It’s been called the signature wound of the wars in Iraq and Afghanistan: More than 375,000 service members have suffered a traumatic brain injury (TBI) since 2000, according to the Defense and Veterans Brain Injury Center (DVBIC). In recent years, an average of about 20,000 TBIs occur annually among service members, most of them occurring during active duty.

TBI presents a significant and lasting problem for the military and veteran communities. Nearly 20 percent of the service members deployed to Iraq and Afghanistan have sustained at least one TBI, and nearly 8 percent of all Iraq and Afghanistan veterans demonstrate persistent post-TBI symptoms for more than six months after the initial injury.

TBI, of course, recognizes no line of demarcation between active-duty and veteran status, and its scope and complexity have compelled the DOD and VA to merge their efforts.

Especially troublesome is that about 75 percent of all TBIs are classified as “mild” – mTBIs, or concussions, whose symptoms are subtle and often initially unnoticed by the injured person or physicians. A growing body of research suggests that once these symptoms – including headaches, sleep disturbances, forgetfulness, fatigue, irritability, and depression – emerge, they have a tendency to persist. A study published last year in the Journal of Neurotrauma reported that 15 percent of people with mTBI have symptoms that last a year or more.

The Department of Defense’s (DOD) TBI research, aimed at returning service members to duty, focuses on developing battlefield screening tools, combat casualty care, and rehabilitation. Investigators for the Department of Veterans Affairs (VA) work to develop tools for screening and diagnosing chronic TBI-related conditions and for administering therapies, treatments, and coping strategies.

TBI, of course, recognizes no line of demarcation between active-duty and veteran status, and its scope and complexity have compelled the DOD and VA to merge their efforts. As early as 1992, largely in response to the Gulf War, they established the Defense and Veterans Head Injury Program. Known today as the DVBIC, it operates at 22 sites around the country to prevent and mitigate the consequences of TBI. In response to an Obama administration executive order, a nationwide research effort, the Chronic Effects of Neurotrauma Consortium (CENC), connected researchers from the VA, DOD, and academia to address the long-term effects of mTBI and its diagnosis and treatment. Dr. William Walker, a TBI expert at the Hunter Holmes McGuire VA Medical Center and Virginia Commonwealth University, is leading the CENC’s centerpiece study, launched last year: an ambitious observational study of more than 1,000 service members and veterans, aimed at learning more about mTBI and how it can be better diagnosed, and perhaps prevented and treated.

In 2011, the DVBIC launched a 15-year set of longitudinal studies aimed at, among other things, explaining why some people recover more slowly from TBI; what kinds of brain changes (i.e., differences in biomarkers or neuroimaging) can account for this difference; and why TBI may or may not be associated with other chronic conditions such as chronic pain, sleep problems, mood disorders, or post-traumatic stress disorder (PTSD).

One of these studies, led by Karen Schwab, Ph.D., a DVBIC researcher and faculty member at the Uniformed Services University of the Health Sciences (USU), found that nearly 50 percent of about 1,500 recently deployed service members who’d suffered mTBIs in Afghanistan or Iraq reported at least one severe or very severe post-concussive symptom three months after returning from their deployment. The report sheds light on the need for focused medical follow-up after a concussion.

 

Blast Injury: A Uniquely Military Problem

For years now, DOD and VA research communities have been investigating the presence of biomarkers – proteins or enzymes, usually – that may be associated with brain injury. The DOD’s work in this area was instrumental in the development of a long-sought diagnostic, the Brain Trauma Indicator (BTI™), which became the first U.S. Food and Drug Administration-approved TBI screening tool in February 2018. Manufactured by Banyan Biomarkers, the Brain Trauma Indicator is a blood-testing kit that measures levels of two proteins (GFAP and UCH-L1) associated with head injury. The tool – a historic culmination of a collaboration among military, academic, and public- and private-sector researchers – will help health care professionals manage patient care and decide whether to perform further diagnosis with neuroimaging, such as a CT scan.

Many active-duty TBIs are caused by something much more complex than a knock on the head: blast injury, the physical trauma resulting from direct or indirect exposure to an explosion. Blast trauma may be caused not only by the blunt or penetrating force of expelled debris, but also by the wave of high pressure, known as blast overpressure, that can travel through tissues and damage cells. When DOD established its Blast Injury Research Program in 2007, it classified blast injuries into five categories, from primary to quinary, based on the mechanism of injury.

Because it often causes harm with no discernible signs of injury, blast trauma is of great concern to DOD researchers, in terms of both military member health and unit readiness. The Office of Naval Research (ONR) in Arlington, Virginia, is overseeing the development of a portable system that can measure the likelihood of blast injury, resulting in a “go/no-go” indicator for unit commanders. Timothy Bentley, Ph.D., a program manager with the ONR’s Warfighter Performance Department, describes the system – Blast Load Assessment Sense and Test, or BLAST – as a three-part assessment tool. The first component is a suite of coin-sized sensors, strategically placed on a service member’s helmet and body armor, that measure three blast forces: linear acceleration, rotational acceleration, and blast overpressure.

Data from these sensors is processed and analyzed using algorithms, the second component of BLAST, to calculate the likelihood of brain injury. “That’s done on a statistical probability basis,” Bentley said. “If you get hit with a certain force, we can make a prediction that you are likely or unlikely to have been injured.” The algorithms being developed for the system can be adapted to factor in a person’s previous exposures to blast forces, which have been shown to cause cumulative damage.

If the numbers indicate a possible injury, a service member will make use of the system’s third component, the “brain gauge,” which Bentley describes as a “neurofunctional assessment tool.” The size of a computer mouse, the gauge emits vibrations to stimulate the fingertips in a variety of patterns; the military member’s ability to recognize these patterns will inform a corpsman’s or medic’s decision to recommend the person either stay in the fight or stand down.

“By using the mechanoreceptors, the touch receptors,” Bentley explained, “we can send a very clean signal to your brain.” Studies of animal models have demonstrated a predictable set of neurological responses to sensory stimuli. “They are conserved into people, and they are very well understood. So we have a solid medical and neurological basis for these inputs and outputs.”

BLAST, or a system like it, may provide a more empirical means of determining service members’ fitness for duty after a blast exposure. Current DOD doctrine requires everyone within 50 meters of an explosion to stand down for 24 hours and undergo a mandatory medical evaluation. This poses two logistical problems, Bentley said: First, forward bases are usually small. “If you’re at a forward operating base that’s 100 meters across, and the shell lands in the middle, is everybody in the base supposed say: ‘Stop the war; we’re all standing down for 24 hours’? Of course, that can’t happen. … They’re looking to make people take [blast injury] seriously and to protect people. But there is no real medical basis for that.”

Second, 24 hours isn’t enough time for a medical exam to detect signs of mTBI. The BLAST system can provide a focused triaging tool that directs symptomatic service members into a more thorough evaluation period, while optimizing unit readiness.

Another promising area of research, developed in collaboration with the University of Miami, is just beginning to explore stem cell therapies that may help augment and support injured brain neurons.

As a naval researcher, Bentley is particularly interested in evaluating the effects of explosions in enclosed spaces, such as ships, where shock waves can be reflected and amplified. Future assessments of the BLAST system are in the works: tests of the sensors on mannequins aboard ships, for example, and a Navy/DVBIC clinical trial at Landstuhl Regional Medical Center in Germany, to test the brain gauge on ground troops – breachers and sappers – who use explosives during their training in breaking down obstacles such as doors and walls. “The sensors we’re making are just coming out of development,” Bentley said, “and we hope to get those into field testing – not on people, but on real explosions – this summer, and by the fall, get them onto people.”

 

Treatments: The Short and Long Haul

The upcoming brain gauge trials at Landstuhl mirror a group of studies recently undertaken through one of the Army’s primary conduits for investigations of TBI and its aftermath, particularly those caused by blast. At the Center for Military Psychiatry and Neuroscience (CMPN) at the Walter Reed Army Institute of Research, the blast-induced neurotrauma research group works to characterize the effects of blast injury. Those evaluations have traditionally been pre-clinical studies, involving the manipulation of blast wave variables among animal models, but according to Lt. Col. Jeffrey Thomas, who directs the CMPN, the center has recently extended these evaluations to include settings, such as breacher and sapper training, in which service members and other professionals encounter explosions.

“We have a very robust and fairly new capability to do field studies in training environments with breachers and sappers,” Thomas said, “and groups that are exposed, through their occupation in the military, to repeated low-level blast exposure. We’re … working with training doctrine commands, operational units, even law enforcement organizations, to do some of these studies both with military and paramilitary organizations.”

Understanding the variables associated with explosive blasts, and particularly of repeated low-level blast exposure, helps shape the research agenda of another CMPN research group, brain trauma neuroprotection and neurorestoration, which investigates how to protect warfighters from TBI and to aid in healing and recovery. Treating and healing injured brain tissue remain elusive goals for the research community, for two main reasons: First, the blood-brain barrier, the filtering mechanism that blocks most pathogens from the brain, also keeps out most drugs. There’s no magic pill for treating TBI, nor is there likely to be one; most drug therapies are aimed at associated symptoms, such as increased cranial pressure or seizures. A DOD-sponsored research team at Indiana University-Purdue University Indianapolis recently discovered a compound that may treat hydrocephalus, the overproduction of cerebrospinal fluid that may follow traumatic injury; last spring, a researcher with the VA Pittsburgh Healthcare System reported lab studies suggesting that lithium treatment may be helpful in promoting recovery in the injured brain.

The second factor complicating TBI pharmacotherapy, Thomas said, is that TBI doesn’t happen in isolation. It often accompanies considerable trauma to the rest of the body. “The drugs used to treat these symptoms,” Thomas said, “may have – and often do have – a deleterious effect on other systems in the body.”

CMPN researchers are looking at ways to overcome both of these obstacles – to escort pharmacological compounds past the blood-brain barrier and to target the systems requiring therapy. “The neuroprotection group is looking at different ways to deliver drug therapies,” said Thomas. “They have an exciting new area of research looking into nanoparticle drug delivery.” Finding – or creating – a molecule small enough to penetrate the blood-brain barrier, and to deliver medicine where it needs to be, will be an important milestone in TBI treatment.

Another promising area of research, developed in collaboration with the University of Miami, is just beginning to explore stem cell therapies that may help augment and support injured brain neurons. “We’re hoping to start doing the basic research, and eventually getting into a clinical trial setting years down the road,” Thomas said. “That is an exciting new effort.”

The work of another branch of CMPN research – behavioral biology, whose primary focus is on strategies for maximizing unit readiness and soldier effectiveness – has implications for long-term recovery and coping mechanisms following TBI. In particular, the center, which houses a world-renowned sleep laboratory, is examining the effects of sleep on TBI recovery.

The CMPN’s blast-induced neurotrauma research group has produced enough data, over the years, to yield insights into downstream neural degenerative disease, Thomas said, “and what’s happening in terms of neuroinflammation in the brain, and what may lead to poor outcomes in older individuals who have been through military service.” In encompassing this continuum, the center’s research program is aimed at achieving better long-term medical outcomes for service members who’ve suffered blast-induced TBI – a goal that connects it with the VA’s vast infrastructure for helping veterans with TBI to heal and make the most of their lives after active-duty service.

“It’s always important for us to design things that are going to make people better when they go into the fight,” Thomas said. “But coming out of the fight … the focus needs to be on taking care of somebody who’s had a TBI as best we can, for a lifetime. It’s a significant investment and we do owe them that.”

This article was first published in the Veterans Affairs & Military Medicine Outlook 2018 Spring publication.