Closed-loop Brain Stimulation for Motor Recovery Post Stroke

用于中风后运动恢复的闭环大脑刺激

• 批准号: 9315041
• 负责人: Tanuj Gulati
• 金额: $ 8.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315041
• 关键词: Adjuvant; Affect; Area; Basic Science; Biological Markers; Brain; Brain Injuries; Cells; Cerebellum; Clinical; Clinical Sciences; Data; Data Analyses; Disabled Persons; Distant; Dose; Educational process of instructing; Educational workshop; Electric Stimulation; Electrocorticogram; Electrophysiology (science); Engineering; Environment; Epilepsy; Etiology; Feedback; Funding; Goals; Grant; Injury; Institutes; Intention; Intervention; Joints; Knowledge; Limb structure; Link; Literature; Mediating; Mentors; Methods; Modeling; Monitor; Motor; Motor Cortex; Motor output; Movement; Neurorehabilitation; Occupations; Outcome; Parkinson Disease; Patients; Peripheral; Peripheral Nerve Stimulation; Phase; Physiological; Physiological Processes; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Preparation; Process; Professional Competence; Rattus; Recovery; Recruitment Activity; Rehabilitation therapy; Research; Research Personnel; Resolution; Resource Development; Resources; Rodent; Rodent Model; Schools; Site; Stroke; System; Techniques; Technology; Testing; Time; Training; United States; Work; Writing; advanced system; awake; base; behavioral outcome; career development; clinically relevant; disability; experience; experimental study; improved; interest; job market; motor function improvement; motor recovery; nervous system disorder; neuroregulation; neurotechnology; novel; optogenetics; post stroke; professor; rehabilitation strategy; relating to nervous system; response; skills; spinal cord and brain injury; stroke recovery; symposium; tenure track; tool

Research: Stroke remains the leading cause of motor disability in the United States. There is a growing body of evidence suggesting that electrical stimulation to multiple brain areas can promote motor recovery. Such stimulation is shown to be beneficial when applied near the injury, or to distant areas, or to multiple regions together. However, the vast majority of this research has used `open-loop stimulation' (OLS) methods, where stimulation is grossly turned on and off over long-periods of time and the results have shown marginal or inconsistent improvements. In contrast, `closed-loop stimulation' (CLS) aims to deliver stimulation during brief periods of time only in response to specific states. Given that neural activity and brain states are highly non-stationary, CLS may be more physiological in that it can be used to promote states that are associated with adaptive plasticity. To implement a CLS, we need to determine the brain states that are best to trigger CLS and will promote plasticity. Mentored Phase: The objective of this proposal during the mentored K99 phase is: (1) to find brain states that can serve as optimal triggers for CLS, and (2) to test if CLS to perilesional cortex promotes recovery better than OLS. I have conducted pilot experiments using multielectrode recordings and stimulation in awake behaving rodents to better understand the neural states that can both induce plasticity and promote motor recovery after stroke (using different stroke models). My preliminary data indicates that neural synchrony in the β-band (12-30 Hz) may be an important trigger for stimulation. I will test the effects of CLS triggered by rise in synchrony in the β-band. Independent Phase: In severe strokes, concurrent stimulation to two motor areas may be better at enhancing cortical excitability. Furthermore, in order to optimize the benefits of CLS, it is important to understand how CLS works. In the independent phase, I will test: (3) the effects of a combined CLS to perilesional cortex and contralesional cerebellum; and (4) the enhanced excitability of M1 cells as the causal substrate of CLS mediated recovery using optogenetic tools. These experiments will combine state-of-the-art multi-resolution electrophysiological monitoring (i.e. spikes, local-field potential, and electrocorticography) with a rodent model of stroke. While this proposed experimental approach is in rodents, using these multiple levels of monitoring, I also seek to identify alternate biomarkers that might be identified through less invasive means (e.g. only using electrocorticography). If successful, these experiments will identify important electrophysiological biomarkers that can be implemented in clinically relevant CLS for stroke recovery. Candidate: my broad interests are in using neural engineering tools for rehabilitation after brain and spinal cord injury. My long-term goal is to become an independent investigator with a lab that combines advanced systems electrophysiological tools with novel rehabilitation strategies focused on advancing new neurotechnologies. I wish to do basic studies in the rodents that utilize multiresolution electrophysiological monitoring. By using these multiple levels of monitoring, it is hoped that translatable biomarkers will be identified. During the training phase of this application, I will gain additional skills in conceptual, technical and career development aspects which will enable me to make a successful transition to an independent position with my own research group. My short-term goals are, (1) to gain expertise in multi-site recordings and stimulation in the motor cortex and the cerebellum, (2) to acquire further proficiency in data analyses skills, (3) to gain expertise in simultaneous optogenetic manipulations and physiology in awake behaving rodents, (4) to improve my knowledge in the clinical aspects of my research (with extensive clinical shadowing with my clinical advisors), (5) to obtain an independent tenure-track assistant professor position and transfer to the R00 portion of this proposal within 2 years, and (6) to successfully obtain R01 funding within 5 years of this proposal. Environment: the vibrant, collaborative research environment (in basic & clinical sciences) at UCSF is conducive to the attainment of these goals. My co-mentors and consultants (some of who are also clinicians) have extensive experience with stroke models in rodents and optogenetics, and also in characterizing physiologic processes in brain injury. Through my collaborators, I also have access to the Gladstone Institute of Neurological Disease, which will aid my pursuit of these research goals. UCSF offers academic courses that I will utilize to gain these research skills. The school also provides a number of career development resources to help postdoctoral fellows gain skills required to achieve independence, including seminars and classes aimed at preparing postdocs for the academic job market and a dedicated resource that helps postdocs apply for academic jobs. I will utilize all of these to enhance my career skills. I will present my scientific work in conferences and regularly in departmental seminars. I will also attend grant writing, lab management, and teaching workshops offered at UCSF.

研究：中风仍然是美国运动残疾的主要原因。越来越多的证据表明，对多个大脑区域的电刺激可以促进运动恢复。这种刺激在受伤附近或遥远地区或多个区域一起施用时被证明是有益的。但是，这项研究的绝大多数使用了“开环刺激”（OLS）方法，其中刺激在长期的时间周期内严重打开和关闭，结果表明，边际或不一致的改善。相比之下，“闭环刺激”（CLS）旨在仅在响应特定状态而在短时间内提供刺激。鉴于神经元活性和大脑状态是高度非平稳的，因此CLS可能更有物质，因为它可用于促进与自适应可塑性相关的状态。要实施CLS，我们需要确定最能触发CL并促进可塑性的大脑状态。 指导阶段：在修改K99阶段的该提案的目的是：（1）找到可以作为CLS最佳触发器的大脑状态，并且（2）测试CLS对周围皮质的CLS是否比OLS更好地促进了恢复。我已经使用多电极记录和刺激行为啮齿动物进行了试点实验，以更好地了解可以诱导可塑性并促进中风后运动恢复的神经状态（使用不同的中风模型）。我的初步数据表明，β波段（12-30 Hz）中的神经同步可能是刺激的重要触发因素。我将测试β波段同步升高触发的CLS的效果。 独立阶段：在严重的笔触中，同时对两个运动区域的刺激可能会更好地增强皮质兴奋。此外，为了优化CLS的好处，了解CLS的工作原理很重要。在独立阶段，我将测试：（3）联合CLS对周围皮层和混凝土小脑的影响； （4）M1细胞作为CLS介导的恢复的因果底物的增强性兴奋性。这些实验将结合最先进的多分辨率电生理监测（即尖峰，局部场电位和电皮质学）与啮齿动物的中风模型。尽管这种提出的实验方法是在啮齿动物中，但使用这些多个级别的监测，我还试图识别可能通过侵入性较低的手段识别的替代生物标志物（例如，仅使用电皮质学）。成功，这些实验将确定可以在临床相关的CLS中实施的重要电生理生物标志物，以恢复中风。 候选人：我广泛的兴趣是使用神经工程工具在大脑和脊髓损伤后进行康复。我的长期目标是通过实验室成为一个独立的研究者，该实验室将高级系统电生理工具与新的康复策略相结合，致力于推进新的神经技术。我希望对使用多分辨率电生理监测的啮齿动物进行基础研究。通过使用这些多个级别的监视，我希望能够确定可翻译的生物标志物。在此应用程序的培训阶段，我将获得概念，技术和职业发展方面的其他技能，这将使我能够成功地与我自己的研究小组一起过渡到独立职位。 My short-term goals are, (1) to gain expertise in multi-site recordings and stimulation in the motor cortex and the cerebellum, (2) to acquire further proficiency in data analyses skills, (3) to gain expertise in simple optogenetic manipulations and physiology in awake behaving rodents, (4) to improve my knowledge in the clinical aspects of my research (with extensive clinical shadowing with my clinical advisors), (5) to obtain独立的终身助理助理教授职位，并在2年内转移到该提案的R00部分，（6）在该提案的5年内成功获得R01资金。 环境：UCSF的充满活力的协作研究环境（基础和临床科学）正在实现这些目标。我的联合和顾问（一些也是临床医生）在啮齿动物和光遗传学中具有广泛的卒中模型经验，并且在表征脑损伤的生理过程方面。通过我的合作者，我还可以进入格拉德斯通神经疾病研究所，这将有助于我追求这些研究目标。 UCSF提供的学术课程我将利用这些课程来获得这些研究技能。该学校还提供了许多职业发展资源，以帮助博士后研究员获得实现独立性所需的技能，包括下水道和旨在为学术就业市场做准备的阶级和班级，以及有助于博士后申请学术工作的专门资源。我将利用所有这些来增强我的职业技能。我将在会议上和部门半手中定期介绍我的科学工作。我还将参加UCSF提供的赠款写作，实验室管理和教学研讨会。