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

项目总结/摘要 本文的工作将为治疗策略的范式转变奠定基础，重点是神经系统疾病。 在解决因固定/废用而造成的身体损伤时，应优先于肌肉系统。 近几十年来，废用性肌无力的科学研究主要集中在肌肉上 萎缩（atrophy）最近的纵向调查和药理学药物试验清楚地表明， 肌肉萎缩与虚弱适度相关，这表明与 神经系统最近的研究假设缺陷在于特定于运动神经元的机制， (MN)编码重复性放电。从历史上看，获得有效的人体MN兴奋性的体内指标， 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，固有MN 兴奋性可以通过配对运动单位分析（PMUA）和颈髓磁共振成像（MRI）来估计。 刺激，以引出颈髓诱发电位（CMEP）。减轻肌肉无力，通过有效的 治疗干预，是一个临床上重要的问题，需要深入了解脊柱 调解力产生的机制。众所周知，机械（肌肉）振动疗法可以提高力量 长时间不使用后的输出，因为振动激活Ia传入，导致慢和快MN 以通过反射弧增加它们各自的放电率。然而，在固定期间的振动是急剧的， 作为加速恢复功能能力的一种方式，没有得到充分利用。PI的核心假设是 固有的MN低兴奋性是废用性肌无力的关键因素，而刺激Ia 传入神经是其阻抗的关键因素。在SA 1中，PI将确定是否铸造固定（模型 废用）降低MN兴奋性。他的假设是制动会降低ΔF和CMEP振幅。在 SA 2，PI将确定在固定期间肌肉振动是否恢复MN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SA 1和2的数据来确定如何 制动后力输出的大部分变化是由于慢速与快速MN的发射变化， 计算机模拟他的假设是：1）快MN的放电率比慢MN的放电率下降得更明显 振动可通过慢和快的兴奋抵消固有的MN低兴奋性 以提高他们的射击率。PI的培训计划将利用“动手”计算机模拟，通过动物 赖特州立大学（WSU）的计算机模型，俄亥俄州大学（WSU）的重要计算机建模课程 和华盛顿州立大学，俄亥俄州州立大学的专业发展计划，granitary培训/讲习班， 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 培训和学生辅导。现有的物质资源和智力/机构支持， 华盛顿州立大学和麻省理工学院，不仅将提供一个良好的环境，为PI成功地实现目标， 这项研究，但将提供PI在获得终身教职的初级教师研究职位的初步步骤。

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.