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，每隔一秒钟就有一个人遭受中风，这是西方国家的头号致残原因。卒中的灾难性负担和减少卒中致残的循证康复干预措施的缺乏是全球卫生保健面临的主要挑战。在动物身上进行的神经回路“重新布线”的研究与在临床领域恢复独立生活的神经康复策略之间存在差距。在巴西Clmnicas医院/圣保罗大学/ Fundagao faculty 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础设施，这在很大程度上要归功于之前由NIH资助的R21拨款的成功。神经刺激实验室与NINDS人类皮质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，外周感觉刺激（PSS）被用于增强卒中患者的训练效果。在PSS中，电流在没有疼痛的情况下被传递到周围神经。我们的R-21基金和其他研究的结果表明，PSS增加的感觉输入增强了大脑运动区域的兴奋性，可以改善手部运动表现。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。大多数改善中风患者运动功能的神经调节研究都集中在轻度手部运动障碍患者身上。这项拨款提案将以R-21的结果为基础，通过使用一种新颖的方法来治疗中风后慢性期中度至重度手部无力的患者，这些患者实际上没有普遍接受的减少手部残疾的选择。在这些患者中，以功能性电刺激（FES）的形式传递到肌肉的电流可以帮助运动表现和运动训练。我们将把FES、PSS和tDCS结合在一个创新的战略中。该资助的第一个目的是比较单次FES与单独tDCS、单独PSS、tDCS + PNS或假性tDCS +假性PSS密切相关对中风后慢性期中度至重度上肢无力患者运动障碍的影响。第二个目的是根据aim 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）结合FES +任务特定训练对日常生活活动能力的影响。在目标2中，干预措施将在六周内对两组中度至重度手部无力的成年中风患者进行管理。提出的范式代表了通过多学科联系打破翻译研究障碍的一步。P.I， Conforto博士，中等收入国家（MIC）机构巴西神经刺激实验室主任，将与来自高收入国家（HIC）机构的研究人员合作：Leonardo Cohen博士，一位领导校内NINDS人类皮质生理学和中风康复科的杰出研究员；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 Machado博士，克利夫兰诊所神经外科神经修复中心主任和外科助理教授，他在神经调节方案方面有丰富的经验。MIC和HIC机构之间的合作将为推进非侵入性皮层神经调节和生物医学工程的研究奠定基础，这些研究需要成熟的卒中康复策略。MIC机构提供的设备和设施将为这一建议提供全面支持。

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.