Pathophysiology of Migraine

  • Thomas Muehlberger


One big problem with the pathophysiology of migraine is that although several components are well known by now, it is still unclear how they fit together. There is no obvious sequence of events, and the difference between cause and consequence often remains obscure. The increasing knowledge about particular aspects of migraine pathophysiology can create a more thorough understanding of its complexity, yet, at the same time, it can paradoxically hamper the chance to find unambiguous answers. This chapter will obviously not provide any answers as to the underlying mechanisms of migraine. Instead, some of the major components will be briefly discussed in view of current theories. The key questions behind most prevailing thoughts on migraine pathophysiology concern the initiation, continuation, and termination of an attack.


  1. 1.
    Blau JN. Migraine: theories of pathogenesis. Lancet. 1992;339:1202–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain. 2008;131:2192–200.CrossRefPubMedGoogle Scholar
  3. 3.
    Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia. 2007;27:1427–39.CrossRefPubMedGoogle Scholar
  4. 4.
    Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 2012;35:507–20.CrossRefPubMedGoogle Scholar
  5. 5.
    Aderjan D, Stankewitz A, May A. Neuronal mechanisms during repetitive trigemino-nociceptive stimulation in migraine patients. Pain. 2010;151:97–103.CrossRefPubMedGoogle Scholar
  6. 6.
    Burstein R, Jakubowski M. Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol. 2005;493:9–14.CrossRefPubMedGoogle Scholar
  7. 7.
    Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365–91.CrossRefPubMedGoogle Scholar
  8. 8.
    Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89–99.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci. 2006;27:S86–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Green MW, Green LM, Rothrock JF. Managing your headaches. 2nd ed. New York: Springer Science Inc.; 2005. p. 75–8.CrossRefGoogle Scholar
  11. 11.
    Charles A. The evolution of a migraine attack - a review of recent evidence. Headache. 2013;53:413–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Charles A. Migraine: a brain state. Curr Opin Neurol. 2013;26:235–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015;35:6619–29.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Moskowitz MA. The visceral organ brain: implications for the pathophysiology of vascular head pain. Neurology. 1991;41:182–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Welch K, Nagesh V, Aurora S, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache. 2001;41:629–37.CrossRefPubMedGoogle Scholar
  16. 16.
    Eklund A, Nichols TE, Knutsson H. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci U S A. 2016;113:7900–5.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Blau JN. Resolution of migraine attacks: sleep and the recovery phase. J Neurol Neurosurg Psychiatry. 1982;45:223–6.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ahn AH, Brennan KC. Unanswered questions in headache: how does a migraine attack stop? Headache. 2012;52:186–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Villanueva L. How does migraine attack stop? Headache. 2012;52:188.CrossRefPubMedGoogle Scholar
  20. 20.
    Chai NC, Shapiro RE, Rapoport AM. Why does vomiting stop a migraine attack? Curr Pain Headache Rep. 2013;17:362.CrossRefPubMedGoogle Scholar
  21. 21.
    Lashley KS. Patterns of cerebral integration indicated by the socotomas of migraine. Arch Neurol Psychiatry. 1941;46:331–9.CrossRefGoogle Scholar
  22. 22.
    Leao A. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359–90.CrossRefGoogle Scholar
  23. 23.
    Eadie MJ. A history of migraine. In: Borsook D, May A, Goadsby PJ, Hargreaves R, editors. The migraine brain. USA: Oxford University Press Inc.; 2012. p. 14.Google Scholar
  24. 24.
    Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8:136–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Goadsby PJ, Akerman S. The trigeminovascular system does not require a peripheral sensory input to be activated—migraine is a central disorder. Focus on ‘effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system’. Cephalalgia. 2012;32:3–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci. 2010;30:8807–14.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R. Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol. 2011;69:855–65.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Noseda R, Constandil L, Bourgeais L, Chalus M, Villanueva L. Changes of meningeal excitability mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain. J Neurosci. 2010;30:14420–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Burstein R, Strassman A, Moskowitz M. Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia. 2012;32:509–11.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lambert GA, Truong L, Zagami AS. Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia. 2011;31:1439–51.CrossRefPubMedGoogle Scholar
  31. 31.
    Levy D, Moskowitz MA, Noseda R, Burstein R. Activation of the migraine pain pathway by cortical spreading depression: do we need more evidence? Cephalalgia. 2012;32:581–2.CrossRefPubMedGoogle Scholar
  32. 32.
    Ebersberger A, Schaible HG, Averbeck B, Richter F. Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache? Ann Neurol. 2001;49:7–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Oshinsky ML, Sanghvi MM, Maxwell CR, Gonzalez D, Spangenberg RJ, Cooper M, Silberstein SD. Spontaneous trigeminal allodynia in rats: a model of primary headache. Headache. 2012;52:1336–49.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhao J, Bree D, Harrington MG, Strassman AM, Levy D. Cranial dural permeability of inflammatory nociceptive mediators: potential implications for animal models of migraine. Cephalalgia. 2017;37:1017–25.CrossRefPubMedGoogle Scholar
  35. 35.
    Woitzik J, Hecht N, Pinczolits A, et al. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology. 2013;80:1095–102.CrossRefPubMedGoogle Scholar
  36. 36.
    Drenckhahn C, Winkler MK, Major S, et al. Correlates of spreading depolarization in human scalp electroencephalography. Brain. 2012;135:853–68.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lauritzen M, Strong AJ. ‘Spreading depression of Leão’ and its emerging relevance to acute brain injury in humans. J Cereb Blood Flow Metab. 2017;37:1553–70.CrossRefPubMedGoogle Scholar
  38. 38.
    Hansen JM, Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Goadsby PJ, Charles A. Migraine headache is present in the aura phase: a prospective study. Neurology. 2012;79:2044–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci. 2014;15:379–93.CrossRefPubMedGoogle Scholar
  40. 40.
    Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9:344–52.CrossRefPubMedGoogle Scholar
  41. 41.
    Olesen J, Friberg L, Olsen TS, Iversen HK, Lassen NA, Andersen AR, Karle A. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol. 1990;28:791–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Blau JN. New and old thoughts on migraine. Br Med J. 1985;291:160.CrossRefGoogle Scholar
  43. 43.
    Charles A. Does cortical spreading depression initiate a migraine attack? Maybe not…. Headache. 2010;50:731–3.CrossRefPubMedGoogle Scholar
  44. 44.
    Christiansen I, Thomsen LL, Daugaard D, Ulrich V, Olesen J. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia. 1999;19:660–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Lauritzen M, Trojaborg W, Olesen J. EEG during attacks of common and classical migraine. Cephalalgia. 1981;1:63–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9:637–44.CrossRefPubMedGoogle Scholar
  47. 47.
    Shevel E. The trigeminovascular system—quo vadis? Headache. 2009;49:785–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4:386–98.CrossRefPubMedGoogle Scholar
  49. 49.
    Akerman S, Holland PR, Hoffmann J. Pearls and pitfalls in experimental in vivo models of migraine: dural trigeminovascular nociception. Cephalalgia. 2013;33:577–92.CrossRefPubMedGoogle Scholar
  50. 50.
    Burstein R. Deconstructing migraine headache into peripheral and central sensitization. Pain. 2001;89:107–10.CrossRefPubMedGoogle Scholar
  51. 51.
    Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123:1703–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Strassman AM, Levy D. Response properties of dural nociceptors in relation to headache. J Neurophysiol. 2006;95:1298–306.CrossRefPubMedGoogle Scholar
  53. 53.
    Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47:614–24.CrossRefPubMedGoogle Scholar
  54. 54.
    Goltz F. On vasoldilatory nerves (article in German). Pflügers Arch Ges Physiol. 1874;9:174–97.CrossRefGoogle Scholar
  55. 55.
    Bayliss WM. On the origin from the spinal cord of the vaso-dilator fibres of the hind-limb, and on the nature of these fibres. J Physiol. 1901;26:173–209.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bayliss WN. Further researches on antidromic nerve-impulses. J Physiol. 1902;28:276–99.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Moskowitz MA, Buzzi MG, Sakas DE, Linnik MD. Pain mechanisms underlying vascular headaches. Progress report 1989. Rev Neurol (Paris). 1989;145:181–93.Google Scholar
  58. 58.
    Lewis T. The nocifensor system of nerves and its reactions. Br Med J. 1937;194:431–5.CrossRefGoogle Scholar
  59. 59.
    Messlinger K. What is a nociceptor? (article in German). Schmerz. 1997;11:353–66.CrossRefPubMedGoogle Scholar
  60. 60.
    Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry. 1938;39:737–63.CrossRefGoogle Scholar
  61. 61.
    Spierings EL. The aura-headache connection in migraine: a historical analysis. Arch Neurol. 2004;61:794–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Ashina M. Vascular changes have a primary role in migraine. Cephalalgia. 2012;32:428–30.CrossRefPubMedGoogle Scholar
  63. 63.
    Drummond PD, Gonski A, Lance JW. Facial flushing after thermocoagulation of the gasserian ganglion. J Neural Neurosurg Psychiatry. 1983;46:611–6.CrossRefGoogle Scholar
  64. 64.
    Lv X, Wu Z, Li Y. Innervation of the cerebral dura mater. Neuroradiol J. 2014;27:293–8.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Filipović B, Matak I, Lacković Z. Dural neurogenic inflammation induced by neuropathic pain is specific to cranial region. J Neural Transm (Vienna). 2014;121:555–63.CrossRefGoogle Scholar
  66. 66.
    Asghar MS, Hansen AE, Amin FM, et al. Evidence for a vascular factor in migraine. Ann Neurol. 2011;69:635–45.CrossRefPubMedGoogle Scholar
  67. 67.
    Charles A. Migraine is not primarily a vascular disorder. Cephalalgia. 2012;32:431–2.CrossRefPubMedGoogle Scholar
  68. 68.
    Brennan KC, Charles A. An update on the blood vessel in migraine. Curr Opin Neurol. 2010;23:266–74.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol. 2006;100:1059–64.CrossRefPubMedGoogle Scholar
  70. 70.
    May A, Büchel C, Turner R, Goadsby PJ. Magnetic resonance angiography in facial and other pain: neurovascular mechanisms of trigeminal sensation. J Cereb Blood Flow Metab. 2001;21:1171–6.CrossRefPubMedGoogle Scholar
  71. 71.
    O’Connor TP, van der Kooy D. Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci. 1986;6:2200–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Davis KD, Dostrovsky JO. Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation. Pain. 1986;25:395–401.CrossRefPubMedGoogle Scholar
  73. 73.
    Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P. Arterial responses during migraine headache. Lancet. 1990;336:837–9.CrossRefPubMedGoogle Scholar
  74. 74.
    Charles A. Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol. 2013;12:419–20.CrossRefPubMedGoogle Scholar
  75. 75.
    Goadsby PJ. The vascular theory of migraine—a great story wrecked by the facts. Brain. 2009;132:6–7.CrossRefPubMedGoogle Scholar
  76. 76.
    Shevel E. The extracranial vascular theory of migraine – a great story confirmed by the facts. Headache. 2011;51:409–17.CrossRefPubMedGoogle Scholar
  77. 77.
    Shevel E. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm (Vienna). 2011;118:525–30.CrossRefGoogle Scholar
  78. 78.
    Tunis MM, Wolff HG. Long-term observations on the reactivity of the cranial arteries in subjects with vascular headaches of the migraine type. Arch Neurol Psychiatry. 1953;70:551–7.CrossRefGoogle Scholar
  79. 79.
    Chapman LF, Ramos AO, Goodell H, Silverman G, Wolff HG. A humoral agent implicated in vascular headache of the migraine type. Arch Neurol. 1960;3:223–9.CrossRefPubMedGoogle Scholar
  80. 80.
    Wolff HG, Tunis MM, Goodell H. Studies on headache: evidence of tissue damage and changes in pain sensitivity in subjects with vascular headaches of the migraine type. Trans Assoc Am Phys. 1953;66:332–41.PubMedGoogle Scholar
  81. 81.
    Shevel E. Headache education for the medical students: Wolff’s postulates. Headache. 2008;48:638–9. author reply 639CrossRefPubMedGoogle Scholar
  82. 82.
    Blau JN. Harold G Wolff: the man and his migraine. Cephalalgia. 2004;24:215–22.CrossRefPubMedGoogle Scholar
  83. 83.
    Silberstein S, Lipton RB, Dodick DW, editors. Wolff’s headache and other head pain. 8th ed. USA: Oxford University Press Inc.; 2008.Google Scholar
  84. 84.
    Dahl E, Edvinsson I. Anatomical organization of cerebral and extracerebral vasculature. In: Olesen J, Edvinsson I, editors. Basic mechanisms in headaches. Amsterdam: Elsevier; 1988. p. 27–47.Google Scholar
  85. 85.
    Edvinsson L, Gulbenkian S, Barroso CP, et al. Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides. 1998;19:1213–25.CrossRefPubMedGoogle Scholar
  86. 86.
    Messlinger K, Dostrovsky JO, Strassman AM. Anatomy and phsiology of head pain. In: Olesen J, et al., editors. The headaches. 3rd ed. Philadelphia: Lippincott Williams & Wlkins; 2006. p. 95–100.Google Scholar
  87. 87.
    Uddman R, Edvinsson L, Jansen I, Stiernholm P, Jensen K, Olesen J, Sundler F. Peptide-containing nerve fibres in human extracranial tissue: a morphological basis for neuropeptide involvement in extracranial pain? Pain. 1986;27:391–9.CrossRefPubMedGoogle Scholar
  88. 88.
    Jansen I, Uddman R, Hocherman M, et al. Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries. Ann Neurol. 1986;20:496–501.CrossRefPubMedGoogle Scholar
  89. 89.
    Jansen I, Uddman R, Ekman R, Olesen J, Ottosson A, Edvinsson L. Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides. 1992;13:527–36.CrossRefPubMedGoogle Scholar
  90. 90.
    Meents JE, Neeb L, Reuter U. TRPV1 in migraine pathophysiology. Trends Mol Med. 2010;16:153–9.CrossRefPubMedGoogle Scholar
  91. 91.
    Del Fiacco M, Quartu M, Boi M, et al. TRPV1, CGRP and SP in scalp arteries of patients suffering from chronic migraine. J Neurol Neurosurg Psychiatry. 2015;86:393–7.CrossRefPubMedGoogle Scholar
  92. 92.
    Cianchetti C, Serci MC, Madeddu F, Cossu S, Ledda MG. Pressure-painful scalp arteries in children and adolescents suffering from migraine. Cephalalgia. 2011;31:1576–9.CrossRefPubMedGoogle Scholar
  93. 93.
    Cianchetti C. The role of the neurovascular scalp structures in migraine. Cephalalgia. 2012;32:778–84.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Thomas Muehlberger
    • 1
  1. 1.Medsteps AGChamSwitzerland

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