Targeting Pathologic Spike-Ripples to Isolate and Disrupt Epileptic Dynamics

针对病理性尖峰波纹来隔离和破坏癫痫动力学

• 批准号: 10526434
• 负责人: Catherine J Chu
• 金额: $ 68.42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526434
• 关键词: Action Potentials; Address; Affect; Animal Experiments; Animal Model; Automobile Driving; Biological; Biological Markers; Brain; Brain Diseases; Brain region; Caring; Clinical; Clinical Data; Computer Models; Computer Simulation; Consumption; Diffuse; Electric Stimulation; Epilepsy; Event; Excision; Failure; Generations; High Frequency Oscillation; Human; Image; Imaging Techniques; Individual; Institution; Intervention; Intractable Epilepsy; Machine Learning; Medical; Methods; Modeling; Modernization; Monitor; Neurons; Operative Surgical Procedures; Optics; Pathologic; Pathologic Processes; Patient Care; Patients; Pattern; Persons; Pharmaceutical Preparations; Physiological; Physiological Processes; Protocols documentation; Recurrence; Refractory; Reproducibility; Research; Resected; Seizures; Signal Transduction; Specificity; Testing; Time; Tissues; Treatment Efficacy; candidate identification; clinical practice; detector; effective therapy; epileptiform; excitatory neuron; experimental study; human data; imaging approach; improved; in silico; in vivo; inhibitory neuron; large datasets; models and simulation; mouse model; neurophysiology; neuroregulation; neurosurgery; novel; prevent; statistics; successful intervention; surgery outcome; voltage

Project Summary Epilepsy is the world’s most common, serious brain disorder, affecting nearly 50 million people worldwide. For one-third of patients, seizures remain poorly controlled despite maximal medical management. In these patients, seizures often arise from a localized brain region, and neurosurgical interventions are the most effective treatment option. When successful, surgical interventions provide cure from seizures, and also prevent or reverse the disabling consequences of uncontrolled seizures. Critical to successful intervention is accurate identification of the core tissue responsible for generating seizures (i.e., the epileptogenic zone). Traditionally, this tissue would be surgically resected, but modern approaches aim to focally disrupt this tissue with targeted electrical stimulation (i.e. neuromodulation). Improvements in epilepsy care are now limited by (i) the inability to accurately identify the epileptogenic zone; (ii) a limited understanding of the mechanisms underlying epileptiform activity; (iii) a lack of understanding of how to target these mechanisms with neurostimulation. The most common approach to identify the epileptogenic zone is through continuous recording of a patient’s cortical electrical activity to capture seizures. However, because seizures are infrequent, this approach is expensive, time consuming, and unpleasant for patients. Moreover, this approach often fails to identify the epileptogenic zone, resulting in unsuccessful neurosurgical intervention in 20-70% of cases. To address this, interictal biomarkers of the epileptogenic zone that manifest between seizures are required. Two such biomarkers have been proposed: (a) interictal discharges or spikes, and (b) high frequency oscillations or ripples. While both signals have been extensively studied, neither accurately delimits the epileptogenic zone. Spikes are specific for epilepsy, but too spatially diffuse to identify the epileptogenic zone. Ripples are spatially focal, but represent both pathologic and physiologic processes. We address these limitations by focusing on the simultaneous occurrence of a spike and ripple, “spike-ripple” discharges, as an improved biomarker for the epileptogenic zone. Spike-ripples commonly occur in patients with epilepsy, improve the spatial specificity of spikes for the epileptogenic zone, and disentangle physiologic from pathologic ripples. Our interdisciplinary team will apply expertise in epilepsy, neurophysiology, neurosurgery, animal experiments, modeling, and statistics to: (i) develop a fully automated spike-ripple detector and compare its clinical utility to predict surgical outcome to spikes and ripples alone, (ii) identify the biological mechanisms that generate spike-ripple discharges using novel voltage imaging techniques in animal models combined with computational models; and (iii) develop principled neurostimulation protocols to disrupt the mechanisms that generate spike-ripples. Completion of these Aims will represent significant progress towards resolving fundamental questions in modern epilepsy research, an understanding of mechanisms in the core epileptogenic network that generate spike-ripples, and a principled approach to neurostimulation to focally disrupt these pathologic dynamics.

项目摘要 癫痫是世界上最常见、最严重的大脑疾病，全世界有近5000万人受到影响。为 三分之一的患者，尽管进行了最大限度的医疗管理，但癫痫发作仍然控制不佳。在这些患者中， 癫痫发作通常发生在局部的大脑区域，神经外科治疗是最有效的。 治疗选项。如果成功，手术干预可以治愈癫痫发作，还可以预防或 扭转不受控制的癫痫发作的致残后果。准确是成功干预的关键 确定导致癫痫发作的核心组织(即致痫区域)。传统上， 这种组织可以通过手术切除，但现代方法的目标是通过靶向局部破坏这种组织。 电刺激(即神经调节)。癫痫治疗的改善现在受到以下因素的限制：(I)无法 准确识别致痫区域；(Ii)对癫痫形成的机制认识有限 (3)缺乏对如何通过神经刺激来针对这些机制的了解。最常见的 识别致痫区域的方法是通过连续记录患者的大脑皮层电 捕捉癫痫发作的活动。然而，由于癫痫发作很少见，这种方法代价高昂，时间 消耗体力，让患者感到不快。此外，这种方法往往无法识别致痫区域， 导致20%-70%的病例神经外科手术失败。为了解决这个问题，发作间期的生物标记物 发作之间出现的致痫区域是必需的。已经提出了两个这样的生物标记物： (A)发作间期放电或尖峰，以及(B)高频振荡或波纹。虽然这两个信号都是 经过广泛研究，两种方法都不能准确地划定致痫区域。棘波是癫痫的专有症状，但也 空间扩散以识别致痫区域。涟漪在空间上是局部的，但同时代表病理性和 生理过程。我们通过关注同时发生的尖峰和 涟漪，“尖峰-涟漪”放电，作为致痫区域的改进生物标志物。常见的尖峰波动 在癫痫患者中发生，改善致痫区域棘波的空间特异性，以及 从生理和病理的涟漪中解脱出来。我们的跨学科团队将运用癫痫方面的专业知识， 神经生理学、神经外科、动物实验、建模和统计：(I)开发全自动 棘波探测仪和比较其在预测手术结果方面的临床应用，(Ii) 用新的电压成像技术识别产生尖峰纹波放电的生物机制 动物模型与计算模型相结合；以及(Iii)开发原则性神经刺激方案以 破坏产生尖峰波动的机制。完成这些目标将是重大进展。 为了解决现代癫痫研究中的基本问题，对癫痫发病机制的理解 产生棘波的核心致痫网络，以及局部神经刺激的原则性方法 打乱了这些病理动态。