Neurostimulation: Why, When, and Which One?

  • Michel Lantéri-MinetEmail author
  • Denys Fontaine
  • Delphine Magis
Part of the Headache book series (HEAD)


Neuromodulation has been proposed for more than a decade to treat primary headaches including cluster headache. Neuromodulation can be separated into invasive techniques, that is, with a surgical procedure to implant the stimulation device, and noninvasive techniques (transcutaneous or transcranial stimulation). For the treatment of cluster headache (CH), the only noninvasive neuromodulation technique studied up to now is vagus nerve stimulation (cervical portion), while invasive neuromodulation has been applied to target the posteroinferior hypothalamic area, the great occipital nerve, or the sphenopalatine ganglion. For each target, we will review key elements in terms of background, efficacy evidence, limits, and mechanisms of action.


  1. 1.
    Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;28:392–5.CrossRefGoogle Scholar
  2. 2.
    Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, et al. Non-invasive vagus nerve stimulation for prevention and acute treatment of chronic cluster headache (PREVA): a randomized controlled study. Cephalalgia. 2016;36:534–46.CrossRefGoogle Scholar
  3. 3.
    Gaul C, Magis D, Liebler E, Straube A. Effects of non-invasive vagus nerve stimulation on attack frequency over time and expended response rates in patients with chronic cluster headache: a post hoc analysis of the randomized, controlled PREVA study. Headache Pain. 2017;18(1):22.CrossRefGoogle Scholar
  4. 4.
    Morris J, Straube A, Diener HC, Ahmed F, Silver N, Walker S, et al. Cost-effectiveness analysis of non-invasive vagus nerve stimulation for the treatment of chronic cluster headache. J Headache Pain. 2016;17:43.CrossRefGoogle Scholar
  5. 5.
    Miller S, Watkins L, Matharu M. Predictors of response to occipital nerve stimulation in refractory chronic headache. Cephalalgia. 2018;38:1267–75. Scholar
  6. 6.
    Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, et al. Non invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018;38:959–69. Scholar
  7. 7.
    Silberstein SD, Mechtler LL, Kudrow DB, Calhoun AH, McClure C, Saper JR, et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016;56:1317–32.CrossRefGoogle Scholar
  8. 8.
    Holle-Lee D, Gaul C. Noninvasive vagus nerve stimulation in the management of cluster headache: clinical evidence and practical experience. Adv Neurol Disord. 2016;9:230–4.CrossRefGoogle Scholar
  9. 9.
    Simon B, Blake J. Mechanism of action of non-invasive cervical vagus nerve stimulation for the treatment of primary headaches. Am J Manag Care. 2017;23(Suppl. 17):S312–6.PubMedGoogle Scholar
  10. 10.
    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. Cephalalgia. 2017;37:1285–93.CrossRefGoogle Scholar
  11. 11.
    Frangos E, Komisaruk BR. Access to vagal projections via cutaneous stimulation of the neck: fMRI evidence in healthy humans. Brain Stimul. 2017;10:19–27.CrossRefGoogle Scholar
  12. 12.
    Mourdoukoutas AP, Truong DQ, Adair DK, Simon BJ, Bikson M. High-resolution multiscale computational model for non-invasive cervical vagus nerve stimulation. Neuromodulation. 2018;21:261–8. Scholar
  13. 13.
    Chen SP, Ay I, de Morais AL, Qin T, Zheng Y, Sadeghian H, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016;157:797–805.CrossRefGoogle Scholar
  14. 14.
    Oshinsky ML, Murphy AL, Hekierski H, Cooper M, Simon B. Non-invasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014;155:1037–42.CrossRefGoogle Scholar
  15. 15.
    Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animals models of primary headache. Neurobiol Dis. 2017;102:96–104.CrossRefGoogle Scholar
  16. 16.
    Franzini A, Ferroli P, Leone M, Broggi G. Stimulation of the posterior hypothalamus for the treatment of chronic intractable cluster headache. Neurosurgery. 2003;52:1095–9.PubMedGoogle Scholar
  17. 17.
    Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic grey matter for intractable cluster headache. N Engl J Med. 2001;345:1428–9.CrossRefGoogle Scholar
  18. 18.
    May A, Bahra A, Buchel C, Frackowiak R, Goadsby P. Hypothalamic activation in cluster headache attacks. Lancet Neurol. 1998;352:275–8.CrossRefGoogle Scholar
  19. 19.
    Akram H, Miller S, Lagrata S, HYam J, Jahanshari M, Hariz M, et al. Ventral tegmental area deep brain stimulation for refractory chronic cluster headache. Neurology. 2016;86:1676–82.CrossRefGoogle Scholar
  20. 20.
    Bartsch T, Pinsker M, Rasche D, Kinfe T, Hertel F, Diener H, et al. Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia. 2008;28:285–95.CrossRefGoogle Scholar
  21. 21.
    Chabardès S, Carron R, Seigneuret E, Torres N, Goetz L, Krainik A, et al. Endoventricular deep brain stimulation of the third ventricle: proof of concept and application to cluster headache. Neurosurgery. 2016;79:806–15.CrossRefGoogle Scholar
  22. 22.
    Fontaine D, Lazorthes Y, Mertens P, Blond S, Géraud G, Fabre N, et al. Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a one-year open extension. J Headache Pain. 2010;11:23–31.CrossRefGoogle Scholar
  23. 23.
    Leone M, Franzini A, Proietti Cecchini A, Bussone G. Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache. Pain. 2013;154:89–94.CrossRefGoogle Scholar
  24. 24.
    Owen S, Green A, Davies P, Stein J, Aziz T, Behrens T, Voets N, et al. Connectivity of an effective hypothalamic surgical target for cluster headache. J Clin Neurosci. 2007;14:955–60.CrossRefGoogle Scholar
  25. 25.
    Schoenen J, Di Clemente L, Vandenheede M, Fumal A, De Pasqua V, Mouchamps M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain. 2005;128:940–7.CrossRefGoogle Scholar
  26. 26.
    Seijo F, Saiz A, Lozano B, Santamarta E, Alvarez-Vega M, Seijo E, et al. Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster headache: experience in five patients with a modified anatomic target. Cephalalgia. 2011;31:1634–41.CrossRefGoogle Scholar
  27. 27.
    Starr P, Barbaro N, Raskin N, Ostrem J. Chronic stimulation of the posterior hypothalamic region for cluster headache: technique and 1-year results in four patients. J Neurosurg. 2007;106:999–1005.CrossRefGoogle Scholar
  28. 28.
    Leone M, May A, Franzini A, Broggi G, Dodick D, Rapoport A, Goadsby P, Schoenen J, Bonavita V, Bussone G. Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. Cephalalgia. 2004;24:934–7.CrossRefGoogle Scholar
  29. 29.
    Marteletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M, et al. Neuromodulation of chronic headache from the European Headache Federation. J Headache Pain. 2013;14:86.CrossRefGoogle Scholar
  30. 30.
    Fontaine D, Lanteri-Minet M, Ouchchane L, Lazorthes Y, Mertens P, Blond S, et al. Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache. Brain. 2010;133:1214–23.CrossRefGoogle Scholar
  31. 31.
    May A, Leone M, Boecker H, Sprenger T, Juergens T, Bussone G, Tolle T. Hypothalamic deep brain stimulation in positron emission tomography. J Neurosci. 2006;26:3589–93.CrossRefGoogle Scholar
  32. 32.
    Ray NJ, Kringembach M, Jenkinson N, Owen S, Davies P, Wang S, et al. Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient. Biomed Imaging Interv J. 2007;3:e25.CrossRefGoogle Scholar
  33. 33.
    Goadsby HP. The hypothalamic orexinergic system: pain and primary headaches. Headache. 2007;47:951–62.CrossRefGoogle Scholar
  34. 34.
    Weiner R, Reed K. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation. 1999;2:217–22.CrossRefGoogle Scholar
  35. 35.
    Wilbrink LA, Teemstra OP, Haan J, van Zwet EW, Evers SM, Spincemaille GH, et al. Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: rationale and protocol of a randomized trial. Cephalalgia. 2013;33(15):1238–47.CrossRefGoogle Scholar
  36. 36.
    Burns B, Watkins L, Goadsby PJ. Treatment of medically intractable cluster headache by occipital nerve stimulation: long-term follow-up of eight patients. Lancet. 2007;369:1099–106.CrossRefGoogle Scholar
  37. 37.
    Burns B, Watkins L, Goadsby PJ. Treatment of intractable chronic cluster headache by occipital nerve stimulation in 14 patients. Neurology. 2009;72:341–5.CrossRefGoogle Scholar
  38. 38.
    de Quintana-Schmidt C, Casajuana Garreta E, Mollet-Teixido J, Garcia-Bach M, Roig C, Clavel-Laria P, Rodriguez-Rodriguez R, Oliver-Abadal B, Batumeus-Jené F. Stimulation of the occipital nerve in the treatment of drug-resistant cluster headache. Rev Neurol. 2010;51:19–26.PubMedGoogle Scholar
  39. 39.
    Fontaine D, Sol JC, Raoul S, Fabre N, Geraud G, Magne C, et al. Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation. Cephalalgia. 2011;31:1101–5.CrossRefGoogle Scholar
  40. 40.
    Fontaine D, Blond S, Lucas C, Regis J, Donnet A, Derrey S, et al. Occipital nerve stimulation improve the quality of life in medically-intractable chronic cluster headache: results of an observational prospective study. Cephalalgia. 2017;37:1173–9.CrossRefGoogle Scholar
  41. 41.
    Leone M, Proietti Cecchini A, Messina G, Franzini A. Long-term occipital nerve stimulation for drug-resistant chronic cluster headache. Cephalalgia. 2017;37:756–63.CrossRefGoogle Scholar
  42. 42.
    Magis D, Allena M, Bolla M, De Pasqua V, Remacle JM, Schoenen J. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 2007;6:314–21.CrossRefGoogle Scholar
  43. 43.
    Magis D, Gerardy PY, Remacle JM, Schoenen J. Sustained effectiveness of occipital nerve stimulation in drug-resistant chronic cluster headache. Headache. 2011;51:1191–201.CrossRefGoogle Scholar
  44. 44.
    Miller S, Watkins L, Matharu M. Treatment of intractable chronic cluster headache by occipital nerve stimulation: a cohort of 51 patients. Eur J Neurol. 2017;24:381–90.CrossRefGoogle Scholar
  45. 45.
    Müeller O, Gaul C, Katsarava Z, Diener H, Sure U, Gasser T. Occipital nerve stimulation for the treatment of chronic cluster headache—lessons learned from 18 months experience. Cen Eur Neurosurg. 2011;72:84–9.CrossRefGoogle Scholar
  46. 46.
    Mueller O, Diener HC, Dammann P, Rabe K, Hagel V, Sure U, et al. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia. 2013;33(16):1283–91.CrossRefGoogle Scholar
  47. 47.
    Schwedt TJ, Dodick DW, Trentman TL, Zimmerman RS. Occipital nerve stimulation for chronic cluster headache and hemicrania continua: pain relief and persistence of autonomic features. Cephalalgia. 2006;26(8):1025–7.CrossRefGoogle Scholar
  48. 48.
    Fontaine D, Vandersteen C, Magis D, Lanteri-Minet M. Neuromodulation of cluster headache. Adv Tech Stand Neurosurg. 2015;42:3–21.CrossRefGoogle Scholar
  49. 49.
    Schwedt TJ, Dodick DW, Trentman TL, Zimmerman RS. Response to occipital nerve block is not useful in predicting efficacy of occipital nerve stimulation. Cephalalgia. 2007;27:271–4.CrossRefGoogle Scholar
  50. 50.
    Bartsch T, Goadsby PJ. Stimulation of the greater occipital nerve induces increased central excitability of dural afferent input. Brain. 2002;125:1496–509.CrossRefGoogle Scholar
  51. 51.
    Bartsch T, Goadsby PJ. Increased responses in trigeminocervical nociceptive neurons to cervical input after stimulation of the dura mater. Brain. 2003;126:1801–13.CrossRefGoogle Scholar
  52. 52.
    Goadsby P, Bartsch T, Dodick D. Occipital nerve stimulation for headache: mechanisms and efficacy. Headache. 2008;48:313–8.CrossRefGoogle Scholar
  53. 53.
    Magis D, Bruno MA, Fumal A, Gerardy PY, Hustinx R, Laureys S, et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol. 2011;11:25.CrossRefGoogle Scholar
  54. 54.
    Ansarinia M, Rezai A, Tepper SJ, Steiner CP, Stump J, Stanton-Hicks M, et al. Electrical stimulation of sphenopalatine ganglion for acute treatment of cluster headaches. Headache. 2010;50:1164–74.CrossRefGoogle Scholar
  55. 55.
    Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, et al. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013;33:816–30.CrossRefGoogle Scholar
  56. 56.
    Jürgens TP, Barloese M, May A, Láinez JM, Schoenen J, Gaul C, et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia. 2017;37(5):423–34.CrossRefGoogle Scholar
  57. 57.
    Miller S, Sinclaire AJ, Davies B, Matharu M. Neurostimulation in the treatment of primary headaches. Pract Neurol. 2016;16:362–75.CrossRefGoogle Scholar
  58. 58.
    Assaf A, Hillerup S, Rostgaard J, et al. Technical and surgical aspects of the sphenopalatine ganglion (SPG) microstimulator insertion procedure. Int J Oral Maxillofac Surg. 2016;45(2):245–54.CrossRefGoogle Scholar
  59. 59.
    Kohlmeier C, Behrens P, Böger A, et al. Improved surgical procedure using intraoperative navigation for the implantation of the SPG microstimulator in patients with chronic cluster headache. Int J Comput Assist Radiol Surg. 2017;12(12):2119–28.CrossRefGoogle Scholar
  60. 60.
    Schytz HW, Barlose M, Guo S, Selb J, Caparso A, Jensen R, et al. Experimental activation of the sphenopalatine ganglion provokes cluster like attacks in humans. Cephalalgia. 2013;33:831–41.CrossRefGoogle Scholar
  61. 61.
    Strand N, Trentman T, Vargas B, Dodick D. Occipital nerve stimulation with the Bion microstimulator for the treatment of medically refractory chronic cluster headache. Pain Physician. 2011;14:435–40.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Michel Lantéri-Minet
    • 1
    Email author
  • Denys Fontaine
    • 2
  • Delphine Magis
    • 3
  1. 1.Pain Department and FHU InovPainCHU Nice and Côte Azur UniversityNiceFrance
  2. 2.Neurosurgical Department FHU InovPainCHU Nice and Côte Azur UniversityNiceFrance
  3. 3.Headache Research UnitUniversity Department of Neurology CHRLiegeBelgium

Personalised recommendations