Detailed Models of Network Bursts and Oscillations

描述（由申请人提供）：癫痫是一种复发性自发性癫痫发作的疾病，影响0.5-1%的人群，在许多情况下仍然是一种难治性疾病。此外，根据脑电信号预测早期癫痫发作的问题仍然很困难。>100 Hz的快速脑振荡（VFO）是致痫组织的定位标志;它们可以发生在发作间期（“发作之间”）电位期间，也可以发生-作为先兆-就在坦率的癫痫发作之前。[Some作者，如A。Bragin和J. Engel，Jr.，区分<~250 Hz的“波纹”和>~250 Hz的“快速波纹”，但目前， 让我们把它们放在一起。然而，VFO也发生在正常的大脑事件中，例如生理性的锐波涟漪（SPW-R）复合体，这些事件在空间记忆的巩固中显得很重要：因此，VFO可能对正常的认知过程至关重要。病理性和生理性VFO事件的相似外观（尽管不是快速波动）表明了共同的机制。因此，我们面临着一个困境：一方面，区分病理性VFO与正常VFO的机制是至关重要的，因为抑制病理性VFO可能会防止癫痫发作，而抑制正常VFO可能会干扰记忆;但另一方面，可能共享的机制意味着这种区别可能并不简单。VFO可以在化学突触被阻断的情况下实验性地发生。大量证据表明VFO起源于锥体神经元通过轴突的缝隙连接偶联。基于电耦合的模型解释了VFO的多种特征，包括频率范围、空间特性（癫痫新皮层）、细胞内电位和突触电流、pH敏感性和药理学。（基于化学突触和/或场效应的VFO的其他模型与实验相冲突，实验显示突触被阻断的VFO持续存在，并且细胞外电位的幅度非常小。VFO的其他方面尚不清楚：例如，生理尖波波纹期间有限的躯体放电;或病理组织一个接一个地产生“波纹”或“快速波纹”的能力，作为明显离散的、可分离的事件。也不知道在生理SPW-R期间，VFO如何叠加在总和突触电位上发生;而在癫痫发作之前，VFO可以自己发生。该提案旨在研究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;并使用啮齿动物实验以及原位和体外记录的人体组织的数据。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机制的精确理解，能够预防或抑制病理性快速脑振荡，同时对正常脑振荡的干扰最小。

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.