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Spreading Depolarizations Are Brain Injury's “Silent Culprit,” Expert Says

Article In Brief

A leading researcher discusses the resurgence of research into the underlying physiological role that spreading depolarization plays in traumatic brain injury.

PHILADELPHIA—Spreading depolarizations have been a “silent culprit” in brain injury for years, but a growing awareness has put the phenomenon back on the radar screen after it was first noticed more than 70 years ago, an expert said here at the AAN Annual Meeting in May.

Jed A. Hartings, PhD, associate professor of neurosurgery at the University of Cincinnati College of Medicine, said the first glimpse of the phenomenon dates back to 1944, when Aristides Leao, PhD, first described “spreading depression of activity in the cerebral cortex.”

He documented suppression of EEG activity that would propagate through the cortex at a rate of a few millimeters per minute and identified this as a marker of a mass depolarization that underlies the inability to generate spontaneous electrical activity in the brain.

“Recent experimental work has demonstrated that this continuum established by Dr. Leao—and then rediscovered in the late 70s—is really essential to our current understanding of how ischemic lesions evolve in the brain,” Dr. Hartings said.

He said the stroke field was full of “exuberance” in the 1980s and 1990s—the 90s were dubbed “the decade of the brain”—after studies showed that neurons could be protected in animals subject to ischemia if they were given an NMDA receptor antagonist, working against the “glutamatergic storm” of excitotoxicity.

“But here we are in 2019,” he said. “We still don't have neuroprotectants for TBI [traumatic brain injury] and stroke, and I want to posit that one of the reasons is that a major mechanism of excitotoxicity has eluded our attention until very recently.”

The Key to Excitotoxicity

He said the idea of spreading depolarization is crucial to the phenomenon of excitotoxicity, in which an overabundance of glutamate over-activates AMPA and NMDA receptors, followed by calcium and sodium entering cells, leading to cytotoxic edema and activation of enzymes that damage organelles and lead to cell death.

In spreading depolarization, after the start of ischemia, there's a decrease in blood flow, followed by a persistent depolarization at the ischemic core, he said. This is the start of a wave that spreads outward into the ischemic penumbra and is prolonged due to the low energy supply there—low but not absent, leaving the possibility of tissue recovery. This wave further spreads to normal tissues, putting other regions at risk.

These depolarizations also spread inward from normal tissue back to the ischemic core, causing further damage to vulnerable penumbral tissue.

“This is the mechanism that's thought to mediate the time-dependent growth of ischemic lesions,” Dr. Hartings said.

Recent work by Bill Shuttleworth, PhD, associate director of the Clinical and Translational Science Center at the University of New Mexico, has shown that after ischemic stroke, glutamate levels in the tissue only show spikes during spreading depolarizations. His group has also shown that it is the glutamate signaling during the depolarization that prolongs it—they could shorten the depolarization while it was happening by applying glutamate-receptor antagonists.

Animal Models

Spreading depolarization has been studied across many animal models, Dr. Hartings said. “In every model in which it's been properly investigated, it's been found that spreading depolarization is a required mechanism for the acute development of brain lesions,” he said.

Research into spreading depolarization has been intensifying since the discovery of their occurrence in the human brain, Dr. Hartings said. “In the last 15 years, a number of centers have been following up on these findings,” he said. “And by this year, more than 800 neurosurgical patients have been monitored at more than a dozen centers in Europe, the U.S. and Japan.”

These studies, Dr. Hartings said, have revealed a “strikingly high” incidence of these events—50 to 60 percent of TBI and intracerebral hemorrhage patients, more than 80 percent of ruptured aneurysms, and almost 100 percent of stroke cases.

Cluster Patterns, Humans

Among 138 TBI patients monitored for up to 10 days in the intensive care unit, about 40 percent had no spreading depolarization events, about 20 percent had sporadic events and about 40 percent had a pattern of repetitive, continuous depolarizations that happened every 15 to 45 minutes over hours or even days. About half of the patients who develop these “clusters” go on to develop a more severe pathology they call “isoelectric spreading depolarization,” development of flatline brain activity that's caused by a series of prior spreading depressions.


“Unlike seizures, which can have paroxysmal motor manifestations, spreading depolarizations cause a loss of neurologic function, which is not easily distinguished from the ischemia that triggers them.”—DR. JED A. HARTINGS

The 40 percent of patients with these “cluster” patterns, they've found, have very high odds for a worse outcome.

“The depolarization activity is an independent factor carrying an odds ratio of anywhere in the range of 2 to 7 for worse outcomes,” even after accounting for baseline factors such as age.

Dr. Hartings calls the phenomena a “silent culprit” in part because they escape detection with classical electrophysiology techniques, because of their low frequency and prolonged time course compared to epileptic activity, and because they cannot be recorded through intact skull with non-invasive scalp EEG.

Also, he explained, “unlike seizures, which can have paroxysmal motor manifestations, spreading depolarizations cause a loss of neurologic function, which is not easily distinguished from the ischemia that triggers them.”

Research has ramped up recently, but the field of study is still underrepresented, he said, especially since—considering migraine with aura, stroke, TBI hospitalizations, and cardiac arrest—spreading depolarization is possibly one of the highest-incidence neurological pathologies.

“The subject—paradoxically, despite its history—is still relatively new and has just kind of experienced a renaissance,” Dr. Hartings said. “ As such, these are massively understudied phenomena.”

Expert Commentary

Ruchira Jha, MD, associate professor of critical care medicine at the University of Pittsburgh, said the recent findings on TBI and spreading depolarizations is “a very exciting first step” toward benefiting patients.

“From the pilot study, it does look like they are at a higher risk for worse outcomes,” she said. But that doesn't mean an intervention is around the corner.

“This could be something that is causing injury—and it can also be a reflection of injury,” she said. “Figuring that out is going to be an important next question, which will potentially guide management. Should we treat them and how aggressively should we treat them?”


“This could be something that is causing injury—and it can also be a reflection of injury. Figuring that out is going to be an important next question, which will potentially guide management. Should we treat them and how aggressively should we treat them?”—DR. RUCHIRA JHA

If it's determined that intervening could affect outcomes, scientists will have to explore how to treat these phenomena with the drugs that are now available, Dr. Jha said, possibly building on animal work that has been done on spreading depolarizations to see how different therapeutic approaches fare.

There is also the problem of accessibility, she said. “Getting this available and accessible all over the country (means) having more centers capable of doing this (and) getting this information about spreading depolarization. Major academic centers that have high volume centers have already had this capability. But it's not something that, as far as I'm aware, has spread out to the community yet.”

The prevalence of interest in spreading depolarizations beyond TBI is also cause for encouragement, she said. “This has implications across the board of a lot of acute brain pathology, which is something else that makes it particularly exciting.”


Drs. Hartings and Jha had nothing to disclose.

Link Up for More Information

• Eriksen N, Pakkenberg B, Rostrup E, et al. Neurostereologic lesion volumes and spreading depolarizations in severe traumatic brain injury patients: A pilot study Neurocrit Care 2019; 30(3):557–568.
• Dreier JP, Major S, Foreman B, et al. Terminal spreading depolarization and electrical silence in death of human cerebral cortex Ann Neurol 2018;83(2):295–310.
• Hartings JA. Spreading depolarization monitoring in neurocritical care of acute brain injury Curr Opin Crit Care 2017;23(2):94–102.