Fig. 1.

Neural pathways involved in pain modulation by vagus nerve stimulation (VNS). Afferent vagal fibers project to the brain mainly via the nucleus tractus solitarius, and then reach higher brain structures that are associated with pain perception, such as the amygdala, hippocampus, hypothalamus, and anterior cingulate cortex. VNS can modulate the activities and connection of these brain areas. The activities of PAG and LC, and their connection with higher brain areas are modulated by vagal activity to regulate the descending pain inhibition systems. The dotted lines represent increased connections by VNS. ACC: anterior cingulate cortex; Amy: amygdala; DMN, dorsal motor nucleus; Hippo, hippocampus; Hypo, hypothalamus; LC, locus coeruleus; MCC, middle cingulate cortex; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; PBN, parabrachial nucleus; PCC, posterior cingulate cortex; PFC, prefrontal cortex; Thal, thalamus.