Investigating the neural correlates of fatigue in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome(ME/CFS)

项目总结/摘要 无休止的病理性疲劳是一种常见的症状，在广泛的疾病，是突出的 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）尽管它几乎无处不在 报道称，人们对疲劳的神经生物学知之甚少。ME/CFS诊断提供了一个明确的医疗 挑战.误诊是常见的，由于缺乏生物标志物，依赖于主观的表型标准 症状与抑郁症重叠ME/CFS患者也存在行政投诉 功能障碍尽管横断面功能磁共振成像研究报告了静息状态和任务的独特变化， 诱发的大脑活动，结果不是特异性的，并显示与抑郁症重叠。一个显著的临床特征， ME/CFS是对运动的反应，称为运动后不适（PEM）。PEM被公认为 急性运动后疲劳严重程度和执行功能障碍增加。相反，患者 抑郁症患者报告症状负担减少。尽管这种已知的不同反应，研究试图 阐明预测生物标志物或运动与大脑功能变化之间的因果关系 活动没有得到充分的尝试。为了解决这一差距，我们开发并测试了 一种新的纵向3天fMRI运动范例在海湾战争疾病（GWI）中的效用; 症状有很大的重叠已发表的研究结果和我们GWI研究的初步证据表明， 我们的范式可能是有效的揭示疲劳的神经生物学在ME/CFS。该提案旨在利用 功能磁共振成像和运动的独特组合，以阐明ME/CFS疲劳的神经相关性。该提案 有三个目标。第一个目的是通过模拟变化来表征与运动相关的疲劳减少 在默认模式网络中的功能连接。第二个目的是展示 运动对更高层次认知神经系统之间因果关系的影响， 连通性分析第三个目标将利用机器学习算法来预测ME/CFS状态， 基线无任务静息状态功能磁共振成像研究结果将提供强有力的证据的病理生理机制 维持ME/CFS疲劳的慢性化。此外，准确和详细的 描述疲劳的神经生物学结构将是开发可靠诊断测试的关键步骤 和潜在的治疗靶点。这一建议的结果将提出一种替代模式， 研究疲劳的神经生物学在广泛的病理状态和潜在的检测， 在临床环境中几乎普遍的症状主诉。

PROJECT SUMMARY/ABSTRACT Unrelenting pathological fatigue is a common symptom across a wide range of diseases and is the prominent feature of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). Despite its near ubiquitous reporting, little is known about the neurobiology of fatigue. ME/CFS diagnoses presents a definitive medical challenge. Misdiagnoses are common due to lack of biomarkers, reliance on a subjective phemonological criteria and symptom overlap with depression. Individuals with ME/CFS also present with complaints of executive dysfunction. Although cross sectional fMRI studies have reported unique changes in resting state and task evoked brain activity, findings are not specific and show overlap with depression. A striking clinical feature of ME/CFS is the response to exercise, known as post-exertional malaise (PEM). PEM is recognized as the incremental increase in fatigue severity and executive dysfunction following acute exercise. In contrast, patients with depression report a decrease in symptom burden. Despite this known divergent response, studies trying to illuminate predictive biomarkers or the causative association between exercise and changes in functional brain activity have not been adequately attempted. To address this gap, we developed and subsequently tested the utility of a novel and longitudinal 3-day fMRI-exercise paradigm on Gulf War Illness (GWI); a disorder with tremendous overlap of symptoms. Published findings and preliminary evidence from our GWI studies suggest our paradigm may be effective in revealing the neurobiology of fatigue in ME/CFS. This proposal aims to harness the unique combination of fMRI and exercise to elucidate neural correlates of fatigue in ME/CFS. The proposal has three aims. The first aim is to characterize exercise associated decrements in fatigue by modeling changes in functional connectivity within the Default Mode Network. The second aim is designed to demonstrate the consequence of exercise on the causal interactions between higher level cognitive neural systems by effective connectivity analysis. The third aim will leverage machine learning algorithms to predict ME/CFS status from baseline task-free resting state fMRI. Findings would provide strong evidence of pathophysiological mechanisms that maintain the chronicity of fatigue in ME/CFS. Furthermore, the importance of an accurate and detailed description of the neurobiological constructs of fatigue will be a critical step in developing reliable diagnostic tests and potential therapeutic targets. Outcomes from this proposal would suggest an alternative paradigm for studying the neurobiology of fatigue in a broad number of pathological states and potential detection of this almost universal symptom complaint in a clinical setting.