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.

Differential Cortical Volume and Surface Morphometry in Youth With Chronic Health Conditions.

Up to 1 in 3 youth in the United States have a childhood-onset chronic health condition (CHC), which can lead to neurodevelopmental disruptions in cognitive functioning and brain structure. However, the nature and extent of structural neurobiomarkers that may be consistent across a broad spectrum of CHCs are unknown. Thus, the purpose of this study was to identify potential differences in brain structure in youth with and without chronic physical health conditions (e.g., diabetes, hemophilia). Here, 49 T1 structural magnetic resonance imaging (MRI) images were obtained from youth with (n = 26) and without (n = 23) CHCs. Images were preprocessed using voxel-based morphometry (VBM) to generate whole-brain voxel-wise gray matter volume maps and whole-brain extracted estimates of cortical surface area and cortical thickness. Multi-scanner harmonization was implemented on surface-based estimates and linear models were used to estimate significant main effects of the group. We detected widespread decreases in brain structure in youth with CHCs as compared to controls in regions of the prefrontal, cingulate, and visual association areas. The insula exhibited the opposite effect, with cases having increased surface area as compared to controls. To our knowledge, these findings identify a novel structural biomarker of childhood-onset CHCs, with consistent alterations identified in gray matter of regions in the prefrontal cortex and insula involved in emotion regulation and executive function. These findings, while exploratory, may reflect an impact of chronic health stress in the adolescent brain, and suggest that more comprehensive assessment of stress and neurodevelopment in youth with CHCs may be appropriate.

A proof-of-concept study of vicarious extinction learning and autonomic synchrony in parent-child dyads and posttraumatic stress disorder.

Though threat-extinction models continue to inform scientific study of traumatic stress, knowledge of learning and extinction as mechanisms linking exposure to psychopathology remains critically limited among youth. This proof-of-concept study advances the study of threat-extinction in youth by determining feasibility of electrodermal stimulation (EDS), vicarious extinction learning via their parent, and social threat learning in pediatric PTSD (pPTSD). Typically developing (TD) and PTSD-diagnosed youth in 45 mother-child dyads completed an extinction learning paradigm. The use of EDS was first investigated in a cohort of TD youth (n = 20) using a 2-day paradigm without vicarious extinction, while direct (for TD and pPTSD) and vicarious (for pPTSD) extinction were investigated in a 3-day paradigm (n = 25). Threat acquisition and extinction were monitored using skin-conductance response (SCR) and behavioral expectations of EDS. Using Bayesian modeling to accommodate this pilot sample, our results demonstrate: (1) EDS-conditioning to be highly feasible and well-tolerated across TD and trauma-exposed youth, (2) Successful direct and vicarious extinction learning in trauma-exposed youth, and (3) PTSD-associated patterns in extinction learning and physiological synchrony between parent-child dyads. In summary, these novel approaches have the potential to advance translational studies in the mechanistic understanding of parent-child transmission of risk and youth psychopathology.

Sex-based variations of prefrontal structure and longitudinal symptoms in pediatric posttraumatic stress disorder.

BACKGROUND: Pediatric posttraumatic stress disorder (pPTSD) is more than three times as likely to develop in trauma-exposed female youth than males. Despite the staggering sex differences in the prevalence rates of pPTSD and symptom expression, relatively little is known about the underlying biomarkers of these sex-based variations in pPTSD as compared to typically development. METHODS: The Youth PTSD study recruited 97 youth, ages of 7 and 18, to undergo comprehensive clinical assessments and T1-weighted MRI to evaluate the extent to which sex can explain PTSD-related variations in brain structure. Whole-brain VBM as well as whole-brain estimates of cortical thickness and surface area were analyzed to identify group-by-sex interactions. Finally, we tested whether current or future symptom severity was predictive of regions exhibiting sex-based variations. RESULTS: Clinically, females with PTSD were significantly more likely to report exposure to and higher severity of interpersonal violence and symptoms of hyperarousal. Sex and PTSD status were predictive of gray matter across the lateral prefrontal cortex (PFC), including the ventrolateral PFC and frontal pole, where increased volume and surface area was found in PTSD females as compared to PTSD males. Interestingly, the ventrolateral prefrontal cortex and frontal pole were negatively predictive of symptoms 1 year later in only males with PTSD. CONCLUSIONS: Together, these results establish that youth with PTSD exhibit sex-based variations in clinical and trauma characteristics and prefrontal cortical structure relative to normative development. This work demonstrates the importance of examining the role that sex may play in the behavioral and neurobiological presentation of pPTSD.

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.

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.

Pediatric PTSD is characterized by age- and sex-related abnormalities in structural connectivity.

Pediatric post-traumatic stress disorder (pPTSD) is a prevalent and pervasive form of mental illness comprising a disparate constellation of psychiatric symptoms. Emerging evidence suggests that pPTSD may be characterized by alterations in functional networks traversing the brain. Yet, little is known about pathological changes in the structural tracts underlying functional connectivity. In adults, PTSD is linked to widespread change in white matter integrity throughout the brain, yet similar studies with youth populations have yet to be conducted. Current understanding of the nature and treatment of pPTSD may be enhanced by examining alterations in white matter, while further untangling effects of age and sex. Here, we assess the microstructure of 12 major white matter tracts in a sample of well-phenotyped youth with PTSD. Measures of fractional anisotropy were derived from diffusion tensor images acquired from 82 unmediated youth (ages 8-18), of whom 39 met criteria for pPTSD. Diagnosis of pPTSD was linked to remarkable age- and sex-linked differences in the microstructure of major white matter tracts including the uncinate fasciculus, cingulum bundle, and inferior longitudinal fasciculus. In each case, youth with PTSD show an absence of increased white matter integrity with age, suggesting an altered pattern of neurodevelopment that may contribute to persistence or worsening of illness. Broadly, our results suggest abnormal white matter development in pediatric PTSD, a finding which may contribute to illness persistence, comorbidity with other disorders, and poorer prognosis across time. Critically, these findings further speak to the nature of pPTSD as a 'whole-brain' disorder.

Longitudinal cortical markers of persistence and remission of pediatric PTSD.

BACKGROUND: Previous studies have identified structural brain abnormalities in pediatric PTSD. However, little is known about what structural brain substrates may confer recovery versus persistence of PTSD in the context of the developing brain. METHODS: This naturalistic longitudinal study used T1-weighted MRI to evaluate cortical thickness and surface area in youth with a PTSD diagnosis (n = 28) and typically developing healthy youth (TD; n = 27) at baseline and one-year follow-up. Of the PTSD group, 10 youth were remitters at one-year follow up while 18 had persistent PTSD. Whole-brain estimates of cortical thickness and surface area were extracted to identify differences in cortical architecture associated with PTSD remission and persistence as compared to typical development. RESULTS: Youth who achieved PTSD remission entered the study with significantly lower trauma exposure and reduced symptom severity as compared to nonremitters. PTSD persistence was associated with decreased surface area over time in the ventrolateral prefrontal cortex (vlPFC) as compared to both remitters and TD youth. In contrast, PTSD remission was associated with expansion of frontal pole surface area and ventromedial PFC (vmPFC) thickness over time. Across clinical groups, vmPFC thickness was further inversely associated with symptom severity. CONCLUSIONS: To our knowledge, these findings represent the first report of cortical substrates underlying persistence versus remission in pediatric PTSD. Together, these findings suggest active structural developmental processes unique to both remission and nonremission in youth with PTSD. In particular, expansion of prefrontal regions implicated in emotion regulation may facilitate recovery from PTSD in youth and would warrant further study.

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.