Exertional Exhaustion in CFS

描述（由申请人提供）：疲劳，广泛的疼痛和压痛是慢性疲劳综合征（CFS）和相关疾病如海湾战争病（GWI）和纤维肌痛（FM）的常见症状。此外，他们有相同的睡眠改变、各种伤害性主诉、偏头痛和全身痛觉过敏。这种重叠表明这些综合征共享特定的神经病理生理机制。中枢致敏是对他们疼痛主诉的一个合乎逻辑的解释，但很难在神经元水平上解释。FM、GWI和CFS的主要临床特征之一是“力竭”。运动、认知或其他压力源可诱发症状复发，症状可能立即发作，也可能延迟至24小时。尽管研究发现慢性疲劳综合症患者的变化与运动有关，但大脑与运动异常反应之间的因果关系尚不清楚。此外，预测向体力衰竭过渡的变化尚未确定。我们开发了一种新的运动压力测试、功能磁共振成像、神经认知测试策略来研究符合1994年CFS标准的GWI受试者的这种现象。我们相信这些结果可以推广到慢性疲劳综合症，并形成对这种疾病的新认识的基础。假设：运动诱发认知、体感和自主神经功能障碍，这是CFS、GWI和FM的共同特征。轴突改变可能是神经病理的原因（SPECIFIC AIM 1）。运动应激源破坏了脆弱的代偿神经机制，通过fMRI揭示了两种自主和认知表型（SPECIFIC AIM 2）。FM的轴突功能障碍可以通过与大脑特定神经递质失调相关的功能连接研究来识别（specific AIM 3）。推论：CFS神经病理学可以基于GWI受试者的运动诱导结果建模。我们的综合运动和功能磁共振成像方案确定了扩散张量成像（DTI）在特定白质束中显著增加的轴向弥散性（AD）的新发现，与对照组相比，这可以预测GWI状态。GWI组也符合CFS标准。接下来，我们发现运动扰乱了神经生理脑网络，导致2种GWI表型，这些表型与运动诱导的自主神经控制、白质完整性、皮质和脑干萎缩以及脑血流动力学的变化有关。基线研究显示有限的横断面“静态”差异，但运动应激源揭示了神经过程的因果关系和显著的“动态”改变。我们建议CFS受试者在客观结果上表现出可比性的二分法。确定CFS亚组将开始确定CFS的客观神经病理机制。这些客观结果可以定义特定的CFS表型，并有助于解释这种疾病的异质性表现。相反，识别其他一致的模式可能为CFS提供新的客观定义的标准。这些机制可以导致客观的诊断测试和确定新的治疗靶点。

DESCRIPTION (provided by applicant): Fatigue, widespread pain and tenderness are common findings in Chronic Fatigue Syndrome (CFS) and allied disorders such as Gulf War Illness (GWI) and Fibromyalgia (FM). In addition, they share sleep alterations, diverse nociceptive complaints, migraine, and systemic hyperalgesia. This overlap suggests that these syndromes share specific mechanisms of neural pathophysiology. Central sensitization is a logical explanation for their pain complaints but has been difficult to explain at the neuronal level. One of the cardinal clinical features of FM, GWI and CFS is "exertional exhaustion". Exercise, cognitive or other stressors induce a relapse of symptoms that may be immediate or can be delayed up to 24 hours. Although studies have found changes associated with exercise in CFS, the causal relationship between the brain and the aberrant response to exercise are unknown. Furthermore, changes that predict the transition to exertional exhaustion have not yet been identified. We developed a novel exercise stress test, fMRI, neurocognitive testing strategy to study this phenomenon in GWI subjects who met 1994 CFS criteria. We believe the outcomes can be generalized to CFS, and form the basis for a new understanding of this disease. Hypothesis: Exercise induces cognitive, somatosensory and autonomic dysfunction that are common features of CFS, GWI, & FM. Axonal alterations may be responsible for the neuropathology (SPECIFIC AIM 1). The exercise stressor disrupts vulnerable compensatory neural mechanisms to reveal two autonomic and cognitive phenotypes via fMRI (SPECIFIC AIM 2). Axonal dysfunction in FM can be identified from functional connectivity studies linked to specific dysregulated neurotransmitters of the brain (SPECIFIC AIM 3). Corollary: CFS neuropathology can be modeled based on exercise-induced outcomes of GWI subjects. Our integrated exercise & fMRI protocol identified the novel finding of significantly increased axial diffusivity (AD) in specific white matter tracts by diffusion tensor imaging (DTI) that was predictive of GWI status compared to controls. GWI groups also met CFS criteria. Next, we found that exercise perturbs neurophysiological brain networks that led to 2 GWI phenotypes that were associated with exercise induced changes in autonomic control, white matter integrity, cortical and brainstem atrophy, and brain blood flow dynamics. Baseline studies showed limited cross-sectional "static" differences, but the exercise stressor revealed causal and significant "dynamic" alterations of neural processes. We propose that CFS subjects will display a comparable dichotomy of objective findings. Identification of CFS subgroups would begin the process of defining objective neuropathological mechanisms in CFS. These objective outcomes may define specific CFS phenotypes and help explain the heterogeneous presentation of this illness. Conversely, identification of other coherent patterns may provide new objectively defined criteria for CFS. These mechanisms can lead to objective diagnostic tests and identification of new targets for treatment.