Intraspinal microstimulation for restoring limb movement

描述(申请人提供)：本项目的总体目标是发展脊髓内微刺激(ISMS)在脊髓损伤(SCI)后恢复肢体功能的应用。椎管内微刺激是一种新的神经假体方法，它需要在脊髓中植入几根比人头发还小的超细电线，并通过这些电线传递电刺激来产生功能性肢体运动。所有的电线都被植入脊髓的一个小区域(只有3厘米长)，该区域包含控制腿部运动的神经回路。先前的实验证明ISMS在成年猫完全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)的刺激可以产生强大的腿部收缩，能够承受脊髓损伤动物后肢的重量，而通过其他微丝的刺激则产生腿部的向上、向前和向后运动。通过产生这些运动的导线协调运动，实现了腿部的负重和运动稳定的原地踏步。本项目的目的是推动这种微型植入物的技术开发，更好地了解ISM如何与脊髓中的神经细胞相互作用，并设计出控制刺激范例的“智能”方法，以在实验室环境外产生行走动作。还将检查微丝植入对脊髓组织的影响，以确定该技术的安全性。椎管内微刺激有望消除常规周围神经电刺激系统用于增强瘫痪患者肢体运动的一些困难。如果被发现是安全的，并且能够可靠地产生行走动作，这个项目的结果可能会导致第一次在患有脊髓损伤的人类志愿者身上进行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微导线阵列，用于植入腰骶髓内。脐带的尺寸将通过高分辨率体内磁共振成像(MRI)扫描获得，以指导每种动物阵列的制造，并跟踪它们随时间的位置。ISM激活脊髓前角通路纤维的程度将通过在ISM过程中对整个腰椎增大过程中单个细胞的局部场电位的细胞外记录和活性依赖的免疫组织化学c-fos标记技术来确定。将在患有完全性脊髓损伤的动物身上研究恢复健壮的地面行走的最佳控制范例，并将开发和测试包含这些控制范例的神经形态芯片。肌电图学、运动学和运动学测量将被用来评估ISMS诱导的瘫痪后肢的运动模式。

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.