Category: Brain Injury

Most people equate "gray matter" with the brain and its higher functions, such as sensation and perception, but this is only one part of the anatomical puzzle inside our heads. Another cerebral component is the white matter, which makes up about half the brain by volume and serves as the communications network.

The gray matter, with its densely packed nerve cell bodies, does the thinking, the computing, the decision-making. But projecting from these cell bodies are the axons — the network cables. They constitute the white matter. Its color derives from myelin–a fat that wraps around the axons, acting like insulation.

Alex Schelgel, first author on a paper in the August 2012 Journal of Cognitive Neuroscience, has been using the white matter as a landscape on which to study brain function. An important result of the research is showing that you can indeed "teach old dogs new tricks." The brain you have as an adult is not necessarily the brain you are always going to have. It can still change, even for the better.

"This work is contributing to a new understanding that the brain stays this plastic organ throughout your life, capable of change," Schlegel says. "Knowing what actually happens in the organization of the brain when you are learning has implications for the development of new models of learning as well as potential interventions in cases of stroke and brain damage."

Schlegel is a graduate student working under Peter Tse, an associate professor of psychological and brain sciences and a coauthor on the paper. "This study was Peter's idea," Schlegel says. "He wanted to know if we could see white matter change as a result of a long-term learning process. Chinese seemed to him like the most intensive learning experience he could think of."

Twenty-seven Dartmouth students were enrolled in a nine-month Chinese language course between 2007 and 2009, enabling Schlegel to study their white matter in action. While many neuroscientists use magnetic resonance imaging (MRI) in brain studies, Schlegel turned to a new MRI technology, called diffusion tensor imaging (DTI). He used DTI to measure the diffusion of water in axons, tracking the communication pathways in the brain. Restrictions in this diffusion can indicate that more myelin has wrapped around an axon.

"An increase in myelination tells us that axons are being used more, transmitting messages between processing areas," Schlegel says. "It means there is an active process under way."

Their data suggest that white matter myelination is precisely what was seen among the language students. There is a structural change that goes along with this learning process. While some studies have shown that changes in white matter occurred with learning, these observations were made in simple skill learning and strictly on a "before and after" basis.

"This was the first study looking at a really complex, long-term learning process over time, actually looking at changes in individuals as they learn a task," says Schlegel. "You have a much stronger causal argument when you can do that."

The work demonstrates that significant changes are occurring in adults who are learning. The structure of their brains undergoes change.

"This flies in the face of all these traditional views that all structural development happens in infancy, early in childhood," Schlegel says. "Now that we actually do have tools to watch a brain change, we are discovering that in many cases the brain can be just as malleable as an adult as it is when you are a child or an adolescent."

The way the body metabolizes a commonly prescribed anti-retroviral drug that is used long term by patients infected with HIV may contribute to cognitive impairment by damaging nerve cells, a new Johns Hopkins research suggests.

Nearly 50 percent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities. It has long been assumed that the disease was causing the damage, but Hopkins researchers say the drug efavirenz may play a key role.

People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades. Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain. Doctors have long believed that it might be possible to alleviate cognitive impairment associated with HIV by getting more drugs into the brain, but researchers say more caution is needed because there may be long-term effects of these drugs on the brain.

"People with HIV infections can't stop taking anti-retroviral drugs. We know what happens then and it's not good," says Norman J. Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine. "But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV."

For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics, researchers obtained samples of blood and cerebrospinal fluid from HIV-infected subjects enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz. Researchers looked for levels of the drug and its various metabolites, which are substances created when efavirenz is broken down by the liver. Performing experiments on neurons cultured in the lab, the investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of 8-hydroxyefavirenz, including the loss of the important spines of the cells.

Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons. The dendritic spine is the information processing point of a neuron, where synapses — the structures that allow communication among brain cells — are located.

In the case of efavirenz, a minor modification in the drug's structure may be able block its toxic effects but not alter its ability to suppress the virus. Namandje N. Bumpus, Ph.D., one of the study's other authors, has found a way to modify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to suppress the HIV virus.

"Finding and stating a problem is one thing, but it's another to be able to say we have found this problem and here is an easy fix," Haughey says.

Haughey says studies like his serve as a reminder that while people infected with HIV are living longer than they were 20 years ago, there are significant problems associated with the drugs used to treat the infection.

"Some people do seem to have this attitude that HIV is no longer a death sentence," he says. "But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It's nothing you should treat lightly."

The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental Health (MH077543, MH075673 and MH71150), the National Institute on Aging (AG034849) and the National Institute of Neurological Disorders and Stroke (NS049465).

Other Hopkins researchers involved in the study include Luis B. Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin McArthur, M.B.B.S., M.P.H.

Low blood levels of vitamin D are associated with an increased number of brain lesions and signs of a more active disease state in people with multiple sclerosis (MS), a new study finds, suggesting a potential link between intake of the vitamin and the risk of longer-term disability from the autoimmune disorder.

But researchers, led by Ellen M. Mowry, M.D., M.C.R., an assistant professor of neurology at the Johns Hopkins University School of Medicine and principal investigator of a multicenter clinical trial of vitamin D supplementation in MS patients, caution that more research is needed to determine if large doses of vitamin D help without harming MS patients.

Mowry's study, conducted mostly when she worked at the University of California, San Francisco, shows a strong correlation between vitamin D levels in the body (measured through blood samples) and the characteristic brain lesions of MS as measured with MRI images. Results were described in the August issue of Annals of Neurology.

"Even though lower levels of vitamin D are associated with more inflammation and lesions in the brain, there is no evidence that taking vitamin D supplements will prevent those symptoms," she says "If we are able to prove that through our currently-enrolling trial, it will change the way people with multiple sclerosis are treated."

In people with MS, the body's immune system attacks the coating of nerve fibers in the brain and spinal cord. The coating, made of a fatty protein called myelin, insulates the nerves and helps them send electrical signals that control movement, speech and other functions. When myelin is attacked, inflammation interferes with message transmission, activity that shows up on an MRI as lesions, which look like white spots.

In the most common form of MS, called relapsing-remitting MS, patients may at times have no symptoms, but at other times may suffer from "attacks" (or "relapses") of symptoms such as blurred vision, numbness and weakness. There is currently no cure for the disease but there are medications to help reduce the number of attacks and to help reduce symptoms left over if a person hasn't fully recovered from an attack.

For the study, Mowry and her colleagues used data from a five-year study of 469 people with MS. Each year, beginning in 2004, researchers drew blood from, and performed MRIs on, the brains of study participants, looking for both new lesions and active spots of disease, which lit up when a contrast dye was used. The investigators found that each 10-nanograms-per-milliliter increase in vitamin D levels was associated with a 15 percent lower risk of new lesions and a 32 percent lower risk of spots of active disease, which require treatment with medication to reduce likelihood of permanent nerve damage. Higher vitamin D levels were also associated with lower subsequent disability.

The impact of vitamin D levels remained even after other factors that can affect disease progress were accounted for, including smoking status, current MS treatment, age and gender.

At least early in MS, the more new lesions and active spots of disease, the more likely a patient is to develop longer-term disability, Mowry says. Some people with relapsing-remitting MS progress to a more serious form due to damage of the underlying nerve cells. From one year to the next, Mowry says, she and her colleagues were able to predict the appearance of new lesions and active disease spots based on vitamin D levels from the year before. Active and new lesions indicate that a patient's MS is not under optimal control.

Previous studies have indicated that lower vitamin D levels are associated with increased relapse risk in certain MS patients. Those studies relied on patients to report their attacks, which is sometimes a less reliable assessment than MRI.

Some patients already take extra vitamin D because of publicity about earlier studies. However, Mowry says that there is no research proving vitamin D alleviates symptoms or suggesting what dose is best or safest. And nothing is known about whether vitamin D can prevent the autoimmune disorder, she says.

"People think vitamin D is available over the counter so it must be safe," Mowry says. "But vitamin D is a hormone, and any medication really does need to be thoroughly tested before we definitely recommend it. That's the main reason why we are now performing a randomized trial of vitamin D supplementation. People with MS should talk with their doctors about the pros and cons of taking vitamin D before starting the supplement."

The research was funded by grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke (K23NS067055 and RO1NS062885), GlaxoSmithKline and Biogen Idec.

Strokes often cause loss or impairment of vital brain functions — such as speech, movement, vision or attention. Restoration of these functions is often possible, but difficult. One of the factors impeding brain plasticity is inflammation. A study on rats, carried out at the Nencki Institute in Warsaw, suggests that effectiveness of neurorehabilitation after a stroke can be improved by anti-inflammatory drugs.

Post-stroke inflammation slows down recovery and impairs brain plasticity, reveal the results from the lab of Professor Małgorzata Kossut at the Nencki Institute in Warsaw. The popular anti-inflammatory drug ibuprofen restores the ability of brain cortex to reorganize — a process necessary for recovery of stroke-damaged functions.

"Our research was conducted on rats, but we have good reasons to suppose that in future our results will help improve effectiveness of rehabilitation of stroke patients," says Prof. Kossut.

The Nencki Institute team stresses that so far there are no proofs that the treatment will be effective in humans and that they did not investigate if the ibuprofen therapy prevents strokes, but concentrated on post-stroke recovery.

The most frequent cause of stroke is blocking of brain arteries. Without supply of oxygen, neurons die quickly. In the region of stroke-induced damage pathological changes cause decrease of brain tissue metabolism, impairment of neurotransmission and edema.

Brain control over physiological and voluntary functions may be lost, depending on the localization of the infarct. Impairments of movement, vision, speech and attention are frequent. In most cases these functions return either partially or completely. Sometimes they return spontaneously, more often after neurorehabilitation.

"In both instances recovery is based on neuroplasticity, the ability of the brain to reorganize, that is to change the properties of neurons and to alter the connections between them," says Dr. Monika Liguz-Lęcznar (Nencki Institute).

After a stroke, neuroplasticity is impaired. Scientists from the Nencki Institute suppose that this may be due to inflammation developing at the site of the stroke. The proof that decreasing inflammation helps neurorehabilitation came from experiments done on rats with experimentally induced stroke. The stroke was localized in a special region of the brain cortex, receiving information from whiskers.

The whiskers are important sensory organs of rodents, allowing the animals to orient themselves in their environment in darkness. Every whisker activates a small, precisely delineated chunk of brain cortex.

In healthy rats neuroplastic changes can be induced by cutting off some of the whiskers, that is by eliminating part of the sensory input to the brain. The brain reacts to that by letting the remaining whiskers take over more cortical space, expand their cortical representation, at the expense of the cut off ones.

"This plastic change does not occur when the site of stroke-induced damage is near the region of cortex 'belonging' to the whiskers. We showed that application of ibuprofen decreases inflammation and restores neuroplasticity — the brain cortex reorganizes like in healthy animals," says Prof. Kossut.

The result obtained on rats indicates that ibuprofen (and probably other anti-inflammatory medicines) may be beneficial in treating stroke patients. Ibuprofen therapy should support brain plasticity by reducing post-stroke inflammation and so speed up recovery of functions lost due to the stroke. If the results on rats are verified in a proper clinical trial, they may be influential in shaping the treatment of stroke patients.

The research of Prof. Kossut's team on the effects of anti-inflammatory drugs on neuroplasticity was funded by the Polish-German Cooperation Program in Neuroscience and grants from the Ministry of Science and Education.

What does it mean to have a head concussion? Much has been written in recent years about the short- and long-term consequences of concussions sustained in sports, combat, and accidents. However, there appear to be no steadfast rules guiding the definition of concussion: the characteristics associated with this type of traumatic head injury have shifted over time and across medical disciplines. Within the context of a larger longitudinal investigation of the biomechanical factors in play that correlate with concussions in collegiate helmeted contact sports, researchers in New England and Virginia used data they obtained to investigate which signs, symptoms, and clinical histories were used by athletic trainers to define concussion in individual players. The investigators found that a heterogeneous collection of acute clinical characteristics currently exists for those events diagnosed as concussion in college athletes engaged in contact sports.

Together with her colleagues, Dr. Duhaime, Director of Pediatric Neurosurgery and of Neurotrauma and Intensive Care in the Neurosurgical Service of Massachusetts General Hospital, examined concussions diagnosed in athletes participating in helmeted contact sports (football and ice hockey) at three universities: Dartmouth, Brown, and Virginia Tech. Both male and female athletes participated in the study. The students' helmets were outfitted with Head Impact Telemetry (HIT) System™ technology to record and measure peak linear and angular acceleration of impacts. The helmets were worn during practice sessions and games throughout two to four seasons. The investigators did not attempt to influence how trainers and team medical personnel defined concussion operationally, but instead relied on the clinical characteristics deemed indicative of concussion by the universities' athletic departments.

More than 486,000 head impacts were recorded in 450 athletes, and concussion was diagnosed in 44 of these athletes (48 concussions) by team medical staff. Unlike concussions more often diagnosed in emergency departments, where a single, identified contact event leads to a loss of consciousness or other clear alteration in consciousness, most diagnoses in this sports setting were based on self-reports by athletes, and only a few were based on changes in athletes' clinical conditions that were observed by others. Thirty-one concussions could be directly associated with a specific impact, whereas a relationship with a specific impact could not be verified in the other cases of concussion. Only half of the athletes noted symptoms immediately after a contact event; in many athletes, the onset of symptoms was delayed. The most common reported symptoms were mental clouding, headache, and dizziness; only one case involved a loss of consciousness. The diagnosis of concussion by trainers often occurred in an even more delayed fashion: the diagnosis was made immediately after the event in 6 cases and at a later time in the other cases (median 17 hours postinjury).

In general, the mean peak linear and angular accelerations for specific impact events that could be directly linked to concussions tended be in the high percentiles for the sports examined; however, there was considerable variability in the ranges of these measurements (mean peak linear acceleration 86.1 ± 42.6 g [range 16.5.9 g], mean peak angular acceleration 3620 ± 2,166 rads/sec2 [range 183,589 rads/sec2]).

The variety of signs and symptoms, the imprecise timing of symptom appearance and relationship to a specific contact event, the lack of externally observed findings, and the broad ranges of the linear and angular accelerations of the impacts that coalesce in a diagnosis of concussion in college sports make it difficult to identify predictors of acute, intermediate, and long-term risks of adverse consequences resulting from sports-related head impacts. By describing the heterogeneity inherent in diagnoses of concussion as a "concussion spectrum," the authors point out the need for renewed efforts to determine which factors — clinical, mechanical, genetic, or others — influence outcomes in patients with single as well as repeated head impacts. The authors point out that while a clinical diagnosis is important to protect players from additional and potentially more serious consequences, it is also possible that athletes who do not receive the diagnosis of "concussion" may be at similar risk. Likewise, it is possible that some players who receive a diagnosis of concussion do not fall into a high-risk category for specific consequences.

The authors note that there is still much to be learned, and that the terminology in use can sometimes oversimplify a more complex set of processes that still need to be teased apart. In their response to an accompanying editorial, they state, "By carefully characterizing exactly what we are talking about and by continued investigation, which will take more time … , neurosurgeons and others will be best positioned to offer effective treatments and to advocate knowledgeably for appropriate injury-prevention strategies."

A team of Canadian scientists and clinicians, led by Dr. Michael Hill of the Calgary Stroke Program at Foothills Medical Centre and University of Calgary's Hotchkiss Brain Institute (HBI), have demonstrated that a neuroprotectant drug, developed by Dr. Michael Tymianski at the Krembil Neuroscience Centre, located at the Toronto Western Hospital, protects the human brain against the damaging effects of stroke.

The study, "Safety and efficacy of NA-1 for neuroprotection in iatrogenic stroke after endovascular aneurysm repair: a randomized controlled trial," published online October 8 in The Lancet Neurology, was conducted concurrently with a laboratory study published in Science Translational Medicine, that predicted the benefits of the stroke drug.

This landmark clinical trial was a randomized, double blinded, multi-centre trial that was conducted in Canada and the USA. The study evaluated the effectiveness of NA-1[Tat-NR2B9c] when it was administered after the onset of small strokes that are incurred by patients who undergo neurointerventional procedures to repair brain aneurysms. This type of small ischemic stroke occurs in over 90% of aneurysm patients after such a procedure, but usually does not cause overt neurological disability.

In the clinical trial, patients were randomized to receive either Tat-NR2B9c or placebo. Those treated with Tat-NR2B9c showed a reduction in the amount of brain damage sustained as a result of the aneurysm repair procedure. Also, in patients who had ruptured brain aneurysm, which comprise a population of patients at very high risk of neurological damage, those treated with Tat-NR2B9c all had good neurological outcomes, whereas only 68% of those treated with placebo had good outcomes.

"The results of this clinical trial represent a major leap forward for stroke research," said Dr. Hill. "There have been over 1,000 attempts to develop such drugs, which have failed to make the leap between success in the lab and in humans."

"This clinical trial is, to our knowledge, the first time that a drug aimed at increasing the resistance of the brain to stroke, has been shown to reduce stroke damage in humans. No efforts should be spared to develop it further," said Dr. Michael Tymianski, who oversaw the development of Tat-NR2B9c from its invention in his lab, through to clinical trials.

Currently, t-PA is the only widely approved acute stroke therapy. It works by unblocking the arteries to the brain, however, this treatment is only beneficial for a portion of stroke victims. It also has serious potential for side-effects, including bleeding in the brain.

"Through our lab research and clinical trial, we now have a better method of predicting whether a stroke drug may be effective in humans and we now have the evidence that there is a neuroprotectant that can prevent damage in the brain caused by reduced blood flow," said Dr. Tymianski, inventor of NA-1 and one of the study's authors. "The benefits of this can be explored not only for stroke, but for other conditions such as vascular dementia."

Journal Reference:

1. Michael D Hill, Renee H Martin, David Mikulis, John H Wong, Frank L Silver, Karel G terBrugge, Geneviève Milot, Wayne M Clark, R Loch MacDonald, Michael E Kelly, Melford Boulton, Ian Fleetwood, Cameron McDougall, Thorsteinn Gunnarsson, Michael Chow, Cheemun Lum, Robert Dodd, Julien Poublanc, Timo Krings, Andrew M Demchuk, Mayank Goyal, Roberta Anderson, Julie Bishop, David Garman, Michael Tymianski. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet Neurology, 2012; DOI: 10.1016/S1474-4422(12)70225-9

Researchers from the University of Exeter Medical School have for the first time identified the mechanism that protects us from developing uncontrollable fear.

Our brains have the extraordinary capacity to adapt to changing environments — experts call this 'plasticity'. Plasticity protects us from developing mental disorders as the result of stress and trauma.

Researchers found that stressful events re-programme certain receptors in the emotional centre of the brain (the amygdala), which the receptors then determine how the brain reacts to the next traumatic event.

These receptors (called protease-activated receptor 1 or PAR1) act in the same way as a command centre, telling neurons whether they should stop or accelerate their activity.

Before a traumatic event, PAR1s usually tell amygdala neurons to remain active and produce vivid emotions. However, after trauma they command these neurons to stop activating and stop producing emotions — so protecting us from developing uncontrollable fear.

This helps us to keep our fear under control, and not to develop exaggerated responses to mild or irrelevant fear triggers — for example, someone who may have witnessed a road traffic accident who develops a fear of cars or someone who may have had a dog jump up on them as a child and who now panics when they see another dog.

The research team used mice in which the PAR1 receptors were genetically de-activated and found that the animals developed a pathological fear in response to even mild, aversive stimuli.

The study was led by Professor Robert Pawlak of University of Exeter Medical School. He said: "The discovery that the same receptor can either awaken neurons or 'switch them off' depending on previous trauma and stress experience, adds an entirely new dimension to our knowledge of how the brain operates and emotions are formed."

Professor Pawlak added: "We are now planning to extend our study to investigate if the above mechanisms, or genetic defects of the PAR1 receptor, are responsible for the development of anxiety disorders and depression in human patients. There is more work to be done, but the potential for the development of future therapies based on our findings is both exciting and intriguing."

The article describing the above findings has recently been published in Molecular Psychiatry.

Scientists at the Krembil Neuroscience Centre, located at the Toronto Western Hospital, University Health Network have developed the first lab study in the world to accurately predict the outcomes of a human clinical for their drug that protects the brain against the damaging effects of stroke.

The study, "A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic non-human primates," published online October 3 in Science Translational Medicine was conducted concurrently with a human clinical trial called ENACT. The purpose of the animal study was to test whether the Toronto team could predict benefits of the stroke drug Tat-NR2B9c in a larger, multi-center trial conducted in humans. This study builds on work previous published in the journal Nature earlier this year, which showed the ability of this drug to reduce brain damage caused by stroke.

Several previous attempts at developing stroke drugs have suggested that certain drugs were effective in reducing stroke damage in small animals such as rats. However, none have shown efficacy in patients suffering from stroke, leaving an unexplained gap between results of studies in animals and those in humans. The landmark research conducted by the Toronto team provides the first path forward in enabling researchers to predict whether or not a drug may work in humans. The UHN scientific team ran a trial in the lab that mimicked the design of a human clinical trial, which was conducted across Canada and the USA.

Both studies evaluated the effectiveness of Tat-NR2B9c when it was administered after the onset of embolic strokes. The laboratory study replicated in animals the small strokes that are incurred by patients who undergo neurointerventional procedures to repair brain aneurysms. This type of small ischemic stroke, which was simulated in a lab setting, occurs in over 90% of aneurysm patients after such a procedure, but usually does not cause overt neurological disability.

In the research lab, animals were randomized to receive either Tat-NR2B9c or placebo. Those treated with Tat-NR2B9c showed a marked reduction in both the numbers and the volumes of strokes when compared with the placebo group.

"The greatest challenge facing stroke researchers today is finding ways to translate their scientific discoveries to situations that can be of clinical benefit to patients" said Dr. Michael Tymianski, a senior scientist at the Toronto Western Research Institute and the study's lead author. "Our work provides a path forward — a method to predict whether a stroke drug may be effective in humans"

Currently, there exists only one widely approved acute stroke therapy: unblocking the arteries to the brain using a drug known as t-PA. However, t-PA has serious potential for side-effects, including causing bleeding in the brain. What is lacking in stroke treatment today is a way to enhance the human brain's resilience to stroke in order to reduce the damage to the brain and preserve neurological function. The challenge that the researchers overcame in the current study was to establish, in a lab setting, a way to predict whether a drug may be effective human patients.

"Not only does this study take us one step closer to having a neuroprotectant drug for stroke patients, it will also provide us with a better way of testing future treatments to ensure they will benefit people," said Dr. Tymianski.