CRCNS: Role of sensory feedback in locomotor recovery after spinal cord injury

描述(由申请人提供)：传入反馈在脊髓损伤(SCI)后通过体重支持的跑步机训练或移植产生神经营养因子的细胞移植所提供的运动控制和恢复中发挥关键作用。然而，我们对运动回路结构的了解是有限的，传入反馈的通道和/或来源在恢复中的作用在很大程度上还没有被探索过。我们建议将Drexel大学医学院开发的运动回路的神经模型与佐治亚理工学院开发的生物力学后肢模型相结合，并利用这个集成模型来研究在正常条件下和在没有感觉反馈的情况下，传入反馈在运动控制中的作用。我们将使用整合的模型证明，在完整的猫中，运动的控制依赖于髋部肌肉的传入反馈来启动摆动，而来自脚踝伸展肌的传入反馈和/或来自足垫的皮肤输入对于站立的控制至关重要。我们假设，在患有脊髓损伤的猫中，训练或神经营养素产生的移植增强了感觉反馈的突触强度，并且这些增加允许回路在没有脊髓上控制的情况下产生稳定的运动模式。开发的模型将使我们能够研究这一假设，并对脊髓损伤后移除某些感觉模式时获得的运动模式缺陷进行预测。对部分去传入或重新支配的肌肉进行的实验将使我们能够检验这些预测，并进一步完善模型。拟议的多学科项目是德雷克塞尔大学医学院和佐治亚理工学院的研究人员之间的合作。在这两个地点都计划进行实验，以确定模型参数并验证模型的预测。实验和建模工作将为脊髓损伤后感觉反馈在运动恢复中的作用提供新的和重要的信息。这项提议的学术价值有几个组成部分。首先，将建立一个全面的脊髓运动神经力学模型，包括猫后肢、运动依赖本体感觉反馈和中枢模式产生器(CPG)。其次，通过将模拟的正常和脊髓运动特征与实验记录的运动特征进行匹配，识别CPG内的反馈权重、通道和连接模式等模型参数。第三，关于感觉反馈在脊髓损伤后运动中的作用的几个假设将通过模型模拟和实验来检验。该模型的结果将增加我们对脊髓运动回路的了解，并可能指导脊髓损伤患者的康复训练工作。该提案将对德雷克塞尔大学的跨部门神经工程项目、医学院的神经科学项目以及佐治亚理工学院的应用生理学和生物医学工程项目产生更广泛的影响，支持这些项目的学生和博士后研究员，并为他们提供机会，真正整合在教育项目中获得的计算和实验神经生理学概念。我们还希望在项目中开发的模型将用于Lemay博士和Prilutsky博士在各自机构教授的关于运动的神经控制和生物力学的课程。

DESCRIPTION (provided by applicant): Afferent feedback plays a critical role in the control of locomotion and in the recovery afforded by body-weight supported treadmill training or graft of neurotrophin producing cellular transplants after spinal cord injury (SCI). Yet our knowledge of the structure of the locomotor circuitry is limited and the roles of the modality and/or origin of the afferent feedback in recovery have been for the most part unexplored. We propose to integrate a neural model of the locomotor circuitry developed at Drexel University College of Medicine with a biomechanical hindlimb model developed at Georgia Institute of Technology, and to use this integrated model to study the roles of afferent feedback in the control of locomotion under normal conditions and in the absence of sensory feedback. We will demonstrate using the integrated model that in the intact cat the control of locomotion is dependent on afferent feedback from the hip muscles for the initiation of swing while afferent feedback from the ankle extensors and/or cutaneous input from the foot pad are critical to the control of stance. We hypothesize that in the cat with spinal cord injury, training or neurotrophin producing transplants enhance the synaptic strengths of the sensory feedback and that these increases allow the circuitry to produce a stable locomotor pattern in the absence of supraspinal control. The model developed will allow us to investigate this hypothesis and make predictions about the motor pattern deficits obtained when certain sensory modalities are removed after spinal cord injury. Experiments with partially deafferented or re-innervated muscles will allow us to test these predictions and further refine the model. The proposed multidisciplinary project is a collaboration between investigators at Drexel University College of Medicine and Georgia Institute of Technology. Experiments are planned at both locations to identify model parameters and verify the model's predictions. The experimental and modeling work will provide new and important information about the roles of sensory feedback in locomotor recovery after SCI. The intellectual merit of this proposal has several components. First, a comprehensive neuromechanical model of spinal locomotion will be developed that includes the cat hindlimb, motion-dependent proprioceptive feedback, and central pattern generator (CPG). Second, model parameters including feedback weights, modality, and connectivity patterns within CPG will be identified by matching simulated normal and spinal locomotion characteristics with those recorded experimentally. Third, several hypotheses about the role of sensory feedback in locomotion post-SCI will be tested using model simulations and experiments. The results of the model will increase our understanding of the spinal locomotor circuitry and may guide rehabilitation training efforts in individuals with spinal cord injury. The proposal will have broader impacts on the interdepartmental Neuroengineering program at Drexel University, the Neuroscience program at The College of Medicine, and the Applied Physiology and Biomedical Engineering programs at Georgia Institute of Technology by supporting students and a postdoctoral fellow from the programs and providing them with the opportunity to truly integrate computational and experimental neurophysiological concepts acquired in the educational programs. We also expect the models developed in the project to be used in classes taught by Drs. Lemay and Prilutsky on the neural control and biomechanics of locomotion at their respective institutions.