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: 10096727
• 负责人: Catherine J Chu
• 金额: $ 69.83万
• 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/10096727
• 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; Pharmaceutical Preparations; Physiological; Physiological Processes; Protocols documentation; Recurrence; Refractory; Research; Resected; Seizures; Signal Transduction; Specificity; Testing; Time; Tissues; Treatment Efficacy; clinical practice; detector; effective therapy; 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、最严重的脑部疾病，影响着全世界近5000万人。为 三分之一的患者，癫痫发作仍然控制不佳，尽管最大的医疗管理。在这些患者中， 癫痫发作通常发生在局部脑区，神经外科干预最有效 治疗选择当成功时，外科手术干预提供癫痫发作的治愈，并且还预防或治疗癫痫发作。 扭转不受控制的癫痫发作的致残后果。成功干预的关键是准确 识别负责产生癫痫发作的核心组织（即，致痫区）。传统上， 该组织将被手术切除，但现代方法旨在用靶向的药物局部破坏该组织， 电刺激（即神经调节）。癫痫治疗的改善现在受到以下限制：（i）无法 准确地识别致痫区;（ii）对癫痫形成机制的了解有限 活动;（iii）缺乏对如何用神经刺激靶向这些机制的理解。最常见的 识别致痫区的方法是通过连续记录患者的皮层电 捕捉癫痫发作。然而，由于癫痫发作不频繁，这种方法成本高，时间长， 对病人来说是痛苦的，不愉快的。此外，这种方法往往无法识别致癫痫区， 导致在20-70%的病例中神经外科干预不成功。为了解决这个问题， 癫痫发作之间出现的致痫区是必需的。已经提出了两种这样的生物标志物： (a)发作间期放电或尖峰，和（B）高频振荡或波纹。虽然这两个信号都是 广泛的研究，既不准确界定癫痫区。尖峰是专门针对癫痫症的，但也 空间扩散以识别致痫区。波纹在空间上是局灶性的，但代表了病理性的和 生理过程我们通过关注尖峰的同时发生来解决这些限制， 涟漪，“尖峰-波纹”放电，作为致痫区的改进的生物标志物。棘波通常 发生在癫痫患者中，改善癫痫区棘波的空间特异性，以及 把生理的涟漪和病理的涟漪分开。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，神经外科学，动物实验，建模和统计学，以：（i）开发一个完全自动化的 棘波-波纹检测器，并比较其临床效用，以预测手术结果，以棘波和波纹单独，（ii） 使用新的电压成像技术识别产生尖峰纹波放电的生物机制 在与计算模型相结合的动物模型中;以及（iii）开发原则性神经刺激协议， 破坏产生尖峰涟漪的机制。这些目标的完成将是重大进展 为了解决现代癫痫研究中的基本问题， 核心癫痫网络，产生尖峰涟漪，和原则性的方法，神经刺激，以集中 破坏这些病理动力学。