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: 10322163
• 负责人: Catherine J Chu
• 金额: $ 68.31万
• 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/10322163
• 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; 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 癫痫病是世界上最常见的严重脑部疾病，影响了全世界的近5000万人 尽管这些患者的医疗管理最大，但三分之一的患者仍无法控制癫痫发作。 癫痫发作通常来自局部大脑区域，神经外科干预是最有效的 治疗选择。 扭转不受控制的癫痫发作的残疾后果。 识别负责产生癫痫发作的核心组织（即癫痫发作）。 这句话将通过外科手术切除 电刺激（即神经调节）。 准确识别癫痫发作区； 活性（iii）缺乏对这些机制靶向神经刺激的理解 识别癫痫发作区的方法是连续记录患者皮质电气的方法。 但是，由于癫痫发作很少，这种方法很昂贵 此外，该方法的食用和非原理。 导致20-70％的Casses的神经性神经干预不成功。 需要癫痫发作之间表现出癫痫发作之间的癫痫发作。 （a）相互作用的放电或峰值，（b）高频振荡或两种信号。 经过广泛的研究，均未准确地划定癫痫发作区。 在空间上散射以鉴定癫痫发作区。 生理过程。 涟漪，“尖峰 - 纹波”放电，作为癫痫发作区的改进生物标志物。 发生在癫痫患者中，提高癫痫发作区的尖峰特异性， 病理涟漪的疾病生理。 神经生理学，神经外科，动物实验，建模和统计数据：（i）发展完全自动化 尖峰纹状体检测器并将其临床比较以预测手术结果与单独的尖峰和涟漪，（ii） 确定使用新型电压成像技术产生尖峰 - 透气排放的生物学机制 在动物模型中，与计算模型相结合； 破坏产生尖峰的机制。 在现代癫痫研究中解决解决方案的问题，对机制的理解 核心癫痫发射网络产生尖峰 - 圆形，以及一种原则性的神经刺激方法 破坏这些病理动力学。