Molecular Psychiatry (2022) 27:514–524

https://doi.org/10.1038/s41380-021-01047-8

EXPERT REVIEW

A neural model of vulnerability and resilience to stress-related

disorders linked to differential susceptibility
1 2
Judith R. Homberg ●
Jadzia Jagiellowicz

Received: 6 August 2020 / Revised: 19 January 2021 / Accepted: 3 February 2021 / Published online: 1 March 2021
© The Author(s), under exclusive licence to Springer Nature Limited 2021

Abstract
Expert opinion remains divided concerning the impact of putative risk factors on vulnerability to depression and other stress-
related disorders. A large body of literature has investigated gene by environment interactions, particularly between the
serotonin transporter polymorphism (5-HTTLPR) and negative environments, on the risk for depression. However, fewer
studies have simultaneously investigated the outcomes in both negative and positive environments, which could explain some
of the inconclusive findings. This is embodied by the concept of differential susceptibility, i.e., the idea that certain common
gene polymorphisms, prenatal factors, and traits make some individuals not only disproportionately more susceptible and
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responsive to negative, vulnerability-promoting environments, but also more sensitive and responsive to positive, resilience-
enhancing environmental conditions. Although this concept from the field of developmental psychology is well accepted and
supported by behavioral findings, it is striking that its implementation in neuropsychiatric research is limited and that
underlying neural mechanisms are virtually unknown. Based on neuroimaging studies that examined how factors mediating
differential susceptibility affect brain function, we posit that environmental sensitivity manifests in increased salience network
activity, increased salience and default mode network connectivity, and increased salience and central executive network
connectivity. These changes in network function may bring about automatic exogenous attention for positive and negative
stimuli and flexible attentional set-shifting. We conclude with a call to action; unraveling the neural mechanisms through which
differential susceptibility factors mediate vulnerability and resilience may lead us to personalized preventive interventions.

Introduction according to both supportive [3–5] and non-supportive

meta-analyses [6, 7], it remains inconclusive whether the
Despite almost 20 years of research, there is still no con- combined effect of the s-allele and stress increases vulner-
sensus on the links between candidate genes and stress- ability to depression. Several arguments pertaining to study
related disorders, such as anxiety, depression, and post- methodology have been proposed to explain the incon-
traumatic stress disorder (PTSD). One candidate gene is the clusive findings respecting the 5-HTTLPR × stress inter-
serotonin transporter-linked polymorphic region (5- action on the risk for depression. Highly divergent samples
HTTLPR). The short (s) allelic variant of this polymorph- [3, 6, 8], study designs [9, 10], measures [3, 4], and ana-
ism is associated with reduced transcription of the serotonin lyses; as well as limited power [6] have limited study
transporter gene as compared with the long (l) allelic variant comparisons. Neglecting to include relevant studies (e.g.,
[1]. It has been well-established that the s-allele is asso- studies addressing childhood adversity) of 5-HTTLR ×
ciated with increased stress sensitivity [2]. However, stress and depression has also been used to explain null
findings [3].
Although it remains unclear which parameters are most
critical for valid meta-analyses of the 5-HTTLPR × stress
* Judith R. Homberg interaction and risk for depression, all studies seem to have
judith.homberg@radboudumc.nl
overlooked the accumulating evidence that the 5-HTTLPR
1
Department of Cognitive Neuroscience, Donders Institute for mediates not only sensitivity to negative but also positive
Brain, Cognition and Behavior, Radboud University Medical environmental stimuli [11–15] (but see [16–18]). Fully
Center, Nijmegen, The Netherlands ignoring positive life events introduces unaccounted het-
2
Highly Sensitive Society, Cambridge, ON, Canada erogeneity into the studies included in the meta-analyses.
A neural model of vulnerability and resilience to stress-related disorders linked to differential. . . 515

Specifically, it is possible that positive life events have for a long time dominated. According to this framework,
“buffered” the effects of negative life stress. In support, some individuals are disproportionately, if not exclusively,
Kaufman [19] reported that maltreated children with the s/s likely to be affected by environmental adversities, leading
genotype and no positive supports had the highest depres- to behavioral disturbances and, potentially, disorders.
sion ratings. However, the presence of positive supports However, from an evolutionary point of view, it is difficult
reduced the risk associated with maltreatment and the s/s to understand why natural selection would have favored
genotype, such that maltreated children with this profile had organisms that are at risk for dysregulation and disorders.
only minimal increases in their depression scores. Further, 5- According to Belsky and Pluess [34], children in a family
HTTLPR s-allele carriers were found to exhibit the highest vary in their susceptibility to their rearing environment to
level of postpartum depression when they had the lowest maximize their fit with the uncertain future. Thus, by pro-
level of education, and the lowest level of postpartum ducing offspring that have greater plasticity and sensitivity,
depression when they had the highest level of education and others that are more stable, parents safeguard part of
[20]. In boys with poor family support, youth with at least their offspring against potential misfit to future environ-
one 5-HTTLPR s-allele had more symptoms of depression mental conditions. Hence, children within a family should
relative to boys homozygous for the l-allele. However, in the differ in developmental strategies, thereby ensuring repro-
presence of high family support, boys with the s-allele had ductive fitness and survival of the family genes, the ultimate
the fewest depression symptoms [21]. A comparable finding goal of Darwinian evolution. Based on this line of thinking,
was obtained by Starr [22]. Of interest, sensitivity to nega- the differential susceptibility framework posits that certain
tive and positive environmental stimuli appears evolutiona- characteristics make some individuals disproportionately
rily conserved, as there is vast evidence that genetic ablation more susceptible and responsive to negative, risk-promoting
of the 5-HTT in rodents increases sensitivity to stress (for environments, but also make them more sensitive and
review, see ref. [23]), as well as sensitivity to (conditioned) responsive to positive, development-enhancing environ-
rewards, such as sucrose [24, 25], psychostimulants [26–28], mental conditions. Hence, the theory encompasses the idea
co-housing with a female [29], environmental enrichment that susceptibility involves responsitivity to environmental
[30], and tactile stimulation [31]. stimuli “for-better-and-for-worse”. Differential suscept-
Overlooking the positive side of the effects of the 5- ibility has been conceptualized in the context of child
HTTLPR s-allele (and other plasticity factors) may be a development, but also has been noted later in life and can
missed opportunity, as it would have a major influence on take place at smaller timescales than over years of devel-
how we conduct and interpret gene association studies. opment [35]. Interestingly, the phenomenon is mediated by
Furthermore, sensitivity to both negative and positive genetic factors, but also by prenatal factors and behavioral
environmental stimuli in a population, or potentially even in traits [36].
a single individual, suggests that seemingly vulnerable Key examples of genetic factors shaping behavior in a
subjects carry innate strengths that can be targeted to differential susceptibility style involve the 5-HTTLPR (see
increase resilience (i.e., the ability to recover or respond to introduction and meta-analysis: [37]), as well as the dopa-
challenges and change), facilitating the prevention of stress- mine DRD4 receptor (7-repeat) [38], monoamine oxidase A
related disorders. The aim of this expert opinion is to (uVNTR low-activity allele [39], DRD2 receptor (A1+)
explore, for the first time, the underlying neural mechan- [40], brain-derived neurotrophic factor (Met allele) [41, 42]
isms. This understanding is not only of high scientific and oxytocin receptor (rs53576 A-allele) [43] genes. To
relevance, but also facilitates prevention and resilience give an example for the DRD4 gene, the most widely stu-
research. That is, understanding the susceptible brain helps died gene next to the 5-HTTLPR s-allele, having the 7-
to align, in the future, vulnerability and preventive inter- repeat allele increased risk for disorganization in children
vention design. Indeed, preventive interventions are most exposed to maternal unresolved loss/trauma, but not when
effective when they tap into the mechanisms that mediate exposed to mothers who had no unresolved loss. Rather,
vulnerability [32]. Before we elaborate on the putative under the latter conditions, they displayed significantly less
neural mechanisms we first position in the next section the disorganization than agemates without the allele that were
behavioral effects, as exemplified by the 5-HTTLPR, in a insensitive to mothers’ unresolved loss status [38]. Like-
larger theoretical context. wise, children with the DRD4 7-repeat allele experiencing
little to no victimization reported significantly lower levels
of externalizing behaviors, but if they experienced high
Differential susceptibility levels of victimization, they reported the highest levels of
externalizing behaviors [44]. In terms of intervention
In the understanding of risk and resilience for (psychiatric) responsivity, it was found that children carrying the DRD4
disorders, the diathesis–stress/dual risk framework [33] has 7-repeat allele benefit most from computer games
516 J. R. Homberg, J. Jagiellowicz

promoting phonemic awareness and, thereby, early literacy counterparts, showed more internalizing and externalizing
[38]. These genes also interact. For instance, children at the behavior problems and lower social and academic adjustment
age of 3 and 6 months carrying the 5-HTTLPR and DRD4 when parenting quality was low, but fewer behavior problems
plasticity alleles evidenced high negative emotionality when and better adjustment when parenting quality was high [53].
maternal depression levels were high, and low negative Finally, a temperament trait called sensory processing sensi-
emotionality when maternal depression levels were low tivity (SPS) has been found to mediate differential suscept-
[45]. Notably, although the serotonergic system is particu- ibility (SPS). SPS [54] is a phenotypic trait characterized by
larly known to mediate internalizing behaviors, and the greater depth of information processing, increased emotional
dopamine system to mediate externalizing behaviors, when reactivity, greater awareness of environmental subtleties, and
the 5-HTTLPR s-allele and DRD4 7—repeat allele are ease of overstimulation [55, 56]. Environmental sensitivity as
combined both types of behaviors are enhanced [46]. As measured by the trait is present in over 100 animal species
another example, although the BDNF methionine allele did [55] and evolutionarily conserved [57]. Prevalence estimates
not operate as a plasticity factor alone, together with the 5- range from 15% to 20% [54] to 31% [58], and the heritability
HTTLPR s-allele it did moderate indiscriminate friendliness of SPS is 0.47 [59]. Thus, the trait is shaped by genetic factors
in institutionalized children, which decreased in response to at a level of 47%, and by environmental factors at a level of
foster-care intervention [47] and increased over time when 53%. The specific genes contributing to this heritability are
they remained institutionalized. The more plasticity alleles largely unknown. So far, a combination of 10 polymorphisms
the children carried, the more their indiscriminate friendli- in seven different dopaminergic genes has been found to be
ness declined over time when receiving foster care and the significantly associated with SPS [60]. Furthermore, the 5-
more it increased if they remained institutionalized [47]. To HTTLPR s-allele was found to be both associated [61] and
address the fact that single-gene variants, also when com- not associated with SPS [62]. The standard measure of SPS in
bined, have small effect sizes [48], the field has been adults is the highly sensitive person scale, and in children the
investigating polygenetic plasticity. For instance, a recent highly sensitive child scale, both of which are psychome-
study explored the moderating role of a genome-wide trically reliable [63, 64]. Studies have found associations
polygenic score based on ~20,000 different gene variants. between SPS and increased levels of stress [65], difficulties in
Children with higher genetic sensitivity responded in a for- emotion regulation [66], physical symptoms of ill health [67],
better-and-for-worse manner to positive and negative par- anxiety and depression [68, 69], and burnout [70]. SPS has
enting regarding emotional problems, an effect that was not also been commonly linked to the Big five personality trait of
seen in children not carrying the genetic sensitivity [49]. Neuroticism, characterized by a tendency toward anxiety and
Regarding prenatal factors (e.g., preterm birth [50], depression [59, 71–73]. Interestingly, the trait also engenders
prenatal stress [51]), an example involves preterm children positive attributes. For example, besides neuroticism, SPS is
tested at 12 months of age who displayed changes in cog- strongly linked to the big five personality trait openness [73].
nitive functioning in accordance with the diathesis–stress Furthermore, SPS is associated with creativity [74], high
model, and changes in social functioning in accordance with degrees of entrepreneurial intention [75], greater accuracy in
the differential susceptibility theory [52]. Further, in pre- the detection of subtleties [76, 77] greater empathy for others
term born toddlers, highest levels of externalizing problems [54], and greater changes in positive affect when exposed to a
were identified upon critical parenting, and lowest levels in positive mood induction video-clip [58]. In terms of differ-
the absence of critical parenting. A comparable finding was ential susceptibility, it has been found that high, but not low,
obtained for internalizing, which was highest in these tod- SPS children displayed reduced externalizing behavior when
dlers when experiencing anxious parenting and lowest when previously exposed to positive parenting, and increased
parents had little anxiety [47]. In an animal study using externalizing behavior (excluding prosocial behavior) when
prairie voles, prenatal stress was applied in the form of previously exposed to negative parenting [78]. Furthermore, a
social defeat stress (controls: no stress), and offspring was large randomized control trial of 2024 individuals that tested
cross-fostered to either high or low-quality rearing by the efficacy of a school-based anti-bullying intervention found
unrelated adults. It was found that prenatally stressed voles that children high, but not low, in SPS showed a significant
were more developmentally responsive to the rearing reduction in victimization and internalizing problems [79].
environment than voles not prenatally stressed [51]. Furthermore, an intervention study in adolescent girls, found
For the behavioral trait “difficult temperament”, a meta- that high, but not low, SPS girls living in a deprived neigh-
analysis showed that children with a more difficult tempera- borhood responded favorably to a school-based resiliency
ment (as compared with an easier temperament) were more program, leading to a significant reduction in depression
vulnerable to negative parenting, but also profited more from symptoms [80].
positive parenting [53]. Furthermore, negatively emotional Although numerous publications have confirmed the dif-
children, compared with their less negatively emotional ferential susceptibility theory, the underlying brain
A neural model of vulnerability and resilience to stress-related disorders linked to differential. . . 517

mechanisms are virtually unknown [81]. This understanding SPS when exposed to childhood adversity [92], and in pre-
requires integration of the differential susceptibility concept term born adults [93]. Moreover, prenatally stressed voles
from the field of developmental psychiatry into that of neu- cross-fostered to high-contact rearing showed the highest
roscience and psychiatry. In the next section, we explore the vasopressin-1a receptor binding in the amygdala [51]. Finally,
potential mechanisms underlying differential susceptibility. DRD4 [94] and BDNF [95] gene variance significantly con-
tributed to individual variability in amygdala reactivity. The
Neural model for differential susceptibility insula, a salience network hub, has furthermore been found to
be hyperactive in 5-HTTLPR s-allele [90] and DRD4-7R [94]
Human cognitive neuroscience research has revealed, using carriers as well as individuals high in SPS [92, 96]. Finally, at
functional magnetic resonance imaging (fMRI), that brain a network level, 5-HTTLPR s-allele carriers [97] and BDNF
regions do not function in isolation but rather are dynami- met allele carriers [98] show increased activity of the salience
cally organized into functional networks of interconnected network. These findings together are indicative of increased
areas [82]. Differential susceptibility may result from the exogeneous, i.e., “bottom–up”, automated attention in sensi-
altered activity of, and interaction between, three brain tive individuals showing differential susceptibility [85].
networks, namely the salience, default, and central execu- Factors that mediate differential susceptibility also
tive networks [83]. The salience network, anchored by the increase the activity of (regions within) the default mode
functional hubs of the anterior insula and the dorsal anterior network. For example, a positive association was found
cingulate cortex, has robust connectivity to the amygdala, between SPS and activity of the temporal lobe,
striatum, and the substantia nigra/ventral tegmental area temporal–parietal junction, and precuneus, which are
[84]. It rapidly detects the most homeostatically relevant regions of the default network, during the performance of a
stimuli and relays them to areas responsible for goal-related visual attention task [76]. Furthermore, the dopaminergic
information processing and thereby mediates exogeneous genes that are associated with SPS have been associated
bottom–up attention [84, 85]. One of the networks receiving with weaker homogeneity of regional spontaneous activity
relevant stimuli from the salience network is the default in the precuneus [99]. Default mode network connectivity is
network, comprising the precuneus, parietal and temporal furthermore increased in association with preterm birth
regions, temporal parietal junction, and the ventromedial [100]. Regarding the connectivity between salience and
prefrontal cortex. The default mode network stores internal default mode network regions, it was found that functional
representations of past experiences and mediates self- connectivity between the amygdala and a cluster including
generated thought [86]. It actively generates mental con- posterior cingulate cortex, precuneus, and visual cortex was
tent to solve a problem or meet a goal. The central executive significantly increased in 5-HTTLPR s-allele carriers [101].
network, including the dorsolateral prefrontal cortex and the During mood recovery, s/s individuals were found to
posterior parietal cortex, is responsible for the allocation of exhibit a significantly reduced anticorrelation between the
top–down attention directed toward stimuli consciously amygdala and posterior cingulate cortex/precuneus [102].
decided on by the individual (endogenous attention) in the At a network level, the connectivity between the default
context of goal-directed behaviors [83]. It competes with mode and salience networks was increased in s-allele car-
the salience network, which mediates exogenous attention, riers [97]. A comparable observation was made in preterm
for resources [87]. Exogenous attention can be con- born individuals [93, 103]. Such increased connectivity may
ceptualized as an interruption of endogenous attention and a lead to deep processing of salient information, and more
re-orientation of such attention to a different stimulus [85]. detailed and readily accessible memories of past
This process is evolutionarily conserved and highly relevant experiences.
for survival [85]. The salience network also has been implicated in
When integrating research from the various factors med- switching between the default mode network and the central
iating differential susceptibility, there seems a substantial executive network [83], leading to an anticorrelation
consensus that the amygdala, a hub of the salience network, is between the latter two networks [104]. This anticorrelation
implicated. For instance, it was found that amygdala reactivity is facilitated through inhibition of the salience network by
to facial expressions served as a moderator of the for-better- the central executive network [87]. In relation to the central
and-for worse relations between socioeconomic resources and executive network, it was found that 5-HTTLPR s-allele
later antisocial behavior and income [88]. Furthermore, the 5- carriers, compared with l-allele carriers, displayed increased
HTTLPR s-allele has been associated with increased amyg- dorsomedial prefrontal cortex activity when processing
dala activity in response to negative and positive emotional threat-predicting cues, possibly as an attempt at threat
stimuli [89, 90], and 5-HTT knockout rats exhibit increased suppression [105]. Similarly, carriers of the MAOA low-
excitability of glutamatergic neurons in the amygdala [91]. compared with the high-expressing genetic variant showed
Amygdala activity is also increased in individuals high on increasing regulatory activity in the dorsolateral prefrontal
518 J. R. Homberg, J. Jagiellowicz

cortex during incongruent (approach negative, avoid posi- create a mental template that allows the brain to devote
tive) conditions, potentially reflecting a compensatory relatively few resources to expected information [113] but
mechanism for stronger emotional reactions [106]. Further, additional cognitive and neural resources to unexpected
the 5-HTTLPR s-allele in combination with the BDNF information [114]. We posit that previous experience
met allele was associated with the highest functional con- moderated by increased reactivity of the salience network in
nectivity between the amygdala and the dorsolateral pre- sensitive individuals [115–117] initially establishes strong
frontal cortex [107]. In preterm born individuals, central expectations, which are stored in the default network. The
executive network activity was decreased, but functional brain will expect new experiences to resemble the stored
connectivity was stronger between parts of the salience and experiences. However, if a stimulus is not in accordance
the central executive network [108]. In sum, central with expectations (i.e., a “surprise”), salience network
executive network activity (as a compensatory mechanism) activity increases in order to gather information to drive
and its connectivity with the salience network may be goal-directed behavior. If necessary, the salience network
increased in sensitive individuals. then recruits the executive control network to reorient
Although the increased connectivity between parts of attention to a different stimulus. This process may be
the salience network and the central executive network “stronger” in sensitive individuals, owing to the increased
may initially be effective to subdue emotional responsivity connectivity between the salience and central executive
to negative valenced information, it may also be fragile control network, allowing them to adjust their attentional
when the load on this control system increases. Con- orientation upon exposure to “surprising” new information
sequent less-efficient control by regions of the executive (Fig. 1). Study results support this model. For instance,
network over limbic structures associated with the salience oxytocin receptor A-allele and 5-HTTLPR s-allele carriers
network, as seen in anxiety and depression [109, 110], exposed to early life stress were found to display increased
may lead to the salience network feeding more negative amygdala reactivity to social cues [118, 119]. In 5-HTTLPR
information to the default mode network, leading to s-allele carriers, lateral prefrontal cortex (central executive
rumination [111, 112]. On the other hand, this same neural control network node) morphology was inversely associated
state may be more “permissive” for the influence of with maintained attention for positive and negative stimuli
positive emotional stimuli. Thus, if there is also less [120], and lateral prefrontal cortex activity increased during
top–down control over positive emotions, as signaled by conflict in an emotional Stroop task (although only for
the salience network, sensitive individuals may notice and negatively valenced irrelevant stimuli) [121]. Further, a
benefit more from positive stimuli. If the salience network study testing individuals high in SPS found that a high-
would be less inhibited by the central executive control quality childhood, in combination with current exposure to
network, the anticorrelation between the default mode and positive stimuli, was associated with increased activity of
central executive control networks may be reduced in areas of the salience and default mode networks. When
sensitive individuals, as has indeed been observed in these same individuals were exposed to negative stimuli,
preterm born children [100]. If so, endogenous attentional activity of salience network regions and default mode and
and goal-directed processes could be more influenced by executive control networks increased [92]. Of interest,
(emotion-based) internal reflections. reward-related regions in the salience network were not de-
Importantly, the brain is not dormant and waiting for a activated when high-SPS individuals with positive child-
stimulus to come in, but rather constantly generating hoods were exposed to negative stimuli, as was the case in
expectations about the environment [113]. Expectancies high-SPS individuals with negative childhoods [92]. Given

Fig. 1 Schematic presentation of a neural model for environmental networks and the greater the influence of (surprising) environmental
sensitivity, derived from findings related to the 5-HTTLPR and factors on attentional set shifting.
SPS. The thicker the arrow, the stronger the connectivity between
A neural model of vulnerability and resilience to stress-related disorders linked to differential. . . 519

that highly sensitive individuals generally tend to focus of the executive control network to solve conflicts, and
more on negative than positive material [72], it appears that thereby to reduce stress caused by increased exogenous
past positive experiences may have “reset” the system away attention for negativity. In experienced meditators, default
from an automatic exogeneous negative reaction to negative mode network activity is reduced and its anticorrelation
stimuli. However, this attention may not be automatically with the central executive control network is increased.
set towards a positive reaction. Interventions can train a Increased activity of the central executive control network
positive response [80, 122], possibly by either emotional also has been shown in a randomized controlled trial [135].
regulation [123, 124] or habituation of salience network The data suggest a neural mechanism by which the central
reactivity to negative stimuli [125]. executive network negatively regulates the default mode
network and is probably responsible for the long-term trait
Attention changes seen in meditators and reported psychological well-
being [136]. As opposed to people with dispositional
The large-scale network findings suggest that sensitivity to mindfulness, who purposely pay attention to sensations in
environmental stimuli relates to changes in exogeneous and the present moment without judging, individuals high in
endogenous attention. Measures assessing exogenous atten- SPS are easily overwhelmed by, and judgemental of, phy-
tion involve tasks in which a particular element is presented sical sensations rather than being intentionally aware of
among irrelevant distractors. As such, healthy s-allele carriers them [137]. Results of a recent study among Japanese stu-
were more distracted by distractors, regardless of their valence dents and workers (N = 635) imply that improving dis-
[125]. Likewise, in patients with PTSD carrying the s-allele, positional mindfulness may be effective in improving
the presentation of trauma-related cues interfered with work- psychological and physical problems in those high in SPS
ing memory task performance [126]. Flexible adjustment of [137]. Because dispositional mindfulness is a trait that can
behavior by modifying endogenous attention can be measured be trained, this shows potential for improving the mental
using tasks measuring attentional set-shifting or cognitive health of highly sensitive people.
flexibility. 5-HTT knockout rats [127] show improved atten-
tional set-shifting compared with controls. Thus, reduced
learned irrelevance may explain this superior performance. Discussion and future direction
These animals also display increased integration of sensory
information [127, 128], and increased openness to the envir- Since the field of psychiatry is focused on disease, it is also
onment [129], all indicating that the animals ignore less of the primarily focused on negative environmental stimuli. In this
irrelevant information present in the environment. DRD4-7R review, we have shown that disease-causing factors related to
carriers were furthermore found to amplify dopamine- differential susceptibility also have the potential to bring
dependent cognitive flexibility [128], and DRD2 carriers resilience when the environment is supportive. This view may
displayed increased cognitive flexibility through reduced solve conflicting findings regarding association studies for
proactive interference by no longer relevant stimuli stress-related disorders, help to better understand the neural
[130, 131]. Likewise, in the Wisconsin Card Sorting Test mechanisms underlying vulnerability, and identify
measuring attentional set shifting, healthy human 5-HTTLPR mechanism-based interventions targeting the vulnerabilities,
s-allele carriers had superior performance compared with l- and calls for the integration of psychological, neuroscience,
allele carriers. From these animals, we knew that inherited and psychiatric research. Although the wealth of data on the
downregulation is associated with reduced latent inhibition single genes mediating differential susceptibility provide a
[132]. However, s-allele carriers with psychiatric disorders base on which to build hypotheses for underlying mechan-
showed a worse performance in the Wisconsin Card Sorting isms, the small effect size of single genes requires a broad
Test [133, 134]. This suggests an inverted U-curve relation- approach matching the complexity and heterogeneity of stress-
ship between set shifting and performance in s-allele carriers related disorders such as depression. Hence, rather than
depending on the health status of the individuals. Strong focusing on single genes, GWAS studies are required in which
automated exogenous attention may be detrimental for positive as well as negative environmental stimuli are inclu-
negative material or in populations at the extremes of the ded. Furthermore, prenatal factors and complex traits such as
spectrum on flexibility, whereas easy distraction by positive SPS also provide a new avenue to understand vulnerability
stimuli and improved attention-shifting ability in healthy and resilience to psychopathologies. We propose that these
individuals, prior to the development of disease, may provide factors can be seen as an intermediate between biological
a mechanism for self-control or interventions in highly sen- mechanisms and vulnerability/resilience and used to advance
sitive populations in the middle of the spectrum. behavioral and mechanistic understanding of both concepts.
One method suitable to better control attention involves Our model links differential susceptibility factors to neural
mindfulness. Mindful meditation may facilitate the ability mechanisms subserving increased exogenous attention
520 J. R. Homberg, J. Jagiellowicz

(increased salience network activity) and increased attentional determined as to whether differential susceptibility factors
set shifting (increased salience and central executive control exert their effects solely at a population level or also at the
network connectivity). Such neural changes could explain how level of the individual. The latter would hold the intriguing
differential susceptibility factors mediate openness to both premise that one’s vulnerability can be transformed into
negative and positive environmental stimuli, and the ability to resilience. The answers to such questions would not only
adjust attentional orientation, and thereby vulnerability and inform differential susceptibility research but also inform
resilience. These biological mechanisms could, after validation, applied research and public policy with respect to early-
serve as biomarkers for vulnerability and resilience. In humans, childhood environments and interventions.
a sufficiently powered fMRI study in which, for instance, a
probabilistic reversal learning task with implementing reward Acknowledgements We thank research assistant Madeleine Ghazarian
for helping with the literature search. This work was supported by the
prediction errors [138] could be applied. Further validation of
Dutch Research Council through the ERANID Grant “STANDUP”
the neural mechanisms requires animal models for environ- awarded to JH. The Dutch Research Council had no role in the
mental sensitivity, for instance, 5-HTT [56], DRD4 [139], or creation of this manuscript.
oxytocin receptor [42] (conditional) knockout or BdnfMet/Met
[140] transgenic animals, or models that spontaneously show Compliance with ethical standards
environmental sensitivity such as specific lines of fish (rainbow
trout) [141]. As the rodent brain harbors the same large-scale Conflict of interest The authors declare that they have no competing
interest.
networks as the human brain does [142], rodent models may be
particularly suited to causally testing the network model. Fur- Publisher’s note Springer Nature remains neutral with regard to
thermore, rodent studies allow causal manipulations through jurisdictional claims in published maps and institutional affiliations.
opto/chemo-genetic manipulations, as well as invasive inves-
tigation of the electrophysiological and molecular correlates of
network activity changes.
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