Electrical, Molecular and Clinical Correlates of Human Interictal Spiking

描述（由申请人提供）：我们已经采取了功能基因组方法来询问为治疗难治性癫痫而手术切除的电映射人类新皮层的附近区域之间的差异。我们确定了一小组基因，显着诱导癫痫灶在几乎所有的患者检查，无论潜在的病变。现在，我们第一次有了高度可靠的癫痫新皮层分子标记物，这些标记物指向了表征新皮层癫痫灶的特定信号通路和神经元群体。虽然目前还不清楚这些基因的诱导是否是异常放电神经元的结果或驱动力，但我们发现许多这些基因的诱导与发作间期尖峰的程度精确相关，这表明所识别的分子途径和发作间期尖峰密切相关。在这个建议中，我们将测量一组定量参数的发作间期尖峰从癫痫手术患者的新皮层，并将这些与癫痫发作的产生和潜在的基因表达和信号通路。这些将被放置在人类大脑的三维结构中，以进一步询问有关人类大脑对人类癫痫的影响的问题。该项目的一个长期目标是了解发作间期尖峰的临床意义，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。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%。它是一种最不为人所知的疾病，可以在广泛的大脑损伤后发展。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，但它们不能“治愈”这种疾病。有可能通过移除电定义的癫痫灶来“治愈”癫痫。移除这些病灶脑区也提供了一个机会，以一种在动物模型中无法实现的方式发现人类癫痫的分子和细胞基础。我们开发的改进的方法来测量尖峰和发作间期尖峰的分子和临床相关性，将有很大的效用，无论是临床管理癫痫患者和新的，有针对性的治疗和诊断策略的发展。

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.