Chronic multi-symptom illnesses (CMI) are complex and poorly understood diseases principally characterized by fatigue, pain, and problems with cognitive function. For Veterans, these diseases are collectively referred to as Gulf War Illnesses (GWI) and affect ~250,000 Gulf War Veterans (GVs) (25-35% of the 1991 GV population). Nearly 50% of GVs seek VA clinical care, and nearly 40% receive disability compensation. To date, the causes of these symptoms are not known, and as a result, no efficacious treatments are available. Moreover, recent evidence suggests that Veterans of more recent conflicts, such as Operations Enduring and Iraqi Freedom, are also experiencing CMI. The general focus of my research is to determine the mechanisms that act to maintain chronic multi- symptom illnesses (CMI) – such as myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and GWI – with a career goal of improving the health and quality of life of deployed Veterans. My research employs multiple state-of-art technologies that allow us to test the central, autonomic, cardiopulmonary, and immune systems of each Veteran that visits my lab. As a result, my research has shown that multiple physiological systems are dysfunctional in both GVs and civilians with CMI. Moreover, dysfunction within these systems is magnified and symptoms are exacerbated following an exercise challenge (i.e., post- exertion malaise [PEM]), providing a controllable model for their study. Thus, a central hypothesis of my research is that dysfunction across multiple physiological systems interacts to produce and maintain the symptoms of GWI, and this dysfunction is best studied by challenging physiological systems and testing how they interact. Data from my lab has shown that GVs with chronic musculoskeletal pain have reduced white matter health and that acute exercise makes them more sensitive to pain compared to healthy GVs. However, my lab has also reported that being physically active has a potential protective effect against both the identified deficits and the symptoms of these diseases. These results suggest that acute and chronic exercise may have differential effects on GV health, important information for developing non-pharmacological therapies that can be used to safely treat GWI. My current VA-sponsored research directly tests our multisystem hypothesis by comparing GVs with GWI to healthy GVs across multiple physiological systems, at rest and following acute exercise challenge; we use advanced statistical methods to test whether interactions among multiple systems significantly explain symptoms of GWI. Capitalizing on the expertise of my lab and my collaborators, we test: 1) central nervous system regulation using structural and functional magnetic resonance imaging; 2) autonomic regulation using brain doppler methods for cerebral blood flow measurement; 3) immune and metabolic regulation using measures of gene expression, metabolomics, and proteomics fro...