Spreading Depolarizations

Spreading depolarizations are a pathologic brain activity and complication thought to play a key role in traumatic brain injury (TBI) and subarachnoid hemorrhage (bleeding stroke). Spreading depolarizations are electrical disturbances that spread through an injured brain like tsunami waves.

Jed Hartings, PhD, a former Major in the U.S. Army’s Medical Service Corps who is now Research Associate Professor in UC’s Department of Neurosurgery, recognized early on that spreading depolarizations were of critical importance to brain-injured war veterans, and this area of research became his life’s work and passion.

Today Dr. Hartings is at the forefront of research on spreading depolarizations and is a founding member of the international organization COSBID (Co-Operative Study on Brain Injury Depolarizations). In 2011 Dr. Hartings was the lead author of two papers about spreading depolarizations that were published in prestigious international journals (Brain and Lancet Neurology). He is making discoveries about how depolarizations impact patients – they contribute to worse outcomes — while investigating new ways to monitor these disruptions.

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In 2012 Dr. Hartings co-authored a study that showed that ketamine halted brain tsunamis after traumatic brain injury and stroke.

Ketamine works by controlling glutamate, a neurotransmitter that normally plays an important role in memory and learning. If glutamate is present in excessive amounts, however, it overstimulates brain cells, causing them to die from “excitotoxicity.”

Ketamine blocks the neuro-excitatory effects of glutamate by interfering with one of its receptors, known as NMDA (N-methyl D-aspartate). In scientific parlance, ketamine is an NMDA receptor antagonist, which means that it works by antagonizing, or inhibiting, the ability of the NMDA receptor to act. Because the NMDA receptor is involved in several areas of brain regulation, the result of this activity may have different results for different types of patients.

Decades of research in animal models have shown that blocking the NMDA receptor is the best way to stop spreading depolarizations. Last year, for the first time, Dr. Hartings and his COSBID colleagues accumulated brain-monitoring data of patients who had suffered spreading depolarizations after head trauma or stroke. During the observational, retrospective study, which included patients treated at the UC Medical Center, the researchers compared spreading depolarizations in patients who were treated with various medications during their hospitalization.

“There was no intention to treat spreading depolarizations with ketamine,” Dr. Hartings said. “But some patients in the European population were given ketamine for other reasons. And we found that when that drug was given, the depolarizations stopped.”

The group’s study was published in the August 2012 issue of the journal Brain.

The next step for Dr. Hartings and his team is to conduct a study that administers ketamine to patients with an intention to treat spreading depolarizations. An application is in process with the U.S. Department of Defense. If the study is funded, Dr. Hartings said, it would be the first “selective inclusion trial” ever for a brain trauma therapy. Whereas study therapies for brain trauma previously have been given to all study participants, ketamine would be delivered only to those who are known to be experiencing spreading depolarizations.