Post by Deborah Joye
What's the science?
Interruption of blood flow to the brain can result in lasting damage within seconds, and “brain death” can occur within minutes. Unless blood flow is restored quickly, a series of progressive and irreversible mechanisms are thought to ultimately led to cell death and decomposition of the brain. The growing consensus has been that brain decomposition happens within a singular, narrowly defined time period after blood flow to the brain has stopped. But death of brain cells may occur in a much more gradual way than previously thought. This week in Nature, Vrselja and colleagues use a newly-developed device to demonstrate that cellular function and circulation can be successfully restored to the mammalian brain up to four hours after death.
How did they do it?
The authors developed a device called BrainEx, which allows them to remove a brain 4 hours after death and flush it continuously (also called perfusion) for 6 hours with a blood-like fluid that promotes recovery from lack of oxygen, prevents excess liquid accumulation, and provides the brain with the energy it needs to function on a cellular level. The researchers tested this device on brains of 6-8-month-old pigs from USDA-regulated food processing facilities. The researchers developed four conditions to compare with the BrainEx and the blood-like fluid: 1) perfusion with a control fluid; 2) perfusion with the specially designed blood-like fluid; 3) no perfusion and kept at room temperature for a total of 10 hours (the total interval of all brains after death – 4 hours after death plus 6 hours of perfusion) and 4) processed 1 hour after death with no perfusion. The authors then quantified circulatory and cellular health of the brain by measuring flow dynamics throughout the brains, relative size of neural landmarks, and integrity and functional properties of different cell types throughout the brain, including excitatory, inhibitory, and glial cells. The authors also investigated whether brains could mount immune responses by injecting brains with lipopolysaccharide (an agent that induces an immune response) and measuring inflammatory responses. Finally, the authors measured energy metabolism and electrical activity to determine whether their device could restore metabolic and electrophysiological activity across the whole brain.
What did they find?
Overall, the researchers found that perfusion with blood-like fluid through the BrainEx device can restore and maintain circulation and cellular life to brains that have been “dead” for four hours. Compared to control groups, the authors observed that brains perfused with the blood-like fluid showed decreases in cell death and preserved neuroanatomical and cellular integrity. Vasculature and glia were also responsive to an agent known to cause immune responses in the brain, indicating a restoration of cellular function. The authors also observed spontaneous synaptic activity and active metabolism. It should be noted that while cellular function was restored, it should not be interpreted that normal brain function was restored. Global electrical activity and integrated brain function associated with awareness, perception, and other higher-order function was not observed.
What's the impact?
This is the first study to demonstrate that degradation of the brain after death is a much larger grey area than previously thought. Instead of rapid degradation within a short time after death, this study reveals that the brain undergoes a prolonged period of degradation. Further, it demonstrates that BrainEx perfusion with blood-like fluid up to four hours after death can restore cellular and circulatory function. This technology presents the exciting possibility of investigating how the brain recovers from large insults like oxygen and blood-flow deprivation.
Vrselja et al., Restoration of brain circulation and cellular functions hours post-mortem, Nature (2019). Access the original scientific publication here.