PurposeTo investigate the activity of default mode network (DMN), frontoparietal network (FPN) and cerebellar network (CN) in drug-resistant epilepsy (DRE) patients undergoing vagus nerve stimulation (VNS).MethodsFifteen patients were recruited and underwent resting-state functional magnetic resonance imaging (fMRI) scans. Independent component analysis and paired sample t-tests were used to examine activity changes of DMN, FPN and CN before and after VNS.ResultsCompared with preoperative patients, DMN exhibited decreased activity in left cuneus/precuneus, left median cingulate gyrus, left superior/middle occipital gyrus, right superior parietal gyrus, right precentral/postcentral gyrus, right rolandic operculum and right insula, while increased activity was observed in right supramarginal gyrus, left fusiform gyrus, right supplementary motor area, left amygdala, and right inferior frontal gyrus. FPN displayed decreased activity in left cuneus, left anterior cingulate gyrus, right precentral gyrus, left middle/inferior frontal gyrus, right middle frontal gyrus, left superior/middle temporal gyrus, left superior/middle occipital gyrus, and right superior parietal gyrus, but increased activity in right inferior temporal gyrus. CN showed decreased activity in left superior/middle frontal gyrus, right inferior frontal gyrus, left supplementary motor area, left precuneus, left postcentral gyrus, left middle occipital gyrus, right middle temporal gyrus, and left inferior cerebellum, while increased activity was detected in bilateral superior cerebellum and right fusiform gyrus.ConclusionsDMN, FPN and CN exhibited distinct changes in DRE patients following VNS. The suppression or activation of sensorimotor, language, memory and emotion-related regions may represent the underlying neurological mechanisms of VNS. However, the contrasting activity patterns between superior and inferior cerebellum require further investigation.