In honor of Veterans Day, TR is highlighting a piece on blast-related brain trauma in Iraq, which originally ran in the May 2008 issue. The piece interweaves the stories of two National Guard sergeants who withstood separate blasts while fighting in Iraq in 2004 and the scientists racing to understand the often invisible wounds that resulted.

Soon after the May 2008 issue of the magazine came out, President Bush signed into law the Traumatic Brain Injury (TBI) Act, which reauthorizes federal programs in prevention, education, research, and community living for people with TBI through 2011. In June of this year, the United States Army also issued a new requirement: all soldiers who experience dizziness or loss of consciousness from a blast, a fall, or some other trauma are to receive immediate medical attention. This is especially important because the impact of repeated mild TBI, which can be easy to shrug off and difficult to diagnose, is still unknown. Veterans won another victory soon after, when the government announced its plans to substantially increase disability benefits for veterans with mild TBI.

A few days into his tour of duty at the 86th Combat Support Hospital in Baghdad, Colonel Geoffrey Ling, a U.S. Army neurologist, noticed something unusual. Soldiers who had sustained severe head injuries in blasts from improvised explosive devices (IEDs) appeared to be in much worse shape than he would have expected given his experience with patients who had suffered seemingly similar injuries in car accidents and assaults. The brains of the injured soldiers were swollen and appeared “a very angry red,” he recalls. Some soldiers were conscious and could talk normally but were stumbling around the hospital, unable to keep their balance. “Their [brain] scans were stone-cold normal, and when you talked to them, they seemed fine,” says Ling, who is now a staff physician at Walter Reed Army Medical Center and a program manager in the Defense Sciences Office at the U.S. Defense Advanced Research Projects Agency (DARPA) in Arlington, VA. “But when I started testing them, like asking them to do addition, they were clearly not normal.”

By the time Ling arrived in Iraq, in 2005, thousands of U.S. soldiers had experienced IED attacks. While many of them had survived the concussive blasts, Ling and other physicians had begun to notice that a worrisome number were showing signs of brain damage. Ling, who is a neuroscientist as well as a neurologist, was puzzled. “Why does this injury look different?” he wondered. “What is it in the blast that’s causing it–the pressure, the noise, the cloud of fume?” After months of treating blast wounds in both American troops and Iraqi security forces, Ling had returned from his tour determined to wage war on brain injury. He knew that the answers to these questions could be crucial to protecting soldiers in the field and screening and treating them when they came home.

Traumatic brain injury has been called the signature injury of the Iraq War, in which increasingly powerful IEDs and rocket-­propelled grenades are the insurgents’ weapons of choice. Because they produce such powerful blasts, these weapons often cause brain injuries. Meanwhile, thanks to better body armor and rapid access to medical care, many soldiers whose injuries would have been fatal in previous wars are returning alive–but with head trauma. “With IEDs, the insurgents have by dumb luck developed a weapon system that targets our medical weakness: treating brain injury,” says Kevin “Kit” Parker, a U.S. Army Reserve captain and assistant professor of biomedical engineering at Harvard University who served in southern Afghanistan in 2002. Doctors do not yet fully understand brain injuries, particularly those caused by blasts, and no effective drug treatments exist. Early evidence suggests that explosions, which account for nearly 80 percent of the brain injuries identified at Walter Reed, cause unique and potentially long-lasting damage.

The extent and impact of the brain-injury epidemic are not yet clear, though the U.S. Congress appropriated $300 million last year for research into traumatic brain injury and post-­traumatic stress disorder. The U.S. Department of Defense reports that approximately 30 percent of those evacuated from the battlefield to ­Walter Reed Army Medical Center have traumatic brain injury (TBI). The problem is probably worse than that: the DOD figure does not include brain injuries in soldiers whose wounds were not severe enough to require evacuation or whose injuries were not identified until after they completed their tours. Post-deployment surveys suggest that 10 to 20 percent of all deployed troops have experienced concussions. At worst, thousands of service members could return home with long-lasting problems, ranging from debilitating cognitive deficits to severe headaches and depression to subtler personality changes and memory deficits.

Military doctors are only beginning to get a grasp on the number of soldiers who have suffered mild traumatic brain injury, the medical term for a concussion. Mild injuries are by far the most common type of brain trauma, but they are more easily missed than moderate and severe injuries (they typically don’t show up on standard brain scans), and the lasting effects, especially of repeated concussions, are not yet clear. Surveys of troops to be redeployed in Iraq suggest that 20 to 40 percent still had symptoms of past concussions, including headaches, sleep problems, depression, and memory difficulties. “We don’t know what it means in terms of long-term functional ability,” says William Perry, past president of the National Academy of Neuropsychology.

An Orange Flash
In November 2004, Stephen Kinney, a U.S. National Guard sergeant from North Chelmsford, MA, was patrolling a main supply route through southern Iraq when a buried artillery shell exploded outside the door of his Humvee. The blast propelled the vehicle into the air, riddling the doors with shrapnel. “All I remember is a big orange flash,” says Kinney, who was thrown against the Humvee’s radio, then against the ceiling, and briefly lost consciousness.

More concerned about a bruised hip and swollen shoulder than about his head, Kinney never considered the possibility of brain injury. The doctor who treated him at a military field hospital in Iraq didn’t ask him about losing consciousness, or about his state of mind after the blast. “There were marines coming in from ­Fallujah with their arms blown off,” says Kinney. “They figured if you weren’t bleeding and had all your limbs, you were doing okay.”

It wasn’t until months after Kinney’s return home the following February that he saw a psychiatrist at the local VA hospital and was evaluated for brain injury. He underwent extensive neuro­psychiatric testing, which assessed cognitive capacities such as memory, attention, and higher-order reasoning, and he was diagnosed with mild traumatic brain injury. When Kinney returned to his job with the post office, he began to notice problems. He had ­trouble remembering names and numbers and often forgot whether he had scanned the bar codes on mailboxes along his route, as mail carriers do every 30 to 60 minutes to log their progress. In addition, though he’d been an avid illustrator (while on duty in Iraq he drew a Christmas card depicting a Humvee parked under a decorated palm tree), he hasn’t taken up his colored pencils since he returned.

Despite the designation “mild,” even a single concussion can produce serious symptoms, including severe headaches, difficulty sleeping, problems with memory and concentration, and even changes in personality. “The spouses say, ‘He is totally different–he used to be a quiet guy and now he’s agitated,’ or ‘He used to be energetic and now has no motivation,’” says Jeffrey Barth, a neuropsychologist at the University of Virginia School of Medicine in Charlottesville who has done pioneering work in the study of concussion. “They can also lose the ability to put everything together and to make good judgments.” About half of people who suffer concussions quickly recover. But in the rest, symptoms can linger indefinitely. About 10 percent of concussion victims have problems severe enough to interfere with daily life and work. “No one knows how to treat it, how long it lasts, and whether it’s safe to leave someone deployed,” says Jon Bowersox, chief of surgery at the Cincinnati VA Medical Center and a colonel in the U.S. Air Force Reserve.

Especially worrying is the prospect that troops in Iraq will suffer repeated concussions, reinjuring their brains while they’re still in a vulnerable state. For soldiers patrolling highways and guiding convoys, exposure to multiple blasts is a given; some have reported encountering tens of blasts in a day. In rare cases, multiple concussions in quick succession can lead to serious injury. But subtler damage may also accumulate, leading to depression and cognitive decline. “It’s still an open question,” says Barth. “How many concussions can you have without having a really bad outcome down the road?”

Anatomy of an Explosion
In Iraq, an IED is often buried near a road or hidden in a car and then triggered remotely. Detonating the device sets off a chemical reaction in which anywhere from a few to hundreds of kilograms of explosive expel their energy in a microsecond, compressing the surrounding air into a powerful shock wave. The explosion can also produce an electromagnetic pulse, a wave of electric and magnetic fields that may cause surges in current and voltage. Though blasts and the resulting injuries have been part of warfare for a long time–after the Napoleonic wars, some speculated that people who mysteriously died near firing cannons were injured by excessive vibration in the air–little is known about exactly how a blast wreaks havoc on the brain. (Before newer types of body armor were available, soldiers exposed to blasts often died of lung injury when pressure waves ruptured air-filled tissue; so blast research has largely been concerned with the lungs rather than the brain.)

Most studies of concussion have focused on blunt trauma, as in a blow to the head, not the effects of blasts. To complicate matters, an explosion can cause multiple types of brain injury. For example, when Kinney’s Humvee was blown up, his brain endured the type of rapid acceleration and rotational forces typically seen in a car crash. Such forces, which can send the brain bouncing around inside the skull, can twist or tear axons–the long, thin fibers that connect nerve cells–and induce bleeding and swelling in the brain. But Kinney also felt the forces unique to blasts: the massive pressure wave, the electromagnetic pulse, and the light, heat, and sound from the explosion, all of which may ravage the brain in ways that haven’t been fully documented.

To better understand what a blast does to the brain, Raul ­Radovitzky, an associate professor of aeronautics and astronautics at MIT, and David F. Moore, a neurologist at Walter Reed Army Medical Center who has a doctorate in fluid dynamics, developed a software model incorporating both the physics of pressure waves and the variable properties of the brain’s tissues. Through magnetic resonance imaging, Moore modeled 11 features of the head, including the skull, the cerebrospinal fluid, the brain’s fluid-filled ventricles, the sinuses, the brain’s layer of white matter, and even the fat layer surrounding the eyes. The researchers used that information to create a computer model of the head, which they subjected to a simulated blast, observing how energy transferred from the air to the head affects the different structures. The model highlights the parts of the brain that endure the greatest stress and are thus most vulnerable to injury.

A movie of one simulation shows a rainbow-colored pressure wave propagating through a cross-sectional slice of the head, ricocheting off the skull, and rippling through the brain seemingly at random. So far, using values approximating a pressure wave that would damage the lungs, the model indicates that pressure from a blast far exceeds the minimum level thought to induce impact-related brain injuries. The researchers have also determined that tissue interfaces, such as the boundary between bone and brain, reflect the waves, so those areas are at greater risk. The pressure wave appears to enter the brain predominantly through the eyes and sinuses, and to a lesser extent through the skull, an observation that could influence the design of protective gear. Radovitzky and Moore are testing a new version of the model that includes a helmet, to evaluate how well it shields against the blast wave. “Blast protection for the head has not been a consideration in the design of body armor,” says Radovitzky. “Maybe a small change to the armor could mediate the damage.”

Across the Potomac River at DARPA, Geoffrey Ling has embarked on a similar quest to determine how blasts injure the brain. But unlike Radovitzky and Moore, whose computer model focuses on the pressure wave and its interaction with brain tissue, Ling and his colleagues are using animals, mostly pigs, to study the damage inflicted by each component of the blast: heat, sound, light, pressure wave. “We want to figure out what in that dirty environment causes [the most] injury,” Ling says. “Say it’s pressure or sound. Then we can go back and look for strategies to defeat them.”

The pigs are immobilized in harnesses and then exposed to an explosion powerful enough to cause moderate to severe brain injuries. Since the animals will not be thrown against a wall or hit with debris, the scientists can study the effects of the explosion in isolation. “When exposed to a survivable blast, they have difficulty walking that lasts for days,” says Ling. The explosions also disrupt appetite–all symptoms that mimic those reported by soldiers with blast-induced concussions.

But another finding is surprising. Most scientists have assumed that blast-related injury comes from the pressure wave. ­Preliminary studies from the DARPA program seem to contradict that hypothe­sis. When pigs were put into a specialized wind tunnel that ­generates shock waves like those accompanying blasts, the scientists did not see the same neurological effects found in pigs exposed to explosions. “We had to ramp up the pressure significantly before we saw [brain-related problems],” says Ling. “That made us step back and say, maybe it’s something else, or not the pressure wave alone.”

Radovitzky and Moore say that Ling’s findings can’t be directly compared with their own. Pigs’ skulls are thicker than humans’, for instance, so the interaction of the pressure wave and the pigs’ brains may be different, too. But the apparent contradiction does illustrate just how difficult it is to understand brain injury.

Ling’s team will soon begin studying other potential causes of injury, such as electromagnetic pulses (EMPs). If the EMP from a blast is powerful enough, it can interfere with nearby electronic devices. “The brain is an electrical organ,” says Ling. “If an EMP pulse can take out a radio, why not short-circuit the brain?”

Meanwhile, the pig studies have shed some light on the ­biology of blast-related brain injury. Animals subjected to explosions show signs of neurodegeneration: according to Ling, preliminary results suggest that some of the pigs’ neural fibers start to break down, triggering cell death primarily in the cerebellum (a brain structure involved in balance and coördination) and the frontal lobes (which play a role in impulse control, judgment, problem solving, complex planning, and motivation). As with the injured soldiers, however, it is not yet clear how the test pigs will fare in the long run–whether they will heal, whether their walking deficits will continue, or whether their initial injuries will set off a spiral of neural degeneration. And perhaps most important, it remains uncertain whether pigs exposed to repeated explosions will suffer exponentially more harm than those whose exposure is more ­limited.

Ling is overseeing a study of marines being trained to set controlled explosions, which should provide some evidence of the effects of successive but milder blasts. “Because [they] expose themselves repeatedly to blast, we can determine if, in fact, these repeated exposures cause mild TBI,” says Ling. The marines will undergo cognitive and neuropsychological testing and intensive brain-imaging studies both before and after their training. And because their blast exposure doesn’t occur on the battlefield, they are unlikely to experience the combat stress that can complicate the diagnosis of brain injury.

Mixed Signals
On May 20, 2004, Jerry Pendergrass’s convoy was ambushed. The National Guard sergeant was standing outside his Humvee when a rocket-propelled grenade landed a few feet behind him and exploded, launching him 15 feet in the air. A few moments later, Pendergrass found himself lying on the ground, shrapnel lodged in his leg and his helmet several yards away. He was conscious but unsure of where he was, classic signs of concussion. Another member of his unit pulled him behind the protective barrier of the disabled Humvee, where they awaited evacuation to a medical checkpoint in a secure zone down the road.

Pendergrass soon returned to duty, ignoring the persistent headaches and the sleep, memory, and balance problems that plagued him after the blast. When his tour was up and he returned home to North Carolina, he took prescription painkillers and drank, trying to wash away both his memories of war and the reality of his health problems. It wasn’t until he began a second tour–and was evacuated two months later for spinal damage linked to the earlier blast–that he realized the full extent of his injuries. He was diagnosed with both mild traumatic brain injury and post-traumatic stress disorder (PTSD)–a condition, first defined in Vietnam veterans, that can develop after exposure to a terrifying event. “Big bangs scare the living fart out of me,” says Pendergrass, in a conference room at the Lakeview Virginia NeuroCare center in Charlottesville, VA. He seems startled by even small noises, jumping as a nearby copy machine is jostled into action.

Pendergrass has spent the last three months at NeuroCare, which is partnered with the Defense and Veterans Brain Injury Center. The small in-patient clinic, with an adjacent residence for patients, offers intensive therapy and is staffed by occupational and physical therapists, speech and language therapists, and clinical psychologists. Pendergrass is getting psychological counseling for PTSD and rehabilitation for his brain injury.

He expects to return home soon, but his recovery is complicated by his dual diagnosis. In blast-injured soldiers, PTSD and mild brain injury often occur together. The two conditions also share symptoms–including depression, memory and attention deficits, sleep problems, and emotional disturbances–and research suggests that they can aggravate each other. A 1998 study of veterans with PTSD found that those exposed to blasts were more likely to have lingering attention deficits and abnormal brain activity that persisted long after the injury. And a study published earlier this year in the New England Journal of Medicine found that the 15 percent of soldiers who reported having suffered concussions had a much greater risk of developing PTSD: 44 percent of soldiers who had lost consciousness on the battlefield met criteria for PTSD, compared with 16 percent of those in the same brigades who suffered other injuries.

However, the two conditions can have different prognoses. While PTSD is a serious anxiety disorder, it can often be treated effectively with psychological and drug therapies. Patients with moderate to severe TBI have a far grimmer prognosis. Even ­people with concussions, who often get better on their own, can have enduring damage: symptoms that linger more than six months may be permanent. No drug treatments have proved effective for curing long-term symptoms, and other therapies are limited. For the most part, patients are simply taught new strategies for dealing with their impairments, such as carrying notepads to help them remember important tasks or designating specific spots for their keys.

Determining the true extent of the Iraq War’s brain-injury epidemic will require sorting out whether individual patients’ persistent symptoms are caused pri­marily by PTSD or by physical trauma. Statistical analysis from the New England Journal of Medicine study found that lasting symptoms could be attributed largely to PTSD and depression rather than to brain injuries themselves. But the conclusion is controversial. “I think that’s minimizing the potential effects of concussion in this equation,” says Barth, the University of Virginia neuropsychologist.

The debate over whether the mental wounds of war are biological or psychological has recurred in one form or another in every major war of the last century, ever since powerful explosives became widespread on the battlefield. During World War I, military doctors coined the term “shell shock” to describe the plight of soldiers who stumbled into army hospitals afflicted by dizziness and confusion, uncontrollable twitching, or an inability to speak. At first, doctors attributed the symptoms to brain damage caused by the frequent explosions that characterized the new trench warfare. But as soldiers who had never been exposed to blasts began reporting similar complaints, military psychiatrists started to suspect a sort of ­combat-­triggered hysteria. A labeling system used by the British army at the time suggests the difficulty of distinguishing between the two problems (and the moral opprobrium attached to those whose condition was deemed psychological). Victims were designated either “shell-shock wounded,” meaning the symptoms arose after the soldier was shelled, or “shell-shock sick,” meaning the symptoms were not linked directly to an explosion. Only those with “wounded” status were awarded pensions and granted the honor of wearing “wound stripes” on their uniforms.

Walter Reed’s David Moore hopes that new imaging technologies will finally resolve the debate by identifying the subtle neurological damage inflicted by concussion. One promising technology is diffusion tensor imaging (DTI), a variation on traditional magnetic resonance imaging (MRI) that highlights white matter, the long nerve fibers connecting brain cells. Recent studies of people with mild traumatic brain injury (from car accidents, for example) suggest that changes in the organization of the brain’s white matter correlate with patients’ cognitive deficits. Preliminary evidence suggests that patients who show the greatest disruption of white matter early on also have the poorest outcomes.

In a large, ongoing study at Walter Reed, which Moore is overseeing, researchers will use DTI to compare returning soldiers who have experienced blasts and report the hallmarks of concussion–loss of consciousness or situational awareness–with a military control group reporting no previous brain injuries. The scientists hope the images will help them identify specific brain changes linked to concussion, which will make it easier to diagnose the injury and predict its outcome.

Overwhelmed
Three years after Geoffrey Ling’s time in Iraq, his war on brain injury has really just begun. Scientists have preliminary evidence that forces unique to blasts can damage the brain directly, independent of any blunt injuries that the blast might also cause. The key questions, however, remain unanswered. Which aspects of the blast do the most damage? How can the military better protect its personnel? And perhaps most important for legions of soldiers on patrol, can repeated exposure to weak blasts lead to long-­lasting brain damage?

The prognosis for soldiers returning home with symptoms of brain damage is not encouraging. Decades of research into ­civilian head trauma have come to very little; treatments that seemed promising in animal models have turned out to be ineffective in human tests. “It’s a completely untapped area of medical development,” says trauma surgeon Jon Bowersox. While the military is testing a handful of existing drugs, there’s a “time mismatch” when it comes to developing new treatments specifically for traumatic brain injury, Bowersox observes. “The military is interested in developing products they can have out during the current war,” he says. “They are not used to the fact that medical development has a longer time line.”

Even the few therapies that do exist will be difficult to deliver to everyone who needs them. “What will we do with all these people?” asks Barth. “We’re talking about thousands. This is going to overwhelm the VA hospitals.” The military is preparing some of those hospitals to better deal with brain injury, hiring neuro­psychologists to make diagnoses and other experts to run rehabilitation programs. But resources are limited. At some of the medical centers, “physicians haven’t had any training in rehabilitation other than clinical medicine,” says Bowersox.

Perhaps the greatest challenge will be to help injured soldiers resume their previous lives. “Young people are not equipped emotionally and financially to handle this,” says Marilyn Price ­Spivack, founder of the Brain Injury Association of Massachusetts, which has recently begun an outreach effort aimed at veterans. “Often they can’t go back to their civilian jobs and are very hard to employ.”

The goal of facilities like NeuroCare is to return people to service or to their civilian jobs. But even a quick visit with some of the patients shows what a long road that will be for many of them. In the clinic, one patient apologizes as he twitches uncontrollably. Another abruptly leaves the room, suddenly overcome with anxiety. And ­Pendergrass, who has had serious balance problems since he was injured, is unlikely to be able to return to his previous job hanging power lines. He doesn’t yet know what he’ll do when he leaves the rehab center.

Emily Singer is TR’s biotechnology and life Sciences editor.