WHEELS IN MOTION

December 14, 2015

AFTER DOUG MARKGRAF WAS HIT BY A TRUCK WHILE RIDING HIS BIKE, HE WASN'T EXPECTED TO LIVE, LET ALONE RECOVER. BUT HE DID, AND NOW HIS TYPE OF TRAUMATIC BRAIN INJURY IS BEING STUDIED, THANKS TO NFL MONEY

IN THE EARLY EVENING of May 31, 2006, Doug Markgraf, a sophomore materials engineering major at Drexel, put on his training gear and helmet and hopped on his bicycle for a ride across West Philadelphia to meet a landlord. The apartment for rent turned out to be just what Markgraf had hoped for—cheap and spacious—so after speaking with the owner, he got back on his bike to report the good news to his roommate, Andy Evenson.

Approaching the intersection of 55th Street and Lancaster Avenue, Markgraf was wondering where in the new place he and Evenson would store the equipment for their engineering project: a chain-mail shirt like the ones medieval knights wore into battle. But Markgraf never finished that thought. At the busy intersection a white Dodge Quad Cab struck him and sped off. Markgraf, thrown several feet, lay unconscious on the side of the road.

Moments later emergency responders transported him three miles to the emergency room at the Hospital of the University of Pennsylvania (HUP); he was then moved to the hospital's Neurologic Intensive Care Unit. The impact of his head hitting the ground had caused bleeding in Markgraf's brain, and an MRI revealed hemorrhages in both cerebral hemispheres and, most damaging, in the brain stem—the part of the brain responsible for consciousness. He had suffered a severe traumatic brain injury, and doctors felt his chance for meaningful recovery was negligible.

Doug's mother, Jen, was taking a bath at home in Abington, Pa., that evening when she heard the cellphone of her husband, Daniel, ring. When the Markgrafs reached the hospital an hour later, they were rushed into a room with two chaplains and a senior physician. "It was so surreal," Jen says. "He's telling us that Doug is totally unresponsive. I'm hearing the words, but they're just not registering." Within hours the hospital hallways were lined with Doug's friends and relatives. "It was like a nonstop vigil," Jen says. "We were never alone."

About five days after the accident Jen started to lose hope. "A few doctors [were] saying there's no brain activity, and I thought, Oh, my God, my son isn't going to make it."

Nine days later, Doug Markgraf woke up.

ON SEPT. 5, 2012, Roger Goodell said that the NFL was donating $30 million to the National Institutes of Health to support research on injuries, with a focus on brain trauma. Fifteen months later the NIH announced the recipients of the NFL grants: two groups that had each pooled resources from different hospitals and university departments. The first group—led by Ann McKee, a professor of neurology and pathology at Boston University, and including imaging teams from Washington University (St. Louis) and Massachusetts General Hospital—was awarded $6 million to define a set of criteria for the stages of chronic traumatic encephalopathy. BU's work on CTE has been covered extensively in the media (SI, Nov. 1, 2010), and it was no surprise that McKee's group was a primary grant recipient. But the other team favored by the NIH, led by Wayne Gordon, a rehabilitation medicine professor at Mount Sinai Hospital in New York City, was unexpected. Many neurologists had never heard of Gordon or his work. And the NIH was handing him $6 million of NFL money to fund research that seemed largely unrelated to football or to concussions.

Gordon had teamed up with scientists at Mass General, Oregon Health Sciences University and the University of Washington to create a proposal to evaluate brain tissue from hundreds of patients living with moderate to severe traumatic brain injury (TBI), of which concussion is a mild form. Unlike CTE, whose symptoms develop over years, TBI occurs immediately, after a distinct dramatic event such as an automobile accident, an explosion or, in football, a high-speed collision. Partly because of car crashes, TBI is the leading cause of death in North America for people ages one to 45. But it's shockingly misunderstood.

"Our means of classification of traumatic brain injury is terrible," says Gordon, 69. "We currently divide folks into three groups: mild, moderate and severe traumatic brain injury. But a mild injury can act like a severe injury and vice versa, and we don't know why." TBI appears to reduce life expectancy by seven years for those who survive the injury, but that too, says Gordon, is "something we don't yet understand."

Gordon and his team are studying the general population to discover ways to better classify patients who have suffered a TBI. But to accomplish that—to understand how the brain changes after a dramatic injury—Gordon needs access to damaged brains that have recovered.

After Markgraf was broadsided by the truck, the force of his head's collision with the ground caused widespread tearing of the neurons and blood vessels in his brain, resulting in a form of TBI called diffuse axonal injury. For him to regain consciousness after two weeks was very unlikely. The first person to notice a hopeful sign was Brian Edlow, a 26-year-old medical student from New York City who was examining Markgraf on his daily rounds. "I'll never forget when Doug first squeezed my hand," Edlow says. "It was one of the most thrilling experiences I can remember."

Over the next few weeks Markgraf slowly regained consciousness but was confused and found it hard to stay awake. "I wanted to go back to sleep at every moment," he says, "because I thought I was in a dream."

Markgraf suffered a host of complicated medical problems, including depression and post-traumatic amnesia. "Brain injury is really frightening," he says. "You wake up and gain awareness, only to realize you can't trust yourself the way you used to. Nothing works the same way." But with aggressive physical therapy and rehabilitation, things slowly began to make sense to him. "It wasn't until doctors prescribed serious antidepressants that I realized that this horrible thing really happened," he says.

Markgraf also had a vestibular disturbance, which disrupted his sense of balance. If he reached for something, he missed his target. If he stood up, he fell over. A frontal-lobe injury caused other impairments: "I had the physical ability to move my legs, but I couldn't control them," he says. "I could move my arms, but they wouldn't go where I wanted. I couldn't make a complete sentence, but in my brain I thought I was fine."

After several weeks at HUP, Markgraf was transferred to MossRehab in Elkins Park, Pa., one of the premier facilities for patients recovering from TBI. As he recuperated, he became fixated on one thing: getting back on his bike. "Cycling was my avenue to do everything," he says. "It's the reason I studied material engineering—I wanted to put better materials in a bike—and it became the driving force behind my rehab."

When Markgraf arrived at MossRehab, he was in a wheelchair and told he'd be lucky to walk again. "I've never done well with someone telling me I can't do something," he says. During weeks of inpatient rehab and about a year as an outpatient, he regained enough strength and coordination to ride a bike again. On June 27, 2011, about a month after the fifth anniversary of his accident, he began a cross-country ride.

Markgraf cycled 3,200 miles from San Francisco to Toms River, N.J., making stops to speak to patients recovering from TBI. It took him two months. "I did it to show everyone what was possible," he says. He also started Project Mend the Mind to increase awareness of TBI and inspire victims of it. He is one of only a few people in the history of medical literature to have achieved such functional independence after so severe an injury.

ONE YEAR after Markgraf's accident, Brian Edlow graduated at the top of his class at the University of Pennsylvania Medical School. He did his residency in neurology and a fellowship in neurocritical care at Mass General and Boston's Brigham and Women's Hospital. He is now a rising star in the burgeoning field of coma and consciousness neuroimaging. He runs a laboratory that develops techniques to predict outcomes in comatose patients. He is also a member of Wayne Gordon's research collaborative.

Armed with a $5 million MRI machine called a Connectome scanner—the most powerful imaging tool in the world—Edlow began scanning patients at Harvard's Martinos Center for Biomedical Imaging around the time of Goodell's press release in 2012. The scanner produces images in three dimensions with unprecedented detail and clarity. Edlow's first patients were healthy volunteers, who would serve as a control group. When he needed to look at a previously damaged brain, one that had recovered from a devastating injury, he knew whom to call.

Six years and seven months after his bike accident, Markgraf underwent a scan at Harvard. By mapping the connectivity of Markgraf's brain, Edlow and his team saw disruptions within neural networks that likely caused his coma, as well as the intact connections that might have enabled him to recover. These networks were previously undetectable by MRI scanners. Markgraf was, essentially, Patient Zero, and his brain provided crucial information for Gordon's grant proposal to the NFL.

"There are few tools that help physicians predict which patients in traumatic coma will make a recovery like Markgraf's," says Edlow, "and which will be like his neighbor in the neurocritical care unit. That patient had the same type of brain injury but died one month later, never having regained consciousness. And we don't really know why."

Gordon, Edlow and their collaborators are using the NFL's grant to analyze hundreds of living patients who have a history of mild, moderate or severe TBI. Participants undergo a neurobehavioral assessment as well as a genomic analysis. When they die, their brains will be shipped to Edlow and his colleagues at the Martinos Center for the same type of high-resolution MRI performed on Markgraf. Each brain will then undergo a detailed microscopic evaluation by pathologists.

The combination of state-of-the-art imaging and microscopic analysis is expected to yield insights into how TBI causes long-term problems with memory, attention, emotional regulation and other functions. Researchers hope the study will lead to the identification of a biomarker (or markers) that will allow for the diagnosis of traumatic brain disease or CTE while people are still alive, providing a foundation for better treatment.

WHAT TIES the two largest grant proposals together is a quest to understand how the brain responds to injury, whether from a series of concussive or subconcussive blows or from a single massive event. What has become clear from the initial work is that there is a wide variability in response to head trauma, from concussion to coma. "A concussion is a response of the brain to head trauma," says Daniel Perl, head of the Center for Neuroscience and Regenerative Medicine's Brain Repository at Uniformed Services University of the Health Sciences in Bethesda, Md., and one of Gordon's collaborators. "It doesn't define the head trauma; it's a response."

This is a subtle and crucial point, and it has significant implications for the NFL's concussion protocol. If a concussion doesn't properly quantify the severity of a blow to the brain, then the NFL, using its current protocol, might be allowing players to remain on the field who shouldn't—players who have a higher threshold before they exhibit concussion symptoms. Absence of concussion does not equal absence of injury. There were 123 documented concussions and head injuries in the NFL in 2014, but that number might represent only a fraction of significant head injuries.

The league is also funding six small pilot programs designed to improve the diagnosis of concussions and to identify potential biomarkers that could be used to track recovery—something that will benefit athletes of all ages. Given the NFL's previous resistance to acknowledging the widespread incidence of brain injuries in football, there's reason to consider its philanthropy a cynical public relations move. Regardless, the money is supporting the kind of research that might someday explain why Doug Markgraf woke up from a coma and the patient in the hospital bed next to him did not.

PHOTOAL TIELEMANS FOR SPORTS ILLUSTRATEDHANDS ON Edlow (below), the neurologist who noted the first sign of Markgraf's recovery, is now a leading researcher into traumatic brain injury. PHOTORICK FRIEDMAN FOR SPORTS ILLUSTRATED[See caption above]

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Eagle (-2)
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