BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. METHODS: Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. RESULTS: Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. CONCLUSIONS: These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.

Cerebral blood flow (CBF) is critically important in the overall maintenance of brain health and has been linked to the degradation of the brain’s structural integrity. Recent emphasis has been placed on understanding CBF as a potential pathological link between psychiatric disorders and brain integrity. Although childhood trauma is a risk factor for the development of psychiatric disorders and has been linked to disruptions in brain structure and function, the mechanisms through which childhood trauma alters brain integrity and development remains unclear. The goal of this study was to understand whether early life trauma was associated with alterations in CBF.

BACKGROUND: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). METHODS: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). RESULTS: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10(-7), p(adj) = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10(-6)), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10(-5), p(adj) = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10(-6), p(adj) = 0.042). CONCLUSIONS: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

Background: Cerebral blood flow (CBF) is critically important in the overall maintenance of brain health, and disruptions in normal flow have been linked to the degradation of the brain's structural integrity and function. Recent studies have highlighted the potential role of CBF as a link between psychiatric disorders and brain integrity. Although interpersonal early life trauma (IP-ELT) is a risk factor for the development of psychiatric disorders and has been linked to disruptions in brain structure and function, the mechanisms through which IP-ELT alters brain integrity and development remain unclear. The goal of this study was to understand whether IP-ELT was associated with alterations in CBF assessed during adulthood. Further, because the cognitive implications of perfusion disruptions in IP-ELT are also unclear, this study sought to investigate the relationship between IP-ELT, perfusion, and cognition.Methods: 179 Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) Veterans and military personnel completed pseudo-continuous arterial spin labeling (pCASL) imaging, clinical interviews, the Traumatic Life Events Questionnaire (TLEQ), and a battery of neuropsychological tests that were used to derive attention, memory, and executive function cognitive composite scores. To determine whether individuals were exposed to an IP-ELT, events on the TLEQ that specifically queried interpersonal trauma before the age of 18 were tallied for each individual. Analyses compared individuals who reported an interpersonal IP-ELT (IP-ELT+, n = 48) with those who did not (IP-ELT-, n = 131).Results: Whole brain analyses revealed that IP-ELT+ individuals had significantly greater CBF in the right inferior/middle temporal gyrus compared to those in the IP-ELT- group, even after controlling for age, sex, and posttraumatic stress disorder (PTSD). Further, perfusion in the right inferior/middle temporal gyrus significantly mediated the relationship between IP-ELT and memory, not attention or executive function, such that those with an IP-ELT had greater perfusion, which, in turn, was associated with poorer memory. Examination of other clinical variables such as current PTSD diagnosis and severity as well as the interaction between IP-ELT and PTSD yielded no significant effects.Conclusions: These results extend prior work demonstrating an association between ELT and cerebral perfusion by suggesting that increased CBF may be an important neural marker with cognitive implications in populations at risk for psychiatric disorders.

BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders. METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

Evidence suggests that blast exposure has profound negative consequences for the health of the human brain, and that it may confer risk for the development of neurodegenerative diseases such as chronic traumatic encephalopathy and Alzheimer's disease (AD). Although the molecular mechanisms linking blast exposure to subsequent neurodegeneration is an active focus of research, recent studies suggest that genetic risk for AD may elevate the risk of neurodegeneration following traumatic brain injury (TBI). However, it is currently unknown if blast exposure also interacts with AD risk to promote neurodegeneration. In this study we examined whether apolipoprotein (APOE) ɛ4, a well-known genetic risk factor for AD, influenced the relationship between blast exposure and white matter integrity in a cohort of 200 Iraq and Afghanistan war veterans. Analyses revealed a significant interaction between close-range blast exposure (CBE) (close range being within 10 m) and APOE ɛ4 carrier status in predicting white matter abnormalities, measured by a voxelwise cluster-based method that captures spatial heterogeneity in white matter disruptions. This interaction remained significant after controlling for TBI, pointing to the specificity of CBE and APOE in white matter disruptions. Further, among veteran ɛ4 carriers exposed to close-range blast, we observed a positive association between the number of CBEs and the number of white matter abnormalities. These results raise the possibility that CBE interacts with AD genetic influences on neuropathological processes such as the degradation of white matter integrity.

Background:Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls.Methods:Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness.Results:Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p’s0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p0.02).Limitations:Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans.Conclusions:These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).

BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

Aim: We compared the performance of multiple testing corrections for candidate gene methylation studies, namely Sidak (accurate Bonferroni), false-discovery rate and three adjustments that incorporate the correlation between CpGs: extreme tail theory (ETT), Gao et al. (GEA), and Li and Ji methods. Materials & methods: The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. Results: For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal. The GEA method tended to be conservative unless a threshold parameter was adjusted. The ETT yielded an appropriate type 1 error rate. Conclusion: For genes with substantial correlation across measured CpGs, GEA and ETT can appropriately correct for multiple testing in candidate gene methylation studies.