Enabling forelimb function with agonist drug and epidural stimulation in SCI

描述（由申请人提供）：我们已经证明，脊髓大鼠和猫的腰骶脊髓回路的生理状态可以通过脊髓硬膜外刺激（EDS）和/或药物管理来调节，以产生在一定速度、负载和方向范围内的负重站立和行走。我们通过在3名运动完全性脊髓损伤（SCI）患者的腰骶脊髓上植入硬膜外电极阵列，将部分研究结果应用于人类。在电极植入后不到一个月的时间里，受试者可以独立站立，在长达7个月的日常EDS和运动训练后，在EDS存在的情况下，双腿的自主控制是明显的，而在没有EDS的情况下，双腿仍然完全瘫痪。我们建议采用类似的刺激策略来恢复上肢功能。我们将包括对脊椎大鼠的广泛测试，以指导我们的策略来测试人类SCI受试者的上肢改善。我们将使用FDA批准的药理学和刺激模式：1)确定最佳刺激参数，即电极放置和刺激强度、频率和持续时间，以促进颈椎脊髓损伤大鼠前肢精细运动功能。使用现有的fda批准的

DESCRIPTION (provided by applicant): We have demonstrated that the physiological state of the lumbosacral spinal circuitry of spinal rats and cats can be modulated with spinal cord epidural stimulation (EDS) and/or administration of pharmacological agents to generate weight-bearing standing and stepping over a range of speeds, loads, and directions. We have translated some of these results to humans by implanting 3 motor complete spinal cord injured (SCI) subjects about three years post-injury with an epidural electrode array over the lumbosacral spinal cord. In less than one month post-electrode implant, the subjects could stand independently, and after up to 7 months of daily EDS and motor training, voluntary control of both legs was evident in the presence of EDS, whereas complete paralysis remained in absence of EDS. We propose to employ a similar stimulation strategy for the recovery of upper limb function. We will include extensive testing of spinal rats to guide our strategy to test for upper extremity improvement in human SCI subjects. We will use off-the-shelf FDA approved pharmacological and stimulation modalities to: 1) Determine the optimal stimulation parameters, i.e., electrode placement and stimulation intensity, frequency and duration, for facilitating forelimb fine motor function in rats with a cervical SCI. Using existing FDA-approved epidural electrodes, we will demonstrate in patients with a cervical SCI that cervical EDS can facilitate arm-hand function. 2) Identify an effective mode of administration, define the dose- response pharmacokinetics, and determine the effectiveness of a monoaminergic agonist to facilitate upper limb function after a cervical SCI. We will assess the effectiveness of existing FDA-approved pharmacological agents (i.e., buspirone and as an alternative, bromocriptine), and determine their effectiveness in improving forelimb control in subjects with a cervical SCI. 3) Define the dose-response properties of monoaminergic agonists when combined with EDS in facilitating forelimb function in rats after a cervical SCI. We will demonstrate the efficacy of ES in combination with a pharmacological intervention in facilitating arm and hand function in humans after a cervical SCI. 4) Determine whether motor training of spinal rats will further enhance the recovery of motor function when combined with pharmacological and/or EDS interventions. 5) Develop a protocol for machine learning to enable rapid selection of the optimal pharmacological and EDS parameters for motor recovery in rats and in human subjects. If successful, this could represent the beginning of a paradigm shift in the use of minimally invasive strategies combined with rehabilitative approaches to realize significant improvement in upper limb function after paralysis.