Disruption of functional gradients in genetic generalized epilepsy and its clinical relevance: evidence from high-density EEG

Genetic Generalized Epilepsy (GGE) represents around 20% of adult epilepsies and involves widespread network dysfunction across both hemispheres. While abnormalities across functional networks are well-documented, the hierarchical organization of these networks in GGE remains unknown. Our goal was to investigate whether GGE alters this hierarchy estimated using gradient analysis based on EEG-informed connectome. We analyzed a high-density EEG dataset from 20 GGE patients and matched healthy controls (HC). Compared to HC, GGE patients had significantly less negative gradient scores in the frontoparietal network (FPN) in the secondary gradient of the beta frequency band (p=0.0201, FDR corrected, quantified as large effect size by Cliffs delta: 0.52). Additionally, in the theta band, the secondary gradient scores in multiple networks were closely associated with epilepsy duration (Spearmans |R|>0.50, all p<0.05, FDR corrected). The findings were robust for different thresholds and not explained by potential confounders. In GGE, FPN moving closer to the other networks might promote the widespread pattern of pathological activity, and the association between gradient scores and epilepsy duration supports a progressive disruption of the network gradients. Altogether, this study presents the first EEG-based evidence of GGE-related gradient signatures and its clinical relevance. Author SummaryGGE represents around 20% of adult epilepsies and involves abnormalities across multiple networks. However, the hierarchical organization of the networks, which could be captured by gradient analysis, associated with GGE remains elusive. Here, we derived the frequency-dependent gradient patterns from high-density EEG of GGE patients and matched healthy controls. In GGE patients, beta band secondary gradient (G2) showed significantly less negative gradient scores in the frontoparietal network compared to HC, indicating a narrowing network hierarchy which might promote the widespread pattern of pathological activity. Additionally, theta band G2 of multiple networks were closely associated with epilepsy duration, suggesting a progressive disruption of network hierarchy as epilepsy advances. This study presents the first EEG-based evidence of GGE-related gradient signatures and its clinical relevance.