Transcriptomic decoding of regional cortical vulnerability to drug-resistant epilepsy using 7T MRI

The mechanism by which genetic risk leads to cortical vulnerability in drug-resistant epilepsy (DRE) remains unclear. This study used 7T structural and resting-state functional MRI to investigate cortical neural activity alterations in 105 DRE patients and 105 healthy controls (HCs), and to explore related genetic mechanisms. Vertex-wise analyses of mean amplitude of low-frequency fluctuation (mALFF) and regional homogeneity (ReHo) revealed that DRE patients primarily exhibited decreased mALFF and increased ReHo in the Cingulo-Opercular Network. Using the Allen Human Brain Atlas, we conducted spatial transcriptomic analysis via partial least squares (PLS) and gene enrichment analysis to identify gene categories associated with these functional changes. The results showed that cortical alterations were related to epilepsy-general genes (e.g., TMEM74, KCNN2, RBFOX1) and brain-relevant genes. Genes positively correlated with mALFF alterations enriched in mitochondrial inner membrane, matrix, and carboxylic acid metabolism; negatively in chromatin remodeling, binding, and postsynapse. Genes positively correlated with ReHo alterations enriched in nucleic acid-related catalytic activity, ribonucleoprotein granule, and centrosome; negatively in amyotrophic lateral sclerosis, mitochondrial membrane, and pyrophosphatase activity. These findings link spatial brain activity abnormalities in DRE to specific genetic signatures and biological pathways, suggesting new mechanistic insights and potential therapeutic targets for this difficult-to-treat condition.