Idiopathic generalized epilepsy with tonic-clonic seizures (IGE-GTCS) has been associated to the thalamo-cortical circuitry. By quantifying the interplay between macroscale functional communities via resting-state fMRI (rs-fMRI) connectome analysis, we assessed the intrinsic organization of this network and its relation to drug-response. Compared to controls, IGE-GTCS showed a more constrained network embedding of the thalamus, while frontocentral neocortical regions expressed increased functional diversity. Findings remained significant after regressing out thalamic volume and cortical thickness, suggesting independence from structural alterations. We observed more marked network imbalances in drug-resistant compared to seizure-free patients. Our findings suggest a pathoconnectomic mechanism of IGE, centered on diverging changes in cortical and thalamic connectivity. More restricted thalamic connectivity could reflect the tendency to engage in recursive thalamo-cortical loops, which may contribute to hyper-excitability.
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