Insights into Brain Injury
New findings provide insight into the damage caused by mild traumatic brain injury and suggest approaches for reducing its harmful effects.
Nationwide, at least 1.7 million traumatic brain injuries occur each year, according to the U.S. Centers for Disease Control and Prevention. About 75% of these are concussions or other mild forms of traumatic brain injury.
Concussions are seldom life-threatening, but they can have serious and lasting effects. The specific damage that occurs in affected brain tissue is poorly understood. In their new study, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) examined the tissue and cellular responses in the brain after a concussion. Their findings appeared online in Nature on December 8, 2013.
NINDS scientist Dr. Lawrence Latour and his colleagues have been studying people who suffered a concussion but whose initial CT scans didn’t reveal physical damage to brain tissue. Using a contrast agent and MRI, they observed fluid leaking into the meninges, the outer covering of the brain, in 49% of 142 patients with concussion.
To more closely examine this type of injury, Dr. Dorian McGavern’s lab at NINDS developed a new, closed-skull model of brain trauma in mice. The model mirrors the effects seen in humans with mild traumatic brain injury. Laser scanning microscopy can safely be used in the mice to visualize brain tissue just beneath the skull surface.
The scientists initially saw cell death in the meninges and at the glial limitans (a thin barrier at the surface of the brain) in the mice. Cell death in the underlying brain tissue (the parenchyma) didn’t occur until 9-12 hours after injury.
When the glial limitans breaks down, harmful molecules can get into the brain. Within an hour of head injury, the researchers observed parts of microglia (immune cells that act as first responders in the brain) extending toward the glial limitans and forming a stable network resembling a honeycomb. Other microglia took forms resembling jellyfish and moved up to the brain surface to repair damage.
These reactions, which have never been seen before in living brains, help to secure the brain’s protective barrier. Previous studies suggested that immune responses in the brain can lead to damage. These findings show that they’re actually beneficial during the first 9-12 hours after a mild traumatic brain injury.
The researchers observed high levels of reactive oxygen species—a type of molecule that damages cells—at the trauma site right after brain injury. To assess whether a local treatment could counteract these effects, the scientists first determined whether the intact skull bone was porous enough to allow small molecules to pass through. They found that it was, and then tested an antioxidant that reduces levels of a reactive oxygen species called glutathione. Glutathione reduced the amount of cell death by 67% when applied to the skull surface 15 minutes after brain injury and by 51% when applied 3 hours after injury.
“This idea that we have a time window within which to work, potentially up to 3 hours, is exciting and may be clinically important,” McGavern says. However, the method hasn’t yet been tested in humans. “Humans have a thicker skull bone and so we would need to evaluate whether the same technique could apply to the human skull bone.”
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Reference: Transcranial amelioration of inflammation and cell death after brain injury. Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Nature. 2013 Dec 8. doi: 10.1038/nature12808. [Epub ahead of print]. PMID: 24317693.
Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the Center for Neuroscience and Regenerative Medicine (CNRM) at the Uniformed Services University of the Health Sciences, a collaborative effort between NIH, the Department of Defense, and the Walter Reed National Military Medical Center.