Abstract
Cortical spreading depression (CSD), a slowly propagated wave of depolarization followed by suppression of brain activity, is a remarkably complex event that involves dramatic changes in neural and vascular function. Since its original description in the 1940s, CSD has been hypothesized to be the underlying mechanism of the migraine aura. Substantial evidence from animal models provides indirect support for this hypothesis, and studies showing that CSD is common in humans with brain injury clearly demonstrate that the phenomenon can occur in the human brain. Considerable uncertainty about the role of CSD in migraine remains, however, and key questions about how this event is initiated, how it spreads, and how it might cause migraine symptoms remain unanswered. This Review summarizes current concepts of CSD and its potential roles in migraine, and addresses ongoing studies aimed at a clearer understanding of this fundamental brain phenomenon.
Key Points
-
Cortical spreading depression (CSD) is a slowly propagating wave of altered brain activity that involves dramatic changes in neuronal, glial and vascular function
-
CSD has recently been extensively characterized in humans via recordings from the exposed brain surface in patients with brain injury
-
The widely accepted hypothesis that CSD is the physiological mechanism underlying the migraine aura is supported by substantial evidence from animal models, but definitive proof in patients with migraine is lacking
-
Studies in animals indicate that CSD can activate pain pathways, but the role of CSD as a potential trigger for migraine headache remains uncertain
-
CSD is a fundamental pattern of brain signalling that provides an opportunity for greater understanding of nervous system physiology, and for the identification of new therapies for migraine and other brain disorders
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Leão, A. A. Spreading depression of activity in the cerebral cortex. J. Neurophysiol. 7, 359–390 (1944).
Leão, A. A. Further observervations on the spreading depression of activity in the cerebral cortex. J. Neurophysiol. 10, 409–414 (1947).
Leão, A. A. Pial circulation and spreading depression of activity in the cerebral cortex. J. Neurophysiol. 7, 391–396 (1944).
Leão, A. A. & Morison, R. S. Propagation of spreading cortical depression. J. Neurophysiol. 8, 33–45 (1945).
Hansen, A. J. & Zeuthen, T. Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol. Scand. 113, 437–445 (1981).
Mutch, W. A. & Hansen, A. J. Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. J. Cereb. Blood Flow Metab. 4, 17–27 (1984).
Dietz, R. M., Weiss, J. H. & Shuttleworth, C. W. Zn2+ influx is critical for some forms of spreading depression in brain slices. J. Neurosci. 28, 8014–8024 (2008).
Hansen, A. J. & Olsen, C. E. Brain extracellular space during spreading depression and ischemia. Acta Physiol. Scand. 108, 355–365 (1980).
Sugaya, E., Takato, M. & Noda, Y. Neuronal and glial activity during spreading depression in cerebral cortex of cat. J. Neurophysiol. 38, 822–841 (1975).
Sheardown, M. J. The triggering of spreading depression in the chicken retina: a pharmacological study. Brain Res. 607, 189–194 (1993).
Tobiasz, C. & Nicholson, C. Tetrodotoxin resistant propagation and extracellular sodium changes during spreading depression in rat cerebellum. Brain Res. 241, 329–333 (1982).
Herreras, O., Largo, C., Ibarz, J. M., Somjen, G. G. & Martin del Rio, R. Role of neuronal synchronizing mechanisms in the propagation of spreading depression in the in vivo hippocampus. J. Neurosci. 14, 7087–7098 (1994).
Canals, S. et al. Longitudinal depolarization gradients along the somatodendritic axis of CA1 pyramidal cells: a novel feature of spreading depression. J. Neurophysiol. 94, 943–951 (2005).
Charles, A. Intercellular calcium waves in glia. Glia 24, 39–49 (1998).
Busija, D. W., Bari, F., Domoki, F., Horiguchi, T. & Shimizu, K. Mechanisms involved in the cerebrovascular dilator effects of cortical spreading depression. Prog. Neurobiol. 86, 417–433 (2008).
Smith, J. M., Bradley, D. P., James, M. F. & Huang, C. L. Physiological studies of cortical spreading depression. Biol. Rev. Camb. Philos. Soc. 81, 457–481 (2006).
Akcali, D., Sayin, A., Sara, Y. & Bolay, H. Does single cortical spreading depression elicit pain behaviour in freely moving rats? Cephalalgia 30, 1195–1206 (2010).
Peeters, M. et al. Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat: therapeutic potential for migraine. J. Pharmacol. Exp. Ther. 321, 564–572 (2007).
Petzold, G. C. et al. Increased extracellular K+ concentration reduces the efficacy of N-methyl-D-aspartate receptor antagonists to block spreading depression-like depolarizations and spreading ischemia. Stroke 36, 1270–1277 (2005).
Lauritzen, M. & Hansen, A. The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression. J. Cereb. Blood Flow Metab. 12, 223–229 (1992).
Faria, L. C. & Mody, I. Protective effect of ifenprodil against spreading depression in the mouse entorhinal cortex. J. Neurophysiol. 92, 2610–2614 (2004).
Nozari, A. et al. Microemboli may link spreading depression, migraine aura, and patent foramen ovale. Ann. Neurol. 67, 221–229 (2010).
van den Maagdenberg, A. M. et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41, 701–710 (2004).
Leo, L. et al. Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. PLoS Genet. 7, e1002129 (2011).
Dreier, J. P. et al. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain 132, 1866–1881 (2009).
Hartings, J. A. et al. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain 134, 1529–1540 (2011).
Woitzik, J. et al. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 80, 1095–1102 (2013).
Lashley, K. S. Patterns of cerebral integration indicated by the scotomas of migraine. Arch. Neurol. Psychiatry 46, 331–339 (1941).
Tfelt-Hansen, P. C. History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia 30, 780–792 (2010).
Bowyer, S. M., Aurora, S. K., Moran, J. E., Tepley, N. & Welch, K. M. Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann. Neurol. 50, 582–587 (2001).
Lauritzen, M., Trojaborg, W. & Olesen, J. EEG during attacks of common and classical migraine. Cephalalgia 1, 63–66 (1981).
Drenckhahn, C. et al. Correlates of spreading depolarization in human scalp electroencephalography. Brain 135, 853–868 (2012).
Eikermann-Haerter, K. et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J. Clin. Invest. 119, 99–109 (2009).
Hansen, J. M., Thomsen, L. L., Olesen, J. & Ashina, M. Coexisting typical migraine in familial hemiplegic migraine. Neurology 74, 594–600 (2010).
Brennan, K. C. et al. Casein kinase Iδ mutations in familial migraine and advanced sleep phase. Sci. Transl. Med. 5, 183ra56 (2013).
Brennan, K. C., Romero-Reyes, M., López Valdés, H. E., Arnold, A. P. & Charles, A. C. Reduced threshold for cortical spreading depression in female mice. Ann. Neurol. 61, 603–606 (2007).
Eikermann-Haerter, K. et al. Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice. Ann. Neurol. 66, 564–568 (2009).
Ayata, C., Jin, H., Kudo, C., Dalkara, T. & Moskowitz, M. A. Suppression of cortical spreading depression in migraine prophylaxis. Ann. Neurol. 59, 652–661 (2006).
Akerman, S. & Goadsby, P. J. Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura. Neuroreport 16, 1383–1387 (2005).
Holland, P. R. et al. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann. Neurol. 72, 559–563 (2012).
Bogdanov, V. B. et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol. Dis. 41, 430–435 (2011).
Hoffmann, U., Dileköz, E., Kudo, C. & Ayata, C. Oxcarbazepine does not suppress cortical spreading depression. Cephalalgia 31, 537–542 (2011).
Tozzi, A. et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc. Natl Acad. Sci. USA 109, 18985–18990 (2012).
Ayata, C. et al. Pronounced hypoperfusion during spreading depression in mouse cortex. J. Cereb. Blood Flow Metab. 24, 1172–1182 (2004).
Brennan, K. C. et al. Distinct vascular conduction with cortical spreading depression. J. Neurophysiol. 97, 4143–4151 (2007).
Chang, J. C. et al. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain 133, 996–1012 (2010).
Piilgaard, H. & Lauritzen, M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J. Cereb. Blood Flow Metab. 29, 1517–1527 (2009).
Iizuka, T. et al. Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation. J. Neurol. Neurosurg. Psychiatry 83, 205–212 (2012).
Bereczki, D. et al. Cortical spreading edema in persistent visual migraine aura. Headache 48, 1226–1229 (2008).
Guedj, E. et al. Partially reversible cortical metabolic dysfunction in familial hemiplegic migraine with prolonged aura. Headache 50, 872–877 (2010).
Gutschalk, A. et al. Multimodal functional imaging of prolonged neurological deficits in a patient suffering from familial hemiplegic migraine. Neurosci. Lett. 332, 115–118 (2002).
Wolf, M. E., Jager, T., Bazner, H. & Hennerici, M. Changes in functional vasomotor reactivity in migraine with aura. Cephalalgia 29, 1156–1164 (2009).
Zhang, X. et al. Activation of central trigeminovascular neurons by cortical spreading depression. Ann. Neurol. 69, 855–865 (2011).
Zhang, X. et al. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J. Neurosci. 30, 8807–8814 (2010).
Charles, A. C., Merrill, J. E., Dirksen, E. R. & Sanderson, M. J. Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6, 983–992 (1991).
Cornell-Bell, A. H., Finkbeiner, S. M., Cooper, M. S. & Smith, S. J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).
Basarsky, T. A., Duffy, S. N., Andrew, R. D. & MacVicar, B. A. Imaging spreading depression and associated intracellular calcium waves in brain slices. J. Neurosci. 18, 7189–7199 (1998).
Peters, O., Schipke, C. G., Hashimoto, Y. & Kettenmann, H. Different mechanisms promote astrocyte Ca2+ waves and spreading depression in the mouse neocortex. J. Neurosci. 23, 9888–9896 (2003).
Chuquet, J., Hollender, L. & Nimchinsky, E. High-resolution in vivo imaging of the neurovascular unit during spreading depression. J. Neurosci. 27, 4036–4044 (2007).
Largo, C., Tombaugh, G. C., Aitken, P. G., Herreras, O. & Somjen, G. G. Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J. Neurophysiol. 77, 9–16 (1997).
Zhou, N., Gordon, G. R., Feighan, D. & MacVicar, B. A. Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression. Cereb. Cortex 20, 2614–2624 (2010).
Colonna, D. M., Meng, W., Deal, D. D., Gowda, M. & Busija, D. W. Neuronal NO promotes cerebral cortical hyperemia during cortical spreading depression in rabbits. Am. J. Physiol. 272, H1315–H1322 (1997).
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. 22, 680–688 (2002).
Schock, S. C. et al. Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance. Brain Res. 1168, 129–138 (2007).
Colonna, D. M., Meng, W., Deal, D. D. & Busija, D. W. Calcitonin gene-related peptide promotes cerebrovascular dilation during cortical spreading depression in rabbits. Am. J. Physiol. 266, H1095–H1102 (1994).
Reuter, U. et al. Perivascular nerves contribute to cortical spreading depression-associated hyperemia in rats. Am. J. Physiol. Heart Circ. Physiol. 274, H1979–H1987 (1998).
Wahl, M., Schilling, L., Parsons, A. A. & Kaumann, A. Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression. Brain Res. 637, 204–210 (1994).
Karatas, H. et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339, 1092–1095 (2013).
Bolay, H. et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat. Med. 8, 136–142 (2002).
Fioravanti, B. et al. Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia 31, 1090–1100 (2011).
Amin, F. M. et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 12, 454–461 (2013).
Charles, A. Vasodilation out of the picture as a cause of migraine headache. Lancet Neurol. 12, 419–420 (2013).
Lambert, G. A., Truong, L. & Zagami, A. S. Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system. Cephalalgia 31, 1439–1451 (2011).
Eikermann-Haerter, K. et al. Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice. J. Neurosci. 31, 5755–5763 (2011).
Burstein, R., Strassman, A. & Moskowitz, M. Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept. Cephalalgia 32, 509–511 (2012).
Goadsby, P. J. & Akerman, S. The trigeminovascular system does not require a peripheral sensory input to be activated—migraine is a central disorder. Focus on 'Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system'. Cephalalgia 32, 3–5 (2012).
Olesen, J. et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann. Neurol. 28, 791–798 (1990).
Woods, R. P., Iacoboni, M. & Mazziotta, J. C. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N. Engl. J. Med. 331, 1689–1692 (1994).
Hadjikhani, N. et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl Acad. Sci. USA 98, 4687–4692 (2001).
Cao, Y., Welch, K. M., Aurora, S. & Vikingstad, E. M. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch. Neurol. 56, 548–554 (1999).
Schott, G. D. Exploring the visual hallucinations of migraine aura: the tacit contribution of illustration. Brain 130, 1690–1703 (2007).
Queiroz, L. P., Friedman, D. I., Rapoport, A. M. & Purdy, R. A. Characteristics of migraine visual aura in Southern Brazil and Northern USA. Cephalalgia 31, 1652–1658 (2011).
Queiroz, L. P. et al. Characteristics of migraine visual aura. Headache 37, 137–141 (1997).
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33, 629–808 (2013).
Jensen, K., Tfelt-Hansen, P., Lauritzen, M. & Olesen, J. Classic migraine. A prospective recording of symptoms. Acta Neurol. Scand. 73, 359–362 (1986).
Hansen, J. M. et al. Migraine headache is present in the aura phase: a prospective study. Neurology 79, 2044–2049 (2012).
Charles, A. Migraine: a brain state. Curr. Opin. Neurol. 26, 235–239 (2013).
Dahlem, M. A. & Hadjikhani, N. Migraine aura: retracting particle-like waves in weakly susceptible cortex. PLoS ONE 4, e5007 (2009).
Fabricius, M. et al. Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clin. Neurophysiol. 119, 1973–1984 (2008).
Author information
Authors and Affiliations
Contributions
Both authors researched data for the article, discussed the content, wrote the text, and reviewed and edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Charles, A., Baca, S. Cortical spreading depression and migraine. Nat Rev Neurol 9, 637–644 (2013). https://doi.org/10.1038/nrneurol.2013.192
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2013.192
This article is cited by
-
Modulation of temporal and occipital cortex by acupuncture in non-menstrual MWoA patients: a rest BOLD fMRI study
BMC Complementary Medicine and Therapies (2024)
-
Are anti-calcitonin gene-related peptide monoclonal antibodies effective in treating migraine aura? A pilot prospective observational cohort study
Neurological Sciences (2024)
-
Normobaric oxygen may attenuate the headache in patients with patent foramen povale and migraine
BMC Neurology (2023)
-
Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation
Nature Metabolism (2023)
-
Glia Signaling and Brain Microenvironment in Migraine
Molecular Neurobiology (2023)