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.

OBJECTIVES: To determine the prevalence of comorbid mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and depression, termed the deployment trauma phenotype (DTP), and its constituent diagnoses' impact on unemployment status in a national cohort of veterans. SETTING: Retrospective analysis of the comprehensive TBI evaluation, a Veterans Affairs-wide protocol for assessing TBI, employment status, and psychiatric impressions. PARTICIPANTS: The final data set consisted of 48 821 veterans. MAIN OUTCOMES AND MEASURES: Frequency of mTBI, PTSD, and depression in isolation and combinations and their association with unemployment status. RESULTS: Age- and education-adjusted risk ratios (RRs) showed that the mTBI-only group was the least likely to be unemployed, RR = 0.65 (0.59-0.71). By contrast, the greatest likelihood of unemployment was associated with membership in the DTP group, RR = 1.45 (1.36-1.56), and the comorbid PTSD and depression group, RR = 1.39 (1.27-1.52). Furthermore, the DTP was nearly 3 times more prevalent (16.4%) in this sample compared with comorbid PTSD and depression (5.7%), indicating that the DTP conveys risk for unemployment to a significantly greater number of individuals. CONCLUSIONS AND RELEVANCE: The comorbid and interactive conditions of PTSD, depression, and mTBI, rather than mTBI in isolation, were linked to significant risk for unemployment in this veteran cohort. These findings suggest that multifaceted assessments and interventions to improve postdeployment reintegration are needed.

OBJECTIVE: This study assessed the strength of military-related concussion-, psychological-, and behavioral-related measures to predict neurobehavioral symptom (NBS) reporting in order to help clarify the extent to which persistent NBS reflect lingering effects of concussion vs other psychological/behavioral factors among veterans. METHODS: Baseline analysis included 351 consecutively enrolled veterans in the Translational Research Center for Traumatic Brain Injury and Stress Disorders longitudinal cohort study. One hundred eighty-six returned for a follow-up evaluation averaging 24 months post baseline. The Neurobehavioral Symptom Inventory (NSI) was used to measure NBS reporting. Predictor variables included diagnosis of military-related mild traumatic brain injury (M-mTBI), psychological measures, including posttraumatic stress disorder, mood, anxiety, and substance abuse disorders, and behavioral measures, including self-reported current pain and sleep impairment. Hierarchical and multivariable regression analyses examined the relationships between the predictor variables and NSI scores. The k-fold cross-validation assessed generalizability and validity of the regressions. RESULTS: Baseline analysis revealed that psychological and behavioral conditions independently accounted for 42.5% of variance in the NSI total score compared to 1.5% for M-mTBI after controlling for psychological and behavioral conditions. Prospective analysis revealed that M-mTBI at baseline did not significantly predict NSI score at follow-up, while psychological and behavioral measures at baseline independently accounted for 24.5% of NSI variance. Posttraumatic stress disorder was the most consistent predictor. Cross-validation analyses supported generalizability of the results. CONCLUSIONS: Psychological and behavioral-related measures are strong predictors of persistent NBS reporting in veterans, while M-mTBI is negligible. NBS more likely reflect influential comorbidities as opposed to brain injury, per se.

While the associations between psychological distress (e.g., posttraumatic stress disorder [PTSD], depression) and sleep dysfunction have been demonstrated in trauma-exposed populations, studies have not fully explored the associations between sleep dysfunction and the wide range of common physical and physiological changes that can occur after trauma exposure (e.g., pain, cardiometabolic risk factors). We aimed to clarify the unique associations of psychological and physical trauma sequelae with different aspects of self-reported sleep dysfunction. A comprehensive psychological and physical examination was administered to 283 combat-deployed trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans. The Pittsburgh Sleep Quality Index (PSQI) and PSQI Addendum for PSTD (PSQI-A) were administered along with measures of PTSD, depression, anxiety, pain, traumatic brain injury, alcohol use, nicotine dependence, and cardiometabolic symptoms. We first performed a confirmatory factor analysis of the PSQI and then conducted regressions with the separate PSQI factors as well as the PSQI-A to identify unique associations between trauma-related measures and the separate aspects of sleep. We found that the PSQI global score was composed of three factors: Sleep Efficiency (sleep efficiency/sleep duration), Perceived Sleep Quality (sleep quality/sleep latency/sleep medication) and Daily Disturbances (sleep disturbances/daytime dysfunction). Linear regressions demonstrated that PTSD symptoms were uniquely associated with the PSQI global score and all three factors, as well as the PSQI-A. For the other psychological distress variables, anxiety was independently associated with PSQI global as well as Sleep Efficiency, Perceived Sleep Quality, and PSQI-A, whereas depression was uniquely associated with Daily Disturbances and PSQI-A. Notably, cardiometabolic symptoms explained independent variance in PSQI global and Sleep Efficiency. These findings help lay the groundwork for further investigations of the mechanisms of sleep dysfunction in trauma-exposed individuals and may help in the development of more effective, individualized treatments.

BACKGROUND: Posttraumatic stress disorder is associated with impairments in sustained attention, a fundamental cognitive process important for a variety of social and occupational tasks. To date, however, the precise nature of these impairments and the posttraumatic stress disorder symptoms associated with them have not been well understood. METHODS: Using a well-characterized sample of returning United States military OEF/OIF/OND Veterans who varied in posttraumatic stress disorder symptoms, we employed a validated sustained attention paradigm designed to probe fluctuations across two attentional states characterized by prior research, including a peak state termed "in the zone" and a less efficient, more error-prone state termed "out of the zone." Rewarded and nonrewarded conditions were employed to examine whether motivating strong task performance could ameliorate sustained attention deficits. Analyses examined associations between attentional state, availability of reward, and posttraumatic stress disorder symptoms. RESULTS: Results indicated that, consistent with prior findings, higher levels of posttraumatic stress disorder symptoms were broadly associated with impaired task performance. This impairment was driven largely by performance deficits during individuals' optimal ("in the zone") attentional state, and follow-up analyses indicated that the performance deficit was primarily associated with anhedonia and emotional numbing symptoms. However, the deficit was partially ameliorated when better performance was rewarded. CONCLUSION: Our results provide a more complex understanding of the sustained attention deficits associated with posttraumatic stress disorder and suggest that external incentives may help to enhance sustained attention performance for affected individuals.

Novel paradigms have allowed for more precise measurements of sustained attention ability and fluctuations in sustained attention over time, as well as the neural basis of fluctuations and lapses in performance. However, in recent years, concerns have arisen over the replicability of neuroimaging studies and psychology more broadly, particularly given the typically small sample sizes. One recently developed paradigm, the gradual-onset continuous performance task (gradCPT) has been validated behaviorally in large samples of participants. Yet neuroimaging studies investigating the neural basis of performance on this task have only been collected in small samples. The present study completed both a robust replication of the original neuroimaging findings and extended previous results from the gradCPT task using a large sample of 140 Veteran participants. Results replicate findings that fluctuations in attentional stability are tracked over time by BOLD activity in task positive (e.g., dorsal and ventral attention networks) and task negative (e.g., default network) regions. Extending prior results, we relate this coupling between attentional stability and on-going brain activity to overall sustained attention ability and demonstrate that this coupling strength, along with across-network coupling, could be used to predict individual differences in performance. Additionally, the results extend previous findings by demonstrating that temporal dynamics across the default and dorsal attention networks are associated with lapse-likelihood on subsequent trials. This study demonstrates the reliability of the gradCPT, and underscores the utility of this paradigm in understanding attentional fluctuations, as well as individual variation and deficits in sustained attention.

OBJECTIVES: This study investigated the relationship between close proximity to detonated blast munitions and cognitive functioning in OEF/OIF/OND Veterans. METHODS: A total of 333 participants completed a comprehensive evaluation that included assessment of neuropsychological functions, psychiatric diagnoses and history of military and non-military brain injury. Participants were assigned to a Close-Range Blast Exposure (CBE) or Non-Close-Range Blast Exposure (nonCBE) group based on whether they had reported being exposed to at least one blast within 10 meters. RESULTS: Groups were compared on principal component scores representing the domains of memory, verbal fluency, and complex attention (empirically derived from a battery of standardized cognitive tests), after adjusting for age, education, PTSD diagnosis, sleep quality, substance abuse disorder, and pain. The CBE group showed poorer performance on the memory component. Rates of clinical impairment were significantly higher in the CBE group on select CVLT-II indices. Exploratory analyses examined the effects of concussion and multiple blasts on test performance and revealed that number of lifetime concussions did not contribute to memory performance. However, accumulating blast exposures at distances greater than 10 meters did contribute to poorer performance. CONCLUSIONS: Close proximity to detonated blast munitions may impact memory, and Veterans exposed to close-range blast are more likely to demonstrate clinically meaningful deficits. These findings were observed after statistically adjusting for comorbid factors. Results suggest that proximity to blast should be considered when assessing for memory deficits in returning Veterans. Comorbid psychiatric factors may not entirely account for cognitive difficulties. (JINS, 2018, 24, 466-475).

The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

BACKGROUND: Recent studies have implicated inflammatory processes in the pathophysiology of posttraumatic stress disorder (PTSD). C-reactive protein (CRP) is a widely-used measure of peripheral inflammation, but little is known about the genetic and epigenetic factors that influence blood levels of C-reactive protein (CRP) in individuals with PTSD. METHODS: Participants were 286 U.S. military veterans of post-9/11 conflicts (57% with current PTSD). Analyses focused on single nucleotide polymorphisms (SNPs) in the CRP gene and DNA methylation at cg10636246 in AIM2-a locus recently linked to CRP levels through results from a large-scale epigenome-wide association study. RESULTS: PTSD was positively correlated with serum CRP levels with PTSD cases more likely to have CRP levels in the clinically-elevated range compared to those without a PTSD diagnosis. Multivariate analyses that controlled for white blood cell proportions, genetic principal components, age and sex, showed this association to be mediated by methylation at the AIM2 locus. rs3091244, a functional SNP in the CRP promoter region, moderated the association between lifetime trauma exposure and current PTSD severity. Analyses also revealed that the top SNPs from the largest genome-wide association study of CRP conducted to date (rs1205 and rs2794520) significantly interacted with PTSD to influence CRP levels. CONCLUSIONS: These findings provide new insights into genetic and epigenetic mechanisms of inflammatory processes in the pathophysiology of PTSD and point to new directions for biomarker identification and treatment development for patients with PTSD.