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Current concept of the pathophysiology of migraine and new targets for its therapy

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Migraine is a common chronic neurological disease. Many neurogenic, vascular, autonomic, and other mechanisms at different levels of the central and peripheral nervous systems are assumed to be implicated in the pathophysiology of headache and other manifestations of migraine. Advances in understanding the neurobiology of migraine have made it possible to clarify the main patterns of neurogenic-vascular relationships that explain the leading clinical manifestations of migraine, as well as to identify some biological markers that have triggered the creation of new targeted therapies for the disease. This review is dedicated to the latest advances in studying the pathophysiology of migraine and to new pharmacological approaches to its treatment.

About the Authors

G. R. Tabeeva
I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia
Russian Federation

Guzyal Rafkatovna Tabeeva

Department of Nervous System Diseases and Neurosurgery

11, Rossolimo St., Build. 1, Moscow 119021

Z. Katsapava
I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia; University of Duisburg-Essen, University Hospital; Evangelical Hospital; EVEX Medical Corporation
Russian Federation

Department of Nervous System Diseases and Neurosurgery, I.M. Sechenov First Moscow State Medical University

Department of Neurology, University of Duisburg-Essen, University Hospital

Department of Neurology, Evangelical Hospital

11, Rossolimo St., Build. 1, Moscow 119021
Hufelandstr. 55, 45122 Essen, Germany
Holbeinstr 10, 59423 Unna, Germany
40 Vazha-Pshavela Avenue, Tbilisi 0177, Georgia 


1. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017 Sep 16;390(10100):1211-59. doi: 10.1016/S0140-6736(17)32154-2

2. Lipton RB, Bigal ME, Diamond M, et al; Advisory Group AMPP. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343-9. doi: 10.1212/01.wnl.0000252808.97649.21

3. Eadie MJ. A history of migriane. In: Borsook D, May A, Goadsby PJ, Hargeaves R, eds. The Migraine Brain. New York: Oxford University Press; 2012. P. 3-16.

4. Willis T, Pordage S. Two Discourses Concerning the Soul of Brutes, which Is that of the Vital and Sensitive of Man: The First Is Physiological, Shewing the Nature, Parts, Powers, And Affections Of The Same; And The Other Is Pathological, Which Unfolds the Diseases Which Affect It and Its Primary Seat, to Wit, the Brain and Nervous Stock, and Treats of Their Cures: With Copper Cuts. London: Dring, Harper and Leigh; 1683.

5. Liveing E. On Megrim, Sick-Headache, and Some Allied Disorders. A Contribution to the Pathology of Nerve-Storms. London: Arts & Boeve Nijmegen; 1873.

6. Wolff HG. Headache and other head pains, 2 nd ed. New York: Oxford University Press; 1963.

7. Goadsby PJ, Holland PR, MartinsOliveira M, et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553-622. doi: 10.1152/physrev.00034.2015

8. Marmura MJ. Triggers, protectors, and predictors in episodic migraine. Curr Pain Headache Rep. 2018 Oct 5;22(12):81. doi: 10.1007/s11916-018-0734-0

9. Akerman S, Holland P, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nature Rev Neurosci. 2011;12:570-84. doi: 10.1038/nrn3057

10. Bernstein C, Burstein R. Sensitization of the trigeminovascular pathway: perspective and implications to migraine pathophysiology. J Clin Neurol. 2012;8:89-99. doi: 10.3988/jcn.2012.8.2.89

11. Charles A. Migraine: a brain state. Curr Opin Neurol. 2013;26:235-9. doi: 10.1097/WCO.0b013e32836085f4

12. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia. 2007;27:1427-39. doi: 10.1111/j.14682982.2007.01500.x

13. Tolner EA, Houben T, Terwindt GM, et al. From migraine genes to mechanisms. Pain. 2015;156 Suppl 1:S64-74. doi: 10.1097/01.j.pain.0000460346.00213.16

14. Van Oosterhout W, van Someren E, Schoonman GG, et al. Chronotypes and circadian timing in migraine. Cephalalgia. 2017. doi: 10.1177/0333102417698953

15. Burstein R, Noseda R, Borsook D. Migraine: Multiple processes, complex pathophysiology. J Neurosci. 2015;35:6619-29. doi: 10.1523/JNEUROSCI.0373-15.2015

16. Maniyar FH, Sprenger T, Monteith T, et al. Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain. 2014;137:232-41. doi: 10.1093/brain/awt320

17. Moulton EA, Becerra L, Johnson A, et al. Altered hypothalamic functional connectivity with autonomic circuits and the locus coeruleus in migraine. PLoS One. 2014 Apr 17;9(4):e95508. doi: 10.1371/journal.pone.0095508

18. Dodick DW. Phase-by-phase review of migraine pathophysiology. Headache. 2018;58:4-16. doi: 10.1111/head.13300

19. Wei X, Yan J, Tillu D, et al. Meningeal norepinephrine produces headache behaviors in rats via actions both on dural afferents and fibroblasts. Cephalalgia. 2015;35:1054-64. doi: 10.1177/0333102414566861

20. Schulte LH, May A. The migraine generator revisited: Continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain. 2016;139:1987-93. doi: 10.1093/brain/aww097

21. Borsook D, Burstein R. The enigma of the dorsolateral pons as a migraine generator. Cephalalgia. 2012;32:803-12. doi: 10.1177/0333102412453952

22. Viana M, Linde M, Sances G, et al. Migraine aura symptoms: duration, succession and temporal relationship to headache. Cephalalgia. 2016;36:413-21. doi: 10.1177/0333102415593089

23. Lashley KS. Patterns of cerebral integration indicated by the scotomas of migraine. Arch Neurol Psychiatry. 1941;46:331-9. doi: 10.1001/archneurpsyc.1941.02280200137007

24. Leao AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359-90. doi: 10.1152/jn.1944.7.6.359

25. 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. doi: 10.1002/ana.410090406

26. Hadjikhani N, Sanchez del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA. 2001;98:4687-92.

27. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365-91. doi: 10.1146/annurev-physiol030212-183717

28. Charles A, Hansen JM. Migraine aura: New ideas about cause, classification, and clinical significance. Curr Opin Neurol. 2015;28:255-60. doi: 10.1097/WCO.0000000000000193

29. Zhang X, Levy D, Noseda R, et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci. 2010 Jun 30;30(26):8807-14. doi: 10.1523/JNEUROSCI.0511-10.2010

30. Lambert GA, Hoskin KL, Zagami AS. Cortico-NRM influences on trigeminal neuronal sensation. Cephalalgia. 2008;28:640-52. doi: 10.1111/j.1468-2982.2008.01572.x

31. Goadsby PJ. Parallel concept of migraine pathogensis. Ann Neurol. 2002;51:140. doi: 10.1002/ana.10025

32. Bartsch T, Goadsby PJ. Anatomy and physiology of pain referral in primary and cervicogenic headache disorders. Headache Curr. 2005;2:42-8. doi: 10.1111/j.17435013.2005.20201.x

33. Noseda R, Jakubowski M, Kainz V, et al. Cortical projections of functionally identified thalamic trigeminovascular neurons: Implications for migraine headache and its associated symptoms. J Neurosci. 2011;31:14204-17. doi: 10.1523/JNEUROSCI.3285-11.2011

34. Messlinger K, Fischer MJ, Lennerz JK. Neuropeptide effects in the trigeminal system: Pathophysiology and clinical relevance in migraine. Keio J Med. 2011;60:82-9. doi: 10.2302/kjm.60.82

35. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain. 2013 Dec;154 Suppl 1:S44-S53. doi: 10.1016/j.pain.2013.07.021

36. Noseda R, Kainz V, Jakubowski M, et al. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13(2):239-45. doi: 10.1038/nn.2475

37. Magis D, Lisicki M, Coppola G. Highlights in migraine electrophysiology: Are controversies just reflecting disease heterogeneity? Curr Opin Neurol. 2016;29:320-30. doi: 10.1097/WCO.0000000000000335

38. Schwedt TJ, Chiang CC, Chong CD, Dodick DW. Functional MRI of migraine. Lancet Neurol. 2015;14:81-91. doi: 10.1016/S1474-4422(14)70193-0

39. Kondrat'eva NS, Anuchina AA, Kokaeva ZG, et al. Genetics of migraine (review). Meditsinskaya genetika. 2016;(1):3-12 (In Russ.).

40. Stewart WF, Staffa J, Lipton RB, Ottman R. Familial risk of migraine: a population-based study. Ann Neurol. 1997;41:166-72. doi: 10.1002/ana.410410207

41. Gervil M, Ulrich V, Kaprio J, Russell MB. Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population-based family twin study of migraine without aura. Eur J Neurol. 2001;8:231-35. doi: 10.1046/j.1468-1331.2001.00188.x

42. Ulrich V, Gervil M, Kyvik KO, et al. Evidence of a genetic factor in migraine with aura: a population based Danish twin study. Ann Neurol. 1999;45:242-6. doi: 10.1002/1531-8249(199902)45:2<242::AIDANA15>3.0.CO;2-1

43. Goadsby PJ. Bench to bedside advances in the 21 st century for primary headache disorders: migraine treatments for migraine patients. Brain. 2016;139(Pt 10):2571-7. doi: 10.1093/brain/aww236

44. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982;298:240-4. doi: 10.1038/298240a0

45. Edvinsson L. The journey to establish CGRP as a migraine target: a retrospective view. Headache. 2015;55:1249-55. doi: 10.1111/head.12656

46. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies – successful translation from bench to clinic. Nat Rev Neurol. 2018 Jun;14(6):338-50. doi: 10.1038/s41582-0180003-1

47. Durham PL, Russo AF. Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci. 1999;19:3423-9. doi: 10.1523/JNEUROSCI.1909-03423.1999

48. Villalon CM, van den Brink AM. The role of 5-hydroxytryptamine in the pathophysiology of migraine and its relevance to the design of novel treatments. Mini Rev Med Chem. 2017;17:928-38. doi: 10.2174/1389557516666160728121050

49. Raffaelli B, Israel H, Neeb L, Reuter U. The safety and efficacy of the 5-HT 1 F receptor agonist lasmiditan in the acute treatment of migraine. Exp Opin Pharmacother. 2017;18:1409-15. doi: 10.1080/14656566.2017.1361406

50. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33:48-56. doi: 10.1002/ana.410330109

51. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28:183-7. doi: 10.1002/ana.410280213

52. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30:1179-86. doi: 10.1177/0333102410368444

53. Raddant AC, Russo AF. Calcitonin generelated peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011 Nov 29;13:e36. doi: 10.1017/S1462399411002067

54. Maasumi K, Michael RL, Rapoport AM. CGRP and migraine: the role of blocking calcitonin gene-related peptide ligand and receptor in the management of migraine. Drugs. 2018 Jun;78(9):913-28. doi: 10.1007/s40265-0180923-5

55. Edvinsson L. The CGRP pathway in migraine as a viable target for therapies. Headache. 2018;58 Suppl 1:33-47. doi: 10.1111/head.13305

56. Silberstein S, Lenz R, Xu C. Therapeutic monoclonal antibodies: what headache specialists need to know. Headache. 2015;55(8):1171-82. doi: 10.1111/head.12642

57. Hansel TT, Kropshofer H, Singer T, et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9(4):325-38. doi: 10.1038/nrd3003

58. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain. 2019 Apr 17;20(1):37. doi: 10.1186/s10194-019-0974-3

59. Bigal ME, Escandon R, Bronson M, et al. Safety and tolerability of LBR-101, a humanized monoclonal antibody that blocks the binding of CGRP to its receptor: results of the phase 1 program. Cephalalgia. 2014;34:483-92. doi: 10.1177/0333102413517775

60. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113-22. doi: 10.1056/NEJMoa1709038

61. Dodick DW, Silberstein SD, Bigal ME, et al. Еffect of Fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999-2008. doi: 10.1001/jama.2018.4853

62. Cohen JM, Dodick DW, Yang R, et al. Fremanezumab as add-on treatment for patients treated with other migraine preventive medicines. Headache. 2017;57:1375-84. doi: 10.1111/head.13156

For citation:

Tabeeva G.R., Katsapava Z. Current concept of the pathophysiology of migraine and new targets for its therapy. Neurology, Neuropsychiatry, Psychosomatics. 2020;12(4):143-152.

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