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To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision.Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration.Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort.This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.

OBJECTIVE Emotion dysregulation is a transdiagnostic risk factor for many mental health disorders and develops in the context of early trauma exposure. Research suggests intergenerational risk associated with trauma exposure and posttraumatic stress disorder (PTSD), such that maternal trauma experiences and related symptoms can negatively impact child outcomes across development. The goals of the present study were to examine child and mother correlates of child PTSD symptoms and the unique roles of child and maternal emotion dysregulation in understanding child PTSD symptoms. METHOD Subjects included 105 African American mother-child dyads from an urban hospital serving primarily low-income minority individuals. RESULTS Correlational results showed that child trauma exposure, child emotion dysregulation, maternal depressive symptoms, maternal emotion dysregulation, and potential for maternal child abuse all were significantly associated with child PTSD symptoms (ps < 0.05). Hierarchical linear regression models revealed that child trauma exposure, maternal depression, and maternal abuse potential accounted for 29% of the variance in child PTSD symptoms (p < 0.001). Both child emotion dysregulation (Rchange² = 0.14, p < .001) and maternal emotion dysregulation (Rchange² = 0.04, p < .05) were significantly associated with child PTSD symptoms independent of other risk factors and potential for maternal abuse was no longer a significant predictor. CONCLUSIONS These results suggest that maternal emotion dysregulation may be an important factor in influencing their child's PTSD symptoms above and beyond child-specific variables. Both maternal and child emotion dysregulation could be valuable treatment targets for improving maternal mental health and parenting behaviors and bolstering child health outcomes, thus reducing intergenerational transmission of risk associated with trauma. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Dissociation, a disruption or discontinuity in psychological functioning, is often linked with worse psychiatric symptoms; however, the prognostic value of dissociation after trauma is inconsistent. Determining whether trauma-related dissociation is uniquely predictive of later outcomes would enable early identification of at-risk trauma populations. The authors conducted the largest prospective longitudinal biomarker study of persistent dissociation to date to determine its predictive capacity for adverse psychiatric outcomes following acute trauma.All data were part of the Freeze 2 data release from the Advancing Understanding of Recovery After Trauma (AURORA) study. Study participants provided self-report data about persistent derealization (N=1,464), a severe type of dissociation, and completed a functional MRI emotion reactivity task and resting-state scan 2 weeks posttrauma (N=145). Three-month follow-up reports were collected of posttraumatic stress, depression, pain, anxiety symptoms, and functional impairment.Derealization was associated with increased ventromedial prefrontal cortex (vmPFC) activation in the emotion reactivity task and decreased resting-state vmPFC connectivity with the cerebellum and orbitofrontal cortex. In separate analyses, brain-based and self-report measures of persistent derealization at 2 weeks predicted worse 3-month posttraumatic stress symptoms, distinct from the effects of childhood maltreatment history and current posttraumatic stress symptoms.The findings suggest that persistent derealization is both an early psychological and biological marker of worse later psychiatric outcomes. The neural correlates of trauma-related dissociation may serve as potential targets for treatment engagement to prevent posttraumatic stress disorder. These results underscore dissociation assessment as crucial following trauma exposure to identify at-risk individuals, and they highlight an unmet clinical need for tailored early interventions.

Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Racism is a chronic stressor fueled by stigma that can result in significant distress and dysfunction as well as negatively affect emotions, behavior, quality of life, and brain health. The effects of stigma and discrimination emerge early in life and have long-term consequences. In this review, we sought to use neuroscience research to describe how stigma, racism, and discrimination can impact brain and mental health. Societal stigmas may be encoded by associative fear learning and pattern completion networks, and experiences of racial discrimination may similarly affect threat-responsive regions and circuits. Race-related differences in brain function and structure supporting threat circuitry are largely attenuated when negative life experiences and discrimination are taken into account. Downstream, chronic activation of the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis in the context of discrimination and stigma can contribute to physical health disparities in minoritized and marginalized groups. Finally, we discuss models that provide a framework for interventions and societal-level strategies across ecologic systems to build resilience and foster posttraumatic growth.

Peer victimization is a developmentally salient stressor that elevates adolescents’ risk for anxiety disorders. However, modifiable mechanisms that explain this link and can be targeted via therapeutic interventions remain poorly understood. Drawing from psychobiological models implicating aberrant threat sensitivity in the development and maintenance of psychopathology, the current study investigated sensitivity to peer-related social threats as a mechanism underlying the association between peer victimization and anxiety. A sample of 197 dyads of early adolescents (M age = 12.02; 46% female) and parents/guardians (M age = 41.46; 90% female) completed online surveys assessing peer victimization, sensitivity to potential (i.e., ambiguous) social threats, and anxiety. Controlling for potentially confounding demographic and psychosocial factors, both self- and parent-reported peer victimization were positively associated with adolescent anxiety symptoms. Additionally, there were significant indirect effects from self- and parent-reported peer victimization to anxiety via social threat sensitivity. Supplemental analyses indicated unique effects of covert, but not overt, peer victimization on social threat sensitivity and anxiety. The findings provide initial evidence that peer victimization experiences lower adolescents’ threshold for interpreting threats in ambiguous social situations, which contributes to heightened anxiety. These results implicate social threat sensitivity as a potential therapeutic target for interrupting links from peer victimization to psychological distress.

Objectives Parental posttraumatic stress disorder (PTSD) increases children's risk for emotional and behavioral problems. We examined parenting stress and parenting behavior quality as mediators of the relation between maternal PTSD and problematic child behaviors in a sample at high risk for trauma exposure. We also examined whether child sex moderated this association. Method Participants were 141 African American mother-child dyads (children aged 8-12). Mothers reported PTSD severity, parenting stress, and child behavior (externalizing, internalizing, and emotional self-control). Parenting behavior quality (accounting for factors including parental warmth and engagement) was assessed from an observational parent-child interaction task. Results Parenting stress, but not observed parenting behavior quality, mediated the relation between maternal PTSD severity and child behaviors. Child sex moderated this association, such that the effect was stronger for girls. Conclusions Maternal PTSD may be associated with negative child behavior outcomes, and this relation appears to be mediated by increased parenting stress. Stress-reducing interventions for parents with PTSD could improve child outcomes, especially for girls. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Measurement practice in experimental psychology is heterogeneous. Psychometric properties of measurement methods are sometimes difficult to establish, leaving researchers with few criteria to select between methods. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values can then serve as validity criterion, to rank methods by their measurement error. This approach requires community consensus on which calibration experiment to use. Here, we develop a consensus process and exemplify it in the field of human fear conditioning. Based on a literature review and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of "learned unconditioned-stimulus (US) expectation". This latent variable and the calibration procedure were chosen to be as theory-free as possible, and to have the widest experimental applicability among the surveyed researchers. Besides establishing a specific calibration procedure for fear conditioning, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of experimental psychology that are in need of measurement refinement.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [−0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Background: Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention. Aims: This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans. Methods: The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21–55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants ( N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events. Results: Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007). Conclusion: Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention. Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9

Background Although aspects of brain morphology have been associated with chronic posttraumatic stress disorder (PTSD), limited work has investigated multimodal patterns in brain morphology that are linked to acute posttraumatic stress severity. In the present study, we utilized multimodal magnetic resonance imaging to investigate if structural covariance networks (SCNs) assessed acutely following trauma were linked to acute posttraumatic stress severity. Methods Structural magnetic resonance imaging data were collected around 1 month after civilian trauma exposure in 78 participants. Multimodal magnetic resonance imaging data fusion was completed to identify combinations of SCNs, termed structural covariance profiles (SCPs), related to acute posttraumatic stress severity collected at 1 month. Analyses assessed the relationship between participant SCP loadings, acute posttraumatic stress severity, the change in posttraumatic stress severity from 1 to 12 months, and depressive symptoms. Results We identified an SCP that reflected greater gray matter properties of the anterior temporal lobe, fusiform face area, and visual cortex (i.e., the ventral visual stream) that varied curvilinearly with acute posttraumatic stress severity and the change in PTSD symptom severity from 1 to 12 months. The SCP was not associated with depressive symptoms. Conclusions We identified combinations of multimodal SCNs that are related to variability in PTSD symptoms in the early aftermath of trauma. The identified SCNs may reflect patterns of neuroanatomical organization that provide unique insight into acute posttraumatic stress. Furthermore, these multimodal SCNs may be potential candidates for neural markers of susceptibility to both acute posttraumatic stress and the future development of PTSD.

The purpose of this study was to characterize trauma exposure and mental health burden among men who have sex with men (MSM) in Hanoi, Vietnam. Participants comprise 100 HIV-positive and 98 high-risk, HIV-negative MSM, ranging from 18 to 29 years of age. Data were collected using the Childhood Trauma Questionnaire, Traumatic Events Inventory, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and PTSD Symptom Scale. A subset of participants (n = 12) were also interviewed to evaluate community perception of the prevalence, causation, and available treatment options for mental health issues within the MSM community in Vietnam. In our sample, 23.2% reported having experienced moderate-to-severe childhood physical abuse; 18.7% physical neglect; 13.6% emotional abuse; 11.1% emotional neglect; and 26.8% sexual abuse. Such trauma exposure continued into adulthood and manifested most commonly in the form of interpersonal violence. Approximately 37.4% of the sample met the criteria for probable PTSD; 26.8% for moderate-to-severe depression; and 20.2% for moderate-to-severe anxiety. Neither exposure nor mental health burden differed by serostatus. Linear regression revealed that childhood emotional abuse was the only sub-type of trauma significantly associated with depression, anxiety, and PTSD symptoms. The majority of interviewees believed that mental health burden was higher among MSM relative to the general population and attributed this to their vulnerability to interpersonal violence and lack of available coping resources. However, few believed that these mental health issues warranted clinical attention, and only one participant was able to identify a mental health service provider. Our findings suggest that trauma exposure and mental health burden are prevalent among MSM, irrespective of serostatus, and much higher than what has been previously reported among the general population in Vietnam.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA–Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15–0.97; r range: 0.21–0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality.

Background: The transition to adulthood is a period of increased risk for emergent psychopathology; emerging adults with a childhood maltreatment history are at risk for poor outcomes. Method: Using a multi-measure, transdisciplinary, cross-sectional design, this study tested whether participant-reported positive parenting, a potential resilience-promoting factor, moderated the association between clinician-rated PTSD symptom severity and a transdiagnostic maladjustment biomarker, fear-potentiated startle (FPS), in a sample of 66 emerging adults ( M years = 18.83, SD = 0.89) with a maltreatment history. We hypothesized that characteristics of effective parenting would moderate the relation between PTSD symptoms and FPS. Results: Results indicated that elevated PTSD, as measured by the CAPS, was associated with a more severe startle reaction. The magnitude of the increase in startle reactivity was moderated by parenting such that those with more positive parenting (Accepting [relative to rejecting]: b = −0.42, p < .001; Psychologically-controlling [relative to autonomy-promoting]: b = 2.96, p = .004) had significantly less reactivity across the task at higher levels of PTSD symptoms. Conclusions: Emerging adults with childhood maltreatment histories, high levels of PTSD symptoms, and who perceive present-day high-quality caregiver support may cope better with novel stressors relative to youth lacking that support, potentially translating to better psychological outcomes.

BackgroundCurrent clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify individuals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,527 structural-MRI; 2,502 resting state-fMRI; and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.ResultsWe found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.ConclusionOur findings highlight the promise offered by machine learning methods for the diagnosis of patients with PTSD. The utility of brain biomarkers across three MRI modalities and the contribution of DVAE models for improving generalizability offers new insights into neural mechanisms involved in PTSD.Significance⍰Classifying PTSD from trauma-unexposed healthy controls (HC) using three imaging modalities performed well (∼75% AUC), but performance suffered markedly when classifying PTSD from trauma-exposed healthy controls (TEHC) using three imaging modalities (∼60% AUC).⍰Using deep learning for feature reduction (denoising variational auto-encoder; DVAE) dramatically reduced the number of features with no concomitant performance degradation.⍰Utilizing denoising variational autoencoder (DVAE) models improves generalizability across heterogeneous multi-site data compared with the traditional machine learning frameworks

OBJECTIVE: Major negative life events, such as trauma exposure, can play a key role in igniting or exacerbating psychopathology. However, few disorders are diagnosed with respect to precipitating events, and the role of these events in the unfolding of new psychopathology is not well understood. The authors conducted a multisite transdiagnostic longitudinal study of trauma exposure and related mental health outcomes to identify neurobiological predictors of risk, resilience, and different symptom presentations. METHODS: A total of 146 participants (discovery cohort: N = 69; internal replication cohort: N = 77) were recruited from emergency departments within 72 hours of a trauma and followed for the next 6 months with a survey, MRI, and physiological assessments. RESULTS: Task-based functional MRI 2 weeks after a motor vehicle collision identified four clusters of individuals based on profiles of neural activity reflecting threat reactivity, reward reactivity, and inhibitory engagement. Three clusters were replicated in an independent sample with a variety of trauma types. The clusters showed different longitudinal patterns of posttrauma symptoms. CONCLUSIONS: These findings provide a novel characterization of heterogeneous stress responses shortly after trauma exposure, identifying potential neuroimaging-based biotypes of trauma resilience and psychopathology.

Early life adversity (ELA) has been linked with increased arousal responses to threat, including increased amygdala reactivity. Effects of ELA on brain function are well recognized, and emerging evidence suggests that caregivers may influence how environmental stressors impact children’s brain function. We investigated the hypothesis that positive interaction between mother and child can buffer against ELA effects on children’s neural responses to threat, and related symptoms. N = 53 mother–child pairs (children ages 8–14 years) were recruited from an urban population at high risk for violence exposure. Maternal caregiving was measured using the Parenting Questionnaire and in a cooperation challenge task. Children viewed fearful and neutral face stimuli during functional magnetic resonance imaging. Children who experienced greater violence at home showed amygdala sensitization, whereas children experiencing more school and community violence showed amygdala habituation. Sensitization was in turn linked with externalizing symptoms. However, maternal warmth was associated with a normalization of amygdala sensitization in children, and fewer externalizing behaviors prospectively up to 1 year later. Findings suggested that the effects of violence exposure on threat-related neural circuitry depend on trauma context (inside or outside the home) and that primary caregivers can increase resilience.

Reduced heart rate variability (HRV) in response to stress is a biomarker of emotion dysregulation (ED) and is related to posttraumatic stress disorder (PTSD), yet less is known about its role with dissociation in trauma-exposed adults. The goals of the current study were to examine unique patterns of associations between ED, dissociation, and PTSD with HRV at 15, 30, and 45 minutes (T1, T2, T3) following an acute psychosocial stressor task in a sample of 49 trauma-exposed, urban-dwelling Black women. Associations with baseline psychophysiology measures were also examined. ED and dissociation were assessed using self-report; PTSD was determined using a semi-structured interview. Heart rate (HR) and HRV, indexed with low frequency/high frequency (LF/HF) ratio and respiratory sinus arrhythmia (RSA), were measured with electrocardiogram recordings. ED and dissociation were positively correlated with LF/HF ratio at T3 (p

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions.MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR< .05).ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (allp-FDR< 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status.ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

A number of studies of posttraumatic stress disorder (PTSD) report thinner cerebral cortical gyri using gyrus-based analysis or thinner foci within the gyri using vertex-based analysis. However, the locations of these findings are inconsistent across studies, and the spatial transformations required during vertex-based analysis may affect the focal findings. A mega-analysis using a large number of subjects from multiple PTSD studies could potentially identify more reproducible cortical thickness abnormalities. Investigating both the vertex and gyral thicknesses simultaneously may verify the vertex-based focal findings using gyral data without imposing any spatial transformation. Here we aggregated data from 24 international laboratories using ENIGMA standardized procedures for 949 adult PTSD patients and 1493 controls without PTSD (age 18 to 65 years). We examined whether gyral and vertex cortical thickness are (a) different between subjects with PTSD and controls and (b) associated with PTSD symptom severity in trauma-exposed subjects. Regions with overlapping thinner cortical gyri and thinner vertex clusters were located in frontal, temporal, parietal, and occipital cortices. Thinner right lateral orbitofrontal and right lingual gyri and concomitantly thinner vertex clusters in the anterior portions of both gyri were associated with PTSD symptom severity. Convergent findings in these locations suggest focally thinner cortex in these gyri, which may be involved in altered processing and regulation of emotion and sensory inputs underlying posttraumatic stress symptoms.

Human studies of fear neurobiology have established neural circuits that are activated to threatening stimuli, whether it be during Pavlovian fear conditioning or in response to naturally occurring threats. This circuitry involves the central and basolateral amygdala, as well as the bed nucleus of the stria terminalis, insula, hippocampus, and regulatory regions such as the anterior cingulate cortex and ventromedial prefrontal cortex. While research has found that fear-based disorders, such as anxiety and post-traumatic stress disorder, as associated with dysfunction in these circuits, there is substantial individual heterogeneity in the clinical presentation of symptoms. Recent work has used data-driven methods to derive brain biotypes that capitalize on the activity of the fear circuit and its interaction with other regions of the brain. These biotypes have great utility in both describing individual variation in psychopathology and in identifying individuals at greater risk for fear-based disorders after an environmental stressor, such as a traumatic event. The review discusses recent examples of how fear neurobiology studies can be leveraged to derive biotypes that may ultimately lead to improved treatment.

Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.

The COVID-19 pandemic is a rare stressor that has precipitated an accompanying mental health crisis. Prospective studies traversing the pandemic's onset can elucidate how pre-existing disease vulnerabilities augured risk for later stress-related morbidity. We examined how pre-pandemic sleep reactivity predicted maladaptive stress reactions and depressive symptoms in response to, and during, the pandemic. This study is a secondary analysis of a randomised controlled trial from 2016 to 2017 comparing digital cognitive behavioural therapy for insomnia (dCBT-I) against sleep education (N = 208). Thus, we also assessed whether dCBT-I moderated the association between pre-pandemic sleep reactivity and pandemic-related distress. Pre-pandemic sleep reactivity was measured at baseline using the Ford Insomnia Response to Stress Test. In April 2020, participants were recontacted to report pandemic-related distress (stress reactions and depression). Controlling for the treatment condition and the degree of COVID-19 impact, higher pre-pandemic sleep reactivity predicted more stress reactions (β = 0.13, ± 0.07 SE, p = 0.045) and depression (β = 0.22, ± 0.07 SE, p = 0.001) during the pandemic. Further, the odds of reporting clinically significant stress reactions and depression during the pandemic were over twice as high in those with high pre-pandemic sleep reactivity. Notably, receiving dCBT-I in 2016-2017 mitigated the relationship between pre-pandemic sleep reactivity and later stress reactions (but not depression). Pre-pandemic sleep reactivity predicted psychological distress 3-4 years later during the COVID-19 pandemic, and dCBT-I attenuated its association with stress reactions, specifically. Sleep reactivity may inform prevention and treatment efforts by identifying individuals at risk of impairment following stressful events.

We present here a unifying framework for affective phenomena: the Human Affectome. By synthesizing a large body of literature, we have converged on definitions that disambiguate the commonly used terms—affect, feeling, emotion, and mood. Based on this definitional foundation, and under the premise that affective states reflect allostatic concerns, we take a goal-directed, enactive perspective. The human affectome is comprised of allostatic features (valence, motivation, and arousal) and allostatic concerns, which differ in the amount of action required to alleviate allostatic load. Allostatic concerns often fall into three ranges: physiological (the most immediate), operational (intermediate to distal), and global. Global concerns involve summations of overall trajectory, general wellbeing, and self-identity. Within this organizational scheme, the human affectome allows vastly different scientific interests to reside within the same theoretical framework and relate to each other. We hope this framework serves as a common focal point for affective research.

The current study investigated the relationship between trauma exposure and psychopathology in a sample of predominately African-American women of low socioeconomic status (SES). Women (N = 7430) were recruited from medical clinics at two large public hospitals in Atlanta, GA, from 2005 to 2017. Women were assessed for sociodemographics, life-course trauma burden, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) utilizing self-report and structured clinical interview assessments. The effects of trauma exposure on current and lifetime PTSD and MDD were examined. Ninety-one percent of women reported trauma exposure, 83% reported a monthly household income of less than $2000, and 41% reported a history of arrest. Regarding psychiatric diagnoses, 30.8% met the criteria for probable MDD, and 32.3% met the criteria for probable PTSD. History of childhood abuse and total lifetime trauma significantly increased PTSD and depressive symptoms with additional incremental trauma exposure. PTSD and depressive symptom scores (95% CI) increased from 5.5 (5.0-6.1) and 8.4 (7.9-9.0) in the no trauma group to 20.8 (20.1-21.5) and 20.4 (19.7-21.2), respectively, in those exposed to four or more types of trauma. These results show high rates of adult and childhood trauma exposure, PTSD, MDD, and an additive effect of lifetime trauma exposure on the development of PTSD and MDD in a sample of low SES African-American women. These findings bring light to the high psychiatric symptom burden in this population and call for increased availability of interventions to address symptoms as well as policies aimed at reducing trauma exposure across the lifespan.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

Parenting behavior is key to understanding transmission of intergenerational trauma-related risk. Emotion dysregulation (ED) and psychological symptoms are associated with negative parenting behaviors, although their unique roles remain unclear. The current study examined associations of ED dimensions, depression, PTSD, and substance use with parenting behaviors in African American mothers. Participants included 98 mother-child dyads recruited from an urban hospital setting. Trauma exposure, ED, depression, substance use, and parenting behaviors (overreactivity, laxness, demandingness, warmth, corporal punishment) were assessed using self-report measures. PTSD was assessed using a semi-structured interview. Correlational results showed significant positive associations between ED and dysfunctional parenting behavior ( p < .001), overreactivity ( p < .001), and laxness ( p < .01) and negative associations with warmth ( p < .01). These associations varied across the dimensions of ED examined. Regression analyses were run to examine the unique effects of ED (separate models for overall and specific dimensions) and psychological symptoms; overall ED and its dimensions accounted for significant variance in parental behaviors ( R2 = .10–.24, p’s < .01), while additional model steps including psychological symptoms were not significant except for the association between depression and lower warmth. In efforts to reduce the intergenerational effects of trauma, parenting interventions that include a direct focus on certain dimensions of ED may be critical.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

The new coronavirus has crossed the species barrier leading to the pandemic of COVID-19. The lengthy circulation of the virus within the human population has enabled the development of many new viral variants, some of which are conducive to further pathogen spread. Notable variants are those that contain mutations within the S gene, particularly within the region that codes for the receptor-binding domain (RBD) that links to the hACE-2 receptor. These mutations are responsible for increased viral transmission and influence disease severity, reliability of clinical tests, as well as vaccine efficacy. At present, the variant first identified in the United Kingdom poses the greatest threat in Europe.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

African Americans living in low-income urban environments are disproportionately exposed to violence compared to other racial groups. Child exposure to community violence is linked to adverse psychological outcomes, including externalizing and internalizing behaviors. Emotion dysregulation may be one psychological process through which externalizing and internalizing behaviors develop in the context of childhood violence exposure. However, limited research exists on how different aspects of emotion dysregulation are affected by community violence exposure in children.The present study examined whether violence exposure was indirectly associated with externalizing and internalizing behaviors via facets of emotion dysregulation in a sample of 94 African American mother-child dyads. Mothers and children completed measures to assess child community violence exposure, externalizing and internalizing behaviors, and emotion dysregulation (anger, sadness, and worry dysregulation).Results indicated that maternal report of child community violence exposure was indirectly associated with externalizing behaviors via anger dysregulation and internalizing behaviors via worry dysregulation. Child report of community violence exposure was also indirectly associated with externalizing behavior via anger dysregulation; however, there were no significant associations with internalizing behavior.These findings suggest that certain components of emotion dysregulation serve as an indirect pathway of influence for community violence exposure on child behavior, and the pathways differ between externalizing and internalizing behavior outcomes. Emotion dysregulation may serve as an important potential treatment target in reducing long-term risks associated with violence exposure in urban communities of color. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Posttraumatic stress disorder (PTSD) is prevalent and associated with significant morbidity. Mild traumatic brain injury (mTBI) concurrent with psychiatric trauma may be associated with PTSD. Prior studies of PTSD-related structural brain alterations have focused on military populations. The current study examined correlations between PTSD, acute mTBI, and structural brain alterations longitudinally in civilian patients (N = 504) who experienced a recent Criterion A traumatic event. Participants who reported loss of consciousness (LOC) were characterized as having mTBI; all others were included in the control group. PTSD symptoms were assessed at enrollment and over the following year; a subset of participants (n = 89) underwent volumetric brain MRI (M = 53 days posttrauma). Classes of PTSD symptom trajectories were modeled using latent growth mixture modeling. Associations between PTSD symptom trajectories and cortical thicknesses or subcortical volumes were assessed using a moderator-based regression. mTBI with LOC during trauma was positively correlated with the likelihood of developing a chronic PTSD symptom trajectory. mTBI showed significant interactions with cortical thickness in the rostral anterior cingulate cortex (rACC) in predicting PTSD symptoms, r = .461-.463. Bilateral rACC thickness positively predicted PTSD symptoms but only among participants who endorsed LOC, p.001. The results demonstrate positive correlations between mTBI with LOC and PTSD symptom trajectories, and findings related to mTBI with LOC and rACC thickness interactions in predicting subsequent chronic PTSD symptoms suggest the importance of further understanding the role of mTBI in the context of PTSD to inform intervention and risk stratification.

Anxiety sensitivity, or fear of anxious arousal, is cross-sectionally associated with a wide array of adverse posttraumatic neuropsychiatric sequelae, including symptoms of posttraumatic stress disorder, depression, anxiety, sleep disturbance, pain, and somatization. The current study utilizes a large-scale, multi-site, prospective study of trauma survivors presenting to emergency departments. Hypotheses tested whether elevated anxiety sensitivity in the immediate posttrauma period is associated with more severe and persistent trajectories of common adverse posttraumatic neuropsychiatric sequelae in the eight weeks posttrauma. Participants from the AURORA study (n = 2,269 recruited from 23 emergency departments) completed self-report assessments over eight weeks posttrauma. Associations between heightened anxiety sensitivity and more severe and/or persistent trajectories of trauma-related symptoms identified by growth mixture modeling were analyzed. Anxiety sensitivity assessed two weeks posttrauma was associated with severe and/or persistent posttraumatic stress, depression, anxiety, sleep disturbance, pain, and somatic symptoms in the eight weeks posttrauma. Effect sizes were in the small to medium range in multivariate models accounting for various demographic, trauma-related, pre-trauma mental health-related, and personality-related factors. Anxiety sensitivity may be a useful transdiagnostic risk factor in the immediate posttraumatic period identifying individuals at risk for the development of adverse posttraumatic neuropsychiatric sequelae. Further, considering anxiety sensitivity is malleable via brief intervention, it could be a useful secondary prevention target. Future research should continue to evaluate associations between anxiety sensitivity and trauma-related pathology.

Parental emotion regulation plays a major role in parent-child interactions, and in turn, neural plasticity in children, particularly during sensitive developmental periods. However, little is known about how parental emotion dysregulation is associated with variation in children's brain structure, which was the goal of this study. Forty-five Black American mother-child dyads were recruited from an intergenerational trauma study; emotion regulation in mothers and their children (age 8-13 years) was assessed. Diffusion-weighted images were collected in children; deterministic tractography was used to reconstruct pathways of relevance to emotion regulation. Metrics of white matter connectivity [fractional anisotropy (FA), mean diffusivity (MD)] were extracted for pathways. Socio-economic variables were also included in statistical models. Maternal emotion dysregulation was the strongest predictor of child fornix MD (r = .35, p = .001), indicating that more severe emotion dysregulation in mothers corresponded with lower fornix connectivity in children. Maternal impulsivity was a strong predictor of child fornix MD (r = .51, p .001). Maternal emotion dysregulation may adversely influence connectivity of the child.s fornix, a hippocampal-striatal pathway implicated in reward processes; these associations remained even after accounting for other socio-environmental factors. Dysregulated maternal emotions may uniquely impact children's adaptation to trauma/stress by affecting networks that support appetitive processing.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

Vulnerability to stress-related sleep disturbances (sleep reactivity) is an established heritable risk factor for insomnia disorder with unclear biological underpinnings. Preliminary research points to a blunted cortisol response to stress as a biological predisposition to familial risk for insomnia, but the role of cortisol response in sleep reactivity is unknown. Therefore, the current studies examined whether sleep reactivity is associated with a blunted cortisol response to two laboratory stressors among participants without insomnia.Two community samples of adults with no lifetime history of insomnia completed the Trier Social Stress Test (N = 35) or the Cold Pressor Task (N = 34). Participants were grouped by insomnia-risk using sleep reactivity scores from the Ford Insomnia Response to Stress Test (FIRST). Physiological responses were measured via markers of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol) and autonomic nervous system (ANS; heart rate, mean arterial pressure, and salivary alpha amylase).Participants with high insomnia-risk (FIRST score18) exhibited blunted cortisol responses to both stressors. There were no group differences in ANS responses across stressors.Insomnia-risk as indicated by sleep reactivity is associated with blunted cortisol responses to psychosocial and physical laboratory stressors among premorbid adults without insomnia disorder. This study replicates previous research and supports a blunted cortisol response to stress as a biomarker for insomnia vulnerability that may be detected using the FIRST. Prospective research is needed to elucidate whether a blunted cortisol response to stress is one mechanism by which sleep reactive individuals may be at risk of developing insomnia.

Adverse social exposures (ASEs) such as low income, low educational attainment, and childhood/adult trauma exposure are associated with variability in brain region measurements of grey matter volume (GMV), surface area (SA), and cortical thickness (CT). These CNS morphometries are associated with stress-related psychiatric illnesses and represent endophenotypes of stress-related psychiatric illness development. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC), may contribute to the biological embedding of the environment but are understudied and not well understood. How 5mC relates to CNS endophenotypes of psychiatric illness is also unclear.In 97 female, African American, trauma-exposed participants from the Grady Trauma Project, we examined the associations of childhood trauma burden (CTQ), adult trauma burden, low income and low education with blood-derived 5mC clusters and variability in brain region measurements in the amygdala, hippocampus and frontal cortex subregions. To elucidate whether peripheral 5mC indexes CNS endophenotypes of psychiatric illness, we tested whether 73 brain/blood correlated 5mC clusters, defined by networks of correlated 5mC probes measured on Illumina’s HumanMethylation Epic Beadchip, mediated the relationship between ASEs and brain measurements.CTQ was negatively associated with rostral middle frontal gyrus (RMFG) SA (β = - 0.231, p = 0.041). Low income and low education were also associated with SA or CT in a number of brain regions. Seven 5mC clusters were associated with CTQ (pmin = 0.002), two with low education (pmin = 0.010), and three with low income (pmin = 0.007). Two clusters fully mediated the relation between CTQ and RMFG SA, accounting for 47% and 35% of variability respectively. These clusters were enriched for probes falling in DNA regulatory regions, as well as signal transduction and immune signaling gene ontology functions. Methylome-network analyses showed enrichment of macrophage migration (p = 9×10-8), T cell receptor complex (p = 6×10-6), and chemokine-mediated signaling (p = 7×10-4) pathway enrichment in association with CTQ.Our results support prior work highlighting brain region variability associated with ASEs, while informing a peripheral inflammation-based epigenetic mechanism of biological embedding of such exposures. These findings could also serve to potentiate increased investigation of understudied populations at elevated risk for stress-related psychiatric illness development.