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）后的运动控制和体重支持的跑步机训练或产生神经营养因子的细胞移植所提供的恢复中起关键作用。然而，我们对运动回路结构的了解是有限的，传入反馈的模式和/或来源在恢复中的作用在很大程度上尚未被探索。我们建议将德雷塞尔大学医学院开发的运动回路神经模型与佐治亚理工学院开发的后肢生物力学模型相结合，并利用该集成模型研究传入反馈在正常情况下和没有感觉反馈的情况下对运动控制的作用。我们将使用综合模型证明，在完整的猫中，运动的控制依赖于臀部肌肉的传入反馈来开始摇摆，而来自踝关节伸肌和/或足垫的皮肤输入的传入反馈对姿态的控制至关重要。我们假设，在脊髓损伤的猫中，训练或产生神经营养因子的移植增强了感觉反馈的突触强度，并且这些增强允许回路在没有脊柱上控制的情况下产生稳定的运动模式。开发的模型将允许我们调查这一假设，并对脊髓损伤后某些感觉模式被移除时获得的运动模式缺陷做出预测。对部分失神经或重新神经支配的肌肉进行实验将使我们能够测试这些预测并进一步完善模型。提议的多学科项目是德雷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。计划在两个地点进行实验，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重要信息。这一建议的智力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、运动依赖的本体感觉反馈和中枢模式发生器（CPG）。其次，模型参数包括反馈权重、模态和CPG内的连接模式，将通过将模拟的正常和脊柱运动特征与实验记录的特征相匹配来识别。第三，我们将通过模型模拟和实验来验证一些关于感觉反馈在脊髓损伤后运动中的作用的假设。该模型的结果将增加我们对脊髓运动回路的理解，并可能指导脊髓损伤个体的康复训练工作。该提案将对德雷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，并为他们提供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的机会。我们也希望在项目中开发的模型能在博士的课堂上使用。Lemay和Prilutsky在各自机构的运动神经控制和生物力学研究。

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.