at a
picture with a key in the left visual field (sent to right hemisphere) and a ring in
the right visual field (sent to left hemisphere) and are asked what they see, they
would say that they only saw a ring because the areas for producing language
are typically in the left hemisphere, not the right. However, if they were asked to
draw what they saw with their left hand, which is also controlled by the right
hemisphere, they would draw the key, but not the ring (Figure 10.1). Myers and
Sperry’s conclusion was that the left hemisphere is much better equipped for
language-related functions compared to the right hemisphere. Dr. Sperry earned
the 1981 Nobel Prize for his work regarding the “effects of disconnecting the
cerebral hemispheres”.
 10.1: LATERALIZATION | 391

Figure 10.1. In a hemifield study of a split brain patient, the picture of a

key is seen in the left visual field and sent to the right hemisphere. The
picture of the ring is sent to the left hemisphere. Credit: Modified from
image by Miquel Perello Nieto via Wikimedia Commons, CC BY-SA 4.0
https://en.wikipedia.org/wiki/Visual_system#/media/
File:Human_visual_pathway.svg

Other studies with split brain patients show that the right hemisphere is better
at recognizing faces than the left hemisphere, and is more likely to process
information holistically rather than in terms of its individual parts. For example,
showing a picture like the one by the artist, Arcimboldo, depicted in Figure 10.2,
gives rise to different perceptions depending on which visual field it is shown in.
If shown in the left visual field (right hemisphere) split brain patients are likely to
perceive a face, but if it is shown in the opposite visual field, they are more likely to
perceive the individual elements that the face is made from, such as the fruits and
the flowers.
392 | 10.1: LATERALIZATION

Figure 10.2. In studies with split brain patients; their perception of

this picture depends on which visual field it appears in. Credit:
National Gallery of Art, CC0, via Wikimedia Commons.
https://commons.wikimedia.org/wiki/File
 10.2 LANGUAGE | 393

10.2 LANGUAGE

Language is one of Homo sapiens’ greatest intellectual evolutionary

accomplishments. Using language, we are able to communicate very complex
concepts, such as survival instructions (Don’t eat those berries because they taste
weird and you’ll get sick) or a shared belief in the existence of complex stories
(Hang stockings by the chimney and you’ll get presents if you were good).
Language, when used in these ways, has a powerful influence on behavior, and
modern humans rely heavily on language in every aspect of society.

Components of language
Speech pathology experts have identified at least four distinct components for
describing different aspects of language. The smallest unit is the phoneme, which
is an individual sound that generally has no meaning on its own. For example,
the word map can be split into three phonemes, “mm”, the short “/ă/”, and “p”
sound. The next larger unit of language is the morpheme, which is a combination
of phonemes. Morphemes are capable of conveying an idea, such as “cat”. Suffixes
such as “-s” and “-ing” also convey ideas (plural and verbs in action, respectively)
are also considered morphemes.
The syntax represents the next higher level of language, which is the
information conveyed when words are combined in a specific way to produce
meaning at the level of phrases and sentences. For example, a statement such as “He
gave a gift to his brother” contains syntactic information identical to “He gave his
brother a gift”, even though the organization is different. The grammatical rules of
many languages tell us the order of nouns, verbs, and objects, and inappropriate
deviation from these rules can change the meaning of the sentence dramatically.
Semantics refers to the understanding of meaning, especially the meaning of
words in relationship to one another in a phrase, sentence, or paragraph. Extracting
meaning from statements not meant to be taken literally (such as a hungry person
exclaiming “I’m so hungry, I could eat a horse!”) and identification of the meaning
394 | 10.2 LANGUAGE
of a word under two different contexts (such as in the sentence “I held a nail
between my fingers, but when I swung the hammer, I hit my nail instead.”) fall
under the category of semantics.

Brain structures involved with language

Whereas the left and right hemispheres of the brain are mostly symmetrical, one of
the biggest asymmetries is related to the structures responsible for language. Myers
and Sperry observed that split-brain people can verbally report observations made
with the left brain, while having difficulty when information is stored by their right
brain. This suggests that the left hemisphere is dominant for language functions. It
is estimated that about 90% of right hand- dominant people and about 50% of left
hand- dominant people use their left hemisphere for language related functions.
However, this does not mean that the other hemisphere does not contribute to
language. The right hemisphere, for example, shows activation during the use of
nonliteral language, such as in metaphor production or irony comprehension. In
addition to the split-brain patient case studies, there are several other significant
pieces of evidence to support left hemispheric dominance for language.
10.2 LANGUAGE | 395
Figure 10.3.
Areas of the
cortex that
receive
blood flow
from
specific
arteries
(left). The
middle
cerebral
artery
(MCA)
provides
perfusion to
frontal,
parietal,
and
temporal
areas that
are
important
for
language.
CT scan of a
patient
after a
stroke of
the MCA,
showing
loss of brain
tissue (red
arrow,
right).
Credit:
https://comm
ons.wikimedi
a.org/wiki/
File:Cerebral_
vascular_terri
tories.jpg
modified by
Austin Lim
https://upload
.wikimedia.or
g/wikipedia/
commons/1/
396 | 10.2 LANGUAGE
11/
1-s2.0-S0967
5868100027
66-gr2.jpg

People with left hemisphere lesions may lose their language capacities. A stroke of
the left middle cerebral artery often leads to a variety of language related deficits.
Unfortunately, similar injuries sometimes happen after brain surgery, traumatic
brain injury, or brain infections, also resulting in language deficits when localized
to the left hemisphere.
Experimental methods have allowed researchers to study the lateralization of
language without causing any permanent damage. The Wada test is the most
reliable method by which hemispheric lateralization of language can be
determined. Named for the Japanese-born neurosurgeon Jun Wada, the test is
a presurgical assessment to minimize the risk of a person losing their language
capacity in the process of brain surgery. The protocol begins with the surgical team
asking the patient to hold up both hands, wiggling their fingers, while counting.
The patient then receives an intravenous infusion of sodium amytal, a GABA
receptor positive allosteric modulator that acts as an anesthetic. When infused into
the internal carotid artery, the drug gets delivered into just one hemisphere of the
brain with little leakage into the other. When the anesthesia perfuses through the
left brain, their right hand loses muscle tone and their fingers will stop moving
(remember the contralateral organization of the motor control system, chapter 10.)
And, if language is lateralized in this hemisphere as it is for most people, they will
also be unable to count during this time. Within seconds, the anesthesia is cleared
from the brain, and the wiggling and counting resume. If the patient is right
hemisphere dominant for language, then they will be able to count, even though
the fingers stop moving. The procedure is then repeated while the anesthetic is
perfused into the other hemisphere.
The Wada test, because of its invasive nature and occasional side effects (pain,
infection, and seizure or stroke in very rare cases), is used less frequently as
functional brain imaging methods have become cheaper and more available
through the 2000s. The fMRI is a preferred test of hemispheric dominance. To
conduct these tests, a person is put into the imaging machine, then asked to
perform a series of language tests, such as listing several items of a given category,
 10.2 LANGUAGE | 397
or listening to a conversation in preparation for follow-up questions. During this
process, the fMRI informs the medical team about which half of the brain shows
greater activity during the language tests. These behavioral tests have been found to
be as accurate as the Wada test in determining lateralization of language functions.
398 | 10.2 LANGUAGE
Figure 10.4.
Non-invasiv
e fMRI
scans
demonstrat
e that left
hemisphere
(negative x)
brain areas
increase in
blood flow
compared
to right
hemisphere
(positive x)
during the
performanc
e of
language
tasks.
Warmer
colors
indicate
increases in
blood flow,
while cooler
colors
represent
decreases.
Credit:
Wegrzyn M,
Mertens M,
Bien CG,
Woermann
FG and
Labudda K
(2019)
Quantifying
the
Confidence in
fMRI-Based
Language
Lateralisation
Through
Laterality
Index
Deconstructi
 10.2 LANGUAGE | 399
on. Front.
Neurol.
10:655. doi:
10.3389/
fneur.2019.00
655

Across the language-dominant hemisphere, there are a few brain regions that
contribute significantly to language functions. When something goes wrong with
these areas, a person may develop aphasia, a language disorder. It is estimated that
about 180,000 new cases of aphasia are diagnosed in the United States annually.
Stroke is a common cause of aphasia, but other neurological insults such as head
trauma, traumatic brain injury, or subdural hematoma can induce aphasia. Just
like nearly everything in biology, there is a wide range of severity, with some cases
being very minor and other cases being much more severe. Speech therapy can help
a patient recover from aphasia, and this progressive restoration of function is a
demonstration of the brain’s capacity for plasticity and remodeling.

Expressive (or non-fluent; or Broca’s)

One of the first language-related cortical structures to be identified was the
posterior inferior frontal gyrus (IFG). Deficits in this area lead to a difficulty
with the production of language. In the 1860’s, a patient named Louis Victor
Lebourgne had a very unusual condition: he could only speak one syllable. For
Lebourgne, the syllable “tan” meant everything, from “yes” to “no” to “hat” to
“thirty-four”. Lebourgne would say “tan” while gesturing emphatically, scream
“TAN TAN!!” when angry, and whisper “tan” when telling secrets. Because of this,
the staff at the hospital called him Patient Tan.
When Patient Tan died, the French physician Paul Broca performed an autopsy
on the brain. Broca discovered a huge lesion about the size of a “chicken’s egg”
in the left hemisphere, just dorsal of the lateral fissure in the frontal lobe. Soon
after, Broca performed autopsies on the brains of seven other patients with similar
language difficulties, all with the same prominent injury to this portion of their
frontal lobe. Because of the work that Broca did in correlating structure with
function, the posterior IFG came to be called Broca’s area (see Figure 10.5).
400 | 10.2 LANGUAGE

Figure 10.5. The posterior IFG, or Broca’s area (labeled as 45 and 44;
purple and yellow) contribute to language production. Credit
:https://upload.wikimedia.org/wikipedia/commons/c/ca/
Broca%E2%80%99s_area_-_BA44_and_BA45.png

Today, we understand that a localized injury to the IFG produces a form of aphasia
called expressive aphasia (also called non- fluent aphasia or Broca’s aphasia).
These patients have difficulty expressing themselves, only speaking in short,
effortful phrases, using just nouns and verbs while omitting tenses, conjunctions,
and prepositions. They speak haltingly, sometimes filling the silences in their
sentences with filler phrases. The patients are profoundly aware of their deficit,
leading to overwhelming frustration with their inability to communicate. They
know what they want to say, but often can’t get it out. Interestingly, these patients
do not have any significant impairment of comprehension.
Patients with IFG injury show similar expressive deficits regardless of the
modality of their language. For example, when asked to write, they write slowly,
using mostly nouns and verbs. Alternatively, patients who use American Sign
Language also lose grammatical syntax and communicate slowly when signing!
 10.2 LANGUAGE | 401
Receptive ( or fluent; or Wernicke’s)
A different brain structure, called the superior temporal gyrus is linked to language
comprehension. This area is sometimes also called Wernicke’s area, named for
the German physician named Carl Wernicke, who studied a group of patients
with a different form of aphasia than Broca’s. These patients had no deficits in
the production of speech, but the words they used were very disorganized. They
could speak complete sentences fluently, but their speech contained almost no
substantial semantic content. Unlike Broca’s patients, Wernicke’s patients had
dramatic impairments in comprehension. This language disorder is receptive
aphasia (or fluent aphasia, or Wernicke’s aphasia.)

Figure 10.6. The superior temporal gyrus, or Wernicke’s area (red),

contributes to language comprehension. Credit:
https://commons.wikimedia.org/wiki/File:Areawerinicke.jpg

While talking, people with receptive aphasia may create new meaningless words
they are unaware of, a symptom called paraphasia. These words could be a
mispronunciation of a word, perhaps sounding like the jumbling of syllables. They
can happen at the level of the phoneme or morpheme, such as saying nonwords
402 | 10.2 LANGUAGE
such as “emchurch” or “plehzd”. They also appear at the level of syntax, when a
person substitutes a word incorrectly for another, as in the sentence “But I seem to
be table you correctly, sir.”
Sometimes, people experience a difficulty with recalling words, a symptom
called anomia. This happens in the middle of a sentence, and may be difficult to
catch in casual conversation, since they will often use vague language (“stuff” or
“things”) or use several words in a roundabout fashion to describe what they are
trying to say, a behavior called circumlocution (“red, it’s green, and yellow means
be cautious, to keep people safe” instead of “traffic light.”)

Conduction aphasia
Early theories suggested that communication between the STG and the IFG is
important for healthy language production and comprehension. Anatomically, a
band of white matter called the arcuate fasciculus spans these areas, originating
in STG and terminating in the IFG. When this structure is injured, people develop
some difficulty with repeating language they hear, a disorder called conduction
aphasia. Generally, these patients display paraphasias when asked to repeat
multisyllable words, often switching phonemes around in a single word.
These patients have no significant deficits in language production or
comprehension, presumably because their IFG and STG are still intact and healthy.
Conduction aphasia is less severe than expressive or receptive aphasia.
 10.2 LANGUAGE | 403

Figure 10.7. The arcuate fasciculus (colored) is a large white matter band
that connects the two major language-related cortical structures.
Credit:https://upload.wikimedia.org/wikipedia/commons/2/2a/
Arcuate_Fasciculus.jpg

Global aphasia
Extensive brain damage to the left IFG, STG, and arcuate fasciculus may cause the
most severe form of aphasia, global aphasia. Patients experience both expressive
and receptive deficits, usually only being able to communicate using only single
words or grunts. They also struggle with repeating words spoken to them.
Following a major stroke to the left middle cerebral artery, global aphasia may first
present, possibly lessening in severity as the brain heals. If their other hemisphere
404 | 10.2 LANGUAGE
is spared, patients with global aphasia can learn to communicate using pantomime
or facial expressions.

The Wernicke-Geschwind model

From case studies of injuries leading to aphasia, a few cortical structures emerge
as being major contributors to language: the IFG, STG, and the arcuate fasciculus
that connects the two. Two neurologists, Carl Wernicke and later Norman
Geschwind, proposed the Wernicke-Geschwind model, which suggests that
information is passed along through language structures in a linear pathway, and
each section is responsible for a different aspect of language.
The model begins with the simple scenario: An interviewer is asking you a
question, and you answer. First, the sound information arrives into A1, the
primary auditory cortex (see chapter 6 for more details). From there, that
information is processed by the STG (Wernicke’s area), which then makes meaning
out of those sounds. Then, that information travels across the arcuate fasciculus.
Then, that information arrives at the IFG (Broca’s area), where neurons carry
information related to the planning of language, such as coordinating the muscle
movements that create the verbal response. Finally, those signals arrive at the motor
cortex, which is then responsible for sending the descending signals to control
the muscles required for speech. Another component of the model proposes an
explanation for the following situation: You read a question on a piece of paper,
and answer the question verbally. Visual information arrives into the V1, the
primary visual cortex. The output of the visual cortices arrives at the angular gyrus,
a parietal lobe structure just posterior to the STG. From here, the signal travels
through STG and continues through motor cortex, following the same pathway
described above.
This Wernicke-Geschwind model (Figure 10.8) was initially helpful for
providing a framework for understanding language. But in modern times, we
regard it as an oversimplified and outdated explanation of a complex behavior.
Sometimes the model fails to accurately predict the nature of a patient’s aphasia
even if the locus of a lesion has been precisely identified. Furthermore, some
injuries to brain areas outside of those structures identified in the model produce
aphasia.
 10.2 LANGUAGE | 405
Modern research indicates that language functions are not strictly localized as
described by the Wernicke-Geschwind model. Instead, language is such a complex
behavior, that the interactions between these areas and more are used in language.

Figure 10.8. The Wernicke-Geschwind model in auditory processing and

responding suggests that information signaling arrives into cortex
through A1, travels through STG, IFG, then M1 (left). In a reading and
responding task, the model suggests that information signaling arrives
into cortex through V1, passes through circuits in the angular gyrus,
then through STG, IFG, then M1 (right). Credit:
https://commons.wikimedia.org/wiki/
File:1605_Brocas_and_Wernickes_Areas-02.jpg modified by Austin Lim

Dyslexia
Affecting an estimated 7-20% of the population, developmental
dyslexia is a pronounced difficulty with identification of phonemes in
printed words and a related difficulty with reading unfamiliar words.
Challenges appear in preschool, when learning to decode phonemes
is an expected developmental milestone. These difficulties are not a
result of intellectual disability. However, dyslexia is not explicitly a
language disorder, since patients generally have no difficulties with
comprehension of spoken word.Genetic factors contribute to risk,
but a definitive neural mechanism behind dyslexia is still unknown.
There are differences in the anatomy and activity of the cerebellum
and some atypical lateralization in temporal, parietal, and occipital
lobes, suggesting that perhaps some atypical communication from
406 | 10.2 LANGUAGE

V1 to the language areas of the brain or memory of previously-

learned words contribute to symptoms.
 CHAPTER 11: EMOTION AND AFFECTIVE NEUROSCIENCE | 407

CHAPTER 11: EMOTION

AND AFFECTIVE
NEUROSCIENCE

This chapter was adapted by Jill Grose-Fifer from:

Lim, A. (2021). Emotion and Stress (edited by Ledmyr, H). Open

neuroscience initiative. https://www.austinlim.com/open-
neuroscience-initiative
Introduction to Psychology (A critical approach) Copyright © 2021 by
Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper; William Jenkins;
Arlene Lacombe; Marilyn Lovett; and Marion Perlmutter is licensed
under a Creative Commons Attribution 4.0 International License,

AND

Hove, M. J., & Martinez, S. A. (2024). Biological psychology. ROTEL

(Remixing Open Textbooks with an Equity Lens) Project.
https://rotel.pressbooks.pub/biologicalpsychology/

They recycled materials from:

Harmon-Jones, E. & Harmon-Jones, C. (2023). Affective neuroscience.

In R. Biswas-Diener & E. Diener (Eds), Noba textbook series:
Psychology. Champaign, IL: DEF publishers. Retrieved from
http://noba.to/qnv3erb9 License: CC BY-NC-SA 4.0 DEED

This chapter provides a brief overview of the neuroscience of emotion. It integrates

findings from human and animal research and describes the brain networks and
associated neurotransmitters involved in basic affective systems.
408 | CHAPTER 11: EMOTION AND AFFECTIVE NEUROSCIENCE

Learning Objectives

• Define affective neuroscience.

• Describe neuroscience techniques used to study emotions in
humans and animals.
• Describe basic historical theories of emotion
• Name five emotional systems and their associated neural
structures and neurotransmitters.
• Give examples of exogenous chemicals (e.g., drugs) that influence
affective systems and discuss their effects.
• Discuss multiple affective functions of the amygdala and the
nucleus accumbens.
• Name several specific human emotions and discuss their
relationship to the affective systems of nonhuman animals.
 11.1: AFFECTIVE NEUROSCIENCE: WHAT IS IT? | 409

11.1: AFFECTIVE NEUROSCIENCE:

WHAT IS IT?

Affect, in psychology, refers to the experience of emotions, moods, and feelings,

so affective neuroscience examines how the brain creates emotional responses.
Emotions are psychological phenomena that involve changes to the body (e.g.,
facial expression), changes in autonomic nervous system activity, feeling states
(subjective responses), and urges to act in specific ways (motivations; Izard, 2010).
Affective neuroscience aims to understand how matter (brain structures and
chemicals) creates one of the most fascinating aspects of the mind—emotions.
Affective neuroscience aims to use unbiased, observable measures that provide
credible evidence to other scientists and laypersons on the importance of emotions.
It also leads to biologically based treatments for affective disorders, such as
depression and bipolar disorder.
410 | 11.1: AFFECTIVE NEUROSCIENCE: WHAT IS IT?

Figure 11. 1. Although we experience emotions all the time, they are
very difficult to describe and study. Fortunately, technological
advances and the tools of neuroscience can make this easier. Credit:
The cap © Flickr
 11.1: AFFECTIVE NEUROSCIENCE: WHAT IS IT? | 411
The human brain and its emotional processes are complex and flexible. In order
to study emotions in humans, human neuroscience must rely primarily on
noninvasive techniques such as electroencephalography (EEG) and functional
magnetic resonance imaging (fMRI) and on studies of individuals with brain
lesions caused by accident or disease. Invasive neuroscience techniques, such as
electrode implantation, lesioning, and hormone administration, are more
powerful experimental tools but can only readily be used in nonhuman animals.
While nonhuman animals possess simpler nervous systems and arguably more
basic emotional responses than humans, affective circuits found in other species,
particularly social mammals such as rats, dogs, and monkeys, function similarly
to human affective networks. Thus, animal research serves as a valuable model for
understanding affective processes in humans.
In humans, emotions and their associated neural systems have additional layers
of complexity and flexibility. Compared to animals, humans experience a vast
variety of nuanced and sometimes conflicting emotions. Humans also respond
to these emotions in complex ways, such that conscious goals, values, and other
cognitions influence behavior in addition to emotional responses. However, in this
chapter, we focus on the similarities between organisms rather than the differences.
We often use the term “organism” to refer to the individual who is experiencing an
emotion or showing evidence of particular neural activations. An organism could
be a rat, a monkey, or a human.
Across species, emotional responses are organized around the organism’s
survival and reproductive needs. Emotions influence perception, cognition, and
behavior to help organisms survive and thrive (Farb et al., 2013). Networks of
structures in the brain respond to different needs, with some overlap between
different emotions. Specific emotions are not located in a single structure of the
brain. Instead, emotional responses involve networks of activation, with many
parts of the brain activated during any emotional process. In fact, the brain circuits
involved in emotional reactions include nearly the entire brain (Berridge &
Kringelbach, 2013). Brain circuits located deep within the brain below the cerebral
cortex are primarily responsible for generating basic emotions (Berridge &
Kringelbach, 2013; Panksepp & Biven, 2012). In the past, research attention was
focused on specific brain structures that will be reviewed in this chapter, but future
research may find that additional areas of the brain are also important in these
processes.
412 | 11.2 THEORIES OF EMOTION

11.2 THEORIES OF EMOTION

Austin Lim, Ph.D. and Helena Ledmyr, PhD, INCF (Editor)

In the 1880s, psychologist William James and physician Carl Lange independently
developed a new theory about the origin of emotion. According to the James-
Lange theory of emotion, the body’s physiological changes come before the
onset of an emotional response. For example, imagine encountering a hungry lion
on the sidewalk. The James-Lange theory tells us that the perception of the threat
of being eaten causes the sympathetic nervous system fight-or-flight” response
(elevated heart rate and blood pressure, increased respiration, and cellular
mobilization of energy), and that these physiological changes trigger the onset of
fear.
Soon after, in the 1920s and 30s, two physiologists named Walter Cannon
and his doctoral student Philip Bard criticized the James-Lange theory. In one
experiment, they surgically removed the entire sympathetic nervous system from
cats, destroying the nerves that regulate vascular dilation, the activity of liver
enzymes, and the reaction that causes the hair standing on end. These cats were
then put before a threatening aggressor. If the James-Lange theory was true, then
the physiological changes should precede the emotive response. However, the cats
exhibited fear/aggression (such as posturing, hissing, and clawing) even without
an intact sympathetic nervous system. Relatedly, patients with spinal cord injuries
have a similar lack of autonomic inputs to the brain, but their capacity for
emotional responding is still intact.
In a second criticism, Cannon and Bard proposed that the physiological changes
seen in sympathetic nervous system activity may arise for a variety of reasons, not
always for emotionally salient reasons. For example, intense exercise causes strong
cardiorespiratory changes; however, we do not necessarily feel a strong emotional
state after this physiological perturbation. Likewise, exogenous administration of
epinephrine, onset of fever, or being in cold temperatures may also trigger some
physiological changes without causing a strong emotional response.
Based on their evidence opposing the James-Lange theory, Cannon and Bard
developed an alternative explanation for the origin of emotions. According to the
 11.2 THEORIES OF EMOTION | 413
Cannon-Bard theory of emotion, the perception of an emotionally charged
stimulus prompts simultaneous but independent activation of both the
autonomic nervous system and the emotional response.

Figure 11.2.
Theories of
emotion.
Credit: Open
neuroscience
initiative

The Cannon-Bard theory also draws attention to the neuroanatomical structures

that trigger the autonomic and emotional responses, with a particular focus on
diencephalon structures such as hypothalamus and thalamus. To localize the
anatomy behind emotional signaling, researchers performed a series of lesion
experiments, systematically injuring different parts of the brain. To their surprise,
when the cortex of the cat was surgically separated from the rest of the nervous
system, a procedure called the decorticate preparation, the cats would exhibit a
hyper-aggressive response to stimuli. For example, an innocuous touch of the tail
would trigger violent clawing, biting, and hissing, behaviors which were described
as sham rage. However, when they lesioned the thalamus, sham rage was no longer
observed. They concluded that rage (and other powerful emotions) is normally
under inhibitory control by the cortex.
414 | 11.2 THEORIES OF EMOTION

Figure 11.3. Decorticated cats express sham rage in response to harmless

stimuli, suggesting that anger is kept under control by cortical
inhibition. Credit:https://pixabay.com/photos/
cat-cat-hissing-angry-pet-5534007/

Just a few years later, in 1937, American neuroanatomist James Papez (pronounced
payps) ascribed emotional behavior to a particular series of brain structures. These
structures, collectively called the Papez circuit, consist of the hypothalamus,
cingulate gyrus, thalamus, and hippocampus. Papez observed unusual aggression
among animals with injury to these structures, suggesting that emotional
responding is distributed across many areas, rather than localized. Paul MacLean
later revised the Papez circuit to include the amygdala, orbitofrontal cortex, and
some part of the basal ganglia, and renamed the circuit — the limbic system (see
Figure 11.5).
In 1939, two researchers named Heinrich Kluver and Paul Bucy described a
unique set of emotional deficits in monkeys after removing both their temporal
lobes, which contain both the amygdala and the hippocampal structures, as well
 11.2 THEORIES OF EMOTION | 415
as association visual areas. These animals fail to display fear or anger, even in
the face of life-threatening stimuli such as a large snake. They also display visual
agnosia (the inability to recognize faces or objects visually), psychic blindness,
hypersexuality, and hyperorality (an inappropriate fixation with using the mouth
to interact with surroundings, such as licking or eating nonfoods). Collectively,
these sets of symptoms are called Kluver-Bucy syndrome.

Figure 11.4. Brain areas associated with emotion. Credit: Hove & Martinez,
Biological Psychology. Credit:structure in the brain © Noba

A new angle to the origin of emotion was proposed by Stanley Schachter and
Jerome E. Singer in 1962. They were interested in how the same physiological
response can be attached to two wildly different emotions – consider the rise in
heart rate and respiration that are associated with encountering that lion (fear), or
when you receive wonderful news (elation), or when you make eye contact with
your romantic partner (love). According to their two-factor theory of emotion,
people use a combination of the physiological response and a cognitive label to
determine the emotion that is most appropriate for a given circumstance. The
416 | 11.2 THEORIES OF EMOTION
cognitive label comes from two parts. One is prior knowledge, such as the thought
processes “lions eat meat if they are hungry, so I should be afraid.” The other part
is observing environmental cues, such as “everyone around me is running away and
screaming, so I should also be afraid.”
To test their theory, Schachter and Singer administered epinephrine to patients.
Epinephrine is a hormone that produces the physiological signs very similar to
those observed in a sympathetic nervous system response: elevation of heart rate,
respiration, blood flow to muscles, and energy utilization. Then, the patient is put
into a waiting room with another “patient”- in actuality an undercover member of
the
research team (the confederate). For one set of patients, the confederate would
act “euphorically,” jokingly playing trash-can basketball, making paper airplanes,
and hula-hooping, all the while exclaiming how much fun they are having, inviting
the patient to play along. For another set of patients, the confederate would act in
anger, expressing irritation before eventually ripping up the survey and storming
out of the study.
When the patients were not told what to expect from the epinephrine, they were
more sensitive to the emotional responses of the confederate. This demonstrated
that environmental cues play a significant role in determining emotion regardless
of physiological state.
 11.2 THEORIES OF EMOTION | 417

Figure 11.5. The Singer-Schachter two-factor theory of emotion

suggests that both the physiological response and a cognitive label
contributes to the emotional response. Credit: Open Neuroscience Initiative.
418 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY

11.3: BASIC EMOTIONS AND

BRAIN CIRCUITRY

Facial Expressions
Although best known for his theory on evolution, naturalist Charles Darwin
published about many other topics in biology, including emotion. Darwin
suggested that emotional responding is similar across different cultures, and to
some extent, even in nonhumans. In his view, the main purpose of emotional
expressions are to communicate survival cues: a relaxed expression conveys safety,
while a fearful expression promotes alertness, since danger may be nearby. Darwin
also suggested that we also gain survival information from non-human behaviors,
for example, a hissing snake or a snarling lion is an immediate threat that should
cause fear or other avoidance behaviors.
More recently, the American psychologist Paul Ekman expanded on Darwin’s
theory, and suggested that there are seven basic universal emotions: Anger,
contempt, disgust, fear, happiness, sadness, and surprise. Like Darwin, Ekman
theorized that all humans, regardless of culture, use similar facial expressions. To
test this hypothesis, Ekman visited a remote village in Papua New Guinea, where
he studied a population that was isolated from any other cultures. As predicted,
these people made the same facial responses in reaction to various emotional
circumstances as they do in other parts of the world. In 1972, Ekman published his
theory of universal facial expressions.
Ekman’s team also created a series of photographs of actors portraying six major
emotion (Anger, contempt, disgust, fear, happiness, sadness, and surprise). This
Ekman 60 faces (EK-60F) test has been widely used to assess whether people
recognize facial emotions. We have learned that people with major depressive
disorder or borderline personality disorder are less able to detect happiness in
others, and people with dementia or Parkinson’s disease identify emotions as being
less intense than typical participants.
Ekman also developed the Facial Action Coding System (FACS), which uses
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 419
facial anatomy to differentiate the characteristics of different expressions. For
example, features of a happy face include the flexing of the zygomaticus major and
orbicularis oculi muscles, which produce an upward turn of the corners of the
mouth and a rising of the cheeks. Other facial features, such as head movement, eye
movement, and larger physical movements are also scored, and are also used to help
identify emotions. The FACS can be used to formally describe why some smiles
appear as genuine (a Duchenne smile, where the smile reaches the muscles of the
upper part of the face) while others look fake or forced (a non-Duchenne smile,
characterized by the turn of the corners of the mouth without much change to the
top of the face).

Figure 11.6. Paul Ekman’s research in Papua New Guinea suggests that
across cultures, humans use similar facial muscle activity patterns to
convey a universal set of emotions. Ekman also developed anatomical
definitions for describing specific emotions.
Credit:https://commons.wikimedia.org/wiki/
File:Facial_Action_Coding_System_-_Paul_Ekman_%26_Wallace_Friesen.png

Cognitive neuroscientists who study emotion often struggle to find appropriate

stimuli to elicit emotions in an ethical way in their human participants. However,
emotional faces are frequently used in affective neuroscience studies because they
have been shown to elicit somewhat similar emotions in the observer, i.e., seeing
pictures of happy faces tends to make you feel more happy. Many emotional faces
activate the amygdala, and disgusted faces activate the insula cortex, the part of the
brain that processes information about taste.
420 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
Fear: The neural system of freezing and
fleeing

Figure 11.7. Because fear is so important for our survival (i.e., fear
informs us when something threatens us), our brains are able to
“recognize” frightening stimuli before we are even consciously aware of
them. Credit: Snake © Noba

Nearly everyone has experienced the prototypical fear response: Imagine reading a
book when you see a spider skittering along the wall. Suddenly, you feel your heart
racing, your breathing increase, your mouth is dry and and your palms sweaty. You
probably won’t notice the dilation of your pupils or the change in liver activity and
digestion, but these also happen when you experience this flight or flight response
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 421
caused by sympathetic nervous system activation. But on closer inspection, you
might realize there was no spider at all – just an small piece of brown fuzz picked
up by a draft. Within minutes, your body’s physiology returns back to normal.
This anecdote points out a few important features about the fear response.
First, the onset of the fear response is quick, and so is the dissipation of the fear.
Second, it is triggered by exposure to a perceived threat, regardless of whether
the stimulus is a genuine threat or not (the overwhelming majority of spiders
are clinically harmless to humans!). Third, the fear response is greatly modified
by knowledge and experience – an spider expert would recognize that the spider
is a harmless house spider and would, instead of fear, display curiosity, interest,
boredom, or other emotions. On the other hand, someone who has been bitten
by a dangerous spider and sent to the hospital when younger would have a much
stronger physiological response.
Fear is likely the most evolutionary ancient emotion, and is highly protective.
When encountering a hungry mountain lion, faces displaying the traits of fear
(enlarged eyes, flared nostrils, and a slightly open mouth accompanying a gasp)
would signal to others nearby that a threat is nearby, which helps initiate
heightened alertness and the appropriate fight-or-flight response.

Amygdala and Fear

The amygdala is strongly implicated in both positive and negative emotional

memory formation. However, the role of the amygdala in fear responses has been
particularly extensively studied. Roughly the shape and size of an almond, the
amygdala is part of the temporal lobe. Generally, the amygdala is subdivided into
several nuclei, including the basolateral amygdala, central nucleus, and cortical
nucleus. A useful nonhuman model for studying emotional learning is the fear
conditioning paradigm. In this test, a rodent is put into a cage. Occasionally, a
sound and light would activate. Shortly after, an unpleasant foot-shock would be
delivered to the animal. Over time, the healthy animal learns that the tone and light
precede the shock to the foot, and upon future presentation of these stimuli, they
will freeze. If the amygdala is lesioned, however, they freeze less, meaning they do
not acquire the emotional memory associated with the stimuli. We also know that
monkeys become fearless when their amygdalae are removed. Amygdala lesions
have been used as a last resort treatment for patients with temporal lobe epilepsy
422 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
or with psychiatric symptoms of pathological and dangerous aggressiveness. These
psychosurgery strategies have been variably successful, but they often have high
complication rates and upwards of a 4% mortality rate. These treatments are rarely
used today (Lim, 2021). Deep brain stimulation may offer a less intrusive and
therefore less risky therapeutic approach (Lim, 2021).

Patient SM is a notable case study of a person who does not

experience the fear response. Born with an extremely rare genetic
condition called Urbach-Wiethe disease, Patient SM progressively
developed calcification in her amygdala bilaterally, causing cell death
and amygdala degeneration. Like other people with Urbach-Wiethe
disease, she had no severe significant cognitive deficits, except for
the inability to experience fear. In one test, she was shown a variety
of emotionally charged videos, then asked to rate the intensity of
each clip with respect to different emotions. SM found clips from
America’s Funniest Home Videos to be just as funny as the control
patients, and she found the clips of disgusting toilets to be just as
repulsive. But, when presented with clips depicting ghost hauntings
or suspenseful serial killers on the loose, SM rated these stimuli as
being non-fearful. Other studies challenged Patient SM with more
concrete threats. Researchers brought SM to a pet store, where she
asked to handle the snakes. She was stopped by an employee before
she put her hand into a tarantula cage out of curiosity. The
researchers also took her to the Waverly Hills Sanatorium haunted
house, where she bravely led a group of strangers through the
house populated by actors dressed as monsters and ghosts.
Although she did not display any fearful behaviors, such as
hesitation to walk through the darkened corridors, patient SM
reported the sensation of exhilaration and enthusiasm, akin to riding
a roller coaster.

She also was asked to recall some of her past real-life, fear-
provoking experiences, such as when she was attacked in a
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 423

domestic violence incident or was held up by a stranger at knife

point in a public park. In none of these cases did she ever report
feeling fear, although she was upset and angered at the situation.
The destruction of her amygdala seemed to make her resilient
against PTSD: the day after being threatened with a knife to her
throat, she walked past the very same park bench.

Slight stimulation of the fear-related areas in the brain causes animals to freeze,
whereas intense stimulation causes them to flee. The fear circuit extends from the
central amygdala to the periaqueductal gray in the midbrain. These structures
are sensitive to glutamate, corticotrophin-releasing factor, adreno-cortico-trophic
hormone, and several different neuropeptides. Benzodiazepines and other
tranquilizers inhibit activation in these areas (Panksepp & Biven, 2012).
Perhaps because fear is so important to survival, two pathways send signals
to the amygdala from the sensory organs. When an individual sees a snake, for
example, the sensory information travels from the eye to the thalamus and then
to the visual cortex. The visual cortex sends the information on to the amygdala,
provoking a fear response. However, the thalamus also quickly sends the
information straight to the amygdala so that the organism can react before
consciously perceiving the snake (LeDoux et al., 1990). The pathway from the
thalamus to the amygdala is fast but less accurate than the slower pathway from
the visual cortex. Damage to the amygdala or areas of the ventral hippocampus
interferes with fear conditioning in both humans and nonhuman animals
(LeDoux, 1996). More recent research shows that the amygdala of the nonhuman
primate can be divided into 13 nuclei and cortical areas (Freese & Amaral, 2009).
These regions of the amygdala perform different functions. The central nucleus
sends outputs involving brain stem areas that result in innate emotional
expressions and associated physiological responses. The basal nucleus is connected
with striatal areas that are involved with actions such as running toward safety.
424 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
Rage: The circuits of anger and attack
Fear and anger are two very closely related emotions. Anger or rage is an arousing,
unpleasant emotion that motivates organisms to approach and attack (Harmon-
Jones et al., 2013). The anger spectrum runs from low (irritation) to high (rage),
and from quick (lashing out) to persistent (vengeful). Strong anger can provoke
anti-social behavior such as violence (Lim, 2021). Anger can be evoked through
goal frustration, physical pain, or physical restraint. In territorial animals, anger
is provoked by a stranger entering the organism’s home territory (Blanchard &
Blanchard, 2003). The neural networks for anger and fear are near one another
but separate (Panksepp & Biven, 2012). They extend from the medial amygdala,
through specific parts of the hypothalamus, and into the periaqueductal gray of
the midbrain. The anger circuits are linked to the appetitive circuits, such that lack
of an anticipated reward can provoke rage. In addition, when humans are angered,
they show increased left frontal cortical activation, supporting the idea that anger is
an approach-related emotion (Harmon-Jones et al., 2013). The neurotransmitters
involved in rage are not yet well understood, but the neurotransmitter and
neuromodulator Substance P (also involved in pain and stress) may play an
important role (Panksepp & Biven, 2012). Other neurochemicals that may be
involved in anger include testosterone (Peterson & Harmon-Jones, 2012) and
arginine-vasopressin (Heinrichs et al., 2009). Several chemicals inhibit the rage
system, including opioids and high doses of antipsychotics, such as
chlorpromazine (Panksepp & Biven, 2012).
Environmental factors such as childhood maltreatment or expectations are
partially responsible for how a person responds to a particular anger-provoking
stimulus. Internal homeostatic conditions also influence the anger response, just
as how low blood sugar increases aggression and drives negative or hateful feelings
in the face of a challenge (the portmanteau “hangry” was added to the Oxford
Dictionary in 2018). Neurobiological factors also contribute to the anger response.
In addition to amygdala circuits, regions in the frontal cortex decrease activity
during acts of aggression, suggesting that frontal circuits actively inhibit the limbic
system, which drive our more “primitive” responses. Altered frontal cortical action
may therefore account for one reason why two different people would react to the
same anger-provoking stimulus in different ways (Lim, 2021).
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 425
Disgust
The insula contributes to interoception, detecting the internal state of the body
and conveying that information for processing. In functional imaging studies,
the insula is involved in the recall or many different emotional stimuli, especially
those emotions that have a sensory component. Notably, the insula is strongly
implicated in the emotion disgust. For example, a patient is placed in an fMRI
scanner while breathing through a mask, which allows the experimenters to change
the smells that are perceived. Patients are then given pleasant smells (such as passion
fruit, pear, or mint), a neutral smell, or unpleasant smells (like ethyl-mercaptan
or isovaleric acid, which smells like skunk or body odor, respectively). There is
increased activity of the anterior insula in response to the unpleasant smells but
not the pleasant smells. The insula also responds to social cues related to disgust
as well. When a patient in an fMRI sees a video of a person smelling something
unpleasant and reacting with a “disgusted” face (the closing of the nostrils and
curling of the upper lip), their anterior insula likewise increases in activity just as if
they had smelled it themselves (Lim, 2021).
In addition to sensory stimuli, feelings of social repugnance (unwarranted
violence, murder) or moral disgust (incest) also increase insula activity.
Atypical insula activity is implicated in behavioral disorders. For example,
insensitivity to disgust can lead to squalor-dwelling conditions (sometimes seen in
excessive hoarding or late cognitive decline), which puts those people at heightened
health risks due to regular exposure to unsanitary conditions. Substance use
disorders, PTSD, and suicide attempts have all been associated with atypical insula
activity (Lim, 2021).

Desire: The neural systems of

reward-seeking
One of the most important affective neuronal systems relates to feelings of desire or
the appetite for rewards. Researchers refer to these appetitive processes using terms
such as “wanting” (Berridge & Kringelbach, 2008), “seeking” (Panksepp & Biven,
2012), or “behavioral activation sensitivity” (Gray, 1987). When the appetitive
system is aroused, the organism shows enthusiasm, interest, and curiosity. These
426 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
neural circuits motivate the animal to move through its environment in search
of rewards such as appetizing foods, attractive sex partners, and other pleasurable
stimuli. When the appetitive system is underaroused, the organism appears
depressed and helpless.
Much evidence for the structures involved in this system comes from animal
research using direct brain stimulation. When an electrode is implanted in the
lateral hypothalamus or in cortical or mesencephalic regions to which the
hypothalamus is connected, animals will press a lever to deliver electrical
stimulation, suggesting that they find the stimulation pleasurable. Other regions
in the desire system also include the amygdala, nucleus accumbens, and frontal
cortex (Panksepp & Biven, 2012). The neurotransmitter dopamine, produced
in the mesolimbic and mesocortical dopamine circuits, activates these regions. It
creates a sense of excitement, meaningfulness, and anticipation. These structures
are also sensitive to drugs such as cocaine and amphetamines, chemicals that have
similar effects to dopamine (Panksepp & Biven, 2012).
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 427

Figure 11.8. Just looking at an image of appealing food should increase

the activity in your left frontal cortex. Yum! Credit: Ice cream © Noba

Research in both humans and nonhuman animals shows that the left frontal
cortex (compared to the right frontal cortex) is more active during appetitive
emotions such as desire and interest. Early researchers noted that persons who
suffered damage to the left frontal cortex developed depression, whereas those
with damage to the right frontal cortex developed mania (Goldstein, 1939). The
relationship between left frontal activation and approach-related emotions has
been confirmed in healthy individuals using EEG and fMRI (Berkman &
Lieberman, 2010). For example, increased left frontal activation occurs in 2- to
3-day-old infants when sucrose is placed on their tongues (Fox & Davidson, 1986),
and in hungry adults as they view pictures of desirable desserts (Gable & Harmon-
428 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
Jones, 2008). In addition, greater left frontal activity in appetitive situations has
been found to relate to dopamine (Wacker et al.,, 2013).

“Liking”: The neural circuits of pleasure

and enjoyment
Surprisingly, the amount of desire an individual feels toward a reward need not
correspond to how much he or she likes that reward. This is because the neural
structures involved in the enjoyment of rewards are different from the structures
involved in the desire for the rewards. “Liking” (e.g., enjoyment of a sweet liquid)
can be measured in babies and nonhuman animals by measuring licking speed,
tongue protrusions, and happy facial expressions, whereas “wanting” (desire) is
shown by the willingness to work hard to obtain a reward (Berridge & Kringelbach,
2008). Liking has been distinguished from wanting in research on topics such as
drug abuse. For example, people who are addicted often desire drugs even when
they know that the ones available will not provide pleasure (Stewart et al., 1984).
Research on liking has focused on a small area within the nucleus accumbens
and on the posterior half of the ventral pallidum. These brain regions are sensitive
to opioids and endocannabinoids. Stimulation of other regions of the reward
system increases wanting but does not increase liking and, in some cases, even
decreases liking. The research on the distinction between desire and enjoyment
contributes to the understanding of human addiction, particularly why individuals
often continue to frantically pursue rewards such as cocaine, opiates, gambling, or
sex, even when they no longer experience pleasure from obtaining these rewards
due to habituation.
The experience of pleasure also involves the orbitofrontal cortex. Neurons
in this region fire when monkeys taste or merely see pictures of desirable foods.
In humans, this region is activated by pleasant stimuli, including money, pleasant
smells, and attractive faces (Gottfried et al., 2002; O’Doherty et al., 2001; 2002;
2003).

Love: The neural systems of care and

 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 429

attachment

Figure 11.9. Just as scientists today distinguish between types of love

like “romantic” and “parental,” so did the ancient Greeks, who used the
terms “eros” and “storge.” Credit: In the mood for love © Flickr

For social animals such as humans, attachment to other members of the same
species produces the positive emotions of attachment: love, warm feelings, and
affection. There are several unique forms of love, each resulting in different
behavioral outcomes. For example, romantic love drives physical attraction, lust,
and sexual activity. Parental love, on the other hand, encourages self-sacrifice and
hyper-attentiveness towards a newborn. The amygdala plays a role in these
behaviors because it sends important messages to the hypothalamus, the brain
430 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
areas that controls the endocrine system. Oxytocin (OT) plays a significant role
in the development and maintenance of prosocial behaviors, acts such as trust,
compassion, and empathy, all actions that enhance interpersonal relationships.
For example, increased blood levels of OT is seen in new couples compared to
unattached singles, and OT release happens during orgasm, which may contribute
to romantic attachment. OT signaling increases dramatically during childbirth
and triggers milk letdown in lactation, which strengthens the mother/child
relationship. Interestingly, while OT generally strengthens the social bonds
between people, it promotes antisocial behaviors against those not perceived to
be within one’s own social group. Disorders of the OT system are believed to
contribute to autism spectrum disorder and psychopathy, two complex conditions
characterized partly by social impairment. Some studies have examined the
therapeutic use of nasal OT for a variety of psychiatric conditions, but the studies
have been unable to demonstrate strong clinical effects despite success in
nonhuman animal models (Lim, 2021).
Dr. Helen Fisher, an anthropologist and a leader in the field of romantic love
research, suggests that this kind of love can be divided into three closely
interconnected components, lust, attraction, and attachment. These three are
guided in part by different signaling pathways, and lead to somewhat different
behavioral outcomes (Lim, 2021).

Exercises

Check out this video of a tour of the brain areas involved in romantic
love

https://theanatomyoflove.com/3d-brain-tour/

Lust

Lust (or libido) refers to a very strong desire for sexual gratification. These
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 431
behaviors are largely driven by the actions of the sex hormones testosterone,
estradiol, and progesterone, released downstream of activation of the HPG axis.
As hormones, they are synthesized from cholesterol and circulate through the
bloodstream to influence the body in many ways. Both testosterone and estradiol
contribute to sex-seeking behaviors in men and women, where increasing
testosterone levels drive up sexual desire.
In the brain, the sex hormones strongly influence the medial preoptic area
(mPOA) of the anterior hypothalamus. The mPOA contains a sexually
dimorphic area, the part of the brain that exhibits the biggest morphological
difference between males and females: in humans, it is about twice as large in males
with double the number of neurons throughout childhood and early adulthood.
In the rat, it is up to 8 times larger in males than females, and if this area is
lesioned, rats exhibit decreased motivation to engage in sex. The amygdala also
plays a significant role in mediating lust, and lesions may either result in
hypersexuality (Kluver-Bucy syndrome) or a decrease in responding to socially-
derived sex cues.

Attraction

Attraction is characterized by high energy investment and preoccupation towards

a small number of people. From an evolutionary perspective, attraction may have
developed to discriminate between multiple reproductive partners, allowing the
focusing of limited resources towards fewer partners.
In Fisher’s theory, attraction is strongly related to the action of dopamine and
norepinephrine. In humans, the reward circuitry discussed above is involved in
feelings of love. Fisher presented pictures of a patient’s romantic partner to them
and identified increases in the blood flow using fMRI to dopaminergic midbrain
areas such as the ventral tegmental area and the striatum. This finding compares
with imaging studies that observed increases in blood flow to insula, premotor, and
hypothalamus as well as striatum in response to highly erotic, sexual imagery. These
studies suggest that romantic love and lust have different driving neural structures
underlying these behaviors. Norepinephrine increases to boost attention, alertness,
and energy, which accounts for the exhilarated feeling you may feel when spending
time with a potential partner (Lim, 201).
432 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
Attachment

Attachment is the long-term accompanied by feelings of comfort and emotional

stability. Attachment also contributes to behaviors that maximize offspring
survivability, such as sharing parenthood responsibilities and protectiveness
towards offspring. The major neurochemical drivers of this form of love are
oxytocin and vasopressin (Lim, 2021).

Parental love
Parental love refers to instinctive affection towards one’s offspring. Parental love
behaviors include nurturing (collecting and sharing resources), protecting
(promoting aggression against “intruders”), and preparing one’s young for their
adult life. In evolutionary theory, parental love serves to improve the odds of
passing of one’s genes through the following generation.
Many behaviors related to mammalian motherhood are accompanied by
changes in neural activity. Nursing, for instance, is feeding behavior that is
regulated through a positive feedback cycle. Offspring suckling activates the
mother’s somatosensory afferents. Through a series of oxytocin-dependent circuits
across the hypothalamus, suckling ultimately increases lactation through the milk
letdown reflex. Oxytocin increases accumulation of milk in the mammary glands
(bottom right), which encourages increased suckling. sensory inputs such as the
sounds of a crying baby can also trigger this reflex. Sometimes, just thinking about
the baby can induce letdown.
 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY | 433

Figure 11.10 Suckling (bottom left) triggers somatosensory inputs, which

send afferents into hypothalamus (top), increasing blood levels of
oxytocin. Credit: 15.23 https://commons.wikimedia.org/wiki/
File:2922_Let_Down_Reflex-new.jpg modified by Austin Lim https://pixabay.
com/photos/breastfeeding-mother-mother-s-love-1570695/ modified by Austin
Lim

The brain changes to facilitate nurturing. For example, after childbirth, the
auditory areas of rodents rewire to become more sensitive to high frequency
sounds. This adaptation allows the mothers to better detect the ultrasonic
vocalizations that are emitted by offspring when they are distressed or hungry.
Olfactory areas also change in order to become more sensitive to the particular
odorants given off by their young, allowing them to better identify their offspring.
434 | 11.3: BASIC EMOTIONS AND BRAIN CIRCUITRY
In humans, these olfactory changes result in decreased aversion towards
traditionally aversive stimuli (urine or fecal matter) when they originate from their
children.
Important regions for maternal nurturing include the dorsal preoptic area
(Numan & Insel, 2003) and the bed nucleus of the stria terminalis (Panksepp,
1998). These regions overlap with the areas involved in sexual desire and are
sensitive to some of the same neurotransmitters, including oxytocin, vasopressin,
and endogenous opioids (endorphins and enkephalins) (Hove & Martinez, 2024).
 11.4 PHYSIOLOGY OF STRESS | 435

11.4 PHYSIOLOGY OF STRESS

Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper;
William Jenkins; Arlene Lacombe; Marilyn Lovett; and
Marion Perlmutter

Researchers have had a difficult time agreeing on an acceptable definition of stress.

Some have conceptualized stress as a demanding or threatening event or situation
(e.g., a high-stress job, overcrowding, and long commutes to work). Such
conceptualizations are known as stimulus-based definitions because they
characterize stress as a stimulus that causes certain reactions.
Others have conceptualized stress in ways that emphasize the physiological
responses that occur when faced with demanding or threatening situations (e.g.,
increased arousal). These conceptualizations are referred to as response-based
definitions because they describe stress as a response to environmental conditions.
For example, the endocrinologist Hans Selye, a famous stress researcher, once
defined stress as the “response of the body to any demand, whether it is caused
by, or results in, pleasant or unpleasant conditions” (Selye, 1976, p. 74). Selye’s
definition of stress is response-based in that it conceptualizes stress chiefly in terms
of the body’s physiological reaction to any demand that is placed on it. Neither
stimulus-based nor response-based definitions provide a complete definition of
stress. Many of the physiological reactions that occur when faced with demanding
situations (e.g., accelerated heart rate) can also occur in response to things that
most people would not consider to be genuinely stressful, such as receiving
unanticipated good news: an unexpected promotion or raise.
If a person appraises an event as harmful and believes that the demands imposed
by the event exceed the available resources to manage or adapt to it, the person
will subjectively experience a state of stress. In contrast, if one does not appraise
the same event as harmful or threatening, she is unlikely to experience stress.
According to this definition, environmental events trigger stress reactions by the
way they are interpreted and the meanings they are assigned. In short, stress is
largely in the eye of the beholder: it’s not so much what happens to you as it is how
you respond (Selye, 1976).
436 | 11.4 PHYSIOLOGY OF STRESS
Early Contributions to the Study of Stress
One of the early pioneers in the study of stress was Walter Cannon, an eminent
American physiologist at Harvard Medical School. In the early part of the 20th
century, Cannon was the first to identify the body’s physiological reactions to
stress.

Figure 11.11 Harvard physiologist Walter

Cannon first articulated and named the
fight-or-flight response, the nervous
system’s sympathetic response to a
significant stressor. Credit: Psychology 2e.
Openstax

Cannon and the Fight-or-Flight Response

Imagine that you are hiking in the beautiful mountains of Colorado on a warm
and sunny spring day. At one point during your hike, a large, frightening-looking
black bear appears from behind a stand of trees and sits about 50 yards from you.
The bear notices you, sits up, and begins to lumber in your direction. In addition
 11.4 PHYSIOLOGY OF STRESS | 437
to thinking, “This is definitely not good,” a constellation of physiological reactions
begins to take place inside you. Prompted by a deluge of epinephrine (adrenaline)
and norepinephrine (noradrenaline) from your adrenal glands, your pupils begin
to dilate. Your heart starts to pound and speeds up, you begin to breathe heavily
and perspire, you get butterflies in your stomach, and your muscles become tense,
preparing you to take some kind of direct action. Cannon proposed that this
reaction, which he called the fight-or-flight response, occurs when a person
experiences very strong emotions—especially those associated with a perceived
threat (Cannon, 1932). During the fight-or-flight response, the body is rapidly
aroused by activation of both the sympathetic nervous system and the endocrine
system. This arousal helps prepare the person to either fight or flee from a perceived
threat.

Figure 11.12. Fight or flight is a physiological response to a stressor.

Credit: Psychology 2e. Openstax

According to Cannon, the fight-or-flight response is a built-in mechanism that

assists in maintaining homeostasis—an internal environment in which
physiological variables such as blood pressure, respiration, digestion, and
temperature are stabilized at levels optimal for survival. Thus, Cannon viewed the
fight-or-flight response as adaptive because it enables us to adjust internally and
externally to changes in our surroundings, which is helpful in species survival.
438 | 11.4 PHYSIOLOGY OF STRESS
Selye and the General Adaptation
Syndrome
Another important early contributor to the stress field was Hans Selye, mentioned
earlier. He would eventually become one of the world’s foremost experts in the
study of stress. As a young assistant in the biochemistry department at McGill
University in the 1930s, Selye was engaged in research involving sex hormones
in rats. Although he was unable to find an answer for what he was initially
researching, he incidentally discovered that when exposed to prolonged negative
stimulation (stressors)—such as extreme cold, surgical injury, excessive muscular
exercise, and shock—the rats showed signs of adrenal enlargement, thymus and
lymph node shrinkage, and stomach ulceration. Selye realized that these responses
were triggered by a coordinated series of physiological reactions that unfold over
time during continued exposure to a stressor. These physiological reactions were
nonspecific, which means that regardless of the type of stressor, the same pattern
of reactions would occur. What Selye discovered was the general adaptation
syndrome, the body’s nonspecific physiological response to stress.

The general adaptation syndrome, consists of three stages: (1) alarm reaction, (2)
stage of resistance, and (3) stage of exhaustion (Selye, 1936; 1976). Alarm reaction
describes the body’s immediate reaction upon facing a threatening situation or
emergency, and it is roughly analogous to the fight-or-flight response described by
Cannon. During an alarm reaction, you are alerted to a stressor, and your body
alarms you with a cascade of physiological reactions that provide you with the
energy to manage the situation. A person who wakes up in the middle of the night
to discover her house is on fire, for example, is experiencing an alarm reaction.
 11.4 PHYSIOLOGY OF STRESS | 439

Figure 11.13. The three stages of Selye’s general adaptation syndrome

are shown in this graph. Prolonged stress ultimately results in
exhaustion. Credit: Psychology 2e. Openstax

If exposure to a stressor is prolonged, the organism will enter the stage of resistance.
During this stage, the initial shock of alarm reaction has worn off and the body has
adapted to the stressor. Nevertheless, the body also remains on alert and is prepared
to respond as it did during the alarm reaction, although with less intensity. For
example, suppose a child who went missing is still missing 72 hours later. Although
the parents would obviously remain extremely disturbed, the magnitude of
physiological reactions would likely have diminished over the 72 intervening hours
due to some adaptation to this event.
If exposure to a stressor continues over a longer period of time, the stage of
exhaustion ensues. At this stage, the person is no longer able to adapt to the
stressor: the body’s ability to resist becomes depleted as physical wear takes its toll
on the body’s tissues and organs. As a result, illness, disease, and other permanent
damage to the body—even death—may occur. If a missing child still remained
missing after three months, the long-term stress associated with this situation may
cause a parent to literally faint with exhaustion at some point or even to develop a
serious and irreversible illness.
440 | 11.4 PHYSIOLOGY OF STRESS
In short, Selye’s general adaptation syndrome suggests that stressors tax the
body via a three-phase process—an initial jolt, subsequent readjustment, and a
later depletion of all physical resources—that ultimately lays the groundwork for
serious health problems and even death. It should be pointed out, however, that
this model is a response-based conceptualization of stress, focusing exclusively on
the body’s physical responses while largely ignoring psychological factors such as
appraisal and interpretation of threats. Nevertheless, Selye’s model has had an
enormous impact on the field of stress because it offers a general explanation for
how stress can lead to physical damage and, thus, disease. As we shall discuss later,
prolonged or repeated stress has been implicated in development of a number of
disorders such as hypertension and coronary artery disease.

The Physiological Basis of Stress

What goes on inside our bodies when we experience stress? The physiological
mechanisms of stress are extremely complex, but they generally involve the work
of two systems—the sympathetic nervous system and the hypothalamic-pituitary-
adrenal (HPA) axis. When a person first perceives something as stressful (Selye’s
alarm reaction), the sympathetic nervous system triggers arousal via the release
of adrenaline from the adrenal glands. Release of these hormones activates the
fight-or-flight responses to stress, such as accelerated heart rate and respiration.
At the same time, the HPA axis, which is primarily endocrine in nature, becomes
especially active, although it works much more slowly than the sympathetic
nervous system. In response to stress, the hypothalamus (one of the limbic
structures in the brain) releases corticotrophin-releasing factor, a hormone that
causes the pituitary gland to release adrenocorticotropic hormone (ACTH). The
ACTH then activates the adrenal glands to secrete a number of hormones into
the bloodstream; an important one is cortisol, which can affect virtually every
organ within the body. Cortisol is commonly known as a stress hormone and helps
provide that boost of energy when we first encounter a stressor, preparing us to run
away or fight. However, sustained elevated levels of cortisol weaken the immune
system.
 11.4 PHYSIOLOGY OF STRESS | 441

Figure 11.14. This diagram shows the functioning of the

hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus activates
the pituitary gland, which in turn activates the adrenal glands,
increasing their secretion of cortisol. Credit: Psychology 2e. Openstax

In short bursts, this process can have some favorable effects, such as providing
extra energy, improving immune system functioning temporarily, and decreasing
pain sensitivity. However, extended release of cortisol—as would happen with
prolonged or chronic stress—often comes at a high price. High levels of cortisol
have been shown to produce a number of harmful effects. For example, increases
in cortisol can significantly weaken our immune system (Glaser & Kiecolt-Glaser,
2005), and high levels are frequently observed among depressed individuals
(Geoffroy, Hertzman, Li, & Power, 2013). In summary, a stressful event causes a
variety of physiological reactions that activate the adrenal glands, which in turn
release epinephrine, norepinephrine, and cortisol. These hormones affect a
number of bodily processes in ways that prepare the stressed person to take direct
action, but also in ways that may heighten the potential for illness.
When stress is extreme or chronic, it can have profoundly negative
consequences. For example, stress often contributes to the development of certain
442 | 11.4 PHYSIOLOGY OF STRESS
psychological disorders, including post-traumatic stress disorder, major depressive
disorder, and other serious psychiatric conditions. Additionally, we noted earlier
that stress is linked to the development and progression of a variety of physical
illnesses and diseases. For example, researchers in one study found that people
injured during the September 11, 2001, World Trade Center disaster or who
developed post-traumatic stress symptoms afterward later suffered significantly
elevated rates of heart disease (Jordan, Miller-Archie, Cone, Morabia, & Stellman,
2011). Another investigation yielded that self-reported stress symptoms among
aging and retired Finnish food industry workers were associated with morbidity 11
years later. This study also predicted the onset of musculoskeletal, nervous system,
and endocrine and metabolic disorders (Salonen, Arola, Nygård, & Huhtala,
2008). Another study reported that male South Korean manufacturing employees
who reported high levels of work-related stress were more likely to catch the
common cold over the next several months than were those employees who
reported lower work-related stress levels (Park et al., 2011). Later, you will explore
the mechanisms through which stress can produce physical illness and disease.
Stress can change the organization of reward areas in the brain. For example, the
front shell of the nucleus accumbens is generally involved in appetitive behaviors,
such as eating, and the back shell is generally involved in fearful defensive behaviors
(Reynolds & Berridge, 2001, 2002). Research using human neuroimaging has also
revealed this front–back distinction in the functions of the nucleus accumbens
(Seymour et al., 2007). However, when rats are exposed to stressful environments,
their fear-generating regions expand toward the front, filling almost 90% of the
nucleus accumbens shell. On the other hand, when rats are exposed to preferred
home environments, their fear-generating regions shrink, and the appetitive
regions expand toward the back, filling approximately 90% of the shell (Reynolds
& Berridge, 2008).

Summary
Stress is a process whereby an individual perceives and responds to events appraised
as overwhelming or threatening to one’s well-being. The scientific study of how
stress and emotional factors impact health and well-being is called health
psychology, a field devoted to studying the general impact of psychological factors
 11.4 PHYSIOLOGY OF STRESS | 443
on health. The body’s primary physiological response during stress, the fight-or-
flight response, was first identified in the early 20th century by Walter Cannon.
The fight-or-flight response involves the coordinated activity of both the
sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis.
Hans Selye, a noted endocrinologist, referred to these physiological reactions to
stress as part of general adaptation syndrome, which occurs in three stages: alarm
reaction (fight-or-flight reactions begin), resistance (the body begins to adapt to
continuing stress), and exhaustion (adaptive energy is depleted, and stress begins to
take a physical toll).
444 | 11.5 STRESS AND ILLNESS

11.5 STRESS AND ILLNESS

Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper;
William Jenkins; Arlene Lacombe; Marilyn Lovett; and
Marion Perlmutter

In this section, we will discuss stress and illness. As stress researcher Robert
Sapolsky (1998) describes,

stress-related disease emerges, predominantly, out of the fact that we so often

activate a physiological system that has evolved for responding to acute physical
emergencies, but we turn it on for months on end, worrying about mortgages,
relationships, and promotions. (p. 6)

The stress response, as noted earlier, consists of a coordinated but complex system
of physiological reactions that are called upon as needed. These reactions are
beneficial at times because they prepare us to deal with potentially dangerous or
threatening situations (for example, recall our old friend, the fearsome bear on the
trail). However, health is affected when physiological reactions are sustained, as can
happen in response to ongoing stress.

Psychophysiological Disorders
If the reactions that compose the stress response are chronic or if they frequently
exceed normal ranges, they can lead to cumulative wear and tear on the body, in
much the same way that running your air conditioner on full blast all summer will
eventually cause wear and tear on it. For example, the high blood pressure that a
person under considerable job strain experiences might eventually take a toll on his
heart and set the stage for a heart attack or heart failure. Also, someone exposed to
high levels of the stress hormone cortisol might become vulnerable to infection or
disease because of weakened immune system functioning (McEwen, 1998).
 11.5 STRESS AND ILLNESS | 445

Robert Sapolsky, a noted Stanford University neurobiologist and

professor, has for over 30 years conducted extensive research on
stress, its impact on our bodies, and how psychological tumult can
escalate stress—even in baboons. Here is a video featuring Dr.
Sapolsky, an excellent in-depth documentary from National
Geographic: Stress, Portrait of a Killer – Full Documentary (2008).

One or more interactive elements has been excluded from this

version of the text. You can view them online here:
https://pressbooks.cuny.edu/psy320/?p=1254#oembed-1

Physical disorders or diseases whose symptoms are brought about or worsened by

stress and emotional factors are called psychophysiological disorders. The physical
symptoms of psychophysiological disorders are real and they can be produced
or exacerbated by psychological factors (hence the psycho and physiological in
psychophysiological).

Table 14.1: Types of Psychophysiological Disorders (adapted from Everly & Lating,
2002)

Type of Psychophysiological Disorder Examples

Cardiovascular hypertension, coronary heart disease

Gastrointestinal irritable bowel syndrome

Respiratory asthma, allergy

Musculoskeletal low back pain, tension headaches

Skin acne, eczema, psoriasis

In addition to stress itself, emotional upset and certain stressful personality traits
have been proposed as potential contributors to ill health. Franz Alexander (1950),
446 | 11.5 STRESS AND ILLNESS
an early-20th-century psychoanalyst and physician, once postulated that various
diseases are caused by specific unconscious conflicts. For example, he linked
hypertension to repressed anger, asthma to separation anxiety, and ulcers to an
unconscious desire to “remain in the dependent infantile situation—to be loved
and cared for” (Alexander, 1950, p. 102). Although hypertension does appear
to be linked to anger (as you will learn below), Alexander’s assertions have not
been supported by research. Years later, Friedman and Booth-Kewley (1987), after
statistically reviewing 101 studies examining the link between personality and
illness, proposed the existence of disease-prone personality characteristics,
including depression, anger/hostility, and anxiety. Indeed, a study of over 61,000
Norwegians identified depression as a risk factor for all major disease-related causes
of death (Mykletun et al., 2007). In addition, neuroticism—a personality trait that
reflects how anxious, moody, and sad one is—has been identified as a risk factor for
chronic health problems and mortality (Ploubidis & Grundy, 2009).
Below, we discuss two kinds of psychophysiological disorders about which a
great deal is known: cardiovascular disorders and asthma. First, however, it is
necessary to turn our attention to a discussion of the immune system—one of the
major pathways through which stress and emotional factors can lead to illness and
disease.

Stress and the Immune System

In a sense, the immune system is the body’s surveillance system. It consists of a
variety of structures, cells, and mechanisms that serve to protect the body from
invading toxins and microorganisms that can harm or damage the body’s tissues
and organs. When the immune system is working as it should, it keeps us healthy
and disease free by eliminating bacteria, viruses, and other foreign substances that
have entered the body (Everly & Lating, 2002).

Immune System Errors

Sometimes, the immune system will function erroneously. For example, sometimes
it can go awry by mistaking your body’s own healthy cells for invaders and
 11.5 STRESS AND ILLNESS | 447
repeatedly attacking them. When this happens, the person is said to have an
autoimmune disease, which can affect almost any part of the body. How an
autoimmune disease affects a person depends on what part of the body is targeted.
For instance, rheumatoid arthritis, an autoimmune disease that affects the joints,
results in joint pain, stiffness, and loss of function. Systemic lupus erythematosus,
an autoimmune disease that affects the skin, can result in rashes and swelling of
the skin. Grave’s disease, an autoimmune disease that affects the thyroid gland, can
result in fatigue, weight gain, and muscle aches (National Institute of Arthritis and
Musculoskeletal and Skin Diseases [NIAMS], 2012).
In addition, the immune system may sometimes break down and be unable
to do its job. This situation is referred to as immunosuppression, the decreased
effectiveness of the immune system. When people experience immunosuppression,
they become susceptible to any number of infections, illness, and diseases. For
example, acquired immune deficiency syndrome (AIDS) is a serious and lethal
disease that is caused by human immunodeficiency virus (HIV), which greatly
weakens the immune system by infecting and destroying antibody-producing cells,
thus rendering a person vulnerable to any of a number of opportunistic infections
(Powell, 1996).

Stressors and Immune Function

The question of whether stress and negative emotional states can influence
immune function has captivated researchers for over three decades, and discoveries
made over that time have dramatically changed the face of health psychology
(Kiecolt-Glaser, 2009). Psychoneuroimmunology is the field that studies how
psychological factors such as stress influence the immune system and immune
functioning. The term psychoneuroimmunology was first coined in 1981, when
it appeared as the title of a book that reviewed available evidence for associations
between the brain, endocrine system, and immune system (Zacharie, 2009). To a
large extent, this field evolved from the discovery that there is a connection between
the central nervous system and the immune system.
Some of the most compelling evidence for a connection between the brain and
the immune system comes from studies in which researchers demonstrated that
immune responses in animals could be classically conditioned (Everly & Lating,
448 | 11.5 STRESS AND ILLNESS
2002). For example, Ader and Cohen (1975) paired flavored water (the
conditioned stimulus) with the presentation of an immunosuppressive drug (the
unconditioned stimulus), causing sickness (an unconditioned response). Not
surprisingly, rats exposed to this pairing developed a conditioned aversion to the
flavored water. However, the taste of the water itself later produced
immunosuppression (a conditioned response), indicating that the immune system
itself had been conditioned. Many subsequent studies over the years have further
demonstrated that immune responses can be classically conditioned in both
animals and humans (Ader & Cohen, 2001). Thus, if classical conditioning can
alter immunity, other psychological factors should be capable of altering it as well.
Hundreds of studies involving tens of thousands of participants have tested
many kinds of brief and chronic stressors and their effect on the immune system
(e.g., public speaking, medical school examinations, unemployment, marital
discord, divorce, death of spouse, burnout and job strain, caring for a relative with
Alzheimer’s disease, and exposure to the harsh climate of Antarctica). It has been
repeatedly demonstrated that many kinds of stressors are associated with poor
or weakened immune functioning (Glaser & Kiecolt-Glaser, 2005; Kiecolt-Glaser,
McGuire, Robles, & Glaser, 2002; Segerstrom & Miller, 2004).
When evaluating these findings, it is important to remember that there is a
tangible physiological connection between the brain and the immune system. For
example, the sympathetic nervous system innervates immune organs such as the
thymus, bone marrow, spleen, and even lymph nodes (Maier, Watkins, & Fleshner,
1994). Also, we noted earlier that stress hormones released during hypothalamic-
pituitary-adrenal (HPA) axis activation can adversely impact immune function.
One way they do this is by inhibiting the production of lymphocytes, white blood
cells that circulate in the body’s fluids that are important in the immune response
(Everly & Lating, 2002).
Some of the more dramatic examples demonstrating the link between stress
and impaired immune function involve studies in which volunteers were exposed
to viruses. The rationale behind this research is that because stress weakens the
immune system, people with high stress levels should be more likely to develop an
illness compared to those under little stress. In one memorable experiment using
this method, researchers interviewed 276 healthy volunteers about recent stressful
experiences (Cohen et al., 1998). Following the interview, these participants were
given nasal drops containing the cold virus (in case you are wondering why
 11.5 STRESS AND ILLNESS | 449
anybody would ever want to participate in a study in which they are subjected to
such treatment, the participants were paid $800 for their trouble). When examined
later, participants who reported experiencing chronic stressors for more than one
month—especially enduring difficulties involving work or relationships—were
considerably more likely to have developed colds than were participants who
reported no chronic stressors.

Figure 11.14. This graph shows the percentages of participants who

developed colds (after receiving the cold virus) after reporting having
experienced chronic stressors lasting at least one month, three months,
and six months (adapted from Cohen et al., 1998). Credit: Psychology 2e.
Openstax

In another study, older volunteers were given an influenza virus vaccination.

Compared to controls, those who were caring for a spouse with Alzheimer’s disease
(and thus were under chronic stress) showed poorer antibody response following
the vaccination (Kiecolt-Glaser, Glaser, Gravenstein, Malarkey, & Sheridan, 1996).
Other studies have demonstrated that stress slows down wound healing by
impairing immune responses important to wound repair (Glaser & Kiecolt-Glaser,
2005). In one study, for example, skin blisters were induced on the forearm.
Subjects who reported higher levels of stress produced lower levels of immune
proteins necessary for wound healing (Glaser et al., 1999). Stress, then, is not so
450 | 11.5 STRESS AND ILLNESS
much the sword that kills the knight, so to speak; rather, it’s the sword that breaks
the knight’s shield, and your immune system is that shield.

Stress and Aging: A Tale of Telomeres

Have you ever wondered why people who are stressed often seem to have a haggard
look about them? A pioneering study from 2004 suggests that the reason is because
stress can actually accelerate the cell biology of aging.
Stress, it seems, can shorten telomeres, which are segments of DNA that protect
the ends of chromosomes. Shortened telomeres can inhibit or block cell division,
which includes growth and proliferation of new cells, thereby leading to more
rapid aging (Sapolsky, 2004). In the study, researchers compared telomere lengths
in the white blood cells in mothers of chronically ill children to those of mothers
of healthy children (Epel et al., 2004). Mothers of chronically ill children would
be expected to experience more stress than would mothers of healthy children.
The longer a mother had spent caring for her ill child, the shorter her telomeres
(the correlation between years of caregiving and telomere length was r = -.40). In
addition, higher levels of perceived stress were negatively correlated with telomere
size (r = -.31). These researchers also found that the average telomere length of
the most stressed mothers, compared to the least stressed, was similar to what you
would find in people who were 9–17 years older than they were on average.
Numerous other studies since have continued to find associations between stress
and eroded telomeres (Blackburn & Epel, 2012). Some studies have even
demonstrated that stress can begin to erode telomeres in childhood and perhaps
even before children are born. For example, childhood exposure to violence (e.g.,
maternal domestic violence, bullying victimization, and physical maltreatment)
was found in one study to accelerate telomere erosion from ages 5 to 10 (Shalev
et al., 2013). Another study reported that young adults whose mothers had
experienced severe stress during their pregnancy had shorter telomeres than did
those whose mothers had stress-free and uneventful pregnancies (Entringer et al.,
2011). Further, the corrosive effects of childhood stress on telomeres can extend
into young adulthood. In an investigation of over 4,000 U.K. women ages 41–80,
adverse experiences during childhood (e.g., physical abuse, being sent away from
home, and parent divorce) were associated with shortened telomere length (Surtees
 11.5 STRESS AND ILLNESS | 451
et al., 2010), and telomere size decreased as the amount of experienced adversity
increased.

Figure 11.15 Telomeres are shorter in adults who experienced more

trauma as children (adapted from Blackburn & Epel, 2012). Credit:
Psychology 2e. Openstax

Efforts to dissect the precise cellular and physiological mechanisms linking short
telomeres to stress and disease are currently underway. For the time being,
telomeres provide us with yet another reminder that stress, especially during early
life, can be just as harmful to our health as smoking or fast food (Blackburn & Epel,
2012).

Cardiovascular Disorders
The cardiovascular system is composed of the heart and blood circulation system.
For many years, disorders that involve the cardiovascular system—known as
cardiovascular disorders—have been a major focal point in the study of
psychophysiological disorders because of the cardiovascular system’s centrality in
the stress response (Everly & Lating, 2002). Heart disease is one such condition.
Each year, heart disease causes approximately one in three deaths in the United
452 | 11.5 STRESS AND ILLNESS
States, and it is the leading cause of death in the developed world (Centers for
Disease Control and Prevention [CDC], 2011; Shapiro, 2005).
The symptoms of heart disease vary somewhat depending on the specific kind of
heart disease one has, but they generally involve angina—chest pains or discomfort
that occur when the heart does not receive enough blood (Office on Women’s
Health, 2009). The pain often feels like the chest is being pressed or squeezed;
burning sensations in the chest and shortness of breath are also commonly
reported. Such pain and discomfort can spread to the arms, neck, jaws, stomach (as
nausea), and back (American Heart Association [AHA], 2012a).

Figure 11.16. Males and females often experience different symptoms of

a heart attack. Credit: Psychology 2e. Openstax

A major risk factor for heart disease is hypertension, which is high blood pressure.
Hypertension forces a person’s heart to pump harder, thus putting more physical
strain on the heart. If left unchecked, hypertension can lead to a heart attack,
stroke, or heart failure; it can also lead to kidney failure and blindness.
Hypertension is a serious cardiovascular disorder, and it is sometimes called the
silent killer because it has no symptoms—one who has high blood pressure may
not even be aware of it (AHA, 2012b).
Many risk factors contributing to cardiovascular disorders have been identified.
These risk factors include social determinants such as aging, income, education,
and employment status, as well as behavioral risk factors that include unhealthy
diet, tobacco use, physical inactivity, and excessive alcohol consumption; obesity
 11.5 STRESS AND ILLNESS | 453
and diabetes are additional risk factors (World Health Organization [WHO],
2013).
Over the past few decades, there has been much greater recognition and
awareness of the importance of stress and other psychological factors in
cardiovascular health (Nusair, Al-dadah, & Kumar, 2012). Indeed, exposure to
stressors of many kinds has also been linked to cardiovascular problems; in the
case of hypertension, some of these stressors include job strain (Trudel, Brisson, &
Milot, 2010), natural disasters (Saito, Kim, Maekawa, Ikeda, & Yokoyama, 1997),
marital conflict (Nealey-Moore, Smith, Uchino, Hawkins, & Olson-Cerny, 2007),
and exposure to high traffic noise levels at one’s home (de Kluizenaar, Gansevoort,
Miedema, & de Jong, 2007). Perceived discrimination appears to be associated
with hypertension among African Americans (Sims et al., 2012). In addition,
laboratory-based stress tasks, such as performing mental arithmetic under time
pressure, immersing one’s hand into ice water (known as the cold pressor test),
mirror tracing, and public speaking have all been shown to elevate blood pressure
(Phillips, 2011).

Are You Type A or Type B?

Sometimes research ideas and theories emerge from seemingly trivial observations.
In the 1950s, cardiologist Meyer Friedman was looking over his waiting room
furniture, which consisted of upholstered chairs with armrests. Friedman decided
to have these chairs reupholstered. When the man doing the reupholstering came
to the office to do the work, he commented on how the chairs were worn in a
unique manner—the front edges of the cushions were worn down, as were the
front tips of the arm rests. It seemed like the cardiology patients were tapping or
squeezing the front of the armrests, as well as literally sitting on the edge of their
seats (Friedman & Rosenman, 1974). Were cardiology patients somehow different
than other types of patients? If so, how?
After researching this matter, Friedman and his colleague, Ray Rosenman, came
to understand that people who are prone to heart disease tend to think, feel, and act
differently than those who are not. These individuals tend to be intensively driven
workaholics who are preoccupied with deadlines and always seem to be in a rush.
According to Friedman and Rosenman, these individuals exhibit Type A behavior
454 | 11.5 STRESS AND ILLNESS
pattern; those who are more relaxed and laid-back were characterized as Type B.
In a sample of Type As and Type Bs, Friedman and Rosenman were startled to
discover that heart disease was over seven times more frequent among the Type As
than the Type Bs (Friedman & Rosenman, 1959).

Figure 11.17. (a) Type A individuals are characterized as intensely driven,

(b) while Type B people are characterized as laid-back and relaxed.
(credit a: modification of work by Greg Hernandez; credit b: modification of work
by Elvert Barnes)

The major components of the Type A pattern include an aggressive and chronic
struggle to achieve more and more in less and less time (Friedman & Rosenman,
1974). Specific characteristics of the Type A pattern include an excessive
competitive drive, chronic sense of time urgency, impatience, and hostility toward
others (particularly those who get in the person’s way).
An example of a person who exhibits Type A behavior pattern is Jeffrey. Even
as a child, Jeffrey was intense and driven. He excelled at school, was captain of the
swim team, and graduated with honors from an Ivy League college. Jeffrey never
seems able to relax; he is always working on something, even on the weekends.
However, Jeffrey always seems to feel as though there are not enough hours in the
day to accomplish all he feels he should. He volunteers to take on extra tasks at
work and often brings his work home with him; he often goes to bed angry late
at night because he feels that he has not done enough. Jeffrey is quick tempered
with his coworkers; he often becomes noticeably agitated when dealing with those
coworkers he feels work too slowly or whose work does not meet his standards.
He typically reacts with hostility when interrupted at work. He has experienced
problems in his marriage over his lack of time spent with family. When caught in
traffic during his commute to and from work, Jeffrey incessantly pounds on his
 11.5 STRESS AND ILLNESS | 455
horn and swears loudly at other drivers. When Jeffrey was 52, he suffered his first
heart attack.
By the 1970s, a majority of practicing cardiologists believed that Type A
behavior pattern was a significant risk factor for heart disease (Friedman, 1977).
Indeed, a number of early longitudinal investigations demonstrated a link between
Type A behavior pattern and later development of heart disease (Rosenman et al.,
1975; Haynes, Feinleib, & Kannel, 1980).
Subsequent research examining the association between Type A and heart
disease, however, failed to replicate these earlier findings (Glassman, 2007; Myrtek,
2001). Because Type A theory did not pan out as well as they had hoped,
researchers shifted their attention toward determining if any of the specific
elements of Type A predict heart disease.
Extensive research clearly suggests that the anger/hostility dimension of Type A
behavior pattern may be one of the most important factors in the development of
heart disease. This relationship was initially described in the Haynes et al. (1980)
study mentioned above: Suppressed hostility was found to substantially elevate the
risk of heart disease for both men and women. Also, one investigation followed
over 1,000 male medical students from 32 to 48 years. At the beginning of the
study, these men completed a questionnaire assessing how they react to pressure;
some indicated that they respond with high levels of anger, whereas others
indicated that they respond with less anger. Decades later, researchers found that
those who earlier had indicated the highest levels of anger were over 6 times more
likely than those who indicated less anger to have had a heart attack by age 55, and
they were 3.5 times more likely to have experienced heart disease by the same age
(Chang, Ford, Meoni, Wang, & Klag, 2002). From a health standpoint, it clearly
does not pay to be an angry young person.
After reviewing and statistically summarizing 35 studies from 1983 to 2006,
Chida and Steptoe (2009) concluded that the bulk of the evidence suggests that
anger and hostility constitute serious long-term risk factors for adverse
cardiovascular outcomes among both healthy individuals and those already
suffering from heart disease. One reason angry and hostile moods might contribute
to cardiovascular diseases is that such moods can create social strain, mainly in
the form of antagonistic social encounters with others. This strain could then
lay the foundation for disease-promoting cardiovascular responses among hostile
456 | 11.5 STRESS AND ILLNESS
individuals (Vella, Kamarck, Flory, & Manuck, 2012). In this transactional model,
hostility and social strain form a cycle.

Figure 11.18. According to the transactional model of hostility for

predicting social interactions (Vella et al., 2012), the thoughts and
feelings of a hostile person promote antagonistic behavior toward
others, which in turn reinforces complimentary reactions from others,
thereby intensifying ones’ hostile disposition and intensifying the
cyclical nature of this relationship. Credit: Psychology 2e. Openstax

For example, suppose Kaitlin has a hostile disposition; she has a cynical, distrustful
attitude toward others and often thinks that other people are out to get her. She is
very defensive around people, even those she has known for years, and she is always
looking for signs that others are either disrespecting or belittling her. In the shower
each morning before work, she often mentally rehearses what she would say to
someone who said or did something that angered her, such as making a political
statement that was counter to her own ideology. As Kaitlin goes through these
mental rehearsals, she often grins and thinks about the retaliation on anyone who
will irk her that day.
Socially, she is confrontational and tends to use a harsh tone with people, which
often leads to very disagreeable and sometimes argumentative social interactions.
As you might imagine, Kaitlin is not especially popular with others, including
 11.5 STRESS AND ILLNESS | 457
coworkers, neighbors, and even members of her own family. They either avoid her
at all costs or snap back at her, which causes Kaitlin to become even more cynical
and distrustful of others, making her disposition even more hostile. Kaitlin’s
hostility—through her own doing—has created an antagonistic environment that
cyclically causes her to become even more hostile and angry, thereby potentially
setting the stage for cardiovascular problems.
In addition to anger and hostility, a number of other negative emotional states
have been linked with heart disease, including negative affectivity and depression
(Suls & Bunde, 2005). Negative affectivity is a tendency to experience distressed
emotional states involving anger, contempt, disgust, guilt, fear, and nervousness
(Watson, Clark, & Tellegen, 1988). It has been linked with the development of
both hypertension and heart disease. For example, over 3,000 initially healthy
participants in one study were tracked longitudinally, up to 22 years. Those with
higher levels of negative affectivity at the time the study began were substantially
more likely to develop and be treated for hypertension during the ensuing years
than were those with lower levels of negative affectivity (Jonas & Lando, 2000).
In addition, a study of over 10,000 middle-aged London-based civil servants who
were followed an average of 12.5 years revealed that those who earlier had scored
in the upper third on a test of negative affectivity were 32% more likely to have
experienced heart disease, heart attack, or angina over a period of years than were
those who scored in the lowest third (Nabi, Kivimaki, De Vogli, Marmot, & Singh-
Manoux, 2008). Hence, negative affectivity appears to be a potentially vital risk
factor for the development of cardiovascular disorders.

Depression and the Heart

For centuries, poets and folklore have asserted that there is a connection between
moods and the heart (Glassman & Shapiro, 1998). You are no doubt familiar with
the notion of a broken heart following a disappointing or depressing event and
have encountered that notion in songs, films, and literature.
Perhaps the first to recognize the link between depression and heart disease was
Benjamin Malzberg (1937), who found that the death rate among institutionalized
patients with melancholia (an archaic term for depression) was six times higher
than that of the population. A classic study in the late 1970s looked at over 8,000
458 | 11.5 STRESS AND ILLNESS
manic-depressive persons in Denmark, finding a nearly 50% increase in deaths
from heart disease among these patients compared with the general Danish
population (Weeke, 1979). By the early 1990s, evidence began to accumulate
showing that depressed individuals who were followed for long periods of time
were at increased risk for heart disease and cardiac death (Glassman, 2007). In one
investigation of over 700 Denmark residents, those with the highest depression
scores were 71% more likely to have experienced a heart attack than were those with
lower depression scores (Barefoot & Schroll, 1996)

Figure 11.19. This graph shows the incidence of heart attacks among men
and women by depression score quartile (adapted from Barefoot & Schroll,
1996).

After more than two decades of research, it is now clear that a relationship exists:
Patients with heart disease have more depression than the general population,
and people with depression are more likely to eventually develop heart disease
and experience higher mortality than those who do not have depression (Hare,
Toukhsati, Johansson, & Jaarsma, 2013); the more severe the depression, the
higher the risk (Glassman, 2007). Consider the following:
In one study, death rates from cardiovascular problems was substantially higher in
depressed people; depressed men were 50% more likely to have died from
 11.5 STRESS AND ILLNESS | 459
cardiovascular problems, and depressed women were 70% more likely (Ösby,
Brandt, Correia, Ekbom, & Sparén, 2001).
A statistical review of 10 longitudinal studies involving initially healthy
individuals revealed that those with elevated depressive symptoms have, on
average, a 64% greater risk of developing heart disease than do those with fewer
symptoms (Wulsin & Singal, 2003).
A study of over 63,000 registered nurses found that those with more depressed
symptoms when the study began were 49% more likely to experience fatal heart
disease over a 12-year period (Whang et al., 2009).

The American Heart Association, fully aware of the established importance of

depression in cardiovascular diseases, several years ago recommended routine
depression screening for all heart disease patients (Lichtman et al., 2008). Recently,
they have recommended including depression as a risk factor for heart disease
patients (AHA, 2014).
Although the exact mechanisms through which depression might produce heart
problems have not been fully clarified, a recent investigation examining this
connection in early life has shed some light. In an ongoing study of childhood
depression, adolescents who had been diagnosed with depression as children were
more likely to be obese, smoke, and be physically inactive than were those who had
not received this diagnosis (Rottenberg et al., 2014). One implication of this study
is that depression, especially if it occurs early in life, may increase the likelihood
of living an unhealthy lifestyle, thereby predisposing people to an unfavorable
cardiovascular disease risk profile.
It is important to point out that depression may be just one piece of the
emotional puzzle in elevating the risk for heart disease, and that chronically
experiencing several negative emotional states may be especially important. A
longitudinal investigation of Vietnam War veterans found that depression, anxiety,
hostility, and trait anger each independently predicted the onset of heart disease
(Boyle, Michalek, & Suarez, 2006). However, when each of these negative
psychological attributes was combined into a single variable, this new variable
(which researchers called psychological risk factor) predicted heart disease more
strongly than any of the individual variables. Thus, rather than examining the
predictive power of isolated psychological risk factors, it seems crucial for future
460 | 11.5 STRESS AND ILLNESS
researchers to examine the effects of combined and more general negative
emotional and psychological traits in the development of cardiovascular illnesses.

Asthma
Asthma is a chronic and serious disease in which the airways of the respiratory
system become obstructed, leading to great difficulty expelling air from the lungs.
The airway obstruction is caused by inflammation of the airways (leading to
thickening of the airway walls) and a tightening of the muscles around them,
resulting in a narrowing of the airways (American Lung Association, 2010).
Because airways become obstructed, a person with asthma will sometimes have
great difficulty breathing and will experience repeated episodes of wheezing, chest
tightness, shortness of breath, and coughing, the latter occurring mostly during the
morning and night (CDC, 2006).

Figure 11.20 In asthma, the airways become inflamed and narrowed.

Credit: Psychology 2e. Openstax

According to the Centers for Disease Control and Prevention (CDC), around
4,000 people die each year from asthma-related causes, and asthma is a
contributing factor to another 7,000 deaths each year (CDC, 2013a). The CDC
 11.5 STRESS AND ILLNESS | 461
has revealed that asthma affects 18.7 million U.S. adults and is more common
among people with lower education and income levels (CDC, 2013b). Especially
concerning is that asthma is on the rise, with rates of asthma increasing 157%
between 2000 and 2010 (CDC, 2013b).
Asthma attacks are acute episodes in which an asthma sufferer experiences the
full range of symptoms. Asthma exacerbation is often triggered by environmental
factors, such as air pollution, allergens (e.g., pollen, mold, and pet hairs), cigarette
smoke, airway infections, cold air or a sudden change in temperature, and exercise
(CDC, 2013b).
Psychological factors appear to play an important role in asthma (Wright,
Rodriguez, & Cohen, 1998), although some believe that psychological factors serve
as potential triggers in only a subset of asthma patients (Ritz, Steptoe, Bobb,
Harris, & Edwards, 2006). Many studies over the years have demonstrated that
some people with asthma will experience asthma-like symptoms if they expect
to experience such symptoms, such as when breathing an inert substance that
they (falsely) believe will lead to airway obstruction (Sodergren & Hyland, 1999).
As stress and emotions directly affect immune and respiratory functions,
psychological factors likely serve as one of the most common triggers of asthma
exacerbation (Trueba & Ritz, 2013).
People with asthma tend to report and display a high level of negative emotions
such as anxiety, and asthma attacks have been linked to periods of high
emotionality (Lehrer, Isenberg, & Hochron, 1993). In addition, high levels of
emotional distress during both laboratory tasks and daily life have been found
to negatively affect airway function and can produce asthma-like symptoms in
people with asthma (von Leupoldt, Ehnes, & Dahme, 2006). In one investigation,
20 adults with asthma wore preprogrammed wristwatches that signaled them to
breathe into a portable device that measures airway function. Results showed
that higher levels of negative emotions and stress were associated with increased
airway obstruction and self-reported asthma symptoms (Smyth, Soefer, Hurewitz,
Kliment, & Stone, 1999). In addition, D’Amato, Liccardi, Cecchi, Pellegrino, &
D’Amato (2010) described a case study of an 18-year-old man with asthma whose
girlfriend had broken up with him, leaving him in a depressed state. She had also
unfriended him on Facebook , while friending other young males. Eventually, the
young man was able to “friend” her once again and could monitor her activity
through Facebook. Subsequently, he would experience asthma symptoms
462 | 11.5 STRESS AND ILLNESS
whenever he logged on and accessed her profile. When he later resigned not to use
Facebook any longer, the asthma attacks stopped. This case suggests that the use of
Facebook and other forms of social media may represent a new source of stress—it
may be a triggering factor for asthma attacks, especially in depressed asthmatic
individuals.
Exposure to stressful experiences, particularly those that involve parental or
interpersonal conflicts, has been linked to the development of asthma throughout
the lifespan. A longitudinal study of 145 children found that parenting difficulties
during the first year of life increased the chances that the child developed asthma
by 107% (Klinnert et al., 2001). In addition, a cross-sectional study of over 10,000
Finnish college students found that high rates of parent or personal conflicts (e.g.,
parental divorce, separation from spouse, or severe conflicts in other long-term
relationships) increased the risk of asthma onset (Kilpeläinen, Koskenvuo,
Helenius, & Terho, 2002). Further, a study of over 4,000 middle-aged men who
were interviewed in the early 1990s and again a decade later found that breaking
off an important life partnership (e.g., divorce or breaking off relationship from
parents) increased the risk of developing asthma by 124% over the time of the study
(Loerbroks, Apfelbacher, Thayer, Debling, & Stürmer, 2009).

Tension Headaches
A headache is a continuous pain anywhere in the head and neck region. Migraine
headaches are a type of headache thought to be caused by blood vessel swelling and
increased blood flow (McIntosh, 2013). Migraines are characterized by severe pain
on one or both sides of the head, an upset stomach, and disturbed vision. They
are more frequently experienced by women than by men (American Academy of
Neurology, 2014). Tension headaches are triggered by tightening/tensing of facial
and neck muscles; they are the most commonly experienced kind of headache,
accounting for about 42% of all headaches worldwide (Stovner et al., 2007). In the
United States, well over one-third of the population experiences tension headaches
each year, and 2–3% of the population suffers from chronic tension headaches
(Schwartz, Stewart, Simon, & Lipton, 1998).
A number of factors can contribute to tension headaches, including sleep
deprivation, skipping meals, eye strain, overexertion, muscular tension caused by
 11.5 STRESS AND ILLNESS | 463
poor posture, and stress (MedicineNet, 2013). Although there is uncertainty
regarding the exact mechanisms through which stress can produce tension
headaches, stress has been demonstrated to increase sensitivity to pain (Caceres &
Burns, 1997; Logan et al., 2001). In general, tension headache sufferers, compared
to non-sufferers, have a lower threshold for and greater sensitivity to pain (Ukestad
& Wittrock, 1996), and they report greater levels of subjective stress when faced
with a stressor (Myers, Wittrock, & Foreman, 1998). Thus, stress may contribute
to tension headaches by increasing pain sensitivity in already-sensitive pain
pathways in tension headache sufferers (Cathcart, Petkov, & Pritchard, 2008).

Summary
Psychophysiological disorders are physical diseases that are either brought about or
worsened by stress and other emotional factors. One of the mechanisms through
which stress and emotional factors can influence the development of these diseases
is by adversely affecting the body’s immune system. A number of studies have
demonstrated that stress weakens the functioning of the immune system.
Cardiovascular disorders are serious medical conditions that have been consistently
shown to be influenced by stress and negative emotions, such as anger, negative
affectivity, and depression. Other psychophysiological disorders that are known
to be influenced by stress and emotional factors include asthma and tension
headaches.

• “Stress, Portrait of a Killer – Full Documentary (2008)” by interface.

Standard YouTube License.
464 | 11.6 REGULATION OF STRESS

11.6 REGULATION OF STRESS

Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper;
William Jenkins; Arlene Lacombe; Marilyn Lovett; and
Marion Perlmutter

As we learned in the previous section, stress—especially if it is chronic—takes a

toll on our bodies and can have enormously negative health implications. When
we experience events in our lives that we appraise as stressful, it is essential that we
use effective coping strategies to manage our stress. Coping refers to mental and
behavioral efforts that we use to deal with problems relating to stress, including its
presumed cause and the unpleasant feelings and emotions it produces.

Coping Styles
Lazarus and Folkman (1984) distinguished two fundamental kinds of coping:
problem-focused coping and emotion-focused coping. In problem-focused
coping, one attempts to manage or alter the problem that is causing one to
experience stress (i.e., the stressor). Problem-focused coping strategies are similar
to strategies used in everyday problem-solving: they typically involve identifying
the problem, considering possible solutions, weighing the costs and benefits of
these solutions, and then selecting an alternative (Lazarus & Folkman, 1984). As
an example, suppose Bradford receives a midterm notice that he is failing statistics
class. If Bradford adopts a problem-focused coping approach to managing his
stress, he would be proactive in trying to alleviate the source of the stress. He might
contact his professor to discuss what must be done to raise his grade, he might
also decide to set aside two hours daily to study statistics assignments, and he may
seek tutoring assistance. A problem-focused approach to managing stress means we
actively try to do things to address the problem.
Emotion-focused coping, in contrast, consists of efforts to change or reduce
the negative emotions associated with stress. These efforts may include avoiding,
minimizing, or distancing oneself from the problem, or positive comparisons with
 11.6 REGULATION OF STRESS | 465
others (“I’m not as bad off as she is”), or seeking something positive in a negative
event (“Now that I’ve been fired, I can sleep in for a few days”). In some cases,
emotion-focused coping strategies involve reappraisal, whereby the stressor is
construed differently (and somewhat self-deceptively) without changing its
objective level of threat (Lazarus & Folkman, 1984). For example, a person
sentenced to federal prison who thinks, “This will give me a great chance to
network with others,” is using reappraisal. If Bradford adopted an emotion-
focused approach to managing his midterm deficiency stress, he might watch a
comedy movie, play video games, or spend hours on Twitter to take his mind off
the situation. In a certain sense, emotion-focused coping can be thought of as
treating the symptoms rather than the actual cause.
While many stressors elicit both kinds of coping strategies, problem-focused
coping is more likely to occur when encountering stressors we perceive as
controllable, while emotion-focused coping is more likely to predominate when
faced with stressors that we believe we are powerless to change (Folkman &
Lazarus, 1980). Clearly, emotion-focused coping is more effective in dealing with
uncontrollable stressors. For example, if at midnight you are stressing over a
40-page paper due in the morning that you have not yet started, you are probably
better off recognizing the hopelessness of the situation and doing something to
take your mind off it; taking a problem-focused approach by trying to accomplish
this task would only lead to frustration, anxiety, and even more stress.
Fortunately, most stressors we encounter can be modified and are, to varying
degrees, controllable. A person who cannot stand her job can quit and look for
work elsewhere; a middle-aged divorcee can find another potential partner; the
freshman who fails an exam can study harder next time, and a breast lump does not
necessarily mean that one is fated to die of breast cancer.

Control and Stress

The desire and ability to predict events, make decisions, and affect outcomes—that
is, to enact control in our lives—is a basic tenet of human behavior (Everly &
Lating, 2002). Albert Bandura (1997) stated that “the intensity and chronicity of
human stress is governed largely by perceived control over the demands of one’s
life” (p. 262). As cogently described in his statement, our reaction to potential
466 | 11.6 REGULATION OF STRESS
stressors depends to a large extent on how much control we feel we have over
such things. Perceived control is our beliefs about our personal capacity to exert
influence over and shape outcomes, and it has major implications for our health
and happiness (Infurna & Gerstorf, 2014). Extensive research has demonstrated
that perceptions of personal control are associated with a variety of favorable
outcomes, such as better physical and mental health and greater psychological well-
being (Diehl & Hay, 2010). Greater personal control is also associated with lower
reactivity to stressors in daily life. For example, researchers in one investigation
found that higher levels of perceived control at one point in time were later
associated with lower emotional and physical reactivity to interpersonal stressors
(Neupert, Almeida, & Charles, 2007). Further, a daily diary study with 34 older
widows found that their stress and anxiety levels were significantly reduced on
days during which the widows felt greater perceived control (Ong, Bergeman, &
Bisconti, 2005).

LEARNED HELPLESSNESS
When we lack a sense of control over the events in our lives, particularly when
those events are threatening, harmful, or noxious, the psychological consequences
can be profound. In one of the better illustrations of this concept, psychologist
Martin Seligman conducted a series of classic experiments in the 1960s (Seligman
& Maier, 1967) in which dogs were placed in a chamber where they received
electric shocks from which they could not escape. Later, when these dogs were
given the opportunity to escape the shocks by jumping across a partition, most
failed to even try; they seemed to just give up and passively accept any shocks
the experimenters chose to administer. In comparison, dogs who were previously
allowed to escape the shocks tended to jump the partition and escape the pain.
 11.6 REGULATION OF STRESS | 467

Figure 11.21. Seligman’s learned helplessness experiments with dogs

used an apparatus that measured when the animals would move from a
floor delivering shocks to one without. CREDIT: Psychology 2e.
Openstax.org

Seligman believed that the dogs who failed to try to escape the later shocks were
demonstrating learned helplessness: They had acquired a belief that they were
powerless to do anything about the noxious stimulation they were receiving.
Seligman also believed that the passivity and lack of initiative these dogs
demonstrated was similar to that observed in human depression. Therefore,
Seligman speculated that acquiring a sense of learned helplessness might be an
important cause of depression in humans: Humans who experience negative life
events that they believe they are unable to control may become helpless. As a
result, they give up trying to control or change the situation and some may become
depressed and show lack of initiative in future situations in which they can control
the outcomes (Seligman, Maier, & Geer, 1968).
Seligman and colleagues later reformulated the original learned helplessness
model of depression (Abramson, Seligman, & Teasdale, 1978). In their
reformulation, they emphasized attributions (i.e., a mental explanation for why
something occurred) that lead to the perception that one lacks control over
negative outcomes are important in fostering a sense of learned helplessness. For
468 | 11.6 REGULATION OF STRESS
example, suppose a coworker shows up late to work; your belief as to what caused
the coworker’s tardiness would be an attribution (e.g., too much traffic, slept too
late, or just doesn’t care about being on time).
The reformulated version of Seligman’s study holds that the attributions made
for negative life events contribute to depression. Consider the example of a student
who performs poorly on a midterm exam. This model suggests that the student
will make three kinds of attributions for this outcome: internal vs. external
(believing the outcome was caused by his own personal inadequacies or by
environmental factors), stable vs. unstable (believing the cause can be changed or is
permanent), and global vs. specific (believing the outcome is a sign of inadequacy
in most everything versus just this area). Assume that the student makes an internal
(“I’m just not smart”), stable (“Nothing can be done to change the fact that I’m
not smart”) and global (“This is another example of how lousy I am at everything”)
attribution for the poor performance. The reformulated theory predicts that the
student would perceive a lack of control over this stressful event and thus be
especially prone to developing depression. Indeed, research has demonstrated that
people who have a tendency to make internal, global, and stable attributions for
bad outcomes tend to develop symptoms of depression when faced with negative
life experiences (Peterson & Seligman, 1984).
Seligman’s learned helplessness model has emerged over the years as a leading
theoretical explanation for the onset of major depressive disorder. When you study
psychological disorders, you will learn more about the latest reformulation of this
model—now called hopelessness theory.

People who report higher levels of perceived control view their health as
controllable, thereby making it more likely that they will better manage their health
and engage in behaviors conducive to good health (Bandura, 2004). Not
surprisingly, greater perceived control has been linked to lower risk of physical
health problems, including declines in physical functioning (Infurna, Gerstorf,
Ram, Schupp, & Wagner, 2011), heart attacks (Rosengren et al., 2004), and both
cardiovascular disease incidence (Stürmer, Hasselbach, & Amelang, 2006) and
mortality from cardiac disease (Surtees et al., 2010). In addition, longitudinal
studies of British civil servants have found that those in low-status jobs (e.g., clerical
and office support staff) in which the degree of control over the job is minimal are
considerably more likely to develop heart disease than those with high-status jobs
 11.6 REGULATION OF STRESS | 469
or considerable control over their jobs (Marmot, Bosma, Hemingway, & Stansfeld,
1997).
The link between perceived control and health may provide an explanation
for the frequently observed relationship between social class and health outcomes
(Kraus, Piff, Mendoza-Denton, Rheinschmidt, & Keltner, 2012). In general,
research has found that more affluent individuals experience better health mainly
because they tend to believe that they can personally control and manage their
reactions to life’s stressors (Johnson & Krueger, 2006). Perhaps buoyed by the
perceived level of control, individuals of higher social class may be prone to
overestimating the degree of influence they have over particular outcomes. For
example, those of higher social class tend to believe that their votes have greater
sway on election outcomes than do those of lower social class, which may explain
higher rates of voting in more affluent communities (Krosnick, 1990). Other
research has found that a sense of perceived control can protect less affluent
individuals from poorer health, depression, and reduced life-satisfaction—all of
which tend to accompany lower social standing (Lachman & Weaver, 1998).
Taken together, findings from these and many other studies clearly suggest that
perceptions of control and coping abilities are important in managing and coping
with the stressors we encounter throughout life.

Social Support
The need to form and maintain strong, stable relationships with others is a
powerful, pervasive, and fundamental human motive (Baumeister & Leary, 1995).
Building strong interpersonal relationships with others helps us establish a
network of close, caring individuals who can provide social support in times of
distress, sorrow, and fear. Social support can be thought of as the soothing impact
of friends, family, and acquaintances (Baron & Kerr, 2003). Social support can take
many forms, including advice, guidance, encouragement, acceptance, emotional
comfort, and tangible assistance (such as financial help). Thus, other people can
be very comforting to us when we are faced with a wide range of life stressors, and
they can be extremely helpful in our efforts to manage these challenges. Even in
nonhuman animals, species mates can offer social support during times of stress.
For example, elephants seem to be able to sense when other elephants are stressed
470 | 11.6 REGULATION OF STRESS
and will often comfort them with physical contact—such as a trunk touch—or an
empathetic vocal response (Krumboltz, 2014).
Scientific interest in the importance of social support first emerged in the 1970s
when health researchers developed an interest in the health consequences of being
socially integrated (Stroebe & Stroebe, 1996). Interest was further fueled by
longitudinal studies showing that social connectedness reduced mortality. In one
classic study, nearly 7,000 Alameda County, California, residents were followed
over 9 years. Those who had previously indicated that they lacked social and
community ties were more likely to die during the follow-up period than those
with more extensive social networks. Compared to those with the most social
contacts, isolated men and women were, respectively, 2.3 and 2.8 times more likely
to die. These trends persisted even after controlling for a variety of health-related
variables, such as smoking, alcohol consumption, self-reported health at the
beginning of the study, and physical activity (Berkman & Syme, 1979).
Since the time of that study, social support has emerged as one of the well-
documented psychosocial factors affecting health outcomes (Uchino, 2009). A
statistical review of 148 studies conducted between 1982 and 2007 involving over
300,000 participants concluded that individuals with stronger social relationships
have a 50% greater likelihood of survival compared to those with weak or
insufficient social relationships (Holt-Lunstad, Smith, & Layton, 2010).
According to the researchers, the magnitude of the effect of social support
observed in this study is comparable with quitting smoking and exceeded many
well-known risk factors for mortality, such as obesity and physical inactivity.

Figure 11.22. Close relationships with others, whether (a) a group of

friends or (b) a family circle, provide more than happiness and
fulfillment—they can help foster good health. Credit a: modification of work
by Nattachai Noogure; credit b: modification of work by Christian Haugen)
 11.6 REGULATION OF STRESS | 471
A number of large-scale studies have found that individuals with low levels of social
support are at greater risk of mortality, especially from cardiovascular disorders
(Brummett et al., 2001). Further, higher levels of social supported have been linked
to better survival rates following breast cancer (Falagas et al., 2007) and infectious
diseases, especially HIV infection (Lee & Rotheram-Borus, 2001). In fact, a person
with high levels of social support is less likely to contract a common cold. In one
study, 334 participants completed questionnaires assessing their sociability; these
individuals were subsequently exposed to a virus that causes a common cold and
monitored for several weeks to see who became ill. Results showed that increased
sociability was linearly associated with a decreased probability of developing a cold
(Cohen, Doyle, Turner, Alper, & Skoner, 2003).
For many of us, friends are a vital source of social support. But what if you
found yourself in a situation in which you lacked friends or companions? For
example, suppose a popular high school student attends a far-away college, does
not know anyone, and has trouble making friends and meaningful connections
with others during the first semester. What can be done? If real life social support
is lacking, access to distant friends via social media may help compensate. In a
study of college freshmen, those with few face-to-face friends on campus but
who communicated electronically with distant friends were less distressed that
those who did not (Raney & Troop-Gordon, 2012). Also, for some people, our
families—especially our parents—are a major source of social support.
Social support appears to work by boosting the immune system, especially
among people who are experiencing stress (Uchino, Vaughn, Carlisle, &
Birmingham, 2012). In a pioneering study, spouses of cancer patients who
reported high levels of social support showed indications of better immune
functioning on two out of three immune functioning measures, compared to
spouses who were below the median on reported social support (Baron, Cutrona,
Hicklin, Russell, & Lubaroff, 1990). Studies of other populations have produced
similar results, including those of spousal caregivers of dementia sufferers, medical
students, elderly adults, and cancer patients (Cohen & Herbert, 1996; Kiecolt-
Glaser, McGuire, Robles, & Glaser, 2002).
In addition, social support has been shown to reduce blood pressure for people
performing stressful tasks, such as giving a speech or performing mental arithmetic
(Lepore, 1998). In these kinds of studies, participants are usually asked to perform
a stressful task either alone, with a stranger present (who may be either supportive
472 | 11.6 REGULATION OF STRESS
or unsupportive), or with a friend present. Those tested with a friend present
generally exhibit lower blood pressure than those tested alone or with a stranger
(Fontana, Diegnan, Villeneuve, & Lepore, 1999). In one study, 112 female
participants who performed stressful mental arithmetic exhibited lower blood
pressure when they received support from a friend rather than a stranger, but only
if the friend was a male (Phillips, Gallagher, & Carroll, 2009). Although these
findings are somewhat difficult to interpret, the authors mention that it is possible
that females feel less supported and more evaluated by other females, particularly
females whose opinions they value.
Taken together, the findings above suggest one of the reasons social support
is connected to favorable health outcomes is because it has several beneficial
physiological effects in stressful situations. However, it is also important to
consider the possibility that social support may lead to better health behaviors,
such as a healthy diet, exercising, smoking cessation, and cooperation with medical
regimens (Uchino, 2009).

Coping with Prejudice and Discrimination

While having social support is quite beneficial, being the recipient of prejudicial
attitudes and discriminatory behaviors is associated with a number of negative
outcomes. In their literature review, Brondolo, Brady, Pencille, Beatty, and
Contrada (2009) describe how racial prejudice and discrimination serve as unique,
significant stressors for those who are the targets of such attitudes and behavior.
Being the target of racism is associated with increased rates of depression, lowered
self-esteem, hypertension, and cardiovascular disease.
Given the complex and pervasive nature of racism as a stressor, Brondolo et al.
(2009) point out the importance of coping with this specific stressor. Their review
is aimed at determining which coping strategies are most effective at offsetting
negative health outcomes associated with racism-related stress. The authors
examine the effectiveness of three coping strategies: focusing on racial identity
to handle race-related stress, anger expression/suppression, and seeking social
support. You’ve learned a bit about social support, so we’ll focus the remainder of
this discussion on the potential coping strategies of focusing on racial identity and
anger expression/suppression.
 11.6 REGULATION OF STRESS | 473
Focusing on racial identity refers to the process by which a person comes to feel
as if he belongs to a given racial group; this may increase a sense of pride associated
with group membership. Brondolo et al. (2009) suggest that a strong sense of racial
identity might help an individual who is the target of racism differentiate between
prejudicial attitudes/behaviors that are directed toward his group as a whole rather
than at him as a person. Furthermore, the sense of belonging to his group might
alleviate the distress of being ostracized by others. However, the research literature
on the effectiveness of this technique has produced mixed results.
Anger expression/suppression refers to the options available as a function of the
anger evoked by racial prejudice and discrimination. Put simply, a target of racist
attitudes and behaviors can act upon her anger or suppress her anger. As discussed
by Brondolo et al. (2009), there has been very little research on the effectiveness of
either approach; the results are quite mixed with some showing anger expression
and others showing anger suppression as the healthier option.
In the end, racism-related stress is a complex issue and each of the coping
strategies discussed here has strengths and weaknesses. Brondolo et al. (2009) argue
that it is imperative that additional research be conducted to ascertain the most
effective strategies for coping with the negative outcomes that are experienced by
the targets of racism.

Stress Reduction Techniques

Beyond having a sense of control and establishing social support networks, there
are numerous other means by which we can manage stress. A common technique
people use to combat stress is exercise (Salmon, 2001). It is well-established that
exercise, both of long (aerobic) and short (anaerobic) duration, is beneficial for
both physical and mental health (Everly & Lating, 2002). There is considerable
evidence that physically fit individuals are more resistant to the adverse effects
of stress and recover more quickly from stress than less physically fit individuals
(Cotton, 1990). In a study of more than 500 Swiss police officers and emergency
service personnel, increased physical fitness was associated with reduced stress,
and regular exercise was reported to protect against stress-related health problems
(Gerber, Kellman, Hartman, & Pühse, 2010).
474 | 11.6 REGULATION OF STRESS

Figure 11.23.Stress reduction techniques may include (a) exercise, (b)

meditation and relaxation, or (c) biofeedback. Credit a: modification of
work by “UNE Photos”/Flickr; credit b: modification of work by Caleb Roenigk;
credit c: modification of work by Dr. Carmen Russoniello)

One reason exercise may be beneficial is because it might buffer some of the
deleterious physiological mechanisms of stress. One study found rats that exercised
for six weeks showed a decrease in hypothalamic-pituitary-adrenal responsiveness
to mild stressors (Campeau et al., 2010). In high-stress humans, exercise has been
shown to prevent telomere shortening, which may explain the common
observation of a youthful appearance among those who exercise regularly
(Puterman et al., 2010). Further, exercise in later adulthood appears to minimize
the detrimental effects of stress on the hippocampus and memory (Head, Singh, &
Bugg, 2012). Among cancer survivors, exercise has been shown to reduce anxiety
(Speck, Courneya, Masse, Duval, & Schmitz, 2010) and depressive symptoms
(Craft, VanIterson, Helenowski, Rademaker, & Courneya, 2012). Clearly, exercise
is a highly effective tool for regulating stress.
In the 1970s, Herbert Benson, a cardiologist, developed a stress reduction
method called the relaxation response technique (Greenberg, 2006). The
relaxation response technique combines relaxation with transcendental
meditation, and consists of four components (Stein, 2001):

• sitting upright on a comfortable chair with feet on the ground and body in a
relaxed position,
• a quiet environment with eyes closed,
• repeating a word or a phrase—a mantra—to oneself, such as “alert mind,
calm body,”
• passively allowing the mind to focus on pleasant thoughts, such as nature or
the warmth of your blood nourishing your body.
 11.6 REGULATION OF STRESS | 475
The relaxation response approach is conceptualized as a general approach to stress
reduction that reduces sympathetic arousal, and it has been used effectively to treat
people with high blood pressure (Benson & Proctor, 1994).
Another technique to combat stress, biofeedback, was developed by Gary
Schwartz at Harvard University in the early 1970s. Biofeedback is a technique that
uses electronic equipment to accurately measure a person’s neuromuscular and
autonomic activity—feedback is provided in the form of visual or auditory signals.
The main assumption of this approach is that providing somebody biofeedback
will enable the individual to develop strategies that help gain some level of
voluntary control over what are normally involuntary bodily processes (Schwartz
& Schwartz, 1995). A number of different bodily measures have been used in
biofeedback research, including facial muscle movement, brain activity, and skin
temperature, and it has been applied successfully with individuals experiencing
tension headaches, high blood pressure, asthma, and phobias (Stein, 2001).

Summary
When faced with stress, people must attempt to manage or cope with it. In general,
there are two basic forms of coping: problem-focused coping and emotion-focused
coping. Those who use problem-focused coping strategies tend to cope better with
stress because these strategies address the source of stress rather than the resulting
symptoms. To a large extent, perceived control greatly impacts reaction to stressors
and is associated with greater physical and mental well-being. Social support has
been demonstrated to be a highly effective buffer against the adverse effects of
stress. Extensive research has shown that social support has beneficial physiological
effects for people, and it seems to influence immune functioning. However, the
beneficial effects of social support may be related to its influence on promoting
healthy behaviors.
476 | 11.7: REFERENCES

11.7: REFERENCES

This chapter was adapted from:

Harmon-Jones, E. & Harmon-Jones, C. (2023). Affective

neuroscience. In R. Biswas-Diener & E. Diener (Eds), Noba
textbook series: Psychology. Champaign, IL: DEF publishers.
Retrieved from http://noba.to/qnv3erb9

Lim, A. (2021). Emotion and Stress (edited by Ledmyr, H). Open

neuroscience initiative. https://www.austinlim.com/open-
neuroscience-initiative

Introduction to Psychology (A critical approach) Copyright © 2021 by

Jill Grose-Fifer; Rose M. Spielman; Kathryn Dumper; William Jenkins;
Arlene Lacombe; Marilyn Lovett; and Marion Perlmutter is licensed
under a Creative Commons Attribution 4.0 International License,

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 CHAPTER 12: BRAIN DAMAGE, NEURODEGENERATION, AND

CHAPTER 12: BRAIN

DAMAGE,
NEURODEGENERATION,
AND NEUROLOGICAL
DISEASES

Learning Objectives

• Describe the symptoms, causes, and treatments of several

examples of brain damage, including tumor, stroke, and traumatic
brain injury
• Understand the less recognized epidemic of traumatic brain injury
caused by intimate partner violence.
• Describe the symptoms, causes, and treatments of several
examples of neurological diseases, including Parkinson’s Disease,
Alzheimer’s Disease, and Multiple Sclerosis.

This chapter is adapted from Hove, M. J., & Martinez, S. A. (2024).

Biological Psychology. ROTEL (Remixing Open Textbooks with an
500 | CHAPTER 12: BRAIN DAMAGE, NEURODEGENERATION, AND

Equity Lens) Project. https://rotel.pressbooks.pub/

biologicalpsychology/
 12.1: INTRODUCTION | 501

12.1: INTRODUCTION

The complexity and capabilities of a well-functioning human brain are truly

astonishing. The three-pound mass of molecules is organized in an intricate web
of billions of neurons and support cells. These interconnected neural networks
coordinate to control our most mundane functions and our most profound
thoughts. The distributed patterns of brain activity enable us to perceive, learn,
experience, create, communicate, empathize, and dream, propelling our species
toward unending innovation and discovery. Yet, for all its capabilities and general
resilience, the brain remains vulnerable.
The delicate balance in a well-functioning brain can be disrupted in many ways
causing various dysfunctions. Brain cells need oxygen and nutrients to
survive–interrupted supply can be devastating. Neurons use neurotransmitters to
communicate–too little or too much can stop communication or kill cells. Brain
cells are fragile and are easily damaged by force or by invading agents. Proteins can
build up and disrupt function. Brain cells can die and cause atrophy.
This chapter delves into the darker side of brain biology: brain damage and
neurodegeneration. We will explore how things can go awry in this intricate organ
and lead to serious alterations in behavior, cognition, and quality of life.
Understanding these aspects is not only crucial for appreciating the brain’s fragility
but also for developing effective therapies for the many types of brain damage and
neurodegeneration.
Brain damage can occur in many ways, including traumatic brain injury, tumor,
stroke, encephalitis (inflammation of the brain often caused by infections),
hydrocephalus (fluid buildup inside the skull that increases pressure), lack of
oxygen, and meningitis (inflammation of the meninges, the protective membrane
around the brain, usually caused by infection). In this section, we’ll go into detail
about three of the most common types of brain damage: brain tumor, stroke,
and traumatic brain injury (TBI). With TBI, we focus on an under-recognized
epidemic–TBI that stems from intimate partner violence.
There are also many forms of neurological diseases and neurodegeneration.
502 | 12.1: INTRODUCTION
In this chapter, we’ll cover three common ones–Parkinson’s disease, Alzheimer’s
disease, and Multiple Sclerosis.
 12.2: STROKE | 503

12.2: STROKE

Overview. A stroke is a medical emergency involving an interruption of blood

flow to the brain. The interrupted blood flow prevents brain tissue from getting
oxygen and nutrients. In turn, neuronal function is impaired within seconds,
and brain cells start to die within minutes. Stroke is the leading cause of long-
term adult disability and was the fifth leading cause of death in the United States
in 2021 (CDC, 2023a). Long-term effects of stroke depend on the extent and
location of the brain damage and include paralysis, problems with cognition or
memory, issues speaking or understanding speech, emotional disturbances, pain,
and unusual bodily sensations (NINDS, 2023a).
Types of Strokes. Strokes can be classified into two major categories: ischemic
(pronounced ‘ih-skee-muhk’) and hemorrhagic (pronounced “heh-mr-a-juhk”).
Most strokes are ischemic. Ischemic strokes are caused by interruption of the
blood supply to one or more regions of the brain. The interruption is most
commonly caused by a blood clot or cellular debris that blocks a blood vessel
in the brain (NINDS, 2023a). A clot might develop at the site of the blockage
(“thrombosis”) or it might create a blockage after moving from another part of the
body (“embolism.”) The third cause of ischemic stroke is “stenosis” in which an
artery narrows, often due to plaques or fatty deposits on artery walls. The other
major category of stroke, hemorrhagic stroke, happens when an artery in the
brain leaks blood or ruptures (breaks open). The leaked blood puts too much
pressure on brain cells and damages them.
504 | 12.2: STROKE

Figure 12.1. A stroke, sometimes called a brain attack, happens in one of

two ways: 1) ischemic strokes occur when an artery is blocked, and 2)
hemorrhagic stroke occurs when a blood vessel ruptures. CREDIT: Stroke
Medical Illustration © CDC is licensed under a Public Domain license

Cell death. After a stroke, some brain cells die because they stop getting the
oxygen and nutrients needed to function. Other brain cells die because they are
damaged by sudden bleeding in or around the brain. Some brain cells die quickly,
but many linger in a compromised or weakened state for several hours. Stroke
causes permanent brain damage over minutes to hours (NINDS, 2023a).
One specific cellular mechanism underlying ischemic-induced cell death is
glutamate excitotoxicity. Glutamate is a major excitatory neurotransmitter
important for memory and long-term potentiation (covered in Chapter 7).
Glutamate is key for healthy brain function, but too much glutamate can kill
neurons–this is known as glutamate excitotoxicity. When a stroke blocks oxygen-
 12.2: STROKE | 505
rich blood supply to the brain, negatively charged ATP levels drop, making the
interior of the neuron more positively charged. This leads to excess glutamate
released into the synapse, which causes the postsynaptic neuron to fire excessively;
calcium ions flood the postsynaptic cell, cytotoxic enzymes are activated, and it
eventually dies. Critically, as a neuron dies, it releases its own glutamate reserves,
which starts the process over in nearby cells. This glutamate excitotoxicity repeats
itself in a vicious cycle that spreads quickly and kills many neurons in a matter of
minutes (Kuang, 2019; Mark, 2001).
Identifying stroke. With stroke, the sooner treatment begins, the better.
Knowing the signs of stroke and calling 911 immediately can help save a relative,
neighbor, or friend. A useful mnemonic for remembering the signs of strokes is
FAST (standing for Facial droop, Arm weakness, Speech difficulty, Time to call
emergency services, see Figure 12.2). With timely treatment, it is possible to save
brain cells and greatly reduce the damage (NINDS, 2023a).

Figure 12.2. Acting F.A.S.T. is key to stroke survival. Face: Does one side
of the face droop when smiling? Arms: Does one arm drift downward
when both arms are raised? Speech: Is speech slurred or strange when
repeating a simple phrase? Time: If you see any of these signs, call
emergency services such as 9-1-1 immediately. CREDIT: FAST Graphic ©
CDC is licensed under a Public Domain license

Treatments. At the emergency room, patients can receive drugs that can dissolve a
clot. These drugs will not work if the stroke occurred more than three hours before
506 | 12.2: STROKE
arriving at the hospital or was caused by a burst blood vessel (Clark et al., 2018).
For those hemorrhagic strokes, surgeons may clip blood vessels to stop bleeding,
drain excess fluid, or even temporarily remove part of the skull to relieve pressure
from swelling.
Recovery from a stroke can take weeks, months, or even years. Some people fully
recover, whereas others have lifelong disabilities. Treatment following a stroke can
include blood pressure medication and healthy lifestyle changes to prevent future
strokes, and physical and speech therapy.
Risk factors of stroke. Despite the possibility of death or long-term disability,
there is some “good news”: About 4 in 5 strokes are preventable (CDC, 2023b).
Risk factors can be categorized as modifiable and nonmodifiable. Risk factors of
stroke that are nonmodifiable are age (older adults have a higher risk), sex (men
have a higher risk), and race/ethnicity (stroke incidence among Black and Hispanic
Americans is almost double that of White Americans, and Black and Hispanic
Americans tend to have strokes at a younger age) (Boehme et al. 2017; NINDS,
2023a). The “good news” is that some risk factors are modifiable and can be
controlled by lifestyle and behavior changes. High blood pressure is the most
important risk factor and can be managed by eating a healthy diet (low fat, low
cholesterol, low salt, whole grains, and veggies), exercising (2.5+ hours per week),
not drinking too much alcohol, and not smoking (smokers are twice as likely to
have a stroke) (CDC, 2023b).
Finally, air pollution, noise pollution, and even light pollution have been linked
to a higher risk of hypertension, stroke, and other cardiovascular diseases (Boehme,
2017; Van Kempen & Babisch, 2012). While these factors are modifiable, they are
not controllable at the individual level, especially for poor people (who have fewer
housing options and often can’t afford to move away from such environmental
hazards) (Crea, 2021). Thus, some prevention measures are best viewed at the
population level, and this underscores the connection between public health and
sensible public policy that mitigates risk factors.

Text Attributions
This section contains material adapted from:
National Institute of Neurological Disorders and Stroke (NINDS) (2023).
 12.2: STROKE | 507
Stroke. https://www.ninds.nih.gov/health-information/disorders/stroke Public
domain.
508 | 12.3: BRAIN TUMORS

12.3: BRAIN TUMORS

A brain tumor is a mass of abnormal cells that form into a growth in the brain.
Tumors occur when something goes wrong with genes that regulate cell growth,
allowing cells to grow and divide out of control (NINDS, 2023c). Tumors can
be noncancerous (benign) or cancerous (malignant). Benign tumors don’t spread
to other body parts and often can be removed surgically. Malignant tumors can
invade surrounding tissue; some malignant brain tumors can be removed entirely
through surgery, whereas others have hard-to-define edges so are difficult to remove
completely.
Tumors can also be categorized as primary tumors, which start within the brain,
and secondary or metastatic tumors, which are caused by cancer cells that break
away from a primary tumor somewhere else in the body and spread to the brain.
Metastatic tumors are more common than primary tumors in the brain and occur
more often in adults than in children.
Symptoms. Brain tumors cause many different symptoms, and they depend on
tumor type, location, size, and rate of growth. In infants, the most obvious sign
of a brain tumor is a rapidly widening head or bulging crown (see Figure 12.3 for
an image of a bulging skull in an adult). In older children and adults, a tumor
can cause headaches, seizures, balance problems, and personality changes. As with
all brain damage and neurological disorders, the effects are location-specific. For
example, a tumor in the frontal lobe might contribute to poor cognition or
inappropriate social behavior; a tumor in the cerebellum might cause poor balance
and movement control; a tumor in emotional regions might cause new bouts of
inappropriate laughter or rage. A good friend reported no symptoms until his face
and head swelled up after a flight; an emergency MRI revealed a tennis-ball sized
meningioma (a tumor in the meninges surrounding the brain; see Figure 3 for a
meningioma in another person). Retrospectively, he said he may have had some
coordination deficits (e.g., causing him to lose to his brother in golf); the tumor
was surgically removed and he has resumed “trouncing” his brother in golf.
 12.3: BRAIN TUMORS | 509

Figure 12.3. A meningioma, a benign tumor that developed in the

meninges (thin membrane covering the brain), has caused a large
hyperostosis (excessive bone growth of the skull). CREDIT: Meningioma of
the sagittal sinus © Wikimedia is licensed under a CC0 (Creative Commons Zero)
license

Diagnosis and Treatment. Diagnosing a brain tumor usually involves a

neurological exam with a doctor, lab tests of blood and urine, and diagnostic
imaging with magnetic resonance imaging (MRI). MRI scans can provide high-
resolution information about tumor cell density and a precise map of the tumor
and neighboring structures (see Figure 12.4 for an MRI scan of a tumor). Surgery
is used to obtain tissue for diagnosis and to remove as much tumor as safely
possible. Radiation therapy and chemotherapy are often used to kill cancer cells
or stop them from spreading. Biological or immunotherapies are being developed
to enhance the body’s immune response and to recognize and fight cancer cells.
Outcomes for treatments differ greatly based on the tumor type, location, degree of
spreading, etc. Malignant glioblastomas, an especially aggressive spreading cancer,
usually have very poor outcomes (median survival of 14 months; Delgado-Lopez,
2016); while benign meningiomas (non-spreading tumors that develop in the
meninges membrane covering the brain) have good outcomes because they haven’t
invaded the brain and can be surgically removed.
510 | 12.3: BRAIN TUMORS

Figure 12.4. A metastatic tumor in the cerebral hemisphere from

lung cancer, shown on magnetic resonance imaging. CREDIT:
Hirnmetastase © Wikimedia

Text Attributions
This section contains material adapted from:
National Institute of Neurological Disorders and Stroke (NINDS) (2023c).
Brain and Spinal Cord Tumors.
https://www.ninds.nih.gov/health-information/disorders/brain-and-spinal-
cord-tumors Public Domain.
 12.4: TRAUMATIC BRAIN INJURY | 511

12.4: TRAUMATIC BRAIN INJURY

A traumatic brain injury (TBI) is an injury to the brain caused by an external force.
TBIs can be caused by a forceful bump, blow, or jolt to the head or body (a “non-
penetrating TBI”), or from an object that pierces the skull and enters the brain (a
“penetrating TBI”). TBI is a major cause of death and disability: the United States
had over 69,000 TBI-related deaths in 2021, and about 15% of all U.S. high-school
students self-reported one or more sports or recreation-related concussions (a type
of TBI) within the preceding 12 months (CDC, 2023c).
Some types of TBI can cause temporary or short-term problems with brain
function, including problems with how the person thinks, understands, moves,
communicates, sleeps, and acts. More serious TBI can lead to severe and
permanent disability or death. TBI severity is categorized as mild, moderate, or
severe; one common way to categorize severity uses a combination of three factors:
1) the Glasgow Coma scale (a test of eye, verbal, and motor responses); 2) duration
of post-traumatic amnesia or memory loss (less than 1 day for mild TBI, more than
7 days for severe TBI); and 3) duration of Loss of Consciousness (0-30 minutes for
mild TBI and more than 24 hours for severe TBI) (Departments of Defense and
Veterans Affairs, 2008). Most TBIs are mild TBIs or concussions.

How TBI affects the brain

Primary effects on the brain include various types of bleeding and tearing forces
that injure nerve fibers and cause inflammation, metabolic changes, and brain
swelling (NINDS, 2023d). Some examples include:

• Diffuse axonal injury (DAI), one of the most common types of brain
injuries, refers to widespread damage to the brain’s myelinated white matter
tracts. DAI usually results from rotational forces (twisting) or sudden
forceful stopping that stretches or tears these axon bundles (see Figure 12.5).
DAI can disrupt and break down communication among neurons. It also
512 | 12.4: TRAUMATIC BRAIN INJURY
leads to the release of brain chemicals that can cause further damage.

Figure 12.5. Diagram of diffuse axonal injury following TBI/concussion.

Many types of damage can occur along the length of the axon, including
stretching/pulling of axons which may affect myelination and
localization of axonal channel proteins, and tearing and shearing, which
will cause loss of axonal integrity. CREDIT: Diffuse Axonal Injury © eCampus
Ontario

• Concussion is a type of mild TBI that may be considered a temporary injury

to the brain but could take several months to heal. A small minority of
individuals report symptoms that persist for years or indefinitely. The
individual can suddenly lose consciousness or have a sudden altered state of
consciousness. A second concussion closely following the first one causes
further damage to the brain, and may result in a slower recovery or the so-
called “second impact syndrome” that could lead to permanent damage or
even death (which is a reason why concussion-monitoring protocols in
sports are critical).
 12.4: TRAUMATIC BRAIN INJURY | 513
• Hematomas are bleeding around the brain caused by a rupture of a blood
vessel. In a hematoma, blood can collect in or around the meninges (the
protective membranes surrounding the brain) or into the brain itself,
damaging the surrounding tissue.

• Contusions are a bruising or swelling of the brain that occurs when very
small blood vessels bleed into brain tissue. Contusions can occur directly
under the impact site (a coup injury) or, more often, on the complete
opposite side of the brain from the impact (a contrecoup injury). Coup and
contrecoup injuries generally occur when the head abruptly decelerates,
which causes the brain to hit one side of the skull and then bounce back and
hit the other side (such as in a high-speed car crash or in shaken baby
syndrome) (Figure 12.6).
514 | 12.4: TRAUMATIC BRAIN INJURY

Figure 12.6. A diagram of the forces on the brain in a coup-contrecoup

injury. CREDIT: Contrecoup © Wikimedia

• The blood-brain barrier that protects the central nervous system from toxins
and pathogens can break down from a TBI. Once the blood-brain barrier is
disrupted, blood and other foreign substances can leak into the space around
neurons and trigger a chain reaction that causes brain swelling. It can also
trigger harmful inflammation or the release of neurotransmitters that can kill
nerve cells when depleted or overexpressed.1
 12.4: TRAUMATIC BRAIN INJURY | 515

Diagnosing and Treating TBIs

All TBIs require immediate assessment by a professional who has experience
evaluating head injuries. A neurological exam will test motor, sensory, and speech
skills, coordination and balance, cognitive and memory performance, and changes
in mood or behavior. An exam might check for a normal pupil response to changes
in light and assign a Glasgow Coma Score. In addition, diagnostic brain imaging
with a CT or MRI scan can help evaluate the extent of the brain injuries and
determine if surgery is needed.
Many factors—including the size, severity, and location of the brain
injury—influence how a TBI is treated and how quickly a person might recover.
Although brain injury often occurs at the moment of head impact, much damage
in a severe TBI develops from secondary injuries that happen days or weeks after
the initial trauma. For this reason, people who receive immediate medical attention
at a certified trauma center tend to have the best health outcomes.
Some people with a mild TBI, such as concussion, may not require treatment
other than rest and over-the-counter pain relievers. For more severe TBIs,
immediate treatment focuses on preventing death, stabilizing vital organ function,
ensuring proper breathing, and preventing further brain damage. Once the patient
is stabilized, a rehabilitation program is employed to help recovery. This may
include physical therapy, occupational therapy, speech-language therapy, cognitive
or vestibular rehabilitation therapy, and psychological support for emotional well-
being. Novel therapies, such as neuroprotective agents and stem cell therapy, are
under active research and hold promise for future treatment possibilities.2

1. This section contains material adapted from: National Institute of Neurological Disorders and Stroke
(NINDS) (2023d). Traumatic Brain Injury (TBI). https://www.ninds.nih.gov/health-information/
disorders/traumatic-brain-injury-tbi Public Domain.
2. This section contains material adapted from: National Institute of Neurological Disorders and Stroke
(NINDS) (2023d). Traumatic Brain Injury (TBI). https://www.ninds.nih.gov/health-information/
disorders/traumatic-brain-injury-tbi Public Domain.
 516 | 12.4: TRAUMATIC BRAIN INJURY

Chronic Traumatic Encephalopathy

(CTE)
A history of experiencing repeated head traumas has been associated with Chronic
Traumatic Encephalopathy (CTE). CTE is a progressive neurological disorder
associated with symptoms that may include problems thinking, understanding,
and communicating; motor disorders (affecting movement); problems with
impulse control and depression; and irritability. CTE occurs in those with
extraordinary exposure to multiple blows to the head, and symptoms generally
start to appear 8-10 years after repeated head injuries (NINDS, 2023d; McKee,
2009). CTE can only be diagnosed after death. After death, a person’s brain is
removed, and doctors check whether the person had CTE or another disease, such
as Alzheimer’s disease, or no disease at all (CDC, 2019). A brain with CTE is
characterized by atrophy (shrinkage) of several brain areas, including the cerebral
hemispheres, the medial temporal lobe, the thalamus, and the brain stem, as well as
dilation of the ventricles (Figure 12.7) (McKee 2009). Microscopic examination
of brain tissue reveals the pathological signature of CTE–phosphorylated tau
protein (p-tau) that builds up in neurons, astrocytes, and cell processes around
small blood vessels of the cortex, typically at the depth of cortical sulci (Asken,
2017; McKee, 2009) (Figure 12.8). The distribution of tau protein in CTE differs
from other tau-related disorders, such as Alzheimer’s Disease. But in both tau
pathologies, tau buildup and the neurofibrillary tangles formed from tau
eventually disrupt brain cells’ ability to communicate with other cells.
Researchers do not know how many people in the United States have CTE.
Some evidence suggests rates around 30% for those with histories of repeated head
injuries (Asken, 2017). Most studies on CTE have focused on a small group of
people who experienced head or brain injuries over many years. People in this
group had their brains donated for research, and according to reports from family
members, they often had problems with thinking, emotions, or behavior while
they were alive (CDC, 2019).3

3. This section contains material adapted from: National Institute of Neurological Disorders and Stroke
 12.4: TRAUMATIC BRAIN INJURY | 517

Figure 12.7. A normal brain (left) and one with advanced CTE (right).
CREDIT: Chronic traumatic encephalopathy © Wikimedia is licensed under a CC
BY-SA (Attribution ShareAlike) license

(NINDS) (2023d). Traumatic Brain Injury (TBI). https://www.ninds.nih.gov/health-information/

disorders/traumatic-brain-injury-tbi Public Domain.
518 | 12.4: TRAUMATIC BRAIN INJURY

Figure 12.8. Electron micrograph of tau protein clusters that occur in

Alzheimer’s Disease and CTE. CREDIT: Electron Micrograph of Tau Clusters ©
NIH is licensed under a Public Domain license

Causes of TBI
Traumatic brain injury has many causes, including falls, vehicle accidents,
gunshots, explosions, and blows to the head. Recently attention has surged on
brain injury in sports, especially soccer (from repeatedly heading the ball; Lipton
et al., 2013), combat sports (e.g., boxing, kickboxing, and mixed martial arts), and
contact sports (e.g., ice hockey, professional wrestling, and American football).
In National Football League (NFL) players, repeated blows to the head over a
career are linked to Traumatic Brain Injury and CTE. These links have been clearly
established since a landmark 2006 study by pathologist Bennet Omalu (famously
depicted by Will Smith in the film “Concussion”). In a convenience sample of
deceased NFL football players who donated their brains for research, 110 of 111
 12.4: TRAUMATIC BRAIN INJURY | 519
had neuropathological evidence of CTE, suggesting that CTE may be related to
playing football [note that participation in the brain-donation program was likely
motivated by players’ and their families’ awareness of links between head trauma
and CTE; this could bias the sample, and accordingly the authors caution that
“estimates of prevalence cannot be concluded or implied from this sample” (Mez
et al., 2017)]. In addition, the high-profile suicides of former NFL players Junior
Seau, Dave Duerson, and Aaron Hernandez, who had signs of CTE in their brains,
thrust the topic of brain injury into the national consciousness.
In spite of extensive attention on professional football, the overall case count
of brain injuries in NFL players (~hundreds per year) is dwarfed by the number
of brain injuries in other domains, such as the military (~thousands per year) or
from intimate partner violence (~millions per year) (Hillstrom, 2022). In the next
section, we turn to Dr. Eve Valera, a professor at Harvard Medical School and
expert on brain injury in intimate partner violence, to discuss this less-recognized
and under-studied epidemic.

Traumatic Brain Injury from Intimate

Partner Violence – By Prof. Eve Valera
Harvard Medical School and Massachusetts General Hospital

Content Notice – This section describes some possible effects on

the brain from Intimate Partner Violence or Domestic Violence. The
content may be distressing, especially for those who have been
directly or indirectly affected by violence.

If you or someone you know has been affected, support resources

are available, for example, through your university’s counseling
center or various health agencies. In the U.S., the National Domestic
Violence Hotline is available 24/7; Text LOVEIS to 22522, call
1-800-799-7233, or visit https://www.thehotline.org/get-help/ . In
520 | 12.4: TRAUMATIC BRAIN INJURY

Canada, services can be found at: https://www.canada.ca/en/public-

health/services/health-promotion/stop-family-violence/services.html

Intimate Partner Violence (IPV) is any violence perpetrated by a current or former

partner, spouse, significant other, girlfriend, or boyfriend with whom one has had
an intimate relationship. Though the term domestic violence (DV) is often used
interchangeably with IPV, DV is broader in scope and also includes child abuse,
elder abuse, and abuse from a child to a parent. IPV does not need to occur within
the home and can occur in the context of a relationship of any length. Globally,
approximately one in three women experience physical or sexual violence in their
lifetime (García-Moreno et al., 2013). Women in peak reproductive age groups–18
to 24-year-olds, followed by 25 to 34-year-olds–experience the highest rates of
IPV (Catalano, 2012). Furthermore, people from groups that are and have been
marginalized, such as people from racial and ethnic minority groups or LGBTQ+
individuals, are at higher risk for more abuse and/or worse consequences (CDC,
2022).
IPV can take many forms, including physical, psychological, and sexual abuse.
When considering physical abuse, 80-90% of injuries are to the head, face, and
neck, with women having their heads punched, slapped, kicked, and slammed
against other objects. These behaviors can result in traumatic brain injuries (TBIs)
in which external forces result in alterations in brain function. Although women
sustain TBIs of all severities, the majority of TBIs are concussions, which are on
the milder end of the TBI spectrum.
Though limited, data show that IPV-related brain injuries are associated with
negative emotional, cognitive, and neural outcomes. For example, women with
higher brain injury scores (based on number, recency, and severity of brain injuries)
performed worse on tests of memory, learning, and cognitive flexibility than
women with lower brain injury scores. Similarly, women with higher brain injury
scores also tended to have higher levels of depression, worry, anxiety, general
distress, and PTSD symptomatology (Valera & Berenbaum, 2003). Higher brain
injury scores and more IPV-related brain injuries were also associated with
measures of functional and structural connectivity within the brain analogous to
 12.4: TRAUMATIC BRAIN INJURY | 521
those occurring in people who sustained brain injuries from accidents or sports
(Valera & Kucyi, 2017; Valera et al., 2019).
Strangulation is another form of IPV and can be defined as “sustained
impairment of air or blood flow through the neck as a result of external pressure”
(Armstrong & Strack, 2016). This can lead to alterations (including losses) in
consciousness. Strangulation-related alterations in consciousness (AIC) can result
in a strangulation-related acquired brain injury. As such, when considering injuries
to the brain from IPV, it is important to consider both TBIs and strangulation-
related brain injuries or what I like to consider “concussion+”. In the only study
to examine the effects of strangulation-related AICs on cognitive and psychological
outcomes, we found that women who sustained strangulation-related AICs
performed more poorly on tests of working and long-term memory and had higher
levels of depression and PTSD symptomatology (Valera et al., 2022).
Preventing intimate partner violence. Intimate partner violence is
preventable. A number of factors may increase or decrease the risk of perpetrating
and experiencing intimate partner violence. To prevent intimate partner violence,
we must understand and address the factors that put people at risk and protect
them from violence. Promoting healthy, respectful, and nonviolent relationships
and communities can help reduce the occurrence of IPV. For example, school
curricula with courses on healthy relationships and communication are crucial.
Efforts such as these and others are critical to prevent the harmful and long-lasting
effects of IPV on individuals, families, and communities (CDC, 2022). See Figure
12.9 for ways to address and prevent intimate partner violence.4

4. This section contains material adapted from: Center for Disease Control and Prevention (CDC)
(2022). Fast Facts: Preventing Intimate Partner Violence https://www.cdc.gov/violenceprevention/
intimatepartnerviolence/fastfact.html Public Domain
522 | 12.4: TRAUMATIC BRAIN INJURY

Figure 12.9. Ways to address and prevent intimate partner violence.

CREDIT: Electron Micrograph of Tau Clusters © NIH is licensed under a Public
Domain license
 12.5: NEUROLOGICAL AND NEURODEGENERATIVE DISORDERS | 523

12.5: NEUROLOGICAL AND

NEURODEGENERATIVE
DISORDERS

Neurodegenerative disorders are illnesses characterized by a loss of nervous

system functioning that are usually caused by neuronal death (Clark et al., 2018).
Although some of these diseases occur in children and young adults, most of them
occur in older adults. These diseases generally worsen over time as more and more
neurons die. The resulting impairments may be predominantly cognitive, as in
Alzheimer’s-type dementia, or predominantly motor, as in Parkinson’s disease, or a
combination of the two, as in Huntington’s disease. The symptoms of a particular
neurodegenerative disease are related to where in the nervous system the death
of neurons occurs. For example, spinocerebellar ataxia is associated with neuronal
death in the cerebellum, which causes problems with balance and walking.
Neurodegenerative disorders include Huntington’s disease, amyotrophic lateral
sclerosis (ALS), Alzheimer’s disease and other types of dementia disorders,
multiple sclerosis (MS), and Parkinson’s disease. Here, we discuss Alzheimer’s,
Parkinson’s disease, and multiple sclerosis in more depth.

Text Attributions
This section contains material adapted from:
Clark, M.A., Douglas, M. & Choi, J. (2023). 35.5 Nervous System Disorders. In
Biology 2e. OpenStax. Access for free at https://openstax.org/books/biology-2e/
pages/35-5-nervous-system-disorders License: CC BY 4.0 DEED.
524 | 12.6: ALZHEIMER'S DISEASE

12.6: ALZHEIMER'S DISEASE

Dementia describes a group of symptoms associated with a decline in memory,

reasoning, or other cognitive skills. Alzheimer’s disease is the most common
cause of dementia in the elderly (Clark et al., 2018). In 2023, an estimated 6.7
million Americans are living with Alzheimer’s disease, and costs for their care are
estimated at $345 billion. Roughly one in every eight people age 65 or older has the
disease. Due to the aging of the baby-boomer generation, there are projected to be
as many as 13 million Alzheimer’s patients in the United States in the year 2050.
Symptoms of Alzheimer’s disease include disruptive memory loss, confusion
about time or place, difficulty planning or executing tasks, poor judgment, and
personality changes. Problems smelling certain scents can also be indicative of
Alzheimer’s disease and may serve as an early warning sign. Many of these
symptoms are also common in people who are aging normally, so it is the severity
and longevity of symptoms that determine whether a person is suffering from
Alzheimer’s.
Alzheimer’s disease was named for Alois Alzheimer, a German psychiatrist who
published a report in 1911 about a woman with severe dementia symptoms. He
examined the woman’s brain following her death and reported the presence of
abnormal clumps, which are now called amyloid plaques, along with tangled brain
fibers called neurofibrillary tangles. Amyloid plaques, neurofibrillary tangles, and
an overall shrinking of brain volume are hallmarks of degeneration in the brains
of Alzheimer’s patients. Loss of neurons in the hippocampus is especially severe in
advanced Alzheimer’s patients. Figure 12.10 compares a normal brain to the brain
of an Alzheimer’s patient.
 12.6: ALZHEIMER'S DISEASE | 525

Figure 12.10. Compared to a normal brain (left), the brain of a patient

with Alzheimer’s disease (right) shows a dramatic neurodegeneration,
particularly at the shrunken hippocampus and enlarged ventricles.
Alzheimer © Openstax is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Amyloid plaques and neurofibrillary tangles are the two main biological markers
associated with Alzheimer’s (The Brain from Top to Bottom, n.d.). Both amyloid
plaques and neurofibrillary tangles are buildups of protein that occur as part of
the normal aging process, but in people with Alzheimer ’s-type dementias, the
amounts of these proteins that build up are far greater.
Amyloid plaques. The beta-amyloid protein involved in Alzheimer’s comes in
several different molecular forms that collect between neurons (NIA, 2017). It is
formed from the breakdown of a larger protein called amyloid-precursor protein.
One form, beta-amyloid 42, is thought to be especially toxic. In the Alzheimer’s
brain, abnormal levels of this naturally occurring protein clump together to form
plaques that collect between neurons and disrupt cell function. Research is
ongoing to better understand how and at what stage of the disease the various
forms of beta-amyloid influence Alzheimer’s disease symptoms.
526 | 12.6: ALZHEIMER'S DISEASE

Figure 12.11. Two amyloid plaques from the brain of a patient with
Alzheimer’s disease. In this photomicrograph, neurites are darkly
stained, and the elements stained pink include the plaque cores. The
black bar is 20 microns (0.02mm) in length. CREDIT: Neuritic abeta
plaques © Wikimedia is licensed under a CC BY-SA (Attribution
ShareAlike) license

Neurofibrillary tangles. Neurofibrillary tangles are abnormal accumulations of

a protein called tau that collect inside neurons. Healthy neurons, in part, are
supported internally by structures called microtubules, which help guide nutrients
and molecules from the cell body to the axon and dendrites. In healthy neurons,
tau normally binds to and stabilizes microtubules. In Alzheimer’s disease, however,
abnormal chemical changes cause tau to detach from microtubules and stick to
other tau molecules, forming threads that eventually join to form tangles inside
neurons (Figure 12). These tangles block the neuron’s transport system, which
harms the synaptic communication between neurons.
 12.6: ALZHEIMER'S DISEASE | 527

Figure 12.12 Diagram of how microtubules disintegrate with Alzheimer’s

disease. Source: National Institute on Aging. CREDIT: Tangles © Wikimedia
is licensed under a CC0 (Creative Commons Zero) license

Emerging evidence suggests that Alzheimer ’s-related brain changes may result
from a complex interplay among abnormal tau and beta-amyloid proteins and
several other factors. It appears that abnormal tau accumulates in specific brain
regions involved in memory. Beta-amyloid clumps into plaques between neurons.
As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau
throughout the brain (NIA, 2017).
A rare form of early-onset Alzheimer’s disease causes dementia beginning
between the ages of 30 and 60; it is usually caused by mutations in one of three
known genes (Clark et al., 2018). The more prevalent, late-onset form of the
disease likely also has a genetic component, although research has not been able to
narrow down the genetic contributors as clearly as with the early-onset form of the
disease. That said, one particular gene, apolipoprotein E (APOE), has a variant that
increases a carrier’s likelihood of getting the disease. One APOE-E4 allele doubles
or triples the chance of getting a diagnosis of Alzheimer’s disease. Having two
copies increases the risk about eight to twelvefold. Many other genes have been
identified that might be involved in the pathology of late-onset Alzheimer’s disease.
528 | 12.6: ALZHEIMER'S DISEASE
Unfortunately, there is no cure for Alzheimer’s disease. Current approved
treatments focus on managing the symptoms of the disease. Because a decrease
in the activity of cholinergic neurons (neurons that use the neurotransmitter
acetylcholine) is common in Alzheimer’s disease, several drugs used to treat the
disease work by increasing acetylcholine neurotransmission, often by inhibiting
the enzyme that breaks down acetylcholine in the synaptic cleft. Many treatments
currently in development use humanized monoclonal antibodies from mouse
models and aim to clear the bad proteins in human patients. While some clinical
trials of compounds have shown clearing of the bad proteins on brain PET scans,
serious side effects such as Amyloid-related imaging abnormalities (ARIA) have
been detected in brain MRI, and the effects on cognition and daily functioning
have been disappointing.
Other clinical interventions focus on behavioral therapies like psychotherapy,
sensory therapy, and cognitive exercises. Since Alzheimer’s disease appears to hijack
the normal aging process, research into prevention is prevalent. Smoking, obesity,
and cardiovascular problems may be risk factors for the disease, so treatments
for those may also help to prevent Alzheimer’s disease. Some studies have shown
that people who remain intellectually active by playing games that are mentally
stimulating, such as crossword puzzles, as well as reading, playing musical
instruments, and being socially active in later life, have a reduced risk of developing
the disease.

Text Attribution:
This section contains material adapted from:
Clark, M.A., Douglas, M. & Choi, J. (2023). 35.5 Nervous System Disorders. In
Biology 2e. OpenStax. Access for free at https://openstax.org/books/biology-2e/
pages/35-5-nervous-system-disorders License: CC BY 4.0 DEED.
National Institute on Aging (NIA) (2017). What Happens to the Brain in
Alzheimer’s Disease? https://www.nia.nih.gov/health/what-happens-brain-
alzheimers-disease Public Domain
“The Brain from Top to Bottom” (n.d.). Retrieved on June 1, 2023 from
https://thebrain.mcgill.ca/
 12.7: PARKINSON’S DISEASE | 529

12.7: PARKINSON’S DISEASE

Like Alzheimer’s disease, Parkinson’s disease is a neurodegenerative disease. It

was first characterized by James Parkinson in 1817. Each year, 50,000-60,000
people in the United States are diagnosed with the disease. Parkinson’s disease
causes the loss of dopamine neurons in the substantia nigra, a midbrain structure
that regulates movement. Loss of these neurons causes many symptoms, including
tremor (shaking of fingers or a limb), slowed movement, speech changes, balance,
posture and gait problems, and rigid muscles. The combination of these symptoms
often causes a characteristic slow, hunched, shuffling walk (Figure 12.13). Patients
with Parkinson’s disease can also exhibit cognitive and psychological symptoms,
such as dementia or emotional problems (Clark et al., 2018).
Although some patients have a form of the disease known to be caused by a
single mutation, for most patients the exact causes of Parkinson’s disease remain
unknown: the disease likely results from a combination of genetic and
environmental factors (similar to Alzheimer’s disease). Post-mortem analysis of
brains from Parkinson’s patients shows the presence of Lewy bodies—abnormal
protein clumps—in dopaminergic neurons. The prevalence of these Lewy bodies
often correlates with the severity of the disease.
There is no cure for Parkinson’s disease, and treatment is focused on easing
symptoms. One of the most commonly prescribed drugs for Parkinson’s is L-
DOPA, which is a chemical that is converted into dopamine by neurons in the
brain. This conversion increases the overall level of dopamine neurotransmission
and can help compensate for the loss of dopaminergic neurons in the substantia
nigra. Other drugs work by inhibiting the enzyme that breaks down dopamine. L-
DOPA can have side effects such as headache, dizziness, psychosis, delusions, and
even an increased risk of pathological gambling. Additionally, the effectiveness of
L-DOPA typically declines after a few years and many symptoms become “dopa-
resistant.”
530 | 12.7: PARKINSON’S DISEASE

Figure 12.13. Parkinson’s patients often have a characteristic hunched

posture and walk with slow, shuffling steps. People with Parkinson’s
also have an elevated fall risk. CREDIT: Parkinson’s disease © Openstax is
licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Parkinson’s disease can also be treated with non-pharmacological methods. For

example, walking difficulties in Parkinson’s have been effectively treated with music
or metronome cues (Hove et al., 2012). Dancing is also an effective technique
for treating motor as well as cognitive and emotional symptoms of Parkinson’s
(Earhart, 2009).
An exciting and invasive tool for treating and relieving symptoms of Parkinson’s
disease is Deep Brain Stimulation (DBS). DBS requires neurosurgery and a
medical device called a neurostimulator that sends electrical impulses through wire
 12.7: PARKINSON’S DISEASE | 531
electrodes implanted in the brain (Figure 14). For movement disorders, electrodes
target brain structures important for motor control. Rigidity, tremor, and
dopamine-induced dyskinesia (uncontrolled involuntary movement) in people
with PD are treated with stimulation in basal-ganglia-system structures, including
the subthalamic nucleus (STN) or the internal segment of the globus pallidus
(GPi). DBS to part of the thalamus (the ventral intermediate nucleus of the
thalamus or VIM) is used to treat symptoms in PD (NINDS, n.d.). PD is treated
by applying high-frequency (> 100 Hz) stimulation to the target site. The patient
can typically control the stimulation; turning on the current often results in an
almost immediate decrease in symptoms such as tremor, and turning stimulation
off leads to a quick return of symptoms. Many videos on the internet demonstrate
the sudden and dramatic effects of DBS.
532 | 12.7: PARKINSON’S DISEASE

Figure 12.14. Deep Brain Stimulation probes shown in an X-ray of the

skull. CREDIT: X-ray of the skull © Wikimedia is licensed under a CC BY-SA
(Attribution ShareAlike) license

Text Attribution:
This section contains material adapted from:
Clark, M.A., Douglas, M. & Choi, J. (2023). 35.5 Nervous System Disorders. In
Biology 2e. OpenStax. Access for free at https://openstax.org/books/biology-2e/
pages/35-5-nervous-system-disorders License: CC BY 4.0 DEED.
National Institute of Neurological Disorders and Stroke (NINDS) (n.d.). Deep
brain stimulation (DBS) for the treatment of Parkinson’s disease and other
 12.7: PARKINSON’S DISEASE | 533
movement disorders. https://www.ninds.nih.gov/about-ninds/impact/ninds-
contributions-approved-therapies/deep-brain-stimulation-dbs-treatment-
parkinsons-disease-and-other-movement-disorders Public Domain.
534 | 12.8: MULTIPLE SCLEROSIS

12.8: MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a disease of the central nervous system that involves
demyelination and neurodegeneration. MS is the most common disabling
neurological disease of young adults with symptom onset generally occurring
between the ages of 20 to 40 years. It affects about 2.5 million people worldwide.
Symptoms of MS include muscle weakness (often in the hands and legs), tingling
and burning sensations, numbness, chronic pain, coordination and balance
problems, fatigue, vision problems, and difficulty with bladder control (Figure
12.15). People with MS also may feel depressed and have trouble thinking clearly
(NINDS, 2023b).
 12.8: MULTIPLE SCLEROSIS | 535

Figure 12.15. Symptoms in Multiple Sclerosis include (clockwise from top

right): white matter lesions, weakness and difficulties walking, spasms,
Babinski sign (an abnormal toe reflex), incontinence, single-sided vision,
blurred vision, double vision, tremor, and internuclear ophthalmoplegia
(a gaze and eye movement abnormality). CREDIT: Symptoms in Multiple
Sclerosis © Wikimedia is licensed under a CC0 (Creative Commons Zero) license

MS involves the loss of oligodendrocytes, the glial cells that generate and maintain
the myelin sheath in the central nervous system. As discussed in Chapter 2, myelin
makes up the brain’s “white matter” and insulates axons for efficient transmission
of action potentials. The loss of oligodendrocytes leads to myelin thinning or
loss, and as the disease progresses, the axons themselves deteriorate (as do cell
bodies in gray matter). Without myelin, a neuron loses its ability to effectively
conduct electrical signals. During the early stages of the disease, a repair mechanism
known as remyelination occurs, but the oligodendrocytes are incapable of fully
restoring the myelin sheath. With each subsequent attack, remyelination becomes
increasingly ineffective, eventually leading to the formation of scar-like plaques
around the damaged axons. These plaques are visible using magnetic resonance
imaging (MRI) and can be as small as a pinhead or as large as a golf ball. They most
commonly affect the white matter in the optic nerve, brain stem, basal ganglia,
536 | 12.8: MULTIPLE SCLEROSIS
and spinal cord (Compston & Coles, 2008). The symptoms of MS depend on the
location and extent of the plaques, as well as the severity of inflammatory reaction.

Figure 12.16. In MS, the immune system cells that normally protect us
from viruses, bacteria, and unhealthy cells mistakenly attack myelin in
the central nervous system. CREDIT:Multiple Sclerosis © Wikimedia is
licensed under a CC0 (Creative Commons Zero) license

MS is considered an autoimmune disorder, in which the body’s immune system,

which usually defends against viruses, bacteria, and unhealthy cells, attacks part
of the body as if it were a foreign substance. In MS, immune cells mistakenly
attack the body’s own oligodendrocytes. Apart from demyelination, another
characteristic sign of MS is inflammation. Inflammation is caused by immune-
system T cells that gain initial entry into the brain after disruptions in the
blood–brain barrier, often following infection. Beyond demyelination and
inflammation, MS involves additional damage to neurons, and it is generally agreed
 12.8: MULTIPLE SCLEROSIS | 537
that MS is driven by the interplay between immune response and
neurodegeneration (Faissner et al., 2019; Pinel & Barnes, 2017).
MS affects people differently. A small number of people with MS will have
a mild course with little to no disability, whereas others will have a progressive
form that steadily worsens and increases disability over time. Most people with
MS, however, have “relapsing-remitting MS” characterized by short periods of
symptoms followed by long stretches of relative quiescence (inactivity). The disease
is rarely fatal, and most people with MS have a normal life expectancy.
Epidemiology and risk factors. The exact causes of who gets MS are not fully
known, but several environmental and genetic risk factors have been identified.

• Females are more frequently affected than males.

• Susceptibility may be inherited, and if one of your parents, siblings (or your
twin) had MS, you are at a higher risk. Dozens of genes have been linked to
vulnerability to MS, and most of these genes are associated with immune-
system function.
• Certain infections have been linked to MS, including Epstein-Barr, the virus
that causes mononucleosis; note that only about 5% of the population has
not been infected by Epstein-Barr, but they have a lower risk for developing
MS.
• MS is more likely to develop in people with low levels of vitamin D (or who
have very limited exposure to sunlight, which helps the skin produce vitamin
D; Note: this is not a recommendation to sunbathe, due to significant skin
cancer risks). Researchers believe that vitamin D may help regulate the
immune system in ways that reduce the risk of MS or autoimmunity in
general.
• People from regions near the equator, where there is a great deal of bright
sunlight, generally have a much lower risk of MS compared to people far
from the equator, for example, in the U.S., Canada, and Europe.
• Finally, studies have found that people who smoke are more likely to develop
MS and have a more aggressive disease course.

Treatments. Although MS has no cure, some conventional treatments can

improve symptoms, reduce the number and severity of relapses, and delay the
disease’s progression. The initial approved medications used to treat MS were
538 | 12.8: MULTIPLE SCLEROSIS
modestly effective, though were poorly tolerated and had adverse side effects.
Several medications with better safety and tolerability profiles have been
introduced, improving the prognosis of MS (McGinley et al., 2021), especially
for relapse-remitting MS, but treatment of the progressive forms of the disease
remains unsatisfactory (Faissner et al., 2019). Many people with MS try some form
of complementary health approach, including yoga, exercise, acupuncture, dietary
supplements, and special diets (such as a diet low in saturated fats and high in
polyunsaturated fatty acids, such as fish oils) (NCCIH, 2019).
Despite extensive ongoing research into treatments and causes of multiple
sclerosis, one take-home message is clear: myelin is critical for a properly
functioning nervous system, and damaged myelin leads to major issues in neural
function and wellbeing (Eagleman & Downar, 2016).

Text Attribution:
This section contains material adapted from:
National Institute of Neurological Disorders and Stroke (NINDS) (2023b).
Multiple Sclerosis. https://www.ninds.nih.gov/health-information/disorders/
multiple-sclerosis Public Domain.
 12.9: REFERENCES | 539

12.9: REFERENCES

Parts of this chapter were adapted

from:
Center for Disease Control and Prevention (CDC) (2022). Fast Facts: Preventing
Intimate Partner Violence https://www.cdc.gov/violenceprevention/
intimatepartnerviolence/fastfact.html
National Center for Complementary and Integrative Health (NCCIH) (2019).
Multiple Sclerosis. https://www.nccih.nih.gov/health/multiple-sclerosis
National Institute of Neurological Disorders and Stroke (NINDS) (n.d.). Deep
brain stimulation (DBS) for the treatment of Parkinson’s disease and other
movement disorders.
https://www.ninds.nih.gov/about-ninds/impact/ninds-contributions-approved-
therapies/deep-brain-stimulation-dbs-treatment-parkinsons-disease-and-other-
movement-disorders
National Institute of Neurological Disorders and Stroke (NINDS) (2023a).
Stroke. https://www.ninds.nih.gov/health-information/disorders/stroke
National Institute of Neurological Disorders and Stroke (NINDS) (2023b).
Multiple Sclerosis. https://www.ninds.nih.gov/health-information/disorders/
multiple-sclerosis
National Institute of Neurological Disorders and Stroke (NINDS) (2023c). Brain
and Spinal Cord Tumors.
https://www.ninds.nih.gov/health-information/disorders/brain-and-spinal-cord-
tumors
National Institute of Neurological Disorders and Stroke (NINDS) (2023d).
Traumatic Brain Injury (TBI). https://www.ninds.nih.gov/health-information/
disorders/traumatic-brain-injury-tbi
National Institute on Aging (NIA) (2017). What Happens to the Brain in
Alzheimer’s Disease? https://www.nia.nih.gov/health/what-happens-brain-
alzheimers-disease
540 | 12.9: REFERENCES
“The Brain from Top to Bottom” (n.d.). Retrieved on June 1, 2023 from
https://thebrain.mcgill.ca/

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Traumatic Brain Injury (TBI). https://www.ninds.nih.gov/health-information/
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544 | 12.9: REFERENCES
 CHAPTER 13: PSYCHOPHARMACOLOGY | 545

CHAPTER 13:
PSYCHOPHARMACOLOGY

This materials was adapted from:

Hove, M. J., & Martinez, S. A. (2024). Biological Psychology. ROTEL

(Remixing Open Textbooks with an Equity Lens) Project.
https://rotel.pressbooks.pub/biologicalpsychology/Their chapter was
adapted from:

Barron, S. (2023). Psychopharmacology. In R. Biswas-Diener & E.

Diener (Eds), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/umx6f2t8 License: CC BY-
NC-SA 4.0 DEED

Psychopharmacology is the study of how drugs affect behavior. If a drug changes

your perception or the way you feel or think, the drug exerts effects on your
brain and nervous system. We call drugs that change the way you think or feel
psychoactive or psychotropic drugs, and almost everyone has used a psychoactive
drug at some point (yes, caffeine and alcohol count). Understanding some basics
about psychopharmacology can help us better understand a wide range of things
that interest psychologists and others. For example, the pharmacological treatment
of certain neurodegenerative diseases, such as Parkinson’s disease, tells us
something about the disease itself. The pharmacological treatments used to treat
psychiatric conditions such as schizophrenia or depression have undergone
amazing development since the 1950s, and the drugs used to treat these disorders
tell us something about what is happening in the brains of individuals with these
conditions. Finally, understanding something about the actions of drugs of abuse
and their routes of administration can help us understand why some psychoactive
drugs are so addictive. In this chapter, we provide an overview of some of these
546 | CHAPTER 13: PSYCHOPHARMACOLOGY
topics and discuss some current controversial areas in the field of
psychopharmacology. The chapter concludes with some examples and animations
of how drugs like alcohol, opiates, cannabis, and caffeine work at the level of
neurotransmitters and synapses.

Learning Objectives

• How do the majority of psychoactive drugs work in the brain?

• How does the route of administration affect how rewarding a
drug might be?
• Why is grapefruit dangerous to consume with many psychotropic
medications?
• Why might individualized drug doses based on genetic screening
be helpful for treating conditions like depression?
• Why is there controversy regarding pharmacotherapy for
children, adolescents, and the elderly?
 13.1: INTRODUCTION | 547

13.1: INTRODUCTION

Psychopharmacology, the study of how drugs affect the brain and behavior, is a
relatively new science, although people have probably been taking drugs to change
how they feel from early in human history (consider the eating of fermented fruit,
ancient beer recipes, and chewing on the leaves of the cocaine plant for stimulant
properties as examples). The word psychopharmacology itself tells us that this is a
field that bridges our understanding of behavior (and brain) and pharmacology,
and the range of topics included within this field is extremely broad.
548 | 13.1: INTRODUCTION

Figure 13.1. Drugs that alter our feelings and behavior do so by affecting the
communication between neurons in the brain. CREDIT: original © Noba is
licensed under a Public Domain license

Virtually any drug that changes the way you feel does this by altering how neurons
communicate with each other. Neurons (86 billion in your nervous system)
communicate with each other by releasing a chemical (neurotransmitter) across a
tiny space between two neurons (the synapse). When the neurotransmitter crosses
the synapse, it binds to a postsynaptic receptor (protein) on the receiving neuron,
and the message may then be transmitted onward. Obviously, neurotransmission
is far more complicated than this—we reviewed neurotransmission in a previous
chapter, and links at the end of this chapter can provide some useful additional
background information—but the first step is understanding that virtually all
 13.1: INTRODUCTION | 549
psychoactive drugs interfere with or alter how neurons communicate with each
other.

There are many neurotransmitters. Some of the most important in terms of

psychopharmacological treatment and drugs of abuse are outlined in Table 13.1.
The neurons that release these neurotransmitters, for the most part, are localized
within specific circuits of the brain that mediate these behaviors. Psychoactive
drugs can either increase activity at the synapse (these are called agonists) or
reduce activity at the synapse (antagonists). Different drugs do this by different
mechanisms, and some examples of agonists and antagonists are presented in Table
2. For each example, the drug’s trade name, which is the name of the drug provided
by the drug company, and generic name (in parentheses) are provided.
550 | 13.1: INTRODUCTION
Table 13.1. How neurotransmitters affect behaviors or diseases

Behaviors of
Diseases Related to
Neurotransmitter Abbreviation
These
Neurotransmitter

Learning and
memory; Alzheimer’s
disease’ muscle
Acetylcholine ACh
movement in the
peripheral nervous
system

Reward circuits;
Motor circuits
Dopamine DA involved in
Parkinson’s disease;
Schizophrenia

Norepinephrine NE Arousal; Depression

Depression;
Serotonin SHT Aggression;
Schizophrenia

Learning; Major
excitatory
Glutamate GLU
neurotransmitter in
the brain

Anxiety disorders;
Epilepsy; Major
GABA GABA inhibitory
neurotransmitter in
the brain

Endorphins, Pain; Analgesia;

Endogenous Opiods
Enkephalins Reward

A very useful link at the end of this chapter shows the various steps involved in
neurotransmission and some ways drugs can alter this.
Table 13.2 provides examples of drugs and their primary mechanism of action,
but it is very important to realize that drugs also have effects on other
neurotransmitters. This contributes to the kinds of side effects that are observed
when someone takes a particular drug. The reality is that no drugs currently
available work exactly where we would like them to be in the brain or only on a
specific neurotransmitter. In many cases, individuals are sometimes prescribed one
 13.1: INTRODUCTION | 551
psychotropic drug but then may also have to take additional drugs to reduce
the side effects caused by the initial drug. Sometimes individuals stop taking
medication because the side effects can be so profound.

Table 13.2. Examples of drugs, their primary mechanism of action, use,

and whether agonists (increase activity at the synapse) or antagonists
(reduce activity at the synapse).

Agonist/
Drug Mechanism Use
Antagonist

Increase Parkinson’s
L-dopa Agonist for DA
Synthesis of DA disease

Adderall (mixed Increase

Agonist for DA,
salts Synthesis of DA, ADHD
NE
amphetamine) NE

Blocks removal of
Ritalin DA, NE and Agonist for DA,
ADHD
(methylphenidate) lesser (5HT) NE mostly
from synapse

Blocks removal of
Aricept Alzheimer’s
ACh from Agonist for ACh
(donepezil) disease
synapse

Depression,
Blocks removal of
Prozac obsessive
5HT from Agonist 5HT
(fluoxetine) compulsive
synapse
disorder

Seroquel Blocks DA and Schizophrenia, Antagonist for

(quetiapine) 5HT receptors bipolar disorder DA, 5HT

Blocks opiod
Alcoholism, Antagonist (for
Revia (naltrexone) post-synaptic
opiod addiction opioids)
receptors
552 | 13.2: PHARMACOKINETICS: WHAT IS IT AND WHY IS IT IMPORTANT?

13.2: PHARMACOKINETICS:
WHAT IS IT AND WHY IS IT
IMPORTANT?

While this section may sound more like pharmacology, it is important to realize
how important pharmacokinetics can be when considering psychoactive drugs.
Pharmacokinetics refers to how the body handles a drug that we take. As
mentioned earlier, psychoactive drugs exert their effects on behavior by altering
neuronal communication in the brain, and the majority of drugs reach the brain
by traveling in the blood. The acronym ADME is often used in pharmacology and
stands for Absorption (how the drug gets into the blood), Distribution (how the
drug gets to the organ of interest – in this chapter, that is the brain), Metabolism
(how the drug is broken down so it no longer exerts its psychoactive effects), and
Excretion (how the drug leaves the body). We will talk about a couple of these to
show their importance for psychoactive drugs.

Drug Administration
There are many ways to take drugs, and these routes of drug administration have a
significant impact on how quickly that drug reaches the brain. The most common
route of administration is oral administration, which is relatively slow and perhaps
surprisingly often the most variable and complex route of administration. Drugs
enter the stomach and then get absorbed by the blood supply and capillaries that
line the small intestine. The rate of absorption can be affected by a variety of
factors, including the quantity and the type of food in the stomach (e.g., fats vs.
proteins). This is why the medicine labels for some drugs (like antibiotics) may
specifically state foods that you should or should NOT consume within an hour
of taking the drug because they can affect the rate of absorption. Two of the
most rapid routes of administration include inhalation (i.e., smoking or gaseous
anesthesia) and intravenous (IV) in which the drug is injected directly into the vein
13.2: PHARMACOKINETICS: WHAT IS IT AND WHY IS IT IMPORTANT? | 553
and hence the blood supply. Both of these routes of administration can get the
drug to the brain in less than 10 seconds. IV administration also has the distinction
of being the most dangerous because if there is an adverse drug reaction, there is
very little time to administer any antidote, as in the case of an IV heroin overdose.

Figure 13.2. A drug delivered by IV reaches the brain more quickly

than if the drug is taken orally. While rapid delivery has advantages,
there are also risks involved with IV administration. CREDIT: IV drug
delivery © Noba is licensed under a CC BY-SA (Attribution ShareAlike) license

Why might how quickly a drug gets to the brain be important? If a drug activates
the reward circuits in the brain AND it reaches the brain very quickly, the drug
has a high risk for abuse and addiction. Psychostimulants like amphetamine or
cocaine are examples of drugs that have a high risk for abuse because they are
554 | 13.2: PHARMACOKINETICS: WHAT IS IT AND WHY IS IT IMPORTANT?
agonists at dopamine (DA) neurons involved in reward AND because these drugs
exist in forms that can be either smoked or injected intravenously. Some argue that
cigarette smoking is one of the hardest addictions to quit, and although part of the
reason for this may be that smoking gets the nicotine into the brain very quickly
(and indirectly acts on DA neurons), it is a more complicated story. For drugs that
reach the brain very quickly, not only is the drug very addictive, but so are the cues
associated with the drug (see Rohsenow et al., 1990). For a crack user, this could
be the pipe that they use to smoke the drug. For a cigarette smoker, however, it
could be something as normal as finishing dinner or waking up in the morning (if
that is when the smoker usually has a cigarette). For both the crack user and the
cigarette smoker, the cues associated with the drug may actually cause craving that
is alleviated by (you guessed it)—lighting a cigarette or using crack (i.e., relapse).
This is one of the reasons individuals who enroll in drug treatment programs,
especially out-of-town programs, are at significant risk of relapse if they later find
themselves in proximity to old haunts, friends, etc. But this is much more difficult
for a cigarette smoker. How can someone avoid eating or avoid waking up in the
morning, etc.? These examples help you begin to understand how important the
route of administration can be for psychoactive drugs.

Drug Metabolism
Metabolism involves the breakdown of psychoactive drugs, and this occurs
primarily in the liver. The liver produces enzymes (proteins that speed up a
chemical reaction), and these enzymes help catalyze a chemical reaction that breaks
down psychoactive drugs. Enzymes exist in “families,” and many psychoactive
drugs are broken down by the same family of enzymes, the cytochrome P450
superfamily. There is not a unique enzyme for each drug; rather, certain enzymes
can break down a wide variety of drugs. Tolerance to the effects of many drugs
can occur with repeated exposure; that is, the drug produces less of an effect over
time, so more of the drug is needed to get the same effect. This is particularly
true for sedative drugs like alcohol or opiate-based painkillers. Metabolic tolerance
is one kind of tolerance, and it takes place in the liver. Some drugs (like alcohol)
cause enzyme induction—an increase in the enzymes produced by the liver. For
example, chronic drinking results in alcohol being broken down more quickly,
13.2: PHARMACOKINETICS: WHAT IS IT AND WHY IS IT IMPORTANT? | 555
so an alcoholic needs to drink more to get the same effect—of course, until so
much alcohol is consumed that it damages the liver (alcohol can cause fatty liver or
cirrhosis).
556 | 13.3: RECENT ISSUES RELATED TO PSYCHOTROPIC DRUGS AND

13.3: RECENT ISSUES RELATED

TO PSYCHOTROPIC DRUGS AND
METABOLISM

Grapefruit Juice and Metabolism

Figure 13.3. Grapefruit can interfere with enzymes in the liver that
help the body to process certain drugs. CREDIT: Grapefruit © Noba is
licensed under a Public Domain license
 13.3: RECENT ISSUES RELATED TO PSYCHOTROPIC DRUGS AND
Certain types of food in the stomach can alter the rate of drug absorption, and
other foods can also alter the rate of drug metabolism. The most well-known is
grapefruit juice. Grapefruit juice suppresses cytochrome P450 enzymes in the liver,
and these liver enzymes normally break down a large variety of drugs (including
some of the psychotropic drugs). If the enzymes are suppressed, drug levels can
build up to potentially toxic levels. In this case, the effects can persist for extended
periods of time after the consumption of grapefruit juice. As of 2013, at least
85 drugs have been shown to interact adversely with grapefruit juice (Bailey et
al., 2013). Some psychotropic drugs that are likely to interact with grapefruit
juice include carbamazepine (Tegretol), prescribed for bipolar disorder; diazepam
(Valium), used to treat anxiety, alcohol withdrawal, and muscle spasms; and
fluvoxamine (Luvox), used to treat obsessive-compulsive disorder and depression.
A link at the end of this chapter gives the latest list of drugs reported to have this
unusual interaction.

Individualized Therapy, Metabolic

Differences, and Potential Prescribing
Approaches for the Future
Mental illnesses contribute to more disability in Western countries than all other
illnesses, including cancer and heart disease. Globally, depression and anxiety
disorders are among the highest causes of health burden, and the mental health
system in most countries is under-resourced (Santomauro et al., 2021). The
numbers of people affected by mental health issues are astonishing, with estimates
that 25% of adults experience a mental health issue in any given year, and this
affects not only the individual but also their friends and family. One in 17 adults
experiences a serious mental illness (Kessler et al., 2005). Newer antidepressants are
probably the most frequently prescribed drugs for treating mental health issues,
although there is no “magic bullet” for treating depression or other conditions.
Pharmacotherapy with psychological therapy may be the most beneficial treatment
approach for many psychiatric conditions, but many questions remain
unanswered. For example, why does one antidepressant help one individual yet
have no effect on another? Antidepressants can take 4 to 6 weeks to start improving
558 | 13.3: RECENT ISSUES RELATED TO PSYCHOTROPIC DRUGS AND
depressive symptoms, and we don’t really understand why. Many people do not
respond to the first antidepressant prescribed and may have to try different drugs
before finding something that works for them. Other people just do not improve
with antidepressants (Ioannidis, 2008). As we better understand why individuals
differ, the easier and more rapidly we will be able to help people in distress.
One area that has received interest recently has to do with an individualized
treatment approach. We now know that there are genetic differences in some of
the cytochrome P450 enzymes and their ability to break down drugs. The general
population falls into the following 4 categories: 1) ultra-extensive metabolizers
break down certain drugs (like some of the current antidepressants) very, very
quickly, 2) extensive metabolizers are also able to break down drugs fairly
quickly, 3) intermediate metabolizers break down drugs more slowly than either
of the two above groups and finally 4) poor metabolizers break down drugs
much more slowly than all of the other groups. Now consider someone receiving a
prescription for an antidepressant—what would the consequences be if they were
either an ultra-extensive metabolizer or a poor metabolizer? The ultra-extensive
metabolizer would be given antidepressants and told it will probably take 4 to
6 weeks to begin working (this is true), but they metabolize the medication so
quickly that it will never be effective for them. In contrast, the poor metabolizer
given the same daily dose of the same antidepressant may build up such high levels
in their blood (because they are not breaking the drug down), that they will have
a wide range of side effects and feel really badly – also not a positive outcome.
What if instead, prior to prescribing an antidepressant, the doctor could take a
blood sample and determine which type of metabolizer a patient actually was?
They could then make a more informed decision about the best dose to prescribe.
New genetic tests are now available to better individualize treatment in this way. A
blood sample can determine (at least for some drugs) which category an individual
fits into, but we need data to determine if this actually is effective for treating
depression or other mental illnesses (Zhou, 2009). Currently, this genetic test is
expensive and not many health-insurance plans cover this screen, but this may be
an important component in the future of psychopharmacology. Again, this is just
one area of research to explain the length of time that it takes for antidepressants to
kick in. Other research is investigating additional processes such as changes in the
cell membrane and neuron DNA as well as changes at receptor sites.
 13.4: OTHER CONTROVERSIAL ISSUES | 559

13.4: OTHER CONTROVERSIAL

ISSUES

Juveniles and Psychopharmacology

A recent Centers for Disease Control (CDC) report has suggested that as many
as 1 in 5 children between the ages of 5 and 17 may have some type of mental
disorder (e.g., ADHD, autism, anxiety, depression) (CDC, 2013). The incidence
of bipolar disorder in children and adolescents has also increased 40 times recently
(Moreno et al., 2007), and it is now estimated that 1 in 36 children have been
diagnosed with an autism spectrum disorder (CDC, 2023). Why has there been
such an increase in these numbers? There is no single answer to this important
question. Some believe that greater public awareness has contributed to increased
teacher and parent referrals. Others argue that the increase stems from changes in
criteria currently used for diagnosing. Still others suggest environmental factors,
either prenatally or postnatally, have contributed to this upsurge.
560 | 13.4: OTHER CONTROVERSIAL ISSUES

Figure 13.4. There are concerns about both the safety and efficacy of drugs
like Prozac for children and teens. CREDIT: shoes © Noba is licensed under a
CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

We do not have an answer, but the question brings up an additional controversy

related to how we should treat this population of children and adolescents. Many
psychotropic drugs used for treating psychiatric disorders have been tested in
adults, but few have been tested for safety or efficacy with children or adolescents.
The most well-established psychotropics prescribed for children and adolescents
are the psychostimulant drugs used for treating attention deficit hyperactivity
disorder (ADHD), and there are clinical data on how effective these drugs are.
However, we know far less about the safety and efficacy in young populations of
the drugs typically prescribed for treating anxiety, depression, or other psychiatric
disorders. The young brain continues to mature until well after age 20, so some
 13.4: OTHER CONTROVERSIAL ISSUES | 561
scientists are concerned that drugs that alter neuronal activity in the developing
brain could have significant consequences. There is an obvious need for clinical
trials in children and adolescents to test the safety and effectiveness of many of
these drugs, which also brings up a variety of ethical questions about who decides
what children and adolescents will participate in these clinical trials, who can give
consent, who receives reimbursements, etc.

The Elderly and Psychopharmacology

Another population that has not typically been included in clinical trials to
determine the safety or effectiveness of psychotropic drugs is the elderly. Currently,
there is very little high quality evidence to guide prescribing for older
people—clinical trials often exclude people with multiple comorbidities (other
diseases, conditions, etc.), which are typical for elderly populations (see Hilmer
& Gnjidict, 2008; Pollock et al., 2008). This is a serious issue because the elderly
consume a disproportionate number of the prescription meds prescribed. The
term polypharmacy refers to the use of multiple drugs, which is very common in
elderly populations in the United States. As our population ages, some estimate
that the proportion of people 65 or older will reach 20% of the U.S. population
by 2030, with this group consuming 40% of the prescribed medications. As shown
in Table 13.3 (from Schwartz & Abernethy, 2008), it is quite clear why the typical
clinical trial that looks at the safety and effectiveness of psychotropic drugs can be
problematic if we try to interpret these results for an elderly population.
562 | 13.4: OTHER CONTROVERSIAL ISSUES
* OTC = Over the counter
Table 13.3. Characteristics if clinical trial subjects vs. actual
patients. (Reprinted by permission from Schwartz & Abernethy,
2008.)

Aged Patients Who Receive

Clinical Trial Subjects
Drug Therapies

One drug Drug of interest and medications

Single does Chronic administration

No disease Multiple diseases

No alcohol, tobacco, OTC* OTC* drugs, nutraceuticals,

drugs, nutraceuticals alcohol, tobacco, and other

20-40 years (vs 60-75 years) 65-100+ years

Caucaisians Caucasians and minorities

Selection bias All corners/socioeconomic basis

Metabolism of drugs is often slowed considerably for elderly populations, so less

of a drug can produce the same effect (or all too often, too much of a drug can
result in a variety of side effects). One of the greatest risk factors for elderly
populations is falling (and breaking bones), which can happen if the elderly
person gets dizzy from too much of a drug. There is also evidence that
psychotropic medications can reduce bone density (thus worsening the
consequences of falls) (Brown & Mezuk, 2012). Although we are gaining
awareness of some of the issuefacing pharmacotherapy in older populations, this
is a very complex area with many medical and ethical questions.
This chapter provided an introduction to some of the important areas in the
field of psychopharmacology. It should be apparent that this chapter just touched
on a number of topics included in this field. It should also be apparent that
understanding more about psychopharmacology is important to anyone interested
in understanding behavior and that our understanding of issues in this field has
important implications for society.
 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS | 563

13.5: HOW DRUGS AFFECT

NEUROTRANSMITTERS

We provide some examples and animations of how drugs like

alcohol, caffeine, cannabis, and opiates work at the level of
neurotransmitters and synapses (The Brain from Top to Bottom,
n.d.). These examples are adapted from the website The Brain from
Top to Bottom. (https://thebrain.mcgill.ca/). Animations and
descriptions of other drugs, including nicotine, amphetamines,
ecstasy, and benzodiazepine, can be found there.

Alcohol
Alcohol passes directly from the digestive tract into the blood vessels. In minutes,
the blood transports the alcohol to all parts of the body, including the brain.
Alcohol affects the brain’s neurons in several ways. It alters their membranes as
well as their ion channels, enzymes, and receptors. Alcohol also binds directly to
the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for
glutamate.
Watch the animation to learn about how a GABA synapse functions without
alcohol and with alcohol. GABA’s effect is to reduce neural activity by allowing
chloride ions to enter the post-synaptic neuron. These ions have a negative
electrical charge, which helps to make the neuron less excitable. This physiological
effect is amplified when alcohol binds to the GABA receptor, probably because it
enables the ion channel to stay open longer and thus let more Cl- ions into the cell.
The neuron’s activity would thus be further diminished, thus explaining the
564 | 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS
sedative effect of alcohol. This effect is accentuated because alcohol also reduces
glutamate’s excitatory effect on NMDA receptors.
However, chronic consumption of alcohol gradually makes the NMDA
receptors hypersensitive to glutamate while desensitizing the GABAergic
receptors. It is this sort of adaptation that would cause the state of excitation
characteristic of alcohol withdrawal.
Alcohol also helps to increase the release of dopamine by a process that is still
poorly understood but that appears to involve curtailing the activity of the enzyme
that breaks down dopamine.

Video 13.1: How alcohol affects the brain. https://thebrain.mcgill.ca/

video/i_03_m_par_alcool.mp4

One or more interactive elements has been excluded from this

version of the text. You can view them online here:
https://pressbooks.cuny.edu/psy320/?p=157#video-157-1

Caffeine
The stimulant effect of coffee comes largely from the way it acts on the adenosine
receptors in the neural membrane. Adenosine is a neuromodulator that has specific
receptors. When adenosine binds to its receptors, neural activity slows down, and
you feel sleepy. Adenosine thus facilitates sleep and dilates the blood vessels,
probably to ensure good oxygenation during sleep.
Caffeine acts as an adenosine-receptor antagonist. This means that it binds to
these same receptors but without reducing neural activity. Fewer receptors are thus
 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS | 565
available to the natural “braking” action of adenosine, and neural activity therefore
speeds up (see animation).
The activation of numerous neural circuits by caffeine also causes the pituitary
gland to secrete hormones that cause the adrenal glands to produce more
adrenaline. Adrenalin is the “fight or flight” hormone, so it increases your attention
level and gives your entire system an extra burst of energy. This is exactly the effect
that many coffee drinkers are looking for.
In general, you get some stimulating effect from every cup of coffee you drink,
and any tolerance you build up is minimal. On the other hand, caffeine can create a
physical dependency. The symptoms of withdrawal from caffeine begin within one
or two days after you stop consuming it. They consist mainly of headaches, nausea,
and sleepiness and affect about one out of every two individuals.
Lastly, like most drugs, caffeine increases the production of dopamine in the
brain’s pleasure circuits, thus helping to maintain the dependency on this drug,
which is consumed daily by 90% of all adults in the U.S.

Video 13.2. How caffeine affects our brain. https://thebrain.mcgill.ca/

video/i_03_m_par_cafeine.mp4

One or more interactive elements has been excluded from this

version of the text. You can view them online here:
https://pressbooks.cuny.edu/psy320/?p=157#video-157-2

Cannabis
The sensations of slight euphoria, relaxation, and amplified auditory and visual
566 | 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS
perceptions produced by marijuana are due almost entirely to its effect on the
cannabinoid receptors in the brain. These receptors are present almost everywhere
in the brain, and an endogenous molecule that binds to them naturally has been
identified: anandamide (Devane et al., 1992). We are thus dealing with the same
kind of mechanism as in the case of opiates that bind directly to the receptors for
endorphins, the body’s natural morphines.
Anandamide is involved in regulating mood, memory, appetite, pain, cognition,
and emotions. When cannabis is introduced into the body, its active ingredient,
Delta-9-tetrahydrocannabinol (THC), can therefore interfere with all of these
functions.
THC begins this process by binding to the CB1 receptors for anandamide.
These receptors then modify the activity of several intracellular enzymes, including
cAMP, whose activity they reduce. Less cAMP means less protein kinase A. The
reduced activity of this enzyme affects the potassium and calcium channels so as
to reduce the amount of neurotransmitters released. The general excitability of the
brain’s neural networks is thus reduced as well.
However, in the reward circuit, just as in the case of other drugs, more dopamine
is released. As with opiates, this paradoxical increase is explained by the fact that the
dopaminergic neurons in this circuit do not have CB1 receptors but are normally
inhibited by GABAergic neurons that do have them. The cannabis removes this
inhibition by the GABA neurons and hence activates the dopamine neurons.
In chronic consumers of cannabis, the loss of CB1 receptors in the brain’s
arteries reduces the flow of blood, and hence of glucose and oxygen, to the brain.
The main results are attention deficits, memory loss, and impaired learning ability.

Video 13.3. How cannabis affects the brain. https://thebrain.mcgill.ca/

video/i_03_m_par_cannabis.mp4
 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS | 567

One or more interactive elements has been excluded from this

version of the text. You can view them online here:
https://pressbooks.cuny.edu/psy320/?p=157#video-157-3

Opiates (heroin, morphine, etc.)

The human body naturally produces its own opiate-like substances and uses them
as neurotransmitters. These substances include endorphins, enkephalins, and
dynorphins, often collectively known as endogenous opioids. Endogenous opioids
are produced within the body and modulate our reactions to painful stimuli. They
also regulate vital functions such as hunger and thirst and are involved in mood
control, immune response, and other processes.
The reason that opiates such as heroin and morphine affect us so powerfully
is that these exogenous substances (originating from outside the body) bind to
the same receptors as our endogenous opioids. There are three kinds of receptors
widely distributed throughout the brain: mu, delta, and kappa receptors.
These receptors, through second messengers, influence the likelihood that ion
channels will open, which in certain cases reduces the excitability of neurons. This
reduced excitability is the likely source of the euphoric effect of opiates and appears
to be mediated by the mu and delta receptors.
This euphoric effect also appears to involve another mechanism in which the
GABA-inhibitory interneurons of the ventral tegmental area come into play. By
attaching to their mu receptors, exogenous opioids reduce the amount of GABA
released (see animation). Normally, GABA reduces the amount of dopamine
released in the nucleus accumbens. By inhibiting this inhibitor, the opiates
ultimately increase the amount of dopamine produced and the amount of pleasure
felt.
Chronic consumption of opiates inhibits the production of cAMP, but this
inhibition is offset in the long run by other cAMP production mechanisms. When
no opiates are available, this increased cAMP production capacity comes to the
fore and results in neural hyperactivity and the sensation of craving the drug.
568 | 13.5: HOW DRUGS AFFECT NEUROTRANSMITTERS

Video 13.4 How opiates affect the brain.

https://thebrain.mcgill.ca/video/i_03_m_par_heroine.mp4

One or more interactive elements has been excluded from this

version of the text. You can view them online here:
https://pressbooks.cuny.edu/psy320/?p=157#video-157-4

Text Attributions
This section contains material adapted from:
The Brain from Top to Bottom website https://thebrain.mcgill.ca/
Content of the site The Brain from Top to Bottom is under copyleft.
Videos
https://thebrain.mcgill.ca/
 13.6: DISCUSSION QUESTIONS AND RESOURCES | 569

13.6: DISCUSSION QUESTIONS

AND RESOURCES

Discussion Questions

1. What are some of the issues surrounding prescribing medications

for children and adolescents? How might this be improved?
2. What are some of the factors that can affect relapse to an
addictive drug?
3. How might prescribing medications for depression be improved in
the future to increase the likelihood that a drug would work and
minimize side effects?

Outside Resources

Video: Neurotransmission

http://www.youtube.com/watch?v=FR4S1BqdFG4

Web: Description of how some drugs work and the brain areas
involved – 1

http://www.drugabuse.gov/news-events/nida-notes/2007/
10/impacts-drugs-neurotransmission
570 | 13.6: DISCUSSION QUESTIONS AND RESOURCES

Web: Description of how some drugs work and the brain areas
involved-2

http://learn.genetics.utah.edu/content/addiction/mouse/

Web: Information about how neurons communicate and the reward

pathways

http://learn.genetics.utah.edu/content/addiction/
rewardbehavior/

Web: National Institute of Alcohol Abuse and Alcoholism

http://www.niaaa.nih.gov/

Web: National Institute of Drug Abuse

http://www.drugabuse.gov/

Web: National Institute of Mental Health

http://www.nimh.nih.gov/index.shtml

Web: Report of the Working Group on Psychotropic Medications for

Children and Adolescents: Psychopharmacological, Psychosocial, and
Combined Interventions for Childhood Disorders: Evidence Base,
Contextual Factors, and Future Directions (2008)

http://www.apa.org/pi/families/resources/child-
medications.pdf

Web: Ways drugs can alter neurotransmission

https://thebrain.mcgill.ca/flash/i/i_03/i_03_m/
i_03_m_par/i_03_m_par .html
 13.7: ADDICTION | 571

13.7: ADDICTION

This module was adapted from:

Young, A. (2023). Addiction. In C.N. Hall (Ed.) Introduction to

Biological Psychology. University of Sussex Library.
https://openpress.sussex.ac.uk/introductiontobiologicalpsychology/

Learning Objectives

• Appreciate the features of reward and reinforcement

• Understand how the effects of drugs on reinforced behaviors
points to a critical role of dopamine
• Understand how abused drugs affect mesolimbic dopamine
transmission
• Appreciate the link between drug self-administration and drug
dependence (addiction).
572 | 13.7: ADDICTION
What is addiction?
Drug addiction, or to give it its more scientific term, dependence, is the taking
of a chemical substance (the drug) for non-nutritional and non-medical reasons,
where the drug-taking behavior is compulsive. An addict feels they have no control
over taking the drug, but instead feels driven to take it. Their lives often become
centered around acquiring and consuming the drug, to the detriment of behaviors
necessary for survival – for example, eating, drinking water – and they often engage
in risky or illegal behavior in order to feed their drug habit. Addicts often develop
a tolerance to the drug, such that they need more of the drug to produce the
‘high’. Drug dependence must be distinguished from drug use and drug abuse.
Drug use is where the substance is taken in small quantities, relatively infrequently,
and importantly with no damage to relationships or daily function. For example,
people often enjoy a glass of wine with a meal, or a drink with friends. If drug use
escalates to frequent and/or excessive taking of the substance, causing disruption
to daily functioning or relationships, but without the compulsivity, this would be
termed drug abuse. Drug dependence, as stated above, is similar to drug abuse,
except that the drug-taking is compulsive, with the addict feeling they have no
control over whether to take the drug.
There are four major stages of drug addiction: initiation, maintenance,
abstinence and relapse, each of which are likely to be driven by different
mechanisms. Initiation is the first stage, where a person takes the drug for the
first time. The main factors which influence initiation are: the ‘pleasant’ feeling
(hedonic impact) from taking the drug; overcoming stress; peer pressure and the
desire to conform to a group; or simply to experiment. For many people, drug
taking never progresses beyond this stage, and whether or not they take a drug is
entirely a conscious decision.
However, where a person becomes dependent, or addicted, this moves on to
the second stage: maintenance. Here the person no longer feels in control of the
decision as to whether to take a drug, but rather feels a compulsion to take it.
The maintenance stage can be long-lasting, and is very often accompanied by an
increasing motivational drive to take the drug, which is driven by a process called
sensitization (see ‘Tolerance and sensitization’ box below). However, there is rarely
 13.7: ADDICTION | 573
an accompanying increase in hedonic impact from taking the drug: indeed very
often hedonic impact decreases, and the drugs may even become aversive.

Tolerance and sensitization

These are forms of neuroadaptation which are important in many

aspects of neuronal function, and are particularly important in
understanding processes of drug addiction.

Tolerance refers to the process where a drug becomes less effective,

that is, it produces a weaker response after repeated administration.
Sensitization, on the other hand, is where the drug becomes more
effective over repeated administration.

Both processes are mediated through changes in cellular function,

including:

• changes in neurotransmitter synthesis, storage and release,

• changes in receptor density,
• changes in reuptake and metabolism of transmitters,
• changes in second messenger signalling,

many of which probably involve upregulation or downregulation of

specific gene expression.

However, at present we do not fully understand how these mechanisms

are controlled. Interestingly, the processes involved in sensitization are
very long-lasting, and some have even suggested that they may be
irreversible, accounting for the enduring changes that underlie
maintenance of addiction. A link with mechanisms of learning has also
been suggested by the observation that antagonists at NMDA-type
glutamate receptors, given into VTA, prevent sensitization. NMDA-
receptors are known to be critically involved in neuroplasticity
574 | 13.7: ADDICTION

mechanisms of learning, and this evidence suggests that similar

processes involving NMDA receptors may underlie drug-induced
sensitization.

Once a person has become dependent, it is likely that the addiction remains with
them for the rest of their life: there is little evidence for true recovery. Therefore
when an addict refrains from taking a drug, they are not normally considered to
be ‘cured’ or ‘recovered’, but rather they are considered to be abstinent. This
reflects the view that the addiction is still present, but is not expressed because the
person no longer takes the drug. However, the motivational drive to take the drug
– that is, the craving – may still be strong. This is underlined by evidence showing
that physiological and neurochemical changes occurring in the brain with the
development of dependence are largely irreversible, as we will see later. Therefore,
abstinent addicts are very prone to restarting their drug taking, termed relapse.
A single intake of the drug can reinstate the maintenance phase in an addict who
may have been abstinent for many years, hence the requirement, in treatment
programs for dependence, that the addict never take the drug. Relapse is driven by
cravings in the individual, which may be brought about by stress or by exposure to
people, items or situations associated to previous drug taking, emphasizing the link
between classical conditioning and drug taking.
When an addicted person stops taking a drug, they often experience withdrawal
symptoms. These are behavioral changes, often opposite to the effects elicited by
the drug, and can be very aversive. In the early stages of abstinence these withdrawal
symptoms are particularly strong and can be extremely unpleasant. Thus, avoiding
withdrawal symptoms provides a strong motivation to take the drug and can
lead to relapse. However, as the period of abstinence increases the withdrawal
symptoms subside, so reducing this as a motivation for reinstatement.

Brain motivation circuits and addiction

Many studies have been undertaken in experimental animals, particularly rats and
mice, but also primates, to investigate the neural circuitry underlying addiction.
 13.7: ADDICTION | 575
These mostly focus on pathways controlling reinforcement and motivation often
termed the reward pathway.

Reward or reinforcement?

Reward is a term widely used in the discussion of dopamine signalling

in the mesolimbic pathway. Indeed, many publications refer to the
mesolimbic pathway as the ‘reward pathway’. However, the term
‘reward’ has several problems in the scientific context. Reward is a
pleasurable experience, and is subjective: what is pleasurable for one
person may not be for another. It also raises problems of assessing
pleasure in experimental animals: how do we know that an animal is
enjoying an experience? Third, the term does not necessarily imply that
it will change behavior.

In scientific terms, for empirical research, we need to avoid subjective

measures: far better to have objective measures. The term
reinforcement refers to the ability of a stimulus, situation, or outcome,
to elicit a behavior. Reinforcement strengthens an animal’s future
bebehavior on exposure to the stimulus. It is an objective measure: we
can simply measure changes in the behavior, for example the number of
operant lever presses. Importantly, also, reinforcement does not imply
pleasure, so in measuring the behavior, we don’t have to worry about
whether the animal is enjoying the experience.

The discovery by Olds and Milner (1956) that rats would work by pressing a lever
to receive mild electrical stimulation to a specific area of the brain, fueled major
research programs looking at this and related pathways in controlling motivation.
They saw that the rats were motivated to stimulate areas of the mesolimbic
pathway electrically: this pathway projects from cell bodies in the ventral tegmental
576 | 13.7: ADDICTION
area (VTA) along the axons of the mesolimbic pathway, to terminals located
primarily in the nucleus accumbens.

Fig 13.5. A rat pressing a lever to receive mild electric stimulation.

CREDIT: Wolfson CC https://openpress.sussex.ac.uk/
introductiontobiologicalpsychology

Subsequent experiments have characterized the mechanism promoting the level

pressing response in greater detail, but, importantly, they have emphasized the
critical role of dopamine in driving the behavior effect. Thus, amphetamine or
cocaine, which enhance dopamine signalling, increase the lever press rate, whereas
giving a dopamine antagonist reduces the lever press rate, indicating that the
reinforcement signal driving the lever pressing behavior is mediated through
dopamine. It is important to note that the anatomical location of brain regions
which support self-stimulation is very specific: if the electrodes are located outside
these localized regions, animals will not self-stimulate. An interesting point here,
in relation to the phenomena of addiction, is that in self-stimulation experiments
 13.7: ADDICTION | 577
such as these, animals will repeatedly press the lever to receive the stimulation
rather than eating or drinking, indicating that the electrical stimulation is a very
strong motivational drive which suppresses the drive to carry out behaviors critical
for survival: addicts often neglect normal nutrition and self-care in order to
maintain their drug-taking.
In a similar procedure, rats and mice will also press a lever in order to receive
injections of certain drugs. In its simplest form the drugs are administered
intravenously (i.v.), through an indwelling cannula in a blood vessel: therefore lever
pressing gives an i.v. injection of the drug. In a modification of the design, drugs
can be administered via a microinjection into local brain areas. There are a number
of drugs which animals will administer intravenously, including amphetamine,
cocaine, nicotine, morphine, heroin and ethanol, and they will also administer
amphetamine or cocaine into the nucleus accumbens and morphine into the VTA.
It should be emphasized that animals will only self-administer certain drugs: the
vast majority of drugs do not support self-administration. Similarly, the brain
regions where animals will self-administer the drugs, VTA and nucleus accumbens,
are very specific and indicates the importance of the mesolimbic pathway.
The importance of the mesolimbic dopamine system can be confirmed with
lesion experiments, using 6-hydroxy-dopamine (6-OHDA), a drug which
specifically kills catecholamine (dopamine and noradrenaline) containing cells.
Following lesions to the mesolimbic pathway, but not to other pathways, animals
will no longer self-administer drugs. Furthermore, enhancing dopamine function
by giving local injections of cocaine or amphetamine into nucleus accumbens also
increases the lever pressing, supporting the role of dopamine in the lever-pressing
response. Paradoxically, many experiments have shown that dopamine antagonists
also increase the lever press rate. However, it was subsequently found that the dose
was critical: at low doses the lever-press rate is increased, but at higher doses it
is entirely abolished. This dose-dependence can be explained by considering that
at low antagonist doses not all receptors are occupied and therefore increasing
the amount of drug self-administered will overcome the effect of the antagonist,
whereas at high antagonist doses, the receptors are completely blocked, and so no
matter how much more drug is administered the effect of the antagonist cannot be
overcome. So it is concluded that the motivational effects of these drugs is mediated
via dopamine neurons in the mesolimbic pathway.
You will recall that stress is a major contributory factor to development of
578 | 13.7: ADDICTION
dependence and relapse in abstinent addicts, and the influence of stress can be
seen in animals trained to self-administer. If rats that had previously been trained
to lever-press to receive self-administration of cocaine are left drug-free for several
weeks, they no longer press the lever when cocaine is once more available,
modelling abstinence. If they then receive a foot shock, they do start pressing the
lever again, reinstating the compulsive self-administration and paralleling the effect
of stress on relapse in people. In the context of the role of stress in reinstatement, it
is notable that this reinstatement is prevented by corticotropin-releasing hormone
antagonists, emphasizing the role of the hypothalamus-pituitary-adrenal axis
mediated stress response to the process.
Measuring rodents’ operant behavior, such as lever pressing, is a good way of
measuring their level of motivation, and as we saw from the experiments above,
they show strong motivation to receive stimuli which activate the dopaminergic
mesolimbic pathway. However these are clearly very artificial behaviors: they do
not mimic activities which the animals undertake naturally. But we just need to
look in the wild at how much effort animals will put in to getting food, be it
a predator chasing down a prey, or annual migrations to new feeding grounds.
Animals have an innate motivation to pursue behaviors which are beneficial to
survival, for example eating, drinking and reproducing. As such, motivational
systems in the brain are highly evolved to reinforce behaviors that enhance animals’
ability to perform these actions. Stimuli associated with these action become
strong predictors of outcome, and strong motivational cues to perform behaviors
leading to consumption.
In the laboratory, too, motivation to pursue beneficial behaviors can be
demonstrated: initial observations by B.F. Skinner in the 1940s, opened the way for
many subsequent operant experiments where rats or mice pressed a lever in order
to receive food or water or even a sexually receptive mate. Moreover, as with self-
stimulation and self-administration, lesion and pharmacology experiments have
shown the importance of dopamine in the mesolimbic pathway for controlling this
behavior. Thus, lever pressing to receive a natural reward (food, water) is abolished
in animals with 6-OHDA lesions of the mesolimbic pathway, or by the application
of dopamine receptor antagonists, and is enhanced by the administration of
amphetamine or cocaine. So the mesolimbic pathway is clearly involved in
motivation to undertake behaviors vital for survival, and self-stimulation and self-
 13.7: ADDICTION | 579
administration tap into this mechanism by promoting activity in the pathway
either electrophysiologically or pharmacologically.
Direct neurochemical measurement in localized brain areas, primarily using
brain microdialysis or fast-scan cyclic voltametry (FSCV) (see ‘Measuring
neurotransmitter release in the brain’ box, below) have shown that dopamine
release in nucleus accumbens, but not in other dopaminergic terminal regions in
the brain, is increased during appetitive behaviors. These behaviors include eating
and drinking, and during electrical stimulation of the VTA, similar to that used
in self-stimulation, therefore largely confirming the importance of dopamine in
motivation processes. Importantly, also, drugs which support self-administration
also increase dopamine release in nucleus accumbens preferentially over other
regions. The mechanisms by which the different drugs increase mesolimbic
dopamine function varies across the different drug types. Some, such as nicotine,
morphine, heroin and alcohol activate the pathway by either direct or indirect
actions on the dendrites and cell body in the VTA, while others, such as
amphetamine and cocaine affect the reuptake of released dopamine in the terminal
regions, including nucleus accumbens.
Considering the site of action of the different drugs accounts for why animals
will self-administer morphine into the VTA and amphetamine and cocaine into
the nucleus accumbens, as these are the regions where the respective drugs activate
mesolimbic function. Therefore, although addictive drugs exhibit very different
primary pharmacology, with only amphetamine and cocaine acting directly on the
dopamine system, and also have very different primary behavioral effects (Table
1), they all share the ability to increase dopamine function selectively in the
mesolimbic pathway and it is this action that is believed to underlie their
motivational effects. The drugs ‘hijack’ the neural pathway in the brain which
controls the animals’ motivation to pursue behaviors essential for survival, and
instead motivate the individual to perform behaviors related to taking the drugs.
580 | 13.7: ADDICTION

Measuring neurotransmitter release in the brain

Measurement of neurotransmitter release in localized brain areas during

behavior and/or in response to drugs is really important in
understanding underlying neurotransmitter actions. Over the last few
decades, two main methods have been employed, both of which can be
used in awake, freely moving experimental animals.

Brain microdialysis involves implanting a small length of dialysis

membrane into the brain, and perfusing it continuously with artificial
cerebrospinal fluid (aCSF). Dissolved substances in the brain extracellular
fluid pass through the membrane, by dialysis, into the aCSF, and can be
measured typically by high performance liquid chromatography (HPLC).
Second, fast-scan cyclic voltammetry (FSCV) measures the
oxidation of chemicals when a voltage is applied to a carbon fibre
microelectrode. Although it is possible to measure some other
neuroactive compounds, the most widespread use of FSCV is to
measure dopamine. Microdialysis has the advantage that many different
compounds can be measured in a single sample, whereas FSCV is mainly
restricted to a single compound, normally dopamine. However,
microdialysis probes are comparatively large (typically 1 to 2 mm long,
0,5 mm diameter) and so have a relatively poor spatial resolution. FSCV,
on the other hand, uses carbon fibre microelectrodes which are much
smaller (typically 100 µm long, 10 µm diameter) which give a much
higher spatial resolution and allow targeting of smaller brain sub-
regions. Microdialysis also has relatively poor temporal resolution, as it
requires collection of enough sample to be able to analyse: most studies
use sample collection times of 1 to 10 minutes, although some have
managed less than a minute. In contrast, FSCV typically makes 10
measurements per second. Therefore FSCV is able to pick up fast
 13.7: ADDICTION | 581

transient changes in response to specific stimuli, whereas microdialysis

can only pick up slower more sustained changes.

Recent developments with genetic markers are opening the way to

novel approaches to measuring many aspects of neurotransmitter
function with high chemical specificity, spatial resolution and temporal
resolution.

Fig 13.6. Diagrammatic representation of the central role of the

mesolimbic pathway in motivation in natural situations beneficial for
survival (the motivation loop) and how addictive drugs interact with
this system (the addiction loop). CREDIT: Wolfson CC
https://openpress.sussex.ac.uk/introductiontobiologicalpsychology

Conditioned place preference tests an animal’s preference for an environment

which is associated with a reinforcer, and can be assessed using a two compartment
testing box. Animals are trained over repeated sessions that one compartment
contains a reinforcer (typically food, sucrose or water), whereas the other
582 | 13.7: ADDICTION
compartment does not. After several training trials, the place preference is tested in
the absence of any reinforcer (that is, both compartments are empty). The animal is
placed back in the testing box, and the time spent in each compartment is recorded.
Animals spend more time in the previously reinforced compartment than in the
control compartment, even though at test there is no reinforcer present.
This shows that the animal has learned which compartment of the test box
contained the reinforcer, and it is motivated to visit that compartment in
preference to the control compartment, even when the reinforcer is no longer
present. This effect is:

1. abolished by 6-OHDA lesions of the mesolimbic pathway;

2. enhanced by drugs which increase dopamine, such as amphetamine and
cocaine; and
3. attenuated by dopamine receptor antagonists.

Therefore, the mesolimbic dopamine pathway is critical for expression of

conditioned place preference.
In a variant of the procedure, instead of a natural reinforcer, drugs can be used.
In this case, during training, the animal is given an injection of a drug and placed
in one compartment or a saline injection and placed in the other compartment.
At test, with no drug present, they show a preference for the compartment in
which they have previously received the drug. The drugs which will induce place
preference, including amphetamine, cocaine, morphine, heroin and alcohol, are
the same ones which animals will self-administer, and all are potentially addictive
drugs in people. One important aspect that the place preference experiments
demonstrates is that animals learn about the environment in which they receive
reinforcing stimuli, be it natural reinforcers or reinforcing drugs, and, given the
choice, they return to that environment, even when the reinforcer is not present.
This indicates that associative learning, or conditioning, is occurring between the
reinforcer and the environment. Similar learning can also be demonstrated to
specific cues: in the lever press experiments described above, if a neutral stimulus
(e.g. a light) is presented immediately before the lever is made available, the animals
will approach the lever when the light stimulus is presented alone, and they will try
to press the lever, even when it is still retracted and unavailable.
Microdialysis and FSCV experiments have shown that, once this learning has
 13.7: ADDICTION | 583
taken place, dopamine release in nucleus accumbens is increased during the
presentation of the light stimulus, even long after the withdrawal of the reinforcer.
Therefore, animals learn to associate specific cues and environment to the
reinforcer, such that they can evoke the both release on dopamine in nucleus
accumbens and reinforced behavior, even in the absence of the reinforcer. These
behaviors in experimental animals strongly resemble behaviors seen in drug
addicts, where cues associated with drug taking (e.g. an empty vodka bottle to
an alcoholic or a needle to a heroine addict), or the environment they associate
with the drug taking can be very strong motivational drivers, or cravings, to take
the drugs. Interestingly these conditioned effects can long outlast the period of
association in both experimental animals and in addicts: so cues and/or
environment can trigger cravings in abstinent addicts even years after they last took
the drug.
In the early stages, drug taking is not addictive: that is, people take the drugs
through choice. A number of psychological factors originating in prefrontal
cortex, including impulsivity and inhibitory self-control, have been shown to be
vulnerability factors for drug taking. Thus, dysregulation of prefrontal control
over mesolimbic circuits may underlie impaired inhibitory self-control exhibited
by many addicts, while, high impulsivity, mediated through abnormalities of the
orbitofrontal area of prefrontal cortex, may explain people’s choice of short-term
gratification of drug taking over long-term benefits of abstinence.
However, at some stage there is a change from use or abuse to the compulsive
drug use characteristic of dependence. As mentioned earlier, this change includes
neuro-adaptive processes involving sensitization of dopamine systems controlling
motivation and seems to be largely irreversible, accounting for enduring cravings
even after long periods of abstinence. Moreover, evidence has shown that there
is a learned component to this process: experimental animals are more likely to
show sensitization (e.g. sensitization of locomotor activity, mediated through
mesolimbic dopamine activity) if tested in the same environment where the initial
drug administration took place. In addition, previous sensitization enhances the
acquisition of self-administration and place preference, effects mediated through
mesolimbic dopamine. With repeated drug administration, drugs may acquire
greater and greater incentive value and become increasingly able to control
behavior. This may parallel the observation in drug addicts where places, acts or
objects associated with drug-taking become especially powerful incentives.
584 | 13.7: ADDICTION
Addictive drugs produce long-lasting changes in brain organization. The brain
systems that are sensitized include the dopaminergic mesolimbic pathway,
responsible for the incentive salience (‘wanting’) of the drug or drug-associated
cues. Systems mediating the pleasurable or euphoric effects of the drug (‘liking’)
are not sensitized. Animal studies have looked at the mechanisms of sensitization
to repeated drug taking. Psychostimulants, including amphetamine and cocaine,
cause increased locomotor activity in rodents, an effect which is mediated through
the mesolimbic pathway: lesions of the mesolimbic pathway abolish it. On
repeated systemic administration (i.e. intravenous, intraperitoneal or
subcutaneous: where the drug accesses the whole brain), the hyperlocomotion
induced by the drug increases, showing a sensitised response. The precise
mechanism of the sensitization is not certain, but it probably involves long-term
and enduring neuro-adaptive changes in the cell body region in the VTA (see box
below).

Localisation of neuroadaptation underlying

sensitization

Rats were given repeated local injections of amphetamine into either

the cell body region of the mesolimbic pathway in the VTA, or the
terminal region in the nucleus accumbens. A third control group received
no injections.

Animals injected into the nucleus accumbens showed a hyperlocomotor

response, which did not increase over repeated injections: that is, there
was no sensitization. Animals given injections into the VTA showed no
behavioral response. This is not surprising, as the pharmacological effect
of amphetamine is at the terminals, it increases release and blocks
reuptake: therefore it is likely to be most effective in the terminal region.
After these repeated local injections, animals were left for a week drug-
 13.7: ADDICTION | 585

free, then given a challenge dose of amphetamine systemically. All

animals showed hyperlocomotion. Animals which had received repeated
drug injections into nucleus accumbens showed a similar level of
hyperlocomotion to the non-injected controls: that is, there was no
sensitization. However, animals which had received drug into the VTA
showed an augmented response compared to the other groups,
indicating that sensitization had taken place.

Therefore, repeated injection into nucleus accumbens evoked a

behavioral response, but not sensitization, whereas repeated injection
into VTA produced no behavioral response, but did cause sensitization,
providing evidence for the critical role of VTA in sensitization.

In summary, there is strong evidence from studies in experimental animals that:

1. dopamine signalling in the mesolimbic pathway drives motivational systems

to promote behaviors critical for survival;
2. addictive drugs impact on this system to promote behaviors associated with
drug-seeking and drug taking;
3. neuro-adaptation in this pathway accounts for the long-term, enduring
nature of dependence and
4. activity in this pathway driven by conditioned associations can cause cravings
to take the drug even after long periods of abstinence.

Therefore activity in this pathway can account for many of the phenomena
associated with addiction in people.

Models of addiction
Several models have been proposed to account for the features of addiction,
prominent amongst which is the incentive sensitization model, proposed by
Robinson and Berridge in 1993. This develops ideas taken from two other
586 | 13.7: ADDICTION
prominent models, the opponent process model and the aberrant learning model,
and it is worth considering these two models briefly first.

Aberrant learning model

According to the aberrant learning model, abnormally strong learning is associated

with drug taking, through two distinct components of learning. First, explicit
learning where the association between action (drug taking) and outcome (drug
effect) is abnormally strengthened leading to drug taking because of an expectation
of the hedonic impact, even when the drug no longer produces that effect. Second,
implicit learning where the action-outcome relationships (as above) change to
more automatic stimulus-response relationship (habit), meaning that the stimulus
evokes the response irrespective of any conscious expectations about the outcome.
While this theory accounts for the motivational drive from stimuli associated
with drug-taking and the ability of these stimuli to promote cravings, it does not
account for the fact that most addicts do not report expectation of a positive
hedonic effect. Therefore it seems unlikely that this could be the motivation for
their drug seeking and taking. Similarly, it does not explain the compulsive nature
of addiction – it implies that drug seeking and taking are purely automatic
behaviors, whereas in fact they appear more as a motivational compulsion. Finally,
it does not explain the behavioral flexibility shown by addicts. The theory would
predict that if the normal route to drug taking were prevented, the addict would
not be able to adapt behavior in order to seek the drug from a different source or via
a different process, whereas in fact addicts do show substantial behavioral flexibility
in these circumstances.

Opponent process model

The opponent process model is well founded in neuroscience, as a mechanism for

homeostatic control of many functions. It posits two processes, the A-process and
the B-process which oppose each other: the A-process is activated by an external
stimulus, leading to a change in functioning, and the B-process is the body’s
reaction to the change brought about by the A-process to return to the set point
level. In the context of drug taking, the A-process represents the direct effect of the
 13.7: ADDICTION | 587
drug, which triggers the B-process, the opponent process, which aims to restore the
homeostatic state. The A-process leads to the hedonic state (‘high’) associated with
taking a drug, while the B-process leads to the aversion from not taking the drug,
for example the withdrawal symptoms. Over repeated drug taking, tolerance builds
up to the A-process, accounting for the reduced hedonic impact of the drugs, while
the B-process is strengthened, leading to withdrawal symptoms, which can only
be eliminated by taking more of the drug. Thus the driving force for drug taking
is to prevent the aversive withdrawal symptoms which occur when the A-process
diminishes, but the B-does not. Thus, people who initially take drugs to gain a
positive hedonic state, are subsequently motivated to continue drug taking to avoid
a negative hedonic state.
This accounts for the drive to take the drug to achieve a homeostatic state, but
does not account for evidence showing that avoiding the negative hedonic state
of withdrawal is not a major motivator for drug taking. Indeed, many addictive
drugs do not evoke strong withdrawal symptoms. Also, withdrawal symptoms
are maximal in the days following abstinence, yet cravings for the drug, and
reinstatement, even after a small dose, can last for years – in alcoholics who have
been abstinent for years, a single alcoholic drink can reinstate the addictive
behavior.

Incentive sensitization model

The incentive sensitization model derives certain aspects from the above models,
but puts them into a motivational framework. It delineates two distinct
components of reinforcement – hedonic impact (‘liking’) and incentive salience
(‘wanting’), which are dissociable behaviorally and physiologically. Robinson &
Berridge use the terms ‘liking’ and ‘wanting’ (in quotation marks) to represent
these very clearly defined behavioral parameters. Thus, when given in quotation
marks, they represent much more specific scientific terms than the everyday usage
of the two words. Incentive learning, both explicit and implicit, which forms the
core of the aberrant learning model, provide the route through which stimuli
associated with the behavior acquire incentive salience – they become salient,
attractive and wanted – and guide behavior.
The incentive sensitization model focuses on how drug cues trigger excessive
motivation for drugs, which drives drug seeking and drug taking behavior. The
588 | 13.7: ADDICTION
subjective pleasure derived from taking the drug, the hedonic impact or ‘liking’,
is due the direct psychopharmacological action of the drug in producing a ‘high’,
reducing social anxiety and/or, increasing socialization. Incentive salience, or
‘wanting’ on the other hand, represents the motivational importance of stimuli,
making otherwise unimportant stimuli able to attract attention, making them
attractive and ‘wanted’. The critical feature of the model is the dissociation
between these two processes, both behaviorally and physiologically, and that the
incentive salience, or ‘wanting’ is sensitized over repeated drug taking, so increasing
the driving force to take drugs, whereas the hedonic impact, or ‘liking’, is
unaffected, or may even reduce, through tolerance. Under normal conditions of
natural reward the two processes work together to motivate behaviors which are
beneficial to survival, it is only in unnatural situations such as taking of addictive
drugs that there is a dissociation between the actions of the two systems, such that
drugs can become exceptionally strong motivators of drug-seeking and drug-taking
behavior. This dissociation of the two components accounts for the observation
that addicts continue to seek and take drugs, even when they derive little or no
pleasure from it, and when they are fully aware of the physical, emotional and
social damage it is causing. Importantly, the dissociation between ‘wanting’ and
‘liking’ has also been demonstrated experimentally, indicating that it is not simply
a theoretical concept, but does actually occur.

The dissociation between ‘wanting’ and ‘liking’

In a series of experiments designed to test whether a dissociation

between ‘wanting’ and ‘liking’ could be demonstrated experimentally,
Berridge and co-workers devised a scoring scheme for measuring facial
expressions related to palatability across several species, through which
they assessed ‘liking’ (Figure 6.3). Amphetamine was shown to have no
effect on ‘liking’, and may have increased aversion.
 13.7: ADDICTION | 589

In order to assess ‘wanting’, a lever press experiment was used in the

same animals. Animals were first trained to press a lever for sucrose
reward, then trained that one auditory stimulus signaled that the a lever
press will deliver sucrose (CS+) but that a different auditory stimulus
signaled that the level press will not deliver sucrose (CS-). Level press
responses to CS+ and CS- were measured as an index of ‘wanting’.

Amphetamine microinjection selectively enhanced lever pressing for

sucrose by the CS+ auditory stimulus, but not by the CS- auditory
stimulus, indicating that amphetamine selectively enhanced the
motivational element, ‘wanting’. Therefore amphetamine had no effect
on, or perhaps decreased, ‘liking’, but enhanced ‘wanting’, providing
experimental evidence for the dissociation of the two which forms the
basis of the incentive.

Figure 6.3 depicts representative hedonic tongue protrusions (reaction

to sweet tastes) and aversive gapes (reaction to bitter tastes) from
adult rat, young primate, and infant human (after Berridge).
590 | 13.7: ADDICTION

Fig. 13.7. Similar facial expressions to ‘nice’ and ‘nasty’ tastes in rodents
and primates. CREDIT: Wolfson CC https://openpress.sussex.ac.uk/
introductiontobiologicalpsychology

Module Summary

(a) Increasing concentrations of amphetamine cause a small decrease in

hedonic reaction, and an increase in aversive reaction, showing that
amphetamine does not increase ‘liking’: indeed, it decreases it.

(b) Amphetamine causes an increase in responding to the auditory

stimulus which has been paired with sucrose (CS+), but not to the
auditory stimulus that was not paired with sucrose (CS-), showing that
amphetamine increases motivational drive, that is ‘wanting’.

The mesolimbic dopamine pathway is primarily involved in control of incentive

salience, while other parts of the basal ganglia circuitry, including those using
 13.7: ADDICTION | 591
opioids and acetylcholine, control the hedonic impact. This accounts for the role
of dopamine is in the incentive salience aspect, but not the hedonic impact aspect:
drugs which enhance dopamine function increase the incentive salience
(‘wanting’), increasing the animals motivation to pursue the goal, without
increasing the hedonic impact (‘liking’). While ‘liking’ of the drug may decrease
with repeated exposure (probably due to tolerance), the motivation to take the
drug increases through sensitization of the incentive salience (incentive
sensitization). Thus the model explains the dissociation between the pleasure
received from taking the drug, and the motivational drive to take it. The
sensitization of the incentive salience is similar to habit learning (aberrant learning
model), but is distinguished from it by the fact that it is only one component of
the response which is sensitized. Related to this, work from Everitt, Robbins and
co-workers suggest that the switch to compulsive drug taking which characterizes
dependence may be mediated by a shift in the specific dopamine pathway
controlling the response, from the neurons terminating in nucleus accumbens,
when responses are primarily goal directed, to neurons terminating more dorsally
in the dorsal striatum when responses become compulsive (e.g. Everitt et al, 2001).

Addictive behaviors
There are a number of behaviors that share a lot of features in common with
drug addiction. Behaviors like gambling and exercise can become compulsive with
individuals carrying out the behaviors to the detriment of normal daily function
or family relationships. A common feature with these behaviors is a dopaminergic
component to the motivation, which may include activation of endorphin (an
endogenous opioid, related to morphine) systems which in turn activate the
mesolimbic dopamine pathway. Therefore some of these so called ‘addictive
behaviors’ share many of characteristics of drug addiction, and evidence suggests
that they may share similar neural mechanisms. A major research focus is aimed at
identifying whether they are indeed different manifestations of the same process or
different processes.
592 | 13.7: ADDICTION
Treatment

Treatment options for drug addiction are fairly limited at present. The best long-
term therapy is abstinence, although, as has been discussed earlier, people, specific
cues and environments associated with drug taking can produce very strong
cravings, often leading to relapse, even after extended periods of abstinence –
you will recall that, in rats, stimuli associated with reinforcement (e,g, drug
administration) evoke dopamine release in nucleus accumbens long after the
withdrawal of the reinforcer. In all therapeutic strategies for treating addiction, a
vital consideration is that the individual must recognise that they have an addiction
and they must be motivated to overcome it. Treatments can be physically and
emotionally demanding, and without the motivation to stop, treatment is rarely
successful.
Psychological therapies have proven fairly successful in sustaining abstinence.
Cognitive behavior therapy (CBT) helps recognize unhealthy behavioral patterns,
identify triggers which may potentially lead to relapse, and develop coping
strategies to overcome them. This may also include contingency management,
which reinforces the positive aspects of avoiding drugs through specific rewards.
Stepped management schemes are a form of group therapy which identifies
negative consequences of addiction and through support networks develops
strategies to overcome them. In the longer term, psychological therapies also look
at aspects in the person’s life beyond their addiction, and particularly any other
pathological conditions they may experience. A key aim is to improve stress
management, since we have seen that stress is a major precipitatory factor in
relapse.
For psychological therapies to be effective, the individual must first stop taking
the drugs, a process often called detoxification: given the compulsive nature of
drug addiction, this in itself can be a major challenge. The four main approaches
used are drug elimination, agonist therapy, antagonist therapy or aversion therapy.
Pharmacological treatments which reduce the impact of withdrawal symptoms
and cravings can also help during the detoxification processes.
Drug elimination is where the person simply does not take the drug any more.
Sometimes the drug is simply withdrawn, in a single step (e.g. very often when
smokers give up smoking), but more often, particularly for more serious
addictions, the daily intake of drug is slowly reduced under clinically controlled
 13.7: ADDICTION | 593
conditions, until the addict is no longer dependent on the drug. One of the main
problems with this approach is that the person normally experiences withdrawal
symptoms, which can be extremely unpleasant in some cases, and are a major
motivator to relapse into a drug-taking habit.
Antagonist therapy is where an antagonist for the addictive drug is given to
block the action of the drug. This form of therapy is rarely used as it induced very
severe withdrawal effects, so much so that when antagonist therapy is used, the
individual is normally anesthetized or heavily sedated. Agonist therapy is probably
the most widely used treatment for coming off drugs. In this case an agonist for the
addicted drug, or in some cases the drug itself, is given but in a very controlled way,
reducing the amount given over a period of time: normally also the drugs and/or
route of delivery is less harmful. Finally, aversion therapy can be effective in some
cases, but is not widely used. This is where drug taking is paired with an aversive
stimulus, such that a conditioned association is made between the drug and the
aversive stimulus. For example an emetic drug is given alongside the addicted drug
to induce sickness, making the addicted drug-taking aversive – you will remember
the important role of conditioning in the development of addiction: well, it can
also be used to treat it.

Key Takeaways

• Drug addiction is the compulsive use of drugs, to the detriment of

daily functioning and relationships.
• Drugs which can become addictive have a wide variety of primary
pharmacology, but all share the property that they provoke
increased dopamine release in the mesolimbic pathway projecting
from VTA in the midbrain to the nucleus accumbens in the
forebrain.
594 | 13.7: ADDICTION

• Many behavioral procedures in experimental animals have shown

that this pathway is important in motivation and that animals
show a strong motivation to work (e.g. press a lever) in order to
receive injections of drugs with addictive potential, providing a
link between natural motivation networks and addiction.
• The incentive sensitization model accounts for the phenomena of
addiction by proposing a dissociation between motivation and
hedonia, which can be demonstrated experimentally, and which
accounts for the observation that drug addicts often report a
heightened drive to take drugs, yet the enjoyment from taking
them is diminished.

References and further reading

Berridge, K. C., & Robinson, T. E. (1998). What is the role of dopamine in reward:
hedonic impact, reward learning, or incentive salience? Brain Research Reviews,
28(3), 309-369. https://doi.org/10.1016/S0165-0173(98)00019-8
Caine, S. B., Negus, S. S., Mello, N. K., Patel, S., Bristow, L., Kulagowski, J.,
Vallone, D., Saiardi, A., & Borrelli, E. (2002). Role of dopamine D2-like
receptors in cocaine self-administration: studies with D2 receptor mutant mice
and novel D2 receptor antagonists. The Journal of Neuroscience, 22(7),
2977-2988. https://doi.org/10.1523/JNEUROSCI.22-07-02977.2002
Di Chiara, G. (1999). Drug addiction as dopamine-dependent associative learning
disorder. European Journal of Pharmacology, 375(1–3), 13-30. https://doi.org/
10.1016/S0014-2999(99)00372-6
Di Chiara, G., & Imperato, A. (1988). Drugs abused by humans preferentially
increase synaptic dopamine concentrations in the mesolimbic system of freely
moving rats. Proceedings of the National Academy of Sciences of the United States
of America [PNAS] 85(14), 5274-5278. https://doi.org/10.1073/
pnas.85.14.5274
Everitt, B. J., Dickinson, A., & Robbins, T. W. (2001). The neuropsychological
 13.7: ADDICTION | 595
basis of addictive behaviour. Brain Research Reviews, 36(2–3), 129-138.
https://doi.org/10.1016/S0165-0173(01)00088-1
Everitt, B. J., & Robbins, T. W. (2016). Drug addiction: Updating actions to
habits to compulsions ten years on. Annual Review of Psychology, 67(1), 23-50.
https://doi.org/10.1146/annurev-psych-122414-033457
Franken, I. H. A. (2003). Drug craving and addiction: integrating psychological
and neuropsychopharmacological approaches. Progress in Neuro-
Psychopharmacology and Biological Psychiatry, 27(4), 563-579. https://doi.org/
10.1016/S0278-5846(03)00081-2
Goodman, A. (2008). Neurobiology of addiction: An integrative review.
Biochemical Pharmacology, 75(1), 266-322. https://doi.org/10.1016/
j.bcp.2007.07.030
Heilig, M., MacKillop, J., Martinez, D., Rehm, J., Leggio, L., & Vanderschuren,
L. J. M. J. (2021). Addiction as a brain disease revised: Why it still matters,
and the need for consilience. Neuropsychopharmacology, 46(10), 1715-1723.
https://doi.org/10.1038/s41386-020-00950-y
Kalivas, P. W., & Weber, B. (1988). Amphetamine injection into the ventral
mesencephalon sensitizes rats to peripheral amphetamine and cocaine. Journal
of Pharmacology and Experimental Therapeutics, 245(3), 1095-1102.
Koob, G.F. (2005). The neurocircuitry of addiction: Implications for treatment.
Clinical Neuroscience Research, 5(2-4), 89-101. https://doi.org/10.1016/
j.cnr.2005.08.005
Koob, G. F., & Volkow, N. D. (2009). Neurocircuitry of addiction.
Neuropsychopharmacology, 35, 217-238. https://doi.org/10.1038/npp.2009.110
Koob, G. F., & Volkow, N. D. (2016). Neurobiology of addiction: A
neurocircuitry analysis. The Lancet Psychiatry, 3(8), 760-773. https://doi.org/
10.1016/S2215-0366(16)00104-8
McKendrick, G., & Graziane, N. M. (2020). Drug-induced conditioned place
preference and its practical use in substance use disorder research. Frontiers
in Behavioral Neuroscience, 14, 582147. https://doi.org/10.3389/
fnbeh.2020.582147
Negus, S. S., & Miller, L. L. (2014). Intracranial self-stimulation to evaluate abuse
potential of drugs. Pharmacological Reviews, 66(3), 869-917. https://doi.org/
10.1124%2Fpr.112.007419
Olds, J., & Milner, P. (1954). Positive reinforcement produced by electrical
596 | 13.7: ADDICTION
stimulation of septal area and other regions of rat brain. Journal of Comparative
and Physiological Psychology, 47(6), 419. https://doi.org/10.1037/h0058775
Robinson, T. E., & Berridge, K. C. (1993). The neural basis of drug craving:
An incentive-sensitization theory of addiction. Brain Research Reviews, 18(3),
247-291. https://doi.org/10.1016/0165-0173(93)90013-P
Robinson, T. E., & Berridge, K. C. (2001). Incentive-sensitization and addiction.
Addiction, 96(1), 103-114. https://doi.org/10.1046/
j.1360-0443.2001.9611038.x
Schultz, W., & Dickinson, A. (2000). Neuronal coding of prediction errors.
Annual Review of Neuroscience, 23, 473-500. https://doi.org/10.1146/
annurev.neuro.23.1.473
Vezina, P. (1993). Amphetamine injected into the ventral tegmental area sensitizes
the nucleus accumbens dopaminergic response to systemic amphetamine: An
in vivo microdialysis study in the rat. Brain Research, 605(2), 332-337.
https://doi.org/10.1016/0006-8993(93)91761-G
Wise, R. A. (1998). Drug-activation of brain reward pathways. Drug and Alcohol
Dependence, 51(1–2), 13-22. https://doi.org/10.1016/S0376-8716(98)00063-5
Wyvell, C. L., & Berridge, K. C. (2000). Intra-accumbens amphetamine increases
the conditioned incentive salience of sucrose reward: Enhancement of reward
“wanting” without enhanced “liking” or response reinforcement. Journal of
Neuroscience, 20(21), 8122-8130. https://doi.org/10.1523/
JNEUROSCI.20-21-08122.2000

About the author

Dr Andrew Young
INSTITUTION: UNIVERSITY OF LEICESTER

Dr Andrew Young obtained a BSc degree in Zoology from the University of

Nottingham, and his Ph.D in Pharmacology from the University of Birmingham.
He then spent four years as a post doctoral researcher at Imperial College, London,
studying glutamate release in the context of mechanisms of epilepsy, before moving
 13.7: ADDICTION | 597
to the Institute of Psychiatry (King’s College, London) for nine years to study
dopamine signalling in models of schizophrenia and addiction. In 1997 he was
appointed as Senior Research Fellow in the School of Psychology at University of
Leicester and is now Associate Professor in that department. His research interests
focus mainly on neurochemical function, particularly dopamine, in attention and
motivation, and in models of schizophrenia and addiction. He teaches topics
in biological psychology and the biological basis of mental disease to both
undergraduate and postgraduate students in the School of Psychology and Biology.
598 | 13.8: REFERENCES

13.8: REFERENCES

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neurocircuitry analysis. The Lancet Psychiatry, 3(8), 760-773. https://doi.org/
10.1016/S2215-0366(16)00104-8
Koob, G.F. (2005). The neurocircuitry of addiction: Implications for treatment.
Clinical Neuroscience Research, 5(2-4), 89-101. https://doi.org/10.1016/
j.cnr.2005.08.005
McKendrick, G., & Graziane, N. M. (2020). Drug-induced conditioned place
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Behavioral Neuroscience, 14, 582147. https://doi.org/10.3389/fnbeh.2020.582147
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addiction. Addiction, 96(1), 103-114. https://doi.org/10.1046/
j.1360-0443.2001.9611038.x
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annurev.neuro.23.1.473
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sensitizes the nucleus accumbens dopaminergic response to systemic
amphetamine: An in vivo microdialysis study in the rat. Brain Research, 605(2),
332-337. https://doi.org/10.1016/0006-8993(93)91761-G
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Alcohol Dependence, 51(1–2), 13-22. https://doi.org/10.1016/
S0376-8716(98)00063-5
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increases the conditioned incentive salience of sucrose reward: Enhancement of
reward “wanting” without enhanced “liking” or response reinforcement. Journal
of Neuroscience, 20(21), 8122-8130. https://doi.org/10.1523/
JNEUROSCI.20-21-08122.2000
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CHAPTER 14: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS | 603

CHAPTER 14:
BIOPSYCHOLOGY OF
PSYCHOLOGICAL
DISORDERS

Materials in this chapter were adapted from:

Hove, M. J., & Martinez, S. A. (2024). Biological psychology. ROTEL

(Remixing Open Textbooks with an Equity Lens) Project.
https://rotel.pressbooks.pub/biologicalpsychology/.

AND

Lim, A. (2021). Open Neuroscience Initiative

https://www.austinlim.com/open-neuroscience-initiative

Learning Objectives

• Describe the concept of psychological disorders

• Identify the formal criteria that must be met for thoughts,
feelings, and behaviors to be considered symptomatic of a
604 | CHAPTER 14: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS

psychological disorder
• Describe the main symptoms of schizophrenia, mood disorders,
anxiety, obsessive-compulsive disorder, and posttraumatic stress
disorder
• Describe the biological factors underlying schizophrenia, mood
disorders, anxiety, obsessive-compulsive disorder, and
posttraumatic stress disorder
14.1: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS OVERVIEW | 605

Most psychological researchers and clinicians agree that mental health is best
understood through a “biopsychosocial” perspective that considers how biological,
psychological, and sociocultural factors contribute to psychopathology. In this
biopsych book, we focus more on biological factors, like brain function and
genetics, that underlie psychological disorders and less on treatment-related aspects
that may be covered in courses on clinical or abnormal psychology.
Psychological disorders emerge from a complex interaction of biological, social,
and environmental factors. How exactly these factors interact to shape
psychological disorders for different individuals remains a challenging question.
The complexity of interacting factors and variability in symptom profiles across
individuals complicates the diagnosis of psychological disorders. In order to
promote consensus in diagnosing psychological disorders, psychological
researchers and clinicians have developed classification systems. These classification
systems traditionally focus on observable symptoms to diagnose a disorder. While
it’s widely recognized that biological factors contribute to psychological
functioning (Wyatt & Midkiff, 2006), biological evidence has been rarely used to
inform diagnosis. In earlier years, this was partly due to technological limitations
(e.g., in neuroimaging and genetic testing) that prevented scientists from
adequately examining biological bases of psychological disorders. Now, given
technological advances, scientists have begun exploring how biological factors,
such as brain structure, brain function, brain chemistry, and genetics, may lead to
psychological disorders and may eventually inform diagnosis.

What are Psychological Disorders?

Perhaps the simplest approach to conceptualizing psychopathology is to label
behaviors, thoughts, and inner experiences that are atypical, distressful,
dysfunctional, and sometimes even dangerous, as signs of a psychological disorder.
For example, if you ask a classmate for a date and you are rejected, you probably
would feel a little dejected. Such feelings would be normal. If you felt extremely
 606 | 14.1: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS
depressed—so much so that you lost interest in activities, had difficulty eating
or sleeping, felt utterly worthless, or contemplated suicide—your feelings would
be atypical, would deviate from the norm, and could signify the presence of a
psychological disorder. However, just because something is atypical, does not
necessarily mean it is disordered.1

The American Psychiatric Association

(APA) Definition of a Psychological
Disorder
A formal definition developed by the American Psychiatric Association (APA,
2022) characterizes a psychological disorder as a condition that consists of the
following:

• There are significant disturbances in thoughts, feelings, and

behaviors. A person must experience inner states (e.g., thoughts and/or
feelings) and exhibit behaviors that are clearly disturbed—that is, unusual,
but in a negative, self-defeating way. Often, such disturbances are troubling
to those around the individual who experiences them. For example, if an
individual is uncontrollably preoccupied by thoughts of germs and spends
hours each day bathing, their inner experiences and behaviors would be
considered atypical and negative (disturbed) and would likely trouble family
members.
• The disturbances reflect some kind of biological, psychological, or
developmental dysfunction. Disturbed patterns of inner experiences and
behaviors should reflect some flaw (dysfunction) in the internal biological,

1. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.1 What Are Psychological Disorders?. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-1-what-are-psychological-disorders License: CC
BY 4.0 DEED.
 14.1: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS OVERVIEW | 607
psychological, and developmental mechanisms that lead to normal, healthy
psychological functioning. For example, the hallucinations observed in
schizophrenia could be a sign of brain abnormalities.
• The disturbances lead to significant distress or disability in one’s life.
A person’s inner experiences and behaviors are considered to reflect a
psychological disorder if they cause the person considerable distress, or
greatly impair their ability to function as a normal individual (often referred
to as functional impairment, or occupational and social impairment). As an
illustration, a person’s fear of social situations might be so distressing that it
causes the person to avoid all social situations (e.g., preventing that person
from being able to attend class or apply for a job).
• The disturbances do not reflect expected or culturally approved
responses to certain events. Disturbances in thoughts, feelings, and
behaviors must be socially unacceptable responses to certain events that
often happen in life. For example, it is perfectly natural (and expected) that a
person would experience great sadness and might wish to be left alone
following the death of a close family member. Because such reactions are in
some ways culturally expected, the individual would not be assumed to
signify a mental disorder.2

Understanding the Classification

Systems of Psychological Disorders
A first step in the study of psychological disorders is systematically discerning
significant signs and symptoms. Arriving at a proper diagnosis—that is,
appropriately identifying and labeling a set of defined symptoms—is crucial. This

2. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.1 What Are Psychological Disorders?. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-1-what-are-psychological-disorders License: CC
BY 4.0 DEED.
608 | 14.1: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS
process enables professionals to use a common language and aids in
communication about the disorder with the patient, colleagues, and the public.
For these reasons, classification systems that systematically organize psychological
disorders are necessary. The current main classification system is the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision
(DSM-5-TR) published by the American Psychiatric Association (2022). Another
classification system used for mental and behavioral disorders is the International
Classification of Diseases (ICD-11) and is primarily used by the World Health
Organization to support the global comparison of morbidity statistics. While the
ICD-11 is also used in medical settings around the globe, the DSM-5 remains
the main instrument for diagnosis. Despite its dominance in the field, using the
DSM-5 for clinical diagnosis has some limitations. For example, individuals
displaying very different symptoms may be diagnosed with the same psychological
disorder, or conversely, individuals displaying very similar symptoms may be
diagnosed with different disorders. Given this variation in symptom display and
the DSM-5’s focus on mapping symptoms onto psychological disorders, it makes
sense that scientists are examining how biological factors may inform
understanding and diagnosing psychological disorders.
Characterizing psychological disorders based on only symptoms is common for
clinical purposes, but is limited for research purposes. For example, the variability
of symptom profiles within and across psychological disorders, as well as
comorbidity (the simultaneous presence of multiple disorders), makes it
challenging for researchers to investigate the neurobiological mechanisms
underlying a specific disorder. Accordingly, the Research Domain Criteria
(RDoC) is a research framework used to investigate mental disorders and is favored
by granting agencies like the National Institute of Mental Health (NIMH) (Insel
et al., 2010). Rather than using diagnostic categories (like “bipolar” or
“schizophrenia”), the RDoC considers psychopathology in the context of six major
domains of neurobehavioral functioning: arousal/regulatory systems, positive
valence systems, negative valence systems, social processes, cognitive systems, and
sensorimotor systems. Each domain is studied across the full spectrum of
functioning in terms of molecular, genetic, behavioral, physiological, and self-
report measures. The RDoC framework also prioritizes studying how biological
and behavioral development and environmental and cultural factors may
contribute to psychopathology. Ultimately, the RDoC framework advances our
 14.1: BIOPSYCHOLOGY OF PSYCHOLOGICAL DISORDERS
understanding about how constellations of different factors, both in isolation and
together, may contribute to the development of psychopathology.
In the rest of this chapter, we give an overview of some common psychological
disorders and their underlying biological factors. Overall, there are hundreds of
psychological disorders (characterized by the DSM-5 in over 1000 pages). Here
we cover a few broad classes that are prevalent and interesting to students:
schizophrenia, mood disorders including depression and bipolar disorder, anxiety,
obsessive-compulsive disorder, and post-traumatic stress disorder.3

3. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.2 Diagnosing and Classifying Psychological Disorders. In Psychology 2e. OpenStax. Access for free
at https://openstax.org/books/psychology-2e/pages/15-2-diagnosing-and-classifying-psychological-
disorders License: CC BY 4.0 DEED.
 610 | 14.2: ANXIETY DISORDERS

What is anxiety? Most of us feel some anxiety almost every day of our lives.
Maybe you have an important upcoming test, presentation, big game, or date.
Anxiety can be defined as a negative mood state that is accompanied by bodily
symptoms such as increased heart rate, muscle tension, a sense of unease, and
apprehension about the future (APA, 2013; Barlow, 2002) (Figure 14.1). In many
ways, the anxiety response is similar to the fight-or-flight response observed during
sympathetic nervous system activity (Lim, 2021).
However, a clinical diagnosis of anxiety is different from the passing anxiety that
we all experience. Anxiety disorders are characterized by excessive and persistent
fear and anxiety, and by related disturbances in behavior (APA, 2013). Anxiety
disorders cause considerable distress. Anxiety disorders are very common:
approximately 25–30% of the U.S. population meets the criteria for at least one
anxiety disorder during their lifetime (Kessler et al., 2005). Also, anxiety disorders
are much more common in women than they are in men; within a 12-month
period, around 23% of women and 14% of men will experience at least one anxiety
disorder (National Comorbidity Survey, 2007). Anxiety disorders are the most
frequently occurring class of mental disorders and are often comorbid with each
other and with other mental disorders (Kessler et al., 2009).1

1. This section contains material adapted from: Barlow, D. H. & Ellard, K. K. (2024). Anxiety and
related disorders. In R. Biswas-Diener & E. Diener (Eds.), Noba textbook series: Psychology.
Champaign, IL: DEF publishers. Retrieved from http://noba.to/xms3nq2c License: CC BY-NC-SA
4.0 DEED - Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 15.4 Anxiety Disorders. In
Psychology 2e. OpenStax. Access for free at https://openstax.org/books/psychology-2e/pages/
15-4-anxiety-disorders License: CC BY 4.0 DEED.
 14.2: ANXIETY DISORDERS | 611

Figure 14.1. Common physical symptoms of anxiety are feeling dizzy, unsteady,
and lightheaded; shortness of breath; chest pain, palpitations and /or accelerated
heart rate; and nausea or abdominal distress. People may also experience
sweating, trembling, feelings of faintness, or a fear of losing control, among
other symptoms. CREDIT: Physical manifestations of a panic attack © OpenStax
is licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Neural mechanisms underlying anxiety

disorders
Anxiety disorders are associated with genetic factors and abnormalities in brain
circuits that regulate and process emotion. Family and twin studies indicate that
anxiety disorders have a moderate genetic heritability (~30-40%; making it less
heritable than schizophrenia or bipolar disorder) (Hettema et al., 2001). More than
612 | 14.2: ANXIETY DISORDERS
200 genes are associated with anxiety disorders, and distinct gene clusters exist
for different anxiety subtypes such as generalized anxiety disorder, social anxiety
disorder, and panic disorder. The identified genes are expressed in brain regions
(e.g., the basal ganglia, hippocampus, and amygdala) that are linked to anxiety and
emotion processing (Karunakaran & Amemori, 2023).
The brain circuits underlying anxiety involve bottom-up signals from the
amygdala that indicate presence of potentially threatening stimuli, and top-down
control mechanisms from the prefrontal cortex that signal the emotional salience
of stimuli (Nuss, 2015). The amygdala is involved in triggering panic attacks
through its central nucleus, which connects with brain structures, particularly in
the brainstem, that control autonomic functions such as respiration and heart rate.
Animal studies have shown that electrically or pharmacologically stimulating the
amygdala’s central nucleus produces behaviors associated with panic (Herdade et
al., 2006). People with an anxiety disorder show hyperactive amygdala response to
stimuli (Etkin & Wager, 2007); these bottom-up signals from the amygdala might
be over-indicating the presence of potentially threatening stimuli. “Top-down”
control originating from prefrontal areas can regulate emotion by inhibiting
amygdala output; however, neuroimaging studies show that people with anxiety
disorders have reduced activation in prefrontal circuits (Etkin, 2010), and
interestingly they required higher levels of prefrontal activation to successfully
reduce negative emotions (Nuss, 2015).
The exact cause of anxiety is still unknown. One theory suggests that anxiety
is a maladaptive evolutionary response to our modern living conditions. The
argument is based on the observation that an anxiety response looks a lot like
a mild version of the fight-or-flight, sympathetic nervous system response: both
elicit cardiovascular and respiratory changes. For 99% of the evolutionary history
of Homo sapiens, we benefited from the sympathetic nervous system as a reflex
to improve the odds of survival in dangerous situations. However, our modern
civilized living conditions over the past few centuries have been very tame in
comparison to the risks that our earlier ancestors experienced. The relative ease of
living has let the main function of the sympathetic nervous system fall into disuse.
The theory argues that people experience GAD because a part of them encourages
sustained activity in the sympathetic nervous system. Although thought-
provoking, this theory can’t be tested experimentally and offers no explanation
about a biological mechanism that can help to develop a therapy (Lim, 2021).
 14.2: ANXIETY DISORDERS | 613
Treatment
Pharmacologically, there are a wide variety of drugs that can be used to treat
anxiety, broadly called anxiolytics. Research examining the role of
neurotransmitters in anxiety-related circuits has focused largely on GABA, the
primary inhibitory neurotransmitter in the brain that reduces neuronal
excitability. Insufficient GABAergic inhibition of neurons might drive the
amygdala hyperactivity seen in anxiety disorders. Therefore GABA receptors are a
primary target for anti-anxiety medication. In animal studies, injections of GABA
agonists (activators) into the amygdala decreased measures of fear and anxiety
(Sanders & Shekhar, 1995). GABA receptors can be modulated by a class of drugs
called benzodiazepines, that include well-known brand names like Valium, Xanax,
and Ativan. Benzodiazepines work by binding to the GABAA receptor complex,
which increases the total conduction of chloride (Cl-) ions across the cell
membrane. The increased concentration of negative chloride ions hyperpolarizes
the neuron’s membrane potential, thereby inhibiting it and making it less likely
to fire. Through this increased neuronal inhibition, benzodiazepines can reduce
anxiety and reduce the amygdala’s response to aversive stimuli (Del-Ben et al.,
2012).
Benzodiazepines were the most common pharmacological treatment for anxiety
for many decades. But due to their highly addictive properties and lack of long-
term effectiveness, benzodiazepines are now recommended only for short-term
treatments of anxiety (2-4 weeks). While GABA is an important target for
modulating anxiety responses in the amygdala, other neurotransmitters such as
serotonin, endocannabinoids, and oxytocin, are also important. Current treatment
guidelines for anxiety disorders now recommend antidepressants, including
serotonin reuptake inhibitors (SSRIs) or serotonin–noradrenaline reuptake
inhibitors (Nuss, 2015). Opioids and norepinephrine inhibitors can also decrease
anxiety (Lim, 2021).
For non-pharmacological treatments, cognitive behavioral therapy (CBT) is well
established, and successful CBT treatment of anxiety disorders has been shown to
stop amygdala hyperactivation (Straube et al., 2006). Finally, even placebos have
been shown to decrease anxiety; when individuals thought they received an anti-
anxiety drug, some showed a lower anxiety response to emotional pictures. Their
614 | 14.2: ANXIETY DISORDERS
placebo response was associated with decreased activation in the amygdala, as well
as increased activation in a modulatory system including the anterior cingulate and
the prefrontal cortex (Petrovic et al., 2005). In sum, irrespective of the technique,
anxiety can be reduced by decreasing activation in the amygdala or increasing
activation in modulatory or emotion-regulating circuits, and ongoing research
seeks to optimize how these networks can be targeted to manage anxiety.
 14.3: POST-TRAUMATIC STRESS DISORDER | 615

Extremely stressful or traumatic events, such as combat, crimes, and natural

disasters, place the people who experience them at an increased risk for developing
psychological disorders such as post-traumatic stress disorder (PTSD). A
diagnosis of PTSD requires that the individual must be exposed to actual or
threatened death, serious injury, or sexual violence. This strict diagnostic criterion
differs from a common misperception that PTSD could stem from lesser stressors,
like for instance, an upsetting but non-violent romantic breakup. Symptoms of
PTSD include intrusive and distressing memories of the event, flashbacks (states
that can last from a few seconds to several days, during which the individual relives
the event and behaves as if the event were occurring at that moment [APA, 2013]),
avoidance of stimuli connected to the event, persistently negative emotional states
(e.g., fear, anger, guilt, and shame), feelings of detachment from others, irritability,
proneness toward outbursts, and an exaggerated startle response (jumpiness). For
PTSD to be diagnosed, these symptoms must occur for at least one month.
Roughly 6% of adults in the United States, including 10-12% of women and
5-6% of men, experience PTSD in their lifetime (Goldstein et al., 2016; Olff,
2017), with higher rates among people exposed to mass trauma and people whose
jobs involve duty-related trauma exposure (e.g., police officers, firefighters, and
emergency medical personnel) (APA, 2013). Nearly 21% of residents of areas
affected by Hurricane Katrina suffered from PTSD one year following the
hurricane (Kessler et al., 2008), and 12.6% of Manhattan residents were observed
as having PTSD 2–3 years after the 9/11 terrorist attacks (DiGrande et al., 2008).

Neural mechanisms underlying

post-traumatic stress disorder
Both the hippocampus and amygdala are involved in emotional processing and
have been linked to PTSD (Figure 14.2). Individuals with PTSD show marked
reductions in the volume of several parts of the hippocampus, which may result
from decreased levels of neurogenesis and dendritic branching (the generation of
616 | 14.3: POST-TRAUMATIC STRESS DISORDER
new neurons and the generation of new dendrites in existing neurons, respectively)
(Wang et al., 2010). However, after effective pharmacological treatment or
cognitive-behavioral therapy for PTSD, hippocampus size increases (Bremner &
Vermetten, 2004; Levy-Gigi et al., 2013).
Recent work highlights how threat reactivity, the hippocampus, and arousal-
related norepinephrine (NE) release may interact to shape PTSD severity. Prior
work highlights how threat reactivity (i.e., how someone responds to threat-related
stressors) is heightened in PTSD. Research in both animals and humans indicates
that norepinephrine, a hormone released in response to stress, is associated with
abnormal threat reactivity in PTSD (Naegeli et al., 2018; Southwick et al. 1999).
Critically, threat is also known to alter hippocampal functioning, such that
reduced hippocampal activity during states of high threat is a reliable neural
signature in individuals with PTSD (Eichenbaum, 2001; Hayes et al., 2011). To
clarify how threat may disrupt hippocampal functioning, a recent review proposed
that threat-related arousal, through heightened NE release, disrupts hippocampal
functioning by shifting information processing away from the hippocampus and
toward other learning structures involved in emotional memories, such as the
amygdala (Clewett & Murty, 2019).
The Advanced Understanding of RecOvery afteR traumA (AURORA) study
is a multi-site longitudinal study that assesses individuals who present to US
emergency departments within 72 hours of exposure to trauma and tracks their
brain and cognitive development for the following year (McClean et al., 2020).
This landmark effort will ultimately generate a comprehensive collection of brain,
biospecimen, and behavioral measures to better characterize trauma-related
disorders, such as PTSD.
To begin exploring the relationship between threat reactivity, hippocampal
functioning, arousal-related NE systems, and PTSD symptoms, one AURORA
study measured responses to fearful faces in the fMRI scanner and fear-based
startle responses to threat cues (a marker of arousal-related NE release) (Tanriverdi
et al., 2022). People with more severe PTSD symptoms two weeks after trauma
showed weaker hippocampal responses to threat, and hippocampus response was
especially reduced in those with a greater fear-based startle. This suggests that
excessive physiological arousal from threat may divert information processing away
from the hippocampus. These findings emphasize the relationship between threat
reactivity, arousal, and hippocampal functioning in understanding how PTSD
 14.3: POST-TRAUMATIC STRESS DISORDER | 617
may or may not emerge after exposure to trauma. Finally, whether or not PTSD
emerges is also influenced by genetics, as genes play an important role in the fear
and stress circuitry (Banerjee et al., 2017).

Figure 14.2. Brain regions typically associated with post-traumatic

stress disorder include the prefrontal cortex, hippocampus, cingulate
cortex, and amygdala. CREDIT: Brain PTSD regions © Wikipedia is licensed
under a CC BY (Attribution) license

Text Attributions
This section contains material adapted from:
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 10.4 Emotion. In
Psychology 2e. OpenStax. Access for free at https://openstax.org/books/
psychology-2e/pages/10-4-emotion License: CC BY 4.0 DEED.
 618 | 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS

Obsessive-compulsive and related disorders are a group of overlapping

disorders that generally involve intrusive, unpleasant thoughts or repetitive
behaviors. Many of us experience unwanted thoughts from time to time (e.g.,
craving double cheeseburgers when dieting), and many of us engage in repetitive
behaviors on occasion (e.g., pacing when nervous). However, obsessive-compulsive
and related disorders elevate the unwanted thoughts and repetitive behaviors to
a status so intense that these cognitions and activities disrupt daily life. Included
in this category are obsessive-compulsive disorder (OCD), body dysmorphic
disorder, and hoarding disorder.1

OCD is marked by the presence of obsessions, compulsions, or both, that are time-
consuming (e.g., more than 1 hour per day), and not attributable to a substance
like a drug, another medical condition, or another mental disorder (APA, 2013).
Obsessions are more than just unwanted thoughts that seem to randomly jump
into our head from time to time, such as recalling an insensitive remark a coworker
made recently, and they are more significant than the minor day-to-day worries we
might have. Rather, obsessions are characterized as persistent, unintentional, and
unwanted thoughts and urges that are highly intrusive, unpleasant, and distressing
(APA, 2013). Common obsessions include concerns about germs and
contamination, doubts (“Did I turn the water off?”), order and symmetry (“I
need all the spoons in the tray to be arranged a certain way”), and urges that
are aggressive or lustful. Usually, the person knows that such thoughts and urges
are irrational and thus tries to suppress or ignore them, but has an extremely

1. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.5 Obsessive-Compulsive and Related Disorders. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-5-obsessive-compulsive-and-related-disorders
License: CC BY 4.0 DEED.
 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS | 619
difficult time doing so. These obsessive symptoms sometimes overlap, such that
someone might have both contamination and aggressive obsessions (Abramowitz
& Siqueland, 2013).

Figure 14.3. (a) Repetitive hand washing and (b) checking (e.g., that a
door is locked) are common compulsions among those with
obsessive-compulsive disorder. CREDIT: hand washing and door check ©
OpenStax is licensed under a CC BY-NC-SA (Attribution NonCommercial
ShareAlike) license

Compulsions are repetitive and ritualistic acts that are typically carried out
primarily as a means to minimize the distress that obsessions trigger or to reduce
the likelihood of a feared event (APA, 2013). Compulsions often include such
behaviors as repeated and extensive hand washing, cleaning, checking (e.g., that a
door is locked), and ordering (e.g., lining up all the pencils in a particular way),
and they also include such mental acts as counting or reciting something to oneself
(Figure 14.3). Compulsions characteristic of OCD are not performed out of
pleasure, nor are they connected in a realistic way to the source of the distress
or feared event. Ultimately, a difficult cycle of obsessive thoughts, anxiety,
compulsions, and temporary relief tends to deeply affect individuals with OCD
(Figure 14.4). Approximately 2.3% of the U.S. population will experience OCD
in their lifetime (Ruscio et al., 2010) and, if left untreated, OCD tends to be
 620 | 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS
a chronic condition creating lifelong interpersonal and psychological problems
(Norberg et al., 2008).2

2. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.5 Obsessive-Compulsive and Related Disorders. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-5-obsessive-compulsive-and-related-disorders
License: CC BY 4.0 DEED.
 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS | 621

Figure 14.4. Visualizing the typical cycle of obsessive-compulsive

disorder. [Image adapted from: https://psychcentral.com/ocd/ocd-cycle].
CREDIT: The OCD Cycle © Michael Hove is licensed under a CC BY-NC-SA
(Attribution NonCommercial ShareAlike) license

Body Dysmorphic Disorder

A disorder that shares similar features to OCD is body dysmorphic disorder,
wherein an individual is preoccupied with a perceived flaw in physical appearance
 622 | 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS
that is either nonexistent or barely noticeable to other people (APA, 2013). These
perceived physical defects cause people to think they are unattractive, ugly, hideous,
or deformed. These preoccupations can focus on any bodily area, but they typically
involve the skin, face, or hair. The preoccupation with imagined physical flaws
drives the person to engage in repetitive and ritualistic behavioral and mental acts,
such as constantly looking in the mirror, trying to hide the offending body part,
comparisons with others, and, in some extreme cases, cosmetic surgery (Phillips,
2005). An estimated 2.4% of the adults in the United States meet the criteria for
body dysmorphic disorder, with slightly higher rates in women than in men (APA,
2013).3

Hoarding Disorder
Although hoarding was traditionally considered a symptom of OCD, considerable
evidence suggests that hoarding represents an entirely different disorder (Mataix-
Cols et al., 2010). People with hoarding disorder cannot bear to part with
personal possessions, regardless of how valueless or useless these possessions are.
As a result, these individuals accumulate excessive amounts of usually worthless
items that clutter their living areas. Often, the quantity of cluttered items is so
excessive that the person is unable to use their kitchen, or sleep in their bed. People
who suffer from this disorder have great difficulty parting with items because they
believe the items might be of some later use, or because they form a sentimental
attachment to the items (APA, 2013). Importantly, a diagnosis of hoarding
disorder is made only if the hoarding is not caused by another medical condition
and is not a symptom of another disorder (e.g., schizophrenia) (APA, 2013).4

3. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.5 Obsessive-Compulsive and Related Disorders. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-5-obsessive-compulsive-and-related-disorders
License: CC BY 4.0 DEED.
4. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.5 Obsessive-Compulsive and Related Disorders. In Psychology 2e. OpenStax. Access for free at
 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS | 623

Neural and genetic mechanisms

underlying obsessive-compulsive and
related disorders
The results of family and twin studies suggest that OCD has a moderate genetic
component. The disorder is five times more frequent in the first-degree relatives
of people with OCD than in people without the disorder (Nestadt et al., 2000).
Additionally, the concordance rate of OCD is 57% for identical twins and 22%
for fraternal twins (Bolton et al., 2007). Studies have implicated about two dozen
potential genes that may be involved in OCD; these genes regulate the function
of three neurotransmitters: serotonin, dopamine, and glutamate (Pauls, 2010).
Many of these studies included small sample sizes and have yet to be replicated, so
additional research is needed.
A brain region believed to play a critical role in OCD is the orbitofrontal cortex
(Kopell & Greenberg, 2008) (Figure 7). In people with OCD, the orbitofrontal
cortex becomes especially hyperactive when they are provoked with tasks in which,
for example, they are asked to look at a photo of a toilet or of pictures hanging
crookedly on a wall (Simon et al., 2010). The orbitofrontal cortex is part of a
group of brain regions that, collectively, is called the OCD circuit and influences
the perceived emotional value of stimuli and the selection of both behavioral and
cognitive responses (Graybiel & Rauch, 2000). As with the orbitofrontal cortex,
other regions of the OCD circuit (e.g., dorsolateral prefrontal cortex, precuneus,
and left superior temporal gyrus) show heightened activity during symptom
provocation (Rotge et al., 2008), which suggests that abnormalities in these regions
may contribute to the symptoms of OCD (Saxena et al., 2001). Consistent with
this network explanation, people with OCD show substantially higher
connectivity of the orbitofrontal cortex with other regions of the OCD circuit
(Beucke et al., 2013).

https://openstax.org/books/psychology-2e/pages/15-5-obsessive-compulsive-and-related-disorders
License: CC BY 4.0 DEED.
624 | 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS

Figure 14.5.. Different regions of the brain are associated with

obsessive-compulsive disorder and related disorders–for example, the
anterior cingulate cortex for hoarding disorder; the prefrontal cortex
for for body dysmorphc disorder; and the orbitofrontel cortex for
obsessive-compulsive disorder. CREDIT: Brain regions © OpenStax is
licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

Neuroimaging studies have also highlighted the role of the prefrontal cortex in
OCD and body dysmorphic disorder. Individuals with body dysmorphic disorder
often show abnormal perception of body areas. An fMRI study showed that when
people with body dysmorphia viewed faces, they had abnormal prefrontal cortex
activity, which may be associated with the perceptual distortions seen in body
dysmorphic disorder (Feusner et al., 2007).
These neuroimaging findings highlight the importance of brain dysfunction
in OCD and body dysmorphic disorder. However, neuroimaging approaches are
limited by their inability to explain differences in obsessions and compulsions, and
correlations between brain abnormalities and OCD symptoms is not evidence of
causality (Abramowitz & Siqueland, 2013).
Several approaches are commonly used to treat OCD. One effective treatment is
a form of Cognitive Behavioral Therapy called exposure and response prevention.
 14.4: OBSESSIVE-COMPULSIVE AND RELATED DISORDERS | 625
In therapy sessions, individuals with OCD are gradually exposed to situations or
objects designed to mildly provoke their obsessions in a safe environment and
are instructed to avoid their compulsive responses. Eventually, the high anxiety
situations become less anxiety provoking and more manageable. Exposure and
response is also very effective with panic disorder (which is an anxiety disorder).
Cognitive Behavioral Therapy is often used in conjunction with pharmacological
treatments for OCD. Selective serotonin reuptake inhibitors (SSRIs) are used to
treat OCD, but often at higher doses than are used to treat depression. Finally,
OCD can be treated effectively with brain stimulation, including both non-
invasive techniques like transcranial magnetic stimulation that uses magnetic
pulses to stimulate the prefrontal cortex (Trevizol et al., 2016), and invasive
techniques like deep brain stimulation that requires surgically implanting a device
deep in the brain that can modulate activity in the OCD brain circuit (Alonso et
al., 2015).5

5. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.5 Obsessive-Compulsive and Related Disorders. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-5-obsessive-compulsive-and-related-disorders
License: CC BY 4.0 DEED.
 626 | 14.5: MOOD DISORDERS

Mood disorders are characterized by severe disturbances in mood and

emotions—most often depression, but also mania and elation (Rothschild, 1999).
All of us experience fluctuations in our moods and emotional states, and often
these fluctuations are caused by events in our lives. We become elated if our favorite
sports team wins the big game and dejected if a romantic relationship ends or if
we lose our job. At times, we feel fantastic or miserable for no clear reason. People
with mood disorders also experience mood fluctuations, but their fluctuations are
extreme, may last longer, distort their outlook on life, and impair their ability to
function.
The DSM-5 includes two general categories of mood disorders: depressive
disorders and bipolar disorders. Depressive disorders are a group of disorders in
which depression is the main feature. Depression is a vague term that, in everyday
language, refers to an intense and persistent sadness. Depression is a heterogeneous
mood state—it consists of a broad spectrum of symptoms that range in severity.
People with depressive disorders often feel sad, discouraged, and hopeless. These
individuals lose interest in activities once enjoyed, often experience a decrease in
drives such as hunger and sex, and frequently doubt personal worth. Depressive
disorders vary by degree, but this chapter highlights the most well-known: major
depressive disorder (sometimes called unipolar depression).
Bipolar disorder and related disorders are a group of disorders in which
mania is the defining feature. Mania is a state of extreme elation and agitation.
When people experience mania, they may become extremely talkative, behave
recklessly, or attempt to take on many tasks simultaneously. The most recognized
of these disorders is bipolar disorder.1

1. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.7 Mood and Related Disorders. In Psychology 2e. OpenStax. Access for free at
https://openstax.org/books/psychology-2e/pages/15-7-mood-and-related-disorders License: CC BY
4.0 DEED.
 14.5: MOOD DISORDERS | 627

Neural mechanisms underlying

depression
Though depression involves an overall reduction in brain activity, some parts of
the brain are more affected than others. In brain-imaging studies using PET scans,
people with depression display abnormally low activity in the prefrontal cortex,
a brain region involved in cognitive control, decision-making, planning, and
emotion regulation.
Abnormal activity in the prefrontal cortex, especially in its lateral, orbitofrontal,
and ventromedial regions, often correlates with the severity of the depression. The
lateral prefrontal cortex is primarily involved in cognitive control, which refers
to the intentional selection of cognitive operations, such as attention, inhibition,
and working memory, in order to carry out behavior. A situation that may require
cognitive control is studying for an exam while resisting the urge to check social
media. The orbitofrontal cortex is mainly involved in decision-making and
reward valuation. This is especially relevant for deferring immediate gratifications
in order to obtain greater long-term benefits. The ventromedial prefrontal
cortex is implicated in a broad range of social and emotional processes such as
value-based decision-making, regulation of negative emotions, and processing of
self-relevant information. Indeed, disruption to these brain regions may contribute
to hallmark characteristics of mood disorders, such as a bias toward negative affect
and increased self-focus.
Some research indicates that the left prefrontal cortex is involved in establishing
positive feelings and the right prefrontal cortex is involved in negative feelings.
Typically, the left prefrontal cortex is thought to help to inhibit the negative
emotions generated by limbic structures such as the amygdala, which show
abnormally high activity in patients with depression. In patients who respond
positively to antidepressants, this amygdala overactivity is reduced. But when the
amygdala remains hyperactive despite antidepressant treatment, that patient is
likely to relapse into depression. Similarly, individuals with reduced hippocampal
volume seem to be more prone to relapse (Young, 2021).
Emerging work has also begun to characterize the genetic contributions to
depressive disorders. Studies have shown that heritability for depressive disorders
is about 40% and the risk of developing depression when a family member has
 628 | 14.5: MOOD DISORDERS
had depression is 1.5-3 times higher than the general population (Fan et al., 2020;
Kendler et al., 2009). Nevertheless, depressive disorders are still thought to arise
from complex gene-environment interactions.2

Neural mechanisms underlying bipolar

disorders
Research on the etiology (i.e., cause), course, and treatment of bipolar disorders
(BD) have made major advances, but the mechanisms underlying episode onset
and relapse remain poorly understood. BD has biological causes and is highly
heritable (McGuffin et al., 2003). One may argue that high heritability
demonstrates that BD is fundamentally a biological phenomenon. However, the
course of BD varies greatly both within a person across time and across people
(Johnson, 2005). The triggers that determine how and when this genetic
vulnerability is expressed are not yet understood; however, evidence suggests that
psychosocial triggers may play an important role in BD risk (Johnson et al., 2008;
Malkoff-Schwartz et al., 1998). Additionally, growing research shows that bipolar
disorders and schizophrenia share similar brain abnormalities and genetic
substrates, which has prompted some researchers to suggest that bipolar disorders
may be closer to psychotic disorders than to depression (Birur et al., 2017;
Lichtenstein et al., 2009).
Biological explanations of BD have also focused on brain function. Many of
the studies using fMRI to characterize BD have focused on processing emotional
stimuli based on the idea that BD is fundamentally a disorder of emotion (APA,
2000). Findings show that regions of the brain involved in emotional processing
and regulation are activated differently in people with BD relative to healthy
controls (Altshuler et al., 2008; Hassel et al., 2008; Lennox et al., 2004). However,

2. This section contains material adapted from: Duboc, B. (2002). The Brain from Top to Bottom.
Mental Disorders: Depression and Manic Depression: Parts of the Brain That Slow Down or Speed
Up in Depression. Access for free at https://thebrain.mcgill.ca/ License: CC (Copyleft).
 14.5: MOOD DISORDERS | 629
in individuals with BD, studies examining how different brain regions respond
to emotional stimuli show mixed results. These mixed findings are partly due to
samples consisting of participants who are at various phases of illness at the time of
testing (manic, depressed, inter-episode) and small sample sizes make comparisons
between subgroups difficult. Additionally, the use of typical lab-based stimuli,
such as facial expressions of anger, may not elicit a sufficiently strong brain
response.
Within the psychosocial level, research has focused on the environmental
contributors to BD. A series of studies shows that environmental stressors,
particularly severe stressors (e.g., loss of a significant relationship), can adversely
impact the course of BD. Following a severe life stressor, people with BD have
substantially increased risk of relapse (Ellicott et al., 1990) and suffer more
depressive symptoms (Johnson et al., 1999). Interestingly, positive life events can
also adversely impact the course of BD. People with BD suffer more manic
symptoms after life events involving attainment of a desired goal (Johnson et al.,
2008). Such findings suggest that people with BD may have a hypersensitivity to
rewards.

Treatment
Mood disorders are also thought to be associated with abnormal levels of certain
neurotransmitters, particularly serotonin and norepinephrine (Thase, 2009).
These neurotransmitters are important regulators of the bodily functions that
are disrupted in mood disorders, including appetite, sex drive, sleep, arousal, and
mood.

A wide variety of drugs are used for the treatment of depression. The first-
generation antidepressants were developed in the 1950s and 1960s. These drugs
acted to increase the action of the monoamine neurotransmitters: primarily
dopamine, norepinephrine, and serotonin. Our body uses an enzyme called
monoamine oxidase (MAO) which degrades these chemicals into inactive
components that do not signal at receptors. These first generation antidepressants
block the action of MAO; biochemically, we call them monoamine oxidase
inhibitors (MAOIs). In the presence of an MAOI, the neurotransmitter signal
 630 | 14.5: MOOD DISORDERS
remains in the synapse longer, similar to how an acetylcholinesterase inhibitor
increases ACh signalin (Lim, 2021).
Most of the MAOIs, while sometimes effective, have fallen out of fashion
clinically because of the adverse side effects associated with their biochemical
activity (however, they are still commonly used in treatment of Parkinson’s
disease). Some of them interact dangerously with foods rich in tyramine
(particularly fermented foods, such as aged cheeses or beer, as well as beans and
processed meats), an amino acid that is degraded by MAO. Excess tyramine can
activate the sympathetic nervous system, and body levels of tyramine can rise to
dangerous levels in the presence of an MAOI, leading to adverse cardiovascular
events like stroke. Many of the common MAOIs, like phenelzine and
isocarboxazid, can be damaging to the liver. Some MAOIs also produce unwanted
side effects, such as psychosis or nausea (Lim, 2021).
A second-generation class of antidepressant drugs called the tricyclic
antidepressants (TCAs), named for the shape of their chemical structure, was
also developed around this time. They generally act as monoamine reuptake
inhibitors, resulting in elevated neurotransmitter signaling. Unfortunately, these
tricyclics may produce many severe side effects, such as seizures, tachycardia, and
heart attacks, so prescriptions must be monitored closely. The tricyclics are still
prescribed today for several other nervous system disorders, ranging from insomnia
to neuropathic pain, but due to their potential cardiotoxicity, they are not often
the first line of treatment in depression (Lim, 2021).

One of the most common classes of medications that are currently prescribed
for MDD are called are third-generation antidepressants, and are focused on
boosting the signaling activity of serotonin (Lim, 2021). These selective serotonin
reuptake inhibitors (SSRIs) inhibit or block the reuptake of serotonin back into
the presynaptic cell, which in turn preserves high levels of serotonin in the synapse
that may ultimately reduce depressive symptoms (Figure 14.5). However, recent
findings show that while serotonin levels rise as quickly as an hour after taking an
SSRI, it typically takes several weeks for SSRIs to actually improve symptoms.3

3. This section contains material adapted from: Gershon, A. & Thompson, R. (2024). Mood disorders.
 14.5: MOOD DISORDERS | 631

Figure 14.5. Many medications designed to treat mood disorders work

by altering neurotransmitter activity in the neural synapse. Selective
serotonin reuptake inhibitors (SSRIs), for example, inhibit the reuptake
of serotonin back into the presynaptic cell, which preserves high levels
of serotonin in the synapse. CREDIT: Neurotransmitter activity © OpenStax is
licensed under a CC BY-NC-SA (Attribution NonCommercial ShareAlike) license

In R. Biswas-Diener & E. Diener (Eds.), Noba textbook series: Psychology. Champaign, IL: DEF
publishers. Retrieved from http://noba.to/aqy9rsxe License: CC BY-NC-SA 4.0 DEED
632 | 14.5: MOOD DISORDERS
For severe or treatment-resistant depression, electroconvulsive therapy (ECT)
is a treatment option. Introduced in 1938, the procedure has since been refined
over the years (it is currently performed under anesthesia) and is considered to be
well-tolerated and highly effective. However, side effects include aches, nausea, and
memory loss (Lim, 2021).
 14.6: SCHIZOPHRENIA | 633

Schizophrenia is a psychological disorder that is characterized by major

disturbances in thought, perception, emotion, and behavior. About 1% of the
population experiences schizophrenia in their lifetime, and the disorder is usually
first diagnosed during early adulthood (early to mid-20s). Many people with
schizophrenia report significant difficulties in some day-to-day activities, such as
holding a job, paying bills, caring for oneself, and maintaining relationships with
others. Although presentation of schizophrenia varies widely, symptoms of
schizophrenia fall into three categories: 1) positive symptoms (symptoms that are
“added”), which include hallucinations and delusions; 2) negative symptoms
(symptoms that are “subtracted” or taken away), which include flat affect and
social withdrawal; and 3) disorganized symptoms, which include disorganized
speech and behavior (APA, 2022).
A hallucination is a perceptual experience that occurs in the absence of external
stimulation. Auditory hallucinations (e.g., hearing voices) occur in roughly two-
thirds of patients with schizophrenia and are by far the most common form of
hallucination (Andreasen, 1987).
Delusions are beliefs that are contrary to reality and are firmly held even in the
face of contradictory evidence. Paranoid delusions refer to the (false) belief that
other people are plotting to harm them. For example, someone with schizophrenia
may believe that their mother is plotting with the FBI to poison their coffee.
People with schizophrenia also may hold grandiose delusions, which refer to
beliefs that one holds special power, unique knowledge, or is extremely important
(e.g., claiming to be Jesus Christ or be a great philosopher). Another type of
delusion is somatic delusion, which is the belief that something highly abnormal
is happening to one’s body (e.g., that one’s kidneys are being eaten by
cockroaches).
Negative symptoms refer to a reduction or absence of normal behaviors related
to motivation, interest, or expression (Correll & Schooler, 2020). Negative
symptoms of schizophrenia include withdrawal from social relationships, reduced
speaking, blunted emotion, and reduced experience of pleasure.
Disorganized thinking refers to disjointed and incoherent thought
 634 | 14.6: SCHIZOPHRENIA
processes—usually detected by what a person says. The person might ramble,
exhibit loose associations (jump from topic to topic), or talk in a way that is so
disorganized and incomprehensible that it seems as though the person is randomly
combining words.
Disorganized or abnormal motor behavior refers to unusual behaviors and
movements: becoming unusually active, exhibiting silly child-like behaviors
(giggling and self-absorbed smiling), engaging in repeated and purposeless
movements, or displaying odd facial expressions and gestures. In some cases, the
person will exhibit catatonic behaviors, which show decreased reactivity to the
environment, such as posturing, in which the person maintains a rigid and bizarre
posture for long periods of time, or catatonic stupor, a complete lack of movement
and verbal behavior.1

Neural mechanisms underlying

schizophrenia
Scientists have identified several neural and biological signatures of schizophrenia.
A highly consistent abnormality in brain structure in schizophrenia is enlarged
ventricles (the cerebrospinal fluid-filled spaces in the brain). The ventricles in
individuals with schizophrenia average around 30% larger than in controls,
showing brain shrinkage in schizophrenia (Figure 14.6) (Horga et al., 2011).
Individuals with schizophrenia tend to have smaller brain volumes of some
subcortical structures including the hippocampus, amygdala, and thalamus (van
Erp et al., 2016) and thinner cortex especially in the frontal and temporal lobe
regions (van Erp et al., 2018). Functional neuroimaging studies have shown that
patients with schizophrenia display hyperactivity in the hippocampus, a neural
structure involved in learning and memory (Kraguljac et al., 2021). This

1. This section contains material adapted from: Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020).
15.8 Schizophrenia. In Psychology 2e. OpenStax. Access for free at https://openstax.org/books/
psychology-2e/pages/15-8-schizophrenia License: CC BY 4.0 DEED.
 14.6: SCHIZOPHRENIA | 635
hippocampal hyperactivity is thought to result in downstream dopamine circuit
dysregulation, which may contribute to distorted interpretations of salience seen
in individuals with schizophrenia. Dopamine dysregulation is one of the most
prominent neural mechanisms underlying schizophrenia, and as a result, the most
common schizophrenia medications target dopaminergic circuitry. In the rest of
this section, we discuss the dopamine hypothesis and stress response in
schizophrenia.

Figure 14.6. Image showing enlarged ventricles that are often observed
in individuals with schizophrenia. Ventricles are cavities in the brain
that are filled with cerebrospinal fluid. CREDIT: Schizophrenia Brain ©
Wikipedia is licensed under a CC BY (Attribution) license

One of the earliest, and perhaps most influential, biological accounts of

schizophrenia is the “dopamine hypothesis of schizophrenia.” The dopamine
hypothesis suggests that excessive dopamine activity may be related to
schizophrenia (Meltzer & Stahl, 1976). This account was originally inspired by
seminal work showing that drugs that decrease dopamine activity may reduce
symptoms related to schizophrenia, and drugs that enhance dopamine activity may
increase symptoms (Carlsson & Lindqvist, 1963). The dopamine hypothesis has
undergone several iterations.
The second iteration of the dopamine hypothesis of schizophrenia (Dopamine
636 | 14.6: SCHIZOPHRENIA
Hypothesis: Version II) proposed that schizophrenia does not simply stem from
excess dopamine throughout the brain, but rather from region-specific dopamine
activity. Researchers proposed distinctions between cortical and subcortical
dopamine levels for negative and positive symptoms. Reduced dopaminergic
engagement in the frontal cortex was linked to negative symptoms (e.g., social
and emotional withdrawal) (Davis et al., 1991), whereas hyperactive dopaminergic
engagement in the subcortical striatum was linked to positive symptoms (i.e.,
delusions, hallucinations) (Pycock et al., 1980). Ultimately, the Version II
hypothesis proposed that reduced dopaminergic engagement in prefrontal areas
led to hyperactive dopaminergic engagement in striatal areas, which contributed to
the hallmark symptoms of schizophrenia.
Version III of the dopamine hypothesis departs from previous hypotheses in
several ways. First, it proposes that dopamine dysregulation may be less relevant
to schizophrenia as a whole, and instead contributes specifically to acute psychosis
(a brief period of delusion, hallucination, or disorganized thinking that dissociates
the individual from reality) (Howes & Kapur, 2009). Psychotic symptoms, such
as delusions and hallucinations, could emerge from excessive dopamine in the
striatum (a subcortical structure involved in processing salience) that causes neutral
items and events to be interpreted as overly important or salient (e.g., “aberrant
salience”) (Figure 14.7) (Kapur et al., 2003).
Version III of the dopamine hypothesis also proposes that the main source of
dopamine dysregulation may not be exclusively at the dopamine type D2 receptor
level. In line with this perspective, recent work shows that newer treatments that
target glutamatergic and dopaminergic mechanisms, other than D2 receptors, are
also effective at reducing schizophrenia symptoms (Krystal, 2021). Version III also
highlights other dimensions driving schizophrenia, such as the environmental,
sociocultural, and genetic risk factors that impact dopamine dysregulation and
their influence on cognitive dysfunction and symptom profiles.
 14.6: SCHIZOPHRENIA | 637

Figure 14.7. Visualizing striatal dopamine dysregulation’s influence on

psychosis: excessive dopamine in striatum could lead to “aberrant
salience” (i.e., ascribing too much importance to a stimulus), and
ultimately, psychosis. Current antipsychotic medication acts
downstream of the primary dopaminergic dysregulation. [Image:
Adapted from Howes, O. D., & Kapur, S. (2009). The dopamine
hypothesis of schizophrenia: Version III—the final common pathway.
Schizophrenia Bulletin, 35(3), 549-562.]. CREDIT: Dopamine hypothesis of
Schizophrenia © Michael Hove is licensed under a CC BY-NC-SA (Attribution
NonCommercial ShareAlike) license

Another influential account is the neural diathesis-stress model of

schizophrenia, which proposes that schizophrenia may result from an interaction
between preexisting vulnerabilities (“diathesis” means vulnerability or
predisposition) and stress caused by life experiences. As discussed in Chapter 8,
schizophrenia is highly heritable and has a strong genetic component (people with
a close genetic relative with schizophrenia, like a parent, sibling, or twin, are more
likely to develop schizophrenia); however, genetically predisposed individuals are
far more likely to develop schizophrenia if they experience significant life
stress—the stressful events can trigger or catalyze the development of the disorder.
Seminal work on neural diathesis-stress model of schizophrenia notes that stress
worsens symptoms of schizophrenia and that the diathesis (or predisposition) is
marked by a heightened stress response (Walker & Diforio, 1997). The model
proposes that the hypothalamic-pituitary-adrenal gland (HPA) axis releases the
hormone cortisol in response to stress and may mediate the effects of stress on
638 | 14.6: SCHIZOPHRENIA
schizophrenia symptoms. HPA-axis dysfunction may arise from hippocampal
abnormalities in schizophrenia, exacerbate dopamine neurotransmission, and
render a hypersensitivity to stress. Together, hippocampal, HPA axis, and
dopamine dysfunction are thought to collectively promote a heightened stress
response that marks a vulnerability to schizophrenia. To combat effects of stress,
researchers highlight resilience or protective factors, including social support, self-
esteem, coping skills, and antipsychotic medication (Pruessner et al., 2017).
While we focus here on the diathesis-stress model for schizophrenia, it is
important to note that diathesis-stress models (i.e., the important interaction
between predisposition and stressful life events) also apply to other psychological
disorders such as depression and anxiety (Arnau-Soler et al., 2019).
 14.7: CONCLUSION | 639

The biological perspective views psychological disorders as linked to biological

factors, such as genetics, chemical imbalances, and brain abnormalities (Spielman
et al., 2020). Widespread evidence indicates that most psychological disorders have
a genetic component. Researchers search for specific genes, genetic mutations,
and epigenetic markers that contribute to mental disorders, and in turn may be
targeted in future genetic-based therapies (e.g., Davidson et al., 2022).
Sophisticated neuroimaging technology has revealed that abnormalities in brain
structure and function are directly involved in many disorders. As imaging
technologies continue to develop, they will continue to improve our
understanding of psychological disorders. Advances in understanding
neurotransmitters and hormones have yielded insights into their role in
psychological disorders, and guide pharmacological treatment approaches.
Over the past decades, biological-based research has made incredible strides in
understanding psychological disorders and informing treatment. However,
biological markers are generally not reliable enough yet to be useful for clinicians
in diagnosing disorders (Abi-Dargham et al., 2023).
In this chapter, we largely focused on pharmacological treatments, but many
treatment approaches are effective. In addition to psychotherapy in its various
forms, other effective treatment approaches include deep brain stimulation to treat
depression, as well as yoga, music therapy, and exercise, as interventions to alleviate
symptoms of anxiety. As biological, psychological, and sociocultural factors all
contribute to psychopathology, it only makes sense that effective treatment
approaches take many various forms.

Text Attributions
This section contains material adapted from:
Spielman, R. M., Jenkins, W. J., & Lovett, M. D. (2020). 15.3 Perspectives
on Psychological Disorders. In Psychology 2e. OpenStax. Access for free at
640 | 14.7: CONCLUSION
https://openstax.org/books/psychology-2e/pages/15-3-perspectives-on-
psychological-disorders License: CC BY 4.0 DEED.
 14.8: DISCUSSION QUESTIONS AND RESOURCES | 641

Discussion Questions

1. What are the formal criteria that indicate the existence of a

psychological disorder?
2. What are the four components of the Version III dopamine
hypothesis in schizophrenia?
3. How might symptoms of OCD be related to abnormal brain
function?
4. How may PTSD symptoms relate to hippocampal functioning in
PTSD?

Outside Resources

Video: 5-minute TED Talk: The Psychology of PTSD

Video: 2-minute Neuroscience: Obsessive-Compulsive Disorder

Video: 2 minute walk-through on Early Neural Development

Video: TED Talk: Toward a new understanding of mental illness

Video: Five psychological disorders share some of the same genes

642 | 14.9: REFERENCES

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 CHAPTER 15: HORMONES AND BEHAVIOR | 655

CHAPTER 15: HORMONES

AND BEHAVIOR

Chapter adapted from: Nelson, R. J. (2023). Hormones & behavior. In

R. Biswas-Diener & E. Diener (Eds), Noba textbook series:
Psychology. Champaign, IL: DEF publishers. Retrieved from
http://noba.to/c6gvwu9m

The goal of this chapter is to introduce you to the topic of hormones and behavior.
This field of study is also called behavioral endocrinology, which is the scientific
study of the interaction between hormones and behavior. This interaction is
bidirectional: hormones can influence behavior, and behavior can sometimes
influence hormone concentrations. Hormones are chemical messengers released
from endocrine glands, and they travel through the blood system to influence the
nervous system to regulate behaviors such as aggression, mating, and parenting of
individuals.

Learning Objectives

• Define the basic terminology and basic principles of

hormone–behavior interactions.
• Explain the role of hormones in behavioral sex differentiation.
656 | CHAPTER 15: HORMONES AND BEHAVIOR

• Explain the role of hormones in aggressive behavior.

• Explain the role of hormones in parental behavior.
• Provide examples of some common hormone–behavior
interactions.
 15.1: INTRODUCTION | 657

15.1: INTRODUCTION

This chapter describes the relationship between hormones and behavior. Many
readers are likely already familiar with the general idea that hormones can affect
behavior. Students are generally familiar with the idea that sex-hormone
concentrations increase in the blood during puberty and decrease as we age,
especially after about 50 years of age. Sexual behavior shows a similar pattern. Most
people also know about the relationship between aggression and anabolic steroid
hormones, and they know that administration of artificial steroid hormones
sometimes results in uncontrollable, violent behavior called “roid rage.” Many
different hormones can influence several types of behavior, but for the purpose of
this chapter, we will restrict our discussion to just a few examples of hormones
and behaviors. Behavioral endocrinologists are interested in how the general
physiological effects of hormones alter the development and expression of behavior
and how behavior may influence the effects of hormones.
To understand the hormone-behavior relationship, it is important to describe
hormones. Hormones are organic chemical messengers produced and released by
specialized glands called endocrine glands. Hormones are released from these
glands into the blood, where they may travel to act on target structures at some
distance from their origin. Hormones are similar in function to
neurotransmitters, the chemicals used by the nervous system in coordinating
animals’ activities. However, hormones can operate over a greater distance and
over a much longer time than neurotransmitters (Focus Topic 1). Examples of
hormones that influence behavior include steroid hormones such as testosterone
(a common type of androgen), estradiol (a common type of estrogens),
progesterone (a common type of progestogen), and cortisol (a common type
of glucocorticoid) (see Table 1, A-B). Several types of protein or peptide (small
protein) hormones also influence behavior, including oxytocin, vasopressin,
prolactin, and leptin.
658 | 15.1: INTRODUCTION

Focus Topic 1: Neural Transmission versus Hormonal

Communication

Although neural and hormonal communication both rely on chemical

signals, several prominent differences exist. Communication in the
nervous system is analogous to traveling on a train. You can use the
train in your travel plans as long as tracks exist between your proposed
origin and destination. Likewise, neural messages can travel only to
destinations along existing nerve tracts. Hormonal communication, on
the other hand, is like traveling in a car. You can drive to many more
destinations than train travel allows because there are many more roads
than railroad tracks. Similarly, hormonal messages can travel anywhere
in the body via the circulatory system; any cell receiving blood is
potentially able to receive a hormonal message.

Neural and hormonal communication differ in other ways as well. To

illustrate them, consider the differences between digital and analog
technologies. Neural messages are digital, all-or-none events that have
rapid onset and offset: neural signals can take place in milliseconds.
Accordingly, the nervous system mediates changes in the body that are
relatively rapid. For example, the nervous system regulates immediate
food intake and directs body movement. In contrast, hormonal
messages are analog, graded events that may take seconds, minutes, or
even hours to occur. Hormones can mediate long-term processes, such
as growth, development, reproduction, and metabolism.

Hormonal and neural messages are both chemical in nature, and they
are released and received by cells in a similar manner; however, there
are important differences. Neurotransmitters, the chemical messengers
used by neurons, travel a distance of only 20–30 nanometers (10-9
m)—to the membrane of the postsynaptic neuron, where they bind with
receptors. Hormones enter the circulatory system and may travel from 1
 15.1: INTRODUCTION | 659

millimeter to more than 2 meters before arriving at a target cell, where

they bind with specific receptors.

Another distinction between neural and hormonal communication is the

degree of voluntary control that can be exerted over their functioning.
In general, there is more voluntary control of neural than of hormonal
signals. It is virtually impossible to will a change in your thyroid
hormone levels, for example, whereas moving your limbs on command
is easy.

Although these are significant differences, the division between the

nervous system and the endocrine system is becoming more blurred as
we learn more about how the nervous system regulates hormonal
communication. A better understanding of the interface between the
endocrine system and the nervous system, called neuroendocrinology, is
likely to yield important advances in the future study of the interaction
between hormones and behavior.

Table 1-A: Prominent Hormones That Influence Behavior

Steroid Hormones

Increases carbohydrate metabolism; mediates

Cortisol
stress respones

Uterine and other female tissue development;

Estradiol regulates sexual motivation and performance
in females and males

Promotes sperm production and male

secondary sexual characteristics; promotes
Testosterone
sexual motivation and behavior, typically by
being converted to estradiol
660 | 15.1: INTRODUCTION
Table 1-B: Prominent Hormones That Influence Behavior

Peptides and
Protein Hormones

Stimulates milk letdown and uterine

Oxytocin contractions during birth; Promotes social
bonding

Many actions relating to reproduction, water

Prolactin balance, and behavior associated with parental
care

Increases oxidation rates in tissue and affects

Thyroxine
neural development

Increases water reabsorption in the kidney and

Vasopressin
affects learning and memory

Hormones coordinate the physiology and behavior of individuals by regulating,

integrating, and controlling bodily functions. Over evolutionary time, hormones
have often been co-opted by the nervous system to influence behavior to ensure
reproductive success. For example, the same hormones, testosterone and estradiol,
that cause gamete (egg or sperm) maturation also promote mating behavior. This
dual hormonal function ensures that mating behavior occurs when animals have
mature gametes available for fertilization. Another example of endocrine
regulation of physiological and behavioral function is provided by pregnancy.
Estrogens and progesterone concentrations are elevated during pregnancy, and
these hormones are often involved in mediating maternal behavior in the
mothers.
Not all cells are influenced by each and every hormone. Rather, any given
hormone can directly influence only cells that have specific hormone receptors for
that particular hormone. Cells that have these specific receptors are called target
cells for the hormone. The interaction of a hormone with its receptor begins a
series of cellular events that eventually lead to the activation of enzymatic pathways
or, alternatively, turn on or turn off gene activation that regulates protein synthesis.
The newly synthesized proteins may activate or deactivate other genes, causing yet
another cascade of cellular events. Importantly, sufficient numbers of appropriate
hormone receptors must be available for a specific hormone to produce any effects.
For example, testosterone is important for male sexual behavior. If men have too
little testosterone, then sexual motivation may be low, and it can be restored by
 15.1: INTRODUCTION | 661
testosterone treatment. However, if men have normal or even elevated levels of
testosterone yet display low sexual drive, then it might be caused by a lack of
receptors, so treatment with additional hormones will not be effective.
How might hormones affect behavior? In terms of behavior, one can think
of humans and other animals as composed of three interacting components: (1)
input systems (sensory systems), (2) integrators (the central nervous system), and
(3) output systems or effectors (e.g., muscles). Hormones do not cause behavioral
changes. Rather, hormones influence these three systems so that specific stimuli
are more likely to elicit certain responses in the appropriate behavioral or social
context. In other words, hormones change the probability that a particular
behavior will be emitted in the appropriate situation (Nelson, 2011). This is a
critical distinction that can affect how we think of hormone-behavior
relationships.
We can apply this three-component behavioral scheme to a simple behavior,
singing in zebra finches. Only male zebra finches sing, and they sing to attract
mates or ward off potential competitors from their territories. If the testes of adult
male finches are removed, then the birds reduce singing, but castrated finches
resume singing if the testes are reimplanted or if they are treated with either
testosterone or estradiol. Although people often consider androgens to be “male”
hormones and estrogens to be “female” hormones, testosterone is commonly
converted to estradiol (Figure 1). Thus, many male-like behaviors are associated
with the actions of estrogens! Indeed, all estrogens must first be converted from
androgens because of the typical biochemical synthesis process. If the converting
enzyme is low or missing, then it is possible for females to produce excessive
androgens and subsequently develop associated male traits. Again, singing
behavior is most frequent when blood testosterone or estrogen concentrations are
high.
662 | 15.1: INTRODUCTION

Figure 1: Biochemical Pathway for Steroid Hormone Synthesis: It is important to

note that testosterone (an androgen) can be converted to another androgen,
DHT, or an estrogen, estradiol. Too much or too little of the converting enzymes
can influence the brain and behavior.

Estrogens are somehow involved in singing, but how might the three-component
framework help us formulate hypotheses to explore the role of estrogen in this
behavior? Estrogens could affect birdsong by influencing the sensory capabilities,
central processing system, or effector organs of a bird. By examining input systems,
we could determine whether estrogens alter the birds’ sensory capabilities, making
the environmental cues that normally elicit singing (like females or competitors)
more salient. Estrogens also could influence the central nervous system, for
example, by altering neuronal architecture or the speed of neural processing.
Finally, the effector organs, like the muscles in a songbird’s vocal apparatus, could
be affected by the presence of estrogens. We do not understand completely how
estrogens, derived from testosterone, influence birdsong, but in most cases,
 15.1: INTRODUCTION | 663
hormones can be considered to affect behavior by influencing one, two, or all
three of these components, and this three-part framework can aid in the design of
hypotheses and experiments to explore these issues.
How might behaviors affect hormones? The birdsong example demonstrates
how hormones can affect behavior, but as noted, the reciprocal relation also
occurs—behavior can affect hormone concentrations. For example, the sight of a
territorial intruder may elevate testosterone concentrations in resident male birds
and thereby stimulate singing or fighting behavior. Similarly, male mice or rhesus
monkeys that lose a fight decrease circulating testosterone concentrations for
several days or even weeks afterward. Comparable results have also been reported
in humans. Testosterone concentrations are affected not only in humans involved
in physical combat but also in those involved in simulated battles. For example,
testosterone concentrations were elevated in winners and reduced in losers of
regional chess tournaments.
664 | 15.1: INTRODUCTION

Figure 2. The expectation of events can influence one’s hormonal activity.

How do you think hormonal activity is affected if you anticipate going on a
date with a romantic interest?

People do not have to be directly involved in a contest to have their hormones

affected by the outcome of the contest. Male fans of the Brazilian and Italian
soccer teams were recruited to provide saliva samples to be assayed for testosterone
before and after the final game of the World Cup soccer match in 1994. Brazil
and Italy were tied, but Brazil won on a penalty kick at the last moment. The
Brazilian fans were elated, and the Italian fans were crestfallen. When the samples
were assayed, 11 of 12 Brazilian fans who were sampled had increased testosterone
concentrations, and 9 of 9 Italian fans had decreased testosterone concentrations,
compared with pre-game baseline values (Dabbs, 2000).
In some cases, hormones can be affected by anticipation of behavior. For
 15.1: INTRODUCTION | 665
example, testosterone concentrations also influence sexual motivation and
behavior in women. In one study, the interaction between sexual intercourse and
testosterone was compared with other activities (cuddling or exercise) in women
(van Anders et al., 2007). On three separate occasions, women provided a saliva
sample from pre-activity, post-activity, and the next morning, analyses showed
that the women’s testosterone was elevated prior to intercourse as compared to
other times. Thus, an anticipatory relationship exists between sexual behavior and
testosterone. Testosterone values were higher post-intercourse compared to
exercise, suggesting that engaging in sexual behavior may also influence hormone
concentrations in women.
 666 | 15.2: SEX DIFFERENCES

15.2: SEX DIFFERENCES

The discussion below focuses on how sex-specific hormonal differences may lead to
differences in brain development and behavior. Although we focus mainly on sex-
related differences, it’s important to recognize that gender-related differences can
also impact brain development and behavior.1 (For a more comprehensive review
of sex versus gender, see Lips, 2020.)
Hens and roosters are different. Cows and bulls are different. Human males
and females are different. Humans, like many animals, are sexually dimorphic (di,
“two”; morph, “type”) in the size and shape of their bodies, their physiology, and
for our purposes, their behavior (cf. Fausto-Sterling, 2000). The behavior of males
and females differs in many ways. Young females generally excel in verbal tasks
relative to young males, who are nearly twice as likely as females to suffer from
dyslexia (reading difficulties) and stuttering. Young males generally perform better
at visuospatial tasks. More than 90% of all anorexia nervosa cases involve young
females. Young males are twice as likely to suffer from schizophrenia. Young males
are much more physically aggressive and generally engage in more rough-and-
tumble play (Berenbaum et al., 2008). Many sex differences, such as the difference
in aggressiveness, persist throughout adulthood. For example, many more males
than females are serving prison sentences for violent behavior. The hormonal
differences between males and females may account for adult sex differences that
develop during puberty, but what accounts for behavioral sex differences among
children prior to puberty and activation of their gonads? While societal and
cultural factors play a role (discussed below), hormones are a major determinant
of sex differences. Hormonal secretions from the developing gonads determine

1. According to the World Health Organization, sex refers to “the different biological and physiological
characteristics of females, males and intersex persons, such as chromosomes, hormones and
reproductive organs.” Gender refers to “the characteristics of women, men, girls and boys that are
socially constructed. This includes norms, behaviors and roles associated with being a woman, man,
girl or boy. Gender varies from society to society and can change over time.”
 15.2: SEX DIFFERENCES | 667
whether the individual develops in a male or female manner. The mammalian
embryonic testes produce androgens, as well as peptide hormones, that steer the
development of the body, central nervous system, and subsequent behavior in a
male direction. The embryonic ovaries of mammals are virtually quiescent and
do not secrete high concentrations of hormones. In the presence of ovaries or in
the complete absence of any gonads, morphological, neural, and later, behavioral
development follows a female pathway.

Figure 3. Sex differences in appearance are often more pronounced in nonhuman

animals than in humans. Male birds particularly, for example, roosters, tend to
have physical features that differ from the females and also differ significantly in
size.

Gonadal steroid hormones have organizational (or programming) effects on the

brain and behavior (Phoenix et al., 1959). The organizing effects of steroid
hormones are relatively constrained to the early stages of development. An
asymmetry exists in the effects of testes and ovaries on the organization of behavior
in mammals. Hormone exposure early in life has organizational effects on
subsequent rodent behavior; early steroid hormone treatment causes relatively
irreversible and permanent masculinization of rodent behavior (mating and
668 | 15.2: SEX DIFFERENCES
aggressiveness). These early hormone effects can be contrasted with the reversible
behavioral influences of steroid hormones provided in adulthood, which are called
activational effects. The activational effects of hormones on adult behavior are
temporary and may wane soon after the hormone is metabolized. Thus, typical
male behavior requires exposure to androgens during gestation (in humans) or
immediately after birth (in rodents) to somewhat masculinize the brain and also
requires androgens during or after puberty to activate these neural circuits. Typical
female behavior requires a lack of exposure to androgens early in life, which leads
to feminization of the brain and also requires estrogens to activate these neural
circuits in adulthood. But this simple dichotomy, which works well with animals
with very distinct sexual dimorphism in behavior, has many caveats when applied
to people.
If you walk through any major toy store, you will likely observe some aisles
filled with pink-packaged toys and adjacent aisles without any pink packages.
Remarkably, you will also see a strong self-segregation of girls and boys in these
aisles. Toy manufacturers are often accused of making toys that are gender biased,
but it seems more likely that boys and girls enjoy playing with specific types and
colors of toys. Indeed, toy manufacturers would immediately increase their sales
if they could sell toys to both sexes. Boys generally prefer toys such as trucks and
balls, and girls generally prefer toys such as dolls. Although it is doubtful that there
are genes that encode preferences for toy cars and trucks on the Y chromosome,
it is possible that hormones might shape the development of a child’s brain to
prefer certain types of toys or styles of play behavior. It is reasonable to believe that
children learn which types of toys and which styles of play are appropriate to their
gender. How can we separate the contribution of physiological mechanisms from
learning in order to understand sex differences in human behaviors?
To untangle the contributions of physiological mechanisms from learning in
sex-specific behaviors, animal models are often used. Unlike in humans, where
sex differences are usually only a matter of degree (often slight), in some animals,
members of only one sex may display a particular behavior. As noted, often only
male songbirds sing. Studies of such strongly sex-biased behaviors are particularly
valuable for understanding the interaction among behavior, hormones, and the
nervous system.
A study of vervet monkeys calls into question the primacy of learning in the
establishment of toy preferences (Alexander & Hines, 2002). Female vervet
 15.2: SEX DIFFERENCES | 669
monkeys preferred girl-typical toys, such as dolls or cooking pots, whereas male
vervet monkeys preferred boy-typical toys, such as cars or balls. There were no sex
differences in preference for gender-neutral toys, such as picture books or stuffed
animals. Presumably, monkeys have no prior concept of “boy” or “girl” toys. Young
rhesus monkeys also show similar toy preferences.

Figure 4. If you think back to the toys and clothing you played with and wore
in your youth, do you think they were more a result of your hormonal activity
or the choices that society and your parents made for you?

What, then, underlies the sex difference in toy preference? It is possible that certain
attributes of toys (or objects) appeal to either boys or girls. Toys that appeal to
boys or male monkeys, in this case, a ball or toy car, are objects that can be moved
actively through space and can be incorporated into active, rough-and-tumble play.
670 | 15.2: SEX DIFFERENCES
The appeal of toys that girls or female vervet monkeys prefer appears to be based
on color. Pink and red (the colors of the doll and pot) may provoke attention in
infants.
Society may reinforce such stereotypical responses to gender-typical toys. The
sex differences in toy preferences emerge by 12 or 24 months of age and seem fixed
by 36 months of age, but are sex differences in toy preference present during the
first year of life? It is difficult to ask preverbal infants what they prefer, but in
studies where the investigators examined the amount of time that babies looked at
different toys, eye-tracking data indicate that infants as young as 3 months showed
sex differences in toy preferences: girls preferred dolls, whereas boys preferred
trucks. Another result that suggests, but does not prove, that hormones are
involved in toy preferences is the observation that girls diagnosed with congenital
adrenal hyperplasia (CAH), whose adrenal glands produce varying amounts of
androgens early in life, played with masculine toys more often than girls without
CAH. Further, a dose-response relationship between the extent of the disorder
(i.e., degree of fetal androgen exposure) and the degree of masculinization of play
behavior was observed. Are the sex differences in toy preferences or play activity, for
example, the inevitable consequences of the differential endocrine environments of
boys and girls, or are these differences imposed by cultural practices and beliefs?
Are these differences the result of receiving gender-specific toys from an early
age, or are these differences some combination of endocrine and cultural factors?
Again, these are difficult questions to unravel in people.
Even when behavioral sex differences appear early in development, there seems
to be some question regarding the influence of societal expectations. One example
is the pattern of human play behavior during which males are more physical; this
pattern is seen in a number of other species, including nonhuman primates, rats,
and dogs. Is the difference in the frequency of rough-and-tumble play between
boys and girls due to biological factors associated with being male or female, or is
it due to cultural expectations and learning? If there is a combination of biological
and cultural influences mediating the frequency of rough-and-tumble play, then
what proportion of the variation between the sexes is due to biological factors,
and what proportion is due to social influences? Importantly, is it appropriate
to talk about “normal” sex differences when these traits virtually always arrange
themselves along a continuum rather than in discrete categories?
Sex differences are common in humans and in nonhuman animals. Because
 15.2: SEX DIFFERENCES | 671
males and females differ in the ratio of androgenic and estrogenic steroid hormone
concentrations, behavioral endocrinologists have been particularly interested in the
extent to which behavioral sex differences are mediated by hormones. The process
of becoming female or male is called sexual differentiation. The primary step in
sexual differentiation occurs at fertilization. In mammals, the ovum (which always
contains an X chromosome) can be fertilized by a sperm bearing either a Y or an
X chromosome; this process is called sex determination. The chromosomal sex
of homogametic mammals (XX) is female; the chromosomal sex of heterogametic
mammals (XY) is male. Chromosomal sex determines gonadal sex. Virtually all
subsequent sexual differentiation is typically the result of differential exposure to
gonadal steroid hormones. Thus, gonadal sex determines hormonal sex, which
regulates morphological sex. Morphological differences in the central nervous
system, as well as in some effector organs, such as muscles, lead to behavioral sex
differences. The process of sexual differentiation is complicated, and the potential
for errors is present. Perinatal exposure to androgens is the most common cause
of anomalous sexual differentiation among females. The source of androgen may
be internal (e.g., secreted by the adrenal glands) or external (e.g., exposure to
environmental estrogens). Turner syndrome results when the second X
chromosome is missing or damaged; these individuals possess dysgenic ovaries and
are not exposed to steroid hormones until puberty. Interestingly, women with
Turner syndrome often have impaired spatial memory.
Female mammals are considered the “neutral” or “default” sex, as additional
physiological steps are required for male differentiation; more steps bring more
possibilities for errors in differentiation. Some examples of male anomalous sexual
differentiation include 5α-reductase deficiency (in which XY individuals are born
with ambiguous genitalia because of a lack of dihydrotestosterone and are reared
as females, but masculinization occurs during puberty) and androgen insensitivity
syndrome or TFM (in which XY individuals lack receptors for androgens and
develop as females). By studying individuals who do not neatly fall into the
dichotic boxes of female or male and for whom the process of sexual differentiation
is atypical, behavioral endocrinologists glean hints about the process of typical
sexual differentiation.
We may ultimately want to know how hormones mediate sex differences in the
human brain and behavior (to the extent to which these differences occur). To
understand the mechanisms underlying sex differences in the brain and behavior,
672 | 15.2: SEX DIFFERENCES
we return to the birdsong example. Birds provide the best evidence that behavioral
sex differences are the result of hormonally induced structural changes in the brain
(Goodson et al., 2005). In contrast to mammals, in which structural differences in
neural tissues have not been directly linked to behavior, structural differences in
avian brains have been directly linked to a sexual behavior—birdsong.

Figure 5: The sexually dimorphic nuclei of the preoptic area (SDN-POA). Gonadal
steroid hormones have organizing effects on the brain and behavior. The
organizing effects of steroid hormones are relatively constrained to the early
stages of development. Exposure to testosterone (which is converted to
estradiol) or estradiol causes masculinization of the brain. These are
cross-sections through the brains of rats that show a male (left), a female
(center), and a female treated with testosterone as a newborn (right). Note that
the SDN-POA (the dark cell bodies) of the male are substantially larger than
those of the untreated female but are equal in size to those of the
testosterone-treated female. The extent to which these sex differences in brain
structure account for sex differences in behavior remains unspecified in
mammals. OC = optic chiasm; SCN = suprachiasmatic nucleus; V = third ventricle.

Sex differences in human brain size have been reported for years. More recently,
sex differences in specific brain structures have been discovered (Figure 5). Sex
differences in a number of cognitive functions have also been reported. Females are
generally more sensitive to auditory information, whereas males are more sensitive
to visual information. Females are also typically more sensitive than males to taste
and olfactory input. Women display less lateralization of cognitive functions than
men. On average, females generally excel in verbal, perceptual, and fine motor
skills, whereas males outperform females on quantitative and visuospatial tasks,
including map reading and direction finding. Although reliable sex differences can
be documented, these differences in ability are slight. It is important to note that
 15.2: SEX DIFFERENCES | 673
there is more variation within each sex than between the sexes for most cognitive
abilities (Figure 6).

Figure 6: The average sex differences in human performance often reflect

significant overlap between the sexes. There are often greater differences in
performance between individuals of the same sex (for example, between Steve
and Rick in the figure) than between individuals of the opposite sex (for
example, between Steve and Jane in the figure).
674 | 15.4: AGGRESSIVE BEHAVIORS

15.4: AGGRESSIVE BEHAVIORS

The possibility for aggressive behavior exists whenever the interests of two or
more individuals are in conflict (Nelson, 2006). Conflicts are most likely to arise
over limited resources such as territories, food, and mates. A social interaction
decides which animal gains access to the contested resource. In many cases, a
submissive posture or gesture on the part of one animal avoids the necessity of
actual combat over a resource. Animals may also participate in threat displays or
ritualized combat in which dominance is determined, but no physical damage is
inflicted.
There is overwhelming circumstantial evidence that androgenic steroid
hormones mediate aggressive behavior across many species. First, seasonal
variations in blood plasma concentrations of testosterone coincide with seasonal
variations in aggression. For instance, aggressive behavior peaks for male deer in
autumn, when they are secreting high levels of testosterone. Second, aggressive
behaviors increase at the time of puberty when the testes become active, and blood
concentrations of androgens rise. Juvenile deer do not participate in the fighting
during the mating season. Third, in any given species, males are generally more
aggressive than females. This is certainly true of deer; relative to males, female deer
rarely display aggressive behavior, and their rare aggressive acts are qualitatively
different from the aggressive behavior of aggressive males. Finally, castration
typically reduces aggression in males, and testosterone replacement therapy restores
aggression to pre-castration levels. There are some interesting exceptions to these
general observations that are outside the scope of this chapter.
As mentioned, males are generally more aggressive than females. Certainly,
human males are much more aggressive than females although research in
developmental psychology notes that females may engage in relational aggression
(e.g., causing harm to social status or relationships) at higher rates than males.
Many more men than women are convicted of violent crimes in North America.
The sex differences in human aggressiveness appear very early. At every age
throughout the school years, many more males than females initiate physical
assaults. Almost everyone will acknowledge the existence of this sex difference,
 15.4: AGGRESSIVE BEHAVIORS | 675
but assigning a cause to behavioral sex differences in humans always elicits much
debate. It is possible that males are more aggressive than females because androgens
promote aggressive behavior, and males have higher blood concentrations of
androgens than females. It is possible that males and females differ in their
aggressiveness because the brains of males are exposed to androgens prenatally,
and the “wiring” of their brains is thus organized in a way that facilitates the
expression of aggression. It is also possible that males are encouraged, and females
are discouraged by family, peers, or others from acting in an aggressive manner.
These three hypotheses are not mutually exclusive, but it is extremely difficult to
discriminate among them to account for sex differences in human aggressiveness.

Figure 7. Researchers have electrically stimulated particular regions in people’s

brains, and these individuals have burst into aggressive, violent behavior,
helping demonstrate that such responses are hardwired into us.
676 | 15.4: AGGRESSIVE BEHAVIORS
What kinds of studies would be necessary to assess these hypotheses? It is usually
difficult to separate out the influences of environment and physiology on the
development of behavior in humans. For example, males and females differ in their
rough-and-tumble play at a very young age, which suggests an early physiological
influence on aggression. However, parents interact with their male and female
offspring differently; they usually play more roughly with male infants than with
females, which suggests that the sex difference in aggressiveness is partially learned.
This difference in parental interaction style is evident by the first week of life.
Because of these complexities in the factors influencing human behavior, the study
of hormonal effects on sex-differentiated behavior has been pursued in nonhuman
animals, for which environmental influences can be held relatively constant.
Animal models for which sexual differentiation occurs postnatally are often used
so that this process can be easily manipulated experimentally.
Again, with the appropriate animal model, we can address the questions posed
above: Is the sex difference in aggression due to higher adult blood concentrations
of androgens in males or because male brains are organized differently by perinatal
hormones? Or does the sex difference in aggression stem from an interaction of
early and current blood androgen concentrations? If male mice are castrated prior
to their sixth day of life, then treated with testosterone propionate in adulthood,
they show low levels of aggression. Similarly, females ovariectomized prior to their
sixth day but given androgens in adulthood do not express male-like levels of
aggression. Treatment of perinatally gonadectomized males or females with
testosterone prior to their sixth day of life and also in adulthood results in a level
of aggression similar to that observed in typical male mice. Thus, in mice, the
increased aggressiveness in males is organized perinatally by androgens but also
requires the presence of androgens after puberty in order to be fully expressed. In
other words, aggression in male mice is both organized and activated by androgens.
Testosterone exposure in adulthood without prior organization of the brain by
steroid hormones does not evoke typical male levels of aggression. Aggressive
behavior is both organized and activated by androgens in many species, including
rats, hamsters, voles, dogs, and possibly some primate species.
 15.5: PARENTAL BEHAVIORS | 677

15.5: PARENTAL BEHAVIORS

Parental behavior can be considered to be any behavior that contributes directly

to the survival of fertilized eggs or offspring that have left the body of the female.
There are many patterns of mammalian parental care. The developmental status of
the newborn is an important factor driving the type and quality of parental care
in a species. Maternal care is much more common than paternal care. The vast
majority of research on the hormonal correlates of mammalian parental behavior
has been conducted on rats. Rats have altricial (underdeveloped) young, and
mothers perform a cluster of stereotyped maternal behaviors, including nest
building, crouching over the pups to allow nursing and provide warmth, pup
retrieval, and increased aggression directed at intruders. If you expose nonpregnant
female rats (or males) to pups, their most common reaction is to huddle far away
from them. Rats avoid new things (neophobia). However, if you expose adult rats
to pups every day, they soon begin to behave maternally. This process is called
concaveation or sensitization and it appears to serve to reduce the adult rats’ fear of
pups.
A new mother needs to act maternally as soon as her offspring arrives—not in
a week. The onset of maternal behavior in rats is mediated by hormones. Several
methods of study, such as hormone removal and replacement therapy, have been
used to determine the hormonal correlates of rat maternal behavior. A fast decline
of blood concentrations of progesterone in late pregnancy, in combination with
high concentrations of estradiol and probably prolactin and oxytocin, induces
female rats to behave maternally almost immediately in the presence of pups.
This pattern of hormones at birth overrides the usual fear response of adult rats
toward pups, and it permits the onset of maternal behavior. Thus, the so-called
maternal “instinct” requires hormones to increase the approach tendency and
lower the avoidance tendency; the quality and type of maternal behaviors, however,
are mediated by both hormones and maternal modeling in rodents as well as
humans.
678 | 15.5: PARENTAL BEHAVIORS

Figure 8. Although cortisol may not directly increase maternal behaviors, the
next time your mom gives you a hug, you know one hormone to thank.

A series of elegant experiments by Alison Fleming and her collaborators studied

the endocrine correlates of the behavior of human mothers and maternal attitudes.
Mothers self-reported on questionnaires approach behaviors, including
affectionate behaviors (e.g., patting, cuddling, or kissing the baby) and vocal
behaviors (e.g., talking, singing, or cooing to the baby). Basic caregiving activities,
such as changing diapers and burping the infants, were also recorded. In these
self-report studies, no relationship between hormone concentrations and maternal
responsiveness, as measured by questionnaires, was found. However, when actual
behavior, rather than questionnaire responses, was compared with hormone
concentrations, a different story emerged. Cortisol concentrations were positively
 15.5: PARENTAL BEHAVIORS | 679
associated with approach behaviors. In other words, women with high
concentrations of cortisol, in samples obtained immediately before or after
nursing, engaged in more physically affectionate behaviors and talked more often
to their babies than mothers with low cortisol concentrations. Additional analyses
revealed that the correlation was even greater for mothers that had reported
positive maternal regard (feelings and attitudes) during gestation. Indeed, nearly
half of the variation in maternal behavior among women could be accounted for
by cortisol concentrations and positive maternal attitudes during pregnancy.
Presumably, cortisol does not induce maternal behaviors directly, but it may act
indirectly on the quality of maternal care by evoking an increase in the mother’s
general level of arousal, thus increasing her responsiveness to infant-generated cues.
New mothers with high cortisol concentrations were also more attracted to their
infant’s odors, were superior in identifying their infants, and generally found cues
from infants highly appealing (Fleming et al., 1997).
The medial preoptic area is critical for the expression of rat maternal behavior.
The amygdala appears to tonically inhibit the expression of maternal behavior.
Adult rats are fearful of pups, a response that is apparently mediated by
chemosensory information. Lesions of the amygdala or afferent sensory pathways
from the vomeronasal organ to the amygdala disinhibit the expression of maternal
behavior. Hormones or sensitization likely act to disinhibit the amygdala, thus
permitting the occurrence of maternal behavior. Although correlations have been
established, direct evidence of brain structural changes in human mothers remains
unspecified (Fleming & Gonzalez, 2009).
Considered together, there are many examples of hormones influencing
behavior and of behavior feeding back to influence hormone secretion. More and
more examples of hormone–behavior interactions have been discovered, including
hormones in the mediation of food and fluid intake, social interactions, salt
balance, learning and memory, stress coping, as well as psychopathology, including
depression, anxiety disorders, eating disorders, postpartum depression, and
seasonal depression. Additional research should reveal how these
hormone–behavior interactions are mediated.
680 | 15.5: DISCUSSION QUESTIONS AND RESOURCES

15.5: DISCUSSION QUESTIONS

AND RESOURCES

Discussion Questions

1. What are some of the problems associated with attempting to

determine causation in a hormone–behavior interaction? What
are the best ways to address these problems?
2. Hormones cause changes in the rates of cellular processes or in
cellular morphology. What are some ways that these hormonally
induced cellular changes might theoretically produce profound
changes in behavior?
3. List and describe some behavioral sex differences that you have
noticed between female and male children. What causes females
and males to choose different toys? Do you think that the sex
differences you have noted arise from biological causes or are
learned? How would you go about establishing your opinions as
fact?
4. Why is it inappropriate to refer to androgens as “male” hormones
and estrogens as “female” hormones?
5. Imagine that you discovered that the brains of architects were
different from those of non-architects—specifically, that the
“drawstraightem nuclei” of the right temporal lobe were enlarged
in architects as compared with non-architects. Would you argue
that architects were destined to be architects because of their
brain organization or that experience as an architect changed
their brains? How would you resolve this issue?
 15.5: DISCUSSION QUESTIONS AND RESOURCES | 681

Outside Resources

Book: Adkins-Regan, E. (2005). Hormones and animal social

behavior. Princeton, NJ: Princeton University Press.

Book: Beach, F. A. (1948). Hormones and behavior. New York: Paul

Hoeber.

Book: Nelson, R. J. (2011). An introduction to behavioral

endocrinology (4th ed.). Sunderland, MA: Sinauer Associates.

Book: Pfaff, D. W. (2009). Hormones, brain, and behavior (2nd ed.).

New York: Academic Press.

Book: Pfaff, D. W., Phillips, I. M., & Rubin, R. T. (2005). Principles of

hormone/behavior relations. New York: Academic Press.

Article: Beach, F. A. (1975). Behavioral endocrinology: An emerging

discipline. American Scientist, 63: 178–187.

Video: Endocrinology Video (Playlist) – This YouTube playlist

contains many helpful videos on the biology of hormones, including
reproduction and behavior. This would be a helpful resource for
students struggling with hormone synthesis, reproduction,
regulation of biological functions, and signaling pathways.

https://www.youtube.com/
playlist?list=PLqTetbgey0aemiTfD8QkMsSUq8hQzv-vA

Video: Paul Zak: Trust, morality – and oxytocin- This Ted talk
explores the roles of oxytocin in the body. Paul Zak discusses
biological functions of oxytocin, such as lactation, as well as
potential behavioral functions, such as empathy.

https://www.youtube.com/watch?v=rFAdlU2ETjU

Video: The Teenage Brain Explained- This is a great video explaining

the roles of hormones during puberty.

https://www.youtube.com/watch?v=hiduiTq1ei8
682 | 15.5: DISCUSSION QUESTIONS AND RESOURCES

Web: Society for Behavioral Neuroendocrinology – This website

contains resources on current news and research in the field of
neuroendocrinology.

http://sbn.org/home.aspx
 15.6: REFERENCES | 683

15.6: REFERENCES

Adapted from:
Nelson, R. J. (2023). Hormones & behavior. In R. Biswas-Diener & E. Diener
(Eds), Noba textbook series: Psychology. Champaign, IL: DEF publishers.
Retrieved from http://noba.to/c6gvwu9m License: CC BY-NC-SA 4.0 DEED

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