The Allure of Transcutaneous Vagus Nerve Stimulation as a Novel Therapeutic Modality

Abstract

The vagus nerve, running from the brainstem through the neck to many peripheral organs, functions as a bidirectional communication pathway between the brain and the body. Its name is a reflection of its widespread distribution throughout the body, as vagus means “wandering” in Latin. The vagus nerve regulates the function of the autonomic nervous system from its efferent projections from the brain to its innervated organs. The brain receives information from these organs by the afferent projections of the vagus. It has been estimated that about 80% of the fibers in the vagus nerve are afferent fibers. This estimation concerning afferent fibers provides the rationale for how stimulating the vagus nerve in the periphery can influence brain function and possibly diseases of the brain. Although afferent projections terminate in the nucleus tractus solitarius in the brainstem, there are direct and indirect ascending projections from the nucleus tractus solitarius to many areas of the brain involved in central autonomic regulation (e.g., midbrain, hypothalamus, and cortex). The nucleus tractus solitarius also sends projections to brain areas involved in mood and emotion, such as the amygdala and hippocampus, as well as the soma for noradrenergic and serotoninergic neurons (1). Human imaging studies show ventral nerve stimulation (VNS) to cause effects in both subcortical and cortical areas (2). Consistent with such results, long-term stimulation of the vagus nerve in rats, using clinically appropriate stimulating parameters, revealed widespread activation throughout the brain (3,4). There is evidence for the efficacy of VNS in several diseases of the brain. The US Food and Drug Administration approved the use of VNS for treatment-resistant epilepsy in 1997 and for treatment-resistant depression in 2005. VNS Therapy (Cyberonics, Inc., Houston, Texas) consists of surgically implanted coiled electrodes to the left vagus nerve. The electrodes are connected to a stimulator pack subcutaneously implanted in the chest area near the clavicle. The device is controlled via a handheld personal computer and can deliver specific intermittent electrical signals from the left vagus nerve to the brain. However, the necessity of surgery with the possibility of perioperative risks as well as the cost of the procedure has limited the widespread use of VNS. For these reasons, its approved use is limited to treatment-resistant depression. By contrast, transcutaneous vagus nerve stimulation (tVNS) makes use of the fact that the vagus nerve is distributed on the surface of the ear such that stimulation can be carried out without surgery. If effective, tVNS has the potential to increase greatly the use of VNS for patients with diseases such as depression, including patients who are not treatment resistant. Hein et al. (5) previously reported on a randomized shamcontrolled add-on study of short-term tVNS in 37 patients with depression, with all but one being treated with some