Researchers evaluate red wine compound for treating concussions in pro boxers

ScienceDaily (May 27, 2011) — UT Southwestern Medical Center researchers are engaging the help of professional boxers and trainers to study whether a component in red wine and grapes could help reduce the short- and long-term effects of concussions.

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Researchers plan to recruit about two dozen professional boxers to take the neuroprotective compound resveratrol after a fight to see if it reduces damage to the brain after impact and helps restore subtle brain functions and connections via its antioxidant effects. If successful, researchers hope the results may be applicable not only to concussions in other sports such as football and hockey, but also to everyday incidents such as falls, auto accidents and other blows to the head.

"We know from animal studies that if we give the drug immediately after or soon after a brain injury, it can dramatically and significantly reduce the damage you see long term," said Dr. Joshua Gatson, assistant professor of surgery in Burn/Trauma/Critical Care and principal investigator for the study. "There haven't been any completed human studies yet, so this is really the first look at resveratrol's effect on traumatic brain injury."

Resveratrol is already being studied as an agent to lower blood sugar levels, for use against cancer, to protect cardiovascular health, and in stroke and Alzheimer's disease treatments.

"Even though resveratrol is found in red wine, you would need 50 glasses of wine to get the required dose to get the protection you would need," said Dr. Gatson.

He came up with the idea for the trial, called the REPAIR study, while watching ESPN. Being a sports fan, he saw frequent concussion issues in football.

"The only treatment available is rest and light exercise, but there is no drug therapy to protect the brain from consecutive concussions, which are actually a lot worse than the initial one," said Dr. Gatson, who investigates biomarkers and novel therapies for traumatic brain injury. "There's been a lot of work with resveratrol showing that it also protects the brain, so we thought this might be the ideal drug."

In this study, researchers are administering the required oral dose once a day for seven days. Pro boxers will take a supplement form of resveratrol within two hours of their match. Researchers will then use neurocognitive tests and novel MRI protocols to track subtle brain activity, inflammation, and restoration of cells and connections.

"The main goal of our research is to protect the brain after each episode so that we can decrease the cumulative effect of these sports concussions," Dr. Gatson said.

Because boxers can have several fights in a short period of time, the researchers decided to target pro boxers with the help of Joseph Mohmed, the study research coordinator, and a coach for USA Boxing, the governing body for all amateur boxing, including the Olympics. Mr. Mohmed also is a former facilities manager at UT Southwestern.

According to the American Association of Neurological Surgeons, 2009 figures showed that 446,788 sports-related head injuries were treated at U.S. hospital emergency rooms, an increase of nearly 95,000 from the year before, in sports ranging from diving and cycling to baseball, basketball, soccer and football. The annual incidence of football-related concussion in the U.S. is estimated at 300,000, with about 47,000 football-related head injuries treated in hospital emergency rooms. In addition, more than 85,000 people were treated for bicycle-related head injuries; about two-thirds of 600 bicycling deaths a year are attributed to traumatic brain injury.

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New procedure to make brain surgery safer

ScienceDaily (May 27, 2011) — To increase patient safety in clinical practice and minimize risks and damage that may arise during surgery, computer support and digital medical imaging are key technologies. Before brain operations, neurosurgeons can now evaluate patient-specific surgical risks, achieve increased safety, and avoid unacceptable risks.

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Brain interventions must be planned so that the neurosurgeon can access and remove the tumor without causing unnecessary damage. Before the brain tumor can be removed, crucial questions must be answered. Where do the functional areas of the cortex (gray matter) of the patient lie? What are the paths of the nerve fiber tracts that connect them? Answering these questions is important because the functional areas of the brain are interconnected via nerve pathways, also known as nerve fiber tracts. These nerve tracts must be protected as much as possible; otherwise, permanent dysfunction could occur. Furthermore, nerve tracts can be pushed or infiltrated by the brain tumor itself. If nerve tracts become damaged during an operation, there is a risk that distant functional areas connected to the tumor-afflicted part of the brain could be affected and induce lasting sensory, motor, and cognitive impairment. Therefore, neurosurgeons attempt to answer these questions for each patient during the planning stage of the brain operation to minimize the risks present in the intervention. To do so, surgeons require medical imagery of each patient's brain anatomy and function that is as realistic and precise as possible. However, medical images contain inaccuracies that arise from the processing, modeling, and reconstruction of patient data.

Solving these problems requires more than merely improving existing imaging methods. Mathematical analysis and models must be integrated to produce information about the location of the tumor, functional areas, and nerve fiber tracts, to increase the accuracy of patient-specific data, and to give the surgeon dependable knowledge.

The Fraunhofer MEVIS Institute for Medical Image Computing in Bremen, Germany has pioneered a procedure that analyzes uncertainty in patient-specific images, modeling, and reconstruction and incorporates this information into reconstructions of patient data. This procedure allows safety margins around nerve tracts in the brain to be more accurately determined. In addition, the reliability of the reconstructed data is calculated to supply the surgeon with accurate information concerning nerve tract locations, paths, and intersections and to construct safety margins around the nerve fiber tracts. By integrating errors in measurement, reconstruction, and modeling, the exact locations of tracts in a space-occupying tumor are calculated. This gives the neurosurgeon a reliable prognosis concerning where the incision in the brain should be made and which safety margins should be chosen to avoid harming nerve tracts and irreversibly damaging important functional areas. Before an intervention, the surgeon can evaluate patient-specific risks. These software assistants will be refined and implemented for neuronavigation in future operations, providing the surgeon with updated information during surgery that can be compared to planning data.

The paths of nerve tracts in the brain and the functional areas that they connect can now be explored by visitors of the "New Paths in Medicine" exhibit on the MS Wissenschaft exhibition ship. The converted inland vessel is underway until September 29, 2011 and docks in 35 different cities. During the "Year of Health Research," visitors can familiarize themselves with the field's newest trends, developments, and research findings. The exhibit showcases a physical three-dimensional model of the brain produced through an innovative printing process based on the medical image data of a real person. This brain model can be touched and viewed from different angles thanks to its rotating base. Nerve tracts can be activated by touching sensors on the physical model that correspond to functional areas of the brain. The brain is displayed on a screen along with the activated nerve tracts that are responsible, for instance, for sight, speech, feeling, and motion. This new form of interactive exhibit was developed by Fraunhofer MEVIS in Bremen together with the Universum® Science Center in Bremen to demonstrate how modern image processing combined with mathematics and intelligent software can help make neurosurgical operations more predictable and safe. The three-dimensional print of the brain was produced by the Fraunhofer-Institut ITWM in Kaiserslautern.

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Changes in brain circuitry play role in moral sensitivity as people grow up

ScienceDaily (May 29, 2011) — People's moral responses to similar situations change as they age, according to a new study at the University of Chicago that combined brain scanning, eye-tracking and behavioral measures to understand how the brain responds to morally laden scenarios.

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Both preschool children and adults distinguish between damage done either intentionally or accidently when assessing whether a perpetrator had done something wrong. Nonetheless, adults are much less likely than children to think someone should be punished for damaging an object, especially if the action was accidental, said study author Jean Decety, the Irving B. Harris Professor in Psychology and Psychiatry at the University of Chicago and a leading scholar on affective and social neuroscience.

The different responses correlate with the various stages of development, Decety said, as the brain becomes better equipped to make reasoned judgments and integrate an understanding of the mental states of others with the outcome of their actions. Negative emotions alert people to the moral nature of a situation by bringing on discomfort that can precede moral judgment, and such an emotional response is stronger in young children, he explained.

"This is the first study to examine brain and behavior relationships in response to moral and non-moral situations from a neurodevelopmental perspective," wrote Decety in the article, "The Contribution of Emotion and Cognition to Moral Sensitivity: A Neurodevelopmental Study," published in the journal Cerebral Cortex. The study provides strong evidence that moral reasoning involves a complex integration between affective and cognitive processes that gradually changes with age.

For the research, Decety and colleagues studied 127 participants, aged 4 to 36, who were shown short video clips while undergoing an fMRI scan. The team also measured changes in the dilation of the people's pupils as they watched the clips.

The participants watched a total of 96 clips that portrayed intentional harm, such as someone being shoved, and accidental harm, such as someone being struck accidentally, such as a golf player swinging a club. The clips also showed intentional damage to objects, such as a person kicking a bicycle tire, and accidental damage, such as a person knocking a teapot off the shelf.

Eye tracking in the scanner revealed that all of the participants, irrespective of their age, paid more attention to people being harmed and to objects being damaged than they did to the perpetrators. Additionally, an analysis of pupil size showed that "pupil dilation was significantly greater for intentional actions than accidental actions, and this difference was constant across age, and correlated with activity in the amygdala and anterior cingulate cortex," Decety said.

The study revealed that the extent of activation in different areas of the brain as participants were exposed to the morally laden videos changed with age. For young children, the amygdala, which is associated the generation of emotional responses to a social situation, was much more activated than it was in adults.

In contrast, adults' responses were highest in the dorsolateral and ventromedial prefrontal cortex -- areas of the brain that allow people to reflect on the values linked to outcomes and actions.

In addition to viewing the video clips, participants were asked to determine, for instance, how mean was the perpetrator, and how much punishment should he receive for causing damage or injury. The responses showed a clear connection between moral judgments and the activation the team had observed in the brain.

"Whereas young children had a tendency to consider all the perpetrator malicious, irrespective of intention and targets (people and objects), as participants aged, they perceived the perpetrator as clearly less mean when carrying out an accidental action, and even more so when the target was an object," Decety said.

When recommending punishments, adults were more likely to make allowances for actions that were accidental, he said. The response showed that they had a better developed prefrontal cortex and stronger functional connectivity between this region and the amygdala than children. Adults were better equipped to make moral judgments. "In addition, the ratings of empathic sadness for the victim, which were strongest in young children, decreased gradually with age, and correlated with the activity in the insula and subgenual prefrontal cortex," which area areas associated with emotional behavior and automatic response to stresses, Decety said. Together, the results are consistent with the view that morality is instantiated by functionally integrating several distributed areas/networks.

The research was supported with a grant from the National Science Foundation. Joining Decety in writing the paper were Kalina Michalska, a postdoctoral scholar, and Katherine Kinzler, an assistant professor, both in the Department of Psychology.

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Blast-related injuries detected in the brains of US military personnel

ScienceDaily (June 2, 2011) — An advanced imaging technique has revealed that some U.S. military personnel with mild blast-related traumatic brain injuries have abnormalities in the brain that have not been seen with other types of imaging.

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The abnormalities were found in the brain's white matter, the wiring system that nerve cells in the brain use to communicate with each other.

The study is reported June 2 in The New England Journal of Medicine by scientists at Washington University School of Medicine in St. Louis and the Landstuhl Regional Medical Center in Landstuhl, Germany.

They evaluated 84 U.S. military personnel evacuated to Landstuhl from Iraq and Afghanistan after exposure to many types of explosive blasts. Abnormalities were found in 18 of 63 patients diagnosed with mild traumatic brain injury, but not among 21 injured in other ways.

Traumatic brain injuries are estimated to have affected as many as 320,000 military personnel in the wars in Iraq and Afghanistan. Most of these are classified as mild traumatic brain injuries, also known as concussions.

"We call these injuries 'mild', but in reality they sometimes can have serious consequences," says senior author David L. Brody, MD, PhD, assistant professor of neurology at Washington University School of Medicine in St. Louis.

In the new study, white matter abnormalities were detected using an advanced magnetic resonance imaging method called diffusion tensor imaging. Diffusion tensor imaging allows scientists to assess the movement of water in tissue. Changes in the patterns of water movement are often linked to injury or disease, but the significance of the abnormalities seen in the military service personnel is not yet fully understood.

Mild traumatic brain injury has been a controversial topic, and the new approach may provide an additional tool to help resolve some of the debate. Much of the controversy has revolved around whether symptoms following mild traumatic brain injuries are due to structural injury to the brain, disruptions in brain chemistry, psychological factors or a combination of these.

"There is still a lot more work to be done before we fully understand whether these abnormalities truly represent significant damage to the brain white matter," says lead author Christine L. Mac Donald, PhD, research instructor in neurology at Washington University. "And if so, how this damage affects attention, memory, emotional regulation, balance, coordination, sleep and other functions. Likewise, the relationship between mild traumatic brain injury and post-traumatic stress disorder is especially important. Our ongoing studies will hopefully start to answer some of these questions."

Researchers have used diffusion tensor imaging to study mild civilian brain injuries previously and did not see abnormalities in the areas highlighted by the new study. These regions included the orbitofrontal cortex, an area involved in emotional regulation and reward-based behaviors, and the cerebellum, an area linked to coordination, movement, organization and planning.

These regions were predicted to be especially vulnerable to blasts based on previously published computer simulations. The results suggest that there may be fundamental differences between blast-related traumatic brain injuries and the sorts of mild traumatic brain injuries sustained by civilians, such as those caused by car accidents, falls, blows to the head and sports injuries.

In addition, advanced imaging also showed abnormalities in parts of the brain known to be harmed in civilian trauma.

Military personnel in the study all had blast-related injuries plus other injuries such as falls, motor vehicle crashes or being struck by blunt objects. The exact contribution of blast effects versus other injuries could not be fully determined in the study.

Up to a year after injury, the white matter abnormalities were still detectible, though their appearance on the scans had changed over time.

The results come from a collaborative team that included Mac Donald, who lived at Landstuhl for five and a half months to work on the study; Col. Stephen F. Flaherty, MD (now retired); and Lt. Col. Raymond Fang, MD, of the military medical staff at Landstuhl Regional Medical Center. The Landstuhl Regional Medical Center has been the central triage point for the wars in Iraq and Afghanistan for many years and is the closest hospital with a reliable MRI scanner.

Brody emphasizes that mild traumatic brain injury is still a diagnosis based on a history of an injury to the head that causes loss of consciousness, memory loss, confusion or other disruption in the function of the brain.

"A negative MRI scan, even with these advanced methods, does not rule out mild traumatic brain injury," he says. "These MRI-based methods show great promise, but are not yet ready to be used in routine clinical practice."

Brody said he believes the approach used in the study may prove helpful in military and civilian contexts and in children and adults.

"Our hope is that these advanced MRI-based methods will one day help make more accurate diagnoses, assist with triage and allow treatment interventions to start early for people with traumatic brain injuries," he says.

Mac Donald CL, Johnson AM, Cooper D, Nelson EC, Werner NJ, Shimony JS, Snyder AZ, Raichle ME, Witherow JR, Fang R, Flaherty SF, Brody DL. Detection of blast-related traumatic brain injury in U.S. military personnel. The New England Journal of Medicine, June 2, 2011.

Funding from the Congressionally Directed Medical Research Program and the National Institutes of Health (NIH) supported this research.

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Iron key to brain tumor drug delivery

ScienceDaily (June 2, 2011) — Brain cancer therapy may be more effective if the expression of an iron-storing protein is decreased to enhance the action of therapeutic drugs on brain cancer cells, according to Penn State College of Medicine researchers.

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Malignant glioblastoma multiforme is a deadly brain tumor for which no long-term effective cure exists. Because drugs in the blood do not pass from the blood vessels to the brain, effective amounts of chemotherapy drugs do not reach the tumor. Increasing dosages damage normal brain tissue and cause significant neurological damage. These dosages also would likely be harmful to other organs in the body. However, by increasing the sensitivity of the cancer cells to drugs, the effectiveness of treatment can be increased.

"About half of all brain tumors are resistant to chemotherapy and new therapeutic strategies are urgently needed to treat this cancer," said James Connor, Ph.D., Distinguished Professor and vice-chairman of neurosurgery.

Connor and his graduate student Xiaoli Liu took advantage of the high iron requirements of the brain cancer cells to target ferritin, a protein that stores iron in all cells.

"High levels of iron are required in cancer cells to meet the energy requirements associated with their rapid growth," Connor said. "In addition, iron is essential for general cell health."

Working with Achuthamangalam Madhankumar, Ph.D., assistant professor of neurosurgery, the researchers used liposomes -- tiny lipid containers -- to deliver a fragment of RNA called interference or siRNA, to tumor cells. The siRNA targets the molecular machinery of the cell so that the protein cannot be made -- a process known as downregulation. By targeting and turning off ferritin in cancer cells, the protective function of H-ferritin disappears and the sensitivity to chemotherapy increases.

Using ferritin siRNA, the protein level decreases by 80 percent within 48 hours providing a window of opportunity for enhanced sensitivity to the chemotherapeutic agent. The researchers studied whether silencing ferritin would lower the effective dosage of BCNU, a chemotherapy drug used in brain tumor treatment and one of the few approved for brain cancer. While BCNU is effective, it has serious side effects limiting its use.

The use of siRNA reduces the amount of BCNU needed for tumor suppression by more than half in mice, according to the researchers, who published their findings in the journal Cancer Research.

"Our results further indicate that a nanoliposomal delivery mechanism can increase the efficacy of siRNA and optimize the amount of siRNA delivered," Connor said. "By silencing the ferritin gene, tumor sensitivity to chemotoxins was increased. The results from this project are a promising initial step toward the development of siRNA gene therapy involving ferritin for the treatment of multiple tumor types."

Other researchers contributing to this project were Becky Slagle-Webb, research assistant, and Jonas M. Sheehan, M.D., associate professor of neurosurgery, Penn State College of Medicine and Nodar Surguladze, Ph.D., deputy director, Institute of Molecular Biology and Biological Physics, Republic of Georgia.

The Tara Leah Witmer Foundation partially supported this research.

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People who have had head injuries report more violent behavior

ScienceDaily (June 2, 2011) — Young people who have sustained a head injury during their lifetime are more likely to engage in violent behavior, according to an eight-year study from the University of Michigan School of Public Health.

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Further, the research found that young people who suffered a recent head injury (within a year of being questioned for the study) were even more likely to report violent behavior.

The report, which appears in the current issue of the journal Pediatrics, is one of the few studies to examine long-term effects of head injuries in a general population of young adults. Most other similar studies were conducted in prison populations.

There's been a recent blitz of media and research attention regarding youth, college and professional athletes who suffer head injuries and concussions while playing. This study is broader, but confirms previous findings about the connection between violence and head injuries, says lead author Sarah Stoddard, a research assistant professor at the School of Public Health.

"These are not necessarily sports-playing injuries," said Stoddard, who also is a research fellow at the U-M School of Nursing. "They could be from a car accident or from previous violent behavior, but it does support some of the sports research that's been going on with concussions."

Stoddard used data from the School of Public Health's Flint Adolescent Study, which looks at many issues regarding urban youth. Marc Zimmerman, professor of public health and chair of the U-M Department of Health Behavior and Health Education, is the principal investigator on that study.

The researchers followed a group of ninth-graders from four schools in Flint, Mich., into young adulthood. They conducted annual interviews over eight years. In years five and six, participants were asked if they had ever sustained a head injury. Those who said yes -- about 23 percent -- reported more violent behavior in year eight of the study.

Moreover, Stoddard and Zimmerman examined the proximal relationship between a head injury and violent behavior and found that an injury reported in year seven of the study predicted violent behavior in year eight.

"We found that the link between a head injury and later violence was stronger when a head injury was more recent, even after controlling for other factors including previous violent behavior," Stoddard said.

The results also suggest that adolescents and young adults who have suffered a head injury that did not interfere with their ability to participate in an hour-long interview may still experience significant adverse developmental or behavioral effects.

The researchers defined a head injury as having been knocked unconscious or sustaining a concussion or a fractured skull.

Traumatic brain injury is a serious public health issue, they say. An estimated 1.7 million people annually sustain a TBI, and that only includes people who get medical care, so the number is likely much higher. Roughly 75 percent of head injuries are mild and many do not receive medical attention, but any TBI disrupts the function of the brain. Long-term impact can include changes in cognition, language and emotion, including irritability, impulsiveness and violence.

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How does anesthesia disturb self-perception?

ScienceDaily (Jan. 24, 2011) — An Inserm research team in Toulouse, led by Dr Stein Silva (Inserm Unit 825 "Brain imaging and neurological handicaps"), working with the "Modelling tissue and nociceptive stress" Host Team (MATN IFR 150), were interested in studying the illusions described by many patients under regional anaesthetic. In their work, to be published in the journal Anesthesiology, the researchers demonstrated that anaesthetising an arm affects brain activity and rapidly impairs body perception.

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The ultimate aim of the work is to understand how neuronal circuits are reorganised at this exact moment in time and to take advantage of anaesthesia to reconfigure them correctly following trauma. This would allow anaesthetic techniques to be used in the future to treat pain described by amputated patients in what are known as "phantom limbs."

Neuroscience research in recent years has shown that the brain is a dynamic structure. Phenomena such as learning, memorising or recovery from stroke are made possible by the brain's plastic properties. Brain plasticity does not, however, always have a beneficial effect.

For example, some amputated patients suffering from chronic pain (known as phantom limb pain) feel as though their missing limb were "still there." Such "phantom limb" illusions are related to the appearance in the brain of incorrect representations of the missing body part.

Persons under regional anaesthetic describe these very same false images.

Based on these observations, Inserm's researchers wished to discover whether anaesthesia could, in addition to fulfilling its primary function, induce comparable phenomena in the brain. If this were so, anaesthetics could be used as new therapeutic tools capable of modulating brain activity.

With this in mind, a team headed by Dr Stein Silva monitored 20 patients who were to have one of their arms anaesthetised before surgery. The patients were shown 3D images of the hand, shot from different angles, and their ability to distinguish the right hand from the left was assessed. Results showed how anaesthesia affected the patients' ability to perceive their body correctly.

The researchers observed three phenomena based on these tests:

All the patients described false sensations in their arm (swelling, difference in size and shape, imagined posture). In general, patients under anaesthetic took longer to distinguish between a left and right hand and made far more mistakes than persons not under anaesthetic. The best results were obtained when the anaesthetised limb was visible.

In other words, anaesthetising the hand (peripheral deafferentation ) modifies brain activity and rapidly changes the way we perceive the outside world and our own body. The teams are now using functional brain imaging to characterise the regions concerned in the brain. They also hope that it will be possible to use anaesthesia for therapeutic purposes in the future by modulating post-lesional plasticity (chronic pain in amputated patients, improved recovery in those suffering from brain lesions).

Inserm researcher Stein Silva, an anaesthetist and the chief author of the study, believes that it will no doubt be necessary to develop new anaesthetic techniques to inhibit or directly stimulate the brain images associated with painful phenomena.

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