Vagus nerve stimulation (VNS) is a
medical treatment
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
that involves delivering electrical impulses to the
vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
. It is used as an add-on treatment for certain types of intractable
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
and
treatment-resistant depression
Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...
.
Medical use
VNS devices are used to treat drug-resistant epilepsy and treatment-resistant
major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
(TR-MDD).
[ ]
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
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
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. Patients with comorbid depression have been found to have mood improvements with VNS therapy.
VNS may provide benefit for particular epilepsy syndromes and seizure types such as
Lennox-Gastaut syndrome,
tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination ...
related epilepsy, refractory absence seizures and
atonic seizures An atonic seizure (also called drop seizure, akinetic seizure, astatic seizure, or drop attack) is a type of seizure that consists of partial or complete loss of muscle tone that is caused by temporary alterations in brain function. These seizures ...
. There are also reports of VNS being successfully utilized in patients with refractory and super-refractory
status epilepticus
Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...
.
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.
Depression
As of 2017, the efficacy of VNS for TR-MDD is unclear.
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".
Mechanism of action
The
vagus
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right v ...
nerve is the tenth
cranial nerve
Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and ...
and arises from a series of rootlets in the
medulla
Medulla or Medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ovary
* Medulla of th ...
; it carries both
afferent (80%) and
efferent
Efferent may refer to:
Anatomical structures
Meaning 'conveying away from a center':
*Efferent arterioles, conveying blood away from the Bowman's capsule in the kidney
*Efferent nerve fiber, carries nerve impulses away from the central nervous sy ...
(20%) fibers. It has the longest and widest distribution of all the cranial nerves and functions as a bidirectional link between the brain and peripheral organs. Afferents from the vagus nerve project to the
nucleus tractus solitarius which subsequently communicates with other regions of the brain including the
dorsal raphe nucleus
The dorsal raphe nucleus is located on the midline of the brainstem and is one of the raphe nuclei. It has rostral and caudal subdivisions.
* The rostral aspect of the ''dorsal'' raphe is further divided into interfascicular, ventral, ventrolatera ...
,
locus coeruleus
The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system.
The locus coerule ...
,
amygdala
The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
and other areas.
There are multiple potential mechanisms which may account for the efficacy of VNS in treating epilepsy and other conditions including:
1. 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.
2. 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.
3. VNS can change the activity of several
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
systems involving
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
and
GABA. These neurotransmitters are involved in both epilepsy and other neuropsychiatric conditions such as depression and anxiety.
4. 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 neuroscience, the default mode network (DMN), also known as the default network, default state network, or anatomically the medial frontoparietal network (M-FPN), is a large-scale brain network primarily composed of the dorsal medial prefro ...
in depressed patients.
Adverse events
There are two categories of adverse events associated with VNS: (1) those related to the surgical procedure and (2) those related to stimulation. 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
A hematoma, also spelled haematoma, or blood suffusion is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillary, capillaries. A he ...
at the surgical site in 1.9% and vocal cord palsy in 1.4%.
The most common stimulation related side effect at 1 year following implantation are
hoarseness
A hoarse voice, also known as dysphonia or hoarseness, is when the voice involuntarily sounds breathy, raspy, or strained, or is softer in volume or lower in pitch. A hoarse voice, can be associated with a feeling of unease or scratchiness in the ...
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.
There is evidence that VNS can induce
sleep apnea
Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...
in as many as 28% of adult patients.
Devices and procedures
The device consists of a generator the size of a matchbox that is implanted under the skin below the person’s
collarbone
The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the right ...
. 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.][
"Wearable" devices are being tested and developed that involve transcutaneous stimulation and do not require surgery. Electrical impulses are targeted at the aurical (ear), at points where branches of the vagus nerve have cutaneous representation; such devices had been tested in clinical trials for treatment resistant major depressive disorder as of 2017.]
History
Early History
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 that 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 Carotid artery may refer to:
* Common carotid artery, often "carotids" or "carotid", an artery on each side of the neck which divides into the external carotid artery and internal carotid artery
* External carotid artery, an artery on each side of t ...
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.
In the 1930s Biley and Bremer demonstrated the direct influence of VNS on the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. This was in contrary to Corning who had intended to use it to reduce cerebral blood flow. In the 1940s and 1950s vagal nerve stimulation was shown to affect EEG activity. Finally, nearly 100 years since Corning, 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.
Later History
In 1997, the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
'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
LivaNova, PLC is an American medical device manufacturer domiciled in the UK. The company develops devices used for cardiac surgery and neuromodulation. The company was formed in 2015 by a $2.7B merger between Houston, Texas-based Cyberonics, I ...
).[
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
Cluster headache (CH) is a neurological disorder characterized by recurrent severe headaches on one side of the head, typically around the eye(s). There is often accompanying eye watering, nasal congestion, or swelling around the eye on the af ...
, 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)
The United States Federal Food, Drug, and Cosmetic Act (abbreviated as FFDCA, FDCA, or FD&C) is a set of laws passed by the United States Congress in 1938 giving authority to the U.S. Food and Drug Administration (FDA) to oversee the safety of f ...
based on the de novo clearance.
In 2020, electroCore's non-invasive VNS was granted an Emergency Use Authorization
An Emergency Use Authorization (EUA) in the United States is an authorization granted to the Food and Drug Administration (FDA) under sections of the Federal Food, Drug, and Cosmetic Act as added to and amended by various Act of Congress, Acts of ...
for treating COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
patients, given Research has shown this pulse train causes airways in the lungs to open its anti-inflammatory effect.
Research
Because the vagus nerve is associated with many different functions and brain regions, clinical research has been done to determine its usefulness in treating other illnesses, including various anxiety disorder
Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
s, obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
, alcohol addiction, chronic heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, prevention of arrhythmias that can cause sudden cardiac death
Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
, autoimmune disorders
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
, irritable bowel syndrome
Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...
, Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, and several chronic pain
Chronic pain is classified as pain that lasts longer than three to six months. In medicine, the distinction between Acute (medicine), acute and Chronic condition, chronic pain is sometimes determined by the amount of time since onset. Two commonly ...
conditions. A recent study showed that chronic VNS showed strong antidepressant and anxiolytic effects, and improved memory performance in an Alzheimer's Disease animal model.
tVNS has also been shown to enhance memory in healthy adults.
VNS has also been studied in small trials of people with neurodevelopmental disorders
Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
, generally who also have had epilepsy, including Landau-Kleffner syndrome, Rett syndrome
Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often h ...
, and autism spectrum disorders
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
. VNS is being studied as of 2018 as a treatment for migraines
Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
and fibromyalgia
Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...
.
Transcutaneous
As of 2015, VNS devices were being developed that were not implanted, but rather transmitted signals through the skin, known as transcutaneous vagus nerve stimulation (tVNS). Electrical impulses are targeted at the auricle of the ear at points where branches of the vagus nerve are close to the surface. It is non-invasive and based on the rationale that there is vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...
distribution on the surface of the ear. tVNS is being studied for stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
and the treatment of depression.
See also
References
Further reading
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{{DEFAULTSORT:Vagus Nerve Stimulation
Electrotherapy
Implants (medicine)
Neurology procedures
Neuroprosthetics
Neurotechnology
Surgery