The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy

Jed A. Hartings, C. William Shuttleworth, Sergei A Kirov, Cenk Ayata, Jason M. Hinzman, Brandon Foreman, R. David Andrew, Martyn G. Boutelle, Kc Brennan, Andrew P. Carlson, Markus A. Dahlem, Christoph Drenckhahn, Christian Dohmen, Martin Fabricius, Eszter Farkas, Delphine Feuerstein, Rudolf Graf, Raimund Helbok, Martin Lauritzen, Sebastian MajorAna I. Oliveira-Ferreira, Frank Richter, Eric S. Rosenthal, Oliver W. Sakowitz, Renán Sánchez-Porras, Edgar Santos, Michael Schöll, Anthony J. Strong, Anja Urbach, M. Brandon Westover, Maren K.L. Winkler, Otto W. Witte, Johannes Woitzik, Jens P. Dreier

Research output: Contribution to journalReview articlepeer-review

241 Scopus citations


A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Original languageEnglish (US)
Pages (from-to)1571-1594
Number of pages24
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number5
StatePublished - May 1 2017


  • Spreading depression
  • brain edema
  • brain ischemia
  • brain trauma
  • cardiac arrest
  • cerebral blood flow
  • cerebrovascular disease
  • diffusion weighted MRI
  • electrophysiology
  • focal ischemia
  • global ischemia
  • neurocritical care
  • neuroprotection
  • neurovascular coupling
  • selective neuronal death
  • stroke
  • subarachnoid hemorrhage
  • system biology
  • two photon microscopy
  • vasospasm

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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