According to some estimates, more than 300,000 United States troops have suffered a traumatic brain injury (TBI) in the current wars in Iraq and Afghanistan. Most of these injuries have resulted from blasts from roadside bombs and other explosives planted by insurgents. The lack of knowledge about how an explosive blast injures the brain has hampered efforts to treat these injuries. Now, two studies offer a potentially important insight, pointing to a mechanism that hadn't been considered before.
The lead author of the studies, Harvard University bioengineer Kevin Kit Parker, says he had a vested interest in the research. Parker shifted his focus from cardiac to brain research after two tours in Afghanistan as a U.S. Army infantry officer. "I kept seeing buddies of mine get hit and thought, 'All right, I'll take a look at this and see if I can get an angle on it.' "
Back at Harvard, Parker and his lab devised a blast simulator for cells. In one study, published today in PLoS ONE, the researchers grew rat neurons in a culture dish and then attached them to a sheet of stretchy polymer. A high-precision motor gave a carefully calibrated tug to the sheet to subject the neurons to mechanical forces Parker calculated to be comparable to those produced by an explosion.
Through a microscope, the researchers saw that the "blast" caused swelling, breakage, and other signs of injuries to the neurons' spindly axons and dendrites, which send and receive signals from other neurons. A series of biochemical experiments found that the mechanical force disrupted proteins called integrins that help anchor cells to the scaffold of protein that surrounds them. Integrins have roles in a wide range of biochemical signaling pathways, but Parker's team identified one particular pathway that seems to play a role in injury to axons. A drug that blocks a component of this cascade called Rho kinase reduced the damage to axons.
That result is intriguing given recent findings of damage to the brain's white matter, which is made up of axons, in Iraq war veterans injured in blasts, Parker says. All the same, he cautions that much more work will be needed to see whether these culture dish findings are relevant to what happens in the brain of a soldier exposed to a blast. "It would be inappropriate to extrapolate from a dish to some dude's head," Parker says.
A second paper from Parker's group, published last week in the Proceedings of the National Academy of Sciences, suggests that the same integrin-signaling mechanism may contribute to vasospasm, another harmful process associated with TBI. In experiments with muscle cells from the lining of blood vessels, the researchers found that a sudden mechanical force flips a genetic switch in these cells, making them more likely to contract. This contraction would choke off the blood supply wherever it occurs in the brain and exacerbate an injury by starving brain tissue of oxygen, Parker says.
"They've duplicated in vitro a finding that has been baffling to clinicians," says Jack Tsao, a neurologist and neuroscientist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Vasospasm typically results after a blow to the head causes bleeding in the space between the brain and the thin tissues that surround it. But in many troops with TBI from blasts, clinicians see stroke-like symptoms indicative of vasospasm even when brain scans show no evidence of bleeding. The new findings provide a possible explanation of how that could occur, Tsao says.
"These are both very elegant papers," says David Hovda, a neuroscientist and director of the Brain Injury Research Center at the University of California, Los Angeles. Most research on the mechanisms of TBI has focused on neurochemical changes at the site of injury, such as metabolic alterations and ion imbalances inside neurons, he says. But the new findings suggest a mechanism that hasn't been considered. The idea that integrins might play a role makes a lot of sense and raises interesting possibilities for treating TBI or minimizing its effects with drugs given prophylactically, he says.
Hovda says he sees no reason why these mechanisms wouldn't contribute to other types of brain injury too, from car accidents to shaken baby syndrome. "I don't think it's specific to blast."