The objective of this study is to understand what goes wrong in Gulf War Illness (GWI). We have previously performed lumbar punctures (spinal taps) in GWI subjects and identified a dozen proteins that were present in GWI but not "healthy control" subjects. This suggested that these proteins may be useful as biomarkers of GWI, and that they may be used to develop new tests for the condition. The pattern of the proteins also provided some ideas about how the brain may be injured in GWI. Long lasting, low-grade injury could lead to the symptoms of GWI and related illnesses such as chronic fatigue syndrome and fibromyalgia.

In order to gain more valuable information about what is going wrong in GWI, we propose to enlist groups of 20 GWI and 20 healthy veterans (HVets) from the period of the Gulf War. All of the subjects will be treated in the same fashion. First, brain scans (functional magnetic resonance imagining, [fMRI]) will be performed to compare the brains of GWI and HVets. Then they will have two days of exercise testing. The exercise will be a standard bicycle exercise stress test to determine fitness. Subjects will also squeeze a hand-held strain gauge until they cannot hold the contraction any longer. This type of muscle contraction is known to stimulate the nervous system and cause and increase in blood pressure and heart rate. However, we have determined that people with chronic fatigue syndrome have blunted responses compared to control subjects. We anticipate this to be true in GWI as well. We anticipate that this exercise will have little effect on the HVets, but will cause some tiredness and fatigue in the GWI subjects.

Therefore, on the second day, we anticipate that GWI subjects will be fatigued and will not be able to perform as efficiently at either the bicycle exercise or isometric hand grip tests. In fact, we propose that the Day 1 exercise will induce some level of fatigue, or "exertional exhaustion" in the GWI group. If so, then we anticipate that the GWI subjects will not be able to perform as effectively on the bicycle stress test or the hand grip as the HVets.

After the Day 2 exercises, the fMRI brain scans will be repeated. Just like the exercise tests, we expect that the GWI subjects will show evidence of poor brain functions in thinking, making decisions, and planning compared to the HVet group. The fMRI scans will tell us which parts of the brain are not functioning as efficiently.

In addition, we will be collecting fluid from around the brain by doing a spinal tap. We anticipate that the fluid will again contain proteins found only in GWI and not in HVets. If so, these proteins can be developed as diagnostic tests for GWI. This would have a tremendous impact on GWI since it may be possible to perform a test and determine if a veteran has this condition or not. That determination would change the way the person was treated.

By studying these proteins in the fluid from around the brain as well as blood and other fluids, it may be possible to identify a pattern of proteins and other mediators that begin to suggest a cause, or causes, for the fatigue and related symptoms in GWI. From these studies, we may be able to piece together the mechanism(s) that go awry in GWI subjects. If so, we could test new drugs and other therapies against the proposed mechanisms to see if they blocked the fatigue or other symptoms. We will be gathering a large amount of information in this study, and have great confidence that the mechanism(s) of GWI will begin to reveal themselves. The time limit for this grant is 3 years, so I would anticipate that we would begin to report our progress in about 2011. While this may seem a long time to wait for a "cure," it is important at this time to be sure we understand what has gone wrong to lead to GWI symptoms, and then to determine the best way to correct those changes. Our work should provide a solid foundation for all GWI investigators, and based on our shared information, we will be able to greatly improve understanding of this illness, and set the stage for the development of new treatments for GWI.