Multi-Scale Cortical Dynamics in Human Epilepsy

人类癫痫的多尺度皮质动力学

• 批准号: 8342922
• 负责人: WILSON TRUCCOLO
• 金额: $ 33.57万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8342922
• 关键词: Address; Animal Model; Area; Behavior; Clinical Trials; Data; Diagnosis; Disease; Early Diagnosis; Early treatment; Electroencephalogram; Enrollment; Epilepsy; Epileptogenesis; Event; Evolution; Excision; Focal Seizure; Foundations; Functional disorder; Goals; High Frequency Oscillation; Human; Incidence; Interneurons; Kindling (Neurology); Lead; Mainstreaming; Methods; Microelectrodes; Modeling; Monitor; Multivariate Analysis; Neocortex; Neurons; Operative Surgical Procedures; Partial Epilepsies; Participant; Patients; Pattern; Physiological; Play; Prevention; Process; Property; Quality of life; Research; Resolution; Rest; Role; Running; Seizures; Sleep; System; Time; Work; base; brain machine interface; meetings; neocortical; nervous system disorder; neuronal patterning; neurophysiology; neuroregulation; nonhuman primate; novel strategies; relating to nervous system; restoration; spatiotemporal; therapy development

DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders. Yet, very little is known about how seizures start, spread and terminate. Progress thus far has been hampered by the challenge of monitoring the activity of ensembles of single neurons in humans. Most studies have been limited to intracranial electroencephalograms (iEEGs). Animal models have been used as an alternative approach, but it remains an open question how well these animal models capture mechanisms underlying human epilepsy. Recent technological advances will allow the present proposal to meet this challenge, through the simultaneous recording of large ensembles of single neurons in humans with focal epilepsy, during interictal, preictal, ictal and postictal periods (Truccolo et al., 2011). Patients with pharmacologically intractable focal epilepsy will be recorded during pre-resection surgery monitoring. This will be accomplished using intracortical 96-microelectrode arrays (96-MEA, 4 mm X 4 mm), in addition to subdural iEEGs. The activity of large neocortical ensembles of single units (SUs), multiunits (MUs) and high-spatial resolution local field potentials (LFPs) will be recorded continuously (24hr/day over a period of ~1-2 weeks). Three specific AIMs will address three main fundamental and inter-related problems in the neurophysiology of human focal epilepsy. AIM 1 will determine the role of interictal discharges (IIDs) in seizure facilitation/inhibition and relate the activation patterns of neuronal ensembles during IIDs and ictal periods. Some previous studies propose that IIDs initiate a condition that preludes the onset of an ictal event. By contrast, other work hypothesizes that IID events actually inhibit the occurrence of seizures. AIM 2 will determine the microphysiology of high frequency oscillations (HFOs) and their role in seizure initiation. Recent studies propose that HFOs (~ 80-250 Hz and > 250 Hz) in local field potentials are a hallmark of seizure initiation and might play a causal role. Yet, the relationship between these HFOs and single neuron activity in human epilepsy is unknown. Importantly, it is also unclear whether these HFOs are specific to epileptogenic neocortex or might have similar incidence rates even in healthy neocortex. We will thus compare the incidence and spatiotemporal properties of HFOs in epileptic neocortex in humans with focal epilepsy and in nonepileptic neocortex in human and nonhuman primates during sleep, rest and wake states. Finally, AIM 3 will determine the temporal evolution of neural synchrony at the level of single neurons during the preictal-to-ictal transition and during the seizure. Contrary to mainstream thought, recent animal models suggest that hyposynchrony, not hypersynchrony, initiates seizures. PUBLIC HEALTH RELEVANCE: The long term aim of this research is the restoration of quality of life and autonomy in people with intractable epileps. Advances in understanding the 3 fundamental problems outlined above could have an important impact on diagnosis and early treatment, the development of new therapies, the localization of epileptogenic areas for surgical procedures, and seizure prediction and early detection for closed-loop seizure control systems. PUBLIC HEALTH RELEVANCE: Epilepsy affects about 50 million people worldwide, 3 million in the US alone. Current pharmacological and surgical approaches to treatment are inadequate and risky for a substantial number of patients. This project will use novel recording technologies that will provide an unprecedented level of detail into the microphysiology and mechanisms underlying intractable epilepsy. The long-term goals of this research are to provide a basis for new therapies and approaches to seizure prevention, in the hopes of restoring the quality of life and autonomy of people suffering from intractable epilepsy.

描述（由申请人提供）：癫痫是最常见的神经系统疾病之一。然而，人们对癫痫发作如何开始、蔓延和终止知之甚少。迄今为止，监测人类单个神经元群活动的挑战阻碍了进展。大多数研究仅限于颅内脑电图（iEEG）。动物模型已被用作替代方法，但这些动物模型如何很好地捕捉人类癫痫的潜在机制仍然是一个悬而未决的问题。最近的技术进步将使本提案能够通过同时记录患有局灶性癫痫的人类在发作间期、发作前、发作和发作后的单个神经元的大型集合来应对这一挑战（Truccolo 等人，2011）。患有药物难治性局灶性癫痫的患者将在切除手术前监测期间进行记录。除了硬膜下 iEEG 之外，这还可以使用皮质内 96 微电极阵列（96-MEA，4 mm X 4 mm）来完成。由单个单元（SU）、多单元（MU）和高空间分辨率局部场电位（LFP）组成的大型新皮质群的活动将 连续记录（约 1-2 周内每天 24 小时）。三个特定的目标将解决人类局灶性癫痫神经生理学中的三个主要基本和相互关联的问题。 AIM 1 将确定发作间期放电 (IID) 在癫痫发作促进/抑制中的作用，并将 IID 和发作期间神经元群的激活模式联系起来。之前的一些研究提出，IID 会引发一种预兆发作事件发生的状况。相比之下，其他研究假设 IID 事件实际上抑制了癫痫发作的发生。 AIM 2 将确定高频振荡 (HFO) 的微生理学及其在癫痫发作中的作用。最近的研究提出，局部场电位中的 HFO（~ 80-250 Hz 和 > 250 Hz）是癫痫发作的标志，并且可能发挥因果作用。然而，这些 HFO 与人类癫痫中单个神经元活动之间的关系尚不清楚。重要的是，还不清楚这些 HFO 是否特定于致癫痫新皮质，或者即使在健康新皮质中也可能具有相似的发病率。因此，我们将比较患有局灶性癫痫的人类癫痫新皮质以及人类和非人类灵长类动物的非癫痫新皮质在睡眠、休息和清醒状态下 HFO 的发生率和时空特性。最后，AIM 3 将确定在发作前到发作过渡期间和癫痫发作期间单个神经元水平上神经同步的时间演化。与主流观点相反，最近的动物模型表明，癫痫发作是低同步性而非超同步性引起的。公共健康相关性：这项研究的长期目标是恢复顽固性癫痫患者的生活质量和自主能力。对上述 3 个基本问题的理解进展可能会对诊断和早期治疗、新疗法的开发、外科手术致癫痫区域的定​​位以及闭环癫痫控制系统的癫痫发作预测和早期检测产生重要影响。 公共卫生相关性：癫痫症影响着全世界约 5000 万人，仅美国就有 300 万人。目前的药物和手术治疗方法对于大量患者来说是不够的且存在风险。该项目将使用新颖的记录技术，为难治性癫痫的微生理学和机制提供前所未有的详细信息。这项研究的长期目标是为预防癫痫发作的新疗法和方法提供基础，以期恢复顽固性癫痫患者的生活质量和自主能力。