Background: Epilepsy imposes a substantial global burden, and drug-resistant epilepsy (DRE) accounts for a disproportionate share of morbidity due to persistent seizures and limited treatment options. Although MRI studies have reported gray-matter (GM) atrophy in DRE, its spatial specificity, accompanying changes in morphometric similarity network (MSN) connectivity strength, and the performance of an MRI-only supportive screening model for identifying DRE remain incompletely understood. We therefore tested whether GM atrophy clusters non-randomly in territories with high neurotransmitter-receptor, cellular, and mitochondrial distributions, whether MSNs are altered, and evaluated the feasibility of an MRI-only model to support DRE identification. Methods: This study first used voxel-based morphometry (VBM) to map group GM atrophy, then constructed MSN from structural MRI features to analyze global, regional, and graph-theoretic metrics; we next tested the spatial correlation of the GM atrophy map with neurotransmitter receptor and cellular/mitochondrial distributions under family-wise FDR control. Finally, we trained classifiers using LASSO-selected MRI features to develop an MRI-based screening/support tool. All analyses were performed separately in two independent cohorts. Results: Both cohorts showed temporo-limbic–anchored GM atrophy, with discovery-cohort stratification indicating broader thalamo–ventral temporal involvement in TLE and more focal cerebellar effects in non-TLE. MSNs showed preserved global indices with focal regional meanMS reductions (isthmus cingulate/medial orbitofrontal/pars triangularis), reproduced in TLE but not other subtype contrasts. The atrophy map co-localized with 5-HT1B and mGluR5 and with mitochondrial Complex I/IV (plus respiratory capacity and a neuronal subtype map) in discovery, while validation showed no FDR-significant correspondences and opposite directions for mGluR5 and respiratory capacity. The MRI-only panel achieved moderate external AUC (~0.75), consistent with a supportive screening application rather than diagnostic replacement. Conclusion: GM atrophy in DRE aligns with neurotransmitter and mitochondrial distributions and coincides with regional meanMS reductions; an MRI-only model aids DRE identification, though causality and clinical utility await validation in larger longitudinal/interventional studies. Keywords: voxel-based morphometry, morphometric similarity networks, JuSpace, clinical prediction model
Zhao et al. (Sun,) studied this question.