A group of really brainy scientists have moved closer to growing “therapeutic” brain cells in the laboratory that can be re-integrated back into patients’ brains to treat a wide range of neurological conditions. According to new research published online in The FASEB Journal, brain cells from a small biopsy can be used to grow large numbers of new personalized cells that are not only “healthy,” but also possess powerful attributes to preserve and protect the brain from future injury, toxins and diseases. Scientists are hopeful that ultimately these cells could be transformed in the laboratory to yield specific cell types needed for a particular treatment, or to cross the “blood-brain barrier” by expressing specific therapeutic agents that are released directly into the brain.

"This work is an example of how integrating basic science and clinical care may reveal privileged opportunities for biomedical research," said Matthew O. Hebb, M.D., Ph.D., FRCSC, a researcher involved in the work from the Departments of Clinical Neurological Sciences (Neurosurgery), Oncology and Otolaryngology at the University of Western Ontario in Ontario, Canada. "It is our hope that the results of this study provide a footing for further advancement of personalized, cell-based treatments for currently incurable and devastating neurological disorders."

Scientists enrolled patients with Parkinson’s disease who were scheduled to have deep brain stimulation (DBS) surgery, a commonly used procedure that involves placing electrodes into the brain. Before the electrodes were implanted, small biopsies were removed near the surface of the brain and multiplied in culture to generate millions of patient-specific cells that were then subjected to genetic analysis. These cells were complex in their make-up, but exhibited regeneration and characteristics of a fundamental class of brain cells, called glia. They expressed a broad array of natural and potent protective agents, called neurotrophic factors.

"From an extremely small amount of brain tissue, we will one day be able to do very big things," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “For centuries, treating the brain effectively and safely has been elusive. This advance opens the doors to not only new therapies for a myriad of brain diseases, but new ways of delivering therapies as well.”

(Source: eurekalert.org)

Researchers at The University of Texas at Dallas have taken a step toward developing a new treatment to aid the recovery of limb function after strokes.

In a study published online in the journal Neurobiology of Disease, researchers report the full recovery of forelimb strength in animals receiving vagus nerve stimulation.

“Stroke is a leading cause of disability worldwide,” said Dr. Navid Khodaparast, a postdoctoral researcher in the School of Behavioral and Brain Sciences and lead author of the study. “Every 40 seconds, someone in the U.S. has a stroke. Our results mark a major step in the development of a possible treatment.”

Vagus nerve stimulation (VNS) is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.

Khodaparast and his colleagues used vagus nerve stimulation precisely timed to coincide with rehabilitative movements in rats. Each of the animals had previously experienced a stroke that impaired their ability to pull a handle.

Stimulation of the vagus nerve causes the release of chemicals in the brain known to enhance learning and memory called neurotransmitters, specifically acetylcholine and norepinephrine. Pairing this stimulation with rehabilitative training allowed Khodaparast and colleagues to improve recovery.

Many rehabilitative interventions try to enhance neuroplasticity (the brain’s ability to change) in conjunction with physical rehabilitation to drive the recovery of lost functions, according to Khodaparast. Unfortunately, up to 70 percent of stroke patients still display long-term impairment in arm function after traditional rehabilitation.

“For years, the majority of stroke patients have received treatment with various drugs and/or physical rehabilitation,” Khodaparast said. “Medications can have widespread effects in the brain and the effects can last for long periods of time. In some cases the side effects outweigh the benefits. Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”

Khodaparast acknowledged the study has some limitations. For example, the animals were young and lacked some of the other illnesses that accompany an aged human population, such as diabetes or hypertension. But Khodaparast and his colleagues said they are optimistic about vagus nerve stimulation as a future tool. They will continue testing in chronically impaired animals with the hopes of translating the technique for stroke patients. Working with MicroTransponder Inc., a partner company in the current study, researchers at the University of Glasgow in Scotland have begun a small-scale trial in humans.

“There is strong evidence that VNS can be used safely in stroke patients because of its extensive use in the treatment of other neurological conditions,” said Dr. Michael Kilgard, professor in neuroscience at UT Dallas and senior author of the study.

Kilgard is also conducting clinical trials using vagus nerve stimulation to treat tinnitus, the medical condition of unexplained ringing in the ears. Kilgard’s lab first demonstrated the ability of vagus nerve stimulation to enhance brain adaptability in a 2011 Nature paper.

(Source: utdallas.edu)

About 70 percent of a person’s intelligence can be explained by their DNA — and those genetic influences only get stronger with age, according to new research from The University of Texas at Austin.

The study, authored by psychology researchers Elliot Tucker-Drob, Daniel Briley and Paige Harden, shows how genes can be stimulated or suppressed depending on the child’s environment and could help bridge the achievement gap between rich and poor students. The findings are published online in Current Directions in Psychological Science.

To investigate the underlying mechanisms at work, Tucker-Drob and his colleagues analyzed data from several studies tracking the cognitive ability and environmental circumstances of twin and sibling pairs. According to the findings, genetic factors account for 80 percent of cognition for children in economically advantaged households. Yet disadvantaged children – who rank lower in cognitive performance across the board – show almost no progress attributable to their genetic makeup.

This doesn’t mean disadvantaged children are genetically inferior. Instead, they have less high-quality opportunities, such as learning resources and parental involvement, to reach their genetic potential, Tucker-Drob says. 

“Genetic influences on cognitive ability are maximized when people are free to select their own learning experiences,” says Tucker-Drob, who is an assistant professor of psychology. “We were born with blueprints; the question is how are we using our experiences to build upon our genetic makeup?”

In a related study, Daniel Briley, a psychology doctoral student, examined how genetic and environmental influences on cognition change over time. Using meta-analytic procedures — the statistical methods used to analyze and combine results from previous, related literature — Briley examined genetic and environmental influences on cognition in twin and sibling pairs from infancy to adolescence.

According to his findings, published in the July issue of Psychological Science, genes influencing cognition become activated during the first decade of life and accelerate over time. The results emphasize the importance of early literacy and education during the first decade of life.

“As children get older, their parents and teachers give them increasing autonomy to do their homework to the best of their ability, pay attention in class, and choose their peer group,” says Briley. “Each of these behaviors likely influences their academic development. If these types of behaviors are influenced by genes, then it would explain why the heritability of cognitive ability increases as children age.”

Tucker-Drob says this research highlights the possibilities for bridging the achievement gap between the rich and poor.

“The conventional view is that genes place an upper limit on the effects of social intervention on cognitive development,” says Tucker-Drob. “This research suggests the opposite. As social, educational and economic opportunities increase in a society, more children will have access to the resources they need to maximize their genetic potentials.”

(Source: utexas.edu)

Findings in bacteria, yeast, mice show how flawed transport gene contributes to the condition

Researchers say it’s clear that some cases of autism are hereditary, but have struggled to draw direct links between the condition and particular genes. Now a team at the Johns Hopkins University School of Medicine, Tel Aviv University and Technion-Israel Institute of Technology has devised a process for connecting a suspect gene to its function in autism.

In a report in the Sept. 25 issue of Nature Communications, the scientists say mutations in one such autism-linked gene, dubbed NHE9, which is involved in transporting substances in and out of structures within the cell, causes communication problems among brain cells that likely contribute to autism.

“Autism is considered one of the most inheritable neurological disorders, but it is also the most complex,” says Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “There are hundreds of candidate genes to sort through, and a single genetic variant may have different effects even within the same family. This makes it difficult to separate the chaff from the grain, to distinguish harmless variations from disease-causing mutations. We were able to use a new process to screen variants in one candidate gene that has been linked to autism, and figure out how they might contribute to the disorder.”

An estimated one in 88 children in the United States is affected by autism spectrum disorders, a group of neurological development conditions marked by varying degrees of social, communication and behavioral problems. Scientists for years have looked for the biological roots of the problem using tools such as genome-wide association studies and gene-linkage analysis, which crunch genetic and health data from thousands of people in an effort to pinpoint disease-causing genetic variants. But while such techniques have turned up a number of gene mutations that may be linked to autism, none of them appear in more than 1 percent of people with the condition. With numbers that low, researchers need a way to screen variants in order to make a definitive link, Rao says.

For the new study, Rao and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders. The gene was already known to be involved in transporting hydrogen, sodium and potassium ions in and out of cellular compartments called endosomes, and the team wondered how this function might be related to neurological conditions.

Rao’s collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria. They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein’s shape and function. Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao’s team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast. “Using yeast to screen the function of variants was a quick, easy and inexpensive way of figuring out which were worth further study, and which we could ignore because they didn’t have any effect,” Rao says. To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains. They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells. Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate. Because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory, Rao says. “Elevated glutamate levels are known to trigger seizures, perhaps explaining why autistic patients with mutations in NHE9 and related genes also have seizures,” she notes.

Rao and her team hope that pinpointing the importance of this trafficking mechanism in autism spectrum disorders may lead to the development of new drugs for autism that alter endosomal pH. As the use of genomic data becomes increasingly commonplace in the future, the step-wise strategy devised by her team can be used to screen gene variants and identify at-risk patients, she says.

(Source: hopkinsmedicine.org)

A mix of serendipity and dogged laboratory work allowed a diverse team of University of Pittsburgh scientists to report in the Oct. 1 issue of Nature Cell Biology that they had solved the mystery of a basic biological function essential to cellular health.

By discovering a mechanism by which mitochondria – tiny structures inside cells often described as “power plants” – signal that they are damaged and need to be eliminated, the Pitt team has opened the door to potential research into cures for disorders such as Parkinson’s disease that are believed to be caused by dysfunctional mitochondria in neurons.

"It’s a survival process. Cells activate to get rid of bad mitochondria and consolidate good mitochondria. If this process succeeds, then the good ones can proliferate and the cells thrive," said Valerian Kagan, Ph.D., D.Sc., a senior author on the paper and professor and vice chair of the Pitt Graduate School of Public Health’s Department of Environmental and Occupational Health. "It’s a beautiful, efficient mechanism that we will seek to target and model in developing new drugs and treatments."

Dr. Kagan, who, as a recipient of a Fulbright Scholar grant, currently is serving as visiting research chair in science and the environment at McMaster University in Ontario, Canada, likened the process to cooking a Thanksgiving turkey.

"You put the turkey in the oven and the outside becomes golden, but you can’t just look at it to know it’s ready. So you put a thermometer in, and when it pops up, you know you can eat it," he said. "Mitochondria give out a similar ‘eat me’ signal to cells when they are done functioning properly."

Cardiolipins, named because they were first found in heart tissue, are a component on the inner membrane of mitochondria. When a mitochondrion is damaged, the cardiolipins move from its inner membrane to its outer membrane, where they encourage the cell to destroy the entire mitochondrion.

However, that is only part of the process, says Charleen T. Chu, M.D., Ph.D., professor and the A. Julio Martinez Chair in Neuropathology in the Pitt School of Medicine’s Department of Pathology, another senior author of the study. “It’s not just the turkey timer going off; it’s a question of who’s holding the hot mitt to bring it to the dining room?” That turns out to be a protein called LC3. One part of LC3 binds to cardiolipin, and LC3 causes a specialized structure to form around the mitochondrion to carry it to the digestive centers of the cell.

The research arose nearly a decade ago when Dr. Kagan had a conversation with Dr. Chu at a research conference. Dr. Chu, who studies autophagy, or “self-eating,” in Parkinson’s disease, was seeking a change on the mitochondrial surface that could signal to LC3 to bring in the damaged organelle for recycling. It turned out they were working on different sides of the same puzzle.

Together with Hülya Bayır, M.D., research director of pediatric critical care medicine, Children’s Hospital of Pittsburgh of UPMC and professor, Pitt’s Department of Critical Care Medicine, and a team of nearly two dozen scientists, the three senior authors worked out how the pieces of the mitochondria signaling problem fit together.

Now that they’ve worked out the basic mechanism, Dr. Chu indicates that many more research directions will likely follow.

"There are so many follow-up questions," she said. "What is the process that triggers the cardiolipin to move outside the mitochondria? How does this pathway fit in with other pathways that affect onset of diseases like Parkinson’s? Interestingly, two familial Parkinson’s disease genes also are linked to mitochondrial removal."

Dr. Bayir explained that while this process may happen in all cells with mitochondria, it is particularly important that it functions correctly in neuronal cells because these cells do not divide and regenerate as readily as cells in other parts of the body.

"I think these findings have huge implications for brain injury patients," she said. "The mitochondrial ‘eat me’ signaling process could be a therapeutic target in the sense that you need a certain level of clearance of damaged mitochondria. But, on the other hand, you don’t want the clearing process to go on unchecked. You must have a level of balance, which is something we could seek to achieve with medications or therapy if the body is not able to find that balance itself."

(Source: upmc.com)

The logo of the 1984 Los Angeles Olympics includes red, white and blue stars, but the white star is not really there: It is an illusion. Similarly, the “S” in the USA Network logo is wholly illusory.

Both of these logos take advantage of a common perceptual illusion where the brain, when viewing a fragmented background, frequently sees shapes and surfaces that don’t really exist.

“It’s hallucinating without taking drugs,” said Alexander Maier, assistant professor of psychology at Vanderbilt University, who headed a team of neuroscientists who has pinpointed the area of the brain that is responsible for these “illusory contours.”

In the Sept. 30 online early edition of the Proceedings of the National Academy of Sciences, Maier’s team reported that they have discovered groups of neurons in a region of the visual cortex called V4 that fire when an individual is viewing a pattern that produces such an illusion and remain quiescent when viewing an almost identical pattern that doesn’t.

Studies have shown that a diverse range of species, including monkeys, cats, owls, goldfish and even honeybees perceive these illusory contours. This has led scientists to propose that they are the byproduct of methods that the brain has evolved to spot predators or prey hiding in the bushes, a capability with considerable survival value.

Although scientists discovered illusory contours more than a century ago, it is only in the last 30 years that they have begun studying them because they reveal the internal mechanisms that the brain uses to interpret sensory input.

The gold square marks the location in the V4 region of a macaque’s visual cortex, where the neurons respond to visual contours. (Alex Maier, Donna Pritchett / Vanderbilt)

In mammals, visual stimuli is processed in the back of the brain in an area called the visual cortex. Efforts to map this area have found that it is made up of five different regions at the back of brain (labeled V1 to V5.)

The primary visual cortex, V1, takes the stimuli coming from the eyes and sorts it by a variety of basic properties, including orientation, color and spatial variation. It also splits the information into two pathways, called the dorsal and ventral streams.

From V1, both streams are routed to the second major area of the visual cortex. V2 performs many of the same functions as V1 but adds some more complex processing, such as recognizing the disparities in the signals coming from the two eyes that produce binocular vision.

From V2, one pathway, sometimes called the “Where Pathway,” goes to V5 and is associated with object location and motion detection. The other pathway, sometimes called the “What Pathway,” goes to V4 and is associated with object representation and form recognition.

“Studies have shown that V4 is involved in both object recognition and visual attention, so we thought it might also be involved with illusory contours,” said Michele Cox, the Vanderbilt graduate student who is first author on the study.

A Kanizsa square (Courtesy of D. Alan Stubbs, University of Maine)

First, the researchers searched for the neurons in V4 that were associated with different locations in the retinas of macaque monkeys. Once these maps were complete, they rewarded the monkeys for staring at a screen containing an example of an illusory contour called a Kanizsa square. This consists of four “Pac-Man” figures with their “mouths” oriented to form the corners of a square. When black Pac-Men are placed on a white background, the brain creates a bright white square connecting them.

While the monkeys were looking at the Kanizsa square, the researchers discovered that the neurons that represented the area in the middle of the Pac-Men, the area covered by the illusory square, began firing. However, when the monkeys viewed the same four Pac-Men with their mouths facing outward – an orientation that doesn’t produce the illusion – these central neurons remained silent.

“Basically, the brain is acting like a detective,” said Maier. “It is responding to cues in the environment and making its best guesses about how they fit together. In the case of these illusions, however, it comes to an incorrect conclusion.”

Two graphs show the activity of neurons in V4 associated with the position of the illusory Kanizsa square. The percentage of neurons firing more than doubles when the monkey views pac-men with their mouths facing inward to produce the illusion (top) compared to their activity level when the monkey is viewing pac-men with their mouths facing outward (bottom). (Michelle Cox and Alex Maier / Vanderbilt)

(Source: news.vanderbilt.edu)