Vagus nerve stimulation

Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. It is used as an add-on treatment for certain types of intractable epilepsy, cluster headaches, treatment-resistant depression and stroke rehabilitation.

Vagus nerve stimulation
Electrical stimulation of vagus nerve.
Other names	Vagal nerve stimulation
[edit on Wikidata]

Medical use

Epilepsy

VNS is used to treat drug-resistant epilepsy.^[1]

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.^[2] 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.^[3] This is because epilepsy surgery is associated with a higher probability of resulting in seizure freedom.^[4] Patients who have poor adherence or tolerance of anti-seizure medications may be good candidates for VNS.^[5]

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.^[6][7][8][9] There are also reports of VNS being successfully utilized in patients with refractory and super-refractory status epilepticus.^[10]

Cluster headaches

The UK National Institute for Health and Care Excellence (NICE) in the UK recommends VNS for cluster headaches.^[11]

Treatment-resistant depression

VNS is used to treat treatment-resistant major depressive disorder (TR-MDD). ^[12] The UK NICE 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."^[13]

Stroke rehabilitation

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.^[14][15]

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.^[16] Approximately 50% of patients had an equal to or greater than 50% reduction in seizures at the time of last follow-up.^[16] 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.^[17] Approximately, 8% have total resolution of seizures.^[18] VNS has also been shown to reduce rates of sudden unexpected death in epilepsy (SUDEP) and to improve quality of life metrics.^[19][20] 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.^[16][18][21]

Long-term cognitive outcomes are at least stable following VNS.^[22]

One study of children with epilepsy found that a post hoc analysis revealed a dose–response correlation for VNS.^[23]

Depression

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".^[24][25]

The review also found that, "Many studies and case series demonstrated the efficacy of VNS as an adjuvant procedure for TRD (treatment resistant depression). The effect occurs with a latency period of 3–12 months and possibly increases with the duration of VNS."^[24] One study of only 10 weeks found no effect.^[26]

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.^[27]

In one study higher electrical dose parameters were associated with response durability.^[28]

Wellbeing

VNS may have positive wellbeing, mood and quality of life effects.^[29][30]

Studies have found improvements in standard patient-reported mood assessment scales in adult patients with epilepsy after using VNS,^[3] and some have found no association between mood change and reduction in seizure frequency.^[31][32] Another study of epilepsy patients measured a general mood improvement, and suggested that VNS may improve unspecific states of indisposition and dysphoria.^[33] Patients with comorbid depression have been found to have mood improvements with VNS therapy.^[34]

Quality of life (QOL) improvement was also associated with VNS use.^[35] 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.^[36]

Anxiety reduction has been associated with VNS use.^[37][38][39] Another study showed improvement in anxiety, depression and QOL scores that were not correlated with a reduction in seizure frequency.^[40]

However these studies were small, and recommendations have been made that larger studies with randomised control groups be undertaken.^[41]

Other possible efficacy areas

Very small studies have shown possible efficacy of VNS for reduction of Sjogren's fatigue,^[42][43] and for bowel inflammatory disease.^[44]

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.^[45][46][47] 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.^[48] There is evidence that VNS has an anti-inflammatory effect through both peripheral and central mechanisms.^[49][44]

Changing neurotransmitter activity

VNS can change the activity of several neurotransmitter systems involving serotonin, norepinephrine and GABA.^[50][51] These neurotransmitters are involved in both epilepsy and other neuropsychiatric conditions such as depression and anxiety.

Changing brain region connectivity

VNS may alter the functional connectivity in several brain regions and enhance synaptic plasticity to reduce excitatory activity involved in seizures.^[52][53] It has also been shown to change the functional connectivity of the default mode network in depressed patients.^[54]

Impacting the gut-brain axis

VNS may influence the vagus nerve, which plays a role in the gut-brain axis.^[55][56]

Indirect stimulation of brain structures

Some believe that indirect stimulation of the thalamus may be a key mechanism in VNS efficacy.^[57]

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%.^[58] The common adverse events included infection in 2.6%, hematoma at the surgical site in 1.9% and vocal cord palsy in 1.4%.^[58]

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%.^[59] 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%.^[59] 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 found sleep apnea in as many as 28% of adults with epilepsy treated with VNS.^[60]

Another small study found significant daytime drowsiness, which could be relieved by reducing the stimulation intensity.^[40]

A range of side effects are possible but rare.^[24]

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.^[61]

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.^[12][62] 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.^[12]

Example of stimulation metrics

The intravenous VNS system produced by LivaNova has stated default settings for use in depression of output power 1.25mA, freqency 20 Hz and pulse width 250µSec, with operation occurring for 30 seconds every 5 minutes (giving a work cycle of 10%).^[24]

External devices

External devices work by transcutaneous stimulation and do not require surgery. Electrical impulses are targeted at the vagus nerve in the neck, or aurical (ear), at points where branches of the vagus nerve have cutaneous representation. GammaCore is recommended by The National Institute for Health and Care Excellence (NICE) for cluster headaches.^[63]

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.^[64]

At this time a widely held theory was that excessive blood flow caused seizures.^[64]

In the 1880s Corning designed a pronged instrument called the “carotid fork” to compress the carotid 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.^[64]

1930s - research on effects on central nervous system

In the 1930s Biley and Bremer demonstrated the direct influence of VNS on the central nervous system.^[65] In the 1940s and 1950s vagal nerve stimulation was shown to affect EEG activity.^[66]

1980s - use for epilepsy

In 1985 neuroscientist Jacob Zabara^[67] proposed that VNS could be used to treat epilepsy.^[68] He then demonstrated its efficacy in animal experiments.^[69] The first human was implanted with a VNS for the treatment of epilepsy in 1988.^[70]

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).^[61]

The FDA approved an implanted VNS for TR-MDD in 2005.^[12]

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, under the de novo pathway.^[71][72] 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.^[73][74]

In 2020, electroCore's non-invasive VNS was granted an Emergency Use Authorization for treating COVID-19 patients, given Research has shown this pulse train causes airways in the lungs to open its anti-inflammatory effect.^[75]

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,^[76] obesity,^[77][78] alcohol addiction,^[79] chronic heart failure,^[80] prevention of arrhythmias that can cause sudden cardiac death,^[81] autoimmune disorders,^[82][83] irritable bowel syndrome,^[84][85][86] Alzheimer's disease,^[87][88] Parkinson's disease,^[89] hypertension,^[90][91] several chronic pain conditions,^[92] inflammatory disorders, fibromyalgia and migraines.^[93][94]

A 2022 study showed that chronic VNS showed strong antidepressant and anxiolytic effects, and improved memory performance in an Alzheimer's Disease animal model.^[95]

See also

• Cranial electrotherapy stimulation
• Deep brain stimulation
• Electrical brain stimulation
• Electrotherapy
• Low field magnetic stimulation
• Transcranial magnetic stimulation

References

1. Panebianco M, Rigby A, Marson AG (14 July 2022). "Vagus nerve stimulation for focal seizures". Cochrane Database of Systematic Reviews. 2022 (7): CD002896. doi:10.1002/14651858.CD002896.pub3. PMC 9281624. PMID 35833911.
2. Wheless JW, Gienapp AJ, Ryvlin P (November 2018). "Vagus nerve stimulation (VNS) therapy update". Epilepsy & Behavior. 88: 2–10. doi:10.1016/j.yebeh.2018.06.032. PMID 30017839. S2CID 51679627.
3. Morris GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C (15 October 2013). "Evidence-based guideline update: Vagus nerve stimulation for the treatment of epilepsy: Report of the Guideline Development Subcommittee of the American Academy of Neurology". Neurology. 81 (16): 1453–1459. doi:10.1212/wnl.0b013e3182a393d1. PMC 3806910. PMID 23986299.
4. Fisher RS, Handforth A (September 1999). "Reassessment: Vagus nerve stimulation for epilepsy [RETIRED]: A Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology". Neurology. 53 (4): 666–669. doi:10.1212/wnl.53.4.666. PMID 10489023. S2CID 20845641.
5. Helmers SL, Duh MS, Guérin A, Sarda SP, Samuelson TM, Bunker MT, Olin BD, Jackson SD, Faught E (October 2011). "Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy". Epilepsy & Behavior. 22 (2): 370–375. doi:10.1016/j.yebeh.2011.07.020. PMID 21872534. S2CID 7869407.
6. Grioni D, Landi A (January 2019). "Does Vagal Nerve Stimulation Treat Drug-Resistant Epilepsy in Patients with Tuberous Sclerosis Complex?". World Neurosurgery. 121: 251–253. doi:10.1016/j.wneu.2018.10.077. PMID 30347295. S2CID 53034756.
7. Braakman HM, Creemers J, Hilkman DM, Klinkenberg S, Koudijs SM, Debeij-van Hall M, Cornips EM (2018). "Improved seizure control and regaining cognitive milestones after vagus nerve stimulation revision surgery in Lennox–Gastaut syndrome". Epilepsy & Behavior Case Reports. 10: 111–113. doi:10.1016/j.ebcr.2018.08.002. PMC 6197149. PMID 30364578.
8. Arya R, Greiner HM, Lewis A, Mangano FT, Gonsalves C, Holland KD, Glauser TA (May 2013). "Vagus nerve stimulation for medically refractory absence epilepsy". Seizure. 22 (4): 267–270. doi:10.1016/j.seizure.2013.01.008. PMID 23391567. S2CID 14917920.
9. Rolston JD, Englot DJ, Wang DD, Garcia PA, Chang EF (October 2015). "Corpus callosotomy versus vagus nerve stimulation for atonic seizures and drop attacks: A systematic review". Epilepsy & Behavior. 51: 13–17. doi:10.1016/j.yebeh.2015.06.001. PMC 5261864. PMID 26247311.
10. Dibué-Adjei M, Brigo F, Yamamoto T, Vonck K, Trinka E (September 2019). "Vagus nerve stimulation in refractory and super-refractory status epilepticus – A systematic review". Brain Stimulation. 12 (5): 1101–1110. doi:10.1016/j.brs.2019.05.011. PMID 31126871. S2CID 153310356.
11. https://www.nice.org.uk/guidance/mtg46/documents/final-scope The Nurosym/Parasym device was used in these studies:
    • Tarn J, Evans E, Traianos E, Collins A, Stylianou M, Parikh J, Bai Y, Guan Y, Frith J, Lendrem D, Macrae V, McKinnon I, Simon BS, Blake J, Baker MR, Taylor JP, Watson S, Gallagher P, Blamire A, Newton J, Ng WF (April 2023). "The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome". Neuromodulation: Technology at the Neural Interface. 26 (3): 681–689. doi:10.1016/j.neurom.2022.08.461. PMID 37032583.
    • Natelson BH, Blate M, Soto T (8 November 2022). Transcutaneous Vagus Nerve Stimulation in the Treatment of Long Covid-Chronic Fatigue Syndrome (Preprint). medRxiv 10.1101/2022.11.08.22281807.
12. Carreno FR, Frazer A (July 2017). "Vagal Nerve Stimulation for Treatment-Resistant Depression". Neurotherapeutics. 14 (3): 716–727. doi:10.1007/s13311-017-0537-8. PMC 5509631. PMID 28585221.
13. "1 Recommendations | Implanted vagus nerve stimulation for treatment-resistant depression | Guidance | NICE". 12 August 2020.
14. "FDA Approves First-of-Its-Kind Stroke Rehabilitation System". Food and Drug Administration. 31 August 2021.
15. Liu CY, Russin J, Adelson DP, Jenkins A, Hilmi O, Brown B, Lega B, Whitworth T, Bhattacharyya D, Schwartz TH, Krishna V, Williams Z, Uff C, Willie J, Hoffman C, Vandergrift WA, Achrol AS, Ali R, Konrad P, Edmonds J, Kim D, Bhatt P, Tarver BW, Pierce D, Jain R, Burress C, Casavant R, Prudente CN, Engineer ND (November 2022). "Vagus nerve stimulation paired with rehabilitation for stroke: Implantation experience from the VNS-REHAB trial". Journal of Clinical Neuroscience. 105: 122–128. doi:10.1016/j.jocn.2022.09.013. PMID 36182812.
16. Englot DJ, Chang EF, Auguste KI (December 2011). "Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response: A review". Journal of Neurosurgery. 115 (6): 1248–1255. doi:10.3171/2011.7.JNS11977. PMID 21838505.
17. Chrastina J, Novák Z, Zeman T, Kočvarová J, Pail M, Doležalová I, Jarkovský J, Brázdil M (July 2018). "Single-center long-term results of vagus nerve stimulation for epilepsy: A 10–17 year follow-up study". Seizure. 59: 41–47. doi:10.1016/j.seizure.2018.04.022. PMID 29738985. S2CID 13700901.
18. Englot DJ, Rolston JD, Wright CW, Hassnain KH, Chang EF (September 2016). "Rates and Predictors of Seizure Freedom With Vagus Nerve Stimulation for Intractable Epilepsy". Neurosurgery. 79 (3): 345–353. doi:10.1227/NEU.0000000000001165. PMC 4884552. PMID 26645965.
19. Englot DJ, Hassnain KH, Rolston JD, Harward SC, Sinha SR, Haglund MM (January 2017). "Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data". Epilepsy & Behavior. 66: 4–9. doi:10.1016/j.yebeh.2016.10.005. PMC 5258831. PMID 27974275.
20. Ryvlin P, So EL, Gordon CM, Hesdorffer DC, Sperling MR, Devinsky O, Bunker MT, Olin B, Friedman D (March 2018). "Long-term surveillance of SUDEP in drug-resistant epilepsy patients treated with VNS therapy". Epilepsia. 59 (3): 562–572. doi:10.1111/epi.14002. PMID 29336017. S2CID 3782079.
21. Englot DJ, Rolston JD, Wang DD, Hassnain KH, Gordon CM, Chang EF (November 2012). "Efficacy of vagus nerve stimulation in posttraumatic versus nontraumatic epilepsy: Clinical article". Journal of Neurosurgery. 117 (5): 970–977. doi:10.3171/2012.8.jns122. PMID 22978542.
22. Lam J, Williams M, Ashla M, Lee DJ (May 2021). "Cognitive outcomes following vagus nerve stimulation, responsive neurostimulation and deep brain stimulation for epilepsy: A systematic review". Epilepsy Research. 172: 106591. doi:10.1016/j.eplepsyres.2021.106591. PMID 33711711. S2CID 231956548.
23. Orosz I, McCormick D, Zamponi N, Varadkar S, Feucht M, Parain D, Griens R, Vallée L, Boon P, Rittey C, Jayewardene AK, Bunker M, Arzimanoglou A, Lagae L (2014). "Vagus nerve stimulation for drug-resistant epilepsy: A European long-term study up to 24 months in 347 children". Epilepsia. 55 (10): 1576–1584. doi:10.1111/epi.12762. PMID 25231724. S2CID 25790247.
24. Reif-Leonhard C, Reif A, Baune BT, Kavakbasi E (September 2022). "Vagusnervstimulation bei schwer zu behandelnden Depressionen". Der Nervenarzt. 93 (9): 921–930. doi:10.1007/s00115-022-01282-6. PMC 9452433. PMID 35380222.
25. Kron T (5 May 2022). "Vagus Nerve Stimulation: A Little-Known Option for Depression". Medscape.
26. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG (September 2005). "Vagus Nerve Stimulation for Treatment-Resistant Depression: A Randomized, Controlled Acute Phase Trial". Biological Psychiatry. 58 (5): 347–354. doi:10.1016/j.biopsych.2005.05.025. PMID 16139580.
27. Assenza G, Tombini M, Lanzone J, Ricci L, Di Lazzaro V, Casciato S, Morano A, Giallonardo AT, Di Bonaventura C, Beghi E, Ferlazzo E, Gasparini S, Giuliano L, Pisani F, Benna P, Bisulli F, De Falco FA, Franceschetti S, La Neve A, Meletti S, Mostacci B, Sartucci F, Striano P, Villani F, Aguglia U, Avanzini G, Belcastro V, Bianchi A, Cianci V, Labate A, Magaudda A, Michelucci R, Verri A, Zaccara G, Pizza V, Tinuper P, Di Gennaro G (November 2020). "Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review". Neurological Sciences. 41 (11): 3075–3084. doi:10.1007/s10072-020-04479-2. PMID 32524324. S2CID 219567684.
28. Aaronson ST, Carpenter LL, Conway CR, Reimherr FW, Lisanby SH, Schwartz TL, Moreno FA, Dunner DL, Lesem MD, Thompson PM, Husain M, Vine CJ, Banov MD, Bernstein LP, Lehman RB, Brannon GE, Keepers GA, O'Reardon JP, Rudolph RL, Bunker M (July 2013). "Vagus Nerve Stimulation Therapy Randomized to Different Amounts of Electrical Charge for Treatment-Resistant Depression: Acute and Chronic Effects". Brain Stimulation. 6 (4): 631–640. doi:10.1016/j.brs.2012.09.013. PMID 23122916.
29. Arredondo K, Patel AD (2023). "Quality of life, neurocognitive outcomes, and mood effects with neurostimulation devices". Neurostimulation for Epilepsy. pp. 229–244. doi:10.1016/B978-0-323-91702-5.00004-9. ISBN 978-0-323-91702-5.
30. Schachter SC (February 2004). "Vagus nerve stimulation: mood and cognitive effects". Epilepsy & Behavior. 5: 56–59. doi:10.1016/j.yebeh.2003.11.007. PMID 14725847.
31. Elger G, Hoppe C, Falkai P, Rush A, Elger CE (December 2000). "Vagus nerve stimulation is associated with mood improvements in epilepsy patients". Epilepsy Research. 42 (2–3): 203–210. doi:10.1016/s0920-1211(00)00181-9. PMID 11074193.
32. Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR (April 2000). "A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation". Epilepsy & Behavior. 1 (2): 93–99. doi:10.1006/ebeh.2000.0046. PMID 12609137.
33. Hoppe C, Helmstaedter C, Scherrmann J, Elger CE (August 2001). "Self-Reported Mood Changes following 6 Months of Vagus Nerve Stimulation in Epilepsy Patients". Epilepsy & Behavior. 2 (4): 335–342. doi:10.1006/ebeh.2001.0194. PMID 12609210. S2CID 22552070.
34. Fan JJ, Shan W, Wu JP, Wang Q (November 2019). "Research progress of vagus nerve stimulation in the treatment of epilepsy". CNS Neuroscience & Therapeutics. 25 (11): 1222–1228. doi:10.1111/cns.13209. PMC 6834923. PMID 31429206.
35. Ryvlin P, Gilliam FG, Nguyen DK, Colicchio G, Iudice A, Tinuper P, Zamponi N, Aguglia U, Wagner L, Minotti L, Stefan H, Boon P, Sadler M, Benna P, Raman P, Perucca E (2014). "The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial". Epilepsia. 55 (6): 893–900. doi:10.1111/epi.12611. PMC 4283995. PMID 24754318.
36. Knorr C, Greuter L, Constantini S, Fried I, Kremer U, Datta AN, Guzman R, Soleman J (2021). "Subgroup analysis of seizure and cognitive outcome after vagal nerve stimulator implantation in children". Child's Nervous System. 37 (1): 243–252. doi:10.1007/s00381-020-04628-0. PMID 32361930. S2CID 218467172.
37. George MS, Ward HE, Ninan PT, Pollack M, Nahas Z, Anderson B, Kose S, Howland RH, Goodman WK, Ballenger JC (April 2008). "A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders". Brain Stimulation. 1 (2): 112–121. doi:10.1016/j.brs.2008.02.001. PMID 20633378.
38. Peña DF, Childs JE, Willett S, Vital A, McIntyre CK, Kroener S (2014). "Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala". Frontiers in Behavioral Neuroscience. 8: 327. doi:10.3389/fnbeh.2014.00327. PMC 4166996. PMID 25278857.
39. Breit S, Kupferberg A, Rogler G, Hasler G (2018). "Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders". Frontiers in Psychiatry. 9: 44. doi:10.3389/fpsyt.2018.00044. PMC 5859128. PMID 29593576.
40. Aihua L, Lu S, Liping L, Xiuru W, Hua L, Yuping W (October 2014). "A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy". Epilepsy Behav. 39: 105–10. doi:10.1016/j.yebeh.2014.08.005. PMID 25240121. S2CID 7913513.
41. Hoppe C (January 2013). "Vagus nerve stimulation: Urgent need for the critical reappraisal of clinical effectiveness". Seizure. 22 (1): 83–84. doi:10.1016/j.seizure.2012.10.001. PMID 23140994.
42. Tarn J, Evans E, Traianos E, Collins A, Stylianou M, Parikh J, Bai Y, Guan Y, Frith J, Lendrem D, MacRae V, McKinnon I, Simon BS, Blake J, Baker MR, Taylor JP, Watson S, Gallagher P, Blamire A, Newton J, Ng WF (2023). "The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants with Primary Sjögren's Syndrome". Neuromodulation: Technology at the Neural Interface. 26 (3): 681–689. doi:10.1016/j.neurom.2022.08.461. PMID 37032583. S2CID 253172246.
43. Inflammation has been associated with both fatigue (see the Wikipedia article on fatigue) and possible VNS mechanism (see below).
44. Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF (2023). "Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: A proof-of-concept clinical trial". Bioelectronic Medicine. 9 (1): 23. doi:10.1186/s42234-023-00124-3. PMC 10583463. PMID 37849000.
45. Fraschini M, Puligheddu M, Demuru M, Polizzi L, Maleci A, Tamburini G, Congia S, Bortolato M, Marrosu F (March 2013). "VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy". Neuroscience Letters. 536: 14–18. doi:10.1016/j.neulet.2012.12.044. PMID 23333601. S2CID 25790383.
46. Sangare A, Marchi A, Pruvost-Robieux E, Soufflet C, Crepon B, Ramdani C, Chassoux F, Turak B, Landre E, Gavaret M (1 December 2020). "The Effectiveness of Vagus Nerve Stimulation in Drug-Resistant Epilepsy Correlates with Vagus Nerve Stimulation-Induced Electroencephalography Desynchronization". Brain Connectivity. 10 (10): 566–577. doi:10.1089/brain.2020.0798. PMC 7757623. PMID 33073582.
47. Joseph NM, Steffan P, Becker D, Wernovsky M, Datta P, Ernst L (June 2022). "Effects of VNS stimulation on electrocorticography in patients with dual neuro- stimulation devices". Journal of Neurology, Neurosurgery & Psychiatry. 93 (6): A3.3–A4. doi:10.1136/jnnp-2022-abn.9. S2CID 249067601.
48. Paudel YN, Shaikh MF, Shah S, Kumari Y, Othman I (October 2018). "Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy". European Journal of Pharmacology. 837: 145–155. doi:10.1016/j.ejphar.2018.08.020. PMID 30125565. S2CID 52048111.
49. Wang Y, Zhan G, Cai Z, Jiao B, Zhao Y, Li S, Luo A (August 2021). "Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms". Neuroscience & Biobehavioral Reviews. 127: 37–53. doi:10.1016/j.neubiorev.2021.04.018. PMID 33894241. S2CID 233328858.
50. Manta S, El Mansari M, Debonnel G, Blier P (March 2013). "Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems". International Journal of Neuropsychopharmacology. 16 (2): 459–470. doi:10.1017/s1461145712000387. PMID 22717062.
51. Furmaga H, Shah A, Frazer A (November 2011). "Serotonergic and Noradrenergic Pathways Are Required for the Anxiolytic-like and Antidepressant-like Behavioral Effects of Repeated Vagal Nerve Stimulation in Rats". Biological Psychiatry. 70 (10): 937–945. doi:10.1016/j.biopsych.2011.07.020. PMID 21907323. S2CID 206101850.
52. Alexander GM, Huang YZ, Soderblom EJ, He XP, Moseley MA, McNamara JO (February 2017). "Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex". Journal of Neurochemistry. 140 (4): 629–644. doi:10.1111/jnc.13931. PMC 6537100. PMID 27973753.
53. Zhu J, Xu C, Zhang X, Qiao L, Wang X, Zhang X, Yan X, Ni D, Yu T, Zhang G, Li Y (August 2020). "A resting-state functional MRI study on the effect of vagal nerve stimulation on spontaneous regional brain activity in drug-resistant epilepsy patients". Behavioural Brain Research. 392: 112709. doi:10.1016/j.bbr.2020.112709. PMID 32479850. S2CID 219123829.
54. Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, Zhang G, Chen X, Shi S, Wang L, Liu R, Hwang J, Li Z, Tao J, Wang Y, Zhu B, Kong J (February 2016). "Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder". Biological Psychiatry. 79 (4): 266–273. doi:10.1016/j.biopsych.2015.03.025. PMC 4838995. PMID 25963932.
55. Breit S, Kupferberg A, Rogler G, Hasler G (2018). "Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders". Frontiers in Psychiatry. 9: 44. doi:10.3389/fpsyt.2018.00044. PMC 5859128. PMID 29593576.
56. Tarn J, Evans E, Traianos E, Collins A, Stylianou M, Parikh J, Bai Y, Guan Y, Frith J, Lendrem D, Macrae V, McKinnon I, Simon BS, Blake J, Baker MR, Taylor JP, Watson S, Gallagher P, Blamire A, Newton J, Ng WF (April 2023). "The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome". Neuromodulation: Technology at the Neural Interface. 26 (3): 681–689. doi:10.1016/j.neurom.2022.08.461. PMID 37032583.
57. Arredondo K, Patel AD (2023). "Quality of life, neurocognitive outcomes, and mood effects with neurostimulation devices". Neurostimulation for Epilepsy. pp. 229–244. doi:10.1016/B978-0-323-91702-5.00004-9. ISBN 978-0-323-91702-5.
58. Révész D, Rydenhag B, Ben-Menachem E (July 2016). "Complications and safety of vagus nerve stimulation: 25 years of experience at a single center". Journal of Neurosurgery: Pediatrics. 18 (1): 97–104. doi:10.3171/2016.1.peds15534. PMID 27015521.
59. Coughlin MK (October 2001). "Long-Term Treatment with Vagus Nerve Stimulation in Patients with Refractory Epilepsy". AORN Journal. 74 (4): 554. doi:10.1016/s0001-2092(06)61692-x.
60. Salvadé A, Ryvlin P, Rossetti AO (February 2018). "Impact of vagus nerve stimulation on sleep-related breathing disorders in adults with epilepsy". Epilepsy & Behavior. 79: 126–129. doi:10.1016/j.yebeh.2017.10.040. PMID 29287215. S2CID 46769980.
61. Edwards CA, Kouzani A, Lee KH, Ross EK (September 2017). "Neurostimulation Devices for the Treatment of Neurologic Disorders". Mayo Clinic Proceedings. 92 (9): 1427–1444. doi:10.1016/j.mayocp.2017.05.005. PMID 28870357.
62. Giordano F, Zicca A, Barba C, Guerrini R, Genitori L (April 2017). "Vagus nerve stimulation: Surgical technique of implantation and revision and related morbidity". Epilepsia. 58 (Suppl 1): 85–90. doi:10.1111/epi.13678. PMID 28386925.
63. https://www.nice.org.uk/guidance/mtg46/documents/final-scope
64. Lanska DJ (12 February 2002). "J.L. Corning and vagal nerve stimulation for seizures in the 1880s". Neurology. 58 (3): 452–459. doi:10.1212/wnl.58.3.452. PMID 11839848.
65. Bailey P, Bremer F (September 1938). "A Sensory Cortical Representation of the Vagus Nerve: With a Note on the Effects of Low Blood Pressure on the Cortical Electrogram". Journal of Neurophysiology. 1 (5): 405–412. doi:10.1152/jn.1938.1.5.405.
66. George MS, Sackeim HA, Rush A, Marangell LB, Nahas Z, Husain MM, Lisanby S, Burt T, Goldman J, Ballenger JC (February 2000). "Vagus nerve stimulation: a new tool for brain research and therapy∗". Biological Psychiatry. 47 (4): 287–295. doi:10.1016/s0006-3223(99)00308-x. PMID 10686263. S2CID 14489190.
67. Squires S (24 March 1998). "Washingtonpost.com: Nation". The Washington Post. p. Z07.
68. Zabara J (September 1985). "Peripheral control of hypersynchronous discharge in epilepsy". Electroencephalography and Clinical Neurophysiology. 61 (3): S162. doi:10.1016/0013-4694(85)90626-1.
69. Zabara J (November 1992). "Inhibition of Experimental Seizures in Canines by Repetitive Vagal Stimulation". Epilepsia. 33 (6): 1005–1012. doi:10.1111/j.1528-1157.1992.tb01751.x. PMID 1464256. S2CID 19290172.
70. Penry JK, Dean JC (June 1990). "Prevention of Intractable Partial Seizures by Intermittent Vagal Stimulation in Humans: Preliminary Results". Epilepsia. 31 (s2): S40-3. doi:10.1111/j.1528-1157.1990.tb05848.x. PMID 2121469. S2CID 32134763.
71. Brauser D (April 18, 2017). "FDA Approves Vagus Nerve Stimulation Device for Cluster Headache". Medscape.
72. "GammaCore Device Classification under Section 513(f)(2)(de novo)". FDA. Retrieved 6 June 2018.
73. Brauser D (January 29, 2018). "FDA Clears Vagus Nerve Stimulator for Migraine Pain". Medscape.
74. "GammaCore 510(k) Premarket Notification". FDA. Retrieved 6 June 2018.
75. Moore SK (22 July 2020). "Handheld Vagus Nerve Stimulator Gets Emergency Approval for COVID-19 Use". IEEE Spectrum.
76. Groves DA, Brown VJ (May 2005). "Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects". Neuroscience and Biobehavioral Reviews. 29 (3): 493–500. doi:10.1016/j.neubiorev.2005.01.004. PMID 15820552. S2CID 3021573.
77. de Lartigue G (October 2016). "Role of the vagus nerve in the development and treatment of diet-induced obesity". The Journal of Physiology. 594 (20): 5791–5815. doi:10.1113/JP271538. PMC 5063945. PMID 26959077.
78. Göbel CH, Tronnier VM, Münte TF (December 2017). "Brain stimulation in obesity". International Journal of Obesity. 41 (12): 1721–1727. doi:10.1038/ijo.2017.150. PMID 28663570. S2CID 20426017.
79. Herremans SC, Baeken C (July 2012). "The current perspective of neuromodulation techniques in the treatment of alcohol addiction: a systematic review". Psychiatria Danubina. 24 (suppl 1): 14–20. PMID 22945180.
80. Abraham WT, Smith SA (February 2013). "Devices in the management of advanced, chronic heart failure". Nature Reviews. Cardiology. 10 (2): 98–110. doi:10.1038/nrcardio.2012.178. PMC 3753073. PMID 23229137.
81. Sabbah HN (August 2011). "Electrical vagus nerve stimulation for the treatment of chronic heart failure". Cleveland Clinic Journal of Medicine. 78 (8 suppl 1): S24–S29. doi:10.3949/ccjm.78.s1.04. PMC 3817894. PMID 21972326.
82. Fox D (4 May 2017), Can Zapping the Vagus Nerve Jump-Start Immunity?: An experimental procedure is exposing links between nervous and immune systems, Scientific American
83. Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP (July 2017). "Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis". Journal of Internal Medicine. 282 (1): 64–75. doi:10.1111/joim.12626. PMID 28547815.
84. Bonaz B, Sinniger V, Pellissier S (2021). "Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases". Frontiers in Neuroscience. 15: 650971. doi:10.3389/fnins.2021.650971. PMC 8019822. PMID 33828455.
85. Payne SC, Furness JB, Burns O, Sedo A, Hyakumura T, Shepherd RK, Fallon JB (2019). "Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation". Frontiers in Neuroscience. 13: 418. doi:10.3389/fnins.2019.00418. PMC 6517481. PMID 31133776.
86. Hamza Z (15 December 2021). "Non-Invasive Nerve Stimulation Shows Promise for Younger IBD Patients". Medpage Today.
87. Merrill CA, Jonsson MA, Minthon L, Ejnell H, Silander HC, Blennow K, Karlsson M, Nordlund A, Rolstad S, Warkentin S, Ben-Menachem E, Sjögren MJ (15 August 2006). "Vagus Nerve Stimulation in Patients With Alzheimer's Disease: Additional Follow-Up Results of a Pilot Study Through 1 Year". The Journal of Clinical Psychiatry. 67 (8): 1171–1178. doi:10.4088/jcp.v67n0801. PMID 16965193.
88. Broncel A, Bocian R, Kłos-Wojtczak P, Kulbat-Warycha K, Konopacki J (February 2020). "Vagal nerve stimulation as a promising tool in the improvement of cognitive disorders". Brain Research Bulletin. 155: 37–47. doi:10.1016/j.brainresbull.2019.11.011. PMID 31790720. S2CID 208344249.
89. Meglio M (3 June 2021). "Noninvasive Vagus Nerve Stimulation for Parkinson Disease Shows Safety, Efficacy". Neurology live.
90. Gierthmuehlen M, Plachta DT (February 2016). "Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication". Hypertension Research. 39 (2): 79–87. doi:10.1038/hr.2015.122. PMID 26581776. S2CID 21184892.
91. Annoni EM, Van Helden D, Guo Y, Levac B, Libbus I, KenKnight BH, Osborn JW, Tolkacheva EG (31 January 2019). "Chronic Low-Level Vagus Nerve Stimulation Improves Long-Term Survival in Salt-Sensitive Hypertensive Rats". Frontiers in Physiology. 10: 25. doi:10.3389/fphys.2019.00025. PMC 6365472. PMID 30766489.
92. Chakravarthy K, Chaudhry H, Williams K, Christo PJ (December 2015). "Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management". Current Pain and Headache Reports. 19 (12): 54. doi:10.1007/s11916-015-0528-6. PMID 26493698. S2CID 8117776.
93. Johnson RL, Wilson CG (2018). "A review of vagus nerve stimulation as a therapeutic intervention". Journal of Inflammation Research. 11: 203–213. doi:10.2147/JIR.S163248. PMC 5961632. PMID 29844694.
94. Puledda F, Goadsby PJ (April 2017). "An Update on Non-Pharmacological Neuromodulation for the Acute and Preventive Treatment of Migraine". Headache. 57 (4): 685–691. doi:10.1111/head.13069. PMID 28295242. S2CID 205161411.
95. Yesiltepe M, Cimen B, Sara Y (15 September 2022). "Effects of chronic vagal nerve stimulation in the treatment of β-amyloid-induced neuropsychiatric symptoms". European Journal of Pharmacology. 931: 175179. doi:10.1016/j.ejphar.2022.175179. PMID 35973478. S2CID 251558829.

Further reading

• Ault A (1 March 2006). "Report casts doubt on VNS approval". Clinical Psychiatry News.
• Feder BJ (September 10, 2006). "Battle Lines in Treating Depression". The New York Times.