Scientific basis

	• There are multiple postulated causes for the Gulf War syndrome but none has been proven.
	• Genotyping studies support the proposal that neurologic symptoms in some Gulf War veterans were caused by chemical exposures, eg, organophosphates.
	• Pyridostigmine, an anticholinesterase, given to soldiers for protection against chemical warfare agents, does not explain some of the perplexing symptoms of Gulf War syndrome.
	• Interaction of genetically-regulated sensitivity of the immune system with chemical exposures that occurred in the Gulf War reprogramed neural functioning.

No single cause of Gulf War syndrome has been proven. Clinical evaluation of 20,000 Persian Gulf War veterans revealed 74 cases of connective tissue disease, 52 noncutaneous malignancies, 42 peripheral neuropathies, 14 cases of interstitial pulmonary fibrosis, and 12 cases of renal insufficiency (27). Various postulated causes include the following:

Exposure to chemical and biological weapons. The position of the United States Defense Department in 1995 was that no evidence implicated chemical or biological weapons as causes of the illnesses suffered by veterans of the Gulf War. However, later alarms from chemical weapons attacks and nerve agent exposure were recorded in the case histories of some of the symptomatic subjects and led to further discussions on this topic.

Genotyping studies have shown that veterans with the neurologic symptoms of Gulf War syndrome are more likely to have the R allele being heterozygous QR or homozygous R rather than being homozygous Q for the paraoxonase/arylesterase 1 gene (12). Type Q is the allozyme of paraoxonase/arylesterase that most efficiently hydrolyzes several organophosphates including sarin, soman, and diazinon. These findings further support the proposal that neurologic symptoms in some Gulf War veterans were caused by environmental chemical exposures.

United States troops were exposed to the organophosphate chemical warfare agents sarin and cyclosarin when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War in 1991. An analysis of neurobehavioral and brain MRI data collected in a study on Gulf War Illness between 2002 and 2007 showed that soldiers who were exposed to sarin and cyclosarin had reduced total gray matter and hippocampal volumes compared to their unexposed peers (03).

Epidemiological evidence from US Military Health Survey performed computer-assisted telephone interviews of a stratified random sample of Gulf War era veterans indicates that exposure to low-level sarin nerve agent in fallout from bombing early in the air campaign contributed more to chronic illness than post-war demolition of Iraqi chemical weapons facilities (16). A chronic effect, Haley syndrome 2, manifested with difficulty processing information, confusion, and ataxia. Meta-analyses of epidemiological studies have consistently linked the symptoms of Gulf war illness to the combined exposure of agents such as organophosphate-based and pyrethroid-based pesticides. Findings in a mouse model of Gulf War agent exposure support neurotoxic effects on the brain following exposure to these agents (40).

Use of anticholinesterases. Pyridostigmine bromide pills were used for protection against chemical weapons during the Gulf War. Interaction between this drug and other chemical exposures has been shown to produce delayed neurotoxicity in animal experimental studies, and sublethal exposures to drug-chemical combinations may have caused delayed-onset neurotoxic variants. A history of advanced acute toxicity after taking pyridostigmine has also been correlated with low PON1 type Q arylesterase activity.

Initial experimental studies suggested that long-term effects of pyridostigmine were induced by the combination of pyridostigmine administration and stress exposure. This allowed the quaternary compound to enter the brain through stress-induced changes in blood-brain barrier permeability. Pyridostigmine has been claimed to inhibit brain cholinesterase, but other studies could not replicate the findings that suggest pyridostigmine can affect brain cholinesterase following stress. However, pyridostigmine by itself or in combination with other factors such as stress and toxic exposures does not explain some of the perplexing symptoms being experienced by many Gulf War veterans.

Exposure to sand. Microimpregnated sand particles served to deplete the immune system of exposed individuals. Simultaneously, the particles acted as vehicles for low-intensity exposure to chemical warfare agents and had a modifying and intensifying effect on the toxicity of exposed individuals.

Exposure to smoke. The hypothesis that attributes Gulf War syndrome to the toxic smoke from incomplete combustion of oil from burning wells is supported by the known toxicology of 2 likely combustion products, nitric oxide and carbon monoxide.

Exposure to pesticides and other chemicals used in military expeditions. Diethyltoluamide (DEET), found in pesticide-containing flea and tick collars and insect repellent, has been recorded in symptomatic subjects.

Vaccination. Among veterans of the Gulf War, a specific relation exists between multiple vaccinations given during deployment and later ill health. Multiple vaccinations in themselves do not seem to be harmful, but combined with the stress of deployment, might lead to adverse health outcomes. Pesticides do not seem to interact with vaccines to cause illness.

Squalene, which may be present in anthrax vaccine, has been implicated in the etiology of Gulf War syndrome, but 1 study found no association between squalene antibody status and chronic multisymptom illness (43).

Chronic infectious diseases. The incidence of infectious diseases during the Gulf War was lower than during previous wars involving American military personnel.

Depleted uranium. A low-level radioactive waste product of the enrichment of natural uranium with U-235 was used in the Gulf War as armor-penetrating ammunition. No evidence has emerged proving the role of this product in human disease.

Psychological stress. Several studies have reported that Gulf War veterans experienced increased levels of psychological stress. Posttraumatic stress disorder has been reported in survivors of various wars.

Abnormalities of the immune system. A study on veterans with Gulf War syndrome explored the relationship between day-to-day fluctuations in immune biomarkers and daily self-reported fatigue severity (42). Results showed greater variability in the expression of eotaxin-1, and higher fatigue severity days were associated with higher IL-1 beta as well as IL-15 levels, supporting the hypothesis that the pathophysiology of Gulf War syndrome involves immune dysregulation. Data from animal and human studies point to a neuroimmune mechanism underlying Gulf War illness, and neuroinflammation due to proinflammatory cytokines in the CNS may be an underlying cause (39). A study found significant human leukocyte antigen (HLA)-related effects on symptoms of Gulf War syndrome attributed to certain alleles of HLA genes (25). These findings support the concept that genetically-regulated sensitivity of the immune system interacts with chemical exposures that occurred in the Gulf War to reprogram neural functioning.

Discussion

	• Gulf War syndrome remains controversial because of conflicting evidence for and against organic injury to the nervous system.
	• A case control study on veterans with factor-derived syndromes supports the hypothesis that symptoms of Gulf War syndrome are due to neurologic injury.
	• Chronic multisystem illness continued to be substantially more prevalent among deployed veterans than among nondeployed veterans 10 years after Gulf War I.
	• Several biomarkers, brain imaging, and electrophysiological studies correlate with symptoms of Gulf War syndrome.
	• Evidence against organic basis is a study on Gulf War syndrome with complaining of severe muscle fatigue, weakness, or myalgias that failed to reveal evidence of a specific neuromuscular disorder by electrophysiological studies and muscle biopsy.
	• A review has concluded that even in the absence of an organic basis, Gulf War syndrome should not be considered an imaginary illness but as a highly complex functional syndrome.

Evidence supporting organic injury to the nervous system. A factor analysis study on 249 Gulf War veterans identified a syndrome made up of 6 subtypes in 63 patients (14):

(1) Impaired cognition (2) Confusion-ataxia (3) Arthro-myo-neuropathy with pain (4) Phobia-apraxia (5) Fever-adenopathy (6) Weakness-incontinence

A blinded, case-control study of 23 veterans with factor analysis-derived syndromes supports the hypothesis that symptoms of many Gulf War veterans are due to neurologic injury involving the central, peripheral, and autonomic nervous systems (13).

In a pilot study, British Gulf War veterans were randomly selected to compare the functional integrity of the peripheral nervous system with a group of healthy, matched, civilian control subjects. Cold threshold, sural nerve latency, and median nerve sensory action potential were abnormal in the veterans compared with the controls (24). The authors suggested further studies.

In vivo proton magnetic resonance spectroscopy studies of the hippocampi of Gulf War veterans showed that N-acetyl aspartate to creatine ratio was significantly lower than that of the entire control group, and points to hippocampal dysfunction (35). These findings support the theory that Gulf War syndrome is a neurologic illness that is in part related to injury to dopaminergic neurons in the basal ganglia.

Dizzy spells are reported to be frequent in veterans with Gulf War syndrome. The findings of audio vestibular testing are compatible with a subtle neurologic injury from organophosphate-induced delayed neurotoxicity.

In a study of United States veterans, those with the most severe form of Gulf War syndrome were found to be seriously impaired after evaluation of the Medical Outcomes Study 36-Item Short Form completed by each subject (15). The ill Gulf War veterans generally scored far worse than did a reference group of patients with conditions that prevented them from working. These included such common illnesses as congestive heart failure, recent acute myocardial infarction, and chronic obstructive pulmonary disease. Reduced levels of the intracellular metabolite N-acetyl aspartate, an objective marker of neuronal injury, were found by magnetic resonance spectroscopy in the most severely ill Gulf War veterans with confusion and ataxia.

The observed incidence of amyotrophic lateral sclerosis in young United States Gulf War veterans exceeded expectations, suggesting a war-related environmental trigger. Studies of a population-based sample of the Gulf War veterans indicate an increased rate of chronic fatigue syndrome. A 2-phase cohort study in the United Kingdom concluded that symptoms in keeping with chronic fatigue syndrome account for a significant part of the symptomatic distress in Gulf War veterans (20). Although deployment-related stress could account for the higher risks of posttraumatic stress disorder, additional factor(s) unique to the Gulf environment may have contributed to the risk of chronic fatigue syndrome among Gulf War veterans. Compared to veterans of another war, United Kingdom Gulf War veterans remain a distinct group with many symptoms of ill health. The excess of illness at follow-up is explained by both higher incidence and greater persistence of symptoms. The bulk of the evidence available shows that the conditions do exist and that the suffering is real, even though their causes are uncertain.

Chronic multisystem illness continues to be substantially more prevalent among deployed veterans than among nondeployed veterans 20 years after Gulf War I, although it manifests similarly in both groups. A study from the United Kingdom also concluded that Gulf War veterans were also approximately 3.5 times more likely than non-Gulf veterans to report multiple chemical sensitivity or chronic multisymptom illness (51). A study of the French veterans of the Gulf War has shown that the most frequent symptoms described since the return from the Gulf were headaches (83%), neurologic or psychological symptoms, and back pain (48). A higher proportion of veterans of the Gulf War reported symptoms of pain than military comparison groups, consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, posttraumatic stress disorder) in these veterans compared with non-Gulf military groups (52). A follow-up study has shown that 14 years after deployment, Gulf War veterans continue to report a higher prevalence of many adverse manifestations compared with Gulf Era veterans who were not deployed to the Gulf (29).

Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes as shown by rCBF studies with arterial spin labeling perfusion MRI and physostigmine challenge (34).

A structural MRI study on Gulf War veterans smaller brainstem volumes was significantly correlated with increased severities of fatigue and depressive symptoms, suggesting the resulting atrophy could mediate Gulf War illness-related symptoms such as fatigue and depression (57).

Event-related potential (ERP) data from veterans with Gulf War syndrome have shown an attenuated P3b to target stimuli that is associated with hyperarousal, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity (54). An ERP study of word finding difficulty in Haley syndrome 2 of Gulf War illness show ERP patterns like those in persons with amnestic mild cognitive impairment indicating disordered thalamic cholinergic neural activity, possibly in the dorsomedial nucleus (53).

Behavioral studies on patients with Gulf War illness suggest that working memory executive strategies, mediated by the cholinergic system, are impaired during high-demand on this type of memory, and functional MRI data support this hypothesis (18).

A review of published research has concluded that exposure to pesticides and/or pyridostigmine bromide are causally associated with neurologic dysfunction in Golf War veterans, whereas exposure to organophosphates and other chemicals in the theater of war is less clear (56). Gene-environment interactions have likely contributed to Gulf War syndrome.

The heterogeneous multisystem manifestations of Gulf War illness are like those of patients with certain mitochondrial disorders. Studies of peripheral blood with quantitative polymerase chain reaction show mtDNA damage in veterans with Gulf War illness, which is consistent with mitochondrial dysfunction (04).

Calcium (Ca2+) signaling plays a role in learning, memory, and mood, and disruptions in Ca2+ homeostasis occur in many neurologic disorders. To determine the role of Ca2+ homeostasis in the development of Gulf War illness, rats were exposed to organophorphorus agent diisopropyl fluorophosphate (DFP), and chronic depressive symptoms as well as cognitive deficits were observed in rats exposed to repeated low-dose DFP (44). Rats with Gulf War illness manifested elevations in hippocampal [Ca2+]i along with a significant increase in the number of neurons displaying these elevations. Because Ca2+ is a major second-messenger molecule, such sustained increases in its levels can activate multiple signaling cascades and alter gene expression of proteins involved in synaptic plasticity and possibly underlie the neuronal injury and chronic morbidities in Gulf War illness.

Evidence against an organic basis for Gulf War syndrome. Twenty Gulf War veterans complaining of severe muscle fatigue, weakness, or myalgias that interfered with their daily activities were investigated by routine laboratory studies, nerve conduction studies, repetitive nerve stimulation, quantitative and single-fiber electromyography, and muscle biopsies (01). The investigators found no evidence of a specific neuromuscular disorder in any of the patients, and exposure to toxins during the Persian Gulf War was an unlikely cause of these patients' symptoms.

A study from the United Kingdom investigated whether the veterans of the Gulf War maintained a pattern of symptom-reporting different from that of active servicemen who had not fought in the Gulf War or who had fought in other conflicts (19). An analysis of 3 factors in the Gulf War cohort: mood, respiratory system, and peripheral nervous system, did not yield any significant differences from the Bosnian and active-duty forces not deployed in any of the conflicts. These findings did not support a unique Gulf War syndrome.

A retrospective review of medical records revealed no objective evidence from electrodiagnostic testing of an increased incidence of neuromuscular disease in Gulf War veteran patients compared with non-Gulf War patients (28).

A U.S. Veterans Administration-sponsored report on Gulf War syndrome released in 2006 concluded that there is no 1 complex of symptoms to suggest those veterans, nearly 30% of all those who served, suffered or still suffer from a single identifiable syndrome. The report found no unique pattern of symptoms. Every pattern identified in Gulf War veterans also seems to exist in other veterans, though it was noted that the symptom rate is higher, which is a serious issue that needs to be resolved. The implication of this report is that Gulf War veterans can now claim benefits only by making an undiagnosed illness claim. The Department of Veterans Affairs has amended its adjudication regulations regarding compensation for disabilities resulting from undiagnosed illnesses suffered by veterans who served in the Persian Gulf War to extend the presumptive period for qualifying for chronic disabilities that must become manifest to a compensable degree (07).

There is a high incidence of posttraumatic stress disorder (PTSD) in veterans with Gulf War syndrome. A magnetic resonance spectroscopic study of the brains of such subjects did not find significant regional brain volume loss, leading the authors to conclude that PTSD is most likely related to exposure to psychological stress during deployment and not due to loss of or persistent injury to neurons in the basal ganglia and pons (55).

Although the pathomechanism of both Gulf War illness and chronic fatigue syndrome is not well understood, some cytokine biomarker expression is common to both conditions, with differences in expression according to sex (50). IL-10 and IL-23 expression was accompanied in male subjects by natural killer cells and Th1 biomarkers IL-12, IL-15, IL-2, and interferon-gamma, whereas in female subjects IL-10 was again identified as a delineator, but this time in the context of IL-17 and Th2 biomarkers IL-4 and IL-5.

Functional MRI studies on Gulf War veterans as compared with normal controls before and after exercise stress tests have shown that those who developed exercise-induced hyperalgesia also had associated cortical atrophy, and baseline working memory failed to compensate (46). These alterations were absent in controls and suggest a relationship between the brain and postexertional malaise in Gulf War illness.

A review has concluded that even in the absence of an organic basis, Gulf War syndrome should not be considered an imaginary illness, but as a highly complex functional syndrome that presents a serious public health problem (02).

Resolution

	• Most of the studies conducted by independent academic centers show evidence for organic damage to the nervous system in patients with Gulf War syndrome.
	• Most of the studies that deny the existence of a Gulf War syndrome with organic damage of the nervous system are based on clinical findings alone.
	• Further research may or may not prove any cause for this syndrome; Gulf War syndrome patients with neurologic problems deserve to be treated like any other patients.
	• Immunosuppressants used arthritis and hormone-based therapies as the best available candidates for treating symptoms of Gulf War syndrome.
	• Several studies on Gulf War syndrome are still going on.

Majority opinion. Most of the studies conducted by independent academic centers show evidence for organic damage to the nervous system in patients with Gulf War syndrome exhibiting neurologic symptoms. This evidence has been substantiated by neurochemical and functional MRI studies. The evidence for an organic basis is increasing with time.

Minority opinion. Most of the studies that deny the existence of a Gulf War syndrome with organic damage of the nervous system are based on clinical findings. Some of the studies tend to dismiss the syndrome as a stress-related disorder.

Further action needed to resolve the controversy. Considerable work still needs to be done for clinicopathological correlations of the syndrome. Neurologic subsets of the syndrome are worthwhile topics for further study considering that important neurochemical study has been done in this area. Perpetuating studies on the molecular basis of this syndrome remains essential in determining why certain individuals are more susceptible to neurotoxicity than others. Advances in neurogenomics would enable studies of genetic variations to be conducted on these patients. It is not possible to study the contribution of genetic or epigenetic factors to the disease because susceptible disease-vulnerable proteins and pathways are different from those in humans. Somatic cells from Gulf War veterans can be converted into pluripotent cell lines that can be differentiated into various cell types, including neurons and other relevant cell types, which will be a resource for Gulf War illness researchers to investigate various hypotheses (45).

Lipid disturbances are present in the blood, both in patients with Gulf War syndrome and in the preclinical rodent models of the disease, indicating the importance of lipidomics as a potential platform for further biomarker discovery (09). Because phospholipids play a role in inflammatory processes, these findings suggest a possible role for inflammatory imbalance in Gulf War syndrome.

The symptom outbreak following the 1991 Gulf War has not abated in a 5-year follow-up of registry veterans, suggesting a substantial need for better understanding and care for these veterans (41). A review of the epidemiological studies, mostly cross-sectional, concluded that ill health in Gulf War veterans remains unexplained and requires further inquiry but is best understood within the medically unexplained symptoms and syndromes constructs (21). Further research is also needed to determine physiological and psychological mechanisms through which such stress could have contributed to the various symptoms of Gulf War syndrome.

Further research may or may not prove any cause for this syndrome. A practical and ethical approach involves treating these patients like any other patients in the general population who have similar symptoms. These veterans have an illness, which is not likely to get better without specific interventions, and the well-being would not be served by engaging in the controversy about the cause or legitimacy of this syndrome.

Individuals suffering from Gulf War syndrome have some characteristics features. A multicenter, randomized clinical trial was conducted to evaluate the compliance in Gulf War syndrome patients with exercise alone or exercise and cognitive-behavioral therapy (37). The overall level of compliance was relatively low. Predictors of compliance included less pain and greater age, motivation, and body-mass index.

Gulf War syndrome has been lumped together with other common conditions such as chronic fatigue syndrome and fibromyalgia into a category termed "medically unexplained physical symptoms” or MUPS (47). Effective management of symptoms is recommended. It has been suggested that 4 conditions –siliconosis, macrophagic myofasciitis, Gulf War syndrome, and postvaccination phenomena–share clinical as well as pathogenic resemblances, and may be included in a common syndrome called “autoimmune /autoinflammatory syndrome induced by adjuvants” (ASIA) or Shoenfeld syndrome (22). All 4 conditions have at least 8 of the 10 main symptoms, ie, myalgia, arthralgias, chronic fatigue, neurologic cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations, and appearance of autoantibodies. According to this concept, inclusion of Gulf War syndrome as part of Shoenfeld syndrome does not require resolution of the etiology.

Although various studies have failed to provide a satisfactory explanation for Gulf War syndrome, many of those affected remain unwell and disabled more than 15 years after returning from combat. This issue cannot be dismissed, and further investigations are recommended to develop effective interventions to relieve their ill-health and distress (23).

Research studies supported by the U.S. Department of Defense conclude that although no specific neurotoxic chemical has been identified that explains the chronic multisymptom illness observed, a firm basis has been established for research in future protection against health and performance risks to the soldier (11).

Several studies are comparing chronic health problems in veterans of other wars and using data from Gulf War veterans for comparison. Activities such as lifting loads are shown to increase the risk of pain-related musculoskeletal disorders, such as backache, in military veterans from various wars. One study found that musculoskeletal disorders in veterans were associated with depression and posttraumatic stress disorder, which should be taken into consideration in management of these patients (30).

In the Millennium Cohort Study, a prospective study representing all United States service branches during 2001-2008 in Iraq and Afghanistan wars, self-reported symptoms were quantified and compared with those in a cohort of subjects from the 1991 Gulf War to identify cases of chronic multisystem disease (49). There was a higher prevalence of reported chronic multisystem disease among deployed compared with nondeployed contemporary members. The recommendation was development of screening tests for early identification of potential long-term chronic disease manifestations. A study by the Committee on Gulf War and Health of the National Academies of Sciences of U.S.A., supported by the Department of Veterans Affairs, found sufficient evidence of an association between deployment to the Gulf War and Gulf War syndrome (05). Listed below are conclusions about other relevant neurologic disorders:

	• Sufficient evidence of a causal relationship to PTSD.
	• Sufficient evidence of an association with chronic fatigue syndrome.
	• Limited/suggestive evidence of an association with amyotrophic lateral sclerosis (ALS), fibromyalgia, and chronic widespread pain.
	• Inadequate/insufficient evidence to determine whether an association exists with neurocognitive performance, headache disorders, and neurodegenerative disorders other than amyotrophic lateral sclerosis.
	• Limited/suggestive evidence of no association with objective measures of peripheral neurologic conditions and multiple sclerosis.

The Gulf War and Health Committee conducted public meetings and study of publications on this topic and reached some conclusions about Gulf War deployment exposures and reproductive effects, adverse pregnancy outcomes, and developmental effects of which the neurodevelopmental effects include the following (38):

	• There is sufficient evidence of an association between prenatal exposure to organophosphate pesticides and neurodevelopmental effects.
	• There is limited or suggestive evidence of an association between prenatal exposure to particulate matter and neurodevelopmental effects.

The committee believes that the results of studying generational effects will ultimately provide new knowledge regarding veterans’ exposures, their reproductive health, and the developmental health of their children and grandchildren.

Management of Gulf War syndrome. Even though there is controversy about this illness, there is need for management strategies. So far there is no effective treatment. A study that compared gene expression patterns in Gulf War syndrome with expression patterns in those same modules in other illnesses identified immunosuppressants used for treating rheumatoid arthritis and hormone-based therapies as the best available candidates for treating symptoms of this syndrome (06).

The concept that Gulf War illness originates from exposure to battlefield neurotoxicants exacerbated by stress requires a treatment strategy that inhibits both immune and stress-related targets. However, development of pharmacotherapy for Gulf War illness is limited by the multiple interplays between the immune inhibitors (interleukin-2 and tumor necrosis factor alpha) and stress-related target (glucocorticoid receptor), leading to frequent drug interactions that require strategies to assess a drug’s specificity for its intended target for improving efficacy and avoiding undesirable off-target effects (26).

In rat models of Gulf War illness, curcumin treatment enhances the expression of antioxidant genes and normalizes the expression of multiple genes related to mitochondrial respiration, leading enhanced neurogenesis and reduction of inflammation as well as oxidative stress with normalized mitochondrial respiration, which may result in improvement of memory and mood function (32). Curcumin has potential clinical applications in patients with Gulf War illness. An open label trial of KPAX002 in Gulf War illness, which is a combination of methylphenidate hydrochloride plus a micronutrient formula designed to support mitochondrial function, resulted in a significant improvement in symptoms (17). A randomized, double-blinded, placebo-controlled trial is required to confirm the observed benefit.

A cross-sectional sample of self-selected veterans with Gulf War syndrome has demonstrated a high current burden of disease and patterns of onset of symptoms, which provides information to better understand the long-term course of Gulf War syndrome that can be integrated into the treatment and diagnosis of impacted veterans (10).

Based on improvements seen in animal models of Gulf War syndrome, several antioxidants and antiinflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular vesicles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials (08).

As of March 2021, 24 clinical trials for Gulf War syndrome are listed on the website: clinicaltrials.gov. Most of these are for treatments such as exercise, acupuncture, transcranial direct current stimulation for relief of pain, individualized mitochondrial cocktail as nutritional supplement, and carnosine.