davis2019 sequent elevations in youth depressive symptoms, but the neural pro- cesses associated with these links are unclear. This study evaluated

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Prenatal Maternal Stress, Child Cortical Thickness, and Adolescent Depressive Symptoms

Elysia Poggi Davis

University of Denver and University of California–Irvine Benjamin L. Hankin University of Illinois–Urbana Champaign Laura M. Glynn

University of California–Irvine and Chapman University Kevin Head University of Denver

Dae Jin Kim Indiana University

Curt A. Sandman University of California–Irvine

Prenatal maternal stress predicts subsequent elevations in youth depressive symptoms, but the neural processes associated with these links are unclear. This study evaluated whether prenatal maternal stress is associated with child brain development, and adolescent depressive symptoms using a prospective design with 74 mother child pairs (40 boys). Maternal stress was assessed during pregnancy, child cortical thickness at age 7, and depressive symptoms at age 12. Prenatal maternal stress was associated with less cortical thickness primarily in frontal and temporal regions and with elevated depressive symptoms; child cortical thickness addi- tionally correlated with adolescent depressive symptoms. The observed associations are consistent with the possibility that cortical thickness in superior frontal regions links associations between prenatal maternal stress and adolescent depressive symptoms.

The developmental origins of health and disease (DOHaD) model articulates how critical inﬂuences during gestation exert lifelong effects on physical and mental health (Barker, 1998; Gluckman & Han- son, 2004). The DOHaD model is consonant with the neurodevelopmental risk hypothesis (Marenco

& Weinberger, 2000), which broadly posits that mental health is inﬂuenced by alterations in the trajectory of brain development that originate early in life. We considered whether application of the neurodevelopmental risk hypothesis to the DOHaD model facilitates understanding of brain systems associated with both fetal experiences and subsequent depressive symptoms in adolescence.

The prenatal period represents a time of extre- mely rapid change in brain development. Human brain development follows an orchestrated series of events including processes such as proliferation,

migration, and differentiation that by far outpaces any other period of the life span (Huttenlocher, 1994; Levitt, 2003). By the end of the second trime- ster, 200 billion neurons have been produced (Bourgeois, 1997; Bourgeois, Goldman-Rakic, &

Rakic, 1994). The brisk neurological advances ren- der the fetus susceptible to various inﬂuences, such as prenatal stress, with lifelong implications for mental health. Maternal experiences of stress, broadly deﬁned, throughout pregnancy provide salient signals during fetal development and affect the organization of the central nervous system.

Here, we deﬁne and conceptualize maternal prenatal experience of stress as consisting of a broad, complex array and admixture of related experiences, including perceptions of exposure to stress- ful negative events alongside self-reported maternal psychological distress, which strongly correlates with perceptions of stress exposure (Harkness & Monroe, 2016). Perceptions of stress have been recognized as critical to mental health research (Barch et al., 2016). Longitudinal

This research was supported by the National Institutes of Health (NIH) HD50662 and HD06582 to Elysia P. Davis;

HD51852, MH109662 and NS041298 to Curt A. Sandman;

HD40967; and P50MH096889 to Elysia P. Davis, Laura M. Glynn and Curt A. Sandman.

Correspondence concerning this article should be addressed to Elysia Poggi Davis, Department of Psychology, University of Denver, 2155 South Race Street, Denver, CO 80208-3500. Elec- tronic mail may be sent to [email protected].

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naturalistic studies measuring various types of prenatal maternal psychological distress and stress hormone exposure show that prenatal maternal distress predicts numerous negative outcomes in the offspring (Van den Bergh, Mulder, Mennes, &

Glover, 2005), including dysregulated stress responses (Davis, Glynn, Waffarn, & Sandman, 2011) and child internalizing symptoms (Davis &

Sandman, 2012; O’Donnell, Glover, Barker, &

O’Connor, 2014; Van den Bergh, Van Calster, Smits, Van Huffel, & Lagae, 2008). These studies indicate that maternal psychological distress, broadly deﬁned, is associated with subsequent child outcomes. Here we focus on maternal perceptions of stress during the prenatal period and the association with brain and behavioral outcomes. As posited by the DOHaD hypothesis, maternal stress during the prenatal period serves as a potent signal that may impact the trajectory of fetal development in preparation for the postnatal environment. In the present study, we tested the hypothesis that prenatal maternal perceptions of stress are associated with individual differences in brain structure during childhood, which in turn will correlate with subsequent depressive symptoms years later in adolescence.

Prospective human research and experimental animal research demonstrate that exposure to early postnatal life stress is associated with persisting consequences for later brain development, particularly in the prefrontal cortex (PFC), amygdala, and hippocampus (e.g., Joels & Baram, 2009; Lupien, McEwen, Gunnar, & Heim, 2009; McEwen, Nasca,

& Gray, 2015). Fewer longitudinal studies with humans have considered the association between prenatal stress and brain development. Yet the fetal brain is especially vulnerable during the prenatal period because of the rapid growth occurring during this time (Levitt, 2003) and because early life is marked by a lifetime peak for stress hormone receptor number (Baram & Hatalski, 1998).

Research with humans illustrates that prenatal maternal distress (anxiety or depression symptoms) is associated with structure and function of the brain including the amygdala (Buss et al., 2012; Qiu et al., 2015; Rifkin-Graboi et al., 2013) and the PFC (Lebel et al., 2016; Mennes, Stiers, Lagae, & Van den Bergh, 2006; Posner et al., 2016; Sandman, Buss, Head, & Davis, 2015) as well as to connectiv- ity between limbic regions and the prefrontal and temporal cortices (Posner et al., 2016; Qiu et al., 2015; Scheinost et al., 2017). Elevated prenatal maternal distress assessed prospectively predicts cortical thinness in childhood with the strongest

associations observed in right frontal regions (Lebel et al., 2016; Sandman et al., 2015). The impact of prenatal maternal distress persists through adult- hood (Favaro, Tenconi, Degortes, Manara, & San- tonastaso, 2015). Prenatal maternal distress is associated with decreased gray matter volume in the medial temporal lobe and amygdala in adult female offspring. Although these studies have evaluated maternal psychological distress rather than speciﬁcally assessing perceived stress, this literature provides prospective evidence for an association between prenatal maternal distress and brain development with associations observed through adult- hood in stress sensitive regions including the prefrontal and temporal cortices as well as in subcortical regions (e.g., amygdala and hippocampus).

These neural systems that are associated with prenatal distress also are associated with depressive symptoms (Koolschijn, van Haren, Lensvelt-Mul- ders, Hulshoff Pol, & Kahn, 2009) suggesting that prenatal stress may increase vulnerability to depression by altering these brain regions. Consistent with this possibility, fetal exposure to a maternal stress hormone (cortisol) predicts both brain structure and internalizing problems measured concurrently in childhood (Buss et al., 2012; Davis, Head, Buss, &

Sandman, 2017; Kim et al., 2016).

Considerable research has evaluated the neural associates of depression. Meta-analytic reviews of structural differences highlight effects of frontal, temporal, and limbic regions in association with depression, although many of the studies included comprised samples of adults (Koolschijn et al., 2009; Schmaal et al., 2017; Zhang et al., 2016). More speciﬁcally, the largest analysis comparing depressed to nondepressed adolescents showed reduction in frontal and temporal regions (e.g., including medial orbitofrontal and superior frontal gyrus, middle temporal, and superior temporal) as well as visual, somatosensory, and motor areas (Schmaal et al., 2017). Moreover, reviews of func- tional imaging in adolescent depression (Hulver- shorn, Cullen, & Anand, 2011; Kerestes, Davey, Stephanou, Whittle, & Harrison, 2014; Miller, Hamilton, Sacchet, & Gotlib, 2015) similarly identify frontal (especially PFC and orbitofrontal), striatal, and limbic areas that are consistent with fronto-limbic circuitry models implicated in poor emotion regulation, as well as other areas (cuneus, insula, superior parietal cortex, and middle temporal cortex) that are outside this circuitry. Indeed, so much evidence has accumulated to establish between groups brain differences in depressed versus healthy controls, especially in PFC and limbic or

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temporal areas, that these neural areas have been identiﬁed as potential neuroimaging biomarkers for identifying clinical depression and perhaps treat- ment prediction (e.g., Lener & Iosifescu, 2015).

However, most of the extant research has been cross-sectional and used between groups case–control designs (e.g., currently depressed vs. healthy controls) that may be limited by ascertainment bias (Horga, Kaur, & Peterson, 2014). Surprisingly little work has focused on neural individual differences that predict later depression.

Prospective longitudinal research, in which brain-imaging data collected earlier in child development that are associated with the later emergence of depressive symptoms, would provide stronger support for the neurodevelopmental risk hypothesis. However, only a few longitudinal studies exist that provide prospective evidence that individual differences in brain structure, when assessed earlier in the life course, predict later depressive symptoms (Ducharme et al., 2013;

Horga et al., 2014; Vulser et al., 2015; Whittle et al., 2014). For example, a sample of never-disor- dered early adolescent girls, who had cortical thickness assessed at baseline, were followed prospectively for 5 years, and results showed that reductions in thickness of the medial orbitofrontal, precentral gyrus, anterior cingulate, and insula predicted future depressive symptoms (Foland- Ross, Gilbert, Joormann, & Gotlib, 2015). Duch- arme et al. (2013) showed that reduced cortical thickness in right ventromedial PFC predicted later anxious and depressive symptoms in their child sample. Given the existing cross-sectional meta-analytic evidence for depression risk alongside the few prospective studies that have found evidence for frontal and temporal regions in pre- dicting depression, we emphasized examination of frontal and temporal cortical thickness as key regions that may relate to earlier prenatal stress exposure as well as depressive symptoms later in adolescence.

Still, of these few longitudinal studies, none have followed a cohort prospectively from pregnancy through to late childhood and then early adolescence to address the hypothesis that prenatal experiences predict individual differences in child brain structure and, in turn, later adolescent depressive symptoms. MRI cortical thickness measures can be used to identify subtle variations in gray matter in the cerebral cortex. This approach has identiﬁed relations between cortical thickness and the development of internalizing problems including depressive symptoms (Ducharme et al., 2013). It has been

proposed that a proﬁle of decreased cortical thickness, including in the frontal cortex, constitutes a neural endophenotype for depression, as a thinner cortex has been observed in both depressed adults and children with risk for depression who have never experienced or been treated with depression (Peterson & Weissman, 2011).

The primary aim of this study was to evaluate whether prenatal maternal stress is associated with individual differences in cortical thickness in childhood and in depressive symptoms in early adolescence. No prospective study has longitudinally connected these threads and evaluated the association between prenatal maternal perceptions of stress and neural mechanisms, which in turn then may relate to the later emergence of depressive symptoms in early adolescence. To address this question we employed a longitudinal within-subject design in which maternal stress was assessed during pregnancy, individual differences in brain structure (cortical thickness) were measured in childhood (7 years of age), and depressive symptoms were assessed during early adolescence (12 years of age).

Method Participants

English-speaking, healthy adult pregnant women with singleton pregnancies were initially recruited prior to 20 gestational weeks. Subjects were excluded if they had (a) tobacco, alcohol, or other drug use in pregnancy; (b) uterine or cervical abnormalities; or (c) presence of any conditions associated with dysregulated neuroendocrine function. As shown in Figure 1, pregnant women were assessed four times throughout gestation and at 2 months postpartum. Subsequently, mother child pairs were assessed during childhood at age 7 and again during early adolescence at age 12.

The present sample included 74 mother–child pairs (40 boys; see Table 1 for descriptive informa- tion, Figure S1 for a consort diagram, and Table S1 for a comparison with eligible participants not in the present study). Mothers gave informed consent and children gave informed assent for all aspects of the protocol, which was approved by the Institu- tional Review Board for protection of human subjects. Every participant had a stable neonatal course (median Apgar= 9, range= 8–10), did not have congenital, chromosomal, or genetic anomalies; and had normal neurological ﬁndings (determined by neuroradiological review of MRI scans) at assessment. The sample of 74 children included in the

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present study did not include data from seven children due to either a neuroradiology report of an anomaly (n = 3) or motion artifact in the MRI scan (n = 4).

Procedure Overview of Data Collection

Maternal perceived stress was assessed at four intervals during pregnancy, Time 1: 15.3 (1.3), Time 2: 19.3 (0.9), Time 3: 31.1 (0.9), and Time 4: 36.7 (0.9) weeks of gestation, as well as postpartum (2.4 [.08] months). During childhood (M= 7.1 years, SD = 0.9), brain development was assessed using structural MRI. In early adolescence (M = 12.1 years, SD= 2.3), depressive symptoms were evaluated via self-report, and maternal perceived stress and depressive symptoms were assessed.

Sociodemographic and Maternal Characteristics

Sociodemographic characteristics were determined by standardized maternal interview. Educa- tion and household income were used to create a socioeconomic status (SES) composite score (Cohen, Doyle, & Baum, 2006). Brieﬂy, household income and years of maternal education were converted to a standardized z-score, and these z-scores were summed to create an SES composite score. These measures serve as indicators of the quality of the postnatal environment that inﬂuence neurodevelopmental trajectories and were considered as covariates in the statistical analyses.

Prenatal and Neonatal Medical Characteristics

Gestational age was determined by a combina- tion of last menstrual period and early uterine size, and was conﬁrmed by obstetric ultrasonographic biometry before 20 gestational weeks (American College of Obstetricians and Gynecologists, 2009).

A research nurse conducted an extensive structured

Figure 1. Women were recruited early in pregnancy and prenatal maternal perceived stress was assessed at four gestational intervals, postpartum, and during childhood and early adolescence. Children were assessed with structural MRI at 7 years of age and adolescent depression symptoms were evaluated at age 12.

Table 1

Sample Characteristics Maternal characteristics

Age at delivery (MSD) 30.56.3

Prenatal medical risk (MSD) 0.40.6 Cohabitating with child's father (%)

Prenatal 86

Current 92

Primiparous (%) 55

Household income (MSD)

Prenatal 63,75029,832

Current 77,16229,717

Education (%)

High school or less 42

Associates degree 11

Bachelors degree 37

Graduate degree 10

Child characteristics

Age at MRI assessment (MSD) 7.10.9 Age at CDI assessment (MSD) 12.12.4

Child CDI score (MSD) 4.03.2

Sex (% male) 54

Birth order (MSD) 1.60.8

Race and ethnicity (%)

Non-Hispanic White 38

Hispanic 27

Asian 5

African American or Black 4

Multi-Ethnic 26

Birth outcome

Gestational age at birth (MSD) 39.21.7

Birth weight (MSD) 3,441573

Apgar score (MSD) 9.00.23

Note. CDI=Children’s Depression Inventory.

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medical interview at prenatal visits. Maternal and infant medical records were reviewed to assess pregnancy complications and birth outcome. These two sources were used to derive an index character- izing prenatal obstetric risk, and this index was considered in covariate analyses (Hobel, 1982).

Ninety-four percent of the women had one or fewer medical risks during their pregnancy.

Child Characteristics

Children’s general intelligence was assessed using the Perceptual Reasoning Index (PRI) of the Wech- sler Intelligence Scale for Children (WISC–IV) with subscales of Matrix Reasoning, Block Design, and Picture Concepts. The PRI is relatively language free and culturally independent (Baron, 2004), and two of the subscales (Matrix Reasoning and Block Design) have strong and signiﬁcant correlations with general intelligence (Baron, 2004; Wechsler, 2002).

Maternal Assessments

Maternal perceptions of stress were evaluated using the well-validated and widely used 10-item version of Cohen’s Perceived Stress Scale (PSS;

Cohen, Kamarck, & Mermelstein, 1983), with strong internal consistency (a =.87–.90) during pregnancy, postpartum, and at the adolescent visit. Maternal prenatal perceived stress scores across gestation were moderately correlated (r values ranged from .31 to .78, p < .05), and PSS scores did not signiﬁ- cantly differ across the four prenatal time points (p values >.28). Thus, these prenatal scores were averaged to create a composite index of perceived stress during pregnancy. The Center for Epidemiological Studies Depression Inventory, which has good internal consistency (a = .84), was used to evaluate maternal depressive symptoms at the adolescent assessment (Santor & Coyne, 1997).

Child Assessments

MRI Acquisition. Structural MRI scans were acquired using a 3-T Philips Achieva system. Pad- ding was placed around the head to minimize head motion, and ear protection was given to all children. To further increase compliance and reduce motion, children were ﬁtted with headphones and allowed to watch a movie of their choice while in the scanner. Following the scanner calibration scans, a high-resolution T1 anatomical scan was acquired in the sagittal plane with 1 mm³ isotropic

voxel dimensions. An Inversion-Recovery Spoiled Gradient Recalled Acquisition sequence with the following parameters were applied: Repetition time = 11 ms, Echo time =3.3 ms, Inversion time = 1,100 ms, Turbo Field Echo factor = 192, Number of slices: 150, no SENSE acceleration, Flip angle= 18⁰. Acquisition time for this protocol was 7 min.

Measurement of Childhood Cortical Thickness Cortical surface reconstruction and thickness measurements were performed using Freesurfer stable release (Version 4.4.0; http://surfer.nmr.mgh.

harvard.edu) on the Linux workstation. The techni- cal details and its validities have been previously described (Fischl & Dale, 2000; Fischl et al., 2002).

Brieﬂy, the processing included intensity inhomo- geneity correction, removal of non-brain tissue, automated Talairach transformation, segmentation of subcortical white matter and deep gray matter regions, intensity normalization, tessellation of the gray and white matter boundary, automated correction of surface topology, surface deformation and inﬂation, transformation to a spherical atlas, and cortical parcellation. Cortical thickness at each surface location (i.e., node or vertex) was computed by the averaged distance (in millimeters) of the closest distance in either direction between pial and white matter surfaces. Cortical parcellation was based on the Desikan–Killiany atlas (Desikan et al., 2006), resulting in 34 cortical regions in each hemisphere.

Procedures for the measurement of cortical thickness have been validated with histological analysis (Rosas et al., 2002) and manual measurements (Salat et al., 2004). All images were visually inspected for processing errors (e.g., non-brain tissue removal, gray and white matter segmentation, and cortical parcellation), and manual corrections, if needed, were performed by one of authors (KH) as described on the Freesurfer web site. Of participants, 54% required such corrections predominantly to remove scull and dura matter. The reconstructed cortical surface model was resampled and concate- nated into a common space (i.e., fsaverage in Free- surfer), and smoothed with a 10-mm full width at half maximum Gaussian kernel.

Adolescent Assessments

Adolescents completed self-report measures of depressive symptoms using the 12-item self-report version of the second edition Children’s Depression Inventory (CDI–2; Kovacs, 2011). The CDI–2 has

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adequate internal consistency (a = .74) and has been validated and used extensively in previous research involving adolescents (Kovacs, 2011).

Data Analytic Plan

Consideration of covariates. Maternal (cohabita- tion with father, SES, race and ethnicity, age, and maternal perceived stress in the early postnatal period, at the time of MRI, and at the time of adolescent assessment with the CDI–2), obstetric (medical risk, birth weight percentile, and gestational age at birth), and child factors (age, sex, birth order, and child WISC PRI score) were evaluated as potential covariates. Potential covariate factors that were statistically associated with the predictor and outcomes (p < .10) were included in the models; other factors that did not achieve this threshold were dropped. Only maternal perceived stress at the time of assessment of child depressive symptoms met criteria for inclusion as a covariate. To rule out the alternative explanation that maternal depression accounted for any associations between prenatal stress and child depressive symptoms, we addition- ally conducted partial correlations considering maternal depressive symptoms at the time of adolescent assessment. Further, to thoroughly address the potential impact of third variables that did not meet statistical criteria we conducted sensitivity analyses and ran models that covaried theoretically relevant constructs (postpartum perceived stress, SES, birth outcome, and child WISC) as well as models that did not.

Prenatal maternal PSS and depressive symptoms in adolescence. Pearson correlations were employed to evaluate the relation between prenatal maternal perceived stress and adolescent depressive symptoms. Next, partial correlations were performed to determine if prenatal maternal perceived stress was associated with adolescent depressive symptoms at 12 years after considering relevant covariates as described above.

Prenatal maternal PSS and child cortical thickness. Regression analyses were employed (using FreeSurfer command line interface) to examine the association between the level of prenatal maternal perceived stress and the cortical thickness of children at 7 years by using age and sex as covariates, in which Pearson’s correlation coefﬁcient was used for the association measure. Initially, an uncorrected threshold of p < .001 was used for the vertex-wise signiﬁcances. The clusterwise Monte-Carlo simula- tions were used to correct for multiple comparisons (Hagler, Saygin, & Sereno, 2006). The method

simulates multiple null data sets and creates a distribution of cluster sizes for the desired corrected p value. In this study, we simulated 10,000 times for the null data set, and only clusters in which prenatal maternal PSS was associated with cortical thickness with corrected p < .05 were reported at the cluster level. After the cluster wise false discovery rate (FDR) corrections for multiple comparisons, the number of vertices with significant associations remaining was determined in each significant cluster in each region of the brain. The number of significant vertices for each cluster (identified based on analyses) was added and divided by the total number of vertices (9100) in that area to provide the percentage of the vertices in which cortical thickness was significantly associated with prenatal maternal perceived stress.

The Indirect Effect Model of Maternal PSS on Later Adolescent Depressive Symptoms and Associations With

Childhood Cortical Thickness?

To probe whether child neural systems associated with exposure to prenatal maternal perceived stress are a plausible mechanism associated with the relation between prenatal stress and adolescent depressive symptoms, we evaluated whether cortical thickness (identiﬁed regions of interest based on analyses described above) at 7 years was associated with adolescent depressive symptoms using Pear- son correlations. We focused on cortical thickness in frontal and temporal regions that were signiﬁ- cantly associated with prenatal maternal perceived stress. For regions that were associated with both prenatal maternal perceived stress and with child depressive symptoms, we used the PROCESS test of indirect effects for SPSS Version 24 (Model 4;

Hayes, 2013) to examine the indirect effect of prenatal maternal perceived stress on adolescent depressive symptoms in association with child cortical thickness. This was tested using 95% bias corrected Conﬁdence Intervals with bootstrapping procedures (5,000 bootstrap resamples; Preacher, Curran, &

Bauer, 2006; Preacher, Rucker, & Hayes, 2007).

Results

Is Prenatal Maternal Stress Associated With Depressive Symptoms in Adolescence?

Elevated levels of maternal prenatal perceived stress, averaged across pregnancy, were associated with higher adolescent depressive symptoms, r (74) = .36, p = .001. Signiﬁcant associations

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remained after covarying maternal perceived stress, partialr(71)= .24p = .044, and maternal depressive symptoms, partial r(71)= .26 p = .037, concurrent

with assessment of child depressive symptoms (see Figure 2). We then tested whether gestational timing affected the association with later child depressive symptoms. Child depressive symptoms were associated with prenatal maternal perceived stress across each of the four gestational intervals (r values ranging from .22 to .45, p values from .058 to .001). These ﬁndings suggest there is not an effect of timing, and thus, subsequent analyses focused on average maternal stress during the prenatal period.

Is Prenatal Maternal Perceived Stress Associated With Thickness of the Cortex in Childhood?

Elevated prenatal maternal perceived stress was associated with child cortical thickness. The association between prenatal maternal perceived stress and child cortical thickness, adjusting for age of the child and sex and after FDR correction for multiple comparisons, is presented in Figure 3. Overall, 10%

of the variance in child cortical thickness is associated with prenatal maternal perceived stress. Specif- ically, 11% of the frontal, 12% of the temporal, 8%

of the parietal, 5% of the cingulate limbic, and 8%

Figure 2. The relation between prenatal maternal perceived stress and depressive symptoms assessed with the Children's Depres- sion Inventory at 12 years of age for boys and girls.

Figure 3. Prenatal maternal perceived stress is associated with cortical thinning in childhood. Blue overlays indicate regions in which prenatal maternal perceived stress is signiﬁcantly associated with cortical thinness after false discovery rate (FDR) correction for multiple comparisons. Red overlays indicate regions in which prenatal maternal perceived stress is signiﬁcantly associated with cortical thickness after FDR correction for multiple comparisons.

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of the occipital cortices were statistically signiﬁ- cantly thinner after FDR correction in association with prenatal maternal stress. As shown in Table 2, children exposed to higher levels of prenatal maternal perceived stress across pregnancy had signiﬁ- cantly thinner cortices bilaterally in the superior frontal cortex, the parsopercularis, and the paracentral cortex. Thinner cortices in relation to exposure to prenatal maternal perceived stress also were

observed in the right frontal cortex, the rostral middle frontal cortex, caudal middle frontal cortex, pars triangularis, parsorbitalis, and lateral orbital frontal cortex. In the temporal cortex, prenatal maternal stress was associated with a thinner cortex bilaterally in the superior temporal cortex, middle temporal cortex, fusiform gyrus, and temporal pole and in the right inferior temporal cortex and left entorhinal cortex. In the parietal cortex, bilateral

Table 2

Percentage of Child Cortical Regions in the Frontal and Temporal Cortices That Are Thinner Based on Exposure to Prenatal Maternal Stress

Left hemisphere Right hemisphere

% R² b(p) 95% CI % R² b(p) 95% CI

Frontal

Superior frontal 7 .175 .418 (<.001) [ .023, .007] 18 .196 .443 (<.001) [ .024, .008]

Medial orbital frontal 0 — — — 2 — — —

Paracentral 27 .117 .342 (.003) [ .026, .006] 30 .185 .431 (<.001) [ .030, .010]

Rostral middle frontal 4 — — — 16 .159 .399 (<.001) [ .024, .007]

Frontal pole 0 — — — 37 .073 .270 (.020) [ .045, .004]

Pars triangularis 1 — — — 33 .120 .346 (.003) [ .029, .006]

Parsorbitalis 0 — — — 13 .051 .225 (.054) [ .037, .000]

Lateral orbital frontal 1 — — — 33 .113 .337 (.003) [ .036, .008]

Parsopercularis 8 .076 .276 (.017) [ .023, .002] 11 .099 .314 (.006) [ .022, .004]

Caudal middle frontal 0 — — — 14 .193 .439 (<.001) [ .025, .009]

Precentral 6 .130 .360 (.002) [ .023, .006] 6 .156 .395 (<.001) [ .024, .007]

Insula 2 — — — 5 .094 .307 (.003) [ .020, .003]

Temporal

Superior temporal 4 — — — 8 .142 .376 (.001) [ .024, .006]

Transverse temporal 0 — — — 0 — — —

Middle temporal 7 .096 .310 (.007) [ .025, .004] 15 .179 .423 (<.001) [ .025, .008]

Banks of the superior temporal sulcus 10 .087 .294 (.011) [ .030, .004] 6 .086 .294 (.011) [ .026, .004]

Inferior temporal 36 .149 .385 (.001) [ .032, .009] 8 .087 .295 (.011) [ .035, .005]

Fusiform 26 .209 .458 (<.001) [ .024, .009] 13 .140 .374 (.001) [ .027, .007]

Parahippocampal 4 — — — 0 — — —

Entorhinal 0 — — — 61 .084 .291 (.012) [ .045, .006]

Temporal pole 12 .039 .199 (.090) [ .063, .005] 7 .033 .181 (.122) [ .071, .009]

Parietal

Precuneus 10 .138 .372 (.001) [ .028, .007] 15 .173 .416 (<.001) [ .026, .009]

Postcentral 2 — — — 6 .105 .325 (.005) [ .033, .006]

Supramarginal 2 — — — 15 .209 .457 (<.001) [ .026, .010]

Superior parietal 18 .147 .383 (.001) [ .024, .007] 8 .146 .381 (.001) [ .043, .012]

Inferior parietal 4 — — — 5 .170 .412 (<.001) [ .022, .007]

Occipital

Cuneus 0 — — — 5 .063 .251 (.031) [ .028, .001]

Lingual 6 .119 .345 (.003) [ .037, .008] 0 — — —

Pericalcarine 0 — — — 0 — — —

Lateral occipital 21 .163 .403 (<.001) [ .026, .008] 7 .115 .339 (.003) [ .022, .005]

Cingulate

Rostral anterior cingulate 0 — — — 0 — — —

Caudal anterior cingulate 0 — — — 0 — — —

Posterior cingulate 15 .150 .387 (.001) [ .027, .008] 4 — — —

Isthmus of cingulate gyrus 10 .074 .273 (.019) [ .037, .003] 0 — — —

Note. Effect size (R²) also presented for each signiﬁcant association.

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associations were observed in the precuneus and the superior parietal cortex, and in the right postcentral, supra marginal, and superior and inferior parietal cortex. In the occipital cortex, bilateral associations were observed in the lingual and the lateral occipital cortex. These clusters were considered regions of interest for subsequent analyses examining associations with adolescent depressive symptoms. Less than 1% of the cortex was thicker in association with elevated prenatal maternal stress.

Sensitivity analyses testing theoretically relevant variables that did not meet criteria as covariates (i.e., postpartum PSS, birth outcome, and SES) showed that inclusion of these variables in the

regression models did not alter the study ﬁndings (see Table S2).

Is Childhood Cortical Thickness Correlated With Both Prenatal Maternal Stress and Adolescent Depressive

Symptoms?

First, the relation was evaluated between the identified regions of interest (cortical areas identified in childhood as associated with prenatal maternal perceived stress) and subsequent adolescent depressive symptoms. Frontal regions of interest where childhood cortical thickness was significantly associated with adolescent depressive symptoms

Figure 4. Thisﬁgure depicts scatter plots as illustrative examples of the relation between prenatal maternal perceived stress with child cortical thickness and child cortical thickness with adolescent depression symptoms. The top panel shows the relation between prenatal maternal perceived stress and left (A) and right (B) superior frontal thickness and the bottom panel shows the relation between child depression symptoms and left (C) and right (D) superior frontal thickness.

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included the superior frontal cortex, leftr(72)= .24, p = .038; rightr(72) = .29,p = .011, and pars striatal frontal cortex, left r(72) = .27, p = .019; right r (72)= .37,p = .001, bilaterally and the right rostral middle frontal cortex, right r(72)= .25, p = .034, and right precentral gyrus, right r(72)= .26, p = .027. Temporal regions of interest that were sig- niﬁcantly thinner in association with adolescent depressive symptoms included the middle temporal cortex bilaterally, left r(72)= .23, p = .046; right r (72)= .21, p = .073, the right superior temporal, right r(72)= .27, p = .022, fusiform, r(72)= .29, p = .013, and the right entorhinal, rightr(72)= .25, p = .029, cortex. The left precuneus was the only parietal region of interest associated with adolescent depressive symptoms, left r(72)= .23, p = .048.

Thus, during childhood these regions were associated both with prenatal maternal stress and with adolescent depressive symptoms. Figure 4 depicts scatters plots as illustrative examples of the relation between prenatal maternal perceived stress and child cortical thickness, and child cortical thickness and adolescent depression symptoms.

For regions of interest that were associated both with prenatal maternal perceived stress and adolescent depressive symptoms, we evaluated whether the statistical model was consistent with the possibility that cortical thickness partially mediates the association between prenatal maternal stress and adolescent depressive symptoms by running the test of indirect effects (see Table 3). Bilaterally, tests of indirect effects were consistent with the possibility that average thickness of the superior frontal cortex partially mediates the association between prenatal stress and adolescent depressive symptoms, although this analysis fell just short of con- ventional statistical signiﬁcance. We then followed up these analyses by evaluating the speciﬁc clusters

[Brodmann’s Areas (BA) 6 and 10] within the superior frontal cortex that were associated with prenatal maternal stress after FDR correction and adolescent depressive symptoms. These analyses are consistent with the possibility that the link between prenatal maternal perceived stress and later adolescent depressive symptoms may be partially mediated by an association with thickness of the identiﬁed clusters in BA6 and 10 within the superior frontal cortex (see Table 3). In summary, the statistical test of indirect effects evaluating the pattern of associations is consistent with the possibility that cortical thickness in BA6 and BA10 of the superior frontal cortex is part of the pathway by which prenatal maternal stress is associated with adolescent depressive symptoms. Test of indirect effects were not statistically signiﬁcant for any of the temporal or parietal regions.

Sex Differences

There was not a signiﬁcant sex difference for youth report of depressive symptoms,t(72)= .83,p = .409.

The magnitude of the correlation between prenatal maternal stress and adolescent depressive symptoms was stronger among girls compared to boys, r (32) = .50,p = .003 vs.r(38)= .21, p = .198 for boys, but sex did not signiﬁcantly moderate the association between prenatal maternal stress and adolescent depressive symptoms or the association between prenatal maternal stress and child cortical thinning (allp values > .10).

Discussion

Depression is a neurodevelopmental phenomenon that unfolds across the life span (Hankin, 2012).

Early stress is one of the strongest predictors of later depression, and rates of depression surge from childhood into late adolescence (Hankin, 2012). The present study applied a neurodevelopmental risk framework for depression over an extended period from pregnancy through early adolescence. Results show that fetal exposure to prenatal maternal stress is associated with reduced cortical thickness during childhood, with the strongest associations observed in frontal and temporal regions. Moreover, statistical tests of indirect effects were consistent with the possibility that reduced cortical thickness during childhood, in a few regions of the frontal cortex (BA6 and 10), may partially mediate associations between maternal prenatal stress and adolescent depressive symptoms.

Table 3

Indirect Effects of Prenatal Maternal Perceived Stress on Adolescent Depression Symptoms Through Child Cortical Thinness in the Supe- rior Frontal Cortex

Location

Left hemisphere Right hemisphere Indirect

effect 95% CI

Indirect

effect 95% CI Superior frontal

(total)

.03^† [ .02, .10] .05^† [ .02, .12]

BA 10 .04^* [.01, .12] .07^* [.09, .16]

BA 6 .20^† [ .05, .09] .30^* [.001, .08]

Note. BA=Brodmann’s Areas.

†p<.10. *p<.05.

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We investigated the relation between prenatal stress and childhood cortical development as a plausible mechanism that may contribute to subsequent adolescent depressive symptoms. Our ﬁnd- ings are consistent with existing research that has examined components of the neurodevelopmental risk model. First, the present ﬁndings complement published studies illustrating that prenatal exposure to maternal distress, including anxiety and depression, is associated with elevated depressive symptoms during adolescence (O’Donnell et al., 2014;

Van den Bergh et al., 2008). Second, results are in line with ﬁndings indicating that prenatal maternal distress is associated with childhood brain structure and function (Lebel et al., 2016; Mennes et al., 2006;

Sandman et al., 2015), and that prefrontal and temporal regions are particularly susceptible to the inﬂuence of early life stress (Pechtel & Pizzagalli, 2011). Third, the observed pattern of associations between reduced cortical thickness primarily in PFC and temporal regions and elevated depressive symptoms are concordant with the existing literature evaluating the neural correlates of depression (Schmaal et al., 2017). Fourth, consistent with prior published research (e.g., Peterson & Weissman, 2011) associations were stronger for the right as compared to the left hemisphere.

Cortical thinning is a normative childhood developmental process that is ongoing during middle childhood, the time we assessed cortical thickness (Muftuler et al., 2011; Sowell et al., 2004). The current analyses, which adjusted for age, illustrate prenatal maternal stress is associated with less thickness in the cortex. It is possible that the decreasing cortical thickness observed in this developmental stage is accelerated by exposure to prenatal stress. Because children were only imaged once, trajectory of cortical thickness cannot be identiﬁed, and it is plausible that the cortex was thinner due to perturbations of earlier developmental processes.

Our ﬁndings are consistent with longitudinal research with multiple scans showing that greater decreases in cortical thickness from childhood through adolescence are associated with emergence of depression (Luby et al., 2016). Structurally, the cerebral cortex is likely less thick as a result of reduction in the density of connections between neurons, decreased dendritic arbor of neurons, or decreased myelination of axons that lie within gray matter (B. Jacobs, Schall, et al., 2001), it and is possible that these processes may be inﬂuenced by prenatal maternal stress.

The mechanistic pathways by which prenatal maternal stress inﬂuences the fetal brain remain

elusive. It is possible that prenatal maternal stress exposes the fetal brain to elevated levels of stress responsive hormones, including maternal cortisol and placental corticotropin releasing hormone (CRH). The fetal cortex is sensitive to prenatal maternal distress and has an abundance of glucocorticoid receptors (Teicher et al., 2003). In animal research, fetal exposure to elevated cortisol mediates the impact of prenatal maternal stress and impacts cortical development (Barbazanges, Piazza, Le Moal, & Maccari, 1996; Tauber et al., 2006).

Experimental rodent models demonstrate that decreased dendritic spine development is a possible mechanism by which prenatal stress and elevated stress hormone exposure impact fetal brain development (Curran, Sandman, Davis, Glynn, & Baram, 2017; Liston & Gan, 2011; Liston et al., 2006). For example, in vitro administration of a stress responsive hormone CRH causes a reduction in dendritic branching in immature cortical neurons (Curran et al., 2017). Further, elevated cortisol concentra- tions impact the myelination of white matter tracks plausibly contributing to decreased cortical thickness (Raschke, Schmidt, Schwab, & Jirikowski, 2008). Although, these stress responsive hormones during pregnancy are associated with human brain development (e.g., Davis, Sandman, Buss, Wing, &

Head, 2013; Sandman et al., 2018), it is important to note that during pregnancy the associations between prenatal maternal experiences of stress and stress hormones are modest (Davis & Sandman, 2010; de Weerth & Buitelaar, 2005). Monk et al.

(2016) suggest that epigenetic changes in DNA methylation of glucocorticoid-related genes in the placenta may be a pathway by which prenatal maternal perceived stress inﬂuences the fetus. They found that higher maternal PSS was related to DNA methylation of glucocorticoid-related genes, and further, these changes partially mediated the relation between maternal PSS and fetal neurodevelopment. Consistent with this possibility, prenatal maternal distress is associated with increased methylation of the glucocorticoid receptor gene in infant as well as increased infant cortisol responses to stress (Oberlander et al., 2008). Observational studies such as ours cannot address causal mechanisms. However, it is plausible that maternal experience of prenatal stress acts via these stress systems to disrupt development of neural processes in the fetus and contributes to cortical development resulting in a developmental trajectory associated with decreased cortical thickness, particularly in stress sensitive brain regions (McEwen et al., 2015;

Pechtel & Pizzagalli, 2011).

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There are substantial connections between stress systems and areas of the brain that have been associated with depression. Decreased cortical thickness and reduced cortical volume are associated with elevated depressive symptoms (Peterson & Weiss- man, 2011; Peterson et al., 2009). Such evidence is observed in association with current symptom severity in adults (Tu et al., 2012), among children exposed to elevated maternal depressive symptoms during pregnancy (Sandman et al., 2015) or childhood (Lupien et al., 2011), and in individuals who are not ill but have familial risk for depression (Peterson et al., 2009). Among children with clinical depression, accelerated cortical thinning has been observed from childhood through adolescence (Luby et al., 2016). Our ﬁndings regarding those brain regions associated with later adolescent depressive symptoms that also showed relations with earlier prenatal stress are consistent with the broader literature on reduced cortical thickness in depression. Speciﬁcally, decreased thickness in the superior frontal cortex has been noted (Schmaal et al., 2017), as has the precentral gyrus (Foland- Ross et al., 2015), rostral middle frontal (Schmaal et al., 2017), middle temporal (Miller et al., 2015;

Schmaal et al., 2017), superior temporal (Schmaal et al., 2017), and left precuneus (Schmaal et al., 2017).

Few studies have longitudinally examined the relation between childhood brain development and the emergence of subsequent depressive symptoms in adolescence (Vulser et al., 2015; Whittle et al., 2014), and indeed, recent reviews have explicitly called for prospective investigations linking together neural risk to the development of psychopathology (Horga et al., 2014). We cannot rule out the possibility that depressive symptoms emerged prior to adolescence. Nonetheless, the present results add to a small but growing literature demonstrating an association between child brain and subsequent elevated individual differences in adolescent depressive symptoms. Frontal regions, including bilateral superior frontal, bilateral pars striatal frontal, and right rostral middle frontal cortex, and precentral gyrus, as well as temporal regions including bilateral middle temporal cortex, right superior temporal cortex, fusiform, and entorhinal cortex, and the parietal cortex, speciﬁ- cally the left precuneus, have lower cortical thickness among children who were exposed to elevated prenatal stress, and these regions were prospectively associated with elevated depressive symptoms during adolescence. These cortical regions are involved in cognitive control of affect (Levesque

et al., 2003; Ochsner et al., 2004; Phan et al., 2005) and in face processing, recognition, and emotional memories (Dolcos, LaBar, & Cabeza, 2005; Herring- ton, Taylor, Grupe, Curby, & Schultz, 2011). In cor- relational studies such as this one, causal relations cannot be determined. However, in concert with the neurodevelopmental risk hypothesis, the observed associations may suggest that cortical thickness in these regions may contribute to risk for later depression (De Raedt & Koster, 2010; Snyder, Miyake, & Hankin, 2015).

Previous research indicates asymmetry in the neural systems believed to be most relevant in associations with depression. Depression is more likely to result after a stroke, or other lesion, occurring in the left hemisphere, especially left frontal region, compared to the right (Robinson & Starkstein, 1989). Various lines of research, including observ- able facial expressed emotion and psychophysiolog- ical assessments electroencephalography converge to show that depression, as well as negative emotions and symptoms commonly afﬁliated with depression, especially sadness, and disgust, are sig- niﬁcantly more associated with right-sided brain activation, whereas positive emotions are more related with left-sided brain activity (Davidson, 1992; Davidson, Ekman, Saron, Senulis, & Friesen, 1990; Henriques & Davidson, 1990). This corpus of research has been explained via individual differences in affective style, such that right frontal brain regions are more associated with negative affect, withdrawal, and behavioral inhibition, and left frontal brain regions relate to positive affect and approach such that low positive affect (e.g., anhe- donia) can constitute a risk to depression (David- son, 1998; Sutton & Davidson, 1997). Such brain asymmetries consistent with individual differences in affective style and depression have been found in adolescents (Tomarken, Dichter, Garber, &

Simien, 2004), children (Shankman et al., 2005), and infants of depressed mothers (Lusby, Goodman, Yeung, Bell, & Stowe, 2016). Further, depressed individuals and individuals with a family history of depression show decreased cortical thickness in the right cerebral cortex as compared to the left (Diener et al., 2012; Peterson et al., 2009; Tu et al., 2012).

Other studies with large samples (e.g., Schmaal et al., 2017) and meta-analytic reviews (e.g., Zhang et al., 2016) similarly show stronger associations with thickness in right frontal brain regions as compared to left regions. The observations in the present study with children similarly show stronger associations among prenatal stress, child cortical thickness, and adolescent depressive symptoms for

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the right hemisphere. These ﬁndings are consistent with the existing hypothesis that decreased cortical thickness in the right hemisphere is a neural signa- ture indicating vulnerability to subsequent depression (Peterson & Weissman, 2011), although this possibility cannot be fully tested in the present investigation.

Statistical tests of indirect effects are consistent with the possibility that cortical thickness in superior frontal regions BA6 and 10 partially mediates the relation between prenatal maternal stress and adolescent depressive symptoms. BA6 is located in the posterior superior frontal cortex. Meta-analytic evidence (Diener et al., 2012) indicates that among depressed adults hyperactivity of BA6 is observed during executive control tasks and tasks involving emotional processing (especially of negative mood).

BA10 comprises the most anterior portion of the PFC and is thought to play a role in executive func- tions including reasoning and problem solving as well as contributing to social cognition (see Gilbert et al., 2006 for meta-analysis). It may be that BA6 and 10 are the primary association between prenatal stress and adolescent depressive symptoms. At the same time, our findings showed other frontal, temporal, and parietal regions that were associated with both prenatal stress and subsequent adolescent depressive symptoms, although these neural areas did not meet formal significance tests for indirect effects. In this study, depressive symptoms were assessed around age 12, which is relatively early in the developmental trajectory of rising depression levels, as depression rates tend to increase from middle to late adolescence (Hankin, 2012). It may be that as levels of depressive symptoms increase over the course of adolescence, additional frontal and temporal regions associated with prenatal stress and early adolescent depressive symptoms would be confirmed as significant statistical media- tors; future follow-up is needed to examine this possibility. Further, we cannot rule out the possibility that depressive symptoms were present prior to the associations with cortical thickness observed at 12 years of age.

Intriguing and suggestive findings were observed with sex, prenatal stress exposure, cortical thickness, and depressive symptoms. Past research has shown that more girls than boys begin to exhi- bit a significantly higher rate of depression starting after ages 12–13 (Hankin et al., 1998, 2015; Salk, Hyde, & Abramson, 2017). Our findings showing no significant gender difference in self-reported depressive symptoms at age 12 are consistent with this developmental epidemiological and emergence

of sex differences in depression literature. Although no mean level sex difference was observed, our results revealed a tendency for a stronger association (larger effect size) between prenatal maternal stress and adolescent depressive symptoms among girls relative to boys. Such an association is consistent with the hypothesis that female fetuses may be more susceptible to the impact of prenatal maternal stress signals on subsequent psychopathology (Davis & Pfaff, 2014; Sandman, Glynn, & Davis, 2013). Male and female fetuses respond differently to early signals of adversity (Clifton, 2010; Glynn &

Sandman, 2012). Boys are significantly more vulnerable to threats to viability throughout gestation, in part due to the accelerated growth of the male as compared to the female fetus (Clifton & Murphy, 2004). In contrast, the female fetus is more responsive to stress signals and is able to adapt its growth trajectories, possibly allowing the female fetus to adapt to intrauterine adversity increasing the likeli- hood of survival (Clifton, 2010). The more nuanced responses of the female fetus to early adversity clearly benefits survival but also may be associated with consequences that emerge later in development (Kim et al., 2016; Sandman et al., 2013). In the present sample, sex did not significantly moderate the association between prenatal maternal perceived stress and adolescent depressive symptoms. How- ever, consistent with the hypothesized greater female vulnerability, the effect size for this relation was stronger among girls as compared to boys, and thus, it is plausible that greater gender asymmetry will emerge as children progress from early to late adolescence.

There are several strengths and limitations of this study that inform interpretation of ﬁndings.

Because this study relied on naturally occurring variations in maternal stress, rather than experimental manipulations, it is not possible to fully sep- arate the effects of prenatal maternal stress from the consequences of other factors that might contribute to this association, including genetic factors or postnatal experiences. Study designs involving children conceived by in vitro fertilization who were not genetically related to their mothers, or research on monozygotic twins who differ as to whether they share a placenta, indicate that the prenatal environment contributes to subsequent child development beyond effects of genetics (N. Jacobs, Van Gestel, et al., 2001; Lewis, Rice, Harold, Collishaw, & Tha- par, 2011). Also, experimental designs that seek to reduce maternal prenatal stress and distress can be used to examine later outcomes and processes in offspring neurodevelopment and risk to

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psychopathology (Davis, Hankin, Swales, & Hoff- man, 2018). We showed that aspects of the child’s postnatal environment, such as maternal perceived stress, maternal depression, and SES do not account for study findings. Although thesefindings suggest an association between prenatal maternal stress and child outcomes, observational designs such as this one cannot fully distinguish between prenatal and postnatal influences. A key strength of the study is that mother–child pairs were assessed using a longitudinal within person design in which prenatal stress, child brain, and adolescent depressive symptoms were measured over a 13-year period from pregnancy through early adolescence and in a nonclinically ascertained sample. Of note, the range distribution of the CDI–2 in the present sample is consistent with that observed and reported in the norming and validation sample for the CDI–2 (Kovacs, 2011). Further, this study addresses a limi- tation of literature relying on maternal report of her own mental health as well as child internalizing problems by directly assessing depressive symptoms via self-report.

A growing literature provides support for the hypothesis that fetal experiences have long-lasting consequences for mental health, yet few studies have longitudinally evaluated plausible biological mechanisms. The present application of the neurodevelopmental risk model tested via associational analyses, suggests a possible pathway by which prenatal stress is associated with adolescent depressive symptoms.

Evidence that prenatal stress exposure may inﬂuence the trajectory of brain development may indicate an opportunity for very early intervention to alter pro- ﬁles of neural development and perhaps improve subsequent mental health.

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