Neurophysiology of Human Cortical Epilepsy

人类皮质癫痫的神经生理学

• 批准号: 8795271
• 负责人: SYDNEY S CASH
• 金额: $ 1.57万
• 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/8795271
• 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; Health; 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; 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.

描述（由申请人提供）：癫痫是一种毁灭性的疾病，影响着 300 万美国人。不幸的是，我们目前对如何定义产生癫痫发作的皮质区域以及这些癫痫发作如何开始和扩散等相互交织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内，癫痫样活动源自深层皮质层，然后通过皮质-皮质连接传播到浅层。因此，癫痫病灶和导致癫痫发作和传播的事件具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癫痫发作之间人类皮层各层的突触活动、内在电流和动作电位来测试这一假设。具体来说，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。我们假设癫痫病灶中的发作间期放电是由深层皮质层中的电流汇和神经元放电增加产生的，而传播的癫痫样放电将在中上皮质层中显示出最初的汇和激活。这些结果与回弹内在电流增强的深层皮质层中反复兴奋活动引起的癫痫样活动一致，并描绘了发作性皮质的微生理学特征。 2. 确定不同皮质层和神经元放电在癫痫发作过程中的作用。我们预计癫痫病灶内深层皮质层的动作电位放电先于明显的癫痫发作。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期间电流吸收的位置。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. 检查神经元群动态在癫痫发作扩散过程中的作用。最后，我们假设从焦点开始，癫痫发作通过投射到上皮质层的直接募集来传播。此外，对于某些区域，随着癫痫发作的进展，更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相关。与从直接招募到多焦点自主事件生成的这种演变一致，皮层区域之间的功能耦合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了人类癫痫发作神经生理学的重要方面。这些结果将使人们对人类癫痫病灶的构成有一个清晰的机制理解。这可以提高医学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。