Brain Morphometric Alterations in Focal to Bilateral Tonic–Clonic Seizures in Epilepsy Associated With Excitatory/Inhibitory Imbalance

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-24 DOI:10.1111/cns.70129

Qiuxing Lin, Wei Li, Yingying Zhang, Yuming Li, Peiwen Liu, Xiang Huang, Kailing Huang, Danyang Cao, Qiyong Gong, Dong Zhou, Dongmei An

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Abstract

Background

Focal to bilateral tonic–clonic seizures (FBTCS) represent the most severe seizure type in temporal lobe epilepsy (TLE), associated with extensive network abnormalities. Nevertheless, the genetic and cellular factors predispose specific TLE patients to FBTCS remain poorly understood. This study aimed to elucidate the relationship between brain morphometric alterations and transcriptional profiles in TLE patients with FBTCS (FBTCS+) compared to those without FBTCS (FBTCS−).

Methods

We enrolled 126 unilateral TLE patients (89 FBTCS+ and 37 FBTCS−) along with 60 age- and gender-matched healthy controls (HC). We assessed gray matter volume to identify morphometric differences between patients and HC. Partial least squares regression was employed to investigate the association between the morphometric disparities and human brain transcriptomic data obtained from the Allen Human Brain Atlas.

Results

Compared with HC, FBTCS+ patients exhibited morphometric alterations in bilateral cortical and subcortical regions. Conversely, FBTCS− patients exhibited more localized alterations. Imaging transcriptomic analysis revealed both FBTCS− and FBTCS+ groups harbored genes that spatially correlated with morphometric alterations. Additionally, pathway enrichment analysis identified common pathways involved in neural development and synaptic function in both groups. The FBTCS− group displayed unique pathway enrichment in catabolic processes. Furthermore, mapping these genes to specific cell types indicated enrichment in excitatory and inhibitory neurons in the FBTCS− group, while FBTCS+ group only enriched in excitatory neurons. The distinct cellular expression differences between FBTCS− and FBTCS+ groups are consistent with the distribution patterns of GABAergic expression.

Conclusion

We applied imaging transcriptomic analysis linking the morphometric changes and neurobiology in TLE patients with and without FBTCS, including gene expression, biological pathways, cell types, and neurotransmitter receptors. Our findings revealed abnormalities in inhibitory neurons and altered distribution patterns of GABAergic receptors in FBTCS+, suggesting that an excitatory/inhibitory imbalance may contribute to the increased susceptibility of certain individuals to FBTCS.

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局灶性至双侧强直-阵挛性癫痫发作的脑形态改变与兴奋/抑制失衡有关

背景局灶性至双侧强直阵挛发作（FBTCS）是颞叶癫痫（TLE）中最严重的发作类型，与广泛的网络异常有关。然而，人们对特定 TLE 患者易患 FBTCS 的遗传和细胞因素仍然知之甚少。本研究旨在阐明患有 FBTCS 的 TLE 患者（FBTCS+）与未患有 FBTCS 的 TLE 患者（FBTCS-）相比，大脑形态改变与转录特征之间的关系。方法我们招募了126名单侧TLE患者（89名FBTCS+患者和37名FBTCS-患者）以及60名年龄和性别匹配的健康对照组（HC）。我们评估了灰质体积，以确定患者与健康对照组之间的形态差异。我们采用偏最小二乘回归法来研究形态计量差异与从艾伦人类脑图谱中获得的人类大脑转录组数据之间的关联。结果与 HC 相比，FBTCS+ 患者双侧皮质和皮质下区域的形态发生了改变。相反，FBTCS- 患者表现出更多的局部改变。成像转录组学分析表明，FBTCS- 和 FBTCS+ 两组均含有与形态改变在空间上相关的基因。此外，通路富集分析确定了两组患者神经发育和突触功能的共同通路。FBTCS- 组在分解代谢过程中显示出独特的通路富集。此外，将这些基因映射到特定细胞类型的结果表明，FBTCS- 组的兴奋性和抑制性神经元表达丰富，而 FBTCS+ 组仅兴奋性神经元表达丰富。FBTCS- 组和 FBTCS+ 组之间明显的细胞表达差异与 GABA 能表达的分布模式一致。结论我们应用成像转录组学分析方法，将有 FBTCS 和无 FBTCS 的 TLE 患者的形态计量变化与神经生物学联系起来，包括基因表达、生物通路、细胞类型和神经递质受体。我们的研究结果显示，FBTCS+患者的抑制性神经元出现异常，GABA能受体的分布模式也发生了改变，这表明兴奋/抑制失衡可能是导致某些个体对FBTCS易感性增加的原因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.