Faculty Bibliography

DNA methylation patterns change with age and can be used to derive an estimate of "epigenetic age," an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n = 79) and without PTSD (n = 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath's epigenetic clock algorithm and Δage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Δage = 3.2), Δage was on average lower compared to those without PTSD (Δage = 5.0; p = 0.02; Cohen's d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Δage (β = -0.35; p = 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD.

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10^-8 (dominant model), P = 7.76 × 10^-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.

BACKGROUND:Approximately half of US service members are married, equating to 1.1 million military spouses, yet the prevalence of psychiatric morbidity among military spouses remains understudied. We assessed the prevalence and correlates of eight mental health conditions in spouses of service members with 2-5 years of service. METHOD/METHODS:We employed baseline data from the Millennium Cohort Family Study, a 21-year longitudinal survey following 9,872 military-affiliated married couples representing all US service branches and active duty, Reserve, and National Guard components. Couples were surveyed between 2011 and 2013, a period of high military operational activity associated with Operation Iraqi Freedom and Operation Enduring Freedom. Primary outcomes included depression, anxiety, posttraumatic stress disorder (PTSD), panic, alcohol misuse, insomnia, somatization, and binge eating, all assessed with validated self-report questionnaires. RESULTS:A total of 35.90% of military spouses met criteria for at least one psychiatric condition. The most commonly endorsed conditions were moderate-to-severe somatization symptoms (17.63%) and moderate-to-severe insomnia (15.65%). PTSD, anxiety, depression, panic, alcohol misuse, and binge eating were endorsed by 9.20%, 6.65%, 6.05%, 7.07%, 8.16%, and 5.23% of spouses, respectively. Having a partner who deployed with combat resulted in higher prevalence of anxiety, insomnia, and somatization. Spouses had lower prevalence of PTSD, alcohol misuse, and insomnia but higher rates of panic and binge eating than service members. Both members of a couple rarely endorsed having the same psychiatric problem. CONCLUSIONS:One third of junior military spouses screened positive for one or more psychiatric conditions, underscoring the need for high-quality prevention and treatment services.

Cognitive models suggest that posttraumtic stress disorder (PTSD) is maintained, in part, as a result of an individual's maladaptive beliefs about one's ability to cope with current and future stress. These models are consistent with considerable findings showing a link between low levels of self-efficacy and PTSD. A growing body of work has demonstrated that perceptions of self-efficacy can be enhanced experimentally in healthy subjects and participants with PTSD, and increasing levels of self-efficacy improves performance on cognitive, affective, and problem-solving tasks. This study aimed to determine whether increasing perceptions of self-efficacy in participants with PTSD would be associated with changes in neural processing. Combat veterans (N = 34) with PTSD were randomized to either a high self-efficacy (HSE) induction, in which they were asked to recall memories associated with successful coping, or a control condition before undergoing resting state fMRI scanning. Two global network measures in four neural circuits were examined. Participants in the HSE condition showed greater right-lateralized path length and decreased right-lateralized connectivity in the emotional regulation and executive function circuit. In addition, area under receiver operating characteristics curve (AUC) analyses found that average connectivity (.71) and path length (.70) moderately predicted HSE group membership. These findings provide further support for the importance of enhancing perceived control in PTSD, and doing so may engage neural targets that could guide the development of novel interventions.

Posttraumatic stress disorder (PTSD) is associated with abnormalities in functional connectivity of a specific cortico-limbic network; however, less is known about white matter abnormalities providing structural connections for this network. This study investigated whether the diagnosis and symptoms of PTSD are associated with alterations in fractional anisotropy (FA), an index reflecting white matter organization, across six, a priori-defined tracts. White matter FA was quantified by diffusion tensor imaging using 3 T-MRI among 57 male, combat-exposed veterans with no history of moderate to severe head injuries or current alcohol dependence: 31 met criteria for PTSD and 26 were demographically comparable, combat-exposed controls without PTSD. Clinician-administered and self-report questionnaires assessed PTSD severity, dissociation, and mood. PTSD + veterans had significantly higher FA than exposed controls in the superior fronto-occipital fasciculus (SFOF) and borderline higher FA in the anterior corona radiata (ACR) and cingulum (CGC), controlling for age and neurovascular comorbidities. When lifetime alcohol use disorders was included, only the association of PTSD with SFOF-FA remained significant. Among PTSD + veterans, higher SFOF-FA was associated with greater mood disturbance, dissociative symptoms, and re-experiencing, while lower FA of the uncinate fasciculus (UF) was associated with greater mood disturbance symptoms. Compared to combat-exposed controls without PTSD, veterans with PTSD exhibited higher white matter FA in the SFOF, and a similar tendency in the ACR and CGC, tracts involved in conflict-processing and spatial attention. Prior alcohol use might explain the associations of PTSD with ACR-FA and CGC-FA but not the association with SFOF-FA.

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebral microhemorrhages are a known marker of mild traumatic brain injury. Blast-related mild traumatic brain injury relates to a propagating pressure wave, and there is evidence that the mechanism of injury in blast-related mild traumatic brain injury may be different from that in blunt head trauma. Two recent reports in mixed cohorts of blunt and blast-related traumatic brain injury in military personnel suggest that the prevalence of cerebral microhemorrhages is lower than in civilian head injury. In this study, we aimed to characterize the prevalence of cerebral microhemorrhages in military service members specifically with chronic blast-related mild traumatic brain injury. MATERIALS AND METHODS/METHODS:Participants were prospectively recruited and underwent 3T MR imaging. Susceptibility-weighted images were assessed by 2 neuroradiologists independently for the presence of cerebral microhemorrhages. RESULTS:Our cohort included 146 veterans (132 men) who experienced remote blast-related mild traumatic brain injury (mean, 9.4 years; median, 9 years after injury). Twenty-one (14.4%) reported loss of consciousness for <30 minutes. Seventy-seven subjects (52.7%) had 1 episode of blast-related mild traumatic brain injury; 41 (28.1%) had 2 episodes; and 28 (19.2%) had >2 episodes. No cerebral microhemorrhages were identified in any subject, as opposed to the frequency of SWI-detectable cerebral microhemorrhages following blunt-related mild traumatic brain injury in the civilian population, which has been reported to be as high as 28% in the acute and subacute stages. CONCLUSIONS:Our results may reflect differences in pathophysiology and the mechanism of injury between blast- and blunt-related mild traumatic brain injury. Additionally, the chronicity of injury may play a role in the detection of cerebral microhemorrhages.