Different connectivity patterns of MRI-negative drug-resistant epilepsy and drug-sensitive epilepsy in cerebellar and subcortical-cortical regions

Controlling cerebellar output may reduce seizure frequency. However, the involvement of the cerebellum in the development of drug resistance remains unclear. This study aims to elucidate the cerebellar-subcortical/cortical connectivity in drug resistance mechanisms using a multimodal approach. We utilized connectivity to select moderation and mediation models to further investigate the contact between the alteration of cerebellar-subcortical/cortical connectivity and drug resistance, taking into account the effect of duration. We compared MRI-negative individuals with drug-resistant epilepsy (DRE), drug-sensitive epilepsy, and healthy controls. The findings revealed a decoupling of connectivity between the cerebellum and subcortical nuclei in DRE. The deviation re sults support the crucial connected role of SCN and cerebellum for drug resistance in epilepsy. Additionally, the results suggest that this increased hyperconnectivity between subcortical and cortical regions, influenced by the cerebellum and the duration of the disease, possibly playing a key role in the development of drug resistance in epilepsy. The thalamus and middle occipital gyrus emerged as particularly significant regions in this context. The cerebellum and duration appear to promote hyperexcitability of functional activity between subcortical and cortical regions, potentially serving as a critical pivot for the development of drug resistance in epilepsy. • The decoupling and unbalanced connectivity of cerebellar and subcortical/cortical regions in DRE. • The cerebellum is involved in hyperconnectivity between subcortical and cortical regions in the DRE.