Semin Neurol 2006; 26(2): 171-180
DOI: 10.1055/s-2006-939917
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Pathophysiology of Migraine

F. Michael Cutrer1
  • 1Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota
Further Information

Publication History

Publication Date:
21 April 2006 (online)

ABSTRACT

The cause and pathophysiology of migraine are not well understood. Over the years research into migraine pathophysiology has focused on the physiology and pharmacology of the headache, the changes in cerebral cortex associated with the symptoms of the aura, and more recently the genetics underlying the migraine syndromes. In this discussion, the neuroanatomical structures activated during migraine attacks, the traditional theories of migraine that serve as the foundation for current research, and the essential findings from current migraine pathophysiological research will be reviewed. Investigations in migraine can be divided into those related to the brain events initiating a migraine attack, those examining the mechanisms of activation and transmission within trigeminal afferent neurons, and those focused on the effect of and the modulation of nociception trigeminal input within the central nervous system.

REFERENCES

  • 1 Rasmussen B K, Jensen R, Schroll M et al.. Epidemiology of headache in a general population: a prevalence study.  J Clin Epidemiol. 1991;  44 1147-1157
  • 2 Lipton R B, Stewart W F, Diamond S, Diamond M L, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II.  Headache. 2001;  41 646-657
  • 3 Headache Classification Subcommittee of the International Headache Society . The International Classification of Headache Disorders, 2nd edition.  Cephalalgia. 2004;  24(suppl 1) 1-160
  • 4 Penfield W. A contribution to the mechanism of intracranial pain.  Assoc Res Nerv Ment Dis. 1935;  15 399-416
  • 5 Ray B S, Wolff H G. Experimental studies on headache: pain-sensitive structures of the head and their significance in headache.  Arch Surg. 1940;  41 813-856
  • 6 Mayberg M R, Zervas N T, Moskowitz M A. Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry.  J Comp Neurol. 1984;  223 46-56
  • 7 Nozaki K, Boccalini P, Moskowitz M A. Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space.  Neuroscience. 1992;  49 669-680
  • 8 DaSilva A FM, Becerra L, Makris N et al.. Somatotopic activation in the human trigeminal pain pathway.  J Neurosci. 2002;  22 8183-8192
  • 9 Sessle B J, Hu J W, Dubner R, Lucier G E. Functional properties of neurons in trigeminal subnucleus caudalis of the cat. II: modulation of responses to noxious and non-noxious stimulation by periaqueductal gray, nucleus raphe magnus, cerebral cortex and afferent influences, and effect of nalaxone.  J Neurophysiol. 1981;  45 193-207
  • 10 Kruger L, Young R F. Specialized features of the trigeminal nerve and its central connections. In: Samii M, Janetta PJ The Cranial Nerves. Berlin; Springer-Verlag 1981: 273-301
  • 11 Wise S P, Jones E G. Cells of origin and trigeminal distribution of descending projections of the rat somatic sensory cortex.  J Comp Neurol. 1977;  175 129-158
  • 12 Jacquin M F, Chiaia N L, Haring J H, Rhoades R W. Intersubnuclear connections within the rat trigeminal brainstem complex.  Somatosens Mot Res. 1990;  7 399-420
  • 13 Renehan W E, Jacquin M F, Mooney R D, Rhoades R W. Structure-function relationship in rat medullary and cervical dorsal horns. II: medullary dorsal horn cells.  J Neurophysiol. 1986;  55 1187-1201
  • 14 Weiller C, May A, Limmroth V et al.. Brain stem activation in spontaneous human migraine attacks.  Nat Med. 1995;  1 658-660
  • 15 Wolff H G. Headache and Other Head Pain. 2nd ed. New York; Oxford University Press 1963
  • 16 Cutrer F M, Sorensen A G, Weisskoff R M et al.. Perfusion-weighted imaging defects during spontaneous migrainous aura.  Ann Neurol. 1998;  43 25-31
  • 17 Ophoff R A, Terwindt G M, Vergouwe M N et al.. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.  Cell. 1996;  87 543-552
  • 18 De Fusco M, Marconi R, Silvestri L et al.. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.  Nat Genet. 2003;  33 192-196
  • 19 Dichgans M, Freilinger T, Eckstein G et al.. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.  Lancet. 2005;  366 371-377
  • 20 Wessman M, Kallela M, Kaunisto M A et al.. A susceptibility locus for migraine with aura, on chromosome 4q24.  Am J Hum Genet. 2002;  70 652-662
  • 21 Bjornsson A, Gudmundsson G, Gudfinnsson E et al.. Localization of a gene for migraine without aura to chromosome 4q21.  Am J Hum Genet. 2003;  73 986-993
  • 22 Carlsson A, Forsgren L, Nylander P-O et al.. Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1  Neurology. 2002;  59 1804-1807
  • 23 Nyholt D R, Dawkins J L, Brimage P J, Goadsby P J, Nocholson G A, Griffiths L R. Evidence for an X-lined genetic component in familial typical migraine.  Hum Mol Genet. 1998;  7 459-463
  • 24 Vanmolkot K R, Kors E E, Hottenga J J et al.. Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.  Ann Neurol. 2003;  54 360-366
  • 25 Marconi R, De Fusco M, Aridon P et al.. Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23.  Ann Neurol. 2003;  53 376-381
  • 26 Kara I, Sazci A, Ergul E, Kaya G, Kilic G. Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk.  Brain Res Mol Brain Res. 2003;  111 84-90
  • 27 Cader Z M, Noble-Topham S, Dyment D A et al.. Significant linkage to migraine with aura on chromosome 11q24.  Hum Mol Genet. 2003;  12 2511-2517
  • 28 Mochi M, Cevoli S, Cortelli P et al.. A genetic association study of migraine with dopamine receptor 4, dopamine transporter and dopamine-beta-hydroxylase genes.  Neurol Sci. 2003;  23 301-305
  • 29 Soragna D, Vettori A, Carraro G et al.. A locus for migraine without aura maps on chromosome 14q21.2-q22.3  Am J Hum Genet. 2003;  72 161-167
  • 30 Kors E E, Haan J, Giffin N J et al.. Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine.  Arch Neurol. 2003;  60 684-688
  • 31 Wieser T, Mueller C, Evers S, Zierz S, Deufel T. 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. 2003;  41 272-275
  • 32 May A, Kaube H, Buchel C et al.. Experimental cranial pain elicited by capsaicin: a PET study.  Pain. 1998;  74 61-66
  • 33 Lashley K S. Patterns of cerebral integration indicated by the scotomas of migraine.  Arch Neurol Psychiatry. 1941;  46 331
  • 34 Leao A AP. Spreading depression of activity in the cerebral cortex.  J Neurophysiol. 1944;  7 359-390
  • 35 Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine.  Ann Neurol. 1981;  9 344-352
  • 36 Lauritzen M, Skyhoj Olsen T, Lassen N A, Paulson O B. Changes of regional cerebral blood flow during the course of classical migraine attacks.  Ann Neurol. 1983;  13 633-641
  • 37 Lauritzen M, Olesen J. Regional cerebral blood flow during migraine attacks by xenon-133 inhalation and emission tomography.  Brain. 1984;  107 447-461
  • 38 Olesen J, Friberg L, Olsen T S et al.. Timing and topography of cerebral blood flow, aura and headache during migraine attacks.  Ann Neurol. 1990;  28 791-798
  • 39 Friberg L, Skyhoj Olsen T, Roland P E, Lassen N A. Focal ischemia caused by instability of cerebrovascular tone during attacks of hemiplegic migraine.  Brain. 1987;  110 917-934
  • 40 Andersen A R, Friberg L, Olsen T S, Olesen J. SPECT demonstration of delayed hyperemia following hypoperfusion in classic migraine.  Arch Neurol. 1988;  45 154-159
  • 41 Skyhoj Olsen T, Friberg L, Lassen N A. Ischemia may be the primary cause of neurologic deficits in classical migraine.  Arch Neurol. 1987;  44 156-161
  • 42 Woods R P, Iacoboni M, Mazziotta J C. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache.  N Engl J Med. 1994;  331 1689-1692
  • 43 Warach S, Gaa J, Siewert B, Wielopolski P, Edelman R R. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging.  Ann Neurol. 1995;  37 231-241
  • 44 Gardner-Medwin A R, van Bruggen N, Williams S R, Ahier R G. Magnetic resonance imaging of propagating waves of spreading depression in the anaesthetised rat.  J Cereb Blood Flow Metab. 1994;  14 7-11
  • 45 Hasegawa Y, Latour L L, Sotak C et al.. Spreading waves of reduced diffusion coefficient of water in the rat brain.  Neurology. 1994;  44(suppl 2) A34
  • 46 Sanchez del Rio M, Bakker D, Wu O et al.. Perfusion weighted imaging during migraine: spontaneous visual aura and headache.  Cephalalgia. 1999;  19 701-707
  • 47 Sorensen A G, Rosen B R. Functional MRI of the brain. In: Atlas SW Magnetic Resonance Imaging of the Brain and Spine. 2nd ed. Philadelphia; Lippincott-Raven Publishers 1996
  • 48 Cao Y, Welch K M, Aurora S, Vikingstad E M. Functional MRI-BOLD of visually triggered headache in patients with migraine.  Arch Neurol. 1999;  56 548-554
  • 49 Cao Y, Aurora S K, Nagesh V, Patel S C, Welch K M. Functional MRI-BOLD of brainstem structures during visually triggered migraine.  Neurology. 2002;  59 72-78
  • 50 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 4687-4692
  • 51 Welch K MA, Levine S R, D'Andrea G, Helpern J A. Brain pH during migraine studied by in-vivo 31-phosphorus NMR spectroscopy.  Cephalalgia. 1988;  8 273-277
  • 52 Welch K MA, Levine S R, D'Andrea G, Helpern J A. Preliminary observations on brain energy metabolites in migraine studied by in vivo 31-phosphorus NMR spectroscopy.  Neurology. 1989;  39 538-541
  • 53 Welch K MA, Barkley G L, Ramadan N M, D'Andrea G. NMR spectroscopic and magnetoencephalographic studies in migraine with aura: support for the spreading depression hypothesis.  Pathol Biol (Paris). 1992;  40 349-354
  • 54 van Harreveld A, Fifekova E. Mechanisms involved in spreading depression.  J Neurobiol. 1973;  4 375-387
  • 55 Ambrosini A, de Noordhout A M, Sandor P S, Schoenen J. Electrophysiological studies in migraine: a comprehensive review of their interest and limitations.  Cephalalgia. 2003;  23(suppl 1) 13-31
  • 56 Aurora S K, Welch K M, Al-Sayed F. The threshold for phosphenes is lower in migraine.  Cephalalgia. 2003;  23 258-263
  • 57 Goadsby P J, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache.  Ann Neurol. 1990;  28 183-187
  • 58 Bolay H, Reuter U, Dunn A K, Huang Z, Boas D A, Moskowitz M A. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model.  Nat Med. 2002;  8 136-142
  • 59 Moskowitz M A, Nozaki K, Kraig R P. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms.  J Neurosci. 1993;  13 1167-1177
  • 60 Kraig R P, Nicholson C. Extracellular ionic variations during spreading depression.  Neuroscience. 1978;  3 1045-1059
  • 61 Obrenovitch T P, Urenjak J, Wang M. Nitric oxide formation during cortical spreading depression is critical for rapid subsequent recovery of ionic homeostasis.  J Cereb Blood Flow Metab. 2002;  22 680-688
  • 62 Lauritzen M, Hansen A J, Kronborg D, Wieloch T. Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge.  J Cereb Blood Flow Metab. 1990;  10 115-122
  • 63 Gursoy-Ozdemir Y, Qiu J, Matsuoka N et al.. Cortical spreading depression activates and upregulates MMP-9.  J Clin Invest. 2004;  113 1447-1455
  • 64 Strassman A M, Raymond S A, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches.  Nature. 1996;  384 560-564
  • 65 Moskowitz M A, Buzzi M G. Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions.  J Neurol. 1991;  238(suppl 1) S18-S22
  • 66 Moskowitz M A, Cutrer F M. Possible importance of neurogenic inflammation within the meninges to migraine headaches. In: Fields HL, Liebeskind JC Progress in Pain Research and Management. Seattle; IASP Press 1993: 43-49
  • 67 Burstein R, Yamamura H, Malick A et al.. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons.  J Neurophysiol. 1998;  79 964-982
  • 68 Yamamura H, Malick A, Chamberlin N L et al.. Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine.  J Neurophysiol. 1999;  81 479-493
  • 69 Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil B J, Bajwa Z H. An association between migraine and cutaneous allodynia.  Ann Neurol. 2000;  47 614-624
  • 70 Burstein R, Cutrer M F, 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 1703-1709
  • 71 Shields K G, Goadsby P J. Propranolol modulates trigeminovascular responses in thalamic ventroposteromedial nucleus: a role in migraine?.  Brain. 2005;  128 86-97
  • 72 Welch K M, Nagesh V, Aurora S K, Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness?.  Headache. 2001;  41 629-637

F. Michael CutrerM.D. 

Department of Neurology, Mayo Clinic College of Medicine

200 First Street SW, Rochester, MN 55905