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： 摘要 颈脊髓损伤 (C-SCI) 是一种常见且经常造成破坏性的战场损伤，可导致多种终生运动、痉挛和疼痛残疾。尽管 SCI 涉及一系列随时间推移而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于单一疗法，这些疗法在多中心临床试验中未能减少运动所需的物理帮助。据报道，运动疗法以及利用经颅磁刺激 (TMS) 来减少各种神经系统疾病的残疾的独立疗法具有积极的治疗益处。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收敛放大的潜力，从而显着增强运动恢复，并减少痉挛、步态和疼痛残疾。痉挛是 SCI 更常见的并发症之一，人们不断寻求新的治疗途径。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性评估。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，这些技术已广泛应用于这个实验室。在本提案中，我们的目标是：1) 比较脊髓 (SC) 单脉冲 TMS (TMSsc) 和跑步机运动训练 (Tm) 的有效性和安全性，在急性 C-SCI 中单独测试和组合测试对兴奋性的影响牵张反射、步态运动学、疼痛敏感性和生理安全性的选定测量方法，2) 比较 TMSsc 和 Tm 运动训练的功效，单独测试和组合测试慢性 C-SCI 对痉挛的效果，步态运动学和疼痛敏感性，3）确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（特别是治疗诱导的特定信号机制上调）。对正常突触前和突触后抑制模式至关重要的三个因子的免疫组织化学 (IHC) 和分子表达：GABA/GABAb 受体和降去甲肾上腺素能 (NE) 纤维投射。此外，还将测试疼痛的特异性分子标记（GCH1、GTP 环化水解酶 1；SP、P 物质；CGRP、降钙素基因相关肽、疼痛和 SC 传入神经萌芽的标记；异凝集素 B4、IB4、小胶质细胞标记） 。假设：我们认为治疗诱导的痉挛测量正常化部分是由 SC 回路中速率依赖性抑制增加介导的，并且这些神经生理学测量将与 GABA/GABAb 受体和 NE 免疫表达的显着上调相关。我们认为，治疗诱导的疼痛结果指标正常化与疼痛标志物 GCH1、SP、CGRP 和 IB4 的免疫表达减少相关。这些发现的转化以及运动和 TMSsc 疗法益处的证明可能会导致在战斗 C-SCI 患者中进行更具体、可能更有效的运动疗法临床试验，最终有利于退伍军人的医疗保健 系统。