PROJECT SUMMARY Stroke-causing illness, disability, and early death is set to double worldwide within the next 15 years. Despite physical therapy, about 50% of stroke survivors have impaired hand function, which strongly impacts activities of daily living and independence; novel treatment methods are urgently required. While most pre-clinical research addressing stroke recovery and rehabilitation focuses on restoring damaged descending movement pathways, dexterous hand function is also reliant on the brain receiving ascending somatosensory input and being able to use it to guide movements. Clinically and in animal models, deficits in somatosensory cortices predict worse recovery of hand function following stroke, though the functional mechanisms by which somatosensory signals support hand function remain poorly characterized. In this proposal, we aim to uncover how somatosensory signals drive motor activity during the acquisition and performance of dexterous manipulation behaviors in intact and post-stroke non-human primates. The main experimental approach of this proposal includes simultaneous high-density, high channel-count acute electrophysiological recordings from the somatosensory thalamus, primary somatosensory cortex, and primary motor cortex in intact and post-stroke non-human primates performing complex manipulation tasks. The main analytical approach includes modeling motor activity evolution as a combination of intrinsic motor cortical dynamics and inputs from somatosensory thalamic and somatosensory cortex. The hypothesis of this proposal is that somatosensory input signals guide the identification of effective motor activity trajectories that become frequently used and less input-dependent with improved manipulation skill. Thus, somatosensory signals are critical for improvement of manipulation skill and recovery of dexterity post-stroke. Completion of this proposal will identify nodes and functional interactions within the sensorimotor system that could be targeted with novel therapies for improving recovery of hand function following stroke. I will complete these aims with the guidance of an exceptional mentoring team led by Dr. Karunesh Ganguly and including Dr. Joni Wallis, Dr. Robert Morecraft, and Dr. Aaron Suminski. During the mentored phase of the award at UCSF, I will develop a state-of-the-art high channel-count, multi-area electrophysiological approach for monitoring the sensorimotor network. I will also conduct the proposed experiments in animals performing object manipulation tasks, pilot a haptic brain-machine-interface task, and focus on professional development in order to facilitate a successful transition into an independent faculty position at an academic institution.

PROJECT NARRATIVE Stroke is the leading cause of disability in the United States, leaving a substantial number of survivors with permanent hand function deficits impairing dexterity. While most pre-clinical research focuses on descending movement pathways, anatomical and clinical studies underscore the critical role of somatosensory signals in recovery. This proposal uses multi-area electrophysiology to monitor functional interactions in the cortical and subcortical sensorimotor circuit during dexterous hand skill acquisition in intact and stroke-injured networks, laying the foundation for future therapies targeting normalization of somatosensory signals to enhance hand function recovery.