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

痉挛是一种衰弱的情况，高达75%的脊髓损伤(SCI)患者会出现这种情况， 大多数人在受伤后一年内经历痉挛发作。目前的药理学方法是减少 痉挛(如巴氯芬、替扎尼定、肉毒杆菌毒素)会导致严重的不良副作用，如镇静。 还有头晕。更重要的是，它们还会引起严重的脊髓反射兴奋性抑制， 显著减少肌肉活动，阻碍传统的康复努力。因此，有一个关键的 需要确定替代途径。在过去的十年里，SCI领域取得了重大突破，它的使用 以刺激为基础的治疗，特别是硬膜外刺激，以进一步调节脊髓的兴奋性 促进脊髓损伤后的功能恢复。尽管前景看好，但这些治疗方法具有侵入性，成本高昂， 并需要高技能和专业化的团队。相比之下，非侵入性经皮脊髓刺激 (TSCS)具有在临床康复环境中迅速适应的潜力。该项目旨在 进一步加深我们对重复6周腰椎TSCS所触发的神经可塑性的理解， 防止痉挛的发展，或在慢性情况下，一旦脊柱过度兴奋，减少痉挛 完全发育成熟。目标1将确定TSCS是否通过修复有助于减少痉挛/反射亢进 腰椎网络中的脊柱抑制。痉挛的行为相关性将随着时间的推移而被监测。在一个 终末实验，TSCS对脊髓抑制通路的影响(同型突触抑制，交互作用 抑制和突触前抑制)将与抑制/兴奋输入的重组相关，以 运动神经元和初级传入。目标2将确定TSCS是否能恢复运动诱发电位(MEP) 起源于脊髓损伤后的损伤上方和下方。在一次终端实验中，由一名 将记录对损伤下方或上方的脊髓的刺激以及脊髓内突触传递。 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 也将接受评估。初级传入神经(VGlut1+/副白蛋白)和降支通路(VGI)的作用 增加运动输出和脊髓损伤诱导的本体感觉传入的正常化将是 已评估。因为痉挛症状，如痉挛和无法控制的反射，使康复和 以活动为基础的治疗，如运动训练，具有挑战性和较低的效果，目标3将确定 在步进式训练计划开始前使用TSCS减少痉挛可以改善运动恢复。 痉挛和运动恢复将随着时间的推移进行评估，并将与脊柱恢复相关 抑制和皮质-网状脊髓传递。建议的研究项目与以下目标一致 NIH/NINDS通过解决目前的知识差距和勾勒出TSCS的机制。 了解非侵入性干预的有益效果的潜在机制对于优化 循证临床实践和快速追踪其在脊髓损伤社区的使用。

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.