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

这是纽约大学医学院神经学家刘安利博士的K23奖申请。刘博士的长期职业目标是成为描述癫痫患者记忆功能障碍机制和开发记忆恢复神经调节技术的领先临床研究者。K23奖将支持她的短期职业目标，即：(1)在癫痫患者中开展前瞻性的以患者为导向的研究；(2)获取信号处理方面的专业知识；(3)运用与行为和神经生理学数据相关的生物统计学和计算方法；(4)过渡到独立的r01资助的研究生涯。为了实现这些目标，刘博士组建了一个优秀的团队，其中包括一位主要导师György Buzsáki博士，一位国际公认的神经振荡、记忆和先进的体内记录技术专家，以及两位共同导师：Orrin Devinsky博士，癫痫和认知领域的领导者，以及Lucas Parra博士，神经信号处理专家。她将有两位科学顾问：莱拉·达瓦奇博士（Lila Davachi）和劳拉·巴尔塞博士（Laura Balcer）。莱拉博士是中颞叶和记忆领域的顶尖学者，劳拉·巴尔塞博士是临床研究设计和生物统计学方面的专家。刘医生得到了神经内科和癫痫科的大力支持。她将接受纽约大学充满活力的科学和医学界的全面培训，包括纽约大学医学院、神经科学中心和数据科学中心。在对癫痫患者编码失败的机制理解上存在根本性的差距。本建议的总体目标是建立一个编码功能模型，解释形成联想记忆所必需的中颞-新皮层网络中的协调事件。刘博士将验证一个中心假设，即信息编码需要海马、内鼻皮层和新皮层之间的耦合节律，而病理性间期事件和电刺激会破坏这些节律。在Aim 1中，40名接受癫痫手术的颅内脑电图（iEEG）患者将参与一项联想记忆任务，随后比较成功和失败的学习试验之间的神经生理差异。在目的2中，16名长期植入海马深度电极的患者将在更长的时间间隔后执行相同的任务，并进行回忆测试。这个提议是创新的，因为刘博士将：(1)建立异常神经活动与正常编码过程之间的关系；(2)通过干扰正常节律的前瞻性干预来检验这种关系；(3)利用一种新颖的、有临床意义的联想记忆任务；(4)包括慢性动态皮质电图患者，允许在可控的实验条件下进行系列测试。预期结果将包括编码功能的详细机制模型，解释病理事件如何导致癫痫人群的学习障碍，并为开发神经刺激方案和恢复记忆功能障碍的行为策略提供合理基础。

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.