室周灰质异位（PNH）是难治性癫痫的常见病因，病灶位置深，抗癫痫药物和手术均疗效不佳，异位灰质与皮层形成的复杂致痫网络亟待探索，发作机制尚未阐明，是目前研究的热点和难点。申请人前期已证实上覆大脑皮层比异位灰质更具致痫性，二者在结构和功能上存在的异常连接是其真正致痫原因；而Filamin A不仅是PNH最常见的致病基因，其突变所致的经典型PNH有特定表型，且与未突变患者相比其白质微结构异常更为广泛。因此提出假说，该基因突变致PNH相关难治性癫痫具有特定的与临床表型相关的癫痫网络特征。申请人拟在扎实的工作基础上，通过整合遗传信息和多模态影像技术，提取Filamin A基因突变影响的关键神经网络环路，评估该基因突变和未突变PNH癫痫患者的脑网络差异，明确此差异与临床表型特征和预后的关系，并采用rTMS对基因相关PNH癫痫患者脑连接水平进行干预，为进一步阐明其病理生理机制及其治疗提供新思路和靶点。

Periventricular nodular heterotopia (PNH) with deep lesions is a common cause of refractory epilepsy. It has always been a hot and difficult point in epilepsy research as no good results can be achieved by drugs or surgery. The complex epileptic network of ectopic gray matter and cortex has not been elucidated. In previous work, we have found that both the heterotopic nodules and particularly the overlying cortex are involved in the epileptogenic network in PNH. Filamin A is the most common gene and the "classical" PNH caused by the mutation of Filamin A has a specific clinical phenotype and prognosis. Moreover, white matter microstructural abnormalities are more extensive than those of PNH patients with Filamin A-nonmutated. Therefore, it is proposed that the Filamin A mutation causes PNH-related refractory epilepsy with phenotype-related epilepsy network characteristics. In this project, we intend to integrate multimodal imaging and genetic information based on the previous solid work. The neural network of PNH-related epilepsy will be deeply explored to extract the key neural network affected by the Filamin A gene mutation, to evaluate the differences in brain connections between patients with and without Filamin A mutations in PNH-related epilepsy, to determine the relationship between this difference and clinical phenotype and prognosis, and to explore the mechanism of rTMS treatment on brain connectivity in patients with PNH and epilepsy. The objective of this project is to provide a new way and target to further clarify its pathophysiological mechanism and its treatment.