Cortical Stimulation to Enhance Recovery after Stroke

描述(由申请人提供)： 卒中后运动恢复伴随着大脑皮层功能和结构的可塑性。在这项翻译研究合作计划(U54)中，一种新的治疗方法旨在通过调节神经可塑性来促进运动恢复，将在大鼠(项目1和2)和非人灵长类动物(项目3)皮质缺血梗死后恢复的模型中进行测试。这种新的方法，皮质刺激(CS)，利用在康复训练过程中应用于梗死区周围皮质的低水平电刺激。在学术界和产业界基础和临床研究人员的这一独特合作中，临床前模型将用于优化即将由业界资助的临床试验的治疗方案。在项目1中，将优化电刺激方案(频率、幅度、时间模式、电极配置和持续时间)，并检查癫痫敏感性。疗效将根据诱发的运动阈值和运动表现进行评估。在项目2中，将通过将CS与不同的康复训练程序(约束诱导运动疗法、REACH训练、杂技训练)相结合来优化康复训练方案。训练程序的效果将通过治疗和随访期间的运动表现来评估。在项目3中，将测试在大鼠模型中确定的最佳参数是否适用于非人类灵长类动物的皮质缺血和恢复模型。此外，在啮齿动物模型中不太可行的治疗参数将在灵长类动物中进行评估。监督/领导核心将组织会议，促进科学交流，协助管理U54核心和项目，并提供数据管理和生物统计支助。这三个项目将在四个地点进行，之所以选择这四个地点，是因为研究人员在中风恢复领域拥有丰富的经验，而且他们组成了一个综合团队，推动了最初的临床前研究。临床前结果将通过临床前小组与临床试验医学总监和U54指导委员会的定期会议被转化为临床计划，讨论a)临床前结果及其对临床计划的影响，以及b)可能影响临床前研究的临床计划结果。预计这一计划将成为引入基于神经科学基本原理的新的脑修复治疗方法的典范。

DESCRIPTION (provided by applicant): Motor recovery after stroke is accompanied by functional and structural plasticity in cerebral cortex. In this Cooperative Program in Translational Research (U54), a new therapeutic approach, intended to enhance motor recovery via modulation of neuroplasticity, will be tested in rat (Projects 1 and 2) and nonhuman primate (Project 3) models of recovery after cortical ischemic infarct. This new approach, Cortical Stimulation (CS), utilizes low-level electrical stimulation over peri-infarct cortex applied during rehabilitative training procedures. In this unique collaboration of basic and clinical researchers in academia and industry, preclinical models will be used to optimize treatment protocols for upcoming clinical trials funded by industry. In Project 1, the electrical stimulation protocol (frequency, amplitude, temporal pattern, electrode configuration and duration) will be optimized and seizure susceptibility will be examined. Efficacy will be assessed with regard to evoked movement thresholds and motor performance. In Project 2, the rehabilitative training protocol will be optimized by combining CS with different rehabilitative training procedures (constraint-induced movement therapy, reach training, acrobatic training). The efficacy of training procedures will be assessed by motor performance during treatment and follow-up. In Project 3, optimal parameters determined in rat models will be tested for generalizability to a nonhuman primate model of cortical ischemia and recovery. Also, treatment parameters that are less feasible in the rodent model will be assessed in primates. An Oversight/Leadership Core will organize meetings, promote scientific exchange, assist in management of U54 cores and projects and provide data management and biostatistical support. The three projects will be performed at four sites, chosen because the investigators have extensive experience in the field of stroke recovery, and because they form an integrated team that has advanced the initial preclinical studies. Preclinical results will be translated into the clinical program by regular meetings of the preclinical group with the medical director for clinical trials and U54 Steering Committee to discuss a) preclinical findings and their impact on the clinical program, and b) findings from the clinical program that may impact the preclinical studies. It is expected that this program will serve as a model for the introduction of new therapeutic approaches to brain repair that are based on underlying neuroscientific principles.