Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy.

Background Transcutaneous auricular Vagal Nerve Stimulation (taVNS) is a non-invasive neurostimulation technique with potential analgesic effects. Several studies based on subjective behavioral responses suggest that taVNS modulates nociception differently with either pro-nociceptive or anti-nociceptive effects. Objective This study aimed to characterize how taVNS alters pain perception, by investigating its effects on event-related potentials (ERPs) elicited by different types of spinothalamic and lemniscal somatosensory stimuli, combined with quantitative sensory testing (detection threshold and intensity ratings). Methods We performed 3 experiments designed to study the time-dependent effects of taVNS and compare with standard cervical VNS (cVNS). In Experiment 1, we assessed the effects of taVNS after 3 hours of stimulation. In Experiment 2, we focused on the immediate effects of the duty cycle (OFF vs. ON phases). Experiments 1 and 2 included 22 and 15 healthy participants respectively. Both experiments consisted of a 2-day cross-over protocol, in which subjects received taVNS and sham stimulation sequentially. In addition, subjects received a set of nociceptive (thermonociceptive CO2 laser, mechanical pinprick) and non-nociceptive (vibrotactile, cool) stimuli, for which we recorded detection thresholds, intensity of perception and ERPs. Finally, in Experiment 3, we tested 13 epileptic patients with an implanted cVNS by comparing OFF vs. ON cycles, using a similar experimental procedure. Results Neither taVNS nor cVNS appeared to modulate the cerebral and behavioral aspects of somatosensory perception. Conclusion The potential effect of taVNS on nociception requires a cautious interpretation, as we found no objective change in behavioral and cerebral responses to spinothalamic and lemniscal somatosensory stimulations.

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