Engineer Navzer D, Kimberley Teresa J, Prudente Cecília N, Dawson Jesse, Tarver W Brent, Hays Seth A
MicroTransponder, Inc., Austin, TX, United States.
Department of Physical Therapy, School of Health and Rehabilitation Sciences, MGH Institute of Health Professions, Boston, MA, United States.
Front Neurosci. 2019 Mar 29;13:280. doi: 10.3389/fnins.2019.00280. eCollection 2019.
Stroke is a leading cause of disability worldwide, and in approximately 60% of individuals, upper limb deficits persist 6 months after stroke. These deficits adversely affect the functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by enhancing functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting these deficits may represent a means to improve quality of life. An increased understanding of the neurobiological processes underlying stroke recovery has led to the development of targeted approaches to improve motor deficits. One such targeted strategy uses brief bursts of Vagus Nerve Stimulation (VNS) paired with rehabilitation to enhance plasticity and support recovery of upper limb function after chronic stroke. Stimulation of the vagus nerve triggers release of plasticity promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex. Timed engagement of neuromodulators concurrent with motor training drives task-specific plasticity in the motor cortex to improve function and provides the basis for paired VNS therapy. A number of studies in preclinical models of ischemic stroke demonstrated that VNS paired with rehabilitative training significantly improved the recovery of forelimb motor function compared to rehabilitative training without VNS. The improvements were associated with synaptic reorganization of cortical motor networks and recruitment of residual motor neurons controlling the impaired forelimb, demonstrating the putative neurobiological mechanisms underlying recovery of motor function. These preclinical studies provided the basis for conducting two multi-site, randomized controlled pilot trials in individuals with moderate to severe upper limb weakness after chronic ischemic stroke. In both studies, VNS paired with rehabilitation improved motor deficits compared to rehabilitation alone. The trials provided support for a 120-patient pivotal study designed to evaluate the efficacy of paired VNS therapy in individuals with chronic ischemic stroke. This manuscript will discuss the neurobiological rationale for VNS therapy, provide an in-depth discussion of both animal and human studies of VNS therapy for stroke, and outline the challenges and opportunities for the future use of VNS therapy.
中风是全球致残的主要原因，约60%的中风患者在中风6个月后上肢功能仍有缺陷。这些缺陷会对上肢的功能使用产生不利影响，并限制日常活动的参与。中风康复的一个重要目标是通过增强功能独立性和参与活动来提高生活质量。由于上肢缺陷是中风后生活质量的最佳预测指标之一，针对这些缺陷的有效干预措施可能是提高生活质量的一种手段。对中风恢复背后神经生物学过程的深入了解，促使了旨在改善运动缺陷的针对性方法的发展。一种这样的靶向策略是使用短暂的迷走神经刺激（VNS）与康复训练相结合，以增强可塑性并支持慢性中风后上肢功能的恢复。刺激迷走神经会触发可塑性促进神经调节剂（如乙酰胆碱和去甲肾上腺素）在整个皮层的释放。神经调节剂与运动训练同时定时参与，可驱动运动皮层中特定任务的可塑性，从而改善功能，并为配对VNS治疗提供了基础。在缺血性中风的临床前模型中进行的多项研究表明，与无VNS的康复训练相比，VNS与康复训练相结合能显著改善前肢运动功能的恢复。这些改善与皮层运动网络的突触重组以及控制受损前肢的残余运动神经元的募集有关，证明了运动功能恢复背后的假定神经生物学机制。这些临床前研究为在慢性缺血性中风后有中度至重度上肢无力的个体中进行两项多中心、随机对照试点试验提供了基础。在两项研究中，与单独的康复训练相比，VNS与康复训练相结合改善了运动缺陷。这些试验为一项旨在评估配对VNS治疗对慢性缺血性中风患者疗效的120例患者的关键研究提供了支持。本手稿将讨论VNS治疗的神经生物学原理，深入讨论VNS治疗中风的动物和人体研究，并概述VNS治疗未来应用的挑战和机遇。
