Study objectives

To test if posttraumatic stress disorder (PTSD) is associated with low brain gamma-aminobutyric acid (GABA) levels and if reduced GABA is mediated by poor sleep quality.

Design

Laboratory study using in vivo proton magnetic resonance spectroscopy (1H MRS) and behavioral testing.

Setting

VA Medical Center Research Service, Psychiatry and Radiology.

Patients or participants

Twenty-seven patients with PTSD (PTSD+) and 18 trauma-exposed controls without PTSD (PTSD-), recruited from United States Army reservists, Army National Guard, and mental health clinics.

Interventions

None.

Measurements and results

1H MRS at 4 Tesla yielded spectra from three cortical brain regions. In parieto-occipital and temporal cortices, PTSD+ had lower GABA concentrations than PTSD-. As expected, PTSD+ had higher depressive and anxiety symptom scores and a higher Insomnia Severity Index (ISI) score. Higher ISI correlated with lower GABA and higher glutamate levels in parieto-occipital cortex and tended to correlate with lower GABA in the anterior cingulate. The relationship between parieto-occipital GABA and PTSD diagnosis was fully mediated through insomnia severity. Lower N-acetylaspartate and glutamate concentrations in the anterior cingulate cortex correlated with higher arousal scores, whereas depressive and anxiety symptoms did generally not influence metabolite concentrations.

Conclusions

Low brain gamma-aminobutyric acid (GABA) concentration in posttraumatic stress disorder (PTSD) is consistent with most findings in panic and social anxiety disorders. Low GABA associated with poor sleep quality is consistent with the hyperarousal theory of both primary insomnia and PTSD. Our data demonstrate that poor sleep quality mediates low parieto-occipital GABA in PTSD. The findings have implications for PTSD treatment approaches.

Exposure to traumatic psychological stress increases risk for disease events and mortality in patients with cardiovascular disease (CVD). While the biological mechanisms of these effects are not known, inflammation may play a key role as it is both elevated by psychological stress and involved in the development and progression of CVD. In a prospective study of patients with stable CVD (n = 979), we examined if higher lifetime trauma exposure was associated with elevated levels of inflammation at baseline and at five-year follow-up, and with greater increases in inflammation over time. Inflammation was indexed by a composite score incorporating the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and resistin. In follow-up analyses, we adjusted for sociodemographic factors, psychiatric disorders and health behaviors that were significantly associated with trauma exposure. Higher trauma exposure was associated with elevated inflammation at baseline (β = .09, p = .01) and at five-year follow-up (β = .09, p = .03). While levels of inflammation increased from baseline to follow-up in the sample, there was no significant association between trauma exposure and rate of change in inflammation. Findings were robust to adjustments for sociodemographic factors and psychiatric disorders, but health behaviors appeared to contribute to the association between trauma and inflammation at follow-up. This is the first large-scale demonstration of an association between lifetime trauma exposure and inflammation. High lifetime exposure to traumatic stress may contribute to an accelerated rate of CVD progression through elevated inflammation.

Mounting evidence highlights specific forms of psychological stress as risk factors for ill health. Particularly strong evidence indicates that childhood adversity and adulthood trauma exposure increase risk for physical and psychiatric disorders, and there is emerging evidence that inflammation may play a key role in these relationships. In a population-based sample from the Health and Retirement Study (n=11,198, mean age 69 ± 10), we examine whether childhood adversity, adulthood trauma, and the interaction between them are associated with elevated levels of the systemic inflammatory marker high sensitivity C-reactive protein (hsCRP). All models were adjusted for age, gender, race, education, and year of data collection, as well as other possible confounds in follow-up sensitivity analyses. In our sample, 67% of individuals had experienced at least one traumatic event during adulthood, and those with childhood adversity were almost three times as likely to have experienced trauma as an adult. Childhood adversities and adulthood traumas were independently associated with elevated levels of hsCRP (β=0.03, p=0.01 and β=0.05, p<0.001, respectively). Those who had experienced both types of stress had higher levels of hsCRP than those with adulthood trauma alone, Estimate=-0.06, 95% CI [-0.003, -0.12], p=0.04, but not compared to those with childhood adversity alone, Estimate=-0.06, 95% CI [0.03, -0.16], p=0.19. There was no interaction between childhood and adulthood trauma exposure. To our knowledge, this is the first study to examine adulthood trauma exposure and inflammation in a large population-based sample, and the first to explore the interaction of childhood adversity and adulthood trauma with inflammation. Our study demonstrates the prevalence of trauma-related inflammation in the general population and suggests that childhood adversity and adulthood trauma are independently associated with elevated inflammation.

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD− controls) and 18 women (10 PTSD+ and 8 age-matched PTSD− controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with q-PCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD.

Since posttraumatic stress disorder (PTSD) was first recognized as a psychiatric disorder, it has generated a great deal of scientific interest. Recent studies on the neurobiology of PTSD provide evidence that PTSD is biologically distinct from other types of traumatic and nontraumatic stress responses. This paper reviews three important directions of neurobiological research in PTSD: noradrenergic axis changes and associated alterations in autonomic responsivity neuroendocrine changes involving the hypothalamic-pituitary-adrenocortical (HPA) axis, and neuroanatomy changes involving the hippocampus. Each section reviews the salient aspects of preclinical research on the biology of stress and their bearing on the understanding of PTSD, and summarizes prominent findings from clinical biological studies of PTSD, Tentative models that integrate current findings from the clinical study of PTSD are reviewed. To conclude, the important methodological and empirical issues that need to be addressed by future studies are indicated.

Study objectives

Trauma-related nightmares are highly prevalent among veterans and are associated with higher-severity insomnia and posttraumatic stress disorder. Cognitive behavioral therapy for insomnia (typically 6-8 sessions) has been shown to reduce trauma-related nightmares. Brief behavioral treatment for insomnia (BBTI, 4 sessions) has been found to be comparable to CBT-I in decreasing insomnia severity; however, the effects of BBTI on nightmares have not been investigated. The current study tested the effects of BBTI on both trauma-related nightmares and nontrauma-related bad dreams using an active control group treated using progressive muscle relaxation therapy. In addition, we tested whether baseline trauma-related nightmare frequency and baseline nontrauma-related bad dream frequency moderated changes in insomnia severity.

Methods

Participants were 91 military veterans with insomnia disorder randomized to BBTI or progressive muscle relaxation therapy. Participants reported insomnia severity on the Insomnia Severity Index and reported trauma-related nightmare frequency and nontrauma-related bad dream frequency on the Pittsburgh Sleep Quality Index-PTSD Addendum.

Results

We found that BBTI significantly reduced trauma-related nightmares from baseline to posttreatment, whereas progressive muscle relaxation therapy did not. However, reductions in trauma-related nightmares were not maintained at the 6-month follow up. Neither BBTI nor progressive muscle relaxation therapy reduced nontrauma-related bad dreams from baseline to posttreatment. We also found that neither baseline trauma-related nightmare frequency nor baseline nontrauma-related bad dream frequency moderated changes in insomnia symptom severity.

Conclusions

Findings from the current study suggest that BBTI may help reduce trauma-related nightmares. Further research is needed to better understand the potential mechanisms underlying how improved sleep may reduce trauma-related nightmares.

Clinical trial registration

Registry: ClinicalTrials.gov; Name: Brief Behavioral Insomnia Treatment Study (BBTI); URL: https://clinicaltrials.gov/ct2/show/NCT02571452; Identifier: NCT02571452.

Citation

Ranney RM, Gloria R, Metzler TJ, Huggins J, Neylan TC, Maguen S. Brief behavioral treatment for insomnia decreases trauma-related nightmare frequency in veterans. J Clin Sleep Med. 2022:18(7):1831-1839.

Posttraumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular disease and several other chronic illnesses. Alterations in the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis in PTSD might contribute to these associations but findings regarding SNS and HPA activity in PTSD are heterogeneous. We measured 24-h urinary catecholamines and cortisol in a large cohort of adult outpatients recruited from 2 Veterans Affairs medical centers. 24-h urinary norepinephrine, epinephrine, dopamine and cortisol were measured by tandem mass spectrometry. Lifetime and current PTSD were assessed with the Clinician Administered PTSD Scale using DSM-IV-TR criteria. Out of 613 participants, 199 (32.5%) had current PTSD, 100 (16.3%) had lifetime but not current PTSD, and 314 (51.2%) never had PTSD. Patients with current PTSD had significantly higher norepinephrine secretion compared to those without PTSD. Patients in the lifetime PTSD group exhibited lower cortisol values compared to those without PTSD. Participants who never had PTSD showed the lowest norepinephrine and the highest cortisol values. All results remained stable when controlling for potentially confounding variables. This study provides evidence for increased norepinephrine secretion and decreased cortisol in PTSD. Future longitudinal studies are needed to determine whether these changes contribute to adverse health outcomes in patients with PTSD.

Background

Little is known about the association between trauma exposure and suicidal ideation across racial/ethnic groups. Our study aim was to determine the association between trauma exposure and suicidal ideation in a nationally representative ethnically diverse sample of adults.

Methods

This study included 14,866 White, Hispanic, Black, and Asian participants 18 years and older involved in the Collaborate Psychiatric Epidemiology Surveys (2001-2003), comprised of three nationally representative studies (NCS-R, NSAL, and NLAAS). Lifetime history of suicidal ideation as assessed in the World Health Organization's World Mental Health Survey Initiative version of the Composite International Diagnostic Interview (WMH-CIDI).

Results

Of the 81% respondents who reported being exposed to trauma as assessed in the WMH-CIDI, 12.1% endorsed lifetime suicidal ideation. Additionally, of the 19% who did not report trauma, 1.1% endorsed lifetime suicidal ideation. Fully adjusted, multivariable logistic regression models revealed two traumas consistently associated with significantly higher odds for suicidal ideation across all four racial groups examined: Assaultive/interpersonal violence and child maltreatment. Asians, in particular, had the highest likelihood for suicidal ideation in both trauma categories, with a near threefold increased odds for assaultive/interpersonal violence exposure (OR: 2.56; 95% CI: 1.71-3.83) and nearly ninefold increased odds for child maltreatment exposure (OR: 8.43; 95% CI: 4.91-14.49).

Discussion

Suicidal ideation in racially/ethnically diverse American adults is strongly associated with assaultive/interpersonal violence and child maltreatment, independent of PTSD, MDD, and substance use. These findings highlight the need for monitoring of suicidal behavior following assaultive/interpersonal trauma and child maltreatment, regardless of the presence of a psychiatric disorder.

Anxiety disorders increase risk for the early development of several diseases of aging. Elevated inflammation, a common risk factor across diseases of aging, may play a key role in the relationship between anxiety and physical disease. However, the neurobiological mechanisms linking anxiety with elevated inflammation remain unclear. In this review, we present a neurobiological model of the mechanisms by which anxiety promotes inflammation. Specifically we propose that exaggerated neurobiological sensitivity to threat in anxious individuals may lead to sustained threat perception, which is accompanied by prolonged activation of threat-related neural circuitry and threat-responsive biological systems including the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory response. Over time, this pattern of responding can promote chronic inflammation through structural and functional brain changes, altered sensitivity of immune cell receptors, dysregulation of the HPA axis and ANS, and accelerated cellular aging. Chronic inflammation, in turn, increases risk for diseases of aging. Exaggerated neurobiological sensitivity to threat may thus be a treatment target for reducing disease risk in anxious individuals.