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. 2026 Sep 30;68(6):e70209. doi: 10.1002/dev.70209

Maternal Depression, Childhood Resting‐State Brain Connectivity, and Adolescent Depression During the COVID‐19 Outbreak

Pan Liu 1,✉, Matthew R J Vandermeer 1, Andrew R Daoust 1, Haley E Green 1, Ola Mohamed Ali 1, Kasey Stanton 2, Kate L Harkness 3, Deanna M Barch 4, Marc F Joanisse 1, Elizabeth P Hayden 1
PMCID: PMC13625808  PMID: 42813829

ABSTRACT

Adolescents of mothers with a history of depression are at increased risk for developing depression themselves. These adolescents may have been especially vulnerable to depression under conditions of stress, such as the beginning of the COVID‐19 pandemic. To understand the complex processes involved in the transmission of maternal depression risk to adolescent offspring in the context of stress, we examined potential mediating and moderating factors that link maternal depression history and offspring depressive symptoms, including resting‐state functional connectivity (rs‐FC) and mothers’ depressive symptoms, in 85 adolescents during the pandemic. Adolescents’ prepandemic rs‐FC between the posterior and anterior cingulate cortices (PCC–ACC) moderated the association between maternal depression history and adolescents’ symptoms during the pandemic, such that maternal depression history predicted adolescents’ symptoms only in youths with heightened PCC–ACC rs‐FC. Mothers’ depressive symptoms during the pandemic mediated and moderated the link between maternal depression history and adolescents’ symptoms. Mothers with a history of depression had greater depressive symptoms early during the pandemic, which were further associated with offspring depressive symptoms. Additionally, maternal depression history predicted depressive symptoms in adolescents whose mothers had lower depressive symptoms during the pandemic. Findings speak to the mediating and moderating processes in the transmission of maternal depression risk to adolescent offspring in the context of the pandemic.

Keywords: adolescence, cortical midline structure, COVID‐19, maternal depression, resting‐state functional connectivity

1. Introduction

Depression is a common, complex mental health disorder that emerges early in life, proliferates during adolescence, and is oftentimes chronic or recurrent. Understanding the risk processes underlying the development of depression is imperative for understanding its etiology and to enhance prevention/intervention strategies. A maternal history of depression is one of the best‐established risk markers for offspring depression, predicting a two‐ to fivefold increase in risk (Cummings and Davies 1994; Gotlib and Colich 2014; Williamson et al. 2004). The transmissive pathways that link maternal depression to offspring outcomes are complex and heterogeneous, involving both mediating and moderating processes (Goodman and Gotlib 1999). Offspring with and without maternal depression history may differ in biological or psychosocial processes that stem from mothers’ depression history, which, in turn, play a mechanistic role in offspring depression (i.e., potential mediators; Baron and Kenny 1986). Following diathesis–stress models of depression (Hankin et al. 2005), vulnerabilities that exacerbate or moderate associations between a maternal depression history and offspring depression have also been reported, such as offspring's intrinsic brain connectivity (Cai et al. 2021), maladaptive stress reactivity (Monti and Rudolph 2017), and exposure to environmental stress (Henry et al. 2020). Further, the same constructs may function as both mediators and moderators in predicting outcomes, given that the same vulnerabilities (e.g., mothers’ distress, offspring neurobiological function) serve as mediators in some studies and moderators in others (Goldstein et al. 2023; Grant et al. 2006). However, very few studies have integrated tests of mediation and moderation of the same vulnerabilities (Goldstein et al. 2023), potentially oversimplifying etiological processes in youth depression risk.

Adolescents with a maternal depression history may be especially sensitive to environmental stress (Henry et al. 2020; Monti and Rudolph 2017). The COVID‐19 pandemic is an unprecedented, ubiquitous stressor with serious mental health implications for the general population (Brooks et al. 2020; Hyland et al. 2020; Kujawa et al. 2020; Odriozola‐González et al. 2020). Pandemic‐related mental health concerns may be particularly salient for adolescents, who are at elevated developmental risk for depression (Birmaher et al. 1996; LeMoult et al. 2020). However, individual variation in stress sensitivity is the rule, rather than the exception (Harkness and Hayden 2020), rendering it crucial to better understand the early processes that portend adolescent depression risk following exposure to large‐scale stress. The pandemic provides a unique opportunity to study how maternal depression history is related to adolescents’ depressive symptoms via mediating and moderating processes in the context of a ubiquitous stressor that may be inherently “depressogenic” (Harkness and Monroe 2016). However, no work has investigated this interesting and important question. In this study, we examined the mediating and moderating processes that account for associations between maternal depression history and adolescent depressive symptoms during the pandemic.

1.1. Intrinsic Brain Activity as a Mediator or Moderator of Maternal Depression Risk

Derived from resting‐state functional magnetic resonance imaging (rs‐fMRI) data, intrinsic brain connectivity, or resting‐state functional connectivity (rs‐FC), is computed as the temporal correlation between the blood‐oxygen‐level‐dependent (BOLD) time series extracted from spatially distinct brain regions. Greater absolute values of the correlation (i.e., closer to 1) indicate stronger functional coupling of activity between regions over time (van den Heuvel and Hulshoff Pol 2010). rs‐FC within the cortical midline structures (CMSs) is a widely studied neural marker of depression and depression risk (Carballedo et al. 2011; Ho et al. 2014, 2015; Perlman et al. 2012). The CMS, sometimes considered part of the default mode network (Nejad et al. 2013), includes the medial prefrontal cortex (mPFC), the anterior cingulate cortex (ACC), and the posterior cingulate cortex (PCC; Northoff and Bermpohl 2004; Northoff et al. 2006), with the PCC likely playing a central role in communicating with other CMS regions and mediating the connectivity within the network (Fransson and Marrelec 2008; Wang et al. 2019). Nondepressed individuals typically show synchronous, increased activity in CMS during introspective or resting states but decreased activity in these regions when engaging in external, non‐introspective tasks (Buckner et al. 2008; Greicius et al. 2003; Mason et al. 2007; Northoff et al. 2006). Youths and adults with depression or depression risk (e.g., maternal depression) exhibit heightened activity in, and connectivity between, CMS regions during resting or introspective states but lower suppression (i.e., less decreased activity) of CMS during external tasks (Chai et al. 2016; Hamilton et al. 2015; Kaiser et al. 2015).

No work has directly examined rs‐FC as a mediator in the association between maternal depression history and offspring depression. However, studies have supported the mediating roles of other neurobiological metrics, including amygdala–prefrontal structural connectivity (Hay et al. 2020) and resting EEG alpha asymmetry (Marino et al. 2019), in linking maternal depression and offspring outcomes. With regard to moderation processes, familial depression risk interacted with children's rs‐FC between regions including mPFC and PCC in predicting children's depressive symptoms; specifically, more negative rs‐FC was associated with depressive symptoms in children with, but not without, a family history of depression (Cai et al. 2021).

1.2. Maternal Depressive Symptoms as a Mediator or Moderator of Risk

Mothers’ lifetime depression is also linked to youth depression via psychosocial and contextual factors. In particular, children's exposure to mothers’ depressive symptoms may mediate and moderate linkages between maternal depression and youth outcomes. Mothers with lifetime depression tend to exhibit greater negative behaviors, affect, and attitudes as well as less adaptive parenting even when they are not experiencing a depressive episode (Lam et al. 2014; Lovejoy et al. 2000), potentially impacting offspring depression vulnerability. Ewell Foster et al. (2008) found a mediating effect of mothers’ behaviors around their offspring on the association between maternal depression history and children's externalizing outcomes, such that mothers with lifetime depression showed fewer positive behaviors around their children, which, in turn, predicted children's externalizing symptoms (Ewell Foster et al. 2008). Further, Goodman et al. (1994) reported a moderating effect of mothers’ negative attitudes toward their children: the link between maternal depression history and offspring psychopathological outcomes was strengthened by the presence of mothers’ negative attitudes (Goodman et al. 1994). These studies implicate maternal behaviors as both mediating and moderating processes in the transmission of risk to offspring. However, no previous work has examined the role of mothers’ depressive symptoms as both a mediator and a moderator in the link between maternal depression history and offspring depression.

1.3. Recent Literature in the Context of the COVID‐19 Pandemic‐Related Stress

Both mediating and moderating processes have been implicated in the development of depression during the pandemic. For example, adolescents’ prepandemic rs‐FC between the amygdala and ACC mediated the associations between prepandemic parental warmth and adolescents’ depressive symptoms during the pandemic; specifically, low prepandemic parental warmth predicted stronger prepandemic amygdala–ACC rs‐FC, which in turn predicted heightened depressive symptoms during the pandemic (Miller et al. 2021). In another study, adolescents’ prepandemic limbic reactivity to neutral versus fearful faces interacted with pandemic‐related stress in predicting internalizing symptoms during the pandemic, such that stress–symptom associations were stronger in adolescents with heightened limbic responses to neutral faces (Weissman et al. 2021). Adolescents’ prepandemic neural activity also interacted with pubertal development in predicting depressive symptoms during the pandemic; specifically, neural patterns associated with suboptimal executive control predicted adolescent depression in the context of more advanced pubertal development (Chahal et al. 2021). Finally, during the first 2 months of the pandemic, parents’ anxious and depressive behaviors interacted with adolescents’ coping styles in predicting adolescent depressive symptoms, such that parental negative behaviors were associated with adolescent symptoms only for adolescents with maladaptive coping styles (Lorenzo et al. 2021). This literature suggests that adolescents’ symptoms during the pandemic outbreak are associated with risk factors assessed both prior to and during the pandemic. However, no study has investigated the mechanisms that account for associations between maternal depression history, one of the strongest early risk markers for offspring depression, and adolescent depressive symptoms during the pandemic.

1.4. The Present Study

Maternal depression is linked to adolescent depression through multiple pathways. To develop a better understanding of relevant etiological processes, we used a preexisting cohort of youths who were assessed for maternal depression history as well as other vulnerabilities both prior to (i.e., rs‐FC) and during the pandemic (i.e., mothers’ depressive symptoms). We examined associations between maternal depression history and adolescents’ depressive symptoms during the pandemic outbreak via mediating and moderating effects of prepandemic rs‐FC and exposure to mothers’ depressive symptoms at pandemic outset. Most past research on the development of depression has examined mediation and moderation separately, although the two processes may occur simultaneously in predicting depression (Goldstein et al. 2023). This study will address this gap by examining the potential mediation and moderation processes in the same model.

Specifically, we used a sample of 87 adolescents from the existing longitudinal cohort, who were oversampled for maternal depression history and assessed in rs‐fMRI 2–3 years prior to the pandemic. During March–April 2020, when the pandemic led to local governments initiating stay‐at‐home orders, we assessed mothers’ depressive symptoms in the home as a marker of youths’ potential exposure to maladaptive maternal behavior, as well as adolescents’ depressive symptoms. Informed by the developmental model of the transmission of maternal depression (Goodman and Gotlib 1999), we treated maternal depression history as the predictor, prepandemic rs‐FC as the first mediator and moderator (M1), mothers’ depressive symptoms at pandemic outset as the second mediator and moderator (M2), and adolescents’ symptoms at pandemic outset as the outcome (Figure 1). We tested this model within a structural equation modeling (SEM) framework, with all direct and indirect effects of M1 and M2 estimated simultaneously while accounting for the interrelationships among variables. With regard to rs‐FC, given the established role of the CMS in depression risk (Nejad et al. 2013) and evidence identifying the PCC as a central hub within the CMS (Fransson and Marrelec 2008; Wang et al. 2019), we adopted a hypothesis‐driven approach focused on the PCC. Specifically, we focused on rs‐FC between the PCC and two anterior CMS regions implicated in self‐referential and affective processing, the mPFC and ACC, yielding two ROI‐to‐ROI pairs: PCC–mPFC and PCC–ACC. Consistent with this a priori framework, we did not examine all possible pairwise connections among CMS regions. Restricting analyses to these theoretically motivated ROIs reduced the number of statistical tests performed, an important consideration given the modest sample size.

FIGURE 1.

FIGURE 1

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An illustration of the hypothesized mediating and moderating associations between variables.

Building on the literature, we hypothesized that associations between maternal depression history and adolescents’ depressive symptoms during the pandemic outbreak would be mediated and moderated by adolescent prepandemic PCC‐based rs‐FC as well as by mothers’ depressive symptoms at pandemic outset. With regard to mediation, we expected that maternal depression history would predict greater maternal depressive symptoms during the pandemic and maladaptive patterns of adolescent rs‐FC (i.e., heightened PCC‐based rs‐FC), both of which would, in turn, predict adolescents’ depressive symptoms at pandemic outset. Regarding moderation, we expected that the link between maternal depression history and adolescents’ symptoms would be strengthened by the presence of maladaptive/heightened patterns of rs‐FC and mothers’ depressive symptoms, a marker of potential offspring exposure to maladaptive maternal behavior, at pandemic onset.

2. Method

2.1. Participants and Procedure

Data were drawn from an ongoing longitudinal study that began at child age 3, when 409 typically developing children (201 boys; M age = 3.43 years, SD = 0.30) and their caregivers were recruited from the community. Children with major medical or psychological problems were excluded, and normative cognitive development was verified by the Peabody Picture Vocabulary Test (PPVT; Dunn and Dunn 2007). Children were mostly White (93.4%), and 50.4% of the families were middle class with an annual income of $40,001–$100,000 at the outset of the study (see (Kryski, et al. 2011; Liu, et al. 2020) for more details).

From 2017 to 2018, 87 children (M age = 11.09 years, SD = 0.66 years; 49 boys) were recruited for MRI assessment. Recruitment targeted high‐ and low‐risk children based on a maternal history of depression (described below), with 29 high‐risk children with a maternal lifetime history of depression (17 boys) and 58 low‐risk children (32 boys) participating. Mothers’ lifetime depression was determined by the Structured Clinical Interview for the DSM‐IV‐TR Axis I Disorders Non‐Patient Edition (SCID; First et al. 1997) conducted by trained clinical psychology graduate students when children were around age 5 (M age = 5.93 years, SD = 0.31 years) and then again around age 11 (the same time as the MRI assessment). Interinterviewer reliability was examined in 10 participants, which showed good interrater reliability indexed by high values of Cohen's kappa (kappa = 1.00) for depressive disorders, panic disorder, and agoraphobia.1

High‐risk children's mothers had at least two major depressive episodes (MDE; n = 26) or one MDE and a major anxiety disorder (n = 3),2 given that both mark risk for offspring depression (Barnett et al. 1991; Kendler et al. 1992). Low‐risk children's mothers had no history of depressive or anxiety disorder. At the time of the MRI assessment, no children had a past or current depressive disorder as indicated by the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version (K‐SAD‐PL; Kaufman et al. 1997) administered by trained graduate students to both the primary caregiver and their child. Interinterviewer reliability of child and caregiver K‐SAD‐PL was examined in 11 participants, none of whom met criteria for any diagnoses; interrater agreement was 100%.3 Of the 87 children, 85 (29 high‐risk; 48 boys) contributed usable rs‐fMRI data (one child had braces; one discontinued). Children also completed the Youth Self‐Report (Achenbach 2007), of which the eight‐item withdrawn‐depressed subscale (YSR‐WD) was used to index self‐reported depressive symptoms at the time of the MRI assessment (Cronbach's α = 0.71 in this sample for this and all other α values presented subsequently).

At the outbreak of the COVID‐19 pandemic in late March 2020, children (now adolescents) again completed the eight‐item withdrawn‐depressed subscale of YSR. As a marker of offspring exposure to their mothers’ depressive behaviors, primary caregivers (all mothers except for one father) self‐reported their own depressive symptoms via the nine‐item Patient Health Questionnaire (PHQ; Kroenke et al. 2001). Of the 85 adolescents with usable prepandemic rs‐fMRI data (48 boys; 29 high‐risk), 63 (M age = 14.26 years, SD = 0.71; 36 boys; 17 high‐risk) and their primary caregivers (62 mothers, one father) completed at least one of the two questionnaire assessments. Given our focus on maternal depression, the one family with a father as the primary caregiver was removed from subsequent analyses. Questionnaires were administered twice, within a 2‐week interval, between March 23 and April 19, 2020. For those who completed both assessments (adolescent n = 16; mother n = 27), a mean score was calculated across the two time points to indicate their depressive symptoms during the early stage of the pandemic. The YSR‐WD and PHQ showed good internal consistency at both assessments (YSR‐WD, Cronbach's α = 0.77 and 0.79; PHQ, Cronbach's α = 0.76 and 0.85).

Of the 85 adolescents who participated in the prepandemic MRI assessment at age 11, those who completed at least one questionnaire assessment during the pandemic outbreak (n = 63) did not differ from those who did not participate in the questionnaire assessments (n = 22) in terms of sex, age, age‐3 PPVT scores, family income, race/ethnicity, prepandemic PCC‐based rs‐FC, or prepandemic depressive symptoms (all ps > 0.34). However, relative to the age 11 assessment, fewer high‐risk adolescents participated in the COVID questionnaire assessments (χ 2(1) = 5.51, p = 0.02). Little's test of missing completely at random (Little 1988) indicated that data were missing completely at random from prepandemic to during‐pandemic data collection, χ 2 = 21.49, df = 27, p = 0.76.

2.2. Prepandemic rs‐fMRI Data Collection and Processing

MRI data were collected at Robarts Research Institute of Western University on a Siemens Magnetom Prisma fit 3T scanner with a 32‐channel head coil. High‐resolution T1‐weighted anatomical images were acquired using a magnetization‐prepared rapid gradient‐echo sequence (TR = 2300 ms, TE = 2.98 ms, TI = 900 ms, flip angle = 9°, 192 slices, field of view = 256 mm, voxel size = 1 × 1 × 1 mm3). Functional T2‐weighted gradient‐echo images were acquired with 48 contiguous axial interleaved slices with a 0‐mm gap (TR = 1000 ms, TE = 30 ms, flip angle = 45°, FOV = 210 mm, voxel size = 3 × 3 × 3 mm3, matrix size = 64 × 64). The rs‐fMRI data were collected over a period of 6 min (360 volumes), during which children were instructed to gaze upon a fixation cross in the center of the screen while remaining still.

rs‐fMRI data were processed using the CONN toolbox 18.a (Whitfield‐Gabrieli and Nieto‐Castanon 2012) in MATLAB 7.14.0 (MathWorks, Inc., Natick, MA). Data were preprocessed following a standard pipeline: functional images were realigned to the first image for motion correction and were corrected for slice timing; the mean realigned functional image was coregistered to each individual's T1 image and normalized to MNI space; the normalized images were then resampled to 2‐mm3 voxels and spatially smoothed with a 6‐mm full width at half maximum Gaussian kernel.

In addition to the basic preprocessing steps, CONN implemented further measures for rs‐FC analysis to account for spurious variances of signals such as physiological and motion‐related noise. For each child, signals from white matter and cerebrospinal fluid were estimated and regressed out using the anatomical CompCor method (Behzadi et al. 2007). Temporal filtering was implemented with a bandpass of 0.008–0.09 Hz. Volumes with frame‐wise displacement exceeding 0.9 mm (Siegel et al. 2014) or average global signal intensity exceeding 5 SDs from the individual's mean were labeled as invalid and ignored in subsequent analysis. Motion parameters (three rotational, three translational, and six first‐order temporal derivatives) and global signals were modeled as nuisance variables. The potential effect of the fixation stimulus (e.g., hemodynamic response function‐convolved resting‐state task block) was also modeled as a confound to control for potential co‐activation of different regions in response to the fixation stimulus. High‐ and low‐risk children did not differ in average frame‐wise displacement or the percentage of invalid volumes (ps > 0.30).

In rs‐FC analyses, we adopted a hypothesis‐driven ROI‐to‐ROI approach to increase analytic sensitivity. Given prior evidence implicating the CMS in depression (Nejad et al. 2013), we selected the PCC as an a priori seed region because of its role as a central hub within the CMS. Three CMS regions, PCC, mPFC, and ACC, were defined using the Harvard–Oxford cortical and subcortical structural atlases (Desikan et al. 2006). Consistent with our PCC‐centered hypothesis, connectivity was examined between the PCC and the other CMS regions, yielding two ROI‐to‐ROI pairs: PCC–mPFC and PCC–ACC. Pearson correlations between the average BOLD time series for each pair were computed for each participant and converted to Fisher's Z‐scores for subsequent analyses.

2.3. Statistical Analysis

Linear regression was conducted within an SEM framework using maximum likelihood estimation to account for missing data (Mplus version 8; Muthén and Muthén 1998–2017).4 Significance of hypothesized effects was determined by 95% bias‐corrected bootstrap confidence intervals (CIs) generated based on 10,000 bootstrap samples. As shown in Figure 1, adolescents’ prepandemic PCC‐based rs‐FC (M1) and mothers’ depressive symptoms at pandemic onset (M2) were tested as both a mediator and a moderator of the association between the predictor (maternal depression history) and the outcome (adolescents’ depressive symptoms). We examined multicollinearity between the predictor and moderators by computing the variance inflation factors (VIFs), which were all below 5, indicating that multicollinearity was nonproblematic (Chatterjee and Simonoff 2013). Children's prepandemic depressive symptoms measured at the time of the rs‐fMRI assessment were included as a covariate. Two analogous models were conducted with either PCC–mPFC or PCC–ACC rs‐FC as M1, respectively. In each model, we focused on the mediating effect of M1 (a1b1) and M2 (a2b2) and the moderating effects of M1 (c1) and M2 (c2) on the predictor–outcome association (c’). The sample sizes for M1‐related effects and M2‐related effects were 85 (participants with usable rs‐fMRI data) and 63 (participants with symptom data at pandemic outset), respectively.

Finally, in exploratory analyses, we also included an interaction term between M1 and M2 (b3), given that these two risk factors may also interact with each other in predicting adolescents’ symptoms. We also examined two moderated mediation effects (a1b3, a2b3) to see if the indirect association between the predictor and the outcome via M1 (or M2) would be moderated by M2 (or M1; e.g., the mediating effect of M1 may be stronger in the presence of higher M2).5

3. Results

3.1. Descriptive Statistics and Bivariate Correlations Between Main Study Variables

Table 1 presents the descriptive statistics of study variables for each risk group and the full sample, as well as the group comparison statistics for each variable. The high‐risk group was younger than the low‐risk group, t(83) = 3.16, p = 0.002. As expected, mothers with a depression history reported greater depressive symptoms at pandemic outset compared to mothers without a depression history, t(61) = −3.56, p < 0.001. Also, as expected, adolescents in the high‐risk group reported marginally higher depressive symptoms compared to their low‐risk peers at pandemic outset, t(61) = −1.85, p = 0.07. No other group differences were found (ps > 0.36). We also compared the sex distribution between the high‐risk group (12 girls, 17 boys) and low‐risk group (25 girls, 31 boys), which was not significant either (χ 2(1) = 0.08, p = 0.77).

TABLE 1.

Descriptive statistics of study variables.

Full

(N = 87)

High‐risk

(n = 29)

Low‐risk

(n = 58)
Mean SD Mean SD Mean SD t df p
Age (years) at pandemic assessment 14.26 0.71 13.94 0.74 14.43 0.63 3.16 83 0.002
Age 11 depressive symptoms 3.37 2.72 3.75 2.89 3.18 2.64 −0.92 83 0.36
Age 11 PCC–mPFC rs‐FC (Fisher's Z) 0.38 0.24 0.35 0.23 0.39 0.25 0.74 83 0.46
Age 11 PCC–ACC rs‐FC (Fisher's Z) −0.12 0.21 −0.13 0.21 −0.11 0.21 0.29 83 0.77
Maternal depressive symptoms at pandemic onset 3.57 3.31 5.72 4.26 2.71 2.4 −3.56 61 <0.001
Adolescent depressive symptoms at pandemic onset 3.08 2.52 4.03 2.37 2.73 2.51 −1.85 61 0.07
Mean frame‐wise displacement during rs‐MRI (mm) 0.20 0.07 0.21 0.09 0.20 0.06 −0.66 83 0.51
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Abbreviations: ACC, anterior cingulate cortex; mPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; rs‐FC, resting‐state functional connectivity; SD, standard deviation.

Table 2 shows the bivariate correlations between major study variables. Prepandemic PCC–mPFC connectivity and prepandemic depressive symptoms at age 11 were negatively correlated. Prepandemic depressive symptoms were correlated with greater head motion (frame‐wise displacement) during rs‐fMRI data collection. Adolescents’ depressive symptoms showed moderate stability between ages 11 and 14. Mothers’ depressive symptoms and their children's depressive symptoms were marginally positively correlated during the early stages of the pandemic.

TABLE 2.

Bivariate correlations between study variables.

    1 2 3 4 5 6 7
1 Age (years) at pandemic assessment
2 Sex (1 = boy, 2 = girl) 0.15
3 Age 11 depressive symptoms 0.04 −0.08
4 Age 11 PCC–mPFC rs‐FC (Fisher's Z) 0.05 0.14 −0.39**
5 Age 11 PCC–ACC rs‐FC (Fisher's Z) 0.21 0.08 0.05 −0.01
6 Maternal depressive symptoms at pandemic onset −0.16 0.02 −0.07 0.02 0.07
7 Adolescent depressive symptoms at pandemic onset 0.08 0.15 0.27* 0.06 0.05 0.23+
8 Mean frame‐wise displacement during rs‐MRI (mm) −0.02 −0.06 0.24* −0.17 −0.01 −0.09 0.11
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Abbreviations: ACC, anterior cingulate cortex; mPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; rs‐FC, resting‐state functional connectivity.

**p < 0.01; *p < 0.05; +p < 0.10.

3.2. Regression Analyses

R‐square statistics indicated that in both the PCC–mPFC and PCC–ACC models, the predictors and covariates accounted for a substantial proportion of the variance of the dependent variable (PCC–mPFC model: R 2 = 0.66, standard error = 0.14, p = 0.00; PCC–ACC model: R 2 = 0.58, standard error = 0.15, p = 0.00). First, as expected, both analogous models demonstrated a significant direct association between maternal history of depression and adolescents’ symptoms early in the pandemic, such that adolescents of mothers with lifetime depression showed greater depressive symptoms at pandemic onset, with their prepandemic symptoms accounted for (β = 2.33, SE = 0.82, 95% CI: [0.78, 3.99]).6 This association was moderated by adolescents’ prepandemic PCC–ACC rs‐FC (β = 3.72, SE = 2.13, 95% CI: [0.13, 10.13]), but not by their prepandemic PCC–mPFC rs‐FC (β = −1.18, SE = 1.72, 95% CI: [−4.72, 1.95]). As shown in Figure 2, decomposing the moderation of PCC–ACC rs‐FC showed that maternal depression history predicted adolescents’ symptoms at pandemic outset only for individuals with higher PCC–ACC rs‐FC (β = 1.30, SE = 0.65, 95% CI: [0.01, 2.60]), but not for those with lower (β = −0.24, SE = 0.62, 95% CI: [−1.47, 0.99]) or mean‐level (β = 0.53, SE = 0.46, 95% CI: [−0.38, 1.44]) PCC–ACC rs‐FC. With regard to mediation, however, neither PCC–mPFC rs‐FC (β = −0.12, SE = 0.23, 95% CI: [−0.97, 0.11]) nor PCC–ACC rs‐FC (β = 0.03, SE = 0.16, 95% CI: [−0.13, 0.57]) mediated the association between maternal depression history and adolescents’ symptoms.

FIGURE 2.

FIGURE 2

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Moderating effects of (a) prepandemic PCC–ACC rs‐FC and (b) mothers’ depressive symptoms at pandemic onset on the association between maternal depression history and adolescents’ depressive symptoms at pandemic onset. PCC, posterior cingulate cortex; ACC, anterior cingulate cortex; rs‐FC, resting‐state functional connectivity; SD, standard deviation; sig., significant; ns, nonsignificant.

In addition, mothers’ depressive symptoms at pandemic onset both mediated (β = 0.92, SE = 0.73, 95% CI: [0.49, 2.74]) and moderated (β = −0.34, SE = 0.17, 95% CI: [−0.72, −0.02]) the link between maternal depression history and adolescents’ symptoms at pandemic onset. Regarding mediation, maternal history of depression predicted greater maternal depressive symptoms at pandemic onset (β = 1.58, SE = 0.57, 95% CI: [0.49, 2.74]), which in turn predicted greater depressive symptoms in adolescents at pandemic onset, above and beyond their prepandemic symptoms (β = 0.58, SE = 0.29, 95% CI: [0.21, 1.37]). Regarding moderation, maternal depression history predicted adolescents’ symptoms at pandemic outset only for those whose mothers showed lower (β = 1.50, SE = 0.68, 95% CI: [0.13, 2.87]), but not higher (β = −0.44, SE = 0.58, 95% CI: [−1.60, 0.72]) or average (β = 0.53, SE = 0.46, 95% CI: [−0.38, 1.44]), depressive symptoms during the pandemic outbreak. Finally, exploratory analyses showed that the interaction between adolescents’ prepandemic rs‐FC and mothers’ depressive symptoms at pandemic onset was also not significant; no moderated mediation effect was significant.

4. Discussion

The transmission of depression risk from mothers to offspring occurs via multiple processes involving both biological and psychosocial factors. To shed light on these processes, we examined mediating and moderating effects of adolescents’ prepandemic rs‐FC and mothers’ depressive symptoms, a marker of potentially maladaptive maternal behavior, in accounting for associations between maternal depression history and adolescent depressive symptoms at pandemic onset. Adolescents’ prepandemic PCC–ACC rs‐FC moderated, but did not mediate, the association between maternal depression history and adolescents’ pandemic symptoms. Specifically, maternal depression history predicted adolescents’ depressive symptoms at pandemic onset solely among those with heightened prepandemic PCC–ACC rs‐FC. Mothers’ depressive symptoms at pandemic outset mediated associations between a maternal depression history and adolescents’ depressive symptoms during the pandemic, such that mothers with lifetime depression reported greater depressive symptoms early in the pandemic, which, in turn, were associated with their adolescents’ symptoms at pandemic outset. Meanwhile, and somewhat unexpectedly, mothers’ depressive symptoms at pandemic outset also moderated the association between maternal lifetime history and adolescents’ symptoms, such that the link between maternal depression history and adolescents’ symptoms at pandemic outset was significant only for adolescents of mothers with relatively low depressive symptoms during the pandemic. This study provides evidence for the mediating and moderating processes that contribute to the longitudinal linkages between maternal depression history and adolescents’ depressive psychopathology at the outset of a global stressor, the COVID‐19 pandemic.

4.1. Prepandemic PCC–ACC rs‐FC as a Moderator of Maternal Depression Risk

Consistent with our hypothesis, the association between maternal depression history and adolescents’ depressive symptoms at pandemic outset was moderated by adolescents’ prepandemic PCC–ACC rs‐FC. In particular, maternal depression history predicted adolescents’ symptoms only among those with heightened prepandemic PCC–ACC rs‐FC, above and beyond adolescents’ prepandemic depressive symptoms. Heightened PCC–ACC rs‐FC is considered a maladaptive pattern of intrinsic brain connectivity, which has been observed in individuals with clinical depression (Berman et al. 2011; Kaiser et al. 2015; Seeley et al. 2007) as well as elevated depression risk (e.g., familial depression history, Chai et al. 2016; subclinical depression, Philippi et al. 2015). This moderation/interaction pattern is also consistent with diathesis–stress models (Hankin et al. 2005; Monroe and Simons 1991), highlighting that the presence of an additional risk factor (e.g., maladaptive rs‐FC) will strengthen the link between a known vulnerability (e.g., maternal depression history) and depressive outcomes.

Specifically, heightened PCC–ACC rs‐FC may reflect maladaptive psychological processes that are associated with depression risk. PCC is thought to support autobiographical memory and retrieval (Spreng et al. 2008) and attention shifting between the external environment and internal mentation (Brewer et al. 2013; Weissman et al. 2006). ACC is involved in the monitoring of socioemotional salience in the external and internal environments as well as attentional control (Seeley et al. 2007). During a resting state without any external tasks and stimuli, participants are likely to engage in spontaneous, introspective thoughts, feelings, and memories (Hurlburt et al. 2015). Given the known functions of PCC and ACC, increased PCC–ACC rs‐FC may reflect excessive activation of self‐related information, internally oriented attention shifts, or increased perceived salience of internally represented stimuli, which are thought to portend risk for depression (see the meta‐analysis by Hamilton et al. [2015]). However, we did not directly measure these psychological processes in the current study; future research will benefit from paradigms that directly elicit and assess these introspective processes in the context of depression risk.

The moderating effect of PCC–mPFC rs‐FC was not significant. We also did not find the expected mediating effect of PCC‐based rs‐FC on the association between maternal depression history and adolescents’ depressive symptoms. Notably, findings on the link between maternal (or parental) lifetime depression and adolescents’ rs‐FC are somewhat mixed. In previous work examining the functional differences in nondepressed youths with and without a maternal (or parental) history of depression, some studies report significant group differences in rs‐FC of the CMS or the default mode network (Chai et al. 2016; Fischer et al. 2018; Hirshfeld‐Becker et al. 2019; Singh et al. 2018), while others do not (Cai et al. 2021; Shapero et al. 2019). These inconsistencies may be related to a number of factors, such as youth age, sex (e.g., Fischer et al. 2018), and different operationalizations of maternal/parental history of depression (clinical interview vs. questionnaire; e.g., Cai et al. 2021). Timing of exposure to maternal depression may also be important, given previous work showing that offspring of mothers who had depression during or prior to pregnancy may be more likely to be born with neural vulnerabilities, due to the fetus’ exposure to an adverse prenatal environment such as neuroendocrine alterations associated with the mother's depression (Dunkel Schetter and Tanner 2012; Kinsella and Monk 2009). In the current sample, we do not have sufficiently precise data concerning the timing of mothers’ lifetime depressive disorder to permit us to examine its associations with offspring brain connectivity in relation to their later depressive psychopathology.

4.2. Maternal Depressive Symptoms as a Mediator and Moderator of Risk

In addition, we found that mothers’ depressive symptoms at pandemic onset, a marker of youths’ potential exposure to maladaptive maternal behavior, both mediated and moderated the link between maternal depression history and adolescents’ depressive symptoms at pandemic outset. Regarding mediation, mothers with lifetime depression reported greater depressive symptoms during the pandemic, which then predicted offspring symptoms at pandemic outset. Mothers with lifetime depression may exhibit more negative affect and behaviors at home and generate greater interpersonal stress with family members (Dodge 1990; Hammen et al. 2004), especially in the context of increased larger‐scale stress. These mothers may also engage in other behaviors, such as negative parenting behaviors, that also increase stress in the home (Gelfand and Teti 1990; Hops et al. 1987). These factors in the immediate home environment may have compromised adolescents’ socioemotional skills (Hammen et al. 2004) in coping with the pandemic‐related stress and, in turn, portend greater depression risk.

Regarding the moderation effect of mothers’ depressive symptoms, maternal depression history predicted adolescents’ symptoms among offspring of mothers with relatively lower, but not higher, depressive symptoms at pandemic outset. Conversely, mothers’ concurrent depressive symptoms were more strongly associated with adolescent symptoms among mothers without a lifetime history of depression, whereas mother–adolescent depressive symptom associations were weak in dyads with a mother with a depression history. As illustrated in Figure 2b, adolescents tended to report relatively elevated depressive symptoms when either their mothers had a lifetime history of depression or their mothers reported elevated depressive symptoms during the pandemic. When one of these maternal risk indicators was already present, variation in the other appeared to provide less additional differentiation in adolescent symptoms. This ceiling‐like pattern suggests that maternal lifetime depression history was particularly informative about adolescent symptoms when mothers’ current symptoms were relatively low, whereas current maternal symptoms were particularly informative when mothers did not have a lifetime depression history. Thus, this interaction suggests that the predictive relevance of maternal depression history and maternal depressive symptoms depends on the presence of the other. Considered together with the mediation finding, we speculate that these results suggest that maternal depressive symptoms may influence offspring via two mechanisms: They may serve as a pathway through which heritable risk is associated with adolescent symptoms, while also moderating the extent to which maternal lifetime history predicts adolescent outcomes. However, given the modest sample size and concurrent assessment of maternal and adolescent symptoms, this pattern requires further exploration in future studies.

4.3. Limitations and Conclusion

One limitation of our study is that we did not directly measure mothers’ maladaptive behaviors at home during the pandemic, but instead used their depressive symptoms as a proxy. However, past research indicates a strong correlation between mothers’ depressive symptoms and their maladaptive behaviors (Hops et al. 1987; Lovejoy et al. 2000). Further, we assessed mothers’ and adolescents’ depressive symptoms at pandemic outset concurrently and cannot speak to the directionality between these two constructs, limiting the interpretation of the observed mediating effect. Future research that directly assesses mothers’ behaviors prior to the assessment of offspring outcomes is important toward providing evidence regarding the mediation processes of interest.

In rs‐FC analysis, we took a hypothesis‐driven, PCC‐centered approach and focused on two ROI‐to‐ROI pairs, PCC–mPFC and PCC–ACC. Considering our modest sample size, this approach conserved the statistical power of the current analyses. Future research with greater sample sizes is needed to examine how rs‐FC across other ROIs contributes to the association between maternal depression history and youth depression. Moreover, adolescents during the pandemic were likely experiencing other stressors beyond the pandemic, such as heightened pubertal development and disrupted peer relations in the context of quarantine and social distancing, that we did not measure or examine in the current study. Future research that integrates these factors will provide a more comprehensive delineation of the risk processes underlying adolescent depression in the context of the pandemic. Further, although oversampling youths with a maternal depression history increased our ability to detect associated risk processes, it may limit the generalizability of findings to community samples. Replication in more representative community samples will be important for determining the extent to which these processes generalize to the broader population. Finally, given our interest in adolescents’ adaptation during the pandemic outbreak when abrupt interruptions occurred, we focused on data collected during the first month of the pandemic. Moving forward, we will explore whether early depressive vulnerabilities predict the trajectories of adolescent adaptation during the persistent course of the pandemic and how these trajectories may be modulated by more specific pandemic‐related stressors (e.g., parents’ unemployment, COVID‐19 infection). We also plan to collect a second wave of neuroimaging data to explore how the pandemic‐related stress has impacted the development of adolescents’ brain functions in the context of psychopathology.

By capitalizing on an established longitudinal cohort, this study provides the first evidence concerning the longitudinal linkages between maternal lifetime history of depression, one of the strongest predictors of youth depression (Gotlib and Colich 2014), and adolescents’ depressive psychopathology during early stages of the COVID‐19 pandemic. We used a multimethod approach incorporating rs‐fMRI measures as well as questionnaires and clinical interviews completed by both adolescents and mothers. Our results showed that maternal depression history was prospectively associated with adolescents’ depressive symptoms at pandemic outset via a mediating effect of exposure to mothers’ depressive symptoms at pandemic outset, as well as moderating effects of youths’ prepandemic neural vulnerability (PCC–ACC rs‐FC) and mothers’ depressive symptoms during the pandemic outbreak.

By including both neurobiological and psychosocial factors in the same model, we provided more nuanced evidence of the transmission of maternal depression risk to adolescent offspring following exposure to a ubiquitous stressor (Goodman and Gotlib 1999). To our knowledge, this is the first study to investigate the potential mechanisms associated with mother‐to‐offspring transmission of depression risk in the context of the COVID‐19 pandemic. Our findings have implications for identifying at‐risk adolescents and developing intervention and prevention strategies for vulnerable individuals and families in the face of a large‐scale stressor (e.g., improving mothers’ adaptation to the stressful situation may help prevent or reduce depressive symptoms in adolescents).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File 1: dev70209‐sup‐0001‐SuppMat.docx

DEV-68-e70209-s001.docx (15.8KB, docx)

Acknowledgments

This work was supported by research funding from the Canadian Institutes of Health Research (MOP86458), the Ontario Mental Health Foundation, and a Social Sciences and Humanities Research Council Insight Grant to E.P.H., as well as a postdoctoral fellowship from the BrainsCAN research initiative to P.L. Neuroimaging costs were subsidized by a Canada First Research Excellence Fund grant to BrainsCAN. Computing infrastructure support was provided by an NVIDIA Corporation grant to M.F.J. The authors would like to thank the families who participated in our study and the many individuals who contributed to data collection.

Endnotes

1

All other diagnoses of SCID demonstrated 100% interrater agreement on the absence of the disorder (i.e., no one met criteria for these diagnoses), preventing the calculation of Cohen's kappa due to the absence of variability.

2

We excluded specific phobia and social anxiety limited to public speaking given that these are less heritable, less impairing, and potentially weaker markers of children's internalizing risk (Kendler et al. 1992).

3

Cohen's kappa could not be calculated due to the absence of variability.

4

We alternatively conducted multiple imputation by running 50 imputations with 10 iterations each on the original data of main study variables and demographics (R mice package; van Buuren and Groothuis‐Oudshoorn 2011), and subjected the averaged data across the 50 imputed datasets to the same regression analysis. Results from the imputed data were highly similar to those yielded by the original data reported in the paper.

5

To test the robustness of the results, we ran two sensitivity analyses by running the same statistical models (a PCC–ACC model and a PCC–mPFC model) with (1) each participant's mean frame‐wise displacement included as a covariate and (2) the participant with a frame‐wise displacement >0.50 mm removed. Results of both analyses generated highly similar results to those reported in the main text (see Supporting Information for details).

6

Results for the effects of maternal history of depression (predictor) were highly similar between the two analogous models. For the purpose of brevity, we reported the results of the model including PCC–ACC rs‐FC as M1 only.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting File 1: dev70209‐sup‐0001‐SuppMat.docx

DEV-68-e70209-s001.docx (15.8KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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