A brain imaging study of veterans with Gulf War illness (GWI) and patients with chronic fatigue syndrome (CFS) (sometimes called myalgic encephalomyelitis), has shown that the two illnesses produce distinctly different, abnormal patterns of brain activity after moderate exercise.
The result of the Georgetown University Medical Center study suggests that GWI and CFS are distinct illnesses, an outcome that could affect the treatment of veterans with Gulf War illness.
The findings were published today in the journal Brain Communications.
While it is estimated that CFS affects 0.2-2% of the U.S. population, GWI is a multi-symptom illness that affects about 25% to 30% of the approximately 700,000 military personnel who participated in the 1990-1991 Persian Gulf War.
The two illnesses share many symptoms, including cognitive and memory problems (often described as “brain fog”), pain, and fatigue following mild to moderate exercise.
Some medical institutions, including the U.S. Department of Veterans Affairs (the VA), list CFS as a symptom of GWI (called chronic multisymptom illness associated with service in the Gulf War by the VA).
“Our results strongly suggest that GWI and CFS represent two distinct disorders of the brain and therefore CFS is not a symptom of GWI,” says Stuart Washington, Ph.D., a post-doctoral fellow and first author on the study.
“Combining of two different disorders could lead to improper treatment of both.” Washington works in the laboratory of James Baraniuk, MD, professor of medicine at Georgetown.
In the study, functional magnetic resonance imaging (fMRI) revealed that the brains of veterans with GWI and those of patients with CFS behaved differently when performing the same memory task after moderate exercise.
Veterans with GWI showed a decrease in brain activity in the periaqueductal gray, a pain processing region within the brainstem, and in the cerebellum, a part of the brain responsible for fine motor control, cognition, pain, and emotion.
On the other hand, patients with CFS showed increased activity in the periaqueductal gray and in parts of the cerebral cortex related to maintaining vigilance and attention. In healthy subjects, these areas of the brain had no changes at all.
A previous study published by this same research group also suggested that the two illnesses are distinct. It showed that exercise causes different changes to the molecular makeup of cerebrospinal fluid in veterans with GWI and patients with CFS.
“Now that CFS and GWI have been shown to affect different regions of the brain, these regions can be more closely examined using neuroimaging and other techniques to further our understanding of the similarities and differences between the two illnesses,” says Baraniuk.
“Once this new information is adopted broadly, diagnoses and treatments for both disorders should improve.”
GWI is a phenomenon that falls under the umbrella of the broader set of conditions termed chronic multisymptom illness (CMI). CMI has been defined by the Institute of Medicine (IOM) as a cluster of medically unexplained, chronic symptoms that can include fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems [8].
In addition to GWI, other types of CMI include myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS).
When CMI occurs in Gulf War veterans (GWVs), it is more specifically referred to as GWI.
Many attempts have been made to further narrow the definition of GWI. In fact, there are at least eight different working definitions for GWI utilized in published studies [9].
Nevertheless, in its 2014 report, the IOM reviewed extant case definitions and found all of them lacking.
The panel recommended the use of two case definitions for research: The Centers for Disease Control and Prevention (CDC) definition and the Kansas definition [8].
According to the CDC definition, which is a highly sensitive definition, patients with GWI are GWVs who have had at least one symptom for at least 6 months in 2 of 3 symptom domains (fatigue, pain, cognitive/mood) [2].
Based on the analysis of data on self-reported symptoms from a population-based follow-up survey fielded in 2012, it has been estimated that this definition would classify 50% of GWVs as GWI cases [10].
In 2000, the Kansas case definition was identified empirically as the pattern of self-reported symptoms that best distinguished veterans who deployed to the GW theater of operations from those who did not [10].
It considers a broader variety of symptoms and has both inclusionary and exclusionary components. The Kansas case definition is more specific than the CDC definition because veterans are excluded from consideration as a GWI case if they have been diagnosed by a physician with unrelated chronic conditions that can produce diverse symptoms like those affecting GWVs, or conditions that might interfere with the veteran’s ability to accurately report their symptoms.
Additionally, veterans must endorse one moderately severe (scale ranges from mild to severe) and/or multiple symptoms of any severity in at least 3 of 6 symptom domains (fatigue, pain, neurological/cognitive/mood, skin, gastrointestinal, respiratory) to meet the Kansas criteria for GWI.
Using the same population-based epidemiologic study of self-reported symptoms conducted in 2012, the Kansas case definition estimates that approximately 34% of GWVs fulfill the GWI criteria [10].
Although it is not known exactly what causes GWI, it has been postulated that the toxic exposures encountered by GWVs are at least partly responsible for their symptoms [11].
The Department of Defense (DoD) estimated that approximately 41,000 service members may have been overexposed to pesticides, approximately 100,000 personnel were possibly exposed to low levels of sarin nerve agent, and another estimated 250,000 ingested pyridostigmine bromide (PB) pills as prophylaxis against perceived chemical weapon exposures [11].
Another prevalent toxic exposure that many troops encountered was smoke from burning oil well fires with the numerous toxic constituents of petrochemical combustion products [12].
Further complicating investigations into a cause, GWI was also reported in an unusually high percentage of veterans of the same era who were not deployed to the war zone [13].
During more than two decades of research, a consensus of the most likely contributing toxic exposures for GWI has emerged, which has shaped the foci of research activities. Many lines of investigation highlight toxic exposures (PB pills, pesticides, and nerve agents) with inhibitory effects against acetylcholinesterase (AChE) [1, 14,15,16,17].
Exposure to these acetylcholinesterase inhibitors (AChEIs) may lead to the manifestation of symptoms arising from dysfunction of central and peripheral cholinergic systems.
Studies in civilian populations have shown a link between occupational exposure to AChEIs and chronic health symptoms that mirror those of veterans suffering from GWI [18,19,20].
Neuronal cell death and reduced AChE activity have also been detected in an animal model of GWI consisting of adult rats that were exposed to stress, PB, diethyltoluamide (DEET), and permethrin [21, 22].
Cognitive deficits and mood dysfunction were also observed in the GWI rat models [23,24,25,26]. This suggests that exposure to AChEIs may be causally linked to health problems observed in GWVs [11].
Researchers investigated the mechanism of action for AChEI effects in rats and found that AChEI-induced tissue hyperactivity, coupled with AChEI’s concurrent inhibition of oxidative phosphorylation (metabolic pathway in which mitochondria reform ATP), results in a high rate of ATP consumption, compromising the cell’s ability to maintain its energy levels.
Thus, it appears that, because of AChEIs exposure, the combination of impaired synthesis of ATP with its greater utilization during tissue hyperactivity results in a significant depletion of ATP [27].
This finding suggests mitochondrial dysfunction as one of the mechanisms underlying GWI. Using these findings as a basis for a new experiment, researchers examined the functionality of mitochondria in veterans suffering from GWI.
Their study supported a role for mitochondrial dysfunction and oxidative stress in GWI [28].
Additional emerging evidence suggests a role for chronic inflammation, perhaps mediated by mitochondrial damage and dysfunction, that is particularly damaging to the central nervous system [11, 13, 23, 25, 29,30,31,32,33,34].
It has been proposed that the neurotoxic effects of AChEIs trigger an inflammatory response that results in tissue damage and dysfunction that produces and perpetuates the chronic symptoms experienced and reported by veterans [6, 14, 35,36,37].
The mechanism by which AChEIs may induce such an inflammatory response is not well understood. The aforementioned studies focusing on mitochondrial dysfunction and AChEI-induced cell damage implicate reactive oxygen species (ROS)-induced neurodegeneration and muscle tissue damage as the underlying cause of GWI symptoms.
A recent study suggests that the AChEI-induced neuroinflammatory response in GWI animal models is independent of acetylcholine (Ach) levels [38].
A related mechanistic theory suggests that AChEI exposure may inhibit microtubule function, disrupting cellular function and contributing to inflammation, especially in neurons.
This dysfunction has been demonstrated in animals [22, 39], human and rat cellular models [40, 41] and, indirectly, in ill GWVs in the form of autoantibodies to neuronal components [15]. This nonneuronal effect of AChEI may represent the ‘missing link’ between relatively short-term exposure to the toxic milieu and chronic health effects.
Although there is some evidence supporting a possible link between stress and chronic symptoms in GWVs [42], the role of stress in the etiology of GWI has been controversial.
Resistance from some stakeholders in acknowledging the role of stress as a contributory factor has led to some research funding programs explicitly excluding proposals that investigate stress as a causal mechanism of GWI [43, 44].
The current prevailing causal theory retains a possible role for stress, especially in the disability associated with symptoms, but emphasizes the toxic exposures in conjunction with a genetic predisposition among the affected GWVs.
Best practices for the management of GWI are codified by the VA/DoD in a Clinical Practice Guideline for the broader syndrome, CMI, which includes GWI. This guideline recommends several evidence-based treatments for CMI, including graded physical activity, cognitive-behavioral therapy, mindfulness-based therapy, and antidepressants (i.e., selective serotonin reuptake inhibitors (SSRI’s), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine).
The expert panel relied on a more sensitive, less specific definition of CMI compared to the IOM report from 2014 and acknowledged that while it recommends these practices for GWI, much of the evidence is drawn from different populations, including studies of patients, often civilians, with ME/CFS, FM, and IBS [45].
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More information: Stuart D Washington et al. Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brain Communications (2020). DOI: 10.1093/braincomms/fcaa070
