Mechanisms of Chronic Migraine

  • Sheena K. Aurora
  • Ninan T. Mathew
Reference work entry


Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. The results of electrophysiological and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brain stem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiological and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine is emerging in which relatively permanent and pervasive central changes have occurred that warrant novel and tolerable treatments. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.


Central Sensitization Chronic Migraine Migraine With Aura Cortical Spreading Depression Cortical Excitability 
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. Afridi SK, Matharu MS, Lee L et al (2005) A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128(Pt 4):932–939PubMedCrossRefGoogle Scholar
  2. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A (2007) Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache 47(7):996–1003, discussion 1004–1007PubMedCrossRefGoogle Scholar
  3. Aurora SK, Barrodale P, Chronicle EP, Mulleners WM (2005) Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness. Headache 45(5):546–552PubMedCrossRefGoogle Scholar
  4. Bigal ME, Lipton RB (2008) Concepts and mechanisms of migraine chronification. Headache 48(1):7–15PubMedCrossRefGoogle Scholar
  5. Bigal M, Rapoport A, Sheftell F, Tepper S, Lipton R (2007) The International Classification of Headache Disorders revised criteria for chronic migraine-field testing in a headache specialty clinic. Cephalalgia 27:230–234CrossRefGoogle Scholar
  6. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD (2003) Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 43(4):336–342PubMedCrossRefGoogle Scholar
  7. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB (2005a) Chronic migraine is an earlier stage of transformed migraine in adults. Neurology 65(10):1556–1561PubMedCrossRefGoogle Scholar
  8. Bigal ME, Sheftell FD, Tepper SJ, Rapoport AM, Lipton RB (2005b) Migraine days decline with duration of illness in adolescents with transformed migraine. Cephalalgia 25(7):482–487PubMedCrossRefGoogle Scholar
  9. Bowyer SM, Aurora KS, Moran JE, Tepley N, Welch KM (2001) Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann Neurol 50(5):582–587PubMedCrossRefGoogle Scholar
  10. Brown LL, Schneider JS, Lidsky TI (1997) Sensory and cognitive functions of the basal ganglia. Curr Opin Neurobiol 7(2):157–163PubMedCrossRefGoogle Scholar
  11. Burstein R, Jakubowski M (2004) Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol 55(1):27–36PubMedCrossRefGoogle Scholar
  12. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH (2000) An association between migraine and cutaneous allodynia. Ann Neurol 47(5):614–624PubMedCrossRefGoogle Scholar
  13. Cady RK, Schreiber CP, Farmer KU (2004) Understanding the patient with migraine: the evolution from episodic headache to chronic neurologic disease. A proposed classification of patients with headache. Headache 44(5):426–435PubMedCrossRefGoogle Scholar
  14. 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
  15. Chudler EH, Dong WK (1995) The role of the basal ganglia in nociception and pain. Pain 60(1):3–38PubMedCrossRefGoogle Scholar
  16. Cooke L, Eliasziw M, Becker WJ (2007) Cutaneous allodynia in transformed migraine patients. Headache 47(4):531–539PubMedGoogle Scholar
  17. De Fusco M, Marconi R, Silvestri 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):192–196PubMedCrossRefGoogle Scholar
  18. de Tommaso M, Valeriani M, Guido M et al (2003) Abnormal brain processing of cutaneous pain in patients with chronic migraine. Pain 101(1–2):25–32PubMedCrossRefGoogle Scholar
  19. de Tommaso M, Losito L, Difruscolo O, Libro G, Guido M, Livrea P (2005) Changes in cortical processing of pain in chronic migraine. Headache 45(9):1208–1218PubMedCrossRefGoogle Scholar
  20. Ferrari A, Leone S, Vergoni AV et al (2007) Similarities and differences between chronic migraine and episodic migraine. Headache 47(1):65–72PubMedCrossRefGoogle Scholar
  21. Freitag FG, Kozma CM, Slaton T, Osterhaus JT, Barron R (2005) Characterization and prediction of emergency department use in chronic daily headache patients. Headache 45(7):891–898PubMedCrossRefGoogle Scholar
  22. Goadsby PJ (2005) Advances in the understanding of headache. Br Med Bull 73–74:83–92PubMedCrossRefGoogle Scholar
  23. Goadsby PJ (2007) Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med 13(1):39–44PubMedCrossRefGoogle Scholar
  24. Hadjikhani N, Sanchez Del Rio M, Wu O et al (2001) Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 98(8):4687–4692PubMedCrossRefGoogle Scholar
  25. Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24(Suppl 1):9–160Google Scholar
  26. Iadarola MJ, Berman KF, Zeffiro TA et al (1998) Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 121(Pt 5):931–947PubMedCrossRefGoogle Scholar
  27. International Headache Society (2007) IHS classification ICDH II. Migraine. Available at: Accessed 3 Dec 2007
  28. Kitaj MB, Klink M (2005) Pain thresholds in daily transformed migraine versus episodic migraine headache patients. Headache 45(8):992–998PubMedCrossRefGoogle Scholar
  29. Lauritzen M (1994) Pathophysiology of the migraine aura. The spreading depression theory. Brain 117(Pt 1):199–210PubMedCrossRefGoogle Scholar
  30. Lipton RB, Bigal ME (2008) Looking to the future: research designs for study of headache disease progression. Headache 48(1):58–66PubMedCrossRefGoogle Scholar
  31. Lovati C, D’Amico D, Rosa S et al (2007) Allodynia in different forms of migraine. Neurol Sci 28(Suppl 2):S220–S221PubMedCrossRefGoogle Scholar
  32. Mathew NT, Stubits E, Nigam MP (1982) Transformation of episodic migraine into daily headache: analysis of factors. Headache 22(2):66–68PubMedCrossRefGoogle Scholar
  33. Moliadze V, Zhao Y, Eysel U, Funke K (2003) Effect of transcranial magnetic stimulation on single-unit activity in the cat primary visual cortex. J Physiol 553(Pt 2):665–679PubMedCrossRefGoogle Scholar
  34. Mongini F, Keller R, Deregibus A, Barbalonga E, Mongini T (2005) Frontal lobe dysfunction in patients with chronic migraine: a clinical-neuropsychological study. Psychiatry Res 133(1):101–106PubMedCrossRefGoogle Scholar
  35. Mulleners WM, Chronicle EP, Palmer JE, Koehler PJ, Vredeveld JW (2001) Suppression of perception in migraine: evidence for reduced inhibition in the visual cortex. Neurology 56(2):178–183PubMedGoogle Scholar
  36. Obermann M, Gizewski ER, Limmroth V, Diener HC, Katsarava Z (2006) Symptomatic migraine and pontine vascular malformation: evidence for a key role of the brainstem in the pathophysiology of chronic migraine. Cephalalgia 26(6):763–766PubMedCrossRefGoogle Scholar
  37. Ophoff RA, Terwindt GM, Vergouwe MN et al (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87(3):543–552PubMedCrossRefGoogle Scholar
  38. Penzien DB, Rains JC, Lipton RB (2008) Introduction to the special series on the chronification of headache: mechanisms, risk factors, and behavioral strategies aimed at primary and secondary prevention of chronic headache. Headache 48(1):5–6CrossRefGoogle Scholar
  39. Scher AI, Midgette LA, Lipton RB (2008) Risk factors for headache chronification. Headache 48(1):16–25PubMedCrossRefGoogle Scholar
  40. Wang HZ, Simonson TM, Greco WR, Yuh WT (2001) Brain MR imaging in the evaluation of chronic headache in patients without other neurologic symptoms. Acad Radiol 8(5):405–408PubMedCrossRefGoogle Scholar
  41. Weiller C, May A, Limmroth V et al (1995) Brain stem activation in spontaneous human migraine attacks. Nat Med 1(7):658–660PubMedCrossRefGoogle Scholar
  42. Welch KM, Nagesh V, Aurora SK, Gelman N (2001) Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 41(7):629–637PubMedCrossRefGoogle Scholar
  43. Welch KM, Cao Y, Aurora S, Wiggins G, Vikingstad EM (1998) MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine. Neurology 51(5):1465–1469PubMedGoogle Scholar
  44. World Health Organization (WHO) (2007) Headache disorders. Available at: Accessed 3 Dec 2007

Copyright information

© Lifting The Burden 2011

Authors and Affiliations

  1. 1.Swedish Headache and Pain CenterSwedish Neurosciences InstituteSeattleUSA
  2. 2.Houston Headache ClinicHoustonUSA

Personalised recommendations