Neuroscience

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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.”

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.”

Filed under TBI brain injury concussion tau protein microtubules neuroscience science

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Concussion secrets unveiled in mice and people 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 immune response 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 brain injury. 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 traumatic brain injury. 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 cell death 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 brain tissue,” 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 mild traumatic brain injury 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 brain 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.

Concussion secrets unveiled in mice and people

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 immune response 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 brain injury.

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 traumatic brain injury. 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 cell death 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 brain tissue,” 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 mild traumatic brain injury 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 brain 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.

Filed under concussion TBI glutathione microglia astrocytes glial limitans neuroscience science

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Blood Test Accurately Diagnoses Concussion and Predicts Long Term Cognitive Disability

A new blood biomarker correctly predicted which concussion victims went on to have white matter tract structural damage and persistent cognitive dysfunction following a mild traumatic brain injury (mTBI). Researchers in the Perelman School of Medicine at the University of Pennsylvania, in conjunction with colleagues at Baylor College of Medicine, found that the blood levels of a protein called calpain-cleaved αII-spectrin N-terminal fragment (SNTF) were twice as high in a subset of patients following a traumatic injury. If validated in larger studies, this blood test could identify concussion patients at increased risk for persistent cognitive dysfunction or further brain damage and disability if returning to sports or military activities.

image

More than 1.5 million children and adults suffer concussions each year in the United States, and hundreds of thousands of military personal endure these mild traumatic brain injuries worldwide. Current tests are not capable of determining the extent of the injury or whether the injured person will be among the 15-30 percent who experience significant, persistent cognitive deficits, such as processing speed, working memory and the ability to switch or balance multiple thoughts.

"New tests that are fast, simple, and reliable are badly needed to predict who may experience long-term effects from concussions, and as new treatments are developed in the future, to identify who should be eligible for clinical trials or early interventions," said lead author Robert Siman, PhD, research professor of Neurosurgery at Penn. "Measuring the blood levels of SNTF on the day of a brain injury may help to identify the subset of concussed patients who are at risk of persistent disability." 

In a study published yesterday in Frontiers in Neurology, Penn and Baylor researchers evaluated blood samples and diffusion tensor images from a subgroup of 38 participants in a larger study of mTBI with ages ranging from 15 to 25 years old. 17 had sustained a head injury caused by blunt trauma, acceleration or deceleration forces, 13 had an orthopaedic injury, and 8 were healthy, uninjured, demographically matched controls.

In taking neuropsychological and cognitive tests over the course of three months, results within the mTBI group varied considerably, with some patients performing as well as the healthy controls throughout, while others showed impairment initially that resolved by three months, and a third group with cognitive dysfunction persisting through three months. The nine patients who had abnormally high levels of SNTF (7 mTBI and 2 orthopaedic patients) also had significant white matter damage apparent in radiological imaging.

"The blood test identified SNTF in some of the orthopaedic injury patients as well, suggesting that these injuries could also lead to abnormalities in the brain, such as a concussion, that may have been overlooked with existing tests," said Douglas Smith, MD, director of the Penn Center for Brain Injury and Repair and professor of Neurosurgery. "SNTF as a marker is consistent with our earlier research showing that calcium is dumped into neurons following a traumatic brain injury, as SNTF is a marker for neurodegeneration driven by calcium overload."

The blood test given on the day of the mild traumatic brain injury showed 100 percent sensitivity to predict concussions leading to persisting cognitive problems, and 75 percent specificity to correctly rule out those without functionally harmful concussions. If validated in larger studies, a blood test measuring levels of SNTF could be helpful in diagnosing and predicting risk of long term consequences of concussion. The Penn and Baylor researchers hope to determine the robustness of these findings with a second larger study, and determine the best time after concussion to measure SNTF in the blood in order to predict persistent brain dysfunction. The team also wants to evaluate their blood test for identifying when repetitive concussions begin to cause brain damage and persistent disability.

(Source: uphs.upenn.edu)

Filed under brain injury brain damage concussion TBI white matter neuroimaging neuroscience science

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Menstrual Cycle Influences Concussion Outcomes Researchers found that women injured during the two weeks leading up to their period (the premenstrual phase) had a slower recovery and poorer health one month after injury compared to women injured during the two weeks directly after their period or women taking birth control pills. The University of Rochester study was published today in the Journal of Head Trauma Rehabilitation. If confirmed in subsequent research, the findings could alter the treatment and prognosis of women who suffer head injuries from sports, falls, car accidents or combat. Several recent studies have confirmed what women and their physicians anecdotally have known for years: Women experience greater cognitive decline, poorer reaction times, more headaches, extended periods of depression, longer hospital stays and delayed return-to-work compared to men following head injury. Such results are particularly pronounced in women of childbearing age; girls who have not started their period and post-menopausal women have outcomes similar to men. Few studies have explored why such differences occur, but senior author Jeffrey J. Bazarian, M.D., M.P.H. says it stands to reason that sex hormones such as estrogen and progesterone, which are highest in women of childbearing age, may play a role. “I don’t think doctors consider menstrual history when evaluating a patient after a concussion, but maybe we should,” noted Bazarian, associate professor of Emergency Medicine at the University of Rochester School of Medicine and Dentistry who treats patients and conducts research on traumatic brain injury and long-term outcomes among athletes. “By taking into account the stage of their cycle at the time of injury we could better identify patients who might need more aggressive monitoring or treatment. It would also allow us to counsel women that they’re more – or less – likely to feel poorly because of their menstrual phase.” Although media coverage tends to focus on concussions in male professional athletes, studies suggest that women have a higher incidence of head injuries than men playing sports with similar rules, such as ice hockey, soccer and basketball. Bazarian estimates that 70 percent of the patients he treats in the URMC Sport Concussion Clinic are young women. He believes the number is so high because they often need more follow-up care. In his experience, soccer is the most common sport leading to head injuries in women, but lacrosse, field hockey, cheerleading, volleyball and basketball can lead to injuries as well. Sex hormone levels often change after a head injury, as women who have suffered a concussion and subsequently missed one or more periods can attest. According to Kathleen M. Hoeger, M.D., M.P.H., study co-author and professor of Obstetrics and Gynecology at the University of Rochester School of Medicine and Dentistry, any stressful event, like a hit to the head, can shut down the pituitary gland in the brain, which is the body’s hormone generator. If the pituitary doesn’t work, the level of estrogen and progesterone would drop quickly.   According to Bazarian, progesterone is known to have a calming effect on the brain and on mood. Knowing this, his team came up with the “withdrawal hypothesis”: If a woman suffers a concussion in the premenstrual phase when progesterone levels are naturally high, an abrupt drop in progesterone after injury produces a kind of withdrawal which either contributes to or worsens post concussive symptoms like headache, nausea, dizziness and trouble concentrating. This may be why women recover differently than men, who have low pre-injury levels of the hormone.      Hoeger and Bazarian tested their theory by recruiting144 women ages 18 to 60 who arrived within four hours of a head hit at five emergency departments in upstate New York and one in Pennsylvania. Participants gave blood within six hours of injury and progesterone level determined the menstrual cycle phase at the time of injury. Based on the results, participants fell into three groups: 37 in the premenstrual/high progesterone group; 72 in the low progesterone group (progesterone is low in the two weeks directly after a period); and 35 in the birth control group based on self-reported use. One month later, women in the premenstrual/high progesterone group were twice as likely to score in a worse percentile on standardized tests that measure concussion recovery and quality of life – as defined by mobility, self-care, usual activity, pain and emotional health – compared to women in the low progesterone group. Women in the premenstrual/high progesterone group also scored the lowest (average 65) on a health rating scale that went from 0, being the worst health imaginable, to 100, being the best. Women in the birth control group had the highest scores (average 77). “If you get hit when progesterone is high and you experience a steep drop in the hormone, this is what makes you feel lousy and causes symptoms to linger,” said Bazarian. “But, if you are injured when progesterone is already low, a hit to the head can’t lower it any further, so there is less change in the way you feel.” The team suspected that women taking birth control pills, which contain synthetic hormones that mimic the action of progesterone, would have similar outcomes to women injured in the low progesterone phase of their cycle. As expected, there was no clear difference between these groups, as women taking birth control pills have a constant stream of sex hormones and don’t experience a drop following a head hit, so long as they continue to take the pill.     “Women who are very athletic get several benefits from the pill; it protects their bones and keeps their periods predictable,” noted Hoeger. “If larger studies confirm our data, this could be one more way in which the pill is helpful in athletic women, especially women who participate in sports like soccer that present lots of opportunities for head injuries.” In addition to determining menstrual cycle phase at the time of injury, Bazarian plans to scrutinize a woman’s cycles after injury to make sure they are not disrupted. If they are, the woman should make an appointment with her gynecologist to discuss the change.

Menstrual Cycle Influences Concussion Outcomes

Researchers found that women injured during the two weeks leading up to their period (the premenstrual phase) had a slower recovery and poorer health one month after injury compared to women injured during the two weeks directly after their period or women taking birth control pills.

The University of Rochester study was published today in the Journal of Head Trauma Rehabilitation. If confirmed in subsequent research, the findings could alter the treatment and prognosis of women who suffer head injuries from sports, falls, car accidents or combat.

Several recent studies have confirmed what women and their physicians anecdotally have known for years: Women experience greater cognitive decline, poorer reaction times, more headaches, extended periods of depression, longer hospital stays and delayed return-to-work compared to men following head injury. Such results are particularly pronounced in women of childbearing age; girls who have not started their period and post-menopausal women have outcomes similar to men.

Few studies have explored why such differences occur, but senior author Jeffrey J. Bazarian, M.D., M.P.H. says it stands to reason that sex hormones such as estrogen and progesterone, which are highest in women of childbearing age, may play a role.

“I don’t think doctors consider menstrual history when evaluating a patient after a concussion, but maybe we should,” noted Bazarian, associate professor of Emergency Medicine at the University of Rochester School of Medicine and Dentistry who treats patients and conducts research on traumatic brain injury and long-term outcomes among athletes. “By taking into account the stage of their cycle at the time of injury we could better identify patients who might need more aggressive monitoring or treatment. It would also allow us to counsel women that they’re more – or less – likely to feel poorly because of their menstrual phase.”

Although media coverage tends to focus on concussions in male professional athletes, studies suggest that women have a higher incidence of head injuries than men playing sports with similar rules, such as ice hockey, soccer and basketball. Bazarian estimates that 70 percent of the patients he treats in the URMC Sport Concussion Clinic are young women. He believes the number is so high because they often need more follow-up care. In his experience, soccer is the most common sport leading to head injuries in women, but lacrosse, field hockey, cheerleading, volleyball and basketball can lead to injuries as well.

Sex hormone levels often change after a head injury, as women who have suffered a concussion and subsequently missed one or more periods can attest. According to Kathleen M. Hoeger, M.D., M.P.H., study co-author and professor of Obstetrics and Gynecology at the University of Rochester School of Medicine and Dentistry, any stressful event, like a hit to the head, can shut down the pituitary gland in the brain, which is the body’s hormone generator. If the pituitary doesn’t work, the level of estrogen and progesterone would drop quickly.  

According to Bazarian, progesterone is known to have a calming effect on the brain and on mood. Knowing this, his team came up with the “withdrawal hypothesis”: If a woman suffers a concussion in the premenstrual phase when progesterone levels are naturally high, an abrupt drop in progesterone after injury produces a kind of withdrawal which either contributes to or worsens post concussive symptoms like headache, nausea, dizziness and trouble concentrating. This may be why women recover differently than men, who have low pre-injury levels of the hormone.     

Hoeger and Bazarian tested their theory by recruiting144 women ages 18 to 60 who arrived within four hours of a head hit at five emergency departments in upstate New York and one in Pennsylvania. Participants gave blood within six hours of injury and progesterone level determined the menstrual cycle phase at the time of injury. Based on the results, participants fell into three groups: 37 in the premenstrual/high progesterone group; 72 in the low progesterone group (progesterone is low in the two weeks directly after a period); and 35 in the birth control group based on self-reported use.

One month later, women in the premenstrual/high progesterone group were twice as likely to score in a worse percentile on standardized tests that measure concussion recovery and quality of life – as defined by mobility, self-care, usual activity, pain and emotional health – compared to women in the low progesterone group. Women in the premenstrual/high progesterone group also scored the lowest (average 65) on a health rating scale that went from 0, being the worst health imaginable, to 100, being the best. Women in the birth control group had the highest scores (average 77).

“If you get hit when progesterone is high and you experience a steep drop in the hormone, this is what makes you feel lousy and causes symptoms to linger,” said Bazarian. “But, if you are injured when progesterone is already low, a hit to the head can’t lower it any further, so there is less change in the way you feel.”

The team suspected that women taking birth control pills, which contain synthetic hormones that mimic the action of progesterone, would have similar outcomes to women injured in the low progesterone phase of their cycle. As expected, there was no clear difference between these groups, as women taking birth control pills have a constant stream of sex hormones and don’t experience a drop following a head hit, so long as they continue to take the pill.    

“Women who are very athletic get several benefits from the pill; it protects their bones and keeps their periods predictable,” noted Hoeger. “If larger studies confirm our data, this could be one more way in which the pill is helpful in athletic women, especially women who participate in sports like soccer that present lots of opportunities for head injuries.”

In addition to determining menstrual cycle phase at the time of injury, Bazarian plans to scrutinize a woman’s cycles after injury to make sure they are not disrupted. If they are, the woman should make an appointment with her gynecologist to discuss the change.

Filed under concussion brain injury estrogen progesterone cognitive decline neuroscience science

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The Concussed Brain at Work: fMRI Study Documents Brain Activation During Concussion Recovery For the first time, researchers have documented irregular brain activity within the first 24 hours of a concussive injury, as well as an increased level of brain activity weeks later—suggesting that the brain may compensate for the injury during the recovery time. The findings are published in the September issue of the Journal of the International Neuropsychological Society Thomas Hammeke, PhD, professor of psychiatry and behavioral medicine at the Medical College of Wisconsin, is the lead author.  Collaborators at the Cleveland Clinic; St. Mary’s Hospital in Enid, Okl.; the University of North Carolina; Franklin College in Franklin, Ind., and the Marshfield Clinic in Marshfield, Wis., co-authored the paper. To study the natural recovery from sports concussion, 12 concussed high school football athletes and 12 uninjured teammates were evaluated at 13 hours and again at seven weeks following concussive injury. The concussed athletes showed the expected postconcussive symptoms, including decreased reaction time and lowered cognitive abilities. Imaging via fMRI (functional magnetic resonance imaging) showed decreased activity in select regions of the right hemisphere of the brain, which suggests the poor cognitive performance of concussion patients is related to that underactivation of attentional brain circuits. Seven weeks post-injury, the concussed athletes showed improvement of cognitive abilities and normal reaction time. However, imaging at that time showed the post-concussed athletes had more activation in the brain’s attentional circuits than did the control athletes. “This hyperactivation may represent a compensatory brain response that mediates recovery,” said Dr. Hammeke. “This is the first study to demonstrate that reversal in activation patterns, and that reversal matches the progression of symptoms from the time of the injury through clinical recovery.” “Deciding when a concussed player should return to the playing field is currently an inexact science,” said Dr. Stephen Rao, director of the Schey Center for Cognitive Neuroimaging at the Cleveland Clinic and a senior author. “Measuring changes in brain activity during the acute recovery period can provide a scientific basis for making this critical decision.” Each year, an estimated 3.8 million people sustain a traumatic brain injury (TBI). TBI is a contributing factor to a third of all injury-related deaths in the United States. More than three-quarters of the TBI’s that occur are concussions or other forms of mild TBI, many of which may go undiagnosed. (Image: Corbis)

The Concussed Brain at Work: fMRI Study Documents Brain Activation During Concussion Recovery

For the first time, researchers have documented irregular brain activity within the first 24 hours of a concussive injury, as well as an increased level of brain activity weeks later—suggesting that the brain may compensate for the injury during the recovery time.

The findings are published in the September issue of the Journal of the International Neuropsychological Society

Thomas Hammeke, PhD, professor of psychiatry and behavioral medicine at the Medical College of Wisconsin, is the lead author.  Collaborators at the Cleveland Clinic; St. Mary’s Hospital in Enid, Okl.; the University of North Carolina; Franklin College in Franklin, Ind., and the Marshfield Clinic in Marshfield, Wis., co-authored the paper.

To study the natural recovery from sports concussion, 12 concussed high school football athletes and 12 uninjured teammates were evaluated at 13 hours and again at seven weeks following concussive injury.

The concussed athletes showed the expected postconcussive symptoms, including decreased reaction time and lowered cognitive abilities. Imaging via fMRI (functional magnetic resonance imaging) showed decreased activity in select regions of the right hemisphere of the brain, which suggests the poor cognitive performance of concussion patients is related to that underactivation of attentional brain circuits.

Seven weeks post-injury, the concussed athletes showed improvement of cognitive abilities and normal reaction time. However, imaging at that time showed the post-concussed athletes had more activation in the brain’s attentional circuits than did the control athletes.

“This hyperactivation may represent a compensatory brain response that mediates recovery,” said Dr. Hammeke. “This is the first study to demonstrate that reversal in activation patterns, and that reversal matches the progression of symptoms from the time of the injury through clinical recovery.”

“Deciding when a concussed player should return to the playing field is currently an inexact science,” said Dr. Stephen Rao, director of the Schey Center for Cognitive Neuroimaging at the Cleveland Clinic and a senior author. “Measuring changes in brain activity during the acute recovery period can provide a scientific basis for making this critical decision.”

Each year, an estimated 3.8 million people sustain a traumatic brain injury (TBI). TBI is a contributing factor to a third of all injury-related deaths in the United States. More than three-quarters of the TBI’s that occur are concussions or other forms of mild TBI, many of which may go undiagnosed.

(Image: Corbis)

Filed under concussion TBI brain injury neuroimaging neurology neuroscience science

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Scientists Develop New Way to Measure Cumulative Effect of Head Hits in Football Scientists at Wake Forest Baptist Medical Center have developed a new way to measure the cumulative effect of impacts to the head incurred by football players. The metric, called Risk Weighted Cumulative Exposure (RWE), can capture players’ exposure to the risk of concussion over the course of a football season by measuring the frequency and magnitude of all impacts, said senior author of the study Joel Stitzel, Ph.D., chair of biomedical engineering at Wake Forest Baptist and associate head of the Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences. The study is published in the current online edition of the Annals of Biomedical Engineering. Based on data gathered throughout a season of high school football games and practices, the researchers used RWE to measure the cumulative risk of injury due to linear and rotational acceleration separately, as well as the combined probability of injury associated with both. “This metric gives us a way to look at a large number of players and the hits they’ve incurred while playing football,” Stitzel said. “We know that young players are constantly experiencing low-level hits that don’t cause visible injury, but there hasn’t been a good way to measure the associated risk of concussion.” Concussion is the most common sports-related head injury, with football players having the highest rate among high school athletes, according to the study. It is estimated that nearly 1.1 million students play high school football in the United States. However, research on the biomechanics of football-related head impacts traditionally has concentrated on the collegiate level rather than on the high school level. With such a large number of players in the sport, it is critical to understand the risk associated with different levels of impact and accurately estimate cumulative concussion risk over the course of a practice, game, season or lifetime, Stitzel said. In the Wake Forest Baptist study, the researchers measured the head impact exposure in 40 high school football players by using sensors placed in their helmets to record linear and rotational acceleration. A total of 16,502 impacts were collected over the course of one football season and the data were analyzed as a group and as individual players. Impacts were weighted according to the associated risk from linear acceleration and rotational acceleration alone, as well as to the combined probability of injury associated with both. This is an improved method of capturing the cumulative effects from each impact because it accounts for nonlinear relationships between impact magnitude and the associated risk of injury, Stitzel said. “All hits involve both linear and rotational acceleration, but rotation coveys the idea that your head is pivoting about the neck whereas linear acceleration is experienced from a direct blow in more of a straight line through the center of mass of the head,” Stitzel said. The median impact for each player ranged from 15.2 to 27.0 g, with an average value of 21.7 g, which shows the wide variability in the force of impacts. The study found that impact frequency was greater during games (15.5) than during practices (9.4). However, overall exposure over the course of the season was greater during practices. This information may help teams reduce exposure to head impacts during practices by teaching proper tackling techniques that could reduce exposure to impacts that may result in a higher concussion rate, the researchers reported. Additionally, the study found a wide variation in player exposure within the team, with a 22-fold variation in the exposure per impact for practices and a 47-fold variation in the exposure for impact for games. Studies like this are vital to understanding the biomechanical basis of head injuries related to football, Stitzel said. The metric fully captures a player’s exposure over the course of the season and will be used in conjunction with other pre- and post-season evaluations, including MRI and neurological tests conducted as part of this study. The research team hopes that this work may ultimately improve helmet safety and design to make football a safer sport. (Image: Getty Images)

Scientists Develop New Way to Measure Cumulative Effect of Head Hits in Football

Scientists at Wake Forest Baptist Medical Center have developed a new way to measure the cumulative effect of impacts to the head incurred by football players.

The metric, called Risk Weighted Cumulative Exposure (RWE), can capture players’ exposure to the risk of concussion over the course of a football season by measuring the frequency and magnitude of all impacts, said senior author of the study Joel Stitzel, Ph.D., chair of biomedical engineering at Wake Forest Baptist and associate head of the Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences.

The study is published in the current online edition of the Annals of Biomedical Engineering.

Based on data gathered throughout a season of high school football games and practices, the researchers used RWE to measure the cumulative risk of injury due to linear and rotational acceleration separately, as well as the combined probability of injury associated with both.

“This metric gives us a way to look at a large number of players and the hits they’ve incurred while playing football,” Stitzel said. “We know that young players are constantly experiencing low-level hits that don’t cause visible injury, but there hasn’t been a good way to measure the associated risk of concussion.”

Concussion is the most common sports-related head injury, with football players having the highest rate among high school athletes, according to the study. It is estimated that nearly 1.1 million students play high school football in the United States. However, research on the biomechanics of football-related head impacts traditionally has concentrated on the collegiate level rather than on the high school level.

With such a large number of players in the sport, it is critical to understand the risk associated with different levels of impact and accurately estimate cumulative concussion risk over the course of a practice, game, season or lifetime, Stitzel said.

In the Wake Forest Baptist study, the researchers measured the head impact exposure in 40 high school football players by using sensors placed in their helmets to record linear and rotational acceleration. A total of 16,502 impacts were collected over the course of one football season and the data were analyzed as a group and as individual players.

Impacts were weighted according to the associated risk from linear acceleration and rotational acceleration alone, as well as to the combined probability of injury associated with both. This is an improved method of capturing the cumulative effects from each impact because it accounts for nonlinear relationships between impact magnitude and the associated risk of injury, Stitzel said.

“All hits involve both linear and rotational acceleration, but rotation coveys the idea that your head is pivoting about the neck whereas linear acceleration is experienced from a direct blow in more of a straight line through the center of mass of the head,” Stitzel said.

The median impact for each player ranged from 15.2 to 27.0 g, with an average value of 21.7 g, which shows the wide variability in the force of impacts.

The study found that impact frequency was greater during games (15.5) than during practices (9.4). However, overall exposure over the course of the season was greater during practices.

This information may help teams reduce exposure to head impacts during practices by teaching proper tackling techniques that could reduce exposure to impacts that may result in a higher concussion rate, the researchers reported.

Additionally, the study found a wide variation in player exposure within the team, with a 22-fold variation in the exposure per impact for practices and a 47-fold variation in the exposure for impact for games.

Studies like this are vital to understanding the biomechanical basis of head injuries related to football, Stitzel said. The metric fully captures a player’s exposure over the course of the season and will be used in conjunction with other pre- and post-season evaluations, including MRI and neurological tests conducted as part of this study.

The research team hopes that this work may ultimately improve helmet safety and design to make football a safer sport.

(Image: Getty Images)

Filed under concussion head injury TBI football risk weighted cumulative exposure neurology neuroscience science

71 notes

Cognitive deficits from concussions still present after two months The ability to focus and switch tasks readily amid distractions was compromised for up to two months following brain concussions suffered by high school athletes, according to a study at the University of Oregon. Research team members, in an interview, said the discovery suggests that some athletes may need longer recovery periods than current practices dictate to lower the risk of subsequent concussions. Conventional wisdom, said lead author David Howell, a graduate student in the UO Department of Human Physiology, says that typical recovery from concussion takes seven to 10 days. "The differences we detected may be a matter of milliseconds between a concussed person and a control subject, but as far as brain time goes that difference for a linebacker returning to competition too soon could mean the difference between another injury or successfully preparing to safely tackle an oncoming running back," Howell said. The findings are based on cognitive exercises used five times over the two months with a pair of sensitive computer-based measuring tools — the attentional network test and the task-switching test. The study focused on the effects of concussions to the frontal region of the brain, which is responsible for working, or short-term, memory and executive function, said Li-Shan Chou, professor of human physiology and director of the UO Motion Analysis Laboratory. The study was published online ahead of print by Medicine & Science in Sports & Exercise, the official journal of the American College of Sports Medicine.

Cognitive deficits from concussions still present after two months

The ability to focus and switch tasks readily amid distractions was compromised for up to two months following brain concussions suffered by high school athletes, according to a study at the University of Oregon.

Research team members, in an interview, said the discovery suggests that some athletes may need longer recovery periods than current practices dictate to lower the risk of subsequent concussions. Conventional wisdom, said lead author David Howell, a graduate student in the UO Department of Human Physiology, says that typical recovery from concussion takes seven to 10 days.

"The differences we detected may be a matter of milliseconds between a concussed person and a control subject, but as far as brain time goes that difference for a linebacker returning to competition too soon could mean the difference between another injury or successfully preparing to safely tackle an oncoming running back," Howell said.

The findings are based on cognitive exercises used five times over the two months with a pair of sensitive computer-based measuring tools — the attentional network test and the task-switching test. The study focused on the effects of concussions to the frontal region of the brain, which is responsible for working, or short-term, memory and executive function, said Li-Shan Chou, professor of human physiology and director of the UO Motion Analysis Laboratory.

The study was published online ahead of print by Medicine & Science in Sports & Exercise, the official journal of the American College of Sports Medicine.

Filed under brain concussion brain injury cognitive deficits psychology neuroscience science

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