The complex etiology behind Gulf War Illness (GWI) has been attributed to the combined exposure to neurotoxicant chemicals, brain injuries, and some combat experiences. Chronic GWI symptoms have been shown to be associated with intensified neuroinflammatory responses in animal and human studies. To investigate the neuroinflammatory responses and potential causes in Gulf War (GW) veterans, we focused on the effects of chemical/biological weapons (CBW) exposure and mild traumatic brain injury (mTBI) during the war. We applied a novel MRI diffusion processing method, Neurite density imaging (NDI), on high-order diffusion imaging to estimate microstructural alterations of brain imaging in Gulf War veterans with and without GWI, and collected plasma proinflammatory cytokine samples as well as self-reported health symptom scores. Our study identified microstructural changes specific to GWI in the frontal and limbic regions due to CBW and mTBI, and further showed distinctive microstructural patterns such that widespread changes were associated with CBW and more focal changes on diffusion imaging were observed in GW veterans with an mTBI during the war. In addition, microstructural alterations on brain imaging correlated with upregulated blood proinflammatory cytokine markers TNFRI and TNFRII and with worse outcomes on self-reported symptom measures for fatigue and sleep functioning. Taken together, these results suggest TNF signaling mediated inflammation affects frontal and limbic regions of the brain, which may contribute to the fatigue and sleep symptoms of the disease and suggest a strong neuroinflammatory component to GWI. These results also suggest exposures to chemical weapons and mTBI during the war are associated with different patterns of peripheral and central inflammation and highlight the brain regions vulnerable to further subtle microscale morphological changes and chronic signaling to nearby glia.

中文翻译：

---

海湾战争疾病退伍军人高阶弥散成像的改变与化学武器暴露和轻度创伤性脑损伤有关

海湾战争病 (GWI) 背后的复杂病因归因于暴露于神经毒性化学品、脑损伤和一些战斗经历的综合作用。在动物和人类研究中，慢性 GWI 症状已被证明与加剧的神经炎症反应有关。为了调查海湾战争 (GW) 退伍军人的神经炎症反应和潜在原因，我们重点研究了战争期间化学/生物武器 (CBW) 暴露和轻度创伤性脑损伤 (mTBI) 的影响。我们在高阶扩散成像上应用了一种新的 MRI 扩散处理方法，神经突密度成像 (NDI)，以估计有和没有 GWI 的海湾战争退伍军人脑成像的微观结构变化，并收集血浆促炎细胞因子样本以及自我报告健康症状评分。我们的研究确定了由 CBW 和 mTBI 引起的额叶和边缘区域 GWI 特有的微观结构变化，并进一步显示了独特的微观结构模式，使得广泛的变化与 CBW 相关，并且在患有 mTBI 的 GW 退伍军人中观察到更多的扩散成像焦点变化战争。此外，脑成像的微观结构改变与血液促炎细胞因子标志物 TNFRI 和 TNFRII 上调相关，并且与自我报告的疲劳和睡眠功能症状测量结果较差相关。综上所述，这些结果表明 TNF 信号介导的炎症会影响大脑的额叶和边缘区域，这可能导致该疾病的疲劳和睡眠症状，并表明 GWI 具有强烈的神经炎症成分。