Genetic landscape of common brain tumors holds key to personalized treatment

Nearly the entire genetic landscape of the most common form of brain tumor can be explained by abnormalities in just five genes, an international team of researchers led by Yale School of Medicine scientists report online in the Jan. 24 edition of the journal Science.  Knowledge of the genomic profile of the tumors and their location in the brain make it possible for the first time to develop personalized medical therapies for meningiomas, which currently are only managed surgically.

Meningioma tumors affect about 170,000 patients in the United States. They are usually benign but can turn malignant in about 10 percent of cases. Even non-cancerous tumors can require surgery if they affect the surrounding brain tissue and disrupt neurological functions. 

Approximately half of the tumors have already been linked to a mutation or deletion of a gene called neurofibromin 2, or NF2. The origins of the rest of the meningiomas had remained a mystery.

The Yale team conducted genomic analyses of 300 meningiomas and found four new genetic suspects, each of which yields clues to the origins and treatment of the condition. Tumors mutated with each of these genes tend to be located in different areas of the brain, which can indicate how likely they are to become malignant.

“Combining knowledge of these mutations with the location of tumor growth has direct clinical relevance and opens the door for personalized therapies,” said Dr. Murat Gunel, the Nixdorff-German Professor of Neurosurgery, professor of genetics and of neurobiology, and senior author of the study. Gunel is also a member of Yale Cancer Center’s Genetics and Genomics Research Program.

When the mind controls the machines

Stroke survivors, as well as patients suffering from other serious conditions, may have to deal with the partial or complete inability to move one or more of their limbs. In the most severe cases, the sufferer may become fully paralyzed and in need of permanent assistance.

The TOBI project (Tools for brain-computer interaction) is financed by the European Commission under the Seventh Framework Programme for Research (FP7) and is coordinated by EPFL. Since 2008 it has focused on the use of the signals transmitted by the brain. The electrical activity that takes place in the brain when the patient focuses on a particular task such as lifting an arm is detected by electroencephalography (EEG) through electrodes placed in a cap worn by the patient. Subsequently, a computer reads the signals and turns them into concrete actions as, for instance, moving a cursor on a screen.

Tests involving more than 100 patients
Based on this idea, researchers from thirteen institutions together with TOBI project partners have developed various technologies aimed at either obtaining better signal quality, making them clearer, or translating them into useful and functional applications. During the research, more than 100 patients or handicapped users had the opportunity to test the devices. Three of the technologies developed within the framework of TOBI were publicly presented at the closing seminar of the research program that took place in Sion from 23 to 25 January 2013.

1. Robotino, for helping rebuild social ties when bedridden. Combining EEG, signal recognition, obstacle sensors and the internet, researchers have been able to develop a small robot equipped with a camera and a screen that can be controlled remotely by physically disabled people. Thanks to this device, the patient can take a virtual walk in a familiar environment, meet her/his relatives and talk to them, even if they are thousands of miles away from each other.
2. Braintree, for writing texts and internet surfing. Researchers have also developed a graphical interface specially adapted for web browsing by severely disabled people. By thinking, the patient is able to move a cursor in a tree structure in order to type a character or choose a command. Depending on the specific situation, the sensors can also detect residual muscular activity to complement the management of the device.
3. Functional electrical stimulation, to restore some basic mobility. Coupling EEG with electrical muscle stimulation can allow a patient to voluntarily control the movement of a paralyzed limb. In some cases, intensive training using this system has allowed the patients to regain control of the limb and keep it without assistance. A report on this technique can be seen in this video.

The results of the TOBI research program have restored patients’ hope. They will constitute the basis of subsequent developments to be conducted among the research partners or at industrial level. As for EPFL, such results will be the core of its health research chairs at the new EPFL Valais Wallis academic cluster, which can also count on the participation and support of the SuvaCare rehabilitation clinic in Sion.

Can You Smell Yourself?

You might not be able to pick your fingerprint out of an inky lineup, but your brain knows what you smell like. For the first time, scientists have shown that people recognize their own scent based on their particular combination of major histocompatibility complex (MHC) proteins, molecules similar to those used by animals to choose their mates. The discovery suggests that humans can also exploit the molecules to differentiate between people.

"This is definitely new and exciting," says Frank Zufall, a neurobiologist at Saarland University’s School of Medicine in Homburg, Germany, who was not involved in the work. "This type of experiment had never been done on humans before."

MHC peptides are found on the surface of almost all cells in the human body, helping inform the immune system that the cells are ours. Because a given combination of MHC peptides—called an MHC type—is unique to a person, they can help the body recognize invading pathogens and foreign cells. Over the past 2 decades, scientists have discovered that the molecules also foster communication between animals, including mice and fish. Stickleback fish, for example, choose mates with different MHC types than their own. Then, in 1995, researchers conducted the now famous “sweaty T-shirt study,” which concluded that women prefer the smell of men who have different MHC genes than themselves. But no studies had shown a clear-cut physiological response to MHC proteins.

In the new work, Thomas Boehm, a biologist at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, and colleagues first tested whether women can recognize lab-made MHC proteins resembling their own. After showering, 22 women applied two different solutions to their armpits and decided which odor they liked better. The experiment was repeated two to six times for each participant. Women preferred to wear a synthetic scent containing their own MHC proteins, but only if they were nonsmokers and didn’t have a cold. The study did not determine which scents women preferred on other people, but past studies on perfume have shown that individuals prefer different smells on themselves than on others.

The researchers wanted to know whether the preferences were truly rooted in the brain’s response to the proteins. So next, they used functional magnetic resonance imaging to measure changes in the brains of 19 different women when they smelled the various solutions, in aerosol form puffed toward their noses. “Sure enough, there again was a clear difference between the response to self and non-self peptides,” Boehm says. “There was a particular region of the brain that was only activated by peptides resembling a person’s own MHC molecules.” The brain had a similar response to all non-self MHC combinations, suggesting that any preference for how other people smell is a preference for non-self, not for particular MHC types.

(Image: Getty)

Oxygen Chamber Can Boost Brain Repair

Stroke, traumatic injury, and metabolic disorder are major causes of brain damage and permanent disabilities, including motor dysfunction, psychological disorders, memory loss, and more. Current therapy and rehab programs aim to help patients heal, but they often have limited success.

Now Dr. Shai Efrati of Tel Aviv University’s Sackler Faculty of Medicine has found a way to restore a significant amount of neurological function in brain tissue thought to be chronically damaged — even years after initial injury. Theorizing that high levels of oxygen could reinvigorate dormant neurons, Dr. Efrati and his fellow researchers, including Prof. Eshel Ben-Jacob of TAU’s School of Physics and Astronomy and the Sagol School of Neuroscience, recruited post-stroke patients for hyperbaric oxygen therapy (HBOT) — sessions in high pressure chambers that contain oxygen-rich air — which increases oxygen levels in the body tenfold.

Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to control periods of non-treatment, reported Dr. Efrati in PLoS ONE. Patients experienced improvements such as a reversal of paralysis, increased sensation, and renewed use of language. These changes can make a world of difference in daily life, helping patients recover their independence and complete tasks such as bathing, cooking, climbing stairs, or reading a book.

Pavlov’s Rats? Rodents Trained to Link Rewards to Visual Cues

In experiments on rats outfitted with tiny goggles, scientists say they have learned that the brain’s initial vision processing center not only relays visual stimuli, but also can “learn” time intervals and create specifically timed expectations of future rewards. The research, by a team at the Johns Hopkins University School of Medicine and the Massachusetts Institute of Technology, sheds new light on learning and memory-making, the investigators say, and could help explain why people with Alzheimer’s disease have trouble remembering recent events.

Results of the study, in the journal Neuron, suggest that connections within nerve cell networks in the vision-processing center can be strengthened by the neurochemical acetylcholine (ACh), which the brain is thought to secrete after a reward is received. Only nerve cell networks recently stimulated by a flash of light delivered through the goggles are affected by ACh, which in turn allows those nerve networks to associate the visual cue with the reward. Because brain structures are highly conserved in mammals, the findings likely have parallels in humans, they say.

“We’ve discovered that nerve cells in this part of the brain, the primary visual cortex, seem to be able to develop molecular memories, helping us understand how animals learn to predict rewarding outcomes,” says Marshall Hussain Shuler, Ph.D., assistant professor of neuroscience at the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

To maximize survival, an animal’s brain has to remember what cues precede a positive or negative event, allowing the animal to alter its behavior to increase rewards and decrease mishaps. In the Hopkins-MIT study, the researchers sought clarity about how the brain links visual information to more complex information about time and reward.

The presiding theory, Hussain Shuler says, assumed that this connection was made in areas devoted to “high-level” processing, like the frontal cortex, which is known to be important for learning and memory. The primary visual cortex seemed to simply receive information from the eyes and “re-piece” the visual world together before presenting it to decision-making parts of the brain.

FDA Approves Clinical Trial of Auditory Brainstem Implant Procedure for Children in the U.S.

L.A.-based House Research Institute and Children’s Hospital Los Angeles announced today that the United States Food and Drug Administration (FDA) has given final approval to begin a clinical trial of an Auditory Brainstem Implant (ABI) procedure for children. The trial is a surgical collaboration sponsored by the House Research Institute in partnership with Children’s Hospital Los Angeles and Vittorio Colletti, MD of the University of Verona Hospital, Verona, Italy.

The ABI was developed at the House Research Institute and is the world’s first successful prosthetic hearing device to stimulate neurons directly at the human brainstem, bypassing the inner ear and hearing nerve entirely. Since the procedure began, more than 1,000 adults worldwide have received the ABI, with surgeons at the House Clinic leading the way.

“This will be the first FDA-approved trial of its kind, and represents a major step forward to bring a sense of hearing to deaf children in the U.S. who are born without a hearing nerve or cochlea (hearing organ) and therefore are unable to benefit from hearing aids or cochlear implants,” said Neil Segil, Ph.D, executive vice president for research, House Research Institute. “Since its development at the House Research Institute in 1979 by Drs. William House and William Hitselberger, the ABI has been successful in providing a sense of sound to many adults in the U.S., however it has never been approved by the FDA for treating deafness in children. This study has the potential to expand the use of this remarkable device, which represents the only effective sensory prosthetic for direct brain stimulation in use today.”

The Pediatric ABI team includes physicians and researchers from the House Research Institute, including Eric Wilkinson, MD, Laurie Eisenberg, Ph.D., Robert Shannon, Ph.D.; Marc Schwartz, MD; Laurel Fisher, Ph.D.; Steve Otto, M.A., and Margaret Winter, M.S., as well as Children’s Hospital Los Angeles’ Mark Krieger, MD and Gordon McComb, MD; and Verona Hospital’s Vittorio Colletti, MD; Marco Carner, MD; and Liliana Colletti, Ph.D.

“We’re excited to have reached this milestone and look forward to being able to offer this amazing technology to children in the United States who currently have no other option for hearing rehabilitation,” said Eric Wilkinson, MD, co-principal investigator and lead physician for the clinical trial.

Brain structure of infants predicts language skills at 1 year

Using a brain-imaging technique that examines the entire infant brain, researchers have found that the anatomy of certain brain areas – the hippocampus and cerebellum – can predict children’s language abilities at 1 year of age.

The University of Washington study is the first to associate these brain structures with future language skills. The results are published in the January issue of the journal Brain and Language.

“The brain of the baby holds an infinite number of secrets just waiting to be uncovered, and these discoveries will show us why infants learn languages like sponges, far surpassing our skills as adults,” said co-author Patricia Kuhl, co-director of the UW’s Institute for Learning & Brain Sciences.

Children’s language skills soar after they reach their first birthdays, but little is known about how infants’ early brain development seeds that path. Identifying which brain areas are related to early language learning could provide a first glimpse of development going awry, allowing for treatments to begin earlier.

“Infancy may be the most important phase of postnatal brain development in humans,” said Dilara Deniz Can, lead author and a UW postdoctoral researcher. “Our results showing brain structures linked to later language ability in typically developing infants is a first step toward examining links to brain and behavior in young children with linguistic, psychological and social delays.”

Researchers map emotional intelligence in the brain

A new study of 152 Vietnam veterans with combat-related brain injuries offers the first detailed map of the brain regions that contribute to emotional intelligence – the ability to process emotional information and navigate the social world.

The study found significant overlap between general intelligence and emotional intelligence, both in terms of behavior and in the brain. Higher scores on general intelligence tests corresponded significantly with higher performance on measures of emotional intelligence, and many of the same brain regions were found to be important to both. (Watch a video about the research.)

The study appears in the journal Social Cognitive & Affective Neuroscience.

“This was a remarkable group of patients to study, mainly because it allowed us to determine the degree to which damage to specific brain areas was related to impairment in specific aspects of general and emotional intelligence,” said study leader Aron K. Barbey, a professor of neuroscience, of psychology and of speech and hearing science at the Beckman Institute for Advanced Science and Technology at the University of Illinois.

A previous study led by Barbey mapped the neural basis of general intelligence by analyzing how specific brain injuries (in a larger sample of Vietnam veterans) impaired performance on tests of fundamental cognitive processes.

In both studies, researchers pooled data from CT scans of participants’ brains to produce a collective, three-dimensional map of the cerebral cortex. They divided this composite brain into 3-D units called voxels. They compared the cognitive abilities of patients with damage to a particular voxel or cluster of voxels with those of patients without injuries in those brain regions. This allowed the researchers to identify brain areas essential to specific cognitive abilities, and those that contribute significantly to general intelligence, emotional intelligence, or both.

They found that specific regions in the frontal cortex (behind the forehead) and parietal cortex (top of the brain near the back of the skull) were important to both general and emotional intelligence. The frontal cortex is known to be involved in regulating behavior. It also processes feelings of reward and plays a role in attention, planning and memory. The parietal cortex helps integrate sensory information, and contributes to bodily coordination and language processing.

“Historically, general intelligence has been thought to be distinct from social and emotional intelligence,” Barbey said. The most widely used measures of human intelligence focus on tasks such as verbal reasoning or the ability to remember and efficiently manipulate information, he said.

“Intelligence, to a large extent, does depend on basic cognitive abilities, like attention and perception and memory and language,” Barbey said. “But it also depends on interacting with other people. We’re fundamentally social beings and our understanding not only involves basic cognitive abilities but also involves productively applying those abilities to social situations so that we can navigate the social world and understand others.”

The new findings will help scientists and clinicians understand and respond to brain injuries in their patients, Barbey said, but the results also are of broader interest because they illustrate the interdependence of general and emotional intelligence in the healthy mind.

Less tau reduces seizures and sudden death in severe epilepsy

Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer’s disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor College of Medicine and the Mayo Clinic in Jacksonville, Fla., in a report in the current issue of the Journal of Neuroscience.

A growing understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease led to the finding that could point the way toward new drugs for seizure disorders said Dr. Jeffrey Noebels, professor of neurology at BCM, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory.

In her research, Jerrah Holth, a graduate student in molecular and human genetics at BCM who was working with mice with the severe form of epilepsy in Noebel’s laboratory, deleted the gene for tau. She found that reducing or eliminating tau also prevented the seizures in a severe form of epilepsy that has been associated with sudden death and reduced deaths in the animals.

In an earlier experiment, Noebels, in collaboration with Dr. Lennart Mucke at the Gladstone Research Laboratory at the University of California San Francisco, found that mice who carried a human gene that leads to accumulation of the beta amyloid protein and the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease, also had epileptic seizures arising in the hippocampus, the region of the brain associated with memory storage and retrieval.

"This led to the paradigm-shifting hypothesis that excessive neuronal network activity, rather than too little, may contribute to lower cognitive performance and dementia in some forms of Alzheimer’s disease. When this happens, the progression of memory loss may accelerate," said Noebels.

The finding also demonstrated the two disorders may share defects in signaling within brain memory circuits.

The two labs went on to show that deleting the second gene for tau ameliorated both cognitive losses and seizures in the mice whose inherited disorder mimicked Alzheimer’s disease found in humans.

Holth’s finding demonstrates that tau is involved in a far broader range of epilepsy than previously suspected, said Noebels. The type of epilepsy she studied resulted from an inherited potassium ion channel defect that affects the flow of the potassium in and out of nerve cells. She found that removing the gene encoding Tau not only dramatically reduced seizures, but prevented the mice from dying early, which typically happens in these animals.

"Even a partial reduction of the amount of tau protein by 50 percent was highly effective," said Holth. Her finding suggests developing new drugs that lower the normal interactions of the tau protein may reduce seizures and sudden unexpected death for persons with intractable epilepsies, a problem in nearly one-third of the 5 million Americans with this disorder.

Currently, Noebels and his colleagues in the Blue Bird Laboratory are studying whether the loss of tau can correct a seizure disorder once it is already established. If these studies prove fruitful, “the pharmacological discovery programs under development for treatment of Alzheimer’s disease may one day find their way to the epilepsy clinic,” said Noebels.

(Image: ALAMY)