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的疾病，并伴有多种躯体症状。ME/CFS的感染、免疫、神经内分泌、睡眠和心理机制已被研究，但统一的病因尚未出现。我们推测，外周组织异常显着有助于ME/CFS的发病机制。在其他特征中，ME/CFS患者在标准化运动挑战后肌内代谢物显著异常，并且运动后即刻ME/CFS肌肉的代谢物流出量显著低于NC。我们认为，这些代谢物的积累会刺激ERGO受体（ERGO）（对肌肉代谢物敏感的传入神经）和肌肉中的伤害感受器，从而导致自主神经系统（ANS）、HPA轴、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，包括深度疲劳和疼痛。我们假设这些途径在ME/CFS中变得敏感，导致外周信号放大到CNS。我们将使用握力运动后局部循环阻断（PH-RCO）方法和定量感觉测试（QST）（包括机械和热阈值）来表征ME/CFS受试者对疲劳和疼痛的外周贡献，包括致敏ERGO和伤害感受器通路。PH-RCO在运动后将运动相关代谢物捕获在肌肉中，从而可以估计外周对疲劳和疼痛的贡献。这导致ERGO和疼痛受体的长期激活[3]以及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，我们提出减少ME/CFS患者肌肉中的ERGO信号传导。为此，我们将使用安慰剂对照的利多卡因注射到几个肌肉群中，以减少ERGO活性，从而减少ME/CFS患者的持续疲劳和疼痛。这种方法有很大的希望，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（科恩d >1.0）。因此，治疗性肌肉注射可能代表临床相关模型，以研究ERGO诱导的疲劳和疼痛对ME/CFS的贡献。为了估计治疗对ME/CFS受试者总体疲劳和疼痛的影响，我们将使用经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受试者的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fMRI来表征ME/CFS与NC受试者相比PH-RCO相关疲劳的脑血流变化。此外，我们将在PHRCO之前和之后对静息状态网络进行神经连接分析，这将表征疲劳引起的连接变化。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贡献，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.