Definition and Overview
Vagus nerve stimulation (VNS) is a neuromodulation therapy that delivers electrical stimulation to the vagus nerve (cranial nerve X) to regulate brain and autonomic nervous system function. Since its first human application in 1988, the FDA approved it as adjunctive therapy for treatment-resistant epilepsy in 1997, with expanded approval for treatment-resistant depression in 2005 [1][2].
The vagus nerve is an extensive nerve originating from the brainstem that extends to the heart, lungs, gastrointestinal tract, and abdominal organs, comprising approximately 75% of the parasympathetic fibers of the autonomic nervous system. VNS electrically activates this nerve, exerting broad effects on brain function and autonomic balance.
Mechanism of Action
Electrical stimulation is transmitted through the vagus nerve to the nucleus tractus solitarius (NTS) in the brainstem, then propagates to the thalamus, amygdala, hypothalamus, and cerebral cortex [4]. Through this pathway, neurotransmitter release (norepinephrine, serotonin, GABA, acetylcholine) is modulated, and the overall excitatory-inhibitory balance of the brain is altered.
The inflammatory reflex is an important mechanism of VNS effects [3]. Efferent vagal fibers signal immune cells in the spleen and viscera to suppress the secretion of inflammatory cytokines such as TNF-alpha and IL-1 beta [3]. Through this mechanism, VNS exerts therapeutic effects in inflammatory conditions.
In terms of autonomic regulation, VNS increases parasympathetic activity and suppresses sympathetic overactivation to restore autonomic balance. Increased heart rate variability, blood pressure stabilization, and decreased heart rate have been reported.
Implanted VNS
Implanted VNS is performed through surgery in which electrodes are wrapped around the vagus nerve on the left side of the neck, and a pulse generator is implanted subcutaneously below the clavicle. The device is programmable, with stimulation intensity, frequency, and duration adjustable on an outpatient basis.
In treatment-resistant epilepsy, approximately 40-50% of patients achieve seizure frequency reduction of 50% or more [1]. The seizure reduction effect tends to increase progressively over time [1]. For treatment-resistant depression, response rates of approximately 30-40% have been reported with long-term treatment exceeding one year, although differences from sham were limited in short-term randomized controlled trials [2].
Common side effects include hoarseness during stimulation, cough, dysphagia, neck discomfort, and dyspnea. Most resolve when stimulation ceases.
Non-Invasive VNS (tVNS)
Auricular tVNS
The auricular branch of the vagus nerve (Arnold's nerve) is distributed in the concha and tragus regions of the ear [4]. When small electrodes are attached to these areas and transcutaneous electrical stimulation is delivered, vagal afferent signals are transmitted through the brainstem to widespread brain regions [4].
fMRI studies have confirmed that auricular tVNS activates brain regions similar to those affected by implanted VNS, including the brainstem, limbic system, and prefrontal cortex [4]. Auricular tVNS has the advantages of fewer side effects, lower cost, and home usability.
Cervical tVNS
This method involves placing electrodes on the neck area and stimulating the cervical vagus nerve through the skin. The GammaCore device has received FDA approval for cluster headache, migraine, and COVID-19-related respiratory distress.
Headache Indications
Non-invasive cervical VNS (gammaCore) has been included as a recommended treatment in European guidelines for acute cluster headache treatment. For migraine prevention, the EVENT study (a randomized controlled trial) reported that auricular VNS significantly reduced attack frequency [5].