Biological

Psychiatry Review

Early Social Adversity, Altered Brain Functional

Connectivity, and Mental Health
Nathalie E. Holz, Oksana Berhe, Seda Sacu, Emanuel Schwarz, Jonas Tesarz,
Christine M. Heim, and Heike Tost

ABSTRACT
Early adverse environmental exposures during brain development are widespread risk factors for the onset of severe
mental disorders and strong and consistent predictors of stress-related mental and physical illness and reduced life
expectancy. Current evidence suggests that early negative experiences alter plasticity processes during develop-
mentally sensitive time windows and affect the regular functional interaction of cortical and subcortical neural net-
works. This, in turn, may promote a maladapted development with negative consequences on the mental and
physical health of exposed individuals. In this review, we discuss the role of functional magnetic resonance imaging–
based functional connectivity phenotypes as potential biomarker candidates for the consequences of early envi-
ronmental exposures—including but not limited to—childhood maltreatment. We take an expanded concept of
developmentally relevant adverse experiences from infancy over childhood to adolescence as our starting point and
focus our review of functional connectivity studies on a selected subset of functional magnetic resonance imaging–
based phenotypes, including connectivity in the limbic and within the frontoparietal as well as default mode networks,
for which we believe there is sufficient converging evidence for a more detailed discussion in a developmental
context. Furthermore, we address specific methodological challenges and current knowledge gaps that complicate
the interpretation of early stress effects on functional connectivity and deserve particular attention in future studies.
Finally, we highlight the forthcoming prospects and challenges of this research area with regard to establishing
functional connectivity measures as validated biomarkers for brain developmental processes and individual risk
stratification and as target phenotypes for mechanism-based interventions.
https://doi.org/10.1016/j.biopsych.2022.10.019

The developing human brain is particularly sensitive to envi-
ronmental influences—both beneficial and detrimental (1–3).
As for risk factors, epidemiological studies point to several
early influences that have a negative impact on maturing neural
networks and increase the likelihood of developing psycho-
logical and somatic disorders later in life (4,5). In a narrow
sense, these risk factors comprise various causes of severe
childhood stress, including maltreatment, abuse, violence,
neglect, separation or loss of a parent, and others (6). More
broadly, they encompass a wide range of overlapping early
adverse exposures (Figure 1A). Some of these are best viewed
as proxy markers for poorly understood causal sub-
components that are plausibly associated with enhanced
stress experience during development [see (7) for review]. Data
from human and animal research show lasting changes in
hypothalamic-pituitary-adrenal axis function as a result of early
adversity (8) and link these findings to shifts in the develop-
mental timing of structural changes during sensitive periods of
increased neuroplasticity, particularly in brain regions with
dense expression of glucocorticoid receptors (e.g., amygdala,
medial prefrontal cortex [mPFC], hippocampus) (9,10). At the
neural systems level, imaging research has provided many new
insights into the neural basis of early environmental factors in
recent years, with a number of brain activation and
morphometry studies pointing to a convergence of the effects
of risk and resilience factors in frontal-limbic brain regions
(1,2,7) (Figure 1B). At the molecular level, early adversity—in
interaction with genetic vulnerability—is biologically
embedded at the level of stress regulatory genes through
epigenetic modifications, e.g., in FKBP5, the FK506 binding
protein 5 gene, with effects on gene expression, immune
activation, and brain function or structure (11,12). Emerging
but still fragmentary research attempts to achieve cross-
system integration by linking molecular-genetic, endocrine,
and/or immune data with neuroimaging data to scrutinize the
complex mechanistic pathways that link exposure to early
adversity with adverse health outcomes (13–15). In this review,
we summarize the literature on the effects of early negative
experiences on functional connectivity markers of neural net-
works. Specifically, we focus on a selected subset of func-
tional magnetic resonance imaging (fMRI)–based phenotypes
for which we believe there is sufficient converging evidence to
warrant a detailed discussion on the findings in a develop-
mental context. We further point out methodological chal-
lenges and knowledge gaps that currently complicate data
interpretation and highlight the prospects and challenges for

430 ª 2022 Society of Biological Psychiatry. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Environmental Risk and Brain Functional Connectivity
the research field as it moves toward using functional con-
nectivity phenotypes as stratification markers for early detec-
tion, prevention, and treatment of the detrimental health effects
of early adverse experiences.
NEUROIMAGING EVIDENCE
Amygdala–Medial Prefrontal Functional
Connectivity
Many human studies linking early stress to neural network
interaction are region-of-interest analyses that focus on
changes in functional connectivity in the amygdala, which
plays a central role in negative emotion and threat processing
(16). These analyses are plausible hypothesis-driven exten-
sions of earlier findings showing the influence of early stressful
experiences on amygdala activation in humans and animal
models (17–19). Particularly extensive empirical evidence for
adaptation to early stress events exists for functional regula-
tory circuits connecting the amygdala to the mPFC and adja-
cent perigenual anterior cingulate cortex (pACC) (Figure 2A)
(20), which has been linked to alterations in hypothalamic-
pituitary-adrenal axis function (21–23), differences in emotion
regulation (24), internalizing psychopathology (25), trauma-
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Figure 1. (A) Schematic representation of
frequently named and often overlapping constructs
of early adverse exposures studied in imaging
research. Keywords are mapped to the approximate
period of exposure during brain development
(y-axis, from prenatal to early adulthood) and the
spatial extent of exposure (x-axis, from person level
to area level). (B) Illustration of brain regions involved
in the regulation of affective, social, and stress re-
sponses (146). Imaging results from previous
morphometry and activation studies indicate spatial
convergence of environmental and genetic risk and
resilience factors in these circuits, particularly in the
perigenual anterior cingulate cortex (ACC)
(1,2,7,146). Adapted from (146) (Nature Publishing
Group). AMY, amygdala; PFC, prefrontal cortex;
vmPFC, ventromedial prefrontal cortex; VS, ventral
striatum.
related proinflammatory states (26), and inflammation-
associated mood deterioration (27,28). These findings make
these circuits plausible players in mediating the negative
psychological and somatic consequences of early stress (29),
although the regional specificity of amygdala-prefrontal con-
nectivity findings can vary across studies and may be
dependent on the fMRI task used (10).
The range of negative environmental influences studied for
this connectivity phenotype is broad and includes highly het-
erogeneous constructs of early negative experiences in terms
of their type, timing, ecological validity (e.g., self-reported or
observed), and proximity to the affected individual. A promi-
nent example is the observation of a premature (i.e., negative)
stimulus-evoked coupling pattern between the amygdala and
mPFC/pACC during emotional face processing in children
exposed to early maternal deprivation (23) or childhood abuse
(30) and in pediatric posttraumatic stress disorder (PTSD) (31).
Similarly, reduced intrinsic (resting-state) coupling between the
amygdala and mPFC has been associated with prenatal stress
exposure (32), cannabis use (33), inflammation (34), and
neighborhood socioeconomic disadvantage (35,36). Notably,
developmental shifts have been demonstrated for these
coupling phenotypes during the transition to adolescence
Figure 2. Functional connectivity affected by
adversity. Alterations (Y[) in functional connectivity
between the amygdala seed and (A) the prefrontal
cortex (PFC) ([perigenual] anterior cingulate cortex,
Brodmann area 10, Brodmann area 11, yellow) and
(B) the hippocampus (HC) (red). Regions were
derived from the WFU PickAtlas. (C) Decreased (Y)
within-network connectivity of the frontoparietal
network (FPN) (green) and (D) increased ([) within-
network connectivity of the default mode network
(DMN) (blue). DMN and FPN (false discovery rate–
corrected p = .01) were extracted from Neurosynth
(https://neurosynth.org) and thresholded at Z . 6 for
visualization purposes.
431
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(35,37,38) and have been linked to a decrease in amygdala
reactivity and separation anxiety (23), fewer anxiety symptoms
in children with lower neighborhood socioeconomic disad-
vantage (35), and higher ability to regulate negative emotion in
adulthood (39).
Overall, these (and other) results suggest several preliminary
conclusions regarding these developmental phenotypes and
point to remaining ambiguities. First, the findings seem to
suggest that task-evoked and intrinsic amygdala-mPFC/pACC
connectivity phenotypes are sensitive to a broader set of early
adverse environmental influences that converge on enhanced
stress exposure during early neurodevelopment (1,7), although
some degree of exposure specificity may exist (e.g., depriva-
tion vs. threat-related adverse experiences) (40). Second, the
findings partially support the mechanistic accounts of the
stress acceleration hypothesis (41,42), which holds that
adversity triggers an accelerated maturation of emotion regu-
latory circuits in the developing brain, thereby shaping the af-
fective behaviors supported by these regions. Alternatively, or
in addition, the relationship between early stress and
amygdala-mPFC/pACC functional connectivity may be rooted
in experience-dependent neuroplasticity, which triggers the
formation of new and elimination of redundant synaptic con-
nections in response to environmental events during sensitive
periods of neurodevelopment (experience-expectant learning)
(43). Both theoretical accounts are supported by studies sug-
gesting effects of early developmental stress on the structural
organization of amygdala-mPFC brain circuits, including
altered amygdala volume in children exposed to poverty (44)
and maltreatment (45), premature amygdala circuit myelin
formation (46), and increased branching and length of mPFC
dendrites (47) in rodent models of early developmental stress.
Third, beyond early system adaptation to childhood stress,
several studies suggest that the assumed age-atypical (i.e.,
abnormally rapid) development of the adult phenotypes of
amygdala-mPFC/pACC coupling may represent a source of
proximal resilience that facilitates exposed children and ado-
lescents to cope with experienced adversities (23,35,37,39).
However, the extent to which these phenotypes contribute to
the long-term psychological and somatic health disadvantages
of early childhood stress remains to be elucidated.
Finally, there are several inconsistencies and unknowns in
the literature regarding the highlighted amygdala-mPFC/pACC
connectivity phenotypes that point to the need for future, more
in-depth research. In particular, the example of stimulus-
evoked versus intrinsic amygdala-mPFC/pACC connectivity
reveals a fundamental problem in interpreting connectivity re-
sults in the context of early adversity, namely that of the poorly
defined natural developmental course of the phenotypes (see
also Definition and Normative Development of Functional
Connectivity Phenotypes) (Figure 3A). Here, the available
data suggest potentially contrasting developmental trajec-
tories as a function of task. For the task-evoked coupling
phenotype (Figure 3B), younger age tends to be associated
with positive coupling and older age tends to be associated
with negative or nonsignificant coupling (23,48) [but see (31,49)
for opposite and (50,51) for absent or no consistent develop-
mental changes], whereas for the intrinsic coupling phenotype
(Figure 3B), age tends to be positively associated with
increasing connectivity (52,53) [see (54) for sex-specific
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effects, (38,55) for opposite developmental changes, and (56)
for a connectivity decrement until adolescence and a subse-
quent increment until early adulthood]. These contrasting tra-
jectories may support the hypothesis that increasing intrinsic
coupling between the amygdala and mPFC/pACC may reflect
increasing structural maturation of the connection between the
regions during development, which, in turn, may facilitate
increasing prefrontal control over the amygdala during nega-
tive affective processing. If this is true, then the observed
positive or negative deviations from the hypothesized different
intrinsic or task-related developmental curves may reflect
fundamentally different biological mechanisms. Therefore,
negative deviations from the task-evoked trajectory could be
interpreted as developmental acceleration, while positive de-
viations could reflect delays, with the opposite interpretation
applying to deviations from the intrinsic connectivity trajectory.
Other inconsistencies and unknowns pertain to the sensitivity
of the developmental connectivity phenotypes to different
types and timings of early adversity, the direction of early
stress–associated effects and behavioral associations, and
variations in the type of functional connectivity methods used
and the mPFC/pACC subregion (and thus the cortical-
amygdala subcircuit) highlighted (14,25,30,34,52,57–59).
Finally, the effects of early stress on these phenotypes seem to
be subject to complex interactions with age, sex, type, and
timing of adversity; the predictability of adversity by the
exposed individual; and likely other as-yet unknown modera-
tors that will require careful disentanglement in future (longi-
tudinal) studies (14,35,46,60,61).
Amygdala-Hippocampus Functional Connectivity
The hippocampus is a key limbic region supporting the
formation of declarative, spatial, and contextual memory. It
is highly sensitive to the stress-induced increases of circu-
lating glucocorticoids and excitatory amino acids and is
historically the first brain structure to demonstrate the
deleterious neuroplastic effects of chronic stress on neuronal
excitability, neurogenesis, and dendritic remodeling (62,63).
The hippocampus and amygdala act synergistically during
the consolidation of emotionally arousing adverse events
and share directly (and indirectly) connecting projections that
are subject to neuroplastic modifications (64). This renders
this circuit a promising mechanistic target for the examina-
tion of the adversity effects and related negative health
outcomes.
The available neuroimaging evidence on early environ-
mental risk exposure effects on amygdala-hippocampus
functional connectivity (Figure 2B) is heterogeneous in many
respects. For example, adults exposed to childhood
maltreatment were found to have increased amygdala-
hippocampus psychophysiological interaction during
emotional face processing (65) and increased amygdala-
hippocampus generalized psychophysiological interaction
during the processing of olfactory stress odors (66). In
contrast, decreased amygdala-hippocampus coupling was
observed in children (generalized psychophysiological inter-
action) during a fear conditioning paradigm (67) and similarly
during the resting state in maltreated adults (68) and in neo-
nates with prenatal exposure to neighborhood crime (69).
 Biological
Environmental Risk and Brain Functional Connectivity Psychiatry

Figure 3. (A) Schematic illustration of the normative modeling approach. Statistical and machine learning approaches are used to characterize the
developmental trajectory of neurobehavioral outcomes (here exemplified for network connectivity and another outcome, phenotype 1) across the life span.
The models capture the variability (dashed ellipses as indicators of centiles) of such outcomes measured in individual subjects (illustrated as spheres) in the
population and can be used to quantify individual-level deviations from the expected developmental trajectory. Deviations observed during vulnerable age
periods can, in turn, provide insight into biological, behavioral, and environmental risk constellations that contribute to the susceptibility for mental and somatic
health outcomes during later life. Normative modeling thus represents a computational framework for disentangling between-subject heterogeneity in such risk
constellations. The dashed square illustrates that methodological factors may contribute to the observed variability in measured outcomes through, e.g.,
functional magnetic resonance imaging task choice or suboptimal measurement reliability. (B, C) Schematic illustration of the possible normative trajectories
and relative adversity-related deviations of emotional task-evoked (B) and intrinsic (C) amygdala–medial prefrontal cortex/anterior cingulate cortex connectivity
phenotypes. Developmental trajectories of connectivity estimates may vary as a function of task, with negative (task-evoked) and positive (intrinsic) slopes
during development (see main text for details). Observed positive or negative deviations from the different possible trajectories may reflect different biological
mechanisms depending on the specific phenotype and developmental stage studied. The dots represent various studies (see below) reporting changes in
these phenotypes as a function of early exposure, and we related the dots to the possible trajectories depending on the age of the individuals at the time of
study and the reported changes in connectivity parameters. The position of the dot above or below the trajectory in a given developmental stage reflects the
direction of the reported result (increased/decreased connectivity), taking contrast or beta estimates into account where possible. The color of the dots reflects
the timing of the adversity (green indicates infancy, orange indicates childhood, blue indicates adolescence, and gray indicates adulthood). Study references:
1
(23), 2(147), 3(31), 4(30), 5(148), 6(65), 7(149), 8(55), 9(150), 10(35), 11(90), 12(151), 13(152). Please note the incomplete and partly contradictory evidence and thus
the necessarily vague and hypothetical character of the relationships presented in this figure (see main text for details). SES, socioeconomic status; SLE,
stressful life event.

Thus, to date, it is difficult to draw conclusions about the
direction of the effects. First, although all these studies defined
similar amygdala-centered seed regions for subsequent ana-
lyses of functional connectivity, the diversity of study partici-
pants and fMRI methods makes their integrative interpretation
challenging. Specifically, differences in the fMRI paradigms
examined, the nature of the coupling parameters studied, and
the age or neural developmental stage of the stress exposure
complicate interpretation. For example, whereas reduced
amygdala-hippocampus psychophysiological interaction
during an emotion task might indicate less consolidation or
processing of emotional information, the uncoupling of
amygdala-hippocampus resting-state connectivity might have
fundamentally different developmental and psychological im-
plications. Second, for these amygdala-hippocampal connec-
tivity phenotypes, there is still insufficient longitudinal evidence
defining the normative development of coupling parameters
across the early and middle life span, rendering the interpre-
tation of deviations difficult. For example, while increased
connectivity has been found in adults who retrospectively re-
ported childhood maltreatment, which could refer to in-
dividuals who have an intact emotional memory trace of early
trauma supported by limbic hyperconnectivity, this connec-
tivity pattern may not apply to children who have been mal-
treated recently and may still be immediately traumatized.
Therefore, adults and children may have qualitatively different
adversity imprints. Accordingly, the observed discrepancy in
the direction of connectivity estimates requires a reference
model of age-related development to clarify whether these
changing patterns reflect domain-specific deviations that are
behaviorally relevant. Finally, studies of the influence of early
negative experiences that have examined connectivity be-
tween the amygdala and hippocampus have mostly been
limited to childhood maltreatment. In contrast, other more
distant health-related adversities, such as low social status,
urbanization, bullying, or experiences of racial/ethnic discrim-
ination, are largely unexplored for this phenotype.
Functional Connectivity in the Frontoparietal and
Default Mode Networks
Compared with studies on the limbic system, studies on the
influence of early adversities on the functional interaction of
cognitive cortical circuits are comparatively scarce and have

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mostly focused on analysis of the frontoparietal network (FPN)
(Figure 2C) and default mode network (DMN) (Figure 2D). For
example, in adolescents exposed to childhood abuse, reduced
seed-based connectivity of the left PFC with inferior parietal
and inferior prefrontal areas during sustained attention has
been reported, which was related to the FKBP5 genotype (70).
A similar reduction in FPN connectivity has been observed in
stress-related psychopathology such as depression (71).
These findings are consistent with observations on the effects
of psychosocial stress, which has been associated with
impaired attentional control and a reversible reduction in
functional connectivity within a frontoparietal attention network
(72). The study on chronic stress (72) is particularly informative
because it represents a direct conceptual extension of previ-
ous animal studies of chronic stress, which facilitates hy-
pothesis generation and data interpretation in the human
tandem study. In animal studies, chronic stress exposure in
rats was found to be associated with impaired attentional shift
and dendritic reorganization of the mPFC (73,74). Taken
together, these findings suggest that stress-associated expe-
riences and disease are associated with reductions in FPN
connectivity and attentional function mediated by these cir-
cuits, which originate in dendritic reorganization of the PFC
and may be influenced by glucocorticoid-regulated genes. In
this context, the functional connectivity alterations and neu-
roplastic changes seem to be reversible upon repeated but
time-limited stress experiences in the adult organism. Whether
a comparable reversibility of alterations is also valid for adverse
childhood experiences, prolonged chronic stress in adulthood,
and stress-associated mental illness remains to be clarified.
Other studies on the effects of early adverse experiences
have targeted the resting-state functional connectivity within
the DMN, a group of cortical areas including the mPFC, medial
temporal lobe, and posterior cingulate cortex that is predom-
inantly active at rest and supports episodic memory and
self-referential information processing (75). Existing evidence
suggests increased resting-state DMN functional connectivity
in infants exposed to repeated conflict between parents, and
the increased connectivity was related to measures of higher
infant negative emotionality (76). A similar increase in DMN
functional connectivity was reported for women with PTSD as
a result of exposure to childhood abuse (77) and in patients
with stress-related psychiatric disorders such as major
depression (78,79) [but see also (80)]. In stress-related psy-
chiatric disorders, heightened DMN functional connectivity has
been interpreted as deficient higher-order downregulation of
DMN activity and has been related to cognitive symptoms that
involve impairments in self-reflective autobiographical func-
tions (e.g., rumination) (81,82). DMN resting-state functional
connectivity reflects, at least to some degree, structural in-
terconnections between DMN areas (83), and impairments in
the structural and maturational covariance of DMN regions in
infants have been related to stress-provoking early-life expe-
riences such as preterm birth (84), which seem to delay or
accelerate the developmental course of the brain in a region-
specific manner (85,86). Taken together, these data are
consistent with the ideas that the observed increase in func-
tional connectivity of the DMN is triggered by early adverse
environmental experiences [but see (87)], is relevant to mental
health, and is the result of early stress–induced structural
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circuit reorganization during vulnerable neurodevelopmental
time windows. At the same time, the developmental course of
this connectivity phenotype has not been fully elucidated, and
it remains unclear whether the observed increase in connec-
tivity reflects an acceleration or a delay in DMN development
caused by early adversity. Similarly, the extent to which this
connectivity risk phenotype is modifiable later in life remains
unclear. Specifically, while it has been shown that functional
connectivity of the DMN can be reduced in patients with
depression and PTSD by transcranial magnetic stimulation (71)
and cognitive psychotherapy (88), it remains unclear to what
extent early developmental changes in the structural and
functional organization of DMN circuits can be positively
affected by such therapies.
Whole-Brain Connectivity Studies
Whole-brain connectivity is a less spatially constrained tech-
nique to study large-scale brain alterations in relation to early
adversities. While a range of machine learning approaches
such as multivariate pattern analyses are promising in terms of
identifying nuanced patterns of activation, they are still un-
derused in the field. Graph-based analyses have been inves-
tigated most prominently [for a review, see (89)]. As such,
global and local brain network organization (e.g., strength of
functional connectivity or network properties) has been
examined as a function of early adversity, including childhood
abuse (90–92), prenatal alcohol (93,94) and opioid (95,96)
exposure, pediatric PTSD (97,98), and early maternal separa-
tion (99). Furthermore, alterations related to early adversity
have been reported in large-scale brain networks such as the
FPN, DMN, salience network, and dorsal attention network,
with the majority based on resting-state data [e.g., (99–101)]
and only a few studies based on stimulus-evoked alterations
following adversities (90,102). As with the region-to-region
connectivity studies, there is currently no consistent picture
regarding the direction of connectivity change [e.g., decreased
(92,94,99,100,102,103) or increased (87,95,97) and its spatial
specificity, e.g., network-specific (91,96) or network-unspecific
(93,101)], even when the adversities and developmental stages
studied were similar (95,96,104). Evidence from longitudinal
connectivity studies is scarce and also points to heteroge-
neous trajectories after adversity (87,105), with childhood
maltreatment related to increased between-network connec-
tivity (87) and blunted developmental network plasticity as a
function of deprivation, neglect, and stressor unpredictability
(105). Again, the methodological and demographic diversity of
the studies is a plausible explanation for these inconsistencies.
AREAS OF TENSION AND PERSPECTIVES FOR
FUTURE RESEARCH
Even though imaging research on brain functional connectivity
has yielded increasing insights into the developmental mecha-
nisms of early risk exposure, our knowledge is still fragmentary,
and the precise processes of biological embedding and the
subsequent molecular, neural, physiological, cognitive,
emotional, and behavioral processes that together lead to the
long-term developmental programming of adverse health out-
comes are still elusive (6). As a result, despite promising ap-
proaches (106,107), there are still no validated diagnostic

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markers or interventions based on functional connectivity for the
identification and mechanism-based treatment of at-risk groups.
The improved mechanistic understanding of the developmental
origins of adversity-related health outcomes and the corre-
sponding developmental phenotypes promises to enable the
stratification of subtypes of disorders and the selection of treat-
ment strategies guided by the identified mechanisms in the future
(6,108,109). Exploring the functional connectivity of the human
brain and achieving a more precise understanding of the complex
interactions of molecular, physiological, and neural systems
across developmental trajectories are certainly only parts of the
challenge ahead but are important scientific building blocks to be
able to better address a large unmet clinical need in the future. It
will be of paramount importance to scrutinize complex cross-
system, multilevel interactions, including the functional con-
nectome, to more fully understand the mechanistic pathways
that link exposure to early adversity with disease outcomes. Next,
we address two selected areas of tension that we believe deserve
special attention.
Conceptualization of Early Adversities and
Individual Resources
Many existing studies of the effects of early adverse influences
on brain functional connectivity have been concerned with
examining one (or a few) early risk exposures, particularly the
effects of retrospectively collected measures of maltreatment
(110). However, the range of negative influences in natural
contexts with demonstrated and/or plausible relevance to brain
development is very complex and includes, among other things,
complex social phenomena (18,111,112). The convergence or
divergence of these different sources of environmental risk and
protection at the neural system level requires further investiga-
tion (113). This poses challenges for future research. First, many
of these risks are heterogeneous and consist of different sub-
components. For example, poverty represents a complex
mixture of stressors, combining conflict-related aspects such as
experiences of violence and loss-related characteristics such as
deprivation and premature death as well as potential biological
hazards such as exposure to toxins or malnutrition [see (114) for
review]. Second, in natural contexts, subsets of these more
complex risk phenomena are significantly correlated with each
other in space and time (Figure 1A). For example, family socio-
economic status is related to neighborhood socioeconomic
status, and both are related to risk of drug exposure and expe-
riences of violence and crime within the family and in the
neighborhood (115). As a result, some of the approaches
currently in use are likely to lump together different types of early
stress exposures with potentially distinct effects on the brain,
complicating data interpretation and potentially diluting asso-
ciations with neural outcomes.
We believe that this research challenge requires a compre-
hensive and harmonized assessment of early exposures in
terms of a standardized exposome map and an equally broad
and harmonized assessment of relevant outcomes (psycho-
logical, somatic, molecular, neural, etc.). The exposome
concept has its origins in toxicology to more comprehensively
describe the lifetime exposure to chemicals and relate it to
adverse health effects (116). It has more recently been adopted
by large-scale, transdisciplinary research collaborations
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(e.g., the Utrecht Exposome Hub), mostly in relation to somatic
health. In psychiatry research, the systematic extension of this
approach to the multifaceted measurement of social and
physical exposures in cohort studies across the life span pro-
vides a more agnostic alternative to current hypothesis-driven
candidate adversity approaches (117). The overarching goal of
such an exposure map would be to identify and understand the
multiple signatures of early environmental exposures that are
important for mental health to gain a more comprehensive un-
derstanding of which factors affect mental health, at what
doses, and through what mechanisms. Although full imple-
mentation of such a comprehensive approach still requires
much developmental work, the basic concept could involve
repeated, standardized, multilevel assessment of nongenomic
exposures across the life span (including their timing, duration,
and intensity) along 4 main axes or layers arranged from prox-
imal to distal relative to the person studied (Figure 4). The first
layer could refer to the individual level, where adverse (e.g., toxin
exposure, physical abuse) and protective exposures are
assessed beginning in the prenatal period along with individual
moderators such as subjective experience (118) and meta-
cognitive protective processes [e.g., perceived predictability
(119,120), agency (121), and control (122,123)]. The second axis
could refer to the level of the family and peers, where time-
tagged, e.g., beneficial and risk-associated influences, are
captured by means of classical questionnaire-based and real-
world digital assessments (e.g., type and frequency of social
contacts, family atmosphere, bullying events). The third axis
could refer to the community level, which may capture, for
example, socioeconomic status, social organization (e.g., ethnic
composition), and violent crime in the neighborhood, while the
fourth axis, the broader ecosystem level, may capture expo-
sures such as pollution, climate and extreme weather events,
and urbanization. The value of more comprehensive risk as-
sessments in psychiatry is supported by initial studies that used
eco-exposome scores to quantify established schizophrenia
risk factors. For example, Pries et al. (124) used a predictive
modeling approach to construct a weighted eco-exposome
score based on social-environmental risks, including maltreat-
ment and bullying, along with cannabis use, winter birth, and
hearing impairment, which distinguished patients from control
subjects and siblings as well as siblings from control subjects. In
addition, this exposome score was related to patient-specific
global functioning (125) and demonstrated transdiagnostic
predictive power (126). Optimally, such a harmonized assess-
ment should occur within and between large national and in-
ternational consortia to increase synergistic added value and
opportunities for common data pooling. Such efforts have
become increasingly popular in neuroscience, as evidenced, for
example, by the large national and international data integration
efforts of the Human Connectome Project (127), the 1000
Functional Connectomes Project (128), and the newly founded
German Center for Mental Health (Deutsches Zentrum für Psy-
chische Gesundheit [DZPG]).
Definition and Normative Development of
Functional Connectivity Phenotypes
The heterogeneity of phenotypic outcomes reported in the
context of early adverse experiences is particularly high in the
435
Biological
Psychiatry
A B
Status Violence
Society
Support Community Agency
Family, peers
T1
Social
Individual
Physical
Home
C Relevant risk and supportive factors for mental health
Biodiversity Neighborhood Noise
Broader Ecosystem
Toxins Weather
nervous system and mental health. Quantifying these aspects requires repeated measurements of the exposome over time in longitudinal studies. (C)
Standardized, longitudinal capture of the exposome is challenging and requires the use of a comprehensive toolkit of traditional questionnaire-based and novel
digital assessment instruments.
field of brain functional connectivity (113). This circumstance is
due to the abundance of possible task scenarios as well as the
regional and analytical variance in derived measures
(129–132). As a consequence, there are few studies in the
literature on early adversity effects that illuminate the exact
functional connectivity phenotype with respect to different
environmental influences or developmental time windows,
making it difficult to gain a common, robust body of knowl-
edge. Complicating matters further, to date, there is insufficient
evidence of statistical quality criteria [e.g., test-retest reliability
(133,134)] and developmental trajectories (37,48–50,135) of
phenotypes.
The definition of the development of functional connectivity
phenotypes with longitudinal imaging is particularly important
for the interpretability of results of studies on the effects of
early stress exposure (136). Here, important methodological
work has been done to establish normative growth chart
models for structural brain development for neuroimaging
phenotypes that capture variation in the population (137,138).
Through quantification of individual deviations from expected
patterns, individual risk signatures during vulnerable periods
can be identified and biologically interpreted in the context of
the reference model. The clinical importance of this approach
has been shown across psychiatric conditions (139,140) and
was validated by showing superiority in predicting psychopa-
thology compared with data fitting without a normative model
(139–141). The use of such reference models for the devel-
opment of functional connectivity trajectories is certainly a
promising step on the way to clarifying the nature of deviations
(i.e., delayed or accelerated) due to early adversity exposure
(Figure 3).
Recruitment, Care, and Participatory Inclusion of
Research Volunteers
Children and adults with early adverse exposures are often
underrepresented in large, open-label MRI datasets. This
poses a major challenge for large-scale studies and requires
more intensive recruitment efforts, especially for retaining
participants in longitudinal studies. Here, it was shown that
flexible scheduling, constant contact persons and investigator
teams, as well as monetary and nonmonetary incentives (e.g.,
436 Biological Psychiatry March 1, 2023; 93:430–441 www.sobp.org/journal
Environmental Risk and Brain Functional Connectivity
Figure 4. (A) Schematic representation of the
exposome concept with 2 main domains (social,
physical) and 4 layers arranged from proximal to
Intensity distal in relation to the person under study. The first
Dura on layer refers to the level of the individual; the second
T3 Timing
T2 Accumula on layer refers to the level of the family, peers, and
Interac on home; the third layer refers to the level of the com-
Dynamic
munity and neighborhood; and the fourth layer refers
to the level of society and the broader ecosystem.
such as exposure to toxins, violent events, or social
Popula on surveys ys
Official sta s cs
support and perceived agency are relevant for all
Ques onnaires levels, and their type and intensity can be quantified.
Geospa al maps ps (B) In addition, the duration, timing, accumulation,
ors
r
E-diaries, Sensors
interaction, and dynamics of risk-related and sup-
portive influences are important for the developing
birthday cards) are decisive factors for the longer-term will-
ingness of traumatized individuals to participate in studies
(142). In addition, using multilevel recruitment strategies, in
which participating families recruit other families (143), and
targeting households and actively engaging schools in at-risk
areas with low socioeconomic status have been shown to be
better recruitment strategies than soliciting referrals through
agencies (144). In addition, inclusion of people with lived
experience (i.e., affected persons, relatives, other stake-
holders) in the research process can be a key driver for the
success of studies. The active inclusion of these partners in
the design of research protocols can improve the quality,
feasibility, user-friendliness, acceptance, and sustainability of
such studies and contribute to the destigmatization of affected
individuals (145).
SUMMARY AND CONCLUSIONS
Exposure to early adverse experiences and trauma is a
pervasive risk factor for the development of major mental and
somatic disorders across the life span and for reduced
longevity. Over and above maltreatment or loss, it encom-
passes a complex and incompletely understood range of early
adverse environmental influences of a different nature and at
different levels of proximity and complexity, many of which are
social in nature or have social and emotional subcomponents.
For the brain functional connectivity phenotypes discussed in
this review, available data indicate a relevance to mental health
and a vulnerability to a broader range of early adversities
converging on enhanced stress exposure. Supporting data
from animal models and humans suggest that early adversity–
induced changes in brain functional connectivity may be
rooted in region-specific neuroplastic reorganization pro-
cesses of the developing brain, which may result in delays or
accelerations of the normative developmental course and
shapes regulatory subcortical and cortical pathways.
Currently, however, the literature on the effects of early
adversity on brain functional connectivity is still patchy and
heterogeneous in terms of the intertwined adverse environ-
mental influences and age groups defined and studied,
the exact connectivity phenotypes and fMRI tasks used, the
normative developments of phenotypes established, and the

Environmental Risk and Brain Functional Connectivity
directions and interpretations of the described adversity-
related changes identified. We anticipate that future neuro-
developmental studies with harmonized assessments of the
nature and timing of early risk and protective environmental
influences and careful definition of functional connectivity
phenotypes with particular attention to their reliability and
reproducibility as well as the modeling of their developmental
trajectories are likely to synergistically complement and
accelerate current knowledge in the field, especially when
pursued in concerted efforts within and among large national
and international consortia.
ACKNOWLEDGMENTS AND DISCLOSURES
This research was supported by grants from the German Research Foun-
dation (DFG) (Grant No. HO 5674/2-1 [to NEH], Research Training Group
GRK2350/1 projects B2 [to HT] and A4 [to NEH]), Collaborative Research
Center TRR 265 project A04 (to HT and CMH), Collaborative Research
center 1158 project B04 (to HT and JT), and Federal Ministry of Education
and Research (Grant No. 01GL1743A [to CMH]). Additional support was
received from DFG (Grant No. EXC257 [to CMH]) and the Radboud Excel-
lence Initiative (to NEH).
The authors report no biomedical financial interests or potential conflicts
of interest.
ARTICLE INFORMATION
From the Donders Institute for Brain, Cognition and Behaviour, Radboud
University, Nijmegen, The Netherlands (NEH); Institute of Medical Psychol-
ogy and Medical Sociology, University Medical Center Schleswig Holstein,
Kiel University, Kiel, Germany (NEH); Department of Child and Adolescent
Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical
Faculty Mannheim/Heidelberg University, Mannheim, Germany (NEH, SS);
Department of Psychiatry and Psychotherapy, Central Institute of Mental
Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim,
Germany (OB, ES, HT); Department of General Internal Medicine and Psy-
chosomatics, University Hospital Heidelberg, Heidelberg, Germany (JT);
Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-
Universität zu Berlin, Institute of Medical Psychology, Berlin, Germany
(CMH); and the College of Health and Human Development, The Pennsyl-
vania State University, University Park, Pennsylvania (CMH).
Address correspondence to Heike Tost, M.D., Ph.D., at Heike.Tost@
zi-mannheim.de.
Received Jun 29, 2022; revised Oct 28, 2022; accepted Oct 31, 2022.
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