Enabling forelimb function with agonist drug and epidural stimulation in SCI

描述(申请人提供)：我们已经证明，脊髓硬膜外刺激(EDS)和/或给药可以调节脊髓大鼠和猫的腰椎脊髓回路的生理状态，以产生负重站立和跨越一定速度、负荷和方向的步态。我们通过将硬膜外电极阵列植入损伤后大约三年的运动性完全性脊髓损伤(SCI)受试者的腰骶脊髓上，将其中的一些结果翻译给人类。在电极植入后不到1个月的时间内，受试者可以独立站立，经过长达7个月的日常EDS和运动训练，在有EDS的情况下双腿明显的自主控制，而在没有EDS的情况下完全瘫痪。我们建议采用类似的刺激策略来恢复上肢功能。我们将包括对脊髓大鼠的广泛测试，以指导我们在人类脊髓损伤受试者中测试上肢改善的策略。我们将使用FDA批准的现有药物和刺激方式来：1)确定最佳刺激参数，即电极位置和刺激强度、频率和持续时间，以促进颈脊髓损伤大鼠的前肢精细运动功能。使用FDA批准的现有产品 硬膜外电极，我们将在颈椎脊髓损伤患者中证明颈椎EDS可以促进手臂-手的功能。2)确定一种有效的给药模式，确定剂量-反应药代动力学，并确定单胺类激动剂促进颈椎脊髓损伤后上肢功能的有效性。我们将评估现有FDA批准的药理学药物(即丁螺环酮和替代药物溴隐亭)的有效性，并确定它们在改善颈椎脊髓损伤受试者前肢控制方面的有效性。3)明确单胺类激动剂与EDS合用促进大鼠颈脊髓损伤后前肢功能的剂量-反应特性。我们将展示ES结合药物干预在促进人类颈椎脊髓损伤后手臂和手功能方面的有效性。4)确定当结合药物和/或EDS干预时，脊髓大鼠的运动训练是否会进一步促进运动功能的恢复。5)开发一种机器学习协议，以便能够快速选择用于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和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著改善。

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.