Bringing the clinic to the lab: the effects of forced and non-forced rehabilitation on functional recovery after spinal cord injury

将临床带入实验室:强制和非强制康复对脊髓损伤后功能恢复的影响

基本信息

  • 批准号:
    10641259
  • 负责人:
  • 金额:
    $ 7.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Sensory-based rehabilitation facilitates functional improvements after spinal cord injury (SCI) in animals and humans. Clinical programs for human patients utilize combinatorial Forced Exercise (FE) and Non-Forced Exercise (NFE) training programs to facilitate functional improvements (think treadmill vs. walking on a track). For FE, it is believed that incoming environmental cues work locally on the spinal level to mitigate functional deficits. While NFE, which enables for trial and error, introduces motor variability into the neural system. Variability helps fine tune descending brain commands to improve motor performance. However, key questions remain: How do different training paradigms change spinal cord circuits and contribute to motor recovery? Answers will help to fine tune these sensory-rehabilitation strategies to optimize functional recovery. The hypothesis of this proposal is that FE and NFE initiate distinct neural rewiring strategies and characterizable differences in functional recovery following SCI. I will use mouse genetic strategies to illuminate anatomical changes in rewiring. Specifically, I will examine the changes in neural circuitry of a premotor network, Deep Dorsal horn spinal cord ParvalBumin+ neurons (dPVs). dPVs receive convergent touch, proprioceptive, and supraspinal information, and are differentially engaged during task-dependent motor behaviors. Changes in inputs onto or outputs from dPVs therefore reflect the contributions of paradoxical training (FE/NFE) in mediating recovery. Specific Aim 1 will test the hypothesis that FE will evoke elevated sensory neural rewiring, while NFE will result in increased descending brain inputs. I will couple genetic approaches with quantitative synaptic analysis to anatomically map corticospinal and touch/proprioceptive inputs onto dPVs. Aim 1’s training potential lies in learning mouse genetics, high resolution quantitative synaptic analysis, and to further hone my biostatistics training. Specific Aim 2 will test the hypothesis that NFE facilitates smooth naturalistic motor movements and behavioral state maps more closely related to the preinjury condition than FE. I will couple muscle activity recordings with highly sensitive computer vision/machine learning to investigate the influence of training (1) granularly on muscle responses (EMGs) and joint activity and (2) holistically on naturalistic behavior. I will also characterize dPVs outputs onto motor neurons using genetic approaches and label affected motor neurons innervating leg muscles with implanted electrodes. Aim 2’s training potential is rooted in cutting-edge computational techniques, muscle recordings, and data interpretation. The collective results will provide an understanding of the (1) supraspinal and sensory integration and evoked motor responses involved in NFE and (2) functional benefits of NFE in complex motor behaviors. My research will break down current barriers of translational preclinical research to help instruct clinical rehabilitation. The high training potential for these Aims has been carefully designed to fill my gap-based knowledge. The impact of this fellowship will foster my successful, impactful, and enduring independent research career in the field of SCI.
基于感觉的康复有助于动物和人类脊髓损伤(SCI)后的功能改善。人类患者的临床项目利用组合强迫运动(FE)和非强迫运动(NFE)训练项目来促进功能改善(想想跑步机与在轨道上行走)。对于FE,人们认为,传入的环境线索在脊柱水平上局部起作用,以减轻功能缺陷。而NFE,它允许尝试和错误,将运动变异性引入神经系统。可变性有助于微调下行大脑命令,以提高运动性能。然而,关键问题仍然存在:不同的训练模式如何改变脊髓回路并有助于运动恢复?答案将有助于微调这些感觉康复策略,以优化功能恢复。这个建议的假设是,FE和NFE启动不同的神经重新布线策略和功能恢复SCI后的特征性差异。我将用老鼠的遗传策略来阐明重新连接时的解剖学变化。具体来说,我将研究前运动网络,深背角脊髓ParvalBumin+神经元(dPVs)的神经回路的变化。dPV接收会聚触摸、本体感受和脊髓上信息,并且在任务依赖性运动行为期间差异地参与。因此,从dPV的输入或输出的变化反映了矛盾训练(FE/NFE)在调解恢复的贡献。具体目标1将检验FE将引起感觉神经重布线升高,而NFE将导致下行脑输入增加的假设。我将结合遗传学方法和定量突触分析,在解剖学上将皮质脊髓和触觉/本体感受输入映射到dPV上。目标1的培训潜力在于学习小鼠遗传学,高分辨率定量突触分析,并进一步磨练我的生物统计学培训。具体目标2将测试的假设,NFE促进顺利的自然运动和行为状态地图更密切相关的损伤前条件比FE。我将把肌肉活动记录与高度敏感的计算机视觉/机器学习结合起来,以研究训练的影响:(1)对肌肉反应(EMG)和关节活动的影响;(2)对自然行为的影响。我还将使用遗传方法表征dPV输出到运动神经元,并使用植入电极标记受影响的支配腿部肌肉的运动神经元。Aim 2的训练潜力植根于尖端的计算技术、肌肉记录和数据解释。集体的结果将提供一个理解(1)脊髓和感觉整合和诱发运动反应参与NFE和(2)功能的好处NFE在复杂的运动行为。我的研究将打破目前转化临床前研究的障碍,以帮助指导临床康复。这些目标的高培训潜力经过精心设计,以填补我的知识空白。这个奖学金的影响将促进我在SCI领域成功,有影响力和持久的独立研究生涯。

项目成果

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