How Does Fasting Trigger Migraine? A Hypothesis

  • Turgay DalkaraEmail author
  • Kıvılcım Kılıç
Migraine (R Cowan, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Migraine


Fasting or skipping meals are well-characterized migraine triggers. However, mechanisms of the fasting-induced migraine headache are unclear. Here, we review the recent developments on brain glycogen metabolism and its modulation by sympathetic activity and propose that insufficient supply of glycogen-derived glucose at the onset of intense synaptic activity may lead to an imbalance between the excitatory and inhibitory terminals, causing collective depolarization of neurons and astrocytes in a network. This may activate perivascular trigeminal afferents by opening neuronal pannexin1 channels and initiating parenchymal inflammatory pathways. Depending on whether or not network depolarization spreads or remains local, fasting may trigger migraine headache with or without aura.


Migraine Headache Fasting Hunger Glucose Hypoglycemia Adrenaline Noradrenaline Sympathetic nervous system Insulin Glucagon Cortisol Growth hormone Glycogen Glucose transporter Astrocyte Brain metabolism 


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Conflict of Interest

Dr. Turgay Dalkara and Dr. Kıvılcım Kılıç reported no potential conflicts of interest relevant to this article.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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  1. 1.
    Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992;42(6):1225–31.PubMedCrossRefGoogle Scholar
  2. 2.
    The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia Int J Headache. 2013;33(9):629–808.Google Scholar
  3. 3.
    •• Hufnagl KN, Peroutka SJ. Glucose regulation in headache: implications for dietary management. Expert Rev Neurother. 2002;2(3):311–7. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  4. 4.
    •• Torelli P, Manzoni GC. Fasting headache. Curr Pain Headache Rep. 2010;14(4):284–91. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  5. 5.
    Mosek A, Korczyn AD. Yom Kippur headache. Neurology. 1995;45(11):1953–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Mosek A, Korczyn AD. Fasting headache, weight loss, and dehydration. Headache. 1999;39(3):225–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Awada A, al Jumah M. The first-of-Ramadan headache. Headache. 1999;39(7):490–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Shah PA, Nafee A. Clinical profile of headache and cranial neuralgias. J Assoc Physicians India. 1999;47(11):1072–5.PubMedGoogle Scholar
  9. 9.
    Topacoglu H et al. Impact of Ramadan on demographics and frequencies of disease-related visits in the emergency department. Int J Clin Pract. 2005;59(8):900–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Abu-Salameh I, Plakht Y, Ifergane G. Migraine exacerbation during Ramadan fasting. J Headache Pain. 2010;11(6):513–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Mitsikostas DD et al. An epidemiological study of headache among the Monks of Athos (Greece). Headache. 1994;34(9):539–41.PubMedCrossRefGoogle Scholar
  12. 12.
    Martin VT, Behbehani MM. Toward a rational understanding of migraine trigger factors. Med Clin N Am. 2001;85(4):911–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Andress-Rothrock D, King W, Rothrock J. An analysis of migraine triggers in a clinic-based population. Headache. 2010;50(8):1366–70.PubMedCrossRefGoogle Scholar
  14. 14.
    Dalton K. Food intake prior to a migraine attack–study of 2,313 spontaneous attacks. Headache. 1975;15(3):188–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Malouf R, Brust JC. Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol. 1985;17(5):421–30.PubMedCrossRefGoogle Scholar
  16. 16.
    • Pearce J. Insulin induced hypoglycaemia in migraine. J Neurol Neurosurg Psychiatry. 1971;34(2):154–6. A landmark article on this subject.PubMedCrossRefGoogle Scholar
  17. 17.
    Blau JN, Pyke DA. Effect of diabetes on migraine. Lancet. 1970;2(7666):241–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Jacome DE. Hypoglycemia rebound migraine. Headache. 2001;41(9):895–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Gray PA, Burtness HI. Hypoglycemic headache. Endocrinology. 1935;19:549–60.CrossRefGoogle Scholar
  20. 20.
    Auer RN. Hypoglycemic brain damage. Metab Brain Dis. 2004;19(3–4):169–75.PubMedCrossRefGoogle Scholar
  21. 21.
    • Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad Sci. 2010;1212:12–28. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  22. 22.
    Hockaday JM, Williamson DH, Whitty CW. Blood-glucose levels and fatty-acid metabolism in migraine related to fasting. Lancet. 1971;1(7710):1153–6.PubMedCrossRefGoogle Scholar
  23. 23.
    De Silva KL, Ron MA, Pearce J. Blood sugar response to glucagon in migraine. J Neurol Neurosurg Psychiatry. 1974;37(1):105–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Cahill Jr GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Hoffmann U et al. Glucose modulation of spreading depression susceptibility. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2013;33(2):191–5.CrossRefGoogle Scholar
  26. 26.
    Bolay H et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8(2):136–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Karatas H et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013;339(6123):1092–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia. 1997;21(1):2–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 2009;31(7):545–52.PubMedCrossRefGoogle Scholar
  30. 30.
    Klepper J et al. Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet. 2001;10(1):63–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Weber YG et al. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology. 2011;77(10):959–64.PubMedCrossRefGoogle Scholar
  32. 32.
    Schneider SA et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord Off J Mov Disord Soc. 2009;24(11):1684–8.CrossRefGoogle Scholar
  33. 33.
    Urbizu A et al. Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation. J Neurol Sci. 2010;295(1–2):110–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Weber YG et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Investig. 2008;118(6):2157–68.PubMedGoogle Scholar
  35. 35.
    Brown AM. Brain glycogen re-awakened. J Neurochem. 2004;89(3):537–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Choi IY, Seaquist ER, Gruetter R. Effect of hypoglycemia on brain glycogen metabolism in vivo. J Neurosci Res. 2003;72(1):25–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Oz G et al. Human brain glycogen metabolism during and after hypoglycemia. Diabetes. 2009;58(9):1978–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Morgenthaler FD et al. Alteration of brain glycogen turnover in the conscious rat after 5h of prolonged wakefulness. Neurochem Int. 2009;55(1–3):45–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Maxwell DS, Kruger L. The fine structure of astrocytes in the cerebral cortex and their response to focal injury produced by heavy ionizing particles. J Cell Biol. 1965;25(2):141–57.PubMedCrossRefGoogle Scholar
  40. 40.
    Obel LF et al. Brain glycogen-new perspectives on its metabolic function and regulation at the subcellular level. Front Neuroenerg. 2012;4:3.CrossRefGoogle Scholar
  41. 41.
    •• Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 2007;55(12):1263–71. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  42. 42.
    •• Dinuzzo M et al. The role of astrocytic glycogen in supporting the energetics of neuronal activity. Neurochem Res. 2012;37(11):2432–8. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  43. 43.
    •• Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32(7):1152–66. An excellent in-depth review.CrossRefGoogle Scholar
  44. 44.
    Swanson RA et al. Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography. Neuroscience. 1992;51(2):451–61.PubMedCrossRefGoogle Scholar
  45. 45.
    Matsui T et al. Brain glycogen decreases during prolonged exercise. J Physiol. 2011;589(Pt 13):3383–93.PubMedCrossRefGoogle Scholar
  46. 46.
    Sickmann HM et al. Functional significance of brain glycogen in sustaining glutamatergic neurotransmission. J Neurochem. 2009;109 Suppl 1:80–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Schousboe A et al. Functional importance of the astrocytic glycogen-shunt and glycolysis for maintenance of an intact intra/extracellular glutamate gradient. Neurotox Res. 2010;18(1):94–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Schousboe A et al. Neuron-glia interactions in glutamatergic neurotransmission: roles of oxidative and glycolytic adenosine triphosphate as energy source. J Neurosci Res. 2011;89(12):1926–34.PubMedCrossRefGoogle Scholar
  49. 49.
    Stobart JL, Anderson CM. Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci. 2013;7:38.PubMedCrossRefGoogle Scholar
  50. 50.
    Barros LF et al. A quantitative overview of glucose dynamics in the gliovascular unit. Glia. 2007;55(12):1222–37.PubMedCrossRefGoogle Scholar
  51. 51.
    Allaman I, Belanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci. 2011;34(2):76–87.PubMedCrossRefGoogle Scholar
  52. 52.
    Petit JM et al. Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism. Eur J Neurosci. 2002;16(6):1163–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol. 2006;209(Pt 12):2304–11.PubMedCrossRefGoogle Scholar
  54. 54.
    Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 2012;35(8):507–20.PubMedCrossRefGoogle Scholar
  55. 55.
    Kılıç K et al. Insufficient astrocytic glycogen turnover may predispose to spreading depression and migraine attacks. Poster presented at: Society for Neuroscience (SfN) Annual Meeting, 2011 Nov 12–16; Washington, DC.Google Scholar
  56. 56.
    Seidel JL, Shuttleworth CW. Contribution of astrocyte glycogen stores to progression of spreading depression and related events in hippocampal slices. Neuroscience. 2011;192:295–303.PubMedCrossRefGoogle Scholar
  57. 57.
    Sandilos JK, Bayliss DA. Physiological mechanisms for the modulation of pannexin 1 channel activity. J Physiol. 2012;590(Pt 24):6257–66.PubMedCrossRefGoogle Scholar
  58. 58.
    MacVicar BA, Thompson RJ. Non-junction functions of pannexin-1 channels. Trends Neurosci. 2010;33(2):93–102.PubMedCrossRefGoogle Scholar
  59. 59.
    Dahlem MA. Migraine generator network and spreading depression dynamics as neuromodulation targets in episodic migraine. ArXiv, 2013. Quantitative Biology.Google Scholar
  60. 60.
    O'Donnell J et al. Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochem Res. 2012;37(11):2496–512.PubMedCrossRefGoogle Scholar
  61. 61.
    •• Peroutka SJ. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44(1):53–64. An excellent in-depth review.PubMedCrossRefGoogle Scholar
  62. 62.
    Gotoh F et al. Noradrenergic nervous activity in migraine. Arch Neurol. 1984;41(9):951–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Havanka-Kannianinen H et al. Cardiovascular reflexes and plasma noradrenaline levels in migraine patients before and during nimodipine medication. Headache. 1987;27(1):39–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Mikamo K, Takeshima T, Takahashi K. Cardiovascular sympathetic hypofunction in muscle contraction headache and migraine. Headache. 1989;29(2):86–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Takeshima T et al. Muscle contraction headache and migraine. Platelet activation and plasma norepinephrine during the cold pressor test. Cephalalgia Int J Headache. 1989;9(1):7–13.Google Scholar
  66. 66.
    Nagel-Leiby S et al. Event-related slow potentials and associated catecholamine function in migraine. Cephalalgia Int J Headache. 1990;10(6):317–29.CrossRefGoogle Scholar
  67. 67.
    Martinez F et al. Catecholamine levels in plasma and CSF in migraine. J Neurol Neurosurg Psychiatry. 1993;56(10):1119–21.PubMedCrossRefGoogle Scholar
  68. 68.
    Boccuni M et al. The pressor hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in migraine. Cephalalgia Int J Headache. 1989;9(4):239–45.Google Scholar
  69. 69.
    Drummond PD. Cervical sympathetic deficit in unilateral migraine headache. Headache. 1991;31(10):669–72.PubMedCrossRefGoogle Scholar
  70. 70.
    Gip P et al. Glucocorticoids influence brain glycogen levels during sleep deprivation. Am J Physiol Regul Integr Comp Physiol. 2004;286(6):R1057–62.PubMedCrossRefGoogle Scholar
  71. 71.
    Allaman I, Pellerin L, Magistretti PJ. Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes. J Neurochem. 2004;88(4):900–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Ziegler DK et al. Circadian rhythms of plasma cortisol in migraine. J Neurol Neurosurg Psychiatry. 1979;42(8):741–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Cataldo AM, Broadwell RD. Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia and pericytes. J Neurocytol. 1986;15(4):511–24.PubMedCrossRefGoogle Scholar
  74. 74.
    Sorg O, Magistretti PJ. Vasoactive intestinal peptide and noradrenaline exert long-term control on glycogen levels in astrocytes: blockade by protein synthesis inhibition. J Neurosci Off J Soc Neurosci. 1992;12(12):4923–31.Google Scholar
  75. 75.
    Brown AM, Tekkok SB, Ransom BR. Glycogen regulation and functional role in mouse white matter. J Physiol. 2003;549(Pt 2):501–12.PubMedCrossRefGoogle Scholar
  76. 76.
    Simpson IA, Carruthers A, Vannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2007;27(11):1766–91.CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute of Neurological Sciences and PsychiatryHacettepe UniversityAnkaraTurkey
  2. 2.Department of Neurology, Faculty of MedicineHacettepe UniversityAnkaraTurkey
  3. 3.Department of Neurology, Faculty of Medicine and, Institute of Neurological Sciences and PsychiatryHacettepe UniversityAnkaraTurkey

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