The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.
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.
1 Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|2 Mayfield Clinic, Cincinnati, OH, USA.
Jed A
JA
Hartings
3 Department of Neuroscience, University of New Mexico School of Medicine, Albuquerque, NM, USA.
C William
CW
Shuttleworth
4 Department of Neurosurgery and Brain and Behavior Discovery Institute, Medical College of Georgia, Augusta, GA, USA.
Sergei A
SA
Kirov
5 Neurovascular Research Unit, Department of Radiology, and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Cenk
C
Ayata
1 Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Jason M
JM
Hinzman
6 Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Brandon
B
Foreman
7 Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
R David
RD
Andrew
8 Department of Bioengineering, Imperial College London, London, United Kingdom.
Martyn G
MG
Boutelle
9 Department of Neurology, University of Utah, Salt Lake City, UT, USA.|10 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT, USA.
K C
KC
Brennan
11 Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Andrew P
AP
Carlson
12 Department of Physics, Humboldt University of Berlin, Berlin, Germany.
Markus A
MA
Dahlem
13 Department of Neurology, Charité University Medicine, Berlin, Germany.
Christoph
C
Drenckhahn
14 Department of Neurology, University of Cologne, Cologne, Germany.
Christian
C
Dohmen
15 Department of Clinical Neurophysiology, Rigshospitalet, Glostrup, Denmark.
Martin
M
Fabricius
16 Department of Medical Physics and Informatics, Faculty of Medicine, and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary.
Eszter
E
Farkas
17 Multimodal Imaging of Brain Metabolism, Max-Planck-Institute for Metabolism Research, Cologne, Germany.
Delphine
D
Feuerstein
17 Multimodal Imaging of Brain Metabolism, Max-Planck-Institute for Metabolism Research, Cologne, Germany.
Rudolf
R
Graf
18 Medical University of Innsbruck, Department of Neurology, Neurocritical Care Unit, Innsbruck, Austria.
Raimund
R
Helbok
15 Department of Clinical Neurophysiology, Rigshospitalet, Glostrup, Denmark.|19 Department of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
Martin
M
Lauritzen
13 Department of Neurology, Charité University Medicine, Berlin, Germany.|20 Center for Stroke Research Berlin, Charité University Medicine, Berlin, Germany.|21 Department of Experimental Neurology, Charité University Medicine, Berlin, Germany.
Sebastian
S
Major
20 Center for Stroke Research Berlin, Charité University Medicine, Berlin, Germany.|21 Department of Experimental Neurology, Charité University Medicine, Berlin, Germany.
Ana I
AI
Oliveira-Ferreira
22 Institute of Physiology/Neurophysiology, Jena University Hospital, Jena, Germany.
Frank
F
Richter
5 Neurovascular Research Unit, Department of Radiology, and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Eric S
ES
Rosenthal
23 Department of Neurosurgery, Klinikum Ludwigsburg, Ludwigsburg, Germany.|24 Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Oliver W
OW
Sakowitz
24 Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Renán
R
Sánchez-Porras
24 Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Edgar
E
Santos
24 Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
Michael
M
Schöll
25 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London.
Anthony J
AJ
Strong
26 Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
Anja
A
Urbach
5 Neurovascular Research Unit, Department of Radiology, and Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
M Brandon
MB
Westover
20 Center for Stroke Research Berlin, Charité University Medicine, Berlin, Germany.
Maren Kl
MK
Winkler
26 Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.|27 Brain Imaging Center, Jena University Hospital, Jena, Germany.
Otto W
OW
Witte
20 Center for Stroke Research Berlin, Charité University Medicine, Berlin, Germany.|28 Department of Neurosurgery, Charité University Medicine, Berlin, Germany.
Johannes
J
Woitzik
13 Department of Neurology, Charité University Medicine, Berlin, Germany.|20 Center for Stroke Research Berlin, Charité University Medicine, Berlin, Germany.|21 Department of Experimental Neurology, Charité University Medicine, Berlin, Germany.
Jens P
JP
Dreier
D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000473:pathology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D013181:Cortical Spreading Depression / Q000502:physiology*; D038524:Diffusion Magnetic Resonance Imaging; D000069280:Electrocorticography; D006801:Humans
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