Closed-loop Brain Stimulation for Motor Recovery Post Stroke

研究：中风仍然是美国运动障碍的主要原因。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，当施加在受伤附近，或远处，或一起对多个区域。然而，这项研究的绝大多数都使用了开环刺激(OLS)方法，即刺激在很长一段时间内被粗略地开启和关闭，结果显示出轻微或不一致的改善。相比之下，“闭合回路刺激”(CLS)的目的是在短时间内仅对特定状态做出反应来提供刺激。鉴于神经活动和大脑状态是高度非静态的，CLS可能更具生理性，因为它可以用来促进与适应性可塑性相关的状态。要实现CLS，我们需要确定最容易触发CLS并将促进可塑性的大脑状态。 指导阶段：这项建议在指导K99阶段的目标是：(1)找到可以作为CLS的最佳触发因素的大脑状态，以及(2)测试CLS对皮层周围的CLS是否比OLS更好地促进康复。我利用多电极记录和刺激对清醒的行为啮齿动物进行了初步实验，以更好地了解中风后(使用不同的中风模型)既能诱导可塑性又能促进运动恢复的神经状态。我的初步数据表明，β频段(12-30赫兹)的神经同步性可能是刺激的重要触发因素。我将测试由β频段的同步上升触发的CLS的效果。 独立期：在严重中风中，同时对两个运动区进行刺激可能更能增强皮质的兴奋性。此外，为了优化CLS的优势，了解CLS的工作原理非常重要。在独立阶段，我将测试：(3)联合CLS对毁损周围皮质和对侧小脑的影响；(4)作为CLS原因底物的M1细胞的兴奋性增强，使用光遗传学工具。这些实验将把最先进的多分辨率电生理监测(即棘波、局部场电位和皮层脑电图术)与中风的啮齿动物模型结合起来。虽然这种拟议的实验方法是在啮齿类动物身上进行的，但使用这些多层次的监测，我也试图确定可以通过侵入性较小的手段(例如，仅使用皮质脑电图术)识别的替代生物标记物。如果成功，这些实验将确定重要的电生理生物标记物，可以在中风康复的临床相关CLS中实施。 候选人：我的主要兴趣是使用神经工程工具进行脑和脊髓损伤后的康复。我的长期目标是成为一名独立的研究员，拥有一个实验室，该实验室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。我希望对利用多分辨率电生理监测的啮齿动物进行基础研究。通过使用这些多层次的监测，希望能够识别出可翻译的生物标志物。在这份申请的培训阶段，我将在概念、技术和职业发展方面获得更多技能，这将使我能够成功地过渡到我自己的研究小组的独立职位。我的短期目标是，(1)获得在运动皮质和小脑的多点记录和刺激方面的专业知识，(2)获得进一步熟练的数据分析技能，(3)在清醒行为的啮齿动物的同步光遗传操作和生理学方面获得专业知识，(4)提高我在临床方面的研究知识(与我的临床顾问一起进行广泛的临床跟踪)，(5)获得一个独立的终身教职跟踪助理教授职位，并在2年内转到本提案的R00部分，以及(6)在本提案的5年内成功获得R01资金。 环境：加州大学旧金山分校充满活力的合作研究环境(在基础和临床科学方面)有助于实现这些目标。我的合作导师和顾问(其中一些人也是临床医生)在啮齿动物和光遗传学的中风模型方面拥有丰富的经验，也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，我还可以访问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学术课程，我将利用这些课程获得这些研究技能。该学院还提供了一些职业发展资源，帮助博士后研究员获得获得独立所需的技能，包括旨在为学术就业市场准备博士后的研讨会和课程，以及帮助博士后申请学术工作的专门资源。我会利用所有这些来提升我的职业技能。我会在会议上介绍我的科学工作，并定期在部门研讨会上介绍我的工作。我还将参加加州大学旧金山分校的拨款撰写、实验室管理和教学研讨会。

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.