New UC Research May Provide Clues to How the Brain Dies

CINCINNATI—It is known that loss of blood and oxygen to the brain can cause significant damage in just minutes, but researchers have not fully understood how exactly it happens or how long doctors have to resuscitate before the damage is irreversible. Now, a study by the University of Cincinnati (UC) Gardner Neuroscience Institute and Charité – Universitätsmedizin Berlin provides a window into what happens in the human brain upon circulatory arrest. 

The results of this study, reported online in the Annals of Neurology, are the first to confirm this sequence of events in humans. 

"The brain is most vulnerable to depletion of oxygen and blood supply,” says Jed Hartings, PhD, research associate professor in the Department of Neurosurgery at the UC College of Medicine and senior author on the study. "We know that massive irreversible injury can occur in less than 10 minutes, but we’ve only had a vague hint of what actually happens in the brain when circulation ceases.”

Until now, researchers have relied on data from animal models. Those studies show that within 20 to 40 seconds, the brain experiences a shutdown when all interneuronal communication ceases. The brain can exist in this quiet mode for a few minutes, but there is then a massive wave of electrochemical energy release, known as "spreading depolarization.” Also described as a "brain tsunami,” this energy loss spreads through the cortex and other areas of the brain, triggering pathophysiological cascades which gradually poison the nerve cells. This wave remains reversible up to a certain point in time: nerve cells will recover fully if circulation is restored before this point is reached. However, if circulation remains disrupted, the cells will die. 

Using state-of-the-art neuromonitoring technology, researchers placed electrodes on the brain of patients to record electrical activity of the cerebral cortex, known as electrocorticography, after severe brain damage. Recordings were then continued after a clinical and family decision to activate "Do Not Resuscitate” orders. They observed first the shutdown of brain activity during circulatory arrest, followed minutes later by terminal spreading depolarization.  

 "These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults,” says Hartings. 

 "We were able to show that terminal spreading depolarization is similar in humans and animals,” explains Jens Drier, MD, professor of the Center for Stroke Research at Charité – Universitätsmedizin Berlin  and lead author on the study. "Knowledge of the processes involved in spreading depolarization is fundamental to the development of additional treatment strategies aimed at prolonging the survival of nerve cells when brain perfusion is disrupted.” 

Hartings adds, "This knowledge may also be of benefit in the debate on organ donation, when death is declared between two and 10 minutes following circulatory arrest. Until terminal spreading depolarization occurs, the brain remains quite viable.” 

Additional researchers include: Sebastian Major, MD, Maren Winkler, MD, Eun-Jeung Kang, MD, Denny Milakara, MD, Coline Lemale, MD, Johannes Woitzik, MD, and Jason M. Hinzman, PhD of Charité – Universitätsmedizin Berlin; Brandon Foreman, MD, University of Cincinnati; Vince DiNapoli, MD, PhD, and Norberto Andaluz, MD, of Mayfield Clinic; and Andrew Carlson, MD of the University of New Mexico. 

The researchers cite no conflicts of interest.