Hu Jie, Cui Bixiao, Wang Zhenming, Wang Jingjuan, Xu Xiaoyin, Lu Jie
Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.
Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China.
Neurobiol Dis. 2025 Aug;212:106967. doi: 10.1016/j.nbd.2025.106967. Epub 2025 May 19.
Temporal lobe epilepsy (TLE) is associated to genetic predisposition, metabolic abnormalities, and disruptions in brain connectivity. However, the relationships between genetic factors, metabolic processes, and brain network dynamics are not yet fully understood. Simultaneous positron emission tomography and function magnetic resonance imaging (PET/fMRI) data were collected from 66 patients with TLE and 38 healthy controls (HCs). We compared differences in brain network dynamics between TLE patients and HCs using the multilayer network model constructed from extensive temporal features extracted from fMRI. Postmortem whole brain gene expression data were then utilized to identify genes associated with alterations in TLE connectome dynamics, with subsequent enrichment analysis for functional annotation, cellular, and disease associations. Mediation analysis further explored the interrelations among gene expression, glucose metabolism as measured by PET, and brain network dynamics as measured by fMRI. Compared with HCs, individuals with TLE exhibited increased module variability primarily in the default mode network and reduced module variability in the attention network. These case-control differences were validated through split-half analyses and remained unaffected by medication or lateralization. These aberrant module variability patterns were associated with gene expression profiles predominantly related to inhibitory neurons, postsynaptic cell components, MAPK signaling pathway, and these genes were significantly enriched relative to established epilepsy-related gene sets. Moreover, we observed that the effect of gene expression profile on the alterations in TLE connectome dynamics was significantly mediated by changes in glucose metabolism. These findings highlight that alterations in brain network dynamics in TLE are associated with transcriptomic signatures, and that glucose metabolic changes partially mediate this relationship, furthering insights into the biological basis of the disorder.
颞叶癫痫（TLE）与遗传易感性、代谢异常以及脑连接性破坏有关。然而，遗传因素、代谢过程和脑网络动力学之间的关系尚未完全明确。我们收集了66例TLE患者和38名健康对照者（HCs）的正电子发射断层扫描和功能磁共振成像（PET/fMRI）同步数据。我们使用从功能磁共振成像中提取的广泛时间特征构建的多层网络模型，比较了TLE患者和HCs之间脑网络动力学的差异。随后利用死后全脑基因表达数据来识别与TLE连接组动力学改变相关的基因，并对功能注释、细胞和疾病关联进行富集分析。中介分析进一步探讨了基因表达、PET测量的葡萄糖代谢以及功能磁共振成像测量的脑网络动力学之间的相互关系。与HCs相比，TLE患者主要在默认模式网络中表现出模块变异性增加，而在注意力网络中模块变异性降低。这些病例对照差异通过对半分析得到验证，且不受药物治疗或脑区定位的影响。这些异常的模块变异性模式与主要与抑制性神经元、突触后细胞成分、丝裂原活化蛋白激酶信号通路相关的基因表达谱有关，并且相对于已确立的癫痫相关基因集，这些基因显著富集。此外，我们观察到基因表达谱对TLE连接组动力学改变的影响在很大程度上是由葡萄糖代谢的变化介导的。这些发现突出表明，TLE中脑网络动力学的改变与转录组特征相关，并且葡萄糖代谢变化部分介导了这种关系，从而进一步深入了解该疾病的生物学基础。
