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Background Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. Methods Cytosine methylation of a relevant promoter of the GR gene ( NR3C1 -1 F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. Results Lower NR3C1 -1 F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1 -1 F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1 -1 F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. Conclusions Alterations in NR3C1 -1 F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear.We quantified interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and C-reactive protein (CRP) in 51 combat-exposed males with PTSD and 51 combat-exposed males without PTSD, and assessed PTSD and depression severity as well as history of early life trauma. To decrease the possibility of Type I errors, we summed standardized scores of IL-1β, IL-6, TNFα, IFNγ and CRP into a total "pro-inflammatory score". PTSD symptom severity was assessed with the Clinician Administered PTSD Scale (CAPS) rating scale.Subjects with PTSD had significantly higher pro-inflammatory scores compared to combat-exposed subjects without PTSD (p=0.006), and even after controlling for early life trauma, depression diagnosis and severity, body mass index, ethnicity, education, asthma/allergies, time since combat and the use of possibly confounding medications (p=0.002). Within the PTSD group, the pro-inflammatory score was not significantly correlated with depressive symptom severity, CAPS total score, or with the number of early life traumas.Combat-related PTSD in males is associated with higher levels of pro-inflammatory cytokines, even after accounting for depression and early life trauma. These results, from one of the largest studies of inflammatory cytokines in PTSD to date, suggest that immune activation may be a core element of PTSD pathophysiology more so than a signature of combat exposure alone.

Heterogeneity in glucocorticoid response to experimental stress conditions has shown to differentiate individuals with healthy from maladaptive real-life stress responses in a number of distinct domains. However, it is not known if this heterogeneity influences the risk for developing stress related disorders or if it is a biological consequence of the stress response itself. Determining if glucocorticoid response to stress induction prospectively predicts psychological vulnerability to significant real life stressors can adjudicate this issue. To test this relationship, salivary cortisol as well as catecholamine responses to a laboratory stressor during academy training were examined as predictors of empirically identified distress trajectories through the subsequent 4 years of active duty among urban police officers routinely exposed to potentially traumatic events and routine life stressors (N = 234). During training, officers were exposed to a video vignette of police officers exposed to real-life trauma. Changes in salivary 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol in response to this video challenge were examined as predictors of trajectory membership while controlling for age, gender, and baseline neuroendocrine levels. Officers who followed trajectories of resilience and recovery over 4 years mounted significant increases in cortisol in response to the experimental stressor, while those following a trajectory of chronic increasing distress had no significant cortisol change in response to the challenge. MHPG responses were not associated with distress trajectories. Cortisol response prospectively differentiated trajectories of distress response suggesting that a blunted cortisol response to a laboratory stressor is a risk factor for later vulnerability to distress following significant life stressors.

Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder, especially in combat veterans. Existing functional neuroimaging studies have provided important insights into the neural mechanisms of PTSD using various experimental paradigms involving trauma recollection or other forms of emotion provocation. However it is not clear whether the abnormal brain activity is specific to the mental processes related to the experimental tasks or reflects general patterns across different brain states. Thus, studying intrinsic spontaneous brain activity without the influence of external tasks may provide valuable alternative perspectives to further understand the neural characteristics of PTSD. The present study evaluated the magnitudes of spontaneous brain activity of male US veterans with or without PTSD, with the two groups matched on age, gender, and ethnicity. Amplitudes of low frequency fluctuation (ALFF), a data driven analysis method, were calculated on each voxel of the resting state fMRI data to measure the magnitudes of spontaneous brain activity. Results revealed that PTSD subjects showed increased spontaneous activity in the amygdala, ventral anterior cingulate cortex, insula, and orbital frontal cortex, as well as decreased spontaneous activity in the precuneus, dorsal lateral prefrontal cortex and thalamus. Within the PTSD group, larger magnitudes of spontaneous activity in the thalamus, precuneus and dorsal lateral prefrontal cortex were associated with lower re-experiencing symptoms. Comparing our results with previous functional neuroimaging findings, increased activity of the amygdala and anterior insula and decreased activity of the thalamus are consistent patterns across emotion provocation states and the resting state.

The hypothalamic-pituitary-adrenal axis is a major stress response system hypothesized to be involved in the pathogenesis of posttraumatic stress disorder (PTSD). However, few studies have prospectively examined the relationships among pre-exposure hypothalamic-pituitary-adrenal activity, acute stress reactions and PTSD.Two hundred ninety-six police recruits were assessed during academy training before critical incident exposure and provided salivary cortisol at first awakening and after 30 minutes. A measure of cortisol awakening response (CAR) was computed as the change in cortisol level from the first to the second collection. At 12, 24, and 36 months following the start of active police service, officers were assessed for peritraumatic distress, peritraumatic dissociation, acute stress disorder (ASD) symptoms, and PTSD symptoms to their self-identified worst duty-related critical incident. Mixed models for repeated measures were used to analyze the effects of CAR on the outcome variables pooled across the three follow-up assessments.After controlling for time of awakening, first awakening cortisol levels, and cumulative critical incident stress exposure, CAR during academy training was associated with greater peritraumatic dissociation, β = .14, z = 3.49, p.0001, and greater ASD symptoms during police service assessed at 12, 24, and 36 months, β = .09, Z = 2.03, p.05, but not with peritraumatic distress, β = .03, z = .81, p = .42, or PTSD symptoms, β = -.004, z = -.09, p = .93.These findings suggest that greater cortisol response to awakening is a pre-exposure risk factor for peritraumatic dissociation and ASD symptoms during police service.

This study examined the relationship between killing or seriously injuring someone in the line of duty and mental health symptoms in a sample of police officers (N = 400) who were first assessed during academy training and at five additional time points over three years. We found that nearly 10% of police officers reported having to kill or seriously injure someone in the line of duty in the first three years of police service. After controlling for demographics and exposure to life threat, killing or seriously injuring someone in the line of duty was significantly associated with PTSD symptoms (p

Background Circulating hematopoietic progenitor cells (PCs; CD34+ and CD34+/KDR+) facilitate neurogenesis and neovascularization, promoting increased cortical thickness and white matter integrity in animal models. However, it unknown whether low PCs are associated with trauma symptoms or neurovascular health among veterans. Objectives Determine whether lower PCs are associated with: (1) posttraumatic stress disorder (PTSD) diagnosis, duration and symptoms, (2) decreased prefrontal cortical (PFC) thickness, and (3) reduced white matter integrity, indexed by white matter hypointensities (WMH), and tracts relevant to fear processing: the Uncinate Fasciculus (UF) and Inferior Fronto-Occipital Fasciculus (IFOF). Methods 100 male and 8 female combat-exposed veterans reported PTSD symptoms (43 PTSD+) and were studied by 3T MRI, acquiring whole brain T1-weighted images and, for a subsample ( n = 54), diffusion tensor images. PCs were characterized by flow cytometry. Results Higher CD34+/KDR+ counts were related to greater PFC thickness (DM-PFC and DL-PFC), while higher CD34+ counts were related to better IFOF (but not UF) integrity and fewer WMH, controlling for age, gender, smoking, cardiovascular comorbidities and head injury. In PTSD+ subjects, CD34+/KDR+ counts were inversely related to time since the worst trauma, but not PTSD diagnosis or current symptoms. Conclusions PCs are associated with enhanced white matter integrity and PFC thickness, with potential implications for neurovascular plasticity and fear processing. In patients with PTSD, PCs may exhibit accelerated depletion with increasing time post-trauma.