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 .
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 .
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 .
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) .
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 .
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 .
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 .
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 .
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 .
Another prevalent toxic exposure that many troops encountered was smoke from burning oil well fires with the numerous toxic constituents of petrochemical combustion products .
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 .
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 .
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 .
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 .
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 .
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 . 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 , 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 .
8Committee on the Development of a Consensus Case Definition for Chronic Multisymptom Illness in 1990-1991 Gulf War Veterans. Board on the health of select populations, Institute of Medicine. Washington (DC): National Academies Press (US); 2014.Google Scholar
9.Coughlin SS, McNeil RB, Provenzale DT, Dursa EK, Thomas CM. Method issues in epidemiological studies of medically unexplained symptom-based conditions in veterans. J Mil Veterans Health. 2013;21(2):4–10.PubMed PubMed Central Google Scholar
10.Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000;152(10):992–1002.CAS PubMed Article Google Scholar
14.Sullivan K, Krengel M, Bradford W, Stone C, Thompson TA, Heeren T, et al. Neuropsychological functioning in military pesticide applicators from the Gulf War: effects on information processing speed, attention and visual memory. Neurotoxicol Teratol. 2018;65:1–13.CAS PubMed Article Google Scholar
15.Abou-Donia MB, Conboy LA, Kokkotou E, El-Masry EM, Jacobson E, Sullivan K. Screening for novel central nervous system biomarkers in veterans with Gulf War illness. Neurotoxicol Teratol. 2017;61:36–46.CAS PubMed Article Google Scholar
16.Steele L, Lockridge O, Gerkovich MM, Cook MR, Sastre A. Butyrylcholinesterase genotype and enzyme activity in relation to Gulf War illness: preliminary evidence of gene-exposure interaction from a case-control study of 1991 Gulf War veterans. Environ Health. 2015;14:4.PubMed PubMed Central Article CAS Google Scholar
17.Steele L, Sastre A, Gerkovich MM, Cook MR. Complex factors in the etiology of Gulf War illness: wartime exposures and risk factors in veteran subgroups. Environ Health Perspect. 2012;120(1):112–28.PubMed Article Google Scholar
18.Mackenzie Ross SM, McManus IC, Harrison V, Mason O. Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review. Crit Rev Toxicol. 2013;43:21–44.Article CAS Google Scholar
19.Ismail AA, Bodner TE, Rohlman DS. Neurobehavioral performance among agricultural workers and pesticide applicators: a meta-analytic study. Occup Environ Med. 2012;69:457–64.CAS PubMed PubMed Central Article Google Scholar
20.Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MC, Sandler DP. Neurologic symptoms in licensed private pesticide applicators in the agricultural health study. Environ Health Perspect. 2005;113:877–82.CAS PubMed PubMed Central Article Google Scholar
21.Abdel-Rahman A, Shetty AK, Abou-Donia MB. Disruption of the blood-brain barrier and neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf War syndrome. Neurobiol Dis. 2002;10:306–26.CAS PubMed Article Google Scholar
22.Abdel-Rahman A, Abou-Donia S, El-Masry E, Shetty A, Abou-Donia M. Stress and combined exposure to low doses of PB, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum. J Toxicol Environ Health A. 2004;67:163–92.CAS PubMed Article Google Scholar
23.Kodali M, Hattiangady B, Shetty GA, Bates A, Shuai B, Shetty AK. Curcumin treatment leads to better cognitive and mood function in a model of Gulf War illness with enhanced neurogenesis, and alleviation of inflammation and mitochondrial dysfunction in the hippocampus. Brain Behav Immun. 2018;69:499–514.CAS PubMed Article Google Scholar
24.Zakirova Z, Tweed M, Crynen G, Reed J, Abdullah L, Nissanka N, et al. Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War illness. PLoS One. 2015;10(3):e0119579.PubMed PubMed Central Article CAS Google Scholar
25.Abdullah L, Evans JE, Joshi U, Crynen G, Reed J, Mouzon B, et al. Translational potential of long-term decreases in mitochondrial lipids in a mouse model of Gulf War illness. Toxicology. 2016;372:22–33.CAS PubMed Article Google Scholar
26.Abdullah L, Evans JE, Bishop A, Reed JM, Crynen G, Phillips J, et al. Lipidomic profiling of phosphocholine containing brain lipids in mice with sensorimotor deficits and anxiety-like features after exposure to Gulf War agents. Neuromolecular Med. 2012;14:349–61.CAS PubMed Article Google Scholar
28.Koslik H, Hamilton G, Golomb BA. Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus magnetic resonance spectroscopy: a case-control study. PLoS One. 2014;9(3):e92887.PubMed PubMed Central Article CAS Google Scholar
29.Chen Y, Meyer JN, Hill H, Lange G, Condon M, Klein JC, et al. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War illness. PLoS One. 2017;12(9):e0184832.PubMed PubMed Central Article CAS Google Scholar
30.Chao LL, Rothlind JC, Cardenas VA, Meyerhoff DJ, Weiner MW. Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans. Neurotoxicology. 2010;31(5):493–501.CAS PubMed PubMed Central Article Google Scholar
33.Shetty GA, Hattiangady B, Upadhya D, Bates A, Attaluri S, Shuai B, et al. Chronic oxidative stress, mitochondrial dysfunction, Nrf2 activation and inflammation in the hippocampus accompany heightened systemic inflammation and oxidative stress in an animal model of Gulf War illness. Front Mol Neurosci. 2017;10:182.PubMed PubMed Central Article CAS Google Scholar
34.Ashbrook DG, Hing B, Michalovicz LT, Kelly KA, Miller JV, de Vega WC, et al. Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: a model of Gulf War illness. J Neuroinflammation. 2018;15(1):86.PubMed PubMed Central Article CAS Google Scholar
35.O’Callaghan JP, Kelly KA, Locker AR, Miller DB, Lasley SM. Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War illness. J Neurochem. 2015;133(5):708–21.CAS PubMed PubMed Central Article Google Scholar
36.Locker AR, Michalovicz LT, Kelly KA, Miller JV, Miller DB, O’Callaghan JP. Corticosterone primes the neuroinflammatory response to Gulf War illness-relevant organophosphates independently of acetylcholinesterase inhibition. J Neurochem. 2017;142(3):444–55.CAS PubMed PubMed Central Article Google Scholar
37.Koo BB, Michalovicz LT, Calderazzo S, Kelly KA, Sullivan K, Killiany RJ, et al. Corticosterone potentiates DFP-induced neuroinflammation and affects high-order diffusion imaging in a rat model of Gulf War illness. Brain Behav Immun. 2018 Jan;67:42–6.CAS PubMed Article Google Scholar
38.Miller JV, LeBouf RF, Kelly KA, Michalovicz LT, Ranpara A, Locker AR, et al. The neuroinflammatory phenotype in a mouse model of Gulf War illness is unrelated to brain regional levels of acetylcholine as measured by quantitative HILIC-UPLC-MS/MS. Toxicol Sci. 2018;165(2):302–13.CAS PubMed Article Google Scholar
39.Abdel-Rahman A, Shetty AK, Abou-Donia MB. Subchronic dermal application of N,N-diethyl m-toluamide (DEET) and permethrin to adult rats, alone or in combination, causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortex and the hippocampus, and Purkinje neuron loss in the cerebellum. Exp Neurol. 2001;172(1):153–71.CAS PubMed Article Google Scholar
40.Gao J, Naughton SX, Beck WD, Hernandez CM, Wu G, Wei Z, et al. Chlorpyrifos and chlorpyrifos oxon impair the transport of membrane bound organelles in rat cortical axons. Neurotoxicology. 2017;62:111–23.CAS PubMed PubMed Central Article Google Scholar
41.Rao AN, Patil A, Brodnik ZD, Qiang L, España RA, Sullivan KA, et al. Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons. Traffic. 2017;18(7):433–41.CAS PubMed PubMed Central Article Google Scholar
42.Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM. Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. Am J Epidemiol. 2003;157(2):141–8.PubMed Article Google Scholar
43.Gulf War Illness. Internet, cited 2018 Mar 9. Retrieved from http://cdmrp.army.mil/gwirp/default.
44.Kalasinksy V, Jaeger R. VA-ORD Gulf War Research: Research program overview. Internet, cited 2017 Dec 12. Retrieved from https://www.va.gov/RAC-GWVI/meetings/apr2017/Kalasinsky.pdf.
45.Department of Veterans Affairs, Department of Defense, Clinical practice guideline on chronic multisymptom illness. Internet, cited 2018 Jan 7. Retrieved from: https://www.qmo.amedd.army.mil/mus/CPGSummary2014.pdf.
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