DESCRIPTION (provided by applicant): The overall goal of this research is to determine the mechanisms of symptom maintenance and exacerbation in Gulf War Veterans (GVs) suffering with Gulf War illness (GWI). To date, the pathophysiology of GWI is poorly understood, and there are currently no confirmed efficacious treatments for these Veterans. Research involving GVs and civilians with similar chronic multi-symptom illnesses (CMI) such as chronic fatigue syndrome and fibromyalgia show that multiple physiological systems are dysfunctional - principally the central, autonomic, and immune systems. 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 the study of GWI. Our central hypothesis is that dysfunction across multiple physiological systems interacts to produce and maintain the symptoms of GWI, and this dysfunction is best studied via a PEM model. Our pilot data demonstrate that compared with healthy controls, patients with CMI (including GVs) demonstrate: (1) enhanced ratings and brain responses to painful stimuli and poor cerebral vascular auto-regulation, (2) augmented ratings and neural responses to fatiguing cognitive tasks, and (3) enhanced symptoms, increased pain sensitivity, and up-regulated gene expression to exercise challenge. These systems have been primarily studied in isolation and need to be studied under the same circumstances and within the same Veterans to determine the pathophysiological significance of their interactions. The primary goals of this project will b accomplished by comparing GVs with GWI to healthy GVs. The specific aims of the project are to determine: (1) baseline function across multiple physiological systems (CNS, autonomic, immune) in GVs with and without GWI; (2) the impact of an exercise challenge on CNS regulation of pain/fatigue, cardiovascular autonomic function, and immune system activity and symptoms in GVs with and without GWI; and (3) whether interactions among multiple systems significantly explain symptoms of GWI. CNS regulation of pain/fatigue will be measured using functional magnetic resonance imaging. Autonomic regulation will be measured via cerebral blood flow and parasympathetic responses to postural challenge. Immune activity will be measured via gene expression of inflammatory mediators (i.e., pro-inflammatory cytokine, metabolic and glucocorticoid receptors). The exercise challenge will consist of a single bout of cycling on a standard cycle ergometer at 70% of predicted peak heart rate for 30 minutes. CNS regulation of paint/fatigue, autonomic regulation, and immune activity will be measured 24 hours post-exercise when Veterans are experiencing PEM. Symptoms will be measured with validated instruments to assess pain, fatigue, and cognitive impairment. Symptoms will be followed for one week after exercise challenge to character...