Latest Views on the Mechanisms of Action of Surgically Implanted Cervical Vagal Nerve Stimulation in Epilepsy

Background: Vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant epilepsy. Although there is a substantial amount of literature aiming at unraveling the mechanisms of action of VNS in epilepsy, it is still unclear how the cascade of events triggered by VNS leads to its antiepileptic effect. Objective: In this review, we integrated available peer-reviewed data on the effects of VNS in clinical and experimental research to identify those that are putatively responsible for its therapeutic effect. The topic of transcutaneous VNS will not be covered owing to the current lack of data supporting the differences and commonalities of its mechanisms of action in relation to invasive VNS.Summary of the Main Findings: There is compelling evidence that the effect is obtained through the stimulation of large -diameter afferent myelinated fibers that project to the solitary tract nucleus, then to the parabrachial nucleus, which in turn alters the activity of the limbic system, thalamus, and cortex. VNS-induced catecholamine release from the locus coeruleus in the brainstem plays a pivotal role. Functional imaging studies tend to point toward a common vagal network that comes into play, made up of the amygdalo-hippocampal regions, left thalamus, and insular cortex.Conclusions: Even though some crucial pieces are missing, neurochemical, molecular, cellular, and electrophysiological changes occur within the vagal afferent network at three main levels (the brainstem, the limbic system [amygdala and hippocampus], and the cortex). At this final level, VNS notably alters functional connectivity, which is known to be abnormally high within the epileptic zone and was shown to be significantly decreased by VNS in responders. The effect of crucial VNS parameters such as frequency or current amplitude on functional connectivity metrics is of utmost importance and requires further investigation.