Background: Evidence suggests that mechanisms that adversely affect cell energy may play an important role in Gulf War Illness (GWI). Exposures that have been linked to GWI have known mechanisms by which cell energy is impaired. Cell energy impairments are known to produce symptoms profiles consistent with those observed in GWI, featuring fatigue, cognitive, and muscle problems (brain and muscle are two highly energy demanding tissues), often attended by gastrointestinal and breathing symptoms, and variably including any of a range of other symptoms. Treatments that support energy have benefited symptoms in GWI. There remains need for testing for energy impairments in GWI and correlation of these with symptoms and function.

Goal: To assess whether defects in cell energy, in tissues that are highly energy dependent, are present in ill Gulf War veterans (GWV) and whether impaired cell energy correlates to symptoms and function in the corresponding organ.

Methods: Participants will include 20 GWV with GWI and 20 unaffected "controls" who are matched to their respective GWI "case" on age, sex, and ethnicity. Neither cases nor controls may have any major diagnosed condition that could produce symptoms that might be confused for symptoms of GWI.

31P-MRS: Cell energy will be assessed by a noninvasive magnetic resonance approach, termed 31phosphorus magnetic resonance spectroscopy (31P-MRS). This measures phosphorus-containing substances like ATP and something called "phosphocreatine" (PCr) and can also assess pH in the cells (which can drop when energy is inadequate). We will measure the time it takes for muscle PCr to recover from exercise, which is a robust index of cell ATP production. We will also measure, in brain and in muscle, the resting PCr and pH within the cells. We hypothesize that PCr recovery after exercise will take longer and that PCr and pH will be lower at rest in GWI relative to healthy control participants. We will also assess cognitive and muscle symptoms and will perform objective testing of cognitive and muscle function. We will evaluate whether the level of impairment on 31P-MRS in brain and in muscle relates to the level of symptoms and impaired function for that organ, in GWI.

Benefit of This Study: This study is the first noninvasive effort to assess for bioenergetic deficits in critical affected tissues in people affected by GWI and to relate these to symptoms and function. There is strong theoretical reason for concern that these cell energy deficits may be central factors driving GWI and GWI condition-defining symptoms of fatigue, muscle symptoms, and mood-cognitive symptoms, but this has not been evaluated. Thus, this study promises to provide pivotal insights into core mechanisms underlying GWI. It has potential to provide a noninvasive objective approach to aid diagnosis of GWI. It may yield a treatment target and may motivate development of new treatments. It may also provide new, objective, noninvasive markers that can be monitored for response to treatment, which is particularly important for the brain, since objective assessments of brain function by testing proficiency are typically severely handicapped in their utility by training effects. Further, it may immediately suggest treatment candidates that may benefit those affected by GWI. If cell energy defects are supported, this study will have strong implications for candidate treatments that may alleviate suffering, reduce symptoms, and improve function in GWI.