Neurophysiology of Human Cortical Epilepsy

人类皮质癫痫的神经生理学

• 批准号: 7785990
• 负责人: SYDNEY S CASH
• 金额: $ 41.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785990
• 关键词: Action Potentials; Address; Affect; Agreement; American; Apical; Area; Behavior; Coupling; Data; Dendrites; Detection; Development; Effectiveness; Electroencephalography; Epilepsy; Etiology; Event; Evolution; Fostering; Generations; Human; Investigation; Lead; Light; Location; Measures; Methods; Microelectrodes; Neurons; Partial Epilepsies; Patients; Pattern; Phase; Physiological; Physiology; Recurrence; Refractory; Relative (related person); Resolution; Role; Seizures; Site; Staging; Stereotyping; Sum; Surgical Management; Synapses; System; Techniques; Testing; Therapeutic; Tissues; base; computerized data processing; directed evolution; hippocampal pyramidal neuron; innovation; neurophysiology; novel; novel strategies; public health relevance; research study; satisfaction; tool

DESCRIPTION (provided by applicant): Epilepsy is a devastating illness affecting 3 million Americans. Unfortunately, we currently have only a rudimentary understanding of the intertwined issues of how to define the cortical areas which generate seizures and how those seizures start and spread. Based on preliminary data we posit that within the seizure onset zone epileptiform activity arises from deep cortical layers and then spreads via cortico-cortical connections to superficial layers. There is, consequently, a discernable physiological signature of the seizure focus and events leading to seizure initiation and propagation. We will test this hypothesis by recording synaptic activity, intrinsic currents, and action potential firing from all layers of human cortex during and between seizures using unique microelectrode arrays. Specifically, we aim to: 1. Demonstrate that the intracolumnar dynamics of interictal discharges depend on the location of that column in the epileptogenic network. We hypothesize that interictal discharges in the epileptogenic focus are generated by current sinks and increased neuronal firing in deep cortical layers, whereas propagated epileptiform discharges will show initial sinks and activation in middle and upper cortical layers. Such results are consistent with epileptiform activity arising from recurrent excitatory activity in deep cortical layers augmented by rebound intrinsic currents and delineate a microphysiological signature of ictogenic cortex. 2. Determine the role of different cortical layers and neuronal firing during seizure initiation. We expect that action potential firing in deep cortical layers within the seizure focus precedes overt seizure initiation. Further, we expect that these same layers are the site of current sinks during discharges that occur at seizure initiation. These features further define the seizure focus, shed light on how seizures start, and may provide a novel method for seizure prediction. 3. Examine the role of neuronal group dynamics during seizure spread. Finally, we hypothesize that from the focus, seizures spread by direct recruitment via projections to upper cortical layers. Further, for certain regions there will be increased involvement of deeper cortical layers as the seizure progresses correlated with an ability of that region to independently generate epileptiform discharges. Consistent with this evolution from direct recruitment to multi-focal autonomous event generation, analysis of functional coupling between cortical regions will show progression from tight to loose association. This description may further differentiate the seizure focus and suggest new strategies for interrupting seizure propagation. These aims address essential aspects of the neurophysiology of human seizures at an unprecedented level of detail and breadth. The results will lead to a clear mechanistic understanding of what constitutes the seizure focus in humans. This can lead to increased effectiveness of surgical management of medically refractory epilepsy, as well as innovative approaches to seizure prediction, detection and termination. PUBLIC HEALTH RELEVANCE: Epilepsy remains a devastating and poorly understood illness. The experiments proposed in this project utilize novel techniques to record detailed neuronal activity directly from human cortex before and during seizures. We hope to use these techniques to better appreciate the differences between cortical tissue that will and will not generate seizures and what happens in those different areas as seizures start and spread. The information obtained will allow us to understand the neuronal dynamics underlying epilepsy at an unprecedented level of resolution. This will foster the development of new approaches to seizure prediction, detection and termination as well as more effective surgical management of medically refractory focal epilepsy.

描述（由申请人提供）：癫痫是一种影响300万美国人的毁灭性疾病。不幸的是，我们目前对如何定义产生癫痫发作的皮层区域以及这些癫痫发作如何开始和传播的相互交织的问题只有初步的了解。根据初步资料，我们认为在癫痫发作区，癫痫样活动起源于深层皮质，然后通过皮质-皮质连接扩散到浅层。因此，存在癫痫发作病灶和导致癫痫发作开始和传播的事件的可辨别的生理特征。我们将测试这一假设，记录突触活动，内在电流和动作电位发射从所有层的人类皮层癫痫发作期间和之间使用独特的微电极阵列。具体而言，我们的目标是：1。证明发作间期放电的柱内动力学取决于该柱在致痫网络中的位置。我们假设，在癫痫灶发作间期放电产生的电流汇和增加神经元放电在深层皮层，而传播癫痫样放电将显示初始汇和激活中，上层皮层。这样的结果是一致的癫痫样活动所产生的经常性兴奋性活动在深层皮层增强反弹的内在电流和描绘的微生理签名的发作性皮层。2.确定癫痫发作开始时不同皮质层和神经元放电的作用。我们预期癫痫发作病灶内皮层深层的动作电位放电早于明显的癫痫发作。此外，我们预计，这些相同的层是在癫痫发作开始时发生的放电过程中的电流汇的网站。这些特征进一步定义了癫痫发作的焦点，揭示了癫痫发作是如何开始的，并可能提供一种新的癫痫发作预测方法。3.检查神经元群动力学在癫痫发作扩散过程中的作用。最后，我们假设，从重点，癫痫发作蔓延的直接招聘通过投影到上皮层。此外，对于某些区域，随着与该区域独立产生癫痫样放电的能力相关的癫痫发作进展，将增加更深皮质层的参与。与这种从直接招募到多焦点自主事件生成的演变相一致，对皮层区域之间的功能耦合的分析将显示从紧密关联到松散关联的进展。这种描述可以进一步区分癫痫发作的重点，并提出新的策略，中断癫痫发作的传播。这些目标以前所未有的细节和广度解决人类癫痫发作的神经生理学的重要方面。结果将导致一个明确的机械理解是什么构成了癫痫发作的重点在人类。这可以提高难治性癫痫手术治疗的有效性，以及癫痫发作预测、检测和终止的创新方法。 公共卫生相关性： 癫痫仍然是一种破坏性和知之甚少的疾病。该项目中提出的实验利用新技术直接记录癫痫发作前和发作期间人类皮层的详细神经元活动。我们希望使用这些技术来更好地了解皮质组织之间的差异，将和不会产生癫痫发作和癫痫发作开始和蔓延时，在这些不同的领域发生了什么。所获得的信息将使我们能够以前所未有的分辨率水平了解癫痫的神经动力学。这将促进癫痫发作预测、检测和终止的新方法的发展，以及对医学难治性局灶性癫痫的更有效的外科治疗。