Mechanisms of action contributing to decrease spasticity and improve motor recovery with repeated transcutaneous stimulation after spinal cord injury

脊髓损伤后反复经皮刺激有助于减少痉挛并改善运动恢复的作用机制

• 批准号: 10097179
• 负责人: Marie-Pascale Cote
• 金额: $ 37.57万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10097179
• 关键词: Acute; Address; Aftercare; Animals; Axon; Baclofen; Behavioral; Botulinum Toxins; Cell Nucleus; Cells; Chronic; Clinic; Clinical; Communities; Contusions; Cytomegalovirus; Development; Dizziness; Electrodes; Equilibrium; Feedback; Goals; H-Reflex; Hindlimb; Homosynaptic Depression; Hyperreflexia; Individual; Injections; Injury; Intervention; Knowledge; Lead; Lesion; Locomotor Recovery; Locomotor training; Lumbar spinal cord structure; Manuals; Measures; Mental Depression; Modeling; Monitor; Motor; Motor Activity; Motor Evoked Potentials; Motor Neurons; Motor output; Movement; Muscle; National Institute of Neurological Disorders and Stroke; Neuronal Plasticity; Neurostimulation procedures of spinal cord tissue; Pathway interactions; Pharmacology; Rattus; Recovery of Function; Reflex action; Rehabilitation therapy; Reporting; Research Project Grants; Sedation procedure; Severities; Site; Spasm; Spinal; Spinal Cord; Spinal cord injury; Stains; Step training; Stretching; Swimming; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic; Time; Toes; Touch sensation; Training Programs; Treatment Protocols; United States National Institutes of Health; awake; base; behavioral outcome; clinical application; clinical practice; clinically relevant; cost; design; evidence base; experience; experimental study; improved; motor function improvement; motor function recovery; motor recovery; presynaptic; prevent; programs; response; restoration; side effect; spasticity; spinal reflex; time use; tizanidine; transcutaneous stimulation; transmission process; treatment strategy

Spasticity is a debilitating condition which emerges in up to ~75% of individuals with spinal cord injury (SCI), with most experiencing spastic episodes one year after injury. Current pharmacological approaches to decrease spasticity (i.e. baclofen, tizanidine, botulinum toxin) lead to significant undesirable side effects such as sedation and dizziness. More importantly, they also induce a profound depression of spinal reflex excitability which significantly reduces muscle activity and impedes conventional rehabilitative efforts. There is therefore a critical need to identify alternate avenues. The last decade has seen a critical breakthrough in the SCI field with the use of stimulation-based therapies, in particular epidural stimulation, to further modulate the excitability of spinal networks and enhance functional recovery after SCI. Although promising, these treatments are invasive, costly, and require highly skilled and specialized teams. In contrast, non-invasive transcutaneous spinal cord stimulation (tSCS) has the potential to be rapidly adapted in clinical rehabilitation settings. This project is designed to advance our understanding of the neuroplasticity triggered by 6 weeks of repeated lumbar tSCS initiated acutely, to prevent the development of spasticity, or chronically, to decrease spasticity once spinal hyperexcitability has fully developed. Aim 1 will determine if tSCS contributes to decrease spasticity/hyperreflexia through restoring spinal inhibition in lumbar spinal networks. Behavioral correlates of spasticity will be monitored over time. In a terminal experiment, the effect of tSCS on spinal inhibitory pathways (homosynaptic depression, reciprocal inhibition, and presynaptic inhibition) will be correlated to the reorganization of inhibitory/excitatory inputs to motoneurons and primary afferents. Aim 2 will determine if tSCS restores motor-evoked potentials (MEPs) originating from above and below the injury after SCI. During a terminal experiment, MEPs initiated by a stimulation to the spinal cord below or above the injury will be recorded as well as synaptic transmission in the cortico-reticulospinal pathway. The modulatory effect of proprioceptive feedback on the MEPs of various origin will also be evaluated. The contribution of primary afferents (VGlut1+/paravalbumin) and descending tracts (vGi) to increased motor output and normalization of the SCI-induced facilitation of proprioceptive afferents will be evaluated. Because spastic symptoms, such as spasms and uncontrollable reflexes, render rehabilitation and activity-based therapies such as locomotor training challenging and less effective, Aim 3 will determine if decreasing spasticity with tSCS prior to the initiation of a step-training program improves locomotor recovery. Spasticity and locomotor recovery will be evaluated over time and will be correlated to the return of spinal inhibition and cortico-reticulospinal transmission. The proposed research project is consistent with the goals of the NIH/NINDS by addressing a current gap in knowledge and delineating the mechanisms of tSCS. Understanding the mechanisms underlying the beneficial effect of non-invasive interventions is critical to optimize evidence-based clinical practice and fast-track its use in the SCI community.

痉挛是一种使人衰弱的疾病，在高达75%的脊髓损伤（SCI）患者中出现， 大多数在受伤一年后出现痉挛。目前的药理学方法减少 痉挛状态（即巴氯芬、替扎尼定、肉毒杆菌毒素）导致显著的不良副作用 头晕更重要的是，它们还诱导脊髓反射兴奋性的深度抑制， 显著降低肌肉活动并阻碍常规的康复努力。因此，有一个关键的 需要找到其他途径在过去的十年里，随着SCI的使用，SCI领域取得了重大突破。 基于刺激的治疗，特别是硬膜外刺激，以进一步调节脊髓的兴奋性， 网络和增强SCI后的功能恢复。虽然有希望，但这些治疗是侵入性的，昂贵的， 需要高技能的专业团队。相反，非侵入性经皮脊髓刺激 （tSCS）具有在临床康复环境中快速适应的潜力。该项目旨在 推进我们对6周急性开始的重复腰椎tSCS触发的神经可塑性的理解， 防止痉挛的发展，或慢性地，一旦脊髓过度兴奋， 充分发展。目标1将确定tSCS是否有助于通过恢复 腰椎网络中的脊髓抑制。随着时间的推移，将监测痉挛的行为相关性。中 终末实验，tSCS对脊髓抑制性通路（同突触抑制，相互抑制）的影响 抑制和突触前抑制）将与抑制性/兴奋性输入的重组相关， 运动神经元和初级传入神经。目标2将确定tSCS是否恢复运动诱发电位（MEP） 脊髓损伤后，损伤的上方和下方都有。在一次终端实验中，欧洲议会议员们发起了一场 将记录对损伤下方或上方的脊髓的刺激以及在损伤区域中的突触传递。 皮质-网状脊髓通路本体感觉反馈对不同来源MEP的调制作用 也将进行评估。初级传入纤维（VGlut 1 +/paravalbumin）和下行束（vGi）的贡献 增加运动输出和SCI诱导的本体感受传入便利化的正常化， 评估。由于痉挛症状，如痉挛和无法控制的反射，使康复和 基于活动的治疗，如运动训练具有挑战性和效果较差，目标3将确定是否 在开始阶梯训练程序之前用tSCS减少痉挛改善运动恢复。 随着时间的推移，将评估痉挛和运动恢复，并将其与脊髓损伤的恢复相关联。 抑制和皮质-网状脊髓传递。拟议的研究项目符合以下目标： NIH/NINDS通过解决目前的知识差距和描述tSCS的机制。 了解非侵入性干预的有益效果的机制对于优化 循证临床实践和快速跟踪其在SCI社区的使用。