Intraspinal microstimulation for restoring limb movement

描述（由申请人提供）：该项目的总体目标是发展脊髓损伤（SCI）后脊髓内微刺激（ISMS）恢复下肢功能的应用。脊髓内微刺激是一种新的神经修复方法，它需要在脊髓中植入一些比人类头发还小的超细金属丝，并通过这些金属丝传递电刺激来产生功能性肢体运动。所有导线都被植入脊髓的一个小区域（只有3厘米长），已知该区域包含控制腿部运动的神经回路。先前的实验证明了ISMS在成年猫完全性脊髓损伤后恢复站立和行走的有效性。通过一些微丝（小于0.3 mA）刺激脊髓损伤动物产生强大的腿部收缩，足以承受后腿的重量，而通过其他微丝的ISMS则产生腿部向上、向前和向后的运动。通过导线协调ISMS产生这些运动，实现了腿部的负重和运动稳定的原地行走。本项目的目标是推进这种微型植入物的技术发展，更好地了解ISMS如何与脊髓中的神经细胞相互作用，并设计“智能”方法来控制刺激范式，以在实验室环境外产生行走运动。微丝植入对脊髓组织的影响也将被检查，以确定该技术的安全性。椎管内微刺激有望消除与传统周围神经电刺激系统相关的一些困难，这些系统用于增强瘫痪个体的肢体运动。如果发现它是安全的，能够可靠地产生行走运动，这个项目的结果可能会导致首次在SCI患者志愿者中进行ISMS试验。实验将在成年猫身上进行。将使用标准化的插入技术构建用于植入腰骶束的微导线阵列。脐带的尺寸将通过高分辨率体内磁共振成像（MRI）扫描获得，以指导每只动物阵列的制造，并随着时间的推移跟踪它们的位置。ISMS激活脊髓前角通道纤维的程度将通过在ISMS期间整个腰骶膨大的单个细胞的局部场电位的细胞外记录和活动依赖的免疫组织化学c-fos标记技术来确定。将在完全性脊髓损伤动物中研究恢复强健的地面行走的最佳控制范例，并开发和测试包含这些控制范例的神经形态芯片。肌电图、运动学和动力学测量将用于评估isms诱导的瘫痪后肢运动模式。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop the use of intraspinal microstimulation (ISMS) for restoring lower extremity function after spinal cord injury (SCI). Intraspinal microstimulation is a new neuroprosthetic approach which entails implanting a few ultra fine wires, smaller than the human hair, in the spinal cord and delivering electrical stimuli through these wires to generate functional limb movements. All wires are implanted in a small region of the cord (only ~3 cm long) known to contain the neural circuits involved in controlling leg movements. Previous experiments demonstrated the effectiveness of ISMS in restoring standing and stepping after complete SCI in adult cats. Stimulation through some microwires (less than 0.3 mA) generated powerful leg contractions capable of carrying the weight of the hind quarters in animals with SCI, while ISMS through other wires generated upward, forward and backward movements of the legs. By coordinating ISMS through wires generating these movements weight-bearing and kinematically stable in-place stepping of the legs was achieved. The aims of the present project are to advance the technical development of this miniature implant, obtain a better understanding of how ISMS interacts with the nerve cells in the spinal cord, and design "smart" methods of controlling the stimulation paradigms to produce walking movements outside the lab environment. The effect of microwire implantation on spinal cord tissue will also be examined to determine the safety of this technique. Intraspinal microstimulation is expected to eliminate several of the difficulties associated with conventional peripheral nerve electrical stimulation systems used for augmenting limb movements in paralyzed individuals. If found to be safe and capable of generating walking movements reliably, the results from this project could lead to the first ISMS trials in human volunteers with SCI. Experiments will be conducted in adult cats. Arrays of microwires will be constructed for implantation in the lumbosacral cord using a standardized insertion technique. Dimensions of the cord will be obtained from high-resolution in vivo magnetic resonance imaging (MRI) scans to guide the fabrication of the arrays for each animal, and to track their location over time. The extent to which ISMS activates fibers-in-passage in the ventral horn of the spinal cord will be determined using extracellular recordings of local field potentials from single cells throughout the lumbosacral enlargement during ISMS, and activity-dependent immunohistochemical c-fos labeling techniques. The best control paradigms for restoring robust over-ground walking will be investigated in animals with complete SCI and a neuromorphic chip incorporating these control paradigms will be developed and tested. Electromyographic, kinematic and kinetic measures will be used to evaluate the ISMS-induced locomotor patterns in the paralyzed hind limbs.