Multi-Scale Cortical Dynamics in Human Epilepsy

描述(申请人提供)：癫痫是最常见的神经系统疾病之一。然而，关于癫痫发作是如何开始、扩散和终止的，人们知之甚少。到目前为止，由于监测人类单个神经元群的活动的挑战，进展受到了阻碍。大多数研究都局限于颅内脑电(IEEGs)。动物模型已被用作替代方法，但这些动物模型能否很好地捕捉人类癫痫的潜在机制仍是一个悬而未决的问题。最近的技术进步将使本提案能够通过同时记录患有局灶性癫痫的人类在发作间期、发作前、发作和发作后的大型单个神经元集合来应对这一挑战(Truccolo等人，2011年)。药物难治性局灶性癫痫患者将在术前监测中记录。这将使用皮质内96微电极阵列(96-MEA，4 mm×4 mm)，以及硬膜下IEEG。大的大脑皮层单个单位(SU)、多单位(MU)和高空间分辨率局域场势(LFP)的活动将 连续记录(1-2周内每天24小时)。三个具体目标将解决人类局灶性癫痫神经生理学中的三个主要基本和相互关联的问题。目的1确定发作间期放电(IIDs)在癫痫易化/抑制中的作用，并将IIDs和发作期神经元的激活模式联系起来。以前的一些研究认为，IID会引发一种情况，是发作事件发生的前奏。相比之下，其他研究假设IID事件实际上抑制了癫痫的发生。目的2将确定高频振荡(HFO)的微生理学及其在癫痫发作启动中的作用。最近的研究表明，局部场电位中的HFO(~80-250赫兹和&GT；250赫兹)是癫痫发作启动的标志，可能起到因果作用。然而，在人类癫痫中，这些HFO与单个神经元活动的关系尚不清楚。重要的是，目前还不清楚这些HFO是否仅限于致痫的新皮质，或者即使在健康的新皮质中也可能有类似的发生率。因此，我们将比较在睡眠、休息和清醒状态下，局灶性癫痫患者的癫痫新皮质以及人类和非人类灵长类动物的非癫痫新皮质中HFO的发生率和时空特性。最后，AIM3将在单个神经元水平上确定发作前到发作过渡期间和癫痫发作期间神经同步性的时间演变。与主流思想相反，最近的动物模型表明，引发癫痫发作的是低同步性，而不是超同步性。

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.