9.

1 Autism

9.1 Autism Meng-Chuan Lai and Simon

Baron-Cohen

OVERVIEW
Autism is a heterogeneous, behaviourally defined, neurodevelopmental condition charac-
terised by early-emerging atypical social communication and restricted, repetitive behav-
iours and interests. The underlying neurocognitive underpinnings may include difficulties
in social processing (particularly ‘mentalising’), executive functioning, as well as strengths in
pattern recognition (attention to detail and rule-based reasoning or ‘systemising’). Each of
these involves atypical brain connectivity. The underlying molecular neurobiology involves
developmentally sensitive and spatiotemporally specific genetic and gene–environmental
(e.g. neuroendocrine-immune) mechanisms, converging on neuronal synaptic functioning
and transcriptional regulation prenatally, and their cascade effects on brain development,
influenced by the autistic person’s interaction with the environmental contexts from early
in life and across the lifespan. Future autism research needs to clarify the relations between
the genes and the environmental factors and their relations to neurocognitive architec-
tures, to identify factors associated with plasticity in developmental trajectories and to
develop neurobiologically informed therapeutics and support strategies that are precisely
tailored to respect individual differences.

9.1.1 Autism: A Behaviourally awareness, autism is now relatively common. Today ~1%
Defined, Heterogeneous of the global population has a formal diagnosis, with a
Neurodevelopmental Condition male:female (sex assigned at birth) ratio of 3–4:1.
Autism is a neurodevelopmental condition defined The current definition of autism encompasses a
behaviourally by early-emerging atypicalities in social heterogeneous group of individuals sharing atypicalities
communication skills (including social–emotional reci- in social communication and restricted and repetitive
procity, non-verbal communication and understanding, behaviours and interests, but who may differ in levels
developing and maintaining typical social relations), of language, intellectual ability, co-occurring medical,
alongside what is called restricted and repetitive behav- neurodevelopmental or psychiatric conditions, and
iours and interests (including stereotyped and repetitive developmental trajectories. This umbrella label describes
behaviours, inflexible adherence to routines, sameness a group of people at the high end of dimensions of autis-
or rituals, and fixated interests), which also includes tic traits that are continuously distributed in the general
idiosyncratic sensory sensitivity. These atypical behav- population. A clinical diagnosis is given when there is
iours emerge in the early years, but the clinical diagno- significant functional impairment related to these high-
sis can be made at any time in life. Decades ago, autism level traits, but the diagnosis encompasses a variety of
was regarded as a rare condition but, due to changing qualitatively different subgroups of individuals. Despite
diagnostic criteria, improved recognition and increased the strong genetic aetiology (heritability estimates are

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 9 Integrated Neurobiology of Specific Syndromes

64–91%) [1], causal factors of autism are diverse. The further compounded by the natural complexity of social
vast heterogeneity across phenotype, neurobiology and interactions, in which non-autistic people often show
aetiology is the rule rather than the exception in autism difficulties understanding autistic people (sometimes
[2], especially considering the neurodevelopmental and referred to as the ‘double empathy problem’).
psychiatric conditions with which it frequently co-occurs Second, reduced orientation to social stimuli is
(e.g. attention deficit hyperactivity disorder (ADHD), not present at birth, but likely emerges in the first few
anxiety disorders) [3]. Current intervention and support months, reflecting a deviation from the typical infant’s
models are primarily behavioural and educational, focus- developmental transition from reflex-like social orientat-
ing on maximising the autistic individual’s potential in ing to an experience-dependent, volitional social orient-
development and learning, minimising their barriers ing [6]. Such deviation (and hence the later clinical autism
to adaptation and creating adequate environmental phenotype) could be an alternative, adaptive develop-
support to optimise the person–environment fit [4]. The mental process with an unusual starting state of attention
autism and neurodevelopmental research field is leverag- allocation (i.e. focal attention, repetition and withdrawal
ing the increasingly large and multi-level data and apply- from social stimuli and contexts) underpinned by neuro-
ing both hypothesis-driven and data-driven approaches biological differences (e.g. synaptic processing) [7].
to decompose this heterogeneity, to move towards the Third, atypical motivation is neither specifically about
goals of precision in intervention and support [2]. social scenarios nor universally impaired in autistic indi-
viduals [8].
9.1.2 The Neurocognitive Bases Finally, although executive dysfunction is common
in autistic individuals, impedes adaptive function and
of Autism explains parts of social and general cognitive features
In the past 50 years, several cognitive models have been
of autism, it does not link directly to the behavioural
empirically examined to understand how the autistic
phenotypes of autism. Further, it does not seem to be
mind works differently, to explain how the behavioural
autism-specific, but rather is present transdiagnostically
profiles of autism unfold and to build a bridge between
with other neurodevelopmental conditions.
behaviour and biology [5]. The main models are summar-
Another way of conceptualising the cognitive features
ised below but see [5] for a contemporary review of cogni-
of autism is viewing them as different or alternative
tive theories of autism. These cognitive models have also
(instead of impaired) ways of information processing [5].
led to evidence-based intervention strategies such as
These domain-general cognitive models posit that autis-
naturalistic developmental behavioural interventions,
tic people, from very early in life have:
social skills and theory of mind training [4]. Although
current evidence finds no ‘grand theory’ for the cogni- (i) an attentional, sensory-perceptual and cognitive
tive basis of autism, each prevailing model explains part pattern biasing towards local details more than
global contexts, which is not simply part of execu-
of the behavioural phenotype and its development in
tive dysfunction but may reflect cognitive strengths
autism, and points to plausible underlying brain circuits
alongside difficulties
or systems that explain a portion of the heterogeneity.
(ii) challenges integrating multimodal and complex
Historically, the ‘deficit models’ of theory of mind
information and, perhaps in relation to this, have
impairment, reduced social orientation and social atypical allocation of attention (‘monotropism’, i.e.
motivation (in very early years) and executive dysfunc- focusing attention on specific interests at any time
tion have been used to explain the unique early-onset and missing things outside of this attention tunnel)
social-communication difficulties in autism, with experi- (iii) an increased tendency to engage in rule-based,
mental supports from relatively small-sample studies. predictable and logical contexts, referred to as
Accumulated evidence reveals a more complex picture. ‘systemising’
First, the primary social cognitive difficulty experi- (iv) reliance on greater weighting of sensory information
enced by autistic individuals lies in intuitive ‘mentalising’ in updating the probabilistic representations of the
(i.e. knowing what other people think or feel). This is environment – an alternative, Bayesian view of autism.

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 9.1 Autism

The brain bases of these cognitive characteristics information-processing cognitive models) has been
have been investigated primarily via neuroimaging proposed [9], findings have been variable. Studies on
methods. This literature is characterised by diverse intrinsic brain functional organisation show mixed find-
findings and is mostly cross-sectional, with a relative ings of hyper- and hypoconnectivity in autistic compared
paucity of longitudinal data from early in life to address to non-autistic individuals, though trends of conver-
causality, developmental mechanisms, plasticity and gence have been shown regarding hypoconnectivity
compensation. The findings (Figure 9.1.1) generally hubs in the sensorimotor regions and hyperconnectivity
suggest that (i) individual variability is substantially hubs in the prefrontal and parietal cortices [10], with vari-
higher in the autistic than the non-autistic population; ous involvement of cortico-subcortical circuitries such
(ii) brain correlates of autism tend to be widely distrib- as enhanced sensory cortex–subcortex connectivity.
uted across cortical and subcortical regions; (iii) high Neurophysiological studies using electro- or magne-
heterogeneity of findings is critically associated with toencephalography tend to show long-range under-
factors such as age, sex, gender, and co-occurring connectivity in autism. Structurally, diffusion imaging
conditions; and (iv) hidden subgroups are likely to be studies tend to show altered white matter organisation
the key to understanding the various neurobiological (e.g. reduced fractional anisotropy) of long-range fibre
bases of autism. tracts including the corpus callosum and various associ-
At the whole-brain level, although an influential ation fibres such as the superior longitudinal fasciculus,
theoretical model of reduced global and occipitofrontal fasciculus, inferior longitudinal fasciculus,
increased local connectivity (corresponding to the uncinate fasciculus and cingulum.
9
Frontal, temporal,
High individual variability parietal cortices
Widely distributed systems
Atypical connectivity

Social
processes

Positive valence
systems

Cognitive
systems

Negative
valence
systems
Arousal and
regulatory Sensorimotor
systems systems
Cortical midline regions Subcortical regions Insula, hippocampus,
(e.g. MPFC, PCC, precuneus) (e.g. amygdala) basal ganglia, etc.

Figure 9.1.1 Neurocognitive architecture associated with autism. The brain substrates of autism are complex, characterised by high
heterogeneity of findings, likely underpinned by substantial individual variability, involvement of widely distributed neural systems, and atypical
structural and functional connectivity. Using the US National Institute of Mental Health Research Domain Criteria framework, the involvements
of three systems (orange boxes) are most frequently reported, followed by emerging findings about other systems (yellow and blue boxes). The
brain representations on the right illustrate regions mostly associated with autism, involving cortical and subcortical structures. These regions are
identified based on a term-based automated meta-analysis conducted via Neurosynth.org on July 14, 2019 with the term ‘autism’, which involved
244 studies and 11,329 activations; ‘hot’ colour shows significant voxels in a uniformity test, indicating the degree to which the voxel is consistently
activated in studies that use the term ‘autism’. Abbreviations: MPFC, medial prefrontal cortex; PCC, posterior cingulate cortex.

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 9 Integrated Neurobiology of Specific Syndromes

Using the US National Institute of Mental Health by increased proliferation of neural progenitor cells that
Research Domain Criteria (RDoC) framework, neuro- leads to surface-area hyper-expansion, which underpins
imaging findings suggest converging atypicality across atypical early sensorimotor and attentional experiences;
all six systems but most atypicality centres around three this results in altered experience-dependent neuronal
of them (Figure 9.1.1). First, atypical social processes are development, in particular reduced postnatal pruning,
commonly identified in autism, demonstrated by func- which further contributes to brain overgrowth, altered
tional and anatomical differences in autistic compared excitation–inhibition balance and atypical connectivity
to non-autistic people in the posterior superior temporal from the second year of life [15]. Such observations are
sulcus, temporoparietal junction, medial prefrontal cortex, in line with the idea that atypical early sensorimotor
fusiform face area, inferior frontal gyrus, amygdala, insula and attentional processes are primary in the emergence
and cingulate cortex, many of these considered the ‘social of autism, which results in downstream alterations in
network’ in the brain. Among these, an altered default- complex information processing and social communica-
mode network and its developmental trajectory, which tion [7, 13].
underlies atypical integration of information about self Further evidence supports the idea that the emer-
and other, is a prominent neurocognitive feature [11]. gence of autism starts prenatally through a cascade of
Second, findings regarding positive valence systems processes [16]. Genetic studies show that the aetiologies
suggest atypical reward processing in autism, which of autism are substantially contributed by large-effect,
encompasses not only decreased social but also decreased germline, heterozygous, rare, de novo coding genetic
non-social reward processing, alongside increased reward mutations [17]. In fact, structural variation and mutations
processing associated with fixated interests [8]. Third, find- to both coding and non-coding regions occur in more
ings in cognitive systems are characterised by altered fron- than 30% of individuals diagnosed with autism. Many
toparietal, dorsal attention and ventral attention networks of these genes are expressed prenatally in the brain, are
[12], alongside altered neuromolecular composition biologically pleiotropic and have diverse functions across
(e.g. signalling via gamma-aminobutyric acid (GABA) developmental timing and anatomical distribution.
neurotransmitters) in primary sensory cortices and their However, they do have spatiotemporal ‘convergence’ in
atypical responses across sensory modalities and during encoding synaptic proteins and involving transcriptional
multimodal perception [13]. For the remaining RDoC regulation (Figure 9.1.2) [16, 17]. Such convergence
systems, atypical negative valence systems in autism (e.g. is particularly evident in affecting cortical deep-layer
amygdala, corticolimbic circuitry) may be highly related to glutamatergic excitatory projection (pyramidal) neurons
the frequent co-occurrence of anxiety, emotion process- during mid-fetal development and, less evidently, in the
ing and regulation challenges [14]. There are fewer inves- cerebellum and medial dorsal nucleus of thalamus early
tigations so far into the arousal and regulatory systems postnatally [17]. Such specific spatiotemporal altera-
and sensorimotor systems in autism, but atypicality has tion suggests that the neurodevelopmental processes
been reported. towards autism start in utero, and hence highlights the
impact of both genetics and prenatal gene–environ-
9.1.3 The Molecular– ment interactions [18]; for example, maternal polycystic
Neurobiological Bases of Autism ovary syndrome (marked by hyperandrogenic hormonal
One important development in the neurobiological status) is associated with a 1.66 times increase in the
understanding of autism is research into very early likelihood of offspring autism [19]. These complex inter-
development, particularly the behavioural and brain actions may involve neuroendocrine–immune (e.g. the
development prior to the emergence of the clinical autism prenatal interaction between steroid hormones, micro-
phenotype in infants who have older autistic siblings. glia, neuronal gene expression and morphology) and
These studies found a predictive feature of emerging microbiome–gut–brain processes, even into postnatal
autism, characterised by cortical surface-area hyper- development [20].
expansion in the first year followed by brain-volume over- The molecular bases of autism also involve
growth in the second year [15]. This may be underpinned common genetic variants, which additively add to the

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 9.1 Autism

Figure 9.1.2 High-confidence non-syndromic autism (nsASD) and selected syndromic ‘risk genes’ encode synaptic proteins and chromatin and
transcriptional regulators. Genetic studies have identified a large number of ‘risk genes’ for autism, many of which have pleiotropic functional
properties. Synapse function, chromatin modification and transcriptional regulation top the list of statistically enriched functional categories. On
the left, a simplified schematic of the major cellular components of neural circuits in the cerebral cortex is shown: pyramid-shaped glutamatergic
excitatory projection neurons, GABAergic inhibitory interneurons and glial cells. On the right is shown the diverse intracellular distribution and
pleiotropic roles of high-confidence (false discovery rate (FDR) < 0.1) nsASD ‘risk genes’ and selected syndromic ‘risk genes’. Red outlined circles
depict a view of the synapse with its many protein products of nsASD ‘risk genes’ (top) and the nsASD proteins in the nucleus (bottom). Proteins
in synaptic signalling pathways encompass cell adhesion, scaffolding and signalling molecules. Nuclear protein products of nsASD ‘risk genes’ are
mainly associated with chromatin modification and transcriptional control, suggesting that alterations in chromatin structure and gene expression
may contribute to autism. Figure reproduced from [17].

aforementioned impact of rare variants [21]. Common and higher educational attainment and intelligence [22].
variant effects are typically small and involve multiple Interestingly, the common-variant association with higher
genes; the largest study up to 2019 (involving 18,381 intelligence and educational attainment is only observed
autistic individuals) shows that the polygenic architecture in individuals with a diagnosis of ‘Asperger’s syndrome’
of autism is significantly shared with the risk of psychiatric and those without intellectual disability, suggesting
disorders (i.e. schizophrenia, major depression), ADHD plausible subgroups of autism at the genetic level.

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 9 Integrated Neurobiology of Specific Syndromes

Conclusions and Outstanding excitation–inhibition balance (e.g. through glutamatergic

or GABAergic systems) and neuropeptides (e.g. oxytocin,
Questions vasopressin and serotonin) [4]. Resolving the neurosci-
Recent progress in genetics and molecular biology
entific puzzles is key to answering the critical clinical
extends our understanding to the neurodevelopmental
question of ‘what works for whom’ in enhancing autistic
underpinnings of autism, both prenatally and postnatally.
individuals’ adaptation and well-being.
In light of the well-recognised multi-level heterogeneity
of autism [2], challenges remain in (i) mapping out the Outstanding Questions
relations between the genes and the environmental
• What are the best ways to decompose the
factors and their relations to neurocognitive architec- phenotypic, neurobiological, aetiological and
tures; (ii) identifying factors related to plasticity in devel- developmental heterogeneity of autism?
opmental trajectories; (iii) developing neurobiologically • How will the progress in neuroscientific
informed therapeutics and support strategies that are understanding of autism be translated into useful
tailored to precision medicine and appreciate individual interventions and supports that improve autistic
differences. While the strongest evidence of early inter- people’s adaptation and well-being?
vention focuses on enhancing caregiver–child synchrony • To what extent and in what way can the
and facilitating autistic children’s joint attention and neurocognitive and neurobiological underpinnings
engagement with caregivers, rapidly emerging clinical of autism be understood as reflecting aspects of
trials are also evaluating agents modulating the neural neurodiversity?

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 9.1 Autism

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National Neuroscience Curriculum Initiative online resources

Found in Translation: Autism Genetics and the Quest for Its Rosetta Stone

Jonathan Goldstein, David A. Ross and Daniel Moreno De Luca

This “stuff is really cool: Kartik Pattabiraman, “Mystery of Autism”

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