A brief history of spreading depolarization research

The beginning


In the 1940s, young Brazilian physiologist Aristides Leão was the first to discover both spreading depression and non-spreading depression of activity in the rabbit brain. He was also the first to describe the propagating slow potential change, normal neurovascular coupling to spreading depolarization and a phenomenon that was later to be called spreading convulsion by van Harreveld and Stamm. Leão coined the two ground breaking translational theories from bench to bedside in this field: 1) the spreading depression theory of the migraine aura, and 2) the connection between migraine aura and stroke based on spreading depolarization as their common pathophysical key element.

Fig. 8

Famous faces in the early years of spreading depolarization research

Aristides Leão

The Brazilian physiologist discovered spreading depression of activity in the rabbit brain and was the first to describe the slow potential change that identifies spreading depolarization, the hyperemic response to spreading depolarization, and spreading convulsion.

Leão AAP Spreading depression of activity in the cerebral cortex
Neurophysiol 7: 359–390, 1944 

Leão AAP Further observations on the spreading depression of activity in the cerebral cortex
Neurophysiol 10: 409–414, 1947

Antonie van Harreveld

Born in the Netherlands, van Harreveld spent his entire career at the California Institute of Technology where his earliest studies were on the innervation of crustacean muscles. He was the first to record a large slow potential change in the asphyxic spinal cord, and linked this to neuronal mass depolarization. He also found that spreading depolarization is the principal mechanism of the cytotoxic edema in gray matter based on electron microscopy, and that it is associated with massive release of glutamate.

Van Harreveld A, Stamm JS. Spreading cortical convulsions and depressions
Neurophysiol 16: 352-366 (1953)

Van Harreveld A, Stamm JS. Cerebral asphyxiation and spreading cortical depression
Am J Physiol. 173(1): 171-175 (1953)

Van Harreveld A, Malhotra SK. Extracellular space in the cerebral cortex of the mouse
J Anat 101(2): 197-207 (1967)

Bernice Grafstein

In a time when women in science were rare, Bernice Grafstein was trained as an electrophysiologist and developed the potassium hypothesis of cortical spreading depression - a work that has become classic in this field. She subsequently shifted her research focus to central nervous system development and regeneration, and is known for her work on intracellular protein transport in both normal and regenerating neurons, as well as other forms of molecular signaling among various cell types in the brain.

Grafstein B. Mechanism of spreading cortical depression 
Neurophysiol. 19(2): 154-171 (1956).

Grafstein B. Subverting the hegemony of the synapse: complicity of neurons, astrocytes, and vasculature in spreading depression and pathology of the cerebral cortex
Brain Res Rev. 66(1-2): 123-32 (2011).

Early Human Studies

  • Human studies on spreading depolarization started in the late 1970s. Miron Sramka invasively recorded potassium induced spreading depolarizations in the human caudate nucleus and hippocampus. 

  • In the early 1980s, Olesen, Larsen and Lauritzen provided the first recordings of the normal neurovascular response to spreading depolarization in patients undergoing migraine aura. 

  • In the early 1990s, Avoli and colleagues provided first evidence of spreading depolarizations in human brain slices from patients with intractable epilepsy.

  • In the mid 1990s, Mayevsky and colleagues provided the first in vivo electrophysiological evidence of spreading depolarizations in one of 14 patients with traumatic brain injury using, a complex multiparametric monitoring system.

  • In the late nineties and early 2000s, significant increases in spreading depolarization velocity and susceptibility were found in mouse models of familial hemiplegic migraine type 1, a rare Mendelian model disease of migraine with aura. It was also observed that cerebral microangiopathies such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are associated with both higher incidence of migraine with aura in patients and higher susceptibility to spreading depolarization in animal models. Furthermore, inverse neurovascular coupling (spreading ischemia) was discovered – a mechanism that may underlie migrainous stroke and ischemic lesion progression.

Co-Operative Studies on Brain Injury Depolarizations (COSBID)

In 2002, Anthony Strong and colleagues were the first to apply a new methodological approach that provided evidence of spreading depolarizations in the human brain following traumatic injury or intracerebral hemorrhage. In the following year, a group of interested investigators launched the CoOperative Studies on Brain Injury Depolarizations (COSBID) to further advance these findings and to use robust invasive recording technology for the detection of spreading depolarizations. The mutual aim was to produce a core data set for four model diseases: subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury and malignant hemispheric stroke. Since then, COSBID has produced remarkable progress in the translation of knowledge on spreading depolarizations from bench to bedside. It has become clear that spreading depolarizations are a fundamental component of the diseases under investigation, occurring in up to 80% of patients monitored.  Meeting at least once annually, COSBID investigators have worked together to develop clinical protocols, improve monitoring methods, and develop analysis techniques.

Video 2

Meet the COSBID group at the International Conference on Spreading Depolarizations (iCSD) where they share and discuss their latest findings in the field.

Selected publications


COSBID is an international group broadly concerned with discovering mechanisms and treatments for secondary brain damage that occurs after acute injury following stroke or trauma. Befitting a translational mission, basic and clinical scientists from diverse backgrounds meet at least once annually and work together to develop clinical protocols, improve monitoring methods, and develop analysis techniques.

COSBID welcomes new collaborators and partners in its pursuit to understand and develop treatments for spreading depolarizations. 

For more information, visit www.cosbid.org

Meetings & active COSBID centers
2003 — 2017

List of meetings

2003 Copenhagen, Denmark
2004 London, UK
2005 Washington DC, USA
2006 Cologne, Germany
2006 Atlanta, USA
2006 Rotterdam, Netherlands
2007 Berlin, Germany
2007 Cologne, Germany
2008 Cambridge, England
2008 Washington DC, USA
2009 Heidelberg, Germany
2010 Barcelona, Spain
2011 Cincinnati, USA
2012 London, UK
2013 Innsbruck, Austria
2014 Boston, USA
2015 Helsingør, Denmark
2016 Albuquerque, USA
2017 Berlin, Germany

Active COSBID centers

Ube, Japan
Cincinnati, Ohio USA
Boston, Massachusetts USA
Albuquerque, New Mexico USA

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