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

• 批准号: 10641259
• 负责人: Jaclyn T. Eisdorfer
• 金额: $ 7.18万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641259
• 关键词: Affect; Afferent Neurons; Anatomy; Animals; Artificial Intelligence; Award; Behavior; Behavioral; Biometry; Brain; Clinic; Clinical; Complex; Computational Technique; Computer Vision Systems; Cues; Data Analyses; Exercise; Exercise Therapy; Fellowship; Fostering; Funding; Goals; Histologic; Human; Implanted Electrodes; Injury; Interneurons; Joints; Knowledge; Label; Learning; Leg; Machine Learning; Maps; Mediating; Mentors; Mentorship; Mission; Modeling; Motor; Motor Neurons; Movement; Muscle; National Institute of Neurological Disorders and Stroke; Neuronal Plasticity; Neurons; Neurosciences; Outcome Measure; Output; Parvalbumins; Patients; Pattern; Performance; Play; Postdoctoral Fellow; Process; Property; Qualitative Methods; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Resolution; Role; Secure; Sensory; Shapes; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Spinal cord posterior horn; Statistical Data Interpretation; Synapses; System; Techniques; Technology; Testing; Therapeutic Intervention; Three-Dimensional Imaging; Touch sensation; Training; Training Programs; Vertebral column; Visualization; Walking; Work; behavioral outcome; career; career development; clinical translation; combinatorial; design; dorsal horn; exercise training; functional improvement; genetic approach; improved; machine learning model; model building; motor behavior; motor recovery; mouse genetics; neural; neural circuit; pre-clinical; pre-clinical research; programs; rehabilitation paradigm; rehabilitation strategy; response; sensory integration; tool; translational barrier; treadmill; treadmill training

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.

动物和人类脊髓损伤（SCI）后，基于感觉的康复设施的功能改善。针对人类患者的临床计划利用组合强制运动（FE）和非锻炼（NFE）培训计划来促进功能改进（想想跑步机与步行赛道）。对于FE来说，据信传入的环境提示在脊柱水平上在本地工作以减轻功能性缺陷。而NFE则可以进行反复试验，将电动机变异性引入神经元系统。可变性有助于微调大脑命令以提高运动性能。但是，仍然存在关键问题：不同的训练范式如何改变脊髓电路并有助于运动回收？答案将有助于微调这些感觉理化策略，以优化功能恢复。该提议的假设是，FE和NFE启动了SCI后功能恢复的明显神经重新启动策略和特征性差异。我将使用小鼠遗传策略来照亮重新布线的解剖变化。具体而言，我将检查前运动前网络的神经元电路的变化，深背脊髓脊髓parvalbumin+神经元（DPV）。 DPV会收敛，本体感受和脊柱上的信息，并且在任务依赖性运动行为过程中参与了不同的参与。因此，来自DPV的输入或输出的变化反映了矛盾训练（FE/NFE）在中介恢复中的贡献。特定的目标1将检验Fe将引起升高的感觉中性重新布线的假设，而NFE将导致脑输入下降。我将将遗传方法与定量合成分析相结合，从而在解剖学上将皮质脊髓和触摸/本体感受输入映射到DPV上。 AIM 1的训练潜力在于学习小鼠遗传学，高分辨率定量突触分析以及进一步磨练我的生物统计学培训。具体目标2将检验以下假设，即NFE促进了与受害前的条件更紧密相关的平稳自然运动运动和行为状态图。我将将肌肉活动记录与高度敏感的计算机视觉/机器学习相结合，以研究训练（1）对肌肉反应（EMG）和关节活动的影响，以及（2）对自然主义行为。我还将使用遗传方法来表征DPVS输出到运动神经元上的输出，并标记为运动神经元用植入电极支配腿部肌肉。 AIM 2的训练潜力植根于先进的计算技术，肌肉记录和数据解释。集体结果将提供对（1）脊柱上和感觉整合的理解，并诱发了NFE涉及的运动响应以及（2）NFE在复杂运动行为中的功能益处。我的研究将打破当前翻译临床前研究的障碍，以帮助指导临床康复。精心设计这些目标的高训练潜力是为了填补我的基于空白的知识。这项奖学金的影响将促进我在SCI领域的成功，有影响力和结束的独立研究生涯。