(Image caption: Uncinate fasiculus, an important tract with the greatest concentration of progesterone receptors, show greater injury in males than females after mild traumatic brain injury (mTBI). (a) Axial and (b) coronal images show regions of decreased fractional anisotropy in male patients with mTBI relative to female mTBI patients, involving the uncinate fasiculus (red) bilaterally.)

Gender May Contribute to Recovery Time After Concussion

A study of concussion patients using diffusion tensor imaging (DTI) found that males took longer to recover after concussion than females did. Results of the study, which show that DTI can be used as a bias-free way to predict concussion outcome, are published online in the journal Radiology.

Each year, more than 17 million Americans suffer a mild traumatic brain injury (mTBI), more commonly known as a concussion, of which approximately 15 percent suffer persistent symptoms beyond three months.

Assessing outcomes and recovery time after concussion can be very subjective. Typically, physicians must rely on patient cooperation to assess injury severity.

"MRI and CT brain images of concussion patients are often normal," said Saeed Fakhran, M.D., assistant professor of neuroradiology at the University of Pittsburgh School of Medicine. "Diffusion tensor imaging is the first imaging technique that shows abnormalities associated with concussion, because it is able to see white matter tracts at a microscopic level."

DTI is an advanced form of MRI that allows researchers to assess microscopic changes in the brain’s white matter. 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. DTI produces a measurement, called fractional anisotropy (FA), of the movement of water molecules 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. Abnormally low FA is associated with cognitive impairment in patients with brain injuries.

The research team examined the medical records and imaging results of 69 patients diagnosed with mTBI between 2006 and 2013, including 47 males and 22 females, and 21 controls consisting of 10 males and 11 females (median age of males: 17; median age of females: 16). Of the 47 males with mTBI, 32 (68 percent) were injured while playing a sport, as were 10 of the 22 females (45 percent).

All patients underwent the same evaluation, including a computerized neurocognitive test and DTI of the brain. The DTI scans of the mTBI patients revealed abnormalities within the uncinate fasciculi (UF), a white matter tract that connects the frontal and temporal lobes of the brain. Although its exact role is controversial, the UF tract is believed to allow temporal lobe-based memory associations to modify behavior though interactions with another area of the brain.

The DTI scans revealed that compared to the female mTBI patients, the male mTBI patients had significantly decreased UF FA values.

"In the future, we would like to look at the issue of gender and concussions more in depth to determine who does better and why," Dr. Fakhran said.

A statistical analysis of the data revealed that UF FA value was a stronger predictor of recovery time than initial symptom severity based on neurocognitive testing. The most substantial risk factor for a recovery time longer than three months was decreased UF FA. Male gender also directly correlated with increased recovery time.

"The potential of DTI and UF FA to predict outcome after concussion has great clinical impact," Dr. Fakhran said. "Currently, we are heavily reliant on patient reporting, and patients may have ulterior motives, such as wanting to get back to play. But you can’t trick an MR scanner."

The average time to symptom recovery for all concussion patients was 54 days. However, compared to the female patients who recovered in an average of 26.3 days, recovery was significantly longer for the male patients (an average of 66.9 days), irrespective of initial symptom severity.

"Male gender and UF FA values are independent risk factors for persistent post-concussion symptoms after three months and stronger predictors of time to recovery than initial symptom severity or neurocognitive test results," Dr. Fakhran said.

He said results of the study indicate a potential role for UF FA values in triaging concussion patients in the future.

"There’s prognostic value in DTI for both children participating in sports as well as for professional athletes," he said. "Lower FA values in the uncinate fasciculi could offer a metric for evaluating the severity of mild traumatic brain injuries and predicting clinical outcome. We’re not at the point where DTI can provide individual prognoses yet, but that’s the hope and goal."

Engineering resilience in the brain

Penn researchers model neural structures on the smallest scales to better understand traumatic brain injury

Compared to the monumental machines of science, things like the International Space Station or the Large Hadron Collider, the human brain doesn’t look like much. However, this three-pound amalgam of squishy cells is one of the most complicated and complex structures in the known universe.

With hundreds of billions of neurons, each with its own inner world of organelles and molecular components, understanding the fundamental wiring of the brain is a major undertaking, one that has received a commitment of at least $100 million worth of federal funding from the National Science Foundation (NSF), the National Institutes of Health and the Defense Advanced Research Projects Agency.

And with all of the brain’s interconnected structures, protecting or repairing this complicated machine means thinking like an engineer.

"The idea is really quite simple," says Vivek Shenoy, an NSF-supported professor of materials science and engineering at the University of Pennsylvania’s School of Engineering and Applied Science. "All of the mechanical properties of cells come from their cytoskeleton and the molecules within it. They’re all reinforcing frames, like the frame in a building. Engineers design buildings and other structural objects to make sure they don’t fail, so it’s the same principle: structural engineering on a very, very small level."

Shenoy applies this approach to a problem very much in the public eye—traumatic brain injury. Even the mildest forms of TBI, better known as concussions, can do irreversible damage to the brain. More serious forms can be fatal.

With a background in mechanical engineering and materials science, one might think that Shenoy’s contribution to this problem involves designing new helmets or other safety devices. Instead, he and his colleagues are uncovering the fundamental math and physics behind one of the core mechanisms of the injury: swelling in axons caused by damage to internal structures known as microtubules. These neural “train tracks” transport molecular cargo from one end of a neuron to another; when the tracks break, the cargo piles up and produces bulges in the axons that are the hallmark of fatal TBIs.

Armed with a better understanding of the mechanical properties of these critical structures, Shenoy and his colleagues are laying the foundations for drugs that could one day bolster neurons’ reinforcing frames, making them more resilient when faced with a TBI-inducing impact.

Train tracks and crossties

The first step toward this understanding was resolving a paradox: Why were the microtubules, the stiffest elements of the axons, the parts that were breaking when loaded with the stress of a blow to the head?

A recent finding from Shenoy’s team shows that the answer rests with a critical brain protein known as tau, which is implicated in several neurodegenerative diseases, including Alzheimer’s. If microtubules are like train tracks, tau proteins are the crossties that hold them together. The protein’s elastic properties help explain why rapid movement of the brain, whether on a football field or a car crash, leads to TBI.

Shenoy’s colleague Douglas Smith, professor of neurosurgery in Penn’s Perelman School of Medicine and director of the Penn Center for Brain Injury and Repair, had previously studied the mechanical properties of axons, subjecting them to strains of different forces and speeds.

"What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage," Smith said. "But at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretches at fast rates."

To explain this rate-dependent response, Shenoy and Smith had to delve deeper inside the structure of microtubules. Based on Smith’s work, other biophysical modelers had previously accounted for the geometry and elastic properties of the axon during a stretching injury, but they did not have good data for representing tau’s role.

"You need to know the elastic properties of tau," Shenoy said, "because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole."

Elastic properties

Shenoy and his colleagues had a sense of tau’s elastic properties but did not have hard numbers until a 2011 experiment from a Swiss and German research team physically stretched out lengths of tau by plucking it with the tip of an atomic force microscope.

"This experiment demonstrated that tau is viscoelastic," Shenoy said. "Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks."

This behavior is because the strands of tau protein are coiled up and bonded to themselves in different places. Pulled slowly, those bonds can come undone, lengthening the strand without breaking it.

"The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far," Shenoy said. "If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break."

With a comprehensive model of the tau-microtubule system, the researchers were able to boil down the outcome of rapid stress loading to equations with only a handful of variables. This mathematical understanding allowed the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus ones that are safe and reversible.

Next steps

Having this mathematical understanding of the interplay between tau and microtubules is only the beginning.

"Predicting what kind of impacts will cause these strain rates is still a complicated problem," Shenoy said. "I might be able to measure the force of the impact when it hits someone’s head, but that force then has to make its way down to the axons, which depends on a lot of different things.

"You need a multiscale model, and our work will be an input to those models on the smallest scale."

In the longer term, however, knowing the parameters that lead to irreversible damage could lead to better understanding of brain injuries and diseases and to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury; Smith’s group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after injuries in which they are stretched.

Ultimately, insights on the molecular level will be inputs to a more comprehensive view of the brain and its many hierarchies of organizations.

"When you’re talking about something’s mechanical properties, stiffness is what comes to mind," Shenoy said. "Biochemistry is what determines that stiffness in the brain’s structures, but that’s only at the molecular level. Once you build it up and formulate things at the appropriate scale, protecting the brain becomes more of a structural engineering problem."

Head injuries can make children loners

New research has found that a child’s relationships may be a hidden casualty long after a head injury.

Neuroscientists at Brigham Young University studied a group of children three years after each had suffered a traumatic brain injury – most commonly from car accidents. The researchers found that lingering injury in a specific region of the brain predicted the health of the children’s social lives.

“The thing that’s hardest about brain injury is that someone can have significant difficulties but they still look okay,” said Shawn Gale, a neuropsychologist at BYU. “But they have a harder time remembering things and focusing on things as well and that affects the way they interact with other people. Since they look fine, people don’t cut them as much slack as they ought to.”

Gale and Ph.D. student Ashley Levan authored a study to be published April 10 by the Journal of Head Trauma Rehabilitation, the leading publication in the field of rehabilitation. The study compared the children’s social lives and thinking skills with the thickness of the brain’s outer layer in the frontal lobe. The brain measurements came from MRI scans and the social information was gathered from parents on a variety of dimensions, such as their children’s participation in groups, number of friends and amount of time spent with friends.

A second finding from the new study suggests one potential way to help. The BYU scholars found that physical injury and social withdrawal are connected through something called “cognitive proficiency.” Cognitive proficiency is the combination of short-term memory and the brain’s processing speed.

“In social interactions we need to process the content of what a person is saying in addition to simultaneously processing nonverbal cues,” Levan said. “We then have to hold that information in our working memory to be able to respond appropriately. If you disrupt working memory or processing speed it can result in difficulty with social interactions.”

Separate studies on children with ADHD, which also affects the frontal lobes, show that therapy can improve working memory. Gale would like to explore in future research with BYU’s MRI facility if improvements in working memory could “treat” the social difficulties brought on by head injuries.

“This is a preliminary study but we want to go into more of the details about why working memory and processing speed are associated with social functioning and how specific brain structures might be related to improve outcome,” Gale said.

Study finds stem cell combination therapy improves traumatic brain injury outcomes

Traumatic brain injuries (TBI), sustained by close to 2 million Americans annually, including military personnel, are debilitating and devastating for patients and their families. Regardless of severity, those with TBI can suffer a range of motor, behavioral, intellectual and cognitive disabilities over the short or long term. Sadly, clinical treatments for TBI are few and largely ineffective.

In an effort to find an effective therapy, neuroscientists at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery in the USF Health Morsani College of Medicine, University of South Florida, have conducted several preclinical studies aimed at finding combination therapies to improve TBI outcomes.

In their study of several different therapies—alone and in combination—applied to laboratory rats modeled with TBI, USF researchers found that a combination of human umbilical cord blood cells (hUBCs) and granulocyte colony stimulating factor (G-CSF), a growth factor, was more therapeutic than either administered alone, or each with saline, or saline alone.

The study appeared in a recent issue of PLoS ONE.

“Chronic TBI is typically associated with major secondary molecular injuries, including chronic neuroinflammation, which not only contribute to the death of neuronal cells in the central nervous system, but also impede any natural repair mechanism,” said study lead author Cesar V. Borlongan, PhD, professor of neurosurgery and director of USF’s Center of Excellence for Aging and Brain Repair. “In our study, we used hUBCs and G-CSF alone and in combination. In previous studies, hUBCs have been shown to suppress inflammation, and G-CSF is currently being investigated as a potential therapeutic agent for patients with stroke or Alzheimer’s disease.”

Their stand-alone effects have a therapeutic potential for TBI, based on results from previous studies. For example, G-CSF has shown an ability to mobilize stem cells from bone marrow and then infiltrate injured tissues, promoting self-repair of neural cells, while hUBCs have been shown to suppress inflammation and promote cell growth.

The involvement of the immune system in the central nervous system to either stimulate repair or enhance molecular damage has been recognized as key to the progression of many neurological disorders, including TBI, as well as in neurodegenerative diseases such as Parkinson’s disease, multiple sclerosis and some autoimmune diseases, the researchers report. Increased expression of MHCII positive cells—cell members that secrete a family of molecules mediating interactions between the immune system’s white blood cells—has been directly linked to neurodegeneration and cognitive decline in TBI.

“Our results showed that the combined therapy of hUBCs and G-CSF significantly reduced the TBI-induced loss of neuronal cells in the hippocampus,” said Borlongan. “Therapy with hUBCs and G-CSF alone or in combination produced beneficial results in animals with experimental TBI. G-CSF alone produced only short-lived benefits, while hUBCs alone afforded more robust and stable improvements. However, their combination offered the best motor improvement in the laboratory animals.”

“This outcome may indicate that the stem cells had more widespread biological action than the drug therapy,” said Paul R. Sanberg, distinguished professor at USF and principal investigator of the Department of Defense funded project. “Regardless, their combination had an apparent synergistic effect and resulted in the most effective amelioration of TBI-induced behavioral deficits.”

The researchers concluded that additional studies of this combination therapy are warranted in order to better understand their modes of action. While this research focused on motor improvements, they suggested that future combination therapy research should also include analysis of cognitive improvement in the laboratory animals modeled with TBI.

Researchers Model a Key Breaking Point Involved in Traumatic Brain Injury

Even the mildest form of a traumatic brain injury, better known as a concussion, can deal permanent, irreparable damage. Now, an interdisciplinary team of researchers at the University of Pennsylvania is using mathematical modeling to better understand the mechanisms at play in this kind of injury, with an eye toward protecting the brain from its long-term consequences.

Their recent findings, published in the Biophysical Journal, shed new light on the mechanical properties of a critical brain protein and its role in the elasticity of axons, the long, tendril-like part of brain cells. This protein, known as tau, helps explain the apparent contradiction this elasticity presents. If axons are so stretchy, why do they break under the strain of a traumatic brain injury?    

Tau’s own elastic properties reveal why rapid impacts deal permanent damage to structures within axons, when applying the same force more slowly causes them to safely stretch. This understanding can now be used to make computer models of the brain more realistic and potentially can be applied toward tau-related diseases, such as Alzheimer’s.

The team consists of Vivek Shenoy, professor of materials science and engineering in the School of Engineering and Applied Science, Hossein Ahmadzadeh, a member of Shenoy’s lab, and Douglas Smith, professor of neurosurgery in Penn’s Perelman School of Medicine and director of the Penn Center for Brain Injury and Repair. 

“One of the main things you see in the brains of patients who have died because of a TBI is swellings along the axons,” Shenoy said. “Inside axons are microtubules, which act like tracks for transporting molecular cargo along the axon. When they break, there’s an interruption in the flow of this cargo and it starts to accumulate, which is why you get these swellings.”  

Smith had previously studied the mechanical properties of axons as a whole. By patterning axons in culture in parallel tracts, Smith and his colleagues could apply a stretch to the axons at different forces and speeds and measure how they responded.

“What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage,” Smith said. “But at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretch at fast rates. So the rate at which stretch is applied is the important component, such as occurs during rapid movement of the brain and stretching of axons due to head impact from a fall, assault or automobile crash.”

This observation still did not explain to researchers why microtubules, the stiffest part of the axon, were the parts that were breaking. To solve that puzzle, the researchers had to delve even deeper into their structure.

Microtubules are closely packed together inside axons, somewhat like a bundle of straws. Binding the individual straws together is the protein tau. Other biophysical modelers had previously accounted for the geometry and elastic properties of the axon during a stretching injury based on Smith’s work but did not have good data for representing tau’s role in the overall behavior of the system when it is loaded with stress over different lengths of time. 

“You need to know the elastic properties of tau,” Shenoy said, “because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole.”

Shenoy and his colleagues had a sense of tau’s elastic properties but did not have hard numbers until a 2011 experiment from a Swiss and German research team physically stretched out lengths of tau by plucking it with the tip of an atomic force microscope.

“This experiment demonstrated that tau is viscoelastic,” Shenoy said. “Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks.”

This behavior is because the strands of tau protein are coiled up and bonded to themselves in different places. Pulled slowly, those bonds can come undone, lengthening the strand without breaking it. 

“The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far,” Shenoy said. “If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break.”

With a comprehensive model of the tau-microtubule system, the researchers were able to boil down the outcome of rapid stress loading to equations with only a handful of variables. This mathematical understanding allowed the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus safe and reversible loading and unloading of stress.

“Predicting what kind of impacts will cause these strain rates is still a complicated problem,” Shenoy said. “I might be able to measure the force of the impact when it hits someone’s head, but that force then has to make its way down to the axons, which depends on a lot of different things.

“You need a multiscale model, and our work will be an input to those models on the smallest scale.”

In the longer term, knowing the parameters that lead to irreversible damage could lead to better understanding of brain injuries and diseases and to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury; Smith’s group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after stretch injury.    

“Intriguingly, it may be no coincidence that tau is also the same protein that forms neurofibrillary tangles, one of the hallmark brain pathologies of chronic traumatic encephalopathy, or CTE, which is linked to a history of concussions and higher levels of TBI,” said Smith. “Uncovering the role of tau at the time of trauma may provide insight into how it is involved in long-term degenerative processes.”