Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences67930510.31857/S0869813925020024UIZPDKREVIEWОБЗОРНЫЕ СТАТЬИReview ArticleUltraslow Signals in the Diagnostics of a StrokeСверхмедленные сигналы в диагностике инсультаVinokurovaD. E.ВинокуроваД. Е.
Russian Federation
dariavinokurova.kfu@gmail.comKazan Federal UniversityКазанский федеральный университет16022025111221023209052025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/679305

The acute phase of ischemic stroke is accompanied by changes in the electrical activity of the cerebral cortex, reflecting the dynamics of pathophysiological processes in the damaged tissue. The first manifestation of ischemia is early depression of activity associated with a sharp suppression of synaptic transmission and an increase in the threshold of action potential generation. Further deterioration of the metabolic crisis in the tissue is marked by the emergence of waves of spreading depolarization (SD) – slow waves of mass depolarization of neurons and glial cells initiating in the area of the greatest deficit and spreading to the surrounding tissues. It has been shown that SDs are the main pathological mechanism causing growth of the ischemic focus, which makes them the most important target for therapeutic effects. In addition to SD, the development of a negative ultraslow potential (NUP) is observed, which is a high-amplitude (up to –100 mV) extracellular potential shift with extremely slow dynamics. It has been shown that the NUP occurs only in the area of developing damage, and its amplitude correlates with the size of the future ischemic damage. The mechanisms of NUP have not been fully studied to date. Both SD and NUP are highly informative markers of ischemic damage, but have extremely slow dynamics (frequency < 0.01 Hz), as a result they are not detectable when recorded in the classical EEG range (0.5–45 Hz). This review discusses the mechanisms underlying early depression of activity, and ultraslow SD and NUP signals in focal stroke, their importance for diagnostics and monitoring of the ischemic process, as well as modern therapeutic approaches to stroke management.

Острая фаза ишемического инсульта сопровождается изменениями электрической активности коры головного мозга, отражающими динамику патофизиологических процессов в поврежденной ткани. Первым проявлением ишемии является ранняя депрессия активности, связанная с резким подавлением синаптической передачи и увеличением порога генерации потенциалов действия. Дальнейшее усиление метаболического кризиса в ткани знаменуется возникновением волн распространяющейся деполяризации (РД) – медленных волн массовой деполяризации нейронов и глиальных клеток, возникающих в области наибольшего дефицита и распространяющихся в окружающие ткани. Показано, что волны РД являются основным патологическим процессом, вызывающим рост ишемического очага, что делает их важнейшей мишенью для терапевтических вмешательств. Помимо РД, наблюдается развитие негативного ультрамедленного потенциала (НУП), который представляет собой высокоамплитудный (до –100 мВ) сдвиг внеклеточного потенциала с чрезвычайно медленной динамикой. Показано, что НУП генерируется только в зоне развивающегося повреждения, а его амплитуда коррелирует с размерами будущего ишемического очага. Механизмы генерации НУП к настоящему времени недостаточно изучены.

Как РД, так и НУП являются высокоинформативными маркерами ишемического повреждения, однако имеют крайне медленную динамику (частота < 0.01 Гц), вследствие чего они не обнаруживаются при регистрации в классическом ЭЭГ-диапазоне (0.5–45 Гц). В настоящем обзоре рассматриваются механизмы, лежащие в основе ранней депрессии активности, сверхмедленных сигналов РД и НУП при фокальном инсульте, их значение для диагностики и мониторинга ишемического процесса, а также обсуждаются современные терапевтические подходы к лечению инсульта.

strokeelectroencephalographyintracortical registrationspreading depolarizationnegative ultraslow potentialEEG correlates of ischemiaинсультэлектроэнцефалографияинтракортикальная регистрацияраспространяющаяся деполяризациянегативный ультрамедленный потенциалЭЭГ-корреляты ишемииРоссийский научный фондRussian Science Foundation24-75-10054Hossmann KA (1994) Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36: 557–565. https://doi.org/10.1002/ana.410360404Foreman BP, Claassen J (2012) Quantitative EEG for the detection of brain ischemia. Crit Care 16: 29–37. https://doi.org/10.1186/cc11230Ajčević M, Furlanis G, Naccarato M, Miladinović A, Buoite Stella A, Caruso P, Cillotto T, Accardo A, Manganotti P (2021) Hyper-acute EEG alterations predict functional and morphological outcomes in thrombolysis-treated ischemic stroke: A wireless EEG study. Med Biol Eng Comput 59: 121–129. https://doi.org/10.1007/s11517-020-02280-zRosenthal ES, Biswal S, Zafar SF, O’Connor KL, Bechek S, Shenoy A V., Boyle EJ, Shafi MM, Gilmore EJ, Foreman BP, Gaspard N, Leslie-Mazwi TM, Rosand J, Hoch DB, Ayata C, Cash SS, Cole AJ, Patel AB, Westover MB (2018) Continuous electroencephalography predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective study of diagnostic accuracy. Ann Neurol 83: 958–969. https://doi.org/10.1002/ana.25232Pulvers JN, Watson JDG (2017) If Time Is Brain Where Is the Improvement in Prehospital Time after Stroke? Front Neurol 8: 617. https://doi.org/10.3389/fneur.2017.00617Dreier JP, Lemale CL, Horst V, Major S, Kola V, Schoknecht K, Scheel M, Hartings JA, Vajkoczy P, Wolf S, Woitzik J, Hecht N (2024) Similarities in the Electrographic Patterns of Delayed Cerebral Infarction and Brain Death After Aneurysmal and Traumatic Subarachnoid Hemorrhage. Transl Stroke Res. https://doi.org/10.1007/s12975-024-01237-wMacrae I (2011) Preclinical stroke research – advantages and disadvantages of the most common rodent models of focal ischaemia. Br J Pharmacol 164: 1062–1078. https://doi.org/10.1111/j.1476-5381.2011.01398.xHeiss W ‐D, Rosner G (1983) Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 14: 294–301. https://doi.org/10.1002/ana.410140307Memezawa H, Smith ML, Siesjo BK (1992) Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23: 552–559. https://doi.org/10.1161/01.STR.23.4.552Von Bornstädt D, Houben T, Seidel JL, Zheng Y, Dilekoz E, Qin T, Sandow N, Kura S, Eikermann-Haerter K, Endres M, Boas DA, Moskowitz MA, Lo EH, Dreier JP, Woitzik J, Sakadžić S, Ayata C (2015) Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. Neuron 85: 1117–1131. https://doi.org/10.1016/j.neuron.2015.02.007Walther J, Kirsch EM, Hellwig L, Schmerbeck SS, Holloway PM, Buchan AM, Mergenthaler P (2023) Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm. Transl Stroke Res 14: 643–666. https://doi.org/10.1007/s12975-022-01090-9Vinokurova D, Zakharov A, Chernova K, Burkhanova-Zakirova G, Horst V, Lemale CL, Dreier JP, Khazipov R (2022) Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia. J Cerebr Blood Flow Metabol 42: 1944–1960. https://doi.org/10.1177/0271678X221107422Hossmann KA (1994) Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36: 557–565. https://doi.org/10.1002/ana.410360404Leao AP (1947) Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 10: 409–414. https://doi.org/10.1152/jn.1947.10.6.409Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17: 439–447. https://doi.org/10.1038/nm.2333Dreier JP, Reiffurth C (2015) The Stroke-Migraine Depolarization Continuum. Neuron 86: 902–922. https://doi.org/10.1016/j.neuron.2015.04.004Dreier 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 (2018) Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol 83: 295–310. https://doi.org/10.1002/ana.25147Oliveira-Ferreira AI, Winkler MKL, Reiffurth C, Milakara D, Woitzik J, Dreier JP (2012) Spreading depolarization, a pathophysiological mechanism of stroke and migraine aura. Future Neurol 7: 45–64. https://doi.org/10.2217/fnl.11.69Lemale CL, Lückl J, Horst V, Reiffurth C, Major S, Hecht N, Woitzik J, Dreier JP (2022) Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization. Front Cell Neurosci 16: 1–29. https://doi.org/10.3389/fncel.2022.837650Hochachka PW, Buck LT, Doll CJ, Land SC (1996) Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A 93: 9493–9498. https://doi.org/10.1073/pnas.93.18.9493Hochachka PW, Lutz PL (2001) Mechanism, origin, and evolution of anoxia tolerance in animals. Compar Biochem Physiol–B Biochem Mol Biol 130: 435–459. https://doi.org/10.1016/S1096-4959(01)00408-0Dienel GA (2019) Brain glucose metabolism: Integration of energetics with function. Physiol Rev 99: 949–1045. https://doi.org/10.1152/physrev.00062.2017Fowler JC (1989) Adenosine antagonists delay hypoxia-induced depression of neuronal activity in hippocampal brain slice. Brain Res 490: 378–384. https://doi.org/10.1016/0006-8993(89)90258-8Zironi I, Aicardi G (2022) Hypoxia Depresses Synaptic Transmission in the Primary Motor Cortex of the Infant Rat—Role of Adenosine A1 Receptors and Nitric Oxide. Biomedicines 10: 2875. https://doi.org/10.3390/biomedicines10112875Dzhala V, Desfreres L, Melyan Z, Ben-Ari Y, Khazipov R (1999) Epileptogenic action of caffeine during anoxia in the neonatal rat hippocampus. Ann Neurol 46: 95–102. https://doi.org/10.1002/1531-8249(199907)46:1<95::AID-ANA14>3.0.CO;2-1Khazipov R, Congar P, Ben-Ari Y (1995) Hippocampal CA1 lacunosum-moleculare interneurons: comparison of effects of anoxia on excitatory and inhibitory postsynaptic currents. J Neurophysiol 74: 2138–2149. https://doi.org/10.1152/jn.1995.74.5.2138Khazipov RN, Bregestovski P, Ben-Ari Y (1993) Hippocampal inhibitory interneurons are functionally disconnected from excitatory inputs by anoxia. J Neurophysiol 70: 2251–2259. https://doi.org/10.1152/jn.1993.70.6.2251Canals S, Larrosa B, Pintor J, Mena MA, Herreras O (2008) Metabolic challenge to glia activates an adenosine-mediated safety mechanism that promotes neuronal survival by delaying the onset of spreading depression waves. J Cerebr Blood Flow Metabol 28: 1835–1844. https://doi.org/10.1038/jcbfm.2008.71Fleidervish IA, Gebhardt C, Astman N, Gutnick MJ, Heinemann U (2001) Enhanced spontaneous transmitter release is the earliest consequence of neocortical hypoxia that can explain the disruption of normal circuit function. J Neurosci 21: 4600–4608. https://doi.org/https://doi.org/10.1523/JNEUROSCI.21-13-04600.2001Rogers JM, Bechara J, Middleton S, Johnstone SJ (2019) Acute EEG Patterns Associated With Transient Ischemic Attack. Clin EEG Neurosci 50: 196–204. https://doi.org/10.1177/1550059418790708Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81: 1065–1096. https://doi.org/10.1152/physrev.2001.81.3.1065Kager H, Wadman WJ, Somjen GG (2002) Conditions for the Triggering of Spreading Depression Studied with Computer Simulations. J Neurophysiol 88: 2700–2712. https://doi.org/10.1152/jn.00237.2002Dreier JP, Isele T, Reiffurth C, Offenhauser N, Kirov SA, Dahlem MA, Herreras O (2013) Is spreading depolarization characterized by an abrupt, massive release of gibbs free energy from the human brain cortex? Neuroscientist 19: 25–42. https://doi.org/10.1177/1073858412453340Zhou N, Rungta RL, Malik A, Han H, Wu DC, MacVicar BA (2013) Regenerative Glutamate Release by Presynaptic NMDA Receptors Contributes to Spreading Depression. J Cerebr Blood Flow Metabol 33: 1582–1594. https://doi.org/10.1038/jcbfm.2013.113Chau L, Davis HT, Jones T, Greene-Chandos D, Torbey M, Shuttleworth CW, Carlson AP (2022) Spreading Depolarization as a Therapeutic Target in Severe Ischemic Stroke: Physiological and Pharmacological Strategies. J Pers Med 12: 1447. https://doi.org/10.3390/jpm12091447Liu F, Lu J, Manaenko A, Tang J, Hu Q (2018) Mitochondria in Ischemic Stroke: New Insight and Implications. Aging Dis 9: 924. https://doi.org/10.14336/AD.2017.1126Ayata C, Lauritzen M (2015) Spreading depression, spreading depolarizations, and the cerebral vasculature. Physiol Rev 95: 953–993. https://doi.org/10.1152/physrev.00027.2014Spong KE, David Andrew R, Meldrum Robertson R (2016) Mechanisms of spreading depolarization in vertebrate and insect central nervous systems. J Neurophysiol 116: 1117–1127. https://doi.org/10.1152/jn.00352.2016Koroleva VI, Vinogradova LV (1990) Spreading depression in the thalamus, hippocampus and caudate nucleus of the rat during electrical stimulation of the parietal area of the cortex. Neirofiziologiia 22: 36–44.Gorji A, Zahn PK, Pogatzki EM, Speckmann E-J (2004) Spinal and cortical spreading depression enhance spinal cord activity. Neurobiol Dis 15: 70–79. https://doi.org/10.1016/j.nbd.2003.09.014Aiba I, Noebels JL (2015) Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models. Sci Transl Med 7: 282ra46. https://doi.org/10.1126/scitranslmed.aaa4050Oliveira-Ferreira AI, Major S, Przesdzing I, Kang EJ, Dreier JP (2020) Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia. J Cerebr Blood Flow Metabol 40: 1274–1289. https://doi.org/10.1177/0271678X19861604Martens‐Mantai T, Speckmann E, Gorji A (2014) Propagation of cortical spreading depression into the hippocampus: The role of the entorhinal cortex. Synapse 68: 574–584. https://doi.org/10.1002/syn.21769Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury. J Cereb Blood Flow Metabol 31: 17–35. https://doi.org/10.1038/jcbfm.2010.191Major S, Huo S, Lemale CL, Siebert E, Milakara D, Woitzik J, Gertz K, Dreier JP (2020) Direct electrophysiological evidence that spreading depolarization-induced spreading depression is the pathophysiological correlate of the migraine aura and a review of the spreading depolarization continuum of acute neuronal mass injury. Geroscience 42: 57–80. https://doi.org/10.1007/s11357-019-00142-7Mayevsky A, Doron A, Manor T, Meilin S, Zarchin N, Ouaknine GE (1996) Cortical spreading depression recorded from the human brain using a multiparametric monitoring system. Brain Res 740: 268–274. https://doi.org/10.1016/S0006-8993(96)00874-8Nedergaard M, Hansen AJ (1988) Spreading depression is not associated with neuronal injury in the normal brain. Brain Res 449: 395–398. https://doi.org/10.1016/0006-8993(88)91062-1Mies G, Paschen W (1984) Regional changes of blood flow, glucose, and ATP content determined on brain sections during a single passage of spreading depression in rat brain cortex. Exp Neurol 84: 249–258. https://doi.org/10.1016/0014-4886(84)90222-XØstergaard L, Dreier JP, Hadjikhani N, Jespersen SN, Dirnagl U, Dalkara T (2015) Neurovascular Coupling during Cortical Spreading Depolarization and -Depression. Stroke 46: 1392–1401. https://doi.org/10.1161/STROKEAHA.114.008077Mingazov B, Vinokurova D, Zakharov A, Khazipov R (2023) Comparative Study of Terminal Cortical Potentials Using Iridium and Ag/AgCl Electrodes. Int J Mol Sci 24: 10769. https://doi.org/10.3390/IJMS241310769Juzekaeva E, Gainutdinov A, Mukhtarov M, Khazipov R (2020) Reappraisal of anoxic spreading depolarization as a terminal event during oxygen–glucose deprivation in brain slices in vitro. Sci Rep 10: 1–12. https://doi.org/10.1038/s41598-020-75975-wGainutdinov A, Juzekaeva E, Mukhtarov M, Khazipov R (2023) Anoxic spreading depolarization in the neonatal rat cortex in vitro. Front Cell Neurosci 17: 1–12. https://doi.org/10.3389/fncel.2023.1106268Hartings JA, York J, Carroll CP, Hinzman JM, Mahoney E, Krueger B, Winkler MKL, Major S, Horst V, Jahnke P, Woitzik J, Kola V, Du Y, Hagen M, Jiang J, Dreier JP (2017) Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction. Brain 140: 2673–2690. https://doi.org/10.1093/brain/awx214Vinokurova D, Zakharov A, Chernova K, Burkhanova-Zakirova G, Horst V, Lemale CL, Dreier JP, Khazipov R (2022) Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia. J Cerebr Blood Flow Metabol 42: 1944–1960. https://doi.org/10.1177/0271678X221107422Dijkhuizen RM, Beekwilder JP, Van Der Worp HB, Berkelbach Van Der Sprenkel JW, Tulleken KAF, Nicolay K (1999) Correlation between tissue depolarizations and damage in focal ischemic rat brain. Brain Res 840: 194–205. https://doi.org/10.1016/S0006-8993(99)01769-2Dreier JP, Fabricius M, Ayata C, Sakowitz OW, William Shuttleworth C, Dohmen C, Graf R, Vajkoczy P, Helbok R, Suzuki M, Schiefecker AJ, Major S, Winkler MKL, 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 K, 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 AMJM, Ferrari MD, Dijkhuizen RM, Shutter LA, Andaluz N, Schulte AP, Macvicar B, Watanabe T, Woitzik J, Lauritzen M, Strong AJ, Hartings JA (2017) Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group. J Cerebr Blood Flow Metabol 37: 1595–1625. https://doi.org/10.1177/0271678X16654496Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan K, 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 MKL, Witte OW, Woitzik J, Dreier JP (2017) The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy. J Cerebr Blood Flow Metabol 37: 1571–1594. 10.1177/0271678X16654495Oliveira-Ferreira AI, Milakara D, Alam M, Jorks D, Major S, Hartings JA, Lückl J, Martus P, Graf R, Dohmen C, Bohner G, Woitzik J, Dreier JP (2010) Experimental and preliminary clinical evidence of an ischemic zone with prolonged negative DC shifts surrounded by a normally perfused tissue belt with persistent electrocorticographic depression. J Cerebr Blood Flow Metabol 30: 1504–1519. https://doi.org/10.1038/jcbfm.2010.40Dreier JP, Alam M, Major S, Dirnagl U, Priller J, Kleeberg J, Kohl-Bareis M, Petzold GC, Victorov I, Obrenovitch TP (2007) Endothelin-1-induced spreading depression in rats is associated with a microarea of selective neuronal necrosis. Exp Biol Med 232: 204–213. https://doi.org/10.3181/00379727-207-2320204Charpier S (2023) Between life and death: the brain twilight zones. Front Neurosci 17: 1–18. https://doi.org/10.3389/fnins.2023.1156368Mackey J, Yamal JM, Parker SA, Silnes K, Rajan SS, Jacob AP, Wang M, Singh N, Jones WJ, Spokoyny I, Navi BB, Saver JL, Grotta JC (2023) Golden Hour Treatment with tPA (Tissue-Type Plasminogen Activator) in the BEST-MSU Study. Stroke 54: 415–425. https://doi.org/10.1161/STROKEAHA.122.039821Nakamura H, Strong AJ, Dohmen C, Sakowitz OW, Vollmar S, Sué M, Kracht L, Hashemi P, Bhatia R, Yoshimine T, Dreier JP, Dunn AK, Graf R (2010) Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain 133: 1994–2006. https://doi.org/10.1093/brain/awq117Lindquist BE (2024) Spreading depolarizations pose critical energy challenges in acute brain injury. J Neurochem 168: 868–887. https://doi.org/10.1111/jnc.15966Schaeffer S, Iadecola C (2021) Revisiting the neurovascular unit. Nat Neurosci 24: 1198–1209. https://doi.org/10.1038/s41593-021-00904-7Lauritzen M, Hansen AJ, Kronborg D, Wieloch T (1990) Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge. J Cerebr Blood Flow Metabol 10: 115–122. https://doi.org/10.1038/jcbfm.1990.14Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden JE, Hill-Eubanks D, Nelson MT (2017) Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci 20: 717–726. https://doi.org/10.1038/nn.4533Koide M, Sukhotinsky I, Ayata C, Wellman GC (2013) Subarachnoid hemorrhage, spreading depolarizations and impaired neurovascular coupling. Stroke Res Treat 2013: 1–10. https://doi.org/10.1155/2013/819340Dreier JP, Körner K, Ebert N, Görner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhäupl KM, Lauritzen M, Dirnagl U (1998) Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cerebr Blood Flow Metabol 18: 978–990. https://doi.org/10.1097/00004647-199809000-00007Macdonald RL, Pluta RM, Zhang JH (2007) Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3: 256–263. https://doi.org/10.1038/NCPNEURO0490Windmüller O, Lindauer U, Foddis M, Einhäupl KM, Dirnagl U, Heinemann U, Dreier JP (2005) Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain 128: 2042–2051. https://doi.org/10.1093/brain/awh545Kramer DR, Fujii T, Ohiorhenuan I, Liu CY (2017) Interplay between cortical spreading depolarization and seizures. Stereotact Funct Neurosurg 95: 1–5. https://doi.org/10.1159/000452841Dreier JP, Winkler MKL, Major S, Horst V, Lublinsky S, Kola V, Lemale CL, Kang EJ, Maslarova A, Salur I, Lückl J, Platz J, Jorks D, Oliveira-Ferreira AI, Schoknecht K, Reiffurth C, Milakara D, Wiesenthal D, Hecht N, Dengler NF, Liotta A, Wolf S, Kowoll CM, Schulte AP, Santos E, Güresir E, Unterberg AW, Sarrafzadeh A, Sakowitz OW, Vatter H, Reiner M, Brinker G, Dohmen C, Shelef I, Bohner G, Scheel M, Vajkoczy P, Hartings JA, Friedman A, Martus P, Woitzik J (2022) Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study. Brain 145: 1264–1284. https://doi.org/10.1093/brain/awab457Du Y, Wang W, Lutton AD, Kiyoshi CM, Ma B, Taylor AT, Olesik JW, McTigue DM, Askwith CC, Zhou M (2018) Dissipation of transmembrane potassium gradient is the main cause of cerebral ischemia-induced depolarization in astrocytes and neurons. Exp Neurol 303: 1–11. https://doi.org/10.1016/j.expneurol.2018.01.019Juzekaeva E, Gainutdinov A, Mukhtarov M, Khazipov R (2018) Dynamics of the hypoxia—induced tissue edema in the rat barrel cortex in vitro. Front Cell Neurosci 12. https://doi.org/10.3389/fncel.2018.00502Dreier JP, Lemale CL, Kola V, Friedman A, Schoknecht K (2018) Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology 134: 189–207. https://doi.org/10.1016/j.neuropharm.2017.09.027Du T, Mestre H, Kress BT, Liu G, Sweeney AM, Samson AJ, Rasmussen MK, Mortensen KN, Bork PAR, Peng W, Olveda GE, Bashford L, Toro ER, Tithof J, Kelley DH, Thomas JH, Hjorth PG, Martens EA, Mehta RI, Hirase H, Mori Y, Nedergaard M (2022) Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema. Brain 145: 787–797. https://doi.org/10.1093/brain/awab293Murphy TH, Li P, Betts K, Liu R (2008) Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines. J Neurosci 28: 1756–1772. https://doi.org/10.1523/JNEUROSCI.5128-07.2008Herreras O, Makarova J (2020) Mechanisms of the negative potential associated with Leão’s spreading depolarization: A history of brain electrogenesis. J Cerebr Blood Flow Metabol 40: 1934–1952. https://doi.org/10.1177/0271678X20935998Andrew RD, Labron MW, Boehnke SE, Carnduff L, Kirov SA (2007) Physiological evidence that pyramidal neurons lack functional water channels. Cereb Cortex 17: 787–802. https://doi.org/10.1093/CERCOR/BHK032Álvarez-Merz I, Fomitcheva IV, Sword J, Hernández-Guijo JM, Solís JM, Kirov SA (2022) Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling. Glia 70: 2108–2130. https://doi.org/10.1002/glia.24241Leao AAP (1944) SPREADING DEPRESSION OF ACTIVITY IN THE CEREBRAL CORTEX. J Neurophysiol 7: 359–390. https://doi.org/10.1152/jn.1944.7.6.359Carter RE, Seidel JL, Lindquist BE, Sheline CT, Shuttleworth CW (2013) Intracellular Zn2+ accumulation enhances suppression of synaptic activity following spreading depolarization. J Neurochem 125: 673–684. https://doi.org/10.1111/JNC.12237Nasretdinov A, Vinokurova D, Lemale CL, Burkhanova-Zakirova G, Chernova K, Makarova J, Herreras O, Dreier JP, Khazipov R (2023) Diversity of cortical activity changes beyond depression during Spreading Depolarizations. Nat Commun 14: 7729. https://doi.org/10.1038/s41467-023-43509-3Nasretdinov A, Evstifeev A, Vinokurova D, Burkhanova-Zakirova G, Chernova K, Churina Z, Khazipov R (2021) Full-band eeg recordings using hybrid ac/dc-divider filters. eNeuro 8. https://doi.org/10.1523/ENEURO.0246-21.2021Zakharov A, Chernova K, Burkhanova G, Holmes GL, Khazipov R (2019) Segregation of seizures and spreading depolarization across cortical layers. Epilepsia 60: 2386–2397. https://doi.org/10.1111/epi.16390Kaufmann D, Theriot JJ, Zyuzin J, Service CA, Chang JC, Tang YT, Bogdanov VB, Multon S, Schoenen J, Ju YS, Brennan KC (2017) Heterogeneous incidence and propagation of spreading depolarizations. J Cerebr Blood Flow Metabol 37: 1748–1762. https://doi.org/10.1177/0271678X16659496Vinokurova D, Zakharov A, Chernova K, Burkhanova-Zakirova G, Horst V, Lemale CL, Dreier JP, Khazipov R (2022) Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia. J Cerebr Blood Flow Metabol 42: 1944–1960. https://doi.org/10.1177/0271678X221107422Shen P, Hou S, Zhu M, Zhao M, Ouyang Y, Feng J (2017) Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP-activated protein kinase-dependent autophagy in a rat cerebral ischemic/reperfusion injury model. J Neurochem 140: 799–813. https://doi.org/10.1111/jnc.13922Dell’Orco M, Weisend JE, Perrone-Bizzozero NI, Carlson AP, Morton RA, Linsenbardt DN, Shuttleworth CW (2023) Repetitive spreading depolarization induces gene expression changes related to synaptic plasticity and neuroprotective pathways. Front Cell Neurosci 17: 1292661. https://doi.org/10.3389/fncel.2023.1292661Grafstein B (1956) MECHANISM OF SPREADING CORTICAL DEPRESSION. J Neurophysiol 19: 154–171. https://doi.org/10.1152/jn.1956.19.2.154Harreveld AV (1959) Compounds in brain extracts causing spreading depression of cerebral cortical activity and contraction of crustacean muscle. J Neurochem 3: 300–315. https://doi.org/10.1111/j.1471-4159.1959.tb12636.xHerreras O, Somjen GG (1993) 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: 283–294. https://doi.org/10.1016/0006-8993(93)91412-LPeters O, Schipke CG, Hashimoto Y, Kettenmann H (2003) Different mechanisms promote astrocyte Ca2+ waves and spreading depression in the mouse neocortex. J Neurosci 23: 9888–9896. https://doi.org/10.1523/jneurosci.23-30-09888.2003Lauritzen M, Hansen AJ (1992) The Effect of Glutamate Receptor Blockade on Anoxic Depolarization and Cortical Spreading Depression. J Cerebr Blood Flow Metabol 12: 223–229. https://doi.org/10.1038/jcbfm.1992.32Petzold GC, Windmüller O, Haack S, Major S, Buchheim K, Megow D, Gabriel S, Lehmann T-N, Drenckhahn C, Peters O, Meierkord H, Heinemann U, Dirnagl U, Dreier JP (2005) 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. https://doi.org/10.1161/01.STR.0000166023.51307.e0Van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, van de Ven RCG, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD (2004) A Cacna1a Knockin Migraine Mouse Model with Increased Susceptibility to Cortical Spreading Depression. Neuron 41: 701–710. https://doi.org/10.1016/S0896-6273(04)00085-6Leo L, Gherardini L, Barone V, De Fusco M, Pietrobon D, Pizzorusso T, Casari G (2011) Increased Susceptibility to Cortical Spreading Depression in the Mouse Model of Familial Hemiplegic Migraine Type 2. PLoS Genet 7: e1002129. https://doi.org/10.1371/journal.pgen.1002129Herreras O, Large C, Ibarz JM, Somien GG, Martin R, Rio’ D (1994) Role of Neuronal Synchronizing Mechanisms in the Propagation of Spreading Depression in the in vivo Hippocampus. J Neurosci 14: 7087-7098. https://doi.org/10.1523/JNEUROSCI.14-11-07087.1994Dere E, Zlomuzica A (2012) The role of gap junctions in the brain in health and disease. Neurosci Biobehav Rev 36: 206–217. https://doi.org/10.1016/j.neubiorev.2011.05.015Nedergaard M, Cooper AJL, Goldman SA (1995) Gap junctions are required for the propagation of spreading depression. J Neurobiol 28: 433–444. https://doi.org/10.1002/neu.480280404Chuquet J, Hollender L, Nimchinsky EA (2007) High-resolution in vivo imaging of the neurovascular unit during spreading depression. J Neurosci 27: 4036–4044. https://doi.org/10.1523/JNEUROSCI.0721-07.2007Theis M, Jauch R, Zhuo L, Speidel D, Wallraff A, Döring B, Frisch C, Söhl G, Teubner B, Euwens C, Huston J, Steinhäuser C, Messing A, Heinemann U, Willecke K (2003) Accelerated Hippocampal Spreading Depression and Enhanced Locomotory Activity in Mice with Astrocyte-Directed Inactivation of Connexin43. J Neurosci 23: 766–776. https://doi.org/10.1523/JNEUROSCI.23-03-00766.2003Kearns KN, Liu L, Soldozy S, Sharifi KA, Shaffrey ME, Park MS, Tvrdik P (2022) Microglia Modulate Cortical Spreading Depolarizations After Ischemic Stroke: A Narrative Review. Neurocrit Care 37: 133–138. https://doi.org/10.1007/s12028-022-01469-4Szalay G, Martinecz B, Lénárt N, Környei Z, Orsolits B, Judák L, Császár E, Fekete R, West BL, Katona G, Rózsa B, Dénes Á (2016) Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 7: 11499. https://doi.org/10.1038/ncomms11499Pusic KM, Pusic AD, Kemme J, Kraig RP (2014) Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment. Glia 62: 1176–1194. https://doi.org/10.1002/glia.22672Makarova J, Ibarz JM, Canals S, Herreras O (2007) A steady-state model of spreading depression predicts the importance of an unknown conductance in specific dendritic domains. Biophys J 92: 4216–4232. https://doi.org/10.1529/biophysj.106.090332Vitale M, Tottene A, Zarin Zadeh M, Brennan K, Pietrobon D (2023) Mechanisms of initiation of cortical spreading depression. J Headache and Pain 24: 1–17. https://doi.org/10.1186/s10194-023-01643-9Chever O, Zerimech S, Scalmani P, Lemaire L, Pizzamiglio L, Loucif A, Ayrault M, Krupa M, Desroches M, Duprat F, Léna I, Cestèle S, Mantegazza M (2021) Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels. J Clin Invest 131: 1–15. https://doi.org/10.1172/JCI142203Andrew RD, Farkas E, Hartings JA, Brennan KC, Herreras O, Müller M, Kirov SA, Ayata C, Ollen-Bittle N, Reiffurth C, Revah O, Robertson RM, Dawson-Scully KD, Ullah G, Dreier JP (2022) Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization. Neurocrit Care 37: 11–30. https://doi.org/10.1007/s12028-021-01429-4Strong AJ, Fabricius M, Boutelle MG, Hibbins SJ, Hopwood SE, Jones R, Parkin MC, Lauritzen M (2002) Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 33: 2738–2743. https://doi.org/10.1161/01.STR.0000043073.69602.09Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, Lauritzen M (2006) Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain 129: 778–790. https://doi.org/10.1093/brain/awh716Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R (2008) Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol 63: 720–728. https://doi.org/10.1002/ana.21390Chung DY, Oka F, Ayata C (2016) Spreading depolarizations: A therapeutic target against delayed cerebral ischemia after subarachnoid hemorrhage. J Clin Neurophysiol 33: 196–202. https://doi.org/10.1097/WNP.0000000000000275Eriksen N, Rostrup E, Fabricius M, Scheel M, Major S, Winkler MKL, Bohner G, Santos E, Sakowitz OW, Kola V, Reiffurth C, Hartings JA, Vajkoczy P, Woitzik J, Martus P, Lauritzen M, Pakkenberg B, Dreier JP (2019) Early focal brain injury after subarachnoid hemorrhage correlates with spreading depolarizations. Neurology 92: E326–E341. https://doi.org/10.1212/WNL.0000000000006814Helbok R, Hartings JA, Schiefecker A, Balança B, Jewel S, Foreman B, Ercole A, Balu R, Ayata C, Ngwenya L, Rosenthal E, Boutelle MG, Farkas E, Dreier JP, Fabricius M, Shuttleworth CW, Carlson A (2020) What Should a Clinician Do When Spreading Depolarizations are Observed in a Patient? Neurocrit Care 32: 306–310. https://doi.org/10.1007/s12028-019-00777-6Chang EF (2015) Towards large-scale, human-based, mesoscopic neurotechnologies. Neuron 86: 68–78. https://doi.org/10.1016/j.neuron.2015.03.037Rungby J (1990) An experimental study on silver in the nervous system and on aspects of its general cellular toxicity. Dan Med Bull 37: 442–449.Major S, Gajovic-Eichelmann N, Woitzik J, Dreier JP (2021) Oxygen-Induced and pH-Induced Direct Current Artifacts on Invasive Platinum/Iridium Electrodes for Electrocorticography. Neurocrit Care 35: 146–159. https://doi.org/10.1007/s12028-021-01358-2Ha S, Akinin A, Park J, Kim C, Wang H, Maier C, Mercier PP, Cauwenberghs G (2017) Silicon-Integrated High-Density Electrocortical Interfaces. Proceed of the IEEE 105: 11–33. https://doi.org/10.1109/JPROC.2016.2587690Masvidal-Codina E, Illa X, Dasilva M, Calia AB, Dragojević T, Vidal-Rosas EE, Prats-Alfonso E, Martínez-Aguilar J, De la Cruz JM, Garcia-Cortadella R, Godignon P, Rius G, Camassa A, Del Corro E, Bousquet J, Hébert C, Durduran T, Villa R, Sanchez-Vives M V., Garrido JA, Guimerà-Brunet A (2019) High-resolution mapping of infraslow cortical brain activity enabled by graphene microtransistors. Nat Mater 18: 280–288. https://doi.org/10.1038/s41563-018-0249-4Karbalaei Akbari M, Siraj Lopa N, Shahriari M, Najafzadehkhoee A, Galusek D, Zhuiykov S (2023) Functional Two-Dimensional Materials for Bioelectronic Neural Interfacing. J Funct Biomater 14: 1–24. https://doi.org/10.3390/jfb14010035Oribe S, Yoshida S, Kusama S, Osawa S ichiro, Nakagawa A, Iwasaki M, Tominaga T, Nishizawa M (2019) Hydrogel-Based Organic Subdural Electrode with High Conformability to Brain Surface. Sci Rep 9: 13379. https://doi.org/10.1038/s41598-019-49772-zKovac S, Speckmann EJ, Gorji A (2018) Uncensored EEG: The role of DC potentials in neurobiology of the brain. Prog Neurobiol 165–167: 51–65. https://doi.org/10.1016/j.pneurobio.2018.02.001Lehmenkühler A, Richter F (2020) Cortical Spreading Depolarization (CSD) Recorded from Intact Skin, from Surface of Dura Mater or Cortex: Comparison with Intracortical Recordings in the Neocortex of Adult Rats. Neurochem Res 45: 34–41. https://doi.org/10.1007/S11064-019-02737-0/FIGURES/5Bastany ZJR, Askari S, Dumont GA, Speckmann EJ, Gorji A (2016) Non-invasive monitoring of spreading depression. Neuroscience 333: 1–12. https://doi.org/10.1016/j.neuroscience.2016.06.056Hofmeijer J, van Kaam CR, van de Werff B, Vermeer SE, Tjepkema-Cloostermans MC, van Putten MJAM (2018) Detecting cortical spreading depolarization with full band scalp electroencephalography: An illusion? Front Neurol 9: 17. https://doi.org/10.3389/fneur.2018.00017Sivakumar S, Tsetsou S, Patel AB, Stapleton CJ, Grannan BL, Schweitzer JS, Chung DY, Rosenthal ES (2022) Cortical Spreading Depolarizations and Clinically Measured Scalp EEG Activity After Aneurysmal Subarachnoid Hemorrhage and Traumatic Brain Injury. Neurocrit Care 37: 49–59. https://doi.org/10.1007/s12028-021-01418-7Hartings JA, Wilson JA, Hinzman JM, Pollandt S, Dreier JP, DiNapoli V, Ficker DM, Shutter LA, Andaluz N (2014) Spreading depression in continuous electroencephalography of brain trauma. Ann Neurol 76: 681–694. https://doi.org/10.1002/ana.24256Robinson D, Hartings J, Foreman B (2021) First Report of Spreading Depolarization Correlates on Scalp EEG Confirmed with a Depth Electrode. Neurocrit Care 35: 100–104. https://doi.org/ 10.1007/s12028-021-01360-8Holder DS (1992) Detection of cortical spreading depression in the anaesthetised rat by impedance measurement with scalp electrodes: implications for non-invasive imaging of the brain with electrical impedance tomography. Clin Phys Physiol Meas 13: 77–86. https://doi.org/10.1088/0143-0815/13/1/007Schiefecker AJ, Kofler M, Gaasch M, Beer R, Unterberger I, Pfausler B, Broessner G, Lackner P, Rhomberg P, Gizewski E, Hackl WO, Mulino M, Ortler M, Thome C, Schmutzhard E, Helbok R (2018) Brain temperature but not core temperature increases during spreading depolarizations in patients with spontaneous intracerebral hemorrhage. J Cerebr Blood Flow Metabol 38: 549–558. https://doi.org/10.1177/0271678X17703940Li C, Narayan RK, Wang P, Hartings JA (2017) Regional temperature and quantitative cerebral blood flow responses to cortical spreading depolarization in the rat. J Cerebr Blood Flow Metabol 37: 1634–1640. https://doi.org/10.1177/0271678X16667131Schumm L, Lemale CL, Major S, Hecht N, Nieminen-Kelhä M, Zdunczyk A, Kowoll CM, Martus P, Thiel CM, Dreier JP, Woitzik J (2022) Physiological variables in association with spreading depolarizations in the late phase of ischemic stroke. J Cerebr Blood Flow Metabol 42: 121–135. https://doi.org/10.1177/0271678X211039628Luckl J, Baker W, Boda K, Emri M, Yodh AG, Greenberg JH (2023) Oxyhemoglobin and Cerebral Blood Flow Transients Detect Infarction in Rat Focal Brain Ischemia. Neuroscience 509: 132–144. https://doi.org/10.1016/j.neuroscience.2022.11.028Chamanzar A, Elmer J, Shutter L, Hartings J, Grover P (2023) Noninvasive and reliable automated detection of spreading depolarization in severe traumatic brain injury using scalp EEG. Commun Med 3: 113. https://doi.org/10.1038/s43856-023-00344-3Kassab A, Le Lan J, Tremblay J, Vannasing P, Dehbozorgi M, Pouliot P, Gallagher A, Lesage F, Sawan M, Nguyen DK (2018) Multichannel wearable fNIRS‐EEG system for long‐term clinical monitoring. Hum Brain Mapp 39: 7–23. https://doi.org/10.1002/hbm.23849Chen W-L, Wagner J, Heugel N, Sugar J, Lee Y-W, Conant L, Malloy M, Heffernan J, Quirk B, Zinos A, Beardsley SA, Prost R, Whelan HT (2020) Functional Near-Infrared Spectroscopy and Its Clinical Application in the Field of Neuroscience: Advances and Future Directions. Front Neurosci 14: 724. https://doi.org/10.3389/fnins.2020.00724Vinciguerra L, Bösel J (2017) Noninvasive Neuromonitoring: Current Utility in Subarachnoid Hemorrhage, Traumatic Brain Injury, and Stroke. Neurocrit Care 27: 122–140. https://doi.org/10.1007/s12028-016-0361-8Lückl 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 (2018) The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex. Brain 141: 1734–1752. https://doi.org/10.1093/brain/awy102Winkler MKL, Dengler N, Hecht N, Hartings JA, Kang EJ, Major S, Martus P, Vajkoczy P, Woitzik J, Dreier JP (2017) Oxygen availability and spreading depolarizations provide complementary prognostic information in neuromonitoring of aneurysmal subarachnoid hemorrhage patients. J Cerebr Blood Flow Metabol 37: 1841–1856. https://doi.org/10.1177/0271678X16641424Dreier JP, Major S, Foreman B., Winkler MKL, Kang E-J, Milakara D, Lemale CL, DiNapoli V, Hinzman JM, Woitzik J, Andaluz N, Carlson A, Hartings JA (2018) Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol 83: 295–310. https://doi.org/http://dx.doi.org/10.1002/ana.25147Carlson AP, Shuttleworth CW, Major S, Lemale CL, Dreier JP, Hartings JA (2019) Terminal spreading depolarizations causing electrocortical silencing prior to clinical brain death: Case report. J Neurosurg 131: 1773–1779. https://doi.org/10.3171/2018.7.JNS181478Dreier JP, Major S, Lemale CL, Kola V, Reiffurth C, Schoknecht K, Hecht N, Hartings JA, Woitzik J (2019) Correlates of spreading depolarization, spreading depression, and negative ultraslow potential in epidural versus subdural electrocorticography. Front Neurosci 13: 1–20. https://doi.org/10.3389/fnins.2019.00373Mutch WAC, Hansen AJ (1984) Extracellular pH Changes during Spreading Depression and Cerebral Ischemia: Mechanisms of Brain pH Regulation. J Cerebr Blood Flow Metabol 4: 17–27. https://doi.org/10.1038/jcbfm.1984.3Kim JS (2019) tPA helpers in the treatment of acute ischemic stroke: Are they ready for clinical use? J Stroke 21: 160–174. https://doi.org/10.5853/jos.2019.00584Papanagiotou P, Ntaios G (2018) Endovascular Thrombectomy in Acute Ischemic Stroke. Circ Cardiovasc Interv 11: 1–10. https://doi.org/10.1161/CIRCINTERVENTIONS.117.005362Lambrinos A, Schaink AK, Dhalla I, Krings T, Casaubon LK, Sikich N, Lum C, Bharatha A, Pereira VM, Stotts G, Saposnik G, Kelloway L, Xie X, Hill MD (2016) Mechanical Thrombectomy in Acute Ischemic Stroke: A Systematic Review. Canad J Neurol Sci 43: 455–460. https://doi.org/10.1017/cjn.2016.30Shi L, Rocha M, Leak RK, Zhao J, Bhatia TN, Mu H, Wei Z, Yu F, Weiner SL, Ma F, Jovin TG, Chen J (2018) A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion. J Cerebr Blood Flow Metabol 38: 2073–2091. https://doi.org/10.1177/0271678X18798162Sun F, Zhou J, Chen X, Yang T, Wang G, Ge J, Zhang Z, Mei Z (2024) No-reflow after recanalization in ischemic stroke: From pathomechanisms to therapeutic strategies. J Cerebr Blood Flow Metabol 44: 857–880. https://doi.org/10.1177/0271678X241237159Mujanovic A, Ng F, Meinel TR, Dobrocky T, Piechowiak EI, Kurmann CC, Seiffge DJ, Wegener S, Wiest R, Meyer L, Fiehler J, Olivot JM, Ribo M, Nguyen TN, Gralla J, Campbell BC, Fischer U, Kaesmacher J (2024) No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data. Int J Stroke 19: 58–67. https://doi.org/10.1177/17474930231180434Törteli A, Tóth R, Berger S, Samardzic S, Bari F, Menyhárt Á, Farkas E (2023) Spreading depolarization causes reperfusion failure after cerebral ischemia. J Cerebr Blood Flow Metabol 43: 655–664. https://doi.org/10.1177/0271678X231153745Klass A, Sánchez-Porras R, Santos E (2018) Systematic review of the pharmacological agents that have been tested against spreading depolarizations. J Cerebr Blood Flow Metabol 38: 1149–1179. https://doi.org/10.1177/0271678X18771440Sakowitz OW, Kiening KL, Krajewski KL, Sarrafzadeh AS, Fabricius M, Strong AJ, Unterberg AW, Dreier JP (2009) Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury. Stroke 40: 519–522. https://doi.org/10.1161/STROKEAHA.109.549303Santos E, Olivares-Rivera A, Major S, Sánchez-Porras R, Uhlmann L, Kunzmann K, Zerelles R, Kentar M, Kola V, Aguilera AH, Herrera MG, Lemale CL, Woitzik J, Hartings JA, Sakowitz OW, Unterberg AW, Dreier JP (2019) Lasting s-ketamine block of spreading depolarizations in subarachnoid hemorrhage: A retrospective cohort study. Crit Care 23: 427. https://doi.org/10.1186/s13054-019-2711-3Frank R, Szarvas PA, Pesti I, Zsigmond A, Berkecz R, Menyhárt Á, Bari F, Farkas E (2024) Nimodipine inhibits spreading depolarization, ischemic injury, and neuroinflammation in mouse live brain slice preparations. Eur J Pharmacol 977: 176718. https://doi.org/10.1016/j.ejphar.2024.176718Haupt M, Gerner ST, Bähr M, Doeppner TR (2023) Neuroprotective Strategies for Ischemic Stroke–Future Perspectives. Int J Mol Sci 24: 4334. https://doi.org/10.3390/ijms24054334Monai H, Wang X, Yahagi K, Lou N, Mestre H, Xu Q, Abe Y, Yasui M, Iwai Y, Nedergaard M, Hirase H (2019) Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke. Proc Natl Acad Sci U S A 116: 11010–11019. https://doi.org/10.1073/pnas.1817347116You JS, Kim JY, Yenari MA (2022) Therapeutic hypothermia for stroke: Unique challenges at the bedside. Front Neurol 13: 951586. https://doi.org/10.3389/fneur.2022.951586Hong JM (2019) Targeted temperature management for ischemic stroke. J Neurocrit Care 12: 67–73. https://doi.org/10.18700/jnc.190100Hirayama Y, Kida H, Inoue T, Sugimoto K, Oka F, Shirao S, Imoto H, Nomura S, Suzuki M (2024) Focal brain cooling suppresses spreading depolarization and reduces endothelial nitric oxide synthase expression in rats. IBRO Neurosci Rep 16: 609–621. https://doi.org/10.1016/j.ibneur.2024.05.001