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Associations Between Early-Life Stress Exposure and Internalizing Symptomatology During the COVID-19 Pandemic: Assessing the Role of Neurobehavioral Mediators

Open AccessPublished:August 05, 2022DOI:https://doi.org/10.1016/j.bpsgos.2022.07.006

      Abstract

      Background

      The ongoing COVID-19 pandemic is a major stressor that has been associated with increased risk for psychiatric illness in the general population. Recent work has highlighted that experiences of early-life stress (ELS) may impact individuals’ psychological functioning and vulnerability for developing internalizing psychopathology in response to pandemic-related stress. However, little is known about the neurobehavioral factors that may mediate the association between ELS exposure and COVID-related internalizing symptomatology. The current study sought to examine the mediating roles of pre-pandemic resting-state frontoamygdala connectivity and concurrent emotion regulation (ER) in the association between ELS and pandemic-related internalizing symptomatology.

      Methods

      Retrospective life-stress histories, concurrent self-reported ER strategies (i.e., reappraisal and suppression), concurrent self-reported internalizing symptomatology (i.e., depression- and anxiety-related symptomatology), and resting-state functional connectivity data from a sample of adults (N = 64, mean age = 22.12 years, female = 68.75%) were utilized.

      Results

      There were no significant direct associations between ELS and COVID-related internalizing symptomatology. Neither frontoamygdala functional connectivity nor ER strategy use mediated an association between ELS and COVID-related internalizing symptomatology (ps > .05). Exploratory analyses identified a significant moderating effect of reappraisal use on the association between ELS and internalizing symptomatology (β = −0.818, p = .047), such that increased reappraisal use buffered the impact of ELS on psychopathology.

      Conclusions

      While frontoamygdala connectivity and ER do not appear to mediate the association between ELS and COVID-related internalizing symptomatology, our findings suggest that the use of reappraisal may buffer against the effect of ELS on mental health during the pandemic.

      Keywords

      The ongoing COVID-19 pandemic is a major global stressor that poses an unprecedented threat to public mental health. Research suggests that greater COVID-19–related stress has been associated with increased risk for mental health disorders, such as depression and anxiety (
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      ). However, there is substantial variability in the degree to which individuals report psychological distress in response to COVID-related stressors (
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      • Ho C.S.
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      Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China.
      ). Though individual differences in reported outcomes following a stressor are common (
      • Bonanno G.A.
      • Mancini A.D.
      Beyond resilience and PTSD: Mapping the heterogeneity of responses to potential trauma.
      ), the specific neurobiological and cognitive factors that account for this reported variance are not entirely understood. Given the enduring nature of the COVID-19 pandemic and its effects on mental health (
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      Mental health and clinical psychological science in the time of COVID-19: Challenges, opportunities, and a call to action.
      ), further understanding of factors that increase risk for the development of psychopathology during the COVID-19 pandemic remains a critical public health need. Moreover, investigations of these factors during such a period of long-standing stress have the potential to yield novel insight into more basic neurobehavioral processes related to the impacts of stress on mental health.
      To date, few studies have isolated factors that may attenuate the association between COVID-related stress and the development of psychopathology during the pandemic. However, work examining the association between exposure to early-life stress (ELS) and subsequent development of psychopathology sheds light on potential mediating factors. Decades of research have documented that experiences of ELS can exert detrimental and lasting effects on later neurobiological and behavioral development (
      • Carr C.P.
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      The role of early life stress in adult psychiatric disorders: A systematic review according to childhood trauma subtypes.
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      • Zaslavsky A.M.
      • Kessler R.C.
      Childhood adversities and adult psychiatric disorders in the National Comorbidity Survey Replication I: associations with first onset of DSM-IV disorders.
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      Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys.
      ). Further, experiences of ELS have been shown to exacerbate the mental health effects of subsequent stress experienced in adulthood (
      • Manyema M.
      • Norris S.A.
      • Richter L.M.
      Stress begets stress: The association of adverse childhood experiences with psychological distress in the presence of adult life stress.
      ,
      • McLaughlin K.A.
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      • Koenen K.C.
      • Gilman S.E.
      Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: A test of the stress sensitization hypothesis in a population-based sample of adults.
      ,
      • Pearlin L.I.
      • Schieman S.
      • Fazio E.M.
      • Meersman S.C.
      Stress, health, and the life course: Some conceptual perspectives.
      ). This process, known as stress sensitization (
      • Hammen C.
      • Henry R.
      • Daley S.E.
      Depression and sensitization to stressors among young women as a function of childhood adversity.
      ), is theorized to occur when chronic exposure to ELS dysregulates the functioning of neurobiological stress response systems, thus reducing an individual’s capacity for adaptive coping in response to subsequent stressful events (
      • Manyema M.
      • Norris S.A.
      • Richter L.M.
      Stress begets stress: The association of adverse childhood experiences with psychological distress in the presence of adult life stress.
      ). Of particular relevance to the present study, recent work from Gotlib et al. (
      • Gotlib I.H.
      • Borchers L.R.
      • Chahal R.
      • Gifuni A.J.
      • Teresi G.I.
      • Ho T.C.
      Early life stress predicts depressive symptoms in adolescents during the COVID-19 pandemic: The mediating role of perceived stress.
      ) found that greater exposure to pre-pandemic ELS experienced at or prior to age 13 years was associated with increased levels of depression-related symptomatology during the pandemic among adolescents, with individuals’ perceptions of stress during the COVID-19 pandemic mediating this association. Additionally, in the same cohort of adolescents, Chahal et al. (
      • Chahal R.
      • Kirshenbaum J.S.
      • Miller J.G.
      • Ho T.C.
      • Gotlib I.H.
      Higher executive control network coherence buffers against puberty-related increases in internalizing symptoms during the COVID-19 pandemic.
      ) found that early pubertal maturation (notably, correlated with ELS among female participants) served as a risk factor for the onset of internalizing psychopathology during the pandemic and that coherence in the executive control network moderated this association. Collectively, this line of work suggests that previous exposure to ELS, particularly around or prior to pubertal development, may be a key determinant of mental health–related outcomes during a subsequent stressor such as the ongoing pandemic and that certain neurobehavioral factors may contribute to this association.
      ELS-related alterations in frontoamygdala circuitry, neural pathways commonly implicated in emotion regulation (ER) processes, may influence later risk for developing psychopathology (
      • Demir Z.
      • Böge K.
      • Fan Y.
      • Hartling C.
      • Harb M.R.
      • Hahn E.
      • et al.
      The role of emotion regulation as a mediator between early life stress and posttraumatic stress disorder, depression and anxiety in Syrian refugees.
      ,
      • Gee D.G.
      Sensitive periods of emotion regulation: Influences of parental care on frontoamygdala circuitry and plasticity.
      ). Though variability in neurodevelopmental outcomes following ELS has been observed, cross-species models have consistently demonstrated the effects of ELS on both structural and functional frontoamygdala circuitry (
      • 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.
      ,
      • Kaiser R.H.
      • Clegg R.
      • Goer F.
      • Pechtel P.
      • Beltzer M.
      • Vitaliano G.
      • et al.
      Childhood stress, grown-up brain networks: Corticolimbic correlates of threat-related early life stress and adult stress response.
      ,
      • Sabatini M.J.
      • Ebert P.
      • Lewis D.A.
      • Levitt P.
      • Cameron J.L.
      • Mirnics K.
      Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation.
      ,
      • Teicher M.H.
      • Samson J.A.
      Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect.
      ,
      • Tottenham N.
      • Sheridan M.A.
      A review of adversity, the amygdala and the hippocampus: A consideration of developmental timing.
      ,
      • Uliana D.L.
      • Gomes F.V.
      • Grace A.A.
      Stress impacts corticoamygdalar connectivity in an age-dependent manner.
      ). These effects can be far reaching and long lasting—exposure to adversity in childhood is associated with decreased structural integrity of white matter tracts linking corticolimbic regions (
      • Hanson J.L.
      • Knodt A.R.
      • Brigidi B.D.
      • Hariri A.R.
      Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress.
      ) and negative static frontoamygdala resting-state functional connectivity (RSFC) (
      • Kaiser R.H.
      • Clegg R.
      • Goer F.
      • Pechtel P.
      • Beltzer M.
      • Vitaliano G.
      • et al.
      Childhood stress, grown-up brain networks: Corticolimbic correlates of threat-related early life stress and adult stress response.
      ,
      • Fan Y.
      • Herrera-Melendez A.L.
      • Pestke K.
      • Feeser M.
      • Aust S.
      • Otte C.
      • et al.
      Early life stress modulates amygdala-prefrontal functional connectivity: Implications for oxytocin effects.
      ) in adulthood. Furthermore, weaker functional connectivity between the amygdala and prefrontal regions following ELS exposure has been implicated in the development of psychopathology across the lifespan (
      • Hanson J.L.
      • Knodt A.R.
      • Brigidi B.D.
      • Hariri A.R.
      Lower structural integrity of the uncinate fasciculus is associated with a history of child maltreatment and future psychological vulnerability to stress.
      ,
      • Peverill M.
      • Sheridan M.A.
      • Busso D.S.
      • McLaughlin K.A.
      Atypical prefrontal–amygdala circuitry following childhood exposure to abuse: Links with adolescent psychopathology.
      ,
      • Shin L.M.
      Amygdala, medial prefrontal cortex, and hippocampal function in PTSD.
      ). As such, examinations of unique patterns of frontoamygdala RSFC in the general population may further our understanding of the relation between ELS and psychopathology. Moreover, though more recent work has used resting-state data to examine patterns of frontolimbic connectivity as a mediator of associations between ELS and psychopathology (
      • Fan Y.
      • Herrera-Melendez A.L.
      • Pestke K.
      • Feeser M.
      • Aust S.
      • Otte C.
      • et al.
      Early life stress modulates amygdala-prefrontal functional connectivity: Implications for oxytocin effects.
      ,
      • Herringa R.J.
      • Birn R.M.
      • Ruttle P.L.
      • Burghy C.A.
      • Stodola D.E.
      • Davidson R.J.
      • Essex M.J.
      Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.
      ,
      • 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.
      ,
      • Brieant A.E.
      • Sisk L.M.
      • Gee D.G.
      Associations among negative life events, changes in cortico-limbic connectivity, and psychopathology in the ABCD Study.
      ), much of the existing literature has relied on task-based paradigms (
      • 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.
      ,
      • 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.
      ). This underutilization of resting-state data has precluded our understanding of intrinsic functional organization in stress-exposed individuals in a more discernible (
      • Greicius M.
      Resting-state functional connectivity in neuropsychiatric disorders.
      ,
      • Smitha K.
      • Akhil Raja K.
      • Arun K.
      • Rajesh P.
      • Thomas B.
      • Kapilamoorthy T.
      • Kesavadas C.
      Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks.
      ) and more reliable (
      • Shehzad Z.
      • Kelly A.C.
      • Reiss P.T.
      • Gee D.G.
      • Gotimer K.
      • Uddin L.Q.
      • et al.
      The resting brain: Unconstrained yet reliable.
      ) manner.
      Additionally, difficulties with ER associated with alterations in frontoamygdala circuitry following ELS may have particularly important implications during times of heightened stress. The regulatory processes (e.g., reappraisal, suppression) by which individuals initiate, maintain, and modify their own reactions to the negative emotions that are often engendered during experiences of heightened stress may influence subsequent psychological states (
      • Tyra A.T.
      • Ginty A.T.
      • John-Henderson N.A.
      Emotion regulation strategies predict PTSS during the COVID-19 pandemic in an American Indian population.
      ,
      • Wang M.
      • Saudino K.
      Emotion regulation and stress.
      ). Recent work has shown that disruptions in ER processes have been associated with increased risk for mental health issues during the COVID-19 pandemic (
      • Tyra A.T.
      • Ginty A.T.
      • John-Henderson N.A.
      Emotion regulation strategies predict PTSS during the COVID-19 pandemic in an American Indian population.
      ,
      • Panayiotou G.
      • Panteli M.
      • Leonidou C.
      Coping with the invisible enemy: The role of emotion regulation and awareness in quality of life during the COVID-19 pandemic.
      ,
      • Restubog S.L.D.
      • Ocampo A.C.G.
      • Wang L.
      Taking control amidst the chaos: Emotion regulation during the COVID-19 pandemic.
      ). For example, Tyra et al. (
      • Tyra A.T.
      • Ginty A.T.
      • John-Henderson N.A.
      Emotion regulation strategies predict PTSS during the COVID-19 pandemic in an American Indian population.
      ) demonstrated that greater use of reappraisal and lesser use of suppression was associated with reduced risk for developing stress-related symptomatology during the COVID-19 pandemic. Importantly, these findings lend support to the notion that reliance on distinct types of ER strategies may be associated with distinct mental health outcomes (
      • Dryman M.T.
      • Heimberg R.G.
      Emotion regulation in social anxiety and depression: A systematic review of expressive suppression and cognitive reappraisal.
      ,
      • Moore S.A.
      • Zoellner L.A.
      • Mollenholt N.
      Are expressive suppression and cognitive reappraisal associated with stress-related symptoms?.
      ). Taken together, the extant literature suggests that both frontoamygdala RSFC and related ER processes may play mediating roles in the association between ELS exposure and the development of psychopathology during the COVID-19 pandemic.

      Specific Aims and Hypotheses

      The proposed registered report examined how exposure to ELS is associated with the development of internalizing symptomatology during the ongoing COVID-19 pandemic, as well as how neurobehavioral factors—assessed both prior to and during the ongoing COVID-19 pandemic—may mediate this association. Aim 1 examined associations between self-reported severity of ELS exposure (operationalized here as severity of stress experienced prior to age 12 years) and internalizing symptomatology during the COVID-19 pandemic (operationalized here as a sum of self-reported depression- and anxiety-related symptomatology). Aim 2 examined the distinct mediating roles of pre-pandemic frontoamygdala RSFC and concurrent ER tendencies on the association between ELS severity and pandemic-related internalizing symptomatology.
      We hypothesized that adults who experienced more severe ELS would report higher levels of internalizing symptomatology during the pandemic. Further, we hypothesized that patterns of frontoamygdala RSFC and self-reported ER would mediate the association between ELS exposure and pandemic-related internalizing symptomatology. Specifically, we posited that weaker frontoamygdala connectivity patterns would be correlated with lower reliance on a prototypically adaptive ER strategy (i.e., reappraisal), and higher reliance on a prototypically maladaptive ER strategy (i.e., suppression). We additionally posited that weaker connectivity, lower use of reappraisal, and higher use of suppression would be associated with higher levels of pandemic-related internalizing symptomatology.

      Methods and Materials

      Participants

      The present study includes 64 adults between ages 18 and 30 years who responded to community postings in New Haven, Connecticut, and study fliers posted online as part of recruitment efforts for a broader, ongoing study (described below) that began recruitment in 2016, and who also responded to a subsequent study invitation in spring 2020. Participant attributes are shown in Table 1. Inclusion criteria are detailed in Supplement 1: Participant inclusion criteria.
      Table 1Participant Attributes (N = 64)
      AttributeMean ± SD (Range) or n (%)
      Sex Assigned at Birth, Female/Male44 (68.75%)/19 (29.69%)
      There was 1 participant with unknown sex assigned at birth.
      Age at Time of Scan, Years22.12 ± 3.47 (18.0–30.8)
      Race/Ethnicity
      Percentages for race/ethnicity do not sum to 100% due to multiracial reporting (i.e., some participants endorsed more than 1 race/ethnicity category).
       Asian14 (21.21%)
       Black or African American7 (10.61%)
       Hispanic or Latinx7 (10.61%)
       Native American1 (1.51%)
       Native Hawaiian or Pacific Islander0
       Non-Hispanic White37 (56.06%)
       Other/unspecified0
      Highest Educational Degree Received
       Less than high school1 (1.56%)
       High school diploma or GED34 (53.13%)
       Bachelor’s degree23 (35.94%)
       Master’s degree4 (6.25%)
       Doctorate1 (1.56%)
       Professional degree (MD, JD, DDS, etc.)1 (1.56%)
      Total Combined Family Income Over the Past 12 Months, US$$69,991 ± 44,197 ($2500–$125,000)
      Mean income calculated from averaging midpoint estimates of participants’ reported income brackets.
      Time Elapsed Between Phase 1 and Phase 2, Months16 ± 10 (3–40)
      a There was 1 participant with unknown sex assigned at birth.
      b Percentages for race/ethnicity do not sum to 100% due to multiracial reporting (i.e., some participants endorsed more than 1 race/ethnicity category).
      c Mean income calculated from averaging midpoint estimates of participants’ reported income brackets.

      Procedure

      The study protocol was approved by the Yale University Institutional Review Board, and all participants identified as being potentially eligible for the broader study provided written, informed consent according to the procedures set forth by the Human Investigation Committee at Yale University. The data used for this study were collected as a part of a broader, ongoing study of the neural mechanisms of fear reduction in children, adolescents, and adults. Phase 1 of the study consisted of 2 study visits. The first visit consisted of a clinical interview assessing lifetime history of stress exposure, a battery of questionnaires related to symptomatology, and a mock magnetic resonance imaging (MRI) scan [described in greater detail in Supplement 4: MRI acquisition protocol (additional information)]. The second visit consisted of an MRI scanning session during which RSFC data were collected on a research-dedicated 3T Siemens Prisma MRI scanner with a 32-channel head coil.
      Participants who successfully completed phase 1 of the study were recontacted via email and telephone in spring 2020 following the onset of the COVID-19 pandemic and were offered the opportunity to participate in phase 2, a follow-up study that involved the completion of an additional set of questionnaires intended to assess coping and mental health during the pandemic. Specific measures completed at each phase are presented in Figure 1. Information about study timing is presented in Supplement 2: Study timing.
      Figure thumbnail gr1
      Figure 1Overview of study design and timing. Constructs that were assessed prior to the pandemic (phase 1) and during the pandemic (phase 2). BDI-II, Beck Depression Inventory-II; ELS, early-life stress; EPII, Epidemic-Pandemic Impacts Inventory; ERQ, Emotion Regulation Questionnaire; fMRI, functional magnetic resonance imaging; SCARED-A, Screen for Child Anxiety Related Emotional Disorders-Adult; UCLA RI, University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index.

      Self-report Measures

      Scoring information and detailed information regarding psychometric properties of measures utilized in the proposed study are provided in Supplement 3: Measures (additional information).

      Demographic Information

      At phase 1, participants were asked to report their age, sex assigned at birth, race and ethnicity, highest education level, and annual household income.

      Early-Life Stress

      At phase 1, all participants completed an extended version of the University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index (
      • Steinberg A.M.
      • Brymer M.J.
      • Decker K.B.
      • Pynoos R.S.
      The University of California at Los Angeles post-traumatic stress disorder reaction index.
      ), a clinician-administered interview regarding their lifetime history of exposure to stress. ELS severity for each participant was calculated by averaging the severity scores reported across all events endorsed prior to age 12 years.

      Emotion Regulation

      At phase 2, ER was assessed using the Emotion Regulation Questionnaire (
      • Gross J.J.
      • John O.P.
      Individual differences in two emotion regulation processes: Implications for affect, relationships, and well-being.
      ). The Emotion Regulation Questionnaire is a widely-used 10-item measure of ER that assesses individuals’ tendency to use 2 distinct ER strategies: reappraisal (6 items) and suppression (4 items). The scale scores for both reappraisal and suppression strategies were used in the current study to assess reliance on both prototypically adaptive and maladaptive ER strategies, respectively.

      Internalizing Symptomatology

      Pre-pandemic (phase 1) and concurrent (phase 2) levels of self-reported depression- and anxiety-related symptomatology were assessed using the Beck Depression Inventory-II (
      • Beck A.T.
      • Steer R.A.
      • Brown G.
      Manual for the Beck Depression Inventory-II.
      ) and the Screen for Child Anxiety Related Emotional Disorders-Adult (
      • Bögels S.M.
      • van Melick M.
      The relationship between child-report, parent self-report, and partner report of perceived parental rearing behaviors and anxiety in children and parents.
      ), respectively. Total standardized scores (z scores) from these measures were summed to create a singular metric of COVID-related internalizing symptomatology.

      COVID-Related Distress and Economic Impact

      At phase 2, the Epidemic-Pandemic Impacts Inventory (
      • Grasso D.J.
      • Briggs-Gowan M.J.
      • Ford J.D.
      • Carter A.S.
      The Epidemic–Pandemic Impacts Inventory (EPII).
      ) was administered to assess the impact of the COVID-19 pandemic across 10 domains of personal and family life (e.g., work and employment, economic, education and training, home life, etc.). We added a single question at the end of each domain that assessed the general degree of distress that participants felt with regard to each specific domain, which we modeled after a line of questions included in the COPE (COVID-19 and Perinatal Experiences) study (
      • Thomason M.E.
      • Graham A.
      • VanTieghem M.R.
      COPE: Coronavirus Perinatal Experiences-Impact Survey (COPE-IS). Available at:.
      ). A cumulative total of these distress-related questions and cumulative total of the number of economic impacts participants reported were used as covariates in the present study.

      RS Functional MRI Acquisition

      At the end of the initial visit to the lab (phase 1), in order to desensitize participants to the scanner environment, all participants completed a 20-minute mock scan session in a dedicated simulator at the scanning facility. During their second visit to the lab (phase 1), participants completed a 3-hour MRI scanning session that included 2 resting-state functional MRI (fMRI) scans, which lasted 5 minutes each. Information regarding mock scan procedures, RS scan procedures, MRI acquisition parameters, and preprocessing of imaging data is presented in Supplement 4: MRI acquisition protocol (additional information).

      Proposed Analyses

      Given strong a priori hypotheses about the effects of stress on frontoamygdala circuitry, we conducted seed-based analyses of resting-state fMRI data to examine RSFC between the basolateral amygdala and the ventromedial prefrontal cortex (regions of interest presented in Figure 2). The mask for the basolateral amygdala was derived from the Jülich histological atlas (
      • Amunts K.
      • Kedo O.
      • Kindler M.
      • Pieperhoff P.
      • Mohlberg H.
      • Shah N.J.
      • et al.
      Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: Intersubject variability and probability maps.
      ), and the mask for the anterior ventromedial prefrontal cortex was derived from the Mackey and Petrides atlas (
      • Mackey S.
      • Petrides M.
      Architecture and morphology of the human ventromedial prefrontal cortex.
      ). The CONN Toolbox (
      • Whitfield-Gabrieli S.
      • Nieto-Castanon A.
      Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks.
      ) was used to examine seed-based connectivity between the basolateral amygdala and anterior ventromedial prefrontal cortex. The blood oxygen level–dependent time course of each region of interest was calculated as the average of the time courses of its constituent voxels. RSFC between the 2 regions of interest was calculated as the Fisher z-transformed correlation coefficient of their time courses. Additional information on our neuroimaging analytic plan is presented in Supplement 5: Analytic plan (additional information).
      Figure thumbnail gr2
      Figure 2Regions of interest. Regions of interest that were used to examine resting-state functional connectivity between the ventromedial prefrontal cortex (left) and basolateral amygdala (right).
      Power considerations are reported in Supplement 6: Power considerations. Serial mediation models were conducted using the PROCESS macro (
      • Hayes A.F.
      Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach.
      ,
      • Hayes A.F.
      Partial, conditional, and moderated moderated mediation: Quantification, inference, and interpretation.
      ) in R version 4.1.2 (R Foundation for Statistical Computing). ELS was specified as the independent variable, with RSFC as the first mediator and ER strategy (i.e., either reappraisal or suppression) as the second mediator (illustrated in Figure 3). Reappraisal and suppression scores were entered as mediators in two separate models. In both models, internalizing symptomatology (composite of anxiety and depression symptoms) was specified as the dependent variable. The following covariates were included in all models: pre-pandemic internalizing symptomatology, age at time of scan, COVID-related distress, economic-related impact experienced during COVID-19, and elapsed time between fMRI scan and completion of pandemic-related questionnaires. All variables were fixed, and nonnormally distributed variables were log-transformed. Within this model, 3 indirect effects were tested sequentially with bootstrapped CIs with 10,000 iterations: 1) the effect of ELS on internalizing symptomatology via RSFC, 2) the effect of ELS on internalizing symptomatology via ER (i.e., reappraisal in model 1 and suppression in model 2), and 3) the effect of ELS on internalizing symptomatology via RSFC and ER (i.e., reappraisal in model 1 and suppression in model 2). The indirect effects were considered significant if the 95% CI did not include zero. All analyses were preregistered on the Open Science Framework (https://osf.io/pvam9/?view_only=9cdd3a08acef41bbbaa195c3a60e7973).
      Figure thumbnail gr3
      Figure 3Analytical models. Hypothesized serial mediation model testing the indirect effect of early-life stress on internalizing symptomatology via resting-state functional connectivity and emotion regulation.
      In addition, we ran several supplementary analyses to examine the robustness of our findings. The first set of supplementary analyses employed a redefined age cutoff for ELS exposure occurring before age 18 years (as compared with ELS exposure occurring before age 12, as operationalized in the primary models). The second set of supplementary analyses examined the effect of the cumulative number of ELS events that an individual experienced as an index of exposure to ELS, rather than as an average of self-reported severity of ELS events, across all models.

      Exploratory Analyses

      In addition to the registered mediation models, we examined a set of moderation models to further elucidate the way in which neurobehavioral factors may influence the relationship between ELS and COVID-related symptomatology. We conducted 3 separate single-variable moderation models, with prepubertal ELS severity scores as the independent variable, COVID-related internalizing symptomatology as the dependent variable, and frontoamygdala RSFC, reappraisal, and suppression each serving as moderating variables in separate models.

      Results

      Descriptive statistics and correlations between the key variables in our primary models are shown in Table 2. Additional descriptive statistics and correlations are presented in Supplement 7: Descriptive and correlation analyses (additional information).
      Table 2Descriptive Statistics and Correlations for Primary Variables (N = 64)
      Mean (SD)ELS Severity (Prepubertal)Frontoamygdala Resting-State Functional ConnectivityReappraisalSuppressionCOVID-Related Internalizing Symptomatology
      ELS Severity (Prepubertal)3.24 (2.40)
      Frontoamygdala Resting-State Functional Connectivity0.16 (0.13)−0.087
      Reappraisal28.33 (6.87)0.142−0.163
      Suppression4.92 (5.470.196−0.1020.098
      COVID-Related Internalizing Symptomatology1.77 (1.65)0.0450.104−0.2100.104
      ELS, early-life stress.

      Mediation Models

      The first primary serial mediation model examined the mediating effect of frontoamygdala RSFC and the use of reappraisal on the relationship between prepubertal ELS severity and COVID-related internalizing symptomatology. Table 3 and Figure 4 display the standardized coefficients for total and direct effects on frontoamygdala connectivity, reappraisal, and COVID-related internalizing symptomatology in the serial mediation model. The direct and positive association between ELS severity and COVID-related internalizing symptomatology was nonsignificant (p > .05). All additional total and direct effects on frontoamygdala connectivity, reappraisal, and COVID-related internalizing symptomatology in this primary model were also nonsignificant. Table 4 shows total, individual, and serial indirect effects for ELS severity on COVID-related internalizing symptomatology via frontoamygdala connectivity and reappraisal with bias-corrected 95% CIs. There were no significant indirect effects of ELS severity on COVID-related internalizing symptomatology via frontoamygdala connectivity or via reappraisal.
      Table 3Standardized Coefficients for Total and Direct Effects of Prepubertal ELS Severity on Frontoamygdala Resting-State Connectivity, Reappraisal, and COVID-Related Internalizing Symptomatology
      Frontoamygdala Connectivity Total/Direct Effect
      Total and direct effect are considered to be equivalent when examining effects between the independent variable and the first mediator in a serial mediation analysis.
      ReappraisalInternalizing Symptomatology
      Total EffectDirect EffectTotal EffectDirect Effect
      ELS Severity (Prepubertal)−0.11580.12600.1012−0.01350.0141
      Frontoamygdala Connectivity−0.21500.12450.0964
      Reappraisal−0.1306
      R20.04830.18940.4824
      ELS, early-life stress.
      a Total and direct effect are considered to be equivalent when examining effects between the independent variable and the first mediator in a serial mediation analysis.
      Figure thumbnail gr4
      Figure 4Serial mediation model results: mediating roles of frontoamygdala connectivity and reappraisal. Association between early-life stress and COVID-related internalizing symptomatology, with frontoamygdala connectivity and reappraisal serving as serial mediators. All effects displayed are standardized, direct effects. No effects were significant (ps > .05).
      Table 4Total, Individual, and Serial Indirect Effects for Prepubertal ELS Severity on Frontoamygdala Connectivity, Reappraisal, and COVID-Related Internalizing Symptomatology
      PathwayIndirect EffectSEBias-Corrected 95% CI
      LowerUpper
      Total Indirect Effect−0.02770.0370−0.10510.0464
      Individual Indirect Effects
       ELS → frontoamygdala connectivity → COVID-related internalizing symptomatology−0.01120.0215−0.06310.0252
       ELS → reappraisal → COVID-related internalizing symptomatology−0.01320.0243−0.05800.0448
      Serial Indirect Effects
       ELS → frontoamygdala connectivity → reappraisal → COVID-related internalizing symptomatology−0.00330.0096−0.02930.0105
      ELS, early-life stress.
      The second primary serial mediation model examined the mediating effect of frontoamygdala RSFC and the use of suppression on the relationship between prepubertal ELS severity and COVID-related internalizing symptomatology. The standardized coefficients for total and direct effects on frontoamygdala connectivity, suppression, and COVID-related internalizing symptomatology are shown in Table 5 and in Figure 5. All total and direct effects on frontoamygdala connectivity, reappraisal, and COVID-related internalizing symptomatology in this primary model were nonsignificant (ps > .05). Table 6 shows total, individual, and serial indirect effects for ELS stress severity on COVID-related internalizing symptomatology via frontoamygdala connectivity and suppression with bias-corrected 95% CIs. No significant indirect effects were found in this model.
      Table 5Standardized Coefficients for Total and Direct Effects of Prepubertal ELS Severity on Frontoamygdala Resting-State Connectivity, Suppression, and COVID-Related Internalizing Symptomatology
      Frontoamygdala Connectivity Total/Direct Effect
      Total and direct effect are considered to be equivalent when examining effects between the independent variable and the first mediator in a serial mediation analysis.
      SuppressionInternalizing Symptomatology
      Total EffectDirect EffectTotal EffectDirect Effect
      ELS Severity (Prepubertal)−0.11580.11930.1074−0.0135−0.0170
      Frontoamygdala Connectivity−0.10270.12460.1417
      Suppression0.1664
      R20.04830.20980.4905
      ELS, early-life stress.
      a Total and direct effect are considered to be equivalent when examining effects between the independent variable and the first mediator in a serial mediation analysis.
      Figure thumbnail gr5
      Figure 5Serial mediation model results: mediating roles of frontoamygdala connectivity and suppression. Association between ELS and COVID-related internalizing symptomatology, with frontoamygdala connectivity and suppression serving as serial mediators. All effects displayed are standardized, direct effects. No effects were significant (ps > .05).
      Table 6Total, Individual, and Serial Indirect Effects for Prepubertal ELS Severity on Frontoamygdala Connectivity, Suppression, and COVID-Related Internalizing Symptomatology
      PathwayIndirect EffectSEBias-Corrected 95% CI
      LowerUpper
      Total Indirect Effect0.00340.0327−0.06420.0731
      Individual Indirect Effects
       ELS → frontoamygdala connectivity → COVID-related internalizing symptomatology−0.01650.0288−0.08830.0272
       ELS → suppression → COVID-related internalizing symptomatology0.01790.0262−0.02330.0821
      Serial Indirect Effects
       ELS → frontoamygdala connectivity → suppression → COVID-related internalizing symptomatology0.00200.0062−0.00450.0192
      ELS, early-life stress.
      Results from supplementary models (i.e., with different operationalizations of ELS exposure) are presented in Supplement 8: Supplemental analyses. Results were highly consistent with primary models in that there were no significant indirect effects across different operationalizations of ELS exposure. However, we did find that cumulative ELS exposure prior to age 12 years had a significant direct and positive association with use of reappraisal (β = 0.277, p = .037).

      Exploratory Analyses

      The first model in our exploratory analyses examined the moderating effect of reappraisal use on the association between average prepubertal ELS severity and COVID-related internalizing symptomatology. We found that a significant interaction between ELS severity and reappraisal (B = −0.818, p = .047) predicted COVID-related symptomatology. There were no significant interaction effects between average ELS severity and use of suppression, or between average prepubertal ELS severity and frontoamygdala connectivity, on COVID-related internalizing symptomatology (ps > .05). The unstandardized coefficients for the effects of ELS severity × neurobehavioral measures on COVID-related symptomatology are displayed in Table 7 and are plotted in Figure 6.
      Table 7Potential Neurobehavioral Moderators of the Association Between Prepubertal ELS Severity and Internalizing Symptomatology Reported During the COVID-19 Pandemic
      Dependent VariableIndependent and Moderating VariablesB (95% CI)
      Unstandardized beta.
      SEt55p Value
      COVID-Related Internalizing SymptomatologyELS severity (prepubertal)0.901 (−0.031 to 1.833)0.4601.958.058
      Reappraisal2.941 (−0.889 to 6.772)1.8901.556.128
      ELS severity × reappraisal−0.818 (−1.625 to −0.010)0.398−2.052.047
      Significant (p < .05).
      COVID-Related Internalizing SymptomatologyELS severity (prepubertal)0.094 (−0.519 to 0.707)0.3030.312.757
      Suppression0.854 (−1.320 to 3.027)1.0730.796.413
      ELS severity × suppression−0.075 (−0.541 to 0.390)0.230−0.328.745
      COVID-Related Internalizing SymptomatologyELS severity (prepubertal)0.103 (−0.444 to 0.650)0.2700.382.704
      Frontoamygdala connectivity3.034 (−8.999 to 15.064)5.9370.511.612
      ELS severity × frontoamygdala connectivity−0.326 (−2.776 to 2.125)1.210−0.269.789
      ELS, early-life stress.
      a Unstandardized beta.
      b Significant (p < .05).
      Figure thumbnail gr6
      Figure 6Exploratory model: moderating role of reappraisal. Plot for the significant interaction between early-life stress (ELS) severity and reappraisal use on COVID-related internalizing symptomatology. Association between ELS and COVID-related internalizing symptomatology is plotted at mean, low (−1 SD), and high (+1 SD) reappraisal use. SE bands represent ±1 SE from the fitted values.

      Discussion

      The current registered report did not find evidence that frontoamygdala connectivity or use of reappraisal or suppression plays a mediating role in the relationship between ELS and COVID-related internalizing symptomatology. However, exploratory analyses demonstrated a significant moderating effect of reappraisal use on the association between prepubertal ELS severity and COVID-related internalizing symptomatology, such that higher reappraisal use buffered the impact of ELS on symptomatology. These findings contribute to a growing literature on specific factors that may serve to buffer against psychopathology during the COVID-19 pandemic.

      ELS and COVID-Related Internalizing Symptomatology

      Past research demonstrates that ELS exposure predicts depression and anxiety in adulthood (
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      ) and that ELS is associated with internalizing symptomatology during the pandemic (
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      ). In the present study, we did not observe any significant direct associations between COVID-related symptomatology and ELS. The lack of significant relationships between ELS and COVID-related mental health was unexpected but not entirely surprising. Several previous studies have identified null, weak, or inconsistent associations between ELS exposure and the presence of psychopathology in later adulthood (
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      ). One possibility is that the null associations in the current study may reflect multifinality––the phenomenon by which the same risk factors (e.g., exposure to adversity early in life) can lead to different developmental trajectories and outcomes (
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      Future directions in childhood adversity and youth psychopathology.
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      Equifinality and multifinality in developmental psychopathology.
      ). The present findings may also stem from empirical and theoretical work that suggests that heterogeneity in ELS, such as differences in chronicity (
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      Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents.
      ) or type of stress (
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      Influences of early-life stress on frontolimbic circuitry: Harnessing a dimensional approach to elucidate the effects of heterogeneity in stress exposure.
      ,
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      Dimensions of deprivation and threat, psychopathology, and potential mediators: A multi-year longitudinal analysis.
      ), may moderate the association between stress exposure and subsequent vulnerability. Our lack of accounting for these differences in our models may be obfuscating present associations between ELS and COVID-related symptomatology.

      Mediating Effects of Frontoamygdala RSFC and Emotion Regulation

      In all tested serial mediation models, there were no significant indirect associations between ELS and COVID-related symptomatology through frontoamygdala RSFC, use of reappraisal, or use of suppression. Direct effects of ELS severity on frontoamygdala connectivity, reappraisal, and suppression were nonsignificant, as were direct effects of frontoamygdala connectivity on reappraisal and suppression. By contrast, supplemental analyses showed that cumulative ELS exposure prior to age 12 years had a significant direct and positive association with use of reappraisal. Though the directionality of this finding is inconsistent with both our hypotheses and past evidence of a negative relation between adversity exposure and reappraisal use (
      • Gruhn M.A.
      • Compas B.E.
      Effects of maltreatment on coping and emotion regulation in childhood and adolescence: A meta-analytic review.
      ), it may be explained in part by past literature suggesting that individuals with a history of adversity exposure may habitually engage in cognitive reappraisal as a coping strategy (
      • El Khawli E.
      • Fan Y.
      • Aust S.
      • Wirth K.
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      • et al.
      Early-Life stress modulates neural networks associated with habitual use of reappraisal.
      ). Additionally, factors unaccounted for in the current analyses, such as past psychotherapy (
      • Troy A.S.
      • Shallcross A.J.
      • Davis T.S.
      • Mauss I.B.
      History of mindfulness-based cognitive therapy is associated with increased cognitive reappraisal ability.
      ), may contribute to the positive association observed here. Future work should continue to examine how exposure to stress early in life may relate to the extent to which one engages in reappraisal-based strategies during the pandemic.
      The lack of observed mediating effects of frontoamygdala connectivity is inconsistent with previous work that has identified a mediating role of corticolimbic circuitry on the association between ELS and psychopathology (
      • Herringa R.J.
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      Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence.
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      Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.
      ). Additionally, in contrast to the current findings, previous work has shown associations between frontoamygdala RSFC and ER abilities (
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      Rethinking feelings: An FMRI study of the cognitive regulation of emotion.
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      Amygdala–frontal connectivity during emotion regulation.
      ). Several factors may have precluded the identification of associations between frontoamygdala connectivity and other key variables such as ELS and ER use in the current study. First, though shown to be more reliable than task-activation paradigms (
      • Greicius M.
      Resting-state functional connectivity in neuropsychiatric disorders.
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      Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks.
      ), fMRI has demonstrated greater variance within and between scanning sessions in comparison with other metrics of connectivity, such as structural connectivity (
      • Honey C.J.
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      Predicting human resting-state functional connectivity from structural connectivity.
      ,
      • Osmanlıoğlu Y.
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      Connectomic consistency: A systematic stability analysis of structural and functional connectivity.
      ). Additionally, between-subject spatial differences in amygdala subdivisions (
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      Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.
      ) may have contributed to the null findings. While we examined predefined anatomical partitions of the amygdala defined across subjects, alternative approaches, such as subject-by-subject connectivity-based parcellation (
      • Eickhoff S.B.
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      Connectivity-based parcellation: Critique and implications.
      ), may allow for a more precise examination of frontoamygdala interactions that better accounts for individual differences in cytoarchitecture. The current null findings likely also point to a need for future examination of a broader network of connections that extend beyond the basolateral amygdala and ventromedial prefrontal cortex, particularly ventrolateral and dorsolateral prefrontal regions that have been implicated in cognitive reappraisal (
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      vlPFC–vmPFC–Amygdala interactions underlie age-related differences in cognitive regulation of emotion.
      ,
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      Prefrontal-subcortical pathways mediating successful emotion regulation.
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      Cognitive reappraisal of emotion: A meta-analysis of human neuroimaging studies.
      ). Finally, variations in neuroimaging preprocessing pipelines and methodological differences can contribute to distinct findings (
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      Variability in the analysis of a single neuroimaging dataset by many teams.
      ). Future work could examine a mediating effect of frontoamygdala circuitry in stress and psychopathology in a multiverse fashion (
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      Increasing transparency through a multiverse analysis.
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      Age-related change in task-evoked amygdala-prefrontal circuitry: A multiverse approach with an accelerated longitudinal cohort aged 4-22 years.
      ) to assess the robustness of findings.

      ER as a Moderating Factor

      While we did not identify mediating effects of frontoamygdala connectivity or ER strategy use in our registered models of ELS and symptomatology, exploratory analyses showed that reappraisal use significantly moderated the relationship between prepubertal ELS severity and COVID-related internalizing symptomatology. Specifically, individuals who reported higher levels of reappraisal use displayed a negative association between ELS severity and symptomatology during the pandemic. By contrast, individuals who reported lower levels of reappraisal use showed a positive association between ELS severity and psychopathology during the pandemic. This finding is consistent with literature that has identified the use of cognitive reappraisal as a buffer against the effects of stress on mental health outcomes (
      • Moore S.A.
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      Are expressive suppression and cognitive reappraisal associated with stress-related symptoms?.
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      • Johnson J.
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      Reappraisal buffers the association between stress and negative mood measured over 14 days: Implications for understanding psychological resilience.
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      • Rodriguez M.
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      Reframing time spent alone: Reappraisal buffers the emotional effects of isolation.
      ,
      • Xu C.
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      Cognitive reappraisal and the association between perceived stress and anxiety symptoms in COVID-19 isolated people.
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      • Janiri D.
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      Emotional dysregulation mediates the impact of childhood trauma on psychological distress: First Italian data during the early phase of COVID-19 outbreak.
      ), as well as with more recent work that has identified links between stress exposure, ER, and COVID-related psychopathology (
      • Janiri D.
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      • Pepe M.
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      • De Martin V.
      • et al.
      Emotional dysregulation mediates the impact of childhood trauma on psychological distress: First Italian data during the early phase of COVID-19 outbreak.
      ,
      • Zhou Y.
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      Mental health and its predictors during the early months of the COVID-19 pandemic experience in the United States.
      ,
      • Low R.S.
      • Overall N.C.
      • Chang V.T.
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      Emotion regulation and psychological and physical health during a nationwide COVID-19 lockdown.
      ,
      • Kalia V.
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      • Hayatbini N.
      Cognitive flexibility and perceived threat from COVID-19 mediate the relationship between childhood maltreatment and state anxiety.
      ,
      • Siegel A.
      • Lahav Y.
      Emotion regulation and distress during the COVID-19 pandemic: The role of childhood abuse [published online ahead of print Jun 4].
      ,
      • Weissman D.G.
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      • Sheridan M.A.
      • et al.
      Contributions of emotion regulation and brain structure and function to adolescent internalizing problems and stress vulnerability during the COVID-19 pandemic: A longitudinal study.
      ). Additionally, the current findings lend support to existing frameworks that are more consistent with a moderating role (as opposed to a mediating role) of ER in the association between stress and psychopathology (
      • Troy A.S.
      • Wilhelm F.H.
      • Shallcross A.J.
      • Mauss I.B.
      Seeing the silver lining: Cognitive reappraisal ability moderates the relationship between stress and depressive symptoms.
      ,
      • Krkovic K.
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      Emotion regulation as a moderator of the interplay between self-reported and physiological stress and paranoia.
      ,
      • Voon D.
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      • Martin G.
      The roles of emotion regulation and ruminative thoughts in non-suicidal self-injury.
      ). Though stressful life events have been associated with difficulties with ER (
      • Demir Z.
      • Böge K.
      • Fan Y.
      • Hartling C.
      • Harb M.R.
      • Hahn E.
      • et al.
      The role of emotion regulation as a mediator between early life stress and posttraumatic stress disorder, depression and anxiety in Syrian refugees.
      ), conceptualizing ER as a moderating factor may be consistent with frameworks proposing that pre-existing strengths and vulnerabilities (e.g., cognitive reappraisal abilities) interact with stress exposure to predict later mental health. Future research will be important for better distinguishing specific conditions in which ER strategies may be acting as modulatory compared with explanatory factors in the association between stress exposure and mental health outcomes.

      Limitations and Conclusions

      In part owing to the unique circumstances of conducting this research in the context of a global pandemic, this study had several limitations. First, although our post hoc power calculation estimated that the sample size would be sufficient to achieve desired power, our sample size was limited by the nature of longitudinal data collection during the pandemic. It is important to consider the null findings in the context of a sample size far smaller than that recommended for examining brain-behavior associations (
      • Marek S.
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      • Montez D.F.
      • Kay B.P.
      • Hatoum A.S.
      • et al.
      Reproducible brain-wide association studies require thousands of individuals.
      ). Second, our post hoc power analysis was conducted for the preregistered mediation analyses and not for the exploratory moderation models. Third, our observational study design limits the ability to draw causal inferences. Assessing ELS prior to adulthood and employing a longitudinal design with additional time points and stricter temporal precedence would allow for a clearer understanding of associations between early experiences, neurobehavioral development, and stress-related psychopathology. Fourth, the average age of participants differed significantly between those that completed all measures required from phase 1 compared with phase 2, indicating a potential source of attrition bias in our sample (detailed further in Supplement 1: Participant inclusion criteria. Last, the majority of our sample identified as non-Hispanic White, were of medium-high socioeconomic status, and had completed or were currently completing a bachelor’s degree. The extent to which these findings generalize to more racially and socioeconomically diverse samples, especially to individuals who may have experienced more financial strain and disproportionate health impacts during the pandemic (
      • Shippee T.P.
      • Akosionu O.
      • Ng W.
      • Woodhouse M.
      • Duan Y.
      • Thao M.S.
      • Bowblis J.R.
      COVID-19 pandemic: Exacerbating racial/ethnic disparities in long-term services and supports.
      ,
      • Condon E.M.
      • Dettmer A.M.
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      • Hagan C.
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      • Mayes L.C.
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      Commentary: COVID-19 and mental health equity in the United States.
      ,
      • Hooper M.W.
      • Nápoles A.M.
      • Pérez-Stable E.J.
      COVID-19 and racial/ethnic disparities.
      ), is unknown. Despite these limitations, the current work adds to an emerging literature documenting that engagement in specific ER strategies may buffer against mental health consequences during stress exposure. Moreover, the registered report format of the current work contributes to a growing effort to reduce publication and research bias in hypothesis-driven deductive scientific research. Finally, our null findings should not dissuade continued efforts to improve the environments in which children develop. The current work should instead motivate researchers to continue to examine how stress exposure impacts later mental health outcomes and should motivate clinicians and policymakers to work to intervene whenever possible.

      Acknowledgments and Disclosures

      This work was supported by a National Institutes of Health Director’s Early Independence Award (Grant No. DP5OD021370 [to DGG]), a Brain & Behavior Research Foundation ( National Alliance for Research on Schizophrenia and Depression ) Young Investigator Award (to DGG), a Jacobs Foundation Early Career Research Fellowship (to DGG), the Society for Clinical Child and Adolescent Psychology (Division 53 of the American Psychological Association ) Richard “Dick” Abidin Early Career Award and Grant (to DGG), a National Science Foundation Graduate Research Fellowship Program Award (Grant No. DGE1752134 [to EMC]), a Society for Clinical Child and Adolescent Psychology (Division 53 of the American Psychological Association ) Donald Routh Dissertation Grant (to EMC), an American Psychological Foundation Elizabeth Munsterberg Koppitz Child Psychology Graduate Fellowship (to EMC), a Dissertation Funding Award from the Society for Research in Child Development (to EMC) , a Dissertation Research Award from the American Psychological Association (to EMC), a National Science Foundation Graduate Research Fellowship Program Award (to JCF), and a Susan Nolen-Hoeksema Postdoctoral Fellowship (to AEB).
      We thank the Yale Center for Research Computing, particularly Dr. Kaylea Nelson, for assistance with analyses conducted on the Milgram cluster. We acknowledge the many contributions of the undergraduate research assistants who coded and entered the early-life stress data used in analyses, including Isabel Santiuste, Lindiwe Mayinja, Elizabeth Kitt, Brandon Lopez, Reta Behnam, Jenny Wang, and Marisa Rogers. Finally, we are grateful to the study participants for their time and participation.
      The authors report no biomedical financial interests or potential conflicts of interest.

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