Currently Viewing:
Supplements Considerations in Non-Invasive Vagus Nerve Stimulation: Clinical Data and Expert Panel Recommendations
Currently Reading
Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches
Bruce Simon, PhD, and Justyna Blake, MSE
The Emerging Role of gammaCore in the Management of Cluster Headache: Expert Panel Recommendations
Stephen D. Silberstein, MD; Anne H. Calhoun, MD, FAHS; Christina Treppendahl, FNP-BC, AQH; David W. Dodick, MD; Alan M. Rapoport, MD; Avinash Mamidi, PharmD, BCPS; Peter Vargas, RPh; Thomas H. Ebert
Participating Faculty

Mechanism of Action of Non-Invasive Cervical Vagus Nerve Stimulation for the Treatment of Primary Headaches

Bruce Simon, PhD, and Justyna Blake, MSE
Two minutes of nVNS rapidly (<5 minutes) decreased periorbital sensitivity for up to 3.5 hours. Previous work from this lab55 showed that glyceryl trinitrate (GTN), a nitric oxide donor that causes prolonged migraine-like headaches in migraineurs but not in healthy controls, causes a further decrease in sensitivity, which correlates with increased levels of extracellular glutamate in the trigeminal nucleus caudalis (TNC). High levels of glutamate in the TNC are a marker for increased trigeminal pain. Allodynic rats that received nVNS had only a 2-fold increase in extracellular glutamate after GTN compared with a nearly 8-fold increase in untreated animals. Even when nVNS was delayed until 2 hours after GTN treatment, the stimulation could still reverse the elevated levels of glutamate, bringing them back to naïve levels, which were maintained for the duration of the experiment. These data suggest that nVNS may treat headache pain by a direct, acute, inhibitory modulation of headache pain pathways that increase nerve activity in the TNC and therefore in its projections to the thalamus and the cortex where the perception of pain occurs.

Chen et al44 looked at the effects of iVNS and nVNS in a rat model of CSD. CSDs are waves of propagating neuronal depolarization thought to be the electrophysiological correlate of migraine aura, which are the visual disturbances reported by migraineurs that often precede headache. The frequency of continuous CSDs, induced by placing a potassium chloride-soaked cotton ball on the dura, or electrical thresholds, determined by measuring the minimal amount of injected current needed to induce a single CSD, are surrogates for cortical excitability. This model has been used to screen migraine drugs now used clinically. These drugs were shown to reduce CSD frequency and increase electrical thresholds, although many weeks of daily infusions were necessary.56

Chen et al44 showed that both iVNS and nVNS reduced CSD frequency by almost 50% and increased electrical thresholds by about 3-fold. Further, the effects of two 2-minute stimulations lasted more than 3 hours and were equally effective on CSDs in the ipsilateral or contralateral hemispheres. If indeed aura precedes and causes a subsequent headache, these results suggest nVNS may work preventively by reducing the frequency of aura and the resulting migraine headaches.

Akerman et al57 studied the effects of nVNS on the firing of trigeminocervical pain neurons in a rat model of migraine-like and cluster-like acute head pain. A single 2-minute dose of ipsilateral or contralateral VNS suppressed dural-evoked trigeminocervical neuronal firing, both spontaneous and noxious, within 15 minutes. This effect was dose dependent, with 2 doses of ipsilateral VNS prolonging suppression of ongoing spontaneous firing for up to 3 hours and of noxious dural-evoked responses for more than 2 hours. As in the previous study, both ipsilateral and contralateral stimulations were equally effective. To model the trigeminal-autonomic pathway implicated in CH, superior salivatory nucleus (SUS)-evoked trigeminocervical neuronal responses were studied. Two doses of VNS suppressed SUS responses for 2.5 hours. The degree of inhibition with VNS (between 20% and 50% for evoked responses) was similar to that found with other abortive headache treatments, including triptans, in the same model, suggesting a similar site of action.58 Consistent with clinical observations, VNS did not affect normal somatosensory nociceptive processing. Further experiments will be needed to determine if the inhibition of firing of trigeminocervical neurons is a direct effect of VNS-induced descending inhibition by release of inhibitory neurotransmitters, like gamma-aminobutyric acid or serotonin, or by an upstream effect on other targets involved in intracranial trigeminovascular nociceptive transmission.

A large body of literature describes the anti-inflammatory effects of VNS (referred to as the cholinergic anti-inflammatory pathway), pioneered by Kevin Tracey and colleagues.4 Stimulating appropriate efferent or afferent fibers of the VN inhibits splenic (and other organ) macrophage production of several inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1, and interleukin-6.4 A recent study in human rheumatoid arthritis patients with iVNS showed a reduction in disease symptom severity that paralleled changes in TNF-α and C-reactive protein, a measure of inflammation.18 nVNS has been shown to also activate this pathway in 2 human studies.59,60 In addition, Brock et al49 showed a sustained elevation of cardiac vagal tone (a measure of parasympathetic activity indicative of VN stimulation) that lasted up to 24 hours after a 2-minute treatment with gammaCore. A reduction in inflammation and an increase in vagal tone may also play a part in the mechanism by which VNS alleviates headache.

Conclusions

Non-invasive stimulation of the cervical branch of the vagus nerve is an exciting new teCHnology that may increase access to the clinical use of VNS by avoiding the need for surgical implantation of a stimulator and for the associated cost and morbidity. Preliminary clinical studies in various primary headache disorders are encouraging. Human studies and modeling have demonstrated that nVNS activates vagus nerve fibers similar to those implicated in the clinical benefits of iVNS. Continuing human and animal research will be necessary to further elucidate the MOA and to help define optimal signal parameters and treatment paradigms for headache and other disorders

1. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;1(2):64-73. doi: 10.1007/s40473-014-0010-5.
2. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol. 2016;594(20):5781-5790. doi: 10.1113/JP271539.
3. Vida G, Peña G, Deitch EA, Ulloa L. α7-cholinergic receptor mediates vagal induction of splenic norepinephrine. J Immunol. 2011;186(7):4340-4346. doi: 10.4049/jimmunol.1003722.
4. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117(2):289-296. doi: 10.1172/JCI30555.
5. Bonaz B, Picq C, Sinniger V, Mayol JF, Clarençon D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil. 2013;25(3):208-221. doi: 10.1111/nmo.12076.
6. Howland RH, Shutt LS, Berman SR, Spotts CR, Denko T. The emerging use of teCHnology for the treatment of depression and other neuropsychiatric disorders. Ann Clin Psychiatry. 2011;23(1):48-62.
7. Sjögren MJ, Hellström PT, Jonsson MA, Runnerstam M, Silander HC, Ben-Menachem E. Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer’s disease: a pilot study. J Clin Psychiatry. 2002;63(11):972-980.
8. Merrill CA, Jonsson MA, Minthon L, et al. Vagus nerve stimulation in patients with Alzheimer’s
disease: additional follow-up results of a pilot study through 1 year. J Clin Psychiatry. 2006;67(8):
1171-1178.
9. Pruitt DT, Schmid AN, Kim LJ, et al. Vagus nerve stimulation delivered with motor training enhances recovery of function after traumatic brain injury. J Neurotrauma. 2016;33(9):871-879. doi: 10.1089/neu.2015.3972.
10. Neren D, Johnson MD, Legon W, Bachour SP, Ling G, Divani AA. Vagus nerve stimulation and other neuromodulation methods for treatment of traumatic brain injury. Neurocrit Care. 2016;24(2):308-319. doi: 10.1007/s12028-015-0203-0.
11. Uteshev VV, Tenovuo O, Gaidhani N. The cholinergic potential, the vagus nerve and challenges in treatment of traumatic brain injury. Curr Pharm Des. 2016;22(14):2083-2092.
12. Kumaria A, Tolias CM. Is there a role for vagus nerve stimulation therapy as a treatment of
traumatic brain injury? Br J Neurosurg. 2012;26(3):316-320. doi: 10.3109/02688697.2012.663517.
13. Ay I, Lu J, Ay H, Gregory Sorensen A. Vagus nerve stimulation reduces infarct size in rat focal
cerebral ischemia. Neurosci Lett. 2009;459(3):147-151. doi: 10.1016/j.neulet.2009.05.018.
14. Mravec B. The role of the vagus nerve in stroke. Auton Neurosci. 2010;158(1-2):8-12. doi: 10.1016/j.autneu.2010.08.009.
15. Hays SA. Enhancing rehabilitative therapies with vagus nerve stimulation. Neurotherapeutics. 2016;13(2):382-394. doi: 10.1007/s13311-015-0417-z.
16. Dawson J, Pierce D, Dixit A, et al. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. 2016;47(1):143-150. doi: 10.1161/STROKEAHA.115.010477.
17. Peña DF, Childs JE, Willett S, Vital A, McIntyre CK, Kroener S. Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala. Front Behav Neurosci. 2014;8:327. doi: 10.3389/fnbeh.2014.00327.
18. Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med. 2017;282(1):64-75. doi: 10.1111/joim.12626.
19. Bonaz B, Sinniger V, Hoffmann D, et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol Motil. 2016;28(6):948-953. doi: 10.1111/nmo.12792.
20. Pellissier S, Dantzer C, Mondillon L. Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn’s disease and irritable bowel syndrome. PLoS One. 2014;9(9):e105328. doi: 10.1371/journal.pone.0105328.
21. De Ridder D, Vanneste S, Engineer ND, Kilgard MP. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series. Neuromodulation. 2014;17(2):170-179. doi: 10.1111/ner.12127.
22. Lehtimäki J, Hyvärinen P, Ylikoski M, et al. Transcutaneous vagus nerve stimulation in tinnitus: a pilot study. Acta Otolaryngol. 2013;133(4):378-382. doi: 10.3109/00016489.2012.750736.
23. Lange G, Janal MN, Maniker A, et al. Safety and efficacy of vagus nerve stimulation in
fibromyalgia: a phase I/II proof of concept trial. Pain Med. 2011;12(9):1406-1413.
doi: 10.1111/j.1526-4637.2011.01203.x.
24. Harris, RE. Elevated excitatory neurotransmitter levels in the fibromyalgia brain. Arthritis Res Ther. 2010;12(5):141. doi: 10.1186/ar3136.
25. Panebianco M, Rigby A, Weston J, Marson AG. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2002;(4):CD002896. doi: 10.1002/14651858.CD002896.
26. Krahl SE. Vagus nerve stimulation for epilepsy: a review of the peripheral mechanisms. Surg Neurol Int. 2012;3(suppl 1):S47-S52. doi: 10.4103/2152-7806.91610.
27. DeGiorgio CM, Krahl SE. Neurostimulation for drug-resistant epilepsy. Continuum (Minneap Minn). 2013;19(3 Epilepsy):743-755. doi: 10.1212/01.CON.0000431397.61970.2b.
28. Rong P, Liu J, Wang L, et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J Affect Disord. 2016;195:172-179. doi: 10.1016/j.jad.2016.02.031.
29. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58(5):364-373.
30. Berry SM, Broglio K, Bunker M, Jayewardene A, Olin B, Rush AJ. A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl). 2013;6:17-35. doi: 10.2147/MDER.S41017.
31. Bajbouj M, Merkl A, Schlaepfer TE, et al. Two-year outcome of vagus nerve stimulation
in treatment-resistant depression. J Clin Psychopharmacol. 2010;30(3):273-281. doi: 10.1097/JCP.0b013e3181db8831.
32. Cecchini AP, Mea E, Tullo V, et al. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data. Neurol Sci. 2009;30(suppl 1):S101-S104. doi: 10.1007/s10072-009-0073-3.
33. Hord ED, Evans MS, Mueed S, Adamolekun B, Naritoku DK. The effect of vagus nerve stimulation on migraines. J Pain. 2003;4(9):530-534.
34. Mauskop A. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia. 2005;25(2):82-86. doi: 10.1111/j.1468-2982.2005.00611.x.
35. Sadler RM, Purdy RA, Rahey S. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia. 2002;22(6):482-484. doi: 10.1046/j.1468-2982.2002.00387.x.
36. Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;228(4):392-395. doi: 10.1111/j.1468-2982.2008.01538.x.
37. Gaul C, Diener HC, Silver N, et al; PREVA Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia. 2016;36(6):534-546. doi: 10.1177/0333102415607070.
38. Silberstein SD, MeCHtler LL, Kudrow DB, et al; ACT1 Study Group. Non-invasive vagus nerve stimulation for the ACute Treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016;56(8):1317-1332. doi: 10.1111/head.12896.
39. Silberstein SD, Calhoun AH, Lipton RB, et al; EVENT Study Group. Chronic migraine headache prevention with non-invasive vagus nerve stimulation: the EVENT study. Neurology. 2016;87(5):529-538. doi: 10.1212/WNL.0000000000002918.
40. Van Leusden JW, Sellaro R, Colzato LS. Transcutaneous vagal nerve stimulation (tVNS): a new
neuromodulation tool in healthy humans? Front Psychol. 2015;6:102. doi: 10.3389/fpsyg.2015.00102.
41. Dietrich S, Smith J, Scherzinger C, et al. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI. Biomed TeCH (Berl). 2008;53(3):104-111. doi: 10.1515/BMT.2008.022.
42. Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: findings from the randomized, double-blind, sham-controlled ACT2 study [AHS abstract PS78]. Headache. 2017;57(S3):113-226.
43. Krahl SE, Senanayake SS, Handforth A. Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia. 2001;42(5):586-589.
44. Chen SP, Ay I, de Morais AL, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016;157(4):797-805. doi: 10.1097/j.pain.0000000000000437.
45. Ay I, Sorensen AG, Ay H. Vagus nerve stimulation reduces infarct size in rat focal cerebral
ischemia: an unlikely role for cerebral blood flow. Brain Res. 2011;1392:110-115.
doi: 10.1016/j.brainres.2011.03.060.
46. Ay I, Nasser R, Simon B, Ay H. Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats. Brain Stimul. 2016;9(2):166-173. doi: 10.1016/j.brs.2015.11.008.
47. Beekwilder JP, Beems T. Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol. 2010;27(2):130-138. doi: 10.1097/WNP.0b013e3181d64d8a.
48. Frangos E, Komisaruk BR. Access to vagal projections via cutaneous electrical stimulation of the neck: fMRI evidence in healthy humans. Brain Stimul. 2017;10(1):19-27. doi: 10.1016/j.brs.2016.10.008.
49. Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimul. 2015;8(3):624-636. doi: 10.1016/j.brs.2014.11.018.
50. Mourdoukoutas AP, Truong DQ, Adair DK, Simon BJ, Bikson M. High-resolution multi-scale
computational model for non-invasive cervical vagus nerve stimulation. Neuromodulation. In press.
51. Polak T, Ehlis AC, Langer JB, et al. Non-invasive measurement of vagus activity in the brainstem–a methodological progress towards earlier diagnosis of dementias? J Neural Transm (Vienna). 2007;114(5):613-619. doi: 10.1007/s00702-007-0625-8.
52. Usami K, Kawai K, Sonoo M, Saito N. Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation. Brain Stimul. 2013;6(4):615-623. doi: 10.1016/j.brs.2012.09.007.
53. Nonis R, D’Ostilio K, Schoenen J, Magis D. Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: an electrophysiological study in healthy volunteers [published online June 26, 2017]. Cephalalgia. doi: 10.1177/0333102417717470.
54. Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Non-invasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155(5):1037-1042. doi: 10.1016/j.pain.2014.02.009.
55. Oshinsky ML, Gomonchareonsiri S. Episodic dural stimulation in awake rats: a model for recurrent headache. Headache. 2007;47(7):1026-1036. doi: 10.1111/j.1526-4610.2007.00871.x.
56. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59(4):652-661. doi: 10.1002/ana.20778.
57. Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminiocervical neurons in animal models of primary headache. Neurobiol Dis. 2017;102:96-104. doi: 10.1016/j.nbd.2017.03.004.
58. Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of trigeminal autonomic cephalalgias: therapeutic characterization. Brain. 2012;135(Pt 12):3664-3675. doi: 10.1093/brain/aws249.
59. Lerman I, Hauger R, Sorkin L, et al. Non-invasive transcutaneous vagus nerve stimulation decreases whole blood culture-derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial. Neuromodulation. 2016;19(3):283-290. doi: 10.1111/ner.12398.
60. Brock C, Brock B, Aziz Q, et al. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha. Neurogastroenterol Motil. 2017;29(5):e12999. doi: 10.1111/nmo.12999.
 
PDF
 
Copyright AJMC 2006-2017 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up
×

Sign In

Not a member? Sign up now!