Intermittent Hypoxia Initiated Motor Plasticity in Individuals with Multiple Sclerosis

间歇性缺氧引发多发性硬化症患者的运动可塑性

• 批准号: 10593412
• 负责人: Molly G Bright
• 金额: $ 21.82万
• 依托单位: REHABILITATION INSTITUTE OF CHICAGO D/B/A SHIRLEY RYAN ABILITYLAB
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-04 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593412
• 关键词: Acute; Adverse effects; Affect; Air; Ankle; Autoimmune; Automobile Driving; Bilateral; Brain imaging; Brain-Derived Neurotrophic Factor; Central Nervous System; Central Nervous System Diseases; Chronic; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Communities; Cross-Over Studies; Cross-Over Trials; Data; Demyelinating Diseases; Development; Disease; Disease remission; Dose; Double-Blind Method; Effectiveness; Enrollment; Exposure to; Frequencies; Functional Magnetic Resonance Imaging; Goals; Hand; Hypoxia; Imaging Techniques; Immune; Individual; Intervention; Light; Limb structure; Longevity; Lower Extremity; MRI Scans; Maps; Measures; Mediating; Monitor; Motor; Motor Neurons; Movement; Multiple Sclerosis; Myelin; Neural Pathways; Neurodegenerative Disorders; Neuronal Plasticity; North America; Oxygen; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Physical activity; Physiological; Placebo Control; Proteins; Protocols documentation; Publishing; Quality of life; Radiology Specialty; Randomized; Recovery; Recovery of Function; Rehabilitation therapy; Relapse; Reporting; Research; Research Personnel; Research Priority; Research Project Grants; Respiratory physiology; Rest; Rodent; Safety; Seminal; Serotonergic System; Spinal cord injury; Spinal cord injury patients; Symptoms; Synapses; Synaptic Transmission; Techniques; Testing; Therapeutic; Therapeutic Effect; Torque; Training; United States; United States National Institutes of Health; Walking; Work; burden of illness; cognitive function; common symptom; design; dexterity; disability; effective therapy; functional disability; functional improvement; functional plasticity; high reward; high risk; improved; insight; loss of function; magnetic resonance imaging biomarker; motor control; motor deficit; motor function improvement; motor function recovery; motor rehabilitation; motor symptom; multiple sclerosis patient; neural; neural circuit; neuroimaging; neuromechanism; novel; novel therapeutic intervention; participant safety; post intervention; programs; rehabilitation strategy; respiratory; serotonin receptor; therapeutic development; walking speed

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.

项目总结/摘要 多发性硬化症（MS）是一种免疫介导的中枢神经系统神经退行性疾病， 导致髓鞘局部损伤，导致功能丧失、残疾和生活质量下降。虽然 改善疾病的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获得最佳恢复。一种克服功能性的潜在方法 与现有运动缺陷相关的损伤是通过开发治疗策略， 神经可塑性本提案的目的是研究一种新型治疗干预的潜力- 急性间歇性缺氧（AIH）-已显示出显着的承诺，以提高神经可塑性的人 脊髓损伤，但尚未在MS中进行研究。AIH是一种短暂的，反复的氧减少， 浓度，其刺激肾上腺素能途径并增强血清素受体的活性。这 导致可塑性相关蛋白的合成增加，从而增强突触传递和驱动 可塑性我们假设重复AIH方案将改善患有AIH的个体的随意肢体功能。 女士我们还假设AIH将诱导中枢神经系统内神经活动的持续变化， 系统，这有助于治疗可塑性。我们用一个双盲的，假对照的 和交叉试验，在已确定有运动缺陷和控制复发活动的MS患者中进行， 给予轻度间歇性缺氧（或假缺氧）5天。我们研究由此产生的影响 通过量化干预后即刻和1周的力量、功能和行走能力的变化。 我们还使用先进的功能性磁共振成像技术来测量神经系统的变化。 主动踝关节屈曲过程中的激活和静止时躯体运动皮层的内在连接， 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。其他临床MRI 将监测入组时和干预后1周的扫描是否有新疾病活动的放射学体征 作为参与者安全监测的一部分。该提案将决定中央启动的程度 神经系统与已知的方法诱导可塑性改善MS的功能，并提供证据， 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告知 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。