# Vagus nerve stimulation

Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. Initially developed by Dr. James Corning to compress or stimulate the carotid sheath, VNS typically refers to an implantable electrode. However, non-invasive VNS delivered transcutaneously via the auricular branch of the vagus nerve, or through the skin to the cervical nerve, is being investigated in clinical research. Invasive VNS is used as an adjunct treatment for certain types of intractable epilepsy, cluster headaches, migraine, treatment-resistant depression and stroke rehabilitation.

## Medical use
### Epilepsy

VNS is used to treat drug-resistant epilepsy. For refractive epilepsy, cervical VNS on the left side is FDA-approved.
In the United States, VNS is approved as adjunctive therapy for those 4 years of age or older with refractory focal onset seizures. In the European Union, VNS is approved as an adjunctive therapy for patients with either generalized or focal onset seizures without any age restrictions. It is recommended that VNS is only pursued following an adequate trial of at least 2 appropriately chosen anti-seizure medications and that the patient is ineligible for epilepsy surgery. This is because epilepsy surgery is associated with a higher probability of resulting in seizure freedom. Patients who have poor adherence or tolerance of anti-seizure medications may be good candidates for VNS.
VNS may provide benefit for particular epilepsy syndromes and seizure types such as Lennox-Gastaut syndrome, tuberous sclerosis complex related epilepsy, refractory absence seizures and atonic seizures. There are also reports of VNS being successfully utilized in patients with refractory and super-refractory status epilepticus.

### Cluster headaches & Migraine

The UK National Institute for Health and Care Excellence (NICE) in the UK recommends VNS for cluster headaches. In 2017 the FDA approved the non-invasive gammaCore VNS system for treatment of episodic cluster headache and expanded its approved usage to acute treatment of pain associated with migraine. A The device was used in these studies:
* Tarn J, Evans E, Traianos E, Collins A, Stylianou M, Parikh J, et al. (April 2023). "The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome". Neuromodulation. 26 (3): 681–689. doi:10.1016/j.neurom.2022.08.461. PMID 37032583.
* Natelson BH, Blate M, Soto T (8 November 2022). Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome (Preprint). medRxiv 10.1101/2022.11.08.22281807.</ref>

### Treatment-resistant depression

VNS is used to treat treatment-resistant major depressive disorder (TR-MDD). For treatment resistant depression, cervical VNS on the left side is FDA-approved. The UK NICE guidance (from 2020) stated that "Evidence on its efficacy is limited in quality." and encouraged further research studies "in the form of randomised controlled trials with a placebo or sham stimulation arm."

### Chronic pain

VNS has been used to treat chronic pain due to various causes, although the mechanisms for this relief has yet to be determined.

### Heart failure

VNS has shown to be of value in treatment of heart failure. One study did not show reduction in death rates, but did show improvement in six minute hall walk duration and quality of life.

### Atrial fibrillation

Animal studies have shown the capacity of low-level VNS to reduce inducibility of atrial fibrillation. This effect has been proposed to be due to inhibition of the ganglionated plexi.

### Stroke treatment and rehabilitation

VNS can be used either invasively or non-invasively to treat ischemic stroke. Invasive VNS can only be applied invasively (by surgery), but non-invasive VNS can be applied in acute settings.
In 2021 the U.S. Food and Drug Administration approved the MicroTransponder Vivistim Paired VNS System (Vivistim System) to treat moderate to severe upper extremity motor deficits associated with chronic ischemic stroke.

### Other medical uses

Beyond its use in epilepsy and depression, VNS has shown potential benefits in treating other conditions such as inflammatory diseases. Ongoing research is exploring the broader applications of VNS in various medical fields.

## Efficacy
### Epilepsy

A meta-analysis of 74 clinical studies with 3321 patients found that VNS produced an average 51% reduction in seizures after 1 year of therapy. Approximately 50% of patients had an equal to or greater than 50% reduction in seizures at the time of last follow-up. Long-term studies have shown that response to VNS increases over time. For instance, a study that followed 74 patients for 10–17 years found a seizure frequency reduction of 50-90% in 38.4%, 51.4%, 63.6% and 77.8% of patients at 1-, 2-, 10- and 17-years following implantation, respectively. Approximately, 8% have total resolution of seizures. VNS has also been shown to reduce rates of sudden unexpected death in epilepsy (SUDEP) and to improve quality of life metrics. A number of predictors of a favorable clinical response have been identified including epilepsy onset > 12 years of age, generalized epilepsy type, non-lesional epilepsy, posttraumatic epilepsy and those who have less than a 10-year history of seizures.
Long-term cognitive outcomes are at least stable following VNS.
One study of children with epilepsy found that a post hoc analysis revealed a dose–response correlation for VNS.

### Depression

A 2022 narrative review concluded that "The use of VNS is an approved, effective and well-tolerated long-term therapy for chronic and treatment-resistant depression. Further sham-controlled studies over a longer observational period are desirable".
The review also found that, "Many studies and case series demonstrated the efficacy of VNS as an adjuvant procedure for TRD (treatment resistant depression). The effect occurs with a latency period of 3–12 months and possibly increases with the duration of VNS." One study of only 10 weeks found no effect.
A 2020 review concluded "Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response.
In one study higher electrical dose parameters were associated with response durability.

### Well-being

VNS may have positive well-being, mood and quality of life effects.
Studies have found improvements in standard patient-reported mood assessment scales in adult patients with epilepsy after using VNS, and some have found no association between mood change and reduction in seizure frequency. Another study of epilepsy patients measured a general mood improvement, and suggested that VNS may improve unspecific states of indisposition and dysphoria. Patients with comorbid depression have been found to have mood improvements with VNS therapy.
Quality of life (QOL) improvement was also associated with VNS use. One study of children with epilepsy found that better quality of life outcomes after VNS implantation were strongly associated with shorter duration of preoperative seizures and implantation at a young age.
Anxiety reduction has been associated with VNS use. Another study showed improvement in anxiety, depression and QOL scores that were not correlated with a reduction in seizure frequency.
However these studies were small, and recommendations have been made that larger studies with randomised control groups be undertaken.

### Heart diseases

In cardiac arrest VNS used in conjunction with cardiopulmonary resuscitation (CPR) has been shown to increase recovery time (return of spontaneous circulation) as well as reduce the number of shocks required when used in conjunction with cardioversion. Numerous pre-clinical studies have shown the effectiveness of VNS in reducing atrial fibrillation and hypertension.

### Other possible efficacy areas

Very small studies have shown possible efficacy of VNS for reduction of Sjogren's fatigue, and for bowel inflammatory disease.
Piezoelectric BaTiO3 particles conjugated with capsaicin were designed as orally Ingested electrostimulators to activate the vagus nervers to combat obesity. This intervention has not yet been tested on the human body.

## Mechanisms of action

The causes of VNS efficacy are not well understood.
Mechanisms which may account for the efficacy of VNS include:

### Cortical desynchronization

There is evidence that VNS results in cortical desynchronization in epilepsy patients who had a favorable clinical response relative to those who did not. This makes sense given that seizures consist of abnormal hypersynchronous activity in the brain.

### Reducing inflammation

Multiple lines of evidence suggest that inflammation plays a significant role in epilepsy as well as associated neurobehavioral comorbidities such as depression, autism spectrum disorder and cognitive impairment. There is evidence that VNS has an anti-inflammatory effect through both peripheral and central mechanisms.

### Changing neurotransmitter activity

VNS can change the activity of several neurotransmitter systems involving serotonin, norepinephrine and GABA. These neurotransmitters are involved in both epilepsy and other neuropsychiatric conditions such as depression and anxiety.

### Changing brain region connectivity

VNS may alter the functional connectivity in several brain regions and enhance synaptic plasticity to reduce excitatory activity involved in seizures. It has also been shown to change the functional connectivity of the default mode network in depressed patients.

### Impacting the gut-brain axis

VNS may influence the vagus nerve, which plays a role in the gut-brain axis.

### Indirect stimulation of brain structures

Some believe that indirect stimulation of the thalamus may be a key mechanism in VNS efficacy.

## Adverse events
### Adverse events related to the surgical procedure

A large 25-year retrospective study of 247 patients found a surgical complication rate of 8.6%. The common adverse events included infection in 2.6%, hematoma at the surgical site in 1.9% and vocal cord palsy in 1.4%.
In some rare cases where the VNS is not effective, surgery may be necessary to remove the VNS system. The surgery may remove both the generator and the lead.

### Side effects of VNS

The most common stimulation related side effect at 1 year following implantation are hoarseness in 28% and paraesthesias in the throat-chin region in 12%. At the third year the rate of stimulation related adverse effects decreased substantially with shortness of breath being the most common and occurring in 3.2%. In general, VNS is well tolerated and side effects diminish over time. Also, side effects can be controlled by changing the stimulation parameters.
One small study found sleep apnea in as many as 28% of adults with epilepsy treated with VNS.
Another small study found significant daytime drowsiness, which could be relieved by reducing the stimulation intensity.
Because vagal tone can reduce heart rate, VNS carries the risk of bradycardia (excessively slow heart rate, and even of stopping the heart.
A range of side effects are possible but rare.

## Devices and procedures
### Intravenous devices

The device consists of a generator the size of a matchbox that is implanted under the skin below the person's collarbone. Lead wires from the generator are tunnelled up to the patient's neck and wrapped around the left vagus nerve at the carotid sheath, where it delivers electrical impulses to the nerve.
Implantation of the VNS device is usually done as an out-patient procedure. The procedure goes as follows: an incision is made in the upper left chest and the generator is implanted into a little "pouch" on the left chest under the collarbone. A second incision is made in the neck, so that the surgeon can access the vagus nerve. The surgeon then wraps the leads around the left branch of the vagus nerve, and connects the electrodes to the generator. Once successfully implanted, the generator sends electric impulses to the vagus nerve at regular intervals. The left vagus nerve is stimulated rather than the right because the right plays a role in cardiac function such that stimulating it could have negative cardiac effects. The "dose" administered by the device then needs to be set, which is done via a magnetic wand; the parameters adjusted include current, frequency, pulse width, and duty cycle.

#### Example of stimulation metrics

The intravenous VNS system produced by LivaNova has stated default settings for use in depression of output power 1.25mA, frequency 20 Hz and pulse width 250 μs, with operation occurring for 30 seconds every 5 minutes (giving a work cycle of 10%).

### External devices

External devices work by transcutaneous stimulation and do not require surgery. Electrical impulses are targeted at the cervical branch of the vagus nerve in the neck, or aurical (ear), at points where branches of the vagus nerve have cutaneous representation. Auricular VNS should be located at the concha or inner tragus.
GammaCore is recommended by The National Institute for Health and Care Excellence (NICE) for cluster headaches.

## History
### 1880s - proposed use to reduce cerebral blood flow

James L. Corning (1855-1923) was an American neurologist who developed the first device for stimulating the vagus nerve towards the end of the 19th century.
At this time a widely held theory was that excessive blood flow caused seizures.
In the 1880s Corning designed a pronged instrument called the “carotid fork” to compress the carotid artery for the acute treatment of seizures. In addition, he developed the “carotid truss” for prolonged compression of the carotid arteries as a long-term preventative treatment for epilepsy. Then he developed the “electrocompressor” which allowed for the compression of the bilateral carotid arteries as well as electrical stimulation of both the vagus and cervical sympathetic nerves. The idea was to reduce cardiac output and to stimulate cervical sympathetic nerves to constrict cerebral blood vessels. Corning reported dramatic benefits however it was not accepted by his colleagues and ultimately was forgotten.

### 1930s - research on effects on central nervous system

In the 1930s Biley and Bremer demonstrated the direct influence of VNS on the central nervous system. In the 1940s and 1950s vagal nerve stimulation was shown to affect EEG activity.

### 1980s - use for epilepsy

In 1985 neuroscientist Jacob Zabara proposed that VNS could be used to treat epilepsy. He then demonstrated its efficacy in animal experiments. The first human was implanted with a VNS for the treatment of epilepsy in 1988.

### 1997 onwards - approved medical uses

In 1997, the US Food and Drug Administration's neurological devices panel met to consider approval of an implanted vagus nerve stimulator (VNS) for epilepsy, requested by Cyberonics (which was subsequently acquired by LivaNova).
The FDA approved an implanted VNS for TR-MDD in 2005.
In April 2017, the FDA cleared marketing of a handheld noninvasive vagus nerve stimulator, called "gammaCore" and made by ElectroCore LLC, for episodic cluster headaches, under the de novo pathway. In January 2018, the FDA cleared a new use of that device, for the treatment of migraine pain in adults under a 510(k) based on the de novo clearance.
In 2020, electroCore's non-invasive VNS was granted an Emergency Use Authorization for treating COVID-19 patients, given Research has shown this pulse train causes airways in the lungs to open its anti-inflammatory effect.

## Research areas

Because the vagus nerve is associated with many different functions and brain regions, clinical research has been done to determine its usefulness in treating many illnesses. These include various anxiety disorders, obesity, alcohol addiction, chronic heart failure, prevention of arrhythmias that can cause sudden cardiac death, autoimmune disorders, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, hypertension, several chronic pain conditions, inflammatory disorders, fibromyalgia and migraines.
A 2022 study showed that chronic VNS showed strong antidepressant and anxiolytic effects, and improved memory performance in an Alzheimer's Disease animal model.