Newly Discovered 'Brain Tsunamis' Provide Scientific Insight Into Biology of Death

A 2018 study may lend credence to what happens during the biological and irreversible death of the brain organ.

Published in the Annals of Neurology, the study inspected spreading depolarization of the human cerebral cortex and provided a better understanding of how the brain responds to energy depletion. Also for the first time, it showed the full electrophysiological signature of dying in the wake of circulatory arrest in the human brain.

Jens Dreier, the study's lead author and a professor at the Center for Stroke Research Berlin, told Newsweek that brain death, which differs from dying in the wake of circulatory arrest, occurs during continued circulatory function.

"For example, an extreme increase in intracranial pressure can cause the brain to die while circulation continues," Dreier said. "However, breathing and circulation must be artificially maintained under these conditions in the intensive care unit. Without this support, breathing stops immediately and the circulation collapses shortly afterwards due to a lack of oxygen. Brain death, then, is a form of dying that exists only in the intensive care unit."

In two other studies, Dreier and other researchers described the full electrophysiological signature of brain death in the human brain for the first time. He said two cases with a typical intracranial pressure crisis followed by brain death will be published soon in the journal Brain as part of a large multicenter study on spreading depolarizations in subarachnoid hemorrhage.

Spreading depolarizations, or "brain tsunamis," are by any measure the largest events possible in the living brain, Dreier said. They are orders of magnitude larger than, for example, epileptic seizures and relate to ionic changes, neurotransmitter changes, electrophysiological changes, and many other pathophysiological aspects.

Spreading depolarizations are associated with a tremendous influx of water into the neurons, he said, which causes them to swell. It can be destructive unless neurons have the energy to recover.

"This is a critical point: spreading depolarization marks the onset of toxic cellular changes that eventually lead to cell death, but is not a marker of cell death per se, since the depolarization is reversible – up to a point – with restoration of the physiological neuronal environment," Dreier said. "Many people say that this is the wave of death, but this is not true. It is a wave that can result in either cell death or recovery."

The current standard for recording spreading depolarizations is subdural electrodes implanted by the neurosurgeon, he added, clarifying that there are no systematic studies in do-not-resuscitate (DNR) patients.

Dreier added that spreading depolarizations occur not only in dying patients but are also the characteristic electrophysiological signature of patients with strokes. There are conditions such as aneurysmal subarachnoid hemorrhage, in which ischemic strokes typically occur about seven days after the initial hemorrhage.

"This leads to a significant worsening of patient outcome," he said. "Patients are usually in the ICU at this point and often in a coma."

Neuromonitoring of spreading depolarizations is increasingly performed in dedicated centers in North America, Europe and Japan, Dreier said. But, as the 2018 study shows, medical options remain limited and patients cannot always be saved.

Spreading depolarizations were discovered in animals by the Brazilian scientist Aristides Leão in 1944. Three years later, he found in the rabbit cortex that cerebral circulatory arrest leads to spreading depolarization.

"Why it then took over 70 years for the phenomenon to be demonstrated in stroke in humans and why the vast majority of neurologists even believed for decades that spreading depolarization did not exist in humans is a very interesting but also complicated story," said Dreier. "Basically, the prime mechanism of damage development in the human brain has been ignored in the more than 1,000 unsuccessful neuroprotection studies in the context of traumatic brain injury and stroke. This was very likely a big mistake."

Although restoration of circulation is the primary goal in emergency treatment, researchers believe that understanding how the brain responds to energy depletion could help predict the time available for resuscitation "until irreversible damage" occurs in the brain.

"This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury," the study stated.

Brain Imaging
A new study is giving researchers a look at how the brain responds to energy depletion. An image of a human brain taken by a PET scan, 2019. FRED TANNEAU/AFP/Getty Images

The methodology employed by researchers involved performing recordings with either electrode strips or electrode arrays in patients with devastating brain injury that resulted in the activation of a "Do Not Resuscitate–Comfort Care" order.

Nine patients underwent what researchers described as "invasive neuromonitoring" at two separate facilities: four at Charité–Universitätsmedizin in Berlin, and five at the University of Cincinnati Medical Center. Written consent was obtained from the patients' legally authorized representatives.

In 2017, U.S. researchers reported the first known instance of brain damage reversal when they treated a drowned 2-year-old girl. After the child was not able to speak, walk or respond to voices, doctors employed various oxygen treatments that significantly reversed her brain damage.

Knowledge of pathologic mechanisms informs treatment strategies that complement the re-establishment of the systemic circulation, the study stated, as neuroprotective interventions could be directed at the depolarization wave with the aim of prolonging survival time.

A list of diseases that Dreier and his fellow researchers have studied involving spreading depolarizations in the human brain include symptoms of migraine aura; alternation of spreading depolarizations with electrographic seizures during status epilepticus; malignant hemispheric stroke; severe traumatic brain injury; aneurysmal subarachnoid hemorrhage; delayed cerebral ischemia; and more.

The list will grow longer and longer in the coming years, Dreier said.

"All of this means that spreading depolarizations are involved in probably more than 50 percent of the severe diseases seen by neurologists in the emergency department," he said. "Yet, even today, many neurologists do not really know what a spreading depolarization is. Max Planck once said: Insight must precede application. You have to know what you are dealing with before you can do anything about it. It is to be hoped that much more research will now be done in the field of spreading depolarization to improve the prognosis of the severe neurological diseases in which it is involved."

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