Familial risk for depression moderates neural circuitry in healthy preadolescents to predict adolescent depression symptoms in the Adolescent Brain Cognitive Development (ABCD) Study.

BACKGROUND: There is an imminent need to identify neural markers during preadolescence that are linked to developing depression during adolescence, especially among youth at elevated familial risk. However, longitudinal studies remain scarce and exhibit mixed findings. Here we aimed to elucidate functional connectivity (FC) patterns among preadolescents that interact with familial depression risk to predict depression two years later. METHODS: 9-10 year-olds in the Adolescent Brain Cognitive Development (ABCD) Study were classified as healthy (i.e., no lifetime psychiatric diagnoses) at high familial risk for depression (HR; n=559) or at low familial risk for psychopathology (LR; n=1203). Whole-brain seed-to-voxel resting-state FC patterns with the amygdala, putamen, nucleus accumbens, and caudate were calculated. Multi-level, mixed-effects regression analyses were conducted to test whether FC at ages 9-10 interacted with familial risk to predict depression symptoms at ages 11-12. RESULTS: HR youth demonstrated stronger associations between preadolescent FC and adolescent depression symptoms (ps<0.001) as compared to LR youth (ps>0.001), primarily among amygdala/striatal FC with visual and sensory/somatomotor networks. CONCLUSIONS: Preadolescent amygdala and striatal FC may be useful biomarkers of adolescent-onset depression, particularly for youth with family histories of depression. This research may point to neurobiologically-informed approaches to prevention and intervention for depression in adolescents.

Leveraging multivariate approaches to advance the science of early-life adversity.

Since the landmark Adverse Childhood Experiences (ACEs) study, adversity research has expanded to more precisely account for the multifaceted nature of adverse experiences. The complex data structures and interrelated nature of adversity data require robust multivariate statistical methods, and recent methodological and statistical innovations have facilitated advancements in research on childhood adversity. Here, we provide an overview of a subset of multivariate methods that we believe hold particular promise for advancing the field's understanding of early-life adversity, and discuss how these approaches can be practically applied to explore different research questions. This review covers data-driven or unsupervised approaches (including dimensionality reduction and person-centered clustering/subtype identification) as well as supervised/prediction-based approaches (including linear and tree-based models and neural networks). For each, we highlight studies that have effectively applied the method to provide novel insight into early-life adversity. Taken together, we hope this review serves as a resource to adversity researchers looking to expand upon the cumulative approach described in the original ACEs study, thereby advancing the field's understanding of the complexity of adversity and related developmental consequences.

Parent Psychopathology and Behavioral Effects on Child Brain-Symptom Networks in the ABCD Study.

OBJECTIVE: Parents play a notable role in the development of child psychopathology. In this study, we investigated the role of parent psychopathology and behaviors on child brain-symptom networks to understand the role of intergenerational transmission of psychopathology. Few studies have documented the interaction of child psychopathology, parent psychopathology, and child neuroimaging. METHOD: We used the baseline cohort of the Adolescent Brain Cognitive Development Study (N = 7,151, female-at-birth = 3,619, aged 9-11 years) to derive brain-symptom networks using sparse canonical correlation analysis with the Child Behavior Checklist and resting-state functional magnetic resonance imaging. We then correlated parent psychopathology symptoms and parental behaviors with child brain-symptom networks. Finally, we used the significant correlations to understand, using the mediation R package, whether parent behaviors mediated the effect of parent psychopathology on child brain connectivity. RESULTS: We observed 3 brain-symptom networks correlated with externalizing (r = 0.19, internalizing (r = 0.17), and neurodevelopmental symptoms (r = 0.18). These corresponded to differences in connectivity between the default mode-default mode, default mode-control, and visual-visual canonical networks. We further detected aspects of parental psychopathology, including personal strength, thought problems, and rule-breaking symptoms to be associated with child brain connectivity. Finally, we found that parental behaviors and symptoms mediate each other's relationship to child brain connectivity. CONCLUSION: The current study suggests that positive parental behaviors can relieve potentially detrimental effects of parental psychopathology, and vice versa, on symptom-correlated child brain connectivity. Altogether, these results provide a framework for future research and potential targets for parents who experience mental health symptoms to help mitigate potential intergenerational transmission of mental illness.

Neural Circuit Markers of Familial Risk for Depression Among Healthy Youths in the Adolescent Brain Cognitive Development Study.

BACKGROUND: Family history of depression is a robust predictor of early-onset depression, which may confer risk through alterations in neural circuits that have been implicated in reward and emotional processing. These alterations may be evident in youths who are at familial risk for depression but who do not currently have depression. However, the identification of robust and replicable findings has been hindered by few studies and small sample sizes. In the current study, we sought to identify functional connectivity (FC) patterns associated with familial risk for depression. METHODS: Participants included healthy (i.e., no lifetime psychiatric diagnoses) youths at high familial risk for depression (HR) (n = 754; at least one parent with a history of depression) and healthy youths at low familial risk for psychiatric problems (LR) (n = 1745; no parental history of psychopathology) who were 9 to 10 years of age and from the Adolescent Brain Cognitive Development (ABCD) Study sample. We conducted whole-brain seed-to-voxel analyses to examine group differences in resting-state FC with the amygdala, caudate, nucleus accumbens, and putamen. We hypothesized that HR youths would exhibit global amygdala hyperconnectivity and striatal hypoconnectivity patterns primarily driven by maternal risk. RESULTS: HR youths exhibited weaker caudate-angular gyrus FC than LR youths (α = 0.04, Cohen's d = 0.17). HR youths with a history of maternal depression specifically exhibited weaker caudate-angular gyrus FC (α = 0.03, Cohen's d = 0.19) as well as weaker caudate-dorsolateral prefrontal cortex FC (α = 0.04, Cohen's d = 0.21) than LR youths. CONCLUSIONS: Weaker striatal connectivity may be related to heightened familial risk for depression, primarily driven by maternal history. Identifying brain-based markers of depression risk in youths can inform approaches to improving early detection, diagnosis, and treatment.

Multivariate links between the developmental timing of adversity exposure and white matter tract integrity in adulthood.

Early-life adversity is pervasive worldwide and represents a potent risk factor for increased mental health burden across the lifespan. However, there is substantial individual heterogeneity in associations between adversity exposure, neurobiological changes, and mental health problems. Accounting for key features of adversity such as the developmental timing of exposure may clarify associations between adversity, neurodevelopment, and mental health. The present study leverages sparse canonical correlation analysis to characterize modes of covariation between age of adversity exposure and the integrity of white matter tracts throughout the brain in a sample of 107 adults. We find that adversity exposure during middle childhood (ages 5-6 and 8-9 in particular) is consistently linked with alterations in white matter tract integrity, such that tracts supporting sensorimotor functions display higher integrity in relation to adversity exposure while tracts supporting cortico-cortical communication display lower integrity. Further, latent patterns of tract integrity linked with adversity experienced across preschool age and middle childhood (ages 4-9) were associated with trauma-related symptoms in adulthood. Our findings underscore that adversity exposure may differentially affect white matter in a function- and developmental-timing specific manner and suggest that adversity experienced between ages 4-9 may shape the development of global white matter tracts in ways that are relevant for adult mental health.

Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort.

BACKGROUND: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes. METHODS: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. RESULTS: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC. CONCLUSIONS: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

Characterizing experiential elements of early-life stress to inform resilience: Buffering effects of controllability and predictability and the importance of their timing.

Key theoretical frameworks have proposed that examining the impact of exposure to specific dimensions of stress at specific developmental periods is likely to yield important insight into processes of risk and resilience. Utilizing a sample of N = 549 young adults who provided a detailed retrospective history of their lifetime exposure to numerous dimensions of traumatic stress and ratings of their current trauma-related symptomatology via completion of an online survey, here we test whether an individual's perception of their lifetime stress as either controllable or predictable buffered the impact of exposure on trauma-related symptomatology assessed in adulthood. Further, we tested whether this moderation effect differed when evaluated in the context of early childhood, middle childhood, adolescence, and young adulthood stress. Consistent with hypotheses, results highlight both stressor controllability and stressor predictability as buffering the impact of traumatic stress exposure on trauma-related symptomatology and suggest that the potency of this buffering effect varies across unique developmental periods. Leveraging dimensional ratings of lifetime stress exposure to probe heterogeneity in outcomes following stress - and, critically, considering interactions between dimensions of exposure and the developmental period when stress occurred - is likely to yield increased understanding of risk and resilience following traumatic stress.

Longitudinal hippocampal circuit change differentiates persistence and remission of pediatric posttraumatic stress disorder.

BACKGROUND: Previous studies have identified functional brain abnormalities in pediatric posttraumatic stress disorder (pPTSD) suggesting altered frontoparietal-subcortical function during emotion processing. However, little is known about how the brain functionally changes over time in recovery versus the persistence of pPTSD. METHODS: This longitudinal study recruited 23 youth with PTSD and 28 typically developing (TD) youth (ages: 8.07-17.99). Within the PTSD group, nine remitted by the 1-year follow-up (Remit) while the remaining 14 persisted (PTSD). At each visit, youth completed an emotional processing task in which they viewed threat and neutral images during functional magnetic resonance imaging (fMRI). Voxelwise activation analyses using linear mixed-effects regression were conducted using a group (TD, Remit, PTSD) by time (baseline, follow-up) by valence (threat, neutral) design. Based on activation findings, a subsequent analysis of hippocampal functional connectivity was performed using a similar model. RESULTS: PTSD youth showed significantly increasing hippocampal activation to threatening images compared to TD youth, while the Remit group showed more similar patterns to TD youth. Subsequent hippocampal functional connectivity analyses reveal the Remit group showed increasing functional connectivity between the hippocampus and visual cortex (V4) while viewing threat stimuli. CONCLUSIONS: These findings represent one of the first preliminary reports of functional brain substrates of persistence and remission in pPTSD. Notably, increased hippocampal activation to threat and decreased connectivity in the hippocampal-V4 network over time may contribute to persistence in pPTSD. These findings suggest potential biomarkers that could be utilized to advance the treatment of pediatric PTSD.

Childhood exposure to interpersonal violence is associated with greater transdiagnostic integration of psychiatric symptoms.

BACKGROUND: Childhood exposure to interpersonal violence (IPV) may be linked to distinct manifestations of mental illness, yet the nature of this change remains poorly understood. Network analysis can provide unique insights by contrasting the interrelatedness of symptoms underlying psychopathology across exposed and non-exposed youth, with potential clinical implications for a treatment-resistant population. We anticipated marked differences in symptom associations among IPV-exposed youth, particularly in terms of 'hub' symptoms holding outsized influence over the network, as well as formation and influence of communities of highly interconnected symptoms. METHODS: Participants from a population-representative sample of youth (n = 4433; ages 11-18 years) completed a comprehensive structured clinical interview assessing mental health symptoms, diagnostic status, and history of violence exposure. Network analytic methods were used to model the pattern of associations between symptoms, quantify differences across diagnosed youth with (IPV+) and without (IPV-) IPV exposure, and identify transdiagnostic 'bridge' symptoms linking multiple disorders. RESULTS: Symptoms organized into six 'disorder' communities (e.g. Intrusive Thoughts/Sensations, Depression, Anxiety), that exhibited considerably greater interconnectivity in IPV+ youth. Five symptoms emerged in IPV+ youth as highly trafficked 'bridges' between symptom communities (11 in IPV- youth). CONCLUSION: IPV exposure may alter mutually reinforcing symptom co-occurrence in youth, thus contributing to greater psychiatric comorbidity and treatment resistance. The presence of a condensed and unique set of bridge symptoms suggests trauma-enriched nodes which could be therapeutically targeted to improve outcomes in violence-exposed youth.

Neurobehavioral correlates of impaired emotion recognition in pediatric PTSD.

Despite broad evidence suggesting that adversity-exposed youth experience an impaired ability to recognize emotion in others, the underlying biological mechanisms remains elusive. This study uses a multimethod approach to target the neurological substrates of this phenomenon in a well-phenotyped sample of youth meeting diagnostic criteria for posttraumatic stress disorder (PTSD). Twenty-one PTSD-afflicted youth and 23 typically developing (TD) controls completed clinical interview schedules, an emotion recognition task with eye-tracking, and an implicit emotion processing task during functional magnetic resonance imaging )fMRI). PTSD was associated with decreased accuracy in identification of angry, disgust, and neutral faces as compared to TD youth. Of note, these impairments occurred despite the normal deployment of visual attention in youth with PTSD relative to TD youth. Correlation with a related fMRI task revealed a group by accuracy interaction for amygdala-hippocampus functional connectivity (FC) for angry expressions, where TD youth showed a positive relationship between anger accuracy and amygdala-hippocampus FC; this relationship was reversed in youth with PTSD. These findings are a novel characterization of impaired threat recognition within a well-phenotyped population of severe pediatric PTSD. Further, the differential amygdala-hippocampus FC identified in youth with PTSD may imply aberrant efficiency of emotional contextualization circuits.

Differential Patterns of Delayed Emotion Circuit Maturation in Abused Girls With and Without Internalizing Psychopathology.

OBJECTIVE: Childhood abuse represents one of the most potent risk factors for developing psychopathology, especially in females. Evidence suggests that exposure to early-life adversity may be related to advanced maturation of emotion processing neural circuits. However, it remains unknown whether abuse is related to early circuit maturation and whether maturation patterns depend on the presence of psychopathology. METHODS: A multisite sample of 234 girls (ages 8-18 years) completed clinical assessment, maltreatment histories, and high-resolution T1-weighted structural MRI. Girls were stratified by abuse history and internalizing disorder diagnosis into typically developing (no abuse/no diagnosis), resilient (abuse/no diagnosis), and susceptible (abuse/current diagnosis) groups. Machine learning models of normative brain development were aggregated in a stacked generalization framework trained to predict chronological age using gray matter volume in whole-brain, emotion, and language circuit parcellations. Brain age gap estimations (BrainAGEs; predicted age minus true chronological age) were calculated as indices of relative circuit maturation. RESULTS: Childhood abuse was related to reduced BrainAGE (delayed maturation) specific to emotion circuits. Delayed emotion circuit BrainAGE was further related to increased hyperarousal symptoms. Childhood physical neglect was associated with increased whole-brain BrainAGE (advanced maturation). Neural contributors to emotion circuit BrainAGE differed in girls with and without an internalizing diagnosis, especially in the lateral prefrontal, parietal, and insular cortices and the hippocampus. CONCLUSIONS: Abuse exposure in girls is associated with a delayed structural maturation pattern specific to emotion circuitry, a potentially adaptive mechanism enhancing threat generalization. Physical neglect, on the other hand, is associated with a broader brain-wide pattern of advanced structural maturation. The differential influence of fronto-parietal cortices and the hippocampus on emotion circuit maturity in resilient girls may represent neurodevelopmental markers of reduced psychiatric risk following abuse.

Differential DNA Methylation Is Associated With Hippocampal Abnormalities in Pediatric Posttraumatic Stress Disorder.

BACKGROUND: Recent findings in neuroimaging and epigenetics offer important insights into brain structures and biological pathways of altered gene expression associated with posttraumatic stress disorder (PTSD). However, it is unknown to what extent epigenetic mechanisms are associated with PTSD and its neurobiology in youth. METHODS: In this study, we combined a methylome-wide association study and structural neuroimaging measures in a Dutch cohort of youths with PTSD (8-18 years of age). We aimed to replicate findings in a similar independent U.S. cohort. RESULTS: We found significant methylome-wide associations for pediatric PTSD (false discovery rate p < .05) compared with non-PTSD control groups (traumatized and nontraumatized youths). Methylation differences on nine genes were replicated, including genes related to glucocorticoid functioning. In both cohorts, methylation on OLFM3 gene was further associated with anterior hippocampal volume. CONCLUSIONS: These findings point to molecular pathways involved in inflammation, stress response, and neuroplasticity as potential contributors to neural abnormalities and provide potentially unique biomarkers and treatment targets for pediatric PTSD.

Abnormal Prefrontal Development in Pediatric Posttraumatic Stress Disorder: A Longitudinal Structural and Functional Magnetic Resonance Imaging Study.

BACKGROUND: Prior studies of pediatric posttraumatic stress disorder (PTSD) have reported cross-sectional and age-related structural and functional brain abnormalities in networks associated with cognitive, affective, and self-referential processing. However, no reported studies have comprehensively examined longitudinal gray matter development and its intrinsic functional correlates in pediatric PTSD. METHODS: Twenty-seven youths with PTSD and 21 nontraumatized typically developing (TD) youths were assessed at baseline and 1-year follow-up. At each visit, youths underwent structural magnetic resonance imaging and resting-state functional magnetic resonance imaging. Regions with volumetric abnormalities in whole-brain structural analyses were identified and used as seeds in exploratory intrinsic connectivity analyses. RESULTS: Youths with PTSD exhibited sustained reductions in gray matter volume (GMV) in right ventromedial prefrontal cortex (PFC) and bilateral ventrolateral PFC. Group-by-time analyses revealed aberrant longitudinal development in dorsolateral PFC, where typically developing youths exhibited normative decreases in GMV between baseline and follow-up, and youths with PTSD showed increases in GMV. Using these regions as seeds, patients with PTSD exhibited atypical longitudinal decreases in intrinsic PFC-amygdala and PFC-hippocampus connectivity, in contrast to increases in typically developing youths. Specifically, youths with PTSD showed decreasing ventromedial PFC-amygdala connectivity as well as decreasing ventrolateral PFC-hippocampus connectivity over time. Notably, volumetric abnormalities in ventromedial PFC and ventrolateral PFC were predictive of symptom severity. CONCLUSIONS: These findings represent novel longitudinal volumetric and connectivity changes in pediatric PTSD. Atypical prefrontal GMV and prefrontal-amygdala/hippocampus development may underlie persistence of PTSD in youths and could serve as future therapeutic targets.

Paradoxical Prefrontal-Amygdala Recruitment to Angry and Happy Expressions in Pediatric Posttraumatic Stress Disorder.

The neural substrates of pediatric posttraumatic stress disorder (PTSD) remain incompletely understood, but likely involve abnormal function and development of emotion processing circuitry. Valence-specific and age-related abnormalities during emotion processing have not been elucidated. We examined implicit emotional face processing in pediatric PTSD, predicting abnormalities specific to threat-related emotion. Youth (ages 8-18 years) with PTSD (n=25) and healthy youth (n=28) completed a dynamic emotional face task during fMRI, viewing faces changing from neutral to angry or happy, or changing shape control. Group and cross-sectional age-related differences in activation and functional connectivity were examined in amygdala/hippocampus, medial prefrontal cortex (mPFC), and whole-brain analyses. The post hoc analyses examined the relationship of neural abnormalities with symptom measures of PTSD, anxiety, and depression. Compared with decreased activation with age in healthy youth, PTSD youth showed increased amygdala activation to emotional faces with age. In a group by emotion interaction, PTSD youth showed dorsal (d)ACC hyperactivation to happy faces relative to healthy youth, with no difference for angry faces. Connectivity analyses revealed paradoxical coupling in prefrontal-amygdala circuits, including dACC-dorsomedial (dm)PFC, amygdala-dmPFC, and amygdala-ventrolateral (vl)PFC. In each case, PTSD youth showed reduced connectivity to angry faces, but increased connectivity to happy faces, the reverse of healthy youth. Valence-abnormal recruitment was associated with greater symptom severity, implicating a role in trauma-related psychopathology in youth. Notably, impaired recruitment during angry faces and heightened recruitment to happy faces may reflect increased salience and ambiguity of positive emotional expressions in pediatric PTSD. Finally, age-related findings suggest a developmental sensitization of the amygdala across emotional expressions in youth with PTSD. These findings provide novel insights into the underlying pathophysiology of pediatric PTSD, extending beyond abnormal neural responses to canonical threat.

Default-Mode Network Abnormalities in Pediatric Posttraumatic Stress Disorder.

OBJECTIVE: Resting-state functional magnetic resonance imaging (rs-fMRI) studies of adult posttraumatic stress disorder (PTSD) have identified default-mode network (DMN) abnormalities, including reduced within-network connectivity and reduced anticorrelation between the DMN and task-positive network (TPN). However, no prior studies have specifically examined DMN connectivity in pediatric PTSD, which may differ due to neurodevelopmental factors. METHOD: A total of 29 youth with PTSD and 30 nontraumatized healthy youth of comparable age and sex completed rs-fMRI. DMN properties were examined using posterior cingulate cortex (PCC) seed-based connectivity and independent component analysis (ICA). RESULTS: Contrary to findings in adult studies, youth with PTSD displayed increased connectivity within the DMN, including increased PCC-inferior parietal gyrus connectivity, and age-related increases in PCC-ventromedial prefrontal cortex connectivity. Strikingly, youth with PTSD also displayed greater anticorrelation between the PCC and multiple nodes within salience and attentional control networks of the TPN. ICA revealed greater anticorrelation between the entire DMN and TPN networks in youth with PTSD. Furthermore, DMN and TPN connectivity strength were positively and negatively associated, respectively, with re-experiencing symptoms of PTSD. CONCLUSION: Pediatric PTSD is characterized by heightened within-DMN connectivity, which may contribute to re-experiencing symptoms of PTSD and is consistent with the role of the DMN in autobiographical memory. At the same time, greater anticorrelation between the DMN and attentional control networks may represent compensatory mechanisms aimed at suppressing trauma-related thought, a notion supported by the inverse relationship between TPN strength and re-experiencing. These findings provide new insights into large-scale network abnormalities underlying pediatric PTSD, which could serve as biomarkers of illness and treatment response.

Abnormal structure of fear circuitry in pediatric post-traumatic stress disorder.

Structural brain studies of adult post-traumatic stress disorder (PTSD) show reduced gray matter volume (GMV) in fear regulatory areas including the ventromedial prefrontal cortex (vmPFC) and hippocampus. Surprisingly, neither finding has been reported in pediatric PTSD. One possibility is that they represent age-dependent effects that are not fully apparent until adulthood. In addition, lower-resolution MRI and image processing in prior studies may have limited detection of such differences. Here we examine fear circuitry GMV, including age-related differences, using higher-resolution MRI in pediatric PTSD vs healthy youth. In a cross-sectional design, 3 T anatomical brain MRI was acquired in 27 medication-free youth with PTSD and 27 healthy non-traumatized youth of comparable age, sex, and IQ. Voxel-based morphometry was used to compare GMV in a priori regions including the medial prefrontal cortex and amygdala/hippocampus. Compared with healthy youth, PTSD youth had reduced GMV but no age-related differences in anterior vmPFC (BA 10/11, Z=4.5), which inversely correlated with PTSD duration. In contrast, although there was no overall group difference in hippocampal volume, a group × age interaction (Z=3.6) was present in the right anterior hippocampus. Here, age positively predicted hippocampal volume in healthy youth but negatively predicted volume in PTSD youth. Within the PTSD group, re-experiencing symptoms inversely correlated with subgenual anterior cingulate cortex (sgACC, Z=3.7) and right anterior hippocampus (Z=3.5) GMV. Pediatric PTSD is associated with abnormal structure of the vmPFC and age-related differences in the hippocampus, regions important in the extinction and contextual gating of fear. Reduced anterior vmPFC volume may confer impaired recovery from illness, consistent with its role in the allocation of attentional resources. In contrast, individual differences in sgACC volume were associated with re-experiencing symptoms, consistent with the role of the sgACC in fear extinction. The negative relationship between age and hippocampal volume in youth with PTSD may suggest an ongoing neurotoxic process over development, which further contributes to illness expression. Future studies employing a longitudinal design would be merited to further explore these possibilities.