Neurophysiology of Human Cortical 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引起癫痫发作的皮质区域以及癫痫发作如何开始和扩散等错综复杂的问题只有初步的了解。根据初步数据，我们假设在癫痫发作区，癫痫样活动起源于深部皮层，然后通过皮质-皮层连接传播到表层。因此，有一个可辨别的生理特征的发作焦点和事件导致发作的开始和传播。我们将通过使用独特的微电极阵列记录在癫痫发作期间和发作之间来自人类皮层各层的突触活动、内在电流和动作电位来验证这一假设。具体来说，我们的目标是：1。证明间隙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，致痫灶的间歇放电是由深部皮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皮层中上层显示初始汇和激活。这些结果与深部皮层反复兴奋性活动引起的癫痫样活动是一致的，这些兴奋性活动由反弹的内在电流增强，并描绘了ictogenic皮层的微生理特征。2. 确定不同皮质层和神经元放电在癫痫发作时的作用。我们预计，在癫痫发作灶内的皮层深层的动作电位放电先于明显的癫痫发作开始。此外，我们预计在癫痫发作时发生的放电过程中，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. 检查癫痫扩散过程中神经元群动力学的作用。最后，我们假设从病灶开始，癫痫发作通过投射到上皮层的直接招募传播。此外，对于某些区域，随着癫痫发作的进展，与该区域独立产生癫痫样放电的能力相关，更深的皮质层将增加参与。与从直接募集到多焦点自主事件产生的进化相一致，分析皮层区域之间的功能耦合将显示从紧密联系到松散联系的进展。这一描述可能进一步区分癫痫发作的焦点，并提出中断癫痫发作传播的新策略。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基本方面。结果将导致一个清楚的机制理解是什么构成了人类的癫痫焦点。这可以提高手术治疗难治性癫痫的有效性，以及癫痫发作预测、检测和终止的创新方法。

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.