Peripheral and Central Mechanisms of Fatigue and Pain in Patients with ME/CFS

描述（由申请人提供）：肌痛性脑炎/慢性疲劳综合征（ME/CFS）是一种以持续至少6个月的深度疲劳为特征并伴有多种躯体症状的疾病。已经研究了ME/CFS的感染、免疫、神经内分泌、睡眠和心理机制，但尚未出现统一的病因。我们假设外周组织异常在ME/CFS发病机制中起重要作用。除其他特征外，ME/CFS患者在标准化运动挑战后肌肉内代谢物明显异常，ME/CFS肌肉的代谢物排出量明显低于NC运动后立即排出量。我们认为，这些代谢物的积累会刺激肌肉中的ERGO受体（对肌肉代谢物敏感的传入神经）和伤害感受器，从而导致自主神经系统（ANS）、HPAaxis、疲劳和疼痛通路激活。这些通路的过度激活会导致ME/CFS的特征性症状，包括深度疲劳和经常疼痛。我们假设这些通路在ME/CFS中变得敏感，导致外周信号到CNS的放大。我们将使用握后运动区域循环闭塞（PH-RCO）方法和定量感觉测试（QST），包括机械和热阈值，表征ME/CFS受试者对疲劳和疼痛的外周贡献，包括致敏的ERGO和伤害感受器通路。PH-RCO捕获运动后肌肉中与运动相关的代谢物，从而估计外周对疲劳和疼痛的影响。这导致ERGO和疼痛受体[3]的长时间激活和随后的运动后疲劳和疼痛。为了测试ERGO与慢性疲劳和疼痛的相关性，我们建议减少ME/CFS患者肌肉中的ERGO信号。为此，我们将使用安慰剂控制的利多卡因注射到几个肌肉群中，以减少ERGO活动，从而减少ME/CFS患者持续的疲劳和疼痛。这种方法具有很大的前景，因为我们的初步数据表明，这种注射可以显著减少疲劳和疼痛（Cohen's d bbb1.0）。因此，治疗性肌肉注射可能是研究ERGO诱导的疲劳和疼痛对ME/CFS的贡献的临床相关模型。为了评估治疗对ME/CFS患者整体疲劳和疼痛的影响，我们将使用经过验证的疲劳和疼痛评估，包括几种疲劳量表和QST。因此，我们将描述肌肉注射对ME/CFS受试者疲劳和疼痛异常的整体和局部影响。为了评估ME/CFS受试者疲劳和疼痛的神经相关性，我们将使用动脉自旋标记（ASL）进行功能性脑成像（fMRI）。我们还将利用功能磁共振成像来表征与NC受试者相比，ME/CFS患者PH-RCO相关疲劳的脑血流量变化。此外，我们将对PHRCO前后的静息状态网络进行神经连通性分析，以表征疲劳引起的连通性变化。总的来说，我们的建议将有助于表征外周和中枢神经系统对ME/CFS患者慢性疲劳和疼痛的影响，这可能会导致这种慢性疾病的新疗法。

DESCRIPTION (provided by applicant): Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by profound fatigue lasting at least 6 months and accompanied by numerous somatic symptoms. Infectious, immunological, neuroendocrine, sleep, and psychological mechanisms for ME/CFS have been investigated but a unifying etiology has yet to emerge. We hypothesize that peripheral tissue abnormalities significantly contribute to ME/CFS pathogenesis. Amongst other features, patients with ME/CFS have substantial abnormalities of intramuscular metabolites following a standardized exercise challenge and metabolite efflux from ME/CFS muscles is significantly lower than in NC immediately post-exercise. We propose that accumulation of these metabolites results in stimulation of ERGOreceptors (ERGO) (afferents sensitive to muscle metabolites) and nociceptors in muscles with resulting autonomic nervous system (ANS), HPAaxis, fatigue, and pain pathway activation. Excessive activation of these pathways then leads to characteristic ME/CFS symptoms including profound fatigue and often pain. We hypothesize that these pathways have become sensitized in ME/CFS resulting in amplification of peripheral signals to the CNS. We will characterize ME/CFS subjects' peripheral contributions to fatigue and pain including sensitized ERGO and nociceptor pathways using the post-handgrip exercise regional circulatory occlusion (PH-RCO) method and quantitative sensory testing (QST), including mechanical and heat thresholds. PH-RCO traps exercise related metabolites in muscles post exercise allowing estimates of peripheral contributions to fatigue and pain. This results in prolonged activation of ERGO and pain receptors [3] and subsequent post-exertional fatigue and pain. In order to test the relevance of ERGOs for chronic fatigue and pain we propose reducing ERGO signaling in muscles of ME/CFS patients. For this purpose we will use placebo controlled lidocaine injections into several muscle groups to reduce ERGO activity and thus ongoing fatigue and pain of ME/CFS patients. This approach holds great promise because our preliminary data have shown that such injections can result in robust reductions of fatigue and pain (Cohen's d >1.0). Thus therapeutic muscle injections may represent a clinically relevant model to study the contributions of ERGO induced fatigue and pain to ME/CFS. To estimate treatment effects on both overall fatigue and pain in ME/CFS subjects, we will utilize validated fatigue and pain assessments, including several fatigue scales and QST. Thus we will characterize overall and local effects of muscle injections on ME/CFS subjects' fatigue and pain abnormalities. In order to assess the neural correlates to fatigue and pain in ME/CFS subjects we will perform functional brain imaging (fMRI) using arterial spin labeling (ASL). We will also utilize fMRI to characterize the cerebral blood flow changes of PH-RCO related fatigue in ME/CFS compared to NC subjects. In addition, we will perform neural connectivity analyses of resting state networks before and after PHRCO which will characterize connectivity changes induced by fatigue. Overall, our proposal will help characterize peripheral and central nervous system contributions to chronic fatigue and pain in patients with ME/CFS that may lead to novel therapies for this chronic illness. PUBLIC HEALTH RELEVANCE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is complex illness associated with non-restorative sleep, pain, and abnormalities of the autonomous system and HPA-axis. Although no unifying hypothesis has been established for the pathogenesis of ME/CFS, most previous work has focuses on central nervous system factors, including infections, trauma, depression, and immune disorders. We hypothesize that peripheral signaling from metabo-receptors in muscles is strongly involved in initiating and maintaining chronic fatigue in ME/CFS. We will test the effects of activation as well as inactivation of these receptors on chronic fatigue and pain. Additionally, we will use quantitative sensory testing to test evidence for peripheral and central sensitization of these patients. Brain imaging will be used to explore the neural correlates of fatigue/pain modulation in normal controls and patients with ME/CFS.