Spreading depolarization: A phenomenon in the brain

R. Aboghazleh, B. Alkahmous, B. Turan, M. C. Tuncer


In 1944, the physiologist Leão while studying epilepsy in the rabbit noticed a sudden temporary cessation of electrocorticographic (ECoG) activity accompanied with a large negative slow potential change recorded by extracellular electrodes, that is later known as spreading depolarizations (SDs). The depression of the brain electrical activity was slowly propagating through the cerebral cortex. The mechanism of propagation is still controversial. SDs and seizures are following each other interchangeably, yet the puzzle needs more investigation to be clarified. SDs have an obvious effect on blood-brain barrier integrity mainly through transcellular and paracellular routs, but not much known about that especially following traumatic brain injury (TBI). The cortical spreading depolarization (CSD) and the depression of brain activity have been recognized following a variety of neurological diseases and brain injuries. CSD has been studied in animal models and recently in humans, and it has been recognized and described as a massive neuronal depolarization accompanied with high level of disturbances in transmembrane ion gradients and significant changes in cerebral blood flow (1-3). Although there is a considerable amount of literatures on SD have been done since 1944, but the biophysical mechanism of SD, the long term effect on the brain structures and functions, and it is role in different disorders are still incompletely understood.

Here, we summarize the history of spreading depolarization and the most accepted hypothesis for mechanism of initiation and propagation of that phenomenon. Most importantly, we present the most updated research on the relationship and interaction between spreading depolarization and traumatic brain injuries, seizure, blood-brain barrier, neurovascular coupling, and other neurological conditions. Learning more about the spreading depolarization will increase our understanding about that phenomenon and may explain its association with different clinical presentations.



spreading depolarization; spreading depression; concussion; traumatic brain injury; blood-brain barrier;

Full Text:



Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med., 17: 439–47, 2011.

Kraio RP, Nicholson C. Extracellular ionic variations during spreading depression. Neuroscience., 3: 1045–59, 1978.

Takano K, Latour LL, Formato JE, Carano RA, Helmer KG, Hasegawa Y, Sotak CH, Fisher M. The role of spreading depression in focal ischemia evaluated bv dffusion mapping. Ann Neurol., 39: 308–18, 1996.

Canals S. Longitudinal Depolarization Gradients Along the Somatodendritic Axis of CA1 Pyramidal Cells: A Novel Feature of Spreading Depression. J Neurophysiol., 94: 943–51, 2005.

Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, Lehmann TN, Sarrafzadeh A, Willumsen L, Hartings JA, Sakowitz OW, Seemann JH, Thieme A, Lauritzen M, Strong AJ. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain., 129: 3224–37, 2006.

Hartings JA, Watanabe T, Bullock MR, Okonkwo DO, Fabricius M, Woitzik J, Dreier JP, Puccio A, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarizations. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain., 134: 1529–40, 2011.

Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, Weber-Carstens S, Dohmen C, Graf R, Strong AJ, Dreier JP, Vajkoczy P; COSBID study group. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology., 80: 1095–102, 2013.

Dreier JP, Fabricius M, Ayata C, Sakowitz OW, Shuttleworth CW, Dohmen C, Graf R, Vajkoczy P, Helbok R, Suzuki M, Schiefecker AJ, Major S, Winkler MK, Kang EJ, Milakara D, Oliveira-Ferreira AI, Reiffurth C, Revankar GS, Sugimoto K, Dengler NF, Hecht N, Foreman B, Feyen B, Kondziella D, Friberg CK, Piilgaard H, Rosenthal ES, Westover MB, Maslarova A, Santos E, Hertle D, Sánchez-Porras R, Jewell SL, Balança B, Platz J, Hinzman JM, Lückl J, Schoknecht K, Schöll M, Drenckhahn C, Feuerstein D, Eriksen N, Horst V, Bretz JS, Jahnke P, Scheel M, Bohner G, Rostrup E, Pakkenberg B, Heinemann U, Claassen J, Carlson AP, Kowoll CM, Lublinsky S, Chassidim Y, Shelef I, Friedman A, Brinker G, Reiner M, Kirov SA, Andrew RD, Farkas E, Güresir E, Vatter H, Chung LS, Brennan KC, Lieutaud T, Marinesco S, Maas AI, Sahuquillo J, Dahlem MA, Richter F, Herreras O, Boutelle MG, Okonkwo DO, Bullock MR, Witte OW, Martus P, van den Maagdenberg AM, Ferrari MD, Dijkhuizen RM, Shutter LA, Andaluz N, Schulte AP, MacVicar B, Watanabe T, Woitzik J, Lauritzen M, Strong AJ, Hartings JA. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group. J Cereb Blood Flow Metab., 37: 1595–625, 2017.

Kager H, Wadman WJ, Somjen GG. Conditions for the Triggering of Spreading Depression Studied With Computer Simulations Downloaded from. J Neurophysiol., 88: 2700–12, 2002.

Leão AAP. Spreading depression of activity in the cerebral cortex. J Physiol., 7: 359–90, 1944.

Lashley KS. Patters of cerebral integration indicated by the scotomas of migraine. Arch NeurPsych., 46: 331-339, 1941.

Fabricius M, Fuhr S, Willumsen L, Dreier JP, Bhatia R, Boutelle MG, Hartings JA, Bullock R, Strong AJ, Lauritzen M. Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain. Clin Neurophysiol., 119: 1973-84, 2008.

Strong AJ, Fabricius M, Boutelle MG, Hibbins SJ, Hopwood SE, Jones R, Parkin MC, Lauritzen M. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke., 33: 2738–43, 2002.

Aboghazleh R, Parker E, Yang LT, Kaufer D, Dreier JP, Friedman A, van Hameren G. Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model. Int J Mol Sci., 22: 11642, 2021.

Woods RP, Iacoboni M, Mazziotta JC. Bilateral Spreading Cerebral Hypoperfusion during Spontaneous Migraine Headache. N Engl J Med., 331: 1689–92, 1994.

Kreisman NR, Lamanna JC. Rapid and Slow Swelling During Hypoxia in the CA1 Region of Rat Hippocampal Slices. J Neurophysiol., 82: 320-9, 1999.

Lauritzen M, Rice ME, Okada Y, Nicholson C. Quisqualate, kainate and NMDA can initiate spreading depression in the turtle cerebellum. Brain Res., 475: 317–27, 1988.

Roitbak AI, Bobrov AV. Spreading depression resulting from cortical punctures. Acta Neurobiol Exp (Wars)., 35: 761-8, 1975.

Strong AJ. Dr. Bernice Grafstein’s paper on the mechanism of spreading depression. J Neurophysiol., 94: 5–7, 2005.

Herreras O, Somjen GG. Analysis of potential shifts associated with recurrent spreading depression and prolonged unstable spreading depression induced by microdialysis of elevated K+ in hippocampus of anesthetized rats. Brain Res., 610: 283–94, 1993.

Hübel N, Hosseini-Zare MS, Žiburkus J, Ullah G. The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization. PLoS Comput Biol., 13: e1005804, 2017.

Kramer DR, Fujii T, Ohiorhenuan I, Liu CY. Cortical spreading depolarization: Pathophysiology, implications, and future directions. J Clin Neurosci., 24: 22–7, 2016.

Herreras O, Somjen GG. Effects of prolonged elevation of potassium on hippocampus of anesthetized rats. Brain Res., 617: 194–204, 1993.

Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci., 15: 379–93, 2014.

Mclachlan RS. Suppression of Spreading Depression of Leao in Neocortex by an N-Methyl-D-Aspartate Receptor Antagonist. J Neurol Sci., 19: 487–91, 1992.

Tang YT, Mendez JM, Theriot JJ, Sawant PM, López-Valdés HE, Ju YS, Brennan KC. Minimum conditions for the induction of cortical spreading depression in brain slices. J Neurophysiol., 112: 2572-9, 2014.

Hansen AJ, Zeuthen T. Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol Scand., 113: 437–45, 1981.

Tottene A, Urbani A, Pietrobon D. Role of different voltage-gated Ca2+channels in cortical spreading depression: Specific requirement of P/Q-type Ca2+channels. Channels (Austin)., 5: 110-4, 2011.

Hill MP, Brotchie JM. Control of glutamate release by calcium channels and k -opioid receptors in rodent and primate striatum. Br J Pharmacol., 127: 275-83, 1999.

Lauritzen M, Hansen AJ. The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression. J Cereb Blood Flow Metab., 12: 223-9, 1992.

Almeida A, Bolaños JP, Medina JM. Nitric oxide mediates glutamate-induced mitochondrial depolarization in rat cortical neurons. Brain Res., 816: 580–6, 1999.

Shuttleworth CW, Connor JA. Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons. J Neurosci., 21: 4225–36, 2001.

Aiba I, Shuttleworth CW. Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons. J Physiol., 590: 5877–93, 2012.

Ambrosio RD, Gordon DS, Winn HR, Ambrosio D, Gordon DS, Richard H. Differential Role of KIR Channel and Na ϩ / K ϩ -Pump in the Regulation of Extracellular K ϩ in Rat Hippocampus., 98104: 87–102, 2018.

Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC. Glutamate Metabolism in the Brain Focusing on Astrocytes. Adv Neurobiol., 11: 13-30, 2014.

Hernándéz-Cáceres J, Macias-González R, Brozek G, Bures J. Systemic ketamine blocks cortical spreading depression but does not delay the onset of terminal anoxic depolarization in rats. Brain Res., 437: 360–4, 1987.

Hertle DN, Dreier JP, Woitzik J, Hartings JA, Bullock R, Okonkwo DO, Shutter LA, Vidgeon S, Strong AJ, Kowoll C, Dohmen C, Diedler J, Veltkamp R, Bruckner T, Unterberg AW, Sakowitz OW; Cooperative Study of Brain Injury Depolarizations (COSBID). Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain., 135: 2390–8, 2012.

Sánchez-Porras R, Zheng Z, Sakowitz OW. Pharmacological modulation of spreading depolarizations. Acta Neurochir Suppl., 120: 153-7, 2015.

Zhou N, Gordon GRJ, Feighan D, MacVicar BA. Transient Swelling, Acidification, and Mitochondrial Depolarization Occurs in Neurons but not Astrocytes during Spreading Depression. Cereb Cortex., 20: 2614–24, 2010.

Parker E, Aboghazleh R, Mumby G, Veksler R, Ofer J, Newton J, Smith R, Kamintsky L, Jones CMA, O'Keeffe E, Kelly E, Doelle K, Roach I, Yang LT, Moradi P, Lin JM, Gleason AJ, Atkinson C, Bowen C, Brewer KD, Doherty CP, Campbell M, Clarke DB, van Hameren G, Kaufer D, Friedman A. Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction. Brain., 139: 16–7, 2021.

Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan KC, Carlson AP, Dahlem MA, Drenckhahn C, Dohmen C, Fabricius M, Farkas E, Feuerstein D, Graf R, Helbok R, Lauritzen M, Major S, Oliveira-Ferreira AI, Richter F, Rosenthal ES, Sakowitz OW, Sánchez-Porras R, Santos E, Schöll M, Strong AJ, Urbach A, Westover MB, Winkler MK, Witte OW, Woitzik J, Dreier JP. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy. J Cereb Blood Flow Metab., 37: 1571–94, 2017.

Dreier JP, Major S, Foreman B, Winkler MKL, Kang EJ, Milakara D, Lemale CL, DiNapoli V, Hinzman JM, Woitzik J, Andaluz N, Carlson A, Hartings JA. Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol., 83: 295–310, 2018.

Menon DK, Schwab K, Wright DW, Maas AI. Position statement: Definition of traumatic brain injury. Arch Phys Med Rehabil., 91: 1637–40, 2010.

Gardner RC, Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci., 66: 75-80, 2015.

Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L, Kraus J, Coronado VG; WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med., 43: 28-60, 2004.

Horn JD Van, Bhattrai A, Irimia A. Multimodal Imaging of Neurometabolic Pathology due to Traumatic Brain Injury. Trends Neurosci., 40: 39–59, 2017.

Agrawal A, Timothy J, Pandit L, Manju M. Post-traumatic epilepsy: An overview. Clin Neurol Neurosurg., 108: 433–9, 2006.

Julien J, Joubert S, Ferland MC, Frenette LC, Boudreau-Duhaime MM, Malo-Véronneau L, et al. Association of traumatic brain injury and Alzheimer disease onset: A systematic review. Ann Phys Rehabil Med., 60: 347–56, 2017.

Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA, et al. Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol., 20: S28-35, 1991.

Mez J, Stern RA, McKee AC. Chronic Traumatic Encephalopathy. Semin Neurol., 40: 351-352, 2020.

Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, Wojnarowicz MW, Casey N, Lu H, Kokiko-Cochran ON, Saman S, Ericsson M, Onos KD, Veksler R, Senatorov VV Jr, Kondo A, Zhou XZ, Miry O, Vose LR, Gopaul KR, Upreti C, Nowinski CJ, Cantu RC, Alvarez VE, Hildebrandt AM, Franz ES, Konrad J, Hamilton JA, Hua N, Tripodis Y, Anderson AT, Howell GR, Kaufer D, Hall GF, Lu KP, Ransohoff RM, Cleveland RO, Kowall NW, Stein TD, Lamb BT, Huber BR, Moss WC, Friedman A, Stanton PK, McKee AC, Goldstein LE. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain., 141: 422–58, 2018.

Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013. MMWR Surveill Summ., 66: 1-16, 2017.

Hartings JA, Strong AJ, Fabricius M, Manning A, Bhatia R, Dreier JP, Mazzeo AT, Tortella FC, Bullock MR; Co-Operative Study of Brain Injury Depolarizations. Spreading Depolarizations and Late Secondary Insults after Traumatic Brain Injury. J Neurotrauma., 26: 1857–66, 2009.

Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, Lauritzen M. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain., 129: 778–90, 2006.

Lückl J, Lemale CL, Kola V, Horst V, Khojasteh U, Oliveira-Ferreira AI, Major S, Winkler MKL, Kang EJ, Schoknecht K, Martus P, Hartings JA, Woitzik J, Dreier JP. The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex. Brain.,141: 1734–52, 2018.

Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R; Co-Operative Study of Brain Injury Depolarisations (COSBID). Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol., 63: 720–8, 2008.

Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, Dreier JP, Hartings JA. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain., 137: 2960–72, 2014.

Dreier JP, Major S, Pannek HW, Woitzik J, Scheel M, Wiesenthal D, Martus P, Winkler MK, Hartings JA, Fabricius M, Speckmann EJ, Gorji A; COSBID study group. Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain., 135: 259–75, 2012.

Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarisations. Spreading depolarisations and outcome after traumatic brain injury: A prospective observational study. Lancet Neurol., 10: 1058–64, 2011.

Van Horn JD, Bhattrai A, Irimia A. Multimodal Imaging of Neurometabolic Pathology due to Traumatic Brain Injury. Trends Neurosci., 40: 39–59, 2017.

McCrory P, Feddermann-Demont N, Dvořák J, Cassidy JD, McIntosh A, Vos PE, Echemendia RJ, Meeuwisse W, Tarnutzer AA. What is the definition of sports-related concussion: A systematic review. Br J Sports Med., 51: 877–87, 2017.

Management of Concussion/mTBI Working Group. VA/DoD Clinical Practice Guideline for Management of Concussion/Mild Traumatic Brain Injury. J Rehabil Res Dev., 46: CP1-68, 2009.

Blyth BJ, Bazarian JJ. Traumatic alterations in consciousness: traumatic brain injury. Emerg Med Clin North Am., 28: 571–94, 2010.

Shaw NA. The neurophysiology of concussion. Prog Neurobiol., 67: 281-344, 2002.

von Baumgarten L, Trabold R, Thal S, Back T, Plesnila N. Role of cortical spreading depressions for secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow Metab., 28: 1353–60, 2008.

Bouley J, Chung DY, Ayata C, Brown RH, Henninger N. Cortical Spreading Depression Denotes Concussion Injury. J Neurotrauma., 36: 1008–17, 2019.

Jiruska P, de Curtis M, Jefferys JGR, Schevon CA, Schiff SJ, Schindler K. Synchronization and desynchronization in epilepsy: controversies and hypotheses. J Physiol., 591: 787–97, 2013.

Mayevsky A, Doron A, Manor T, Meilin S, Zarchin N, Ouaknine GE. Cortical spreading depression recorded from the human brain using a multiparametric monitoring system. Brain Res., 740: 268–74, 1996.

Vespa PM, O'Phelan K, Shah M, Mirabelli J, Starkman S, Kidwell C, Saver J, Nuwer MR, Frazee JG, McArthur DA, Martin NA. Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome. Neurology., 60: 1441–6, 2003.

Claassen J, Mayer SA, Kowalski RG, Emerson RG, Hirsch LJ. Detection of electrographic seizures with continuous EEG monitoring in critically ill patients. Neurology., 62: 1743–8, 2004.

Foreman B, Lee H, Okonkwo DO, Strong AJ, Pahl C, Shutter LA, Dreier JP, Ngwenya LB, Hartings JA. The Relationship Between Seizures and Spreading Depolarizations in Patients with Severe Traumatic Brain Injury. Neurocrit Care. 2022 Feb 16. doi: 10.1007/s12028-022-01441-2. Online ahead of print.

Gorji A, Speckmann E-J. Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur J Neurosci., 19: 3371–4, 2004.

Eickhoff M, Kovac S, Shahabi P, Ghadiri MK, Dreier JP, Stummer W, Speckmann EJ, Pape HC, Gorji A. Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues. Exp Neurol., 253: 1–15, 2014.

Koroleva VI, Bures J. Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp Brain Res., 51: 291–7, 1983.

Marrannes R, Willems R, De Prins E, Wauquier A. Evidence for a role of the N-methyl-d-aspartate (NMDA) receptor in cortical spreading depression in the rat. Brain Res., 457: 226–40, 1988.

Serlin Y, Shelef I, Knyazer B, Friedman A. Anatomy and physiology of the blood-brain barrier. Semin Cell Dev Biol., 38: 2-6, 2015.

Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis., 37: 13–25, 2010.

Hawkins BT, Davis TP. The Blood-Brain Barrier/Neurovascular Unit in Health and Disease. Pharmacol Rev., 57: 173-85, 2005.

Keaney J, Campbell M. The dynamic blood-brain barrier. FEBS J., 282: 4067–79, 2015.

Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH, Moskowitz MA. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest., 113: 1447–55, 2004.

Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci., 11: 1696–701, 2006.

Van Lint P, Libert C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol., 82: 1375–81, 2007.

Elkington PTG, O’Kane CM, Friedland JS. The paradox of matrix metalloproteinases in infectious disease. Clin Exp Immunol., 142: 12–20, 2005.

Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res., 576: 203–7, 1992.

Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size. Stroke., 29: 1020-30, 1998.

Rosell A, Ortega-Aznar A, Alvarez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke., 37: 1399–406, 2006.

Guilfoyle MR, Carpenter KLH, Helmy A, Pickard JD, Menon DK, Hutchinson PJA. Matrix Metalloproteinase Expression in Contusional Traumatic Brain Injury: A Paired Microdialysis Study. J Neurotrauma., 32: 1553–9, 2015.

Cottier KE, Galloway EA, Calabrese EC, Tome ME, Liktor-Busa E, Kim J, Davis TP, Vanderah TW, Largent-Milnes TM. Loss of Blood-Brain Barrier Integrity in a KCl-Induced Model of Episodic Headache Enhances CNS Drug Delivery. eNeuro., 5: ENEURO.0116-18.2018, 2018.

Sadeghian H, Lacoste B, Qin T, Toussay X, Rosa R, Oka F, Chung DY, Takizawa T, Gu C, Ayata C. Spreading depolarizations trigger caveolin-1-dependent endothelial transcytosis HHS Public Access. Ann Neurol., 84: 409–23, 2018.

Yisarakun W, Supornsilpchai W, Chantong C, Srikiatkhachorn A, Maneesri-le Grand S. Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model. Microvasc Res., 94: 36–46, 2014.

Oláh G, Herédi J, Menyhárt A, Czinege Z, Nagy D, Fuzik J, Kocsis K, Knapp L, Krucsó E, Gellért L, Kis Z, Farkas T, Fülöp F, Párdutz A, Tajti J, Vécsei L, Toldi J. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood-brain barrier permeability. Drug Des Devel Ther., 7: 981–7, 2013.

Vazana U, Veksler R, Pell GS, Prager O, Fassler M, Chassidim Y, Roth Y, Shahar H, Zangen A, Raccah R, Onesti E, Ceccanti M, Colonnese C, Santoro A, Salvati M, D'Elia A, Nucciarelli V, Inghilleri M, Friedman A. Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery. J Neurosci., 36: 7727–39, 2016.

Nilsson P, Ronne-Engström E, Flink R, Ungerstedt U, Carlson H, Hillered L. Epileptic seizure activity in the acute phase following cortical impact trauma in rat. Brain Res., 637: 227–32, 1994.

Palmer AM, Marion DW, Botscheller ML, Bowen DM, Dekosky ST. Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. Neuroreport., 6: 153-6, 1994.

Vespa P, Prins M, Ronne-Engstrom E, Caron M, Shalmon E, Hovda DA, Martin NA, Becker DP. Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury: a microdialysis study. J Neurosurg., 89: 971-82, 2009.

Folkersma H, Foster Dingley JC, van Berckel BN, Rozemuller A, Boellaard R, Huisman MC, Lammertsma AA, Vandertop WP, Molthoff CF. Increased cerebral (R)-[ 11 C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study. J Neuroinflammation., 8: 67, 2011.

Schoknecht K, Kikhia M, Lemale CL, Liotta A, Lublinsky S, Mueller S, Boehm-Sturm P, Friedman A, Dreier JP. The role of spreading depolarizations and electrographic seizures in early injury progression of the rat photothrombosis stroke model. J Cereb Blood Flow Metab., 41: 413-430, 2021.

Prager O, Chassidim Y, Klein C, Levi H, Shelef I, Friedman A. Dynamic in vivo imaging of cerebral blood flow and blood-brain barrier permeability. Neuroimage., 49: 337–44, 2010.

Muoio V, Persson PB, Sendeski MM. The neurovascular unit - concept review. Acta Physiol., 210: 790–8, 2014.

Hillman EMC. Coupling mechanism and significance of the BOLD signal: a status report. Annu Rev Neurosci., 37: 161–81, 2014.

Østergaard L, Dreier JP, Hadjikhani N, Jespersen SN, Dirnagl U, Dalkara T. Neurovascular Coupling during Cortical Spreading Depolarization and -Depression. Stroke., 46: 1392–401, 2015.

Phillips AA, Chan FH, Zheng MMZ, Krassioukov AV, Ainslie PN. Neurovascular coupling in humans: Physiology, methodological advances and clinical implications. J Cereb Blood Flow Metab., 36: 647–64, 2015.

Hamilton NB. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics., 2: 5, 2010.

Staddon JM, Rubin LL. Cell adhesion, cell junctions and the blood-brain barrier. Curr Opin Neurobiol., 6: 622–7, 1996.

Winkler MK, Chassidim Y, Lublinsky S, Revankar GS, Major S, Kang EJ, Oliveira-Ferreira AI, Woitzik J, Sandow N, Scheel M, Friedman A, Dreier JP. Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: Possible link to blood-brain barrier dysfunction. Epilepsia., 53: 22–30, 2012.

Akgören N, Fabricius M, Lauritzen M. Importance of nitric oxide for local increases of blood flow in rat cerebellar cortex during electrical stimulation. Proc Natl Acad Sci U S A., 91: 5903–7, 1994.

Pereira de Vasconcelos a, Baldwin R a, Wasterlain CG. Nitric oxide mediates the increase in local cerebral blood flow during focal seizures. Proc Natl Acad Sci U S A., 92: 3175-9, 1995.

Hoffmann U, Ayata C. Neurovascular coupling during spreading depolarizations. Acta Neurochir Suppl., 115: 161-5, 2013.

de Crespigny A, Rother J, van Bruggen N, Beaulieu C, Moseley ME. Magnetic resonance imaging assessment of cerebral hemodynamics during spreading depression in rats. J Cereb Blood Flow Metab., 18: 1008–17, 1998.

Faraci FM, Sobey CG. Role of potassium channels in regulation of cerebral vascular tone. J Cereb Blood Flow Metab., 18: 1047–63, 1998.

Nielsen AN, Fabricius M, Lauritzen M. Scanning laser-Doppler flowmetry of rat cerebral circulation during cortical spreading depression. J Vasc Res., 37: 513–22, 2000.

Balança B, Meiller A, Bezin L, Dreier JP, Marinesco S, Lieutaud T. Altered hypermetabolic response to cortical spreading depolarizations after traumatic brain injury in rats. J Cereb Blood Flow Metab., 37: 1670–86, 2017.

Lauritzen M. Pathophysiology of the migraine aura. Brain., 117: 199–210, 1994.

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: 1517–27, 2009.

Ayata C, Shin HK, Salomone S, Ozdemir-Gursoy Y, Boas DA, Dunn AK, Moskowitz MA. Pronounced Hypoperfusion During Spreading Depression in Mouse Cortex. J Cereb Blood Flow Metab., 24: 1172-82, 2004.

Jeffcote T, Hinzman JM, Jewell SL, Learney RM, Pahl C, Tolias C, Walsh DC, Hocker S, Zakrzewska A, Fabricius ME, Strong AJ, Hartings JA, Boutelle MG. Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. Neurocrit Care., 20: 21–31, 2014.

Shin HK, Dunn AK, Jones PB, Boas DA, Moskowitz MA, Ayata C. Vasoconstrictive neurovascular coupling during focal ischemic depolarizations. J Cereb Blood Flow Metab., 26: 1018–30, 2006.

Koide M, Sukhotinsky I, Ayata C, Wellman GC. Subarachnoid hemorrhage, spreading depolarizations and impaired neurovascular coupling. Stroke Res Treat., 2013: 819340.

Lauritzen M, Hansen AJ, Kronborg D, Wieloch T. Cortical Spreading Depression is Associated with Arachidonic Acid Accumulation and Preservation of Energy Charge. J Cereb Blood Flow Metab., 10: 115–22, 1990.

Windmüller O, Lindauer U, Foddis M, Einhäupl KM, Dirnagl U, Heinemann U, Dreier JP. Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain., 128: 2042–51, 2005.

Mutch WAC, Hansen AJ. Extracellular pH Changes during Spreading Depression and Cerebral Ischemia: Mechanisms of Brain pH Regulation. J Cereb Blood Flow Metab., 4: 17–27, 1984.

Somjen GG. Ions in the brain : normal function, seizures, and stroke [Internet]. Oxford University Press., 470 pp, 2004.

Takano T, Tian GF, Peng W, Lou N, Lovatt D, Hansen AJ, Kasischke KA, Nedergaard M. Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci., 10: 754–62, 2007.

DOI: https://doi.org/10.12871/aib.v160i1-2.4931


  • There are currently no refbacks.