Therapeutic potential of combined locomotor training and TMS in SCI

产品说明： 摘要颈脊髓损伤（C-SCI）是一种常见的战场创伤，可导致广泛的终身运动、痉挛和疼痛残疾。尽管SCI涉及一系列随时间演变的众多病理生理事件，但针对治疗开发的研究几乎完全集中在单一疗法上，这些疗法在多中心临床试验中未能减少运动所需的物理辅助。据报道，积极的治疗效益，运动疗法，并独立地，治疗利用经颅磁刺激（TMS），以减少残疾的各种神经条件。拟议的研究旨在测试运动训练和TMS相结合产生内源性神经可塑性和修复机制的会聚放大的潜力，以显着提高运动恢复，并减少痉挛，步态和疼痛残疾。痉挛是SCI较常见的并发症之一，新的治疗方法正在不断探索。多学科研究将量化治疗对残疾的影响，潜在机制的变化，并使用一系列剂量和组合在急性和慢性治疗窗口提供全面的神经和生理安全性评估。提出了三个互补的具体目标，这些目标是基于支持性初步数据，并将采用本实验室已广泛采用的一系列最先进的多器官系统监测、行为、神经生理学、免疫组织化学（IHC）和基于分子的技术。在本提案中，我们的目标是：1）比较脊髓（SC）的单脉冲TMS（TMSsc）和跑步机运动训练（Tm）的功效和安全性，在急性C-SCI中单独和组合测试对牵张反射的兴奋性、步态运动学、疼痛敏感性和生理安全性的选定测量，2）比较TMSsc和Tm运动训练的功效，在慢性C-SCI中单独和联合测试痉挛、步态运动学和疼痛敏感性，3）鉴定与损伤和治疗引起的痉挛、步态和疼痛变化相关的关键神经生物学过程（特别是治疗引起的特定信号传导机制的上调）。对正常突触前和突触后抑制模式至关重要的三种因子的免疫组织化学（IHC）和分子表达：GABA/GABAb受体和下行去甲肾上腺素能（NE）纤维投射。此外，还将检测疼痛的特异性分子标志物（GCH 1，GTP环化水解酶1; SP，P物质; CGRP，降钙素基因相关肽，疼痛和SC传入神经发芽的标志物; Isolectin B4，IB 4，小胶质细胞标志物）。假设：我们认为，治疗诱导的痉挛措施的正常化将在一定程度上，介导的增加率依赖性抑制在SC电路，这些神经生理措施将与GABA/GABAb受体和NE的免疫表达的显着上调。我们认为，治疗诱导的疼痛结果指标的正常化与疼痛标志物GCH 1、SP、CGRP和IB 4的免疫表达降低相关。这些发现的转化以及运动疗法和TMSsc疗法的益处的证明可能会导致在战斗C-SCI患者中进行更具体和潜在更有效的运动疗法临床试验，最终使退伍军人的医疗保健受益 系统

DESCRIPTION: Abstract Cervical spinal cord injury (C-SCI) is a common and frequently devastating battlefield injury that can result in a broad range of life-long locomotor, spasticity, and pain disabilities. Although SCI involves a cascade of numerous pathophysiological events that evolve over time, research aimed at therapy development has almost exclusively focused on single therapies which have failed in multicenter clinical trials to decrease physical assistance required for locomotion. Positive therapeutic benefits have been reported for locomotor therapy and, independently, for therapy utilizing transcranial magnetic stimulation (TMS) to reduce disability in a variety of neurologic conditions. The proposed studies are designed to test the potential for the combination of locomotor training and TMS to produce convergent amplification of endogenous neuroplastic and repair mechanisms to significantly enhance locomotor recovery, and reduce spasticity, gait and pain disability. Spasticity is one of the more common complications of SCI for which new therapeutic avenues are continually being pursued. Multidisciplinary studies will quantitate therapeutic impact on disability, changes in underlying mechanisms, and provide comprehensive neurological and physiological safety assessments at acute and chronic therapeutic windows using a range of doses and combinations. Three complementary specific aims are proposed that are based upon supporting preliminary data and which will employ a battery of state of the art multi-organ systems monitoring, behavioral, neurophysiological, immunohistochemical (IHC), and molecular-based techniques that have been extensively employed in this laboratory. In this proposal we aim to: 1) compare the efficacy and safety of single pulse TMS of the spinal cord (SC) (TMSsc), and treadmill locomotor training (Tm), tested alone and in combination in acute C-SCI on the excitability of stretch reflexes, gait kinematics, pain sensitivity, and selected measures of physiological safety, 2) compare the efficacy of TMSsc and Tm locomotor training, tested alone and in combination in chronic C-SCI on spasticity, on gait kinematics and pain sensitivity, 3) identify key neurobiological processes (particularly, therapy induced up-regulation of specific signaling mechanisms) correlated with changes induced by injury and treatment in regard to spasticity, gait, and pain. Immunohistochemical (IHC) and molecular expression of three factors that are essential for normal pattern of presynaptic and postsynaptic inhibition: GABA/GABAb receptors and descending noradrenergic (NE) fiber projection. In addition, specific molecular markers for pain (GCH1, GTP cyclohydrolase 1; SP, Substance P; CGRP, calcitonin gene-related peptide, a marker for pain and sprouting of SC afferents; Isolectin B4, IB4, marker for microglia) will be tested. Hypothesis: We propose that therapy induced normalization of spasticity measures will in part, be mediated by increased rate-dependent inhibition in the SC circuits, and these neurophysiological measures will correlate with significant up-regulation of immuno-expression of GABA/GABAb receptors and NE. We propose that therapy induced normalization of outcome measures for pain will correlate with reduced immune-expression of pain markers GCH1, SP, CGRP, and IB4. Translation of these findings and the demonstration of benefit from locomotor and TMSsc therapies could lead to more specific and potentially more effective locomotor therapy clinical trials in combat C-SCI patients which ultimately benefit the veterans' health care system.