Intraspinal Microstimulation for Restoring Limb Movement

描述（由申请人提供）：本项目的目的是评价脊髓内微刺激（ISMS）在恢复脊髓损伤（SCI）后腿部功能方面的长期疗效。并研究由ISMS诱导的神经元和肌肉可塑性的某些方面。这项拨款支持的主要活动将是提供脊髓位置和刺激参数，用于SCI后长期恢复稳定的负重站立和行走。ISMS有望消除与用于增强瘫痪个体肢体运动的常规外周神经功能性电刺激（FES）系统相关的若干困难。 该项目的初始阶段需要在成年猫的急性实验中绘制脊髓的腰骶区，一周前进行了完全脊髓横断（T11）。一旦确定脊髓内的目标位置，在SCI后产生可靠的伸肌和屈肌肢体运动，将在完整猫的脊髓每侧长期植入12至15根微导丝。将记录ISMS刺激阈值和引发的肢体反应，随后将在T11时对猫进行脊髓化。将应用模式化和强直性ISMS来产生后肢的负重站立和迈步。刺激课程每周进行5次（最长至脊柱化后6个月），并将随时间评估ISMS诱导的站立和踏步质量。 还将在整个实验过程中评估反射传递功效的变化，并将其用于估计损伤水平以下脊髓回路中ISMS诱导重组的水平。然后对动物实施安乐死，并检查其脊髓，以确定电极头端的位置，并评价微导丝植入和长期ISMS对神经损伤的影响。将对后肢肌肉进行免疫组织化学分析，以确定ISMS对纤维类型转化的影响。最后，将在完全骶骨脊髓横断导致尾部麻痹和痉挛的成年大鼠中确定ISMS在痉挛性高张力条件下产生功能性肢体运动的功效。

DESCRIPTION (provided by applicant): The goal of this project is to evaluate the long-term efficacy of intraspinal microstimulation (ISMS) in restoring leg function after spinal cord injury (SCI). and to investigate certain aspects of neuronal and muscular plasticity induced by ISMS. The principal activity supported by this grant will be to provide spinal cord locations and stimulation parameters for long-term restoration of stable, weight-bearing standing and stepping after SCI. ISMS is expected to eliminate several of the difficulties associated with conventional peripheral nerve functional electrical stimulation (FES) systems used for augmenting limb movements in paralyzed individuals. The initial phase of the project entails mapping the lumbosacral region of the spinal cord during acute experiments in adult cats with complete spinal transections (T11) performed a week earlier. Once target locations within the spinal cord that yield reliable extensor and flexor limb movements after SCI are determined, 12 to 15 microwires will be chronically implanted in each side of the cord in intact cats. ISMS stimulus thresholds and elicited limb responses will be documented and the cats will be subsequently spinalized at T11. Patterned and tonic ISMS will be applied to generate weight-bearing standing and stepping of the hindlimbs. Stimulation sessions will take place 5 times per week (up to 6 months post-spinalization) and the quality of standing and stepping induced by ISMS will be assessed over time. Changes in the efficacy of reflex transmission will also be assessed throughout the experiments and will be used to estimate the level of ISMS-induce reorganization in spinal circuitry below the level of the lesion. The animals will then be euthanized and their spinal cords will be examined to determine the location of electrode tips and evaluate the effect of microwire implantation and long-term ISMS on neural damage. Immunohistochemical analysis of hindlimb muscles will be performed to determine the effect of ISMS on fiber type transformation. Finally, the efficacy of ISMS in generating functional limb movements under conditions of spastic hypertonus will be determined in adult rats with complete sacral cord transections rendering the tail paralyzed and spastic.