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Early social adversity, altered brain functional connectivity, and mental health

  • Nathalie E. Holz
    Affiliations
    Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands

    Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig Holstein, Kiel University, Kiel, Germany

    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany
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  • Oksana Berhe
    Affiliations
    Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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  • Seda Sacu
    Affiliations
    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany
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  • Emanuel Schwarz
    Affiliations
    Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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  • Jonas Tesarz
    Affiliations
    Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
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  • Christine M. Heim
    Affiliations
    Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Psychology, Berlin, Germany

    College of Health and Human Development, The Pennsylvania State University, University Park, PA, USA
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  • Heike Tost
    Correspondence
    Corresponding Author: Heike Tost, MD PhD, Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Square J5, 68159 Mannheim, Germany.
    Affiliations
    Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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Open AccessPublished:November 08, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.10.019

      Abstract

      Early adverse environmental exposures during brain development are widespread risk factors for the onset of severe mental disorders and a strong and consistent predictor of stress-related mental and physical illness and reduced life expectancy. Current evidence suggests that early negative experiences alter plasticity processes in developmentally sensitive time-windows and affect the regular functional interaction of cortical and subcortical neural networks. This may, in turn, promote a maladapted development with negative consequences on mental and physical health of exposed individuals. In this review, we discuss the role of fMRI-based functional connectivity phenotypes as potential biomarker candidates of the consequences of early environmental 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 fMRI-based phenotypes, including connectivity in the limbic and within the frontoparietal as well as within default mode networks, for which we believe there is sufficient converging evidence for a more detailed discussion in a developmental context. Further, 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, individual risk stratification, and as target phenotypes for mechanism-based interventions.

      Keywords

      1. Introduction

      The developing human brain is particularly sensitive to environmental influences − both beneficial and detrimental (
      • Holz N.E.
      • Tost H.
      • Meyer-Lindenberg A.
      Resilience and the brain: a key role for regulatory circuits linked to social stress and support.
      ,
      • Meyer-Lindenberg A.
      • Tost H.
      Neural mechanisms of social risk for psychiatric disorders.
      ,
      • Teicher M.H.
      • Samson J.A.
      • Anderson C.M.
      • Ohashi K.
      The effects of childhood maltreatment on brain structure, function and connectivity.
      ). As for the risk factors, epidemiological studies point to several early influences that have a negative impact on maturing neural networks and that increase the likelihood of developing psychological and somatic disorders later in life (
      • Gee D.G.
      Early Adversity and Development: Parsing Heterogeneity and Identifying Pathways of Risk and Resilience.
      ,

      Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of C, Family H, Committee on Early Childhood A, Dependent C, et al. (2012): The lifelong effects of early childhood adversity and toxic stress. Pediatrics 129: e232-246.

      ). 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 (
      • Heim C.M.
      • Entringer S.
      • Buss C.
      Translating basic research knowledge on the biological embedding of early-life stress into novel approaches for the developmental programming of lifelong health.
      ). 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 subcomponents that are plausibly associated with enhanced stress experience during development (see (
      • Tost H.
      • Champagne F.A.
      • Meyer-Lindenberg A.
      Environmental influence in the brain, human welfare and mental health.
      ) for review). Data from human and animal research show lasting changes in hypothalamic-pituitary-adrenocortical axis (HPA) function as a result of early adversity (
      • VanTieghem M.
      • Korom M.
      • Flannery J.
      • Choy T.
      • Caldera C.
      • Humphreys K.L.
      • et al.
      Longitudinal changes in amygdala, hippocampus and cortisol development following early caregiving adversity.
      ) and link these findings to shifts in the developmental 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) (
      • Lupien S.J.
      • McEwen B.S.
      • Gunnar M.R.
      • Heim C.
      Effects of stress throughout the lifespan on the brain, behaviour and cognition.
      ,
      • VanTieghem M.R.
      • Tottenham N.
      Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology.
      ). 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 (
      • Holz N.E.
      • Tost H.
      • Meyer-Lindenberg A.
      Resilience and the brain: a key role for regulatory circuits linked to social stress and support.
      ,
      • Meyer-Lindenberg A.
      • Tost H.
      Neural mechanisms of social risk for psychiatric disorders.
      ,
      • Tost H.
      • Champagne F.A.
      • Meyer-Lindenberg A.
      Environmental influence in the brain, human welfare and mental health.
      ) (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 the FK506 binding protein 5 (FKBP5) gene, with impact on gene expression, immune activation, and brain function or structure (
      • Matosin N.
      • Halldorsdottir T.
      • Binder E.B.
      Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model.
      ,
      • Wesarg C.
      • Veer I.M.
      • Oei N.Y.L.
      • Daedelow L.S.
      • Lett T.A.
      • Banaschewski T.
      • et al.
      The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults.
      ). Emerging, yet still fragmentary research attempts to achieve cross-system integration by linking molecular-genetic, endocrine, and/or immune data with neuroimaging data, in order to scrutinize the complex mechanistic pathways that link exposure to early adversity with adverse health outcomes (
      • Fani N.
      • King T.Z.
      • Shin J.
      • Srivastava A.
      • Brewster R.C.
      • Jovanovic T.
      • et al.
      Structural and Functional Connectivity in Posttraumatic Stress Disorder: Associations with Fkbp5.
      ,
      • Burghy C.A.
      • Stodola D.E.
      • Ruttle P.L.
      • Molloy E.K.
      • Armstrong J.M.
      • Oler J.A.
      • et al.
      Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence.
      ,
      • Holz N.E.
      • Buchmann A.F.
      • Boecker R.
      • Blomeyer D.
      • Baumeister S.
      • Wolf I.
      • et al.
      Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume.
      ). Below, we summarize the literature on the effects of early negative experiences on functional connectivity markers of neural networks. Specifically, we focus this review on a selected subset of fMRI-based phenotypes for which we believe there is sufficient converging evidence to discuss the findings in more detail in a developmental context. We further point out methodological challenges and knowledge gaps that currently complicate data interpretation and highlight the prospects and challenges for the research field as it moves toward using functional connectivity phenotypes as stratification markers for early detection, prevention, and treatment of the detrimental health effects of early adverse experiences.
      Figure thumbnail gr1
      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 responses (
      • Tost H.
      • Meyer-Lindenberg A.
      Puzzling over schizophrenia: schizophrenia, social environment and the brain.
      ). 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 ACC (
      • Holz N.E.
      • Tost H.
      • Meyer-Lindenberg A.
      Resilience and the brain: a key role for regulatory circuits linked to social stress and support.
      ,
      • Meyer-Lindenberg A.
      • Tost H.
      Neural mechanisms of social risk for psychiatric disorders.
      ,
      • Tost H.
      • Champagne F.A.
      • Meyer-Lindenberg A.
      Environmental influence in the brain, human welfare and mental health.
      ,
      • Tost H.
      • Meyer-Lindenberg A.
      Puzzling over schizophrenia: schizophrenia, social environment and the brain.
      ). Abbreviations: anterior cingulate cortex, ACC; prefrontal cortex, PFC; ventral medial prefrontal cortex, vmPFC; amygdala, AMY; ventral striatum, VS. Image is adapted from ref. (
      • Tost H.
      • Meyer-Lindenberg A.
      Puzzling over schizophrenia: schizophrenia, social environment and the brain.
      ) (Nature Publishing Group).

      2. Neuroimaging evidence

      2.1 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 (
      • LeDoux J.E.
      Brain mechanisms of emotion and emotional learning.
      ). These analyses are plausible hypothesis-driven extensions of earlier findings showing the influence of early stressful experiences on amygdala activation in humans and animal models (
      • Bilek E.
      • Itz M.L.
      • Stossel G.
      • Ma R.
      • Berhe O.
      • Clement L.
      • et al.
      Deficient Amygdala Habituation to Threatening Stimuli in Borderline Personality Disorder Relates to Adverse Childhood Experiences.
      ,
      • Kraaijenvanger E.J.
      • Pollok T.M.
      • Monninger M.
      • Kaiser A.
      • Brandeis D.
      • Banaschewski T.
      • et al.
      Impact of early life adversities on human brain functioning: A coordinate-based meta-analysis.
      ,
      • Rosenkranz J.A.
      • Venheim E.R.
      • Padival M.
      Chronic stress causes amygdala hyperexcitability in rodents.
      ). Particularly extensive empirical evidence for adaptation to early stress events exists for functional regulatory circuits connecting the amygdala to mPFC and the adjacent perigenual anterior cingulate cortex (pACC, Figure 2A) (
      • Etkin A.
      • Egner T.
      • Kalisch R.
      Emotional processing in anterior cingulate and medial prefrontal cortex.
      ), which has been linked to alterations in HPA axis function (
      • Urry H.L.
      • van Reekum C.M.
      • Johnstone T.
      • Kalin N.H.
      • Thurow M.E.
      • Schaefer H.S.
      • et al.
      Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults.
      ,
      • Hakamata Y.
      • Komi S.
      • Moriguchi Y.
      • Izawa S.
      • Motomura Y.
      • Sato E.
      • et al.
      Amygdala-centred functional connectivity affects daily cortisol concentrations: a putative link with anxiety.
      ,
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ), differences in emotion regulation (
      • Silvers J.A.
      • Insel C.
      • Powers A.
      • Franz P.
      • Helion C.
      • Martin R.E.
      • et al.
      vlPFC-vmPFC-Amygdala Interactions Underlie Age-Related Differences in Cognitive Regulation of Emotion.
      ), internalizing psychopathology (
      • Marusak H.A.
      • Thomason M.E.
      • Peters C.
      • Zundel C.
      • Elrahal F.
      • Rabinak C.A.
      You say 'prefrontal cortex' and I say 'anterior cingulate': meta-analysis of spatial overlap in amygdala-to-prefrontal connectivity and internalizing symptomology.
      ), trauma-related pro-inflammatory states (
      • Kraynak T.E.
      • Marsland A.L.
      • Hanson J.L.
      • Gianaros P.J.
      Retrospectively reported childhood physical abuse, systemic inflammation, and resting corticolimbic connectivity in midlife adults.
      ), and inflammation-associated mood deterioration (
      • Mehta N.D.
      • Haroon E.
      • Xu X.
      • Woolwine B.J.
      • Li Z.
      • Felger J.C.
      Inflammation negatively correlates with amygdala-ventromedial prefrontal functional connectivity in association with anxiety in patients with depression: Preliminary results.
      ,
      • Harrison N.A.
      • Brydon L.
      • Walker C.
      • Gray M.A.
      • Steptoe A.
      • Critchley H.D.
      Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity.
      ). These findings make these circuits plausible players in mediating the negative psychological and somatic consequences of early stress (
      • Miller G.E.
      • Chen E.
      • Parker K.J.
      Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms.
      ), although the regional specificity of amygdala-prefrontal connectivity findings can vary across studies and may be dependent on the fMRI task employed (
      • VanTieghem M.R.
      • Tottenham N.
      Neurobiological Programming of Early Life Stress: Functional Development of Amygdala-Prefrontal Circuitry and Vulnerability for Stress-Related Psychopathology.
      ).
      Figure thumbnail gr2
      Figure 2Functional connectivity affected by adversity. Alterations in functional connectivity between the amygdala seed and (A) the prefrontal cortex ((perigenual) anterior cingulate cortex, BA 10, BA 11, yellow) and (B) the hippocampus (red). Regions were derived from the wfu picktatlas. (C) Decreased within-network connectivity of the frontoparietal network (green) and (D) increased within-network connectivity of the default mode network (blue). DMN and FPN networks (FDR corrected p=.01) are extracted from Neurosynth (https://neurosynth.org) and thresholded at Z>6 for visualization purposes. Abbreviations: prefrontal cortex, PFC; hippocampus, HC; frontoparietal network, FPN; default-mode network, DMN.
      The range of negative environmental influences studied for this connectivity phenotype is broad and includes very heterogeneous 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 prominent 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 (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ), childhood abuse (
      • Peverill M.
      • Sheridan M.A.
      • Busso D.S.
      • McLaughlin K.A.
      Atypical Prefrontal-Amygdala Circuitry Following Childhood Exposure to Abuse: Links With Adolescent Psychopathology.
      ), and in pediatric posttraumatic stress disorder (
      • Wolf R.C.
      • Herringa R.J.
      Prefrontal-Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder.
      ). Similarly, reduced intrinsic (resting-state) coupling between the amygdala and mPFC has been associated with prenatal stress exposure (
      • Humphreys K.L.
      • Camacho M.C.
      • Roth M.C.
      • Estes E.C.
      Prenatal stress exposure and multimodal assessment of amygdala-medial prefrontal cortex connectivity in infants.
      ), cannabis (
      • Grewen K.
      • Salzwedel A.P.
      • Gao W.
      Functional Connectivity Disruption in Neonates with Prenatal Marijuana Exposure.
      ), inflammation (
      • Graham A.M.
      • Rasmussen J.M.
      • Rudolph M.D.
      • Heim C.M.
      • Gilmore J.H.
      • Styner M.
      • et al.
      Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age.
      ) and neighborhood socioeconomic disadvantage (
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ,
      • Rakesh D.
      • Seguin C.
      • Zalesky A.
      • Cropley V.
      • Whittle S.
      Associations Between Neighborhood Disadvantage, Resting-State Functional Connectivity, and Behavior in the Adolescent Brain Cognitive Development Study: The Moderating Role of Positive Family and School Environments.
      ). Notably, developmental shifts have been demonstrated for these coupling phenotypes during the transition to adolescence (
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ,
      • Gee D.G.
      • Humphreys K.L.
      • Flannery J.
      • Goff B.
      • Telzer E.H.
      • Shapiro M.
      • et al.
      A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.
      ,
      • Jalbrzikowski M.
      • Larsen B.
      • Hallquist M.N.
      • Foran W.
      • Calabro F.
      • Luna B.
      Development of White Matter Microstructure and Intrinsic Functional Connectivity Between the Amygdala and Ventromedial Prefrontal Cortex: Associations With Anxiety and Depression.
      ), and have been linked to a decrease in amygdala reactivity and separation anxiety (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ), fewer anxiety symptoms in children with lower neighborhood socioeconomic disadvantage (
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ), and higher ability to regulate negative emotion in adulthood (
      • Lee H.
      • Heller A.S.
      • van Reekum C.M.
      • Nelson B.
      • Davidson R.J.
      Amygdala-prefrontal coupling underlies individual differences in emotion regulation.
      ).
      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 (
      • Holz N.E.
      • Tost H.
      • Meyer-Lindenberg A.
      Resilience and the brain: a key role for regulatory circuits linked to social stress and support.
      ,
      • Tost H.
      • Champagne F.A.
      • Meyer-Lindenberg A.
      Environmental influence in the brain, human welfare and mental health.
      ), although some degree of exposure specificity may exist (e.g., deprivation vs. threat-related adverse experiences) (
      • McLaughlin K.A.
      • Sheridan M.A.
      • Lambert H.K.
      Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience.
      ). Second, the findings partially support the mechanistic accounts of the "stress acceleration hypothesis" (
      • Callaghan B.L.
      • Tottenham N.
      The Stress Acceleration Hypothesis: Effects of early-life adversity on emotion circuits and behavior.
      ,
      • Frankenhuis W.E.
      • de Weerth C.
      Does Early-Life Exposure to Stress Shape or Impair Cognition?.
      ), which holds that adversity triggers an accelerated maturation of emotion regulatory circuits in the developing brain, thereby shaping the affective 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 connections in response to environmental events during sensitive periods of neurodevelopment (“experience-expectant learning“) (
      • Greenough W.T.
      • Black J.E.
      • Wallace C.S.
      Experience and brain development.
      ). Both theoretical accounts are backed by studies suggesting effects of early developmental stress on the structural organization of amygdala-mPFC brain circuits, including altered amygdala volume in children exposed to poverty (
      • Luby J.
      • Belden A.
      • Botteron K.
      • Marrus N.
      • Harms M.P.
      • Babb C.
      • et al.
      The effects of poverty on childhood brain development: the mediating effect of caregiving and stressful life events.
      ) and maltreatment (
      • Whittle S.
      • Dennison M.
      • Vijayakumar N.
      • Simmons J.G.
      • Yucel M.
      • Lubman D.I.
      • et al.
      Childhood maltreatment and psychopathology affect brain development during adolescence.
      ), premature amygdala circuit myelin formation (
      • Ono M.
      • Kikusui T.
      • Sasaki N.
      • Ichikawa M.
      • Mori Y.
      • Murakami-Murofushi K.
      Early weaning induces anxiety and precocious myelination in the anterior part of the basolateral amygdala of male Balb/c mice.
      ) and increased branching and length of mPFC dendrites (
      • Muhammad A.
      • Carroll C.
      • Kolb B.
      Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex.
      ) 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 facilitating exposed children and adolescents to cope with the experienced adversities (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ,
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ,
      • Gee D.G.
      • Humphreys K.L.
      • Flannery J.
      • Goff B.
      • Telzer E.H.
      • Shapiro M.
      • et al.
      A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.
      ,
      • Lee H.
      • Heller A.S.
      • van Reekum C.M.
      • Nelson B.
      • Davidson R.J.
      Amygdala-prefrontal coupling underlies individual differences in emotion regulation.
      ). 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 vs. intrinsic amygdala-mPFC/pACC connectivity reveals a fundamental problem in interpreting connectivity results in the context of early adversity, namely that of the poorly defined natural developmental course of the phenotypes (see also section 3.2 and Figure 3A). Here, the available data suggest potentially contrasting developmental trajectories 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 with negative or nonsignificant coupling (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ,
      • Wu M.
      • Kujawa A.
      • Lu L.H.
      • Fitzgerald D.A.
      • Klumpp H.
      • Fitzgerald K.D.
      • et al.
      Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.
      ) [but see also (
      • Wolf R.C.
      • Herringa R.J.
      Prefrontal-Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder.
      ,
      • Vink M.
      • Derks J.M.
      • Hoogendam J.M.
      • Hillegers M.
      • Kahn R.S.
      Functional differences in emotion processing during adolescence and early adulthood.
      ) for opposite and (
      • Zhang Y.
      • Padmanabhan A.
      • Gross J.J.
      • Menon V.
      Development of Human Emotion Circuits Investigated Using a Big-Data Analytic Approach: Stability, Reliability, and Robustness.
      ,
      • Bloom P.A.
      • VanTieghem M.
      • Gabard-Durnam L.
      • Gee D.G.
      • Flannery J.
      • Caldera C.
      • et al.
      Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.
      ) for absent or no consistent developmental changes], whereas for the intrinsic coupling phenotype (Figure 3B), age tends to be positively associated with increasing connectivity (
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Gee D.G.
      • Humphreys K.L.
      • Telzer E.
      • et al.
      The development of human amygdala functional connectivity at rest from 4 to 23 years: a cross-sectional study.
      ,
      • Qin S.
      • Young C.B.
      • Supekar K.
      • Uddin L.Q.
      • Menon V.
      Immature integration and segregation of emotion-related brain circuitry in young children.
      ) [ see (
      • Alarcon G.
      • Cservenka A.
      • Rudolph M.D.
      • Fair D.A.
      • Nagel B.J.
      Developmental sex differences in resting state functional connectivity of amygdala sub-regions.
      ) for sex-specific effects, (
      • Jalbrzikowski M.
      • Larsen B.
      • Hallquist M.N.
      • Foran W.
      • Calabro F.
      • Luna B.
      Development of White Matter Microstructure and Intrinsic Functional Connectivity Between the Amygdala and Ventromedial Prefrontal Cortex: Associations With Anxiety and Depression.
      ,
      • Pagliaccio D.
      • Luby J.L.
      • Bogdan R.
      • Agrawal A.
      • Gaffrey M.S.
      • Belden A.C.
      • et al.
      Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.
      ) for opposite developmental changes, and (
      • Odriozola P.
      • Dajani D.R.
      • Burrows C.A.
      • Gabard-Durnam L.J.
      • Goodman E.
      • Baez A.C.
      • et al.
      Atypical frontoamygdala functional connectivity in youth with autism.
      ) for a connectivity decrement until adolescence and a subsequent increment until early adulthood]. These contrasting trajectories may support the hypothesis that increasing intrinsic coupling between the amygdala and the 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 negative 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. Negative deviations from the task-evoked trajectory could therefore be interpreted as developmental acceleration, while positive deviations 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, as well as variations in the type of functional connectivity methods used and mPFC/pACC subregion (and thus cortical-amygdala subcircuit) highlighted (
      • Burghy C.A.
      • Stodola D.E.
      • Ruttle P.L.
      • Molloy E.K.
      • Armstrong J.M.
      • Oler J.A.
      • et al.
      Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence.
      ,
      • Marusak H.A.
      • Thomason M.E.
      • Peters C.
      • Zundel C.
      • Elrahal F.
      • Rabinak C.A.
      You say 'prefrontal cortex' and I say 'anterior cingulate': meta-analysis of spatial overlap in amygdala-to-prefrontal connectivity and internalizing symptomology.
      ,
      • Peverill M.
      • Sheridan M.A.
      • Busso D.S.
      • McLaughlin K.A.
      Atypical Prefrontal-Amygdala Circuitry Following Childhood Exposure to Abuse: Links With Adolescent Psychopathology.
      ,
      • Graham A.M.
      • Rasmussen J.M.
      • Rudolph M.D.
      • Heim C.M.
      • Gilmore J.H.
      • Styner M.
      • et al.
      Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age.
      ,
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Gee D.G.
      • Humphreys K.L.
      • Telzer E.
      • et al.
      The development of human amygdala functional connectivity at rest from 4 to 23 years: a cross-sectional study.
      ,
      • Underwood R.
      • Tolmeijer E.
      • Wibroe J.
      • Peters E.
      • Mason L.
      Networks underpinning emotion: A systematic review and synthesis of functional and effective connectivity.
      ,
      • Javanbakht A.
      • King A.P.
      • Evans G.W.
      • Swain J.E.
      • Angstadt M.
      • Phan K.L.
      • et al.
      Childhood Poverty Predicts Adult Amygdala and Frontal Activity and Connectivity in Response to Emotional Faces.
      ,
      • Fonzo G.A.
      • Flagan T.M.
      • Sullivan S.
      • Allard C.B.
      • Grimes E.M.
      • Simmons A.N.
      • et al.
      Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder.
      ). Finally, the effects of early stress on these phenotypes appear to be subject to complex interactions with age, sex, type and timing of adversity, its predictability by the exposed individual, and likely other as yet unknown moderators that will require careful disentanglement in future (longitudinal) studies (
      • Burghy C.A.
      • Stodola D.E.
      • Ruttle P.L.
      • Molloy E.K.
      • Armstrong J.M.
      • Oler J.A.
      • et al.
      Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence.
      ,
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ,
      • Ono M.
      • Kikusui T.
      • Sasaki N.
      • Ichikawa M.
      • Mori Y.
      • Murakami-Murofushi K.
      Early weaning induces anxiety and precocious myelination in the anterior part of the basolateral amygdala of male Balb/c mice.
      ,
      • Perlman S.B.
      • Pelphrey K.A.
      Developing connections for affective regulation: age-related changes in emotional brain connectivity.
      ,
      • Johnson F.K.
      • Delpech J.C.
      • Thompson G.J.
      • Wei L.
      • Hao J.
      • Herman P.
      • et al.
      Amygdala hyper-connectivity in a mouse model of unpredictable early life stress.
      ).
      Figure thumbnail gr3
      Figure 3Panel 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 lifespan. 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. fMRI task choice or suboptimal measurement reliability. Panels B and C: Schematic illustration of the possible normative trajectories and relative adversity-related deviations of emotional task-evoked (B) and intrinsic (C) amygdala-mPFC/ACC 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 = infancy, orange = childhood, blue = adolescence, gray = adulthood). Study references: 1 (
      • Gee D.G.
      • Gabard-Durnam L.J.
      • Flannery J.
      • Goff B.
      • Humphreys K.L.
      • Telzer E.H.
      • et al.
      Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation.
      ), 2 (
      • Silvers J.A.
      • Lumian D.S.
      • Gabard-Durnam L.
      • Gee D.G.
      • Goff B.
      • Fareri D.S.
      • et al.
      Previous Institutionalization Is Followed by Broader Amygdala-Hippocampal-PFC Network Connectivity during Aversive Learning in Human Development.
      ), 3 (
      • Wolf R.C.
      • Herringa R.J.
      Prefrontal-Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder.
      ), 4 (
      • Peverill M.
      • Sheridan M.A.
      • Busso D.S.
      • McLaughlin K.A.
      Atypical Prefrontal-Amygdala Circuitry Following Childhood Exposure to Abuse: Links With Adolescent Psychopathology.
      ), 5 (
      • Herringa R.J.
      • Burghy C.A.
      • Stodola D.E.
      • Fox M.E.
      • Davidson R.J.
      • Essex M.J.
      Enhanced prefrontal-amygdala connectivity following childhood adversity as a protective mechanism against internalizing in adolescence.
      ), 6 (
      • Jedd K.
      • Hunt R.H.
      • Cicchetti D.
      • Hunt E.
      • Cowell R.A.
      • Rogosch F.A.
      • et al.
      Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity.
      ), 7 (
      • Park A.T.
      • Leonard J.A.
      • Saxler P.K.
      • Cyr A.B.
      • Gabrieli J.D.E.
      • Mackey A.P.
      Amygdala-medial prefrontal cortex connectivity relates to stress and mental health in early childhood.
      ), 8 (
      • Pagliaccio D.
      • Luby J.L.
      • Bogdan R.
      • Agrawal A.
      • Gaffrey M.S.
      • Belden A.C.
      • et al.
      Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.
      ), 9 (
      • Thomason M.E.
      • Marusak H.A.
      • Tocco M.A.
      • Vila A.M.
      • McGarragle O.
      • Rosenberg D.R.
      Altered amygdala connectivity in urban youth exposed to trauma.
      ), 10 (
      • Ramphal B.
      • DeSerisy M.
      • Pagliaccio D.
      • Raffanello E.
      • Rauh V.
      • Tau G.
      • et al.
      Associations between Amygdala-Prefrontal Functional Connectivity and Age Depend on Neighborhood Socioeconomic Status.
      ), 11 (
      • Cisler J.M.
      Childhood Trauma and Functional Connectivity between Amygdala and Medial Prefrontal Cortex: A Dynamic Functional Connectivity and Large-Scale Network Perspective.
      ), 12 (
      • Jiang N.
      • Xu J.
      • Li X.
      • Wang Y.
      • Zhuang L.
      • Qin S.
      Negative Parenting Affects Adolescent Internalizing Symptoms Through Alterations in Amygdala-Prefrontal Circuitry: A Longitudinal Twin Study.
      ), 13 (
      • Herringa R.J.
      • Birn R.M.
      • Ruttle P.L.
      • Burghy C.A.
      • Stodola D.E.
      • Davidson R.J.
      • et al.
      Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.
      ). Abbreviations: SLE = stressful life events, SES = socioeconomic status. 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).

      2.2 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 circulating 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 (
      • McEwen B.S.
      • Nasca C.
      • Gray J.D.
      Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex.
      ,
      • McEwen B.S.
      Plasticity of the hippocampus: adaptation to chronic stress and allostatic load.
      ). 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 (
      • Yang Y.
      • Wang J.Z.
      From Structure to Behavior in Basolateral Amygdala-Hippocampus Circuits.
      ). This renders this circuit a promising mechanistic targets for the examination of the adversity effects and related negative health outcomes.
      The available neuroimaging evidence on early environmental 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 (PPI) during emotional face processing (
      • Jedd K.
      • Hunt R.H.
      • Cicchetti D.
      • Hunt E.
      • Cowell R.A.
      • Rogosch F.A.
      • et al.
      Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity.
      ) and increase amygdala-hippocampus generalized psychophysiological interaction (gPPI) during the processing of olfactory stress odors (
      • Maier A.
      • Heinen-Ludwig L.
      • Gunturkun O.
      • Hurlemann R.
      • Scheele D.
      Childhood Maltreatment Alters the Neural Processing of Chemosensory Stress Signals.
      ). In contrast, decreased amygdala-hippocampus coupling was observed in children (gPPI) during fear conditioning paradigm (
      • DeCross S.N.
      • Sambrook K.A.
      • Sheridan M.A.
      • Tottenham N.
      • McLaughlin K.A.
      Dynamic Alterations in Neural Networks Supporting Aversive Learning in Children Exposed to Trauma: Neural Mechanisms Underlying Psychopathology.
      ) and similarly during resting-state in maltreated adults (
      • van der Werff S.J.
      • Pannekoek J.N.
      • Veer I.M.
      • van Tol M.J.
      • Aleman A.
      • Veltman D.J.
      • et al.
      Resting-state functional connectivity in adults with childhood emotional maltreatment.
      ) and in neonates with prenatal exposure to neighborhood crime (
      • Brady R.G.
      • Rogers C.E.
      • Prochaska T.
      • Kaplan S.
      • Lean R.E.
      • Smyser T.A.
      • et al.
      The Effects of Prenatal Exposure to Neighborhood Crime on Neonatal Functional Connectivity.
      ).
      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 analyses of functional connectivity, the diversity of study participants 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 PPI amygdala-hippocampus connectivity 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 implications. Second, for these amygdala-hippocampal connectivity phenotypes, there is still insufficient longitudinal evidence defining the normative development of coupling parameters across the early and middle life span, rendering the interpretation of deviations difficult. For example, while increased connectivity has been found in adults who retrospectively reported childhood maltreatment, which could refer to individuals who have an intact emotional memory trace of early trauma supported by limbic hyperconnectivity, this connectivity pattern may not apply to children who have been recently maltreated 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 between the amygdala and hippocampus have been mostly limited to childhood maltreatment. In contrast, other more distant health-related adversities, such as low social status, urbanization, bullying, or experiences of racial/ethnic discrimination, are largely unexplored for this phenotype.

      2.3 Functional connectivity in frontoparietal and default-mode networks

      Compared to the limbic system, studies on the influence of early adversities on the functional interaction of cognitive cortical circuits are comparatively scarce and have mostly focused on the analysis of frontoparietal (FPN, Figure 2C) and default-mode networks (DMN, Figure 2D). For example, in adolescents exposed to childhood abuse reduced seed-based connectivity of the left prefrontal cortex with inferior parietal and inferior prefrontal areas during sustained attention has been reported, which related to FKBP5 genotype (
      • Hart H.
      • Lim L.
      • Mehta M.A.
      • Chatzieffraimidou A.
      • Curtis C.
      • Xu X.
      • et al.
      Reduced functional connectivity of fronto-parietal sustained attention networks in severe childhood abuse.
      ). A similar reduction in frontoparietal network connectivity has been observed in stress-related psychopathology such as depression (
      • Liston C.
      • Chen A.C.
      • Zebley B.D.
      • Drysdale A.T.
      • Gordon R.
      • Leuchter B.
      • et al.
      Default mode network mechanisms of transcranial magnetic stimulation in depression.
      ). 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 (
      • Liston C.
      • McEwen B.S.
      • Casey B.J.
      Psychosocial stress reversibly disrupts prefrontal processing and attentional control.
      ). The latter study on chronic stress is particularly informative because it represents a direct conceptual extension of previous animal studies of chronic stress, which facilitates hypothesis generation and data interpretation in the human tandem study. In the animal studies, chronic stress exposure in rats was associated with impaired attentional shift and dendritic reorganization of the mPFC (
      • Liston C.
      • Miller M.M.
      • Goldwater D.S.
      • Radley J.J.
      • Rocher A.B.
      • Hof P.R.
      • et al.
      Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting.
      ,
      • Radley J.J.
      • Rocher A.B.
      • Janssen W.G.
      • Hof P.R.
      • McEwen B.S.
      • Morrison J.H.
      Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress.
      ). Taken together, these findings suggest that stress-associated experiences and disease are associated with reductions in frontoparietal network connectivity and attentional function mediated by these circuits, which originate in dendritic reorganization of the prefrontal cortex and may be plausibly influenced by glucocorticoid-regulated genes. In this context, the functional connectivity alterations and neuroplastic changes appear to be reversible upon repeated but time-limited stress experience 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 mPFC, medial temporal lobe, and posterior cingulate cortex that is predominantly active at rest and supports episodic memory and self-referential information processing (
      • Greicius M.D.
      • Krasnow B.
      • Reiss A.L.
      • Menon V.
      Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.
      ). Here, 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 (
      • Graham A.M.
      • Pfeifer J.H.
      • Fisher P.A.
      • Carpenter S.
      • Fair D.A.
      Early life stress is associated with default system integrity and emotionality during infancy.
      ). A similar increase in DMN functional connectivity was reported for adult females suffering from posttraumatic stress disorder (PTSD) as a result of exposure to childhood abuse (
      • Bluhm R.L.
      • Williamson P.C.
      • Osuch E.A.
      • Frewen P.A.
      • Stevens T.K.
      • Boksman K.
      • et al.
      Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma.
      ) and in patients with stress-related psychiatric disorders such as major depression (
      • Greicius M.D.
      • Flores B.H.
      • Menon V.
      • Glover G.H.
      • Solvason H.B.
      • Kenna H.
      • et al.
      Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus.
      ,
      • Broyd S.J.
      • Demanuele C.
      • Debener S.
      • Helps S.K.
      • James C.J.
      • Sonuga-Barke E.J.
      Default-mode brain dysfunction in mental disorders: a systematic review.
      ) (but see also (
      • Javaheripour N.
      • Li M.
      • Chand T.
      • Krug A.
      • Kircher T.
      • Dannlowski U.
      • et al.
      Altered resting-state functional connectome in major depressive disorder: a mega-analysis from the PsyMRI consortium.
      )). In stress-related psychiatric disorders, heightened DMN functional connectivity has been interpreted as deficient higher-order down-regulation of DMN activity and have been related to cognitive symptoms that involve impairments in self‐reflective autobiographical functions (e.g., rumination) (
      • Sheline Y.I.
      • Barch D.M.
      • Price J.L.
      • Rundle M.M.
      • Vaishnavi S.N.
      • Snyder A.Z.
      • et al.
      The default mode network and self-referential processes in depression.
      ,
      • St Jacques P.L.
      • Kragel P.A.
      • Rubin D.C.
      Neural networks supporting autobiographical memory retrieval in posttraumatic stress disorder.
      ). DMN resting-state functional connectivity reflects, at least to some degree, structural interconnections between DMN areas (
      • Greicius M.D.
      • Supekar K.
      • Menon V.
      • Dougherty R.F.
      Resting-state functional connectivity reflects structural connectivity in the default mode network.
      ), and impairments in the structural and maturational covariance of DMN regions in infants has been related to stress-provoking early-life experiences such as preterm birth (
      • Lammertink F.
      • van den Heuvel M.P.
      • Hermans E.J.
      • Dudink J.
      • Tataranno M.L.
      • Benders M.J.N.L.
      • et al.
      Early-life stress exposure and large-scale covariance brain networks in extremely preterm-born infants.
      ), which appears to delay or accelerate the developmental course of the brain in a region-specific manner (
      • Karolis V.R.
      • Froudist-Walsh S.
      • Kroll J.
      • Brittain P.J.
      • Tseng C.J.
      • Nam K.W.
      • et al.
      Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation.
      ,
      • Padilla N.
      • Alexandrou G.
      • Blennow M.
      • Lagercrantz H.
      • Aden U.
      Brain Growth Gains and Losses in Extremely Preterm Infants at Term.
      ). Taken together, these data are consistent with the ideas that the observed increase in functional connectivity of the DMN is triggered by early adverse environmental experiences (but see (
      • Rakesh D.
      • Kelly C.
      • Vijayakumar N.
      • Zalesky A.
      • Allen N.B.
      • Whittle S.
      Unraveling the Consequences of Childhood Maltreatment: Deviations From Typical Functional Neurodevelopment Mediate the Relationship Between Maltreatment History and Depressive Symptoms.
      )), relevant to mental health, and the result of early stress-induced structural 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 connectivity reflects an acceleration or 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 (TMS) (
      • Liston C.
      • Chen A.C.
      • Zebley B.D.
      • Drysdale A.T.
      • Gordon R.
      • Leuchter B.
      • et al.
      Default mode network mechanisms of transcranial magnetic stimulation in depression.
      ) and cognitive psychotherapy (
      • Vuper T.C.
      • Philippi C.L.
      • Bruce S.E.
      Altered resting-state functional connectivity of the default mode and central executive networks following cognitive processing therapy for PTSD.
      ), 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.

      2.4 Whole-brain connectivity studies

      Whole-brain connectivity is a less spatially constrained technique to study large-scale brain alterations in relation to early adversities. While a range of machine learning approaches such as multivariate pattern analyses (MVPA) are promising in terms of identifying nuanced patterns of activation, but still underutilized in the field, graph-based analyses have most prominently been investigated (for a review see 89). As such, global and local brain network organization (e.g., strength of functional connectivity or network properties) as a function of early adversity, including childhood abuse (
      • Cisler J.M.
      Childhood Trauma and Functional Connectivity between Amygdala and Medial Prefrontal Cortex: A Dynamic Functional Connectivity and Large-Scale Network Perspective.
      ,
      • Li J.
      • Zhang G.
      • Wang J.
      • Liu D.
      • Wan C.
      • Fang J.
      • et al.
      Experience-dependent associations between distinct subtypes of childhood trauma and brain function and architecture.
      ,
      • Wang L.
      • Dai Z.
      • Peng H.
      • Tan L.
      • Ding Y.
      • He Z.
      • et al.
      Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect.
      ), prenatal alcohol (
      • Long X.
      • Kar P.
      • Gibbard B.
      • Tortorelli C.
      • Lebel C.
      The brain's functional connectome in young children with prenatal alcohol exposure.
      ,
      • Wozniak J.R.
      • Mueller B.A.
      • Bell C.J.
      • Muetzel R.L.
      • Hoecker H.L.
      • Boys C.J.
      • et al.
      Global functional connectivity abnormalities in children with fetal alcohol spectrum disorders.
      ) and opioid exposure (
      • Merhar S.L.
      • Jiang W.
      • Parikh N.A.
      • Yin W.
      • Zhou Z.
      • Tkach J.A.
      • et al.
      Effects of prenatal opioid exposure on functional networks in infancy.
      ,
      • Radhakrishnan R.
      • Vishnubhotla R.V.
      • Zhao Y.
      • Yan J.
      • He B.
      • Steinhardt N.
      • et al.
      Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure.
      ), pediatric PTSD (
      • Suo X.
      • Lei D.
      • Li K.
      • Chen F.
      • Li F.
      • Li L.
      • et al.
      Disrupted brain network topology in pediatric posttraumatic stress disorder: A resting‐state fMRI study.
      ,
      • Yang J.
      • Lei D.
      • Qin K.
      • Pinaya W.H.
      • Suo X.
      • Li W.
      • et al.
      Using deep learning to classify pediatric posttraumatic stress disorder at the individual level.
      ) and early maternal separation (
      • Herzberg M.P.
      • McKenzie K.J.
      • Hodel A.S.
      • Hunt R.H.
      • Mueller B.A.
      • Gunnar M.R.
      • et al.
      Accelerated maturation in functional connectivity following early life stress: Circuit specific or broadly distributed?.
      ) has been examined. Furthermore, alterations related to early adversity have been reported in large-scale brain networks such as the FPN, DMN, salience network (SN), and dorsal attention network (DAN) with the majority based on resting-state data (e.g., (
      • Herzberg M.P.
      • McKenzie K.J.
      • Hodel A.S.
      • Hunt R.H.
      • Mueller B.A.
      • Gunnar M.R.
      • et al.
      Accelerated maturation in functional connectivity following early life stress: Circuit specific or broadly distributed?.
      ,
      • Fan J.
      • Taylor P.A.
      • Jacobson S.W.
      • Molteno C.D.
      • Gohel S.
      • Biswal B.B.
      • et al.
      Localized reductions in resting‐state functional connectivity in children with prenatal alcohol exposure.
      ,
      • Huang D.
      • Liu Z.
      • Cao H.
      • Yang J.
      • Wu Z.
      • Long Y.
      Childhood trauma is linked to decreased temporal stability of functional brain networks in young adults.
      )) and only few studies on stimulus-evoked alterations following adversities (
      • Cisler J.M.
      Childhood Trauma and Functional Connectivity between Amygdala and Medial Prefrontal Cortex: A Dynamic Functional Connectivity and Large-Scale Network Perspective.
      ,
      • Zakiniaeiz Y.
      • Yip S.W.
      • Balodis I.M.
      • Lacadie C.M.
      • Scheinost D.
      • Constable R.T.
      • et al.
      Altered functional connectivity to stressful stimuli in prenatally cocaine-exposed adolescents.
      ). As with the region-to-region connectivity studies, there is currently no consistent picture regarding the direction of connectivity change (e.g., decreased (
      • Wang L.
      • Dai Z.
      • Peng H.
      • Tan L.
      • Ding Y.
      • He Z.
      • et al.
      Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect.
      ,
      • Wozniak J.R.
      • Mueller B.A.
      • Bell C.J.
      • Muetzel R.L.
      • Hoecker H.L.
      • Boys C.J.
      • et al.
      Global functional connectivity abnormalities in children with fetal alcohol spectrum disorders.
      ,
      • Herzberg M.P.
      • McKenzie K.J.
      • Hodel A.S.
      • Hunt R.H.
      • Mueller B.A.
      • Gunnar M.R.
      • et al.
      Accelerated maturation in functional connectivity following early life stress: Circuit specific or broadly distributed?.
      ,
      • Fan J.
      • Taylor P.A.
      • Jacobson S.W.
      • Molteno C.D.
      • Gohel S.
      • Biswal B.B.
      • et al.
      Localized reductions in resting‐state functional connectivity in children with prenatal alcohol exposure.
      ,
      • Zakiniaeiz Y.
      • Yip S.W.
      • Balodis I.M.
      • Lacadie C.M.
      • Scheinost D.
      • Constable R.T.
      • et al.
      Altered functional connectivity to stressful stimuli in prenatally cocaine-exposed adolescents.
      ,
      • Pang Y.
      • Zhao S.
      • Li Z.
      • Li N.
      • Yu J.
      • Zhang R.
      • et al.
      Enduring effect of abuse: childhood maltreatment links to altered theory of mind network among adults.
      ), increased (
      • Rakesh D.
      • Kelly C.
      • Vijayakumar N.
      • Zalesky A.
      • Allen N.B.
      • Whittle S.
      Unraveling the Consequences of Childhood Maltreatment: Deviations From Typical Functional Neurodevelopment Mediate the Relationship Between Maltreatment History and Depressive Symptoms.
      ,
      • Merhar S.L.
      • Jiang W.
      • Parikh N.A.
      • Yin W.
      • Zhou Z.
      • Tkach J.A.
      • et al.
      Effects of prenatal opioid exposure on functional networks in infancy.
      ,
      • Suo X.
      • Lei D.
      • Li K.
      • Chen F.
      • Li F.
      • Li L.
      • et al.
      Disrupted brain network topology in pediatric posttraumatic stress disorder: A resting‐state fMRI study.
      ) and its spatial specificity (e.g., network specific (
      • Li J.
      • Zhang G.
      • Wang J.
      • Liu D.
      • Wan C.
      • Fang J.
      • et al.
      Experience-dependent associations between distinct subtypes of childhood trauma and brain function and architecture.
      ,
      • Radhakrishnan R.
      • Vishnubhotla R.V.
      • Zhao Y.
      • Yan J.
      • He B.
      • Steinhardt N.
      • et al.
      Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure.
      ), network unspecific (
      • Long X.
      • Kar P.
      • Gibbard B.
      • Tortorelli C.
      • Lebel C.
      The brain's functional connectome in young children with prenatal alcohol exposure.
      ,
      • Huang D.
      • Liu Z.
      • Cao H.
      • Yang J.
      • Wu Z.
      • Long Y.
      Childhood trauma is linked to decreased temporal stability of functional brain networks in young adults.
      )), even when the adversities and developmental stages studied were similar (
      • Merhar S.L.
      • Jiang W.
      • Parikh N.A.
      • Yin W.
      • Zhou Z.
      • Tkach J.A.
      • et al.
      Effects of prenatal opioid exposure on functional networks in infancy.
      ,
      • Radhakrishnan R.
      • Vishnubhotla R.V.
      • Zhao Y.
      • Yan J.
      • He B.
      • Steinhardt N.
      • et al.
      Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure.
      ,
      • Salzwedel A.
      • Chen G.
      • Chen Y.
      • Grewen K.
      • Gao W.
      Functional dissection of prenatal drug effects on baby brain and behavioral development.
      ). Evidence is scarce with respect to longitudinal connectivity studies and also points to heterogeneous trajectories after adversity (
      • Rakesh D.
      • Kelly C.
      • Vijayakumar N.
      • Zalesky A.
      • Allen N.B.
      • Whittle S.
      Unraveling the Consequences of Childhood Maltreatment: Deviations From Typical Functional Neurodevelopment Mediate the Relationship Between Maltreatment History and Depressive Symptoms.
      ,
      • Chahal R.
      • Miller J.G.
      • Yuan J.P.
      • Buthmann J.L.
      • Gotlib I.H.
      An exploration of dimensions of early adversity and the development of functional brain network connectivity during adolescence: Implications for trajectories of internalizing symptoms.
      ) with childhood maltreatment relating to increased between-network connectivity (
      • Rakesh D.
      • Kelly C.
      • Vijayakumar N.
      • Zalesky A.
      • Allen N.B.
      • Whittle S.
      Unraveling the Consequences of Childhood Maltreatment: Deviations From Typical Functional Neurodevelopment Mediate the Relationship Between Maltreatment History and Depressive Symptoms.
      ), and blunted developmental network plasticity as a function of deprivation, neglect and stressor unpredictability (
      • Chahal R.
      • Miller J.G.
      • Yuan J.P.
      • Buthmann J.L.
      • Gotlib I.H.
      An exploration of dimensions of early adversity and the development of functional brain network connectivity during adolescence: Implications for trajectories of internalizing symptoms.
      ). Again, the methodological and demographic diversity of the studies is a plausible explanation for these inconsistencies.

      3. Areas of tension and perspectives for future research

      Even though imaging research on brain functional connectivity has yielded increasing insights into the developmental mechanisms 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 outcomes, are still elusive (
      • Heim C.M.
      • Entringer S.
      • Buss C.
      Translating basic research knowledge on the biological embedding of early-life stress into novel approaches for the developmental programming of lifelong health.
      ). As a result, despite promising approaches (
      • Guerrero Moreno J.
      • Biazoli Jr., C.E.
      • Baptista A.F.
      • Trambaiolli L.R.
      Closed-loop neurostimulation for affective symptoms and disorders: An overview.
      ,
      • Sitaram R.
      • Ros T.
      • Stoeckel L.
      • Haller S.
      • Scharnowski F.
      • Lewis-Peacock J.
      • et al.
      Closed-loop brain training: the science of neurofeedback.
      ), there are still no validated diagnostic 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 corresponding developmental phenotypes promises to enable the stratification of subtypes of disorders and the selection of treatment strategies guided by the identified mechanisms in the future (
      • Heim C.M.
      • Entringer S.
      • Buss C.
      Translating basic research knowledge on the biological embedding of early-life stress into novel approaches for the developmental programming of lifelong health.
      ,
      • Heim C.
      • Plotsky P.M.
      • Nemeroff C.B.
      Importance of studying the contributions of early adverse experience to neurobiological findings in depression.
      ,
      • Nemeroff C.B.
      • Heim C.M.
      • Thase M.E.
      • Klein D.N.
      • Rush A.J.
      • Schatzberg A.F.
      • et al.
      Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma.
      ). 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 connectome, to more fully understand the mechanistic pathways that link exposure to early adversity with disease outcomes. In the following, we address two selected areas of tension that we believe deserve special attention.

      3.1 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 (
      • Colich N.L.
      • Rosen M.L.
      • Williams E.S.
      • McLaughlin K.A.
      Biological aging in childhood and adolescence following experiences of threat and deprivation: A systematic review and meta-analysis.
      ). 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 (
      • Kraaijenvanger E.J.
      • Pollok T.M.
      • Monninger M.
      • Kaiser A.
      • Brandeis D.
      • Banaschewski T.
      • et al.
      Impact of early life adversities on human brain functioning: A coordinate-based meta-analysis.
      ,
      • Pollok T.M.
      • Kaiser A.
      • Kraaijenvanger E.J.
      • Monninger M.
      • Brandeis D.
      • Banaschewski T.
      • et al.
      Neurostructural traces of early life adversities: A meta-analysis exploring age- and adversity-specific effects.
      ,
      • Smith K.E.
      • Pollak S.D.
      Rethinking Concepts and Categories for Understanding the Neurodevelopmental Effects of Childhood Adversity.
      ). The convergence or divergence of these different sources of environmental risk and protection at the neural system level requires further investigation (
      • McLaughlin K.A.
      • Weissman D.
      • Bitran D.
      Childhood Adversity and Neural Development: A Systematic Review.
      ). This poses challenges for research in the future. First, many of these risks are heterogeneous consist of different subcomponents. 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 (
      • Holz N.E.
      • Laucht M.
      • Meyer-Lindenberg A.
      Recent advances in understanding the neurobiology of childhood socioeconomic disadvantage.
      ) 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 socioeconomic status is related to neighborhood socioeconomic status, and both are related with risk of drug exposure and experiences of violence and crime within the family and in the neighborhood (
      • McMahon S.D.
      • Grant K.E.
      • Compas B.E.
      • Thurm A.E.
      • Ey S.
      Stress and psychopathology in children and adolescents: is there evidence of specificity?.
      ). 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 associations with neural outcomes.
      We believe that this research challenge requires a comprehensive and harmonized assessment of early exposures in terms of a “standardized exposome map” and an equally broad and harmonized assessment of relevant outcomes (psychological, 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 (
      • Wild C.P.
      Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology.
      ). It has more recently been adopted by large-scale, transdisciplinary research collaborations (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 lifespan provides a more agnostic alternative to current hypothesis-driven candidate adversity approaches (
      • Guloksuz S.
      • van Os J.
      • Rutten B.P.F.
      The Exposome Paradigm and the Complexities of Environmental Research in Psychiatry.
      ). 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 in order to gain a more comprehensive understanding of which factors affect mental health, at what doses and through what mechanisms. Although full implementation of such a comprehensive approach still requires much developmental work, the basic concept could involve repeated, standardized, multilevel assessment of nongenomic exposures across the lifespan (including their timing, duration and intensity) along four main axes or layers arranged from proximal to distal relative to the person studied (Figure 4). The first layer could refer to the individual level, where, beginning in the prenatal period adverse (e.g., toxin exposure, physical abuse) and protective exposures are assessed along with individual moderators such as the subjective experience (
      • Danese A.
      • Widom C.S.
      Objective and subjective experiences of child maltreatment and their relationships with psychopathology.
      ) and metacognitive protective processes (e.g., perceived predictability (
      • Ellis B.J.
      • Figueredo A.J.
      • Brumbach B.H.
      • Schlomer G.L.
      Fundamental Dimensions of Environmental Risk : The Impact of Harsh versus Unpredictable Environments on the Evolution and Development of Life History Strategies.
      ,
      • Davis E.P.
      • Stout S.A.
      • Molet J.
      • Vegetabile B.
      • Glynn L.M.
      • Sandman C.A.
      • et al.
      Exposure to unpredictable maternal sensory signals influences cognitive development across species.
      ), agency (
      • Moscarello J.M.
      • Hartley C.A.
      Agency and the Calibration of Motivated Behavior.
      ), and control (
      • Monninger M.
      • Pollok T.M.
      • Aggensteiner P.M.
      • Kaiser A.
      • Reinhard I.
      • Hermann A.
      • et al.
      Coping under stress: Prefrontal control predicts stress burden during the COVID-19 crisis.
      ,
      • Maier S.F.
      • Watkins L.R.
      Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor.
      ). 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 captures, 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 exposures such exposures as pollution, climate and extreme weather events, and urbanization. The value of more comprehensive risk assessments in psychiatry is supported by initial studies that used eco-exposome scores (ES) to quantify established schizophrenia risk factors. For example, Pries et al. (
      • Pries L.K.
      • Lage-Castellanos A.
      • Delespaul P.
      • Kenis G.
      • Luykx J.J.
      • Lin B.D.
      • et al.
      Estimating Exposome Score for Schizophrenia Using Predictive Modeling Approach in Two Independent Samples: The Results From the EUGEI Study.
      ) used a predictive modeling approach to construct a weighted ES based on social-environmental risks, including maltreatment and bullying, along with cannabis use, winter birth and hearing impairment, which distinguished patients from controls and siblings, as well as siblings from controls. In addition, this ES related to patient-specific global functioning (
      • Erzin G.
      • Pries L.K.
      • van Os J.
      • Fusar-Poli L.
      • Delespaul P.
      • Kenis G.
      • et al.
      Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.
      ) and demonstrated transdiagnostic predictive power (
      • Pries L.K.
      • van Os J.
      • Ten Have M.
      • de Graaf R.
      • van Dorsselaer S.
      • Bak M.
      • et al.
      Association of Recent Stressful Life Events With Mental and Physical Health in the Context of Genomic and Exposomic Liability for Schizophrenia.
      ). Optimally, such a harmonized assessment should occur within and between large national and international 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 (HCP) (
      • Elam J.S.
      • Glasser M.F.
      • Harms M.P.
      • Sotiropoulos S.N.
      • Andersson J.L.R.
      • Burgess G.C.
      • et al.
      The Human Connectome Project: A retrospective.
      ), the 1000 Functional Connectomes Project (
      • Biswal B.B.
      • Mennes M.
      • Zuo X.N.
      • Gohel S.
      • Kelly C.
      • Smith S.M.
      • et al.
      Toward discovery science of human brain function.
      ) and the newly founded German Center for Mental Health (Deutsches Zentrum für Psychische Gesundheit, DZPG).
      Figure thumbnail gr4
      Figure 4A: Schematic representation of the exposome concept with two main domains (social, physical) and four layers arranged from proximal to distal in relation to the person under study. The first layer refers to the level of the individual, the second layer refers to the level of the family, peers, and home, the third layer refers to the level of the community and neighborhood, and the fourth layer refers to the level of society and the broader ecosystem. Relevant risk and supportive factors for mental health, such as exposure to toxins, violent events, or social support and perceived agency, are relevant for all levels and their type and intensity can be quantified. B: In addition, the duration, timing, accumulation, interaction, and dynamics of risk-related and supportive influences are important for the developing 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.

      3.2 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 field of brain functional connectivity (
      • McLaughlin K.A.
      • Weissman D.
      • Bitran D.
      Childhood Adversity and Neural Development: A Systematic Review.
      ). This circumstance is due to the abundance of possible task scenarios as well as the regional and analytical variance in derived measures (
      • Rogers B.P.
      • Morgan V.L.
      • Newton A.T.
      • Gore J.C.
      Assessing functional connectivity in the human brain by fMRI.
      ,
      • Mohanty R.
      • Sethares W.A.
      • Nair V.A.
      • Prabhakaran V.
      Rethinking Measures of Functional Connectivity via Feature Extraction.
      ,
      • Bullmore E.
      • Sporns O.
      Complex brain networks: graph theoretical analysis of structural and functional systems.
      ,
      • Fornito A.
      • Zalesky A.
      • Breakspear M.
      Graph analysis of the human connectome: promise, progress, and pitfalls.
      ). As a consequence, there are few studies in the literature on early adversity effects that illuminate the exact same functional connectivity phenotype with respect to different environmental influences or developmental time windows, making it difficult to gain a common, robust body of knowledge. Complicating matters further, to date, there is insufficient evidence of statistical quality criteria (e.g., test-retest reliability (
      • Braun U.
      • Plichta M.M.
      • Esslinger C.
      • Sauer C.
      • Haddad L.
      • Grimm O.
      • et al.
      Test-retest reliability of resting-state connectivity network characteristics using fMRI and graph theoretical measures.
      ,
      • Haller S.P.
      • Kircanski K.
      • Stoddard J.
      • White L.K.
      • Chen G.
      • Sharif-Askary B.
      • et al.
      Reliability of neural activation and connectivity during implicit face emotion processing in youth.
      )) and developmental trajectories (
      • Gee D.G.
      • Humphreys K.L.
      • Flannery J.
      • Goff B.
      • Telzer E.H.
      • Shapiro M.
      • et al.
      A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.
      ,
      • Wu M.
      • Kujawa A.
      • Lu L.H.
      • Fitzgerald D.A.
      • Klumpp H.
      • Fitzgerald K.D.
      • et al.
      Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.
      ,
      • Vink M.
      • Derks J.M.
      • Hoogendam J.M.
      • Hillegers M.
      • Kahn R.S.
      Functional differences in emotion processing during adolescence and early adulthood.
      ,
      • Zhang Y.
      • Padmanabhan A.
      • Gross J.J.
      • Menon V.
      Development of Human Emotion Circuits Investigated Using a Big-Data Analytic Approach: Stability, Reliability, and Robustness.
      ,
      • Bilek E.
      • Schafer A.
      • Ochs E.
      • Esslinger C.
      • Zangl M.
      • Plichta M.M.
      • et al.
      Application of high-frequency repetitive transcranial magnetic stimulation to the DLPFC alters human prefrontal-hippocampal functional interaction.
      ) of phenotypes.
      The definition of the development of functional connectivity phenotypes with longitudinal imaging is particularly important for the interpretability of study results on the effects of early stress exposure (
      • Tottenham N.
      Early Adversity and the Neotenous Human Brain.
      ). 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 (
      • Marquand A.F.
      • Kia S.M.
      • Zabihi M.
      • Wolfers T.
      • Buitelaar J.K.
      • Beckmann C.F.
      Conceptualizing mental disorders as deviations from normative functioning.
      ,
      • Rutherford S.
      • Kia S.M.
      • Wolfers T.
      • Fraza C.
      • Zabihi M.
      • Dinga R.
      • et al.
      The normative modeling framework for computational psychiatry.
      ). 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 (
      • Holz N.E.
      • Floris D.L.
      • Llera A.
      • Aggensteiner P.M.
      • Kia S.M.
      • Wolfers T.
      • et al.
      Age-related brain deviations and aggression.
      ,
      • Wolfers T.
      • Doan N.T.
      • Kaufmann T.
      • Alnaes D.
      • Moberget T.
      • Agartz I.
      • et al.
      Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models.
      ) and was validated by showing superiority in predicting psychopathology compared to data fitting without a normative model (
      • Holz N.E.
      • Floris D.L.
      • Llera A.
      • Aggensteiner P.M.
      • Kia S.M.
      • Wolfers T.
      • et al.
      Age-related brain deviations and aggression.
      ,
      • Wolfers T.
      • Doan N.T.
      • Kaufmann T.
      • Alnaes D.
      • Moberget T.
      • Agartz I.
      • et al.
      Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models.
      ,
      • Parkes L.
      • Moore T.M.
      • Calkins M.E.
      • Cook P.A.
      • Cieslak M.
      • Roalf D.R.
      • et al.
      Transdiagnostic dimensions of psychopathology explain individuals' unique deviations from normative neurodevelopment in brain structure.
      ). The use of such reference models for the development of functional connectivity trajectories are certainly promising on the way to clarifying the nature of deviations (i.e., delayed or accelerated) due to early adversity exposure (Figure 3).

      3.3 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 non-monetary incentives (e.g., birthday cards) are decisive factors for the longer-term willingness of traumatized individuals to participate in studies (
      • Vogel A.
      • Comtesse H.
      • Rosner R.
      Challenges in recruiting and retaining adolescents with abuse-related posttraumatic stress disorder: lessons learned from a randomized controlled trial.
      ). In addition, using multilevel recruitment strategies, in which participating families recruit other families (
      • Garavan H.
      • Bartsch H.
      • Conway K.
      • Decastro A.
      • Goldstein R.Z.
      • Heeringa S.
      • et al.
      Recruiting the ABCD sample: Design considerations and procedures.
      ), 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 (
      • Stateva M.
      • Minton J.
      • Beckett C.
      • Doolan M.
      • Ford T.
      • Kallitsoglou A.
      • et al.
      Challenges recruiting families with children at risk of anti-social behaviour into intervention trials: Lessons from the Helping Children Achieve (HCA) study.
      ). In addition, inclusion of people with lived experience (i.e., affected persons, relatives, other stakeholders) 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 (
      • Macaulay A.C.
      • Jagosh J.
      • Seller R.
      • Henderson J.
      • Cargo M.
      • Greenhalgh T.
      • et al.
      Assessing the benefits of participatory research: a rationale for a realist review.
      ).

      4. 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 lifespan and reduced longevity. Over and above maltreatment or loss, it encompasses a complex and incompletely understood range of early adverse environmental influences of 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 relevance to mental health and 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 processes of the developing brain, which may result in delays or accelerations of the normative developmental course and shapes regulatory subcortical and cortical pathways. However, at the present time, the literature on the effects of early adversity on brain functional connectivity is still patchy and heterogeneous in terms of the intertwined adverse environmental influences and age groups defined and studied, the exact connectivity phenotypes and fMRI tasks used, the normative developments of phenotypes established, and the directions and interpretations of the described adversity-related changes identified. We anticipate that future neurodevelopmental studies with harmonized assessments of the nature and timing of early risk and protective environmental influences, 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.

      Uncited reference

      • Ho T.C.
      • Dennis E.L.
      • Thompson P.M.
      • Gotlib I.H.
      Network-based approaches to examining stress in the adolescent brain.
      .
      5. Acknowledgments and disclosures
      This research was supported by grants from the German Research Foundation (DFG HO 5674/2-1 [to NH], Research Training Group GRK2350/1 projects B2 [to HT] and A4 [to NH]), Collaborative Research Center TRR 265 project A04 [to HT and CH], Collaborative Research Center 1158 project B04 [to HT and JT] and BMBF 01GL1743A [to CH]. Additional support was received from DFG EXC257 [to CH] and the Radboud Excellence Initiative [to NH]. The authors report no biomedical financial interests or potential conflicts of interest.

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