Revealing brain damage from battlefield to playing field

NEW YORK (Reuters) - Traumatic brain injury, the signature wound of the Iraq and Afghanistan wars, is doubly cruel: it leaves many victims emotionally shattered and cognitively crippled. But because mild and moderate brain injuries do not show up on CT or other imaging, doctors and even family members are often skeptical that any real damage exists.

Now the first experiment of its kind documents exactly what "the invisible injury" - at least the kind caused by blast waves or repeated physical impacts - does to the brain: Crumpled axons, which carry signals between neurons; gummed-up neurons like those in Alzheimer's disease; strangled blood vessels.

An injured brain is so littered with the chewed-up remains of neurons and other cells that "it looks like autophagy - the brain eating itself alive," said Lee Goldstein, an Alzheimer's researcher at the Boston University School of Medicine and co-leader of the study.

The discovery promises to help such injuries be taken more seriously, and might lead to preventives or treatments. It comes at a time when both the Pentagon and the National Football League are struggling with the legacy of head injuries.

Tens of thousands of U.S. troops have sustained such injuries and some have committed suicide or other acts of violence. In one horrific case, an Army staff sergeant who had sustained head trauma is accused of murdering 17 Afghan civilians in March.

The invisibility of many head injuries "is a huge problem," said retired U.S. Army General Peter Chiarelli, chief executive officer of One Mind, a non-profit group promoting brain research. "The ER doc will say, ?why am I wasting my time with this guy when I have people with visible injuries?'"

Adding to the urgency: the recent suicides of former pro football players who sustained head injuries during their playing days. The most recent, former San Diego Chargers linebacker Junior Seau, fatally shot himself earlier this month.

MAKING 'THE INVISIBLE INJURY' VISIBLE

For the new study, published Wednesday in the journal Science Translational Medicine, scientists compared three groups of brains. Four came from military veterans who had suffered the blast of an improvised explosive device (IED) or a concussion. Four belonged to young athletes who had concussions. And scores were from mice that had been exposed to a blast akin to that from an IED 17 feet (five meters) away packed with 12 pounds (5.4 kilograms) of TNT, comparable to an IED made from a 120-mm artillery round.

None of the brains had obvious injury. "If you hold them in your hand you don't see any damage," said neuropathologist Ann McKee of the Boston University School of Medicine and the Veterans Affairs New England Healthcare System, co-leader of the new study. "CT and MRI don't see it. It takes a microscope, even an electron microscope."

With that scrutiny the damage was clear. Specialized cells called astrocytes extended what BU's Goldstein called "little feet" that wrapped themselves around blood vessels. Axons crumbled and wound up in cellular garbage cans. Long strings of proteins called tau formed, as seen in Alzheimer's disease.

The damage was strikingly similar to what scientists have seen in the brains of ex-football players who had sustained head injuries and, after death, were found to have chronic traumatic encephalopathy (CTE), the condition once known as boxer's dementia.

CTE can cause depression, aggression, impulsivity and memory loss and has been linked to suicide. "Men become very aggressive, develop a hair-trigger temper, and their judgment is off," said Goldstein. "These are all part and parcel of damage to the brain."

Age offered no protection. In the new study, the athletes ranged in age from 17 to 27 when they died. They are the youngest head-injury victims ever found with CTE.

Until this study, scientists could not be sure that head injuries, from an IED or a linebacker, caused the brain or behavioral changes. That's where the lab mice came in. While anesthetized and in a special tube, they were exposed to blasts akin to those suffered by U.S. troops in Iraq and Afghanistan.

Even though a shock wave barreled through the animals' skulls at 336 miles per hour, "there was no bleeding, no contusions, no rips in the tissue," said Goldstein, who led the mouse part of the study. "They looked for all the world like what we see in human cases of traumatic brain injury - the invisible injury that people have been talking about since World War One."

The mice's behavior changed, too: they could not remember or learn as well after the blast as before it. "This matches what veterans (exposed to IEDs) say: ?I'm thinking slow and I can't remember,'" said Goldstein.

The three lines of evidence - from veterans, athletes and lab mice - suggest a common mechanism by which head injury causes CTE and CTE impairs mental function.

Blasts in a war zone and head trauma on a gridiron both break axons and stretch neurons, said McKee, a football fan who has four bobble-head dolls of retired NFL quarterback Brett Favre in her office. That stretching makes their membranes more porous, allowing calcium ions to flood into the neuron and activating enzymes that alter tau proteins just as they are altered in Alzheimer's. As a result, said McKee, "the neuron is no longer functional."

It may not even take such dramatic impacts to impair mental skills. A second study released on Wednesday showed that some college football and hockey players had lower scores on thinking and memory tests after a season of enduring repeated but minor hits to the head.

The players, outfitted with special helmets that measured head impacts, experienced an average of 469 during the season, scientists led by Thomas McAllister of the Geisel School of Medicine at Dartmouth reported in the journal Neurology.

TREATING AND PREVENTING

There are no approved treatments for traumatic brain injury. One experimental drug from BHR Pharma, a subsidiary of Besins Healthcare SA, is in the last stage of human testing.

But the study suggests the military should re-examine soldiers' protective gear. Heavy helmets that protect against impacts and even bullets "are like putting a bowling ball on top of a match stick," said Goldstein, exacerbating the destructive acceleration and deceleration from a blast wave.

When the mice's heads were immobilized, though, an identical blast produced no brain damage. That finding "has invaluable implications for future safety measures," said psychologist Jennifer Wilde of the University of Oxford, who was not involved in the study. Namely: "special helmets to help keep soldiers heads still during a blast."

The results also suggest that head trauma should be treated immediately instead of waiting for symptoms. The BU scientists "are working on field-deployable treatments," Goldstein said, including anti-inflammatory drugs and agents that target leaky blood vessels.

The U.S. military tries "to identify TBI as soon as possible and provide effective treatment," said Pentagon spokesperson Cynthia Smith. That policy pertains "regardless of whether the injury is obvious and severe, or subtle and hidden." All service members in a vehicle collision or rollover or within 150 feet of a blast undergo a mandatory medical evaluation.

The new study also confirms the physical reality of psychological illnesses that the military and others have sometimes dismissed. "Post-traumatic stress disorder has been regarded as a purely psychological illness, because we've been looking at brains with CT and MRI," said neuropathologist Bennet Omalu, chief medical examiner of San Joaquin County in California and co-founder of the Brain Injury Research Institute. BIRI hopes to examine Seau's brain, which the BU lab is also in the running for.

"CT and MRI don't have the resolution to show the cellular and sub-cellular changes you can get from a concussion or sub-concussive injury," said Omalu. "Now we can see that PTSD is likely to be a manifestation of traumatic brain damage."

(Reporting by Sharon Begley; Editing by Michele Gershberg and Eric Beech)

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