Menstrual Cycle Influences Concussion Outcomes

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Researcher Seeks to Help Those Who Can’t Speak for Themselves

When people appear comatose, how can we know their wishes?

A Michigan Technological University researcher says many non-communicative individuals may actually be able to express themselves better than is widely thought.

Syd Johnson, assistant professor of philosophy, has just published a paper in the American Journal of Bioethics: Neuroscience that argues that even patients with severe brain injuries  could have more self-determination and empowerment. “New research with people using just their brains to communicate reveals that more of them might be able to make their own decisions,” she says. 

Those decisions can literally be life and death, and the first question a caregiver should ask is “How do we determine if they are capable—as an ordinary person would be—of making these decisions?” Johnson asks.

She says because of their brain injuries, many have limited attention spans or movement/speech disorders that make it very difficult to communicate. “That’s why it’s important to find ways of assessing their wellbeing other than by asking them,” she says. “Being able to do that would open up the possibility of assessing quality of life even in those who have never been able to communicate, such as infants or people born with severe cognitive disabilities.”

And that leads to the tough questions, Johnson points out.

“Who makes the decision that someone desires, or not, to live in this state? Who makes the life assessment for people: to treat them or to allow them to die.”

The range of potential patients runs the gamut from grandparents to infants, Johnson says. Sometimes you can’t ask them, including those with cognitive disabilities, but sometimes you can.

She acknowledges the complexity of the issue, especially when decisions involve quality of life. “We assume they don’t want to live that way, but sometimes, are they okay?”

She uses the example of locked-in syndrome, where patients can blink “yes” or “no.” A majority says they are doing okay.

“So, then do we make a decision based on what we think it is like to be in that position?” Johnson says.

Many people adjust to this new way of life, she says, and it’s important for caregivers to get into their mind, to recognize what might be a foreign viewpoint for an able-bodied person.

“Then there are the misdiagnosed,” Johnson says. “As many as 40 percent could be conscious at some level, even in a permanent vegetative state. Even in a nursing home, it can be that no one is assessing them, and they might improve. Nobody is diagnosing anymore, and they are treated as if they are not ever going to get better.”

Researchers around the globe have begun to address these issues, and new evidence is coming in, thanks in part to fMRI: functional magnetic resonance imaging—a technique that directly measures the blood flow in the brain that can provide information on brain activity.

“Even EEGs [electroencephalograms, which measure electrical activity in the brain] can be used,” she says. “The patients can be asked questions and given two things to think about for answers: playing tennis for yes, walking around in their house for no. And different parts of their brain will light up. People can be conscious while appearing outwardly unconscious.”

The end-result could mean reassessing the quality of life, Johnson says. Some patients can be asked—the so-called “covertly aware” patients who are conscious but can communicate only with technological assistance.

“Just as importantly, we might be able to use technology to objectively measure aspects of quality of life even in patients who cannot communicate at all,” Johnson says.

The ethical issues loom.

“A person’s quality of life is inherently subjective, and the aim of quality of life assessment has always been to find ways to objectively measure that subjective state of being,” she says. “New technologies like fMRI might be able to provide a different kind of objective assessment of subjective wellbeing—by looking at brain activity—in those individuals who are unable to tell us how they’re doing.”

A new way to monitor induced comas

After suffering a traumatic brain injury, patients are often placed in a coma to give the brain time to heal and allow dangerous swelling to dissipate. These comas, which are induced with anesthesia drugs, can last for days. During that time, nurses must closely monitor patients to make sure their brains are at the right level of sedation — a process that MIT’s Emery Brown describes as “totally inefficient.”

“Someone has to be constantly coming back and checking on the patient, so that you can hold the brain in a fixed state. Why not build a controller to do that?” says Brown, the Edward Hood Taplin Professor of Medical Engineering in MIT’s Institute for Medical Engineering and Science, who is also an anesthesiologist at Massachusetts General Hospital (MGH) and a professor of health sciences and technology at MIT.

Brown and colleagues at MGH have now developed a computerized system that can track patients’ brain activity and automatically adjust drug dosages to maintain the correct state. They have tested the system  — which could also help patients who suffer from severe epileptic seizures — in rats and are now planning to begin human trials.

Maryam Shanechi, a former MIT grad student who is now an assistant professor at Cornell University, is the lead author of the paper describing the computerized system in the Oct. 31 online edition of the journal PLoS Computational Biology.

Tracking the brain

Brown and his colleagues have previously analyzed the electrical waves produced by the brain in different states of activity. Each state — awake, asleep, sedated, anesthetized and so on — has a distinctive electroencephalogram (EEG) pattern.

When patients are in a medically induced coma, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. This pattern, known as burst suppression, allows the brain to conserve vital energy during times of trauma.

As a patient enters an induced coma, the doctor or nurse controlling the infusion of anesthesia drugs tries to aim for a particular number of “bursts per screen” as the EEG pattern streams across the monitor. This pattern has to be maintained for hours or days at a time.

“If ever there were a time to try to build an autopilot, this is the perfect time,” says Brown, who is a professor in MIT’s Department of Brain and Cognitive Sciences. “Imagine that you’re going to fly for two days and I’m going to give you a very specific course to maintain over long periods of time, but I still want you to keep your hand on the stick to fly the plane. It just wouldn’t make sense.”

To achieve automated control, Brown and colleagues built a brain-machine interface — a direct communication pathway between the brain and an external device that typically assists human cognitive, sensory or motor functions. In this case, the device — an EEG system, a drug-infusion pump, a computer and a control algorithm — uses the anesthesia drug propofol to maintain the brain at a target level of burst suppression.

The system is a feedback loop that adjusts the drug dosage in real time based on EEG burst-suppression patterns. The control algorithm interprets the rat’s EEG, calculates how much drug is in the brain, and adjusts the amount of propofol infused into the animal second-by-second.

The controller can increase the depth of a coma almost instantaneously, which would be impossible for a human to do accurately by hand. The system could also be programmed to bring a patient out of an induced coma periodically so doctors could perform neurological tests, Brown says.

This type of system could take much of the guesswork out of patient care, says Sydney Cash, an associate professor of neurology at Harvard Medical School.

“Much of what we do in medicine is making educated guesses as to what’s best for the patient at any given time,” says Cash, who was not part of the research team. “This approach introduces a methodology where doctors and nurses don’t need to guess, but can rely on a computer to figure out — in much more detail and in a time-efficient fashion — how much drug to give.”

Monitoring anesthesia

Brown believes that this approach could easily be extended to control other brain states, including general anesthesia, because each level of brain activity has its own distinctive EEG signature.

“If you can quantitatively analyze each state’s signature in real time and you have some notion of how the drug moves through the brain to generate those states, then you can build a controller,” he says.

There are currently no devices approved by the U.S. Food and Drug Administration (FDA) to control general anesthesia or induced coma. However, the FDA has recently approved a device that controls sedation not using EEG readings.

The MIT and MGH researchers are now preparing applications to the FDA to test the controller in humans.

Traumatic Brain Injury Research Advances with $18.8M NIH Award

The National Institutes of Health is awarding $18.8 million over five years to support worldwide research on concussion and traumatic brain injury.

The NIH award, part of one of the largest international research collaborations ever coordinated by funding agencies, will be administered through UC San Francisco.

The award supports a team of U.S. researchers at more than 20 institutions throughout the country who are participating in the International Traumatic Brain Injury (InTBIR) Initiative, a collaborative effort of the European Commission, the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH) and the U.S. Department of Defense (DOD).

Although the potential long-term harms due to concussions and blows to the head have gained more attention recently – due in part to media coverage of the experiences of athletes and of soldiers returning from the Middle East – traumatic brain injuries, or TBI, that results from automobile crashes or other common accidents impacts many more people.

Many of those who are affected by TBI are never diagnosed, according to UCSF neurosurgeon Geoffrey Manley, MD, PhD, a principal investigator for the grant who will serve as the U.S. research team’s primary liaison to the NIH, and the chief of neurosurgery at the UCSF-affiliated San Francisco General Hospital, a Level-1 trauma center. SFGH was the first medical center in the nation to achieve certification from the Joint Commission for the treatment of TBI.

The U.S. Centers for Disease Control and Prevention estimates that 2 percent of the U.S. population now lives with TBI-caused disabilities, at an annual cost of about $77 billion.

“Each year in the United States, at least 1.7 million people seek medical attention for TBI,” Manley said. “It is a contributing factor in a third of all injury-related deaths.”

In the work funded by the NIH grant – which also is supported by contributions from the private sector and from the nonprofit One Mind for Research – the researchers aim to refine and improve diagnosis and treatment of TBI, which often has insidious health effects, but which frequently is undiagnosed, misdiagnosed, inadequately understood and undertreated, according to Manley.

New Approach to Lead to Patient-Specific Treatments

“After three decades of failed clinical trials, a new approach is needed,” Manley said. “We expect that our approach will permit researchers to better characterize and stratify patients, will allow meaningful comparisons of treatments and outcomes, and will improve the next generation of clinical trials. The work will advance our understanding of TBI and lead to more effective, patient-specific treatments.”

Since 2009, Manley and Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging at UCSF, have helped lay the groundwork for the continuing TBI research by leading the NIH-funded TRACK-TBI project, through which they and their research collaborators have demonstrated the value of gathering common data across research sites, including a standardized approach to imaging, clinical data, bio-specimens, and tracking outcomes.

Already, TRACK-TBI researchers have made progress toward more useful classification and prognosis of TBI.

Earlier this year, they reported that cases of concussion, or TBI that are classified as “mild” by standard criteria but that show abnormalities on early magnetic resonance imaging (MRI) scans, are much more likely to have worse outcomes three months after the scan in comparison to cases in which scans reveal no abnormalities. Furthermore, the researchers found that elevated blood levels of a protein released during brain injury was associated with the likelihood of an abnormal CT scan.

The new NIH award funds a continuation and expansion of TRACK-TBI. Among the goals is the creation of a widely accessible, comprehensive “TBI information commons” to integrate clinical, imaging, proteomic, genomic and outcome biomarkers from subjects across the age and injury spectra. Another goal is to establish the value of biomarkers that will improve classification of TBI and better optimize selection and assignment of patients for clinical trials.

The researchers also aim to evaluate measures to assess patient outcomes across all phases of recovery and at all levels of TBI severity, to determine which tests, treatments, and services are effective and appropriate – depending on the nature of TBI in particular patients.

In addition to Manley and Mukherjee, principal investigators for the newly funded project include Claudia Robertson, MD, Baylor College of Medicine; Joseph Giacino, PhD, Harvard University; Ramon Diaz-Arrastia, MD, PhD, Uniformed Services University of the Health Sciences; David Okonkwo, MD, PhD, University of Pittsburgh; and Nancy Temkin, PhD, University of Washington. Each of these leading experts has worked in the TBI field for two decades or more.

“The principal investigators bring expertise in neurosurgery, neurology, neuroradiology, critical care medicine, rehabilitation medicine, neuropsychology and biostatistics, all of which are essential and do not reside in any single individual,” Manley said.

International Funding and Collaboration

TRACK-TBI clinical enrollment sites throughout the United States will enroll 3,000 patients across the spectrum of mild to severe brain injuries. Clinical, imaging, proteomic, genomic and clinical outcome databases will be linked into a shared platform that will promote a model for collaboration among scientists within InTBIR and elsewhere.

In addition to the U.S. award, the European Commission, the executive body of the European Union, has awarded €35.2 million to fund the Collaborative European NeuroTrauma Effectiveness-TBI (CENTER-TBI) consortium, also part of the InTBIR. This project will collect data in over 5,000 patients across Europe, where 38 scientific institutes and more than 60 hospitals will participate.

In Canada, CIHR and its national partners also have made a multimillion dollar investment in TBI research, the details of which will be formally announced in the near future.

The InTBIR Scientific Advisory Committee met in Vancouver, British Columbia, on Oct. 17-18, and awardees from all three jurisdictions (EU, USA, Canada) now are aligning efforts to share resources and collaborate on strategies for achieving the InTBIR goals.

Brain scans show unusual activity in retired American football players

A new study has discovered profound abnormalities in brain activity in a group of retired American football players

Although the former players in the study were not diagnosed with any neurological condition, brain imaging tests revealed unusual activity that correlated with how many times they had left the field with a head injury during their careers.

Previous research has found that former American football players experience higher rates of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The new findings, published in Scientific Reports, suggest that players also face a risk of subtle neurological deficits that don’t show up on normal clinical tests.

Hidden problems

The study involved 13 former National Football League (NFL) professionals who believed they were suffering from neurological problems affecting their everyday lives as a consequence of their careers.

The former players and 60 healthy volunteers were given a test that involved rearranging coloured balls in a series of tubes in as few steps as possible. Their brain activity was measured using functional magnetic resonance imaging (fMRI) while they did the test.

The NFL group performed worse on the test than the healthy volunteers, but the difference was modest. More strikingly, the scans showed unusual patterns of brain activity in the frontal lobe. The difference between the two groups was so marked that a computer programme learned to distinguish NFL alumni and controls at close to 90 per cent accuracy based just on their frontal lobe activation patterns.

“The NFL alumni showed some of the most pronounced abnormalities in brain activity that I have ever seen, and I have processed a lot of patient data sets in the past,” said Dr Adam Hampshire, lead author of the study, from the Department of Medicine at Imperial College London.

The frontal lobe is responsible for executive functions: higher-order brain activity that regulates other cognitive processes. The researchers think the differences seen in this study reflect deficits in executive function that might affect the person’s ability to plan and organise their everyday lives.

“The critical fact is that the level of brain abnormality correlates strongly with the measure of head impacts of great enough severity to warrant being taken out of play. This means that it is highly likely that damage caused by blows to the head accumulate towards an executive impairment in later life.”

Early detection

Dr Hampshire and his colleagues at the University of Western Ontario, Canada suggest that fMRI could be used to reveal potential neurological problems in American football players that aren’t picked up by standard clinical tests. Brain imaging results could be useful to retired players who are negotiating compensation for neurological problems that may be related to their careers. Players could also be scanned each season to detect problems early.

The findings also highlight the inadequacy of standard cognitive tests for detecting certain types of behavioural deficit.

“Researchers have put a lot of time into developing tests to pick up on executive dysfunction, but none of them work at all well. It’s not unusual for an individual who has had a blow to the head to perform relatively well on a neuropsychological testing battery, and then go on to struggle in everyday life.

“The results tell us something very interesting about the human brain, which is that after damage, it can work harder and bring extra areas on line in order to cope with cognitive tasks. It is likely that in more complicated real world scenarios, this plasticity is insufficient and consequently, the executive impairment is no longer masked. In this respect, the results are also of relevance to other patients who suffer from multiple head injuries.

“Of course, this is a relatively preliminary study. We really need to test more players and to track players across seasons using brain imaging.”