Brain Dysfunction in Gulf War Illness: Pathophysiology and Treatment

Ashok K. Shetty^1*Kimberly Sullivan^2*Liang Qiang^3*

• ¹Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University School of Medicine, College Station, Texas, Texas, United States
• ²Department of Environmental Health, Boston University School of Public Health, Boston, United States
• ³Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, United States

treatments. The significant findings from the studies on GW veterans are summarized in the following section.A study involving 703 Gulf War (GW) veterans assessed their vulnerability to poor health outcomes using a frailty index as a proxy. The findings indicated that, as a group, GW veterans are not frailer than non-GW veterans. However, GW veterans who met the criteria for severe Chronic Multisymptom Illness (CMI) and Kansas GWI were found to be significantly frailer than both other GW veterans and non-GW veterans (Chao, 2023). Additionally, the study revealed that GW veterans who met the CMI criteria had higher rates of dementia compared to control GW veterans. Based on these results, the researchers recommended that GW veterans with CMI consider adopting lifestyle changes known to lower the risk of dementia. In another study, Chao and colleagues evaluated the cognitive status of 952 Gulf War veterans using established neuropsychological criteria and the Montreal Cognitive Assessment (MoCA). They found that 17% of these veterans exhibited mild cognitive impairment (MCI) (Chao et al., 2024). Importantly, MCI was found to be linked with CMI, a history of depression, and prolonged exposures related to deployment. A study conducted by Zhang and associates examined 98 veterans who had been deployed during the Gulf War and 90 veterans deployed to Iraq and Afghanistan. The investigation revealed that veterans from both groups had significantly smaller volumes in specific brainstem subregions, along with larger volumes of gray matter in the periaqueductal area (Zhang et al., 2024). Additionally, all veterans showed reduced integrity in the brainstem-spinal cord and brainstem-subcortical tracts. Notably, GWI veterans exhibited structural deficits in the brainstem that were significantly associated with increased sleep difficulties and higher levels of pain. In a study involving 54 Gulf War veterans, Van Riper and colleagues reported significant increases in strength after 16 weeks of low-to-moderate intensity resistance exercise training. Significantly, this training did not worsen symptoms such as pain, fatigue, or mood (Van Riper et al., 2025). However, the study did not find any correlation between strength, symptoms, and brain structure.The following section summarizes the new findings from animal models of GWI within this research collection. Carpenter and colleagues examined the progression of structural changes over 12 months in two mouse models: the pyridostigmine bromide (PB) and permethrin (PER) model, and the PB, N,N-diethyl-meta-toluamide (DEET,) corticosterone (CORT) and Diisopropyl fluorophosphate (DFP) model (Carpenter et al., 2024). The study reported that both models exhibited ventricular enlargement and reductions in hippocampal volumes as they aged. Additionally, the PB/DEET/CORT/DFP model showed decreased brainstem and total brain volumes, while the PB/PER model experienced reduced cortical thickness (Carpenter et al., 2024). In another study, Mozhui and colleagues used a mouse model exposed to CORT and DFP, reporting the differential expression of 67 methylated genes associated with various symptoms of GWI. This finding suggests that GWI may be linked to significant epigenetic changes (Mozhui et al., 2024). Additionally, research conducted by Shaikh et al. involved a mouse model exposed to PB, chlorpyrifos, and DEET, demonstrating that an Ayurvedic Withania somnifera root extract treatment could offer neuroprotection, particularly by preventing the loss of dendritic spines on neurons (Shaikh et al., 2024). Furthermore, an investigation by Terry and associates revealed that acute exposure to DFP not only results in persistent cognitive impairments but also increases signs of cellular senescence in the brain (Terry et al., 2024).In addition to the original research articles discussed above, the research topic collection includes a review article that describes the latent phenotype of GWI. The review summarized a possible link between the dysregulated of immune and endocrine signaling and progressive cognitive impairments in GWI (Burzynski and Reagan, 2024). The dysregulated immune and endocrine signaling comprised chronic neuroinflammation, as well as disruptions in central cholinergic signaling, which are particularly seen in the presence of stressors. Additional perspectives in the review include the implication of repeated activation of a sensitized cholinergic system. It is proposed that dysregulated acetylcholine signaling can lead to the potentiation of peripheral and central inflammation, as well as accelerate cognitive decline (Burzynski and Reagan, 2024). Such possibilities are supported by clinical data demonstrating exacerbation of GWI-related cognitive impairments when GWI patients undergo an exercise challenge (Burzynski and Reagan, 2024).In summary, the article collection in this Research Topic provides several novel insights on the pathophysiology of GWI.