Abstract
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.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992;42(6):1225–31.
The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia Int J Headache. 2013;33(9):629–808.
•• 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.
•• Torelli P, Manzoni GC. Fasting headache. Curr Pain Headache Rep. 2010;14(4):284–91. An excellent in-depth review.
Mosek A, Korczyn AD. Yom Kippur headache. Neurology. 1995;45(11):1953–5.
Mosek A, Korczyn AD. Fasting headache, weight loss, and dehydration. Headache. 1999;39(3):225–7.
Awada A, al Jumah M. The first-of-Ramadan headache. Headache. 1999;39(7):490–3.
Shah PA, Nafee A. Clinical profile of headache and cranial neuralgias. J Assoc Physicians India. 1999;47(11):1072–5.
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.
Abu-Salameh I, Plakht Y, Ifergane G. Migraine exacerbation during Ramadan fasting. J Headache Pain. 2010;11(6):513–7.
Mitsikostas DD et al. An epidemiological study of headache among the Monks of Athos (Greece). Headache. 1994;34(9):539–41.
Martin VT, Behbehani MM. Toward a rational understanding of migraine trigger factors. Med Clin N Am. 2001;85(4):911–41.
Andress-Rothrock D, King W, Rothrock J. An analysis of migraine triggers in a clinic-based population. Headache. 2010;50(8):1366–70.
Dalton K. Food intake prior to a migraine attack–study of 2,313 spontaneous attacks. Headache. 1975;15(3):188–93.
Malouf R, Brust JC. Hypoglycemia: causes, neurological manifestations, and outcome. Ann Neurol. 1985;17(5):421–30.
• Pearce J. Insulin induced hypoglycaemia in migraine. J Neurol Neurosurg Psychiatry. 1971;34(2):154–6. A landmark article on this subject.
Blau JN, Pyke DA. Effect of diabetes on migraine. Lancet. 1970;2(7666):241–3.
Jacome DE. Hypoglycemia rebound migraine. Headache. 2001;41(9):895–8.
Gray PA, Burtness HI. Hypoglycemic headache. Endocrinology. 1935;19:549–60.
Auer RN. Hypoglycemic brain damage. Metab Brain Dis. 2004;19(3–4):169–75.
• Tesfaye N, Seaquist ER. Neuroendocrine responses to hypoglycemia. Ann N Y Acad Sci. 2010;1212:12–28. An excellent in-depth review.
Hockaday JM, Williamson DH, Whitty CW. Blood-glucose levels and fatty-acid metabolism in migraine related to fasting. Lancet. 1971;1(7710):1153–6.
De Silva KL, Ron MA, Pearce J. Blood sugar response to glucagon in migraine. J Neurol Neurosurg Psychiatry. 1974;37(1):105–7.
Cahill Jr GF. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.
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.
Bolay H et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8(2):136–42.
Karatas H et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013;339(6123):1092–5.
Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia. 1997;21(1):2–21.
Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 2009;31(7):545–52.
Klepper J et al. Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet. 2001;10(1):63–8.
Weber YG et al. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology. 2011;77(10):959–64.
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.
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.
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.
Brown AM. Brain glycogen re-awakened. J Neurochem. 2004;89(3):537–52.
Choi IY, Seaquist ER, Gruetter R. Effect of hypoglycemia on brain glycogen metabolism in vivo. J Neurosci Res. 2003;72(1):25–32.
Oz G et al. Human brain glycogen metabolism during and after hypoglycemia. Diabetes. 2009;58(9):1978–85.
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.
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.
Obel LF et al. Brain glycogen-new perspectives on its metabolic function and regulation at the subcellular level. Front Neuroenerg. 2012;4:3.
•• Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 2007;55(12):1263–71. An excellent in-depth review.
•• 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.
•• 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.
Swanson RA et al. Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography. Neuroscience. 1992;51(2):451–61.
Matsui T et al. Brain glycogen decreases during prolonged exercise. J Physiol. 2011;589(Pt 13):3383–93.
Sickmann HM et al. Functional significance of brain glycogen in sustaining glutamatergic neurotransmission. J Neurochem. 2009;109 Suppl 1:80–6.
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.
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.
Stobart JL, Anderson CM. Multifunctional role of astrocytes as gatekeepers of neuronal energy supply. Front Cell Neurosci. 2013;7:38.
Barros LF et al. A quantitative overview of glucose dynamics in the gliovascular unit. Glia. 2007;55(12):1222–37.
Allaman I, Belanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci. 2011;34(2):76–87.
Petit JM et al. Sleep deprivation modulates brain mRNAs encoding genes of glycogen metabolism. Eur J Neurosci. 2002;16(6):1163–7.
Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol. 2006;209(Pt 12):2304–11.
Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci. 2012;35(8):507–20.
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.
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.
Sandilos JK, Bayliss DA. Physiological mechanisms for the modulation of pannexin 1 channel activity. J Physiol. 2012;590(Pt 24):6257–66.
MacVicar BA, Thompson RJ. Non-junction functions of pannexin-1 channels. Trends Neurosci. 2010;33(2):93–102.
Dahlem MA. Migraine generator network and spreading depression dynamics as neuromodulation targets in episodic migraine. ArXiv, 2013. Quantitative Biology.
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.
•• Peroutka SJ. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44(1):53–64. An excellent in-depth review.
Gotoh F et al. Noradrenergic nervous activity in migraine. Arch Neurol. 1984;41(9):951–5.
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.
Mikamo K, Takeshima T, Takahashi K. Cardiovascular sympathetic hypofunction in muscle contraction headache and migraine. Headache. 1989;29(2):86–9.
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.
Nagel-Leiby S et al. Event-related slow potentials and associated catecholamine function in migraine. Cephalalgia Int J Headache. 1990;10(6):317–29.
Martinez F et al. Catecholamine levels in plasma and CSF in migraine. J Neurol Neurosurg Psychiatry. 1993;56(10):1119–21.
Boccuni M et al. The pressor hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in migraine. Cephalalgia Int J Headache. 1989;9(4):239–45.
Drummond PD. Cervical sympathetic deficit in unilateral migraine headache. Headache. 1991;31(10):669–72.
Gip P et al. Glucocorticoids influence brain glycogen levels during sleep deprivation. Am J Physiol Regul Integr Comp Physiol. 2004;286(6):R1057–62.
Allaman I, Pellerin L, Magistretti PJ. Glucocorticoids modulate neurotransmitter-induced glycogen metabolism in cultured cortical astrocytes. J Neurochem. 2004;88(4):900–8.
Ziegler DK et al. Circadian rhythms of plasma cortisol in migraine. J Neurol Neurosurg Psychiatry. 1979;42(8):741–8.
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.
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.
Brown AM, Tekkok SB, Ransom BR. Glycogen regulation and functional role in mouse white matter. J Physiol. 2003;549(Pt 2):501–12.
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.
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Dr. Turgay Dalkara and Dr. Kıvılcım Kılıç reported no potential conflicts of interest relevant to this article.
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Dalkara, T., Kılıç, K. How Does Fasting Trigger Migraine? A Hypothesis. Curr Pain Headache Rep 17, 368 (2013). https://doi.org/10.1007/s11916-013-0368-1
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DOI: https://doi.org/10.1007/s11916-013-0368-1