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. 2025 Aug 2;35(5):e70028. doi: 10.1002/hipo.70028

Evidence of Disrupted Hippocampal Gray‐ and White‐Matter Development in Adolescent Anxiety Disorders, Independent From Early‐Life Stress

Karina Pedroza‐Sotelo 1, Hillary Schwarb 1,2, Randy P Auerbach 3, Satrajit S Ghosh 4,5, Aude Henin 6,4, Stefan G Hofmann 7, Diego A Pizzagalli 4,8, Anastasia Yendiki 4,9, Susan Whitfield‐Gabrieli 4,5,10, John D E Gabrieli 10, Nicholas A Hubbard 1,2,✉
PMCID: PMC12317425  PMID: 40751564

ABSTRACT

Early‐life stress and depression among youths are linked to hippocampal gray‐ and white‐matter alterations. Less is known about hippocampal alterations in adolescent anxiety disorders (Anx) or the role that stress or comorbid depressive disorders (Anx + Dep) might play. Here, structural‐ and diffusion‐MRI along with early‐life stress‐exposure reports were acquired from 197 adolescents (13.58–17.00 years) with Anx, Anx + Dep, and those without (Controls). A normative model externally validated on a large, healthy sample revealed that Anx were more likely than Controls and Anx + Dep to exhibit undersized hippocampal gray‐matter volumes for their ages. Volume reductions among Anx were further localized to subfield CA1. No significant gray‐matter differences were observed between Anx + Dep and Controls. Standardized probabilistic tractography in hippocampal white‐matter pathways demonstrated that, relative to Controls, Anx and Anx + Dep exhibited lower fractional anisotropy specifically in the cingulum‐temporal branch. All effects were specific to hippocampal structures. Group differences were not accounted for by early‐life stress exposures, despite Anx and Anx + Dep reporting more than Controls. Findings indicated that gray‐matter expansion, principally within CA1, may be disrupted among adolescents with anxiety disorders, but not those with comorbid depression. The progressive strengthening of hippocampal‐cortical circuits occurring during adolescence may also be disrupted in adolescents with anxiety disorders, regardless of depression.

Keywords: adolescence, anxiety, depression, development, early‐life stress, hippocampus

Cognitive processes supported by the hippocampus, like the retrieval of contextual‐fear memories, make it a critical target for understanding the neurodevelopment of anxiety and depressive disorders (Ghasemi et al. 2022; Patel et al. 2019). Structural alterations related to early‐life stressors or trauma, such as hippocampal gray‐matter atrophy and reduced fractional anisotropy (FA) in hippocampal white‐matter pathways, have been shown to predict future depressive episodes and symptoms during adolescence (Huang et al. 2012; Rao et al. 2010; Weissman et al. 2020). These and other findings suggest that hippocampal structural alterations might not be directly tied to having depression itself, but rather reflect stress‐related biological vulnerabilities for new or worsening depression (Paquola et al. 2016). Less is known about hippocampal structural alterations in adolescent anxiety disorders (Anx) or the roles that early‐life stress or comorbid depressive disorders (Anx + Dep) might play in these alterations.

Studies on youth Anx have shown hippocampal alterations consistent with those related to early‐life stress exposures and adolescent depression, such as gray‐matter atrophy (Gold et al. 2017; Mueller et al. 2013). The extent to which stress or comorbid depression could account for these alterations is unclear. For instance, while some studies link early‐life stress exposures to both anxiety and reduced hippocampal gray‐matter volumes (Gorka et al. 2014), others fail to show evidence that could support this link (Lipschutz et al. 2024). Further, early‐life stress exposures have been shown to account for hippocampal atrophy observed in adults with depressive disorders (Paquola et al. 2016). However, it is not known whether these exposures would similarly drive hippocampal alterations among adolescents with Anx + Dep or their peers with Anx alone.

Adolescence is a remarkable period for hippocampal development. Hippocampal gray matter continues to expand into one's mid‐ to late teens, and its major white‐matter pathways strengthen (e.g., show increasing FA) until young adulthood (Dick et al. 2022; Keresztes et al. 2017; Lebel and Beaulieu 2011; Tamnes et al. 2018). Here, our guiding hypothesis was that these maturational processes are disrupted in Anx and Anx + Dep (cf. Gold et al. 2017; Huang et al. 2012; Mueller et al. 2013). Thus, we predicted that adolescents with Anx (n = 54; current Anx, no depressive disorder history) and Anx + Dep (n = 75; current Anx and past or current depressive disorder) would exhibit smaller hippocampal gray‐matter volumes and lower FA in major hippocampal white‐matter pathways compared to controls (n = 63; no past or current history of Anx or depressive disorders). It is possible that such effects would reflect greater exposure to early‐life stressors among those with anxiety and/or depressive disorders (LeMoult et al. 2020; ter Meulen et al. 2021). Consequently, if early‐life stress exposures were the determining factor for hippocampal structural alterations in adolescents with Anx or Anx + Dep, controlling for these was expected to eliminate structural differences observed between those adolescents compared to Controls (Opel et al. 2014; see Paquola et al. 2016).

We examined data from 192 adolescents passing quality‐assurance protocols and providing T1‐ and T2‐weighted, as well as diffusion‐weighted images, as part of a Human Connectome Project of adolescent anxiety and depression (M age = 15.43 [range: 13.58–17.00]; 65% Female). See Supporting Information (SI) for detailed group characteristics. Image acquisition, quality assurance, preprocessing, and clinical protocols are described elsewhere and briefly in the SI (Hubbard et al. 2020, 2024; Siless et al. 2020).

Where indicated, one‐tailed tests were used for clinical‐ and control‐group comparisons consistent with our directional hypotheses. Two‐tailed tests were used for all other analyses. We had no hypotheses regarding lateralization, and bilateral hippocampal volumes were strongly correlated across all groups (see SI); thus, all tests examined bilateral averages. Early‐life stress was operationalized using chronic‐stress exposures—the total number of stressors (lasting at least 1 month) adolescents reported experiencing during their lifetimes (via STRAIN; Slavich et al. 2019; see SI). Chronic‐stress exposures were included as covariates in multiple regressions to determine their impact on observed Group differences (Opel et al. 2014; see Paquola et al. 2016). Anx and Anx + Dep adolescents reported significantly more chronic‐stress exposures (as well as acute‐stress exposures) relative to Controls (ps < 0.05; see SI). Medication status did not alter the significance of primary findings (see SI).

We first tested the relative likelihood of Anx and Anx + Dep adolescents exhibiting smaller total hippocampal volumes than what would be expected in typical development using a predictive model optimized on a large and diverse, healthy sample (via CentileBrain; Ge et al. 2024; see SI). This afforded explicit evaluation of volumetric differences in the context of typical neurodevelopment. Specifically, normative‐deviation scores obtained from this pretrained model (z = [Actual vol. – Predicted vol.]/RMSE pretrain_model) quantified the extent to which each adolescent exhibited smaller or larger hippocampal volumes than expected for their age, sex, and head size. A binary variable distinguished adolescents who exhibited smaller‐than‐expected hippocampal volumes from those who did not (cf. Grice et al. 2020) via thresholding normative‐deviation scores falling at or below a moderate negative effect (z ≤  −0.50). Thus, adolescents below this threshold exhibited hippocampal volumes that were at least moderately small based upon normative developmental expectations—operationalized here as undersized.

Anx adolescents were more likely to exhibit undersized hippocampi compared to Controls (Figure 1). Surprisingly, no such effects were observed when comparing Anx + Dep and Controls, and Anx adolescents were more likely to exhibit undersized hippocampi than those with Anx + Dep (Figure 1). Specificity was examined by testing a proximal region also relevant to anxiety and depression, as well as sharing a similar developmental trajectory with hippocampi (i.e., amygdala). The odds of undersized amygdalae were not significantly different between groups (ps > 0.05; see SI). Anx adolescents were also significantly more likely to exhibit undersized hippocampi than undersized amygdalae (p > 0.05; see SI).

FIGURE 1.

FIGURE 1

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Proportion of adolescents with normatively undersized total hippocampal gray‐matter volumes. aAnx more likely than Controls to exhibit undersized hippocampi, p = 0.002. bAnx more likely than Anx + Dep to exhibit undersized hippocampi, p = 0.027. cAnx + Dep not found to be more likely than Controls to exhibit undersized hippocampi, p = 0.266. Anx = anxiety disorders, Anx + Dep = anxiety and comorbid depressive disorders, Control = no anxiety‐ or depressive‐disorder history. OR = odds ratio [CI95], **p  ≤ 0.01, *p  ≤ 0.05, ns = p > 0.05.

A multivariate logistic regression (χ2 = 12.50, p = 0.006) indicated that Anx adolescents were still more likely to exhibit undersized hippocampi compared to controls (ORadj = 2.92 [CI95: 1.24–6.88], p = 0.015) and Anx + Dep (ORadj = 2.87 [CI95: 1.29–6.40], p = 0.010) despite controlling for chronic‐stress exposures, which were not significant in the model (β = 0.287, p = 0.144). Testing effects of acute‐stress exposures (lasting only a few days) and a composite index of socioeconomic status (SES) yielded similar results (see SI).

Cornu ammonis (CA) subfields and dentate gyrus (DG) were delineated to localize subregional volume reductions, which may also afford greater sensitivity to detect effects of depression and early‐life stress (Roddy et al. 2019; Teicher et al. 2012). Subregions were delineated using a pretrained neural network and a manually labeled histological atlas (via Hippunfold; DeKraker et al. 2022; see SI). Average volume within bilateral CA1, CA3, and a combined CA4‐DG subregion was investigated (Figure 2A). CA2 was not examined due to its modest size, and it was not combined with other regions given its distinct functions (see Kay and Frank 2019; SI). Volume estimates were residualized, controlling for sex, age, total intracranial volume, and alignment with the hippocampal template (see SI). Bonferroni corrections limited family‐wise error rate for primary tests of Group effects across the three subregions.

FIGURE 2.

FIGURE 2

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(A) Subregion masks from example adolescent. Top: Cropped and upscaled sagittal mask images from Hippunfold workflow (0.2 mm3 isotropic voxel; margin outline added for contrast). Bottom: Axial images resampled back to native resolution (0.8 mm3 isotropic voxel) for masks used in analyses. Figures S1–S3 for additional images. (B) Means and standard errors of bilateral CA1 volume residualized z‐scores; no significant differences observed for CA3 or CA4‐DG (see SI). aAnx smaller CA1 volumes than controls, one‐tailed p corrected = 0.041. bAnx smaller CA1 volumes than Anx + Dep, p corrected = 0.039. cAnx + Dep not found to have smaller CA1 volumes than Controls, one‐tailed p corrected = 0.582. Anx = anxiety disorders, Anx + Dep = anxiety and comorbid depressive disorders, Control = no anxiety‐ or depressive‐disorder history. d = Cohen's d effect size, *p corrected  ≤ 0.05, ns = p corrected > 0.05.

Anx adolescents exhibited smaller CA1 volumes compared to Controls and their peers with Anx + Dep (Figure 2B). Significant differences were not observed between Anx + Dep and Controls (Figure 2B). Group effects were not significant for CA3 or CA4‐DG (pscorrected > 0.05; see SI). Group effects on CA1 volume remained consistent without residualizing for alignment with the hippocampal template, and while residualizing CA1 volumes for adolescents' pubertal maturation stage, as well as while residualizing for CA3 and CA4‐DG volumes (see SI).

Multiple regression on CA1 (F = 2.88, p = 0.037) demonstrated that Anx adolescents still exhibited trending effects of smaller volumes than Controls (d adj = −0.319, one‐tailed p = 0.055) and significantly smaller volumes than Anx + Dep adolescents (d adj = −0.506, p = 0.009) despite controlling for chronic‐stress exposures, which were not significant in the model (β = −0.129, p = 0.150). Findings were similar for acute‐stress exposures and SES, except SES showed a significant relationship with CA1 volumes (see SI).

The microstructural properties of two major hippocampal white‐matter pathways were examined using diffusion‐weighted images and standardized probabilistic tractography (via xtract; Warrington et al. 2020; see SI). FA was averaged within the bilateral fornix and the temporal branch of the cingulum bundle (CB‐T; Figure 3A). FornixFA and CB‐TFA T FA were residualized, controlling for age and sex. Bonferroni corrections limited the family‐wise error rate for primary tests of group effects across the two tracts.

FIGURE 3.

FIGURE 3

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(A) Fornix and temporal branch of the cingulum bundle (CB‐T) sample‐wide reconstructions used to evaluate group effects on fractional anisotropy (FA). Top: Volumes from Desikan–Killany atlas illustrate hippocampus proximity to fornix (dorsal) and CB‐T (ventral). Masks were smoothed for display. (B) Means and standard errors of bilateral CB‐TFA residualized z‐scores; no significant differences observed for FornixFA (see Main Text). aAnx lower CB‐TFA than Controls, one‐tailed p corrected = 0.002. bAnx and Anx + Dep not found to differ in CB‐TFA, p corrected = 0.553. cAnx + Dep lower CB‐TFA than Controls, one‐tailed p corrected = 0.025. Anx = anxiety disorders, Anx + Dep = anxiety and comorbid depressive disorders, Control = no anxiety‐ or depressive‐disorder history. d = Cohen's d effect size, **p corrected  ≤ 0.01, *p corrected  ≤ 0.05, ns = p corrected > 0.05.

Anx and Anx + Dep adolescents exhibited significantly reduced CB‐TFA compared to Controls (Figure 3B). No such effects were observed for FornixFA (d range = −0.232–0.021, one‐tailed pscorrected > 0.05) and, unlike hippocampal gray matter, no significant differences were observed between Anx and Anx + Dep adolescents in CB‐TFA (Figure 3B) or FornixFA (d = −0.254, p corrected = 0.314). Group effects on CB‐TFA retained significance while residualizing FA estimates for adolescents' pubertal maturation stage (see SI). Tests of other cingulum branches further confirmed the specificity of these effects for CB‐T (see SI). Multiple regression (F = 4.23, p = 0.006) indicated that the CB‐TFA reductions observed for Anx (d adj = −0.680, one‐tailed p < 0.001) and Anx + Dep adolescents (d adj = −0.579, one‐tailed p = 0.004) compared to Controls retained significance despite controlling for chronic‐stress exposures, which were not significant in the model (β = 0.105, p = 0.232). Findings were similar for acute‐stress exposures and SES (see SI).

Our findings showed that adolescents with Anx were more likely than controls to exhibit undersized hippocampi for their respective ages. Although newly examined here through the lens of normative development, this finding was broadly consistent with extant work (Gold et al. 2017; Mueller et al. 2013). Reduced gray‐matter volumes were further localized to CA1. Preclinical evidence underscores this area's influence in regulating anxiogenic processes, like fear generalization and threat anticipation (Ratigan et al. 2023; Wu et al. 2017), indicating that CA1 atrophy or maturational disruptions could play a mechanistic role in the development or maintenance of Anx.

Although adolescent Anx was related to reduced hippocampal gray matter, these effects might have been masked for those with current depression; perhaps, via inflammation (see Colasanto et al. 2020). Some findings have shown that youths' current depressive symptoms, but not their anxious symptoms or traits, were related to larger hippocampal volumes (Smolker et al. 2022). Adults with Anx + Dep were also characterized by increased mean diffusivity within CA1 and other subfields compared to their peers with Anx alone (Cha et al. 2016), indicating possible differences in hippocampal gray‐matter inflammation. Reexamination of our findings demonstrated that the gray‐matter reductions observed for Anx adolescents compared to those with Anx + Dep were only significant when compared to Anx + Dep adolescents with current, but not past, depressive diagnoses (see SI). While this indicates that concurrent depression influenced these differences, more targeted approaches are needed to determine the contribution of inflammation or other potential mediators.

Adolescents with Anx and those with Anx + Dep exhibited lower FA compared to Controls within major hippocampal‐cortical (i.e., CB‐T), but not subcortical (i.e., fornix) or other cingulum, white‐matter pathways. CB‐T is the nexus for hippocampal communication with posteromedial cortical areas (Bubb et al. 2018). This communication is key for autobiographic‐ and episodic‐memory construction (Ritchey and Cooper 2020), signifying the prospect of CB‐T circuits bearing transdiagnostic relevance to depressive and anxiety disorders. Indeed, persistent negative thoughts concerning one's self that are used to construct past (i.e., rumination) or simulate future (i.e., worry) events are cardinal features of depression and anxiety, and both presumably involve dysregulation of hippocampal and posteromedial communication (e.g., Burkhouse et al. 2017; Figueroa et al. 2017; see Butterfield et al. 2023; Heller and Bagot 2020). Additionally, interventions targeting autobiographical memory construction have shown promise for reducing the activation of broader anxiety‐ and depression‐relevant schema (i.e., negative self‐beliefs) following a negative event (Moscovitch et al. 2023).

Despite adolescents with Anx and Anx + Dep reporting more early‐life stress exposures than Controls (see SI), these were not a determinant of their hippocampal alterations. Specifically, significant group differences in hippocampal gray‐ and white‐matter mostly persisted or were not accounted for by controlling for chronic‐ and acute‐stress exposures, as well as broader environmental factors (i.e., SES). This was not likely due to measurement limitations as chronic‐stress exposures and SES demonstrated expected associations with hippocampal volumes when testing across all adolescents (Piccolo and Noble 2018; see SI). As this work did not specifically sample adolescents with more severe forms of early‐life stressors (e.g., physical/sexual abuse), our findings cannot rule out the possibility that such exposures would exert greater influence on hippocampal structural alterations in Anx or Anx + Dep adolescents who experienced them (cf. Weissman et al. 2020). However, even if confirmed, this would not necessarily contradict the current findings, which were observed regardless of the absence of those more severe stress exposures.

This study provided new evidence of disruption in the developmental expansion of hippocampal gray matter, principally CA1, among adolescents with anxiety disorders, but not those with comorbid depressive disorders. Developmental strengthening of hippocampal‐posteromedial cortical circuits may also be disrupted in adolescent anxiety disorders, regardless of depression. Contrary to findings in depression (Paquola et al. 2016), we found no evidence to support that early‐life stress exposures better accounted for the observed structural alterations. Thus, it is unlikely that these reflected stress‐related vulnerabilities for adolescent anxiety disorders (cf. Opel et al. 2014); instead, the observed hippocampal alterations may be more directly tied to the development or maintenance of the disorders themselves. Longitudinal imaging spanning childhood to young adulthood is still needed to determine the precise and intersecting impacts of anxiety, comorbid depression, and stress on hippocampal developmental trajectories. However, the observed alterations provide critical targets for interventions seeking to leverage the plasticity of hippocampal gray‐ and white matter during adolescence to promote beneficial and possibly lasting changes in its capacity to regulate anxiogenic processes (e.g., Moscovitch et al. 2023).

Conflicts of Interest

Over the past 3 years, Dr. Pizzagalli has received consulting fees from Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Sage Therapeutics, Sama Therapeutics, and Takeda; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, DARPA, Millennium Pharmaceuticals, NIMH and Wellcome Leap; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. In the past 3 years, Dr. Auerbach has received consulting fees and equity from Get Sonar Inc. He also has received consulting fees from RPA Health Consulting Inc. and Covington & Burling LLP, which is representing a social media company in litigation.

Supporting information

Data S1.

HIPO-35-0-s001.docx (13.2MB, docx)

Acknowledgments

This project was supported by the National Institute of Mental Health, U01MH108168 (J.D.E.G., S.W.G.). N.A.H. was partially supported by the Brain and Behavior Research Foundation (#27970) and the NIGMS (P20GM130461‐6206). A.Y. was partially supported by R01EB021265 and U01EB026996. D.A.P. was partially supported by R37MH068376 and R01MH101521. S.S.G. was partially supported by R01EB020740 and P41EB019936. R.P.A. was partially supported by R01MH135488, R01MH119771. S.G.H. was partly supported by R01AT007257, R01MH099021, the James S. McDonnell Foundation, the Alexander von Humboldt Foundation (as part of the Alexander von Humboldt Professur), the Hessische Ministerium für Wissenschaft und Kunst (as part of the LOEWE Spitzenprofessur), the DYNAMIC center, funded by the LOEWE program of the Hessian Ministry of Science and Arts (Grant Number: LOEWE1/16/519/03/09.001(0009)/98), and SFB/Transregio 393. This project was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other sponsor.

Pedroza‐Sotelo, K. , Schwarb H., Auerbach R. P., et al. 2025. “Evidence of Disrupted Hippocampal Gray‐ and White‐Matter Development in Adolescent Anxiety Disorders, Independent From Early‐Life Stress.” Hippocampus 35, no. 5: e70028. 10.1002/hipo.70028.

Funding: This project was supported by the National Institute of Mental Health to J.D.E.G., S.W.G. (U01MH108168). N.A.H. was partially supported by the Brain and Behavior Research Foundation (#27970) and the NIGMS (P20GM130461‐6206). A.Y. was partially supported by R01EB021265 and U01EB026996. D.A.P. was partially supported by R37MH068376 and R01MH101521. S.S.G. was partially supported by R01EB020740 and P41EB019936. R.P.A. was partially supported by R01MH135488 and R01MH119771. S.G.H. was partly supported by R01AT007257 and R01MH099021, the James S. McDonnell Foundation, the Alexander von Humboldt Foundation (as part of the Alexander von Humboldt Professur), the Hessische Ministerium für Wissenschaft und Kunst (as part of the LOEWE Spitzenprofessur), the DYNAMIC center, the LOEWE program of the Hessian Ministry of Science and Arts (LOEWE1/16/519/03/09.001(0009)/98), and SFB/Transregio (393). This project was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043.

Data Availability Statement

Data were provided by the Boston Adolescent Neuroimaging of Anxiety and Depression (BANDA) Consortium's Human Connectome Project, supported by 1U01MH108168 (PIs: Susan Whitfield‐Gabrieli, John Gabrieli). Data used in this report were/are openly available via the BANDAv1.1 repository hosted at the National Institute of Mental Health Data Archive (https://doi.org/10.15154/3TK5‐PB47). Medication history data were not included in the BANDAv1.1 repository at the time of analysis.

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Associated Data

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

Supplementary Materials

Data S1.

HIPO-35-0-s001.docx (13.2MB, docx)

Data Availability Statement

Data were provided by the Boston Adolescent Neuroimaging of Anxiety and Depression (BANDA) Consortium's Human Connectome Project, supported by 1U01MH108168 (PIs: Susan Whitfield‐Gabrieli, John Gabrieli). Data used in this report were/are openly available via the BANDAv1.1 repository hosted at the National Institute of Mental Health Data Archive (https://doi.org/10.15154/3TK5‐PB47). Medication history data were not included in the BANDAv1.1 repository at the time of analysis.

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