Neuroscience

Tests of a new long-acting version of one of the oldest multiple sclerosis (MS) drugs on the market show it worked significantly better than placebo in reducing the number of patient relapses and developments of new or active lesions, researchers report. Most important, they add, the updated version was effective even though injections were given every two weeks instead of every other day, and it appears that fewer patients develop resistance to it.

The industry-funded, international clinical trial led by a Johns Hopkins scientist found that pegylated interferon beta worked far better than placebo for people with the most common form of MS. The beneficial effects seen in this study were comparable to what was found in previous studies in which the standard formulation of interferon beta (which must be taken more frequently) was compared to placebo.

In a report on the trial, published May 1 in The Lancet Neurology, the researchers say they also found that while roughly 20 percent of MS patients typically develop antibodies against the drug that ultimately neutralize its effects, fewer than 1 percent in the new study did, suggesting far more patients could benefit from the new formulation.

“While this isn’t a brand new blockbuster drug, I do think it will improve compliance and tolerability and therefore positively impact the quality of life of people with MS who take interferon beta,” says study leader Peter A. Calabresi, M.D., a professor of neurology at the Johns Hopkins University School of Medicine. “If it gets FDA approval, this new formulation would allow patients to get the same effect, but instead of the burden of injecting themselves every other day, they only have to do it twice a month. For an MS patient, that’s a huge advance.”

“The data are very, very clear,” Calabresi adds. “We can make things easier for our patients without dangerous side effects just by tweaking what we know to be a safe, 20-year-old drug.”

MS is considered an autoimmune disorder, caused when the immune system wrongly attacks a person’s own tissues; in this case, it’s the fatty protein myelin sheath that insulates nerves that send electrical signals to control movement, speech and other functions. The immune system primes so-called T cells in the body’s lymph nodes, preparing them to seek out and destroy myelin, a process that can lead to debilitating symptoms such as blurred vision, weakness and numbness.

In 1993, interferon beta became the first drug federally approved for MS because of its ability to block certain types of immune cell activation and the trafficking of immune cells into the brain. While some studies suggest its effects are modest in controlling MS, Calabresi says it works very well in some patients, overall reducing relapses by one-third and inflammation as measured using MRI by more than two-thirds.

Side effects trouble many patients — including flu-like symptoms that tend to occur in the six to eight hours after each injection — but Calabresi says the drug is safer for routine care than some newer oral medications.

Calabresi says his team was eager to test the new formulation, because many MS patients forgo its benefits because of the frequent injection schedule and side effects.

The new version modifies interferon beta by attaching polyethylene glycol (PEG) polymer chemical chains that stabilize the drug. PEG has been proven safe in other medications, shampoos, toothpaste and moisturizers.

For the study, researchers recruited more than 1,500 subjects with MS from 183 sites in 26 countries. For a year, one-third of patients got a placebo shot every two weeks, one-third got 125 micrograms of pegylated interferon beta shots every two weeks and the third group got 125 micrograms of pegylated interferon beta-1a once a month, with a placebo shot given at every other visit.

After a year, those who got pegylated interferon beta-1a every two weeks experienced a 36 percent reduction in the yearly relapse rate compared to the placebo group; the every-four-week group saw a 28 percent reduction. MRI scans revealed 67 percent fewer new or active lesions in the two-week group, while those injected every four weeks only had 28 percent fewer of those lesions.

Both the two- and four-week groups had 38 percent reduction in disability progression on a scale that measures walking speed, vision, strength and sensation, as compared to a placebo group.

The new formulation appeared just as safe as the older one, though Calabresi says that the flu-like symptoms from the long-acting drug lasted closer to 24 hours after each injection in some patients. He called this a trade-off his patients would deem worthwhile.

Data presented April 29 at the American Academy of Neurology suggests that receiving pegylated interferon beta every two weeks is the best dosing schedule.

Multiple sclerosis researchers have found that brain reserve and cognitive reserve confer a long-term protective effect against cognitive decline.

“Our research aims to answer these questions,” explained Dr. DeLuca. “Why do some people with MS experience disabling symptoms of cognitive decline, while others maintain their cognitive abilities despite neuroimaging evidence of significant disease progression? Can the theories of brain reserve and cognitive reserve explain this dichotomy? Can we identify predictors of cognitive decline?”

In this study, memory, cognitive efficiency, vocabulary (a measure of intellectual enrichment/cognitive reserve), brain volume (a measure of brain reserve), and disease progression on MRI, were evaluated in 40 patients with MS at baseline and at 4.5-year followup. After controlling for disease progression, scientists looked at the impact of brain volume and intellectual enrichment on cognitive decline.

Results supported the protective effects of brain reserve and cognitive reserve,” noted Dr. Sumowski. “Patients with greater intellectual enrichment experienced lesser degrees of cognitive decline. Those with greater brain reserve showed a protective effect for cognitive efficiency. This study not only confirms these protective effects of brain and cognitive reserve, it shows that these beneficial effects persist for years.”

Neuroscientists at Mayo Clinic in Florida have defined a subtype of Alzheimer’s disease (AD) that they say is neither well recognized nor treated appropriately.

The variant, called hippocampal sparing AD, made up 11 percent of the 1,821 AD-confirmed brains examined by Mayo Clinic researchers — suggesting this subtype is relatively widespread in the general population. The Alzheimer’s Association estimates that 5.2 million Americans are living with AD. And with nearly half of hippocampal sparing AD patients being misdiagnosed, this could mean that well over 600,000 Americans make up this AD variant, researchers say.

In an oral presentation at the annual meeting of the American Academy of Neurology in Philadelphia, scientists say hippocampal sparing AD often produces symptoms that are substantially different from the most commonly known form of AD, which affects the hippocampus, the center of memory.

The patients, mostly male, are afflicted at a much younger age, and their symptoms can be bizarre — behavioral problems such as frequent and sometimes profane angry outbursts, feelings that their limbs do not belong to them and are controlled by an “alien” unidentifiable force, or visual disturbances in the absence of eye problems, researchers say.

They also decline at a much faster rate than do patients with the most common form of AD.

“Many of these patients, however, have memories that are near normal, so clinicians often misdiagnose them with a variety of conditions that do not match the underlying neuropathology,” says the study’s lead author, Melissa Murray, Ph.D., an assistant professor of neuroscience at Mayo Clinic in Florida.

Many of these patients are diagnosed with frontotemporal dementia, a disorder characterized by changes in personality and social behavior, or corticobasal syndrome, characterized by movement disorders and cognitive dysfunction. Language dysfunction is also more common in hippocampal sparing AD, although patients do not have vocal or hearing deficits.

“What is tragic is that these patients are commonly misdiagnosed and we have new evidence that suggests drugs now on the market for AD could work best in these hippocampal sparing patients — possibly better than they work in the common form of the disease,” Dr. Murray says.

The researchers benefit greatly from one of the largest brain banks in the country — more than 6,500 brain donations — as well as a collaborative environment between neuroscience research and neurology at Mayo Clinic, she says.

Both hallmark proteins of AD — amyloid beta (Aβ), which forms Aβ plaques, and tau, which produces tangles — are found across all subtypes of AD, including hippocampal sparing AD. The researchers developed a mathematical algorithm to classify AD subtypes using tangle counts. “What is fascinating is that all the AD patient subtypes had the same amount of amyloid, but for some reason tau tangles were found in strategic cortical regions disproportionate to the hippocampus.”

In these patients, tau preferentially damages and eventually destroys neurons in parts of the brain involved in behavior, motor awareness and recognition, as well as use of speech and vision, Dr. Murray says.

She says she hopes this research, the second high-profile Mayo study to highlight hippocampal sparing AD, will “open the minds” of clinicians who are trying to diagnose dementia, helping them understand that loss of memory is not present in every AD patient.

“Our studies support the notion that dementia related to AD does not necessarily equate to a loss of memory, and points to the need for more research in amyloid and tau imaging biomarkers to help clinicians accurately diagnose AD — regardless of subtype,” Dr. Murray says.

A new study has provided insight into the behavioral damage caused by repeated blows to the head. The research provides a foundation for scientists to better understand and potentially develop new ways to detect and prevent the repetitive sports injuries that can lead to the condition known as chronic traumatic encephalopathy (CTE).

The research – which appears online this week in the Journal of Neurotrauma – shows that mice with mild, repetitive traumatic brain injury (TBI) develop many of the same behavioral problems, such as difficultly sleeping, memory problems, depression, judgment and risk-taking issues, that have been associated with the condition in humans.

One of the barriers to potential treatments for TBI and CTE is that no model of the disease exists. Animal equivalents of human diseases are a critical early-stage tool in the scientific process of understanding a condition, developing new ways to diagnose it, and evaluating experimental therapies. 

“This new model captures both the clinical aspects of repetitive mild TBI and CTE,” said Anthony L. Petraglia, M.D., a neurosurgeon with the University of Rochester School of Medicine and Dentistry and lead author of the study. “While public awareness of the long-term health risk of blows to the head is growing rapidly, our ability to scientifically study the fundamental neurological impact of mild brain injuries has lagged.”

There has been a great deal of discussion in recent years regarding concussions as a result of blows to the head in sports. An estimated 3.8 million sports-related concussions occur every year. Mild traumatic brain injury is also becoming more common in military personnel deployed in combat zones. Over time, the frequency and degree of these injuries can lead short and long-term neurological impairment and, in extreme examples, to CTE, a form of degenerative brain disease. 

The experiments described in the study were designed in a manner that simulates the type of mild TBI that may occur in sports or other blows to the head. The researchers evaluated the mice’s performance in a series of tasks designed to measure behavior. These included tests to measure spatial and learning memory, anxiety and risk-taking behavior, the presence of depression-like behavior, sleep disturbances, and the electrical activity of their brain. The mice with repetitive mild TBI did poorly in every test and this poor performance persisted over time.

“These results resemble the spectrum of neuro-behavioral problems that have been reported and observed in individuals who have sustained multiple mild TBI and those who were subsequently diagnosed with CTE, including behaviors such as poor judgment, risk taking, and depression,” said Petraglia.  

Petraglia and his colleagues also used the model to examine the damage that was occurring in the brains of the mice over time. The results, which will be published in a forthcoming paper, provide insight on the interaction between the brains repair mechanisms – in the forms of astrocytes and microglia – and the protein tau, which can have a toxic effect when triggered by mild traumatic brain injury. 

“Undoubtedly further work is needed,” said Petraglia. “However, this study serves as a good starting point and it is hoped that with continued investigation this novel model will allow for a controlled, mechanistic analysis of repetitive mild TBI and CTE in the future, because it is the first to encapsulate the spectrum of this human phenomenon.”

You know what you’re going to say before you say it, right? Not necessarily, research suggests. A study from researchers at Lund University in Sweden shows that auditory feedback plays an important role in helping us determine what we’re saying as we speak. The study is published in Psychological Science, a journal of the Association for Psychological Science.

“Our results indicate that speakers listen to their own voices to help specify the meaning of what they are saying,” says researcher Andreas Lind of Lund University, lead author of the study.

Theories about how we produce speech often assume that we start with a clear, preverbal idea of what to say that goes through different levels of encoding to finally become an utterance.

But the findings from this study support an alternative model in which speech is more than just a dutiful translation of this preverbal message:

“These findings suggest that the meaning of an utterance is not entirely internal to the speaker, but that it is also determined by the feedback we receive from our utterances, and from the inferences we draw from the wider conversational context,” Lind explains.

For the study, Lind and colleagues recruited Swedish participants to complete a classic Stroop test, which provided a controlled linguistic setting. During the Stroop test, participants were presented with various color words (e.g., “red” or “green”) one at a time on a screen and were tasked with naming the color of the font that each word was printed in, rather than the color that the word itself signified.

The participants wore headphones that provided real-time auditory feedback as they took the test — unbeknownst to them, the researchers had rigged the feedback using a voice-triggered playback system. This system allowed the researchers to substitute specific phonologically similar but semantically distinct words (“grey”, “green”) in real time, a technique they call “Real-time Speech Exchange” or RSE.

Data from the 78 participants indicated that when the timing of the insertions was right, only about one third of the exchanges were detected.

On many of the non-detected trials, when asked to report what they had said, participants reported the word they had heard through feedback, rather than the word they had actually said. Because accuracy on the task was actually very high, the manipulated feedback effectively led participants to believe that they had made an error and said the wrong word.

Overall, Lind and colleagues found that participants accepted the manipulated feedback as having been self-produced on about 85% of the non-detected trials.

Together, these findings suggest that our understanding of our own utterances, and our sense of agency for those utterances, depend to some degree on inferences we make after we’ve made them.

Most surprising, perhaps, is the fact that while participants received several indications about what they actually said — from their tongue and jaw, from sound conducted through the bone, and from their memory of the correct alternative on the screen — they still treated the manipulated words as though they were self-produced.

This suggests, says Lind, that the effect may be even more pronounced in everyday conversation, which is less constrained and more ambiguous than the context offered by the Stroop test.

“In future studies, we want to apply RSE to situations that are more social and spontaneous — investigating, for example, how exchanged words might influence the way an interview or conversation develops,” says Lind.

“While this is technically challenging to execute, it could potentially tell us a great deal about how meaning and communicative intentions are formed in natural discourse,” he concludes.

When police in Spain tried to locate two murder victims last year, they sought assistance on places to search from a tool that measured the brain activity of the convicted and confessed killers.

The technology, known as Brain Fingerprinting, developed by the American-based company Government Works Inc., basically seeks to use brain wave data in response to certain stimuli or details to determine whether a person is telling the truth. U.S. courts have sparingly allowed the higher-tech version of the traditional polygraph test or lie detector, and it has aided in both exoneration and conviction in American cases.

As the use of Brain Fingerprinting has expanded beyond the United States, a University of Kansas researcher argues the technology is based on an incorrect assumption about how human memory works.

"At the very least, we need to ask them to do several more methodological checks and make sure that whenever these technologies are used in legal contexts, we make clear the limitations of that technology," said Sarah Robins, an assistant professor of philosophy who studies the philosophy of neuroscience and related issues in neuroethics. “Maybe there’s a stronger claim here that this should never make it into court, but my stance is to say: ‘Let’s think about the technology and the assumptions behind it.’”

Robins details the theoretical issues surrounding Brain Fingerprinting in her essay “Memory Traces, Memory Errors, and the Possibility of Neural Lie Detection,” which will appear in “Brain Theory,” edited by Charles Wolfe. Also in Wolfe’s book, John Symons, a KU professor of philosophy, has co-authored the chapter “Computing with Bodies: Morphology, Function, and Computational Theory.”

Wolfe, a research fellow of the Department of Philosophy and Moral Sciences at the University of Ghent in Belgium, is scheduled to speak at 7 p.m. Friday, May 2, at the Kansas Room of the Kansas Union.

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Scientists’ inability to replicate research findings using mice and rats has contributed to mounting concern over the reliability of such studies.

Now, an international team of pain researchers led by scientists at McGill University in Montreal may have uncovered one important factor behind this vexing problem: the gender of the experimenters has a big impact on the stress levels of rodents, which are widely used in preclinical studies.

In research published online April 28 in Nature Methods, the scientists report that the presence of male experimenters produced a stress response in mice and rats equivalent to that caused by restraining the rodents for 15 minutes in a tube or forcing them to swim for three minutes. This stress-induced reaction made mice and rats of both sexes less sensitive to pain.

Female experimenters produced no such effects.

“Scientists whisper to each other at conferences that their rodent research subjects appear to be aware of their presence, and that this might affect the results of experiments, but this has never been directly demonstrated until now,” says Jeffrey Mogil, a psychology professor at McGill and senior author of the paper.

The research team, which included pain experts from Haverford College and the Karolinska Institutet in Sweden and a chemosensory expert from Université de Montreal, found that the effect of male experimenters on the rodents’ stress levels was due to smell. This was shown by placing cotton T shirts, worn the previous night by male or female experimenters, alongside the mice; the effects were identical to those caused by the presence of the experimenters, themselves.

Further experiments proved that the effects were caused by chemosignals, or pheromones, that men secrete from the armpit at higher concentrations than women. These chemosignals signal to rodents the presence of nearby male animals. (All mammals share the same chemosignals).

These effects are not limited to pain. The researchers found that other behavioural assays sensitive to stress were affected by male but not female experimenters or T-shirts.

“Our findings suggest that one major reason for lack of replication of animal studies is the gender of the experimenter – a factor that’s not currently stated in the methods sections of published papers,” says Robert Sorge, a psychology professor at the University of Alabama, Birmingham. Sorge led the study as a postdoctoral fellow at McGill.

The good news, Mogil says, is that “the problem is easily solved by simple changes to experimental procedures. For example, since the effect of males’ presence diminishes over time, the male experimenter can stay in the room with the animals before starting testing.  At the very least, published papers should state the gender of the experimenter who performed the behavioral testing.”

Experimental studies have shown that deep brain stimulation (DBS) within the subcallosal cingulate (SCC) white matter of the brain is an effective treatment for many patients with treatment-resistant depression. Response rates are between 41 percent and 64 percent across published studies to date. One of the proposed mechanisms of action is through modulation of a network of brain regions connected to the SCC. Identifying the critical connections within this network for successful antidepressant response is an important next step.  

A new study using MRI analysis of the white matter connections examined the architecture of this network in patients who demonstrated significant response to SCC DBS. Researchers found that all responders showed a common pattern defined by three distinct white matter bundles passing through the SCC. Non-responders did not show this pattern.

The study is published online in the journal Biological Psychiatry, with the title “Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.”

"This study shows that successful DBS therapy is not due solely to local changes at the site of stimulation but also in those regions in direct communication with the SCC," says Helen Mayberg, MD, senior author of the article, professor of psychiatry, neurology and radiology and the Dorothy C. Fuqua Chair in Psychiatric Imaging and Therapeutics at Emory University School of Medicine.

"Precisely delineating these white matter connections appears to be very important to a successful outcome with this procedure. From a practical point of view, these results may help us to choose the optimal contact for stimulation and eventually to better plan the surgical placement of the DBS electrodes."

Led by researchers at Emory University, Case Western Reserve University and Dartmouth University, the study included 16 patients with treatment-resistant depression who previously received SCC DBS at Emory. Computerized tomography was used post-operatively to localize the DBS contacts on each electrode. The activation volumes around the active contacts were modeled for each patient. Sophisticated neuroimaging combined with computerized analysis was used to derive and visualize the specific white matter fibers affected by ongoing DBS.

Therapeutic outcome was evaluated at six months and at two years. Six of the patients had responded positively to DBS at six months, and by two years these six plus six more patients responded positively. All shared common involvement of three distinct white matter bundles: the cingulum, the forceps minor and the uncinate fasciculus.

The conversion of six of the patients who were not responding at six months to being responders at two years was explained by the inclusion of all three bundles due to changes in stimulation settings. Non-responders at both six months and two years showed incomplete involvement of these three tracts. 

"In the past, placement of the electrode relied solely on anatomical landmarks with contact selection and stimulation parameter changes based on a trial-and-error method," says Patricio Riva-Posse, MD, Emory assistant professor of psychiatry and behavioral sciences and first author of the paper. "These results suggest that clinical outcome can be significantly influenced by optimally modulating the response network defined by tractography. This obviously will need to be tested prospectively in additional subjects here and by other teams exploring the use of this experimental treatment."

This new information will allow us to develop a refined algorithm for guiding surgical implantation of electrodes and optimizing the response through fine tuning of stimulation parameters,” notes Mayberg. “That said, improving anatomical precision alone doesn’t account for all non-responders, so that is an important next focus of our research.”

The researchers now plan to study DBS therapy in a prospective protocol of similar treatment-resistant depressed patients, using presurgical mapping of an individual patient’s network structure, precisely targeting the three SCC fiber bundles, and systematically testing the stimulation contacts.

A brain area activated by group decisions can distinguish people more likely to conform to the will of a group, say researchers from UCL.

The team, led by Dr Tali Sharot, UCL Affective Brain Lab, monitored the brain activity of individuals in groups of five people choosing food or drink they’d like to consume before and after being told the most popular choice in their group.

The results showed that people were likely to conform to the most popular choice in their group if their original preference was different.

Caroline Charpentier (UCL Institute of Cognitive Neuroscience) said: “Most people don’t think their everyday decisions, such as having eggs on toast for breakfast or a pint of lager at the pub, are influenced by other people’s preferences.”

She added: “But our results suggest that when other people make different choices than you, for example your friends order beer while you order wine, your brain records this information and this signal is mirrored in your brain later on, for example when you order another drink, making you more likely to choose beer, even if you initially preferred wine”.

The team, led by Dr Tali Sharot, used functional magnetic resonance imaging (fMRI) to monitor the brain responses of 20 volunteers during a decision-making task, while 78 more volunteers completed the task simultaneously on computers located outside the MRI room. They came to the lab in small groups of five.

In one session, volunteers were shown 60 pairs of food and drink items and asked to select which item of each pair they would prefer to consume at the end of the experiment. Straight after making this choice, the participants were told which item most people in their group selected. This part of the experiment provided the volunteers with social feedback.

Volunteers then took part in a following session a few minutes later, when they opted again for which item they would prefer to consume from the same series of pairs, but this time made the choice for themselves and did not receive any social feedback.  

After the experiment, the participants completed a personality questionnaire that assessed trait conformity, which measures their general tendency to follow other people’s ideas and behaviours. Comparison of results from the choice experiment and conformity questionnaire indeed showed that people who scored high on trait conformity were about twice as likely to change their food choices to agree with the group decision as people who scored low for conformity.

What differed between the brains of people who were more likely to conform and people who held on to their own opinion?

The imaging study showed that the orbito-frontal cortex (OFC) – a region at the front of the brain that has been associated with emotional and social behaviour – was active during the two choice sessions and distinguished between these two groups of people.

Miss Charpentier said: “The orbito-frontal cortex was the only region specifically activated, and the first area to react to group disagreement. This region was activated both at the time of the initial social conflict (when your friends all choose beer while you prefer wine) and also later when you make an individual choice (when you order another drink for yourself).”

The OFC has previously been associated with emotions and social behaviour. Some clinical studies have suggested that people with brain damage in the OFC may behave inappropriately in groups.

Miss Charpentier concluded: “When OFC activity during the initial social conflict is mirrored in your brain at a later time when you make an individual choice, you are more likely to change your choice and follow the group. This is what happens in ‘high conformers’. In other words, it is the temporal dynamics of the OFC that distinguishes “conformers” from people who hold on to their own initial opinion”.

Each year, approximately 2 million traumatic brain injuries (TBIs) occur in the USA, according to the Centers for Disease Control and Prevention. That number includes troops wounded in Iraq and Afghanistan, for whom TBI is considered an invisible wound of war, one that has few successful treatments. “We have nothing beyond ibuprofen for most TBIs,” said Dr. Angus Scrimgeour, who has been investigating the effects of low zinc diets on cell stress following a blast injury. “The adult brain does not self-repair from this kind of trauma.”

Scrimgeour works for the US Army Research Institute of Environmental Medicine and recently looked at the effects of 5-weeks of low and adequate zinc diets on a specific protein in muscle cells called MMP. The study recreated blast injuries in 32 rats similar to what soldiers experience from IEDs, including loss of consciousness. An equal number of rats served as a control group. Results suggest that zinc supplementation reduces blast-induced cell stress. He presented the results of his research at the American Society for Nutrition’s Scientific Sessions & Annual Meeting at EB on Sunday, April 27.

“We know that soldiers’ brain tissue cannot repair on low zinc diets,” said Scrimgeour. “And they are losing zinc through diarrhea and sweating.” The question moving forward is whether prevention through diet supplementation or post-blast treatment works best to repair behavioral deficits associated with mild TBI.

Scrimgeour added that further research is planned to investigate nutrient combinations for treating mild TBI, including omega-3, vitamin D, glutamine and/or zinc. Although the Army is conducting this research, the results can be applied outside of the military, according to Scrimgeour. “As the blast impact experienced by Soldiers are similar to those experienced during head injuries received in a car accident or during an NFL concussion, these findings could translate from the Soldier to the civilian population.” Scrimgeour cautioned, however, that what works in animals doesn’t always work in soldiers, which is why more research is needed.

Almost half of all homeless men who took part in a study by St. Michael’s Hospital had suffered at least one traumatic brain injury in their life and 87 per cent of those injuries occurred before the men lost their homes.

While assaults were a major cause of those traumatic brain injuries, or TBIs, (60 per cent) many were caused by potentially non-violent mechanisms such as sports and recreation (44 per cent) and motor vehicle collisions and falls (42 per cent).

The study, led by Dr. Jane Topolovec-Vranic, a clinical researcher in the hospital’s Neuroscience Research Program, was published in the journal CMAJ Open.

Dr. Topolovec-Vranic said it’s important for health care providers and others who work with homeless people to be aware of any history of TBI because of the links between such injuries and mental health issues, substance abuse, seizures and general poorer physical health.

The fact that so many homeless men suffered a TBI before losing their home suggests such injuries could be a risk factor for becoming homeless, she said. That makes it even more important to monitor young people who suffer TBIs such as concussions for health and behavioural changes, she said.

Dr. Topolovec-Vranic looked at data on 111 homeless men aged 27 to 81 years old who were recruited from a downtown Toronto men’s shelter. She found that 45 per cent of these men had experienced a traumatic brain injury, and of these, 70 per cent were injured during childhood or teenage years and 87 per cent experienced an injury before becoming homeless.

In men under age 40, falls from drug/alcohol blackouts were the most common cause of traumatic brain injury while assault was the most common in men over 40 years old.

Recognition that a TBI sustained in childhood or early teenage years could predispose someone to homelessness may challenge some assumptions that homelessness is a conscious choice made by these individuals, or just the result of their addictions or mental illness, said Dr. Topolovec-Vranic.

This study received funding from the Canadian Institutes of Health Research and the Ontario Neurotrauma Foundation.

Separately, a recent study by Dr. Stephen Hwang of the hospital’s Centre for Research on Inner City Health, found the number of people who are homeless or vulnerably housed and who have also suffered a TBI may be as high as 61 per cent—seven times higher than the general population.

Dr. Hwang’s study, published in the Journal of Head Trauma Rehabilitation, is one of the largest studies to date investigating TBI in homeless populations. The findings come from the Health and Housing in Transition Study, which tracks the health and housing status of homeless and vulnerably housed people in Toronto, Vancouver and Ottawa.

Methylphenidate, also known as Ritalin, may prevent the depletion of self-control, according to research published in Psychological Science, a journal of the Association for Psychological Science.

Self-control can be difficult — sticking with a diet or trying to focus attention on a boring textbook are hard things to do. Considerable research suggests one potential explanation for this difficulty: Exerting self-control for a long period seems to “deplete” our ability to exert self-control effectively on subsequent tasks.

“It is as if self-control is a limited resource that ‘runs out’ if it is used too much,” says lead researcher Chandra Sripada of the University of Michigan. “If we could figure out the brain mechanisms that cause regulatory depletion, then maybe we could find a way to prevent it.”

Previous research has implicated the neurotransmitters dopamine and norepinephrine in regulatory processing. Sripada and University of Michigan collaborators Daniel Kessler and John Jonides decided to see whether manipulating levels of these transmitters might affect regulatory depletion.

The researchers tested 108 adult participants, all of whom took a drug capsule 60 minutes prior to testing. Half of the participants received a capsule that contained methylphenidate, a medication used to treat ADHD that increases brain dopamine and norepinephrine. The other half received a placebo capsule. The study was double-blind, so neither the participants nor the researchers knew at the time of testing who had received which capsule.

The participants then completed a computer-based task in which they were required to press a button when a word containing the letter e appeared on screen. Some were given modified instructions that asked them to refrain from pressing the button if the letter e was next to or one extra letter away from another vowel — this version of the task was designed to tax participants’ self-control.

All of the participants then completed a second computer task aimed at testing their ability to process competing information and exert regulatory control in order to make a correct response.

In line with the researchers’ hypotheses, participants who received the placebo and performed the taxing version of the first task showed greater variability in how quickly they responded in the second task, compared to those whose self-control hadn’t been depleted in the first task.

But for those participants who took the methylphenidate capsule, the first task didn’t have an effect on later performance — the methylphenidate seemed to counteract the self-regulatory depletion incurred by the harder version of the first task.

“These results indicate that depletion of self-control due to prior effort can be fully blocked pharmacologically,” says Sripada. “The task we give people to deplete their self-control is pretty cognitively demanding, so we were surprised at how effective methylphenidate was in blocking depletion of self-control.”

Sripada and colleagues suggest that methylphenidate may help to boost performance of the specific circuits in the brain’s prefrontal cortex that are normally compromised after sustained exertion of self-control.

This doesn’t mean, however, that those of us looking to boost our self-control should go out and get some Ritalin:

“Methylphenidate is a powerful psychotropic medicine that should only be taken with a prescription,” says Sripada. “We want to use this research to better understand the brain mechanisms that lead to depletion of self-control, and what interventions — pharmacological or behavioral — might prevent this.”

With a new generation of military veterans returning home from Iraq and Afghanistan, post-traumatic stress disorder (PTSD) has become a prominent concern in American medical institutions and the culture at-large. Estimates indicate that as many as 35 percent of personnel deployed to Iraq and Afghanistan suffer from PTSD. New research from the University of South Carolina School of Medicine is shedding light on how PTSD is linked to other diseases in fundamental and surprising ways.

The rise in PTSD has implications beyond the impact of the psychiatric disorder and its immediate consequences, which include elevated suicide risk and inability to lead a normal life, that result in approximately $3 billion in lost productivity every year. Over time, these PTSD patients will continue to experience increased risks of a myriad of medical conditions like cardiovascular disease, diabetes, gastrointestinal disease, fibromyalgia, musculoskeletal disorders and others, all of which share chronic inflammation as a common underlying cause.

The mechanisms that trigger PTSD, and that cause PTSD patients to suffer from higher rates of chronic-inflammation-related medical conditions remain unknown. Additionally, PTSD is incurable, and though there are available treatments, they are often not completely effective. In an effort to get to the root of PTSD, and begin to understand the links between PTSD and the secondary diseases that often come with it, a team at the University of South Carolina School of Medicine is investigating PTSD through the lens of inflammation. They have recently published findings of a new study, “Dysregulation in microRNA Expression is Associated with Alterations in Immune Functions in Combat Veterans with Post-traumatic Stress Disorder,” in the journal PLOS ONE.

In this study, led by Drs. Prakash Nagarkatti and Mitzi Nagarkatti, the authors investigated microRNA profiles and tried to establish a link between the microRNA and inflammation in combat veterans of the Persian Gulf, Iraq and Afghanistan wars who are PTSD patients at the Dorn VA Medical Center. MicroRNA are small, noncoding RNA that can switch human genes on and off, effectively controlling gene expression. Some specific types of microRNA are known to regulate genes involved in inflammation, making them a kind of marker that can indicate when inflammation is present.

The microRNA role in PTSD has not been investigated previous to this study, which found that the PTSD patients had significant alterations in microRNA expression. The study analyzed 1163 microRNA and found that the expression of microRNA that regulate genes involved in inflammation were altered in PTSD patients. The alterations were found to be linked to heightened inflammation in these patients.

Dr. Mitzi Nagarkatti sums up the significance of this study as follows: “We are very excited about these results. Thus far, no one had looked at the role of microRNA in the blood of PTSD patients. Thus, our finding that the alterations in these small molecules are connected to higher inflammation seen in these patients is very interesting and helps establish the connection between war trauma and microRNA changes.”

In addition to the alterations in microRNA expression, the study also found that PTSD patients had higher levels of inflammation caused by certain types of immune cells called T cells. These T cells produced higher levels of inflammatory mediators called cytokines, specifically interferon-gamma and interleukin-17. This finding was especially interesting because one of the inflammation-associated microRNAs, miR-125a, which specifically targets increased production of interferon-gamma, was found to have decreased expression in the PTSD patients studied. Overall, these results suggested that trauma may cause alterations in the expression of microRNA which promote inflammation in PTSD patients.

Commenting on this, Dr. Prakash Nagarkatti said, “These studies form the foundation to further analyze the role of microRNA in PTSD. Trauma experienced during war may trigger changes in microRNA which may in turn cause various clinical disorders seen in PTSD patients. Our long-term goal is to identify whether PTSD patients express a unique signature profile of microRNA which can be used towards early detection, prevention and treatment of PTSD.”

Researchers at Aarhus University, Denmark, have drawn up the most detailed ‘image of the enemy’ to date of one of the body’s most important players in the development of Parkinson’s disease. This provides much greater understanding of the battle taking place when the disease occurs – knowledge that is necessary if we are to understand and treat Parkinsonism. However, it also raises an existential question because part of the conclusion is that we do not live forever!

Parkinson’s disease is one of the most common neurological disorders, with about 7000 people suffering from the disease in Denmark alone. There is no cure, and the symptoms continue to get worse. The disease occurs because different nerves in the brain die. These include the nerve cells that form dopamine, which is known as the brain’s ‘reward substance’ and which also helps control our fine motor skills.

A group of researchers from Aarhus University, the University of Southern Denmark (SDU) and the University of Cambridge has just published two studies in the prestigious Journal of the American Chemical Society (JACS) and Angewandte Chemie. These studies provide the best insight to date into the behaviour of a particular protein state that plays an important role in Parkinson’s disease. In other words, they have created a detailed image of what is presumed to be the arch enemy we are up against in our understanding of Parkinsonism. It is an advanced antagonist, and one that functions with a considerable degree of unpredictability. “Fighting the enemy is by no means a Sunday outing,” say the main authors of the results – Professor Daniel Otzen, Aarhus University, and his colleagues Nikolai Lorenzen and Wojciech Paslawski, who recently defended their PhD dissertations on this subject at Aarhus University’s Interdisciplinary Nanoscience Centre (iNANO).

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Scientists have known that abnormal brain growth is associated with autism spectrum disorder. However, the relationship between the two has not been well understood.

(Image: Thinkstock)

Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that mutations in a specific gene that is disrupted in some individuals with autism results in too much growth throughout the brain, and yet surprisingly specific problems in social interactions, at least in mouse models that mimic this risk factor in humans.

“What was striking is that these were basically normal animals in terms of behavior, but there were consistent deficits in tests of social interaction and recognition—which approximate a major symptom of autism,” said Damon Page, a TSRI biologist who led the study. “This suggests that when most parts of the brain are overgrown, the brain somehow adapts to it with minimal effects on behavior in general. However, brain circuits relevant to social behavior are more vulnerable or less able to tolerate this overgrowth.”

The study, which focuses on the gene phosphatase and tensin homolog (PTEN), was recently published online ahead of print by the journal Human Molecular Genetics.

Autism spectrum disorder is a neurodevelopmental disorder involving a range of symptoms and disabilities involving social deficits and communication difficulties, repetitive behaviors and interests, and sometimes cognitive delays. The disorder affects in approximately one percent of the population; some 80 percent of those diagnosed are male.

In a previous study, Page and colleagues found that mutations in Pten causes increased brain size and social deficits, with both symptoms being exacerbated by a second “hit” to a gene that regulates levels of the neurotransmitter serotonin in the brain. In the new study, the TSRI team set out to explore whether mutations in Pten result in widespread or localized overgrowth within the brain, and whether changes in brain growth are associated with broad or selective deficits in tests of autism-relevant behaviors in genetically altered mice. The team tested mice for autism spectrum disorder-related behaviors including mood, anxiety, intellectual, and circadian rhythm and/or sleep abnormalities.

The researchers found that Pten mutant mice showed altered social behavior, but few other changes—a more subtle change than would have been predicted given broad expression and critical cellular function of the gene.

Intriguingly, some of the more subtle impairments were sex-specific. In addition to social impairments, males with the mutated gene showed abnormalities related to repetitive behavior and mood/anxiety, while females exhibited additional circadian activity and emotional learning problems.

The results raise the question of how mutations in PTEN, a general regulator of growth, can have relatively selective effects on behavior and cognitive development. One idea is that PTEN mutations may desynchronize the normal pattern of growth in key cell types—the study points to dopamine neurons—that are relevant for social behavior.

“Timing is everything,” Page said. “Connections have to form in the right place at the right time for circuits to develop normally. Circuitry involved in social behavior may turn out to be particularly vulnerable to the effects of poorly coordinated growth.”

A new study suggests that targeting B cells, which are a type of white blood cell in the immune system, may be associated with reduced disease activity for people with multiple sclerosis (MS). The study is released today and will be presented at the American Academy of Neurology’s 66th Annual Meeting in Philadelphia, April 26 to May 3, 2014.

For the study, 231 people with relapsing-remitting MS received either a placebo or one of several low dosages of the drug ofatumumab, which is an anti-B cell antibody, for 24 weeks, with the first 12 weeks making up the placebo-controlled period. The main objective was to determine the effects of ofatumumab dosing regimens compared to placebo on the total number of new brain lesions assessed every four weeks over a 12-week period.

All dose groups including placebo showed lesion activity in the first four weeks with lesion suppression in all ofatumumab dose groups from weeks four to12. Researchers measured the amount of B cells in participants and compared that to the total number of new brain lesions that appeared on brain scans, which is a marker of disease activity.

The researchers found that when B cells were reduced to below a threshold of 64 cells per microliter, disease activity, as measured by appearance of new brain lesions, was significantly reduced. On average, participants had an annualized rate of less than one new brain lesion per year when B cells were maintained below a threshold of 32 to 64 cells per microliter, compared with 16 lesions without treatment.

The most common side effects, defined as those occurring in at least five percent of participants and at a rate twice that of placebo for weeks zero to12, were injection-related reaction, dizziness, anxiety, fever, respiratory tract infection and nerve pain.

Study author Daren Austin, PhD, of GlaxoSmithKline in Uxbridge, United Kingdom, and a member of the American Academy of Neurology, said the study results also suggest that peripheral, rather than central, B cells may be the most relevant target for anti-B cell therapy.

“These results need to be validated, of course, but the findings are interesting,” Austin said. “They provide new insight into the mechanism of B cells in MS and present a possible new target threshold for exploring the potential benefit of anti-B cell therapy.” Ofatumumab is not approved anywhere in the world for use in the treatment of multiple sclerosis.

Ellen’s (not her real name) adoptive parents weren’t surprised when the school counselor suggested that she might have attention deficit hyperactivity disorder (ADHD).

Several professionals had made this suggestion over the years. Given that homework led to one explosion after another, and that at school Ellen, who is eleven, spent her days jiggling up and down in her seat, unable to concentrate for more than ten minutes, it seemed a reasonable assumption. Yet her parents always felt that ADHD didn’t quite capture the extent of Ellen’s issues over the years. Fortunately the school counsellor was familiar with fetal alcohol spectrum disorder (FASD). When she learned that Ellen’s birth mother had consumed alcohol during pregnancy, she raised the possibility that Ellen’s problems could be attributable to FASD and referred her for further assessment.

It’s a familiar story, and most of us reading about Ellen would assume that she did indeed suffer from ADHD.

But now researchers from McGill have suggested that there may be an overreporting of attention problems in children with FASD, simply because parents and teachers are using a misplaced basis for comparison. They are testing and comparing children with FASD with children of the same physical or chronological age, rather than with children of the same mental age, which is often quite a lot younger.

“Because the link between fetal alcohol syndrome and ADHD is so commonly described in the literature, both parents and teachers are more likely to expect these children to have attention problems,” says Prof. Jacob Burack, a professor in McGill’s Dept. of Educational and Counselling Psychology and the senior author on a recent study on the subject. “But what teachers often don’t recognize is that although the child they are dealing with is eleven years old in chronological terms, they are actually functioning at the developmental age of an eight-year old. That’s a pretty big difference. And when you use mental age as the basis of comparison, many of the attention problems that have been described in children with FASD no longer seem of primary importance.”

The researchers recruited children with FASD whose average chronological age was just under twelve years old. But their average mental age, determined by standard tests, was actually closer to nine-and-a-half years old. (The children were recruited through the Asante Centre for Fetal Alcohol Syndrome in British Columbia, and though the number of children studied may appear small, this is a fairly typical size for studies on FASD, given the difficulties of the diagnostic process.)

These children were then compared with children who were developing typically and whose average chronological age was about eight-and-a-half years old and whose average mental age was similar to that of the group of children diagnosed with FASD.

After using tests to measure specific aspects of attention, the researchers then compared the performance of children with FASD on these tests with the results of children of the same mental age. What they found was that while children like Ellen had difficulties with certain kinds of attention skills, notably in terms of shifting attention from one object to another, there were other areas, such as focus, where they had no significant difficulties at all. So, if we were to compare these aspects of attention to a hockey game, typically these children would have no difficulty focusing on the puck in the arena, but would have problems following the puck being passed from one player to another.

This suggests to Dr. Kimberly Lane, the PhD student who conducted the research, that there is a need to develop a more nuanced understanding of attention skills. “We use words like attention loosely, but it’s really an umbrella term that covers various aspects of attending to different people or events or environments,” says Dr. Lane. “By using more complex assessment techniques of various aspects of attention it will be possible to get a better picture of the attention difficulties faced by children with FASD,” she adds.

“But no matter what the tests say, it’s important for teachers and parents to understand that.the difficulties these children have with attention may be less important than their more general problems, and we need to work with them as they are.”

Johns Hopkins researchers report that they have identified a protein essential to the formation of the tiny brain region in mice that coordinates sleep-wake cycles and other so-called circadian rhythms.

(Image caption: An illustration of the activity patterns of normal mice (left). An illustration of the activity patterns mice whose “master clock,” or SCN, has been disrupted (right). Credit: Cell Reports, Bedont et al.)

By disabling the gene for that key protein in test animals, the scientists were able to home in on the mechanism by which that brain region, known as the suprachiasmatic nucleus or SCN, becomes the body’s master clock while the embryo is developing.

The results of their experiments, reported in the tk issue of Cell Reports, are an important step toward understanding how to better manage the disruptive effects experienced by shift workers, as well as treatment of people with sleep disorders, the researchers say.

“Shift workers tend to have higher rates of diabetes, obesity, depression and cancer. Many researchers think that’s somehow connected to their irregular circadian rhythms, and thus to the SCN,” says Seth Blackshaw, Ph.D., an associate professor in the Department of Neuroscience and the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. “Our new research will help us and other researchers isolate the specific impacts of the SCN on mammalian health.”

Blackshaw explains that every cell in the body has its own “clock” that regulates aspects such as its rate of energy use. The SCN is the master clock that synchronizes these individual timekeepers so that, for example, people feel sleepy at night and alert during the day, are hungry at mealtimes, and are prepared for the energy influx that hits fat cells after eating. “A unique property of the SCN is that if its cells are grown in a dish, they quickly synchronize their clocks with each another,” Blackshaw says.

But while evidence like this gave researchers an idea of the SCN’s importance, they hadn’t completely teased its role apart from that of the body’s other clocks, or from other parts of the brain.

The Johns Hopkins team looked for ways to knock down SCN function by targeting and disabling certain genes that disrupt only the formation of the SCN clock. They analyzed which genes were active in different areas of developing mouse brains to identify those that were “turned on” only in the SCN. One of the “hits” was Lhx1, a member of a family of genes whose protein products affect development by controlling the activity of other genes. When the researchers turned off Lhx1 in the SCN of mouse embryos, the grown mice lacked distinctive biochemical signatures seen in the SCN of normal mice.

The genetically modified mice behaved differently, too. Some fell into a pattern of two to three separate cycles of sleep and activity per day, in contrast to the single daily cycle found in normal mice, while others’ rhythms were completely disorganized, Blackshaw says. Though an SCN is present in mutant mice, it communicates poorly with clocks elsewhere in the body.

Blackshaw says he expects that the mutant mice will prove a useful tool in finding whether disrupted signaling from the SCN actually leads to the health problems that shift workers experience, and if so, how this might happen. Although mouse models do not correlate fully to human disease, their biochemical and genetic makeup is closely aligned.

Blackshaw’s team also plans to continue studying the biochemical chain of events surrounding the Lhx1 protein to determine which proteins turn the Lhx1 gene on and which genes it, in turn, directly switches on or off. Those genes could be at the root of inherited sleep disorders, Blackshaw says, and the proteins they make could prove useful as starting points for the development of new drugs to treat insomnia and even jet lag.