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.

Who Decides in the Brain?

Whether in society or nature, decisions are often the result of complex interactions between many factors. Because of this it is usually difficult to determine how much weight the different factors have in making a final decision. Neuroscientists face a similar problem since decisions made by the brain always involve many neurons. Working in collaboration, the University of Tübingen and the Max Planck Institute for Biological Cybernetics, supported within the framework of the Bernstein Network, researchers lead by CIN professor Matthias Bethge have now shown how the weight of individual neurons in the decision-making process can be reconstructed despite interdependencies between the neurons.

When we see a person on the other side of the street who looks like an old friend, the informational input enters the brain via many sensory neurons. But which of these neurons are crucial in passing on the relevant information to higher brain areas, which will decide who the person is and whether to wave and say ‘hello’? A research group lead by Matthias Bethge has now developed an equation that allows them to calculate to what degree a given individual sensory neuron is involved in the decision process.

To approach this question, researchers have so far considered the information about the final decision that an individual sensory neuron carries. Just as an individual is considered suspicious if he or she is found to have insider information about a crime, those sensory neurons whose activity contains information about the eventual decision are presumed to have played a role in reaching the final decision. The problem with this approach is that neurons – much like people – are constantly communicating with each other. A neuron which itself is not involved in the decision may simply have received this information from a neighboring neuron and “joined in” the conversation. Actually, the neighboring cell sends out the crucial signal transmitted to the higher decision areas in the brain.

The new formula that has been developed by scientists addresses this by accounting not just for the information in the activity of any one neuron but also for the communication that takes place between them. This formula will now be used to determine whether only a few neurons that carry a lot of information are involved in the brain’s decision process, or whether the information contained in very many neurons gets combined. In particular, it will be possible to address the more fundamental question: In which decisions does the brain use information in an optimal way, and for which decisions is its processing suboptimal?

New implant replaces impaired middle ear

Functionally deaf patients can gain normal hearing with a new implant that replaces the middle ear. The unique invention from the Chalmers University of Technology has been approved for a clinical study. The first operation was performed on a patient in December 2012.

With the new hearing implant, developed at Chalmers in collaboration with Sahlgrenska University Hospital in Gothenburg, the patient has an operation to insert an implant slightly less than six centimetres long just behind the ear, under the skin and attached to the skull bone itself. The new technique uses the skull bone to transmit sound vibrations to the inner ear, so-called bone conduction.

“You hear 50 percent of your own voice through bone conduction, so you perceive this sound as quite natural”, says Professor Bo Håkansson, of the Department of Signals and Systems, Chalmers.

The new implant, BCI (Bone Conduction Implant), was developed by Bo Håkansson and his team of researchers. Unlike the type of bone-conduction device used today, the new hearing implant does not need to be anchored in the skull bone using a titanium screw through the skin. The patient has no need to fear losing the screw and there is no risk of skin infections arising around the fixing.

The first operation was performed on 5 December 2012 by Måns Eeg-Olofsson, Senior Physician at Sahlgrenska University Hospital, Gothenburg, and went entirely according to plan.

“Once the implant was in place, we tested its function and everything seems to be working as intended so far. Now, the wound needs to heal for six weeks before we can turn the hearing sound processor on”, says Måns Eeg-Olofsson, who has been in charge of the medical aspects of the project for the past two years.

The technique has been designed to treat mechanical hearing loss in individuals who have been affected by chronic inflammation of the outer or middle ear, or bone disease, or who have congenital malformations of the outer ear, auditory canal or middle ear. Such people often have major problems with their hearing. Normal hearing aids, which compensate for neurological problems in the inner ear, rarely work for them. On the other hand, bone-anchored devices often provide a dramatic improvement.

In addition, the new device may also help people with impaired inner ear. “Patients can probably have a neural impairment of down to 30-40 dB even in the cochlea. We are going to try to establish how much of an impairment can be tolerated through this clinical study”, says Bo Håkansson.

If the technique works, patients have even more to gain. Earlier tests indicate that the volume may be around 5 decibels higher and the quality of sound at high frequencies will be better with BCI than with previous bone-anchored techniques. Now it’s soon time to activate the first patient’s implant, and adapt it to the patient’s hearing and wishes. Then hearing tests and checks will be performed roughly every three months until a year after the operation.

“At that point, we will end the process with a final X-ray examination and final hearing tests. If we get good early indications we will continue operating other patients during this spring already”, says Måns Eeg-Olofsson.

The researchers anticipate being able to present the first clinical results in early 2013. But when will the bone-conduction implant be ready for regular patients?

“According to our plans, it could happen within a year or two. For the new technique to quickly achieve widespread use, major investments are needed right now, at the development stage”, says Bo Håkansson.

The secrets of a tadpole’s tail and the implications for human healing

Scientists at The University of Manchester have made a surprising finding after studying how tadpoles re-grow their tails which could have big implications for research into human healing and regeneration.

It is generally appreciated that frogs and salamanders have remarkable regenerative capacities, in contrast to mammals, including humans. For example, if a tadpole loses its tail a new one will regenerate within a week. For several years Professor Enrique Amaya and his team at The Healing Foundation Centre in the Faculty of Life Sciences have been trying to better understand the regeneration process, in the hope of eventually using this information to find new therapies that will improve the ability of humans to heal and regenerate better.

In an earlier study, Professor Amaya’s group identified which genes were activated during tail regeneration. Unexpectedly, that study showed that several genes that are involved in metabolism are activated, in particular those that are linked to the production of reactive oxygen species (ROS) - chemically reactive molecules containing oxygen. What was unusual about those findings is that ROS are commonly believed to be harmful to cells.

Professor Amaya and his group decided to follow up on this unexpected result and their new findings will be published in the next issue of Nature Cell Biology.