Gulf War Illness: Neurological Impacts, Pathophysiological Insights, and Therapeutic Prospects

Gulf War Illness (GWI) is a chronic, multi-system condition affecting a substantial proportion of veterans deployed during the 1990-1991 Gulf War. Neurological complications, including cognitive impairment, musculoskeletal pain, fatigue, depression, and migraine, represent a major clinical burden. Evidence implicates neuroinflammation, oxidative stress, mitochondrial dysfunction, and epigenetic dysregulation as central mechanisms, with emerging data suggesting early tauopathy and sex-specific immune responses. Neuroimaging studies reveal hippocampal atrophy, white matter disruptions, and increased translocator protein (TSPO) binding, while biomarker analyses identify elevated C-reactive protein (CRP), leptin, and matrix metalloproteinases. Genetic factors, such as HLA alleles, may modulate susceptibility. Animal models corroborate these findings, demonstrating hippocampal dysfunction, neurotransmitter imbalance, and neuroimmune activation following exposure to Gulf War-related chemicals. Therapeutic evidence supports cognitive behavioral therapy (CBT), exercise, and mindfulness-based interventions, with ongoing trials exploring vagus nerve stimulation, anti-inflammatory agents, and mitochondrial-targeted therapies. This review synthesizes current knowledge on GWI-related neurological dysfunction, highlights diagnostic and therapeutic advances, and underscores the need for biomarker-driven, sex-specific, and personalized approaches to improve outcomes for affected veterans.