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Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations

Nature Reviews Neuroscience volume 15, pages 379–393 (2014)Cite this article

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Key Points

  • Cortical spreading depression (CSD) is a slowly propagating wave of rapid, near-complete depolarization of brain cells that lasts for about 1 minute and silences brain electrical activity for several minutes; it can be induced in normally metabolizing tissue by depolarizing stimuli that increase extracellular K+ concentration ([K+]e) above a critical value. Longer-lasting spreading depolarizations arise in metabolically compromised brain tissue.

  • CSD initiation depends on the activation of ion channels located in dendrites of pyramidal cells and on the generation of a net self-sustaining inward current that initiates a positive-feedback cycle leading to a regenerative increase in [K+]e and regenerative depolarization. NMDA receptors (NMDARs) and voltage-gated Ca2+ channel (in particular Cav2.1)-dependent release of glutamate have a key role in the positive-feedback cycle that ignites CSD; depending on the method of induction, [Ca2+]e-independent glutamate release may contribute.

  • CSD propagation is probably mediated by interstitial diffusion of K+ released during the depolarization (accompanied by [K+]e-dependent glutamate release), initiating the positive-feedback cycle that ignites CSD in contiguous grey matter.

  • The mechanisms initiating CSD and spreading depolarizations are different. Besides NMDARs, other ion channels and processes (probably including persistent voltage-gated Na+ channels and mitochondrial depolarization) seem to be crucial for the initiation of spreading depolarizations.

  • Propagating depolarizing events in brain have been linked to neurovascular disorders such as migraine and stroke. In migraine, CSD has been linked to migraine aura, trigeminal activation and headache as well as the actions of preventative drugs.

  • It has been increasingly recognized that spreading depolarizations compromise energy metabolism and blood flow, contributing to poor tissue outcome when they erupt in the injured brain. Hence, there is an increasing demand for treatment strategies that selectively block initiation, propagation or enhance recovery to mitigate the impact of chaos and commotion that surrounds CSD and spreading depolarizations.

Abstract

Punctuated episodes of spreading depolarizations erupt in the brain, encumbering tissue structure and function, and raising fascinating unanswered questions concerning their initiation and propagation. Linked to migraine aura and headache, cortical spreading depression contributes to the morbidity in the world's migraine with aura population. Even more ominously, erupting spreading depolarizations accelerate tissue damage during brain injury. The once-held view that spreading depolarizations may not exist in the human brain has changed, largely because of the discovery of migraine genes that confer cortical spreading depression susceptibility, the application of sophisticated imaging tools and efforts to interrogate their impact in the acutely injured human brain.

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Figure 1: CSD: electrophysiological features and associated ionic changes.
Figure 2: CSD initiation.
Figure 3: Anoxic depolarization initiation.
Figure 4: Trigeminovascular activation by CSD.

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Acknowledgements

The support of the Italian Ministry of University and Research (PRIN2010) and of the University of Padova (Strategic Project 2008 and Progetto Ateneo 2012) to D.P. is gratefully acknowledged. The authors gratefully thank A. Tottene for help with the figures.

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Authors and Affiliations

  1. Department of Biomedical Sciences and CNR Institute of Neuroscience, University of Padova, Padova, 35121, Italy

    Daniela Pietrobon

  2. Departments of Radiology and Neurology, Stroke and Neurovascular Regulation Laboratory, 149 13th Street, Room 6403, Massachusetts General Hospital, Charlestown, 02129, Massachusetts, USA

    Michael A. Moskowitz

  3. Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA

    Michael A. Moskowitz

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  1. Daniela Pietrobon
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Correspondence to Daniela Pietrobon or Michael A. Moskowitz.

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PowerPoint slides

Glossary

Ischaemic penumbra

The peri-infarct zone of brain tissue that remains vulnerable but viable for several hours after a stroke because of a collateral blood supply.

Interstitial direct current potential

The local mean value of extracellular voltage.

Stratum radiatum

A layer of the hippocampus that contains a portion of the apical dendrites of CA1 pyramidal cells and the axons (Schaffer collaterals) of the CA3 pyramidal cells that form synapses onto the CA1 dendrites.

Oligaemia

A mild or moderate reduction in blood flow to the brain.

Familial hemiplegic migraine

(FHM). An autosomal dominant subtype of classic migraine that is typically associated with prolonged one-sided weakness (motor aura) and is sometimes accompanied by visual, sensory and/or language auras.

K+ spatial buffering

The mechanism by which functionally coupled highly K+-permeable glial cells transfer K+ from regions of increased extracellular K concentration ([K+]e) to regions of lower [K+]e; K+ entry in regions of high [K+]e causes a glial depolarization that spreads through the glial syncytium and generates a net driving force, causing K+ outflow in regions of lower [K+]e.

Gliotransmitters

Transmitter molecules that are released by glial cells and participate in intercellular communication between neurons and glial cells.

Infarct volume

The volume of tissue that dies after the interruption of blood flow in the brain.

Trigeminovascular system

A network of peripheral and central axonal projections from trigeminal ganglion cells that transmit impulses centrally from the meninges and its blood vessels.

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Pietrobon, D., Moskowitz, M. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci 15, 379–393 (2014). https://doi.org/10.1038/nrn3770

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