Vagus nerve stimulator The vagus nerve stimulator (VNS) is a miniature implantable device used to assist in the treatment of drug-refractory epilepsy and depression. It usually consists of a pulse generator, spiral electrodes, flexible leads, and an in vitro control device. The pulse generator is placed in the subcutaneous tissue below the left midclavicular line, the spiral electrode is wrapped around the vagus nerve, the flexible lead is buried in a subcutaneous tunnel that connects the spiral electrode to the pulse generator, and the in vitro control device is used to set the stimulation parameters. After the stimulation parameters are set, the vagus nerve is stimulated by intermittent electrical pulses from the pulse generator, and the vagus nerve excitation is transmitted to the nucleus accumbens for processing and propagation to different areas of the brain, thus achieving the purpose of treating neurological diseases. The vagus nerve is the tenth cranial nerve, which arises from the medulla oblongata and carries both afferent and efferent fibers. The afferent fibers of the vagus nerve are connected to the nucleus tractus solitarius and thus to other brain regions of the central nervous system. Although it is not known how vagal stimulation modulates mood and controls seizures, researchers have proposed mechanisms of action that include altering norepinephrine release from the isolated nucleus to the blue spot, increasing inhibitory GABA levels associated with vagal stimulation, and suppressing abnormal cortical activity through the reticular activation system. 2. History of development In 1997, the U.S. Food and Drug Administration (FDA) approved the use of vagus nerve stimulator (VNS) as an adjunctive treatment for drug-refractory epilepsy, and in 2005, the FDA approved the use of VNS for the treatment of refractory depression. Although the American Psychiatric Association has approved the use of vagus nerve stimulators for the treatment of refractory depression, there is still controversy regarding this approval. According to Dr. John Rush, vice chairman of the Department of Psychiatry at the University of Texas Southwestern Medical Center in Dallas, the results of the vagus nerve stimulator trial study showed that 40% of patients improved by more than 50% according to the Hamilton Depression Inventory (which should be listed at the end of the reference). Many other studies have also demonstrated the effectiveness of vagus nerve stimulators for the treatment of depression. However, the results of these clinical studies have not been validated by follow-up comparisons in patients who do not carry the device. In the only randomized controlled trial, VNS did not have a significant increase in efficacy compared to patients with the implanted device without the stimulation turned on. Charles E. Donovan authored “Out of the Black Hole – A Patient’s Guide to Vagus Nerve Stimulation and Depression” in the research study topic of a research trial of vagus nerve stimulation for refractory depression 3. Stimulation Methods 1) Direct vagus nerve stimulation This is the only widely used method of vagus nerve stimulation treatment available. It requires a vagus nerve stimulator to be surgically implanted into the body. Cyberonics’ vagus nerve stimulator consists of a pulse signal generator, a lead system with electrodes, and a fixation clip to fix the lead to the vagus nerve. The pulse generator is encapsulated in a titanium case, the size of a pocket watch, and powered by a lithium battery. The battery life of the pulse generator varies from 1 to 16 years, depending on the strength of the signal sent, the pulse width, the time interval between nerve stimulation, and the frequency of stimulation. Cyberonics’ vagus nerve stimulator is typically implanted through an outpatient procedure. The procedure is as follows: an incision is made in the upper left corner of the chest and the pulse generator is implanted into a small “pocket” in the left chest below the collarbone. A second incision is made in the neck so that the surgeon has access to the vagus nerve. The surgeon then wraps the wire around the left branch of the vagus nerve and connects the electrode to the generator. Once successfully implanted, the pulse generator sends electrical pulses to the vagus nerve at regular intervals. Since the right vagus nerve interferes with cardiac function, stimulating it would damage the heart, so only the left vagus nerve can be stimulated. 2) Transcutaneous Vagus Nerve Stimulation (t-VNS) This method allows stimulation of the vagus nerve without surgery, using electrical pulses to stimulate areas where the vagus nerve branches have cutaneous manifestations, such as the ear. It is important to note that the nasal turbinates have also been used as a target for transcutaneous vagus nerve stimulation (t-VNS). 4. vagus nerve stimulation for other diseases Kevin J. Tracey found that by inhibiting the production of pro-inflammatory cytokines, vagus nerve stimulators can suppress inflammation. Thus, vagus nerve stimulation can be used to treat inflammatory diseases such as arthritis, colitis, local ischemia, myocardial infarction, congestive heart failure, etc. Action potentials transmitted in the vagus nerve activate the inflammatory reflex efferent arm, the neural circuit that focuses on the spleen to inhibit TNF and other pro-inflammatory cytokines produced by macrophages. This efferent arc is also known as the cholinergic anti-inflammatory pathway. Because this strategy targets the inhibition of TNF and other pro-inflammatory cytokine release, vagus nerve stimulation can be used instead of anti-inflammatory antibodies to treat inflammation. A study published in Science in 2011 (Sept 15, 2011 DOI: 10.1126/science.1209985) demonstrated that the presence of acetylcholine synthesizing T cells in the spleen due to vagus nerve stimulation can suppress the inflammatory response/TNF-α. 5. Other uses Because the vagus nerve is associated with many different functional and brain regions The vagus nerve is associated with many different functions and brain regions, so researchers are conducting scientific research on the use of vagus nerve stimulators in the treatment of other disorders. These disorders include: various anxiety disorders, Alzheimer’s disease, migraine, fibromyalgia, obesity, tinnitus, alcohol addiction, atrial fibrillation, autism, bulimia, combustion-induced organ dysfunction, chronic heart failure, chronic intractable eruption, pathological personality disorder, coronary artery disease, severe myoclonic epilepsy in infants (also known as Dravet syndrome, which is a type of refractory epilepsy syndrome type), sudden dizziness or weakness, heat stroke, intestinal epithelial barrier rupture, diffuse slow spine-slow wave epileptic encephalopathy in childhood (also known as Lennox-Gastaut syndrome, a specific type of epileptic syndrome), mood disorders in the elderly population, myocarditis, multiple sclerosis, obsessive-compulsive disorder, peripheral arterial occlusive disease, postoperative cognitive dysfunction, Rasmussen’s encephalitis, severe mental illness, sepsis, transient focal cerebral ischemia, traumatic hemorrhagic shock, traumatic brain injury, visceral pain response to emotional memory, etc. Other brain stimulation techniques used to treat depression include electroconvulsive therapy (ECT) and transcranial microcurrent stimulation (CES). Research on deep brain stimulation for depression is ongoing; transcranial magnetic stimulation (TMS) for depression and epilepsy; and trigeminal nerve stimulation (TNS) for epilepsy is being studied at UCLA. 6. Side effects 1) Heart disease It has been reported that conductor testing during implantation of the device will cause cardiac arrhythmias and delayed cardiovascular adverse effects. 2) Sleep apnea Studies have shown that patients with vagus nerve stimulator (VNS) implants have intermittent reductions in respiratory flow during sleep. This appears to be due to increased vagal tone when the vagal control measures outweigh the heartbeat. Clinically significant sleep breathing disorders associated with vagus nerve stimulators (VNS) have been identified in pediatric and adult patient populations. Most patients treated with VNS have an increased postoperative apnea hypoventilation index (AHI), with approximately 1/3 of patients presenting with mild obstructive sleep apnea and a minority presenting with severe obstructive sleep apnea associated with VNS. The following measures can usually be used to mitigate such obstructive adverse effects: reduce the frequency and intensity of VNS stimulation; place the patient in a non-supine position during sleep; and apply positive airway pressure ventilation. Screening out symptoms of obstructive sleep apnea (OSA) in epileptic patients with VNS implants is also important because adequate treatment of undiagnosed and untreated OSA symptoms will likely result in better control of epilepsy. In patients who develop obstructive sleep apnea (OSA) phenomena as a result of vagus nerve stimulator (VNS) implantation, vagus nerve stimulator implantation is risky. Therefore, postoperative clinical screening for the development of OSA symptoms is required. Continuous positive airway pressure ventilation (CPAP) is a viable treatment option for patients who develop OSA after VNS implantation. Other options are to increase the duration or frequency of stimulation with a vagus nerve stimulator. With the increasing number of OSA phenomena and the number of patients undergoing the procedure, it is important to properly diagnose and treat the symptoms of obstructive sleep apnea due to vagus nerve stimulator implantation. If a patient experiences symptoms such as loud snoring, intermittent respiratory arrest, behavioral changes, fatigue, or drowsiness after surgery, this will alert the patient and his or her family that obstructive sleep apnea may have developed. However, these phenomena are not easy to detect, so a sleep study (diagnostic polysomnography) is usually required to diagnose the presence of obstructive sleep apnea. The fact that the patients are mostly children with associated cognitive deficits makes it more difficult to diagnose OSA symptoms without a sleep study. Vagus nerve stimulators cause supraglottic and laryngeal recurrent nerve irritation and can produce voice changes (66%), cough (45%), pharyngitis (35%), sore throat (28%), hoarseness (very rare), symptomatic laryngeal muscle spasm and upper airway obstruction (rare). In addition, increased muscle tone (presumably in the upper body) may occur during periods of stimulation. Because the cardiac efferent fibers of the left vagus nerve are proportionally reduced, placing the vagus stimulator on this side may reduce the arrhythmias produced by vagal stimulation, but does not provide good control of reversible slow arrhythmias. Other nonspecific symptoms include headache, nausea, vomiting, dyspepsia, dyspnea, and sensory abnormalities. A randomized controlled trial of vagus nerve stimulators for epilepsy conducted in the United States showed an increase in seizures in 1/3 of patients using a specific vagus nerve stimulator, including an increase of more than 25 percentage points in 17% of patients. In each study there was an increase of more than 100 percentage points in patients. In the E05 study, the range rose to 234 percentage points, while in the E04 study, the maximum range rose even to 680 percentage points.