Vagus nerve stimulation

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. 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. Cluster headaches and 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. 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. 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. Chronic pain VNS has been used to treat chronic pain due to various causes, although the mechanisms for this relief have yet to be determined. Heart failure VNS has shown to be of value in the treatment of heart failure. One study did not show a reduction in death rates, but did show improvement in six-minute hall walk duration and quality of life. Invasive VNS can only be applied invasively (by surgery), but non-invasive VNS can be used in acute settings. == 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. 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 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. 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, 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. 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. Clinical trials show VNS reduces inflammation in COVID patients. In patients with long COVID, VNS is efficacious in reducing inflammatory markers and chronic fatigue. Other possible efficacy areas Very small studies have shown possible efficacy of VNS for reduction of Sjogren's fatigue, and for inflammatory bowel disease. Piezoelectric BaTiO3 particles conjugated with capsaicin were designed as orally ingested electrostimulators to activate the vagus nerves 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. The vagus nerve has projects reaching directly in the nucleus of the solitary tract and affects a range of subcortical structures including the locus coeruleus, which serves as the primary source of cortical noradrenaline in the brain. Stimulation of the vagus nerve in rats has been shown to consistently elevate cortical noradrenaline levels in both the short and long-term. Chronic stimulation of the vagus nerve has also been noted to increase serotonin release and firing in the dorsal raphe nuclei. Impacting the gut-brain axis VNS influences the vagus nerve, which plays a role in the gut-brain axis. Research has shown that VNS has an anti-inflammatory effect in patients with irritable bowel syndrome. Additionally, VNS has been shown to restore dysbiosis in IBD. 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%. 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%. 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. 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. The GammaCore transcutaneous cervical VNS system 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 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). 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 indicating VNS causes an opening of end terminals in the airways and an anti-inflammatory effect. In 2021, the same gammaCore nVNS device received Section 510(k) clearance from the FDA to expand its usage for patients with two forms of trigeminal autonomic cephalagia--hemicrania continua and paroxysmal hemicrania. ==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. == See also ==