Department of Neurological Sciences, University of Vermont, Burlington, VT 05405.
Department of Neurological Sciences, University of Vermont, Burlington, VT 05405
J Neurosci. 2023 Jul 5;43(27):5076-5091. doi: 10.1523/JNEUROSCI.2205-22.2023. Epub 2023 Jun 8.
The epileptic brain is distinguished by spontaneous seizures and interictal epileptiform discharges (IEDs). Basic patterns of mesoscale brain activity outside of seizures and IEDs are also frequently disrupted in the epileptic brain and likely influence disease symptoms, but are poorly understood. We aimed to quantify how interictal brain activity differs from that in healthy individuals, and identify what features of interictal activity influence seizure occurrence in a genetic mouse model of childhood epilepsy. Neural activity across the majority of the dorsal cortex was monitored with widefield Ca imaging in mice of both sexes expressing a human variant ( ) and wild-type controls (WT). Ca signals during seizures and interictal periods were classified according to their spatiotemporal features. We identified 52 spontaneous seizures, which emerged and propagated within a consistent set of susceptible cortical areas, and were predicted by a concentration of total cortical activity within the emergence zone. Outside of seizures and IEDs, similar events were detected in and WT mice, suggesting that the spatial structure of interictal activity is similar. However, the rate of events whose spatial profile overlapped with where seizures and IEDs emerged was increased, and the characteristic global intensity of cortical activity in individual mice predicted their epileptic activity burden. This suggests that cortical areas with excessive interictal activity are vulnerable to seizures, but epilepsy is not an inevitable outcome. Global scaling of the intensity of cortical activity below levels found in the healthy brain may provide a natural mechanism of seizure protection. Defining the scope and structure of an epilepsy-causing gene variant's effects on mesoscale brain activity constitutes a major contribution to our understanding of how epileptic brains differ from healthy brains, and informs the development of precision epilepsy therapies. We provide a clear roadmap for measuring how severely brain activity deviates from normal, not only in pathologically active areas, but across large portions of the brain and outside of epileptic activity. This will indicate where and how activity needs to be modulated to holistically restore normal function. It also has the potential to reveal unintended off-target treatment effects and facilitate therapy optimization to deliver maximal benefit with minimal side-effect potential.
癫痫大脑的特征是自发性癫痫发作和发作间期癫痫样放电 (IEDs)。在癫痫大脑中，发作间期和 IED 之外的中尺度脑活动的基本模式也经常被打乱，并且可能影响疾病症状，但了解甚少。我们旨在量化发作间期脑活动与健康个体之间的差异，并确定发作间期活动的哪些特征会影响儿童癫痫的遗传小鼠模型中的癫痫发作。在表达人类变异体 ( ) 和野生型对照 (WT) 的雌雄小鼠的大部分背侧皮层中进行宽场 Ca 成像以监测神经活动。根据其时空特征对癫痫发作和发作间期的 Ca 信号进行分类。我们识别出 52 例自发性癫痫发作，这些发作在一组一致的易感皮层区域内出现并传播，并且可以通过在出现区域内的总皮层活动浓度来预测。在癫痫发作和 IED 之外，在 和 WT 小鼠中也检测到了类似的事件，这表明发作间期活动的空间结构相似。然而，其空间分布与癫痫发作和 IED 出现区域重叠的事件发生率增加，并且单个 小鼠的皮质活动的特征全局强度可以预测其癫痫活动负担。这表明皮质区域内过度的发作间期活动容易发生癫痫发作，但癫痫发作并非不可避免的结果。皮质活动强度的全局缩放低于健康大脑中的水平可能提供了一种自然的抗癫痫保护机制。定义导致癫痫的基因变异对中尺度脑活动的影响范围和结构是我们理解癫痫大脑与健康大脑的区别的主要贡献，并为精准癫痫治疗的发展提供信息。我们提供了一条清晰的路线图，用于衡量脑活动偏离正常水平的严重程度，不仅在病理性活跃区域，而且在大脑的大部分区域以及癫痫活动之外。这将指示需要在哪里以及如何调节活动以整体恢复正常功能。它还有可能揭示意想不到的非靶向治疗效果，并促进治疗优化，以最大限度地发挥效益并最小化潜在的副作用。
