Gait ignition after SCI

SCI 后步态点火

• 批准号: 9757825
• 负责人: James David Guest
• 金额: $ 49.35万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757825
• 关键词: Acute; Adverse effects; Anatomy; Animal Model; Animal Testing; Animals; Area; Axon; Basal Ganglia; Bilateral; Brain; Chest; Chronic; Clinical; Clinical Research; Communities; Contusions; Data; Deep Brain Stimulation; Electric Stimulation; Electrodes; Family suidae; Felis catus; Frequencies; Future; Gait; Gait abnormality; Goals; Histologic; Human; Implant; Individual; Injury; Laboratories; Lead; Location; Locomotion; Locomotor training; Magnetic Resonance Imaging; Maps; Medical; Methods; Midbrain structure; Miniature Swine; Modality; Modeling; Motor; Motor Cortex; Movement Disorders; Neurons; Paralysed; Parkinson Disease; Pathway interactions; Performance; Persons; Phase; Physiologic pulse; Probability; Procedures; Rattus; Refractory; Reporting; Reproducibility; Risk; Scanning; Severities; Signal Transduction; Site; Speed; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Structure; Testing; Therapeutic; Thoracic Injuries; Thoracic spinal cord structure; Walking; Wheelchairs; Width; Work; base; clinically relevant; combinatorial; functional electrical stimulation; improved; locomotor control; motor control; motor recovery; neuronal circuitry; neuroregulation; neurosurgery; neurotransmission; novel; pre-clinical; public health relevance; reconstruction; rehabilitation strategy; response; secondary injury complication; side effect; stem; treatment optimization

 DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) is an effective, relatively safe, reversible, and adjustable treatment modality for medically-refractory movement disorders. It has had little application in persons with spinal cord injury (SCI), even though a significant percentage of new and chronic injuries are classified as motor incomplete and have spared connections. Recent work in our laboratory has pointed to a potential target for locomotor control after partial SCI. This is the mesencephalic locomotor region or MLR, a major coordinating center for activation of both locomotor command and descending modulatory pathways. Based on our studies, DBS of the MLR (mlrDBS) enhances neurotransmission along descending pathways innervating locomotor-generating neurons of the spinal cord. Furthermore, mlrDBS produces immediate and highly significant improvements in gait, locomotor speed and endurance in animals with mild and clinically relevant mid-thoracic contusion (moderate and severe) injuries. To achieve maximal clinical benefit from DBS and to minimize potential adverse effects, DBS electrodes need to be placed precisely into the target structure and the stimulation parameters must be optimized. This is especially important for its use after SCI since pathways responsible for generating locomotion are compromised and clinical benefit will depend upon utilizing the surviving pathways to the fullest extent possible. Unfortunately, there is great controversy concerning the anatomical location of the optimal site for mlrDBS in humans, indicating the importance of large animal testing to minimize the probability of negative or suboptimal clinical results, collateral damage to structures surrounding the MLR, as well as unwanted clinical side effects from stimulation. As part of our long-term goal of developing and optimizing treatments for SCI paralysis, the overall objective of this application is to determine the therapeutic potential of mlrDBS to improve walking following anatomically incomplete, acute and chronic SCI in a large animal model. We hypothesize that locomotion may be facilitated in either acute or chronic stages of injury. We shall pursue the following specific aims: In Aim 1, we propose to first identify and characterize the MLR in uninjured animals, establishing optimal stimulation sites and parameters of stimulation for controlling locomotor responses. In Aim 2, we will assess the ability of mlrDBS to enhance locomotor performance following acute and chronic incomplete thoracic SCI once optimal location and stimulation parameters have been established. The study will provide testing of this novel application of DBS in a large animal preclinical setting, to establish efficacy and to delimi the potential benefits of this procedure as a rehabilitation strategy for differing grades of injur. We expect this work to lead to a Phase 1 clinical study and establish a baseline for future work concerning combinatorial strategies utilizing supplementary transmitter replacement in combination with locomotor training and functional electrical stimulation.

 描述（由应用提供）：深度脑刺激（DBS）是一种有效，相对安全，可逆且可调的治疗方式，可用于医学上浪漫的运动障碍。它在脊髓损伤（SCI）的人身上几乎没有应用，即使很大一部分新的和慢性损伤被归类为运动不完整并保留了连接。我们实验室的最新工作指出了部分SCI后的运动能力控制的潜在目标。这是Messencephalic运动区域或MLR，这是运动命令和下降调节途径的主要协调中心。基于我们的研究，MLR（MLRDB）的DBS沿脊髓的运动神经元神经神经元的下降途径增强了神经传递。此外，MLRDBS在轻度和临床相关的胸膜中性挫伤（中度和重度）损伤的动物中，步态，运动速度和耐力的立即和显着改善。为了从DBS获得最大的临床益处并最大程度地减少潜在的不良影响，需要精确地将DBS电子放入目标结构中，并且必须优化模拟参数。这对于在SCI之后使用尤其重要，因为负责产生运动的途径受到损害，临床益处将取决于最大程度地使用生存途径。不幸的是，关于MLRDB的最佳位置在人类中的解剖位置存在极大的争议，这表明大型动物测试的重要性是最大程度地减少阴性或次优临床结果的概率，对周围结构的附带损害 MLR以及刺激的不良临床副作用。作为我们开发和优化SCI瘫痪治疗方法的长期目标的一部分，该应用的总体目的是确定MLRDBS在大型动物模型中解剖不完整，急性和慢性SCI后MLRDBS改善步行的治疗潜力。我们假设可以在急性或慢性损伤阶段制备运动。我们将为以下钱包。具体目的：在AIM 1中，我们建议首先识别和表征未受伤的动物中的MLR，建立最佳的刺激位点和刺激参数以控制运动反应。在AIM 2中，一旦建立了最佳位置和刺激参数，我们将评估MLRDB在急性和慢性不完整的胸腔SCI后增强运动性能的能力。这项研究将对DBS在大型动物临床前环境中的这种新颖应用进行测试，以确立效率并为差异化，作为区分损伤水平的康复策略的潜在益处。我们预计这项工作将导致一项1期临床研究，并建立一个基线，以实现与运动训练相结合的补充发射器替换和功能性电刺激结合使用补充发射机的组合策略。

项目成果

In vivo Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig.

• DOI: 10.3389/fnana.2020.599701
• 发表时间: 2020
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Chang SJ;Santamaria AJ;Sanchez FJ;Villamil LM;Pinheiro Saraiva P;Rodriguez J;Nunez-Gomez Y;Opris I;Solano JP;Guest JD;Noga BR
• 通讯作者: Noga BR

Deep brain stimulation of midbrain locomotor circuits in the freely moving pig.

• DOI: 10.1016/j.brs.2021.02.017
• 发表时间: 2021-05
• 期刊: BRAIN STIMULATION
• 影响因子: 7.7
• 作者: Chang, Stephano J.;Santamaria, Andrea J.;Sanchez, Francisco J.;Villamil, Luz M.;Saraiva, Pedro Pinheiro;Benavides, Francisco;Nunez-Gomez, Yohjans;Solano, Juan P.;Opris, Ioan;Guest, James D.;Noga, Brian R.
• 通讯作者: Noga, Brian R.

Combined neuromodulatory approaches in the central nervous system for treatment of spinal cord injury.

• DOI: 10.1097/wco.0000000000000999
• 发表时间: 2021-12-01
• 期刊: Current opinion in neurology
• 影响因子: 4.8
• 作者: Noga BR;Guest JD
• 通讯作者: Guest JD