Detailed Models of Network Bursts and Oscillations

描述(由申请人提供)：癫痫是一种反复发作的自发性癫痫，影响0.5%-1%的人口，在许多情况下仍然是一种顽固性疾病。此外，根据大脑电信号预测早期癫痫发作的问题仍然很困难。100赫兹的非常快的脑震荡(VFO)是致痫组织的一个位置标记；它们可以发生在发作间歇期(“发作之间”)的电位中，也可以发生在坦率的癫痫发作之前。[有些作者，如A.Bragin和J.Engel，Jr.，将~250赫兹的“涟漪”与~250赫兹的“快涟漪”区分开来，但目前， 让我们把它们混为一谈。]然而，VFO也发生在正常的大脑事件中，如生理尖波波纹(SPW-R)复合波，这些事件似乎对巩固空间记忆很重要：因此，VFO可能对正常的认知过程至关重要。病理和生理VFO事件的相似外观(尽管不是快速涟漪)表明有共同的机制。因此，我们面临着一个两难境地：一方面，区分病理性VFO和正常VFO的机制是至关重要的，因为抑制病理性VFO可能会阻止癫痫发作，而抑制正常VFO可能会干扰记忆；但另一方面，可能的共同机制意味着这种区分可能不是直接的。在化学突触被阻断的条件下，VFO可以在实验中发生。大量证据表明，VFO起源于锥体神经元通过轴突的缝隙连接耦合。基于电耦合的模型考虑了VFO的多种特征，包括频率范围、空间特性(在癫痫新皮质中)、细胞内电位和突触电流、pH敏感性和药理学。(其他基于化学突触和/或场效应的VFO模型与实验相抵触，这些实验表明，在突触被阻断的情况下，VFO持续存在，而且细胞外电位的幅度非常小。)VFO的其他方面尚不清楚：例如，生理尖锐波纹期间有限的躯体放电；或病理组织作为明显离散的、可分离的事件一个接一个地产生“涟漪”或“快速涟漪”的能力。也不知道在生理性SPW-R期间，VFO是如何叠加在总和突触电位上发生的；而在癫痫发作之前，VFO可以自己发生。这项建议寻求研究VFO的这些和其他方面，使用高度详细和高度简化的网络模型；并使用来自啮齿动物实验的数据以及在原位和体外记录的人体组织。计算模型将是预测性的，并激励进一步的实验和最终的临床研究。一个长期的目标是利用对VFO机制的精细理解，能够在对正常脑震荡的最小扰动的情况下预防或抑制病理性的快速脑震荡。

DESCRIPTION (provided by applicant): Epilepsy, a condition of recurrent spontaneous seizures, affects 0.5-1% of the population, and remains an intractable condition in many cases. Additionally, the problem of anticipating incipient seizures, based on brain electrical signals, remains difficult. Very fast brain oscillations (VFOs) at >100 Hz are a locational marker of epileptogenic tissue; they can occur during interictal ("between-seizure") potentials, and also can occur - as a harbinger - just prior to frank seizures. [Some authors, such as A. Bragin and J. Engel, Jr., distinguish "ripples" at <~250 Hz from "fast ripples" at >~250 Hz, but for the present, let us lump them together.] VFO, however, also occurs during normal brain events, such as physiological sharp-wave ripple (SPW-R) complexes, events that appear important in the consolidation of spatial memories: thus, VFO may be critical for normal cognitive processes. The similar appearance of pathological and physiological VFO events (although not fast ripples) suggests shared mechanisms. We are therefore faced with a dilemma: on the one hand, it is essential to distinguish the mechanisms underlying pathological vs. normal VFO, because suppressing pathological VFO might prevent seizures, while suppressing normal VFO might interfere with memory; but on the other hand, the likely sharing of mechanisms implies that this distinction may not be straightforward. VFO can occur experimentally in conditions when chemical synapses are blocked. A large body of evidence suggests that VFO originates from gap junctional coupling of pyramidal neurons, via axons. Models based on electrical coupling account for multiple features of VFO, including the frequency range, spatial properties (in epileptic neocortex), intracellular potentials and synaptic currents, pH sensitivity, and pharmacology. (Other models of VFO, based on chemical synapses and/or field effects have run afoul of experiments showing persistence of VFO with synapses blocked, and of the very small amplitudes of the extracellular potentials.) Other aspects of VFO are not understood: for example, the limited somatic firing during physiological sharp- wave ripples; or the ability of pathological tissue to generate either "ripples" or "fast ripples", one after the other, as apparently discrete, separable events. Nor is it known how, during a physiological SPW-R, VFO occurs superimposed upon summated synaptic potentials; while, prior to a seizure, VFO can occur by itself. This proposal seeks to investigate these and other aspects of VFO, using both highly detailed and also highly simplified network models; and using data from rodent experiments as well as human tissue recorded in situ and in vitro. The computational models will be predictive and motivate further experimental and eventually clinical investigations. A long-term goal is to use refined understanding of VFO mechanisms to be able to prevent or suppress pathological fast brain oscillations, with minimal perturbation of the normal ones.