Pathophysiology of Migraine: Current Status and Future Directions

  • Jakob Møller HansenEmail author
  • Dan LevyEmail author
Part of the Headache book series (HEAD)


Around 10 % of the global adult population has active migraine. The public health burden of migraine is high because migraine attacks are associated with temporary disability and substantial impairment in activities. As such, migraine is ranked as one of the most disabling conditions. The widespread disability produced by migraine is therefore an important target for treatment.

The hallmark of migraine is the head pain, but a plethora of other clinical symptoms is needed for a headache to be qualified as a migraine according to the current diagnostic criteria.

There has been tremendous progress in our acceptance, understanding and treatment possibilities of migraine, but to optimize migraine management, it is important that we continue to improve our understanding of the basic migraine mechanisms. An understanding of migraine pathophysiology must encompass the varied clinical symptoms and relate these findings to anatomy and physiology.


Vasoactive Intestinal Peptide Migraine Attack Migraine Patient Migraine With Aura Cortical Spreading Depression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Jensen R, Stovner LJ (2008) Epidemiology and comorbidity of headache. Lancet Neurol 7(4):354–361PubMedGoogle Scholar
  2. 2.
    Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M (2001) Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41(7):646–657PubMedGoogle Scholar
  3. 3.
    Menken M, Munsat TL, Toole JF (2000) The global burden of disease study: implications for neurology. Arch Neurol 57(3):418–420PubMedGoogle Scholar
  4. 4.
    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2197–2223PubMedGoogle Scholar
  5. 5.
    Lipton RB, Stewart WF, Scher AI (2001) Epidemiology and economic impact of migraine. Curr Med Res Opin 17(Suppl 1):s4–s12PubMedGoogle Scholar
  6. 6.
    Ligthart L, de Vries B, Smith AV, Ikram MA, Amin N, Hottenga JJ et al (2011) Meta-analysis of genome-wide association for migraine in six population-based European cohorts. Eur J Hum Genet 19(8):901–907PubMedCentralPubMedGoogle Scholar
  7. 7.
    Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS et al (2010) Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 42(10):869–873PubMedCentralPubMedGoogle Scholar
  8. 8.
    Lafreniere RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N et al (2010) A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 16(10):1157–1160PubMedGoogle Scholar
  9. 9.
    Deprez L, Peeters K, Van Paesschen W, Claeys KG, Claes LR, Suls A et al (2007) Familial occipitotemporal lobe epilepsy and migraine with visual aura: linkage to chromosome 9q. Neurology 68(23):1995–2002PubMedGoogle Scholar
  10. 10.
    Tikka-Kleemola P, Artto V, Vepsalainen S, Sobel EM, Raty S, Kaunisto MA et al (2010) A visual migraine aura locus maps to 9q21-q22. Neurology 74(15):1171–1177PubMedCentralPubMedGoogle Scholar
  11. 11.
    Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, Launer LJ et al (2011) Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 43(7):695–698PubMedCentralPubMedGoogle Scholar
  12. 12.
    Esserlind AL, Christensen AF, Le H, Kirchmann M, Hauge AW, Toyserkani NM et al (2013) Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine. Eur J Neurol 20(5):765–772PubMedGoogle Scholar
  13. 13.
    Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM et al (2012) Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet 44(7):777–782PubMedCentralPubMedGoogle Scholar
  14. 14.
    IHS (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33(9):629–808Google Scholar
  15. 15.
    Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87(3):543–552PubMedGoogle Scholar
  16. 16.
    Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S et al (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366(9483):371–377PubMedGoogle Scholar
  17. 17.
    De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L et al (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33(2):192–196PubMedGoogle Scholar
  18. 18.
    Cuenca-Leon E, Corominas R, Montfort M, Artigas J, Roig M, Bayes M et al (2009) Familial hemiplegic migraine: linkage to chromosome 14q32 in a Spanish kindred. Neurogenetics 10(3):191–198PubMedGoogle Scholar
  19. 19.
    Riant F, Roze E, Barbance C, Meneret A, Guyant-Marechal L, Lucas C et al (2012) PRRT2 mutations cause hemiplegic migraine. Neurology 79(21):2122–2124PubMedGoogle Scholar
  20. 20.
    Pietrobon D, Moskowitz MA (2014) Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci 15(6):379–393PubMedGoogle Scholar
  21. 21.
    Lauritzen M (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117(Pt 1):199–210PubMedGoogle Scholar
  22. 22.
    van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T et al (2004) A Cacna1a knock-in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41(5):701–710PubMedGoogle Scholar
  23. 23.
    Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz SI, Waeber C, Baum MJ et al (2009) Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest 119(1):99–109PubMedCentralPubMedGoogle Scholar
  24. 24.
    van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE et al (2010) High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann Neurol 67(1):85–98PubMedGoogle Scholar
  25. 25.
    Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, Pizzorusso T et al (2011) Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet 7(6):e1002129PubMedCentralPubMedGoogle Scholar
  26. 26.
    Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA (2002) Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8(2):136–142PubMedGoogle Scholar
  27. 27.
    Chanda ML, Tuttle AH, Baran I, Atlin C, Guindi D, Hathaway G et al (2013) Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. Pain 154(8):1254–1262PubMedGoogle Scholar
  28. 28.
    Hullugundi SK, Ansuini A, Ferrari MD, van den Maagdenberg AM, Nistri A (2014) A hyperexcitability phenotype in mouse trigeminal sensory neurons expressing the R192Q Cacna1a missense mutation of familial hemiplegic migraine type-1 (FHM1). Neuroscience 266:244–254PubMedGoogle Scholar
  29. 29.
    Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N et al (2005) Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434(7033):640–644PubMedGoogle Scholar
  30. 30.
    Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y et al (2013) Casein kinase idelta mutations in familial migraine and advanced sleep phase. Sci Transl Med 5(183):183ra56, 1–11PubMedCentralPubMedGoogle Scholar
  31. 31.
    Thomsen LL, Kruuse C, Iversen HK, Olesen J (1994) A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1(1):73–80PubMedGoogle Scholar
  32. 32.
    Baca S, Barth A, Mody I, Charles A (ed) (2014) Optogenetic elicitation of cortical spreading depression in unanesthetized, head-restrained mice. 4th European Headache and Migraine Trust International Congress: EHMTIC 2014, Copenhagen. 18 Sept 2014Google Scholar
  33. 33.
    van Oosterhout F, Michel S, Deboer T, Houben T, van de Ven RC, Albus H et al (2008) Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice. Ann Neurol 64(3):315–324PubMedGoogle Scholar
  34. 34.
    Kirchmann M, Thomsen LL, Olesen J (2006) The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura. Am J Med Genet B Neuropsychiatr Genet 141B(3):250–256PubMedGoogle Scholar
  35. 35.
    Netzer C, Todt U, Heinze A, Freudenberg J, Zumbroich V, Becker T et al (2006) Haplotype-based systematic association studies of ATP1A2 in migraine with aura. Am J Med Genet B Neuropsychiatr Genet 141B(3):257–260PubMedGoogle Scholar
  36. 36.
    Jen JC, Kim GW, Dudding KA, Baloh RW (2004) No mutations in CACNA1A and ATP1A2 in probands with common types of migraine. Arch Neurol 61(6):926–928PubMedGoogle Scholar
  37. 37.
    Wieser T, Mueller C, Evers S, Zierz S, Deufel T (2003) Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing. Clin Chem Lab Med 41(3):272–275PubMedGoogle Scholar
  38. 38.
    Martin VT, Behbehani MM (2001) Toward a rational understanding of migraine trigger factors. Med Clin North Am 85(4):911–941PubMedGoogle Scholar
  39. 39.
    Andress-Rothrock D, King W, Rothrock J (2010) An analysis of migraine triggers in a clinic-based population. Headache 50(8):1366–1370PubMedGoogle Scholar
  40. 40.
    Pavlovic JM, Buse DC, Sollars CM, Haut S, Lipton RB (2014) Trigger factors and premonitory features of migraine attacks: summary of studies. Headache 54(10):1670–1679PubMedGoogle Scholar
  41. 41.
    Lipton RB, Pavlovic JM, Haut SR, Grosberg BM, Buse DC (2014) Methodological issues in studying trigger factors and premonitory features of migraine. Headache 54(10):1661–1669PubMedGoogle Scholar
  42. 42.
    Ierusalimschy R, Moreira Filho PF (2002) Precipitating factors of migraine attacks in patients with migraine without aura. Arq Neuropsiquiatr 60(3-A):609–613PubMedGoogle Scholar
  43. 43.
    Hauge A, Kirchmann M, Olesen J (2010) Trigger factors in migraine with aura. Cephalalgia 30(3):346–353PubMedGoogle Scholar
  44. 44.
    Hansen JM, Hauge AW, Ashina M, Olesen J (2011) Trigger factors for familial hemiplegic migraine. Cephalalgia 31(12):1274–1281PubMedGoogle Scholar
  45. 45.
    Kelman L (2007) The triggers or precipitants of the acute migraine attack. Cephalalgia 27(5):394–402PubMedGoogle Scholar
  46. 46.
    Yadav RK, Kalita J, Misra UK (2010) A study of triggers of migraine in India. Pain Med 11(1):44–47PubMedGoogle Scholar
  47. 47.
    Friedman DI, De ver Dye T (2009) Migraine and the environment. Headache 49(6):941–952PubMedGoogle Scholar
  48. 48.
    Levy D (2012) Endogenous mechanisms underlying the activation and sensitization of meningeal nociceptors: the role of immuno-vascular interactions and cortical spreading depression. Curr Pain Headache Rep 16(3):270–277PubMedGoogle Scholar
  49. 49.
    Noseda R, Burstein R (2013) Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain 154 Suppl 1: 10.1016/j.pain.2013.07.021
  50. 50.
    Hougaard A, Amin FM, Hauge AW, Ashina M, Olesen J (2013) Provocation of migraine with aura using natural trigger factors. Neurology 80(5):428–431PubMedGoogle Scholar
  51. 51.
    Moffett AM, Swash M, Scott DF (1974) Effect of chocolate in migraine: a double-blind study. J Neurol Neurosurg Psychiatry 37(4):445–448PubMedCentralPubMedGoogle Scholar
  52. 52.
    Marcus DA, Scharff L, Turk D, Gourley LM (1997) A double-blind provocative study of chocolate as a trigger of headache. Cephalalgia 17(8):855–862; discussion 00PubMedGoogle Scholar
  53. 53.
    Gibb CM, Davies PT, Glover V, Steiner TJ, Clifford Rose F, Sandler M (1991) Chocolate is a migraine-provoking agent. Cephalalgia 11(2):93–95PubMedGoogle Scholar
  54. 54.
    May A, Goadsby PJ (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. J Cereb Blood Flow Metab 19(2):115–127PubMedGoogle Scholar
  55. 55.
    Edvinsson L, Goadsby PJ (1995) Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia 15(4):272–276PubMedGoogle Scholar
  56. 56.
    Pietrobon D, Moskowitz MA (2013) Pathophysiology of migraine. Annu Rev Physiol 75:365–391PubMedGoogle Scholar
  57. 57.
    Edvinsson L, Petersen KA (2007) CGRP-receptor antagonism in migraine treatment. CNS Neurol Disord Drug Targets 6(4):240–246PubMedGoogle Scholar
  58. 58.
    Burstein R, Jakubowski M (2005) Unitary hypothesis for multiple triggers of the pain and strain of migraine. J Comp Neurol 493(1):9–14PubMedGoogle Scholar
  59. 59.
    Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298(5871):240–244PubMedGoogle Scholar
  60. 60.
    Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J et al (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304(5922):129–135PubMedGoogle Scholar
  61. 61.
    van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21(5):649–678PubMedGoogle Scholar
  62. 62.
    Tajti J, Uddman R, Edvinsson L (2001) Neuropeptide localization in the “migraine generator” region of the human brainstem. Cephalalgia 21(2):96–101PubMedGoogle Scholar
  63. 63.
    Eftekhari S, Warfvinge K, Blixt FW, Edvinsson L (2013) Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system. J Pain 14(11):1289–1303PubMedGoogle Scholar
  64. 64.
    Eftekhari S, Edvinsson L (2011) Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level. BMC Neurosci 12:112PubMedCentralPubMedGoogle Scholar
  65. 65.
    Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, Zeng Z, Purcell M et al (2013) In vivo quantification of calcitonin gene-related peptide (CGRP) receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography (PET) tracer [11C]MK-4232. J Pharmacol Exp Ther 347(2):478–486PubMedGoogle Scholar
  66. 66.
    Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Hargreaves RJ (1999) Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol 126(6):1478–1486PubMedCentralPubMedGoogle Scholar
  67. 67.
    Storer RJ, Akerman S, Goadsby PJ (2004) Calcitonin gene-related peptide (CGRP) modulates nociceptive trigeminovascular transmission in the cat. Br J Pharmacol 142(7):1171–1181PubMedCentralPubMedGoogle Scholar
  68. 68.
    Summ O, Charbit AR, Andreou AP, Goadsby PJ (2010) Modulation of nociceptive transmission with calcitonin gene-related peptide receptor antagonists in the thalamus. Brain 133(Pt 9):2540–2548PubMedGoogle Scholar
  69. 69.
    Zaidi M, Bevis PJ, Abeyasekera G, Girgis SI, Wimalawansa SJ, Morris HR et al (1986) The origin of circulating calcitonin gene-related peptide in the rat. J Endocrinol 110(1):185–190PubMedGoogle Scholar
  70. 70.
    Hoffmann J, Wecker S, Neeb L, Dirnagl U, Reuter U (2012) Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF. Cephalalgia 32(9):659–667PubMedGoogle Scholar
  71. 71.
    Levy D, Burstein R, Strassman AM (2005) Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: implications for the pathophysiology of migraine. Ann Neurol 58(5):698–705PubMedGoogle Scholar
  72. 72.
    Pedersen-Bjergaard U, Nielsen LB, Jensen K, Edvinsson L, Jansen I, Olesen J (1991) Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle. Peptides 12(2):333–337PubMedGoogle Scholar
  73. 73.
    Sun RQ, Lawand NB, Willis WD (2003) The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 104(1–2):201–208PubMedGoogle Scholar
  74. 74.
    Sun RQ, Lawand NB, Lin Q, Willis WD (2004) Role of calcitonin gene-related peptide in the sensitization of dorsal horn neurons to mechanical stimulation after intradermal injection of capsaicin. J Neurophysiol 92(1):320–326PubMedGoogle Scholar
  75. 75.
    Mao J, Coghill RC, Kellstein DE, Frenk H, Mayer DJ (1992) Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation. Brain Res 574(1–2):157–163PubMedGoogle Scholar
  76. 76.
    Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H (1987) Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res 403(2):350–354PubMedGoogle Scholar
  77. 77.
    Russo AF (2014) Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 55:533–552PubMedGoogle Scholar
  78. 78.
    Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23(2):193–196PubMedGoogle Scholar
  79. 79.
    Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187PubMedGoogle Scholar
  80. 80.
    Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J (2000) Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks. Pain 86(1–2):133–138PubMedGoogle Scholar
  81. 81.
    Tvedskov JF, Lipka K, Ashina M, Iversen HK, Schifter S, Olesen J (2005) No increase of calcitonin gene-related peptide in jugular blood during migraine. Ann Neurol 58(4):561–568PubMedGoogle Scholar
  82. 82.
    Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ et al (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70(16):1304–1312PubMedGoogle Scholar
  83. 83.
    Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X et al (2008) Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372(9656):2115–2123PubMedGoogle Scholar
  84. 84.
    Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U et al (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350(11):1104–1110PubMedGoogle Scholar
  85. 85.
    Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X et al (2009) Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology 73(12):970–977PubMedCentralPubMedGoogle Scholar
  86. 86.
    Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X et al (2014) Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 83(11):958–966PubMedGoogle Scholar
  87. 87.
    Sixt ML, Messlinger K, Fischer MJ (2009) Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus. Brain 132(11):3134–3141PubMedGoogle Scholar
  88. 88.
    Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M et al (2014) Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13(11):1100–1107PubMedGoogle Scholar
  89. 89.
    Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS (2014) Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 13(9):885–892PubMedGoogle Scholar
  90. 90.
    Jansen-Olesen I, Gulbenkian S, Engel U, Cunha e Sa M, Edvinsson L (2004) Peptidergic and non-peptidergic innervation and vasomotor responses of human lenticulostriate and posterior cerebral arteries. Peptides 25(12):2105–2114PubMedGoogle Scholar
  91. 91.
    Baeres FM, Moller M (2004) Origin of PACAP-immunoreactive nerve fibers innervating the subarachnoidal blood vessels of the rat brain. J Cereb Blood Flow Metab 24(6):628–635PubMedGoogle Scholar
  92. 92.
    Gulbenkian S, Uddman R, Edvinsson L (2001) Neuronal messengers in the human cerebral circulation. Peptides 22(6):995–1007PubMedGoogle Scholar
  93. 93.
    Hansen JM, Sitarz J, Birk S, Rahmann AM, Oturai PS, Fahrenkrug J et al (2006) Vasoactive intestinal polypeptide evokes only a minimal headache in healthy volunteers. Cephalalgia 26(8):992–1003PubMedGoogle Scholar
  94. 94.
    Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M (2008) Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 28(3):226–236PubMedGoogle Scholar
  95. 95.
    Birk S, Sitarz JT, Petersen KA, Oturai PS, Kruuse C, Fahrenkrug J et al (2007) The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers. Regul Pept 140(3):185–191PubMedGoogle Scholar
  96. 96.
    Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132(Pt 1):16–25PubMedGoogle Scholar
  97. 97.
    Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI et al (2014) Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 137(Pt 3):779–794PubMedGoogle Scholar
  98. 98.
    Hosoya M, Onda H, Ogi K, Masuda Y, Miyamoto Y, Ohtaki T et al (1993) Molecular cloning and functional expression of rat cDNAs encoding the receptor for pituitary adenylate cyclase activating polypeptide (PACAP). Biochem Biophys Res Commun 194(1):133–143PubMedGoogle Scholar
  99. 99.
    Lutz EM, Sheward WJ, West KM, Morrow JA, Fink G, Harmar AJ (1993) The VIP2 receptor: molecular characterisation of a cDNA encoding a novel receptor for vasoactive intestinal peptide. FEBS Lett 334(1):3–8PubMedGoogle Scholar
  100. 100.
    Harmar AJ, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR et al (1998) International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Pharmacol Rev 50(2):265–270PubMedGoogle Scholar
  101. 101.
    Schytz HW, Olesen J, Ashina M (2010) The PACAP receptor: a novel target for migraine treatment. Neurotherapeutics 7(2):191–196PubMedGoogle Scholar
  102. 102.
    Giffin NJ, Ruggiero L, Lipton RB, Silberstein SD, Tvedskov JF, Olesen J et al (2003) Premonitory symptoms in migraine: an electronic diary study. Neurology 60(6):935–940PubMedGoogle Scholar
  103. 103.
    Kelman L (2004) The premonitory symptoms (prodrome): a tertiary care study of 893 migraineurs. Headache 44(9):865–872PubMedGoogle Scholar
  104. 104.
    Schoonman GG, Evers DJ, Terwindt GM, van Dijk JG, Ferrari MD (2006) The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients. Cephalalgia 26(10):1209–1213PubMedGoogle Scholar
  105. 105.
    Charles A (2013) The evolution of a migraine attack – a review of recent evidence. Headache 53(2):413–419PubMedGoogle Scholar
  106. 106.
    Maniyar FH, Sprenger T, Schankin C, Goadsby PJ (2014) Photic hypersensitivity in the premonitory phase of migraine–a positron emission tomography study. Eur J Neurol 21(9):1178–1183PubMedGoogle Scholar
  107. 107.
    Salazar G, Fragoso M, Vergez L, Sergio P, Cuello D (2011) Metoclopramide as an analgesic in severe migraine attacks: an open, single-blind, parallel control study. Recent Pat CNS Drug Discov 6(2):141–145PubMedGoogle Scholar
  108. 108.
    Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G (1995) The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 346(8980):923–926PubMedGoogle Scholar
  109. 109.
    Bergerot A, Storer RJ, Goadsby PJ (2007) Dopamine inhibits trigeminovascular transmission in the rat. Ann Neurol 61(3):251–262PubMedGoogle Scholar
  110. 110.
    Cao Y, Aurora SK, Nagesh V, Patel SC, Welch KM (2002) Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 59(1):72–78PubMedGoogle Scholar
  111. 111.
    Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ (2014) Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137(Pt 1):232–241PubMedGoogle Scholar
  112. 112.
    Afridi SK, Kaube H, Goadsby PJ (2004) Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 110(3):675–680PubMedGoogle Scholar
  113. 113.
    Borsook D, Burstein R (2012) The enigma of the dorsolateral pons as a migraine generator. Cephalalgia 32(11):803–812PubMedCentralPubMedGoogle Scholar
  114. 114.
    Moulton EA, Becerra L, Johnson A, Burstein R, Borsook D (2014) Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine. PLoS One 9(4):e95508PubMedCentralPubMedGoogle Scholar
  115. 115.
    Holland P, Goadsby PJ (2007) The hypothalamic orexinergic system: pain and primary headaches. Headache 47(6):951–962PubMedGoogle Scholar
  116. 116.
    Hoffmann J, Supronsinchai W, Akerman S, Andreou AP, Winrow CJ, Renger J et al (2014) Evidence for orexinergic mechanisms in migraine. Neurobiol Dis 74C:137–143Google Scholar
  117. 117.
    Chabi A, Zhang Y, Jackson S, Cady R, Lines C, Herring WJ et al (2014) Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia 2014 Aug 8. pii: 0333102414544979. doi:  10.1177/0333102414544979 [Epub ahead of print]
  118. 118.
    Russell MB, Rasmussen BK, Thorvaldsen P, Olesen J (1995) Prevalence and sex-ratio of the subtypes of migraine. Int J Epidemiol 24(3):612–618PubMedGoogle Scholar
  119. 119.
    Russell MB, Olesen J (1996) A nosographic analysis of the migraine aura in a general population. Brain 119(Pt 2):355–361PubMedGoogle Scholar
  120. 120.
    Leão AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7(6):359–390Google Scholar
  121. 121.
    Charles A, Brennan K (2009) Cortical spreading depression-new insights and persistent questions. Cephalalgia 29(10):1115–1124PubMedGoogle Scholar
  122. 122.
    Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK et al (2013) Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 80(12):1095–1102PubMedGoogle Scholar
  123. 123.
    Drenckhahn C, Winkler MK, Major S, Scheel M, Kang EJ, Pinczolits A et al (2012) Correlates of spreading depolarization in human scalp electroencephalography. Brain 135(Pt 3):853–868PubMedCentralPubMedGoogle Scholar
  124. 124.
    Strong AJ, Fabricius M, Boutelle MG, Hibbins SJ, Hopwood SE, Jones R et al (2002) Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 33(12):2738–2743PubMedGoogle Scholar
  125. 125.
    Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B et al (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A 98(8):4687–4692PubMedCentralPubMedGoogle Scholar
  126. 126.
    Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R (2010) Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci 30(26):8807–8814PubMedCentralPubMedGoogle Scholar
  127. 127.
    Zhang X, Levy D, Kainz V, Noseda R, Jakubowski M, Burstein R (2011) Activation of central trigeminovascular neurons by cortical spreading depression. Ann Neurol 69(5):855–865PubMedCentralPubMedGoogle Scholar
  128. 128.
    Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Kocak E, Sen ZD et al (2013) Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339(6123):1092–1095PubMedGoogle Scholar
  129. 129.
    Noseda R, Constandil L, Bourgeais L, Chalus M, Villanueva L (2010) Changes of meningeal excitability mediated by corticotrigeminal networks: a link for the endogenous modulation of migraine pain. J Neurosci 30(43):14420–14429PubMedGoogle Scholar
  130. 130.
    Hansen JM, Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK et al (2012) Migraine headache is present in the aura phase: a prospective study. Neurology 79(20):2044–2049PubMedCentralPubMedGoogle Scholar
  131. 131.
    Wolff H (1963) Headache and other head pain. Oxford University Press, New YorkGoogle Scholar
  132. 132.
    Mayberg M, Langer RS, Zervas NT, Moskowitz MA (1981) Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science 213(4504):228–230PubMedGoogle Scholar
  133. 133.
    Liu-Chen LY, Mayberg MR, Moskowitz MA (1983) Immunohistochemical evidence for a substance P-containing trigeminovascular pathway to pial arteries in cats. Brain Res 268(1):162–166PubMedGoogle Scholar
  134. 134.
    Olesen J, Burstein R, Ashina M, Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8(7):679–690PubMedGoogle Scholar
  135. 135.
    Cushing H (1904) The sensory distribution of the fifth cranial nerve. Bull Johns Hopk Hosp XV:213–232Google Scholar
  136. 136.
    Ray B, Wolff H (1940) Experimental studies on headache. Pain sensitive structures of the head and their significance in headache. Arch Surg 41:813–856Google Scholar
  137. 137.
    Lassen LH, Jacobsen VB, Haderslev PA, Sperling B, Iversen HK, Olesen J et al (2008) Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients. J Headache Pain 9(3):151–157PubMedCentralPubMedGoogle Scholar
  138. 138.
    Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD (2008) Migraine headache is not associated with cerebral or meningeal vasodilatation–a 3T magnetic resonance angiography study. Brain 131(Pt 8):2192–2200PubMedGoogle Scholar
  139. 139.
    Asghar MS, Hansen AE, Amin FM, van der Geest RJ, van der Koning P, Larsson HBW et al (2011) Evidence for a vascular factor in migraine. Ann Neurol 69(4):635–645PubMedGoogle Scholar
  140. 140.
    Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1(7):658–660PubMedGoogle Scholar
  141. 141.
    Afridi SK, Giffin NJ, Kaube H, Friston KJ, Ward NS, Frackowiak RS et al (2005) A positron emission tomographic study in spontaneous migraine. Arch Neurol 62(8):1270–1275PubMedGoogle Scholar
  142. 142.
    Ahn AH (2010) On the temporal relationship between throbbing migraine pain and arterial pulse. Headache 50(9):1507–1510PubMedCentralPubMedGoogle Scholar
  143. 143.
    Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ et al (2013) Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 12(5):454–461PubMedGoogle Scholar
  144. 144.
    Farkkila M, Diener HC, Geraud G, Lainez M, Schoenen J, Harner N et al (2012) Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 11(5):405–413PubMedGoogle Scholar
  145. 145.
    Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR (2009) Neurobiology of migraine. Neuroscience 161(2):327–341PubMedGoogle Scholar
  146. 146.
    Goadsby PJ, Akerman S (2012) 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 32(1):3–5PubMedGoogle Scholar
  147. 147.
    Burstein R, Strassman A, Moskowitz M (2012) Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia 32(6):509–511PubMedCentralPubMedGoogle Scholar
  148. 148.
    Levy D (2010) Migraine pain and nociceptor activation–where do we stand? Headache 50(5):909–916PubMedGoogle Scholar
  149. 149.
    Iversen HK, Olesen J, Tfelt-Hansen P (1989) Intravenous nitroglycerin as an experimental model of vascular headache. Basic characteristics. Pain 38(1):17–24PubMedGoogle Scholar
  150. 150.
    Ashina M, Hansen JM (2010) Pharmacological migraine provocation: a human model of migraine. Handb Clin Neurol 97:773–779PubMedGoogle Scholar
  151. 151.
    Olesen J, Tfelt-Hansen P, Ashina M (2009) Finding new drug targets for the treatment of migraine attacks. Cephalalgia 29(9):909–920PubMedGoogle Scholar
  152. 152.
    Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J (1997) Nitric oxide synthase inhibition in migraine. Lancet 349(9049):401–402PubMedGoogle Scholar
  153. 153.
    Read SJ, Hirst WD, Upton N, Parsons AA (2001) Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan. Brain Res 891(1–2):69–77PubMedGoogle Scholar
  154. 154.
    Schwedt TJ, Larson-Prior L, Coalson RS, Nolan T, Mar S, Ances BM et al (2013) Allodynia and descending pain modulation in migraine: a resting state functional connectivity analysis. Pain Med 15(1):154–165PubMedCentralPubMedGoogle Scholar
  155. 155.
    Mainero C, Boshyan J, Hadjikhani N (2011) Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Ann Neurol 70(5):838–845PubMedCentralPubMedGoogle Scholar
  156. 156.
    Shuhendler AJ, Lee S, Siu M, Ondovcik S, Lam K, Alabdullatif A et al (2009) Efficacy of botulinum toxin type A for the prophylaxis of episodic migraine headaches: a meta-analysis of randomized, double-blind, placebo-controlled trials. Pharmacotherapy 29(7):784–791PubMedGoogle Scholar
  157. 157.
    Jackson JL, Kuriyama A, Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307(16):1736–1745PubMedGoogle Scholar
  158. 158.
    Burstein R, Zhang X, Levy D, Aoki KR, Brin MF (2014) Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: therapeutic implications for migraine and other pains. Cephalalgia 34(11):853–869PubMedCentralPubMedGoogle Scholar
  159. 159.
    Dahlem MA, Hadjikhani N (2009) Migraine aura: retracting particle-like waves in weakly susceptible cortex. PLoS One 4(4):e5007PubMedCentralPubMedGoogle Scholar
  160. 160.
    Fauci A, Braunwald E, Kasper DL et al (2008) Harrison’s principles of internal medicine, 17th edn. McGraw-Hill, New YorkGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Neurology, Faculty of Health SciencesGlostrup Hospital, Danish Headache Center, University of CopenhagenGlostrup, CopenhagenDenmark
  2. 2.Department of Anesthesia Critical Care and Pain MedicineBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA

Personalised recommendations