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Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n=30) with comorbid PTSD and depression and non-TBI participants from primary (n=42) and confirmatory (n=28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (p < .05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events.

Depending on the traumatic event, a significant fraction of trauma survivors subsequently develop PTSD. The additional variability in PTSD risk is expected to arise from genetic susceptibility. Unfortunately, several genome-wide association studies (GWAS) have failed to identify a consistent genetic marker for PTSD. The heritability of intermediate phenotypes such as regional brain volumes is often 80% or higher. We conducted a GWAS of subcortical brain volumes in a sample of recent military veteran trauma survivors (n = 157), grouped into PTSD (n = 66) and non-PTSD controls (n = 91). Covariates included PTSD diagnosis, sex, intracranial volume, ancestry, childhood trauma, SNP×PTSD diagnosis, and SNP×childhood trauma. We identified several genetic markers in high linkage disequilibrium (LD) with rs9373240 (p = 2.0 × 10−7, FDR q = 0.0375) that were associated with caudate volume. We also observed a significant interaction between rs9373240 and childhood trauma (p-values = 0.0007–0.002), whereby increased trauma exposure produced a stronger association between SNPs and increased caudate volume. We identified several SNPs in high LD with rs34043524, which is downstream of the TRAM1L1 gene that were associated with right lateral ventricular volume (p = 1.73 × 10−7; FDR q = 0.032) and were also associated with lifetime alcohol abuse or dependence (p = 2.49 × 10−7; FDR q = 0.0375). Finally, we identified several SNPs in high LD with rs13140180 (p = 2.58 × 10−7; FDR q = .0016), an intergenic region on chromosome 4, and several SNPs in the TMPRSS15 associated with right nucleus accumbens volume (p = 2.58 × 10−7; FDR q = 0.017). Both TRAM1L1 and TMPRSS15 have been previously implicated in neuronal function. Key results survived genome-wide multiple-testing correction in our sample. Leveraging neuroimaging phenotypes may offer a shortcut, relative to clinical phenotypes, in mapping the genetic architecture and neurobiological pathways of PTSD.

U.S. Coast Guard (CG) personnel face occupational stressors (e.g., search and rescue) which compound daily life stressors encountered by civilians. However, the degree CG personnel express stress-related mental health symptoms of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is understudied as a military branch, and little is known concerning the interplay of vulnerabilities and neurocognitive outcomes in CG personnel. The current study addressed this knowledge gap, recruiting 241 active duty CG personnel (22% female) to assess mental health, personality, and neurocognitive function. Participants completed a battery of scales: PTSD Checklist with military and non-military prompts to screen for PTSD, Psychological Health Questionnaire 8 for MDD, and scales for behaviorally inhibited (BI) temperament, and distressed (Type D) personality. Neurocognitive performance was assessed with the Defense Automated Neurobehavioral Assessment (DANA) battery. Cluster scoring yielded an overall rate of PTSD of 15% (95% CI: 11–20%) and 8% (95% CI: 3–9%) for MDD. Non-military trauma was endorsed twice that of military trauma in those meeting criteria for PTSD. Individual vulnerabilities were predictive of stress-related mental health symptoms in active duty military personnel; specifically, BI temperament predicted PTSD whereas gender and Type D personality predicted MDD. Stress-related mental health symptoms were also associated with poorer reaction time and response inhibition. These results suggest rates of PTSD and MDD are comparable among CG personnel serving Boat Stations to those of larger military services after combat deployment. Further, vulnerabilities distinguished between PTSD and MDD, which have a high degree of co-occurrence in military samples. To what degree stress-related mental healthy symptoms and attendant neurocognitive deficits affect operational effectiveness remains unknown and warrant future study.

Background: Clozapine and lithium increase neurosteroids in rodents, and both drugs demonstrate antisuicidal actions. We therefore hypothesized that neurosteroid levels may be reduced in patients with schizophrenia or bipolar disorder who completed suicide. Aims: To investigate neurosteroid levels in the parietal cortex and posterior cingulate in schizophrenia and bipolar patients who died by suicide, and compare them with patients with these disorders who died of other causes. Method: Neurosteroid levels were quantified by gas chromatography/mass spectrometry in the parietal cortex and posterior cingulate. Mann–Whitney analyses were conducted in exploratory post hoc analyses to investigate neurosteroids as possible biomarker candidates for suicide. Results: The study showed that pregnenolone was significantly decreased in the parietal cortex in the combined group of patients with schizophrenia or bipolar disorder who died by suicide (n = 13) compared with patients with these disorders who died of other causes (n = 17, p = .02). Pregnenolone levels were also lower in the parietal cortex in the individual group of schizophrenia patients who died by suicide (n = 4) compared with schizophrenia patients who died of other causes (n = 11) p = .04). Conclusion: Pregnenolone alterations may be relevant to the neurobiology of suicide in schizophrenia and bipolar disorder.

Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of disability and mortality in both developed and developing societies. The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI. To inform this plan, the Workgroup (a) assessed the current state of the science and ongoing research and (b) identified research gaps to inform future development of research priorities for the neurotrauma research portfolio. The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI.

IMPORTANCE: In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. OBJECTIVE: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. INTERVENTIONS: Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. RESULTS: A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. ...

The United States (US) Department of Veterans Affairs (VA) Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC) Post-Deployment Mental Health (PDMH) multi-site study examines post-deployment mental health in US military Afghanistan/lraq-era veterans. The study includes the comprehensive behavioral health characterization of over 3600 study participants and the genetic, metabolomic, neurocognitive, and neuroimaging data for many of the participants. The study design also incorporates an infrastructure for a data repository to re-contact participants for follow-up studies. The overwhelming majority (94%) of participants consented to be re-contacted for future studies, and our recently completed feasibility study indicates that 73–83% of these participants could be reached successfully for enrollment into longitudinal follow-up investigations. Longitudinal concurrent cohort follow-up studies will be conducted (5–10+ years post-baseline) to examine predictors of illness chronicity, resilience, recovery, functional outcome, and other variables, and will include neuroimaging, genetic/epigenetic, serum biomarker, and neurocognitive studies, among others. To date, the PDMH study has generated more than 35 publications from the baseline data and the repository has been leveraged in over 20 publications from follow-up studies drawing from this cohort. Limitations that may affect data collection for a longitudinal follow-up study are also presented.

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 x 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 x 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 x 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 x 10(-6), p(adj) = 0.042). Conclusions The cross replication observed in independent cohorts is evidence that ...

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.