GLUCOCORTICOID RESPONSIVITY IN VETERANS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Many Gulf War Veterans (GWV) suffer from unexplained medical symptoms known collectively as Chronic Multi-symptom Illness (CMI), presumed to have their origin in some aspect of deployment. As defined by the CDC, the illness is a chronic multi-system illness (CMI), reflecting a disturbance in mood and cognition, characterized by feeling depressed, moody or anxious, and having difficulty remembering, concentrating, finding words or sleeping as well as musculoskeletal symptoms and fatigue.1 These symptoms may also be present in psychiatric conditions associated with stress such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Not surprisingly, PTSD is prominent among veterans with CMI, and conversely, many GWV with PTSD have symptoms of CMI. The association between symptoms of CMI and PTSD has led our group to examine GWV using a similar neuroendocrine battery to that which we developed to elucidate neuroendocrine aspects of PTSD, and to a lesser extent, MDD, in other combat veterans with PTSD. An analysis of our data demonstrated that glucocorticoid-related alterations in GWV appeared to be strongly associated with the presence of health symptoms (i.e., of CMI), independently from their associations with PTSD. These findings raised the possibility of an interaction between PTSD and CMI with respect to glucocorticoid-related characteristics and the underlying brain alterations and cognitive processes that might be mediated by them. Although CMI has been associated with exposure to the Gulf, it is not unique to Gulf War veterans; it has also been found, at lower prevalence rates in veterans of Kosovo and Bosnia and is anticipated to similarly affect veterans of OIF/OEF . The unique neuroendocrine alterations in PTSD, and their likely associations with CMI, provide a rationale for using the double-blind placebo-controlled hCORT challenge test to study PTSD and CMI in veterans of recent wars (the first Gulf War, Bosnia, Kosovo, OIF, OEF). In our funded MERIT grant, we focused on the hippocampus because the hippocampus is an area rich in both Type I and Type II glucocorticoid receptors (GR), , and much excitement had been generated by the findings of smaller hippocampal volumes in PTSD. , , , , , , Our pilot data will support that such enthusiasm was warranted, as the hippocampus does appear to be more responsive to hCORT in VV with PTSD compared to those without PTSD. However, the hippocampus is not the only area of the brain with large concentrations of GR, nor is it the only region implicated in memory performance, or PTSD. In view of the possibility of an interaction between PTSD and CMI with respect to glucocorticoid-related characteristics, the proposed study is a 2 x 2 design (PTSD+, PTSD- and CMI+, CMI-) in which the functional neuroanatomy of glucocorticoid responsiveness and its relationship to memory performance will be evaluated in four groups (PTSD+CMI+, PTSD+CMI-, PTSD-CMI+, PTSD-CMI-), each comprised of 16 trauma-exposed veterans. We focus on glucocorticoid responsiveness because of the importance of the hypothalamic-pituitary-adrenal (HPA) axis in the regulation of psychiatric symptoms related to mood and PTSD,18 and also its role in physical and somatic processes and cognition. Two neuroendocrine challenges will be performed to assess glucocorticoid responsiveness: a double-blind placebo-controlled (17.5 mg) hCORT challenge procedure during which neuroendocrine, functional neuroanatomic, and memory performance indices will be assessed, and the low dose (0.50 mg) dexamethasone (DEX) suppression test (DST). Measures of glucocorticoid responsiveness, memory performance, and brain volumes and rGMR of several ROI's including the anterior cingulate, amygdala and hippocampus, will be obtained on the placebo and hCORT challenge days. To date, there is almost no information on the neuroendocrine characteristics associated with CMI subdivided on the basis of presence or absence of PTSD, or on how these characteristics are linked with either functional neuroanatomy, poor memory performance, which is a major symptom domain of CMI, and a frequently complaint among those with PTSD, or both. Aim 1: To investigate the effects of CMI and PTSD and their interaction in responsiveness to glucocorticoids at baseline and in response to hCORT and DEX challenge. In the hCORT challenge procedure, the critical measure of glucocorticoid responsiveness will be the maximum decrease from pre-infusion levels of ACTH (i.e., ACTH suppression) following placebo and 17.5 mg hCORT administration. In the DEX challenge, glucocorticoid responsiveness will be estimated by the percent suppression of cortisol, ACTH, and lymphocyte GR number in response to 0.5mg DEX ingestion. For Aims 1-3, the overall effects of CMI (with or without PTSD) and of PTSD (with or without CMI) will be assessed by analysis of covariance (ANCOVA). The interaction of CMI and PTSD refers to the difference between the effects of CMI in the absence or presence of PTSD, and, equivalently, the difference of the effects of PTSD in the absence or presence of CMI. Based on the literature on PTSD in other veteran cohorts and on our pilot data, we hypothesize that PTSD will be associated with greater ACTH suppression in response to hCORT, and greater percent suppression or cortisol, ACTH and lymphocyte GR number in response to DEX. There is much less literature on CMI on which to base hypotheses, but based on our pilot data, we hypothesize that CMI will be associated with decreased ACTH suppression in response to hCORT and reduced percent suppression or cortisol, ACTH and lymphocyte GR number in response to DEX. Aim 2: To investigate the effects of CMI and PTSD and their interaction in baseline memory performance following placebo and hCORT administration. At baseline, we will assess immediate and delayed auditory and visual memory, retention, implicit and explicit memory, and proactive and retroactive interference, since these components of memory are thought be sensitive to hippocampal damage. , , The cognitive functions will be measured using the California Verbal Learning Test (CVLT) and the WAIS and WMS. . Following placebo and hCORT infusions, we will measure verbal learning, attention, and working memory using three neuropsychological tests of explicit memory shown to be vulnerable to glucocorticoid administration. , , Verbal learning, as measured by immediate and delayed paragraph recall (measured by percent savings at delay, a measure of retention), will be tested using the Wechsler Memory Scale (WMS-III). Attention will be assessed using the Digit Span Forward (DSF) subtest of the WMS-III. Working memory will be measured by the Digit Span Backwards (DSB), and the Letter-Number Sequence (LNS) subtests of the WMS-III. Based on our pilot data in GWV with PTSD, we hypothesize that PTSD will be associated with greater decrements in measures of recall and attention in response to hCORT than GWV without PTSD. Other aspects of cognitive performance, such as attention, may not be affected or may even improve. We do not have pilot data in CMI on which to base hypotheses for this measure; however, if CMI is associated with less glucocorticoid responsiveness, as suggested by our pilot data, it may be associated with less of a decrement in memory performance in response to Hcort. Aim 3: To correlate simultaneously obtained measures of glucocorticoid responsiveness, hippocampal volume, and memory performance, within groups of subjects with and without PTSD and with and without CMI. For each pair of variables, the correlation will pool results within each of the four groups of subjects. This differs from the correlation that would result from including all subjects in a single analysis, since it excludes from consideration the group mean differences assessed in Aims 1 and 2. A 95% confidence interval will also be obtained for each correlation. We will also test whether relationship between changes in these measures depend on the levels of the variables at baseline. We hypothesize that simultaneously obtained measures of glucocorticoid responsiveness and of memory performance will be highly correlated. Based on the literature, we also hypothesize that PTSD will be associated with smaller hippocampal volumes. To the extent that poor memory performance in PTSD is a reflection of altered glucocorticoid responsiveness and/or smaller hippocampal volume, we hypothesize that correlations among these measures will be higher in the PTSD group. II. BACKGROUND & SIGNIFICANCE