Associations between risky alcohol use, disability, and problem-solving impairment among Veterans with Gulf War Illness: Secondary data analysis of a randomized clinical trial.

OBJECTIVE: Gulf War Illness (GWI) and alcohol use are both major sources of disability among Gulf War Veterans. The goal of this secondary data analysis was to examine associations between risky alcohol use, problem-solving impairment, and disability among Veterans in a randomized clinical trial of problem-solving treatment (PST) for GWI. We examined cross-sectional associations and conducted longitudinal analyses to test if alcohol use moderated treatment outcome of PST. METHODS: Participants were 268 United States military Veterans with GWI randomized to PST or a control intervention. Participants were assessed at four timepoints. Measures included the World Health Organization Disability Assessment Schedule 2.0 (WHO-DAS 2.0), Problem Solving Inventory (PSI), and Alcohol Use Disorders Identification Test-Concise (AUDIT-C). We conducted multivariate regression (cross-sectional) and mixed model analyses (longitudinal) with separate models for WHO-DAS 2.0 and PSI. All models included AUDIT-C and household income. This analysis was pre-registered on the Open Science Framework. RESULTS: Cross-sectional analyses revealed a significant negative association with small effect size between AUDIT-C and WHO-DAS 2.0 (p = 0.006; f2 = 0.05); worse disability was associated with less risky alcohol use. There was no evidence that risky alcohol use moderated effects of PST on disability or PSI. CONCLUSION: If replicated, the cross-sectional findings suggest high levels of disability may deter heavy drinking among Veterans with GWI. We did not find evidence that risky alcohol use moderated treatment outcome of PST for GWI. More research is needed to identify moderators of GWI interventions and to understand risky drinking among Veterans with complex health problems.

Vagal nerve stimulation as a possible non-invasive treatment for chronic widespread pain in Gulf Veterans with Gulf War Illness.

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.

Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990-1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006.

BACKGROUND: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). METHODS: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene-gene and gene-environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. CONCLUSIONS: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

Predicting post-exertional malaise in Gulf War Illness based on acute exercise responses.

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 (VO2), carbon dioxide (VCO2), 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/VCO2, 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/VO2), peak leg muscle pain, fatigue, and lower VCO2, VO2, 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 R2 = 0.15, Adjusted R2 = 0.03, p = 0.34). SIGNIFICANCE: The PEM response was not related to the selected combination of cardiorespiratory and perceptual responses to exercise.

Gulf War veterans exhibit broadband sleep EEG power reductions in regions overlying the frontal lobe.

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.

Neurotoxicant exposures and rates of Chronic Multisymptom Illness and Kansas Gulf War Illness criteria in Gulf War deployed women veterans.

AIMS: This study analyzed deployment-related exposures and risk of Persian Gulf War Illness (GWI) in women veterans from the Veterans Affairs (VA) Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB CSP#585). MAIN METHODS: We examined the associations between GW deployment-related exposures and case definitions for GWI in deployed GW women. Multivariate regression analyses controlling for demographic outcomes were performed. KEY FINDINGS: Surveys were obtained from 202 GW deployed women veterans. Self-reported exposure to smoke from oil well fires as well as chemical and biological warfare were the only exposures significantly associated with the Center for Disease Control and Prevention (CDC) GWI criteria. Seventy-nine women were excluded from the rest of the analyses as they met Kansas GW illness exclusion criteria. Eligible women who self-reported deployment-related exposure to smoke from oil wells, pyridostigmine bromide (PB) pills, pesticide cream, pesticide treated uniforms, and insect baits were significantly more likely to meet the Kansas GWI criteria (n = 123) than those unexposed and exposures were related to Kansas symptom subdomain endorsements. SIGNIFICANCE: These results suggest that women GW veterans reporting deployment related exposures of pesticide, oil well fire and PB pills are significantly more likely to meet the Kansas GWI criteria in this national cohort of GW women suggesting its utility in future studies. In addition, based on these results it appears that women exposed to particular toxicants during the war may benefit from more targeted treatment strategies dependent upon the mechanism of exposure of their toxicant induced outcomes.

Post-exertional malaise in veterans with gulf war illness.

Post-exertional malaise (PEM) is a potentially debilitating aspect of Gulf War Illness (GWI) that has received limited research attention. The purpose of the present investigation was to determine symptom severity changes following exercise in Veterans with GWI compared to control Veterans without GWI (CO). Sixty-seven Veterans (n = 39 GWI; n = 28 CO) underwent a 30-minute submaximal exercise challenge at 70% of heart rate reserve. Symptom measurements (e.g. fatigue, pain) occurred pre-, immediately post-, and 24-hour post-exercise. Self-reported physical and mental health, and physiological and perceptual responses to exercise were compared between groups using descriptive statistics, independent samples t-tests and repeated measures Analysis of Variance (RM-ANOVA). Post-exertional malaise was modeled using Group by Time (2 × 3) doubly-multivariate, RM-MANOVAs for (1) mood, (2) pain and (3) GWI-related symptoms, respectively (α = 0.05). Data were analyzed for the full sample of Veterans with GWI (n = 39) compared to CO (n = 28) and a subsample of Veterans (n = 18) who endorsed "feeling unwell after physical exercise or exertion" ("PEM endorsers") during screening. Veterans with GWI reported significantly lower physical and mental health. Groups exercised at similar relative exercise intensities, but GWI perceived exercise as more painful and fatiguing. Group-by-Time interactions were not significant for the entire sample for the three PEM models, however limiting the GWI sample to "PEM endorsers" resulted in significant interactions for Pain- and GWI-related PEM models. These results indicate that not all GVs with GWI experience PEM 24 h after exercise, and that more research is needed to determine the extent that exercise worsens symptoms in GWI.

Progression of intervention-focused research for Gulf War illness.

The Persian Gulf War of 1990 to 1991 involved the deployment of nearly 700,000 American troops to the Middle East. Deployment-related exposures to toxic substances such as pesticides, nerve agents, pyridostigmine bromide (PB), smoke from burning oil wells, and petrochemicals may have contributed to medical illness in as many as 250,000 of those American troops. The cluster of chronic symptoms, now referred to as Gulf War Illness (GWI), has been studied by many researchers over the past two decades. Although over $500 million has been spent on GWI research, to date, no cures or condition-specific treatments have been discovered, and the exact pathophysiology remains elusive.Using the 2007 National Institute of Health (NIH) Roadmap for Medical Research model as a reference framework, we reviewed studies of interventions involving GWI patients to assess the progress of treatment-related GWI research. All GWI clinical trial studies reviewed involved investigations of existing interventions that have shown efficacy in other diseases with analogous symptoms. After reviewing the published and ongoing registered clinical trials for cognitive-behavioral therapy, exercise therapy, acupuncture, coenzyme Q10, mifepristone, and carnosine in GWI patients, we identified only four treatments (cognitive-behavioral therapy, exercise therapy, CoQ10, and mifepristone) that have progressed beyond a phase II trial.We conclude that progress in the scientific study of therapies for GWI has not followed the NIH Roadmap for Medical Research model. Establishment of a standard case definition, prioritized GWI research funding for the characterization of the pathophysiology of the condition, and rapid replication and adaptation of early phase, single site clinical trials could substantially advance research progress and treatment discovery for this condition.

Iraq and Afghanistan Veterans report symptoms consistent with chronic multisymptom illness one year after deployment.

Many Veterans returning from service in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) experience chronic pain. What is not known is whether for some OIF/OEF Veterans this pain is part of a larger condition of diffuse multisystem symptoms consistent with chronic multisymptom illness (CMI). We use data from a prospective longitudinal study of OIF/OEF Veterans to determine the frequency of CMI. We found that 1 yr after deployment, 49.5% of OIF/OEF Veterans met criteria for mild to moderate CMI and 10.8% met criteria for severe CMI. Over 90% of Veterans with chronic pain met criteria for CMI. CMI was not completely accounted for either by posttraumatic stress disorder or by predeployment levels of physical symptoms. Veterans with symptoms consistent with CMI reported significantly worse physical health function than Veterans who did not report symptoms consistent with CMI. This study suggests that the presence of CMI should be considered in the evaluation of OIF/OEF Veterans. Further, it suggests the pain management for these Veterans may need to be tailored to take CMI into consideration.