Definition and Overview
Vagus nerve stimulation (VNS) is a neuromodulation treatment that modulates the function of the brain and autonomic nervous system by delivering electrical stimulation to the vagus nerve, the 10th cranial nerve. Since it was first applied to humans in 1988, the FDA approved it as an adjuvant treatment for treatment-resistant epilepsy in 1997, and the approved indications were expanded to include treatment-resistant depression in 2005.
The vagus nerve is an extensive nerve that starts from the brainstem and extends to the heart, lungs, digestive tract, and abdominal organs, and makes up about 75% of the parasympathetic nerve fibers of the autonomic nervous system. VNS electrically activates these nerves and has far-reaching effects on brain function and autonomic balance.
Mechanism of Action
Electrical impulses are transmitted to the nucleus tractus solitarius (NTS) of the brainstem through the vagus nerve, and then spread to the thalamus, amygdala, hypothalamus, and cerebral cortex. Through this pathway, the release of neurotransmitters (norepinephrine, serotonin, GABA, and acetylcholine) is regulated, and the excitatory-inhibitory balance throughout the brain changes.
Anti-inflammatory reflex is an important effect mechanism of VNS. Vagal efferent fibers send signals to immune cells in the spleen and intestines to suppress the secretion of inflammatory cytokines such as TNF-alpha and IL-1β. Through this mechanism, VNS exerts a therapeutic effect on inflammatory diseases.
In terms of autonomic nervous system regulation, VNS restores autonomic balance by increasing parasympathetic nerve activity and suppressing sympathetic nerve overactivity. Increased heart rate variability, stabilization of blood pressure, and reduction of heart rate are reported.
Invasive VNS (Implanted VNS)
Invasive VNS is performed by wrapping an electrode around the vagus nerve on the left side of the neck and inserting an electrical stimulation device (pulse generator) into the skin under the collarbone. The device is programmable, and stimulation intensity, frequency, and duration are controlled on an outpatient basis.
In treatment-resistant epilepsy, it is reported that approximately 40-50% of patients experience a reduction in seizure frequency of more than 50%. The seizure-reducing effect tends to increase gradually over time. In treatment-resistant depression, the response rate was reported to be approximately 30-40% when treated for more than 1 year, but the difference from placebo was limited in short-term randomized controlled trials.
Common side effects include hoarseness during stimulation, cough, difficulty swallowing, throat discomfort, and difficulty breathing. In most cases, it disappears after stimulation ends.
Noninvasive VNS (tVNS)
Auricular tVNS
The ear branch of the vagus nerve (Arnold's nerve) is distributed to the conchae or tragus of the ear. When small electrodes are attached to this area and transcutaneous electrical stimulation is delivered, vagal afferent signals are transmitted through the brainstem to a wide range of brain regions.
fMRI studies have confirmed that ear tVNS activates brain regions similar to invasive VNS, including the brainstem, limbic system, and prefrontal cortex. Auricular tVNS has the advantages of having few side effects, low cost, and being able to be used at home.
Cervical tVNS
This is a method of placing an electrode on the neck and stimulating the cervical vagus nerve through the skin. The GammaCore device is FDA approved for cluster headaches, migraines, and respiratory failure related to COVID-19.
Headache indications
Non-invasive cervical VNS (gammaCore) has been included as a recommended treatment in European guidelines for the acute treatment of cluster headache. In migraine prevention, the effect of ear VNS on significantly reducing attack frequency was reported in a randomized controlled trial (EVENT study).