Development of a personalized neurostimulation protocol for memory mapping in epilepsy

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The proposed K01 application will strongly support Dr. Erik Kaestner's long-term career goal of becoming an independent clinically focused scientist using neurostimulation and cognitive neuroscience approaches to improve patients' cognitive function. Patients with drug-resistant temporal lobe epilepsy (TLE) often undergo surgical resection or ablation of medial temporal structures (MTL) critical to memory to alleviate seizures. Consequently, up to 40% of surgical interventions end with significant memory decline post-surgery. Currently, there is no procedure that accurately predicts post-surgical memory decline. An opportunity is presented by standard pre-surgical workflow in which patients are implanted with electrodes for surgical planning and are often stimulated for seizure mapping. I propose an innovative method for predicting post-operative memory decline following surgery by using electrical stimulation to induce transient, functional lesions in the MTL during a memory test. Although stimulation parameters are established for mapping seizures, they have not yet been established for transient disruption to test memory. The targeted research project aims to: 1) map the spread of electrical stimulation in the brain to ensure spatial specificity for memory mapping and 2) develop a stimulation and memory test paradigm for the mapping of memory critical structures. This project is directly relevant to Aims III.2 and IV.2 of the 2020 NINDS Benchmarks for Epilepsy. The mentored research in this proposal will be supplemented with structured training activities that will enable Dr. Kaestner to achieve the following career goals: 1) develop expertise in the clinical applications of cognitive neuroscience to patient-oriented outcomes, 2) develop proficiency in the study design and conduct of neurostimulation approaches, and 3) professional development in the conduct of high-impact translational research. To facilitate the successful completion of these training objectives and career goals, Dr. Kaestner has assembled an accomplished, multidisciplinary mentoring team with specific, project-relevant expertise which includes 4 practicing clinician-scientists. This includes a primary mentor (Carrie McDonald) who is an expert in post-surgical clinical outcomes in TLE, a co- mentor (Daniel Drane) who has helped pioneer innovations in surgical approaches to preserve cognitive function, and a co-mentor (Nigel Pedersen) who uses neurostimulation approaches as both a clinical neurologist and a researcher. My consultants include UCSD's epilepsy neurosurgeon (Sharona Ben-Haim), an electrical engineer (Shadi Dayeh), and a neurophysiologist (Eric Halgren) who are experts in applying innovative electrophysiological techniques in a surgical context. Additionally, I will receive statistical support from the local biostatistics unit at the Clinical and Translational Research Institute at the University of California San Diego (Xin Tu). The proposed research study, comprehensive training plan, strong mentorship team, and robust infrastructure will place Dr. Kaestner in a unique position to conduct translational neurostimulation research to improve cognitive outcomes and quality of life for patients.