Development of a personalized neurostimulation protocol for memory mapping in epilepsy

拟议中的K01应用程序将有力地支持埃里克·凯斯特纳博士的长期职业目标，即成为一名独立的专注于临床的科学家，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。耐药的颞叶癫痫(TLE)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)以减轻癫痫发作。因此，高达40%的外科干预措施在术后以显著的记忆衰退告终。目前，还没有一种程序可以准确预测手术后记忆力的下降。手术前的标准工作流程提供了一个机会，在这种工作流程中，患者被植入电极以进行手术规划，并经常被刺激进行癫痫定位。我提出了一种创新的方法，通过在记忆测试期间使用电刺激在MTL中诱导暂时性的功能性损害来预测手术后记忆下降。虽然已经建立了用于定位癫痫发作的刺激参数，但尚未建立用于测试记忆的瞬时干扰的刺激参数。这项有针对性的研究项目旨在：1)绘制电刺激在大脑中的传播图，以确保记忆映射的空间特异性；2)开发用于绘制记忆关键结构图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。这项建议中的指导研究将辅之以结构化的培训活动，使凯斯特纳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方面的专业知识，以患者为导向；2)精通神经刺激方法的研究设计和实施；3)在进行高影响力的转化性研究方面进行专业发展。为了促进这些培训目标和职业目标的顺利完成，凯斯特纳博士组建了一支经验丰富的多学科指导团队，该团队拥有与项目相关的特定专业知识，其中包括4名执业临床医生兼科学家。这其中包括一位主要导师(Carrie McDonald饰)，她是TLE手术后临床结果方面的专家；共同导师(Daniel Drane饰)，他帮助开创了外科方法的创新，以保护认知功能；以及一位共同导师(Nigel Pedersen)，他既是临床神经科医生，也是研究人员，使用神经刺激方法。我的顾问包括加州大学圣迭戈分校的癫痫神经外科医生(Sharona Ben-Him)、电气工程师(Shadi Dayeh)和神经生理学家(Eric Halgren)，他们都是在外科环境中应用创新电生理技术的专家。此外，我还将得到加州大学圣地亚哥分校(新图)临床与翻译研究所当地生物统计部门的统计支持。拟议的研究研究、全面的培训计划、强大的指导团队和强大的基础设施将使凯斯特纳博士处于独特的地位，可以进行转化性神经刺激研究，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.