Combined brain and peripheral nerve stimulation to enhance beneficial effects of

描述（由申请人提供）：在世界范围内，每隔一秒就有人中风，这是西方国家残疾的头号原因。中风的灾难性负担和基于证据的康复干预措施的缺乏，以减少中风造成的残疾，是全球卫生保健面临的一个重大挑战。在动物研究中证明神经元回路的“重新布线”与在临床领域中恢复独立生活的神经康复策略的可用性之间存在差距。在巴西的Hospital das Clmnicas/圣保罗大学/ Fundagao Faculdade de Medicina的神经刺激实验室，已经开发了实施中风康复研究的基本基础设施，这在很大程度上是由于之前由NIH资助的成功的R21赠款。神经刺激实验室和NINDS的人类皮层生理学和中风康复科之间建立了强有力的伙伴关系。在R21项目中，应用外周感觉刺激（PSS）来增强脑卒中患者的训练效果。在PSS中，电流在没有疼痛的情况下传递到外周神经。通过PSS增加感觉输入增强了大脑运动区域的兴奋性，并可以改善手部运动性能，正如我们的R-21赠款和其他研究的结果所证明的那样。另一种增强运动功能的无痛新兴技术是经颅直流电刺激（tDCS），它可以非侵入性地增强大脑的兴奋性。大多数改善中风运动功能的神经调节研究都集中在轻度手部运动障碍的患者身上。这项拨款提案将建立在R-21的结果基础上，通过使用一种新的方法来治疗中风后慢性期中度至重度手部无力的患者，对他们来说，几乎没有普遍接受的选择来减少手部残疾。在这些患者中，以功能性电刺激（FES）的形式输送到肌肉的电流可以帮助运动表现和运动训练。我们将在创新战略中将联合收割机FES、PSS和tDCS结合起来。本研究的第一个目的是比较单次FES与单独tDCS、单独PSS、tDCS + PNS或假tDCS +假PSS密切相关对卒中后慢性期中重度上肢无力患者运动障碍的影响。第二个目的是根据目的1的结果比较几次最强大的神经调节干预的效果，以及安慰剂（假PSS/tDCS）与FES +特定任务训练相结合对进行日常生活活动能力的影响。在目标2中，将对两组中度至重度手无力的成年中风患者进行为期六周的干预。所提出的范式代表了一个跨学科的联系，以打破翻译研究的障碍向前迈进了一步。私家侦探，Conforto博士是巴西中等收入国家（MIC）机构神经刺激实验室的负责人，他将与来自高收入国家（HIC）机构的研究人员合作：列奥纳多科恩博士是一位杰出的研究员，他领导着Intramural NINDS的人类皮层生理学和中风康复科; P. Hunter Peckham博士，FES的杰出研究员和先驱，凯斯西储大学生物医学工程教授; Andre马查多博士，克利夫兰诊所神经外科神经恢复中心主任和外科助理教授，他在神经调节方案方面拥有丰富的经验。MIC和HIC机构之间的合作将为推进非侵入性皮质神经调节和生物医学工程的研究奠定基础，这是中风康复策略成熟所需的。中等收入国家机构拥有设备和设施，将为这一建议提供充分支持。 公共卫生相关性：脑血管疾病是全球残疾的主要原因。中风的灾难性负担在低收入和中等收入国家更为严重，缺乏循证康复干预措施是全球卫生保健面临的一个重大挑战。脑卒中后上肢无力是常见的，但目前尚无普遍接受的治疗方法来有效改善中重度运动障碍患者的手功能。这些是最需要康复干预的患者。该项目通过测试一种新方法的效果来解决这一重要问题。我们将非侵入性地刺激大脑和周围神经，以增强中度至重度手部无力患者在电刺激设备辅助下的运动训练效果。这笔赠款将为制定对低收入、中等收入和高收入国家都有价值的改变游戏规则的中风康复战略奠定基础。

DESCRIPTION (provided by applicant): Worldwide, every other second someone suffers a stroke, the #1 cause of disability in western countries. The catastrophic burden of stroke and the scarcity of evidence-based rehabilitation interventions to decrease disability from stroke represent a major challenge to global health care. There is a gap between studies in animals demonstrating "rewiring" of neuronal circuits and availability of neurorehabilitative strategies to restore independent living in the clinical domain. Basic infrastructure to implement research in stroke rehabilitation has been developed at the Neurostimulation Laboratory at Hospital das Clmnicas/ Sao Paulo University/ Fundagao Faculdade de Medicina, Brazil, in great part due to a previous successful R21 grant funded by NIH. A strong partnership was developed between the Neurostimulation Laboratory and the Human Cortical Physiology and Stroke Rehabilitation Section at NINDS. In the R21 grant, peripheral sensory stimulation (PSS) was applied to enhance effects of training in patients in with stroke. In PSS, electrical currents are delivered to peripheral nerves, in the absence of pain. Increase in sensory input by PSS enhances excitability of brain motor areas and can improve hand motor performance, as demonstrated by results from our R-21 grant and from other studies. Another painless emerging technique to enhance motor function is transcranial direct current stimulation (tDCS) that enhances brain excitability non-invasively. Most neuromodulation research to improve motor function in stroke has focused on patients with mild hand motor impairment. This grant proposal will build on results of the R-21, by using a novel approach to treat patients with moderate to severe hand weakness in the chronic phase after stroke, to whom there are virtually no universally accepted options to decrease hand disability. In these patients, electrical currents delivered to muscles in the form of functional electrical stimulation (FES) can assist movement performance and motor training. We will combine FES, PSS and tDCS in an innovative strategy. The first aim of this grant is to compare effects of a single session of FES in close association with either tDCS alone, PSS alone, tDCS + PNS or sham tDCS + sham PSS, on motor impairment of patients with moderate to severe upper limb weakness in the chronic phase after stroke. The second aim is to compare the effects of several sessions of the most powerful neuromodulation intervention according to results of Aim 1, and effects of placebo (sham PSS/tDCS) combined with FES + task-specific training, on the ability to perform activities of daily living. In Aim 2, the interventions will be administered over six weeks to two groups of adult stroke patients with moderate to severe hand weakness. The proposed paradigm represents a step forward to break barriers in translational research by means of a multidisciplinary link. The P.I., Dr. Conforto, chief of the Neurostimulatation Laboratory in Brazil, the middle-income country (MIC) institution, will collaborate with researchers from high-income country (HIC) institutions: Dr. Leonardo Cohen, an eminent researcher that leads the Human Cortical Physiology and Stroke Rehabilitation Section at Intramural NINDS; Dr. P. Hunter Peckham, a distinguished researcher and pioneer on FES, who is Professor of Biomedical Engineering at the Case Western Reserve University; Dr. Andre Machado, Director of the Center for Neurological Restoration and Assistant Professor of Surgery in the Neurosurgery Department at the Cleveland Clinic, who has extensive experience in neuromodulation protocols. The collaboration between MIC and HIC institutions will set the stage for advancing research on non-invasive cortical neuromodulation and biomedical engineering, needed to ripen strategies for stroke rehabilitation. Equipment and facilities are available at the MIC institution that will provide full support to this proposal. PUBLIC HEALTH RELEVANCE: Cerebrovascular disease is a major cause of disability worldwide. The catastrophic burden of stroke is more dramatic in low- and middle- income countries, and the scarcity of evidence-based rehabilitation interventions represents a major challenge to global health care. Upper limb weakness is frequent after stroke, but there is no universally accepted treatment to effectively improve hand function in patients with moderate and severe motor impairment. These are the patients in deepest need of rehabilitative interventions. This project addresses this important issue, by testing effects of a novel approach. We will non-invasively stimulate the brain and peripheral nerves in order to enhance effects of motor training aided by an electrical stimulation device in patients with moderate to severe hand weakness. This grant will set the stage to develop game-changer strategies for stroke rehabilitation valuable to low-, middle- and high-income countries.