OBJECTIVES: Vagus nerve stimulation (VNS) can improve depression. Cognitive models of depression highlight an over-representation of negative thoughts and memories, with depressed individuals showing memory facilitation for negative material. We hypothesized that the antidepressant action of VNS may emerge through corrective influences on 'negativity bias' in memory. We therefore examined the impact of VNS on emotional memory and its underlying brain activity. METHODS: We tested a single patient undergoing VNS for treatment-resistant depression (TRD). Stimulation was set at a 30/66-second on/off cycle during three encoding blocks when the patient viewed randomly presented positive, negative, and neutral words. Following each block, VNS was switched off and the patient identified previously seen words from distractors in a subsequent recognition memory task. The patient was scanned using functional magnetic resonance imaging (fMRI) during the first encoding block. RESULTS: There was robust recall of negative material viewed during 'off' cycles of VNS but subsequent memory of negative words was attenuated during active VNS ('on' cycles). VNS did not influence memory for neutral and positive words. With neuroimaging, direct modulatory effects of VNS were observed in dorsomedial, dorsolateral, and orbital regions of the prefrontal cortex. Moreover, during encoding of negative words, compared with positive and neutral words, VNS also modulated activity within orbitofrontal, ventromedial and polar prefrontal cortices, midcingulate cortex, and brain stem. CONCLUSIONS: Our observations show that VNS can interfere with memory of negative information, an effect that may contribute to its antidepressant role. Neuroimaging implicated regions including the ventral and medial prefrontal cortex as an underlying neural substrate. Copyright © 2007 by American Psychosomatic Society.