Mechanisms of disrupted memory encoding in epilepsy patients - Resubmission - 1

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This is a K23 award application for Dr. Anli Liu, a neurologist at NYU School of Medicine. Dr. Liu’s long- term career goals are to become a leading clinical investigator in describing the mechanisms of memory dysfunction in epilepsy patients and developing neuromodulation techniques for memory restoration. The K23 award will support her short-term career goals which are: (1) to conduct prospective patient-oriented research in epilepsy patients; (2) to gain expertise in signal processing; (3) to implement biostatistical and computational methods relevant to behavioral and neurophysiological data; and (4) to transition into an independent R01-funded research career. To achieve these goals, Dr. Liu has assembled an outstanding team of a primary mentor, Dr. György Buzsáki, an internationally recognized expert in neural oscillations, memory and advanced in vivo recording techniques, and two co-mentors: Dr. Orrin Devinsky, a leader in epilepsy and cognition, and Dr. Lucas Parra, a specialist in neural signal processing. She will have two scientific advisors: Dr. Lila Davachi, a leading scholar in mesial temporal lobe and memory, and Dr. Laura Balcer, an expert in clinical research design and biostatistics. Dr. Liu has strong institutional support from the Department of Neurology and the Division of Epilepsy. She will receive comprehensive training from NYU’s vibrant scientific and medical communities, including the NYU School of Medicine, Center for Neural Science, and Data Science Center. There is a fundamental gap in mechanistic understanding of why encoding fails in epilepsy patients. The overall objective of this proposal is to develop a model of encoding function, explaining the coordinated events in a mesial temporal-neocortical network necessary to form associative memories. Dr. Liu will test the central hypothesis that coupled rhythms between hippocampus, entorhinal cortex, and neocortex are required to encode information, and that pathological interictal events and electrical stimulation can disrupt these rhythms. In Aim 1, 40 patients undergoing intracranial electroencephalography (iEEG) for epilepsy surgery will participate in an associative memory task, followed by comparison of the neurophysiological differences between successful and failed learning trials. In Aim 2, 16 patients with chronically implanted hippocampal depth electrodes will perform the same task with recall tested after more prolonged time intervals. The proposal is innovative because Dr. Liu will: (1) establish a relationship between abnormal neural activity and normal encoding processes; (2) test this relationship with prospective interventions to perturb normal rhythms; (3) utilize a novel, clinically meaningful associative memory task; and (4) include patients with chronic ambulatory electrocorticography, which permits serial testing under controlled experimental conditions. The expected outcomes will include a detailed mechanistic model of encoding function, which explains how pathological events contribute to impaired learning in an epilepsy population, and a rational foundation for development of neurostimulation protocols and behavioral strategies to restore memory dysfunction.