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/或施用药物来调节，以在一定范围的速度、负载和方向上产生负重站立和迈步。 我们通过在 3 名运动完全脊髓损伤 (SCI) 受试者受伤后大约三年的腰骶脊髓上植入硬膜外电极阵列，将其中一些结果转化为人类。 电极植入后不到一个月，受试者就可以独立站立，并且经过长达 7 个月的每日 EDS 和运动训练后，在存在 EDS 的情况下，双腿的自主控制能力很明显，而在没有 EDS 的情况下，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。 我们将对脊髓大鼠进行广泛的测试，以指导我们测试人类 SCI 受试者上肢改善的策略。 我们将使用 FDA 批准的现成药理学和刺激方式来： 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 SCI 大鼠的前肢精细运动功能。 使用现有 FDA 批准的 硬膜外电极，我们将在颈椎 SCI 患者中证明颈椎 EDS 可以促进臂手功能。 2) 确定有效的给药方式，定义剂量反应药代动力学，并确定单胺能激动剂在颈椎 SCI 后促进上肢功能的有效性。 我们将评估 FDA 批准的现有药物（即丁螺环酮和替代品溴隐亭）的有效性，并确定它们在改善颈椎 SCI 受试者前肢控制方面的有效性。 3) 确定单胺能激动剂与 EDS 联合使用以促进颈椎 SCI 后大鼠前肢功能的剂量反应特性。 我们将证明 ES 与药物干预相结合在促进颈部 SCI 后人类手臂和手功能方面的功效。 4) 确定脊髓大鼠的运动训练与药物和/或 EDS 干预相结合是否会进一步增强运动功能的恢复。 5) 开发机器学习协议，以便能够快速选择大鼠和人类受试者运动恢复的最佳药理学和 EDS 参数。 如果成功，这可能代表着使用微创策略与康复方法相结合的范式转变的开始，以实现瘫痪后上肢功能的显着改善。

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.