Gulf War Illness (GWI) is a chronic and multi-symptomatic disorder affecting 25 to 30 percent of military veterans who served in the 1990-1991 Persian Gulf War. Symptoms vary, but typically include fatigue, muscle pain, cognitive problems and more. The cause of GWI is currently unknown, although hypotheses have included: pesticides, pills containing pyridostigmine bromide, sarin, cyclosarin, and emissions from oil well fire.
In 2000, researchers made one of the most important clinical findings regarding GWI to date—veterans experience more severe symptoms and general illness exacerbation following physical, cognitive, emotional or other exertion. Now, researchers from Georgetown University Medical Center have expanded upon this discovery.
James Baraniuk, Stuart Washington and Rakib Rayhan used functional magnetic resonance imaging (fMRI) to show that, based on physiological changes in the brain, GWI patients can actually be characterized into two distinct groups post-physical exercise. This suggests a more complex illness that previously thought, but also better informs multiple strategies for future treatments of GWI patients.
The work builds off a 2013 study by Baraniuk and Rayhan in which they assessed changes in heart rate before exercise and after 5 minutes of standing post-exercise. Three distinct groups were (accidentally) identified and used in the current study: 1) GWI-START, who presented with a heart rate exceeding 30 bpm, but returned to normal within 24 to 48 hours after exercise; 2) GWI-POTS, those with an elevated heart rate during all periods of standing; and 3) GWI-STOPP, those who did not experience an elevated heart rate, but complained of pain reminiscent of phantom limb pain.
"At the time, Rakib Rayhab was working in my lab as a research associate," Baraniuk, a professor in Georgetown's department of medicine, told Laboratory Equipment. "The reason he split the groups in the first place was that he did not know this finding should not exist. That is, he found a signal and followed it to it's logical conclusion." In this case, Rayhab's conclusion drove the entire project and became a major discovery, one for which he was honored as the first student to win a NIH Teaching Fellowship Award.
Expanding on almost a decade of prior research, Baraniuk and Washington, a post-doc fellow and lead author of the 2019 study published in Brain Communications, imaged the brains of the three subgroups of veterans with GWI before and after moderate exercise, as well as healthy control patients. The following day, the groups had a second stress test and a memory test during brain imaging.
Prior to exercise, there were no differences in fMRI scans between veterans. However, that changed after exercise with subgroups showing significantly different activation levels in multiple regions of interest in the brain. All groups of GWI veterans showed differences in brain activity compared to healthy patients—who showed no changes at all—but the type of abnormal brain activity was different between the groups.
The two veteran groups prone to racing heart rates—GWI-START and GWI-POTS—both presented with a significant decrease in brain activity in the cerebellum, the part of the brain responsible for fine motor control, cognition, pain and emotion. In contrast, the GWI-STOPP group not prone to racing heart rates had a significant increase in brain activity in a different part of the brain that is responsible for planning of body movements and is also associated with chronic pain.
According to the researchers, these results suggest brain activity can be used to distinguish the GWI-START from the GWI-STOPP phenotype. “The exercise stressor paradigm affected different neural mechanisms in the GWI phenotypes,” write the study authors. “Distinct neural networks may mediate the cognitive dysfunction, post-exertional malaise, and exertional exhaustion in these veterans.”
Baraniuk's lab is not done, though. They are currently using informatics tools to assess changes in miRNA in GWI subjects, as well as working on a separate GWI projects using EEG in parallel with, and to complement, the MRI findings.
“There are additional analyses that we need to do to characterize the effects in these subjects," said Baraniuk. "Other papers that we hope will be published soon will provide mre information, and help plan the optimal future studies."
Photo: A Kuwaiti oil field set afire by retreating Iraqi troops burns in the distance beyond an abandoned Iraqi T-55A tank following Operation Desert Storm in 1991. Credit: Georgetown University.