Locomotor function following transcutaneous electrical spinal cord stimulation in individuals with hemiplegic stroke

项目摘要 在美国720多万中风幸存者中，约有70%经历持续的步态缺陷，包括 步行速度降低，不对称的步行模式，以及下肢协调性降低，这限制了他们的 社区援助能力。目前的康复方法是基于这样的假设， 在保留脊髓的同时损害运动皮层功能，因此集中于刺激同侧或 在步态训练期间激活对侧运动皮层以激活休眠或新的通路。虽然动物模型 中风揭示了颈和腰脊髓的继发性变性，这表明脊髓损伤 脊髓可能影响功能恢复，很少或没有研究阐明脊髓变化 在人类中风后。我们的目的是评估脊髓刺激结合步态训练的效果 并研究这些影响的潜在机制。在初步工作中，我们测量了脊柱 诱发运动电位（sEMP）产生的非侵入性，经皮电脊髓刺激在10 中风幸存者、10名年龄匹配的健康对照者和10名年轻健康受试者。刺激阈值为 脑卒中存活者的潜伏期显著高于对照组，而麻痹侧的潜伏期显著延迟 与非麻痹侧相比，表明中风对下游脊髓回路的继发性影响， 下行通路我们还发现，脊髓刺激+专注于步态训练（n=4）相比， 对于单独的步态训练（n=4），显著改善了步长对称性、步行速度（10米步行试验， 10 MWT）和步行耐力（6分钟步行试验，6 MWT）;这些改善超过了最低限度 慢性中风的临床重要差异。这些结果支持了我们的假设，即脊髓刺激可能 增加步态训练功效。在目标1中，我们将评估脊髓刺激和假手术的短期效果。 刺激，有或没有以步态为重点的步态训练，对步态功能（主要结果：步长 对称性）和皮质脊髓回路。在目标2中，我们将进行一项随机临床试验 评估在卒中患者中使用刺激或假刺激进行集中步态训练的长期效果 存活者（每组n=25）。主要结果将是步长对称性;次要结果包括 时间步态对称性，速度（10 MWT），肌肉激活（肌电图），步行耐力（6 MWT）， 能量消耗（Cosmed K4 B2）、上下肢功能（Fugl-Meyer评估）、健康状况 （中风影响量表-16）和社区活动（可穿戴传感器，Actigraph LLC）。我们亦会研究 脊髓刺激作用的潜在机制，通过检查下肢肌肉中引起的sEMP， 皮质脊髓轴突的皮质/皮质下刺激和皮质内抑制。这项工作将（一）确定短- 和脊髓刺激的长期影响，（ii）验证脊髓刺激作为一种非侵入性的方法，以恢复 慢性中风中的步态，（iii）确定可以确定对脊髓刺激的反应的临床测量，以及（iv） 确定潜在的神经调节机制，这可能提供额外的治疗选择。

Project Abstract Approximately 70% of the more than 7.2 million U.S. stroke survivors experience persistent gait deficits, including reduced walking speed, asymmetrical walking patterns, and reduced lower limb coordination, which limit their capacity for community ambulation. Current rehabilitation approaches are based on the assumption that stroke impairs motor cortex function while the spinal cord is preserved and thus focus on stimulating the ipsilateral or contralateral motor cortex during gait training to activate dormant or new pathways. Although animal models of stroke reveal secondary degeneration of the cervical and lumbar spinal cord, suggesting that damage to the spinal cord may effect functional recovery, little or no research has been done to elucidate spinal cord changes in humans after stroke. Our objective is to evaluate the effects of spinal stimulation combined with gait training after stroke and to investigate mechanisms underlying these effects. In preliminary work, we measured spinally evoked motor potentials (sEMPs) generated by non-invasive, transcutaneous electrical spinal stimulation in 10 stroke survivors, 10 age-matched healthy controls, and 10 young healthy subjects. Stimulation thresholds were significantly higher in stroke survivors than in controls and latency was significantly delayed in the paretic side compared to the non-paretic side, indicating secondary effects of stroke on downstream spinal circuitry and descending pathways. We also showed that spinal stimulation + symmetry-focused gait training (n=4) compared to gait training alone (n=4), significantly improved step-length symmetry, walking speed (10-meter walk test, 10MWT), and walking endurance (6-minute walk test, 6MWT); these improvements exceeded the minimal clinically important difference for chronic stroke. These results support our hypothesis that spinal stimulation may increase gait training efficacy. In Aim 1, we will evaluate the short-term effects of spinal stimulation and sham stimulation, with or without symmetry-focused gait training, on gait function (primary outcome: step-length symmetry) and corticospinal circuitry in 25 stroke survivors. In Aim 2, we will conduct a randomized clinical trial to evaluate the long-term effects of symmetry-focused gait training with stim or sham stimulation in stroke survivors (n=25 per group). The primary outcome will be step-length symmetry; secondary outcomes include temporal gait symmetry, speed (10MWT), muscle activation (electromyography), walking endurance (6MWT), energy expenditure (Cosmed K4B2), upper and lower limb function (Fugl-Meyer Assessment), health status (Stroke Impact Scale-16), and community activity (wearable sensors, Actigraph LLC). We will also investigate mechanisms underlying the effects of spinal stimulation by examining sEMPs elicited in lower limb muscles by cortical/subcortical stimulation of corticospinal axons and intracortical inhibition. This work will (i) identify short- and long-term effects of spinal stimulation, (ii) validate spinal stimulation as a non-invasive method to restore gait in chronic stroke, (iii) identify clinical measures that may determine response to spinal stimulation, and (iv) identify underlying neuromodulatory mechanisms, which may provide additional treatment options.