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

这是纽约大学医学院神经病学家刘安丽博士的K23奖项申请。刘博士的长期职业目标是成为描述癫痫患者记忆障碍机制的领先临床研究员，并开发用于记忆恢复的神经调节技术。K23奖项将支持她的短期职业目标：(1)在癫痫患者中进行预期的以患者为导向的研究；(2)获得信号处理方面的专业知识；(3)实施与行为和神经生理数据相关的生物统计学和计算方法；以及(4)过渡到由R01资助的独立研究生涯。为了实现这些目标，刘博士组建了一支杰出的团队，其中包括一位主要导师、国际公认的神经振荡、记忆和先进活体记录技术专家格奥尔基·布兹萨基博士，以及两位共同导师：癫痫和认知领域的领导者奥林·德文斯基博士，以及神经信号处理专家卢卡斯·帕拉博士。她将有两名科学顾问：莱拉·达瓦奇博士，内侧颞叶和记忆方面的领先学者，以及劳拉·巴尔塞尔博士，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机构支持。她将接受纽约大学充满活力的科学和医疗社区的全面培训，包括纽约大学医学院、神经科学中心和数据科学中心。对于癫痫患者编码失败的原因，在机制理解上存在着根本的差距。这一建议的总体目标是开发一个编码功能的模型，解释形成联想记忆所必需的中间时间-新皮质网络中的协调事件。刘博士将验证这一中心假设，即海马体、内嗅觉皮质和新皮质之间需要耦合的节律来编码信息，病理性发作间歇事件和电刺激可以扰乱这些节律。在目标1中，40名接受癫痫手术的患者将参与一项联想记忆任务，然后比较成功和失败的学习试验的神经生理学差异。在目标2中，16名长期植入海马区深度电极的患者将执行相同的任务，并在更长的时间间隔后进行回忆测试。这项建议是创新的，因为刘博士将：(1)建立异常神经活动和正常编码过程之间的关系；(2)通过前瞻性干预来测试这种关系，以扰乱正常的节律；(3)利用一项新的、具有临床意义的联想记忆任务；以及(4)纳入慢性动态皮层脑电图仪的患者，这可以在受控的实验条件下进行系列测试。预期的结果将包括编码功能的详细机制模型，该模型解释了病理事件如何导致癫痫人群中学习障碍，以及为开发神经刺激方案和行为策略以恢复记忆功能障碍的合理基础。

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.