Promising new finding for therapies to treat persistent seizures in epileptic patients

In a promising finding for epileptic patients suffering from persistent seizures known as status epilepticus, researchers reported today that new medication could help halt these devastating seizures. To do so, it would have to work directly to antagonize NMDA receptors, the predominant molecular device for controlling synaptic activity and memory function in the brain.

"Despite the development of new medications to prevent seizures, status epilepticus remains a life-threatening condition that can cause extensive brain damage in the patients that survive these persistent seizures," said David E. Naylor, MD, PhD, a lead researcher at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) and corresponding author of the new study. "Our research holds promise for the development of new therapies to treat this devastating condition because we have found a potential new target for medical intervention that should bolster the current standard therapies to treat the acute seizures. It may also prevent the long-term adverse effects of persistent seizure activity on the brain."

The research, reported online in the Neurology of Disease journal, used animal models to assess cellular activity in the brain during persistent seizures. It found that the seizure activity seemed to force the NMDA receptors from the interior to the surface of nerve cells causing their activity to increase by approximately 38%.

"The increased presence of the NMDA receptors on the cell surface during these seizures may explain the successful use of NMDA antagonists – medication that inhibits the activity of the NMDA receptors in the brain – in the latter stages of a seizure, long after other medications have stopped working," said Dr. Naylor. "We concluded that medications that suppress the activity of the NMDA receptors, in conjunction with other medications, may be successful in stopping persistent seizures. Further research is, of course, needed."

Scanning the Brain: Scientists Examine the Impact of fMRI Over the Past 20 Years

Understanding the human brain is one of the greatest scientific quests of all time, but the available methods have been very limited until recently. The development of functional magnetic resonance imaging (fMRI) — a tool used to gauge real-time brain activity by measuring changes in blood flow — opened up an exciting new landscape for exploration.

Now, twenty years after the first fMRI study was published, a group of distinguished psychological scientists reflect on the contributions fMRI has made to our understanding of human thought. Their reflections are published as part of a special section of the January 2013 issue of Perspectives on Psychological Science, a journal of the Association for Psychological Science.

In the last two decades, many researchers have used fMRI to try to answer various questions about the brain and mind. But some are not convinced of its usefulness.

“Despite the many new methods and results derived from fMRI research, some have argued that fMRI has done very little to advance knowledge about cognition and, in particular, has done little to advance theories about cognitive processes,” write Mara Mather, Nancy Kanwisher, and John Cacioppo, editors of the special section.

The aim of the special section is to tackle the question of how fMRI results have (or have not) changed the way we think about human psychology and the brain, resulting in a collection of 12 provocative articles.

Some of the authors argue that fMRI has fundamentally changed that way that researchers think about the aging mind. According to researchers Tor Wager and Lauren Atlas, fMRI may also provide a more direct way of measuring pain.

Others discuss the contributions fMRI has made to the longstanding debate about whether cognitive operations are modular or distributed across domains. And some emphasize the reciprocal relationship between fMRI and cognitive theories, highlighting how each informs the others.

As appealing as fMRI images might be, researchers Martha Farah and Cayce Hook find little support for the claim that fMRI data has a “seductive allure” that makes it more persuasive than other types of data.

In their concluding commentary, Mather, Cacioppo, and Kanwisher argue that fMRI does provide unique insights to our understanding of cognition. But, as powerful as it is, the researchers acknowledge that there are some questions fMRI will never answer.

“The best approach to answering questions about cognition,” say Mather, Cacioppo, and Kanwisher, “is a synergistic combination of behavioral and neuroimaging methods, richly complemented by the wide array of other methods in cognitive neuroscience.”

(Image courtesy of Glasgow University)

New Technique Helps Stroke Victims Communicate

Stroke victims affected with loss of speech caused by Broca’s aphasia have been shown to speak fluidly through the use of a process called “speech entrainment” developed by researchers at the University of South Carolina’s Arnold School of Public Health.

Aphasia, a severe communication problem caused by damage to the brain’s left hemisphere and characterized by halting speech, occurs in about one-third of people who have a stroke and affects personal and professional relationships. Using the speech entrainment technique, which involves mimicking other, patients showed significant improvement in their ability to speak.

The results of the study are published in a recent issue of the neurology journal Brain.

"This is the first time that we have seen people with Broca’s aphasia speak in fluent sentences,” said Julius Fridriksson, the study’s lead researcher and a professor with the Department of Communication Sciences and Disorders at the Arnold School. “It is a small study that gives us an understanding of how the brain functions after a stroke, and it offers hope for thousands of people who suffer strokes each year."

In Fridriksson’s study, 13 patients completed three separate behavioral tasks that were used to understand the effects of speech entrainment on speech production. During the “speech entrainment–audio visual" portion of the study, participants attempted to mimic a speaker in real-time whose mouth was made visible on the 3.5-inch screen of an iPod Touch and whose speech was heard via headphones.

The “speech entrainment–audio only” condition involved real-time mimicking speech presented via headphones with the screen of the iPod blank. During a spontaneous speech condition, patients spoke about a given topic without external aid.

Each patient also completed a three-week training phase where they practiced speech every day with the aid of speech entrainment. Overall, the training resulted in improved spontaneous speech production, something that is relatively rare in this population. Ultimately the patients were able to produce a short script about their stroke to tell to other people.

Neuroimaging results from the patient subjects have also given Fridriksson and his research team a greater understanding of the mechanism involved in speech entrainment.

"Preliminary results suggest that training with speech entrainment improves speech production in Broca’s aphasia, providing a potential therapeutic method for a disorder that has been shown to be particularly resistant to treatment," Fridriksson said.

Possible role for Huntington’s gene discovered

About 20 years ago, scientists discovered the gene that causes Huntington’s disease, a fatal neurodegenerative disorder that affects about 30,000 Americans. The mutant form of the gene has many extra DNA repeats in the middle of the gene, but scientists have yet to determine how that extra length produces Huntington’s symptoms.

In a new step toward answering that question, MIT biological engineers have found that the protein encoded by this mutant gene alters patterns of chemical modifications of DNA. This type of modification, known as methylation, controls whether genes are turned on or off at any given time.

The mutant form of this protein, dubbed “huntingtin,” appears to specifically target genes involved in brain cell function. Disruptions in the expression of these genes could account for the neurodegenerative symptoms seen in Huntington’s disease, including early changes in cognition, says Ernest Fraenkel, an associate professor of biological engineering at MIT.

Fraenkel’s lab is now investigating the details of how methylation might drive those symptoms, with an eye toward developing potential new treatments. “One could imagine that if we can figure out, in more mechanistic detail, what’s causing these changes in methylation, we might be able to block this process and restore normal levels of transcription early on in the patients,” says Fraenkel, senior author of a paper describing the findings in this week’s issue of the Proceedings of the National Academy of Sciences.

Lead author of the paper is Christopher Ng, an MIT graduate student in biological engineering. Other authors are MIT postdoc Ferah Yildirim; recent graduates Yoon Sing Yap, Patricio Velez and Adam Labadorf; technical assistants Simona Dalin and Bryan Matthews; and David Housman, the Virginia and D.K. Ludwig Professor of Biology.

Research Reveals Exactly How the Human Brain Adapts to Injury

For the first time, scientists at Carnegie Mellon University’s Center for Cognitive Brain Imaging (CCBI) have used a new combination of neural imaging methods to discover exactly how the human brain adapts to injury. The research, published in Cerebral Cortex, shows that when one brain area loses functionality, a “back-up” team of secondary brain areas immediately activates, replacing not only the unavailable area but also its confederates.

“The human brain has a remarkable ability to adapt to various types of trauma, such as traumatic brain injury and stroke, making it possible for people to continue functioning after key brain areas have been damaged,” said Marcel Just, the D. O. Hebb Professor of Psychology at CMU and CCBI director. “It is now clear how the brain can naturally rebound from injuries and gives us indications of how individuals can train their brains to be prepared for easier recovery. The secret is to develop alternative thinking styles, the way a switch-hitter develops alternative batting styles. Then, if a muscle in one arm is injured, they can use the batting style that relies more on the uninjured arm.”

For the study, Just, Robert Mason, senior research psychologist at CMU, and Chantel Prat, assistant professor of psychology at the University of Washington, used functional magnetic resonance imaging (fMRI) to study precisely how the brains of 16 healthy adults adapted to the temporary incapacitation of the Wernicke area, the brain’s key region involved in language comprehension. They applied Transcranial Magnetic Stimulation (TMS) in the middle of the fMRI scan to temporarily disable the Wernicke area in the participants’ brains. The participants, while in the MRI scanner, were performing a sentence comprehension task before, during and after the TMS was applied. Normally, the Wernicke area is a major player in sentence comprehension.

The research team used the fMRI scans to measure how the brain activity changed immediately following stimulation to the Wernicke area. The results showed that as the brain function in the Wernicke area decreased following the application of TMS, a “back-up” team of secondary brain areas immediately became activated and coordinated, allowing the individual’s thought process to continue with no decrease in comprehension performance.

The brain’s back-up team consisted of three types of brain regions: (1) contralateral areas —areas that are in the mirror-image location of the brain; (2) areas that are right next to the impaired area; and (3) a frontal executive area.

“The first two types of back-up areas have similar brain capabilities as the impaired Wernicke area, although they are less efficient at the capability,” Just said. “The third area plays a strategic role as in responding to the initial impairment and recruiting back-up areas with similar capabilities.”

Additionally, the research showed that impairing the Wernicke area also negatively affected the cortical partners with which the Wernicke area had been working. “Thinking is a network function,” Just explained. “When a key node of a network is impaired, the network that is closely collaborating with the impaired node is also impaired. People do their thinking with groups of brain areas, not with single brain areas.”

Mason, the study’s lead author, noted that following the TMS, the impaired area and its partners gradually returned to their previous levels of coordinated activity, while the back-up team of brain areas was still in place. “This means, that for some period of time, there were two cortical teams operating simultaneously, explaining why performance is sometimes improved by TMS,” he said.

This research builds on Just’s previous research on brain resilience after stroke and brain training to remediate dyslexia. The studies are motivated by a computational theory, called 4CAPS, that provides an account of how autonomous brain systems dynamically self-organize themselves in response to changing circumstances, which the researchers believe to be the basis of fluid intelligence.

Childhood trauma leaves its mark on the brain

EPFL scientists have found that childhood trauma leaves a lasting imprint on the brain – a structural change that is related to a predisposition to violence.

It is well known that violent individuals are often themselves the victims of psychological trauma experienced in childhood. Some of these individuals also exhibit alterations in their orbitofrontal cortex. But is there a connection between these physical changes in the brain and a psychologically traumatic childhood? Can one’s experiences modify the physical structure of the brain?

An EPFL team led by Professor Carmen Sandi, member of the National Centers for Competence in Research SYNAPSY, has demonstrated for the first time a correlation between psychological trauma and specific changes in the brain that are related to aggressive behavior. In rats, the experience of pre-adolescent trauma led to aggressive behavior accompanied by structural and functional changes in the brain – the same changes that have been observed in violent human beings. In other words, psychological wounds inflicted in childhood leave a lasting biological trace that persists in the adult brain. The team’s findings have been published in the January 15 edition of the journal Translational Psychiatry.

“This research shows that people exposed to trauma in childhood don’t only suffer psychologically, but their brain also gets altered,” explains Sandi, who is head of EPFL’s Laboratory of Behavioral Genetics and director of the Brain Mind Institute. “This adds an additional dimension to the consequences of abuse, and obviously has scientific, therapeutic and social implications.”

Remarkable results
The researchers were able to unravel the biological foundations of violence using a cohort of male rats that were exposed to psychologically stressful situations when young. After observing that these experiences led to aggressive behavior when the rats reached adulthood, they examined what was happening in the animals’ brains to see if the traumatic period had left a lasting mark.

“In a challenging social situation, the orbitofrontal cortex of a healthy individual is activated in order to inhibit aggressive impulses and to maintain normal interactions,” explains Sandi. “But in the rats we studied, we noticed that there was very little activation of the orbitofrontal cortex. This, in turn, reduces their ability to moderate their negative impulses. This reduced activation is accompanied by the overactivation of the amygdala, a region of the brain that’s involved in emotional reactions.” Other researchers who have studied the brains of violent human individuals have observed the same deficit in orbitofrontal activation and the same concomitant reduced inhibition of aggressive impulses. “It’s remarkable; we didn’t expect to find this level of similarity,” says Sandi.

Antidepressants and cerebral plasticity
The scientists also measured changes in the expression of certain genes in the brain. The neurobiologists focused on genes known to be involved in aggressive behavior for which there are polymorphisms (genetic variants) that predispose carriers to an aggressive attitude. They looked at whether the psychological stress experienced by the rats caused a modification in these genes’ expression. “We found that the level of MAOA gene expression increased in the prefrontal cortex,” says Sandi. This alteration was linked to an epigenetic change; in other words, the traumatic experience ended up causing a long-term modification of this gene’s expression.

Finally, the researchers tried to see if an MAOA gene inhibitor, in this case an antidepressant, could reverse the increase in aggressive behavior induced by the juvenile stress. The treatment was effective. The team will now concentrate its efforts on trying to better understand these mechanisms, and explore whether a treatment could possibly reverse these changes in the brain, and above all, to shed light on whether some people are more vulnerable than others depending on their genetic makeup. “This research could also reveal the possible ability of antidepressants – an ability that’s increasingly being suspected – to renew cerebral plasticity,” says the professor.

Exploring the Brain’s Relationship to Habits

The basal ganglia, structures deep in the forebrain already known to control voluntary movements, also may play a critical role in how people form habits, both bad and good, and in influencing mood and feelings.

"This system is not just a motor system," says Ann Graybiel. "We think it also strongly affects the emotional part of the brain."

Graybiel, an investigator at the McGovern Institute of the Massachusetts Institute of Technology and professor in MIT’s department of brain and cognitive sciences, believes that a core function of the basal ganglia is to help humans develop habits that eventually become automatic, including habits of thought and emotion.

"Many everyday movements become habitual through repetition, but we also develop habits of thought and emotion," she says."If cognitive and emotional habits are also controlled by the basal ganglia, this may explain why damage to these structures can lead not only to movement disorders, but also to repetitive and intrusive thoughts, emotions and desires."           

Graybiel’s research focuses on the brain’s relationship to habits—how we make or break them—and the neurobiology of the habit system. She and her team have identified and traced neural loops that run from the outer layer of the brain—“the thinking cap,” as she calls it—to a region called the striatum, which is part of the basal ganglia, and back again. These loops, in fact, connect sensory signals to habitual behaviors.

Her work ultimately could have an impact not just on such classic movement disorders as Parkinson’s and Huntington’s diseases, but in other conditions where repetitive movements commonly occur, such as Tourette Syndrome, autism, or obsessive-compulsive disorder, the latter when sufferers experience unwanted and repeated thoughts, feelings, ideas, sensations or behaviors that make them feel driven to do something, for example, repeatedly washing their hands.

Moreover, the research could have an immediate value for trying to understand “what happens in the brain as addiction occurs, as bad habits form, not just good habits,” she says. “There are many psychiatric and neurologic conditions in which these same brain regions are disordered.

"These conditions may in part be influenced by the very system we are working on," Graybiel adds. "We are working with models of anxiety and depression, stress and some of these movement disorders."

It turns out that the emotional circuits of the brain have strong ties to the striatum, she says. Graybiel’s research suggests that activity in the striatum strongly affects the emotional decisions that people make: whether to accept a good outcome or a potentially bad one, for example, and that there are circuits favoring good outcomes, and, surprisingly, other circuits that favor bad ones.

"This work ties into new research suggesting that there are brain systems for ‘good’ and brain systems for ‘bad,’" she says. "What is intriguing is that we may have identified the circuits that decide between the two."

Major step toward an Alzheimer’s vaccine

A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain’s natural defense mechanisms in people with Alzheimer’s disease. This major breakthrough, details of which are presented today in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer’s disease and a vaccine to prevent the illness.

One of the main characteristics of Alzheimer’s disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system’s defenders, are unable to eliminate this substance, which forms deposits called senile plaques.

The team led by Dr. Serge Rivest, professor at Université Laval’s Faculty of Medicine and researcher at the CHU de Québec research center, identified a molecule that stimulates the activity of the brain’s immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant by GSK for many years, and its safety is well established.

In mice with Alzheimer’s symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice’s ability to learn new tasks showed significant improvement in cognitive function over the same period.

The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer’s disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. “The vaccine could be given to people who already have the disease to stimulate their natural immunity,” said Serge Rivest. “It could also be administered as a preventive measure to people with risk factors for Alzheimer’s disease.”

"When our team started working on Alzheimer’s disease a decade ago, our goal was to develop better treatment for Alzheimer’s patients," explained Professor Rivest. "With the discovery announced today, I think we’re close to our objective."

(Photo: ALAMY)

Transmission of Tangles in Alzheimer’s Mice Provides More Authentic Model of Tau Pathology

Brain diseases associated with the misformed protein tau, including Alzheimer’s disease and frontotemporal lobar degeneration with tau pathologies, are characterized by neurofibrillary tangles (NFTs) comprised of pathological tau filaments. Tau tangles are also found in progressive supranuclear palsy, cortical basal degeneration and other related tauopathies, including chronic traumatic encephalopathy due to repetitive traumatic brain injuries sustained in sports or on the battle field.

By using synthetic fibrils made from pure recombinant protein, Penn researchers provide the first direct and compelling evidence that tau fibrils alone are entirely sufficient to recruit and convert soluble tau within cells into pathological clumps in neurons, followed by transmission of tau pathology to other inter-connected brain regions from a single injection site in an animal model of tau brain disease.

The laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published their findings in the Journal of Neuroscience this week.

“Our new model of tau pathology spread provides an explanation to account for the stereotypical progression of Alzheimer’s and other related tauopathies by implicating the cell-to-cell transmission of pathological tau in this process,” says Lee.