The role of the brain stem in GWVI pathology

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Gulf War Veterans’ Illness (GWVI) is characterized by multiple chronic symptoms including wide-spread pain and sleep disturbances. This project will focus on brainstem structures and white matter pathways that specifically link the hypothalamus, periaqueductal gray and locus coeruleus (along the hypothalamic-pituitary- adrenal axis), and investigate their role in modulating pain and sleep disturbances associated with GWVI. We hypothesize that GWVI is associated with damage of specific brainstem white matter circuits and nuclei known to modulate pain signaling and sleep-wake cycles resulting in dysregulation of these critical functions. We propose state-of-the-art brain imaging techniques to assess the brainstem fiber integrity and volume changes of key brainstem nuclei and correlate these imaging measures with GWVI-related pain and sleep measures, specifically. To test the novel hypothesis of pain modulation deficits in GWVI, we will additionally use conditioned pain modulation (CPM) to evaluate the efficacy of descending pain modulation stimulated by a noxious peripheral stimulus. The translation of our findings into new therapeutic trials is very probable given that there are several novel candidate interventions that would allow the targeting of these brainstem structures. Our hypotheses will be tested in an observational study comparing 50 GWVI Veterans and 50 non- symptomatic Gulf War era (GWE) Veterans. After screening, confirmation of eligibility, and consenting all Veterans will undergo a 2-day assessment. Day 1 will comprise a battery of cognitive / functional tests and a conditioned pain modulation (CPM) test. On Day 2, MRI exams will be performed on each patient and the remaining cognitive/functional testing will be completed. Both visits will be no more than one week apart. This 4-year proposal will include 100 participants (2 groups of 50 each) with outcome measures collected at appropriate time points.