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Introduction: Excess rates of Gulf War illness (GWI) and irritable bowel syndrome (IBS), two chronic multisymptom illnesses, have long been documented among nearly 700,000 veterans who served in the 1990-1991 Persian Gulf War. We sought to report the prevalence, characteristics, and association of GWI and IBS decades after the war in a clinical cohort of deployed Gulf War veterans (GWVs) who were evaluated at the Department of Veterans Affairs' War Related Illness and Injury Study Center (WRIISC) for unexplained chronic symptoms., Materials and Methods: We analyzed data gathered from clinical intake questionnaires of deployed GWVs who were evaluated at WRIISC clinics between 2008 and 2020. We applied Centers for Disease Control (CDC) criteria to determine the prevalence of severe GWI. IBS was identified using Rome IV diagnostic criteria (current IBS) and veterans' self-reported "history of physician-diagnosed IBS." We examined associations between IBS and GWI using bivariate analyses and multivariable logistic regression., Results: Among the N = 578 GWVs evaluated by the WRIISC, severe GWI (71.8%), history of physician-diagnosed IBS (50.3%) and current IBS (42.2%) were all highly prevalent. Nearly half of GWVs with severe GWI met Rome criteria for IBS (45.8%), and over half reported a history of physician-diagnosed IBS (56.1%). In multivariable models, severe GWI was significantly associated both with current IBS (adjusted odds ratio (aOR): 1.68, 95% CI: 1.11, 2.54) and with veteran-reported history of physician-diagnosed IBS (aOR: 2.15, 95% CI: 1.43, 2.23). IBS with diarrhea (IBS-D) was the most common subtype among GWVs with current IBS (61.1%). However, IBS-mixed affected a significantly greater proportion of veterans with severe GWI, compared to veterans who did not have severe GWI (P = .03)., Conclusions: More than 20 years after the Persian Gulf War, our findings indicate a high degree of comorbidity between severe GWI and IBS among deployed GWVs seeking care for unexplained illnesses. Our results suggest GWVs with GWI should be screened for IBS for which evidence-based treatments are available and could potentially reduce symptom burden. Conversely, symptoms of IBS should trigger additional evaluation for non-gastrointestinal symptoms in deployed Gulf War veterans to identify possible GWI and ensure a comprehensive approach to care., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex ® , a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI., Methods: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests., Results: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus., Conclusions: The use of an FDA-approved CBD (Epidiolex ® ) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation., (© 2024. The Author(s).)

Introduction: The War-Related Illness and Injury Study Center at the VA New Jersey Health Care System (WRIISC-VANJ) serves as one of the three tertiary referral centers for combat deployed Veterans of all eras with medically unexplained or difficult-to-diagnose conditions that may be related to deployment-related exposures. Many of the Veterans seen at the WRIISC experience chronic multisymptom illness (CMI), also known as Gulf War Illness (GWI). Given the complexity and interconnectedness of symptoms, Veterans with GWI are often unlikely to produce meaningful results when addressing single symptoms. Further, Veterans with GWI often have co-morbid cognitive and behavioral health conditions (e.g., TBI, PTSD, Depression), which further compromise their self-efficacy in following treatment recommendations. Thus, the WRIISC-NJ, in collaboration with Wellness Solutions Group, developed a virtual Functional Medicine-based Interdisciplinary and Integrative Intervention to improve the health of Veterans by assisting them in implementing lifestyle changes., Methods: The 6-month telehealth program included functional medicine assessments, nutrition and adaptive exercise coaching, mindfulness meditation and yoga, guest health lectures, character strength coaching, and targeted nutritional supplements. Aspects of the program were tailored to the unique clinical needs of each Veteran. Participants completed baseline and 6 month follow-up assessments of physical and emotional symptoms and overall functioning. Follow-up scores were compared with baseline data., Results: The program was well received by Veterans with attendance across all offered sessions ranging from 70 to 100%. Further, at the end of the clinical pilot program, improvements were demonstrated in physical and mental health symptoms, intentional weight loss/gain, functional movement, and sleep quality., Conclusions: These preliminary results demonstrate the possibility of creating positive health outcomes across multiple health indicators in medically complex combat-deployed Veterans. Our early success and participant enthusiasm for this clinical pilot program also illustrate an opportunity to provide individualized, innovative solutions for the evaluation and treatment of Veterans with GWI., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-γ, IL-6, IL-1β, TNF-α) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression ( p < 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), ( p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (β = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-γ was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), ( p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-γ, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work.

Gulf War Illness (GWI) is characterized by a wide range of symptoms that manifests largely as gastrointestinal symptoms. Among these gastrointestinal symptoms, motility disorders are highly prevalent, presenting as chronic constipation, stomach pain, indigestion, diarrhea, and other conditions that severely impact the quality of life of GWI veterans. However, despite a high prevalence of gastrointestinal impairments among these veterans, most research attention has focused on neurological disturbances. This perspective provides a comprehensive overview of current in vivo research advancements elucidating the underlying mechanisms contributing to gastrointestinal disorders in GWI. Generally, these in vivo and in vitro models propose that neuroinflammation alters gut motility and drives the gastrointestinal symptoms reported in GWI. Additionally, this perspective highlights the potential and challenges of in vitro bioengineering models, which could be a crucial contributor to understanding and treating the pathology of gastrointestinal related-GWI., (© 2024. The Author(s).)

Background: Gulf War illness (GWI)/Chronic Multisymptom Illness (CMI) is a disorder related to military service in the 1991 Gulf War (GW). Prominent symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI/CMI symptom, anecdotally some GW veterans have reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson's and Alzheimer's disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans., Methods: Eighty deployed GW veterans (mean age: 59.9  ±7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from healthy control (HC) participants from the Parkinson's Progression Markers Initiative (PPMI) study were downloaded for comparison., Results: GW veterans had a mean UPSIT score of 27.8  ± 6.3 (range 9-37) and a mean MoCA score of 25.3  ± 2.8 (range 19-30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman's ρ = 0.39, p < 0.001). There were no significant differences in UPSIT or MoCA scores between GW veterans with and without history of COVID or between those with and without Kansas GWI exclusionary conditions., Conclusions: We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans, 99% of whom had CMI. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: One-third of veterans returning from the 1990-1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI., Methods: Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWI H ) and GWI with low probability of PTSD symptoms (GWI L ). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWI H , GWI L , and healthy control groups., Results: GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWI L subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWI L subgroup was found to be delineated from both GWI H and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms., Conclusion: We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively., (© 2024. The Author(s).)

Objective: The aim of the study is to investigate relationships between inflammatory analytes and symptoms of pain and fatigue in Gulf War illness (GWI)., Methods: In this preliminary study, 12 male veterans meeting GWI criteria provided daily blood samples and symptom ratings over 25 days. Linear mixed models were used to analyze associations between symptoms and sera concentrations of cytokines, acute phase proteins, insulin, and brain-derived neurotropic factor., Results: Analyses included 277 days with both blood draws and self-reports. Days with worse fatigue severity were associated with higher C-reactive protein and serum amyloid A, and lower eotaxin 1. Muscle pain and joint pain were associated with leptin, monocyte chemoattractant protein 1, and interferon γ-induced protein. Joint pain was further associated with serum amyloid A and eotaxin 3., Conclusions: Gulf War illness involves fatigue and pain associated with inflammation. Conventional and novel anti-inflammatories should be further explored for the treatment of GWI., Competing Interests: Younger, Hodgin, and Jones have no relationships/conditions/circumstances that present potential conflict of interest., (Copyright © 2021 American College of Occupational and Environmental Medicine.)

Background: Gulf War Illness (GWI) is a chronic, multi-symptomatic disorder characterized by fatigue, muscle pain, cognitive problems, insomnia, rashes, and gastrointestinal issues affecting an estimated 30% of the ~ 750,000 returning military Veterans of the 1990-1991 Persian Gulf War. Female Veterans deployed to combat in this war report medical symptoms, like cognition and respiratory troubles, at twice the rate compared to non-deployed female Veterans of the same era. The heterogeneity of GWI symptom presentation complicates diagnosis as well as the identification of effective treatments. This is exacerbated by the presence of co-morbidities. Defining subgroups of the illness may help alleviate these complications. One clear grouping is along the lines of gender. Our aim is to determine if women with GWI can be further subdivided into distinct subgroups based on post-traumatic stress disorder (PTSD) symptom presentation., Methods: Veterans diagnosed with GWI (n = 35) and healthy sedentary controls (n = 35) were recruited through the Miami Veterans Affairs Medical Health Center. Symptoms were assessed via the RAND short form health survey, the multidimensional fatigue inventory, and the Davidson trauma scale. Hierarchal regression modeling was performed on measures of health and fatigue with PTSD symptoms as a covariate. This was followed by univariate analyses conducted with two separate GWI groups based on a cut-point of 70 for their total Davidson trauma scale value and performing heteroscedastic t-tests across all measures., Results: Based on the distinct differences found in PTSD symptomology regarding all health and trauma symptoms, two subgroups were derived within female GWI Veterans. Hierarchical regression models displayed the comorbid effects of GWI and PTSD, as both conditions had measurable impacts on quality of life and fatigue (ΔR 2 = 0.08-0.672), with notable differences in mental and emotional measures. Overall, a cut point analysis indicated poorer quality of life and greater fatigue within all measures for women with GWI and PTSD symptoms in comparison to those women with GWI without PTSD symptoms and healthy controls., Conclusions: Our current findings support the understanding that comorbid symptoms of GWI and PTSD subsequently result in poorer quality of life and fatigue, along with establishing the possibility of varying clinical presentations., (© 2022. The Author(s).)

Aims: Widespread pain and headache are common in Gulf War Illness with suboptimal treatments available. We tested the efficacy of non-invasive, transcutaneous vagal nerve stimulation (nVNS) for relief of widespread pain and migraine in Gulf War Veterans with GWI., Main Methods: A 10-week double-blind, randomized controlled trial of nVNS used the gammaCore (ElectroCore, Inc.) compared to sham stimulation with the same device followed by a 10-week open-label follow up with active nVNS. The primary outcome was a numerical pain rating at the end of the blinded period. Secondary outcomes included physical function, migraine frequency and severity, and impression of change during the blinded and open-label periods. Two-factor MANOVA models tested for significant differences between groups from baseline to end of the blinded period and during the open-label period., Key Findings: Among 27 participants enrolled and issued a nVNS device, there was a slight improvement in pain ratings from baseline to the end of the blinded phase [6.18 (±0.82) vs. 5.05 (±2.3); p = 0.040] which did not differ between active and sham nVNS. Physical function was also slightly improved overall without group differences. There were no significant changes in migraine frequency or severity during the blinded period. Twenty participants started in the open-label phase; no statistically significant changes in pain, physical function, migraine measures, or impression of change were noted during this phase., Significance: Veterans with GWI actively treated with nVNS reported no improvement in either widespread pain or migraine frequency or severity relative to Veterans with GWI who received sham nVNS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

By its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target., (© 2021. The Author(s).)

Aims: Nearly a third of U.S. veterans who deployed in support of the 1990-1991 Persian Gulf War are affected by Gulf War illness (GWI). Here we aimed to characterize whether subjective sleep complaints in GWI veterans are associated with objective sleep EEG disturbances relative to healthy veterans and controls; and whether Gulf War veterans show alterations in neural activity during sleep that differentiate them from healthy subjects., Main Methods: We used high-density EEG (HDEEG) to assess regional patterns of rapid eye movement (REM) sleep and non-REM (NREM) sleep between three groups: Gulf War male veterans with fatigue and GWI, Gulf War male veterans without fatigue or GWI, and control males. The groups were matched relative to age, sex and obstructive sleep apnea. Topographic comparisons of nocturnal NREM and REM sleep were made between groups for all frequency bands., Key Findings: Topographic analysis revealed a broadband reduction in EEG power in a circumscribed region overlying the frontal lobe in both groups of Gulf War veterans, regardless of GWI and fatigue. This frontal reduction in neural activity was present, to some extent, across all frequency bands in NREM and REM sleep., Significance: Given that our findings were observed in all Gulf War veterans, it appears unlikely that frontal sleep HDEEG power reductions prove wholly responsible for fatigue symptoms. These results provide avenues for research which may someday contribute to improved clinical care of formerly deployed veterans of the Persian Gulf War., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans., Materials and Methods: We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990-91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures., Key Findings: Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions., Significance: These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI., (Published by Elsevier Inc.)

Gulf War illness (GWI) is a chronic and multi-symptomatic disorder affecting veterans who served in the Gulf War. The commonly reported symptoms in GWI veterans include mood problems, cognitive impairment, muscle and joint pain, migraine/headache, chronic fatigue, gastrointestinal complaints, skin rashes, and respiratory problems. Neuroimaging studies have revealed significant brain structure alterations in GWI veterans, including subcortical atrophy, decreased volume of the hippocampus, reduced total grey and white matter, and increased brain white matter axial diffusivity. These brain changes may contribute to or increase the severities of the GWI-related symptoms. Epidemiological studies have revealed that neurotoxic exposures and stress may be significant contributors to the development of GWI. However, the mechanism underlying how the exposure and stress could contribute to the multi-symptomatic disorder of GWI remains unclear. We and others have demonstrated that rodent models exposed to GW-related agents and stress exhibited higher extracellular glutamate levels, as well as impaired structure and function of glutamatergic synapses. Restoration of the glutamatergic synapses ameliorated the GWI-related pathological and behavioral deficits. Moreover, recent studies showed that a low-glutamate diet reduced multiple symptoms in GWI veterans, suggesting an important role of the glutamatergic system in GWI. Currently, growing evidence has indicated that abnormal glutamate neurotransmission may contribute to the GWI symptoms. This review summarizes the potential roles of glutamate dyshomeostasis and dysfunction of the glutamatergic system in linking the initial cause to the multi-symptomatic outcomes in GWI and suggests the glutamatergic system as a therapeutic target for GWI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Post-exertional malaise (PEM) is poorly understood in Gulf War Illness (GWI). Exercise challenges have emerged as stimuli to study PEM; however, little attention has been paid to unique cardiorespiratory and perceptual responses during exercise. This study tested whether select exercise parameters explained variability in PEM responses., Main Methods: Visual analog scale (0-100) versions of the Kansas questionnaire were used for daily symptom measurements one week before and one week after 30-min of cycling at 70% heart rate reserve in 43 Veterans with GWI and 31 Veteran controls (CON). Cardiopulmonary exercise testing (CPET) methods were used to measure oxygen (VO 2 ), carbon dioxide (VCO 2 ), ventilation (VE), heart rate, work rate, and leg muscle pain. Symptom changes and CPET parameters were compared between groups with independent samples t-tests. Linear regression (GLM) with VE/VCO 2 , cumulative work, leg muscle pain, and self-reported physical function treated as independent variables and peak symptom response as the dependent variable tested whether exercise responses predicted PEM., Key Findings: Compared to CON, Veterans with GWI had greater ventilatory equivalent for oxygen (VE/VO 2 ), peak leg muscle pain, fatigue, and lower VCO 2 , VO 2 , power, and cumulative work during exercise (p < 0.05), and greater peak symptom responses (GWI = 38.90 ± 29.06, CON = 17.84 ± 28.26, g = 0.70, p < 0.01). The final GLM did not explain significant variance in PEM (Pooled R 2  = 0.15, Adjusted R 2  = 0.03, p = 0.34)., Significance: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise., (Published by Elsevier Inc.)

Aims: To examine whether cognitive behavioral therapy for insomnia (CBT-I), delivered by telephone, improves sleep and non-sleep symptoms of Gulf War Illness (GWI)., Main Methods: Eighty-five Gulf War veterans (21 women, mean age: 54 years, range 46-72 years) who met the Kansas GWI case definition, the Centers for Disease Control and Prevention (CDC) case definition for Chronic Multisymptom Illness (CMI), and research diagnostic criteria for insomnia disorder were randomly assigned to CBT-I or monitor-only wait list control. Eight weekly sessions of individual CBT-I were administered via telephone by Ph.D. level psychologists to study participants. Outcome measures included pre-, mid-, and post-treatment assessments of GWI and insomnia symptoms, subjective sleep quality, and continuous sleep monitoring with diary. Outcomes were re-assessed 6-months post-treatment in participants randomized to CBT-I., Key Findings: Compared to wait list, CBT-I produced significant improvements in overall GWI symptom severity, individual measures of fatigue, cognitive dysfunction, depression and anxiety, insomnia severity, subjective sleep quality, and sleep diary outcome measures. The beneficial effects of CBT-I on overall GWI symptom severity and most individual GWI symptom measures were maintained 6-months after treatment., Significance: GWI symptoms have historically been difficult to treat. Because CBT-I, which is associated with low stigma and is increasingly readily available to veterans, improved both sleep and non-sleep symptoms of GWI, these results suggest that a comprehensive approach to the treatment of GWI should include behavioral sleep interventions., (Published by Elsevier Inc.)

Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a key role in the pathology of this disorder. GWI courses with gut microbiota alterations and their metabolites (e.g. short chain fatty acids -SCFA-), which can be aggravated by lifestyle risk factors such as a high fat diet (HF). To investigate the causative role of the gut microbiome, non-absorbable antibiotics (Abx) were administered to mice treated with GWI agents and concomitantly fed with a HF. In light of the wide use of Abx as pseudo-germ-free models, we evaluated the effects of Abx exposure on GWI and HF on body weight, food intake, gut microbiota changes and levels of the SCFA acetate. Results show that HF decreased food intake while increasing body weight in both controls and GWI. Exposure to Abx prevented these HF effects by offsetting the body weight gain in GWI. GWI and HF led to decreases in α-diversity, disruptions in the composition and structure of the gut bacterial community and decreases in acetate levels. This Abx-induced remodeling of the gut microbiome was characterized by an expansion of Proteobacteria, decreases in Bacteroidetes and Firmicutes, and overall increases in acetate levels, as well as by the proliferation of potential pathobionts. Therefore, the use of Abx may not represent a dependable approach to deplete the gut microbiome and its advantages as a pseudo germ-free model warrant further investigation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: Gulf War Illness (GWI) is a prevalent and disabling condition characterized by persistent physical symptoms. Clinical practice guidelines recommend self-management to reduce the disability from GWI. This study evaluated which GWI self-management strategies patients currently utilize and view as most effective and ineffective., Materials and Methods: Data were collected from 267 Veterans during the baseline assessment of a randomized clinical trial for GWI. Respondents answered 3 open-ended questions regarding which self-management strategies they use, view as effective, and view as ineffective. Response themes were coded, and code frequencies were analyzed., Key Findings: Response frequencies varied across questions (in-use: n = 578; effective: n = 470; ineffective: n = 297). Healthcare use was the most commonly used management strategy (38.6% of 578), followed by lifestyle changes (28.5% of 578), positive coping (13% of 578), and avoidance (13.7% of 578). When asked about effective strategies, healthcare use (25.9% of 470), lifestyle change (35.7% of 470), and positive coping (17.4% of 470) were identified. Avoidance was frequently identified as ineffective (20.2% of 297 codes), as was invalidating experiences (14.1% of 297) and negative coping (10.4% of 297)., Significance: Patients with GWI use a variety of self-management strategies, many of which are consistent with clinical practice guidelines for treating GWI, including lifestyle change and non-pharmacological strategies. This suggests opportunities for providers to encourage effective self-management approaches that patients want to use., (Copyright © 2021. Published by Elsevier Inc.)

Chronic diffuse body pain is unequivocally highly prevalent in Veterans who served in the 1990-91 Persian Gulf War and diagnosed with Gulf War Illness (GWI). Diminished motor cortical excitability, as a measurement of increased resting motor threshold (RMT) with transcranial magnetic stimulation (TMS), is known to be associated with chronic pain conditions. This study compared RMT in Veterans with GWI related diffuse body pain including headache, muscle and joint pain with their military counterparts without GWI related diffuse body pain. Single pulse TMS was administered over the left motor cortex, using anatomical scans of each subject to guide the TMS coil, starting at 25% of maximum stimulator output (MSO) and increasing in steps of 2% until a motor response with a 50 µV peak to peak amplitude, defined as the RMT, was evoked at the contralateral flexor pollicis brevis muscle. RMT was then analyzed using Repeated Measures Analysis of Variance (RM-ANOVA). Veterans with GWI related chronic headaches and body pain (N = 20, all males) had a significantly (P < 0.001) higher average RMT (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state. The impact of this observed supraspinal functional impairment on other GWI related symptoms and the potential use of TMS in rectifying this abnormality and providing relief for pain and co-morbid symptoms requires further investigation.Trial registration: This study was registered on January 25, 2017, on ClinicalTrials.gov with the identifier: NCT03030794. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03030794 .

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1β in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1β, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.

Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen's d . Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms ( p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry ( p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p < 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.

Pain is a diagnostic criterion for Gulf War Illness (GWI), Chronic Fatigue Syndrome (CFS), and fibromyalgia (FM). The physical sign of systemic hyperalgesia (tenderness) was assessed in 920 women who were stratified by 2000 Kansas GWI, 1994 CFS, and 1990 FM criteria. Pressure was applied by dolorimetry at 18 traditional tender points and the average pressure causing pain determined. GWI women were the most tender (2.9 ± 1.6 kg, mean ± SD, n = 70), followed by CFS/FM (3.1 ± 1.4 kg, n = 196), FM (3.9 ± 1.4 kg, n = 56), and CFS (5.8 ± 2.1 kg, n = 170) compared to controls (7.2 ± 2.4 kg, significantly highest by Mann-Whitney tests p < 0.0001, n = 428). Receiver operating characteristics set pressure thresholds of 4.0 kg to define GWI and CFS/FM (specificity 0.85, sensitivities 0.80 and 0.83, respectively), 4.5 kg for FM, and 6.0 kg for CFS. Pain, fatigue, quality of life, and CFS symptoms were equivalent for GWI, CFS/FM and CFS. Dolorimetry correlated with symptoms in GWI but not CFS or FM. Therefore, women with GWI, CFS and FM have systemic hyperalgesia compared to sedentary controls. The physical sign of tenderness may complement the symptoms of the Kansas criteria as a diagnostic criterion for GWI females, and aid in the diagnosis of CFS. Molecular mechanisms of systemic hyperalgesia may provide new insights into the neuropathology and treatments of these nociceptive, interoceptive and fatiguing illnesses.

At least one-fourth of US veterans who served in the 1990-1991 Gulf War (GW) are affected by the chronic symptomatic illness known as Gulf War illness (GWI). This condition typically includes some combination of fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. To date, effective treatments for GWI have been elusive. Photobiomodulation (PBM) describes the non-pharmacological, non-thermal use of light to stimulate, heal, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. Significant benefits have been reported following application of transcranial PBM to humans with acute stoke, traumatic brain injury (TBI), and dementia. This report describes the first documentation of improved GWI symptoms in two GW veterans following 12 weeks of PBM treatments., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI. Accordingly, the goal of this study was to determine how responses to an immune challenge (lipopolysaccharide; LPS) or stress impacts inflammation, acetylcholine (ACh) neurochemistry and behavior in an experimental model of GWI. Rats with a history of PB treatment exhibited potentiated increases in C-reactive protein levels in response to a submaximal LPS challenge compared to control rats, indicating that prior treatment with this cholinesterase inhibitor leads to exacerbated inflammatory responses to a subsequent immune challenge. ACh responses to LPS administration were decreased in the hippocampus, but not prefrontal cortex (PFC), in rats with a prior history of PB treatment or stress exposure. Additionally, ACh release in response to acute immobilization stress was attenuated in the PFC and hippocampus in these groups. These attenuated cholinergic responses were accompanied by impairments in contextual and cue-based fear learning. The results of this study suggest that stress and LPS challenges adversely affect central ACh neurochemistry in a rodent model of GWI and support the hypothesis that dysregulated immune responses are mechanistically linked to the neurological complications of GWI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Chronic multisymptom illness (CMI) is more prevalent among deployed than nondeployed veterans from the first Gulf War. Objective physiologic markers of CMI are lacking. The purpose of this study is to determine whether measurable abnormalities in the autonomic nervous system or hypothalamic-pituitary adrenal axis would distinguish CMI cases (CMI+) from controls (CMI-) among deployed veterans of the 1990-1991 Gulf War., Methods: This is a cross-sectional case-control cohort study that examined deployed veterans who participated in the Phase III study: National Health Survey of Gulf War Veterans and Their Families. Autonomic nervous system and hypothalamic-pituitary adrenal axis function-related measures included: 24-hour heart-rate variability, urinary catecholamines and cortisol, hypertension, insulin sensitivity, dyslipidemia, body fat, bone mineral density, and ultrasensitive C-reactive protein., Results: Veterans of the first Gulf War with CMI (n = 73) and without the condition (n = 111) were studied. Sociodemographic characteristics were similar. Veterans with CMI reported poorer mental and physical functioning, greater use of prescription medications, and more nonroutine clinic visits. These veterans were also more likely to have fibromyalgia syndrome, irritable bowel syndrome, metabolic syndrome, and among males, a larger waist-to-hip ratio. Lower values for a nonlinear heart-rate-variability parameter-the short-term fractal scaling exponent (DFA1), reflecting an increased randomness of beat-to-beat changes in heart rate-were observed in veterans with CMI than those veterans without it (1.28±0.16vs 1.35±0.15; p=0.005). Hypothalamic-pituitary-adrenal axis function measures were similar between the two groups., Conclusion: In this cohort of deployed veterans from the first Gulf War, we identified abnormal heart-rate variability in veterans with CMI compared to veterans without the condition, which suggests abnormal functioning of the autonomic nervous system and possible long-term cardiovascular effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Previous studies suggest that autonomic dysfunction may be an underlying factor in Gulf War Illness. This study examined self-reported symptoms of autonomic dysfunction and their relationship with physical functioning among veterans with Gulf War Illness., Materials and Methods: We abstracted medical records of Gulf War Veterans clinically evaluated at the New Jersey War Related Illness and Injury Study Center between 2010 and 2016. The outcome measure was the Veteran version of the Short Form Health Survey (VR-36) physical functioning scale. Autonomic function was assessed using a composite variable constructed from the chart abstraction to mimic the Composite Autonomic Symptom Scale (COMPASS-31)., Results: Seventy-six veterans were included in the final analysis. The autonomic symptom burden score was 45 (±14). Increased autonomic symptom burden, greater mental health burden (PTSD/depression), and greater body mass index were individually associated with poorer physical functioning. A general linear regression containing these variables revealed that patients with both PTSD and depression (b = -15.2, p = 0.03) or either PTSD or depression (b = -22.7, p < 0.01) had lower physical functioning than those without; the other variables became not significant (body mass index: p = 0.07; autonomic function: p = 0.89)., Conclusion: The average autonomic function score indicated significant burden in Gulf War Veterans, consistent with published research. We did not detect an independent association between autonomic symptom burden and physical functioning, likely due to the non-specific nature of the measure used to capture autonomic symptoms or the stronger association between mental health conditions and physical functioning. Future work utilizing valid and standardized instruments to clinically evaluate autonomic function is warranted.

Purpose: Long-term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level., Experimental Design: We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ., Results: The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure., Conclusions and Clinical Relevance: The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long-term consequences of combined PB and PER exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER., (© 2017 The Authors. PROTEOMICS - Clinical Applications published by WILEY-VCH Verlag GmbH & Co. KGaA.)

Introduction: Despite the fact that many veterans returned from the 1991 Gulf War (GW) with complaints of memory difficulties, most neuropsychological studies to date have found little evidence of a correspondence between subjective and objective measures of cognitive function in GW veterans. However, if GW veterans complain about memory problems, it is likely that they experience memory problems in their daily lives. In this respect, it is notable that the past studies that have investigated the relationship between subjective and objective measures of cognitive function in GW veterans used composite measures to quantify subjective complaints and batteries of neuropsychological tests that assessed multiple domains to objectively measure cognitive function. The study's focus on memory was motivated by the suggestive evidence that subjective memory complaint may be a harbinger of further cognitive decline and increased risk for dementia., Materials and Methods: This study examined the association between subjective memory complaint (probed with single question: "Do you have difficulty remembering things?") and performance on a single objective test of verbal learning and memory (i.e., California Verbal Learning Test, CVLT-II) in a sample of 428 deployed GW veterans., Results: GW veterans who endorsed memory difficulties performed more poorly on CVLT-II measures of total learning, retention, and delayed recall than GW veterans without subjective memory complaints (p < 0.001), even after accounting for demographic (e.g., age, sex, education) and clinical variables (e.g., diagnoses of current post-traumatic stress disorder [PTSD], depressive disorder, and/or anxiety disorder) that could potentially contribute to memory deficits. Among GW veterans who met the Centers for Disease Control and Prevention criteria for chronic multisymptom illness (N = 272), subjective memory complaint significantly predicted CVLT-II retention scores (β = -0.12, p = 0.04) and marginally predicted CVLT-II delayed recall scores (β = -0.11, p = 0.05) over and above potentially confounding demographic and clinical variables., Conclusion: This study suggests that deployed GW veterans with subjective memory complaints have objective memory impairments. In light of the evidence linking subjective memory complaint to increased risk for dementia in the elderly, these findings suggest that aging GW veterans with subjective memory complaints should be closely monitored for further cognitive decline., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Objective: In 1995, the Centers for Disease Control and Prevention defined chronic multisymptom illness (CMI), a symptom complex in deployed veterans (DVs) of the 1991 Gulf War 1. The specific aim of this work is to determine the prevalence of CMI in spouses of DV and nondeployed veterans (NDVs) and whether veteran CMI is associated with spouse CMI, and to describe the physical and psychological profile of spouses with CMI., Materials and Methods: To determine whether veteran CMI was associated with CMI in their spouses, we used retrospective data from the "National Health Survey of Gulf War Veterans and Their Families." Cross-sectional data were collected from spouses of veterans enrolled in the study, including those of 482 DVs and 532 NDVs who participated in an in-person examination between 1999 and 2001. In addition to a physical examination, this study evaluated health-related quality of life (Medical Outcomes Study Short-Form 36, SF-36), psychological symptoms, and post-traumatic stress disorder (PTSD) status, and measured a variety of common laboratory tests. Statistical analyses included Fisher's Exact Test (or Mantel-Haenszel χ 2 test for linear trend) as well as odds ratios (ODs) and 95% confidence intervals (CIs) for categorical data. For continuous outcomes, two-sample t-tests were used to compare mean responses among spouses of DV and NDV with and without CMI, and between spouses of DV and NDV with CMI only. Logistic or linear regression models were developed for multiple-covariate analysis to assess if any of the associations we found in the unadjusted analyses would change. The project was approved by the Hines Cooperative Studies Program Human Rights Committee, the Institutional Review Boards at each participating site, and the Brockton VAMC., Results: The prevalence of CMI in spouses was 19.5% (DV) and 17.3% (NDV) (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 0.84, 1.59). Spouses were more likely to have CMI if their veteran partner had CMI (OR: 1.49; 95% CI: 1.01, 2.19) or PTSD (OR: 1.84; 95% CI: 1.01, 3.37). Deployment was not a predictor of CMI. Spouses with CMI reported poorer SF-36 physical and mental component scores; worse symptoms of depression, anxiety, and post-traumatic stress; and a higher percentage had probable PTSD, more nonroutine clinic visits, more hospitalization, more prescription medications, and more psychotropic medication use compared with spouses without CMI regardless of the deployment status of their veteran spouses., Conclusion: Spouses of veterans with CMI report worse physical and mental functioning than spouses of veterans without CMI, regardless of the veteran's deployment status. Strengths of the study include that all participants were selected independently of veteran medical or psychiatric illness, and all underwent comprehensive health assessments. Weaknesses of the study include that data were not collected blindly, and that we made minor modifications of the Centers for Disease Control and Prevention diagnosis, such as defining fatigue and musculoskeletal pain more restrictively. The impact of veteran CMI on their spouse's health is likely to be significant in terms of medical cost and morbidity. Efforts to reduce the impact of CMI in the future should include identifying soldiers who are more vulnerable, such as those with prior GWI or PTSD., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

Objectives: Previously we established that symptoms reported by 1990-1991 Gulf War veterans were correlated and exhibited a pattern with 3 factors (psychophysiological distress, somatic distress and arthroneuromuscular distress), and this pattern was similar to that observed in a military comparison group. In this follow-up study, we examined whether the patterns of symptomatology have changed over time., Methods: Using data on 56 symptoms that was collected in 2000-2003 (wave 1) and 2011-2012 (wave 2) from an Australian cohort of Gulf War veterans (veterans) and a military comparison group, exploratory factor analysis was conducted and Tucker's Congruence Coefficient (TCC) was used to determine factor structure similarity across study groups and waves., Results: The results showed that the 3 factors observed at wave 1 were still present at wave 2, and factor structures across study groups and study waves were fairly similar, with TCC ranging 0.86-0.92. Veterans consistently reported more symptoms across all 3 factors. Veterans' symptomatology specific to psychophysiological distress increased between waves 1 and 2 (ratio of means 1.15; 95% CI 1.07 to 1.25) but psychophysiological distress symptomatology was constant in the comparison group (ratio of means 0.97; 95% CI 0.89 to 1.06). Somatic and arthroneuromuscular distress symptomatology significantly increased over time for both study groups, although at a similar rate., Conclusions: While the symptom groupings (measured by the 3 factors) remained unchanged at 10 years of follow-up, and remained comparable between Gulf War and comparison group, symptomatology continued to be elevated in Gulf War veterans than in the comparison group, and was most evident for psychophysiological distress., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990-1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 ± 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, p=0.00004) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.

An exaggerated response to emotional stimuli is among the many symptoms widely reported by veterans of the 1991 Persian Gulf War. These symptomologies have been attributed to damage and dysfunction associated with deployment-related exposures. We collected event-related potential data from 22 veterans meeting Haley criteria for Gulf War (GW) Syndromes 1-3 and from 8 matched GW veteran controls, who were deployed but not symptomatic, while they performed a visual three-condition oddball task where images authenticated to be associated with the 1991 Persian Gulf War were the distractor stimuli. Hyperarousal reported by ill veterans was significantly greater than that by control veterans, but this was not paralleled by higher amplitude P3a in their ERP responses to GW-related distractor stimuli. Whereas previous studies of PTSD patients have shown higher amplitude P3b responses to target stimuli that are placed amid trauma-related nontarget stimuli, ill veterans in this study showed P3b amplitudes to target stimuli - placed amid GW-related nontarget stimuli - that were significantly lower than those of the control group. Hyperarousal scores reliably predicted P3b, but not P3a, amplitudes. Although many factors may contribute to P3b amplitude differences - most notably depression and poor sleep quality, symptoms that are prevalent in the GW syndrome groups - our findings in context of previous studies on this population are consistent with the contention that dysfunction in cholinergic and dopaminergic neurotransmitter systems, and in white matter and basal ganglia may be contributing to impairments in GW veterans., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

An exaggerated response to emotional stimuli is one of the several symptoms widely reported by veterans of the 1991 Persian Gulf War. Many have attributed these symptoms to post-war stress; others have attributed the symptoms to deployment-related exposures and associated damage to cholinergic, dopaminergic, and white matter systems. We collected event-related potential (ERP) data from 20 veterans meeting Haley criteria for Gulf War Syndromes 1-3 and from 8 matched Gulf War veteran controls, who were deployed but not symptomatic, while they performed an auditory three-condition oddball task with gunshot and lion roar sounds as the distractor stimuli. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans; different ERP profiles emerged to account for their hyperarousability. Syndromes 2 and 3, who have previously shown brainstem abnormalities, show significantly stronger auditory P1 amplitudes, purported to indicate compromised cholinergic inhibitory gating in the reticular activating system. Syndromes 1 and 2, who have previously shown basal ganglia dysfunction, show significantly weaker P3a response to distractor stimuli, purported to indicate dysfunction of the dopaminergic contribution to their ability to inhibit distraction by irrelevant stimuli. All three syndrome groups showed an attenuated P3b to target stimuli, which could be secondary to both cholinergic and dopaminergic contributions or disruption of white matter integrity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Complex disorders like Gulf War Illness (GWI) often defy diagnosis on the basis of a single biomarker and may only be distinguishable by considering the coexpression of multiple markers measured in response to a challenge. We demonstrate the practical application of such an approach using an example where blood was collected from 26 GWI, 13 healthy control subjects, and 9 unhealthy controls with Chronic Fatigue at three points during a graded exercise challenge. A 3-way multivariate projection model based on 12 markers of endocrine and immune function was constructed using a training set of n = 10 GWI and n = 11 healthy controls. These groups were separated almost completely on the basis of two coexpression patterns. In a separate test set these same features allowed for discrimination of new GWI subjects (n = 16) from unhealthy (n = 9) and healthy control subjects with a sensitivity of 70% and a specificity of 90%.

Poor performance on tasks requiring response inhibition has been observed among chronically ill veterans of the 1991 Persian Gulf War. Semantic difficulties have also been reported. We collected event-related potential (ERP) and behavioral data from 25 Gulf War veterans who complained of cognitive difficulties and from 23 matched controls, who were deployed but not symptomatic, while they performed a GO-NOGO task that required both a semantic decision and inhibitory processing. A significantly greater false-alarm rate among the ill veterans was accompanied in the ERP data by significantly reduced amplitude in the NOGO P3, consistent with previous ERP studies of other patient groups that have shown poor inhibitory response performance. This supports the contention that the ill veterans' deficit lies more in inhibiting than in detecting task-related differences in the stimuli., (Published by Elsevier B.V.)

Unlabelled: Our study sought to 1) determine if deployment status is associated with chronic widespread pain (CWP), and 2) evaluate whether veterans with CWP have greater psychiatric comorbidity, higher health care utilization, and poorer health status than veterans without CWP. Five years after the conclusion of the first Gulf War (August 1990 to June 1991), we conducted a cross-sectional study of veterans who listed Iowa as the home of record using a stratified sampling design to determine their health status. We compared the prevalence of CWP between deployed and nondeployed veterans. Logistic and multiple linear regression models were constructed to test whether CWP was associated with comorbidities and health-related outcomes of interest. Five hundred ninety of 3695 veterans interviewed (16%) had CWP. Gulf deployment was associated with higher prevalence of CWP than deployment elsewhere (OR = 2.03, 95%CI = 1.60-2.58), after adjustment. Both deployed and nondeployed veterans with CWP reported more health care utilization and comorbidities and lower health-related quality of life scores than veterans without CWP. Deployed veterans were more likely to have CWP than nondeployed veterans, and CWP was associated with poor health outcomes. Military and medical personnel should be aware that efforts to prevent, identify, and treat CWP in veterans returning from the current war may be needed., Perspective: This article indicates that deployed veterans may have an increased risk for development of CWP, which is associated with greater healthcare utilization and comorbidity and lower quality of life. The risk of poor health outcomes suggests that veterans returning from the present conflict should be screened for CWP on their return.

Background: Following the 1991 Gulf War, some veterans expressed concerns regarding their reproductive health. Our objective was to assess whether an association exists between deployment to the 1991 Gulf War and self-reported adverse pregnancy outcomes., Methods: Using a modified Dillman technique with telephone follow-up, we conducted a survey via a postal questionnaire from February 1996-August 1997 to compare selected reproductive outcomes among 10,000 US veterans deployed to the 1991 Gulf War with those of 10,000 nondeployed Gulf War era veterans., Results: A total of 8742 individuals responded to the survey, a response rate of 51 percent. Using multivariable analyses, results showed no differences in number of reported pregnancies between Gulf War veterans and nondeployed veterans. Among 2233 female and 2159 male participants, there were no differences in birth weight of infants born to Gulf War veterans compared with nondeployed Gulf War era veterans. In multivariable models, male and female Gulf War veterans did not significantly differ in risk for ectopic pregnancies, stillbirths, or miscarriages when compared with nondeployed veterans of the same era., Conclusions: These results do not suggest an association between service in the 1991 Gulf War and adverse reproductive outcomes for both male and female veterans during the 4 years after the war.

Objective: We sought to determine the predictors of incident chronic widespread pain (CWP), specifically, the effect of preexisting symptoms, stress, and psychosocial factors in the subsequent development of CWP among veterans from the first Gulf War (GW)., Methods: We conducted a structured telephone survey (baseline) of military personnel originally from Iowa who were either eligible for or deployed to Operation Desert Shield/Desert Storm, approximately 5 years postconflict. We conducted a follow-up, clinical, in-person study of those who met a priori-defined outcomes of symptoms of cognitive dysfunction, depression, or CWP, and also a sample of those who did not meet any of the outcomes of interest., Results: A total of 370 of 602 evaluated GW veterans were free of CWP 5 years postconflict. At follow-up, 69 (19%) of these had developed CWP. A positive family history of medically unexplained persistent symptoms [odds ratio (OR)=4.8 (2.3, 13.2)] was strongly associated with CWP. At baseline, individuals who reported preexisting symptoms of bronchitis [OR=4.9 (1.9, 12.3)] and cognitive dysfunction [OR=2.1 (1.1, 4.2)] were more likely to develop CWP. Alcohol use [OR=0.2 (0.1, 0.7)] was protective against CWP. Rather than combat-related exposure per se, the perception of stress at the time of the GW [OR=1.6 (1.1, 2.3)] correlated with CWP., Discussion: Among the GW veterans evaluated longitudinally in this study, family history, predeployment symptoms, and the level of perceived stress during the GW were associated with subsequent development of CWP.

Explanatory models for the increased prevalence of ill health in Gulf veterans compared to those not deployed to the Gulf War 1990-1991 remain elusive. This article addresses whether multi-symptom reporting in Gulf veterans are types of medically unexplained symptoms and whether the alleged Gulf War Syndrome is best understood as a medically unexplained syndrome. A review of the epidemiological studies, overwhelmingly cross-sectional, describing ill health was conducted including those that used factor analysis to search for underlying or latent clinical constructs. The overwhelming evidence was that symptoms in Gulf veterans were either in keeping with currently defined psychiatric disorders such as depression and anxiety or were medically unexplained. The application of factor analysis methods had varied widely with a risk of over interpretation in some studies and limiting the validity of their findings. We concluded that ill health in Gulf veterans and the alleged Gulf War Syndrome is best understood within the medically unexplained symptoms and syndromes constructs. The cause of increased reporting in Gulf veterans are still not clear and requires further inquiry into the interaction between sociological factors and symptomatic distress.

Background: Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects., Methods: Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 mul/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 mul/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis., Results: Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of >or=1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were alpha-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described., Conclusion: This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared.

Objective: To investigate autonomic abnormalities in male and female fibromyalgia (FM) and Gulf War illness (GWI) patients by comparing heart rate variability (HRV) with that of age- and sex-matched healthy controls., Methods: Subjects included 26 (19 women, 7 men) with FM, 11 (6 men, 5 women) with GWI, and 36 (18 men,18 women) healthy controls. HRV was determined from Holter recordings obtained in the Clinical Research Center. Analysis of variance compared 24-hour, daytime, and nighttime HRV by sex within groups and by group within sex., Results: In women with FM or GWI, HRV was significantly lower than in men with FM or GWI. HRV was similar in male and female controls. When HRV was compared by group within sex, HRV was significantly decreased in women with FM or GWI and no significant differences were seen for men with these conditions., Conclusion: Decreased HRV in FM and GWI appears to be sex dependent. Results suggest that different mechanisms may be operative in symptom expression in men and women with this spectrum of illness.

Purpose: To test the hypothesis that subtle abnormalities of the autonomic nervous system underlie the chronic symptoms reported by many Gulf War veterans, such as chronic diarrhea, dizziness, fatigue, and sexual dysfunction., Methods: Twenty-two ill Gulf War veterans and 19 age-, sex-, and education-matched control veterans underwent measurement of circadian rhythm of heart rate variability by 24-hour electrocardiography, ambulatory blood pressure recording, Valsalva ratio testing, sympathetic skin response evaluation, sweat imprint testing, and polysomnography. Investigators were blinded to case- or control-group status., Results: High-frequency spectral power of heart rate variability increased normally 2.2-fold during sleep in controls but only 1.2-fold in ill veterans (P <0.0001). In ill veterans as compared with controls, it was lower at night (P = 0.0006), higher during the morning (P = 0.007), but no different during the rest of the day (P = 0.8). The mean heart rate of ill veterans also declined less at night (P = 0.0002), and their corrected QT intervals tended to be longer over the full 24 hours (P = 0.07), particularly at night (P = 0.03). Blunting of the nocturnal heart rate dip in ill veterans was confirmed by 24-hour automatic ambulatory blood pressure monitoring (P = 0.05) and polysomnography (P = 0.03). These differences remained significant after adjusting for potential confounders. Cases and controls were similar on measures of sympathetic adrenergic and sudomotor function, sleep architecture, respiratory function, and circadian variation in blood pressure and body temperature., Conclusion: Some symptoms of Gulf War syndrome may be due to subtle autonomic nervous system dysfunction.

My postdoctoral training under Dr. Gerard Smith began me on a lifetime of investigation on the role of stress, hormones, and disease. The first set of experiments asked what hormone, if any, best reflected the range of aroused behaviors. We found that catecholamines performed substantially better than glucocorticoids did, despite the belief that glucocorticoids were sensitive indices of stress. But we also learned that hormones themselves were nowhere near as good in monitoring stress than motor behaviors were. In a second set of experiments, we tried to understand how stress affected medical disease. We learned that stress can produce disease in a healthy organism but has its most profound effects when disease already exists. Finally, in the early 1990s, I shifted my focus on stress and disease to a broader problem in behavioral medicine, namely, medically unexplained fatigue and pain. Among the studies we have done investigating these disorders, we looked specifically at veterans of the first Gulf War--many of whom developed problems with severe fatigue. A critical question in the literature asked if unexplained fatigue was simply a physical component of concurrent posttraumatic stress disorder (PTSD). In a large epidemiological study, we found that PTSD tracked stressor intensity in a stepwise fashion, while fatiguing illness increased with stressor intensity only on the milder side of the intensity spectrum. This result indicated that the two ailments are both stress sensitive but dissimilar.

Genes associated with muscle metabolism and physical endurance were evaluated for variants that may contribute to the etiology of medically unexplained severe and chronic fatigue. Subjects included 49 Gulf War veterans and 61 nonveterans with chronic fatigue syndrome (CFS) or idiopathic chronic fatigue (ICF) and 30 veterans and 45 nonveterans who served as healthy controls. Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. The I allele frequency was decreased in affected versus unaffected veterans (0.15 versus 0.48; odds ratio [OR], 5.08; 95% confidence interval [CI], 1.97-13.35; P < 0.0001). Correspondingly, the II genotype was decreased fourfold in affected veterans (0.08 versus 0.35; OR = 5.87; 95% CI: 1.21-28.36; P = 0.02), and the DD genotype was increased twofold (0.78 versus 0.39; OR, 5.4; 95% CI, 1.6-18.4; P = 0.007). Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype (OR, 8.30; 95% CI, 1.50-56.09; P = 0.009).

Background: There are no prospective cohort studies of prognostic factors on the outcome of Gulf War veterans. We aimed to test the hypotheses that Gulf War veterans who were older; had more severe symptoms; had more exposures during deployment; had increased psychological distress and believed they had 'Gulf War syndrome' would experience greater fatigue and poorer physical functioning at follow-up., Method: Gulf War veterans who responded to an earlier retrospective cohort study were followed with a postal survey. More symptomatic individuals were oversampled. Outcome was measured on the Chalder fatigue questionnaire, the General Health Questionnaire and the Medical Outcome Study Short-Form 36., Results: Of those surveyed, 73.8% responded. We found some evidence for four of the five hypotheses. More self-reported exposures at baseline were not associated with poorer outcome, but older people, those with more severe symptoms at baseline, those with psychological distress and who believed they were suffering from 'Gulf War syndrome' had more fatigue at follow-up. Officer status was associated with a better outcome. A similar lack of association was found for exposures and physical functioning and GHQ-12 score. 'Gulf War syndrome' attribution was associated with a worse outcome for GHQ-12 and physical functioning even after controlling for severity of symptoms at baseline., Conclusions: This study suggests that while multiple vaccination and military exposures are important risk factors for the onset of symptoms in Gulf War veterans, these are not important risk factors for persistence of such symptoms. Instead the severity of the initial symptoms; psychological distress and attributions may be more important determinants of outcome.

Purpose: The Centers for Disease Control (CDC)-1994 definition of chronic fatigue syndrome (CFS) is very broad, and there have been suggestions that it lacks specificity. To test this, we have compared three groups of patients, all of whom fulfill the criteria but self-report different etiologies., Methods: Patients with self-reported symptoms which developed sporadically (sCFS, n=48); after Gulf War service (GW, n=24); and following exposure to organophosphate insecticides (OP, n=25) underwent a clinical examination, completed the MOS SF-36 quality of life and Hospital Anxiety and Depression scales, and were assessed for major and minor criteria for CDC-1994 CFS., Results: Significant differences in simple clinical measures and outcome measures were observed between groups. The GW group had significantly more severe physical symptoms-fatigue, muscle and multi-joint pain-than OP or sCFS, and the sCFS group was significantly less impaired than the other two groups in terms of role emotional and mental health. In all three groups, a majority of patients exhibited muscle weakness in the lower limbs, and significant numbers of patients had absent or abnormal reflexes., Conclusions: Differences in simple, easily performed clinical outcome measurements can be observed between groups of patients, all of whom fulfill the CDC-1994 criteria for CFS. It is likely that their response to treatment may also vary. The specificity of the CFS case definition should be improved to define more homogeneous groups of patients for the purposes of treatment and research.

Purpose: To enumerate Gulf-War (GW) exposed conceptions and to compare reproductive outcomes of GW-exposed pregnancies with postwar conceptions of women Gulf War veterans (GWV) and women nondeployed veterans (NDV)., Methods: Deployment data and inpatient records from 153 military hospitals identified servicewomen who were pregnant between August 1990 and May 1992 and belonged to military units that were deployed to the Gulf War. Postal surveys were used in 1997 and 1998 to elicit reproductive history; responses were validated against military hospitalization records. Reproductive outcomes of GW-exposed pregnancies were compared with postwar conceptions of women GWVs and NDVs., Results: 3285 women had a pregnancy-related admission; of these, 1558 completed the questionnaire. Self-reported reproductive outcomes and dates, gestational data, and individual deployment dates identified 415 Gulf War-exposed pregnancies, 298 GWV postwar conceptions, and 427 NDV conceptions. Compared with NDV conceptions, adverse reproductive outcomes were similar among GW-exposed pregnancies. However, spontaneous abortions [NDV: 9.1%, GWV postwar: 22.8%, adjusted odds ratio (OR)=2.92, 95% confidence interval (CI): 1.9, 4.6] and ectopic pregnancies (NDV: 1.4%, GWV postwar: 10.7%, adjusted OR=7.70, 95% CI, 3.0, 20) were elevated for GWV postwar conceptions., Conclusion: GW-exposed conceptions and nondeployed conceptions had similar outcomes. However, GWV postwar conceptions were at increased risk for ectopic pregnancies and spontaneous abortions.