Modeling shockwaves through the brain

Since the start of the military conflicts in Iraq and Afghanistan, more than 300,000 soldiers have returned to the United States with traumatic brain injury (TBI) caused by exposure to bomb blasts — and in particular, exposure to improvised explosive devices, or IEDs. Symptoms of traumatic brain injury can range from the mild, such as lingering headaches and nausea, to more severe impairments in memory and cognition.

Since 2007, the U.S. Department of Defense has recognized the critical importance and complexity of this problem, and has made significant investments in traumatic brain injury research. Nevertheless, there remain many gaps in scientists’ understanding of the effects of blasts on the human brain; most new knowledge has come from experiments with animals.

Now MIT researchers have developed a scaling law that predicts a human’s risk of brain injury, based on previous studies of blasts’ effects on animal brains. The method may help the military develop more protective helmets, as well as aid clinicians in diagnosing traumatic brain injury — often referred to as the “invisible wounds” of battle.

“We’re really focusing on mild traumatic brain injury, where we know the least, but the problem is the largest,” says Raul Radovitzky, a professor of aeronautics and astronautics and associate director of the MIT Institute for Soldier Nanotechnologies (ISN). “It often remains undetected. And there’s wide consensus that this is clearly a big issue.”

While previous scaling laws predicted that humans’ brains would be more resilient to blasts than animals’, Radovitzky’s team found the opposite: that in fact, humans are much more vulnerable, as they have thinner skulls to protect much larger brains.

A group of ISN researchers led by Aurélie Jean, a postdoc in Radovitzky’s group, developed simulations of human, pig, and rat heads, and exposed each to blasts of different intensities. Their simulations predicted the effects of the blasts’ shockwaves as they propagated through the skulls and brains of each species. Based on the resulting differences in intracranial pressure, the team developed an equation, or scaling law, to estimate the risk of brain injury for each species.

“The great thing about doing this on the computer is that it allows you to reduce and possibly eventually eliminate animal experiments,” Radovitzky says.

The MIT team and co-author James Q. Zheng, chief scientist at the U.S. Army’s soldier protection and individual equipment program, detail their results this week in the Proceedings of the National Academy of Sciences.

Air (through the) head

A blast wave is the shockwave, or wall of compressed air, that rushes outward from the epicenter of an explosion. Aside from the physical fallout of shrapnel and other chemical elements, the blast wave alone can cause severe injuries to the lungs and brain. In the brain, a shockwave can slam through soft tissue, with potentially devastating effects.

In 2010, Radovitzky’s group, working in concert with the Defense and Veterans Brain Injury Center, a part of the U.S. military health system, developed a highly sophisticated, image-based computational model of the human head that illustrates the ways in which pressurized air moves through its soft tissues. With this model, the researchers showed how the energy from a blast wave can easily reach the brain through openings such as the eyes and sinuses — and also how covering the face with a mask can prevent such injuries. Since then, the team has developed similar models for pigs and rats, capturing the mechanical response of brain tissue to shockwaves.

In their current work, the researchers calculated the vulnerability of each species to brain injury by establishing a mathematical relationship between properties of the skull, brain, and surrounding flesh, and the propagation of incoming shockwaves. The group considered each brain structure’s volume, density, and celerity — how fast stress waves propagate through a tissue. They then simulated the brain’s response to blasts of different intensities.

“What the simulation allows you to do is take what happens outside, which is the same across species, and look at how strong was the effect of the blast inside the brain,” Jean says.

In general, they found that an animal’s skull and other fleshy structures act as a shield, blunting the effects of a blast wave: The thicker these structures are, the less vulnerable an animal is to injury. Compared with the more prominent skulls of rats and pigs, a human’s thinner skull increases the risk for traumatic brain injury.

Shifting the problem

This finding runs counter to previous theories, which held that an animal’s vulnerability to blasts depends on its overall mass, but which ignored the role of protective physical structures. According to these theories, humans, being more massive than pigs or rats, would be better protected against blast waves.

Radovitzky says this reasoning stems from studies of “blast lung” — blast-induced injuries such as tearing, hemorrhaging, and swelling of the lungs, where it was found that mass matters: The larger an animal is, the more resilient it may be to lung damage. Informed by such studies, the military has since developed bulletproof vests that have dramatically decreased the number of blast-induced lung injuries in recent years.

“There have essentially been no reported cases of blast lung in the last 10 years in Iraq or Afghanistan,” Radovitzky notes. “Now we’ve shifted that problem to traumatic brain injury.”

In collaboration with Army colleagues, Radovitzky and his group are performing basic research to help the Army develop helmets that better protect soldiers. To this end, the team is extending the simulation approach they used for blast to other types of threats.

His group is also collaborating with audiologists at Massachusetts General Hospital, where victims of the Boston Marathon bombing are being treated for ruptured eardrums.

“They have an exact map of where each victim was, relative to the blast,” Radovitzky says. “In principle, we could simulate the event, find out the level of exposure of each of those victims, put it in our scaling law, and we could estimate their risk of developing a traumatic brain injury that may not be detected in an MRI.” 

Joe Rosen, a professor of surgery at Dartmouth Medical School, sees the group’s scaling law as a promising window into identifying a long-sought mechanism for blast-induced traumatic brain injury. 

“Eighty percent of the injuries coming off the battlefield are blast-induced, and mild TBIs may not have any evidence of injury, but they end up the rest of their lives impaired,” says Rosen, who was not involved in the research. “Maybe we can realize they’re getting doses of these blasts, and that a cumulative dose is what causes [TBI], and before that point, we can pull them off the field. I think this work will be important, because it puts a stake in the ground so we can start making some progress.”

Compound protects brain cells after traumatic brain injury

A new class of compounds has now been shown to protect brain cells from the type of damage caused by blast-mediated traumatic brain injury (TBI). Mice that were treated with these compounds 24-36 hours after experiencing TBI from a blast injury were protected from the harmful effects of TBI, including problems with learning, memory, and movement.

Traumatic brain injury caused by blast injury has emerged as a common health problem among U.S. servicemen and women, with an estimated 10 to 20 percent of the more than 2 million U.S. soldiers deployed in Iraq or Afghanistan having experienced TBI. The condition is associated with many neurological complications, including cognitive and motor decline, as well as acquisition of psychiatric symptoms like anxiety and depression, and brain tissue abnormalities that resemble Alzheimer’s disease.

"The lack of neuroprotective treatments for traumatic brain injury is a serious problem in our society," says Andrew Pieper, senior study author and associate professor of psychiatry, neurology, and radiation oncology at the University of Iowa Carver College of Medicine. “Everyone involved in this work is motivated to find a way to offer hope for patients, which today include both military personnel and civilians, by establishing a basis for a new treatment to combat the deleterious neuropsychiatric outcomes after blast injury.”

It is known that TBI, as well as certain neurodegenerative diseases, damages axons—the tendril-like fibers that sprout from brains cells (neurons) and form the connections called synapses. In TBI, axon damage is followed by death of the neuron. The new study, published Sept. 11 in the journal Cell Reports, shows that a group of compounds, called the P7C3 series, blocks axon damage and preserves normal brain function following TBI.

Pieper led the team of scientists that discovered the P7C3 compound several years ago at UT Southwestern Medical Center. Subsequent studies showed that the root compound and its active analogs protect newborn neurons from cell death and also protect mature neurons in animal models of neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

The researchers have also previously shown efficacy of P7C3 molecules in brain injury due to concussion, and plan to investigate whether these compounds might be applicable in stroke as well, given that there appear to be common factors mediating neuronal cell death in these conditions.

By tweaking the structure of the original P7C3 compound, Pieper and his colleagues Joseph Ready and Steven McKnight, at UT Southwestern Medical Center, have further improved its potency and drug-like properties. In the latest study, Pieper’s team at the UI Carver College of Medicine, including co-first authors graduate student Terry Yin, senior technician Jeremy Britt, and graduate student Hector De Jesus-Cortes, tested the neuroprotective effects of the newest version, (-)-P7C3-S243, which can be given orally, in mice with blast-induced TBI.

In the study, blast-induced TBI caused learning, memory, and movement problems in the mice, which resemble the problems experienced by people affected by TBI. The researchers found that (-)-P7C3-S243 prevented acute memory and learning impairment caused by TBI. The compound also prevented TBI-associated balance and coordination problems in mice exposed to blast-injury. By examining the brain tissue at a cellular level, the team also found that the protection afforded to brain functions after injury was matched by preservation of normal neuronal axon structure and synaptic neurotransmission.

Importantly, the compound still produced its protective effects even when treatment was delayed until 24 to 36 hours after the blast injury.

"Seeing protection even when the compound was given this long after injury was important because it represents a liberal window of time within which almost all patients would be expected to be able to access treatment after injury," Pieper says.

The team also found that learning, memory, and coordination problems caused by the TBI persisted in untreated mice at least eight months after the single injury occurred, suggesting that the compound actually prevented these problems rather simply speeding up a normal recovery process.

In a separate study led by Pieper’s colleagues McKnight and Ready at UT Southwestern, and also published on Sept. 11 in the journal Cell, the team has identified the biological mechanism by which P7C3 compounds act in the brain. The compounds activate the molecular pathway that preserves neuronal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD).

"Based on the well-established role of NAD in axonal degeneration, the ability of (-)-P7C3-S243 to protect mice after blast-mediated traumatic brain injury is likely related to preservation of NAD levels," Pieper explains. "Now that we understand the mechanism of action of the P7C3 class of compounds, we can see why they should have therapeutic utility in an unusually broad spectrum of neurodegenerative conditions, without impeding any of a number of other normal forms of cell death.

"Our ultimate goal is to facilitate development of a new class of neuroprotective drugs with wide applicability to treating patients with TBI and other currently untreatable forms of neurodegeneration," he adds.

Xenon gas protects the brain after head injury

Head injury is the leading cause of death and disability in people aged under 45 in developed countries, mostly resulting from falls and road accidents. The primary injury caused by the initial mechanical force is followed by a secondary injury which develops in the hours and days afterwards. This secondary injury is largely responsible for patients’ mental and physical disabilities, but there are currently no drug treatments that can be given after the accident to stop it from occurring.

Scientists at Imperial College London found that xenon, given within hours of the initial injury, limits brain damage and improves neurological outcomes in mice, both in the short term and long term. The findings, published in the journal Critical Care Medicine, could lead to clinical trials of xenon as a treatment for head injury in humans.

Although xenon is chemically inert, this does not mean it is biologically inactive. Xenon has been known to have general anaesthetic properties since the 1950s. Previous studies at Imperial have found that xenon can protect brain cells from mechanical injury in the lab, but this new study is the first time such an effect has been shown in live animals, a vital step before any new treatments can be tested in humans.

Mice were anaesthetised before having a controlled mechanical force applied to the brain. Some were then treated with xenon at different concentrations and at different times after injury.

Mice treated with xenon performed better in tests assessing their neurological deficits, such as movement and balance problems, in the days after injury and after one month. They also had less brain damage, even if treatment was delayed up to three hours after the injury.

Dr Robert Dickinson from the Department of Surgery and Cancer at Imperial College London, who led the study, said: “After a blow to the head, most of the damage to the brain doesn’t occur immediately but in the hours and days afterwards. At present we have no specific drugs to limit the spread of the secondary injury, but we think that is the key to successful treatment.

“This study shows that xenon can prevent brain damage and disability in mice, and crucially it’s effective when given up to at least three hours after the injury. It’s feasible that someone who hits their head in an accident could be treated in the hospital or in an ambulance in this timeframe.

“These findings provide crucial evidence to support doing clinical trials in humans.”

Brain injuries no match for sPIF treatment

Researchers at Yale School of Medicine and their colleagues have uncovered a new pathway to help treat perinatal brain injuries. This research could also lead to treatments for traumatic brain injuries and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.

The findings are published in the Sept. 8 issue of Proceedings of the National Academy of Sciences.

The MicroRNA molecule let-7 is known to cause the death of neurons in the central nervous system. The research team found that a synthetic molecule derived from the embryo called PreImplantation Factor (sPIF) protects against neuronal death and brain injury by targeting let-7. 

“We would never have connected the dots between PIF and let-7 without prior knowledge and experience on let-7 and H19, a developmentally regulated gene that is highly expressed in the developing embryo,” said senior author Dr. Yingqun Huang, associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Using a rat perinatal brain injury model, Huang and the team found that sPIF rescued damaged neurons and reduced inflammation. The team performed a series of in vivo and in vitro experiments and found that sPIF helped to stop the production of let-7. “We showed that sPIF works by destabilizing the key microRNA processing protein called KH-type splicing regulatory protein,” said Huang.

Lead author Martin Mueller, who helped develop the rat perinatal brain injury model, was surprised at the consistency of the results from both the in vivo and in vitro studies. “Collectively, our findings suggest that sPIF mitigates brain damage through a novel pathway,” said Mueller. “We saw more cortical brain volume and more neurons restored in brain damaged animals receiving sPIF.”

“For the first time, we have clear indication to pursue a new line of investigation in the treatment of perinatal brain injury, and possibly traumatic brain injury,” said co-author Dr. Michael Paidas, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Paidas, who is also vice chair of obstetrics at Yale, has helped to identify PIF’s effects with co-author Eytan R. Barnea, founder of the Society for the Investigation of Early Pregnancy (SIEP) and chief scientific officer of BioIncept, LLC. Barnea discovered and characterized PIF and described key elements of its mode of action.

Based on this promising data, the FDA has awarded sPIF fast-track designation and allowed a phase 1 sPIF clinical trial to treat patients with autoimmune liver disease at the University of Miami.

Longitudinal study explores white matter damage, cognition after traumatic axonal injury

Traumatic Axonal Injury is a form of traumatic brain injury that can have detrimental effects on the integrity of the brain’s white matter and lead to cognitive impairments. A new study from the Center for BrainHealth at The University of Texas at Dallas investigated white matter damage in the acute and chronic stages of a traumatic axonal injury in an effort to better understand what long-term damage may result.

The study, published online July 21 in the Journal of Neurotrauma, looked at 13 patients ages 16 to 60 with mild to severe brain injuries from the intensive care unit at a Level I trauma center. This group was matched to a cohort of 10 healthy individuals resembling the age, gender, and ethnicity of the patients. White matter integrity was measured using diffusion tensor imaging (DTI) in the acute stage of injury, at day one, and again at the chronic stage, seven months post-injury. In addition, neuropsychological assessments measured cognitive performance including processing speed, attention, learning and memory at both stages after injury.

“We intended to determine whether DTI could not only identify early compromise to white matter, but also demonstrate an association with functional and neuropsychological outcomes months post-injury,” said Carlos Marquez de la Plata, Ph.D., Assistant Director of Rehabilitation Research at Pate Rehabilitation in Dallas, Texas.

The study’s findings suggest DTI may be used to detect meaningful changes in white matter as early as one day after a traumatic brain injury. White matter integrity measured at the chronic stage was also found to significantly correlate with cognitive processing speed.

“On the first day after the injury, we found white matter integrity was compromised due to swelling in the brain,“ said the study’s lead author Alison Perez. “As the swelling subsided over time and the brain began to repair itself, we found that many of the damaged neurons that were unable to repair themselves began to die off, which appears to slow the speed of cognitive processing.”

Interestingly, the degree of white matter compromise detected early after injury was associated with markers of injury severity such as the number of days in the intensive care unit and hospital, but not to outcomes months later. 

At seven months post-injury, many of the patients’ cognitive performance improved including processing speed, divided attention, and short and long-term memory. In addition, patients with better white matter integrity at the chronic stage had the fastest processing speed.

By studying the long-term effects of a traumatic axonal injury at both the acute and chronic stages, researchers hope to assist in the advancement of future assessment and treatment options after a traumatic brain injury.

Forty per cent of female prisoners enter correctional system with a traumatic brain injury

A study published today found that almost 40 per cent of Ontario female prisoners have a history of traumatic brain injury (TBI). Unlike the men participating in the study, half of these women sustained a TBI before committing their first crime.

The study, led by Dr. Angela Colantonio, senior scientist, Toronto Rehabilitation Institute, was based on a survey of men and women in Ontario correctional facilities. Published in the Journal of Correctional Health Care, it is the first Canadian study of its kind.

Typically caused by a blow to the head, TBI is a leading c​ause of death and disability worldwide. It kills 11,000 Canadians every year. TBI is commonly caused by falls, motor vehicle collisions,physical assault or sports injuries.

"We observed a striking gender difference. Female inmates with a TBI, compared to males, were much more likely to have suffered physical or sexual abuse as children," said Colantonio, Canadian Institutes of Health Research (CIHR) Research Chair in Gender, Work, and Health, University of Toronto. "Our research suggests the need to screen offenders and others with a history of abuse for TBI."

Dr. Colantonio highlights the need to identify inmates or others at risk of incarceration with a history of a TBI so they can receive appropriate support and treatment. This will allow the system to help prevent future offences by better assisting with the transition back into society. For example, helping individuals secure and maintain employment.

"Right now, we don’t know very much about how brain injuries affect women in the correctional system," said Colantonio. "This study indicates a need for more research, and for programs that address TBI and mental health problems among people at risk of incarceration."

Such programs should include training for correctional staff to help them recognize TBI symptoms in inmates, such as slowness to act or a failure to respond to directions. This behaviour may be misinterpreted as defiance, resulting in punishment instead of treatment.

A report last year from the Office of the Correctional Investigator showed the number of women in Canadian prisons had increased 40 per cent since 2008. The same report also found that 85 per cent of incarcerated women said they had a history of physical abuse.

"Now that we have identified this as an issue, we need to work with community organizations and correctional systems to prevent inappropriate incarceration of females with traumatic brain injury and to provide treatment so they have a better chance when they return to society," said Dr. Geoff Fernie, institute director, research, Toronto Rehabilitation Institute.

Restoring Active Memory Program Poised to Launch

Teams will develop and test implantable therapeutic devices for memory restoration in patients with memory deficits caused by disease or trauma

DARPA has selected two universities to initially lead the agency’s Restoring Active Memory (RAM) program, which aims to develop and test wireless, implantable “neuroprosthetics” that can help servicemembers, veterans, and others overcome memory deficits incurred as a result of traumatic brain injury (TBI) or disease.

The University of California, Los Angeles (UCLA), and the University of Pennsylvania (Penn) will each head a multidisciplinary team to develop and test electronic interfaces that can sense memory deficits caused by injury and attempt to restore normal function. Under the terms of separate cooperative agreements with DARPA, UCLA will receive up to $15 million and Penn will receive up to $22.5 million over four years, with full funding contingent on the performer teams successfully meeting a series of technical milestones. DARPA also has a cooperative agreement worth up to $2.5 million in place with Lawrence Livermore National Laboratory to develop an implantable neural device for the UCLA-led effort.

“The start of the Restoring Active Memory program marks an exciting opportunity to reveal many new aspects of human memory and learn about the brain in ways that were never before possible,” said DARPA Program Manager Justin Sanchez. “Anyone who has witnessed the effects of memory loss in another person knows its toll and how few options are available to treat it. We’re going to apply the knowledge and understanding gained in RAM to develop new options for treatment through technology.”

TBI is a serious cause of disability in the United States. Diagnosed in more than 270,000 military servicemembers since 2000 and affecting an estimated 1.7 million U.S. civilians each year, TBI frequently results in an impaired ability to retrieve memories formed prior to injury and a reduced capacity to form or retain new memories following injury. Despite the scale of the problem, no effective therapies currently exist to mitigate the long-term consequences of TBI on memory. Through the RAM program, DARPA seeks to accelerate the development of technology needed to address this public health challenge and help servicemembers and others overcome memory deficits by developing new neuroprosthetics to bridge gaps in the injured brain.

“We owe it to our service members to accelerate research that can minimize the long-term impacts of their injuries,” Sanchez said. “Despite increasingly aggressive prevention efforts, traumatic brain injury remains a serious problem in military and civilian sectors. Through the Restoring Active Memory program, DARPA aims to better understand the underlying neurological basis of memory loss and speed the development of innovative therapies.”

Specifically, RAM performers aim to develop and test wireless, fully implantable neural-interface medical devices that can serve as “neuroprosthetics”—technology that can effectively bridge the gaps that interfere with an individual’s ability to encode new memories or retrieve old ones.

To start, DARPA will support the development of multi-scale computational models with high spatial and temporal resolution that describe how neurons code declarative memories—those well-defined parcels of knowledge that can be consciously recalled and described in words, such as events, times, and places. Researchers will also explore new methods for analysis and decoding of neural signals to understand how targeted stimulation might be applied to help the brain reestablish an ability to encode new memories following brain injury. “Encoding” refers to the process by which newly learned information is attended to and processed by the brain when first encountered.

Building on this foundational work, researchers will attempt to integrate the computational models developed under RAM into new, implantable, closed-loop systems able to deliver targeted neural stimulation that may ultimately help restore memory function. These studies will involve volunteers living with deficits in the encoding and/or retrieval of declarative memories and/or volunteers undergoing neurosurgery for other neurological conditions.

Unique to the UCLA team’s approach is a focus on the portion of the brain known as the entorhinal area. UCLA researchers previously demonstrated that human memory could be facilitated by stimulating that region, which is known to be involved in learning and memory. Considered the entrance to the hippocampus—which helps form and store memories—the entorhinal area plays a crucial role in transforming daily experience into lasting memories. Data collected during the first year of the project from patients already implanted with brain electrodes as part of their treatment for epilepsy will be used to develop a computational model of the hippocampal-entorhinal system that can then be used to test memory restoration in patients.

After developing an advanced, new wireless neuromodulation device—featuring ten-times smaller size and much higher spatial resolution than existing devices—the UCLA team will implant such devices into the entorhinal area and hippocampus of patients with traumatic brain injury.

The Penn team’s approach is based on an understanding that memory is the result of complex interactions among widespread brain regions. Researchers will study neurosurgical patients who have electrodes implanted in multiple areas of their brains for the treatment of various neurological conditions. By recording neural activity from these electrodes as patients play computer-based memory games, the researchers will measure “biomarkers” of successful memory function—patterns of activity that accompany the successful formation of new memories and the successful retrieval of old ones. Researchers could then use those models and a novel neural stimulation and monitoring system—being developed in partnership with Medtronic—to restore brain memory function. The investigational system will simultaneously monitor and stimulate a number of brain sites, which may lead to better understandings of the brain and how brain stimulation therapy can potentially restore normal brain function following injury or the onset of neuropsychological illness.

In addition to human clinical efforts, RAM will support animal studies to advance the state-of-the-art of quantitative models that account for the encoding and retrieval of complex memories and memory attributes, including their hierarchical associations with one another. This work will also seek to identify any characteristic neural and behavioral correlates of memories facilitated by therapeutic devices.