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种有用工具是计算建模。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、连接以及突触消息传递的时间特征。各种各样的细胞几何形状和神经元的数量已经被实现，以描述连接的细胞网络的活动的各种特征，所有这些都是为了重现各种实验结果。我们建议在目前的努力，比较和校准的活动来自一个单一的房室霍奇金-赫胥黎为基础的模型与一个更复杂的多房室细胞模型，在这两种情况下，细胞的排列和连接在一个建筑上逼真的方式来模仿新皮层。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，以扩展建模区域并仍提供有意义的电生理相关性。我们将专门研究来自模型中作为癫痫病灶的区域的爆发活动。这项比较工作将用于追求以下目标：目的1）使用混合室组织测量校准的结构上真实的神经元网络内的发作传播速率，并对该传播作为第II/III层和第V层锥体细胞系统中的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、层状的特异性药物阻断来测量发作发作的潜在活动阈值，以与实验进行比较。目的3）比较我们的模拟研究中获得的结果与记录从一个新的硬膜下网格设计，包括标准电极元件和微丝的局部场电位测量。这些研究的目的是以定量的方式提供关于癫痫发作空间扩散和时间演变的信息，作为邻近或内在病理学的函数。我们计划对相对较大的皮层区域（6.4 mm X 6.4 mm）进行建模，同时检查非常高精度的较小（250 <m X 250 <m）表示的活动。 公共卫生相关性：这项资助描述了一个计算机模型的发展，该模型可以准确地描绘癫痫发作在现实皮层结构中的演变。这将为理解癫痫发作动力学和新药物或刺激疗法的应用提供额外的工具。估计癫痫发作的起源，传播速度和病理行为所涉及的组织体积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.