Electrical, Molecular and Clinical Correlates of Human Interictal Spiking

描述(由申请人提供)：我们采用了一种功能基因组方法来询问在治疗药物难治性癫痫时，通过手术切除的电子地图显示的人类新皮质附近区域有什么不同。我们确定了一小群基因，这些基因在几乎所有接受检查的患者中的癫痫灶都有显著诱导，而不考虑潜在的病变。现在，我们第一次有了高度可靠的癫痫新皮质分子标志物，可以指向特定的信号通路和神经元群体，以表征新皮质癫痫灶。虽然目前尚不清楚这些基因的诱导是异常放电神经元的结果还是驱动力，但我们发现其中许多基因的诱导与发作间期放电的程度精确相关，这表明所识别的分子通路与发作间期放电密切相关。在这项建议中，我们将测量一组癫痫手术患者新皮质发作间期放电的定量参数，并将这些参数与癫痫发作的发生以及潜在的基因表达和信号通路联系起来。这些将被放置在人脑的三维结构中，以询问关于人脑与人类癫痫的关系的进一步问题。该项目的一个长期目标是了解发作间期尖峰放电的临床意义，以帮助指导未来的临床决策。另一个目标是了解电活动与分子和细胞通路之间的关系，这将有助于我们开发新的、生物驱动的人类癫痫诊断和治疗方法。与公共卫生相关：癫痫是一种常见的神经疾病，影响多达1%的世界人口。这是最不为人所知的疾病之一，在受到广泛的大脑侮辱后可能会发展成这种疾病。目前，还没有预防癫痫的治疗方法，虽然现有的药物可以减少癫痫发作的频率，但它们并不能“治愈”这种疾病。通过切除电学上确定的癫痫灶来“治愈”癫痫是可能的。切除这些大脑局部区域也提供了一个机会，以一种在动物模型中无法实现的方式来发现人类癫痫的分子和细胞基础。我们开发的测量发作间期放电的分子和临床相关性的改进方法将对癫痫患者的临床治疗和开发新的、有针对性的治疗和诊断策略具有很大的实用价值。

DESCRIPTION (provided by applicant): We have taken a functional genomic approach to ask what is different between nearby regions of electrically-mapped human neocortex removed surgically for the treatment of medically refractory epilepsy. We identified a small group of genes that are significantly induced at epileptic foci in almost all patients examined, regardless of underlying lesion. For the first time now, we have highly reliable molecular markers of epileptic neocortex that point to a specific signaling pathways and populations of neurons that characterize neocortical epileptic foci. While it is still not clear whether the induction of these genes are a consequence or a driving force of abnormally firing neurons, we found that the induction of many of these genes correlate precisely with the degree interictal spiking suggesting that the molecular pathways identified and interictal spiking are closely related. In this proposal, we will measure a group of quantitative parameters of interictal spiking from the neocortex of patients undergoing epilepsy surgery and relate these to the generation of seizures and the underlying gene expression and signaling pathways. These will be placed within the 3-dimensional structure of the human brain to ask further questions about the human brain's infoldings on human epilepsy. One long-term goal for this project is to develop an understanding of the clinical significance of interictal spiking to help guide future clinical decisions. Another goal is to understand the relationships between electrical activity with molecular and cellular pathways that will help us develop new, biologically-driven, diagnostics and therapeutics for human epilepsy. PUBLIC HEALTH RELEVANCE: Epilepsy is a common neurological disorder affecting up to 1% of the world's population. It is one of the least understood disorders that can develop after a wide range of brain insults. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not "cure" the disorder. It is possible to "cure" epilepsy by removing electrically-defined epileptic foci. Removal of these focal brain regions also presents an opportunity to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. The improved methods we develop to measure spiking and the molecular and clinical correlates of interictal spiking will have great utility both for clinical management of patients with epilepsy and for the development of novel, targeted treatment and diagnostic strategies.