Vagus nerve is the longest mixed cranial nerve associated structurally with the post olivary sulcus of the medulla oblongata. The literal translation of the vagus is 'wanderer,' which aptly represents its widespread interfacing of cortex, brainstem, hypothalamus, and the body. Its afferent and efferent pathways comprise about 80% and 20%, respectively. With a premise that venous hyperemia caused seizures, James Corning, a 19th-century neurologist from New York, devised instrumented carotid compression along with vagus nerve stimulation as a treatment intervention for seizures. His observations were not put to the test until the latter part of the 20th century. In the 1980s, various observational studies emerged in the cybernetic use of a vagus nerve stimulator (VNS) in refractory epilepsy.[1][2] 

Currently, VNS is a Food and Drug Administration (FDA) approved treatment for various conditions like chronic epilepsy, refractory epilepsy, and depression. It is also being investigated in various other conditions like autoimmune and chronic inflammatory disorders.[3]

Vagus nerve connects many visceral organs with the brainstem and the cortex given its widespread course and distribution compared to the rest of the cranial nerves through the autonomic nervous system interface. It originates in the medulla oblongata as eight to ten rootlets from four nuclei, namely:[4][5]

1. Dorsal Motor Nucleus: This nucleus gives rise to the preganglionic parasympathetic visceromotor fibers.
2. Nucleus Tractus Solitarius (NTS): This nucleus receives the viscerosensory input from the gastrointestinal and respiratory system as well as the afferent taste input via the chorda tympani nerve of the 7th cranial nerve. These sensory afferents constitute over 80% of the vagus nerve. The projections from NTS are extensive, involving different regions of the brain, brainstem (including locus coeruleus and raphe nucleus), and the hypothalamus.[6]
3. Nucleus Ambiguous: This nucleus is associated with efferent outputs associated with the 9, 10, and 11 cranial nerves. It also contains the preganglionic parasympathetic neurons that innervate the postganglionic parasympathetic neurons to the heart.
4. Spinal Nucleus of Trigeminal Nerve: This nucleus receives general somatic sensory input from the back of the ear and the external auditory meatus.

The vagus nerve, after originating from the medulla oblongata, exits the cranium through the jugular foramen and travels down the neck within the carotid sheath along with the common carotid artery and the internal jugular vein.

The premise of the vagal nerve stimulation is to activate various neurochemical coordinates arising from the NTS to different parts of the brain. The FDA approved indications are:

1. Epilepsy:An implantable vagus nerve stimulator was used in 1988 in a patient with pharmaco-resistant epilepsy for the first time.[7] Initially, in 1997, the US FDA approved VNS to treat pharmaco-refractory partial-onset seizures in patients above 12 years of age. Later in 2017, extended for use in children above four years of age. Fewer side effects meant broader clinical applications beyond the approved guidelines to additional conditions like Lennox Gestaut syndrome, Rett syndrome, and epilepsy in pregnant women due to the lack of detrimental and teratogenic side effects.[8][9][10] Studies have also shown that the risk of sudden unexpected death in epilepsy (SUDEP) is reduced with the long-term use of VNS.[11]Mechanisms of action: A precise mechanism of action is still inconclusive, but the following are generally agreed based on human and animal studies. In animal epilepsy models, VNS has caused abruption of an ongoing seizure and a decrease in the frequency of chronic seizures.[12][13] Zabara postulated that high synchronization of the cortical and thalamocortical loops are the basis of the complex partial seizures in animal models, VNS intervention breaks these synchronized networks and thus mitigate a seizure activity.[14] NTS projections to the raphe nuclei and the locus coeruleus play an important role in the VNS neuromodulation therapy, purportedly by increasing the serotonergic and noradrenergic transmission, evidenced by the increased levels of serotonin, noradrenaline (NA) and its metabolites in the CSF of the patients undergoing VNS stimulation. Serotonin and NA have known anti-seizure effects.[15][16][17]
2. Depression: The use of VNS for treatment-resistant depression was approved in 2005. [18] This approval was preceded by several controlled and uncontrolled studies that observed improved standardized mood scores following treatment with VNS in patients with treatment-resistant depression.[19][20] It was also observed that the patients with clinical refractory depression who claimed improvement due to VNS use relapsed into clinical depression after the removal of a VNS device or repairs arising due to battery issues of the device.[21][22] A meta-analysis revealed a substantial difference in response rates between those treated as usual versus those treated as usual with adjunctive VNS therapy.[23]Mechanisms of action: Again, the exact role of VNS in the treatment of clinically refractory depression is inconclusive; however various explanations as to why the VNS works include; better NA synaptic transmission through the locus coeruleus and other pathways and VNS mediated changes to the anti-convulsant system in the brain, which improves depression.[18][24]

Other Investigational Clinical Applications:Vagus nerve plays an important role in conveying information about peripheral proinflammatory cytokines in the body to the brain (NTS) as the vagal afferents are sensitive to the presence of interleukins and prostaglandins.[25][26] In turn, NTS relays this information to various levels like the hypothalamus, limbic lobe, and the pituitary leading to activation of the hypothalamo-pituitary adrenal (HPA) axis leading to the release of cortisol from the adrenal cortex. The anti-inflammatory role of the vagal efferents is mediated through the vagovagal reflex, where vagal afferents activate the vagal efferents. The vagal cholinergic output from the dorsal motor nucleus inhibits the release of cytokines like TNFα from the macrophages, and this is commonly termed as the cholinergic anti-inflammatory pathway.[27][28] These anti-inflammatory abilities of the vagus nerve make it a target for modulation by VNS to affect the inflammatory conditions of the gut like the inflammatory bowel disease (IBD), and also other non-gut inflammations like rheumatoid arthritis (RA), diabetes mellitus (DM), sepsis, cardiovascular diseases, Alzheimer disease, and chronic pain.[27]

1. Vagotomy: Since the right vagus nerve supplies the sinoatrial node, the VNS is usually implanted in the left vagus nerve to prevent any cardiac dysrhythmias.[29] So, VNS cannot be used in patients who had a bilateral or left cervical vagotomy.
2. Diathermy: Since diathermy treatment (therapeutic ultrasound, microwave or shortwave) could cause heating of the VNS system, well above temperatures that could cause tissue damage to the nerves and blood vessels, it is contraindicated in people who have VNS implants.[30] There is no contraindication to diagnostic ultrasound.

Commonly used vagus nerve stimulator devices consist of an implantable, non-rechargeable battery-powered VNS therapy pulse generator and the VNS therapy lead. There is also an external programming system that is used to change the stimulation setting according to the requirement. They require new batteries in about six years. The VNS therapy lead is placed surgically around the left vagus nerve in the carotid sheath and connected to a subcutaneous programmable pacemaker device that is placed over the left chest wall.

Electrical signals generated from the pulse generator are transmitted to the vagus nerve via the VNS therapy lead. The patients can deactivate (turn OFF) or give an additional burst of stimulation on demand by placing or swiping the magnet provided to them over the pulse generator, respectively. The previously programmed stimulation resumes after the magnet is removed. The device has three modes, manual, automatic, and chronic.[31][32][33]