Enabling forelimb function with agonist drug and epidural stimulation in SCI

使用激动剂药物和硬膜外刺激在 SCI 中启用前肢功能

• 批准号: 9358722
• 负责人: REGGIE EDGERTON
• 金额: $ 120.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9358722
• 关键词: Agonist; Algorithms; Ankle; Bromocriptine; Buspirone; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical Trials; Complement; Devices; Dose; Drug Kinetics; Effectiveness; Electrodes; FDA approved; Felis catus; Food; Forelimb; Frequencies; Goals; Hand; Hand functions; Hip region structure; Human; Implant; Implanted Electrodes; Individual; Injury; Intervention; Knee; Leg; Lesion; Lower Extremity; Machine Learning; Methodology; Modality; Motor; Motor Skills; Oral; Paralysed; Patients; Pharmaceutical Preparations; Pharmacology; Physiological; Posture; Preparation; Property; Protocols documentation; Rattus; Recovery; Rehabilitation therapy; Retrieval; Series; Speed; Spinal; Spinal Cord; Spinal cord injury; Testing; Thoracic spinal cord structure; Time; Toes; Training; Translating; Treatment Efficacy; Upper Extremity; Weight-Bearing state; arm; arm function; design; human subject; improved; injured; learning strategy; minimally invasive; motor function recovery; motor recovery; neural circuit; neuroregulation; public health relevance; response

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.

描述（由申请人提供）：我们已经证明，可以通过脊髓硬膜外刺激（EDS）（EDS）和/或给药来调节脊髓大鼠和猫的腰椎脊柱回路的生理状态，以在速度，负载和方向上产生承重站立和踩踏体重。 我们通过植入3年后三年的3年脊髓损伤（SCI）受试者将其中一些结果转化为人类，并在腰椎脊髓上有硬膜外电极阵列。 在电极植入物后不到一个月的时间里，受试者可以独立站立，在每天进行7个月的ED和运动训练后，在EDS存在的情况下，对双腿的自愿控制很明显，而在没有EDS的情况下，完全麻痹仍保持不变。 我们建议采用类似的刺激策略来恢复上肢功能。 我们将包括对脊柱大鼠的广泛测试，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）确定最佳的刺激参数，即电极放置和刺激强度，频率和持续时间，以促进具有宫颈SCI大鼠的前肢良好运动功能。 使用现有的FDA批准 硬膜外电极，我们将在宫颈SCI的患者中证明宫颈ED可以促进手臂功能。 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宫颈SCI后促进上肢功能的有效性。 我们将评估现有的FDA批准药理学剂（即胰蛋白酶和替代性溴封然）的有效性，并确定它们在改善宫颈SCI受试者的前肢控制方面的有效性。 3）当与宫颈SCI后的大鼠促进前肢功能结合使用EDS时，定义单胺能激动剂的剂量反应特性。 我们将证明ES与药理干预措施在宫颈SCI后促进人体的手臂和手部功能相结合的功效。 4）确定脊柱大鼠的运动训练是否会与药理学和/或EDS干预结合使用时是否会进一步增强运动功能的恢复。 5）制定一种用于机器学习的方案，以便能够快速选择大鼠和人类受试者运动恢复运动的最佳药理和EDS参数。 如果成功的话，这可能代表了使用微创策略的使用范式转变的开始，并结合了康复方法，以实现瘫痪后上肢功能的显着改善。

项目成果

Who is who after spinal cord injury and repair? Can the brain stem descending motor pathways take control of skilled hand motor function?

• DOI: 10.4103/1673-5374.165318
• 发表时间: 2015-11-01
• 期刊: NEURAL REGENERATION RESEARCH
• 影响因子: 6.1
• 作者: Garcia-Alias, Guillermo;Edgerton, V. Reggie
• 通讯作者: Edgerton, V. Reggie

Evaluation of optimal electrode configurations for epidural spinal cord stimulation in cervical spinal cord injured rats.

• DOI: 10.1016/j.jneumeth.2015.03.012
• 发表时间: 2015-05-30
• 期刊: JOURNAL OF NEUROSCIENCE METHODS
• 影响因子: 3
• 作者: Alam, Monzurul;Garcia-Alias, Guillermo;Shah, Prithvi K.;Gerasimenko, Yury;Zhong, Hui;Roy, Roland R.;Edgerton, V. Reggie
• 通讯作者: Edgerton, V. Reggie

Electrical neuromodulation of the cervical spinal cord facilitates forelimb skilled function recovery in spinal cord injured rats.

• DOI: 10.1016/j.expneurol.2017.02.006
• 发表时间: 2017-05
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Alam M;Garcia-Alias G;Jin B;Keyes J;Zhong H;Roy RR;Gerasimenko Y;Lu DC;Edgerton VR
• 通讯作者: Edgerton VR

Transcutaneous Electrical Spinal Stimulation Promotes Long-Term Recovery of Upper Extremity Function in Chronic Tetraplegia.

• DOI: 10.1109/tnsre.2018.2834339
• 发表时间: 2018-06
• 期刊: IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society
• 作者: Inanici F;Samejima S;Gad P;Edgerton VR;Hofstetter CP;Moritz CT
• 通讯作者: Moritz CT

Use of multivariate linear regression and support vector regression to predict functional outcome after surgery for cervical spondylotic myelopathy.

• DOI: 10.1016/j.jocn.2015.04.002
• 发表时间: 2015-09
• 期刊: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
• 作者: Hoffman H;Lee SI;Garst JH;Lu DS;Li CH;Nagasawa DT;Ghalehsari N;Jahanforouz N;Razaghy M;Espinal M;Ghavamrezaii A;Paak BH;Wu I;Sarrafzadeh M;Lu DC
• 通讯作者: Lu DC