NIH and NFL will research long-term effects of concussions

This article outlines research that will be done on the long-term effects and consequences of concussions. This research will be done as a partnership between the National Institutes of Health (NIH) and the National Football League (NFL).

The U.S. National Institutes of Health is teaming up with the National Football League on research into the long-term effects of repeated head injuries and improving concussion diagnosis.

The projects will be supported largely through a $30 million donation made last year to the Foundation for the National Institutes of Health by the NFL, which is wrestling with the issue of concussions and their impact on current and former players.

There's growing concern about the potential long-term effects of repeated concussions, particularly among those most at risk, including football players and other athletes and members of the military.

Current tests can't reliably diagnosis concussion. And there's no way to predict which patients will recover quickly, suffer long-term symptoms or develop a progressive brain disease called chronic traumatic encephalopathy (CTE), according to an NIH press statement released Monday.

"We need to be able to predict which patterns of injury are rapidly reversible and which are not. This program will help researchers get closer to answering some of the important questions about concussion for our youth who play sports and their parents," Story Landis, director of the National Institute of Neurological Disorders and Stroke (NINDS), said in the news release.

Two of the projects will receive $6 million each and will focus on determining the extent of long-term changes that occur in the brain years after a head injury or after numerous concussions. They will involve researchers from NINDS, the National Institute of Child Health and Human Development and academic medical centers.

One of the projects will attempt to define a clear set of criteria for various stages of CTE. It will also seek to distinguish it from Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease) and other degenerative brain diseases that as of now can only be determined in brain tissue samples collected after death. The objective is to find medical signs of CTE that might eventually be used to diagnose the illness in living people.

The other project will seek to identify the long-term effects of mild, moderate and severe traumatic brain injury (TBI) and compare them with features of CTE. The goal is to identify signs that could be used to diagnose brain degeneration linked to traumatic brain injury in patients.

While the two projects focus on different aspects of traumatic brain injury, "their combined results promise to answer critical questions about the chronic effects of single versus repetitive injuries on the brain, how repetitive TBI (traumatic brain injury) might lead to CTE, how commonly these changes occur in an adult population, and how CTE relates to neurodegenerative disorders like Alzheimer's disease," Landis said.

Six other pilot projects will receive a total of just over $2 million and last up to two years. They will concentrate on improving the diagnosis of concussions and identifying potential medical signs that can be used to assess a patient's recovery. If the early results are promising, these projects may form the basis of more extensive research, the news release said.

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Zebrafish help find model to treat childhood epilepsy

A study by the National Institute of Health (NIH) shows that zebrafish may help model a treatment for Dravet syndrome, a severe childhood epilepsy.

According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.

Scott C. Baraban, Ph.D., and his colleagues at the University of California, San Francisco (UCSF), carefully assessed whether the mutated zebrafish could serve as a model for DS, and then developed a new screening method to quickly identify potential treatments for DS using these fish. This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health and builds on pioneering epilepsy zebrafish models first described by the Baraban laboratory in 2005.

Dravet syndrome is commonly caused by a mutation in the Scn1a gene, which encodes for Nav1.1, a specific sodium ion channel found in the brain. Sodium ion channels are critical for communication between brain cells and proper brain functioning.

The researchers found that the zebrafish that were engineered to have the Scn1a mutation that causes DS in humans exhibited some of the same characteristics, such as spontaneous seizures, commonly seen in children with DS. Unprovoked seizure activity in the mutant fish resulted in hyperactivity and whole-body convulsions associated with very fast swimming. These types of behaviors are not seen in normal healthy zebrafish.

“We were also surprised at how similar the mutant zebrafish drug profile was to that of Dravet patients,” said Dr. Baraban. “Antiepileptic drugs shown to have some benefits in patients (such as benzodiazepines or stiripentol) also exhibited some antiepileptic activity in these mutants. Conversely, many of the antiepileptic drugs that do not reduce seizures in these patients showed no effect in the mutant zebrafish.”

In this study, the researchers developed a fast and automated drug screen to quickly test the effectiveness of various compounds in mutant zebrafish. The researchers tracked behavior and measured brain activity in the mutant zebrafish to determine if the compounds had an impact on seizures.

“Scn1a mutants seize often, so it is relatively easy to monitor their seizure behavior at baseline and then again after a drug application,” said Dr. Baraban. “Using zebrafish placed individually in a 96-part petri dish we can accurately quantify this seizure behavior. In this way, we can test almost 100 fish at one time and quickly determine whether a drug candidate has any effect on these spontaneous seizures.”

In the first such application of this approach, UCSF researchers screened 320 compounds and found that clemizole was most effective in inhibiting seizure activity. Clemizole is approved by the U.S. Food and Drug Administration and has a safe toxicology profile. “This finding was completely unexpected. Based on what is currently known about clemizole, we did not predict that it would have antiepileptic effects,” said Dr. Baraban.

These findings suggest that Scn1a mutant zebrafish may serve as a good model of DS and that the drug screen may be effective in quickly identifying novel therapies for epilepsy.

Dr. Baraban also noted that someday these experiments can be “personalized,” by looking at mutated zebrafish that use genetic information from individual patients.

This research was funded by the Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) program at NIH that supports innovative research with the potential for big impact in biomedical science.

“The goal of the EUREKA program is to provide a means to test high-risk ideas to see if they are worth pursuing further. These kinds of ideas often come from left field and are very creative. Since they are so unique, however, there may not be any existing preliminary data to support the hypothesis or demonstrate feasibility. EUREKA grants provide an opportunity to gather this information,” said Brandy Fureman, Ph.D., program director at NINDS.

This particular study was chosen in response to a request by NINDS to help spur novel research on epilepsy. “This research was selected for a EUREKA grant because it proposed a well-designed, inventive model of genetic epilepsy that could accelerate the pace of drug-screening for this devastating form of pediatric epilepsy” said Dr. Fureman.

Dr. Fureman noted that these findings not only describe a novel model of Dravet syndrome, but the positive results with an unexpected FDA-approved drug may lead to new therapeutic avenues. “There is more work to be done, but I am very pleased to see these initial results. These kinds of new directions are exactly what we hoped to stimulate with the EUREKA program,” she said.

For more information about Dravet syndrome and epilepsy, please visit:

• http://www.ninds.nih.gov/disorders/dravet_syndrome/dravet_syndrome.htm
• http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm

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Enzymes may be why autism develops

A study from the NIH shows that a group of enzymes may be the cause that autism develops.

A group of enzymes in the brain appears to be key to the activity of many genes linked to autism, a new study reveals.

Experts hope the findings will shed light on the causes of autism, and possibly lead to new treatments.

The study results, published online Aug. 28 in the journal Nature, hint that if disruptions in enzymes called topoisomerases occur during brain development, they might contribute to the development of autism spectrum disorders.

The enzymes are found throughout the body, and their main job is to "untangle the knots" in cells' DNA so the cells can function and reproduce themselves normally, explained senior researcher Mark Zylka, an associate professor of cell biology at the University of North Carolina at Chapel Hill.

Topoisomerases have been well studied for their role in helping tumor cells to spread, and drugs that inhibit the enzymes are already used to treat certain cancers.

There have also been hints, though, that topoisomerases might contribute to autism. Last year, researchers reported that some people with autism spectrum disorders have mutations in these enzymes.

"But we've known little about how they work in the brain," said Zylka.

In lab experiments with mouse and human brain cells, Zylka's team found that a topoisomerase-inhibiting drug reduced the activity of 49 genes that past studies have linked to autism. That points to the importance of topoisomerases in the normal expression of those genes.

"A single drug down-regulated all of those genes," Zylka said.

That does not mean, however, that topoisomerase inhibitors should be tested for treating autism. If anything, Zylka explained, you would want a drug that enhances the enzymes' actions.

But now researchers can look for compounds that do just that.

What's more, the findings point to a biological process that ties together dozens of different genes that are suspected of being involved in autism. "Well over 300 (autism-linked) genes have been identified now," Zylka said. "That list looks daunting, but the goal is to figure out how all these genes are connected," he said.

"It can be overwhelming when you look at the list of genes," agreed Andy Shih, senior vice president for scientific affairs for the advocacy group Autism Speaks.

But if you can zero in on the "biological pathways" linking those genes, "it all starts to make sense," said Shih, who was not involved in the study.

In the United States, it's estimated that at least one in every 88 children has an autism spectrum disorder, with the severity ranging widely from child to child. Some kids have little or no ability to speak, and focus obsessively on just a few interests; other kids speak and have normal to above-normal intelligence, but may have problems socializing and communicating more subtly -- for example, trouble using and "reading" gestures, body language and facial expressions.

No one knows what causes autism spectrum disorders, but experts believe that it's a complex mix of genetic vulnerability and environmental exposures -- possibly chemicals or microbes.

Shih pointed to an "interesting" fact about topoisomerases: Their activity is believed to be influenced by environment, including compounds in food and in the physical world. So, he said, studying the enzymes might help researchers pinpoint some of the environmental factors that contribute to autism spectrum disorders.

"We've been talking for a long time about the interaction between genes and environment in autism," Shih said. Topoisomerases could offer a way for scientists to begin to connect the dots.

Zylka agreed, and said his team is searching for environmental compounds that inhibit topoisomerases -- and may, therefore, be important for pregnant women or young children to avoid.

There is still, however, a long way to go in fully understanding the underpinnings of autism spectrum disorders. "We've just scratched the surface of what's going wrong in the brain" in autism, Zylka said.

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NIH's Information on Concussions

The following was released by the National Institutes of Health on concussions. They discussed how serious concussions are, especially repeat concussions, and gave symptoms to take notice of.

Your brain is your body’s command center. Its soft, sensitive tissues float in a cushioning fluid within the hard and sturdy skull. But a swift blow to the head or violent shaking can override these protections and lead to a mild type of brain injury known as a concussion. 

More than 1 million mild traumatic brain injuries occur nationwide each year. These injuries can be caused by falls, car crashes or recreational activities like bike riding, skateboarding, skiing or even playing at the playground. More than half of concussions occur in children—often when playing organized sports such as football and soccer. 

“Although concussions are considered to be a mild brain injury, they need to be taken seriously. They should not be treated as minor injuries that quickly resolve,” says Dr. Beth Ansel, an expert on rehabilitation research at NIH. With proper care, most people recover fully from a concussion. “But in some cases, a concussion can have a lasting effect on thinking, attention, learning and memory,” Ansel adds. 

A single concussion is also known to raise your risk for having another concussion—and a second concussion may be more severe. It’s important to learn to recognize the causes and symptoms of concussion so you can take steps to prevent or treat these head injuries.

“The skull is designed to prevent most traumas to the brain, but it doesn’t really prevent the brain from moving around inside the skull,” says Dr. Frederick Rivara, a specialist in pediatric injuries and prevention at the University of Washington in Seattle. “A concussion can arise from the brain moving either rapidly back and forth or banging against the side of the skull.” This sudden movement can stretch and damage brain tissue and trigger a chain of harmful changes within the brain that interfere with normal brain activities. 

More serious brain injuries that involve skull fracture, bleeding in the brain or swelling of the brain can be detected with X-rays or other imaging methods. But concussions can be more difficult to identify. 

“A concussion isn’t visible from the outside, and you can’t see it with standard imaging tools like MRI and CAT scans,” says Dr. Christopher Giza, a pediatric brain specialist at the University of California, Los Angeles. “Instead we look for the signs and symptoms of abnormal brain function to make a diagnosis.”

Common symptoms include nausea, headache, confusion, dizziness and memory problems. Loss of consciousness occurs in about 1 in 10 concussions. A person with a concussion might have trouble answering basic questions and move in an awkward, clumsy way. 

“Symptoms can arise quickly, or they can be delayed and appear over the next day or two,” Rivara adds.

For about 9 in 10 people with concussions, symptoms disappear within 7 to 10 days. Scientists have been working to learn more about those who take longer to recover. In one NIH-funded study, Dr. Keith Yeates of Ohio State University looked at 8- to 15-year-olds treated in an emergency room for mild traumatic brain injury.

“We found that the majority of these kids recovered quite quickly or showed no increase in symptoms at all,” Yeates says. “But a subgroup of kids, about 10% or 20%, showed a dramatic onset of symptoms after their injury and persistent symptoms that in some cases remained even 12 months after the injury.” 

Body-related symptoms, such as headache and dizziness, tended to fade fairly quickly, the researchers found. But thinking-related symptoms, including problems with memory and paying attention, tended to linger in some kids throughout the year-long study. Children who had lost consciousness or had some additional abnormality that showed up on MRI scans after the injury had an increased risk for lasting problems. 

“These kids were also more likely to have what looked like significant reductions in overall quality of life. And there was some evidence they were more likely to have academic problems than the kids without persistent symptoms,” Yeates says.

Yeates and others continue to explore ways to predict a person’s response to concussion. Much remains unknown about the underlying biology and outcomes of mild head injuries. Some NIH-funded researchers are looking at how injury and recovery processes differ in immature and adult brains. Other scientists are examining the problems that can arise from repeated injuries to the brain. 

Researchers know that immediately after a concussion, the brain is especially vulnerable to having a second, more serious injury. But it’s not clear why—or how long that vulnerable period lasts. Giza and his colleagues have found that a single mild injury reduces the brain’s use of the sugar glucose as a fuel, at least in rats. A second mild injury 24 hours later leads to an even steeper drop in glucose use and memory problems that last longer. But when the brain has several days to recover, and the use of glucose returns to normal, a second mild brain injury seems to be no worse than the first.

“The finding suggests that when you superimpose 2 injuries on top of each other, the consequences can be greater,” Giza says. The brain’s use of glucose might be a way to assess risk and recovery time. “But we don’t yet have a clear understanding of what happens in the human brain after first and second injuries,” Giza adds.  

Studies have found that the risk for a second injury is greatest in the 10 days following an initial concussion. If you suspect that someone has a concussion, make sure they stop whatever activity they’re doing, especially if they’re involved in a sport. Their brain dysfunction might not only cloud their thinking. It can also slow reaction times and affect their balance so they become more likely to have another injury. 

“If someone has symptoms of concussion, they shouldn’t try to finish the quarter or finish the game. They need to be taken out of play right away and be seen by a health care provider,” Rivara says. “The current recommendations are to avoid physical activity for a period of time until all the symptoms have resolved, and then have a gradual return to play.” 

Take steps to avoid concussions. “Wear helmets when appropriate, such as if you’re bicycling, skate-boarding or riding a horse,” says Rivara. Athletes can decrease their risk of concussion by wearing proper headgear and following the rules of good sportsmanship. Make living areas safer for seniors by removing tripping hazards such as throw rugs and clutter in walkways, and install handrails on both sides of stairways. 

“The bottom line is that we still need to determine the best ways to prevent, accurately diagnose, treat and assess outcomes after mild traumatic brain injury,” says Ansel.

While this research continues, do what you can to prevent concussions. Learn to recognize the symptoms. And make sure that people with signs of concussion stop their activities and seek medical attention.

Stop activity if you have these symptoms. Athletes should not return to play until evaluated by a health care provider. 

• Headache or “pressure” in head
• Nausea or vomiting
• Balance problems or dizziness
• Double or blurry vision
• Sensitivity to light or noise
• Feeling sluggish or groggy
• Concentration or memory problems
• Confusion
• Feeling “down” or “not right”
• Changes to sleep patterns

Adapted from the U.S. Centers for Disease Control and Prevention

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The Importance of Slumber from the NIH

This article from the National Institutes of Health discusses the importance and benefits from getting a good night's sleep.

We have so many demands on our time—jobs, family, errands—not to mention finding some time to relax. To fit everything in, we often sacrifice sleep. But sleep affects both mental and physical health. It’s vital to your well-being.

Of course, sleep helps you feel rested each day. But while you’re sleeping, your brain and body don’t just shut down. Internal organs and processes are hard at work throughout the night. 

“Sleep services all aspects of our body in one way or another: molecular, energy balance, as well as intellectual function, alertness and mood,” says Dr. Merrill Mitler, a sleep expert and neuroscientist at NIH.

When you’re tired, you can’t function at your best. Sleep helps you think more clearly, have quicker reflexes and focus better. “The fact is, when we look at well-rested people, they’re operating at a different level than people trying to get by on 1 or 2 hours less nightly sleep,” says Mitler.          

“Loss of sleep impairs your higher levels of reasoning, problem-solving and attention to detail,” Mitler explains. Tired people tend to be less productive at work. They’re at a much higher risk for traffic accidents. Lack of sleep also influences your mood, which can affect how you interact with others. A sleep deficit over time can even put you at greater risk for developing depression.

But sleep isn’t just essential for the brain. “Sleep affects almost every tissue in our bodies,” says Dr. Michael Twery, a sleep expert at NIH. “It affects growth and stress hormones, our immune system, appetite, breathing, blood pressure and cardiovascular health.”

Research shows that lack of sleep increases the risk for obesity, heart disease and infections. Throughout the night, your heart rate, breathing rate and blood pressure rise and fall, a process that may be important for cardiovascular health. Your body releases hormones during sleep that help repair cells and control the body’s use of energy. These hormone changes can affect your body weight. 

“Ongoing research shows a lack of sleep can produce diabetic-like conditions in otherwise healthy people,” says Mitler. 

Recent studies also reveal that sleep can affect the efficiency of vaccinations. Twery described research showing that well-rested people who received the flu vaccine developed stronger protection against the illness. 

A good night’s sleep consists of 4 to 5 sleep cycles. Each cycle includes periods of deep sleep and rapid eye movement (REM) sleep, when we dream. “As the night goes on, the portion of that cycle that is in REM sleep increases. It turns out that this pattern of cycling and progression is critical to the biology of sleep,” Twery says.

Although personal needs vary, on average, adults need 7 to 8 hours of sleep per night. Babies typically sleep about 16 hours a day. Young children need at least 10 hours of sleep, while teenagers need at least 9 hours. To attain the maximum restorative benefits of sleep, getting a full night of quality sleep is important, says Twery.  

Sleep can be disrupted by many things. Stimulants such as caffeine or certain medications can keep you up. Distractions such as electronics—especially the light from TVs, cell phones, tablets and e-readers—can prevent you from falling asleep.

As people get older, they may not get enough sleep because of illness, medications or sleep disorders. By some estimates, about 70 million Americans of all ages suffer from chronic sleep problems. The 2 most common sleep disorders are insomnia and sleep apnea.

People with insomnia have trouble falling or staying asleep. Anxiety about falling asleep often makes the condition worse. Most of us have occasional insomnia. But chronic insomnia—lasting at least 3 nights per week for more than a month—can trigger serious daytime problems such as exhaustion, irritability and difficulty concentrating.

Common therapies include relaxation and deep-breathing techniques. Sometimes medicine is prescribed. But consult a doctor before trying even over-the-counter sleep pills, as they may leave you feeling unrefreshed in the morning. 

People with sleep apnea have a loud, uneven snore (although not everyone who snores has apnea). Breathing repeatedly stops or becomes shallow. If you have apnea, you’re not getting enough oxygen, and your brain disturbs your sleep to open your windpipe. 

Apnea is dangerous. “There’s little air exchange for 10 seconds or more at a time,” explains Dr. Phyllis Zee, a sleep apnea expert at Northwestern University. “The oxygen goes down and the body’s fight or flight response is activated. Blood pressure spikes, your heart rate fluctuates and the brain wakes you up partially to start your breathing again. This creates stress.” 

Apnea can leave you feeling tired and moody. You may have trouble thinking clearly. “Also, apnea affects the vessels that lead to the brain so there is a higher risk of stroke associated with it,” Zee adds.

If you have mild sleep apnea, you might try sleeping on your side, exercising or losing weight to reduce symptoms. A CPAP machine, which pumps air into your throat to keep your airway open, can also help. Another treatment is a bite plate that moves the lower jaw forward. In some cases, however, people with sleep apnea need surgery. 

“If you snore chronically and wake up choking or gasping for air, and feel that you’re sleepy during the day, tell your doctor and get evaluated,” Zee advises.

NIH is currently funding several studies to gain deeper insights into sleep apnea and other aspects of sleep. One 5-year study of 10,000 pregnant women is designed to gauge the effects of apnea on the mother’s and baby’s health. Zee says this study will shed more light on apnea and the importance of treatment.

Good sleep is critical to your health. To make each day a safe, productive one, take steps to make sure you regularly get a good night’s sleep. 

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