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/或给予药理学药物进行调节，以在一定范围的速度、负荷和方向上产生负重站立和踏步。 我们已经将这些结果中的一些翻译到人类身上，通过在损伤后约三年在3名运动完全性脊髓损伤（SCI）受试者的腰骶脊髓上植入硬膜外电极阵列。 在电极植入后不到一个月内，受试者就可以独立站立，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，双腿的自主控制明显，而在没有EDS的情况下，完全瘫痪仍然存在。 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，以指导我们的策略来测试人类SCI受试者的上肢改善。 我们将使用现成的FDA批准的药理学和刺激方式：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，以促进颈脊髓损伤大鼠的前肢精细运动功能。 使用现有FDA批准的 硬膜外电极，我们将证明在颈部脊髓损伤患者的颈部EDS可以促进手臂的手功能。 2)确定一种有效的给药方式，确定剂量-反应药代动力学，并确定单胺能激动剂促进颈脊髓损伤后上肢功能的有效性。 我们将评估现有FDA批准的药理学药物的有效性（即，丁螺环酮和作为替代的溴隐亭），并确定它们在改善颈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联合使用促进大鼠颈脊髓损伤后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椎SCI后人类手臂和手功能方面的疗效。 4)确定当与药理学和/或EDS干预相结合时，脊髓大鼠的运动训练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。 如果成功的话，这可能代表着使用微创策略结合康复方法实现瘫痪后上肢功能显著改善的范式转变的开始。

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.