Multi-Scale Cortical Dynamics in Human Epilepsy

描述（由申请人提供）：癫痫是最常见的神经系统疾病之一。然而，人们对癫痫发作如何开始、传播和终止知之甚少。迄今为止，监测人类单个神经元集合活动的挑战阻碍了进展。大多数研究仅限于颅内脑电图（iEEG）。动物模型已被用作替代方法，但这些动物模型如何捕获人类癫痫的潜在机制仍然是一个悬而未决的问题。最近的技术进步将允许本提议通过在发作间期、发作前期、发作期和发作后期同时记录患有局灶性癫痫的人类中单个神经元的大集合来应对这一挑战（Truccolo等人，2011年）。在切除术前监测期间，将记录难治性局灶性癫痫患者。除硬膜下iEEG外，还将使用皮质内96微电极阵列（96-MEA，4 mm X 4 mm）完成。单单位（SU）、多单位（MU）和高空间分辨率局部场电位（LFP）的大的新皮层集合的活动将 连续记录（24小时/天，持续约1 - 2周）。三个具体的AIM将解决人类局灶性癫痫的神经生理学中三个主要的基本和相互关联的问题。目的1将确定发作间期放电（IIDS）在癫痫发作易化/抑制中的作用，并将IIDS和发作期间神经元集合的激活模式联系起来。一些先前的研究提出，IIDS引发了一种条件，预示着发作事件的发生。相比之下，其他工作假设IID事件实际上抑制癫痫发作的发生。AIM 2将确定高频振荡（HFO）的微生理学及其在癫痫发作中的作用。最近的研究表明，局部场电位中的HFO（~80 - 250 Hz和> 250 Hz）是癫痫发作开始的标志，可能起因果作用。然而，这些HFO与人类癫痫中单个神经元活动之间的关系尚不清楚。重要的是，目前还不清楚这些HFO是否特异于致癫痫新皮层，或者即使在健康的新皮层中也可能具有相似的发病率。因此，我们将比较的发病率和时空特性的HFO在癫痫新皮层在人类与局灶性癫痫和非癫痫新皮层在人类和非人类灵长类动物在睡眠，休息和清醒状态。最后，AIM 3将在单个神经元水平上确定在发作前到发作过渡期间和发作期间神经同步性的时间演变。与主流观点相反，最近的动物模型表明，引发癫痫发作的是同步性不足，而不是同步性过度。

DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological disorders. Yet, very little is known about how seizures start, spread and terminate. Progress thus far has been hampered by the challenge of monitoring the activity of ensembles of single neurons in humans. Most studies have been limited to intracranial electroencephalograms (iEEGs). Animal models have been used as an alternative approach, but it remains an open question how well these animal models capture mechanisms underlying human epilepsy. Recent technological advances will allow the present proposal to meet this challenge, through the simultaneous recording of large ensembles of single neurons in humans with focal epilepsy, during interictal, preictal, ictal and postictal periods (Truccolo et al., 2011). Patients with pharmacologically intractable focal epilepsy will be recorded during pre-resection surgery monitoring. This will be accomplished using intracortical 96-microelectrode arrays (96-MEA, 4 mm X 4 mm), in addition to subdural iEEGs. The activity of large neocortical ensembles of single units (SUs), multiunits (MUs) and high-spatial resolution local field potentials (LFPs) will be recorded continuously (24hr/day over a period of ~1-2 weeks). Three specific AIMs will address three main fundamental and inter-related problems in the neurophysiology of human focal epilepsy. AIM 1 will determine the role of interictal discharges (IIDs) in seizure facilitation/inhibition and relate the activation patterns of neuronal ensembles during IIDs and ictal periods. Some previous studies propose that IIDs initiate a condition that preludes the onset of an ictal event. By contrast, other work hypothesizes that IID events actually inhibit the occurrence of seizures. AIM 2 will determine the microphysiology of high frequency oscillations (HFOs) and their role in seizure initiation. Recent studies propose that HFOs (~ 80-250 Hz and > 250 Hz) in local field potentials are a hallmark of seizure initiation and might play a causal role. Yet, the relationship between these HFOs and single neuron activity in human epilepsy is unknown. Importantly, it is also unclear whether these HFOs are specific to epileptogenic neocortex or might have similar incidence rates even in healthy neocortex. We will thus compare the incidence and spatiotemporal properties of HFOs in epileptic neocortex in humans with focal epilepsy and in nonepileptic neocortex in human and nonhuman primates during sleep, rest and wake states. Finally, AIM 3 will determine the temporal evolution of neural synchrony at the level of single neurons during the preictal-to-ictal transition and during the seizure. Contrary to mainstream thought, recent animal models suggest that hyposynchrony, not hypersynchrony, initiates seizures.