Vagus nerve stimulation
- 1 Vagus nerve action
- 2 Approval and endorsement
- 3 Patients
- 4 Other uses
- 5 Adverse effects
- 6 Anti-inflammatory activities of vagus nerve stimulation
- 7 Methods of stimulation
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Vagus nerve action
Vagus, the tenth cranial nerve, arises from the medulla and carries both afferent and efferent fibers. The afferent vagal fibers connect to the nucleus of the solitary tract which in turn projects connections to other locations in the central nervous system. Little is understood about exactly how vagal nerve stimulation modulates mood and seizure control but proposed mechanisms include alteration of norepinephrine release by projections of solitary tract to the locus coeruleus, elevated levels of inhibitory GABA related to vagal stimulation and inhibition of aberrant cortical activity by reticular activation system.
Approval and endorsement
In 1997, the United States Food and Drug Administration (FDA) approved the use of VNS as an adjunctive therapy for partial-onset epilepsy. In 2005, the FDA approved the use of VNS for treatment-resistant depression (TRD).
Although the use of VNS for TRD has been endorsed by the American Psychiatric Association, the FDA's approval of VNS for TRD remains controversial. According to Dr. A. John Rush, vice chairman for research in the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas, results of the VNS pilot study showed that 40 percent of the treated patients displayed at least a 50 percent or greater improvement in their condition, according to the Hamilton Depression Rating Scale. Many other studies concur that VNS is indeed efficacious in treating depression. However, these findings do not take into account improvements over time in patients without the device. In the only randomized controlled trial VNS failed to perform any better when turned on than in otherwise similar implanted patients whose device was not turned on.
Charles E. Donovan, a study subject in the investigational trial of vagus nerve stimulation therapy for treatment-resistant depression, wrote Out of the Black Hole: The Patient's Guide to Vagus Nerve Stimulation and Depression.
Because the vagus nerve is associated with many different functions and brain regions, research is being done to determine its usefulness in treating other illnesses, including various anxiety disorders, Alzheimer's disease, migraines, fibromyalgia, obesity, and tinnitus.
- Alcohol addiction
- Atrial fibrillation
- Bulimia nervosa
- Burn-induced organ dysfunction
- Chronic heart failure
- Chronic intractable hiccups
- Comorbid personality disorders
- Coronary artery disease
- Dravet syndrome
- Inhibits heroin seeking behavior in rats
- Intestinal epithelial barrier breakdown
- Lennox-Gastaut syndrome
- Mood disorders in elderly population
- Multiple sclerosis
- Obsessive compulsive disorder
- Peripheral arterial occlusion disease
- Postoperative cognitive dysfunction in elderly patients
- Rasmussen's encephalitis
- Severe mental diseases
- Spinal trigeminal neuronal
- Transient focal cerebral ischemia
- Trauma-hemorrhagic shock
- Traumatic brain injury
- Vaginal-Cervical self-stimulation in women with complete spinal cord injury
- Visceral pain-related affective memory
Other brain stimulation techniques used to treat depression include Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES). Deep brain stimulation is currently under study as a treatment for depression. Transcranial magnetic stimulation (TMS) is under study as a therapy for both depression and epilepsy. Trigeminal Nerve Stimulation (TNS) is being researched at UCLA as a treatment for epilepsy.
Intermittent decrease in respiratory flow during sleep has consistently been demonstrated in patients with VNS implants. This seems to be due to an increase in vagal tone, a measure of the control the vagus nerve has over the heartbeat. Clinically significant sleep disordered breathing associated with VNS has been described in pediatric and adult patient populations. Most patients undergoing VNS treatment experience an increase of apnoea hypopnoea index (AHI) post treatment, up to approximately one third develop mild obstructive sleep apnoea post treatment, and a minority of patients develop severe obstructive sleep aponea related to VNS therapy. These obstructive events can be alleviated by decreasing the frequency or intensity of VNS stimulation, by having the patient sleep in non-supine position or by applying positive airway pressure.
Screening for obstructive sleep apnoea (OSA) in patients with a seizure disorder who are undergoing a VNS implant is also important because adequate treatment of previously undiagnosed and untreated OSA is likely to result in better seizure control in these patients.
Patients undergoing vagal nerve stimulator placement are at risk for developing OSA related to the VNS and should therefore be screened clinically for the presence of OSA after the procedure. Continuous Positive Airway Pressure (CPAP) is a viable therapeutic option for patients who develop OSA related to the VNS. Other options include increasing the cycle length or stimulation frequency of the device. With increasing number of indications and the number of patients undergoing the procedure, awareness of this causation is important for appropriate diagnosis and treatment of OSA related to vagal nerve stimulators.
Symptoms such as loud snoring or intermittent cessation of breathing during the night or daytime symptoms as behavioral changes, fatigue and sleepiness may alert the patient or parent to the presence of obstructive sleep apnoea, but these symptoms are generally insensitive and a sleep study (diagnostic polysomnography) is generally required to diagnose the presence of obstructive sleep apnoea. The fact that many of these patients are children and may have associated cognitive deficits makes diagnosing the problem even more difficult without a sleep study.
VNS causes stimulation of the superior and recurrent laryngeal nerves and is associated with problems ranging from alteration of voice(66%), coughing(45%), pharyngitis(35%) and throat pain(28%) and hoarseness (very common) to frank laryngeal muscle spasm and upper airway obstruction (rare). "Increased muscle tension," presumably in the upper body, may be experienced during the stimulation period. The left vagus has proportionally lesser number of cardiac efferent fibers and placing the stimulator on this side potentially limits the arrhythmogenic effects of vagal stimulation but reversible bradyarrhythmias associated with vagal nerve stimulators have been well described. Other nonspecific symptoms include headache, nausea, vomiting, dyspepsia, dyspnea and paresthesia.
In the treatment of epilepsy, randomized control trials conducted in the United States indicated that one-third of the patients using a particular vagus nerve stimulation device had some type of an increase in seizures, with 17 percent having greater than a 25 percent increase. In each of the studies, there were patients who had greater than a 100 percent increase. In the E05 study, the range went up to a 234 percent increase, while in the E04 study, it went even higher, to a 680 percent maximum range.
Anti-inflammatory activities of vagus nerve stimulation
The discovery by Kevin J. Tracey that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production has led to significant interest in the potential to use this approach for treating inflammatory diseases ranging from arthritis to colitis, ischemia, myocardial infarction, and congestive heart failure. Action potentials transmitted in the vagus nerve activate the efferent arm of the Inflammatory Reflex, the neural circuit that converges on the spleen to inhibit the production of TNF and other pro-inflammatory cytokines by macrophages there. This efferent arc is also known as the Cholinergic anti-inflammatory pathway Because this strategy targets the release of TNF and other pro-inflammatory cytokines, it may be possible to use vagus nerve stimulation instead of anti-inflammatory antibodies (e.g., Remicade or Enbrel) to treat inflammation.
A recent study published in Science (Sept 15, 2011 DOI : 10.1126/science.1209985) demonstrated the existence of acetylcholine-synthesizing T-cells in the spleen that respond to vagal stimulation, resulting in suppression of inflammatory response / TNF-alpha via macrophages.
Methods of stimulation
Direct vagus nerve stimulation
This is currently the only widely used method of therapeutic VNS. It requires the surgical implantation of a stimulator device.
The Cyberonics VNS devices consist of a titanium-encased generator about the size of a pocket watch with a lithium battery to fuel the generator, a lead wire system with electrodes, and an anchor tether to secure leads to the vagus nerve. The battery life for the pulse generator is "between 1 [and] 16 years, depending on the settings [ie how strong the signal being sent is, the length of time the device stimulates the nerve each time, and how frequently the device stimulates the nerve]."
Implantation of the Cyberonics 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 clavicle. 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 device is currently only made by Cyberonics, Inc. However, other "wearable" devices are being tested and developed by other companies that involve transcutaneous stimulation and do not require surgery. These devices are similar to TENS (Transcutaneous Electrical Nerve Stimulation) devices that are often used for pain management.
Transcutaneous vagus nerve stimulation (t-VNS)
This method allows for the stimulation of the vagus nerve without surgical procedure. Electrical impulses are targeted at the aurical (ear), at points where branches of the vagus nerve have cutaneous representation. Specifically the concha has been target for t-VNS.
- Electrical brain stimulation
- Deep brain stimulation
- Transcranial Magnetic Stimulation
- Cranial Electrotherapy Stimulation
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- Clinical trial number NCT00294281 for "Vagus Nerve Stimulation for Treating Adults With Severe Fibromyalgia" at ClinicalTrials.gov
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- Medical Devices That Can Kill
- Report casts doubt on VNS approval
- Vagal inhibition
- The VNS Message Board
- Cyberonics Home Page.
- VNS: A New Tool for Brain Research and Therapy (PDF file).
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- VNS Message Board - Independent forum where VNS patients share their experiences
- FDA OKs Brain Stimulator for Depression - Comments on vagus nerve stimulation for depression
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- The VNS From A Patient's Point Of View
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-  Australian VNS Information
- http://www.fda.gov/foi/warning_letters/archive/g5129d.pdf[dead link] FDA Warning Letter to Cyberonics, Inc.
- Vagus Nerve Stimulation
- Cyberonics Receives Third Determination Letter
- International Neuromodulation Society
- North American Neuromodulation Society
- Therapeutic Neuromodulation Weblog