Journal of Neural Transmission (2019) 126:1187–1202

https://doi.org/10.1007/s00702-018-01965-y

PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE

Imaging stress: an overview of stress induction methods in the MR

scanner
Hannes Noack1,4 · Leandra Nolte2 · Vanessa Nieratschker1,3 · Ute Habel2,5 · Birgit Derntl1,3,4

Received: 8 August 2018 / Accepted: 13 December 2018 / Published online: 10 January 2019
© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Abstract
Processing of acute stress has potential implications for mental and physical health. At the same time, individuals differ
largely in how strongly they react to stress. Neuroimaging paradigms have been developed to characterize the neural under-
pinnings of the stress response in general and to understand the mechanisms that differentiate high and low susceptible indi-
viduals. The goal of the present review was to summarize the current literature on psychosocial stress in the brain imaging
environment. That is, we focused on the most common neuroimaging paradigms that have been used to induce acute stress
and map out the questions that have been addressed with respect to the determinants, the consequences, and the processing
of stress. We identified four major paradigms that have been used with different scientific aims. The Montreal Imaging Stress
Test and the ScanSTRESS involve cognitive challenge and social-evaluative threat and yielded a stress-related network
including most significantly the perigenual ACC, the hippocampus, and the amygdala. The social-evaluative threat paradigm
was used to predict the autonomic stress response on the basis of multivariate pattern analysis. The aversive video paradigm,
on the other hand, was mainly used to investigate the consequences of stress on emotional and cognitive processes and their
neural correlates. We conclude our review with a critical evaluation of methodological and conceptual issues in the study
of the neural correlates of acute stress.

Keywords Stress · Cortisol · Fmri · Hippocampus · PgACC​

Introduction birthday party. Thankfully, our body supports us in meeting

these challenges by providing us with additional energy so
In our daily life, we are sometimes confronted with challeng- that we feel more energetic, more alert and more attentive
ing situations such as giving public presentations, having a than we would normally do under different circumstances.
deadline pending, or entertaining visitors at our own little Originally, Selye (1956) described stress as the stereotypic,
orchestrated physical defense response to external chal-
lenges, which can be highly adaptive for meeting momentary
* Hannes Noack needs. If the challenges persist, however, Selye suggested,
hannes.noack@med.uni‑tuebingen.de the organism would enter phases of resistance, and finally
1
Department of Psychiatry and Psychotherapy, Medical breakdown with severe implications for mental and physi-
School, University of Tübingen, Calwerstrasse 14, cal health (Cohen et al. 2007; Gianaros and Wager 2015;
72076 Tübingen, Germany McEwen 2007). Importantly, subsequent theorizing deem-
2
Department of Psychiatry, Psychotherapy phasized the role of the stressor per se and rather pointed
and Psychosomatics, Faculty of Medicine, RWTH Aachen attention towards the cognitive appraisal of that stressor
University, Aachen, Germany (Lazarus 1993). According to Lazarus’ appraisal theory,
3
Werner Reichardt Centre for Integrative Neuroscience, there are two factors that determine the stress response:
University of Tübingen, Tübingen, Germany In a first step, we would evaluate the significance of the
4
Lead Graduate School, University of Tübingen, Tübingen, present situation for our personal well-being (e.g., does our
Germany job depend on the performance) and in a second step, we
5
JARA Institute of Brain Structure Function Relationship would evaluate whether we have the emotional and prob-
Institute for Neuroscience and Medicine (INM10), lem-related means to tackle the pending threat (e.g., are we
Forschungszentrum Jülich, Jülich, Germany

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1188 H. Noack et al.

well-prepared or not). In line with this theorizing, empirical (Joels and de Kloet 1993) and, therefore, plays a key role in
research has shown that stress can be elicited most reliably the negative feedback loop that regulates HPA axis activ-
if stakes are high and when the situation is novel, unpre- ity (de Kloet et al. 2005; McEwen 2001; Pruessner et al.
dictable, and uncontrollable (Mason 1968). Besides threats 2010; Thiel and Dretsch 2011). The role of the PFC for HPA
to the physical integrity (Peyron et al. 2000)—which are axis regulation is also often discussed (e.g., Herman 2011;
typically rather rare (Herman 2011)—threats to the social McEwen 2007). Herman (2011) suggests, for example, that
self (i.e., social esteem and status) have shown to be par- infralimbic regions have an excitatory effect, whereas pre-
ticularly effective (Dickerson and Kemeny 2004). To the limbic regions like the ACC have an inhibitory effect on
degree that stress results from an extended evaluation of HPA axis activity (Boehringer et al. 2015; Pruessner et al.
the situation and the individual coping resources, stress is 2008). Notably, the amygdala has mainly excitatory influ-
essentially a reaction of the brain and the investigation of the ences (Herman et al. 2005) but is becoming desensitized as
brain response to stressful situations has received increasing glucocorticoid levels rise (Henckens et al. 2010).
interest over the last decade (for reviews see Dedovic et al. The network described above was mainly derived on the
2009a; Kogler et al. 2015b). Once a situation is deemed basis of lesion, pharmacological, and experimental studies
challenging, excitatory projections of the amygdala and the in animals, with human functional studies becoming more
medial prefrontal cortex through the bed nucleus of the stria and more frequent only during the last 15 years. The present
terminalis elicit the two major pathways of the physiologi- review is intended to give an overview over the progress
cal stress response (Herman 2011). There is the autonomic being made using brain imaging techniques to investigate
response on the one hand, which is mediated by the sympa- acute stress reactions. As such, the review follows up on
thetic nervous system and the catecholamines secreted by previous summaries of research using psychosocial stress
the adrenal medulla. It has a fast, directly activating effect induction methods within the scanner environment (Dedovic
on the organism by accelerating heart rate, increasing blood et al. 2009a; Kogler et al. 2015b) and pursues two major
pressure and respiration to prepare a flight-or-fight response goals. (1) We want to map out the research questions that
(Cannon 1929). The hypothalamus–pituitary–adrenal (HPA) have been addressed using these methods, differentiating
axis, on the other hand, mainly results in the secretion of between the determinants, the consequences, and the stress
the steroid hormone cortisol from the adrenal cortex. Com- response itself: that is, we asked which groups have been
pared to the autonomic axis, the HPA axis is rather slow and compared with respect to the stress response of the brain
has a protracted response to the stressor, peaking typically (i.e., determinants) and which measures have been investi-
around 20 min after stressor onset (Kirschbaum et al. 1993). gated under stressed and relaxed states (i.e., consequences)?
This is because signaling occurs entirely on the basis of As previous behavioral research indicated large inter-indi-
hormonal communication: once a stressor is detected in the vidual (Kudielka et al. 2009; Pruessner et al. 2010) and intra-
central nervous system (CNS), corticotropin-releasing hor- individual differences in the stress response (Lupien et al.
mone (CRH) and arginine vasopressin (AVP) are secreted 2009), functional imaging data could potentially help to bet-
from the paraventricular nucleus of the hypothalamus into ter characterize the neural basis of these differences. Simi-
the portal blood system. Arriving at the anterior pituitary, larly, acute stress has been shown to have a differential effect
CRH and AVP induce the synthesis and secretion of adreno- on different cognitive processes, such as executive control
corticotropic hormone (ACTH) into the bloodstream, which functions (Shields et al. 2016) and emotional processes
again induces the synthesis and secretion of cortisol in the such as emotional face perception (van Marle et al. 2009)
adrenal cortex. Cortisol in turn has diverse complementary or reward processing (Porcelli et al. 2012). Delineating the
effects on the organism including metabolic, immunological, mental processes and mapping the brain activity in response
and neural changes, aiming at preparing the body to deal to acute stress (i.e., processes) and during cognitive perfor-
with imminent threat and restorative functions dampening mance after stress could be helpful in determining, which
the effects of the autonomic system and HPA axis itself (de cognitive and emotional processes will be compromised and
Kloet et al. 2005; Thiel and Dretsch 2011). The latter is which not, e.g., due to interfering activations in similar brain
achieved through direct negative feedback effects of cortisol regions. (2) We believe that reporting a standard set of vari-
on hypothalamus and the pituitary. In addition, however, ables would be helpful to systematically characterize stress
other brain structures such as the medial prefrontal cortex reactions induced by different tasks in different populations
(mPFC), anterior cingulate cortex (ACC), hippocampus, and but also to ease latter meta-analytic endeavors. Therefore,
amygdala are also implicated in the regulation of the HPA we evaluated the current state of affairs: which physiological
axis activity (Herman et al. 2005; Kiem et al. 2013). The and psychological measures were typically used to investi-
hippocampus has received particular attention in this regard gate the efficacy of the induction method, which measures
because it has a high density of glucocorticoid receptors were taken to diminish potential anticipatory stress effects
and inhibitory connections to the paraventricular nucleus in the scanner environment (Gossett et al. 2018), and which

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Imaging stress: an overview of stress induction methods in the MR scanner 1189

reporting policy had been adopted, that is, was there any “incorrect”, “timeout”) as well as on their own average per-
information on effect sizes of the stress-related measures, formance relative to the average performance of all other
the ratio of cortisol responders and non-responders, and the participants on a mock performance bar. During the stress
activation pattern during the stress induction reported? condition, showing a progress bar enforces the time limit.
Unbeknownst to the participant, the time limit is dependent
on previous performance and increases or decreases adap-
Methods tively such that, overall, participants typically achieve at per-
formance level of 20–45% correct. Social stress is intensified
Our literature research was conducted during May and June by additional negative verbal feedback given by the experi-
2018 using Web of Science©. An initial search for keywords menter in between two runs of the task (Chung et al. 2016a).
“acute stress” AND [fMRI OR (functional AND magnetic)] In the control condition, there is no time limit for solving
AND healthy resulted in only 34 original articles including the arithmetic tasks and participants are told that their per-
studies that reported on patient populations. Thus, to fur- formance is not being recorded or evaluated. The task was
ther extend our search, we included keywords addressing originally invented as a block design (Dedovic et al. 2005)
specific stress induction paradigms, such as paced auditory of 14 min duration, but can also be used in an event-related
serial addition test (PASAT), “serial subtraction”, “mental design with a randomized presentation of rest, control and
arithmetic” and “social evaluative threat”. In addition, we stress condition and the respective feedbacks with jitters
inspected the lists of articles citing those articles, which had included (eventMIST; Dedovic et al. 2009b).
initially presented new stress induction paradigms (Dedovic The MIST is the most frequently applied fMRI stress
et al. 2005; Lederbogen et al. 2011; Quaedflieg et al. 2013; paradigm that was used in N = 17 studies with a total of
Streit et al. 2014; van Marle et al. 2009). The final sample N = 716 (427 male) healthy participants aged between 17
of our research yielded a total of 45 original articles report- and 57 years by now.
ing on 1904 participants (see Table 1). The central research Psychophysiological stress indices were included in all
questions of these studies are summarized in the Fig. 1, studies apart from two. Cortisol measures were collected
separating between the determinants of the stress response, in 13 studies from which 10 found a significant baseline to
its consequences on other processes and the description of peak increase of salivary cortisol (Boehringer et al. 2015;
the process of the stress response per se. Dedovic et al. 2009b; Khalili-Mahani et al. 2010; Lederbo-
Note that our summary of induction methods in the scan- gen et al. 2011; Pruessner et al. 2008; Shermohammed et al.
ner environment is not complete but rather focusses on the 2017; Tomova et al. 2017; Wheelock et al. 2016; Zschucke
paradigms that have been used in more than three different et al. 2015). However, five studies reported a significant
studies. As a result, implementations of the cold pressor test decrease in cortisol values during the MIST (Chung et al.
(e.g., Schwabe et al. 2008; Schwabe and Schachinger 2018; 2016a, b; Gossett et al. 2018; Kogler et al. 2015a, 2017).
Smeets et al. 2012), which are often used outside the scan- The cortisol non-responder rate which was calculated in
ner, will not be discussed in detail here. We would still like four studies varied between 47.5 and 65.0% (Dedovic et al.
to mention that there are two implementations of the CPT, 2009b; Khalili-Mahani et al. 2010; Pruessner et al. 2008;
where participants have to immerse their non-dominant Wheelock et al. 2016). As another marker of the autonomic
hand in ice-cold water (Porcelli et al. 2008) or a cold arm- stress response, heart rate was analyzed in five studies that
wrap (Porcelli et al. 2012). Another implementation of the indicate an increase in heart rate in beats per minute in the
Maastricht Acute Stress Test (MAST; Smeets et al. 2012), stress phase of the MIST (Boehringer et al. 2015; Gossett
which combines the CPT with social-evaluative pressure and et al. 2018; Kogler et al. 2015a; Lederbogen et al. 2011;
a serial subtraction task, was used in one study (Quaedflieg Shermohammed et al. 2017; Wheelock et al. 2016). Moreo-
et al. 2013, 2015), where the cold pressor was provided by ver, in five studies, the MIST elicited an elevated skin con-
a MR-compatible thermode. ductance response as an indicator of sympathetic activation
(Chung et al. 2016a, b; Gossett et al. 2018; Kogler et al.
The Montreal Imaging Stress Task (MIST) 2015a; Wheelock et al. 2016). An effect on the subjective
emotional stress response was shown in ten studies in terms
The MIST is an adaptation of the Trier Mental Challenge of an increase in perceived stress level (Boehringer et al.
Test (Pruessner et al. 1999) for the scanning environment. 2015; Chung et al. 2016a, b; Inagaki et al. 2016; Shermo-
It essentially combines the stress-eliciting effects of high hammed et al. 2017; Tomova et al. 2017; Wheelock et al.
cognitive demand with negative social evaluation. That is, 2016; Zschucke et al. 2015), increase in negative and
participants are required to solve a sequence of mental arith- decrease in positive affect (Kogler et al. 2015a, 2017) and
metic tasks under time pressure while receiving feedback increased state anxiety (Chung et al. 2016a, b; Zschucke
on their current task response via a text field (“correct”, et al. 2015). In terms of psychological consequences, the

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Table 1  Overview of included studies

Study Task N HPA SAM Subjective BOLD GLM Cortisol
during stress responders/non-
responders

Cousijn et al. AV 41/41 Cort ANOVA HR, sAA PANAS No NA

(2012)
Cousijn et al. AV 41/41 Cort ANOVA HR, sAA PANAS No NA
(2010)
Everaerd et al. AV 120/120 Cort post–pre HRV, HR, BP, sAA PANAS No NA
(2015)
Henckens et al. AV 18/18 Cort AUCi HR, PD PANAS No NA
(2009)
Henckens et al. AV 120/120 Cort % HRV, HR, BP, sAA PANAS No NA
(2016)
Hermans et al. AV 80/53 Cort AUCi HR, sAA PANAS WB NA
(2011)
Ossewaarde et al. AV 28/0 Cort ANOVA HR PANAS No NA
(2010)
Ossewaarde et al. AV 29/0 Cort ANOVA HR, HRV PANAS No NA
(2011)
Qin et al. (2012) AV 29/0 Cort ANOVA HR, HRV PANAS No NA
Qin et al. (2009) AV 44/44 Cort ANOVA HR, PD PANAS No NA
van Marle et al. AV 27/0 Cort ANOVA HRV, HR PANAS No NA
(2009)
van Marle et al. AV 27/0 Cort ANOVA HRV, HR PANAS No NA
(2010)
Young et al. (2017) AV 112/112 Cort post HR, BP PANAS No NA
Porcelli et al. CPT 12/6 NA NA NA ROI NA
(2008), Exp 2
Porcelli et al. armwrap CPT 32/16 Cort AUCi NA Subjective No NA
(2012)
Quaedflieg et al. iMAST 42/21 Cort max-pre sAA Subjective No 26/16
(2013)
Quaedflieg et al. iMAST 42/21 Cort ANOVA HR, Resp Subjective No 27/12
(2015)
Boehringer et al. MIST 25/11 Cort max-pre HR, BP Subjective ROI NA
(2015)
Chung et al. MIST 31/0 Cort post–pre SCR PANAS, STAI, ROI NA
(2016a) subjective
Chung et al. MIST 46/16 Cort post–pre SCR PANAS, STAI, WB NA
(2016b) subjective
Dedovic et al. MIST 22/22 Cort ANOVA NA NA No NA
(2005)
Dedovic et al. eventMIST 28/0 Cort ANOVA NA STAI, POMS WB 10/17
(2009b)
Goodman et al. MIST (mod) 51/29 NA NA NA ROI NA
(2016)
Gossett et al. MIST 57/36 Cort ANOVA HR, SCR NA No NA
(2018)
Inagaki et al. MIST 36/20 NA HR, Resp Subjective ROI NA
(2016)
Khalili-Mahani MIST 23/23 Cort ANOVA, NA NA WB + ROI 9/10
et al. (2010) AUCi, AUCg
Kogler et al. MIST 43/20 Cort post–pre, SCR PANAS, subjec- WB + ROI NA
(2015a) AUCi tive, anger
Kogler et al. (2017) MIST 80/40 Cort ANOVA NA PANAS, ESR WB + ROI NA

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Imaging stress: an overview of stress induction methods in the MR scanner 1191

Table 1  (continued)
Study Task N HPA SAM Subjective BOLD GLM Cortisol
during stress responders/non-
responders

Lederbogen et al. MIST 32/16 Cort post–pre HR, BP Subjective WB + ROI NA

(2011)
Pruessner et al. MIST 40/20 Cort ANOVA, NA NA WB 21/19
(2008) AUCi
Shermohammed MIST + TSST 54/27 Cort ANOVA HR, SCR Subjective No NA
et al. (2017)
Tomova et al. MIST 67/67 Cort ANOVA, NA Subjective No NA
(2017) AUCi, AUCg,
max-pre
Wheelock et al. MIST 53/30 Cort ANOVA HR, SCR STAI, subjective WB + ROI 22/30
(2016)
Zschucke et al. MIST 36/36 Cort ANOVA, sAA PANAS, STAI, WB NA
(2015) max-pre subjective
Akdeniz et al. ScanSTRESS 80/39 Cort max-pre HR Subjective, SERS WB + ROI 47/33
(2014) 46/20 Cort max-pre HR Subjective, SERS WB + ROI 29/16
Dahm et al. (2017) ScanSTRESS 86/36 Cort ANOVA, NA Subjective WB + ROI 55/28
AUCi, AUCg,
max-pre
Lederbogen (2011) ScanSTRESS 47/26 Cort post–pre HR, BP Subjective WB + ROI NA
Streit et al. (2017) ScanSTRESS 65/33 Cort ANOVA HR NA WB + ROI 22/20
Streit et al. (2014) ScanSTRESS 42/22 Cort, ACTH, HR NA WB + ROI 22/20
ANOVA
Eisenbarth et al. SET 18/9 NA HR, SCR Subjective anxiety WB NA
(2016)
Ho et al. (2014) SET 33/0 Post–pre NA NA No NA
Hughes and Beer SET 18/6 NA NA NA No NA
(2013)
Tobia et al. (2017) SET 16/0 NA NA Retrospec. subjec- No NA
tive
Wager et al. (2009) SET 30/10 NA HR NA WB NA
van Ast et al. TSST 21/16 Sal NA PANAS Yes NA
(2016)

Task: stress induction paradigm with Montreal Imaging Stress Test (MIST), ScanSTRESS, aversive video paradigm (AV), social-evaluative
threat (SET), cold pressor test (CPT), imaging Maastricht Acute Stress Test (iMAST), Trier Social Stress Test (TSST)
N number of participants/male number of participants, HPA measures of HPA axis activity: cortisol (cort) and the corresponding analytical
approach, SAM measures of sympatho-medullary system: heart rate (HR), heart rate variability (HRV), blood pressure (BP), pupil delation (PD),
respiration (Resp), skin conductance response (SCR), salivary alpha-amylase (sAA); subjective response measures: subjective stress scales (sub-
jective), positive and negative affect (PANAS), state-trait-anxiety (STAI), subjective emotional response scale (SERS), profile of mood states
(POMS); BOLD was stress-related brain activity reported and if yes, which approach was used? (WB whole brain, ROI region of interest, no no
stress-related brain activity reported)

MIST increased prosocial behavior in the dictator game to the fMRI environment were only reported in two MIST
but no effect on cognitive reappraisal of negative emotions studies with a duration of 20 and 60 min (Gossett et al. 2018;
was observed (Shermohammed et al. 2017; Tomova et al. Shermohammed et al. 2017).
2017). Overall, the MIST seems to elicit a physiological Patterns of stress-related brain activity were reported
and psychological stress response in the majority of stud- in 14 studies. Early reports on the neural signature of the
ies. However, the inconsistent findings regarding the cortisol stress response to the MIST suggested stress-related deac-
response need further consideration in future research and tivation in the limbic system, including the insula, hip-
may be a specific problem of the fMRI environment (Gos- pocampus, amygdala, ACC, and ventral striatum (Dedovic
sett et al. 2018). Relaxing phases prior to stress that could et al. 2009b; Pruessner et al. 2008), but the picture has
address the problem of the anticipatory stress response due grown more diverse over the past 10 years. First, 7 of the

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1192 H. Noack et al.

Fig. 1  A map of topics that have been investigated using stress induction paradigms in the scanner environment

14 studies did not report any stress-related deactivations At the level of physiological determinants, the impact of
(Boehringer et al. 2015; Chung et al. 2016a, b; Dedovic sex on stress reactivity has been investigated in three studies.
et al. 2005; Inagaki et al. 2016; Lederbogen et al. 2011; To date, however, the results do not converge on a clear pat-
Wheelock et al. 2016). To the contrary, activation rather tern of sex-related difference in the stress response. Whereas
than deactivation has been shown for the ACC (Boehringer two studies reported stronger stress-related activation in
et al. 2015; Inagaki et al. 2016; Lederbogen et al. 2011; males than females (Chung et al. 2016b; Kogler et al. 2017),
Zschucke et al. 2015), the hippocampus (for whole brain one study showed females showed stronger activation of the
analyses see Boehringer et al. 2015; for ROI analyses see; superior temporal gyrus than males (Kogler et al. 2015a).
Chung et al. 2016a, b; Dedovic et al. 2009b; Kogler et al. Two physiological biomarkers, that have been linked to the
2015a) and the amygdala (Chung et al. 2016a; Kogler et al. prevalence of stress-related mental disease in the past, the
2015a). In an attempt to pinpoint the association between cortisol awakening response and salivary levels of uric acid,
HPA axis activity and brain activation, three studies have been studied with respect to stress-related neural activ-
included contrasts between responders and non-responders ity, showing differential signatures. Whereas stress-related
in their analysis of the stress-related brain response. Two increase in perigenual ACC activity correlated with the mag-
of the studies showed stronger deactivation in the lim- nitude of the cortisol awakening response (Boehringer et al.
bic system in responders as compared to non-responders 2015), salivary uric acid levels correlated with hippocampal
(Dedovic et al. 2009b; Pruessner et al. 2008), whereas activation (Goodman et al. 2016). Studying physical fitness
Wheelock et al. (2016) found stronger activation in the as a potential resilience factors for the development of men-
vmPFC, posterior cingulate cortex, insula and superior tal diseases showed in fact a beneficial effect in terms of the
temporal gyrus in non-responders, and Khalili-Mahani cortisol response, which was paralleled by a lowered stress-
et al. (2010) did not observe a stress-by-group interaction. related PFC and heightened hippocampal activity (Zschucke
Using correlational approaches to study brain correlates et al. 2015). Psychological factors that have been shown to
of stress-related changes in salivary cortisol, three studies correlate with neural activity during the MIST are social
found associations with hippocampal deactivation (Khal- support, trait anxiety, and self-esteem (Chung et al. 2016b;
ili-Mahani et al. 2010; Lederbogen et al. 2011; Pruessner Inagaki et al. 2016; Kogler et al. 2017). Finally, Lederbogen
et al. 2008), one with the amygdala (Lederbogen et al. et al. (2011) investigated the effects of current and early life
2011) and one with the perigenual ACC (Boehringer et al. environmental conditions as a determinant for acute stress
2015). In terms of the determinants of the stress response, reactivity. Constructing an urbanicity score, which integrates
physiological, psychological, and environmental factors the time spent in either rural, small-town, or metropolitan
have been addressed (see Fig. 1). environments, these authors showed a positive relationship

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Imaging stress: an overview of stress induction methods in the MR scanner 1193

between urbanicity and perigenual ACC activation. Cur- under the curve with respect to increase (AUCi Dahm et al.
rent residence in any of the three environmental categories 2017). Another study, which reported on data previously
was positively associated with amygdala activity, however. reported elsewhere (Lederbogen et al. 2011), found no gen-
Notably, amygdala but not perigenual ACC activation cor- eral increase in serum ACTH or salivary cortisol over the
related positively with stress-related changes in cortisol in stress induction (Streit et al. 2014). In fact, a considerable
this study, underscoring the insight that there are differential number of participants showed marked decline in both HPA
processes implicated in the regulation of acute stress that are axis measures over the baseline period, suggesting relief
susceptible to different determinants. from anticipatory stress. Separating groups on the basis of
changes in cortisol and ACTH respectively, supported this
ScanSTRESS assumption, showing marked increase in the responder and
decrease in the non-responder group. Referring to the fast,
The ScanSTRESS paradigm is a rather recently developed autonomous responses to the stress as compared to the con-
stress task for the neuroimaging environment and was also trol conditions, two studies reported increased heart rates in
inspired by the classic Trier Social Stress Test (Kirschbaum the stress compared to the control conditions (Akdeniz et al.
et al. 1993). Similar to the MIST, participants have to solve 2014; Streit et al. 2014). Finally, subjective stress level was
challenging cognitive tasks (here serial subtraction and assessed in all three data sets, but only Akdeniz et al. (2014)
mental rotation) under time pressure, but social evaluation reported a significant increase of self-reported stress.
threat is enforced through the presence of a jury panel of On the neural level, all studies reported on the brain activ-
two researchers in white lab coats in the control room of the ity via contrasting stress blocks with control blocks. Across
fMRI scanner. Participants are told that the jury will moni- studies, stress processing involved a distributed network
tor their performance as well as their mimics and behavior with activations in the ventral striatum, insula, posterior
via a live video of their faces. A mock camera is installed hippocampus, amygdala and deactivations in the subgenual,
on the head coil for that purpose. During the task, partici- perigenual or rostral ACC, depending on the study (Akdeniz
pants can also see the jury panel via a live video stream and et al. 2014; Dahm et al. 2017; Lederbogen et al. 2011; Streit
receive direct visual feedback—such as “Work faster!” or et al. 2014). Dahm et al. (2017) even reported a more pro-
“Error!”—on their performance. The jury members directly nounced differentiation of the stress-related brain response
elicit feedback when pressing a big red buzzer that is visible after participants were confronted with the additional nega-
in the live video. Task difficulty and speed are adapted to tive verbal feedback by the jury panel. Notably, one study
individual’s performance resulting in frequent failure and (Akdeniz et al. 2014) found a positive association between
subsequent negative feedback, which both should enforce stress-related activity in the perigenual ACC and changes
the impression of uncontrollability. In contrast to the stress in salivary cortisol levels and heart rate after the feedback
condition, social-evaluative threat and cognitive challenge break again, similar to reports from the MIST (Boehringer
are largely relaxed during the control condition. Participants et al. 2015).
engage in an easy figure and number matching tasks without In terms of inter-individual determinants of the stress
time pressure and the social feedback is deemphasized, as response, the ScanSTRESS has been used to study envi-
the jury panel does not react to the participants’ performance ronmental factors related to urbanicity and pertaining to
anymore and the video screen is overlaid by a large red cross. an ethnic minority (Akdeniz et al. 2014; Lederbogen et al.
Stress and control conditions are presented block-wise with 2011), physiological factors such as genes and sex (Streit
each block taking 80 s rest in between. Additional verbal et al. 2014, 2017), and psychological factors such as consci-
feedback is provided by the jury panel after the first half of entiousness (Dahm et al. 2017). As target regions for map-
the paradigm: one jury member states that the participant’s ping individual differences, authors focused on the ACC
performance was below average and the data cannot be used und amygdala as prominent regions in the stress regulatory
unless he or she tries harder in the second half. Altogether, system. Findings reported above for the MIST, showing
the ScanSTRESS paradigm takes 23 min. that urban upbringing was related to stress-related perigen-
So far, the ScanSTRESS was reported in five articles with ual ACC activity but current residence was associated to
a reported total of n = 315 healthy participants (165 males). amygdala activity, were replicated using the ScanSTRESS
Since two of these reports presented re-analyses of subsam- (Lederbogen et al. 2011; Streit et al. 2014). These findings
ples of previous data (Streit et al. 2014, 2017), the actual were further qualified in an analysis of gene x environment
total sample size is reduced to n = 259 healthy participants interactions. Variations in the neuropeptide S receptor gene,
(131 male) aged between 19 and 43 years. which is associated with stress-related phenotypes, modu-
Regarding the physiological stress effect, two studies lated the association between stress-related amygdala activ-
found a significant increase of salivary cortisol reported as ity and urban upbringing, with a significantly stronger effect
baseline to peak increase (Akdeniz et al. 2014) and area in cortisol responders than in non-responders (Streit et al.

13
1194 H. Noack et al.

2014). The role of the perigenual ACC in mediating envi- 2009) and emotional responses to acute stress (Tobia et al.
ronmental aspects over the lifespan was further underlined 2017), only little information is available on the impact of
by the finding that ethic minority groups, who differ in terms SET on HPA axis activity. Only one study analyzed corti-
of perceived chronic stress, also differed in stress-related sol responses in an exclusively female sample and no main
perigenual ACC activity (Akdeniz et al. 2014). Finally, one effect of stress induction was reported (Ho et al. 2014).
study investigated the effect of conscientiousness on subjec- Yet, another two studies observed a significant increase in
tive experiences of acute stress during the ScanSTRESS and the autonomic stress response including heart rate (Eisen-
its neural correlates (Dahm et al. 2017). In fact, the authors barth et al. 2016; Wager et al. 2009) and skin conductance
found a positive correlation between conscientiousness and response (Eisenbarth et al. 2016).
subjective stress but not cortisol response. Within female Neural activation during the SET paradigm was mostly
participants, the association between stress and conscien- used for advanced approaches to analyze fMRI data, namely
tiousness tended to differ between females who were taking machine learning (Eisenbarth et al. 2016), multi-level path
oral contraceptives and those who were not. At the neural modeling (Wager et al. 2009), and dynamic functional con-
level, these authors did not observe sex-related differences at nectivity (Tobia et al. 2017) or the comparison of different
the level of average activation patterns. A mediation analysis models (Sobel and Lindquist 2014). These approaches iden-
suggested that the influence of stress-related amygdala and tified a limbic network that is correlated with heart rate and
insula activity on individual salivary cortisol responses was skin conductance response during SET and a further asso-
further mediated by conscientiousness. ciation of heart rate and activity in the ACC, orbitofrontal
Overall, previous studies indicate that the ScanSTRESS cortex, putamen and amygdala was reported. Networks that
paradigm is a promising new tool for investigating neural are related to emotions during SET are partly overlapping
correlates of social-evaluative threat, which, through the use including the cingulate and amygdala as well as the vmPFC
of direct video feedback, may further emphasize the feeling and anterior insula (Tobia et al. 2017).
of social evaluation within the participant. As there are only Two more studies used different ways to induce social-
three original data sets reported to date, many open ques- evaluative threat. In one study with n = 21 participants (11
tions remain and wait for further investigation. males), participants actually gave the speech they prepared
in the fMRI scanner in a different room and then turned back
The social‑evaluative threat paradigm (SET) into the scanner for an n-back working memory task (Van
Ast et al. 2016). This resulted in a significant increase of
This stress paradigm has its roots in the classic Trier Social salivary cortisol levels in the stress group and detrimental
Stress Test (TSST), where participants are asked to speak effects on working memory but no effect on negative sub-
about themselves in front of an emotionally disengaged com- jective affect was observed. In a second study with n = 18
mittee of two people wearing white lab coats (Kirschbaum participants (6 males), participants were photographed and
et al. 1993). Before entering the scanner, participants are received ostensible feedback during fMRI about their lik-
provided with earphones and a microphone. Then, after per- ability (Hughes and Beer 2013).
forming anatomical scans first, participants are told that they To sum up, it needs future research to show if the SET
will have to prepare for a speech that will be audiotaped in is an effective and valid stress induction method and com-
the scanner and then judged by other students on persuasive- parable to other stress paradigms. Nevertheless, modeling
ness, organization, and intellectual quality. They are further approaches of brain activation that take into account physi-
told that some participants will be selected on a random ological and emotional stress markers seem promising for
basis not to give the speech. They are then asked to relax and stress research in general.
look at a central fixation cross. This 2-min baseline period
of relaxation serves as a baseline condition. After the end
of this baseline period, the topic of the speech (“Why am I The aversive video paradigm
a good friend?”) is provided and participants are asked to
prepare a strict 7-min speech within the following 2 min. This procedure makes use of the aversive effect of violent
Thereafter, participants are told that they will not have to video scenes, which—according to the authors—will be per-
give the speech and are asked to relax once more for another ceived as novel, unpredictable, and uncontrollable, thereby
2.5 min as a second baseline phase. Altogether, the paradigm activating the human psychological stress response. Par-
takes 7 min. ticipants are asked to immerse themselves while watching
Five studies with a total sample size of n = 155 partici- these 1:30–2:20 min long scenes by taking an eye-witness
pants (25 males) have applied the standardized protocol of perspective (scenes taken from Irrevérsible, G. Noé). In a
the SET induction so far. As these studies mainly focused control condition, participants watch neutral video clips of
on the cardiovascular (Eisenbarth et al. 2016; Wager et al. the same length comparable in amount of speech, human

13
Imaging stress: an overview of stress induction methods in the MR scanner 1195

presence, luminance and language (Comment j’ai tué mon et al. 2011; Qin et al. 2009; van Stegeren 2009; Young et al.
père, A. Fontaine). 2017). Also, all studies reported a significant increase of
To date, the aversive video paradigm was used in 13 stud- negative effect in the aversive video condition, while no dif-
ies with a reported total sample size of n = 763 healthy par- ferences were observed for positive affect. Overall, the aver-
ticipants (609 males) aged between 18 and 38 years. How- sive video paradigm elicited a robust physical and affective
ever, some studies reanalyzed previously published samples stress response.
(Cousijn et al. 2010, 2012; Everaerd et al. 2015; Henckens The aversive video paradigm was mainly used to inves-
et al. 2016; Qin et al. 2012; van Marle et al. 2009, 2010) tigate the consequences of stress on emotional and cogni-
leading to a reduced actual sample size of n = 417 partici- tive processing and only one study reported on the neural
pants (335 males). correlates of the stress response per se. Using a model-free
The stress and control condition were usually applied in approach to analyze the brain response to the video mate-
two sessions, separated by 20 min, several days, or 1 month rial, Hermans et al. (2011) identified stronger activation
in between participants or crossover designs (Cousijn et al. in the aversive compared to the neutral video condition in
2010, 2012; Everaerd et al. 2015; Henckens et al. 2009) regions promoting salience processing (e.g., insular cortex
The video scenes were exclusively used to induce stress and IC, dACC, AMG, mPFC), as well as regions involved in
to study its consequences on other cognitive or emotional sensory and attentional reorienting (thalamus, inferotempo-
paradigms and their neural correlates. Nine studies also ral, temporoparietal junction). The authors suggest that the
reported a relaxation period for participants to acclimate to observed activity differences result from large-scale network
the experimental setting before moving into the scanner to reorganization engaging the salience network in a stress-
gain more valid baseline measurements. The duration of the related manner. Yet, although network strength was corre-
relaxation period ranged from 30 to 90 min and commonly lated with cortisol as well as salivary alpha-amylase levels, a
included filling out questionnaires, instructions and practice pharmacological follow-up study showed that network reor-
trials of the tasks but also relaxing nature documentaries ganization was mainly driven by noradrenergic activity. For
in some cases (Everaerd et al. 2015; Henckens et al. 2009, studying the effects of stress on emotional processing, the
2016; Ossewaarde et al. 2010, 2011; Qin et al. 2009, 2012; dynamic facial expression task was used. Here, participants
van Marle et al. 2009, 2010; Young et al. 2017). passively view blocks of faces morphing dynamically into
The effectiveness of the paradigm in eliciting a physi- happy or fearful expressions. Only one of five studies using
ological stress response was assessed in all 13 studies with this paradigm reported a main effect of the aversive video
at least 2 different parameters. Significantly higher salivary stress induction on amygdala activation (van Marle et al.
cortisol output in the stress condition was observed in all 2009). However, interaction effects with individual differ-
studies apart from one (Ossewaarde et al. 2010). Yet, not all ences emerged so that greater amygdala activation during
studies found an actual increase of cortisol response caused emotional face processing was associated with the reduced-
by the aversive videos. In three studies, cortisol values stead- function variant of the ADRA2B gene, high neuroticism
ily decreased over time in both the stress and control group, scores, low basal levels and a high stress induced increase
probably due to diurnal rhythm and habituation to the scan- of cortisol, and an early menstrual cycle phase (Cousijn et al.
ner environment, but decreased not as steep in the stress 2010; Henckens et al. 2010; Ossewaarde et al. 2010).
group leading to a significant difference after the first movie For studying the consequences on cognitive perfor-
clip of four clips in total (Ossewaarde et al. 2010, 2011; Qin mance, the n-back working memory task and the picture
et al. 2009, 2012; van Marle et al. 2009, 2010; Young et al. encoding task were applied. Two studies investigating
2017). Compared to other stress studies, however, these par- stress-related changes in working memory, yielded incon-
ticipants would have been characterized as non-responders. sistent results with one study showing stress-related reduc-
In this regard, no study reported the proportion of cortisol tions in hippocampus and amygdala activity (Cousijn et al.
responders and non-responders. As a sympathetic stress 2012) and another study showing stress-related reduc-
marker in saliva, alpha-amylase levels were included in four tions in DLPFC activity (Qin et al. 2009). In an attempt
studies resulting in inconsistent findings: in three studies to investigate the underpinnings of stress-related changes
analyzing the same sample, alpha-amylase increased during in memory formation, another two studies used picture-
violent movies (Cousijn et al. 2010, 2012; Hermans et al. encoding tasks where stress lead to increased activation
2011), whereas two other studies found no effect (Everaerd in visual- and attention-related regions (Henckens et al.
et al. 2015; Henckens et al. 2009). Apart from that, all 13 2009; Qin et al. 2012). Moreover, functional connectiv-
studies reported a significant increase of heart rate in beats ity after the aversive movie paradigm was investigated by
per minute and 7 studies further found a decreased heart two studies of which one found an enhanced functional
rate variability in the stress condition (Cousijn et al. 2010; coupling between amygdala and the dorsal ACC, anterior
Everaerd et al. 2015; Henckens et al. 2016; Ossewaarde insula and locus coeruleus (van Marle et al. 2010) and the

13
1196 H. Noack et al.

other an increased association of physiological arousal and which again may inform an even more specific study of
salience network cohesion (Young et al. 2017). inter-individual determinants.
All in all, the aversive video paradigm elicits a reliable
autonomic and HPA axis stress response. Experimental design

Careful design of stress induction methods is essential

especially because the HPA axis response unfolds over
Discussion many minutes and has complex effects on subsequent stress
responses (de Kloet et al. 2005; Sapolsky et al. 2000). Great
In this review, we sought to summarize the progress in care is therefore needed to establish stable baseline condi-
research on the brain response to acute stress. We identi- tions. The importance of the issue has been impressively
fied four major paradigms that were repeatedly used in demonstrated in a recent study, showing that the mere antici-
the scanner and described practical aspects such as sam- pation of being immersed in the scanner environment elic-
ple characteristics, reported peripheral measures, and the ited similar degrees of HPA axis activity as one of the most
effectiveness in eliciting a reliable stress response. In addi- effective stress induction methods available (TSST; Gossett
tion, we tried to map the current topics in stress research et al. 2018). Further complicating the matter, the authors
by summarizing the determinants and consequences of reported a reliable decrease of cortisol levels from baseline
the neural stress response as well as aspects of the stress to post-stress, suggesting that higher baseline levels may
response itself (Fig. 1). disrupt the cortisol response to the stressor during fMRI.
Notably, these studies differed considerably in their That is, stress responses to the scanning environment and
designs, possibly inducing different kinds of threat and the experimental stressor will likely mix if acclimatization
thereby eliciting different cognitive and emotional coping periods within the scanner are not sufficiently long (approx.
processes. For example, three of the described methods 45 min) and, in addition, participants with a particularly
capitalized on the stress-inducing effect of social evalua- strong response to the scanning environment will mistak-
tion (MIST and ScanSTRESS) or its anticipation (SET). enly be classified as non-responders if baseline levels are
Two of these procedures additionally induced cognitive not sufficiently accounted for. Despite considerable efforts,
load and time pressure (MIST and ScanSTRESS), whereas these two demands are likely not sufficiently met in most
the other mainly capitalized on the emotional aspects of of the articles reviewed here. Incomplete reporting of the
social evaluation without further cognitive challenge exact acclimatization procedures in most of the studies (only
(SET). Finally, the aversive video paradigm, which was nine report on acclimatization) make it difficult however, to
built on the threatening effect of being confronted with thoroughly evaluate its effect. In those studies, where accli-
highly aversive video material, was different from the oth- matization was mentioned explicitly, participants typically
ers in as much as there was no direct need for action and performed on other tasks or questionnaires outside of the
there was no social evaluation. We thus believe that—due scanner for periods of 20–90 min. In an attempt to minimize
to their design—the different stress paradigms yield the scanner-specific artifacts, some studies have familiarized
possibility to construct task designs that emphasize dif- their participants with the environment either through the
ferent aspects of the stress response and that could be use of mock scanners (Gianaros et al. 2012), by familiarizing
used to ask more specific questions. A rigorous system- and testing them on separate days (Dahm et al. 2017), or by
atic characterization of the differences and commonali- recruiting only scanner-experienced participants (Cousijn
ties of the different paradigms with respect to subjective, et al. 2010, 2012; Streit et al. 2014).
peripheral, and neural correlates would allow researchers Finally, as circulating cortisol levels vary greatly during
to pick the most suitable method for their needs, thereby the course of the day (Weitzman et al. 1971), control for
exploiting the existing resources more fruitfully. As we time-of-day-effects is imperative for optimal experimental
have shown here, such comparative analyses are difficult designs in stress research. In an attempt to minimize the
today, because the different approaches have been used to effect of confounding circadian factors, most studies (19)
address different and partly non-overlapping aspects of the were conducted during afternoon till early evening. Again,
stress response. In the following discussion, we raise sev- the impact is difficult to determine, however, as information
eral critical aspects of stress research in the scanner envi- on the time of day of testing was simply not reported in the
ronment that may be helpful in bringing these approaches remainder of the studies (with the exception of one study
closer together. Looking at experimental designs, periph- that explicitly tested participants during the entire day; Ho
eral measures, and the neural signature, we discuss ways et al. 2014).
to purify the study of the process of the stress response, A related problem derives from the sequence of alternat-
ing stress and control conditions in block but especially in

13
Imaging stress: an overview of stress induction methods in the MR scanner 1197

event-related designs (e.g., Dedovic et al. 2009b). Again, this set of samples (see Table 1). Pruessner et al. (2003) have
due to the sluggishness of the autonomic and the HPA axis shown for example that—depending on how the samples
response, stress-related regulatory brain activity will be pre- are aggregated-different aspects like baseline differences
sent during both, the control and the stress conditions—at (e.g., area under the curve with respect to ground; AUCg)
least after several minutes. Although maximum levels of or differences in change (area under the curve with respect
free serum cortisol typically peak at 20–30 min past stressor to increase; AUCi) can be emphasized. Other approaches
onset (Kirschbaum et al. 1993), i.e., when most of the induc- like picking the maximum individual level of the post-stress
tion procedures will have terminated, early non-genomic samples have also been used. These approaches seem prefer-
effects of cortisol increase may still be unfolding and pos- able to simple pre–post measures, as they draw information
sibly suppressing the autonomic stress response in late tri- from more sampling time points, however, compared to the
als (de Kloet et al. 2005; Sapolsky et al. 2000). In addition, AUC, they are not optimal in terms of reliability because
sympathetic innervation and the release of catecholamines they omit information contained in those samples with sub-
from the adrenal medulla are much faster in inducing arousal maximal cortisol levels. Thus, aggregate measures of the
and thereby influencing brain network dynamics (Young cortisol stress response may strongly differ in reliability as
et al. 2017). Thus, to the degree that brain regulation of the well as their conceptual meaning, which should be consid-
stress response in general is of interest, the within-subjects ered when these measures are taken either to separate groups
experimental designs, which are currently used, might not be or to investigate correlations with neural activity. Yet, in
optimally suited. To our knowledge, no systematic attempt establishing the effectiveness of the stress induction on sali-
has been undertaken to assess the magnitude of the effects vary cortisol levels, most of the studies simply resorted to
of cumulating levels of stress hormones on brain activation ANOVAs investigating whether cortisol levels differed at
during control conditions. However, fixed-sequence proce- one of the many sampling time points.
dures with control condition being always presented first and In addition to these differences in measurement, there
stress conditions taking place later have been reported (e.g., were also differences between studies in how the cortisol
Goodman et al. 2016; Kogler et al. 2015a; Zschucke et al. responses were incorporated into the analysis of behavioral
2015). Despite increasing the sensitivity of the task to stress- and neural effects. Whereas some studies formed groups post
related differences in brain activation, they bear the caveat of hoc on the basis of individual cortisol responses contrasting
confounding time-order effects. Otherwise, between-subjects cortisol responders with non-responders (e.g., Dahm et al.
designs (e.g., van Marle et al. 2009), where stress and con- 2017; Dedovic et al. 2009b; Pruessner et al. 2008; Streit
trol conditions are performed in different groups, could also et al. 2014), others just reported average brain activation
mitigate the issue at the cost of lower power due to notori- irrespective of the cortisol responses of the individual par-
ously large inter-individual differences in the stress response ticipants (e.g., Kogler et al. 2015a; van Marle et al. 2009)
(Kudielka et al. 2009). and yet again, others focused exclusively on the cardiovas-
Finally, we found inconsistencies across studies regard- cular stress response (e.g., Wager et al. 2009). According to
ing the way the HPA axis activity was operationalized. The the results by Gossett et al. (2018), the conceptual meaning
cortisol stress response is a slow and highly non-linear pro- of the separation between responders and non-responders
cess and the reliability of measured stress-related changes must be reconsidered, as it may not hold as a good proxy
therefore depends on at least two different choices: First, category for inter-individual differences in the stress reactiv-
sampling frequency and phase may determine whether we ity if the issue of acclimatization is not properly considered.
are able to detect maximal amplitude changes or not. If In addition to this conceptual concern described above, there
saliva samples are taken only at baseline and once after the are other critical issues associated with artificially dichoto-
stress induction (Cousijn et al. 2010, 2012; Henckens et al. mizing a continuous measure post hoc. Most of all, it sug-
2016; Hermans et al. 2011; Kogler et al. 2017; Wheelock gests a qualitative difference between groups that may not be
et al. 2016), the estimated mean magnitude of the stress- warranted by the inter-individual distribution of the cortisol
related cortisol level change will strongly depend on the responses. To the degree that the sample distribution of cor-
exact timing of the post-stress sample. In addition, the reli- tisol change is a Gaussian, centered over zero, for example,
ability of the measure will be attenuated to the degree that the separation would just represent random deviations to
the trajectories of the individual cortisol responses differ the one or the other side of the continuum. Finally, dichoto-
and will therefore be sampled at different distances to the mizing is not advisable from a statistical point of view as it
individual maximum. To overcome this limitation, other reduces the information contained within the explanatory
studies sampled salivary cortisol between five and nine variable (e.g., change in cortisol) thereby diminishing its
times over the course of the experiment, thereby increas- explanatory power (Fedorov et al. 2009). Yet, as individu-
ing the chances to sample the individual maximum more als differ largely in their stress response, just pooling these
closely. The other choice now refers to the integration of individuals without any reference to a valid marker of the

13
1198 H. Noack et al.

physiological stress response also bears the potential for overlapping brain regions (Gianaros and Wager 2015), while
inconclusive results—the greater the specific stress-related not be tightly correlated across individuals. In a recent study,
inter-individual difference in brain activity, the stronger the Ali et al. (2017) showed that participants experienced sub-
potential bias. jective stress during the TSST despite their autonomic and
endocrine stress response being suppressed through phar-
Peripheral measures macological interventions. Clearly, the problem is not new
and different approaches have been pursued to overcome it:
The autonomic system and the HPA axis responses to stress first, at the level of task design, the careful construction of
are strongly interwoven in their action especially during control conditions has been used to target specific compo-
early, acute phases of the stress response (de Kloet et al. nents of the response. Introducing the eventMIST, Dedovic
2005). It does not come as a surprise then that both systems et al. (2009b) tried to purify aspects of numerical cognition
are influenced by similar conditions such as early life stress from negative feedback and social evaluation. Notably, par-
(Carroll et al. 2017; McEwen 2007). Yet, activation of both ticipants are confronted with some mathematical challenge
is not equivalent and may well complement or counteract also in the standard implementation of the control condi-
each other. Thus, the full picture of group differences in tion of the MIST but compared to the stress condition social
stress reactivity can only be understood if both measures evaluation, time pressure and difficulty are relaxed so that
and their interrelation are carefully considered. We found additional control conditions could be helpful. Using the
that 26 of the 45 the studies in this review provided the basis ScanSTRESS paradigm, Akdeniz et al. (2014) used addi-
for such interactional analysis by reporting on dependent tional control experiments to verify the specificity of stress-
measures of both systems. However, only few studies per- related activity differences in different ethnic groups (see
formed analyses, which explicitly targeted the interplay of also Lederbogen et al. 2011). To this end, they devised an
autonomous and HPA axis activity. n-back and an emotional face-matching task in an attempt
to control for task-related emotional and cognitive aspects,
The neural signature of acute stress respectively.
To directly link stress-related neural activity changes
The four major stress induction paradigms presented here to either HPA axis, autonomic or subjective stress percep-
are rather complex, possibly drawing on multiple cognitive tion, univariate correlational or mediational analyses have
and emotional processes in parallel, such as appraisal of a been used. Comparing the neural stress response of cortisol
threat, emotion-focused, and problem-focused cognitive responders from non-responders allows to identify activity
coping strategies (Lazarus 1993). In the MIST, participants patterns that are specifically linked to the activation of the
deal with time pressure, more difficult numerical problems, HPA axis (see Table 1). Also, univariate correlation analyses
social evaluation, threat of failure, and increasing levels of have been applied to associate functional connectivity (Tobia
arousal, all at the same time. Not surprisingly, the neural et al. 2017) or activity in certain ROIs with target meas-
response to this challenge is also complex, incorporating a ures of stress, suggesting a link between vmPFC activity
large network of limbic, prefrontal, subcortical, temporal, and subjective stress experience (Wheelock et al. 2016) and
and parietal regions. Notably, the exact pattern of activation between perigenual ACC (Akdeniz et al. 2014; Boehringer
and deactivation does not always match between studies, et al. 2015), amygdala, or hippocampus (e.g., Khalili-
e.g., using whole brain analyses, stress-related activation Mahani et al. 2010; Lederbogen et al. 2011; Pruessner et al.
of the amygdala has been reported (e.g., Zschucke et al. 2008) activity and stress-related changes in salivary cortisol
2015), but also deactivation (e.g., Pruessner et al. 2008) or concentrations. Multivariate approaches have been used to
absent activity changes (e.g., Chung et al. 2016a, b; Kogler predict individual cardiovascular (Eisenbarth et al. 2016;
et al. 2015a) and similar patterns emerged for other brain Wager et al. 2009) and skin conductance (Eisenbarth et al.
regions such as the hippocampus and the perigenual ACC. 2016) responses to social-evaluative threat and emotional
Notwithstanding these inconsistencies, which could be responses to the perception of aversive pictures (Chang et al.
solved by means of meta-analytic approaches (e.g., Kogler 2015) from brain activation. Using the latter approach bears
et al. 2015b), there is an additional conceptual challenge great potential for the investigation of different aspects of the
that needs to be addressed, namely to disentangle activa- stress response, because different signatures can be poten-
tion associated with the specific task components at hand tially identified relative to the autonomic, the HPA axis, and
(e.g., cognitive and emotional challenge) from activation the subjective stress response. The approach allows to go
that is specifically linked to the physiological response as beyond analysis of single ROIs, thereby increasing the avail-
well as the subjective assessment of the situation. Distin- able information as well as decreasing the problem of mul-
guishing the latter two components is important in as much tiple testing that is usually present in univariate approaches
as appraisal and cardiovascular regulation seem to draw on (Cremers et al. 2017).

13
Imaging stress: an overview of stress induction methods in the MR scanner 1199

Thus far, literature has mainly looked at the link between differences such as physical fitness (Zschucke et al. 2015),
neural signatures and physiological measures from a func- emotion regulation strategies (Kogler et al. 2015a), and envi-
tional perspective, asking the question how the brain modu- ronmental factors have received only little attention to date.
lates changes in autonomic and HPA activity. Importantly,
however, changes in cardiovascular (Shmueli et al. 2007),
or respiratory (Birn et al. 2006) activity may induce non-
neuronal fluctuations in the BOLD signal at a level similar to Conclusions
task-related activity changes (Caballero-Gaudes and Reyn-
olds 2017). The issue is particularly relevant in the field of We conclude that great progress has been made in the under-
stress research as the task conditions (stress and control) standing of the neural correlates of acute stress. Research
typically differ with respect to cardiovascular and respiratory over the past 15 years has yielded specific regions, which
parameters and as a consequence peripheral noise effects are possibly involved in the regulation of the HPA axis, the
may not be equally distributed across conditions. Although cardiovascular and the subjective response to stress. Yet,
there are several ways to handle these sources of noise— several inconsistencies in the exact activation patterns—even
e.g., based on external measures of cardiac or respiratory across studies using the same induction paradigm—limit the
activity like electrocardiography (ECG) or photoplethys- conclusions, however, and deserve further investigation. The
mography (PPG)—and most of the studies reviewed here stress reaction is a complex phenomenon involving different
have acquired these data for quantification of the autono- physiological and psychological processes. Efforts have been
mous stress response, none of the studies explicitly stated made to disentangle these different components, but to date a
to have used denoising methods to clean the BOLD signal coherent neuropsychological model, which would also allow
from peripheral noise. for more specific analyses regarding inter-individual differ-
ences, is lacking. Yet, due to the diversity in experimental
Inter‑individual differences designs, induction methods, and analytical strategies, the
construction of such a model appears to be within reach.
Determining the exact processes and neural signatures that
Acknowledgements We thank Maxi Bürkle and Melina Grahlow for
influence the various stress outcomes does not just have their support in collecting the references and making the figure. This
academic value, as extreme or chronic stress has potential research was supported by the Deutsche Forschungsgemeinschaft
implications for physical and mental health (Gianaros and (DFG; DE 2319/6-1 awarded to BD, UH, and VN).
Wager 2015; McEwen 2007). To understand and to possibly
diminish these implications must be a major goal for stress Compliance with ethical standards
research. Consequently, Pruessner et al. (2010, p. 181) noted
Conflict of interest The authors declare that they have no conflict of
that: “One of the most interesting aspects of investigating
interest.
stress and the regulation of the HPA axis are inter-individ-
ual differences—why are some people more vulnerable to
the effects of stress and develop stress-related diseases […]
while others show remarkable resilience?”. In fact, in behav- References
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