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，对多个大脑区域进行电刺激可以促进运动恢复。这种刺激被证明是有益的，当施加在损伤附近，或远处的区域，或多个区域在一起。然而，这项研究的绝大多数都使用了“开环刺激"方法，即长时间内严重开启和关闭刺激，结果显示出边际或不一致的改善。相比之下，“闭环刺激"的目的是仅在响应特定状态的短时间内提供刺激。鉴于神经活动和大脑状态是高度不稳定的，CLS可能更具生理学意义，因为它可以用于促进与适应性可塑性相关的状态。为了实现CLS，我们需要确定最适合触发CLS并促进可塑性的大脑状态。 指导阶段：在指导的K99阶段期间，该提议的目标是：（1）找到可以用作CLS的最佳触发的大脑状态，以及（2）测试对病灶周围皮质的CLS是否比OLS更好地促进恢复。我在清醒的啮齿动物中使用多电极记录和刺激进行了试点实验，以更好地了解可以诱导可塑性和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）的神经同步可能是刺激的重要触发因素。我将测试β波段同步上升触发的CLS效应。 独立阶段：在严重中风中，同时刺激两个运动区可能更好地增强皮层兴奋性。此外，为了优化CLS的优势，重要的是要了解CLS的工作原理。在独立阶段，我将测试：（3）联合CLS对病灶周围皮质和病灶对侧小脑的影响;以及（4）使用光遗传学工具，M1细胞作为CLS介导恢复的因果底物的兴奋性增强。这些实验将结合联合收割机最先进的多分辨率电生理监测（即尖峰、局部场电位和皮质电描记术）和啮齿动物中风模型。虽然这种拟议的实验方法是在啮齿动物中，使用这些多水平的监测，我还试图确定替代的生物标志物，可能通过侵入性较小的手段（例如，只使用皮层电图）。如果成功，这些实验将确定重要的电生理生物标志物，可以在临床相关的CLS中风恢复实施。 候选人：我广泛的兴趣是在脑和脊髓损伤后使用神经工程工具进行康复。我的长期目标是成为一名独立的研究者，拥有一个将先进的系统电生理工具与专注于推进新神经技术的新型康复策略相结合的实验室。我希望在啮齿类动物中进行基础研究，利用多分辨率电生理监测。通过使用这些多层次的监测，希望能够识别出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额外技能，这将使我能够成功过渡到我自己的研究小组的独立职位。我的短期目标是，（1）获得多位点记录和运动皮层和小脑刺激的专业知识，（2）进一步熟练掌握数据分析技能，（3）获得清醒行为啮齿动物同步光遗传学操作和生理学的专业知识，（4）提高我在临床方面的研究知识（与我的临床顾问广泛的临床阴影），（5）获得独立的终身助理教授职位，并在2年内转移到本提案的R 00部分，以及（6）在本提案的5年内成功获得R 01资金。 环境：UCSF充满活力的合作研究环境（基础和临床科学）有利于实现这些目标。我的共同导师和顾问（其中一些也是临床医生）在啮齿动物中风模型和光遗传学方面以及在表征脑损伤的生理过程方面拥有丰富的经验。通过我的合作者，我还可以进入格莱斯顿神经疾病研究所，这将有助于我追求这些研究目标。加州大学旧金山分校提供的学术课程，我将利用获得这些研究技能。学校还提供了一些职业发展资源，以帮助博士后获得实现独立所需的技能，包括旨在为学术就业市场做好准备的研讨会和课程，以及帮助博士后申请学术工作的专用资源。我会利用这些来提高我的职业技能。我将在会议上和定期在部门研讨会上介绍我的科学工作。我还将参加加州大学旧金山分校提供的赠款写作，实验室管理和教学研讨会。