FDA authorizes marketing of first blood test to aid in the evaluation of concussion in adults

The U.S. Food and Drug Administration today permitted marketing of the first blood test to evaluate mild traumatic brain injury (mTBI), commonly referred to as concussion, in adults. The FDA reviewed and authorized for marketing the Banyan Brain Trauma Indicator in fewer than 6 months as part of its Breakthrough Devices Program.

Most patients with a suspected head injury are examined using a neurological scale, called the 15-point Glasgow Coma Scale, followed by a computed tomography or CT scan of the head to detect brain tissue damage, or intracranial lesions, that may require treatment; however, a majority of patients evaluated for mTBI/concussion do not have detectable intracranial lesions after having a CT scan. Availability of a blood test for concussion will help health care professionals determine the need for a CT scan in patients suspected of having mTBI and help prevent unnecessary neuroimaging and associated radiation exposure to patients.

“Helping to deliver innovative testing technologies that minimize health impacts to patients while still providing accurate and reliable results to inform appropriate evaluation and treatment is an FDA priority. Today’s action supports the FDA’s Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging—an effort to ensure that each patient is getting the right imaging exam, at the right time, with the right radiation dose,” said FDA Commissioner Scott Gottlieb, M.D. “A blood-testing option for the evaluation of mTBI/concussion not only provides health care professionals with a new tool, but also sets the stage for a more modernized standard of care for testing of suspected cases. In addition, availability of a blood test for mTBI/concussion will likely reduce the CT scans performed on patients with concussion each year, potentially saving our health care system the cost of often unnecessary neuroimaging tests.”

According to the U.S. Centers for Disease Control and Prevention, in 2013 there were approximately 2.8 million TBI-related emergency department visits, hospitalizations and deaths in the U.S. Of these cases, TBI contributed to the deaths of nearly 50,000 people. TBI is caused by a bump, blow or jolt to the head or a penetrating head injury that disrupts the brain’s normal functioning. Its severity may range from mild to severe, with 75 percent of TBIs that occur each year being assessed as mTBIs or concussions. A majority of patients with concussion symptoms have a negative CT scan. Potential effects of TBI can include impaired thinking or memory, movement, sensation or emotional functioning.

“A blood test to aid in concussion evaluation is an important tool for the American public and for our Service Members abroad who need access to quick and accurate tests,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health. “The FDA’s review team worked closely with the test developer and the U.S. Department of Defense to expedite a blood test for the evaluation of mTBI that can be used both in the continental U.S. as well as foreign U.S. laboratories that service the American military.”

The Brain Trauma Indicator works by measuring levels of proteins, known as UCH-L1 and GFAP, that are released from the brain into blood and measured within 12 hours of head injury. Levels of these blood proteins after mTBI/concussion can help predict which patients may have intracranial lesions visible by CT scan and which won’t. Being able to predict if patients have a low probability of intracranial lesions can help health care professionals in their management of patients and the decision to perform a CT scan. Test results can be available within 3 to 4 hours.

The FDA evaluated data from a multi-center, prospective clinical study of 1,947 individual blood samples from adults with suspected mTBI/concussion and reviewed the product’s performance by comparing mTBI/concussion blood tests results with CT scan results. The Brain Trauma Indicator was able to predict the presence of intracranial lesions on a CT scan 97.5 percent of the time and those who did not have intracranial lesions on a CT scan 99.6 percent of the time. These findings indicate that the test can reliably predict the absence of intracranial lesions and that health care professionals can incorporate this tool into the standard of care for patients to rule out the need for a CT scan in at least one-third of patients who are suspected of having mTBI.

The Brain Trauma Indicator was reviewed under the FDA’s De Novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no prior legally marketed device.

The FDA is permitting marketing of the Brain Trauma Indicator to Banyan Biomarkers, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Havana Embassy Staff: ‘Concussion Without Concussion’?

JAMA study finds real brain injuries, but no hard evidence as to the cause


Action Points

  • Persistent cognitive, vestibular, and oculomotor dysfunction, sleep impairment and headaches were observed among US government personnel in Cuba, associated with reports of directional audible and/or sensory phenomena of unclear origin, and without history of head trauma.
  • Note that the initial symptoms appeared to be auditory related and an expert panel concluded that the findings of the triage otolaryngology evaluations most likely were related to neurotrauma from a non-natural source.

Examinations of U.S. Embassy personnel who developed neurological symptoms in 2016 while stationed in Havana, Cuba, indicated that they really did sustain brain injuries, even though none of the individuals experienced head trauma, researchers reported in JAMA.

The embassy employees reported persistent cognitive, vestibular, and oculomotor problems plus sleep impairment and headaches after experiencing an intensely loud, unusual noise or sensation of unknown origin, according to Douglas Smith, MD, and colleagues at the University of Pennsylvania in Philadelphia.

The symptoms resemble mild brain traumatic injury, or concussion, they reported in JAMA. It is unclear if or how the noise is related to the symptoms, and the report shed no light on what else might have caused the symptoms. Some have speculated that the embassy personnel were attacked with an acoustic weapon beamed from outside the embassy.

“These patients are having problems with working memory, sustained attention, and concentration,” co-author Randel Swanson II, DO, PhD, said in an accompanying podcast interview. Like concussion patients, work takes more energy for these people because they lack cognitive reserve. “Something’s happened to the network and it takes them so much more energy so they’re fatigued and by the end of the day, they have massive headaches,” he said.

“This is really concussion without concussion,” Smith added.

In late 2016, U.S. government personnel in Havana reported various neurological symptoms after experiencing strange sounds, described mostly as loud and high pitched, that were associated with a sensation described as pressure-like or vibratory. Initial symptoms appeared to be auditory related and led to a triage program centered on otolaryngology evaluations for embassy community members at the University of Miami. Sixteen individuals who heard the sound presented neurological signs and symptoms that resembled a concussion. Over time, eight additional people reported similar problems.

In July 2017, the U.S. Department of State convened an expert panel which concluded that the triage findings most likely were related to neurotrauma from a non-natural source and recommended further study at the University of Pennsylvania Center for Brain Injury.

Of 24 individuals with suspected exposure to the noise or sensation, 21 completed multidisciplinary evaluation an average of 203 days later. The group included 10 men (average age 39) and 11 women (average age 47).

Nearly all — 20 of 21 people, or 95% — reported immediate neurological symptoms associated with the noise. One individual woke from sleep with acute symptoms including headache, unilateral ear pain, and hearing changes, but did not experience the phenomena.

Twenty embassy personnel reported persistent symptoms — ones that lasted for more than 3 months — that included cognitive (81%), balance (71%), and auditory (68%) problems, sleep impairment (86%), and headaches (76%).

Objective findings included cognitive (76%), vestibular (81%), and oculomotor (71%) abnormalities, the researchers noted. Three individuals experienced moderate to severe sensorineural hearing loss. Fifteen people (71%) required medication for sleep dysfunction and 12 (57%) for headache. Fourteen people stopped working; seven eventually returned to work with restrictions, home exercise programs, and cognitive rehabilitation. All 21 patients had MRI neuroimaging and most had conventional findings within normal limits.

Several important factors need to be considered in this case series, observed Christopher Muth, MD, of Rush University Medical Center in Chicago, and Steven Lewis, MD, of Lehigh Valley Health Network in Allentown, Pennsylvania, in an accompanying editorial.

While the embassy employees were in a common geographic area when their symptoms first appeared, not everyone had the same symptoms. It’s unclear whether individuals who developed symptoms later knew about previous reports, they noted.

“Furthermore, the quantitative results for specific tests (e.g., neuropsychological tests) are not yet available for all affected patients, so independent assessment as to the scope and severity of deficits among all individuals remains challenging,” they wrote.

And the analogy to concussion may be not be quite right because many of the symptoms described also occur in conditions like persistent postural-perceptual dizziness (PPPD), they noted, although “PPPD alone does not appear to explain the entirety of the symptoms reported nor the clustering of individuals affected.”

The symptoms have raised outside concerns about delusional disorders or mass psychogenic illness. But several of the manifestations in this group of patients — including the oculomotor and vestibular testing abnormalities — could not have been manipulated, the researchers maintained.

“Furthermore, mass psychogenic illness is often associated with transient, benign symptoms with rapid onset and recovery often beginning with older individuals,” they wrote. “In contrast, the Havana cohort experienced persisting disability of a significant nature and are broadly distributed in age.”

“Rather than seeking time away from the workplace, the patients were largely determined to continue to work or return to full duty, even when encouraged by healthcare professionals to take sick leave,” they added.

The researchers plan further neuroimaging to evaluate the embassy employees. “Since the clinical features appear so similar to concussion, we will use diffusion tensor imaging and advanced MRI that examines the connectivity of the brain’s network,” Smith told MedPage Today. “This is commonly shown disrupted in concussion. However, if we do find changes, we anticipate that the distribution will be different than in concussion, where some findings are related to head impact.”

In the meantime, the State Department issued a level 3 travel advisory to Cuba, recommending that Americans reconsider trips there due to “health attacks directed at U.S. Embassy Havana employees.”

Blood Test for Concussion OK’d

Helps inform management, including decision on whether CT scan is indicated

 A blood test aimed at guiding management of patients suspected of having concussion won FDA approval on Wednesday, the agency said.

The test, which measures levels of two proteins in blood, does not by itself provide a firm yes/no as to whether a patient has suffered a brain injury. Rather, it’s an indicator of the likelihood that a CT scan will show intracranial lesions, and hence may be valuable in deciding whether CT scans are indicated.

Currently, it’s routine to order a CT scan for all patients with suspected closed head injuries, the FDA noted, but most scans do not show detectable lesions. The blood test is thus expected to cut down on these unhelpful scans and the associated radiation exposure.

Developed by Banyan Biomarkers, the Brain Trauma Indicator test is a quantitative assay for ubiquitin carboxy-terminal hydrolase L1 and glial fibrillary acidic protein, which are released into the blood following neural injury. The test should be performed within 12 hours of injury; results are available in 3-4 hours, the FDA said.

Trial data involving nearly 2,000 individuals with with suspected concussion or mild traumatic brain injury (mTBI) showed that the test was 97.5% accurate in identifying those with visible lesions on CT scans, and 99.6% accurate in predicting those who did not show such lesions.

“These findings indicate that the test can reliably predict the absence of intracranial lesions and that healthcare professionals can incorporate this tool into the standard of care for patients to rule out the need for a CT scan in at least one-third of patients who are suspected of having mTBI,” the agency said.

New Data Challenge Beliefs About Concussion

Experts respond to recent study implicating repetitive small blows to the head

New research is challenging the notion that the serious brain damage now seen in professional football players is caused mainly by blows to the head leading to overt concussions.

In a study published in Brain, researchers from Boston University examined the brains of eight teenagers and young adults. Four had “recent sports-related closed-head impact injuries sustained 1 day to 4 months prior to death.” Four had no such history. The researchers found evidence of chronic traumatic encephalopathy (CTE) in the four teenagers who had recent head injury. “These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy,” the researchers concluded. It may be the best evidence yet that it is the routine head impacts that occur on virtually every play, and not concussions per se, that cause CTE.

This research raises questions about the NFL’S efforts to deal with concussions. It also may influence what advice physicians give to parents who ask about whether their children should play youth football.

Below, the NFL’s chief medical officer, a professor of emergency medicine and neurosurgery, and a pediatrician discuss these questions.

Allen Sills, MD, NFL chief medical officer, past co-director of the Vanderbilt Sports Concussion Center

“Important research advancements have been made over the last several years around traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), which have aided awareness and understanding around this important issue. As highlighted in the most recent study, repetitive hits to the head have been consistently implicated as a cause of CTE by this research group. How and why exactly this manifests, who is at risk, and why — these are questions that we as researchers and clinicians are working to answer.

“As the research community continues to explore these critical questions, the NFL has made significant strides to try to better protect our players and reduce contact to the head including implementing data-driven rules; changes intended to eliminate potentially dangerous tactics and reduce the risk of injuries, especially to the head and neck; enforcing limits on contact practice; and mandating ongoing health and safety education for players and training for club and non-affiliated medical personnel.

“For kids, being active, getting outside, playing sports, particularly team sports, is important. There are also concerns about the risks involved in playing sports, including football, which is why it has been encouraging to see similar developments at the youth level such as the certification of over 130,000 youth and high school coaches through USA Football’s Heads Up program; USA Football’s National Practice Guidelines — including limits on full contact; Pop Warner’s initiatives, from no intentional head-to-head contact to requiring players who suffer a suspected head injury to receive medical clearance from a concussion specialist before returning to play; and 50 states have a Return to Play law, which can help reduce the rates of recurrent concussions. We hope that all youth sports will continue to take measures to reduce head contact through similar rules changes, education, and improved protective equipment.”

Jeffrey Bazarian, MD, MPH, professor of emergency medicine, physical medicine and rehabilitation, neurology, neurosurgery, and public health science, University of Rochester

The National Football League has done an admirable job of supporting research to better identify, prevent and treat sport-related concussions. But more recent research data suggest that the real threat to the long-term neurologic health of contact athletes like football players is not concussion, but the repetitive head hits that do not result in acute symptoms of concussion. These head hits are experienced by all players during nearly every football practice and game. They have been associated with acute changes in brain function and structure, and with short-term cognitive deficits. They have also been reported to have clinically-relevant, long-term adverse consequences on the brain. Repetitive head hits experienced by football players should be reconceived as an occupational exposure that can be assessed, controlled, and managed. The NFL is uniquely positioned to foster research to identify, prevent, and treat the neurologic consequences of these hits, and would be wise to turn its attention in the direction of repetitive head hits as soon as possible.

Steven Hicks, MD, assistant professor of pediatrics, Penn State Health and Milton S. Hershey Medical Center

As a general pediatrician, I believe we can do several things to make sports like football (with high concussion risk) safer for our children: 1) be open to rule changes that may make the game safer by minimizing concussive events; 2) ensure that medical personnel are on the sideline at games, to accurately assess potential concussions and ensure that concussion guidelines are followed; 3) teach children to tackle safely and reduce full-contact scenarios in daily practice; and 4) support research that improves our understanding, prevention, and treatment of concussions. Making decisions about youth football participation will require us to balance risks and benefits. By minimizing concussion risks on the field we can hopefully find ways to allow children to continue to benefit from participation in this team sport.

Brain changes seen in youth football players without concussion.

Researchers have found measurable brain changes in children after a single season of playing youth football, even without a concussion diagnosis, according to a new study.

MR images of left inferior fronto-occipital fasciculus (top) before and (middle) after the playing season, and (bottom) the overlay. In the overlay (bottom), the red region is after the season and the blue region is before the season.

Researchers have found measurable brain changes in children after a single season of playing youth football, even without a concussion diagnosis, according to a new study published online in the journal Radiology.

According to USA Football, there are approximately 3 million young athletes participating in organized tackle football across the country. Numerous reports have emerged in recent years about the possible risks of brain injury while playing youth sports and the effects it may have on developing brains. However, most of the research has looked at changes in the brain as a result of concussion.

“Most investigators believe that concussions are bad for the brain, but what about the hundreds of head impacts during a season of football that don’t lead to a clinically diagnosed concussion? We wanted to see if cumulative sub-concussive head impacts have any effects on the developing brain,” said the study’s lead author, Christopher T. Whitlow, M.D., Ph.D., M.H.A., associate professor and chief of neuroradiology at Wake Forest School of Medicine in Winston-Salem, N.C.

The research team studied 25 male youth football players between the ages of 8 and 13. Head impact data were recorded using the Head Impact Telemetry System (HITs), which has been used in other studies of high school and collegiate football to assess the frequency and severity of helmet impacts. In this study, HITs data were analyzed to determine the risk weighted cumulative exposure associated with a single season of play.

The study participants underwent pre- and post-season evaluation with multimodal neuroimaging, including diffusion tensor imaging (DTI) of the brain. DTI is an advanced MRI technique, which identifies microstructural changes in the brain’s white matter. In addition, all games and practices were video recorded and reviewed to confirm the accuracy of the impacts.

The brain’s white matter is composed of millions of nerve fibers called axons that act like communication cables connecting various regions of the brain. Diffusion tensor imaging produces a measurement, called fractional anisotropy (FA), of the movement of water molecules in the brain and along axons. In healthy white matter, the direction of water movement is fairly uniform and measures high in FA. When water movement is more random, FA values decrease, which has been associated with brain abnormalities in some studies.

The results showed a significant relationship between head impacts and decreased FA in specific white matter tracts and tract terminals, where white and gray matters meet.

“We found that these young players who experienced more cumulative head impact exposure had more changes in brain white matter, specifically decreased FA, in specific parts of the brain,” Dr. Whitlow said. “These decreases in FA caught our attention, because similar changes in FA have been reported in the setting of mild TBI.”

It is important to note that none of the players had any signs or symptoms of concussion.

“We do not know if there are important functional changes related to these findings, or if these effects will be associated with any negative long-term outcomes,” Dr. Whitlow said. “Football is a physical sport, and players may have many physical changes after a season of play that completely resolve. These changes in the brain may also simply resolve with little consequence. However, more research is needed to understand the meaning of these changes to the long-term health of our youngest athletes.”

Shock Waves May Create Dangerous Bubbles in the Brain

Lab experiments show how people who survive explosions may still carry cellular damage that can cause psychological problems

A bomb blast engulfs a mountainside near the town of Barg-e Matal in Afghanistan. 
 Advances in body armor and helmet design mean that more soldiers will survive being close to a blast from a roadside bomb or enemy fire. But many people come back from the battlefield with brain injuries that aren’t immediately visible and are hard to detect even with advanced scans. The trouble is that it’s unclear just what a blast wave does to the brain.

Christian Franck, an assistant professor of engineering at Brown University, is trying to change that by imaging small groups of brain cells in 3D and taking movies of neurons exposed to tiny shocks. The idea is to see exactly how individual brain cells change shape and react in the hours after trauma.

Some 25,000 servicemen and women suffered traumatic brain injuries in 2014, according to the U.S. Department of Defense. Only 303 of the injuries were “penetrating,” or the kind that leave visible wounds. The rest were from various forms of concussion caused by events such as explosives, falls and vehicle accidents.

Most of those injuries—about 21,000—were considered mild, which means that the person was confused, disoriented or suffered memory loss for less than 24 hours or was unconscious for 30 minutes or less. Such patients don’t usually get brain scans, and if they do, the images generally look normal.

Christian Franck, an assistant professor of engineering at Brown University, is trying to change that by imaging small groups of brain cells in 3D and taking movies of neurons exposed to tiny shocks. The idea is to see exactly how individual brain cells change shape and react in the hours after trauma.

Some 25,000 servicemen and women suffered traumatic brain injuries in 2014, according to the U.S. Department of Defense. Only 303 of the injuries were “penetrating,” or the kind that leave visible wounds. The rest were from various forms of concussion caused by events such as explosives, falls and vehicle accidents.

Most of those injuries—about 21,000—were considered mild, which means that the person was confused, disoriented or suffered memory loss for less than 24 hours or was unconscious for 30 minutes or less. Such patients don’t usually get brain scans, and if they do, the images generally look normal.

That’s a problem, Franck says, because psychological problems arising from concussive head injuries can come from cell-level damage, since the brain “rewires” as it tries to heal.

“The rewiring takes place after the insult, so you don’t notice,” Franck says. “We want to see at the cellular scale how fast these cells are being deformed. With blunt trauma we have a much bigger database. With explosions, it’s mostly people in the armed services, and they’re having a hard time because they’d like to access treatment and get help, but they don’t know what to screen for.”

Past experiments with rats have shown brain damage from explosive blasts, especially to the hippocampus, but did not look at the cellular level. And while previous studies in humans have examined brain cells in head injury cases, the tissue has only come from patients who were already dead.

Since we can’t peer inside a live human brain as it is being concussed, Franck grew cells from rat brains on biological scaffolding inside a gel-like substance. The setup allows the cells to grow in clusters similar to how they would bunch up in a brain.

The cells aren’t as densely packed and are not doing all the things that brain cells would usually do, but they do provide a rough analogue. Franck can then expose these brain-like bundles to shock waves to see what happens.

A blast wave is different from, say, getting hit in the head with a brick, because the time scale is much shorter, Franck says. A typical smack in the head happens over the course of a few thousandths of a second, whereas a blast wave lasts for just millionths of a second. In addition, the effects of a blast wave don’t have a single, focused point of origin, as with a physical strike.

Franck is working with a hypothesis that shock waves from explosions cause a phenomenon in the human brain called cavitation—the same process that makes bubbles in the water near a boat propeller. The theory of cavitation in brains isn’t new, and there is pretty solid evidence that cavitation happens, but we don’t have the right observations yet to clinch it as the cause of cell damage.

According to the theory, as a blast happens near a soldier, shock waves move through the skull and create small regions of low pressure in the liquids that surround and permeate the brain. When the pressure in some regions gets low enough, a small space or cavity opens up. A tiny fraction of a second later, the low-density region collapses.

Since the cavities aren’t perfectly spherical, they collapse along their long axes, and any cells nearby either get crushed inside the cavity or get hit with a blast of high-density fluid shooting from the ends. It seems obvious that such an event would damage and kill cells, but it’s far from clear what that damage looks like.

That’s why Franck made movies of his lab-grown brain cells and presented his findings this week at the 68th annual meeting of the American Physical Society’s Division of Fluid Dynamics in Boston. To simulate cavitation from an explosion, he fired laser beams at the cellular clumps. The brief laser shots heated up bits of the gel holding together the cell matrix, creating cavities.

He used a white LED coupled to a microscope and a diffraction grating, which generates images from two different perspectives to scan the laser-blasted cells repeatedly. Each snapshot makes a 3D picture of the cells using the two images to generate a kind of 3D movie. Franck then watched the cells for a day to see what they did and if they died.

The experiment showed clear indication of cell damage due to cavitation. But it’s just a first step: The inside of a brain is not uniform, which makes calculating the actual impact of cavitation difficult. In addition, modeling the effects of a blast wave is hard, because the fluid involved is fairly complex, says Jacques Goeller, an engineer at Advanced Technology and Research Corporation who is now semi-retired. He experimented with putting the heads of corpses in the paths of shock waves, which provided indirect evidence for cavitation during a blast.

But another complicating factor is that skulls vibrate at certain frequencies, which can affect how much they deform and trigger cavitation. “As the skull is vibrating, it can cause another series of bubbles,” Goeller says.

On the bright side, in Franck’s experiment it’s possible to control the size of the bubbles and their position, as well as the properties of the gel. That means future research can use the same setup to test multiple possible scenarios.

The injuries these lab cells suffer can then be compared to real brains from concussion victims to get a better picture of what’s happening. That should make it easier to develop treatments and diagnoses.

Franck agrees, though, that there’s still some way to go before researchers know for sure how blasts affect the brain. “It’s a lot of work in progress still,” he said. “We’re about half way through this.”

Experimental Collar Minimizes Effects of Concussion

An experimental collar reduces signs of brain damage in athletes who play contact sports, researchers report.

“This device clearly has potential to reduce the effects of concussions,” said Amit Reches, PhD, from ElMindA, a brain imaging company in Herzliya, Israel.

The collar compresses the jugular vein, increasing the volume of blood in the cranium and reducing the brain slosh that occurs with sudden motion, explained Gregory Myer, PhD, from Cincinnati Children’s Hospital Medical Center.

In trials of hockey and football players, those who wore the collar showed fewer changes in their brain structure, measured by diffusion tensor imaging, and in their brain functioning, measured by electroencephalography, Drs Reches and Myer reported.

The pair presented results from the trial of 14 male high-school hockey players here at the American College of Sports Medicine 2016 Annual Meeting. The study will be published in Frontiers in Neurology next week, and a related trial of 62 football players will be published next week in the British Journal of Sports Medicine, Dr Myer said.

The collar might help prevent concussions outside of sports as well, he told Medscape Medical News.

Potential Military and Car-Safety Applications

“If the theory is correct, it could have large-scale application in the military,” Dr Myer pointed out. And “it could affect how seat belts and child seats are made.”
Concerns about traumatic brain injury in sports have grown in recent years, with reports that many athletes, particularly football players, suffer long-term damage from repeated impact to the head.

Although helmets can protect against skull fractures and lacerations, they do not mitigate the effects of sudden acceleration and deceleration that occur within the skull, Dr Myer explained.

Inventor David Smith got the idea for the collar by observing woodpeckers who subject their brains to shock waves when they chisel trees with their beaks. He noticed that they use their tongues to constrict their own jugular veins, according to Dr Myer.

Slight pressure on the jugular vein decreases return blood flow and increases compensatory volume in the cerebrum. “It’s basically putting a kink in the hose,” said Dr Myer. This leaves less room for the brain to move with each impact, he added.

The rate of football-related concussion is lower at high altitudes because of a similar increase in volume in the cranium, research has shown.

This approach is innovative.
The collar is not uncomfortable, said Dr Myer. He compared it to wearing a necktie. “It doesn’t take a lot of pressure to close down a vein,” he said. “We’re not trying to increase intracranial pressure. We’re trying to build up compensatory reserve. It’s similar to what you would see lying down.”

To test the effects, Dr Myer and his colleagues randomly assigned seven hockey players to wear the collar and seven to not wear the collar. Mean age of the players was 16.3 years.

Players’ brains were assessed before and in the middle of the hockey season, and any impact on a player’s brain during play was measured with an accelerometer. The researchers had hoped to crossover the groups at midseason, but only four of those not wearing the collar were willing to start wearing it at that point.

Head impacts were similar in the two groups.

The researchers found that diffusion tensor measures of disruption increased significantly from preseason to midseason in the white matter of the boys who did not wear the collars, particularly in the corpus callosum, corona radiata, and internal and external capsule (P < .05).

Brain network activation, a measure of neurologic functioning imaged by electroencephalography, was different in the collar and noncollar groups.

In the players who did not wear the collar, there was a significant correlation between changes in white matter and changes in brain network activation (Spearman’s rho, 0.89; P < .001).

Likewise, there was a correlation between boys who experienced more head impacts during the half-season and more changes in the brain network activation (Spearman’s rho, 0.82; P = .023).

Such correlations proved even stronger in the soon-to-be-published study of 62 football players, Dr Myer reported.

After the presentation, one person in the audience wanted to know if any adverse reactions could be attributed to the collar.

“That’s an important question,” Dr Myer responded. “We have done a lot of safety trials,” but so far, tests of oxygen uptake, urinalysis, and blood analysis have not shown any adverse effects. And the collar does not appear to affect an athlete’s power, strength, vertical jump, reaction time, or hearing, he said.

Athletes did not seem to mind wearing the collar, he added. In fact, the compliance rate was 94%.

Session moderator Kevin Guskiewicz, PhD, from the University of North Carolina at Chapel Hill, asked whether the white matter in the players who did not wear the collar eventually returns to normal.

“We think so, but we don’t know,” said Dr Myer.

This approach is “innovative,” said Erik Swartz, PhD, from the University of New Hampshire in Durham.

“It’s certainly interesting to try to get inside the brain,” he told Medscape Medical News. “Of course, it’s a small study. But I do like that they are trying to get at the physiological differences.”

Researchers film early concussion damage, describe brain’s response to injury.

There is more than meets the eye following even a mild traumatic brain injury. While the brain may appear to be intact, new findings reported in Nature suggest that the brain’s protective coverings may feel the brunt of the impact.

Using a newly developed mouse trauma model, senior author Dorian McGavern, Ph.D., scientist at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, watched specific cells mount an  to the injury and try to prevent more widespread damage. Notably, additional findings suggest a similar immune response may occur in patients with mild head injury.

In this study, researchers also discovered that certain molecules, when applied directly to the mouse skull, can bypass the brain’s protective barriers and enter the brain. The findings suggested that, in the mouse trauma model, one of those molecules may reduce effects of .

Although concussions are common, not much is known about the effects of this type of damage. As part of this study, Lawrence Latour, Ph.D., a scientist from NINDS and the Center for Neuroscience and Regenerative Medicine, examined individuals who had recently suffered a concussion but whose initial scans did not reveal any physical damage to brain tissue. After administering a commonly used dye during MRI scans, Latour and his colleagues saw it leaking into the meninges, the outer covers of the brain, in 49 percent of 142 patients with concussion.

To determine what happens following this mild type of injury, researchers in Dr. McGavern’s lab developed a new model of brain trauma in mice.

“In our mice, there was leakage from blood vessels right underneath the skull bone at the site of injury, similar to the type of effect we saw in almost half of our patients who had mild . We are using this mouse model to look at meningeal trauma and how that spreads more deeply into the brain over time,” said Dr. McGavern.

Dr. McGavern and his colleagues also discovered that the intact skull bone was porous enough to allow small molecules to get through to the brain. They showed that smaller molecules reached the brain faster and to a greater extent than larger ones. “It was surprising to discover that all these protective barriers the brain has may not be concrete. You can get something to pass through them,” said Dr. McGavern.

The researchers found that applying glutathione (an antioxidant that is normally found in our cells) directly on the skull surface after brain injury reduced the amount of  by 67 percent. When the researchers applied glutathione three hours after injury, cell death was reduced by 51 percent. “This idea that we have a time window within which to work, potentially up to three hours, is exciting and may be clinically important,” said Dr. McGavern.

Glutathione works by decreasing levels of reactive oxygen species (ROS) molecules that damage cells. In this study, high levels of ROS were observed at the trauma site right after the physical brain injury occurred. The massive flood of ROS set up a sequence of events that led to cell death in the brain, but glutathione was able to prevent many of those effects.

In addition, using a powerful microscopic technique, the researchers filmed what was happening just beneath the skull surface within five minutes of injury. They captured never-before-seen details of how the brain responds to traumatic injury and how it mobilizes to defend itself.

Initially, they saw cell death in the meninges and at the glial limitans (a very thin barrier at the surface of the brain that is the last line of defense against dangerous molecules). Cell death in the underlying brain tissue did not occur until 9-12 hours after injury. “You have death in the lining first and then this penetrates into the brain tissue later. The goal of therapies for brain injury is to protect the ,” said Dr. McGavern.

Almost immediately after head injury, the glial limitans can break down and develop holes, providing a way for potentially harmful molecules to get into the brain. The researchers observed microglia (immune cells that act as first responders in the brain against dangerous substances) quickly moving up to the brain surface, plugging up the holes.

Findings from Dr. McGavern’s lab indicate that microglia do this in two ways. According to Dr. McGavern, “If the astrocytes, the cells that make up the glial limitans, are still there, microglia will come up to ‘caulk’ the barrier and plug up gaps between individual astrocytes. If an astrocyte dies, that results in a larger space in the glial limitans, so the microglia will change shape, expand into a fat jellyfish-like structure and try to plug up that hole. These reactions, which have never been seen before in living brains, help secure the barrier and prevent toxic substances from getting into the brain.”

Studies have suggested that immune responses in the brain can often lead to severe damage. Remarkably, the findings in this study show that the inflammatory response in a model is actually beneficial during the first 9-12 hours after injury.

Mild traumatic brain injuries are a growing public health concern. According to a report from the Centers of Disease Control and Prevention, in 2009 at least 2.4 million people suffered a traumatic injury and 75 percent of those injuries were mild. This study provides insight into the damage that occurs following head trauma and identifies potential therapeutic targets, such as antioxidants, for reducing the damaging effects.

Report Finds ‘Culture of Resistance’ on Youth Concussion.

Young athletes in the United States face a “culture of resistance” to telling a coach or parent they might have a concussion, according to a new report from the Institute of Medicine and National Research Council. 

The 306-page report, “Sports-Related Concussions in Youth: Improving the Science, Changing the Culture,” was released during a briefing today at the National Academy of Sciences in Washington, DC.

“Even though there is an increased willingness to report a concussion, there is still the desire on the part of the athlete not to report it because they feel they are letting their teammates down; on the part of the coaches because it upsets the team they have on the field, or their own belief that, ‘I had these, I’m okay, it’s just part of the sport’; and on the part of the parents who want to see their children excel and be accepted,” said Robert Graham, MD, chair of the committee that wrote the report.

Attitude Adjustment

Efforts are needed to “change the culture,” said Dr. Graham, who is director of the National Program Office for Aligning Forces for Quality at George Washington University in Washington, DC.

Over 9 months, the committee did a comprehensive review of the literature on concussions in youth sports with athletes aged 5 to 21 years. 

“The findings of our report justify the concerns about sports concussions in young people,” said Dr. Graham. “However, there are numerous areas in which we need more and better data.  Until we have that information, we urge parents, schools, athletic departments, and the public to examine carefully what we do know, as with any decision regarding risk, so they can make more informed decisions about young athletes playing sports,” he added.

The reported number of individuals aged 19 and under treated in US emergency departments for concussions and other nonfatal sports- and recreation-related traumatic brain injuries (TBIs) increased from 150,000 in 2001 to 250,000 in 2009.

“This could possibly be due to an increase in awareness or reporting of concussions,” committee member Tracey Covassin, PhD, director of the undergraduate athletic training program at Michigan State University in East Lansing. “However, we do not know the true incidence of concussions as several concussions go unreported, as well as a lack of consistency in terminology with different studies that have reported different definitions of concussions.”

The committee found that the majority of research into concussions is at the high school and collegiate levels, with very few to no data reported below the high school level.

The committee also found a “shift” in the incidence of concussions, with more reported at the high school level than the collegiate level, Dr. Covassin said.

Football, ice hockey, lacrosse, wrestling, and soccer are associated with the highest rates of reported concussions for male athletes at the high school and college levels, while soccer, lacrosse, and basketball are associated with the highest rates of reported concussions for female athletes at these levels of play.

Limited Evidence Helmets Cut Risk

The committee found little evidence that current sports helmet designs cut the risk for concussions. 

“What the literature tells us is that diffuse brain injuries like concussion are caused by a combination of linear and rotational forces,” explained committee member Kristy Arbogast, PhD, engineering core director, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia in Pennsylvania. “What we do know is that helmets reduce that linear portion. There is limited evidence that they can manage the rotational components of the impact. This is in part due to standards.”

The committee stressed, however, that properly fitted helmets, face masks, and mouth guards should still be used because they reduce the risk for other injuries.

The committee also examined the scientific literature on concussion recognition, diagnosis, and management. They found that the signs and symptoms of concussion are usually placed into 4 categories — physical, cognitive, emotional, and sleep — with patients having 1 or more symptoms from 1 or more categories. 

Most youth athletes with concussion will recover within 2 weeks of the injury, but in 10% to 20% of cases concussion symptoms persist for several weeks, months, or even years. 

Return to Play

The committee advises that a concussed athlete return to play only when he or she has recovered demonstrably and is no longer having any symptoms. An individualized treatment plan that includes physical and mental rest may be beneficial for recovery from a concussion, but current research does not suggest a standard or universal level and duration of rest needed, the committee notes.

Athletes who return to play before complete recovery are at increased risk for prolonged recovery or more serious consequences if they sustain a second concussion. “The evidence is pretty clear” on this, said committee member Arthur Maerlender, PhD, director of pediatric neuropsychological services at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The literature also suggests that single and multiple concussions can lead to impairments in the areas of memory and processing speed.  However, it remains unclear whether repetitive head impacts and multiple concussions sustained in youth lead to long-term neurodegenerative disease, such as chronic traumatic encephalopathy, the committee said.

It notes, however, that surveys of retired professional athletes provide some evidence that a history of multiple concussions increases risk for depression. In a survey of more than 2500 retired professional football players, approximately 11% reported having clinical depression. “Very little” research has evaluated the relationship between concussions and suicidal thoughts and behaviors, the committee notes.

In youth sports, several organizations have called for a “hit count” to limit the amount of head contact a player receives over a given amount of time. Although this concept is “fundamentally sound,” the committee found that implementing a specific threshold for the number of impacts or the magnitude of impacts per week or per season is without scientific basis.

The committee calls for establishing a national surveillance system to accurately determine the number of sports-related concussions, identify changes in the brain following concussions in youth, conduct studies to assess the consequences and effects of concussions over a life span, and evaluate the effectiveness of sports rules and playing practices in reducing concussions. 

Pentagon’s giant blood serum bank may provide PTSD clues.

The massive repository of genetic material is poised to advance research—just don’t bother asking for your samples back.

Nestled inside a generic-looking office building here in suburban Maryland, down the hall from cable-provider Comcast, sits the largest blood serum repository in the world.


Seven freezers, each roughly the size of a high school basketball court, are stacked high with row upon row of small cardboard boxes containing tubes of yellow or pinkish blood serum, a liquid rich in antibodies and proteins, but devoid of cells. The freezers hover at –30 degrees Celsius—cold enough to make my pen dry up and to require that workers wear protective jumpsuits, hats, gloves and face masks. Four more empty freezers, which are now kept at room temperature, await future samples.

The bank of massive freezers—and its contents—is maintained by the Department of Defense (DoD). The cache of government-owned serum may provide unique insights into the workings of various maladies when linked with detailed information on service members’ demographics, deployment locations and health survey data. New research projects tapping the precious serum could lead to breakthroughs in some of the hottest topics in military research—including the hunt for biomarkers for post-traumatic stress disorder and suicide risk. But DoD’s policy of keeping its samples in perpetuity—even after troops leave the force—could raise a few eyebrows.

From humble beginnings

The military started collecting serum samples 28 years ago as a by-product of its HIV surveillance. Since then serum has been routinely collected from leftover blood from HIV tests or standard post-deployment health check-ups and then frozen for future reference. Now the Department of Defense Serum Repository (DoDSR) has swelled to include 55.5 million samples of serum from 10 million individuals—mostly service members, veterans or military applicants. The armed forces use DoDSR for general health surveillance to track infectious diseases and to shape health policies. But the repository is also ripe for targeted research programs.

Annually the facility may field as many as 100 requests to use some of the serum from that icy reserve. Sixty-two requests received the green light to sample from DoDSR last year, half of them for research and half for clinical testing of an individual patient’s samples. In the past five years DoDSR has filled 278 such requests. But not all DoDSR uses are medical: they have also played a role in criminal proceedings, serving as a reference point for female victims in two rape cases, says Mark Rubertone, who oversees the DoDSR. “The value of the specimens does not go away, even after [service members] leave the military,” he says.

Even with the promise of ongoing health surveillance and potential research that would benefit the force, not all contributors to the repository are enthusiastic about—or even necessarily aware of—their participation. DoDSR does not discard serum samples, even if individual service members or military applicants request that their samples be removed. Fewer than 10 individuals have asked for the removal of their samples, according to Rubertone. But the requests are likely rare because service members and their families are not actively aware of the serum, even though they may know that their blood—in one form or another—is on file, Rubertone acknowledges. Thus far, no one has successfully retrieved his or her biological materials from the facility.

A RAND Corp. report on the facility, published in 2010 (after an earlier draft was revealed via Wikileaks), pointed out that nearly 900,000 samples in the repository were not from active duty or reservist personnel—they were from so-called “dependent beneficiaries” in service members’ families. Those numbers have since grown, to a “couple million” samples, according to the DoDSR count. The biological material from military family members often ends up in the repository after beneficiaries receive pregnancy care or visit a sexually transmitted infection clinic. The data accompanying those samples are more sparse and so the serum specimens are not as useful for studies, although they are still kept in the repository. Another 4 percent of the samples come from civilians who applied for military service but did not join.

Research payoffs

Researchers who draw on the serum bank note that the wealth of longitudinal data from DoDSR enables cutting-edge research. Take, for example, several projects that are searching for biomarkers of post-traumatic stress disorder. By matching up pre- and post-deployment DNA from individuals who developed PTSD and also comparing the genetic material with DNA from a control population, researchers are hoping to discern clues about when and how PTSD becomes apparent at a genetic level, impacting the DNA building blocks via DNA methylation and perhaps the silencing of certain genes. Related work is also focusing on microRNA—a small, noncoding RNA molecule—that helps regulate numerous biological processes and serves as a fingerprint for disease development.

Meanwhile, other researchers are studying serum to garner clues about links between traumatic brain injury (TBI) and DNA methylation among individuals who served in Iraq and Afghanistan, gleaning information from samples on 150 service members with mild to severe TBI, along with 50 control subjects. Because individuals—both on and off the battlefield—can suffer from mild TBI and not know it, identifying a biomarker could help speed up clinical care, says study investigator Jennifer Rusiecki, an epidemiologist at Uniformed Services University of the Health Sciences in Bethesda, Md.

Without the serum available through DoDSR and its accompanying information, some of this work would likely be impossible. “I’m not aware of other banks that have this data,” Rusiecki says. All told, almost 75 publications have depended on data gleaned from the samples in these freezers. Still more projects have drawn on them but did not make it into print. And because the repository’s stated purpose is health surveillance, the samples would not be chucked even if all the studies were halted, DoDSR’s Rubertone says.



The military has instituted safeguards to prevent misuse of the serum reserve. All studies conducted with DoDSR serums are required to have a military co-investigator, a policy DoD put in place to help ensure that the serum is being used for military-relevant purposes. Researchers must also receive approval from their home institutions’ institutional review boards, groups that ensure investigators will guard patients’ confidentiality and adhere to ethical research principles.

Unfortunately, despite the scale of the military repository, blood serum has its limits as a medical resource. For research and health surveillance, the serum can only tell you so much, says Capt. Kevin Russell, the director of the Armed Forces Health Surveillance Center that oversees DoDSR. Because the serum samples are not linked to very specific exposure information—such as exactly where a service member was stationed or what he or she encountered while deployed—they only stand in as a surrogate for exposure. At the moment DoD is exploring whether other materials—urine, throat cultures, blood clots—or perhaps new technologies could enhance their repository. Nevertheless, it would be “unlikely” that Defense would get rid of its serum reserve or stop adding new samples, Russell says. And so four freezers remain empty, waiting.

Source: Nature