Contribution of Intrinsic Alpha-Motoneuron Excitability to Disuse-Induced Muscle Weakness

内在α运动神经元兴奋性对废用性肌无力的影响

基本信息

批准号：
10294948
负责人：
Nathan Wages
金额：
$ 7.05万
依托单位：
OHIO UNIVERSITY ATHENS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294948
关键词：
Activities of Daily Living Address Anatomy Animal Model Area Atrophic Attenuated Clinical Computer Models Computer Simulation Data Defect Development Educational workshop Elbow Elderly Environment Evoked Potentials Fire - disasters Flexor Foundations Frequencies Goals Grant Human Immobilization Impairment Individual Intervention Investigation Knowledge Link Magnetism Manuscripts Measures Mechanics Mediating Mentorship Modality Modeling Motor Motor Neurons Muscle Muscle Spindles Muscle Weakness Muscular Atrophy Nature Nerve Degeneration Nervous system structure Neurologic Ohio Output Pharmaceutical Preparations Pharmacology Physiologic pulse Physiology Positioning Attribute Production Program Development Property Randomized Reflex action Research Research Personnel Resources Role Scientist Spinal Students System Techniques Therapeutic Intervention Training Universities Upper arm Work base clinically significant electric impedance experimental study faculty research functional disability functional restoration improved in vivo indexing muscle aging muscle strength muscular system neuromechanism physically handicapped post intervention recruit sensory input sex symposium technological innovation tenure track therapeutically effective treatment strategy vibration young adult

项目摘要

PROJECT SUMMARY/ABSTRACT The work herein, will lay the foundation for a paradigm shift in treatment strategies, focusing on the nervous system, over the muscular system, when addressing physical impairments resulting from immobilization/disuse. The scientific focus on disuse-induced muscle weakness in recent decades has been primarily on muscle wasting (atrophy). Recent longitudinal investigations, and pharmacological drug trials, have clearly demonstrated muscle wasting to be moderately associated with weakness, suggesting a link with an impairment in the neurological system. Research has recently postulated a defect lies in mechanisms specific to the ɑ-motoneuron (MN), which encode repetitive firing. Historically, obtaining valid in vivo indices of human MN excitability has been difficult, but recent technological innovations have afforded scientists this capability. Notably, intrinsic MN excitability can be estimated via paired motor unit analysis (PMUA), and by applying cervicomedullary magnetic stimulation, to elicit a cervicomedullary evoked potential (CMEP). Attenuating muscle weakness, via effective therapeutic interventions, is a clinically significant issue necessitating an in-depth understanding of the spinal mechanism(s) mediating force production. Mechanical (muscle) vibration therapy is well-known to improve force output following prolonged periods of disuse, as vibration activates Ia afferents, which cause slow and fast MNs to increase their respective firing rates via a reflex arc. However, vibration during immobilization is drastically under-utilized as a modality to accelerate the restoration of functional capacity. The PI’s central hypothesis is intrinsic MN hypo-excitability is a key contributor to disuse-induced muscle weakness, while stimulation of Ia afferents is a key contributor to its impedance. In SA 1, the PI will determine if cast-immobilization (a model of disuse) decreases MN excitability. His hypothesis is immobilization will decrease ΔF and CMEP amplitude. In SA 2, the PI will determine if muscle vibration during immobilization restores MN excitability. His hypothesis is vibration will restore ΔF and CMEP amplitude. In SA 3, the PI will use data from SA 1 and 2 to determine how much of the change in force output after immobilization is due to changes in firing of slow vs. fast MNs via computer modeling. His hypotheses are: 1) fast MNs’ firing rate will decrease more significantly than that of slow MNs after immobilization, and 2) vibration will counteract intrinsic MN hypo-excitability by exciting slow and fast MNs to enhance their firing rates. The PI’s training plan will utilize “hands-on” computer simulation via animal models at Wright State University (WSU), significant computer modeling coursework at Ohio University (OU) and WSU, a Professional Development Program at Ohio State University, grantsmanship training/workshops, podium presentations at (inter)national conferences, manuscript compositions/submissions, grant/lab budgetary training, and student mentorship. The physical resources and the intellectual/institutional support available at WSU and OU, will not only provide an excellent environment for the PI to succeed in accomplishing the goals of this study, but will provide the PI with the initial steps in obtaining a tenure-track junior faculty research position.

项目概要/摘要本文的工作将为治疗策略的范式转变奠定基础，重点关注神经当解决因固定/废弃而导致的身体损伤时，系统优先于肌肉系统。近几十年来，科学界对废用性肌肉无力的关注主要集中在肌肉上。最近的纵向和药理学药物试验已清楚地证明了消耗（萎缩）。肌肉萎缩与虚弱有一定的相关性，这表明与肌肉损伤有关最近的研究假设 ɑ 运动神经元的特定机制存在缺陷。 (MN)，它重复编码放电历史上，获得人类 MN 兴奋性的有效体内指数。虽然这很困难，但最近的技术创新为科学家提供了这种能力，值得注意的是，内在的 MN。兴奋性可以通过配对运动单位分析（PMUA）和应用颈髓磁来估计刺激，通过有效减弱肌肉无力来引发颈髓诱发电位（CMEP）。治疗干预是一个临床上重要的问题，需要深入了解脊柱众所周知，机械（肌肉）振动疗法可以提高力量。长时间不用后的输出，因为振动激活 Ia 传入神经，导致 MN 缓慢和快速通过反射弧增加各自的发射率然而，固定期间的振动是剧烈的。作为加速功能恢复的方式，PI 的中心假设是未被充分利用。内在的 MN 低兴奋性是废用性肌无力的一个关键因素，而 Ia 的刺激在 SA 1 中，传入神经是其阻抗的关键因素，PI 将确定是否固定（模型）。他的假设是固定会降低 ΔF 和 CMEP 幅度。 SA 2，PI 将确定固定期间的肌肉振动是否会恢复 MN 的兴奋性。他的假设是。振动将恢复 ΔF 和 CMEP 振幅在 SA 3 中，PI 将使用来自 SA 1 和 2 的数据来确定如何恢复。固定后力量输出的大部分变化是由于慢速 MN 与快速 MN 的发射变化所致他的计算机模型假设是：1）快的 MN 的放电率会比慢的 MN 下降得更显着。固定后的 MN，以及 2) 振动将通过缓慢和快速的兴奋来抵消内在的 MN 低兴奋性 MN 提高发射率的训练计划将利用动物的“动手”计算机模拟。莱特州立大学 (WSU) 的模型，俄亥俄大学 (OU) 的重要计算机建模课程和 WSU，俄亥俄州立大学的专业发展计划，资助培训/研讨会，在（国际）国家会议上的讲台演讲、手稿撰写/提交、赠款/实验室预算培训和学生指导。提供的物质资源和智力/机构支持。 WSU 和 OU，不仅会为 PI 成功实现以下目标提供良好的环境：这项研究，但将为 PI 提供获得终身教授初级教职研究职位的初步步骤。