Neurophysiology of Human Cortical Epilepsy

描述(申请人提供)：癫痫是一种毁灭性的疾病，影响着300万美国人。不幸的是，我们目前对如何界定产生癫痫发作的皮质区域以及这些癫痫发作如何开始和蔓延的相互交织的问题只有一个初步的了解。根据初步数据，我们假设癫痫样活动在癫痫发作的起始区内来自深层皮质，然后通过皮质-皮质连接扩散到浅层。因此，癫痫发作的焦点和导致癫痫发作开始和传播的事件有可辨别的生理特征。我们将通过使用独特的微电极阵列记录癫痫发作期间和发作之间人类大脑皮层各层的突触活动、内在电流和动作电位激发来验证这一假设。具体地说，我们的目标是：1.证明发作间期放电的柱内动力学依赖于该柱在致痫网络中的位置。我们假设致痫灶的发作间期放电是由深皮质层的电流汇和神经元放电增加产生的，而传播性癫痫样放电将在中层和上层表现为初始的汇和激活。这些结果与皮层深层反复兴奋活动引起的癫痫样活动是一致的，并被反弹的内源性电流增强，并描绘了致畸皮质的微生理特征。2.确定不同皮层和神经元放电在癫痫发作启动过程中的作用。我们预计在癫痫发作开始之前，癫痫灶内深层皮层的动作电位放电。此外，我们预计，在癫痫发作发生时的放电过程中，这些相同的层是电流汇的位置。这些特征进一步定义了癫痫发作的焦点，阐明了癫痫发作是如何开始的，并可能为癫痫发作预测提供一种新的方法。3.探讨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，从焦点，癫痫发作通过投射直接招募传播到上层皮质。此外，对于某些区域，随着癫痫发作的进展，较深皮质层的参与将增加，这与该区域独立产生癫痫样放电的能力有关。与这种从直接招募到多焦点自主事件生成的演变相一致，对大脑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。这种描述可能会进一步区分癫痫发作的焦点，并提出新的策略来阻断癫痫发作的传播。这些目标以前所未有的细节和广度处理人类癫痫发作的神经生理学的基本方面。这一结果将导致对人类癫痫发作焦点的明确机制理解。这可以提高难治性癫痫的外科治疗的有效性，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： 癫痫仍然是一种毁灭性的疾病，人们对此知之甚少。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大脑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将会和不会导致癫痫发作的皮质组织之间的差异，以及当癫痫发作开始和蔓延时，这些不同区域发生了什么。所获得的信息将使我们能够以前所未有的分辨率了解癫痫背后的神经元动力学。这将有助于开发新的癫痫发作预测、检测和终止方法，以及对难治性局灶性癫痫进行更有效的外科治疗。

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.