Multi-Scale Cortical Dynamics in Human Epilepsy

摘要 癫痫是最常见的神经系统疾病之一，全世界约有6500万人受到影响。其中， 25%-35%的人对药物治疗没有反应，尽管有新的抗癫痫药物的开发 在过去的几十年里。阻碍开发更好的癫痫治疗方法的主要障碍之一 癫痫发作，如用于预防和减轻癫痫的闭环神经调节，是缺乏的 了解癫痫发作如何在皮质和皮质下区域引发、扩散和终止。进展 到目前为止，由于在多个尺度上测量人类神经活动的挑战， 单个神经元和大规模大脑网络的集合。此外，以前的大多数研究都集中在 癫痫发作起始区引发癫痫的生物物理机制。局灶性癫痫发作的一个被忽视的方面 局部和大规模病理性神经元网络的形成/维持是时变性的 大脑动力学对癫痫发作的启动和扩散的敏感性(泛化)。我们假设这些 病理性多尺度网络通过癫痫样时空的反复激活而维持 不仅在癫痫发作期间，而且在发作间期和发作前也是如此。我们将解决这些问题 在药物难治性局灶性癫痫患者中，通过 皮质内96微电极阵列(96-MEA，4 mm×4 mm)和经颅内的大规模脑网络 脑电(Truccolo等人，2011、2014；Wagner等人，2015)。在这些多个水平上的神经活动将是 连续记录24小时/天，持续时间约1-2周。此外，我们将确定关联 反复出现的病理模式和大脑对兴奋和刺激传播的敏感性变化之间的关系 用最新开发的实时闭环式颅内神经动力学主动探测癫痫发作 电刺激平台(Sarma等人，2016)。三个具体目标将：(1)检验假设 多尺度发作模式不仅在癫痫发作期间反复出现，而且在发作间歇期也重复出现，成为 静息状态网络的曲目；(2)检验癫痫发作启动的前体生物标志物包括 多尺度发作网络模式的再激活；(3)检验癫痫发作模式再激活的假设 发作间歇期伴随着大脑对局部和大规模扩散的敏感性增加 兴奋性：用闭合环电刺激探测神经动力学。

ABSTRACT Epilepsy is one of the most common neurological disorders affecting ~65 million people worldwide. Of those, 25-35% are not responsive to pharmacological treatment, despite the development of new antiepileptic drugs in the previous decades. One of the main barriers hindering the development of better therapies for epileptic seizures, such as closed-loop neuromodulation for seizure prevention and abatement, is the lack of understanding of how seizures initiate, spread and terminate over cortical and subcortical regions. Progress thus far has been hampered by the challenge of measuring in humans neural activity at the multiple scales of ensembles of single neurons and large-scale brain networks. In addition, most previous studies have focused on biophysical mechanisms for seizure initiation at seizure onset zones. An overlooked aspect of focal seizures is the formation/maintenance of local and large-scale pathological neuronal networks and the time-varying susceptibility of brain dynamics to seizure initiation and spread (generalization). We hypothesize that these pathological multiscale networks are maintained via the recurring activation of epileptiform spatiotemporal patterns not only during seizures but also during interictal and preictal periods. We will address these problems in patients with pharmacologically intractable focal epilepsy by recording ensemble of single-neurons via intracortical 96-microelectrode arrays (96-MEA, 4 mm X 4 mm) and large-scale brain networks via intracranial EEGs (Truccolo et al., 2011, 2014; Wagner et al., 2015). Neural activity at these multiple levels will be recorded continuously 24hr/day, over a period of ~1-2 weeks. Furthermore, we will determine the association between recurrent pathological patterns and changes in the brain's susceptibility to spread of excitation and seizures by actively probing neural dynamics with a recently developed real-time closed-loop intracranial electrical stimulation platform (Sarma et al., 2016). Three specific AIMs will: (1) Test the hypothesis that multiscale ictal patterns recur not only during seizures but also during interictal periods, becoming part of the resting state networks' repertoire; (2) Test the hypothesis that precursor biomarkers of seizure initiation include the reactivation of multiscale ictal network patterns; (3) Test the hypothesis that ictal pattern reactivation during interictal periods is accompanied by increases in the brain's susceptibility to both local and large-scale spread of excitation: probing neural dynamics with closed-loop electrical stimulation.