Intermittent Hypoxia Initiated Motor Plasticity in Individuals with Multiple Sclerosis

项目摘要/摘要 多发性硬化症(MS)是一种免疫介导的中枢神经系统退行性疾病 导致局部髓鞘损伤，导致功能丧失、残疾和生活质量下降。虽然 疾病修正药物可以帮助减少复发的频率和新症状的出现，这种方法 不足以从现有症状中最佳恢复。克服功能障碍的一种潜在方法 与现有运动缺陷相关的损害是通过制定治疗策略来导致 神经可塑性。这项提议的目的是调查一种新的治疗干预的潜力- 急性间歇性低氧(AIH)--已显示出增强人的神经可塑性的重大前景 具有脊髓损伤但尚未在AIH女士中研究的构成了短暂的、反复的氧气减少 刺激5-羟色胺能途径并增强5-羟色胺受体活性的浓度。这 导致可塑性相关蛋白合成增加，加强突触传递和驱动 可塑性。我们假设，重复的AIH方案将改善患有以下疾病的患者的自主肢体功能 We女士还假设AIH将导致中枢神经内神经活动的持续变化 系统，这有助于治疗可塑性。我们使用双盲、假对照的方法检验这一假设。 在已有运动缺陷并控制复发活动的多发性硬化症患者中进行交叉试验 给予轻度间歇性低氧(或假低氧)5天。我们考察了由此产生的影响 通过量化干预后即刻和1周后力量、功能和步行能力的变化。 我们还使用先进的功能磁共振成像技术来测量神经的变化 踝关节随意屈曲时的激活和静息状态下躯体运动皮质的内在连通性 在成功的运动康复策略中，两者都显示出与可塑性相关的变化。额外的临床核磁共振 将监测登记时的扫描和干预后1周的新疾病活动的放射学迹象 作为参与者安全监测的一部分。这项提议将决定在多大程度上启动中央银行 神经系统通过一种已知的诱导可塑性的方法改善多发性硬化症的功能，并为 驱动这些治疗效果的神经机制。从这项工作中获得的见解将向 开发更有效的治疗方法，将日常AIH与特定任务训练相结合，以改善 MS患者的功能和生活质量

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system that causes localized damage to myelin, resulting in loss of function, disability, and reduced quality of life. Although disease-modifying drugs can help reduce the frequency of relapses and onset of new symptoms, this approach is insufficient for optimal recovery from existing symptoms. One potential approach to overcome functional impairments related to existing motor deficits is through development of therapeutic strategies that induce neuroplasticity. The objective of this proposal is to investigate the potential of a novel therapeutic intervention — Acute Intermittent Hypoxia (AIH) — that has shown significant promise to enhance neuroplasticity in persons with spinal cord injury but has not yet been studied in MS. AIH constitutes a brief, repeated reduction in oxygen concentration which stimulates the serotonergic pathway and enhances activity of serotonin receptors. This results in increased synthesis of plasticity-related proteins that potentiate synaptic transmission and drive plasticity. We hypothesize that a repeated AIH protocol will improve voluntary limb function in individuals with MS. We also hypothesize that AIH will induce sustained changes in neural activity within the central nervous system, which contribute to therapeutic plasticity. We test this hypothesis using a double-blind, sham-controlled and crossover trial in MS patients with established motor deficits and controlled relapse activity who are administered mild doses of intermittent hypoxia (or sham hypoxia) for five days. We examine the resulting effects by quantifying changes in strength, function and walking performance immediately and 1-week post-intervention. We also use advanced functional magnetic resonance imaging techniques to measure changes in neural activation during voluntary ankle flexion and intrinsic connectivity in the somatomotor cortices at rest, which have both shown plasticity-related changes during successful motor rehabilitation strategies. Additional clinical MRI scans at enrollment and 1-week post-intervention will be monitored for radiologic signs of new disease activity as part of participant safety monitoring. This proposal will determine the extent to which priming the central nervous system with an approach known to induce plasticity improves function in MS, and provide evidence of the neural mechanisms driving these therapeutic effects. The insights gained from this work will inform the development of more effective therapies combining daily AIH with task specific training for improvement of function and quality of life in individuals with MS.