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Interplay between Cortical Spreading Depolarization and Seizures

Kramer D.R. · Fujii T. · Ohiorhenuan I. · Liu C.Y.

Author affiliations

Department of Neurosurgery, University of Southern California, Los Angeles, CA, USA

Corresponding Author

Daniel R. Kramer, MD

1200 N. State Street, Suite 3300

Los Angeles, CA 90033 (USA)

E-Mail drk_431@usc.edu

Related Articles for ""

Stereotact Funct Neurosurg 2017;95:1-5

Abstract

Cortical spreading depolarization (CSD) is an electrophysiologic phenomenon found mostly in the setting of neurologic injury resulting in the disturbance of ion homeostasis and leading to changes in the local vascular response. The bioelectric etiology of CSD shares similarities to those in epileptic disorders, yet the relationship between seizures and CSD is unclear, with several studies observing cortical depression before, during, and after seizure activity, thus obscuring our understanding of whether CSD activity potentiates or limits seizures and vice versa. Cortical sampling has exhibited how the redistribution of ion concentrations in the intra- and extracellular environments interplay between the excitation of seizures and the electrical depression of CSD. Modeling of both environments has suggested that CSD synchronizes the affected tissue, creating a favorable environment for seizure activity; however, other studies have demonstrated the opposite: epileptiform activity initiating waves of CSD. Further studies have underscored the role of the vascular response and subsequent ischemia in CSD that contributes to epileptogenesis. Investigations in migraine, traumatic brain injury, and other neurologic injuries suggest that several drugs may target CSD. Manipulations in the occurrence and nature of CSD can potentially alter the threshold for seizure activity, and perhaps minimize immediate and long-term sequelae associated with epilepsy.

© 2017 S. Karger AG, Basel


Keywords

Cortical spreading depolarization · Spreading depression · Epileptiform activity · Epilepsy · Vasospasm · Electrocorticography ·


Introduction

Cortical spreading depolarization (CSD), at its most fundamental level, is a pathologic disruption of cortical electrical activity resulting from a spreading loss of ion homeostasis. Since its discovery by Leao in 1944, this phenomenon has been studied extensively in both animal and, more recently, human models [1,2]. From this work, we now understand that cortical excitation seen in CSD can occur from a variety of insults, and the subsequent depression of electrical activity that follows leads to secondary changes in blood flow as well as neuronal and astrocyte damage.

Mechanism of CSD and Vascular Response

A variety of biological states, such as hypoxia, hypoglycemia, subarachnoid hemorrhage, traumatic brain injury, stroke, and seizures, has been shown to initiate the onset of CSD [2,3,4,5,6]. It is believed that the blood-brain barrier is disrupted by this inciting insult, allowing for changes in extracellular concentrations of ions including a decrease in magnesium concentrations and elevation in potassium levels [7,8,9]. Such changes alter the local neuronal microenvironment and trigger a cascade of cellular events ultimately leading to glutamate-induced toxicity [10]. Glutamate release, in turn, activates both sodium and calcium channels via N-methyl-D-aspartate (NMDA) receptors. This results in a rapid influx of large cations down their concentration gradient, leading to the loss of the normal membrane potential [2,11]. Mechanisms to restore membrane potentials, such as the sodium-potassium pumps, fail to counter this disruptive change, and the affected neurons begin to swell from the osmotic shift associated with the influx of cations [2]. These damaged neurons no longer permit electrical activity and an overall depression in cortical activity is observed. This sequence of depolarization and depression spreads slowly at a rate on the order of 2-6 mm/min with a predilection for surrounding injured tissue [12].

In addition to the changes in electrical activity, a vascular response is seen with CSD that leads to secondary injury in injured brain states. In healthy brains, depolarization leads to the release of glutamate and nitric oxide, a crucial signaling molecule, allowing for local vasodilatation and increased blood flow [13,14]. Hyperemia and improved oxygen delivery meets the demand of energy expenditure required for the repolarization of the neuron [15]. In damaged tissue, however, the loss of ion homeostasis manifests in an acidic microenvironment with elevated levels of potassium, both of which promote vasoconstriction [16,17,18]. With this pathological decrease in blood flow, the necessary hyperemic response cannot be achieved and energy demands to restore membrane potential are not met. The result is a vicious cycle; these areas become ischemic from perfusion-demand mismatch due to this altered vascular response, and are further susceptible to the ongoing spread of CSD, perpetuating the cellular damage caused by the inciting insult to the brain.

Neuronal Injury Leading to CSD

CSD was first described in humans through cerebral blood flow studies of migraines capturing the oligemia consistent with the scale and timing of CSD as described above [12,19,20]. It was initially difficult to study the electrical disruption of CSD through the use of scalp electroencephalography, as it is believed that the scalp, calvarium, and meninges filter out the low frequency changes [2,19]. In the preceding decades, invasive techniques, such as electrocorticography using subdural electrodes, have allowed for in vivo observation of the CSD phenomenon. In doing so, the occurrence of CSD has been observed in the setting of a variety of central nervous system injuries.

In traumatic brain injury, several studies have utilized electrocorticography in patients who require craniotomy as part of their acute management [21,22]. These studies have found worse outcomes in patients whose electrocorticography recordings showed the occurrence of CSD following the inciting trauma. Moreover, the presence of CSD correlated with low blood pressure, abnormal cerebral pressure, and fever, all of which have been associated with increased morbidity in trauma patients [23].

Similarly, in cases of malignant strokes, studies have found a high incidence of CSD occurrence, varying from 35 to 88% of patients. The frequency and duration of these CSD events are significantly associated with the size of the infarct [19,24,25,26,27,28,29,30]. As described above, the pathologic vascular response in relation to the distorted electrochemical signaling of CSD correlates with ischemic damage in the peri-infarct region leading to expansion of the affected area [29,31,32,33,34].

This oligemic response becomes increasingly important in the case of aneurysmal subarachnoid hemorrhage. One of the most concerning complications of this type of hemorrhage is the cerebral ischemia brought on by delayed cerebral ischemia (DCI) [35,36]. Recently, the term DCI has been used more extensively given that only half of the cases of radiographic vasospasm are associated with ischemia [37]. The cause of the vascular change associated with DCI remains relatively unknown, yet our understanding of the abnormal vascular response in the setting of CSD makes it a plausible mechanism. In experiments using subdural electrodes, the cortical regions in which CSD electrical activity have been recorded correlate strongly with arteriolar vasoconstriction, which is angiographically occult [2,35]. In animal models, nimodipine and increased fluids, both treatments for vasospasm, were shown to reverse the reduced perfusion seen with CSD [38]. CSD events also aligned consistently with areas of DCI [2,35]. The current evidence is compelling regarding CSD as a mechanism for the observed secondary ischemic damage in subarachnoid hemorrhage.

CSD and Epilepsy

Current research reveals a complex and ambiguous relationship between seizures and CSD. Excitotoxic states are a common mechanism to both seizures, with neuronal activation, and CSD, with neuronal deactivation. Seizures have been seen prior to, during, and following CSD [39,40,41,42,43,44]. Additionally, the individual states themselves appear to be interrelated.

Seizures have been known to create an environment conducive to CSD. In the human hippocampal slices of epileptic patients, the neurons appear to be primed for CSD; with mere blockage of T-type calcium channels or adding enough extracellular potassium to the microenvironment, investigators were able to induce CSD [45]. Koroleva and Bures [44 ]administered sodium-penicillin to rat cortex, which induced seizures; however, they also noted occasional CSD occurring after the ictal activity. After several minutes, when the tissue recovered, the first spike produced another CSD event, which continued for up to 20 cycles. Similarly, pentylenetetrazol, a drug known to cause seizures at high doses, was seen to cause cortical depression at low doses in rats [46]. In recent animal models, CSD activity was seen to reverberate for several cycles and last for durations of up to four and a half minutes following epileptiform activity (EA) [47]. Given the depression of electrical activity accompanying CSD, it may be the cause of the postictal state. Koroleva and Bures [44] noted that an increase in spreading depression occurred during postictal depression, with repetitive cycles occurring for several minutes. Slow recovery of focal and global cognitive states is an unexplained phenomenon of seizures and the occurrence of a depressive process following EA may explain the loss of function.

Contrarily, CSD may lead to EA. The presence of cortical depression in rat cortex led to states of excitability similar to that seen just prior to seizures [40]. During a later phase, after cortical depression, a neuronal state of hyperexcitability with less hyperpolarization may prime it for EA [48,49]. Cellular swelling, noted as a prominent feature in CSD, increases EA. It is thought that the expansion of the intracellular space leads to generation of a slow inward current and the generation of action potentials through NMDA receptors [50]. Following induction of spreading depression, enhanced NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptor-binding sites were noted in rat hippocampus, which may lower the threshold for EA [51]. The addition of the GABA receptor antagonist bicuculline to rat and human cortices at both low and high concentrations induced seizures in chronically epileptic rat and human slices; however, low doses induced cortical spreading depression but not EA in nonepileptic rat slices [52]. Researchers using human models of hippocampal slices have postulated that CSD results in a synchronizing effect, setting the stage for a hyperexcitable state conducive for increased frequency and amplitude of spontaneous seizure activity [39]. This may be reflective of the upregulation of excitatory receptors like NMDA [51]. Spikes are seen to return immediately following a CSD event, and these tissues may be susceptible to synchronization for a long period of time [44]. Additionally, low concentrations of extracellular magnesium and high extracellular potassium seen in CSD have also been shown to produce seizure-like activity [42,53].

Given that CSD results in depolarized neurons, it is reasonable to infer that a wave of CSD would interrupt a seizure. Indeed, in rat cortex, the induction of seizures led to some CSD activity, which halted the seizures [44]. Similarly, a depression in absence seizures occurring in a rat model was noted after induction of CSD with mechanical stimulation; the cessation of seizures lasted up to an hour [54,55]. The opposite interaction has also been noted; repetitive stimulation produced EA, which blocked cortical depression in rats [56]. However, most studies suggest CSD and EA potentiate each other. Overall, no clear relationship has been observed between CSD and etiology, type, or location of epilepsy. A link has been seen between posttraumatic and postaneurysmal subarachnoid hemorrhage-related seizures and CSD [40,43,57]. In familial hemiplegic migraine, shared genetic mutations in voltage-gated channels lead to both epilepsy and migraine, with a proposed underlying mechanism of CSD leading to hypersynchronization leading to either seizure or spreading depression and migraine [58].

Several therapeutic agents used experimentally have shown promise for treating both seizures and CSD, again suggesting a common mechanism. A derivative of valproic acid, an antiepileptic agent, called sec-butylpropylacetamide reduced CSD events through GABA-mediated potentiation and reduction in NMDA receptor activity [59]. Likewise, eugenol, an aromatic molecule, has been previously described to have both antiepileptic and antiheadache properties. In animal models, systemic introduction of eugenol was shown to reduce both EA and spreading depression [60]. Mechanistically, NMDA receptors play a central role in both EA and CSD. Antiepileptic antagonists of the NMDA receptors, such as ketamine, were shown to halt CSD activity; however, antiepileptics without NMDA properties, such as diazepam, did not affect CSD activity [61].

Conclusion

The association between CSD and seizure activity has been investigated in both animal and human studies over the past several decades. Although the excitotoxic mechanisms of CSD are similar to those seen in epileptic disorders, the exact relationship between these 2 phenomena has yet to be elucidated. Seizures seem to result in reverberating CSD, and CSD has been shown to prime damaged neurons for further seizure activity. Other studies have shown that depolarized neurons in CSD are capable of interrupting the wave of seizures. With greater understanding from future studies, manipulations in the occurrence and duration of CSD can potentially alter the threshold for seizure activity, and perhaps minimize secondary damage and long-term sequelae associated with a variety of neurological injuries. This complex relationship deserves further research with the hopes of diminishing both disorders.


References

  1. Leao AA: The slow voltage variation of cortical spreading depression of activity. Electroencephalogr Clin Neurophysiol 1951;3:315-321.
  2. Dreier JP: The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 2011;17:439-447.
  3. Somjen GG: Aristides Leao's discovery of cortical spreading depression. J Neurophysiol 2005;94:2-4.
  4. Dreier JP, Kleeberg J, Petzold G, Priller J, Windmüller O, Orzechowski HD, Lindauer U, Heinemann U, Einhaupl KM, Dirnagl U: Endothelin-1 potently induces Leao's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain 2002;125:102-112.
  5. Teive HA, Kowacs PA, Maranhao Filho P, Piovesan EJ, Werneck LC: Leao's cortical spreading depression: from experimental ‘‘artifact'' to physiological principle. Neurology 2005;65:1455-1459.
  6. Petzold GC, Haack S, von Bohlen Und Halbach O, Priller J, Lehmann TN, Heinemann U, Dirnagl U, Dreier JP: Nitric oxide modulates spreading depolarization threshold in the human and rodent cortex. Stroke 2008;39:1292-1299.
  7. Kramer DR, Fujii T, Ohiorhenuan I, Liu CY: Cortical spreading depolarization: pathophysiology, implications, and future directions. J Clin Neurosci 2016;24:22-27.
  8. 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 2012;53(suppl 6):22-30.
  9. Lapilover EG, Lippmann K, Salar S, Maslarova A, Dreier JP, Heinemann U, Friedman A: Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis 2012;48:495-506.
  10. Kraig RP, Nicholson C: Extracellular ionic variations during spreading depression. Neuroscience 1978;3:1045-1059.
  11. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, Bonsi P, Picconi B, Cupini LM, Materazzi S, Geppetti P, Sarchielli P, Calabresi P: Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci USA 2012;109:18985-18990.
  12. Lauritzen M: Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994;117:199-210.
  13. Attwell D, Iadecola C: The neural basis of functional brain imaging signals. Trends Neurosci 2002;25:621-625.
  14. Attwell D, Laughlin SB: An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001;21:1133-1145.
  15. 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 1990;10:115-122.
  16. Windmüller O, Lindauer U, Foddis M, Einhaupl KM, Dirnagl U, Heinemann U, Dreier JP: Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain 2005;128:2042-2051.
  17. Iadecola C, Zhang F, Xu X: SIN-1 reverses attenuation of hypercapnic cerebrovasodilation by nitric oxide synthase inhibitors. Am J Physiol 1994;267:R228-R235.
    External Resources
  18. Lee TJ: Nitric oxide and the cerebral vascular function. J Biomed Sci 2000;7:16-26.
    External Resources
  19. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ: Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 2011;31:17-35.
  20. Olesen J, Larsen B, Lauritzen M: Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981;9:344-352.
  21. 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 2011;10:1058-1064.
  22. 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 2011;134:1529-1540.
  23. 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 2009;26:1857-1866.
  24. 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 2008;63:720-728.
  25. Offenhauser N, Windmüller O, Strong AJ, Fuhr S, Dreier JP: The gamut of blood flow responses coupled to spreading depolarization in rat and human brain: from hyperemia to prolonged ischemia. Acta Neurochir Suppl 2011;110:119-124.
  26. Nakamura H, Strong AJ, Dohmen C, Sakowitz OW, Vollmar S, Sue M, Kracht L, Hashemi P, Bhatia R, Yoshimine T, Dreier JP, Dunn AK, Graf R: Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain 2010;133:1994-2006.
  27. 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 2002;33:2738-2743.
  28. 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 2013;80:1095-1102.
  29. Mies G, Iijima T, Hossmann KA: Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport 1993;4:709-711.
  30. Hartings JA, Rolli ML, Lu XC, Tortella FC: Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci 2003;23:11602-11610.
    External Resources
  31. 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 by diffusion mapping. Ann Neurol 1996;39:308-318.
  32. Back T, Ginsberg MD, Dietrich WD, Watson BD: Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology. J Cereb Blood Flow Metab 1996;16:202-213.
  33. Busch E, Gyngell ML, Eis M, Hoehn-Berlage M, Hossmann KA: Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J Cereb Blood Flow Metab 1996;16:1090-1099.
  34. Gill R, Andine P, Hillered L, Persson L, Hagberg H: The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat. J Cereb Blood Flow Metab 1992;12:371-379.
  35. Woitzik J, Dreier JP, Hecht N, Fiss I, Sandow N, Major S, Winkler M, Dahlem YA, Manville J, Diepers M, Muench E, Kasuya H, Schmiedek P, Vajkoczy P; COSBID Study Group: Delayed cerebral ischemia and spreading depolarization in absence of angiographic vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 2012;32:203-212.
  36. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010;41:2391-2395.
  37. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:1711-1737.
  38. Dreier JP, Windmüller O, Petzold G, Lindauer U, Einhaupl KM, Dirnagl U: Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats. Neurosurgery 2002;51:1457-1465; discussion 1465-1457.
  39. Gorji A, Speckmann EJ: Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur J Neurosci 2004;19:3371-3374.
  40. 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 2014;253:1-15.
  41. Gorji A: Spreading depression: a review of the clinical relevance. Brain Res Brain Res Rev 2001;38:33-60.
  42. Mody I, Lambert JD, Heinemann U: Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysiol 1987;57:869-888.
    External Resources
  43. 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 2008;119:1973-1984.
  44. Koroleva VI, Bures J: Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp Brain Res 1983;51:291-297.
  45. Gorji A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ: Spreading depression in human neocortical slices. Brain Res 2001;906:74-83.
  46. Koroleva VI, Vinogradova LV, Bures J: Reduced incidence of cortical spreading depression in the course of pentylenetetrazol kindling in rats. Brain Res 1993;608:107-114.
  47. Koroleva VI, Bures J: Circulation of cortical spreading depression around electrically stimulated areas and epileptic foci in the neocortex of rats. Brain Res 1979;173:209-215.
  48. Berger M, Speckmann EJ, Pape HC, Gorji A: Spreading depression enhances human neocortical excitability in vitro. Cephalalgia 2008;28:558-562.
  49. Ghadiri MK, Kozian M, Ghaffarian N, Stummer W, Kazemi H, Speckmann EJ, Gorji A: Sequential changes in neuronal activity in single neocortical neurons after spreading depression. Cephalalgia 2012;32:116-124.
  50. Lauderdale K, Murphy T, Tung T, Davila D, Binder DK, Fiacco TA: Osmotic edema rapidly increases neuronal excitability through activation of NMDA receptor-dependent slow inward currents in juvenile and adult hippocampus. ASN Neuro 2015;7: 1759091415605115.
  51. Haghir H, Kovac S, Speckmann EJ, Zilles K, Gorji A: Patterns of neurotransmitter receptor distributions following cortical spreading depression. Neuroscience 2009;163:1340-1352.
  52. Kohling R, Koch UR, Hagemann G, Redecker C, Straub H, Speckmann EJ: Differential sensitivity to induction of spreading depression by partial disinhibition in chronically epileptic human and rat as compared to native rat neocortical tissue. Brain Res 2003;975:129-134.
  53. Kager H, Wadman WJ, Somjen GG: Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations. J Neurophysiol 2000;84:495-512.
    External Resources
  54. Samotaeva IS, Tillmanns N, van Luijtelaar G, Vinogradova LV: Intracortical microinjections may cause spreading depression and suppress absence seizures. Neuroscience 2013;230:50-55.
  55. Vinogradova LV, Kuznetsova GD, Coenen AM: Audiogenic seizures associated with a cortical spreading depression wave suppress spike-wave discharges in rats. Physiol Behav 2005;86:554-558.
  56. Koroleva VI, Bures J: Stimulation induced recurrent epileptiform discharges block cortical and subcortical spreading depression in rats. Physiol Bohemoslov 1982;31:385-400.
    External Resources
  57. 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 2012;135:259-275.
  58. Rogawski MA: Migraine and epilepsy-shared mechanisms within the family of episodic disorders; in Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds): Jasper's Basic Mechanisms of the Epilepsies, ed 4. Bethesda, National Center for Biotechnology Information, 2012.
  59. Kaufmann D, Bates EA, Yagen B, Bialer M, Saunders GH, Wilcox K, White HS, Brennan KC: sec-Butylpropylacetamide (SPD) has antimigraine properties. Cephalalgia 2016;36:924-935.
  60. Muller M, Pape HC, Speckmann EJ, Gorji A: Effect of eugenol on spreading depression and epileptiform discharges in rat neocortical and hippocampal tissues. Neuroscience 2006;140:743-751.
  61. 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 1988;457:226-240.

Author Contacts

Daniel R. Kramer, MD

1200 N. State Street, Suite 3300

Los Angeles, CA 90033 (USA)

E-Mail drk_431@usc.edu


Article / Publication Details

First-Page Preview
Abstract of Review

Received: December 18, 2015
Accepted: October 18, 2016
Published online: January 14, 2017
Issue release date: March 2017

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ISSN: 1011-6125 (Print)
eISSN: 1423-0372 (Online)

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References

  1. Leao AA: The slow voltage variation of cortical spreading depression of activity. Electroencephalogr Clin Neurophysiol 1951;3:315-321.
  2. Dreier JP: The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 2011;17:439-447.
  3. Somjen GG: Aristides Leao's discovery of cortical spreading depression. J Neurophysiol 2005;94:2-4.
  4. Dreier JP, Kleeberg J, Petzold G, Priller J, Windmüller O, Orzechowski HD, Lindauer U, Heinemann U, Einhaupl KM, Dirnagl U: Endothelin-1 potently induces Leao's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain 2002;125:102-112.
  5. Teive HA, Kowacs PA, Maranhao Filho P, Piovesan EJ, Werneck LC: Leao's cortical spreading depression: from experimental ‘‘artifact'' to physiological principle. Neurology 2005;65:1455-1459.
  6. Petzold GC, Haack S, von Bohlen Und Halbach O, Priller J, Lehmann TN, Heinemann U, Dirnagl U, Dreier JP: Nitric oxide modulates spreading depolarization threshold in the human and rodent cortex. Stroke 2008;39:1292-1299.
  7. Kramer DR, Fujii T, Ohiorhenuan I, Liu CY: Cortical spreading depolarization: pathophysiology, implications, and future directions. J Clin Neurosci 2016;24:22-27.
  8. 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 2012;53(suppl 6):22-30.
  9. Lapilover EG, Lippmann K, Salar S, Maslarova A, Dreier JP, Heinemann U, Friedman A: Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis 2012;48:495-506.
  10. Kraig RP, Nicholson C: Extracellular ionic variations during spreading depression. Neuroscience 1978;3:1045-1059.
  11. Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, Bonsi P, Picconi B, Cupini LM, Materazzi S, Geppetti P, Sarchielli P, Calabresi P: Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci USA 2012;109:18985-18990.
  12. Lauritzen M: Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994;117:199-210.
  13. Attwell D, Iadecola C: The neural basis of functional brain imaging signals. Trends Neurosci 2002;25:621-625.
  14. Attwell D, Laughlin SB: An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001;21:1133-1145.
  15. 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 1990;10:115-122.
  16. Windmüller O, Lindauer U, Foddis M, Einhaupl KM, Dirnagl U, Heinemann U, Dreier JP: Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain 2005;128:2042-2051.
  17. Iadecola C, Zhang F, Xu X: SIN-1 reverses attenuation of hypercapnic cerebrovasodilation by nitric oxide synthase inhibitors. Am J Physiol 1994;267:R228-R235.
    External Resources
  18. Lee TJ: Nitric oxide and the cerebral vascular function. J Biomed Sci 2000;7:16-26.
    External Resources
  19. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ: Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 2011;31:17-35.
  20. Olesen J, Larsen B, Lauritzen M: Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981;9:344-352.
  21. 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 2011;10:1058-1064.
  22. 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 2011;134:1529-1540.
  23. 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 2009;26:1857-1866.
  24. 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 2008;63:720-728.
  25. Offenhauser N, Windmüller O, Strong AJ, Fuhr S, Dreier JP: The gamut of blood flow responses coupled to spreading depolarization in rat and human brain: from hyperemia to prolonged ischemia. Acta Neurochir Suppl 2011;110:119-124.
  26. Nakamura H, Strong AJ, Dohmen C, Sakowitz OW, Vollmar S, Sue M, Kracht L, Hashemi P, Bhatia R, Yoshimine T, Dreier JP, Dunn AK, Graf R: Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain 2010;133:1994-2006.
  27. 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 2002;33:2738-2743.
  28. 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 2013;80:1095-1102.
  29. Mies G, Iijima T, Hossmann KA: Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport 1993;4:709-711.
  30. Hartings JA, Rolli ML, Lu XC, Tortella FC: Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci 2003;23:11602-11610.
    External Resources
  31. 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 by diffusion mapping. Ann Neurol 1996;39:308-318.
  32. Back T, Ginsberg MD, Dietrich WD, Watson BD: Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology. J Cereb Blood Flow Metab 1996;16:202-213.
  33. Busch E, Gyngell ML, Eis M, Hoehn-Berlage M, Hossmann KA: Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J Cereb Blood Flow Metab 1996;16:1090-1099.
  34. Gill R, Andine P, Hillered L, Persson L, Hagberg H: The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat. J Cereb Blood Flow Metab 1992;12:371-379.
  35. Woitzik J, Dreier JP, Hecht N, Fiss I, Sandow N, Major S, Winkler M, Dahlem YA, Manville J, Diepers M, Muench E, Kasuya H, Schmiedek P, Vajkoczy P; COSBID Study Group: Delayed cerebral ischemia and spreading depolarization in absence of angiographic vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 2012;32:203-212.
  36. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010;41:2391-2395.
  37. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology: Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:1711-1737.
  38. Dreier JP, Windmüller O, Petzold G, Lindauer U, Einhaupl KM, Dirnagl U: Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats. Neurosurgery 2002;51:1457-1465; discussion 1465-1457.
  39. Gorji A, Speckmann EJ: Spreading depression enhances the spontaneous epileptiform activity in human neocortical tissues. Eur J Neurosci 2004;19:3371-3374.
  40. 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 2014;253:1-15.
  41. Gorji A: Spreading depression: a review of the clinical relevance. Brain Res Brain Res Rev 2001;38:33-60.
  42. Mody I, Lambert JD, Heinemann U: Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysiol 1987;57:869-888.
    External Resources
  43. 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 2008;119:1973-1984.
  44. Koroleva VI, Bures J: Cortical penicillin focus as a generator of repetitive spike-triggered waves of spreading depression in rats. Exp Brain Res 1983;51:291-297.
  45. Gorji A, Scheller D, Straub H, Tegtmeier F, Kohling R, Hohling JM, Tuxhorn I, Ebner A, Wolf P, Werner Panneck H, Oppel F, Speckmann EJ: Spreading depression in human neocortical slices. Brain Res 2001;906:74-83.
  46. Koroleva VI, Vinogradova LV, Bures J: Reduced incidence of cortical spreading depression in the course of pentylenetetrazol kindling in rats. Brain Res 1993;608:107-114.
  47. Koroleva VI, Bures J: Circulation of cortical spreading depression around electrically stimulated areas and epileptic foci in the neocortex of rats. Brain Res 1979;173:209-215.
  48. Berger M, Speckmann EJ, Pape HC, Gorji A: Spreading depression enhances human neocortical excitability in vitro. Cephalalgia 2008;28:558-562.
  49. Ghadiri MK, Kozian M, Ghaffarian N, Stummer W, Kazemi H, Speckmann EJ, Gorji A: Sequential changes in neuronal activity in single neocortical neurons after spreading depression. Cephalalgia 2012;32:116-124.
  50. Lauderdale K, Murphy T, Tung T, Davila D, Binder DK, Fiacco TA: Osmotic edema rapidly increases neuronal excitability through activation of NMDA receptor-dependent slow inward currents in juvenile and adult hippocampus. ASN Neuro 2015;7: 1759091415605115.
  51. Haghir H, Kovac S, Speckmann EJ, Zilles K, Gorji A: Patterns of neurotransmitter receptor distributions following cortical spreading depression. Neuroscience 2009;163:1340-1352.
  52. Kohling R, Koch UR, Hagemann G, Redecker C, Straub H, Speckmann EJ: Differential sensitivity to induction of spreading depression by partial disinhibition in chronically epileptic human and rat as compared to native rat neocortical tissue. Brain Res 2003;975:129-134.
  53. Kager H, Wadman WJ, Somjen GG: Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations. J Neurophysiol 2000;84:495-512.
    External Resources
  54. Samotaeva IS, Tillmanns N, van Luijtelaar G, Vinogradova LV: Intracortical microinjections may cause spreading depression and suppress absence seizures. Neuroscience 2013;230:50-55.
  55. Vinogradova LV, Kuznetsova GD, Coenen AM: Audiogenic seizures associated with a cortical spreading depression wave suppress spike-wave discharges in rats. Physiol Behav 2005;86:554-558.
  56. Koroleva VI, Bures J: Stimulation induced recurrent epileptiform discharges block cortical and subcortical spreading depression in rats. Physiol Bohemoslov 1982;31:385-400.
    External Resources
  57. 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 2012;135:259-275.
  58. Rogawski MA: Migraine and epilepsy-shared mechanisms within the family of episodic disorders; in Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds): Jasper's Basic Mechanisms of the Epilepsies, ed 4. Bethesda, National Center for Biotechnology Information, 2012.
  59. Kaufmann D, Bates EA, Yagen B, Bialer M, Saunders GH, Wilcox K, White HS, Brennan KC: sec-Butylpropylacetamide (SPD) has antimigraine properties. Cephalalgia 2016;36:924-935.
  60. Muller M, Pape HC, Speckmann EJ, Gorji A: Effect of eugenol on spreading depression and epileptiform discharges in rat neocortical and hippocampal tissues. Neuroscience 2006;140:743-751.
  61. 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 1988;457:226-240.