Electrical, Molecular and Clinical Correlates of Human Interictal Spiking

描述（由申请人提供）：我们采用了功能基因组方法来研究为治疗医学难治性癫痫而手术切除的电图人类新皮层附近区域之间的差异。我们发现了一小群基因，这些基因在几乎所有被检查的患者的癫痫灶中都被显著诱导，而不管潜在的病变如何。现在，我们第一次有了高度可靠的癫痫新皮层分子标记，这些分子标记指出了特定的信号通路和神经元群，这些神经元群表征了新皮层癫痫灶。虽然目前尚不清楚这些基因的诱导是神经元异常放电的结果还是驱动力，但我们发现，许多这些基因的诱导与间隔尖峰的程度精确相关，这表明已确定的分子途径与间隔尖峰密切相关。在这个提议中，我们将测量一组癫痫手术患者新皮层间期尖峰的定量参数，并将这些参数与癫痫发作的产生以及潜在的基因表达和信号通路联系起来。这些将被放置在人类大脑的三维结构中，以进一步了解人类大脑对人类癫痫的影响。该项目的一个长期目标是发展对间隔尖峰的临床意义的理解，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途径之间的关系，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。公共卫生相关性：癫痫是一种常见的神经系统疾病，影响世界人口的1%。这是最不为人所知的疾病之一，它可能在广泛的脑损伤后发展。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。通过移除电定义的癫痫病灶来“治愈”癫痫是可能的。切除这些局灶性脑区也为发现人类癫痫的分子和细胞基础提供了机会，而这在动物模型中是无法实现的。我们开发的测量尖峰的改进方法以及间隙尖峰的分子和临床相关性将对癫痫患者的临床管理以及开发新的靶向治疗和诊断策略都有很大的帮助。

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.