Epilepsy was the first and the most studied VNS research topic;

tVNS was found to be a safe and well-tolerated treatment, and it may be particularly useful for people who do not respond well to other forms of epilepsy treatment (Yuan and Silberstein, 2016c).

The vagus nerve is involved in the regulation of seizure activity and stimulating it has been shown to reduce the frequency and severity of seizures in some people.

The anti-epileptic effect of VNS is proposed to occur through the desynchronization of neuronal activity, hippocampal plasticity, anti-inflammation, and modulation of neurotransmitter release.  While acute VNS may desynchronize aberrant electrical conduction, chronic VNS may act through complex neuromodulatory changes (Yuan and Silberstein, 2016c).

Long-term VNS reduces seizures through the modulation of the neurotransmitters norepinephrine (NE), serotonin, and/or gamma-aminobutyric acid (GABA)(Yuan and Silberstein, 2016c).

VNS increases extracellular hippocampal NE, which is a potential biomarker for the efficacy of VNS in temporal lobe epilepsy. The P3 component of the event-related potential (ERP),  is a biomarker for predicting VNS response in epilepsy, and reflects the phasic activity of the neuromodulatory LC-NE system (Yuan and Silberstein, 2016c).

In short, long-term VNS may exert anti-epileptic or even anti-epileptogenic effects primarily through modulation of the NST, LC, DRN, and many other regions, affecting their synaptic plasticity and neurotransmitter release (Yuan and Silberstein, 2016a, 2016c).