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.

Chance finding reveals new control on blood vessels in developing brain

Zhen Huang freely admits he was not interested in blood vessels four years ago when he was studying brain development in a fetal mouse.

Instead, he wanted to see how changing a particular gene in brain cells called glia would affect the growth of neurons.

The result was hemorrhage, caused by deteriorating veins and arteries, and it begged for explanation.

"It was a surprising finding," says Huang, an assistant professor of neuroscience and neurology at the University of Wisconsin-Madison. "I was mainly interested in the neurological aspect, how the brain develops and wires itself to prepare for all the wonderful things it does."

But chance favors the prepared mind, as Louis Pasteur said, and Huang knew he needed to follow up on the suggestion that glia, normally considered “helpers” for the neurons, would affect the growth of blood vessels. For one thing, blood flow is a big deal in the brain, says Huang, whose collaborators included Shang Ma, in the graduate program in cellular and molecular biology at UW-Madison. “We know the brain is very energy-intensive. Per unit of volume, it consumes 10 times as much oxygen as the rest of the body.”

Although it makes intuitive sense that blood vessel development should be guided by neuronal development in some fashion, Huang spent years making sure he wasn’t being mislead by his experiment. Now, he’s satisfied himself, and his scientific reviewers, and the journal PLOS Biology has just published his study.

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.

UCI neuroscientists create fiber-optic method of arresting epileptic seizures

UC Irvine neuroscientists have developed a way to stop epileptic seizures with fiber-optic light signals, heralding a novel opportunity to treat the most severe manifestations of the brain disorder.

Using a mouse model of temporal lobe epilepsy, Ivan Soltesz, Chancellor’s Professor and chair of anatomy & neurobiology, and colleagues created an EEG-based computer system that activates hair-thin optical strands implanted in the brain when it detects a real-time seizure.

These fibers subsequently “turn on” specially expressed, light-sensitive proteins called opsins, which can either stimulate or inhibit specific neurons in select brain regions during seizures, depending on the type of opsin.

The researchers found that this process was able to arrest ongoing electrical seizure activity and reduce the incidence of severe “tonic-clonic” events.

“This approach is useful for understanding how seizures occur and how they can be stopped experimentally,” Soltesz said. “In addition, clinical efforts that affect a minimum number of cells and only at the time of a seizure may someday overcome many of the side effects and limitations of currently available treatment options.”

Study results appear online in Nature Communications.

More than 3 million Americans suffer from epilepsy, a condition of recurrent spontaneous seizures that occur unpredictably, often cause changes in consciousness, and can preclude normal activities such as driving and working. In at least 40 percent of patients, seizures cannot be controlled with existing drugs, and even in those whose seizures are well controlled, the treatments can have major cognitive side effects.

Although the study was carried out in mice, not humans, Soltesz said the work could lead to a better alternative to the currently available electrical stimulation devices.

Temple scientists find cancer-causing virus in the brain, potential connection to epilepsy

Researchers at Shriner’s Hospital Pediatric Research Center at the Temple University School of Medicine, and the University of Pennsylvania have evidence linking the human papillomavirus 16 (HPV16) – the most common cause of cervical cancer – to a common form of childhood epilepsy. They have shown for the first time that HPV16 may be present in the human brain, and found that when they added a viral protein to the brains of fetal mice, the mice all demonstrated the same developmental problems in the cerebral cortex associated with this type of epilepsy, called focal cortical dysplasia type IIB (FCDIIB). The findings suggest that the virus could play a role in the development of epilepsy.

The results also mean that doctors may have to re-think their approach to treating this type of epilepsy, and perhaps consider other therapeutic options related to HPV, an infectious disease.

"This is a novel mechanism, and it fills a gap in our understanding about the development of congenital brain malformations," said Peter Crino, MD, PhD, Professor of Neurology at Temple University School of Medicine, and a member of Shriner’s Hospital Pediatric Research Center, and the senior author of a recent report in the Annals of Neurology.

"If our data are correct, future treatment of cortical dysplasia could include targeted therapy against HPV16 infection, with the goal of halting seizures. Identifying an infectious agent as part of the pathogenesis of brain malformations could open up an array of new therapeutic approaches against various forms of epilepsy."

(Image: ASME.org)

Science Needs a Second Opinion: Researchers Find Flaws in Study of Patients in “Vegetative State”

A team of researchers led by Weill Cornell Medical College is calling into question the published statistics, methods and findings of a highly publicized research study that claimed bedside electroencephalography (EEG) identified evidence of awareness in three patients diagnosed to be in a vegetative state.

The new reanalysis study led by Weill Cornell neurologists Drs. Andrew Goldfine, Jonathan Victor, and Nicholas Schiff, published in the Jan. 26 issue of the journal Lancet, reports the statistical results and methodology used by a research team led by University of Western Ontario scientists and published online Nov. 9, 2011, also in the Lancet, was flawed in a number of crucial ways. Due to these errors, the reanalysis concludes it is impossible to determine whether or not these vegetative state study subjects demonstrated any degree of awareness during the testing.

Read more

(Image: RightBrainPhotography)

Children’s complex thinking skills begin forming before they go to school

New research at the University of Chicago and the University of North Carolina at Chapel Hill shows that children begin to show signs of higher-level thinking skills as young as age 4 ½. Researchers have previously attributed higher-order thinking development to knowledge acquisition and better schooling, but the new longitudinal study shows that other skills, not always connected with knowledge, play a role in the ability of children to reason analytically. 

The findings, reported in January in the journal Psychological Science, show for the first time that children’s executive function has a role in the development of complicated analytical thinking. Executive function includes such complex skills as planning, monitoring, task switching, and controlling attention. High early executive function skills at school entry are related to higher than average reasoning skills in adolescence. 

Growing research suggests that executive function may be trainable through pathways, including preschool curriculum, exercise and impulse control training. Parents and teachers may be able to help encourage development of executive function by having youngsters help plan activities, learn to stop, think, and then take action, or engage in pretend play, said lead author of the study, Lindsey Richland, assistant professor of comparative human development at the University of Chicago.

Although important to a child’s education, “little is known about the cognitive mechanisms underlying children’s development of the capacity to engage in complex forms of reasoning,” Richland said.

The new research is reported in the paper “Early Executive Function Predicts Reasoning Development” and follows the development of complex reasoning in children from before the time they go to school until they are 15. Richland’s co-author is Margaret Burchinal, senior scientist at the Frank Porter Graham Child Development Institute at the University of North Carolina at Chapel Hill.

(Image: Shutterstock)

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.

New Brain Circuit Sheds Light on Development of Voluntary Movements

All parents know the infant milestones: turning over, learning to crawl, standing, and taking that first unassisted step. Achieving each accomplishment presumably requires the formation of new connections among subsets of the billions of nerve cells in the infant’s brain. But how, when and where those connections form has been a mystery.

Now researchers at Duke Medicine have begun to find answers. In a study reported Jan. 23, 2013, in the scientific journal Neuron, the research team describes the entire network of brain cells that are connected to specific motor neurons controlling whisker muscles in newborn mice.

A better understanding of such motor control circuits could help inform how human brains develop, potentially leading to new ways of restoring movement in people who suffer paralysis from brain injuries, or to the development of better prosthetics for limb replacement.

“Whiskers to mice are like fingers to humans, in that both are moving touch sensors,” said lead investigator Fan Wang, PhD, associate professor of cell biology and member of the Duke Institute for Brain Sciences. “Understanding how the mouse’s brain controls whisker movements may tell us about neural control of finger movements in people.”

Mice are active at night, so they rely heavily on whiskers to detect and discriminate objects in the dark, brushing their whiskers against objects in a rhythmic back-and-forth sweeping pattern referred to as “whisking”. But this whisking behavior does not appear until about two weeks after birth, when young mice start to explore the world outside their nest.

To learn how motor control of whiskers takes place, Wang and postdoctoral fellow Jun Takatoh used a new technique that takes advantage of the rabies virus’ ability to spread through connected nerve cells. A disabled form of the virus used to vaccinate pets was created with the ability to express a fluorescent protein. The researchers were able to trace its path through a network of brain cells directly connected to the motor neurons controlling whisker movement.

“The precision of this mapping method allowed us to ask a key question, namely are parts of the whisker motor control circuitry not yet connected in newborn mice, and are such missing links added later to enable whisking?” Wang said.

By taking a series of pictures in the fluorescently labeled brains during the first two weeks after birth, the research team chronicled the developing circuits before and after mice start whisking.

“When we traced the circuit it was stunning in the sense that we didn’t realize there are so many pools of neurons located throughout the brainstem that are connected to whisker motor neurons,” said Wang. “It’s remarkable that a single motor neuron receives so many inputs, and somehow is able to integrate them.”

At the same time whisking movements emerge, motor neurons receive a new set of inputs from a region of the brainstem called the LPGi. A single LPGi neuron is connected to motor neurons on both sides of the face, putting them in perfect position to synchronize the movements of left and right whiskers.

To learn more about the new circuit formed between LPGi and motor neurons, Wang and Takatoh drew on the expertise of Duke colleague Richard Mooney, PhD, professor of neurobiology, and his student Anders Nelson. Together, the researchers were able to record the labeled neurons and found the LPGi neurons communicate with motor neurons using glutamate, the main neurotransmitter that stimulates the brain. They further discovered that LPGi neurons receive direct inputs from the motor cortex.

“This makes sense because exploratory whisking is a voluntary movement under control of the motor cortex,” Wang said. “Excitatory input is needed for initiating such movements, and LPGi may be critical for relaying signals from the motor cortex to whisker motor neurons.”

The researchers will next explore the connectivity by using genetic, viral and optical tools to see what happens when certain components of the circuits are activated or silenced during various motor tasks.