Skip to main content

Pathophysiology of Migraine

  • Chapter
  • First Online:
Migraine Surgery
  • 537 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Blau JN. Migraine: theories of pathogenesis. Lancet. 1992;339:1202–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  3. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia. 2007;27:1427–39.

    Article  CAS  PubMed  Google Scholar 

  4. Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 2012;35:507–20.

    Article  CAS  PubMed  Google Scholar 

  5. Aderjan D, Stankewitz A, May A. Neuronal mechanisms during repetitive trigemino-nociceptive stimulation in migraine patients. Pain. 2010;151:97–103.

    Article  PubMed  Google Scholar 

  6. Burstein R, Jakubowski M. Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol. 2005;493:9–14.

    Article  PubMed  Google Scholar 

  7. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365–91.

    Article  CAS  PubMed  Google Scholar 

  8. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89–99.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dalkara T, Zervas NT, Moskowitz MA. From spreading depression to the trigeminovascular system. Neurol Sci. 2006;27:S86–90.

    Article  PubMed  Google Scholar 

  10. Green MW, Green LM, Rothrock JF. Managing your headaches. 2nd ed. New York: Springer Science Inc.; 2005. p. 75–8.

    Book  Google Scholar 

  11. Charles A. The evolution of a migraine attack - a review of recent evidence. Headache. 2013;53:413–9.

    Article  PubMed  Google Scholar 

  12. Charles A. Migraine: a brain state. Curr Opin Neurol. 2013;26:235–9.

    Article  PubMed  Google Scholar 

  13. Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015;35:6619–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moskowitz MA. The visceral organ brain: implications for the pathophysiology of vascular head pain. Neurology. 1991;41:182–6.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Blau JN. Resolution of migraine attacks: sleep and the recovery phase. J Neurol Neurosurg Psychiatry. 1982;45:223–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ahn AH, Brennan KC. Unanswered questions in headache: how does a migraine attack stop? Headache. 2012;52:186–7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Villanueva L. How does migraine attack stop? Headache. 2012;52:188.

    Article  PubMed  Google Scholar 

  20. Chai NC, Shapiro RE, Rapoport AM. Why does vomiting stop a migraine attack? Curr Pain Headache Rep. 2013;17:362.

    Article  PubMed  Google Scholar 

  21. Lashley KS. Patterns of cerebral integration indicated by the socotomas of migraine. Arch Neurol Psychiatry. 1941;46:331–9.

    Article  Google Scholar 

  22. Leao A. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359–90.

    Article  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  36. Drenckhahn C, Winkler MK, Major S, et al. Correlates of spreading depolarization in human scalp electroencephalography. Brain. 2012;135:853–68.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  42. Blau JN. New and old thoughts on migraine. Br Med J. 1985;291:160.

    Article  CAS  Google Scholar 

  43. Charles A. Does cortical spreading depression initiate a migraine attack? Maybe not…. Headache. 2010;50:731–3.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  45. Lauritzen M, Trojaborg W, Olesen J. EEG during attacks of common and classical migraine. Cephalalgia. 1981;1:63–6.

    Article  CAS  PubMed  Google Scholar 

  46. Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9:637–44.

    Article  PubMed  Google Scholar 

  47. Shevel E. The trigeminovascular system—quo vadis? Headache. 2009;49:785–6.

    Article  PubMed  Google Scholar 

  48. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4:386–98.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  50. Burstein R. Deconstructing migraine headache into peripheral and central sensitization. Pain. 2001;89:107–10.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  52. Strassman AM, Levy D. Response properties of dural nociceptors in relation to headache. J Neurophysiol. 2006;95:1298–306.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  54. Goltz F. On vasoldilatory nerves (article in German). Pflügers Arch Ges Physiol. 1874;9:174–97.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bayliss WN. Further researches on antidromic nerve-impulses. J Physiol. 1902;28:276–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Moskowitz MA, Buzzi MG, Sakas DE, Linnik MD. Pain mechanisms underlying vascular headaches. Progress report 1989. Rev Neurol (Paris). 1989;145:181–93.

    CAS  Google Scholar 

  58. Lewis T. The nocifensor system of nerves and its reactions. Br Med J. 1937;194:431–5.

    Article  Google Scholar 

  59. Messlinger K. What is a nociceptor? (article in German). Schmerz. 1997;11:353–66.

    Article  CAS  PubMed  Google Scholar 

  60. Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry. 1938;39:737–63.

    Article  CAS  Google Scholar 

  61. Spierings EL. The aura-headache connection in migraine: a historical analysis. Arch Neurol. 2004;61:794–9.

    Article  PubMed  Google Scholar 

  62. Ashina M. Vascular changes have a primary role in migraine. Cephalalgia. 2012;32:428–30.

    Article  PubMed  Google Scholar 

  63. Drummond PD, Gonski A, Lance JW. Facial flushing after thermocoagulation of the gasserian ganglion. J Neural Neurosurg Psychiatry. 1983;46:611–6.

    Article  CAS  Google Scholar 

  64. Lv X, Wu Z, Li Y. Innervation of the cerebral dura mater. Neuroradiol J. 2014;27:293–8.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  66. Asghar MS, Hansen AE, Amin FM, et al. Evidence for a vascular factor in migraine. Ann Neurol. 2011;69:635–45.

    Article  PubMed  Google Scholar 

  67. Charles A. Migraine is not primarily a vascular disorder. Cephalalgia. 2012;32:431–2.

    Article  PubMed  Google Scholar 

  68. Brennan KC, Charles A. An update on the blood vessel in migraine. Curr Opin Neurol. 2010;23:266–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol. 2006;100:1059–64.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  71. O’Connor TP, van der Kooy D. Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci. 1986;6:2200–7.

    Article  PubMed  Google Scholar 

  72. Davis KD, Dostrovsky JO. Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation. Pain. 1986;25:395–401.

    Article  CAS  PubMed  Google Scholar 

  73. Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P. Arterial responses during migraine headache. Lancet. 1990;336:837–9.

    Article  CAS  PubMed  Google Scholar 

  74. Charles A. Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol. 2013;12:419–20.

    Article  PubMed  Google Scholar 

  75. Goadsby PJ. The vascular theory of migraine—a great story wrecked by the facts. Brain. 2009;132:6–7.

    Article  PubMed  Google Scholar 

  76. Shevel E. The extracranial vascular theory of migraine – a great story confirmed by the facts. Headache. 2011;51:409–17.

    Article  PubMed  Google Scholar 

  77. Shevel E. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm (Vienna). 2011;118:525–30.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  81. Shevel E. Headache education for the medical students: Wolff’s postulates. Headache. 2008;48:638–9. author reply 639

    Article  PubMed  Google Scholar 

  82. Blau JN. Harold G Wolff: the man and his migraine. Cephalalgia. 2004;24:215–22.

    Article  PubMed  Google Scholar 

  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. 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. 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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  90. Meents JE, Neeb L, Reuter U. TRPV1 in migraine pathophysiology. Trends Mol Med. 2010;16:153–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  93. Cianchetti C. The role of the neurovascular scalp structures in migraine. Cephalalgia. 2012;32:778–84.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Muehlberger, T. (2018). Pathophysiology of Migraine. In: Migraine Surgery. Springer, Cham. https://doi.org/10.1007/978-3-319-78117-4_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78117-4_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-78116-7

  • Online ISBN: 978-3-319-78117-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics