Detection of spreading depolarizations in a middle cerebral artery occlusion model in swine

  • 8 Accesses



The main objective of this study was to generate a hemodynamically stable swine model to detect spreading depolarizations (SDs) using electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging and laser speckle flowmetry (LSF) after a 30-h middle cerebral artery (MCA) occlusion (MCAo) in German Landrace Swine.


A total of 21 swine were used. The study comprised a training group (group 1, n = 7), a group that underwent bilateral craniectomy and MCAo (group 2, n = 10) and a group used for 2,3,5-triphenyltetrazolium (TTC) staining (group 3, n = 5).


In group 2, nine animals that underwent MCAo survived for 30 h, and one animal survived for 12 h. We detected MCA variants with 2 to 4 vessels. In all cases, all of the MCAs were occluded. The intensity changes exhibited by IOS and LSF after clipping were closely correlated and indicated a lower blood volume and reduced blood flow in the middle cerebral artery territory. Using IOS, we detected a mean of 2.37 ± (STD) 2.35 SDs/h. Using ECoG, we detected a mean of 0.29 ± (STD) 0.53 SDs/h. Infarctions were diagnosed using histological analysis. TTC staining in group 3 confirmed that the MCA territory was compromised and that the anterior and posterior cerebral arteries were preserved.


We confirm the reliability of performing live monitoring of cerebral infarctions using our MCAo protocol to detect SDs.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Arikan F, Martínez-Valverde T, Sánchez-Guerrero Á et al (2017) Malignant infarction of the middle cerebral artery in a porcine model. A pilot study. PLoS One 12(2):e0172637

  2. 2.

    Ayata C (2013) Spreading depression and neurovascular coupling. Stroke J Cereb Circ 44(6 Suppl 1):S87–S89

  3. 3.

    Baltan S, Besancon EF, Mbow B, Ye Z, Hamner MA, Ransom BR (2008) White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci 28(6):1479–1489

  4. 4.

    Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW (2018) Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg:1–7

  5. 5.

    Cheng YD, Al-Khoury L, Zivin JA (2004) Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx J Am Soc Exp Neurother 1(1):36–45

  6. 6.

    Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17(4):439–447

  7. 7.

    Dreier JP, Fabricius M, Ayata C et al (2017) Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J Cereb Blood Flow Metab 37(5):1595–1625

  8. 8.

    Duberstein KJ, Platt SR, Holmes SP, Dove CR, Howerth EW, Kent M, Stice SL, Hill WD, Hess DC, West FD (2014) Gait analysis in a pre- and post-ischemic stroke biomedical pig model. Physiol Behav 125:8–16

  9. 9.

    Gorelova NA, Koroleva VI, Amemori T, Pavlík V, Burĕs J (1987) Ketamine blockade of cortical spreading depression in rats. Electroencephalogr Clin Neurophysiol 66(4):440–447

  10. 10.

    Hartings JA, Shuttleworth CW, Kirov SA et al (2016) The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy. J Cereb Blood Flow Metab.

  11. 11.

    Imai H, Konno K, Nakamura M et al (2006) A new model of focal cerebral ischemia in the miniature pig. J Neurosurg 104(2 Suppl):123–132

  12. 12.

    Klass A, Sánchez-Porras R, Santos E (2018) Systematic review of the pharmacological agents that have been tested against spreading depolarizations. J Cereb Blood Flow Metab.

  13. 13.

    Leao AAP (1947) Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol 10(6):409–414

  14. 14.

    Leo AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7(6):359–390

  15. 15.

    Lückl J, Lemale CL, Kola V et al (2018) The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex. Brain J Neurol.

  16. 16.

    Mangla S, Choi JH, Barone FC, Novotney C, Libien J, Lin E, Pile-Spellman J (2015) Endovascular external carotid artery occlusion for brain selective targeting: a cerebrovascular swine model. BMC Res Notes.

  17. 17.

    Nakamura H, Strong AJ, Dohmen C et al (2010) Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain J Neurol 133(Pt 7):1994–2006

  18. 18.

    Obrenovitch TP, Chen S, Farkas E (2009) Simultaneous, live imaging of cortical spreading depression and associated cerebral blood flow changes, by combining voltage-sensitive dye and laser speckle contrast methods. NeuroImage 45(1):68–74

  19. 19.

    Oliveira-Ferreira AI, Milakara D, Alam M et al (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 Cereb Blood Flow Metab 30(8):1504–1519

  20. 20.

    Platt SR, Holmes SP, Howerth EW et al (2014) Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model. Exp Transl Stroke Med 6(1):5

  21. 21.

    Sánchez-Porras R, Santos E, Schöll M, Kunzmann K, Stock C, Silos H, Unterberg AW, Sakowitz OW (2017) Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain. J Cereb Blood Flow Metab 37(5):1720–1734

  22. 22.

    Sánchez-Porras R, Santos E, Schöll M, Stock C, Zheng Z, Schiebel P, Orakcioglu B, Unterberg AW, Sakowitz OW (2014) The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex. Neuropharmacology.

  23. 23.

    Santos E, León F, Silos H, Sanchez-Porras R, Shuttleworth CW, Unterberg A, Sakowitz OW (2016) Incidence, hemodynamic, and electrical characteristics of spreading depolarization in a swine model are affected by local but not by intravenous application of magnesium. J Cereb Blood Flow Metab 36(12):2051–2057

  24. 24.

    Santos E, Schöll M, Sánchez-Porras R, Dahlem MA, Silos H, Unterberg A, Dickhaus H, Sakowitz OW (2014) Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain. NeuroImage 99:244–255

  25. 25.

    Santos E, Schöll M, Sanchez-Porras R, Kentar M, Orakcioglu B, Unterberg A, Dickhaus H, Sakowitz OW (2013) Cortical spreading depression dynamics can be studied using intrinsic optical signal imaging in gyrencephalic animal cortex. Acta Neurochir Suppl 118:93–97

  26. 26.

    Schöll MJ, Santos E, Sanchez-Porras R et al (2016) Large field-of-view movement-compensated intrinsic optical signal imaging for the characterization of the haemodynamic response to spreading depolarizations in large gyrencephalic brains. J Cereb Blood Flow Metab.

  27. 27.

    Sun X, Wang Y, Chen S, Luo W, Li P, Luo Q (2011) Simultaneous monitoring of intracellular pH changes and hemodynamic response during cortical spreading depression by fluorescence-corrected multimodal optical imaging. NeuroImage 57(3):873–884

  28. 28.

    Tanaka Y, Imai H, Konno K et al (2008) Experimental model of lacunar infarction in the gyrencephalic brain of the miniature pig: neurological assessment and histological, immunohistochemical, and physiological evaluation of dynamic corticospinal tract deformation. Stroke J Cereb Circ 39(1):205–212

  29. 29.

    Van Harreveld A, Hawes RC (1946) Asphyxial depolarisation in the spinal cord. Am J Phys 147(4):669–684

  30. 30.

    Winkler MK, 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 Cereb Blood Flow Metab 37(5):1841–1856

  31. 31.

    Wright EA, d’Esterre CD, Morrison LB, Cockburn N, Kovacs M, Lee T-Y (2016) Absolute cerebral blood flow infarction threshold for 3-hour ischemia time determined with CT perfusion and 18F-FFMZ-PET imaging in a porcine model of cerebral ischemia. PLoS ONE 11(6):e0158157

  32. 32.

    Yan T, Chopp M, Chen J (2015) Experimental animal models and inflammatory cellular changes in cerebral ischemic and hemorrhagic stroke. Neurosci Bull 31(6):717–734

  33. 33.

    Yin C, Zhou F, Wang Y, Luo W, Luo Q, Li P (2013) Simultaneous detection of hemodynamics, mitochondrial metabolism and light scattering changes during cortical spreading depression in rats based on multi-spectral optical imaging. NeuroImage 76:70–80

Download references

Author information

Correspondence to Modar Kentar.

Ethics declarations

Conflict of Interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony, or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed in accordance with the Institutional Animal Care and Use Committee in Karlsruhe, Baden Württemberg, Germany (Protocols No. G-13/15, G-148-15, G-69/16).

Animal Experiments

All procedures performed in studies involving animals were in accordance with the University of Heidelberg Animal Ethics Policy.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Tropical Collection on Vascular Neurosurgery-Ischemia

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kentar, M., Mann, M., Sahm, F. et al. Detection of spreading depolarizations in a middle cerebral artery occlusion model in swine. Acta Neurochir (2020) doi:10.1007/s00701-019-04132-8

Download citation


  • Cerebral blood flow
  • Cerebral blood volume
  • Laser speckle flowmetry
  • Gyrencephalic brain
  • Intrinsic optical signal imaging
  • Spreading depolarizations
  • Stroke