Computational Modeling of Epileptic Activity Using a Hybrid Compartment Technique

描述(由申请人提供)：试图理解影响癫痫的变量的巨大参数空间的一个有用的工具是计算模型。计算机建模允许用户快速改变描述性变量，例如离子通道和突触属性、连接和突触消息的时间特征。为了描述连接的细胞网络的活动的各种特征，人们采用了各种细胞几何结构和神经元数量，所有这些都是为了重现各种实验结果。在目前的工作中，我们建议将基于单室Hodgkin-Huxley模型的活动与更复杂的多室细胞模型进行比较和校准，在这两种情况下，细胞都以建筑现实的方式排列和连接，以模拟新大脑皮层。此外，更简单的单室模型将被用作更精确的多室模型的周围边界区域，以努力扩展建模区域并仍然提供有意义的电生理关联。我们将具体检查模型中作为癫痫灶的区域所产生的爆发活动。这项比较工作将被用来追求以下目标：目的1)测量使用混合隔室组织的校准的结构真实的神经元网络中的发作期扩散速率，并对这种扩散作为层II/III层和层V层锥体细胞系统中连接性的函数进行敏感性分析。目的2)在该模型的背景下，通过分级的、层流特异性的药物阻断来测量发作的潜在活动阈值，以便与实验进行比较。目的3)将我们模拟研究的结果与一种新的硬膜下网格设计的记录进行比较，该设计结合了标准电极元件和用于局部场电位测量的微丝。这些研究的目的是以定量的方式提供癫痫发作的空间扩散和时间演变的信息，作为邻近或内在病理的函数。我们计划对相对较大的皮质区域(6.4 mm×6.4 mm)进行建模，同时检查非常高精度的较小(250&lt；m X 250&lt；m)表示的活动。 与公共健康相关：这笔赠款描述了一种计算机模型的开发，该模型准确地描绘了现实皮质结构中癫痫发作的演变。这将为了解癫痫发作动力学和新药或刺激疗法的应用提供另一种工具。对癫痫发作来源、扩散速度和参与病理行为的组织体积的估计将有助于理解癫痫的破坏性影响。

DESCRIPTION (provided by applicant): One useful tool in trying to understand the vast parameter space of variables influencing epilepsy is computational modeling. Computer modeling allows the user to quickly change descriptive variables such as ion channels and synaptic properties, connections, and the temporal characteristics of synaptic messaging. A variety of cell geometries and numbers of neurons have been implemented in an effort to describe various features of the activities of linked cellular networks all in an attempt to reproduce various experimental findings. We propose in this current effort to compare and calibrate the activity derived from a single compartment Hodgkin-Huxley based model with a more sophisticated multicompartmental cellular model where in both cases the cells are arranged and connected in an architecturally realistic fashion to mimic neocortex. Additionally, the simpler single compartment model will be used as the surrounding boundary region for the more precise multicompartment model in an effort to expand the modeled region and still provide meaningful electrophysiologic correlates. We will examine specifically bursting activity derived from a region of the model which acts as an epileptic focus. This comparative work will be used to pursue the following aims: Aim 1) To measure the rate of ictal spread within a calibrated architecturally realistic neuronal network using a hybrid compartment organization, and to perform a sensitivity analysis of this spread as a function of connectivities in the Layer II/III and Layer V pyramidal cell systems. Aim 2) To measure the underlying activity threshold for ictal onset through graded, laminar specific pharmacologic blockade in the context of this model for comparison with experiment. Aim 3) To compare the results obtained in our simulation studies with recordings obtained from a new subdural grid design incorporating standard electrode elements and microwires for local field potential measurements. The goal of these studies is to provide information in a quantitative manner on seizure spatial spread and temporal evolution as a function of neighboring or intrinsic pathology. We plan to model relatively large regions of cortex (6.4 mm X 6.4 mm), while examining the activity of a very high precision smaller (250 <m X 250 <m) representation. PUBLIC HEALTH RELEVANCE: This grant describes the development of a computer model that accurately portrays seizure evolution in a realistic cortical architecture. This would provide an additional tool in understanding seizure dynamics and the application of new drug or stimulation therapies. Estimates of seizure origin, rate of spread and the volume of tissue involved in pathologic behavior will aid in understanding the disruptive effects of epilepsy.