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 ?-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 ?-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.
Stroke is the leading cause of motor disability in the United States. Neuromodulation through electrical stimulation holds promise in improving motor function, but has shown inconsistent results. This proposal aims to investigate whether a stimulation system that delivers stimulation precisely at the time of movement intention works better than conventional stimulation systems, and how does the stimulation affect the ongoing brain activity, which will help implement better neurostimulation systems for stroke.
