Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

The role of recurrent trauma on post-traumatic stress disorder symptoms and substance use among trauma exposed youth.

Comorbidity between post-traumatic stress disorder (PTSD) and substance use disorder may be explained by a prospective trauma risk conferred by both conditions. The current study modeled concurrent and prospective associations of trauma, PTSD symptoms, and substance use (SU) behavior among trauma exposed youth (ages 8-20). Clinical interviews assessed trauma exposure, PTSD symptom severity, and SU behavior at baseline and at six- and 12-month follow up study visits (N = 2,069). Structural equation models assessed the associations of trauma, PTSD symptoms, and SU behavior. Lifetime trauma was associated with more severe PTSD symptoms and SU behaviors, whereas trauma exposure during the study was only associated with PTSD symptoms. PTSD symptom severity was prospectively associated with trauma exposure. PTSD symptom severity and SU behavior at follow-up study visits were prospectively associated. These results highlight the dynamic interplay between trauma, PTSD symptoms, and SU behavior during youth, a developmental period during which complex psychiatric presentations can have longstanding consequences for health.

Development of a brief bedside tool to screen women sexual assault survivors for risk of persistent posttraumatic stress six months after sexual assault.

This study aims to develop and validate a brief bedside tool to screen women survivors presenting for emergency care following sexual assault for risk of persistent elevated posttraumatic stress symptoms (PTSS) six months after assault. Participants were 547 cisgender women sexual assault survivors who presented to one of 13 sexual assault nurse examiner (SANE) programs for medical care within 72 h of a sexual assault and completed surveys one week and six months after the assault. Data on 222 potential predictors from the SANE visit and the week one survey spanning seven broadly-defined risk factor domains were candidates for inclusion in the screening tool. Elevated PTSS six months after assault were defined as PCL-5 > 38. LASSO logistic regression was applied to 20 randomly selected bootstrapped samples to evaluate variable importance. Logistic regression models comprised of the top 10, 20, and 30 candidate predictors were tested in 10 cross-validation samples drawn from 80% of the sample. The resulting instrument was validated in the remaining 20% of the sample. AUC of the finalized eight-item prediction tool was 0.77 and the Brier Score was 0.19. A raw score of 41 on the screener corresponds to a 70% risk of elevated PTSS at 6 months. Similar performance was observed for elevated PTSS at one year. This brief, eight-item risk stratification tool consists of easy-to-collect information and, if validated, may be useful for clinical trial enrichment and/or patient screening.

Language processing following childhood poverty: Evidence for disrupted neural networks.

Childhood poverty is related to deficits in multiple cognitive domains including adult language function. It is unknown if the brain basis of language is disrupted in adults with childhood poverty backgrounds, controlling for current functioning. Fifty-one adults (age 24) from an existing longitudinal study of childhood poverty, beginning at age 9, were examined on behavioral phonological awareness (LP) and completed an event-related fMRI speech/print processing LP task. Adults from childhood poverty backgrounds exhibited lower LP in adulthood. The middle-income group exhibited greater activation of the bilateral IFG and hippocampus during language processing. In psychophysiological interaction (PPI) analyses, the childhood poverty group exhibited greater coupling between ventral Broca's and the middle temporal gyrus (MTG) as well as coupling between Wernicke's region and bilateralization. Childhood poverty disrupts language processing neural networks in adulthood, after controlling for LP, suggesting that poverty in childhood influences the neurophysiological basis for language processing into adulthood.

Long-term mental health and resilience of the first responders in Japanese ground self-defense forces engaging body recovery after the great east Japan earthquake.

Handling human remains is extremely difficult and stressful task, and it can contribute to the development of stress-related mental health problems. To prevent disaster from the development of mental disorders in first responders, it will be important to elucidate factors sustaining psychological well-being following the events requiring handling of human remains. Japanese Ground Self-Defense Forces (JGSDF) first responders (n = 146), involved in human remains recovery after the Great East Japan Earthquake (GEJE) participated. We examined the psychological resilience (S-H Resilience Test), depressive symptoms (SDS), and psychological distress (GHQ-28) 6 years after GEJE, in three groups; Group A: no contact no view of human remains, B: view only of human remains, and C: direct handling of human remains. S-H Resilience test evaluated the 3 subclasses of resilience; Social Support, Self Efficacy, Sociality. One-way ANOVA revealed the significant difference in resilience scores between Group B and C without any differences in depressive symptoms or psychological distress among the 3 groups. Multiple regression analyses revealed that depressive symptoms and resilience were associated with psychological distress in all participants. Path analyses showed that whereas one subtype of resilience indirectly reduced psychological distress through lower depressive symptoms in Group A (Social Support) and Group B (Sociality), both subtypes of resilience indirectly reduced psychological distress by lowering depressive symptoms in Group C. These findings suggest that exposure to higher stressful situation may decrease the psychological resilience based on the S-H Resilience test, and two subtypes of resilience may be necessary to sustain the psychological well-being.

Impact of PTSD treatment on postconcussive symptoms in veterans: A comparison of sertraline, prolonged exposure, and their combination.

Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms.

The role of resilience in the development of depression, anxiety, and post-traumatic stress disorder after trauma in children and adolescents.

This investigation, conducted within the Texas Childhood Trauma Research Network, investigated the prospective relationships between resiliency and emergent internalizing symptoms among trauma-exposed youth. The cohort encompassed 1262 youth, aged 8-20, from twelve health-related institutions across Texas, who completed assessments at baseline and one- and six-month follow-ups for resiliency, symptoms of depression, generalized anxiety, posttraumatic stress disorder (PTSD), and other demographic and clinical characteristics. At baseline, greater resilience was positively associated with older age, male (vs female) sex assigned at birth, and history of mental health treatment. Unadjusted for covariates, higher baseline resilience was associated with greater prospective depression and PTSD symptoms but not anxiety symptoms. Upon adjusting for demographic and clinical factors, higher baseline resilience was no longer associated with depression, PTSD, or anxiety symptoms. Our analyses demonstrate that the predictive value of resilience on psychopathology is relatively small compared to more readily observable clinical and demographic factors. These data suggest a relatively minor prospective role of resilience in protecting against internalizing symptoms among trauma-exposed youth and highlight the importance of controlling for relevant youth characteristics when investigating a protective effect of resilience on internalizing symptoms.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

Linking trauma to mental health in the statewide Texas Youth Depression and Suicide Research Network (TX-YDSRN).

Rates of youth depression and suicide are rising worldwide and represent public health crises. The present study examined the relationship between trauma history and symptoms of depression, suicidal ideation, and anxiety among suicidal and depressed youth. A diverse group of 1000 8-20-year-olds enrolled in the statewide Texas Youth Depression and Suicide Research Network (TX-YDSRN) reported their trauma history (Traumatic Events Screening Inventory for Children) and symptoms of depression (Patient Health Questionnaire for adolescents; PHQ-A), anxiety (Generalized Anxiety Disorder scale; GAD-7), and suicidality (Concise Health Risk Tracking scale; CHRT-SR). Nearly half of the sample reported exposure to multiple categories of traumatic experiences. Number of trauma exposure categories significantly predicted PHQ-A and GAD-7 scores. Exposure to interpersonal trauma and to sexual trauma were significantly associated with PHQ-A, GAD-7, and CHRT-SR scores. The number of trauma exposure categories was associated with increased levels of anxiety and depression; however, only exposure to interpersonal or sexual trauma was associated with more suicidality. Clinicians should assess trauma exposure in patients seeking psychiatric care, especially for interpersonal and sexual trauma, which may be predictive of increased risk for suicidality in depressed youth. Future work should disentangle the effects of specific trauma types from multiple trauma exposure.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

Greater Early Posttrauma Activation in the Right Inferior Frontal Gyrus Predicts Recovery From Posttraumatic Stress Disorder Symptoms.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with altered emotion processing and modulation in specific brain regions, i.e., the amygdala, insula, and medial prefrontal and anterior cingulate cortices. Functional alterations in these regions, recorded shortly after trauma exposure, may predict changes in PTSD symptoms. METHODS: Survivors (N = 104) of a traumatic event, predominantly a motor vehicle accident, were included. Functional magnetic resonance imaging was used to assess brain activation 1, 6, and 14 months after trauma exposure (T1, T2, and T3, respectively). Participants performed the Shifted-attention Emotional Appraisal Task, which probes 3 affective processes: implicit emotional processing (of emotional faces), emotion modulation by attention shifting (away from these faces), and emotion modulation by appraisal (of the participants' own emotional response to these faces). We defined regions of interest based on task-related activations, extracted beta weights from these regions of interest, and submitted them to a series of analyses to examine relationships between neural activation and PTSD severity over the 3 time points. RESULTS: At T1, a regression model containing activations in the left dorsolateral prefrontal cortex, bilateral inferior frontal gyrus (IFG), and medial prefrontal cortex during emotion modulation by appraisal significantly predicted change in PTSD symptoms. More specifically, greater right IFG activation at T1 was associated with greater reduction in symptom severity (T1-T3). Exploratory analysis also found that activation of the right IFG increased from T1 to T3. CONCLUSIONS: The results suggest that greater early posttrauma activation during emotion appraisal in the right IFG, a region previously linked to cognitive control in PTSD, predicts recovery from PTSD symptoms.

Fear Extinction Learning in Posttraumatic Stress Disorder.

Impairments in fear extinction processes have been implicated in the genesis and maintenance of debilitating psychopathologies, including Posttraumatic stress disorder (PTSD). PTSD, classified as a trauma- and stressor-related disorder, is characterized by four symptom clusters: intrusive recollections of trauma, avoidance of trauma-related stimuli, alterations in cognition and mood, and hyperarousal. One of the key pathological feature associated with the persistence of these symptoms is impaired fear extinction, as delineated in multiple studies employing Pavlovian fear-conditioning paradigms. These paradigms, comprising fear acquisition, extinction, extinction recall, and fear renewal phases, have illuminated the neurobiological substrates of PTSD. Dysfunctions in the neural circuits that mediate these fear learning and extinction processes can result in failure to extinguish fear responses and retain extinction memory, giving rise to enduring experience of fear and anxiety. The protective avoidance behaviors observed in individuals with PTSD further exacerbate intrusive symptoms and pose challenges to effective treatment strategies. A comprehensive analysis of fear conditioning and extinction processes, along with the underlying neurobiology, could significantly enhance our understanding of PTSD pathophysiology. This chapter delineates the role of fear extinction processes in PTSD, investigates the underlying neurobiological substrates, and underscores the therapeutic implications, while also identifying future research directions.

Texas Youth Depression and Suicide Research Network (TX-YDSRN) research registry and learning healthcare network: Rationale, design, and baseline characteristics.

BACKGROUND: American youth are seriously impacted by depression and suicide. The Texas Youth Depression and Suicide Research Network (TX-YDSRN) Participant Registry Study was initiated in 2020 to develop predictive models for treatment outcomes in youth with depression and/or suicidality. This report presents the study rationale, design and baseline characteristics of the first 1000 participants. METHODS: TX-YDSRN consists of the Network Hub (coordinating center), 12 medical school "Nodes" (manage/implement study), each with 1-5 primary care, inpatient, and/or outpatient Sub-Sites (recruitment, data collection). Participants are 8-20-year-olds who receive treatment or screen positive for depression and/or suicidality. Baseline data include mood and suicidality symptoms, associated comorbidities, treatment history, services used, and social determinants of health. Subsequent assessments occur every two months for 24 months. RESULTS: Among 1000 participants, 68.7 % were 12-17 years, 24.6 % were ≥ 18 years, and 6.7 % were < 12. Overall, 36.8 % were non-Hispanic Caucasian, 73.4 % were female, and 79.9 % had a primary depressive disorder. Nearly half of the sample reported ≥1 suicide attempt, with rates similar in youth 12-17 years old (49.9 %) and those 18 years and older (45.5 %); 29.9 % of children <12 reported at least one suicide attempt. Depression and anxiety scores were in the moderate-severe range for all age groups (Patient Health Questionnaire for Adolescents [PHQ-A]: 12.9 ± 6.4; Generalized Anxiety Disorder [GAD-7]: 11.3 ± 5.9). LIMITATIONS: The sample includes youth who are receiving depression care at enrollment and may not be representative of non-diagnosed, non-treatment seeking youth. CONCLUSIONS: The TX-YDSRN is one of the largest prospective longitudinal cohort registries designed to develop predictive models for outcome trajectories based on disorder heterogeneity, social determinants of health, and treatment availability.

Stressful life events and incident depression among U.S. military personnel.

PURPOSE: Although stressful life events (i.e., stressors) and depression are often assumed to be linked, the relation between stressors and incident depression is rarely studied, particularly in the military. The National Guard is a part-time subset of the U.S. military for whom civilian life stressors may be particularly salient, due to the soldiers' dual roles and frequent transitions between military and civilian life. METHODS: We used a dynamic cohort study of National Guard members from 2010 to 2016 to investigate the relationship between recent stressful experiences (e.g., divorce) and incident depression, with an exploratory analysis of effect modification by income. RESULTS: Respondents endorsing at least one of nine past-year stressful events (a time-varying exposure, lagged by 1 year) had almost twice the adjusted rate of incident depression compared to those with no stressful events (HR = 1.8; 95% CI 1.4, 2.4). This association may be modified by income: among individuals making under $80,000 per year, those with past-year stressors had twice the rate of depression compared to those with no stressors, but among those making over $80,000, past-year stressors were associated with only 1.2 times the rate of depression. CONCLUSION: Stressful life events outside of deployment are important determinants of incident depression among National Guard servicemembers, but the effect of these events may be buffered by higher income.

DNA methylation GrimAge acceleration in US military veterans with PTSD.

Epigenetic alterations in DNA methylation might mediate gene expression effects of trauma underlying PTSD symptoms, or effects of PTSD on related health problems. PTSD is associated with all-cause morbidity and premature mortality, suggesting accelerated biological aging. We measured genome-wide DNA methylation (Illumina MethylationEPIC BeadChip) in whole blood in a treatment study for combat-related PTSD - "PROGrESS", a multisite RCT comparing sertraline plus enhanced medication management (SERT + EMM), prolonged exposure (PE) therapy plus placebo (PE + PLB), and the combination (SERT + PE). DNA methylation was measured in 140 US military veterans who served in Iraq and/or Afghanistan (112 current PTSD cases enrolled in a PTSD treatment study and 28 veterans without PTSD history controls), and also 59 non-trauma exposed controls at baseline posttreatment (24 weeks after baseline). Increased DNA methylation GrimAge acceleration (p = 8.8e-09) was observed in patients with PTSD compared to a pooled control group (trauma exposed and non-trauma exposed), suggesting a higher risk of premature mortality in those with PTSD. There was no difference in GrimAge acceleration between combat trauma and non-trauma exposed controls. No treatment-related changes in GrimAge acceleration were found in within-subject comparisons of PTSD patients pre- to post-treatment.

Do diurnal salivary cortisol curves carry meaningful information about the regulatory biology of the HPA axis in healthy humans?

Salivary cortisol stress biomarkers have been extensively used in epidemiological work to document links between stress and ill health. There has been little effort to ground field friendly cortisol measures in the hypothalamic-pituitary-adrenal (HPA) axis regulatory biology that is likely relevant to delineating mechanistic pathways leading from stress exposure to detrimental health outcomes. Here, we utilized a healthy convenience sample (n = 140) to examine normal linkages between extensively collected salivary cortisol measures and available laboratory probes of HPA axis regulatory biology. Participants provided 9 saliva samples per day over 6 days within a month, while engaging in usual activities, and also participated in 5 regulatory tests (adrenocorticoptripin stimulation, dexamethasone/corticotropin-releasing-hormone stimulation, metyrapone, dexamethasone suppression, and Trier Social Stress Test). Logistical regression was used to test specific predictions linking cortisol curve components to regulatory variables and to explore widely for non-predicted associations. We found support for 2 of 3 original hypotheses, showing associations (1) between cortisol diurnal decline and feedback sensitivity as measured by dexamethasone suppression, and (2) between morning cortisol levels and adrenal sensitivity. We did not find links between central drive (metyrapone test) and end of day salivary levels. We confirmed an a priori expectation of limited linkage between regulatory biology and diurnal salivary cortisol measures, beyond those predicted. These data support an emerging focus on measures related to diurnal decline in epidemiological stress work. They raise questions about the biological meaning of other curve components, including morning cortisol levels, and perhaps CAR (Cortisol Awakening Response). If morning cortisol dynamics are linked to stress, more work on adrenal sensitivity in stress adaptation and stress-health links may be warranted.

Evaluating the Evidence for Brain-Based Biotypes of Psychiatric Vulnerability in the Acute Aftermath of Trauma.

OBJECTIVE: The weak link between subjective symptom-based diagnostic methods for posttraumatic psychopathology and objectively measured neurobiological indices forms a barrier to the development of effective personalized treatments. To overcome this problem, recent studies have aimed to stratify psychiatric disorders by identifying consistent subgroups based on objective neural markers. Along these lines, a promising 2021 study by Stevens et al. identified distinct brain-based biotypes associated with different longitudinal patterns of posttraumatic symptoms. Here, the authors conducted a conceptual nonexact replication of that study using a comparable data set from a multimodal longitudinal study of recent trauma survivors. METHODS: A total of 130 participants (mean age, 33.61 years, SD=11.21; 48% women) admitted to a general hospital emergency department following trauma exposure underwent demographic, clinical, and neuroimaging assessments 1, 6, and 14 months after trauma. All analyses followed the pipeline outlined in the original study and were conducted in collaboration with its authors. RESULTS: Task-based functional MRI conducted 1 month posttrauma was used to identify four clusters of individuals based on profiles of neural activity reflecting threat and reward reactivity. These clusters were not identical to the previously identified brain-based biotypes and were not associated with prospective symptoms of posttraumatic psychopathology. CONCLUSIONS: Overall, these findings suggest that the original brain-based biotypes of trauma resilience and psychopathology may not generalize to other populations. Thus, caution is warranted when attempting to define subtypes of psychiatric vulnerability using neural indices before treatment implications can be fully realized. Additional replication studies are needed to identify more stable and generalizable neuroimaging-based biotypes of posttraumatic psychopathology.

Longitudinal volumetric evaluation of hippocampus and amygdala subregions in recent trauma survivors.

The hippocampus and the amygdala play a central role in post-traumatic stress disorder (PTSD) pathogenesis. While alternations in volumes of both regions have been consistently observed in individuals with PTSD, it remains unknown whether these reflect pre-trauma vulnerability traits or acquired post-trauma consequences of the disorder. Here, we conducted a longitudinal panel study of adult civilian trauma survivors admitted to a general hospital emergency department (ED). One hundred eligible participants (mean age = 32.97 ± 10.97, n = 56 females) completed both clinical interviews and structural MRI scans at 1-, 6-, and 14-months after ED admission (alias T1, T2, and T3). While all participants met PTSD diagnosis at T1, only n = 29 still met PTSD diagnosis at T3 (a "non-Remission" Group), while n = 71 did not (a "Remission" Group). Bayesian multilevel modeling analysis showed robust evidence for smaller right hippocampus volume (P+ of ~0.014) and moderate evidence for larger left amygdala volume (P+ of ~0.870) at T1 in the "non-Remission" group, compared to the "Remission" group. Subregion analysis further demonstrated robust evidence for smaller volume in the subiculum and right CA1 hippocampal subregions (P+ of ~0.021-0.046) in the "non-Remission" group. No time-dependent volumetric changes (T1 to T2 to T3) were observed across all participants or between groups. Results support the "vulnerability trait" hypothesis, suggesting that lower initial volumes of specific hippocampus subregions are associated with non-remitting PTSD. The stable volume of all hippocampal and amygdala subregions does not support the idea of consequential, progressive, stress-related atrophy during the first critical year following trauma exposure.

Rare copy number variation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.