The default mode network (DMN) has been used to study disruptions of functional connectivity in a wide variety of psychiatric and neurological conditions, including posttraumatic stress disorder (PTSD). Studies indicate that the serotonin system exerts a modulatory influence on DMN connectivity; however, no prior study has examined associations between serotonin receptor gene variants and DMN connectivity in either clinical or healthy samples. We examined serotonin receptor single nucleotide polymorphisms (SNPs), PTSD, and their interactions for association with DMN connectivity in 134 White non-Hispanic veterans. We began by analyzing candidate SNPs identified in prior meta-analyses of relevant psychiatric traits and found that rs7997012 (an HTR2A SNP), implicated previously in anti-depressant medication response in the Sequenced Treatment Alternatives for Depression study (STAR^*D; McMahon et al., 2006), interacted with PTSD to predict reduced connectivity between the posterior cingulate cortex (PCC) and the right medial prefrontal cortex and right middle temporal gyrus (MTG). rs130058 (HTR1B) was associated with connectivity between the PCC and right angular gyrus. We then expanded our analysis to 99 HTR1B and HTR2A SNPs and found two HTR2A SNPs (rs977003 and rs7322347) that significantly moderated the association between PTSD severity and the PCC-right MTG component of the DMN after correcting for multiple testing. Finally, to obtain a more precise localization of the most significant SNP × PTSD interaction, we performed a whole cortex vertex-wise analysis of the rs977003 effect. This analysis revealed the locus of the pre-frontal effect to be in portions of the superior frontal gyrus, while the temporal lobe effect was centered in the middle and inferior temporal gyri. These findings point to the influence of HTR2A variants on DMN connectivity and advance knowledge of the role of 5-HT_2A receptors in the neurobiology of PTSD.

Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.

The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans (n =537, n =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes. As hypothesized, polygenic risk positively predicted externalizing psychopathology and negatively predicted performance on inhibitory control tasks. Gene-by-environment effects were also evident, with trauma exposure predicting greater impulsivity and less working memory capacity, but only at high levels of genetic liability. As expected, polygenic risk was not associated with internalizing psychopathology or episodic memory performance. This is the first independent replication of the polygenic score as a measure of genetic predispositions for externalizing and provides preliminary evidence that executive dysfunction is a heritable vulnerability for externalizing psychopathology.

OBJECTIVE: Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are common among US veterans of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND). We postulated that these injuries may modulate pain processing in these individuals and affect their subjective pain levels. DESIGN: Cross-sectional. SUBJECTS: 310 deployed service members of OEF/OIF/OND without a lifetime history of moderate or severe TBI were included in this study. METHODS: All participants completed a comprehensive evaluation for Blast Exposure, mTBI, PTSD, and Pain Levels. The Boston Assessment of TBI-Lifetime Version (BAT-L) was used to assess blast exposure and potential brain injury during military service. The Clinician-Administered PTSD Scale (CAPS) characterized presence and severity of PTSD. The Visual Analog Scale (VAS) was used to assess pain intensity over the previous month before the interview, with higher scores indicative of worse pain. Statistical analysis was performed by ANOVA and results were adjusted for co-morbidities, clinical characteristics and demographic data. RESULTS: In comparison to control participants (veterans without mTBI or current PTSD), veterans with both current PTSD and mTBI reported the highest pain intensity levels, followed by veterans with PTSD only (P  0.0001 and P = 0.0005, respectively). Pain levels in veterans with mTBI only were comparable to control participants. CONCLUSIONS: Comorbid PTSD and mTBI is associated with increased self-reported pain intensity. mTBI alone was not associated with increased pain.

Degenerative brain changes in Alzheimer's disease may occur in reverse order of normal brain development based on the retrogenesis model. This study tested whether evidence of reverse myelination was observed in mild cognitive impairment (MCI) using a data-driven analytic approach based on life span developmental data. Whole-brain high-resolution diffusion tensor imaging scans were obtained for 31 patients with MCI and 79 demographically matched healthy older adults. Comparisons across corpus callosum (CC) regions of interest (ROIs) showed decreased fractional anisotropy (FA) in the body but not in the genu or splenium; early-, middle-, and late-myelinating ROIs restricted to the CC revealed decreased FA in late- but not early- or middle-myelinating ROIs. Voxelwise group differences revealed areas of lower FA in MCI, but whole-brain differences were equally distributed across early-, middle-, and late-myelinating regions. Overall, results within the CC support the retrogenesis model, although caution is needed when generalizing these results beyond the CC.

BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline. METHODS: This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging. RESULTS: Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ∼.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β=.13, p=.032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β=-.17, p=.009) and indirectly linked to poorer working memory performance via this region (indirect β=-.05, p=.029). Horvath DNAm age estimates were not associated with PTSD or neural integrity. CONCLUSIONS: Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.

BACKGROUND: Metabolic syndrome (MetS), defined by a constellation of cardiometabolic pathologies, is highly prevalent among veterans, especially veterans with posttraumatic stress disorder (PTSD), and poses a major risk for adverse health outcomes, including neurodegeneration and mortality. Given this, we evaluated 1) the association between MetS and neural integrity, indexed by cortical thickness; 2) the relationship between PTSD and MetS; and 3) whether PTSD was associated with cortical thickness indirectly through MetS. METHODS: The sample consisted of 346 U.S. military veterans (89.3% male; 71.4% white) who deployed to Iraq, Afghanistan, or both. Neuroimaging data were available for 274 participants. RESULTS: In whole-brain analyses, MetS was negatively associated with cortical thickness in two left and four right hemisphere regions, as follows: bilateral temporal lobe, including temporal pole, fusiform gyrus, and insula, and extending into occipital cortex (left hemisphere) and orbitofrontal cortex (right hemisphere); bilateral precuneus, posterior cingulate, calcarine, and occipital-parietal cortex; and right rostral anterior cingulate cortex and central sulcus/postcentral gyrus. Path models showed that PTSD predicted MetS (β = .19, p .001), which was associated with reduced cortical thickness (β = -.29 to -.43, all p .001). CONCLUSIONS: Results from this young veteran sample provide evidence that PTSD confers risk for cardiometabolic pathology and neurodegeneration and raise concern that this cohort may be aging prematurely and at risk for substantial medical and cognitive decline. This study highlights the need to identify the molecular mechanisms linking PTSD to MetS and effective interventions to reduce PTSD-related health comorbidities.

Although there is mounting evidence that greater PTSD symptoms are associated with reduced executive functioning, it is not fully understood whether this association is more global or specific to certain executive function subdomains, such as inhibitory control. We investigated the generality of the association between PTSD symptoms and executive function by administering a broad battery of sensitive executive functioning tasks to a cohort of returning Operation Enduring Freedom/Operation Iraqi Freedom Veterans with varying PTSD symptoms. Only tasks related to inhibitory control explained significant variance in PTSD symptoms as well as symptoms of depression, while measures of working memory, measures of switching, and measures simultaneously assessing multiple executive function subdomains did not. Notably, the two inhibitory control measures that showed the highest correlation with PTSD and depressive symptoms, measures of response inhibition and distractor suppression, explained independent variance. These findings suggest that greater posttraumatic psychological symptoms are not associated with a general decline in executive functioning but rather are more specifically related to stopping automatic responses and resisting internal and external distractions.

OBJECTIVE: Mild traumatic brain injury is the signature injury of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND), yet its identification and diagnosis is controversial and fraught with challenges. SETTING: In 2007, the Department of Veterans Affairs (VA) implemented a policy requiring traumatic brain injury (TBI) screening on all individuals returning from deployment in the OEF/OIF/OND theaters of operation that lead to the rapid and widespread use of the VA TBI screen. The Boston Assessment of TBI-Lifetime (BAT-L) is the first validated, postcombat semistructured clinical interview to characterize head injuries and diagnose TBIs throughout the life span, including prior to, during, and post-military service. PARTICIPANTS: Community-dwelling convenience sample of 179 OEF/OIF/OND veterans. MAIN MEASURES: BAT-L, VA TBI screen. RESULTS: Based on BAT-L diagnosis of military TBI, the VA TBI screen demonstrated similar sensitivity (0.85) and specificity (0.82) when administered by research staff. When BAT-L diagnosis was compared with historical clinician-administered VA TBI screen in a subset of participants, sensitivity was reduced. CONCLUSIONS: The specificity of the research-administered VA TBI screen was more than adequate. The sensitivity of the VA TBI screen, although relatively high, suggests that it does not oversample or "catch all" possible military TBIs. Traumatic brain injuries identified by the BAT-L, but not identified by the VA TBI screen, were predominantly noncombat military injuries. There is potential concern regarding the validity and reliability of the clinician administered VA TBI screen, as we found poor correspondence between it and the BAT-L, as well as low interrater reliability between the clinician-administered and research-administered screen.

Understanding the factors that influence veterans' functional outcome after deployment is critical to provide appropriately targeted care. Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) have been related to disability, but other psychiatric and behavioral conditions are not as well examined. We investigated the impact of deployment-related psychiatric and behavioral conditions on disability among 255 OEF/OIF/OND service members and veterans. Structured clinical interviews assessed TBI and the psychiatric conditions of depression, PTSD, anxiety, and substance use. Self-report questionnaires assessed disability and the behavioral conditions of sleep disturbance and pain. Over 90% of participants had a psychiatric and/or behavioral condition, with approximately half presenting with ≥ 3 conditions. Exploratory factor analysis revealed 4 clinically relevant psychiatric and behavioral factors which accounted for 76.9% of the variance: (a) depression, PTSD, and military mTBI (deployment trauma factor); (b) pain and sleep (somatic factor); (c) anxiety disorders, other than PTSD (anxiety factor); and (d) substance abuse or dependence (substance use factor). Individuals with the conditions comprising the deployment trauma factor were more likely to be substantially disabled than individuals with depression and PTSD, but no military mTBI, OR = 3.52; 95% CI [1.09, 11.37]. Depression, PTSD, and a history of military mTBI may comprise an especially harmful combination associated with high risk for substantial disability.