Therapeutic potential of combined locomotor training and TMS in SCI

说明： 摘要颈髓损伤(C-SCI)是一种常见且经常造成破坏性的战场损伤，可导致多种终身运动、痉挛和疼痛残疾。尽管脊髓损伤涉及一系列随时间演变的病理生理事件，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失败，以减少运动所需的物理辅助。据报道，运动疗法和利用经颅磁刺激(TMS)减少各种神经系统疾病的残疾的治疗都有积极的疗效。这项拟议的研究旨在测试运动训练和TMS相结合的潜力，以产生内源性神经可塑性和修复机制的聚合放大，从而显著增强运动恢复，减少痉挛、步态和疼痛残疾。痉挛是脊髓损伤较常见的并发症之一，人们一直在寻求新的治疗途径。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评估。提出了三个互补的具体目标，这些目标基于支持初步数据，并将采用本实验室广泛采用的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。在这项建议中，我们的目标是：1)比较单脉冲脊髓TMS(SC)和跑步机运动训练(TM)在急性C-SCI中单独和联合测试对伸展反射的兴奋性、步态运动学、疼痛敏感性和选定的生理安全措施的有效性和安全性；2)比较在慢性C-SCI中单独和联合测试的TMS和TM运动训练对痉挛、步态运动学和疼痛敏感性的有效性；3)确定与损伤和治疗引起的痉挛、痉挛、步态运动学和疼痛敏感性相关的关键神经生物学过程(特别是治疗诱导的特定信号机制上调)步态和疼痛。免疫组织化学(IHC)和分子表达对正常突触前和突触后抑制模式至关重要的三个因素：GABA/GABAB受体和去甲肾上腺素(NE)下行纤维投射。此外，还将测试疼痛的特异性分子标记(GCH1，GTP环水解酶1；SP，P物质；CGRP，降钙素基因相关肽，SC传入的标记；Isolectin B4，IB4，小胶质细胞的标记)。假设：我们认为，治疗诱导的痉挛测量的正常化将在一定程度上由SC回路中增加的速率依赖的抑制所介导，这些神经生理学测量将与GABA/GABAB受体和NE的免疫表达显著上调相关。我们认为，治疗诱导的疼痛结局指标的正常化将与疼痛标记物GCH1、SP、CGRP和IB4的免疫表达减少相关。翻译这些发现并展示运动疗法和运动疗法的益处可能会导致在战斗C-SCI患者中进行更具体、可能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.