Therapeutic potential of combined locomotor training and TMS in SCI

联合运动训练和 TMS 在 SCI 中的治疗潜力

• 批准号: 8784815
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784815
• 关键词: 3-Dimensional; Acute; Animal Model; Behavioral; Calcitonin Gene-Related Peptide; Cervical spinal cord injury; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Communities; Data; Dose; Event; Exercise; Fiber; GTP Cyclohydrolase; Gait; Guidelines; H-Reflex; Health; Healthcare Systems; Human; Immune; Immunohistochemistry; Individual; Injury; Intervention; Isolectin; Laboratories; Lead; Life; Locomotion; Locomotor Recovery; Locomotor training; Measures; Mediating; Mental Depression; Methods; Microglia; Modality; Molecular; Monitor; Motor Evoked Potentials; Neurobiology; Neurologic; Outcome Measure; Pain; Pattern; Physiologic pulse; Physiological; Process; Protocols documentation; Quality of life; Receptor Signaling; Relative (related person); Reporting; Research; Research Design; Safety; Signal Transduction; Spinal Cord; Spinal cord injury patients; Stimulus; Substance P; Synapses; System; Techniques; Testing; Therapeutic; Therapy Clinical Trials; Time; Transcranial magnetic stimulation; Translations; Treatment Effectiveness; Treatment Efficacy; Up-Regulation; Veterans; Work; abstracting; base; body system; combat; comparative efficacy; design; disability; dosage; efficacy testing; evidence base; functional improvement; gamma-Aminobutyric Acid; injured; kinematics; molecular marker; multidisciplinary; neurophysiology; noradrenergic; novel therapeutics; postsynaptic; pre-clinical; presynaptic; public health relevance; receptor; rehabilitation strategy; repaired; response; safety testing; stretch reflex; therapeutic target; therapy development

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.

描述： 抽象的宫颈脊髓损伤（C-SCI）是一种常见且经常毁灭性的战场损伤，可能导致广泛的终身运动，痉挛和疼痛障碍。尽管SCI涉及一系列随着时间的流逝而发展的众多病理生理事件，但旨在治疗开发的研究几乎完全集中在多中心临床试验中失败的单一疗法上，以减少运动所需的身体援助。已经报道了对运动治疗的阳性治疗益处，并独立地使用经颅磁刺激（TMS）来减少各种神经系统疾病的残疾。拟议的研究旨在测试运动训练和TMS结合的潜力，以产生内源性神经塑性和修复机制的收敛扩增，从而显着增强运动能力的恢复，并减少痉挛，步态和疼痛障碍。痉挛是不断追求新的治疗途径的SCI的最常见并发症之一。多学科研究将量化对残疾的治疗影响，基本机制的变化，并在急性和慢性治疗窗口中使用各种剂量和组合提供全面的神经和生理安全评估。提出了三个互补的特定目的，这些目标是基于支持初步数据的三个互补目的，这些数据将采用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，这些技术已在该实验室中广泛使用。 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运动训练，单独测试，在慢性C-SCI上进行痉挛，步态运动学和疼痛敏感性，3）确定与痉挛性，步态和疼痛有关的变化和治疗而与受伤和治疗相关的关键神经生物学过程（尤其是治疗引起的特定信号机制的上调）。免疫组织化学（IHC）和分子表达的三个因素，这些因素对于正常的突触前和突触后抑制作用至关重要：GABA/GABAB受体以及降甲肾上腺素能（NE）纤维投影。此外，将测试疼痛的特异性分子标记（GCH1，GTP环氢酶1; SP，物质P; CGRP，降钙素基因相关的肽，SC传入疼痛和发芽的标志物；隔离蛋白B4，IB4，IB4，IB4，Microglia的标记）。假设：我们提出，治疗诱导的痉挛度量的归一化将部分由SC回路的速率依赖性抑制作用介导，这些神经生理学测量将与GABA/GABA/GABAB受体和NE的免疫表达的显着上调相关。我们建议治疗引起的疼痛结果指标的归一化将与疼痛标记物GCH1，SP，CGRP和IB4的免疫表达降低有关。这些发现的翻译以及从运动和TMSSC疗法获得的益处的表现可能会导致战斗C-SCI患者的更具体和可能更有效的运动疗法临床试验，这最终使退伍军人的医疗保健受益 系统。