ObjectiveTo study the intrinsic organization of the thalamocortical circuitry in patients with generalized epilepsy with tonic-clonic seizures (GTCS) via resting-state fMRI (rs-fMRI) connectome analysis and to evaluate its relation to drug response.MethodsIn a prospectively followed-up sample of 41 patients and 27 healthy controls, we obtained rs-fMRI and structural MRI. After 1 year of follow-up, 27 patients were classified as seizure-free and 14 as drug-resistant. We examined connectivity within and between resting-state communities in cortical and thalamic subregions. In addition to comparing patients to controls, we examined associations with seizure control. We assessed reproducibility in an independent cohort of 21 patients.ResultsCompared to controls, patients 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. Findings were similar in the reproducibility dataset.ConclusionsOur findings suggest a pathoconnectomic mechanism of generalized epilepsy centered on diverging changes in cortical and thalamic connectivity. More restricted thalamic connectivity could reflect the tendency to engage in recursive thalamocortical loops, which may contribute to hyperexcitability. Conversely, increased connectional diversity of frontocentral networks may relay abnormal activity to an extended bilateral territory. Network imbalances were observed shortly after diagnosis and related to future drug response, suggesting clinical utility.