Fatigue, widespread pain and tenderness are common findings in Chronic Fatigue Syndrome (CFS) and allied disorders such as Gulf War Illness (GWI) and Fibromyalgia (FM). In addition, they share sleep alterations, diverse nociceptive complaints, migraine, and systemic hyperalgesia. This overlap suggests that these syndromes share specific mechanisms of neural pathophysiology. Central sensitization is a logical explanation for their pain complaints but has been difficult to explain at the neuronal level. One of the cardinal clinical features of FM, GWI and CFS is "exertional exhaustion". Exercise, cognitive or other stressors induce a relapse of symptoms that may be immediate or can be delayed up to 24 hours. Although studies have found changes associated with exercise in CFS, the causal relationship between the brain and the aberrant response to exercise are unknown. Furthermore, changes that predict the transition to exertional exhaustion have not yet been identified. We developed a novel exercise stress test, fMRI, neurocognitive testing strategy to study this phenomenon in GWI subjects who met 1994 CFS criteria. We believe the outcomes can be generalized to CFS, and form the basis for a new understanding of this disease. Hypothesis: Exercise induces cognitive, somatosensory and autonomic dysfunction that are common features of CFS, GWI, &FM. Axonal alterations may be responsible for the neuropathology (SPECIFIC AIM 1). The exercise stressor disrupts vulnerable compensatory neural mechanisms to reveal two autonomic and cognitive phenotypes via fMRI (SPECIFIC AIM 2). Axonal dysfunction in FM can be identified from functional connectivity studies linked to specific dysregulated neurotransmitters of the brain (SPECIFIC AIM 3). Corollary: CFS neuropathology can be modeled based on exercise-induced outcomes of GWI subjects. Our integrated exercise &fMRI protocol identified the novel finding of significantly increased axial diffusivity (AD) in specific white matter tracts by diffusion tensor imaging (DTI) that was predictive of GWI status compared to controls. GWI groups also met CFS criteria. Next, we found that exercise perturbs neurophysiological brain networks that led to 2 GWI phenotypes that were associated with exercise induced changes in autonomic control, white matter integrity, cortical and brainstem atrophy, and brain blood flow dynamics. Baseline studies showed limited cross-sectional "static" differences, but the exercise stressor revealed causal and significant "dynamic" alterations of neural processes. We propose that CFS subjects will display a comparable dichotomy of objective findings. Identification of CFS subgroups would begin the process of defining objective neuropathological mechanisms in CFS. These objective outcomes may define specific CFS phenotypes and help explain the heterogeneous presentation of this illness. Conversely, identification of other coherent patterns may provide new objectively defined criteria for CFS. These mechanisms can lead to objective diagnostic tests and identification of new targets for treatment.

Public Health Relevance

An exercise challenge - fMRI study in subjects who met criteria for both Chronic Fatigue Syndrome and Gulf War Illness revealed: (A) significant differences in white matter integrity in specific brain tracts that distinguished CFS/GWI from control subjects, and (B) two potential illness phenotypes based on significant differences in autonomic, neurocognitive, brain blood flow, and other purely objective outcomes. These exercise-induced alterations reveal mechanisms of CFS neuropathology, and provide opportunities for a new diagnostic test and insights into targets for development of drugs and other treatments.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Whittemore, Vicky R
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Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
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