Filamin A基因突变致室周灰质异位相关难治性癫痫脑网络特征及其干预

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.

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。

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。既往对其全脑水平的潜在功能神经基础知之甚少，对基因相关影像学表型更是处于起步阶段。本项目发现PNH患者在边缘和小脑网络以及枕叶皮层网络总体效率较低，基于种子点的功能连接分析证实了患者远程癫痫网络中的活动和区域间连接受到破坏，小脑和边缘系统表现出显著拓扑结构改变，表明这些枢纽区域可能与PNH癫痫网络的全脑回路相关。对于伴有Filamin A基因突变的PNH癫痫患者则具有特征性的影像学表现、临床表型及预后，其癫痫网络影像学特征也与未突变的PNH癫痫患者不同，癫痫关联白质区域内微结构改变有显著变化。我们进一步应用多模态影像学技术，从神经影像学的角度对伴有Filamin A突变的PNH相关癫痫人群的神经网络进行了阐述，发现其低频振荡振幅存在明显差异，且静息态功能连接明显减弱。在神经调控干预方面，对于深部病变如脑室周围结节，我们也通过多模态影像学技术明确PNH相关难治性癫痫致痫网络，精准定位与深部病变存在结构和功能连接的过度兴奋皮质，即上覆皮层，初步发现能明显减少癫痫发作频率，提示可通过无创的形式调节无法进入的深部病变以达到抗癫痫的目的。这些发现为我们更好地理解PNH癫痫患者的病理生理学机制和精准神经调控治疗打下了良好的基础，为进一步阐明其病理生理机制及其治疗提供了新思路和靶点。

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