Development of a personalized neurostimulation protocol for memory mapping in epilepsy

拟议的K 01应用程序将有力地支持Erik Kaestner博士的长期职业目标，即成为一名独立的临床科学家，使用神经刺激和认知神经科学方法来改善患者的认知功能。患有耐药性颞叶癫痫（TLE）的患者经常接受手术切除或消融对记忆至关重要的内侧颞叶结构（MTL）以缓解癫痫发作。因此，高达40%的手术干预在术后会导致记忆力显著下降。目前，还没有准确预测术后记忆衰退的方法。标准的术前工作流程提供了一个机会，在该工作流程中，患者被植入电极以进行手术规划，并且通常被刺激以进行癫痫发作标测。我提出了一种创新的方法，通过使用电刺激在记忆测试过程中诱导MTL的短暂功能性病变来预测术后记忆衰退。虽然建立了用于映射癫痫发作的刺激参数，但尚未建立用于测试记忆的瞬时中断的刺激参数。目标研究项目旨在：1）绘制大脑中电刺激的传播，以确保记忆映射的空间特异性; 2）开发用于映射记忆关键结构的刺激和记忆测试范式。该项目与2020年NINDS癫痫基准的目标III.2和IV.2直接相关。本提案中的指导研究将辅以结构化培训活动，使Kaestner博士能够实现以下职业目标：1）发展认知神经科学临床应用的专业知识，以实现以患者为导向的结果，2）发展研究设计和神经刺激方法实施的熟练程度，以及3）进行高影响力转化研究的专业发展。为了促进这些培训目标和职业目标的成功完成，Kaestner博士组建了一个具有特定项目相关专业知识的多学科指导团队，其中包括4名执业临床医生-科学家。这包括一位主要导师（Carrie McDonald），他是TLE术后临床结局方面的专家;一位共同导师（丹尼尔Drane），他帮助开创了保护认知功能的手术方法创新;以及一位共同导师（奈杰尔Pedersen），他作为临床神经学家和研究人员使用神经刺激方法。我的顾问包括UCSD的癫痫神经外科医生（Sharona Ben-Haim），电气工程师（Shadi Dayeh）和神经生理学家（Eric Halgren），他们是在手术环境中应用创新电生理技术的专家。此外，我将获得加州大学圣地亚哥分校（新图）临床和转化研究所当地生物统计学部门的统计支持。拟议的研究，全面的培训计划，强大的导师团队和强大的基础设施将使Kaestner博士处于一个独特的位置，进行转化神经刺激研究，以改善患者的认知结果和生活质量。

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.