Vagus nerve stimulation (VNS) is amedical treatment that involves delivering electrical impulses to thevagus nerve. Initially developed byJames Leonard Corning to compress or stimulate the carotid sheath, VNS typically refers to an implantable electrode.[1] 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.[2] Invasive VNS is used as an adjunct treatment for certain types of intractableepilepsy, cluster headaches, migraine,[3]treatment-resistant depression and stroke rehabilitation.
VNS is used to treat drug-resistant epilepsy.[4] For refractive epilepsy, cervical VNS on the left side isFDA-approved.[5][6]
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 eithergeneralized or focal onset seizures without any age restrictions.[7] It is recommended that VNS is only pursued following an adequate trial of at least 2 appropriately chosenanti-seizure medications and that the patient is ineligible for epilepsy surgery.[8] This is because epilepsy surgery is associated with a higher probability of resulting in seizure freedom.[9] Patients who have pooradherence or tolerance of anti-seizure medications may be good candidates for VNS.[10]
VNS may provide benefit for particular epilepsy syndromes and seizure types such asLennox-Gastaut syndrome,tuberous sclerosis complex related epilepsy, refractory absence seizures, andatonic seizures.[11][12][13][14] There are also reports of VNS being successfully utilized in patients with refractory and super-refractorystatus epilepticus.[15]Several clinical studies, including a long-term retrospective review published in 2020, have reported that VNS can reduce seizure frequency in patients with drug-resistant epilepsy associated with structural brain lesions.[16]
The UK National Institute for Health and Care Excellence (NICE) in the UK recommends VNS for cluster headaches.[17] 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.[18] Two randomized, double-blind, and sham-controlled studies have administered nVNS to patients with episodic cluster headaches; both demonstrated a significant effect in reducing acute cluster attacks.[19][20][21]
VNS is used to treat treatment-resistantmajor depressive disorder (TR-MDD).[22] For treatment resistant depression, cervical VNS on the left side is FDA-approved.[5] The UKNICE 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."[23]
VNS has shown to be of value in the treatment ofheart failure.[25] One study did not show a reduction in death rates, but did show improvement in six-minute hall walk duration and quality of life.[25]
Animal studies have shown the capacity of low-level VNS to reduce inducibility ofatrial fibrillation.[25] This effect has been proposed to be due to inhibition of theganglionated plexi.[25]
VNS can be used either invasively or non-invasively to treat ischemic stroke.[26] Invasive VNS can only be applied invasively (by surgery), but non-invasive VNS can be used in acute settings.[26]
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.[27][28]
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.[29] Approximately 50% of patients had an equal to or greater than 50% reduction in seizures at the time of last follow-up.[29] 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.[30] Approximately, 8% have total resolution of seizures.[31] VNS has also been shown to reduce rates of sudden unexpected death in epilepsy (SUDEP) and to improve quality of life metrics.[32][33] 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.[29][31][34]
Long-term cognitive outcomes are at least stable following VNS.[35]
One study of children with epilepsy found that a post hoc analysis revealed a dose–response correlation for VNS.[36]
A 2022 narrative review concluded that VNS is an effective and well-tolerated therapy for chronic and treatment-resistant depression. Importantly, the review also noted that the therapeutic effect of VNS in this context may take 3–12 months to materialize but may be persistent long-term.[37][38] One study of only 10 weeks found no effect.[39]
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.[40]
In one study higher electrical dose parameters were associated with response durability.[41]
VNS may have positive well-being, mood and quality of life effects.[42][43]
Studies have found improvements in standard patient-reported mood assessment scales in adult patients with epilepsy after using VNS,[8] and some have found no association between mood change and reduction in seizure frequency.[44][45]Another study of epilepsy patients measured a general mood improvement, and suggested that VNS may improve unspecific states of indisposition and dysphoria.[46]Patients with comorbid depression have been found to have mood improvements with VNS therapy.[47]
Quality of life (QOL) improvement was also associated with VNS use.[48] 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.[49]
In 2020 during theCOVID-19 pandemic, the gammaCore Sapphire CV non-invasive VNS system was granted emergency use authorization for suspected COVID-19 patients experiencing "asthma-related dyspnea and reduced airflow, and for whom approved drug therapies are not tolerated or provide insufficient symptom relief."[50] Clinical trials show VNS reduces inflammation in COVID patients.[51] In patients withlong COVID, VNS is efficacious in reducing inflammatory markers and chronic fatigue.[52]
Very small studies have shown possible efficacy of VNS for reduction ofSjogren'sfatigue,[53][54] and for inflammatory bowel disease.[55]
PiezoelectricBaTiO3 particles conjugated withcapsaicin were designed as orally ingested electrostimulators to activate the vagus nerves to combatobesity. This intervention has not yet been tested on the human body.[56]
There is evidence that VNS results in cortical desynchronization in epilepsy patients who had a favorable clinical response relative to those who did not.[57][58][59] This makes sense given that seizures consist of abnormal hypersynchronous activity in the brain.
Multiple lines of evidence suggest thatinflammation plays a significant role in epilepsy as well as associated neurobehavioral comorbidities such as depression, autism spectrum disorder and cognitive impairment.[60] There is evidence that VNS has ananti-inflammatory effect through both peripheral and central mechanisms.[61][55]
VNS can change the activity of severalneurotransmitter systems involvingserotonin,norepinephrine,acetylcholine, dopamine, andGABA.[62][63] The vagus nerve has projects reaching directly in thenucleus of the solitary tract[64] and affects a range of subcortical structures including thelocus coeruleus, which serves as the primary source of cortical noradrenaline in the brain.[65] Stimulation of the vagus nerve in rats has been shown to consistently elevate cortical noradrenaline levels in both the short and long-term.[66] Chronic stimulation of the vagus nerve has also been noted to increase serotonin release and firing in thedorsal raphe nuclei.[66] Other studies in rats have also demonstrated a VNS-dependent increase in dopamine concentrations within theprefrontal cortex andnucleus accumbens.[67]
VNS influences the vagus nerve, which plays a role in thegut-brain axis.[68][69] Research has shown that VNS has an anti-inflammatory effect in patients with irritable bowel syndrome.[68] VNS has been shown to reduce cytokine production as well as modulate gut permeability in patients prior to severe burn injuries.[70] Additionally, VNS has been shown to restore dysbiosis in IBD.[70]
A large 25-year retrospective study of 247 patients found a surgical complication rate of 8.6%.[71] The common adverse events included infection in 2.6%,hematoma at the surgical site in 1.9% and vocal cord palsy in 1.4%.[71]
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.[72]
The most common stimulation related side effect at 1 year following implantation arehoarseness in 28% andparaesthesias in the throat-chin region in 12%.[73] 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%.[73] 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 foundsleep apnea in as many as 28% of adults with epilepsy treated with VNS.[74]
Another small study found significant daytime drowsiness, which could be relieved by reducing the stimulation intensity.[75]
Because vagal tone can reduceheart rate, VNS carries the risk ofbradycardia (excessively slow heart rate, and even of stopping the heart.[25]
A range of side effects are possible but rare.[37]
The device consists of a generator the size of a matchbox that is implanted under the skin below the person'scollarbone. Lead wires from the generator are tunnelled up to the patient's neck and wrapped around the left vagus nerve at thecarotid sheath, where it delivers electrical impulses to the nerve.[76]
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.[22][77] 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.[22]
The intravenous VNS system produced byLivaNova 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%).[37] The non-invasive gammaCore device delivers 5000 Hz pulses at a frequency of 25 Hz at an intensity of up to 60mA or 30V. Stimulations may be administered for up to two minutes in one sitting, and a maximum of 30 stimulations can be delivered over a 24h period.[78]
External devices work bytranscutaneous stimulation and do not require surgery. Electrical impulses are targeted at thecervical branch of the vagus nerve in the neck, oraurical (ear), at points where branches of the vagus nerve have cutaneous representation. Auricular VNS should be located at theconcha or inner tragus.[79]
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.[81]
At this time a widely held theory was that excessive blood flow caused seizures.[81]
In the 1880s Corning designed a pronged instrument called the "carotid fork" to compress thecarotid 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.[81]
1930s - research on effects on central nervous system
In the 1930s Biley and Bremer demonstrated the direct influence of VNS on thecentral nervous system.[82] In the 1940s and 1950s vagal nerve stimulation was shown to affect EEG activity.[83]
In 1985 neuroscientist Jacob Zabara[84] proposed that VNS could be used to treat epilepsy.[85] He then demonstrated its efficacy in animal experiments.[86] The first human was implanted with a VNS for the treatment of epilepsy in 1988.[87]
In 1997, the USFood 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 byLivaNova).[76]
The FDA approved an implanted VNS for TR-MDD in 2005.[22]
In April 2017, the FDA cleared marketing of a handheld noninvasive vagus nerve stimulator, called "gammaCore" and made by ElectroCore LLC, for episodiccluster headaches, under thede novo pathway.[88][89] In January 2018, the FDA cleared a new use of that device, for the treatment of migraine pain in adults under a510(k) based on thede novo clearance.[90][91]
In 2020, electroCore's non-invasive VNS was granted anEmergency Use Authorization for treatingCOVID-19 patients, given research indicating VNS causes an opening of end terminals in the airways and an anti-inflammatory effect.[92]
A 2022 study showed that chronic VNS showed strong antidepressant and anxiolytic effects, and improved memory performance in an Alzheimer's Disease animal model.[113]
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