Neurophysiology of Cluster Headache and Other Trigeminal Autonomic Cephalalgias

  • Gianluca Coppola
  • Armando Perrotta
  • Francesco Pierelli
  • Giorgio Sandrini
Part of the Headache book series (HEAD)


“Cluster headache and other trigeminal autonomic cephalalgias” is a category of primary headaches characterized by strictly unilateral headache with concomitant ipsilateral facial autonomic features. Their pathophysiology is not fully understood. Many neurophysiological techniques have been used in attempts to disentangle the pathophysiological mechanisms underlying these elusive brain disorders. Overall, these investigations have revealed side-to-side differences, in virtually all the sensory modalities explored (both pain-related and non-pain-related), in patients (almost always cluster headache patients) versus healthy controls. Signs of peripheral and central sensitization of the trigeminal system, as well as of the extracephalic spinal pain processing system, have been detected using blink and lower limb withdrawal reflexes in cluster headache. In some cases, acute or prophylactic treatments can reverse these dysfunctions. The use of improved selection criteria and more refined neurophysiological techniques, especially if combined with neuroimaging data, should lead to greater understanding of the nature of the brain dysfunction in trigeminal autonomic cephalalgias.


Cluster headache Trigeminal autonomic cephalalgias EEG Evoked potentials Reflex Polysomnography Sleep TMS Pain mechanisms 



Blink reflex


Cluster headache


Cold pressor test


Deep brain stimulation




Event-related potentials


Healthy controls


Intensity dependence of cortical auditory evoked potentials


Laser evoked potentials


Local field potentials


Nociceptive blink reflex


Non-rapid eye movement


Nociceptive withdrawal reflex


Rapid eye movement


Somatosensory evoked potentials


Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms


Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing


Trigeminal autonomic cephalalgias


Transcranial magnetic stimulation


Temporal summation threshold


Visual evoked potential


  1. 1.
    Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629–808.CrossRefGoogle Scholar
  2. 2.
    Sandrini G, Friberg L, Coppola G, et al. Neurophysiological tests and neuroimaging procedures in non-acute headache (2nd edition). Eur J Neurol. 2011;18:373–81.CrossRefGoogle Scholar
  3. 3.
    Silvestri R, Narbone MC, De Domenico P, et al. Generalized EEG abnormalities in cluster headache. Ital J Neurol Sci. 1996;17:179.CrossRefGoogle Scholar
  4. 4.
    Martens D, Oster I, Gottschlling S, et al. Cerebral MRI and EEG studies in the initial management of pediatric headaches. Swiss Med Wkly. 2012;142:w13625.PubMedGoogle Scholar
  5. 5.
    Leone M, Franzini A, Bussone G. Stereotactic stimulation of posterior hypothalamic gray matter in a patient with intractable cluster headache. N Engl J Med. 2001;345:1428–9.CrossRefGoogle Scholar
  6. 6.
    Broggi G, Franzini A, Leone M, et al. Update on neurosurgical treatment of chronic trigeminal autonomic cephalalgias and atypical facial pain with deep brain stimulation of posterior hypothalamus: results and comments. Neurol Sci. 2007;28(Suppl 2):S138–45.CrossRefGoogle Scholar
  7. 7.
    Bartsch T, Pinsker MO, Rasche D, et al. Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series. Cephalalgia. 2008;28:285–95.CrossRefGoogle Scholar
  8. 8.
    Cordella R, Carella F, Leone M, et al. Spontaneous neuronal activity of the posterior hypothalamus in trigeminal autonomic cephalalgias. Neurol Sci. 2007;28:93–5.CrossRefGoogle Scholar
  9. 9.
    Brittain J-S, Green AL, Jenkinson N, et al. Local field potentials reveal a distinctive neural signature of cluster headache in the hypothalamus. Cephalalgia. 2009;29:1165–73.CrossRefGoogle Scholar
  10. 10.
    Nager W, Münte TF, Marco-Pallares J, et al. Beta-oscillations in the posterior hypothalamus are associated with spontaneous cluster headache attack. J Neurol. 2010;257:1743–4.CrossRefGoogle Scholar
  11. 11.
    Barloese MCJ. Neurobiology and sleep disorders in cluster headache. J Headache Pain. 2015;16:78.CrossRefGoogle Scholar
  12. 12.
    Manzoni GC, Terzano MG, Bono G, et al. Cluster headache—clinical findings in 180 patients. Cephalalgia. 1983;3:21–30.CrossRefGoogle Scholar
  13. 13.
    Chervin RD, Zallek SN, Lin X, et al. Timing patterns of cluster headaches and association with symptoms of obstructive sleep apnea. Sleep Res Online. 2000;3:107–12.PubMedGoogle Scholar
  14. 14.
    Della Marca G, Vollono C, Rubino M, et al. A sleep study in cluster headache. Cephalalgia. 2006;26:290–4.CrossRefGoogle Scholar
  15. 15.
    Vetrugno R, Pierangeli G, Leone M, et al. Effect on sleep of posterior hypothalamus stimulation in cluster headache. Headache. 2007;47:1085–90.CrossRefGoogle Scholar
  16. 16.
    Dexter JD, Riley TL. Studies in nocturnal migraine. Headache. 1975;15:51–62.CrossRefGoogle Scholar
  17. 17.
    Pfaffenrath V, Pöllmann W, Rüther E, et al. Onset of nocturnal attacks of chronic cluster headache in relation to sleep stages. Acta Neurol Scand. 1986;73:403–7.CrossRefGoogle Scholar
  18. 18.
    Kayed K, Sjaastad O. Nocturnal and early morning headaches. Ann Clin Res. 1985;17:243–6.PubMedGoogle Scholar
  19. 19.
    Kudrow L, McGinty DJ, Phillips ER, et al. Sleep apnea in cluster headache. Cephalalgia. 1984;4:33–8.CrossRefGoogle Scholar
  20. 20.
    Chervin RD, Zallek SN, Lin X, et al. Sleep disordered breathing in patients with cluster headache. Neurology. 2000;54:2302–6.CrossRefGoogle Scholar
  21. 21.
    Graff-Radford SB, Newman A. Obstructive sleep apnea and cluster headache. Headache. 2004;44:607–10.CrossRefGoogle Scholar
  22. 22.
    Pelin Z, Bozluolcay M. Cluster headache with obstructive sleep apnea and periodic limb movements during sleep: a case report. Headache. 2005;45:81–3.CrossRefGoogle Scholar
  23. 23.
    Terzaghi M, Ghiotto N, Sances G, et al. Episodic cluster headache: NREM prevalence of nocturnal attacks. time to look beyond macrostructural analysis? Headache. 2010;50:1050–4.CrossRefGoogle Scholar
  24. 24.
    Zaremba S, Holle D, Wessendorf TE, et al. Cluster headache shows no association with rapid eye movement sleep. Cephalalgia. 2012;32:289–96.CrossRefGoogle Scholar
  25. 25.
    Polich J, Ehlers CL, Dalessio DJ. Pattern-shift visual evoked responses and EEG in migraine. Headache. 1986;26:451–6.CrossRefGoogle Scholar
  26. 26.
    Boiardi A, Carenini L, Frediani F, et al. Visual evoked potentials in cluster headache: central structures involvement. Headache. 1986;26:70–3.CrossRefGoogle Scholar
  27. 27.
    Boiardi A, Frediani F, Leone M, et al. Cluster headache: Lack of central modulation? Funct Neurol. 1988;3:79–87.PubMedGoogle Scholar
  28. 28.
    Kagan R, Kainz V, Burstein R, et al. Hypothalamic and basal ganglia projections to the posterior thalamus: possible role in modulation of migraine headache and photophobia. Neuroscience. 2013;248:359–68.CrossRefGoogle Scholar
  29. 29.
    Bussone G, Sinatra MG, Boiardi A, et al. Brainstem auditory evoked potential (BAEPs) in cluster headache (CH): new aspects for a central theory. Headache. 1986;26:67–9.CrossRefGoogle Scholar
  30. 30.
    Afra J, Ertsey C, Bozsik G, et al. Cluster headache patients show marked intensity dependence of cortical auditory evoked potentials during and outside the bout. Cephalalgia. 2005;25:36–40.CrossRefGoogle Scholar
  31. 31.
    Firenze C, Del Gatto F, Mazzotta G, et al. Somatosensory-evoked potential study in headache patients. Cephalalgia. 1988;8:157–62.CrossRefGoogle Scholar
  32. 32.
    Cosentino G, Brighina F, Brancato S, et al. Transcranial magnetic stimulation reveals cortical hyperexcitability in episodic cluster headache. J Pain. 2015;16:53–9.CrossRefGoogle Scholar
  33. 33.
    Evers S, Bauer B, Suhr B, et al. Cognitive processing in primary headache: a study on event-related potentials. Neurology. 1997;48:108–13.CrossRefGoogle Scholar
  34. 34.
    Evers S, Bauer B, Suhr B, et al. Cognitive processing is involved in cluster headache but not in chronic paroxysmal hemicrania. Neurology. 1999;53:357–63.CrossRefGoogle Scholar
  35. 35.
    Wang R, Dong Z, Chen X, et al. Cognitive processing of cluster headache patients: evidence from event-related potentials. J Headache Pain. 2014;15:66.CrossRefGoogle Scholar
  36. 36.
    Casale MS, Baratto M, Cervera C, et al. Auditory evoked potential abnormalities in cluster headache. Neuroreport. 2008;19:1633–6.CrossRefGoogle Scholar
  37. 37.
    van Vliet J, Vein A, Le Cessie S, et al. Impairment of trigeminal sensory pathways in cluster headache. Cephalalgia. 2003;23:414–9.CrossRefGoogle Scholar
  38. 38.
    Holle D, Gaul C, Zillessen S, et al. Lateralized central facilitation of trigeminal nociception in cluster headache. Neurology. 2012;78:985–92.CrossRefGoogle Scholar
  39. 39.
    Ellrich J, Jung K, Ristic D, et al. Laser-evoked cortical potentials in cluster headache. Cephalalgia. 2007;27:510–8.CrossRefGoogle Scholar
  40. 40.
    Pavesi G, Granella F, Brambilla S, et al. Blink reflex in cluster headache: evidence of a trigeminal system dysfunction. Cephalalgia. 1987;6:100–2.CrossRefGoogle Scholar
  41. 41.
    Raudino F. The blink reflex in cluster headache. Headache. 1990;30:584–5.CrossRefGoogle Scholar
  42. 42.
    Sandrini G, Alfonsi E, Ruiz L, et al. Impairment of corneal pain perception in cluster headache. Pain. 1991;47:299–304.CrossRefGoogle Scholar
  43. 43.
    Lozza A, Schoenen J, Delwaide PJ. Inhibition of the blink reflex R2 component after supraorbital and index finger stimulations is reduced in cluster headache: an indication for both segmental and suprasegmental dysfunction? Pain. 1997;71:81–8.CrossRefGoogle Scholar
  44. 44.
    Sprenger T, Willoch F, Miederer M, et al. Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study. Neurology. 2006;66:1108–10.CrossRefGoogle Scholar
  45. 45.
    Magis D, Bruno MA, Fumal A, et al. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study. BMC Neurol. 2011;11:25.CrossRefGoogle Scholar
  46. 46.
    Formisano R, Cerbo R, Ricci M, et al. Blink reflex in cluster headache. Cephalalgia. 1987;7:353–4.CrossRefGoogle Scholar
  47. 47.
    Perrotta A, Serrao M, Sandrini G, et al. Reduced habituation of trigeminal reflexes in patients with episodic cluster headache during cluster period. Cephalalgia. 2008;28:950–9.CrossRefGoogle Scholar
  48. 48.
    Coppola G, Di Lorenzo C, Bracaglia M, et al. Lateralized nociceptive blink reflex habituation deficit in episodic cluster headache: correlations with clinical features. Cephalalgia. 2015;35:600–7.CrossRefGoogle Scholar
  49. 49.
    Perrotta A, Coppola G, Anastasio MG, et al. Trait- and frequency-dependent dysfunctional habituation to trigeminal nociceptive stimulation in trigeminal autonomic cephalalgias. J Pain. 2018;19:1040–8. Scholar
  50. 50.
    Holle D, Zillessen S, Gaul C, et al. Habituation of the nociceptive blink reflex in episodic and chronic cluster headache. Cephalalgia. 2012;32:998–1004.CrossRefGoogle Scholar
  51. 51.
    Di Lorenzo C, Coppola G, Pierelli F. A case of cluster headache treated with rotigotine: clinical and neurophysiological correlates. Cephalalgia. 2013;33:1272–6.CrossRefGoogle Scholar
  52. 52.
    Magis D, Allena M, Bolla M, et al. Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study. Lancet Neurol. 2007;6:314–21.CrossRefGoogle Scholar
  53. 53.
    Haane DYP, Plaum A, Koehler PJ, et al. High-flow oxygen therapy in cluster headache patients has no significant effect on nociception specific blink reflex parameters: a pilot study. J Headache Pain. 2016;17:7.CrossRefGoogle Scholar
  54. 54.
    Haane DY, Koehler PJ. Nociception specific supraorbital nerve stimulation may prevent cluster headache attacks: serendipity in a blink reflex study. Cephalalgia. 2014;34:920–6.CrossRefGoogle Scholar
  55. 55.
    Sandrini G, Serrao M, Rossi P, et al. The lower limb flexion reflex in humans. Prog Neurobiol. 2005;77:353–95.CrossRefGoogle Scholar
  56. 56.
    Sandrini G, Antonaci F, Lanfranchi S, et al. Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache. Cephalalgia. 2000;20:647–52.CrossRefGoogle Scholar
  57. 57.
    Perrotta A, Serrao M, Ambrosini A, et al. Facilitated temporal processing of pain and defective supraspinal control of pain in cluster headache. Pain. 2013;154:1325–32.CrossRefGoogle Scholar
  58. 58.
    Nappi G, Sandrini G, Alfonsi E, et al. Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache. Headache. 2002;42:125–31.CrossRefGoogle Scholar
  59. 59.
    Fernández-de-las-Peñas C, Ortega-Santiago R, Cuadrado ML, et al. Bilateral widespread mechanical pain hypersensitivity as sign of central sensitization in patients with cluster headache. Headache. 2011;51:384–91.CrossRefGoogle Scholar
  60. 60.
    Bono G, Antonaci F, Sandrini G, et al. Pain pressure threshold in cluster headache patients. Cephalalgia. 1996;16:62–6.CrossRefGoogle Scholar
  61. 61.
    Ellrich J, Ristic D, Yekta SS. Impaired thermal perception in cluster headache. J Neurol. 2006;253:1292–9.CrossRefGoogle Scholar
  62. 62.
    Jürgens TP, Leone M, Proietti-Cecchini A, et al. Hypothalamic deep-brain stimulation modulates thermal sensitivity and pain thresholds in cluster headache. Pain. 2009;146:84–90.CrossRefGoogle Scholar
  63. 63.
    Antonaci F, Sandrini G, Danilov A, et al. Neurophysiological studies in chronic paroxysmal hemicrania and hemicrania continua. Headache. 1994;34:479–83.CrossRefGoogle Scholar
  64. 64.
    Leone M, Bussone G. Pathophysiology of trigeminal autonomic cephalalgias. Lancet Neurol. 2009;8:755–64.CrossRefGoogle Scholar
  65. 65.
    Iacovelli E, Coppola G, Tinelli E, et al. Neuroimaging in cluster headache and other trigeminal autonomic cephalalgias. J Headache Pain. 2012;13:11–20.CrossRefGoogle Scholar
  66. 66.
    Graff-Radford SB, Teruel A. Cluster headache and obstructive sleep apnea: are they related disorders? Curr Pain Headache Rep. 2009;13:160–3.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Gianluca Coppola
    • 1
  • Armando Perrotta
    • 2
  • Francesco Pierelli
    • 1
    • 2
  • Giorgio Sandrini
    • 3
    • 4
  1. 1.Department of Medico-Surgical Sciences and BiotechnologiesSapienza University of Rome Polo PontinoLatinaItaly
  2. 2.INM-Neuromed, Headache ClinicPozzilli (IS)Italy
  3. 3.Headache Science Center and Headache UnitNational Neurological Institute C. Mondino FoundationPaviaItaly
  4. 4.Department of Brain and Behavioral SciencesUniversity of PaviaPaviaItaly

Personalised recommendations