With novel technique, new study is first to definitively map the early development of PTSD

Disease proceeds along two independent tracks, suggesting new treatment approaches

December 12, 2019

Science Daily/University of Vermont

Only 23 percent of people who experience trauma develop PTSD. New research offers new clues on identifying which trauma victims will develop the disorder and suggests potential interventions. Researchers used a mobile phone app to gather information from patients in the critical 30 days after the trauma event - when symptoms interact to create the full blown disorder - the first time such extensive information has been gathered

Most people who experience severe trauma recover their health. But 23 percent develop PTSD, a difficult-to-treat illness that combines intrusive thoughts about the trauma, avoidance of reminders of it, low mood and an exaggerated startle reaction. Which trauma victims will develop the disorder and which will be spared is not well understood.

A study just published in the journal Depression and Anxiety both offers new clues on identifying potential PTSD candidates among the population of trauma sufferers and suggests potential interventions that could prevent its development.

The study is the first to gather extensive data from trauma victims during the first 30 days after the traumatic event, a critical period says Matthew Price, associate professor of Psychological Sciences at the University of Vermont and lead author of the study.

"Getting PTSD is not like the flu where you wake up one day with a virus and feel sick," Price said. "It's a complex system where a range of symptoms develop, build on themselves and influence each other over time. After about a month, the die is cast, so to understand and prevent PTSD, it's very important to map the dynamics of how things develop early on."

The nature of the disease has made that difficult, Price says. Researchers either had little access to trauma victims, who often left the hospital abruptly, or weren't comfortable being interviewed numerous times during the acute post-trauma phase.

The new study took a novel approach. Using a mobile phone app, a non-intrusive method of gathering information, researchers were able to text trauma victims a series of questions, which they answered when it was convenient, in each of the 30 days after the trauma event.

The questions were crafted so they yielded day-by-day information about the key symptoms that characterize PTSD and were asked in such a way that researchers could track their development over time.

Two independent tracks

Then the research team used a statistical technique called short term dynamic modeling to determine which symptoms acted as influencers, causing other symptoms to develop and gain strength, which symptoms arose from those influencers and which operated independently.

"For one series of symptoms, the symptom chain looked a lot like fear conditioning," Price said. "People first had intrusive, unpleasant thoughts about what happened to them, which led them to avoid doing things that remind them of their trauma, and that avoidance led to hypervigilance." The sequence reflects a commonly accepted theoretical framework for PTSD development.

But feelings of depression seemed to operate independently of the fear conditioning symptoms, Price said.

"Depression wasn't influenced by other symptoms and wasn't an influencer; it was off on its own and self-perpetuating."

That's very different from full blown PTSD, Price said, where fear conditioning and depression are tightly integrated, and suggests a treatment approach that is very different from what is currently done.

"The most commonly used strategy right now is to wait and see," he said. "The research shows that, by contrast -- as challenging as it is to treat victims soon after the trauma -- it's critically important to intervene early to head off the development of full blown PTSD. Prevention is a preferred strategy because many individuals who go on to develop PTSD do not seek out treatment right away. Instead, these folks can suffer for months or years before getting the help they need."

The research suggests that intervention could happen along two tracks, Price said.

On the hand one hand, patients could undergo a form of exposure therapy to address the fear-based cluster of symptoms. On the other, a more cognitive-based approach could address developing depression.

Which trauma victims are most likely to develop PTSD?

The research findings suggest that those who are "having a strong reaction to trauma cues, who shortly after a trauma seem to be very reactive to things that remind them of their trauma, would probably be good people to look out for," Price says.

But the questions around PTSD are still very much unanswered, Price said.

"This research is trying to piece together what this process may look like as it unfolds so that we can start to develop treatments that might be able to deliver it in this very acute phase. There is much more work to do."

https://www.sciencedaily.com/releases/2019/12/191212122540.htm

Veterans study suggest two sub-types of Gulf War illness

December 12, 2019

Science Daily/Georgetown University Medical Center

Brain imaging of veterans with Gulf War illness show varying abnormalities after moderate exercise that can be categorized into two distinct groups -- an outcome that suggests a more complex illness that previously thought.

Researchers at Georgetown University Medical Center, using functional magnetic resonance imaging (fMRI), have shown the Gulf War Illness patients have one of two different of kinds of changes after exercise when compared with healthy patients. The results clarify that Gulf War illness (GWI) leads to measurable physiological changes in the brain, suggesting multiple strategies for future treatments of Gulf War illness patients.

GWI affects about 25% to 30% of veterans from the 1990-1991 Persian Gulf War. Cognitive and memory problems (often described as "brain fog"), pain, and fatigue following mild to moderate exertion are similar to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

In a study published December 12 in the journal Brain Communications (10.1093/braincomms/fcz039), researchers in the laboratory of James Baraniuk, MD, professor of medicine at Georgetown University Medical Center, imaged the brains of veterans with Gulf War illness before and after moderate exercise. The following day, the groups had a second stress test and a memory test during brain imaging.

There were no differences in fMRI scans between veterans before exercise. The veterans were then divided into those who had previously shown racing heart rates after standing up and those who did not. According to Stuart Washington, PhD, a post-doctoral fellow and lead author on the study, both groups of Gulf War illness veterans had differences in brain activity compared to healthy patients, but the type of abnormal brain activity was different between the groups. After exercise, the veterans prone to racing heart rates had a significant decrease in brain activity in the cerebellum, the part of the brain responsible for fine motor control, cognition, pain, and emotion. In contrast, the group not prone to racing heart rates had a significant increase in brain activity in a different part of the brain that is responsible for planning of body movements and is also associated with chronic pain. The healthy patients had no changes at all.

"While these findings present new challenges to treating people with Gulf War illness, they also present new opportunities," says Washington.

"Gulf War illness remains a debilitating disease, but we are getting a better handle on the cognitive dysfunction," explains Baraniuk. "Now that different regions of the brain have been associated with two subtypes of GWI, we can study these regions through imaging and other techniques to improve diagnosis and, perhaps, to study future treatments."

He concludes, "We are grateful to the veterans who participated in this research because they are providing the answers to medical questions and leading the charge to new therapies for GWI."

https://www.sciencedaily.com/releases/2019/12/191212081930.htm

Concussion alters how information is transmitted within the brain

December 3, 2019

Science Daily/Radiological Society of North America

Damage from concussion alters the way information is transmitted between the two halves of the brain, according to a new study presented today at the annual meeting of the Radiological Society of North America (RSNA).

Research has shown that the corpus callosum, a bundle of nerve fibers that carries signals between the brain's left and right hemispheres, is vulnerable to damage from mild traumatic brain injury, commonly known as concussion. Less is known about the impact of this damage on cognitive function.

To learn more, researchers at New York University (NYU) School of Medicine in New York City compared the condition of the corpus callosum in 36 patients with recent concussion to that of 27 healthy controls. They studied the participants' brains with two innovative advances, including an MRI technique that uses measures of water diffusion to provide a microscopic view of the brain's signal-carrying white matter.

"Looking at how water molecules are diffusing in the nerve fibers in the corpus callosum and within the microenvironment around the nerve fibers allows us to better understand the white matter microstructural injury that occurs," said study co-author Melanie Wegener, M.D., resident physician at NYU Langone Health in New York City.

Dr. Wegener and colleagues combined the MRI findings with results from the study's second innovative advance, called an Interhemispheric Speed of Processing Task, a test developed at NYU Langone that evaluates how well the two hemispheres in the brain communicate with each other.

For the test, the participants were told to sit in a chair and focus their gaze on the letter X that was displayed on a screen directly in front of them. The researchers then flashed three-letter words to the right or the left of the X and asked the participants to say those words as quickly as possible. When the researchers evaluated this reaction time in both patients with concussion and healthy controls, they noticed an interesting phenomenon.

"There is a definite and reproducible delay in reaction time to the words presented to the left of the X compared with words presented to the right visual field," Dr. Wegener said. "This shows it takes time for information to cross the corpus callosum from one hemisphere to the other, which is measured by the difference in response time between words presented to different sides of our visual field."

This delay is likely due to the fact that language function is most often located in the brain's left hemisphere. This means that information presented to the left visual field is first transmitted to the right visual cortex in the brain and then has to cross over the corpus callosum to get to the left language center. In contrast, words that are presented to the right visual field do not need to cross the corpus callosum.

Performance on the test correlated with brain findings on MRI. In the healthy controls, reaction time corresponded with several diffusion measures in the splenium, an area of the corpus callosum located between the right visual cortex and the left language center. No such correlation was found in the concussion patients, suggesting microstructural changes relating to injury.

"We saw a correlation between white matter microstructure injury and the clinical status of the patient," Dr. Wegener said. "This information could ultimately help with treatment in patients who have mild traumatic brain injury."

For instance, Dr. Wegener said, patients could undergo MRI immediately after a concussion to see if they experienced any clinically important white matter injury and thus may benefit from early intervention.

"Another thing we can do is use MRI to look at patients' brains during treatment and monitor the microstructure to see if there is a treatment-related response," she said.

https://www.sciencedaily.com/releases/2019/12/191203082910.htm

Concussion recovery not clear cut for children

December 2, 2019

Science Daily/University of Queensland

Sleep problems, fatigue and attention difficulties in the weeks after a child's concussion injury could be a sign of reduced brain function and decreased grey matter.

Researchers from The University of Queensland have studied persistent concussion symptoms and their link to poorer recovery outcomes in children.

UQ Child Health Research Centre Research Fellow Dr Kartik Iyer said information from the study could help parents and doctors assess the risk of long-term disability.

"In the MRI scans of children with persistent concussion symptoms, poor sleep was linked to decreases in brain grey matter and reduced brain function," Dr Iyer said.

"Identifying decreases in brain function can allow us to predict if a child will recover properly.

"This knowledge can help clinicians ensure a child receives targeted rehabilitation such as cognitive behaviour therapy, medication to improve sleep, or safe and new emerging therapies such as non-invasive brain stimulation to potentially reduce symptoms."

Researchers were able to predict with 86 per cent accuracy how decreases in brain function impacted recovery two months post-concussion.

"Generally, children with persistent concussion symptoms will have alterations to their visual, motor and cognitive brain regions but we don't have a clear understanding of how this develops and how it relates to future recovery," Dr Iyer said.

"It can have a serious impact on their return to normal activities, including time away from school, difficulties with memory and attentiveness, disturbances to sleeping habits and changes to mood -- all of which affect healthy brain development."

Most children recover fully after a concussion, but one in 10 has persistent symptoms.

"It is critical that children who receive a head injury see a doctor and get professional medical advice soon after their injury has occurred," he said.

"While playing sports or riding bicycles or scooters, children should wear proper protective head gear to minimise the impact of a head injury."

For children with persistent concussion symptoms, a child-friendly non-invasive brain stimulation therapy is being trialled at UQ's KidStim laboratory.

Families interested in contacting the study team and registering their interest can contact the Acquired Brain Injury team.

https://www.sciencedaily.com/releases/2019/12/191202102046.htm

Concussions in high school athletes may be a risk factor for suicide

November 25, 2019

Science Daily/University of Texas Health Science Center at Houston

Concussion, the most common form of traumatic brain injury, has been linked to an increased risk of depression and suicide in adults. Now new research published by The University of Texas Health Science Center at Houston (UTHealth) suggests high school students with a history of sports-related concussions might be at an increased risk for suicide completion.

The research, which recently appeared in the November issue of the Journal of Affective Disorders, examined the link between self-reported history of concussion and risk factors for suicide completion. It was the first study to include a nationally representative sample of high school students. According to the Centers for Disease Control and Prevention, suicide is the second-leading cause of death in Americans ages 10 to 34.

"It's important to remember that when it comes to concussions, there's no visual test to confirm them. Unfortunately, you can't take your child to have a lab test done to diagnose one," said Dale Mantey, the study's lead author, a doctoral student at UTHealth School of Public Health in Austin.

Common symptoms of a concussion include loss of consciousness, headache, confusion, and change in mood.

The study examined survey data collected from more than 13,000 high school students in the United States. Participants were asked if they had received a concussion related to sports or physical activity in the last year, as well as a range of questions to measure potential suicidal behaviors. Approximately 15% of students surveyed reported having suffered a concussion.

Researchers discovered that teenagers who reported having a concussion in the last year were more likely to report feelings of depression, suicidal ideations, and planned or previous suicide attempts. Of the portion of students who reported a history of concussions, approximately 36% reported they had felt sad or hopeless (compared to 31.1% of all teens) and around 21% had thoughts of suicide (compared to 17%).

Male participants with a reported concussion in the last year were twice as likely to report having attempted suicide and three times more likely to report a history of receiving medical treatment for an attempted suicide than those who did not have a recent concussion.

The study also revealed female students with a history of concussions had greater odds to report all risk factors of suicide. They were more likely to have reported feeling sad or hopeless, having suicidal ideations, a planned suicide attempt, having attempted suicide, and were twice as likely to indicate a history of receiving medical treatment for an attempted suicide compared to females who did not report a concussion in the last year. A recently published article in the journal Pediatrics revealed female high school athletes have higher concussion rates than their male counterparts.

The researchers noted that while the study did control for commonly associated suicide risk factors like sexual orientation and a history of being bullied, it did not account for other risk factors like drug or alcohol use. There were no measures of preconcussion mental health for survey participants.

"Concussions are a traumatic brain injury and they are even worse for young people with developing brains," said Steven H. Kelder, PhD, MPH, senior author and Beth Toby Grossman Distinguished Professor in Spirituality and Healing at UTHealth School of Public Health in Austin. "These injuries can have long-term effects such as memory issues and sleep disturbances."

According to the National Suicide Prevention Lifeline, warning signs of suicide can include talking about feeling hopeless, withdrawing or social isolation, extreme mood swings, and reckless or anxious behavior.

"Everyone needs to be aware of the warning signs and the risks that come with concussions -- parents, teachers, coaches, but also the students themselves," Mantey said. "If there is any concern that a child may have suffered a concussion, it is critical to seek medical attention. If a child is diagnosed with a concussion, everyone in their support network should look for changes in mood or behavior that may be warning signs of reduced mental well-being."

https://www.sciencedaily.com/releases/2019/11/191125145546.htm

How brain injury can lead to post-traumatic stress disorder

UCLA team finds that the brain processes fear differently after injury

November 4, 2019

Science Daily/University of California - Los Angeles

Post-traumatic stress disorder in U.S. military members frequently follows a concussion-like brain injury. Until now, it has been unclear why. A UCLA team of psychologists and neurologists reports that a traumatic brain injury causes changes in a brain region called the amygdala; and the brain processes fear differently after such an injury.

"Is one causing the other, and how does that occur?" asked senior author Michael Fanselow, who holds the Staglin Family Chair in Psychology at UCLA and is the director of UCLA's Staglin Music Festival Center for Brain and Behavioral Health. "We're learning."

Two groups of rats were studied. Through surgery, a concussion-like brain injury was produced in 19 of the rats. Sixteen other rats -- a control group -- also had the surgery, but did not sustain a brain injury. All of the rats were then exposed to a low level of noise, followed by a series of moderate, brief foot shocks. The foot shocks were frightening to the rats, but not very painful, Fanselow said. Because the rats learned to associate the noise with the shock, they became afraid of the noise.

Rats tend to stand still when they experience fear. When they recall a frightening memory, they freeze. Their heart rate and blood pressure go up -- and the stronger the memory, the more they freeze, Fanselow said. On the experiment's third day, the researchers again exposed the rats to the same place where they had been shocked, but did not give them any additional shocks, and studied their reactions.

The rats in the control group did freeze, but the rats that received the brain injury froze for a much longer time. The researchers discovered that even without receiving a foot shock, the rats that had a brain injury showed a fear response to the noise.

"Sensitivity to noise is a common symptom after concussion, which suggested to us that this might partly explain why fear reactions to certain stimuli are increased after brain injury," said Ann Hoffman, a UCLA researcher in psychology and lead author of the research, which is published in the journal Scientific Reports.

"It's almost as if the white noise acted like the shock," Fanselow said. "The noise itself became scary to them, even though it wasn't much noise. They treated it almost like a shock."

The researchers studied the amygdala, which is known to be crucial in learning fear. People with anxiety disorders have increased activity in the amygdala, and PTSD has been linked to increased activity in the amygdala.

The amygdala is made up of neurons, and a rat's amygdala has about 60,000. The researchers discovered that five times as many neurons in the amygdala were active during the white noise in the rats with the brain injury than in the control group, Hoffman said.

The amygdala listens to other brain areas that provide it with information. "The amygdala makes a decision whether a situation is frightening, and when it decides a situation is frightening, it generates a fear response," Fanselow said.

Another new discovery the researchers report is that after the traumatic brain injury, the brain processes sounds from a more primitive part of the brain -- the thalamus -- than from a more sophisticated, highly evolved area of the brain -- the auditory cortex. The thalamus provides a more simplistic, crude representation of sound than the auditory cortex. About four times as many neurons were active in a network from the thalamus to the amygdala in the rats with the injury than in the control group rats, Hoffman said.

The study raises the question of whether it is possible to get the brain's amygdala back to normal following a concussion-like injury, perhaps through behavioral therapy or a pharmaceutical. If so, that could benefit members of the military, as well as civilians who have had serious brain injuries, Fanselow said. He and his team will continue their research in an effort to answer this question.

https://www.sciencedaily.com/releases/2019/11/191104130446.htm

Young adults with PTSD may have a higher risk of stroke in middle age

October 18, 2019

Science Daily/American Heart Association

Young adults who suffer from posttraumatic stress disorder (PTSD) may be more likely to experience a transient ischemic attack (TIA) or major stroke event by middle age, raising the risk as much as other better-known risk factors, according to new research published in Stroke, a journal of the American Stroke Association, a division of the American Heart Association.

"Stroke has a devastating impact on young patients and their families, many of whom struggle to cope with long-term disability, depression and economic loss during their most productive years," said Lindsey Rosman, Ph.D., lead author of the study and assistant professor of medicine in the division of cardiology at the University of North Carolina School of Medicine in Chapel Hill. "Ten to 14% of ischemic strokes occur in adults ages 18 to 45, and we don't really have a good understanding of the risk factors for stroke in this age group."

While PTSD has previously been shown to increase the risk of heart disease and stroke in older adults, this is the first study to demonstrate a link between trauma-induced stress disorders and the risk of TIA and stroke in young and middle-aged adults, an age group that has experienced a striking increase in stroke events over the past decade.

Although this study was conducted solely in veterans, PTSD is a debilitating mental condition that affects nearly 8 million adults in the U.S. and about 30 percent of veterans. People who observe or directly experience a traumatic event such as sexual assault, gun violence/mass shooting, military combat or a natural disaster may develop long-lasting symptoms of anxiety, avoidance, hypervigilance, anger/irritability, flashbacks and nightmares. "PTSD is not just a veteran issue, it's a serious public health problem," Rosman said.

Researchers analyzed medical data from more than one million young and middle-aged veterans enrolled in healthcare services provided by the Veterans Health Administration (mostly males, age 18-60, average age of 30, 2 out of 3 white) and had served in recent conflicts in Iraq and Afghanistan. None had previously experienced a TIA or stroke.

During 13 years of follow-up, 766 veterans had a TIA, and 1,877 had an ischemic stroke. Researchers also found:

·      29% were diagnosed with PTSD, and veterans with PTSD were twice as likely to have a TIA, raising the risk more than established risk factors such as diabetes and sleep apnea.

·      Veterans with PTSD were 62% more likely to have a stroke, raising the risk more than lifestyle factors such as obesity and smoking.

·      Veterans with PTSD were more likely to engage in unhealthy behaviors, such as smoking and getting little exercise, that raise the rise for stroke.

·      Even after adjusting for multiple stroke risk factors, co-existing psychiatric disorders, such as depression and anxiety, as well as drug and alcohol abuse, veterans with PTSD were still 61% more likely to have a TIA and 36% more likely to have a stroke than veterans without PTSD.

·      There was a stronger link between PTSD and stroke in men than in women.

"Clinicians should be aware that mental health conditions such as PTSD are increasingly prevalent among young people and may have major implications for their risk of stroke," Rosman said. "Our findings raise important questions about whether early recognition and successful treatment of PTSD can prevent or decrease the likelihood of developing stroke in those exposed to violence, trauma and severe adversity."

Although the study showed a strong relationship between PTSD and early TIA and stroke, it wasn't designed to prove that PTSD causes either condition. Additionally, because the analysis was conducted in younger veterans, the results may not be generalizable to non-veterans or older adults who may have more conventional stroke risk factors, such as atrial fibrillation and heart failure.

"We need to improve stroke prevention in young adults by developing targeted screening programs and age-appropriate interventions. Addressing mental health issues including PTSD may be an important part of a broader public health initiative to reduce the growing burden of stroke in young people," Rosman said.

https://www.sciencedaily.com/releases/2019/10/191018181023.htm

Widely available drug reduces head injury deaths

Early treatment with tranexamic acid could save 'hundreds of thousands of lives worldwide'

October 15, 2019

Science Daily/London School of Hygiene & Tropical Medicine

A low cost and widely available drug could reduce deaths in traumatic brain injury patients by as much as 20%, depending on the severity of injury, according to a major study published in The Lancet. [1] The researchers say that tranexamic acid (TXA), a drug that prevents bleeding into the brain by inhibiting blood clot breakdown, has the potential to save hundreds of thousands of lives.

Led by the London School of Hygiene & Tropical Medicine, the global randomised trial included more than 12,000 head injury patients who were given either intravenous tranexamic acid or a placebo. [2] It found that administration of TXA within three hours of injury reduced the number of deaths. This effect was greatest in patients with mild and moderate traumatic brain injury (20% reduction in deaths), while no clear benefit was seen in the most severely injured patients. The trial found no evidence of adverse effects and there was no increase in disability in survivors when the drug was used. [3,4,5]

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide with an estimated 69 million new cases each year. [6] The CRASH-3 (Clinical Randomisation of an Antifbrinolytic in Significant Head Injury) trial is one of the largest clinical trials ever conducted into head injury. Patients were recruited from 175 hospitals across 29 countries.

Bleeding in or around the brain due to tearing of blood vessels is a common complication of TBI and can lead to brain compression and death. Although patients with very severe head injuries are unlikely to benefit from tranexamic acid treatment because they often have extensive brain bleeding prior to hospital admission and treatment, the study found a substantial benefit in patients with less severe injuries who comprise the majority (over 90%) of TBI cases. [7]

Ian Roberts, Professor of Clinical Trials at the London School of Hygiene & Tropical Medicine, who co-led the study, said: "We already know that rapid administration of tranexamic acid can save lives in patients with life threatening bleeding in the chest or abdomen such as we often see in victims of traffic crashes, shootings or stabbings. This hugely exciting new result shows that early treatment with TXA also cuts deaths from head injury. It's an important breakthrough and the first neuroprotective drug for patients with head injury.

"Traumatic brain injury can happen to anyone at any time, whether it's through an incident like a car crash or simply falling down the stairs. We believe that if our findings are widely implemented they will boost the chances of people surviving head injuries in both high income and low income countries around the world."

Because TXA prevents bleeds from getting worse, but cannot undo damage already done, early treatment is critical. The trial data showed a 10% reduction in treatment effectiveness for every 20-minute delay, suggesting that patients should be treated with TXA as soon as possible after head injury. [8,9]

Antoni Belli, Neurosurgeon and Professor of Trauma Neurosurgery at the University of Birmingham and co-investigator for trial, said: "This is a landmark study. After decades of research and many unsuccessful attempts, this is the first ever clinical trial to show that a drug can reduce mortality after traumatic brain injury. Not only do we think this could save hundreds of thousands of lives worldwide, but it will no doubt renew the enthusiasm for drug discovery research for this devastating condition."

Dr Ben Bloom, Consultant in Emergency Medicine at Barts Health NHS Trust, the UK's largest recruiter into the trial with more than 500 patients enrolled, said: "Treating traumatic brain injury is extremely challenging with very few treatment options available for patients. Thanks to these latest results, which are applicable to patients with head injuries of any cause and of all demographics, clinicians now have a potentially powerful new treatment available to them."

The most common causes of TBI worldwide are road traffic crashes (which predominantly affect young adults) or falls (which are a major problem in older adults), and the incidence is increasing. In both cases, patients can experience permanent disability or death. Representatives from the charity that supports roach crash victims in the UK, Roadpeace, were involved in the design of the trial.

Amy Aeron-Thomas, Justice and Advocacy Manager from Roadpeace and co-author on the paper said: "It's always better to prevent road crashes in the first place, but these results show that if a crash can't be prevented, death can still be avoided. Given the time to treatment implications, it's more important than ever that the post-crash response is as efficient as possible."

CRASH-3 follows successful previous research involving 20,000 trauma patients, which showed that TXA reduced deaths due to bleeding outside of the skull by almost a third if given within three hours. Based on those trial results, tranexamic acid was included in guidelines for the pre-hospital care of trauma patients. However, patients with isolated traumatic brain injury were specifically excluded. [10]

The authors noted some limitations of the trial, including wide confidence intervals despite the large trial size, and the fact that more patients with un-survivable head injuries were included in the trial than anticipated, which diluted the treatment effect.

The trial was jointly funded by the Department for International Development (DFID), the Medical Research Council (MRC), the National Institute for Health Research (NIHR), (through the Department of Health and Social Care), and Wellcome. The early phase of the trial was funded was funded by The JP Moulton Charitable Foundation. [11]

Notes to Editors

1. Tranexamic acid is a low cost and widely available drug as many different companies sell it. Costs vary slightly per country. In the UK, 500mg is roughly £1.55, so the total dose used in CRASH-3 is about £6.20 (https://bnf.nice.org.uk/medicinal-forms/tranexamic-acid.html). In Malaysia, 500mg is 3.30 Malaysian Ringitt (64p) so around £2.50 for the CRASH-3 dose https://www.pharmacy.gov.my/v2/en/apps/drug-price

2. Patients were randomly allocated to receive a loading dose of 1 g of tranexamic acid infused over 10 minutes, started immediately after randomisation, followed by an intravenous infusion of 1 g over 8 hours, or matching placebo.

3. Among patients treated within 3 hours of injury, there was a reduction in the risk of head injury death with tranexamic acid in mild to moderate head injury (RR=0·78 95%CI 0·64-0·95), numbers of deaths can be seen in figure 3 of the paper (TXA group = 166 / 2846 (5.8%), placebo group = 207 / 2769 (7.5%). In severe head injury (RR=0·99, 95%CI 0·91-1·07) there was no clear evidence of a reduction (p-value for heterogeneity 0·030). The impact of baseline GCS in a regression analysis showed evidence (p=0·007) that tranexamic acid is more effective in less severely injured patients.

4. The most common classification system for TBI severity is based on the Glasgow Coma Scale (GCS) score determined at the time of injury. A total score of 3-8 indicates severe TBI, a score of 9-12 indicates moderate TBI, and a score of 13-15 indicates mild TBI.

5. The risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction was similar in the tranexamic acid and placebo groups. There was no evidence that tranexamic acid increased fatal or non-fatal stroke (RR=1.08). The risk of seizures was similar between groups (RR=1.09).

6. Sixty-nine million (95% CI 64-74 million) individuals are estimated to suffer TBI from all causes each year (https://www.ncbi.nlm.nih.gov/pubmed/29701556).

7. Mild TBI occurs with far greater frequency than moderate or severe TBI -- nearly 10-fold the burden of both moderate and severe injury. Of the estimated 69 million TBIs that occur each year, 81% will be mild, 11% will be moderate, and 8% will be severe (https://www.ncbi.nlm.nih.gov/pubmed/29701556).

8. Early treatment was more effective in patients with mild and moderate head injury (p=0·005) but there was no obvious impact of time to treatment in severe head injury (p=0·73). This is consistent with the hypothesis that tranexamic acid improves outcome by reducing intracranial bleeding.

9. The left hand graph of Figure 4 marked "Mild and Moderate GCS score" shows how treatment benefit is related to time on the risk ratio scale. When the treatment effect for mild and moderate patients is modelled using logistic regression with a time treatment interaction term adjusting for GCS, age and systolic blood pressure, the odds ratio is reduced by approximately 10% for every 20 minute delay.

10. A previous trial (CRASH-2) of 20,211 bleeding trauma patients from hospitals in 40 countries showed that TXA reduces bleeding deaths by a third if given soon after injury (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60835-5/fulltext)

11. Funds to support the drug and placebo costs in the run-in phase of the trial were provided by Pfizer.

https://www.sciencedaily.com/releases/2019/10/191015113316.htm

PTSD nearly doubles infection risk

October 15, 2019

Science Daily/Boston University School of Medicine

A new study is the first to examine the relationship between post-traumatic stress disorder (PTSD) and dozens of infection types in a nationwide cohort. Researchers found that PTSD affects infection risks for men and women differently, having, for example, more of an effect on a woman's risk of urinary tract infection and a man's risk of skin infection

First-of-its-kind study finds people with PTSD were 1.8 times as likely to have any infection as those without PTSD, ranging from being 1.3 times as likely to have meningitis, to 1.7 times as likely to have influenza, to 2.7 times as likely to have viral hepatitis.

A new Boston University School of Public Health (BUSPH) study is the first to examine the relationship between post-traumatic stress disorder (PTSD) and dozens of infection types in a nationwide cohort. Published in the journal Epidemiology, it is also the first to find that PTSD affects infection risks for men and women differently, having, for example, more of an effect on a woman's risk of urinary tract infection and a man's risk of skin infection.

"Our study adds to the growing evidence suggesting that PTSD and chronic severe stress are damaging for physical health," says BUSPH doctoral candidate Ms. Tammy Jiang, who led the study. This underscores the public health importance of PTSD prevention and treatment interventions, she says.

Ms. Jiang and colleagues from BUSPH, Aarhus University Hospital in Denmark, the University of Vermont, and the Emory University Rollins School of Public Health used Danish national records to look at the health histories of every Danish-born Danish citizen who received a PTSD diagnosis from 1995 through 2011, and matched each person with a comparison group of Danes of the same sex and age. The researchers then compared the Danes' histories of hospital care for 28 different kinds of infections. After adjusting for other physical and mental health diagnoses and for marriage/registered partnership, the researchers found that people with PTSD were 1.8 times as likely to have any infection than those without PTSD, as well as calculating the increased risk for each of the 28 kinds of infection.

Next, the researchers compared men and women with PTSD. They found that having PTSD had more of an effect on a woman's risk for several kinds of infection -- most notably urinary tract infection -- than on a man's risk. Having PTSD also had more of an effect on a man's risk of certain other kinds of infection, most notably skin infection.

https://www.sciencedaily.com/releases/2019/10/191015131421.htm

Rare sleep disorder common among veterans with PTSD

Findings may provide insight about development of neurodegenerative conditions like Parkinson's disease

October 11, 2019

Science Daily/Oregon Health & Science University

Military veterans with post-traumatic stress disorder or concussion suffer from a thrashing form of sleep behavior at a rate that is far higher than the general population, according to a new study by researchers at the VA Portland Health Care System and Oregon Health & Science University. The finding was published online this week in the journal SLEEP.

Researchers next want to probe whether the disorder, known as REM sleep behavior disorder, or RBD, might provide an early signal of the development of neurodegenerative conditions such as Parkinson's disease.

Normally during sleep that coincides with rapid eye movement, or REM sleep, muscles are effectively paralyzed. In cases of RBD, brain control of muscle paralysis is impaired, resulting in people acting out dreams during REM sleep, sometimes causing injuries to themselves or their partners. It is estimated to effect less than 1% of the general population.

That proportion rose to 9% of the 394 veterans in this study, and further swelled to 21% among those with PTSD.

"This is important because, in the general population, RBD has been linked to Parkinson's disease, and RBD often precedes classic symptoms of Parkinson's by years," said senior author Miranda Lim, M.D., Ph.D., a staff physician at the VA and assistant professor of neurology, medicine and behavioral neuroscience in the OHSU School of Medicine. "We don't know whether veterans who have PTSD and higher rates of RBD will go on to develop Parkinson's, but it is an important question we need to answer."

Researchers suspect chronic stress on the brain may play a role in causing the sleep disorder in veterans with PTSD, as many veterans have been exposed to concussion which potentially accelerates neurodegenerative processes.

Each study participant underwent an overnight sleep study at the VA Portland Health Care System between 2015 and 2017 to determine the presence of dream enactment during episodes of REM sleep. Muscle activity was monitored continuously during the 8 hours of the study in order to diagnose RBD. The study found that those with PTSD had over 2-fold increased odds of RBD compared to veterans without PTSD.

"RBD seems to be highly prevalent in veterans with a history of trauma," said lead author Jonathan Elliott, Ph.D., a research physiologist at the Portland VA and assistant professor of neurology in the OHSU School of Medicine.

Doctors involved in the study, including co-authors Kristianna Weymann, Ph.D., R.N., a clinical assistant professor in OHSU School of Nursing, and Dennis Pleshakov, a student at the OHSU School of Medicine, will continue to track research participants with RBD, looking for early signs of Parkinson's or other neurodegenerative conditions.

Although there are several therapies to ease some of the symptoms of Parkinson's, including tremor and fatigue, so far there has been no definitive therapy to prevent it.

Clinical trials for promising therapies are usually conducted well after patients have been diagnosed with Parkinson's, at a stage which may be too late to reverse the symptoms. Lim said that identifying patients with RBD presents an opportunity to identify people earlier in the disease course, and potentially provides a more viable window to test promising interventions.

"By the time a patient shows classic symptoms of Parkinson's, it may be too late," Lim said. "If you could intervene when people first start to show RBD, maybe you could prevent later symptoms of Parkinson's."

https://www.sciencedaily.com/releases/2019/10/191011095919.htm

Blood-brain barrier damage occurs even with mild head trauma

September 25, 2019

Science Daily/American Associates, Ben-Gurion University of the Negev

In a new study of adolescent and adult athletes, researchers at Ben-Gurion University of the Negev, Stanford University and Trinity College in Dublin have found evidence of damage to the brain's protective barrier, without a reported concussion.

For the first time, the researchers were able to detect damage to the blood-brain barrier (BBB), which protects the brain from pathogens and toxins, caused by mild traumatic brain injury (mTBI). The results were published this month in the Journal of Neurotrauma.

The researchers studied high-risk populations, specifically professional mixed martial arts (MMA) fighters and adolescent rugby players, to investigate whether the integrity of the blood-brain barrier (BBB) is altered and to develop a technique to better diagnose mild brain trauma.

"While the diagnosis of moderate and severe TBI is visible through magnetic resonance imaging [MRI] and computer-aided tomography scanning [CT], it is far more challenging to diagnose and treat mild traumatic brain injury, especially a concussion which doesn't show up on a normal CT," explains Prof. Alon Friedman, M.D., Ph.D. Dr. Friedman is a groundbreaking neuroscientist and surgeon, who established the Inter-Faculty Brain Sciences School at BGU.

The study shows that mild impact in professional MMA and adolescent rugby can still lead to a leaky BBB. If in a larger study the results are similar, the brain imaging techniques being developed could be used to monitor athletes to better determine safer guidelines for "return to play."

In this study, MMA fighters were examined pre-fight for a baseline and again within 120 hours following competitive fight. The rugby players were examined pre-season and again post-season or post-match in a subset of cases. Both groups were evaluated using advanced MRI protocol developed at BGU, analysis of BBB biomarkers in the blood and a mouthguard developed at Stanford with sensors that track speed, acceleration and force at nearly 10,000 measurements per second.

Ten out of 19 adolescent rugby players showed signs of a leaky blood-brain barrier by the end of the season. Eight rugby players were scanned post-match and two had barrier disruptions. The injuries detected were lower than the current threshold for mild head trauma. The researchers were also able to correlate the level of blood-brain barrier damage seen on an MRI with measurements from the mouthguard sensors.

"The current theory today is that it is the outer surface of the brain that is damaged in a concussion since, during an impact, the brain ricochets off of skull surfaces like Jell-O," Dr. Friedman says. "However, we can see now that the trauma's effects are evident much deeper in the brain and that the current model of concussion is too simplistic."

In the next phase of research, the group plans to conduct a similar study in a larger cohort to determine whether BBB disruptions heal on their own and how long that takes.

"It is likely that kids are experiencing these injuries during the season but aren't aware of them or are asymptomatic," Dr. Friedman says. "We hope our research using MRI and other biomarkers can help better detect a significant brain injury that may occur after what seems to be a 'mild TBI' among amateur and professional athletes."

https://www.sciencedaily.com/releases/2019/09/190925133626.htm

Female athletes seek specialty care for concussion later than males

September 17, 2019

Science Daily/Children's Hospital of Philadelphia

Female athletes seek specialty medical treatment later than male athletes for sports-related concussions (SRC), and this delay may cause them to experience more symptoms and longer recoveries. Researchers from the Sports Medicine Program at Children's Hospital of Philadelphia (CHOP), reported these findings after analyzing electronic health records of sports participants aged 7 to 18.

The study raises the question of whether, in youth and high school sports, inequities in medical and athletic trainer coverage on the sidelines are contributing to delayed identification and specialized treatment of concussion for female athletes, leading to more symptoms and longer recovery trajectories. The study was published in the Clinical Journal of Sports Medicine.

"There is speculation in the scientific community that the reasons adolescent female athletes might suffer more symptoms and prolonged recoveries than their male counterparts include weaker neck musculature and hormonal differences," says senior author Christina Master, MD, a pediatric and adolescent primary care sports medicine specialist and Senior Fellow at CHOP's Center for Injury Research and Prevention. "We now see that delayed presentation to specialty care for concussion is associated with prolonged recovery, and that is something we can potentially address."

Dr. Master and her team analyzed a dataset containing records of 192 children between 7 and 18 who were diagnosed with an SRC and seen by a sports medicine specialist. Females took longer to present to specialist care and had longer recovery trajectories than males. The median days to presentation for a subspecialty evaluation was 15 for females with SRC and 9 for males. This delay is important since time to presentation to specialized care greater than 1 week has been described as a factor associated with prolonged recovery.

Five distinct outcomes indicating return to preinjury function were measured to determine "recovery" in this group of athletes. By looking at average-days-to-recovery for female and male patients across these outcomes, researchers found that females returned to school later (4 vs. 3 days), returned to exercise later (13 vs. 7 days), had neurocognitive recovery later (68 vs. 40 days), had later vision and vestibular (balance) recovery (77 vs. 34 days) and returned to full sport far later (119 vs. 45 days).

Importantly, when researchers limited the analysis to those female and male patients that presented to the specialty practice for evaluation within the first 7 days of injury, the differences between males and females on all outcomes disappeared.

In sports where females sustain the highest rates of concussion- -- including those in this cohort of patients -- specifically soccer, basketball, and cheerleading, there is generally less sideline medical coverage for games and inconsistent athletic training coverage for practice because they are categorized as "moderate-risk sports" based on all-cause injury. In stark contrast, many high school leagues require athletic training coverage at all football, ice hockey and men's basketball practices and games.

"It is possible that the lack of athletic training coverage at the time of injury may affect the time to concussion recognition during the first critical hours and days after injury," says Dr. Master. "This period is a window of opportunity where specific clinical management, such as immediate removal from play, activity modification and sub-symptom threshold exercise is correlated with more rapid recovery."

Those who study pediatric concussion have been investigating why some concussions take longer to resolve than others so that they can identify those concussions early and implement appropriate concussion management plans to hopefully prevent persistent post-concussion symptoms. This study builds on that knowledge and suggests a tangible cause and solution: close the gap in athletic training and medical coverage between female and male sports.

https://www.sciencedaily.com/releases/2019/09/190917075828.htm

Routine sparring in boxing can affect brain performance

September 12, 2019

Science Daily/University of Stirling

Routine sparring in boxing can cause short-term impairments in brain-to-muscle communication and decreased memory performance, according to new research.

The findings emerged from a University of Stirling study that assessed boxers before and after a nine-minute sparring session -- where athletes trade punches without the aim of incapacitating each other.

This study, alongside the team's 2016 research into the impact of heading footballs, is one of the first to show that routine impact in sport -- thought to be innocuous -- results in measurable changes in the brain. Experts believe the findings raise further questions around the safety of other sports, where similar routine impacts occur, and say further research is required.

Dr Thomas Di Virgilio, a Lecturer in Sport, led the latest study alongside colleagues in the Stirling Brains multi-disciplinary research team. He said: "There are still questions surrounding the relationship between repetitive routine head impacts -- such as heading in football or sparring in boxing -- and brain health. The truth is that we do not currently know how much impact is safe.

"For many years, a debate has taken place around the safety of boxing, however, these discussions often focus on heavy blows inflicted during competitive fights. In contrast, we looked at subconcussive impacts -- those that are below the concussion threshold -- inflicted during training sessions.

"Our findings are important because they show that routine practices may have immediate effects on the brain. Furthermore, athletes may be at greater risk of injury if the communications between the brain and muscles are impaired."

The team assessed the motor control and cognitive function of 20 boxers and Muay Thai (Thai boxing) athletes before and after a nine-minute sparring session (three rounds of three minutes). Measurements were taken immediately after the session, and then one-hour and 24 hours later.

Motor control was measured using transcranial magnetic stimulation -- which uses magnetic fields to stimulate the nerve cells in the brains of participants -- to understand how it communicates with the muscles. The participants also completed a series of tests (the Cambridge Neuropsychological Test Automated Battery), providing objective measures of cognitive function.

The team found that, one hour after sparring, the participants showed impaired brain-to-muscle communications and decreased memory performance, relative to controls. After 24 hours, these effects returned to baseline.

Dr Di Virgilio added: "We have previously shown that the repetitive heading of footballs results in short-term changes to brain function and this latest study sought to understand whether similar effects were observed in training practices in other sports. Although transient, we found that brain changes observed after sparring are reminiscent of effects seen following brain injury.

"As with our previous research into heading footballs, it is not possible to say whether there is a 'safe' threshold when it comes to the level of impact in sparring. Further research is required to help sportspeople -- and the academic community -- fully understand the dangers posed by subconcussive impacts, routine in sport, and any measures that can be taken to mitigate against these risks."

Dr Di Virgilio worked alongside Stirling colleagues Dr Angus Hunter, Dr Magdalena Ietswaart, Professor Lindsay Wilson and Professor David Donaldson.

Dr Hunter said: "Importantly, this is a breakthrough study using pioneering techniques enabling us to understand how impaired brain to muscle signalling alters electrical recruitment patterns of leg muscle. In the short-term this may negatively affect fine motor control and thus athletic performance."

https://www.sciencedaily.com/releases/2019/09/190912100941.htm

Abnormal gut bugs tied to worse cognitive performance in vets with PTSD and cirrhosis

Study involved more than 90 combat veterans

September 12, 2019

Science Daily/Veterans Affairs Research Communications

A study involving military veterans with PTSD and cirrhosis of the liver points to an abnormal mix of bacteria in the intestines as a possible driver of poor cognitive performance -- and as a potential target for therapy.

The study appeared Aug. 28, 2019, in the American Journal of Physiology.

Lead author Dr. Jasmohan Bajaj says the findings add to the substantial evidence linking gut health and brain function. He says they offer particular hope for people with PTSD and cirrhosis -- a common combination in the VA patient population.

"There is room for improvement in terms of the response to current therapies for PTSD," he says. "Targeting the gut microbiota might be an effective way to address the altered gut-brain axis in these patients and improve cognitive function, as well as other parameters of mental and physical health."

Bajaj is a physician-researcher with the McGuire Veterans Affairs Medical Center and Virginia Commonwealth University in Richmond.

Cirrhosis, or scarring of the liver, is prevalent in veterans with PTSD. Common causes include alcohol use disorder, obesity, and hepatitis C. Some patients with cirrhosis develop a complication called hepatic encephalopathy, which affects brain function. They become mentally sluggish and confused, and in severe cases can even lose consciousness.

PTSD, for its part, can also impair cognition. This can occur whether or not patients are taking drugs, such as antidepressants or sedatives, that act on the brain.

The researchers wanted to tease out the impact of abnormal gut microbiota in these conditions, and see whether those with cirrhosis and PTSD had different gut profiles than those with cirrhosis but no PTSD.

Bajaj's team took stool samples from 93 male veterans with cirrhosis, about a third of whom had combat-related PTSD. The other men had been exposed to combat during their military service but had not developed PTSD.

All the veterans completed a battery of cognitive exams. The tests covered areas such as reaction time, spatial ability, memory, and problem-solving.

Compared with the non-PTSD group, the men with PTSD had poorer cognitive performance.

Those with PTSD had microbiota that were less diverse, meaning they had fewer types of bacteria overall. This was true even after the researchers controlled for severity of cirrhosis, prior episodes of hepatic encephalopathy, alcohol use, and psychotropic medication use.

These veterans, along with the relative lack of diversity in their gut, tended to have more potentially harmful types of bacteria, such as Enterococcus and Escherichia/Shigella, and fewer beneficial ones, such as Lachnospiraceae and Ruminococcaceae.

In the study, higher levels of Enterococcus were associated with worse cognitive performance. The Ruminococcaceae family of bacteria, among others, was associated with better performance.

Ruminococcaceae bacteria are prevalent in healthy guts. These beneficial bugs help break down complex carbohydrates, such as those in unprocessed whole grains and legumes. People with healthier diets of this type tend to have higher counts of these organisms.

The same bacteria have been found to be scarcer in people with depression. There has been little study of their role in PTSD.

Could it be that the psychiatric drugs often used to treat PTSD affected these patients' microbiota? The study found that veterans with PTSD had similar gut profiles regardless of what medications they were on for the condition. This suggests the altered gut microbiome is a result of PTSD itself, and not any drug treatment.

One question the study couldn't answer was whether the combat trauma that triggered PTSD also triggered the bacterial changes, or whether those changes resulted over time from the chronic stress of PTSD.

Bajaj says it's hard to tease out that answer without prospectively following service members and veterans over many years, starting from before their deployments, and periodically sampling their gut bacteria. Such a study would be difficult to conduct.

In any case, he believes it's possible that restoring the gut microbiota to a healthy, normal balance could help ease PTSD symptoms -- especially when cirrhosis is also in play. But that idea has to be validated in studies.

"We need more research, including basic lab studies and clinical trials, to understand whether therapies that can change the gut microbiota can help these patients, and which particular types of bacteria are most beneficial," says Bajaj. He cited probiotic supplements or fecal transplants as two possible therapy approaches.

Recently, VA's Office of Research and Development launched an initiative to increase the number of such studies. Bajaj was among a group of more than 20 clinicians and biomedical scientists who helped develop a "roadmap" outlining VA's plans to fund work in this area over the next few years.

https://www.sciencedaily.com/releases/2019/09/190912165122.htm

Repetitive impacts key to understanding sports-associated concussions

September 9, 2019

Science Daily/Trinity College Dublin

Scientists at Trinity College Dublin have announced a significant advance in our understanding of mild head trauma (concussive brain injury) and how it may be managed and treated in the future. It seems that repetitive impacts -- as opposed to single events -- cause the all-important damage to blood vessels in the brain.

Mild head trauma has come to the fore in recent years as being associated with collision and combat sports. However, it is also a very common injury in children and young adults and represents a significant challenge to physicians due to the lack of any robust biomarkers or objective imaging approaches to manage the injury.

"This was a hypothesis-driven project whereby we challenged the hypothesis that repetitive head trauma would induce damage to small blood vessels in the brain that we would then be able to image with a novel form of MRI-based brain scans," said Dr Matthew Campbell, Assistant Professor at Trinity.

The study, which was undertaken by the Trinity-led Concussion Research Interest Group (CRIG) used both sensor-enabled mouthguard technology developed by the group of Professor David Camarillo at Stanford University and dynamic contrast-enhanced MRI to confirm the number and severity of head impacts that would lead to the appearance of "leaky" blood vessels within the brain.

Participants of combat and collision sports such as mixed martial arts (MMA) and rugby took part in the clinical research study, which took four years to complete and is part of a wider longitudinal study, which is still ongoing.

Concussive brain injuries

While it is clear that concussive brain injuries cause clinical symptoms such as dizziness, nausea and confusion, these symptoms all occur independent of any adverse findings on CT or MRI scans, and/or without the presence of any clear blood-based biomarkers. Therefore, the clinical management of concussive brain injuries is challenging and needs new technologies to assist in diagnosis and rehabilitation.

Dr Colin Doherty, Consultant Neurologist at St James's Hospital and clinical lead on the study, added: "Our findings, for the first time, suggest that repetitive head trauma can lead to an MRI signal that we can definitively link to the number and severity of impacts to the head. It appears that the repetitive nature of these impacts as opposed to single events are causing damage to the capillaries of the brain."

The study reports that repetitive impacts to the head, not necessarily just concussions, are likely able to induce changes to the micro-vessels of the brain. It is these changes that are then readily visible when using a novel form of MRI-based imaging.

While the study was based on a selected group of MMA fighters and rugby players, the findings could eventually pave the way for more robust and objective return-to-play guidelines and improved player safety in the longer term.

"This study has highlighted the critical importance of continued efforts to study the underlying effects of concussive brain injuries in all sports. It is imperative that the governing bodies take note of these findings and work together to protect athletes now and in the future," added co-author Professor Mick Molloy, former Chief Medical Officer of World Rugby.

https://www.sciencedaily.com/releases/2019/09/190909130227.htm

Player athleticism increases head impact exposure in youth football

September 6, 2019

Science Daily/Wake Forest Baptist Medical Center

Speed, agility and strength are definitely assets on the football field. But when it comes to hits to the head, those talents may actually increase exposure for the young athletes who account for about 70% of this country's football players.

A study of youth league football players by researchers at Wake Forest School of Medicine, part of Wake Forest Baptist Health, found that higher vertical jumping ability and faster times in speed and agility drills were generally associated with higher head impact exposure, especially in games as compared to practices.

"Previous studies have shown the severity and number of head impacts increases with the level of play in football, but we have found that there is significant variability in head impact exposure among individuals playing at the same level," said Jillian E. Urban, Ph.D., assistant professor of biomedical engineering at Wake Forest School of Medicine and the study's senior author. "Differences in position account for some of that variation at the high school and college levels, but less so in youth football. Our objective was to see if there is a relationship in youth football between head impact exposure and physical ability as measured by commonly used drills, and our results suggest there is."

The study, published in the current issue of the journal Medicine & Science in Sports & Exercise, quantified head impact exposure in terms of the number of hits experienced by players, the severity of each hit in terms of peak linear and rotational head acceleration and a measure that combines the number and severity of hits recorded in a season, known as risk-weighted cumulative exposure.

The researchers analyzed performance on four physical ability tests (vertical jump, 40-yard dash and two agility drills) and on-field head impact data from all practices and games in one season for 51 players age 9 to 13. These players were members of four teams in leagues in the same region operating under the same national youth football organization. A total of 13,770 head impacts were measured with the Head Impact Telemetry (HIT) System, which includes sensors embedded in football helmets and a sideline data-collection unit plus a video-confirmation component.

The study found that all four physical performance measures were significantly correlated with the total number of head impacts measured during practices and games over the course of a season and with the risk-weighted cumulative exposure measured during games. The strongest relationships were between 40-yard dash speed and the risk-weighted cumulative exposure measured during games.

The relationships between physical performance measures and head impact exposure during practices were not as strong as those with head impact exposure during games.

"Players with higher measures of physical performance may experience greater head impact exposure because they are on the field for more plays, engage in more contact while playing, arrive at points of contact at higher speeds and may prioritize using their athletic ability over technical skill when engaging in contact," Urban said. "Physical performance measures may aid in identifying young athletes at greater risk of head impact exposure but additional research is needed to better understand if this could be part of intervention strategies for reducing the risk of head injuries in youth football."

Urban said further research in this area should include a larger number of players from a variety of different organizations, regions, and demographic backgrounds; additional assessments of physical abilities, such as upper-body strength; and consideration of other factors, including playing time in games, player aggression and attitudes and behaviors related to tackling.

https://www.sciencedaily.com/releases/2019/09/190906172422.htm

PTSD linked to increased risk of ovarian cancer

September 5, 2019

Science Daily/Harvard T.H. Chan School of Public Health

Women who experienced six or more symptoms of post-traumatic stress disorder (PTSD) at some point in life had a twofold greater risk of developing ovarian cancer compared with women who never had any PTSD symptoms, according to a new study from researchers at Harvard T.H. Chan School of Public Health and Moffitt Cancer Center.

The findings indicate that having higher levels of PTSD symptoms, such as being easily startled by ordinary noises or avoiding reminders of the traumatic experience, can be associated with increased risks of ovarian cancer even decades after women experience a traumatic event. The study also found that the link between PTSD and ovarian cancer remained for the most aggressive forms of ovarian cancer.

The findings were published in Cancer Research, on September 5, 2019.

"In light of these findings, we need to understand whether successful treatment of PTSD would reduce this risk, and whether other types of stress are also risk factors for ovarian cancer," said co-author Andrea Roberts, research scientist at Harvard T.H. Chan School of Public Health.

Ovarian cancer is the deadliest gynecologic cancer and the fifth most common cause of cancer-related death among U.S. women. Studies in animal models have shown that stress and stress hormones can accelerate ovarian tumor growth, and that chronic stress can result in larger and more invasive tumors. A prior study found an association between PTSD and ovarian cancer in humans, but the study included only seven women with ovarian cancer and PTSD.

"Ovarian cancer has been called a 'silent killer' because it is difficult to detect in its early stages; therefore identifying more specifically who may be at increased risk for developing the disease is important for prevention or earlier treatment," said co-author Laura Kubzansky, Lee Kum Kee Professor of Social and Behavioral Sciences at Harvard Chan School.

To better understand how PTSD may influence ovarian cancer risk, researchers analyzed data from the Nurses' Health Study II, which tracked the health of tens of thousands of women between 1989 and 2015 through biennial questionnaires and medical records. Participants were asked about ovarian cancer diagnosis on each questionnaire, and information was validated through a review of medical records.

In 2008, 54,763 Nurses' Health Study II participants responded to a supplemental questionnaire focused on lifetime traumatic events and symptoms associated with those events. Women were asked to identify the event they considered the most stressful, and the year of this event. They were also asked about seven PTSD symptoms they may have experienced related to the most stressful event.

Based on the responses, women were divided into six groups: no trauma exposure; trauma and no PTSD symptoms; trauma and 1-3 symptoms; trauma and 4-5 symptoms; trauma and 6-7 symptoms; and trauma, but PTSD symptoms unknown.

After adjusting for various factors associated with ovarian cancer, including oral contraceptive use and smoking, the researchers found that women who experienced 6-7 symptoms associated with PTSD were at a significantly higher risk for ovarian cancer than women who had never been exposed to trauma. Women with trauma and 4-5 symptoms were also at an elevated risk, but the risk did not reach statistical significance.

The study also showed that women who experienced 6-7 symptoms associated with PTSD were at a significantly higher risk of developing the high-grade serous histotype of ovarian cancer -- the most common and aggressive form of the disease.

"Ovarian cancer has relatively few known risk factors -- PTSD and other forms of distress, like depression, may represent a novel direction in ovarian cancer prevention research," said Shelley Tworoger, associate center director of population science at Moffitt. "If confirmed in other populations, this could be one factor that doctors could consider when determining if a woman is at high risk of ovarian cancer in the future."

Other Harvard Chan School researchers who contributed to the study included Karestan Koenen and Yongjoo Kim. Tianyi Huang of Brigham and Women's Hospital and Harvard Medical School was also a co-author.

https://www.sciencedaily.com/releases/2019/09/190905094044.htm

Soldiers, athletes could improve outcomes from traumatic brain injuries

September 4, 2019

Science Daily/Purdue University

A traumatic brain injury is often easily suspected and can be confirmed and treated if necessary following an injury using a blood analysis, but scientists are reporting that even one mild blast to the brain can cause very subtle but permanent damage as well. Urine analysis taken within one week of a mild to traumatic brain injury also can provide faster diagnosis and treatment for such injuries. 

"We're finding that even a mild blast can cause long-term, life-changing health issues," said Riyi Shi, a professor of neuroscience and biomedical engineering in Purdue University's Department of Basic Medical Sciences. "The individual appears to be fine, and it's difficult to tell if you just look at a person. But the fact is that these types of hits are multiplied over years and often ignored until someone reaches an age when other factors come into play. Identifying and treating these incidents sooner can help mitigate issues later in life."

 A study led by Shi reports that checking the urine within seven days following such an injury, even a mild injury with no immediately obvious symptoms, could be less invasive, faster and help reduce the risk of long-term health issues including Parkinson's disease.

 "Even at one day post injury, a simple urine analysis can reveal elevations in the neurotoxin acrolein. The presence of this "biomarker" alerts us to the injury, creating an opportunity for intervention," said Shi, who has appointments in Purdue's College of Veterinary Medicine and Weldon School of Biomedical Engineering. "This early detection and subsequent treatment window could offer tremendous benefits for long-term patient neurological health."

 The research paper, titled "Acrolein-mediated Alpha-synuclein Pathology Involvement in the Early Post-injury Pathogenesis of Mild Blast-induced Parkinsonian Neurodegeneration," was published in July in the Journal of Molecular and Cellular Neuroscience.

 "Most people have heard that traumatic brain injuries are linked to Parkinson's, Alzheimer's and other neurodegenerative diseases, dating back as far as to Muhammad Ali and even earlier," Shi said. "The seriousness of this relationship is readily apparent; however, we want to, for the first time, implement a mechanism or protocol capable of connecting brain injuries to these diseases. We can accomplish this by testing for acrolein, which is well-researched and already recognized as a very important pathological factor in Parkinson's disease. This study establishes a solid link between the two and opens the door for faster treatments utilizing acrolein urine tests during the days following a traumatic episode."

 In the research study, a urine analysis tested for an increased elevation of acrolein or oxidative stress within one week following a neurological injury.

 "What's important is that urine tests can be performed much easier than blood tests or other more invasive medical procedures currently available," Shi said. "And it has been shown that individuals who experience brain injuries are three times more likely than their age-matched peers to develop neurological disease. If we can establish a protocol to routinely test urine following a traumatic brain injury, we can improve treatment options earlier and potentially offer better long-term outcomes."

 More than 500,000 people in the U.S. are currently living with Parkinson's disease, and another 50,000 people are diagnosed with this neurodegenerative disorder every year, according to the National Institutes of Health.

https://www.sciencedaily.com/releases/2019/09/190904154005.htm

Number of years in NFL, certain positions portend greater risk for cognitive, mental health problems

August 30, 2019

Science Daily/Harvard Medical School

Study shows link between longer NFL career and higher risk of cognitive, mental health problems. Risk persisted over time, even 20 years following injury. Certain positions also carried elevated risk for cognitive problems, depression and anxiety. Running backs, linebackers, defensive linemen had the greatest risk for cognitive problems.

Longer NFL careers and certain playing positions appear to each spell greater long-term risk for serious cognitive problems such as confusion, memory deficits, depression and anxiety in former football players, according to a new report published Aug. 30 in The American Journal of Sports Medicine.

The study is believed to be the first to explore the interplay between career length, position and cognitive and mental health outcomes among professional football players.

The analysis -- based on a survey of nearly 3,500 former NFL players -- was conducted by investigators at the Harvard T.H. Chan School of Public Health and Harvard Medical School as part of the ongoing Football Players Health Study at Harvard University.

The study results show that players who experienced concussions had elevated risk for serious cognitive problems, depression and anxiety, which persisted over time, as long as 20 years following injury. The investigators caution that their analysis relied on players' memories of experiencing concussion rather than on diagnosis at the time of injury. And the findings do not mean that everyone with concussion will necessarily experience cognitive or mental health problems, they add. Contrary to previous reports, the new research did not find a link between starting football at a young age and cognitive problems in adulthood.

On one level, the researchers say, many of their findings make intuitive sense and confirm what some might have already suspected: The longer players remain in the game, the more likely they are to suffer a head injury, which increases the risk for neurocognitive problems. It also affirms that certain positions are more prone to concussions and, therefore, players in them face greater risk for experiencing the downstream of effects of head injury.

Nonetheless, the researchers said, the analysis is the first to document and quantify the risk that stems from lengthier careers and certain high-impact positions.

Specifically, the analysis showed that players who reported the most concussion symptoms had 22-fold risk of reporting serious long-term cognitive problems and six times the risk of having symptoms of depression and anxiety, compared with those who reported the fewest symptoms.

"Our findings confirm what some have suspected -- a consistently and persistently elevated risk for men who play longer and who play in certain positions," said study lead investigator Andrea Roberts, a research scientist at the Harvard T.H. Chan School of Public Health. "Our results underscore the importance of preventing concussions, vigilant monitoring of those who suffer them and finding new ways to mitigate the damage from head injury."

For the study, former players, average age 53, were asked about the number of seasons played in the NFL, their positions and any history of blows to the head or neck followed by symptoms of concussion such as dizziness, confusion, vision problems, loss of consciousness, nausea, headaches and seizures, among other symptoms. Based on the number and severity of symptoms, players were given a concussion score.

Overall, one in eight players (12 percent) reported signs of serious cognitive problems. By comparison, about 2 percent of people in the general population in the United States report such problems. Age made no difference in the interplay between concussion and cognitive problems, the study showed. Those under age 52 reported serious cognitive problems at a similar rate as the rest (13 percent), a finding that suggests neurocognitive decline was likely not a function of mere aging. Alarmingly, that risk remained magnified even in those 45 and younger. Indeed, 30 percent of players 45 and younger who had the most concussions reported serious cognitive problems.

To gauge whether the number of seasons played and position type were linked to depression, anxiety and cognitive problems, the researchers used standard questionnaires commonly used to screen for the presence of such disorders. The researchers compared the proportion of players with serious cognitive problems among individuals with various career lengths -- one season, two to four seasons, five to six seasons, seven to nine seasons and 10 seasons or more. Overall, those with the longest careers -- 10 seasons or more -- were twice as likely to report severe cognitive problems compared with players who'd played a single season -- 12.6 percent in the 10-plus season group reported signs of severe cognitive problems, compared with 5.8 percent in the single-season category. The risk crept up proportionally with the number of seasons played, growing progressively higher as the number of years increased. Every five seasons of play carried a nearly 20 percent increase in risk for serious cognitive problems.

Which position one played also mattered. To evaluate the risk-position link, the researchers divided players into three groups based on the average concussion symptoms per year that players reported in each position. Kickers, punters and quarterbacks had the fewest symptoms per year, followed by wide receivers, defensive backs, linemen and tight ends. The groups with the highest number of symptoms included running backs, linebackers and special teams.

Those in the group with the most concussion symptoms had twice the risk for serious cognitive problems -- 15 percent of those in this group had cognitive difficulties -- compared with those reporting the fewest concussion symptoms (6 percent). Those with the most concussions also had a nearly 50 percent greater risk for depression and anxiety, compared with those playing in the group with the fewest concussion symptoms. One in four in the first group had symptoms indicative of depression, compared with 15 percent of players reporting problems in the latter one, while 27 percent had signs of anxiety, compared with 16 percent in the group with the fewest concussions. Those who played in the mid-range group had a 75 percent higher risk of cognitive problems and a 40 percent elevation in risk for depression and anxiety, compared with players in the group with the fewest symptoms.

Nearly one in four players reported symptoms of anxiety (26 percent) and depression (24 percent), and nearly one in five (18 percent) reported symptoms of both conditions. Career length influenced risk for depression, with every five seasons boosting the risk by 9 percent. The number of seasons, however, was not linked to greater anxiety risk.

The age at which an individual started playing organized football did not affect risk. Indeed, outcomes were similar between those who began playing the game before age 12 and those who began later. The findings, however, pertain solely to former NFL players and not necessarily to the general population, the researchers caution. The question of when a child should start playing organized football remains very much open, and should be made by each individual family, the researchers said.

"The overarching goal of the Football Players Health Study is to unravel risk factors and disease mechanisms and to inform interventions that preserve and optimize player health and wellness," said study senior author Marc Weisskopf, the Cecil K. and Philip Drinker Professor of Environmental Epidemiology and Physiology at the Harvard T.H. Chan School of Public Health. "These latest findings confirm much of what we know but they add much needed granularity and specificity to risk magnitude by career length and position."

"Clearly, not everyone who sustains a concussion is destined for cognitive trouble, but the results of the research highlight just how critical it is to continue to find ways to prevent head injuries from occurring in the first place because of the many downstream and long-lasting effects on physical, cognitive and mental health," said Ross Zafonte, the Earle P. and Ida S. Charlton Professor of Physical Medicine and Rehabilitation and head of the Department of Physical Medicine and Rehabilitation at Harvard Medical School. Zafonte is also principal investigator of the Football Players Health Study.

The research was supported by National Football League Players Association (NFLPA).

https://www.sciencedaily.com/releases/2019/08/190830082619.htm

New medication may be able to improve effects of psychological treatment for PTSD

August 29, 2019

Science Daily/Linköping University

A medication that boosts the body's own cannabis-like substances, endocannabinoids, shows promise to help the brain un-learn fear memories when these are no longer meaningful. These results, obtained in an early-stage, experimental study on healthy volunteers at Linköping University in Sweden, give hope that a new treatment can be developed for post-traumatic stress disorder, PTSD. The study has been published in the scientific journal Biological Psychiatry.

"We have used a medication that blocks the way the body breaks down its own cannabis-like substances, or 'endocannabinoids'. Our study shows that this class of medications, called FAAH inhibitors, may offer a new way to treat PTSD and perhaps also other stress-related psychiatric conditions. The next important step will be to see if this type of medication works in patients, particularly those with PTSD," says Leah Mayo, senior post-doctoral fellow and lead investigator on the study, which was carried out in the laboratory of Professor Markus Heilig at the Center for Social and Affective Neuroscience, CSAN, Linköping University.

Post-traumatic stress disorder, PTSD, arises in some -- but not all -- people who have experienced life-threatening events. A person affected by PTSD avoids reminders of the trauma, even when the danger is long gone. Over time, these patients become tense, withdrawn, and experience sleep difficulties. This condition is particularly common among women, where it is often the result of physical or sexual abuse. It is highly debilitating, and current treatment options are limited.

PTSD is currently best treated using prolonged exposure therapy, PE. In this treatment, patients are repeatedly exposed to their traumatic memory with the help of a therapist. This ultimately allows patients to acquire new learning: that these memories no longer signal imminent danger. Although clinically useful, effects of PE are limited. Many patients do not benefit, and among those who do, fears frequently return over time. The scientists who carried out the current study examined whether fear extinction learning, the principle behind PE therapy, can be boosted by a medication.

The researchers tested a pharmaceutical that affects the endocannabinoid system, which uses the body's own cannabis-like substances to regulate fear and stress-related behaviors. The experimental medication results in increased levels of anandamide, a key endocannabinoid, in regions of the brain that control fear and anxiety. The medication accomplishes this by blocking an enzyme, FAAH (fatty acid amide hydrolase), that normally breaks down anandamide. The FAAH inhibitor tested by the researchers was originally developed for use as a pain killer, but was not effective enough when tested clinically.

This early-stage experimental study was randomised, placebo-controlled and double-blind, which means that neither the participants nor the scientists knew who was receiving the active drug (16 people) and who was receiving placebo (29 people). Participants were healthy volunteers. After taking the drug for 10 days, they underwent several psychological and physiological tests. In one of these, participants learned to associate a highly unpleasant sound, that of fingernails scraping across a blackboard, with a specific visual cue -- an image of a red or blue lamp. Once they had learned to respond with fear to the previously innocuous image of the lamp, they were repeatedly re-exposed to it, but now in the absence of the unpleasant sound. This allowed them to unlearn the fear memory. The following day, the scientists measured how well participants remembered this new learning: that the lamp was no longer a threat signal. This process of un-learning fear is the same principle on which PE therapy for PTSD is based.

"We saw that participants who had received the FAAH inhibitor remembered the fear extinction memory much better. This is very exciting," say Leah Mayo.

"Numerous promising treatments coming out of basic research on psychiatric disorders have failed when tested in humans. This has created quite a disappointment in the field. This is the first mechanism in a long time where promising results from animal experiments seem to hold up when put to test in people. The next step, of course, is to see whether the treatment works in people with PTSD," adds professor Markus Heilig.

https://www.sciencedaily.com/releases/2019/08/190829115420.htm