Olfactory and cognitive decrements in 1991 Gulf War veterans with gulf war illness/chronic multisymptom illness.

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.

Effects of a diet low in excitotoxins on PTSD symptoms and related biomarkers.

Post-traumatic stress disorder (PTSD) develops after trauma exposure and involves symptoms of avoidance, intrusive re-experiencing, mood and cognitive dysfunction, and hypervigilance. PTSD is often comorbid with Gulf War Illness (GWI), a neurological condition involving widespread pain, cognitive dysfunction, digestive problems, and other symptoms, in Gulf War veterans. PTSD tends to be more severe when comorbid with GWI. Low cortisol and elevated homocysteine levels have been found in PTSD, making them potential PTSD biomarkers. The low-glutamate diet, which aims to reduce excitotoxicity by eliminating the consumption of free glutamate and aspartate, has been shown to significantly reduce GWI and PTSD symptoms. This study examined whether changes in serum cortisol and homocysteine are associated with reduced PTSD severity in veterans with GWI after one month on the low-glutamate diet, and whether reducing the consumption of dietary excitotoxins was associated changes in PTSD and serum biomarkers. Data were analyzed for 33 veterans. No serum biomarkers significantly changed post-diet; however, cortisol increased as dietary excitotoxin consumption decreased, which held in a multivariable linear regression after adjustment for sex. Reduced dietary excitotoxin consumption was also associated with reduced hyperarousal symptoms, which held in a multivariable linear regression after adjustment for sex. Cortisol increase was associated with reduced avoidance symptoms after adjustment for change in BMI, and was marginally associated with overall PTSD reduction. Change in homocysteine was not significantly related to dietary adherence nor change in PTSD. Results suggest that reducing the consumption of dietary excitotoxins may normalize cortisol levels, which has been associated with alleviating PTSD.

Improving care for veterans' environmental exposure concerns: applications of the consolidated framework for implementation research in program evaluation.

BACKGROUND: Healthcare systems, like the US Department of Veterans Affairs (VA), need policies and procedures for delivering care to special populations including those with environmental exposure concerns. Despite being common and pervasive, especially among Veterans, environmental exposures are largely overlooked by healthcare providers. To successfully implement care for Veterans with military environmental exposure concerns, an understanding of contextual factors impeding care on the provider (e.g., knowledge and beliefs) and organizational (e.g., leadership's priorities) level is needed. Our goal was to conduct an operational needs assessment of providers to examine provider educational needs regarding Veterans' military environmental exposure concerns. METHODS: In 2020, we surveyed 2,775 VA medical and behavioral health providers. Our cross-sectional assessment was informed by the Consolidated Framework for Implementation Research (CFIR) and assessed barriers and facilitators to the uptake and application of knowledge regarding interdisciplinary care for environmental exposure concerns. The web-based survey was emailed to providers across the United States representing a variety of disciplines and practice settings to reflect the interdisciplinary approach to care for environmental exposures. We used bivariate statistics to investigate the intervention setting, inner setting, and individual characteristics of providers regarding care for environmental exposure concerns. RESULTS: Approximately one-third of VA medical and behavioral health clinicians report low to no knowledge of environmental exposure concerns. We find 88% of medical and 91% of behavioral health providers report they are ready to learn more about environmental exposures. Half of medical and behavioral health providers report they have access to information on environmental exposures and less than half report care for environmental exposures is a priority where they practice. CONCLUSIONS: Our findings suggest interdisciplinary providers' knowledge of and discussion with Veterans about environmental exposures may be influenced by contextual factors at the organizational level. Considering individual-level factors and organizational culture is important to consider when supporting care for environmental exposures. Since this needs assessment, VA established targeted programs to improve care related to military environmental exposures in response to legislation; future exploration of these same variables or contextual factors is warranted.

Living With Toxic Wounds: The Voices and Visual Self-Representations of Gulf War Veterans.

Operations Desert Shield and Storm occurred over 30 years ago, yet many of those who were deployed continue to experience chronic and debilitating symptoms, now recognized as Gulf War Illness (GWI). While efforts have been made to explore clinical treatments for GWI, misperceptions and skepticism about its complex nature and a lack of consensus on its etiology impede progress in this area. A critical necessity remains to better understand the experiences, needs, and concerns of veterans with GWI. In this qualitative research study, 40 Gulf War veterans were interviewed about their perceptions regarding symptoms of physical health, cognitive functioning, quality of life, and the quality of care received. In addition, they depicted their experiences through an artistic elicitation collage. Through a grounded theory method, key findings indicated that there are remaining hurdles, such as challenging symptoms, persisting unknowns about the illness, and variations in treatment quality. Veterans have mostly managed and coped with GWI, but they voice the need for acknowledgment and support. The main implication from this study is the significance of both clinical and institutional validation and recognition of the GWI experience as well as the need for specific support systems.

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness.

Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.

Impact of the first Gulf war on multiple sclerosis risk in Kuwait: a quasi-experimental study.

OBJECTIVE: It has been reasoned that stressful life events tend to alter immune function thereby increasing the susceptibility to autoimmune diseases including multiple sclerosis (MS). Using the database of Kuwait National MS Registry, this quasi-experimental study assessed the impact of the first Gulf War (Iraqi invasion of Kuwait in 1990) on MS risk in Kuwait. METHODS: MS incidence data from 1980 to 2019 were obtained from the Kuwait National MS Registry. Annual age-standardized incidence rates (ASIRs) (per 105 person-years) were computed using the World Standard Population as a reference. Interrupted time series analysis with the option of autoregressive order (1) was used to evaluate the impact of the first Gulf War on MS risk by treating 1990 as an intervention year. RESULTS: Estimated baseline annual ASIR (per 105 person-years) was 0.38 (95% CI: -1.02, 1.78; p = 0.587). MS ASIRs (per 105 person-years) tended to increase significantly every year prior to 1990 by 0.45 (ASIR per 105 person-years = 0.45; 95% CI: 0.15, 0.76; p = 0.005). During the first year of the first Gulf War, there seemed to be a non-significant increase (step change) in ASIRs (per 105 person-years) of MS (ASIR per 105 person-years = 0.85; 95% CI: - 5.16, 6.86; p = 0.775) followed by a non-significant increase in the annual trend in MS ASIRs per 105 person-years (relative to the preintervention trend i.e., the difference between the pre-first Gulf War versus the post-first Gulf War trends) by 0.65 (ASIR per 105 person-years = 0.65; 95% CI: - 0.22, 1.52; p = 0.138). However, a postestimation measure of the post-first Gulf War trend was statistically significant (ASIR per 105 person-years = 1.10; 95% CI: 0.40, 1.80; p = 0.003), which implies that the post-first Gulf War trend in the annual ASIRs (per 105 person-years) inclined to be the same as was the pre-first Gulf War (i.e., counterfactual of the pre-first Gulf War trend in annual ASIRs (per 105 person-years) as if no first Gulf War took place).The Durbin-Watson test statistic (d = 1.89) showed almost non-significant autocorrelations across the time series observations on ASIRs (per 105 person-years). CONCLUSIONS: This study suggests that the first Gulf War was not significantly associated with the increasing trend in MS risk at population level in Kuwait neither with any short-term change nor with secular trend. Future studies may consider confirming the role of conflict-related stress or other stressful life events in potential exacerbation of MS risk along with unraveling biologically plausible mechanistic pathways.

Nontraditional Occupational Exposures to Crude Oil Combustion Disasters and Respiratory Disease Risk: A Narrative Review of Literature.

PURPOSE OF REVIEW: Burning of petroleum products has been consistently associated with adverse respiratory health effects. Combustion of crude oil, specifically, produces toxic byproducts, but there have been relatively few studies of health effects. Burning of crude oil is increasingly employed as a means of mitigating environmental disasters despite the potential health risks to workers involved in clean-up efforts. Here, we review epidemiological studies of respiratory effects following unique crude oil burning events to (1) characterize respiratory health effects from this nontraditional occupational exposure and (2) identify approaches used to characterize exposures that could be applied to future disaster-related studies. RECENT FINDINGS: We searched PubMed and EMBASE for references from inception to January 30, 2023. We also manually screened references cited in eligible articles. We identified 14 eligible publications. Our review suggests that exposure to crude oil combustion has adverse respiratory effects, including reduced lung function and increased occurrence of respiratory symptoms and disease. However, the evidence is inconsistent, and quality of data varied across studies. While some studies used quantitative, modeled exposure estimates, most used self-reported proxies of exposure. Although disasters involving crude oil combustion are relatively rare, limited evidence suggests that some worker populations may be at risk for respiratory effects from burning exposures in disaster settings. Future studies that use improved exposure assessment methods (e.g., personal monitors, remote sensing data) may help further quantify the respiratory risk from crude oil burning exposures.

Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.

BACKGROUND: During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community. METHODS: The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI. RESULTS: Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans. CONCLUSIONS: This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.

Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Strategies for cost-effective remediation of widespread oil-contaminated soils in Kuwait, an environmental legacy of the first Gulf War.

The Kuwaiti oil fire during the first Gulf War resulted in the formation of approximately 300 "oil lakes" of varying sizes that covered over 110 km2 of the desert land. This threatens the fragile desert ecosystems and human health. Following the award of over US$2 billion to the State of Kuwait by the United Nations, large-scale remediation of the oil-contaminated soils has now been on the agenda. However, how to implement the remediation program in a cost-effective way represents a major challenge. In this study, cost-effective remediation strategies were developed based on field and laboratory investigations in a typical oil lake area. Overall, most of the lighter petroleum hydrocarbons (PHCs) were lost due to evaporation. Long-chain aliphatic PHCs dominated the PHCs in the investigated oil lake area. This has implications for developing remediation strategies. Toxicity assessment results showed that the majority of soils pose a low environmental risk with a hazard index <1. Therefore, intensive treatment of these PHCs may not be necessary for these soils. Although active treatment methods are needed to remove the contaminants as soon as practical for the relatively small areas of high contamination, more cost-effective passive methods should be considered to minimize the remedial costs for the larger area of the non-hotspot areas. Given the extremely low risk in terms of groundwater contamination by the contaminated soils, it may not be necessary to remove the soils from the contaminated sites. A low-cost capping method should be sufficient to minimize human exposure to the PHC-contaminated soils.

The association of military sexual assault and nonsuicidal self-injury in U.S. Gulf War-I era veterans.

Military sexual assault (MSA) is a prevalent issue among military personnel that has been linked to adverse mental and physical health outcomes, including posttraumatic stress disorder (PTSD) and suicidal thoughts and behaviors. The present study sought to investigate the relationship between MSA and nonsuicidal self-injury (NSSI) in a national sample of Gulf War-I Era U.S. veterans. The study analyzed data from 1,153 Gulf War-I veterans collected through a cross-sectional survey that assessed demographic information, clinical outcomes, military background, and history of MSA and NSSI. MSA was found to be significantly associated with NSSI at the bivariate level (OR = 2.19, p < .001). Further, MSA remained significantly associated with NSSI (AOR = 2.50, p = .002) after controlling for relevant demographics and clinical outcomes. Veterans with a history of MSA were approximately two and half times more likely to engage in NSSI than veterans who had not experienced MSA. The present findings provide preliminary evidence linking MSA and NSSI. Further, the findings highlight the importance of assessing MSA and NSSI in veteran populations, particularly among those seeking treatment for PTSD.

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness.

BACKGROUND: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. METHODS: Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. RESULTS: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. CONCLUSION: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

Development of KVO treatment strategies for chronic pain in a rat model of Gulf War Illness.

We examined whether combinations of Kv7 channel openers could be effective modifiers of deep tissue nociceptor activity; and whether such combinations could then be optimized for use as safe analgesics for pain-like signs that developed in a rat model of GWI (Gulf War Illness) pain. Voltage clamp experiments were performed on subclassified nociceptors isolated from rat DRG (dorsal root ganglion). A stepped voltage protocol was applied (-55 to -40 mV; Vh = -60 mV; 1500 ms) and Kv7 evoked currents were subsequently isolated by linopirdine subtraction. Directly activated and voltage activated K+ currents were characterized in the presence and absence of Retigabine (5-100 µM) and/or Diclofenac (50-140 µM). Retigabine produced substantial voltage dependent effects and a maximal sustained current of 1.14 pA/pF ± 0.15 (ED50: 62.7 ± 3.18 µM). Diclofenac produced weak voltage dependent effects but a similar maximum sustained current of 1.01 ± 0.26 pA/pF (ED50: 93.2 ± 8.99 µM). Combinations of Retigabine and Diclofenac substantially amplified resting currents but had little effect on voltage dependence. Using a cholinergic challenge test (Oxotremorine, 10 µM) associated with our GWI rat model, combinations of Retigabine (5 uM) and Diclofenac (2.5, 20 and 50 µM) substantially reduced or totally abrogated action potential discharge to the cholinergic challenge. When combinations of Retigabine and Diclofenac were used to relieve pain-signs in our rat model of GWI, only those combinations associated with serious subacute side effects could relieve pain-like behaviors.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

The low glutamate diet improves cognitive functioning in veterans with Gulf War Illness and resting-state EEG potentially predicts response.

Objectives: Gulf War Illness (GWI) is a chronic, multi-symptom disorder with underlying central nervous system dysfunction and cognitive impairments. The objective of this study was to test the low glutamate diet as a novel treatment for cognitive dysfunction among those with GWI, and to explore if baseline resting-state electroencephalography (EEG) could predict cognitive outcomes.Methods: Cognitive functioning was assessed at baseline, after one-month on the diet, and across a two-week double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG) relative to placebo.Results: Significant improvements were seen after one-month on the diet in overall cognitive functioning, and in all other domains tested (FDR p < 0.05), except for memory. Challenge with MSG resulted in significant inter-individual response variability (p < 0.0001). Participants were clustered according to baseline resting-state EEG using k-means clustering to explore the inter-individual response variability. Three distinct EEG clusters were observed, and each corresponded with differential cognitive effects during challenge with MSG: cluster 1 had cognitive benefit (24% of participants), cluster 2 had cognitive detriment (42% of participants), and cluster 3 had mild/mixed effects (33% of participants).Discussion: These findings suggest that the low glutamate diet may be a beneficial treatment for cognitive impairment in GWI. Future research is needed to understand the extent to which resting-state EEG can predict response to the low glutamate diet and to explore the mechanisms behind the varied response to acute glutamate challenge.

A cellular approach to understanding and treating Gulf War Illness.

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness.

Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to GWI remain unclear. One possible exposure that has been attributed to GWI are chemical warfare agents (CWAs). While there are treatments for isolated symptoms of GWI, the number of respiratory and cognitive/neurological issues continues to rise with minimum treatment options. This issue does not only affect veterans of the GW, importantly these chronic multisymptom illnesses (CMIs) are also growing amongst veterans who have served in the Afghanistan-Iraq war. What both wars have in common are their regions and inhaled exposures. In this review, we will describe the CWA exposures, such as sarin, cyclosarin, and mustard gas in both wars and discuss the various respiratory and neurocognitive issues experienced by veterans. We will bridge the respiratory and neurological symptoms experienced to the various potential mechanisms described for each CWA provided with the most up-to-date models and hypotheses.

The insecticide deltamethrin enhances sodium channel slow inactivation of human Nav1.9, Nav1.8 and Nav1.7.

The insecticide deltamethrin of the pyrethroid class mainly targets voltage-gated sodium channels (Navs). Deltamethrin prolongs the opening of Navs by slowing down fast inactivation and deactivation. Pyrethroids are supposedly safe for humans, however, they have also been linked to the gulf-war syndrome, a neuropathic pain condition that can develop following exposure to certain chemicals. Inherited neuropathic pain conditions have been linked to mutations in the Nav subtypes Nav1.7, Nav1.8, and Nav1.9. Here, we examined the effect of deltamethrin on the human isoforms Nav1.7, Nav1.8, and Nav1.9_C4 (chimera containing the C-terminus of rat Nav1.4) heterologously expressed in HEK293T and ND7/23 cells using whole-cell patch-clamp electrophysiology. For all three Nav subtypes, we observed increased persistent and tail currents that are typical for Nav channels modified by deltamethrin. The most surprising finding was an enhanced slow inactivation induced by deltamethrin in all three Nav subtypes. An enhanced slow inactivation is contrary to the prolonged opening caused by pyrethroids and has not been described for deltamethrin or any other pyrethroid before. Furthermore, we found that the fraction of deltamethrin-modified channels increased use-dependently. However, for Nav1.8, the use-dependent potentiation occurred only when the holding potential was increased to -90 mV, a potential at which the tail currents decay more slowly. This indicates that use-dependent modification is due to an accumulation of tail currents. In summary, our findings support a novel mechanism whereby deltamethrin enhances slow inactivation of voltage-gated sodium channels, which may, depending on the cellular resting membrane potential, reduce neuronal excitability and counteract the well-described pyrethroid effects of prolonging channel opening.

A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain.

More than a quarter of veterans of the 1990-1991 Persian Gulf War suffer from Gulf War Illness (GWI), a chronic, multi-symptom illness that commonly includes musculoskeletal pain. Exposure to a range of toxic chemicals, including sarin nerve agent, are a suspected root cause of GWI. Moreover, such chemical exposures induce a neuroinflammatory response in rodents, which has been linked to several GWI symptoms in rodents and veterans with GWI. To date, a neuroinflammatory basis for pain associated with GWI has not been investigated. Here, we evaluated development of nociceptive hypersensitivity in a model of GWI. Male Sprague Dawley rats were treated with corticosterone in the drinking water for 7 days, to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate. These exposures alone were insufficient to induce allodynia. However, an additional sub-threshold challenge (a single intramuscular injection of pH 4 saline) induced long-lasting, bilateral allodynia. Such allodynia was associated with elevation of markers for activated microglia/macrophages (CD11b) and astrocytes/satellite glia (GFAP) in the lumbar dorsal spinal cord and dorsal root ganglia (DRG). Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1ß and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia was reversed by treatment with either minocycline, the TLR4 inhibitor (+)-naltrexone, or IL-10 plasmid DNA. Together, these results point to a role for neuroinflammation in male rats in the model of musculoskeletal pain related to GWI. Therapies that alleviate persistent immune dysregulation may be a strategy to treat pain and other symptoms of GWI.

Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness.

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 Veterans of the 1991 Persian Gulf War. GWI-related chemical (GWIC) exposure promotes immune activation that correlates with cognitive impairment and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation and neurological symptoms remain unclear. Here we show that acute exposure of murine macrophages to GWIC potentiates innate immune signaling and inflammatory cytokine production. Using an established mouse model of GWI, we report that neurobehavioral changes and neuroinflammation are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. In addition, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment and hippocampal astrocyte hypertrophy. In contrast, male mice display a GWIC-dependent upregulation of proinflammatory cytokines in the plasma that is not present in female mice. Our results indicate that STING and NLRP3 are key mediators of the cognitive impairment and inflammation observed in GWI and provide important new information on sex differences in this model.