Neuroscience

May 22, 2012

University of Georgia researchers have developed a map of the human brain that shows great promise as a new guide to the inner workings of the body’s most complex and critical organ.

With this map, researchers hope to create a next-generation brain atlas that will be an alternative option to the atlas created by German anatomist Korbinian Brodmann more than 100 years ago, which is still commonly used in clinical and research settings.

Tianming Liu, assistant professor of computer science in the UGA Franklin College of Arts and Sciences, and his students Dajiang Zhu and Kaiming Li identified 358 landmarks throughout the brain related to memory, vision, language, arousal regulation and many other fundamental bodily operations. Their findings were published in the April issue of Cerebral Cortex.

The landmarks were discovered using diffusion tensor imaging, a sophisticated neuroimaging technique that allows scientists to visualize nerve fiber connections throughout the brain. Unlike many other neuroimaging studies, their map does not focus only on one section of the brain but rather the whole cerebral cortex.

"Previously, researchers would examine at most three or four small brain networks," Liu said. "We want to examine the whole brain connection, and this is the so-called connectome."

The new map provides a clearer picture of how different areas of the brain are physically connected and how these connections relate to basic brain function. Liu and his team examined hundreds of healthy young adults to establish the landmarks, which they call dense individualized and common connectivity-based cortical landmarks, or DICCCOL.

After extensive testing and comparison, the team determined that these nodes are present in every normal brain, meaning they can be used as a basis of comparison for those with damaged brain tissue or altered brain function.

"DICCCOL is very similar to a GPS system," Zhu said, "only it’s a GPS map of the human brain."

Now, thanks in part to a five-year, $1.6 million grant from the National Institutes of Health, Liu and collaborators Xiaoping Hu and Claire Coles at Emory University are preparing to test their brain map by comparing healthy brains with those of children whose brains were damaged by exposure to cocaine while in the womb.

Prenatal cocaine exposure, or PCE, can cause serious damage to brain networks. Because of this, analysis of the damage provides Liu and his team with an excellent opportunity to evaluate the usefulness of their map.

After comparing the PCE brains to those of healthy individuals, they hope to determine the segments of the brain responsible for physical or mental disabilities observed in children exposed to cocaine.

"The PCE brain is disrupted in a systematic way; the whole brain is wrongly wired," Liu said. "We want to test our map in one of the worst cases, and then we will know if it will work in other cases."

Once the robustness of their map is established, Liu and his team hope that it may prove useful in the evaluation of many other brain disorders, such as Alzheimer’s disease, Parkinson’s disease or stroke.

"This really is a fundamental technology," Liu said. "When we establish these DICCCOLS, we can very easily extend this project to other populations, to other brain diseases."

More information: Liu’s team published their DICCCOL data sets, which includes the source code and diffusion tensor images, at http://dicccol.cs.uga.edu so other researchers may use the findings in their own experiments.

The article, “DICCCOL: Dense Individualized and Common Connectivity-Based Cortical Landmarks,” is available at http://cercor.oxfordjournals.org/content/early/2012/04/05/cercor.bhs072.short

Provided by University of Georgia

Source: medicalxpress.com

ScienceDaily (May 21, 2012) — Seventy-two percent of teenagers participating in a study experienced reduced hearing ability following exposure to a pop rock performance by a popular female singer.

Seventy-two percent of teenagers participating in a study experienced reduced hearing ability following exposure to a pop rock performance by a popular female singer. (Credit: © DWP / Fotolia)

M. Jennifer Derebery, MD, House Clinic physician, along with the House Research Institute tested teens’ hearing before and after a concert and presented the study findings at the American Otologic Society meeting on April 21, 2012. The study has been accepted for publication in an upcoming issue of Otology & Neurotology.

The hearing loss that may be experienced after a pop rock concert is not generally believed to be permanent. It is called a temporary threshold shift and usually disappears within 16-48 hours, after which a person’s hearing returns to previous levels.

“Teenagers need to understand a single exposure to loud noise either from a concert or personal listening device can lead to hearing loss,” said M. Jennifer Derebery, MD, lead author and physician at the House Clinic. “With multiple exposures to noise over 85 decibels, the tiny hair cells may stop functioning and the hearing loss may be permanent.”

In the study, twenty-nine teenagers were given free tickets to a rock concert. To ensure a similar level of noise exposure for the teens, there were two blocks of seats within close range of each other. The seats were located in front of the stage at the far end of the venue approximately 15-18 rows up from the floor.

Parental consent was obtained for all of the underage study participants. The importance of using hearing protection was explained to the teenagers. Researchers then offered hearing protection to the subjects and encouraged them to use the foam ear plugs. However, only three teenagers chose to do so.

Three adult researchers sat with the teenagers. Using a calibrated sound pressure meter, 1,645 measurements of sound decibel (dBA) levels were recorded during the 26 songs played during the three hour concert. The sound levels ranged from 82-110 dBA, with an average of 98.5 dBA. The mean level was greater than 100 dBA for 10 of the 26 songs.

The decibel levels experienced at the concert exceeded what is allowable in the workplace, according to Occupational Safety and Health Administration (OSHA). OSHA safe listening guidelines set time limits for exposures to sound levels of 85 dB and greater in the workplace. The volumes recorded during the concert would have violated OSHA standards in less than 30 minutes. In fact, one third of the teen listeners showed a temporary threshold shift that would not be acceptable in adult workplace environments.

Following the concert, the majority of the study participants also were found to have a significant reduction in the Distortion Product Otoacoustic Emissions (OAE) test. This test checks the function of the tiny outer hair cells in the inner ear that are believed to be the most vulnerable to damage from prolonged noise exposure, and are crucial to normal hearing, the ability to hear soft (or low level sounds), and the ability to understand speech, especially in noisy environments. With exposure to loud noise, the outer hair cells show a reduction in their ability to function, which may later recover. However, it is known that with repeated exposure to loud noise, the tiny hair cells may become permanently damaged. Recent animal research suggests that a single exposure to loud noise may result in permanent damage to the hearing nerve connections themselves that are necessary to hear sound.

Following the concert, 53.6 percent of the teens said they did not think they were hearing as well after the concert. Twenty-five percent reported they were experiencing tinnitus or ringing in their ears, which they did not have before the concert.

Researchers are especially concerned, because in the most recent government survey on health in the United States National Health and Nutrition Examination Survey (NHANES) 2005-2006, 20% of adolescents were found to have at least slight hearing loss, a 31% increase from a similar survey done from 1988-1994.

The findings of the study clearly indicate more research is necessary to determine if the guidelines for noise exposure need to be revised for teenagers. More research is also needed to determine if teenager’s ears are more sensitive to noise than adults.

“It also means we definitely need to be doing more to ensure the sound levels at concerts are not so loud as to cause hearing loss and neurological damage in teenagers, as well as adults,” said Derebery. “Only 3 of our 29 teens chose to use ear protection, even when it was given to them and they were encouraged to do so. We have to assume this is typical behavior for most teen listeners, so we have the responsibility to get the sound levels down to safer levels.”

Researchers recommend teenagers and young adults take an active role in protecting their hearing by utilizing a variety of sound meter ‘apps’ available for smart phones. The sound meters will give a rough estimate of the noise level allowing someone to take the necessary steps to protect their hearing such as wearing ear plugs at a concert.

In addition, Derebery and the study co-authors would like to see concert promoters and the musicians themselves take steps to lower sound levels as well as encourage young concert goers to use hearing protection.

Source: Science Daily

ScienceDaily (May 21, 2012) — Turns out it’s not bad being top dog, or in this case, top baboon.

Wounded baboon. (Credit: Image courtesy of University of Notre Dame)

A new study by University of Notre Dame biologist Beth Archie and colleagues from Princeton and Duke Universities finds that high-ranking male baboons recover more quickly from injuries and are less likely to become ill than other males.

Archie, Jeanne Altmann of Princeton and Susan Alberts of Duke examined health records from the Amboseli Baboon Research Project in Kenya. They found that high rank is associated with faster wound healing. The finding is somewhat surprising, given that top-ranked males also experience high stress, which should suppress immune responses. They also found that social status is a better predictor of wound healing than age.

"In humans and animals, it has always been a big debate whether the stress of being on top is better or worse than the stress of being on the bottom," said Archie, lead researcher on the study. "Our results suggest that, while animals in both positions experience stress, several factors that go along with high rank might serve to protect males from the negative effects of stress."

"The power of this study is in identifying the biological mechanisms that may confer health benefits to high-ranking members of society," said George Gilchrist, program director in the National Science Foundation (NSF)’s Division of Biology, which funded the research. "We know that humans have such benefits, but it took meticulous long-term research on baboon society to tease out the specific mechanisms. The question remains of causation: Is one a society leader because of stronger immune function or vice versa?"

The researchers examined 27 years of data on naturally occurring illness and injuries in wild male baboons, which is a notably large data set. Although research of health and disease in animals in laboratory settings has been quite extensive, this study is one of most comprehensive ever conducted on animals in a natural setting.

The research team investigated how differences in age, physical condition, stress, reproductive effort and testosterone levels contribute to status-related differences in immune functions. Previous research found that high testosterone levels and intense reproductive efforts can suppress immune function and are highest among high-ranking males.

However, Archie and her colleagues found that high-ranking males were less likely to become ill and recovered faster from injuries and illnesses than low-ranking males. The authors suggest that chronic stress, old age and poor physical condition associated with low rank may suppress immune function in low-ranking males.

"The complex interplay among social context, physiology and immune system-mediated health costs and benefits illustrates the power of interdisciplinary research," said Carolyn Ehardt, NSF program director for biological anthropology, which co-funded the research. "This research begins to tease apart the trade-offs in both high and low status in primates, including ourselves, which may lead to understanding the effects of social status on death and disease — not inconsequential for society as a whole."

Source: Science Daily

ScienceDaily (May 21, 2012) — Johns Hopkins scientists have discovered a protein that appears to play an important regulatory role in deciding whether stem cells differentiate into the cells that make up the brain, as well as countless other tissues. This finding, published in the April Developmental Cell, could eventually shed light on developmental disorders as well as a variety of conditions that involve the generation of new neurons into adulthood, including depression, stroke, and posttraumatic stress disorder.

Researchers have long known that a small group of proteins called Notch plays a pivotal role in helping the immature cells present in embryos to develop into the variety of cells present throughout the body, including those that make up the brain, blood, kidneys and muscles.

"Notch signaling is involved in almost all aspects of tissue development," explains study leader Valina Dawson, Ph.D., a professor in the departments of Neurology, Neuroscience, and Physiology and co-director of the Stem Cell and Neuroregeneration Programs at the Institute for Cell Engineering at the Johns Hopkins University School of Medicine.

However, she says, even for researchers who have been studying Notch for decades, how this small group of proteins manages the development of such a diverse array of tissues and organs in the body remains unknown. It’s a pivotal mystery to solve, Dawson adds, since problems in Notch signaling seem to be involved in various cancers, Alzheimer’s disease, juvenile stroke and many other health problems.

In their new study, Dawson and her colleagues shed light on one way Notch proteins might be regulated, through a protein they recently discovered in the lab. This protein seemed to be involved in development, but at first, the researchers didn’t know its function.

To determine what purpose this protein serves in cells, Dawson, postdoctoral fellow Zhikai Chi, M.D., Ph.D., and their colleagues started by trying to determine what other proteins it’s able to bind to. By adding the mystery protein to cell cultures that expressed a variety of other proteins, they determined that the unknown protein altered cellular activity in those expressing Notch.

Since Notch is involved intimately in determining the fate of brain precursor cells, driving neural stem cells to proliferate and determining whether they become neurons or supporting cells known as glia, the researchers next examined how this mystery protein affected brain development in mouse embryos. They found that by increasing expression of the unknown protein, more neurons developed in certain parts of the developing brain, including the intermediate zone and cortical plate. In contrast, decreasing expression led to fewer neurons. Taken together, Dawson says, these experiments provided even more evidence that their unknown protein was somehow influencing Notch.

To determine exactly how the mystery protein was affecting Notch, the researchers examined the effect of the protein on neural stem cells in the process of differentiating into mature cell types. Increasing the amount of the unknown protein swayed development as if Notch wasn’t working. Since the unknown protein appeared to prevent Notch from acting on cells, the researchers named it Botch for “blocks Notch.”

With Botch’s role now clear, the researchers turned next to the mechanism behind how this protein exerts its influence. A series of experiments suggests that Botch interacts with Notch in the Golgi body, a cellular organelle involved in modifying proteins. For Notch to act in development, an immature version of this protein needs to be cleaved in order for the protein to be rearranged. Botch appears to prevent this pivotal modification from taking place, reducing the amount of mature Notch available to do its job.

Because Botch appears to play such an important role in regulating Notch, Dawson says, it could be involved in a number of diseases in which the generation of new neurons is misregulated. She and her colleagues are already performing some preliminary experiments to determine whether Botch expression might vary from the norm in diseases such as depression, which has been linked to a decrease in neurogenesis in the brain’s hippocampus. Eventually, researchers might be able to develop drugs that act on Botch to restart stalled neurogenesis, potentially treating depression and other diseases in which a lack of neurogenesis is thought to play a role.

"There are potentially some very large neurological problems that could be addressed through changing Botch activity," Dawson says.

Source: Science Daily

May 21, 2012

New nerve cells formed in a select part of the brain could hold considerable sway over how much you eat and consequently weigh, new animal research by Johns Hopkins scientists suggests in a study published in the May issue of Nature Neuroscience.

The idea that the brain is still forming new nerve cells, or neurons, into adulthood has become well-established over the past several decades, says study leader Seth Blackshaw, Ph.D., an associate professor in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. However, he adds, researchers had previously thought that this process, called neurogenesis, only occurs in two brain areas: the hippocampus, involved in memory, and the olfactory bulb, involved in smell.

More recent research suggests that a third area, the hypothalamus — associated with a variety of bodily functions, including sleep, body temperature, hunger and thirst — also produces new neurons. However, the precise source of this neurogenesis and the function of these newborn neurons remained a mystery.

To answer these questions, Blackshaw and his colleagues used mice as a model system. The researchers started by investigating whether any particular part of the hypothalamus had a high level of cell growth, suggesting that neurogenesis was occurring. They injected the animals with a compound called bromodeoxyuridine (BrdU), which selectively incorporates itself into newly replicating DNA of dividing cells, where it’s readily detectable. Within a few days, the researchers found high levels of BrdU in an area of the hypothalamus called the median eminence, which lies on the base of the brain’s fluid-filled third ventricle.

Further tests showed that these rapidly proliferating cells were tanycytes, a good candidate for producing new neurons since they have many characteristics in common with cells involved in neurogenesis during early development. To confirm that tanycytes were indeed producing new neurons and not other types of cells, Blackshaw and his colleagues selectively bred mice that produced a fluorescent protein only in their tanycytes. Within a few weeks, they found neurons that also fluoresced, proof that these cells came from tanycyte progenitors.

With the source of hypothalamic neurogenesis settled, the researchers turned to the question of function. Knowing that many previous studies have suggested that animals raised on a high-fat diet are at significantly greater risk of obesity and metabolic syndrome as adults, Blackshaw’s team wondered whether hypothalamic neurogenesis might play a role in this phenomenon.

The researchers fed mice a diet of high-fat chow starting at weaning and looked for evidence of neurogenesis at several different time points. While very young animals showed no difference compared with mice fed normal chow, neurogenesis quadrupled in adults that had consistently eaten the high-fat chow since weaning. These animals gained more weight and had higher fat mass than animals raised on normal chow.

When Blackshaw and his colleagues killed off new neurons in the high-fat eaters by irradiating just their median eminences with precise X-ray beams, the mice gained significantly less weight and fat than animals who had eaten the same diet and were considerably more active, suggesting that these new neurons play a critical role in regulating weight, fat storage and energy expenditure.

"People typically think growing new neurons in the brain is a good thing — but it’s really just another way for the brain to modify behavior," Blackshaw explains. He adds that hypothalamic neurogenesis is probably a mechanism that evolved to help wild animals survive and helped our ancestors do the same in the past. Wild animals that encounter a rich and abundant food source would be well-served to eat as much as possible, since such a resource is typically scarce in nature.

Being exposed to such a resource during youth, and consequently encouraging the growth of neurons that would promote more food intake and energy storage in the future, would be advantageous. However, Blackshaw explains, for lab animals as well as people in developed countries, who have nearly unlimited access to abundant food, such neurogenesis isn’t necessarily beneficial — it could encourage excessive weight gain and fat storage when they’re not necessary.

If the team’s work is confirmed in future studies, he adds, researchers might eventually use these findings as a basis to treat obesity by inhibiting hypothalamic neurogenesis, either by irradiating the median eminence or developing drugs that inhibit this process.

Provided by Johns Hopkins University School of Medicine

Source: medicalxpress.com

May 21, 2012

A substance in human mesenchymal stem cells that promotes growth appears to spur restoration of nerves and their function in rodent models of multiple sclerosis (MS), researchers at Case Western Reserve University School of Medicine have found.

Their study appeared in the online version of Nature Neuroscience on Sunday, May 20.

In animals injected with hepatocyte growth factor, inflammation declined and neural cells grew. Perhaps most important, the myelin sheath, which protects nerves and their ability to gather and send information, regrew, covering lesions caused by the disease.

"The importance of this work is we think we’ve identified the driver of the recovery," said Robert H. Miller, professor of neurosciences at the School of Medicine and vice president for research at Case Western Reserve University.

Miller, neurosciences instructor Lianhua Bai and biology professor Arnold I. Caplan, designed the study. They worked with Project Manager Anne DeChant, and research assistants Jordan Hecker, Janet Kranso and Anita Zaremba, from the School of Medicine; and Donald P. Lennon, a research assistant from the university’s Skeletal Research Center.

In MS, the immune system attacks myelin, risking injury to exposed nerves’ intricate wiring. When damaged, nerve signals can be interrupted, causing loss of balance and coordination, cognitive ability and other functions. Over time, intermittent losses may become permanent.

Miller and Caplan reported in 2009 that when they injected human mesenchymal stem cells into rodent models of MS, the animals recovered from the damage wrought by the disease. Based on their work, a clinical trial is underway in which MS patients are injected with their own stem cells.

In this study, the researchers first wanted to test whether the presence of stem cells or something cells produce promotes recovery. They injected mice with the medium in which mesenchymal stem cells, culled from bone marrow, grew.

All 11 animals, which have a version of MS, showed a rapid reduction in functional deficits.

Analysis showed that the disease remained on course unless the molecules injected were of a certain size; that is, the molecular weight ranged between 50 and 100 kiloDaltons.

Research by others and results of their own work indicated hepatocyte growth factor, which is secreted by mesenchymal stem cells, was a likely instigator.

The scientists injected animals with 50 or 100 nanograms of the growth factor every other day for five days. The level of signaling molecules that promote inflammation decreased while the level of signaling molecules that counter inflammation increased. Neural cells grew and nerves laid bare by MS were rewrapped with myelin. The 100-nanogram injections appeared to provide slightly better recovery.

To test the system further, researchers tied up cell-surface receptors, in this case cMet receptors that are known to work with the growth factor.

When they jammed the receptors with a function-blocking cMet antibody, neither the mesenchymal stem cell medium nor the hepatocyte growth factor injections had any effect on the disease. In another test, injections of an anti-hepatocyte growth factor also blocked recovery.

The researchers will continue their studies, to determine if they can screen mesenchymal stem cells for those that produce the higher amounts of hepatocyte growth factor needed for effective treatment. That could lead to a more precise cell therapy.

"Could we now take away the mesenchymal stem cells and treat only with hepatocyte growth factor?” Miller asked. “We’ve shown we can do that in an animal but it’s not clear if we can do that in a patient.”

They also plan to test whether other factors may be used to stimulate the cMet receptors and induce recovery.

Provided by Case Western Reserve University

Source: medicalxpress.com

May 21, 2012

Max Planck scientists discover brain cells in monkeys that may be linked to self-awareness and empathy in humans.

The anterior insular cortex is a small brain region that plays a crucial role in human self-awareness and in related neuropsychiatric disorders. A unique cell type – the von Economo neuron (VEN) – is located there. For a long time, the VEN was assumed to be unique to humans, great apes, whales and elephants. Henry Evrard, neuroanatomist at the Max Planck Institute for Biological Cybernetics in Tübingen, Germany, now discovered that the VEN occurs also in the insula of macaque monkeys. The morphology, size and distribution of the monkey VEN suggest that it is at least a primal anatomical homolog of the human VEN. This finding offers new and much-needed opportunities to examine in detail the connections and functions of a cell and brain region that could have a key role in human self-awareness and in mental disorders including autism and specific forms of dementia.

The insular cortex, or simply insula, is a hidden cortical region folded and tucked away deep in the brain – an island within the cortex. Within the last decade, the insula has emerged from darkness as having a key role in diverse functions usually linked to our internal bodily states, to our emotions, to our self-awareness, and to our social interactions. The very anterior part of the insula in particular is where humans consciously sense subjective emotions, such as love, hate, resentment, self-confidence or embarrassment. In relation to these feelings, the anterior insula is involved in various psychopathologies. Damage of the insula leads to apathy, and to the inability to tell what feelings we or our conversational partner experience. These inabilities and alteration of the insula are also encountered in autism and other highly detrimental neuropsychiatric disorders including the behavioural variant of frontotemporal dementia (bvFTD).

The von Economo neuron (VEN) occurs almost exclusively in the anterior insula and anterior cingulate cortex. Until recently it was believed that the VEN is only present in humans, great apes and some large-brained mammals with complex social behaviour such as whales and elephants. In contrast to the typical neighbouring pyramidal neuron that is present in all mammals and all brain regions, the VEN has a peculiar spindle shape and is about three times as large. Their numeral density is selectively altered in autism and bvFTD. Henry Evrard and his team, at the Max Planck Institute for Biological Cybernetics in Tübingen now discovered VENs in the anterior insula in macaque monkeys. His present work provides compelling evidence that monkeys possess at least a primitive form of the human VEN although they do not have the ability to recognize themselves in a mirror, a behavioural hallmark of self-awareness.

"This means, other than previously believed, that highly concentrated VEN populations are not an exclusivity of hominids, but also occurs in other primate species", explains Henry Evrard. "The VEN phylogeny needs to be reexamined. Most importantly, the very much-needed analysis of the connections and physiology of these specific neurons is now possible.” Knowing the functions of the VEN and its connections to other regions of the brain in monkeys could give us clues on the evolution of the anatomical substrate of self-awareness in humans and may help us in better understanding serious neuropsychiatric disabilities including autism, or even addictions such as to drugs or smoking.

Provided by Max Planck Society

Source: medicalxpress.com

ScienceDaily (May 20, 2012) — To learn its signature melody, the male songbird uses a trial-and-error process to mimic the song of its father, singing the tune over and over again, hundreds of times a day, making subtle changes in the pitch of the notes. For the male Bengalese finch, this rigorous training process begins around the age of 40 days and is completed about day 90, just as he becomes sexually mature and ready to use his song to woo females.

To learn its signature melody, the male songbird uses a trial-and-error process to mimic the song of its father, singing the tune over and over again, hundreds of times a day, making subtle changes in the pitch of the notes. (Credit: © fasphotographic / Fotolia)

To accomplish this feat, the finch’s brain must receive and process large quantities of information about its performance and use that data to precisely control the complex vocal actions that allow it to modify the pitch and pattern of its song.

Now, scientists at UCSF have shown that a key brain structure acts as a learning hub, receiving information from other regions of the brain and figuring out how to use that information to improve its song, even when it’s not directly controlling the action. These insights may help scientists figure out new ways to treat neurological disorders that impair movement such as Huntington’s disease and Parkinson’s disease.

The research is reported as an advanced online publication on May 20, 2012 by the journal Nature, and will appear at a later date in the journal’s print edition.

Years of research conducted in the lab of Michael Brainard, PhD, an associate professor of physiology at UCSF, has shown that adult finches can keep track of slight differences in the individual “syllables,” or notes, they play and hear, and make mental computations that allow them to alter the pitch.

For previous experiments, Brainard and his colleagues developed a training process that induced adult finches to calibrate their song. They created a computer program that could recognize the pitch of every syllable the bird sang. The computer also delivered a sound the birds didn’t like — a kind of white noise — at the very moment they uttered a specific note. Within a few hours, the finches learned to alter the pitch of that syllable to avoid hearing the unpleasant sound.

In the new research, the UCSF neuroscientists used their technology to investigate how the learning process is controlled by the brain. A prevailing theory suggests that new learning is controlled by a “smart” brain structure called the basal ganglia, a cluster of interconnected brain regions involved in motor control and learning.

"It’s the first place where the brain is putting two and two together," said Jonathan Charlesworth, a recent graduate of UCSF’s neuroscience PhD program and the first author of the new paper. "If you remove the basal ganglia in a bird that hasn’t yet learned to sing, it will never learn to do so."

Once a basic, frequently repeated skill such as typing, singing the same song or shooting a basketball from the free-throw line is learned, the theory suggests, control of that activity is carried out by the motor pathway, the part of the nervous system that transmits signals from the brain to muscles. But for the basic routine to change — for a player to shoot from another spot on the basketball court or a bird to sing at a different pitch — the basal ganglia must again get involved, providing feedback that allows learning based on trial and error, the theory suggests.

What remained unclear is what makes the basal ganglia so “smart” and enables them to support such detailed trial-and-error learning. Was it something to do with their structure? Or were they getting information from elsewhere?

The scientists sought to answer this question by blocking the output of a key basal ganglia circuit while training male finches to alter their song using the white-noise blasts. As long as the basal ganglia were kept from sending signals to the motor pathway, the finches didn’t change their tune or show signs of learning. But when Brainard’s team stopped blocking the basal ganglia, something surprising happened: the finches immediately changed the pitch of their song, with no additional practice.

"It’s as if a golfer went to the driving range and was terrible, hitting the ball into the trees all day and not getting any better," said Charlesworth. "Then, at the end of the day, you throw a switch and all of a sudden you’re hitting the fairway like you’re Tiger Woods."

Normally, you’d expect improvement in skill performance like this to take time as the basal ganglia evaluates information, makes changes and gets new feedback, Brainard said.

"The surprise here is that the basal ganglia can pay attention, observe what other motor structures are doing and get information even when they aren’t involved in motor control," Brainard said. "They covertly learned how to improve skill performance and this explains how they did it."

These findings suggest that the basal ganglia’s “smartness” is due in large part to the steady flow of information they receive about the commands of other motor structures. It also portrays the basal ganglia as far more versatile than previously understood, able to learn how to calibrate fine-motor skills by acting as a specialized hub that receives information from various parts of the brain and responds to that information with new directives.

The findings also support the notion that problems in the basal ganglia circuit’s ability to receive information and learn from it may help trigger the movement disorders that are symptoms of Huntington’s and Parkinson’s, Brainard said.

Source: Science Daily

ScienceDaily (May 19, 2012) — Preliminary results from an ongoing, large-scale study by Yale School of Medicine researchers shows that oxytocin — a naturally occurring substance produced in the brain and throughout the body — increased brain function in regions that are known to process social information in children and adolescents with autism spectrum disorders (ASD).

Preliminary results from an ongoing, large-scale study by Yale School of Medicine researchers shows that oxytocin — a naturally occurring substance produced in the brain and throughout the body— increased brain function in regions that are known to process social information in children and adolescents with autism spectrum disorders (ASD). (Credit: Image courtesy of Yale University)

A Yale Child Study Center research team that includes postdoctoral fellow Ilanit Gordon and Kevin Pelphrey, the Harris Associate Professor of Child Psychiatry and Psychology, will present the results on May 19 at the International Meeting for Autism Research.

"Our findings provide the first, critical steps toward devising more effective treatments for the core social deficits in autism, which may involve a combination of clinical interventions with an administration of oxytocin," said Gordon. "Such a treatment approach will fundamentally improve our understanding of autism and its treatment."

Social-communicative dysfunctions are a core characteristic of autism, a neurodevelopmental disorder that can have an enormous emotional and financial burden on the affected individual, their families, and society.

Gordon said that while a great deal of progress has been made in the field of autism research, there remain few effective treatments and none that directly target the core social dysfunction. Oxytocin has recently received attention for its involvement in regulating social abilities because of its role in many aspects of social behavior and social cognition in humans and other species.

To assess the impact of oxytocin on the brain function, Gordon and her team conducted a first-of-its-kind, double-blind, placebo-controlled study on children and adolescents aged 7 to 18 with ASD. The team members gave the children a single dose of oxytocin in a nasal spray and used functional magnetic resonance brain imaging to observe its effect.

The team found that oxytocin increased activations in brain regions known to process social information. Gordon said these brain activations were linked to tasks involving multiple social information processing routes, such as seeing, hearing, and processing information relevant to understanding other people.

Source: Science Daily

ScienceDaily (May 18, 2012) — Exercise clears the mind. It gets the blood pumping and more oxygen is delivered to the brain. This is familiar territory, but Dartmouth’s David Bucci thinks there is much more going on.

Exercise clears the mind. It gets the blood pumping and more oxygen is delivered to the brain. This is familiar territory, but Dartmouth’s David Bucci thinks there is much more going on. (Credit: © Galina Barskaya / Fotolia)

"In the last several years there have been data suggesting that neurobiological changes are happening — [there are] very brain-specific mechanisms at work here," says Bucci, an associate professor in the Department of Psychological and Brain Sciences.

From his studies, Bucci and his collaborators have revealed important new findings:

• The effects of exercise are different on memory as well as on the brain, depending on whether the exerciser is an adolescent or an adult.
• A gene has been identified which seems to mediate the degree to which exercise has a beneficial effect. This has implications for the potential use of exercise as an intervention for mental illness.

Bucci began his pursuit of the link between exercise and memory with attention deficit hyperactivity disorder (ADHD), one of the most common childhood psychological disorders. Bucci is concerned that the treatment of choice seems to be medication.

"The notion of pumping children full of psycho-stimulants at an early age is troublesome," Bucci cautions. "We frankly don’t know the long-term effects of administering drugs at an early age — drugs that affect the brain — so looking for alternative therapies is clearly important."

Anecdotal evidence from colleagues at the University of Vermont started Bucci down the track of ADHD. Based on observations of ADHD children in Vermont summer camps, athletes or team sports players were found to respond better to behavioral interventions than more sedentary children. While systematic empirical data is lacking, this association of exercise with a reduction of characteristic ADHD behaviors was persuasive enough for Bucci.

Coupled with his interest in learning and memory and their underlying brain functions, Bucci and teams of graduate and undergraduate students embarked upon a project of scientific inquiry, investigating the potential connection between exercise and brain function. They published papers documenting their results, with the most recent now available in the online version of the journal Neuroscience.

Bucci is quick to point out that “the teams of both graduate and undergraduates are responsible for all this work, certainly not just me.” Michael Hopkins, a graduate student at the time, is first author on the papers.

Early on, laboratory rats that exhibit ADHD-like behavior demonstrated that exercise was able to reduce the extent of these behaviors. The researchers also found that exercise was more beneficial for female rats than males, similar to how it differentially affects male and female children with ADHD.

Moving forward, they investigated a mechanism through which exercise seems to improve learning and memory. This is “brain derived neurotrophic factor” (BDNF) and it is involved in growth of the developing brain. The degree of BDNF expression in exercising rats correlated positively with improved memory, and exercising as an adolescent had longer lasting effects compared to the same duration of exercise, but done as an adult.

"The implication is that exercising during development, as your brain is growing, is changing the brain in concert with normal developmental changes, resulting in your having more permanent wiring of the brain in support of things like learning and memory," says Bucci. "It seems important to [exercise] early in life."

Bucci’s latest paper was a move to take the studies of exercise and memory in rats and apply them to humans. The subjects in this new study were Dartmouth undergraduates and individuals recruited from the Hanover community.

Bucci says that, “the really interesting finding was that, depending on the person’s genotype for that trophic factor [BDNF], they either did or did not reap the benefits of exercise on learning and memory. This could mean that you may be able to predict which ADHD child, if we genotype them and look at their DNA, would respond to exercise as a treatment and which ones wouldn’t.”

Bucci concludes that the notion that exercise is good for health including mental health is not a huge surprise. “The interesting question in terms of mental health and cognitive function is how exercise affects mental function and the brain.” This is the question Bucci, his colleagues, and students continue to pursue.

Source: Science Daily

May 18, 2012

University of Iowa neuroscientist John Wemmie, M.D., Ph.D., is interested in the effect of acid in the brain. His studies suggest that increased acidity or low pH, in the brain is linked to panic disorders, anxiety, and depression. But his work also suggests that changes in acidity are important for normal brain activity too.

University of Iowa researchers have developed an MRI-based method to detect and monitor pH changes in living brains. The image shows MRI brain scans of human subject breathing air (left) or air containing 7.5 percent carbon dioxide (middle). The difference between the two scans (shown right) shows increased brain acidity in red caused by carbon dioxide inhalation as measured by the new MRI-based strategy. Credit: Vincent Magnotta, University of Iowa

"We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, a UI associate professor of psychiatry. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s studies have shown that these acid-sensing proteins are required for normal fear responses and for learning and memory in mice. However, while you can buy a kit to measure the pH (acidity) of your garden soil, there currently is no easy way to measure pH changes in the brain.

Wemmie teamed up with Vincent Magnotta, Ph.D., UI associate professor of radiology, psychiatry, and biomedical engineering, and using Magnotta’s expertise in developing MRI (magnetic resonance imaging)-based brain imaging techniques, the researchers developed and tested a new, non-invasive method to detect and monitor pH changes in living brains.

According to Wemmie, the new imaging technique provides the best evidence so far that pH changes do occur with normal function in the intact human brain. The findings were published May 7 in the Proceedings of the National Academy of Sciences (PNAS) Early Edition.

Specifically, the study showed the MRI-based method was able to detect global changes in brain pH in mice. Breathing carbon dioxide, which lowers pH (makes the brain more acidic), increased the signal, while bicarbonate injections, which increases brain pH, decreased the MRI signal. The relationship between the signal and the pH was linear over the range that was tested.

Importantly, the method also seems able to detect localized brain activity. When human volunteers viewed a flashing checkerboard — a classic experiment that activates a particular brain region involved in vision — the MRI method detected a drop in pH in that region. The team also confirmed the pH drop using other methods.

"Our study tells us, first, we have a technique that we believe can measure pH changes in the brain, and second, this MRI-based technique suggests that pH changes do occur with brain function,” Magnotta says.

"The results support our original idea that brain activity can change local pH in human brains during normal activity, meaning that pH change in conjunction with the pH-sensitive receptors could be part of a signaling system that affects brain activity and cognitive function," Wemmie adds

A new way to view brain activity

Importantly, this technique may also provide a new way to image the brain

Currently, functional MRI (fMRI) measures brain activity by detecting a signal that’s due to oxygen levels in the blood flowing to active brain regions. The UI team showed that their method responds to pH changes but is not influenced by changes in blood oxygenation. Conversely, fMRI does not respond to changes in pH.

"What we show is our method of detecting brain activity probably depends on pH changes and, more than that, it is distinct from the signal that fMRI measures," says Wemmie. "This gives us another tool to study brain activity."

pH and brain function

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.

“Brain activity is likely different in people with brain disorders, such as bipolar or depression and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day; could this signal be abnormal or perturbed in human psychiatric disease? And if so, it might be a target for manipulation and treatment?”

Provided by University of Iowa

Source: medicalxpress.com

May 18, 2012

It has been known for years that eating too many foods containing “bad” fats, such as saturated fats or trans fats, isn’t healthy for your heart. However, according to new research from Brigham and Women’s Hospital (BWH), one “bad” fat—saturated fat—was found to be associated with worse overall cognitive function and memory in women over time. By contrast, a “good” fat—mono-unsaturated fat was associated with better overall cognitive function and memory.

This study is published online by Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society, on May 18, 2012.

The research team analyzed data from the Women’s Health Study—originally a cohort of nearly 40,000 women, 45 years and older. The researchers focused on data from a subset of 6,000 women, all over the age of 65. The women participated in three cognitive function tests, which were spaced out every two years for an average testing span of four years. These women filled out very detailed food frequency surveys at the start of the Women’s Health Study, prior to the cognitive testing.

"When looking at changes in cognitive function, what we found is that the total amount of fat intake did not really matter, but the type of fat did,” explained Olivia Okereke, MD, MS, BWH Department of Psychiatry.

Women who consumed the highest amounts of saturated fat, which can come from animal fats such as red meat and butter, compared to those who consumed the lowest amounts, had worse overall cognition and memory over the four years of testing. Women who ate the most of the monounsaturated fats, which can be found in olive oil, had better patterns of cognitive scores over time.

"Our findings have significant public health implications," said Okereke. "Substituting in the good fat in place of the bad fat is a fairly simple dietary modification that could help prevent decline in memory."

Okereke notes that strategies to prevent cognitive decline in older people are particularly important. Even subtle declines in cognitive functioning can lead to higher risk of developing more serious problems, like dementia and Alzheimer disease.

Provided by Brigham and Women’s Hospital

Source: medicalxpress.com

May 17, 2012

Around 1 in 50 people in the general population and 1 in 6 of those aged over 40 years experience neuropathy (damage to the nerves of the peripheral nervous system), which can cause numbness, tingling, pain, or weakness. The most common cause of neuropathy is diabetes, and up to half of diabetes patients can be affected. Currently, among the only treatments for neuropathy are glucose control (which often only delays it) and pain management. Yet less than half of patients are treated for pain, despite the availability of many effective therapies . Growing evidence suggests that various metabolic risk factors, including prediabetes, could be linked with neuropathy and thus be targets for new disease-modifying drugs. The issues are discussed in a Review in the June issue of The Lancet Neurology, by Dr Brian C Callaghan and colleagues, all of the University of Michigan, Ann Arbor, MI, USA.

Diabetes can cause various patterns of so-called diabetic neuropathy, but the most common presentation is a distal symmetrical polyneuropathy (DSP), in which symptoms begin in the feet and spread up the limbs. Patients experience decreased quality of life, both physically and mentally. DSP can cause balance problems, which may lead to falls. Neuropathy is one of three main risk factors for falls in patients with diabetes, along with retinopathy and vestibular dysfunction. Patients with diabetic DSP are two to three times more likely to fall than those with diabetes and no neuropathy. Additionally, patients with severe DSP are at risk of ulcerations and lower-extremity amputations, with 15% developing an ulcer during the course of their disease. Diabetes is the leading cause of lower-extremity amputations, roughly 80 000 of which are undertaken in the USA every year in patients with the disorder. Indeed, patients with diabetes are 15 times more likely than people without diabetes to have this life-changing complication.

Overall, costs associated with diabetic neuropathy in the USA are estimated to be between 4•6 and 13•7 billion dollars, with most of the expense attributed to those with type 2 diabetes. Therefore, neuropathy is associated with a quarter of the total costs of diabetes care in the USA.

Since the data linking prediabetes (a condition with higher than normal blood sugar levels, but not yet high enough for a diabetes diagnosis) with neuropathy are conflicting, a comprehensive study is needed to establish whether or not it is one of the metabolic drivers that underlie the onset and progression of neuropathy. The answer has direct implications for potential therapies for many patients with neuropathy. Currently one third of adult Americans meet criteria for prediabetes, but less than 5% of these people have received a formal diagnosis of prediabetes from their health-care providers and only a small percentage are being treated .Establishing a causal relation between prediabetes and neuropathy would change the clinical management of a substantial number of patients.

Research suggests that various metabolic factors (components of ‘metabolic syndrome’) other than blood glucose control—such as levels of LDL (bad) cholesterol and high blood pressure—might have a role in the development of neuropathy. The authors say that there are promising lines of investigation that could lead to improved prevention and treatment of the disorder. The magnitude of the effect of glucose control on neuropathy is much smaller in patients with type 2 diabetes than in those with type 1 diabetes. In view of this small effect size and the fact that many patients with type 2 diabetes continue to develop neuropathy despite adequate glucose control, discovery of modifiable risk factors for neuropathy is essential. Callaghan and colleagues are currently conducting such a study.

The authors conclude: “Components of the metabolic syndrome, including prediabetes, are potential risk factors for neuropathy, and studies are needed to establish whether they are causally related to neuropathy. These lines of enquiry will have direct implications for the development of new treatments for diabetic neuropathy.”

Provided by Lancet

Source: medicalxpress.com

ScienceDaily (May 17, 2012) — Training the brain to reduce pain could be a promising approach for treating phantom limb pain and complex regional pain syndrome, according to an internationally known neuroscience researcher speaking May 17 at the American Pain Society’s Annual Scientific Meeting.

G. Lorimer Moseley, PhD, professor of clinical neurosciences at University of South Australia and Neuroscience Research Australia, and head of the Body in Mind research team, told the plenary session audience that the brain stores maps of the body that are integrated with neurological systems that survey, regulate, and protect the integrity of the body physically and psychologically. These cortical maps govern movement, sensation and perception, and there is growing evidence, according to Moseley, showing that disruptions of brain maps occur in people with chronic pain. The best evidence is from those with phantom limb pain and complex regional pain syndrome, but there is also data from chronic back pain.

Moseley’s research is focused on the role of the brain and mind in chronic and complex pain disorders. Through collaborations with clinicians, scientists and patients, the Body in Mind team is exploring how the brain and its representation of the body change when pain persists, how the mind influences physiological regulation of the body, how the changes in the brain and mind can be normalized with treatment.

"We’re learning that chronic pain is associated with disruption of brain maps of the body and of the space around the body. When the brain determines the location of a sensory event, it integrates the location of the event in the body with a map of space. Disruption of these processes might be contributing to the problem," said Moseley. He added that it is possible for the body to be unharmed but the brain will respond by causing pain because it misinterpreted a benign stimulus as an attack. "We want to gradually train the brain to stop trying to protect body tissue that doesn’t need protecting."

Moseley said the brain can “rewire” itself, a process called neuroplasticity. Often painful stimuli triggered by a broken bone or other trauma cause the brain to rewire and, as a result, the damage signal is never switched off after the initial body trauma is resolved. The result: Chronic pain. So if the brain is capable of changing to cause persistent pain, can it be changed back to normal to alleviate pain?

"The brain is the focal point of the pain experience, but the plasticity phenomena can be harnessed to help alleviate pain," Moseley said.

He further stated that disrupted cortical body maps may contribute to the development or maintenance of chronic pain and, therefore, could be viable targets for treatment. One treatment approach involves targeting motor systems through a process Moseley calls graded motor imagery. It relies on using visual images to help the brain change its perceptions of the body after prolonged pain stimuli. “For someone with phantom limb pain, the brain’s body map still includes the severed arm or leg, and without any real stimuli from the region, it continues to produce pain,” Moseley explained.

He reported that studies with graded motor imagery have shown encouraging results in complex regional pain syndrome and in phantom limb pain.

"Our work shows that the complex neural connections in the brain not only are associated with chronic pain, they can be reconnected or manipulated through therapy that alters brain perceptions and produce pain relief," said Moseley.

Source: Science Daily

ScienceDaily (May 17, 2012) — Mental distractions make pain easier to take, and those pain-relieving effects aren’t just in your head, according to a report published online on May 17 in Current Biology, a Cell Press publication.

The findings based on high-resolution spinal fMRI (functional magnetic resonance imaging) as people experienced painful levels of heat show that mental distractions actually inhibit the response to incoming pain signals at the earliest stage of central pain processing.

"The results demonstrate that this phenomenon is not just a psychological phenomenon, but an active neuronal mechanism reducing the amount of pain signals ascending from the spinal cord to higher-order brain regions," said Christian Sprenger of the University Medical Center Hamburg-Eppendorf.

Those effects involve endogenous opioids, which are naturally produced by the brain and play a key role in the relief of pain, the new evidence shows.

The research group asked participants to complete either a hard or an easy memory task, both requiring them to remember letters, while they simultaneously applied a painful level of heat to their arms.

When study participants were more distracted by the harder of the two memory tasks, they did indeed perceive less pain. What’s more, their less painful experience was reflected by lower activity in the spinal cord as observed by fMRI scans. (fMRI is often used to measure changes in brain activity, Sprenger explained, and recent advances have made it possible to extend this tool for use in the spinal cord.)

Sprenger and colleagues then repeated the study again, this time giving participants either a drug called naloxone, which blocks the effects of opioids, or a simple saline infusion. The pain-relieving effects of distraction dropped by 40 percent during the application of the opioid antagonist compared to saline, evidence that endogenous opioids play an essential role.

The findings show just how deeply mental processes can go in altering the experience of pain, and that may have clinical importance.

"Our findings strengthen the role of cognitive-behavioral therapeutic approaches in the treatment of pain diseases, as it could be extrapolated that these approaches might also have the potential to alter the underlying neurobiological mechanisms as early as in the spinal cord," the researchers say.

Source: Science Daily

May 17, 2012

Fool me once, shame on you. Fool me twice, shame on my parahippocampal gyrus.

Read Montague, Ph.D., and colleagues at the Virginia Tech Carilion Research Institute discovered two distinct sites for suspicion in the brain: the amygdala, which correlates strongly with a baseline distrustfulness, and the parahippocampal gyrus, which acts like a cerebral lie detector. Credit: Virginia Tech

Scientists at the Virginia Tech Carilion Research Institute have found that suspicion resides in two distinct regions of the brain: the amygdala, which plays a central role in processing fear and emotional memories, and the parahippocampal gyrus, which is associated with declarative memory and the recognition of scenes.

"We wondered how individuals assess the credibility of other people in simple social interactions," said Read Montague, director of the Human Neuroimaging Laboratory and the Computational Psychiatry Unit at the Virginia Tech Carilion Research Institute, who led the study. "We found a strong correlation between the amygdala and a baseline level of distrust, which may be based on a person’s beliefs about the trustworthiness of other people in general, his or her emotional state, and the situation at hand. What surprised us, though, is that when other people’s behavior aroused suspicion, the parahippocampal gyrus lit up, acting like an inborn lie detector.”

The scientists used functional magnetic resonance imaging, or fMRI, to study the neural basis of suspicion. Seventy-six pairs of players, each with a buyer and a seller, competed in 60 rounds of a simple bargaining game while having their brains scanned. At the beginning of each round, the buyer would learn the value of a hypothetical widget and suggest a price to the seller. The seller would then set the price. If the seller’s price fell below the widget’s given value, the trade would go through, with the seller receiving the selling price and the buyer receiving any difference between the selling price and the actual value. If the seller’s price exceeded the value, though, the trade would not execute, and neither party would receive cash.

The authors found, as detailed in a previous paper, that buyers fell into three strategic categories: 42 percent were incrementalists, who were relatively honest about the widget’s value; 37 percent were conservatives, who adopted the strategy of withholding information; and 21 percent were strategists, who were actively deceptive, mimicking incrementalist behavior by sending high suggestions during low-value trials and then reaping greater benefits by sending low suggestions during high-value trials.

The sellers had a monetary incentive to read the buyers’ strategic profiles correctly, yet they received no feedback about the accuracy of the information they were receiving, so they could not confirm any suspicions about patterns of behavior. Without feedback, the sellers were forced to decide whether they should trust the buyers based on the pricing suggestions alone. “The more uncertain a seller was about a buyer’s credibility,” Montague said, “the more active his or her parahippocampal gyrus became.”

The authors believe a person’s baseline suspicion may have important consequences for his or her financial success. “People with a high baseline suspicion were often interacting with fairly trustworthy buyers, so in ignoring the information those buyers provided, they were giving up potential profits,” said Meghana Bhatt, the first author on the research paper. “The ability to recognize credible information in a competitive environment can be just as important as detecting untrustworthy behavior.”

The findings may also have implications for such psychiatric conditions as paranoia and anxiety disorders, said Montague. “The fact that increased amygdala activation corresponds to an inability to detect trustworthy behavior may provide insight into the social interactions of people with anxiety disorders, who often have increased activity in this area of the brain,” he said.

Provided by Virginia Tech

Source: medicalxpress.com

ScienceDaily (May 16, 2012) — A well-known genetic risk factor for Alzheimer’s disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report May 16 in the journal Nature.

The left photo shows destructive proteins (green) lining blood vessels in living brain tissue of mice with the human ApoE4 gene; after the drug cyclosporine A is added, the harmful proteins are nearly gone (right). (Credit: Image courtesy of University of Rochester Medical Center)

The results come from a team of scientists investigating why a gene called ApoE4 makes people more prone to developing Alzheimer’s. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer’s disease than people who do not.

A team of scientists from the University of Rochester, the University of Southern California, and other institutions found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer’s.

"We are beginning to understand much more about how ApoE4 may be contributing to Alzheimer’s disease," said Robert Bell, Ph.D., the post-doctoral associate at Rochester who is first author of the paper. "In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer’s disease in the same way it does in cardiovascular disease or abdominal aneurysm. This establishes a new vascular target to fight Alzheimer’s disease."

The team found that ApoE4 makes it more likely that cyclophilin A will accumulate in large amounts in cells that help maintain the blood-brain barrier, a network of tightly bound cells that line the insides of blood vessels in the brain and carefully regulates what substances are allowed to enter and exit brain tissue.

ApoE4 creates a cascade of molecular signaling that weakens the barrier, causing blood vessels to become leaky. This makes it more likely that toxic substances will leak from the vessels into the brain, damaging cells like neurons and reducing blood flow dramatically by choking off blood vessels.

Doctors have long known that the changes in the brain seen in Alzheimer’s patients — the death of crucial brain cells called neurons — begins happening years or even decades before symptoms appear. The steps described in Nature discuss events much earlier in the disease process.

The idea that vascular problems are at the heart of Alzheimer’s disease is one championed for more than two decades by Berislav Zlokovic, M.D., Ph.D., the leader of the team and a neuroscientist formerly with the University of Rochester Medical Center and now at USC. For 20 years, Zlokovic has investigated how blood flow in the brain is affected in people with the disease, and how the blood-brain barrier allows nutrients to pass into the brain, and harmful substances to exit the brain.

At Rochester, Zlokovic struck up a collaboration with Bradford Berk, M.D., Ph.D.,a cardiologist and CEO of the Medical Center. For more than two decades Berk has studied cyclophilin A, showing how it promotes destructive forces in blood vessels and how it’s central to the forces that contribute to cardiovascular diseases like atherosclerosis and heart attack.

"As a cardiologist, I’ve been interested in understanding the role of cyclophilin A in patients who suffer from cardiovascular illness," said Berk, a professor at the Aab Cardiovascular Research Institute. "Now our collaboration in Rochester has resulted in the discovery that it also has an important role in Alzheimer’s disease. The finding reinforces the basic research enterprise — you never know when knowledge gained in one area will turn out to be crucial in another."

In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue.

When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent.

The team outlined the chain of events involved. Briefly:

• When ApoE4 is present, cyclophilin A is much more plentiful;
• Cyclophilin A causes an increase in a the inflammatory molecule NF Kappa B;
• NF Kappa B boosts levels of certain types of molecules known as MMPs or matrix metalloproteinases that are known to damage blood vessels, reducing blood flow.

Altogether, the activity results in a dramatic boost in the amount of toxic substances in brain tissue. And when the cascade is interrupted at any of several points — when ApoE4 is not present, when cyclophilin A is blocked or shut off, or when NF Kappa B or the MMPs are inhibited — the blood-brain barrier is restored, blood flow returns to normal, and toxic substances do not leak into brain tissue.

For many years, researchers studying Alzheimer’s disease have been focused largely on amyloid beta, a protein structure that accumulates in the brains of patients with Alzheimer’s disease. The latest works points up the importance of other approaches, said Zlokovic, an adjunct professor at Rochester. At USC, Zlokovic is also deputy director of the Zilkha Neurogenetic Institute, director of the Center for Neurodegeneration and Regeneration, and professor and chair of the Department of Physiology and Biophysics.

"Our study has shown major neuronal injury resulting from vascular defects that are not related to amyloid beta," said Zlokovic. "This damage results from a breakdown of the blood-brain barrier and a reduction in blood flow.

"Amyloid beta definitely has an important role in Alzheimer’s disease," added Zlokovic. "But it’s very important to investigate other leads, perhaps where amyloid beta isn’t as centrally involved."

Source: Science Daily

ScienceDaily (May 16, 2012) — What can a fish tell us about human brain development? Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth.

Here are images of live zebrafish that were studied for genetics and head size to give insight into human head size. The top fish does not have the gene KCTD13 and its head size and brain size are larger; the middle fish is normal; the fish on the bottom expresses too much of the gene and has the smallest head and brain size. (Credit: Christelle Golzio, Duke Center for Human Disease Modeling and Duke Department of Cell Biology)

Researchers at Duke University Medical Center transplanted a set of human genes into a zebrafish and then used it to identify genes responsible for head size at birth.

Head size in human babies is a feature that is related to autism, a condition that recent figures have shown to be more common than previously reported, 1 in 88 children in a March 2012 study. Head size is also a feature of other major neurological disorders, such as schizophrenia.

"In medical research, we need to dissect events in biology so we can understand the precise mechanisms that give rise to neurodevelopmental traits," said senior author Nicholas Katsanis, Ph.D., Jean and George Brumley Jr., MD, Professor of Developmental Biology, and Professor of Pediatrics and Cell Biology. "We need expert scientists to work side by side with clinicians who see such anatomic and other problems in patients, if we are to effectively solve many of our medical problems."

The study was published online in Nature journal on May 16.

Katsanis knew that a region on chromosome 16 was one of the largest genetic contributors to autism and schizophrenia, but a conversation at a European medical meeting pointed him to information that changes within that same region of the genome also were related to changes in a newborn’s head size.

The problem was difficult to address because the region had large deletions and duplications in DNA, which are the most common mutational mechanisms in humans. “Interpretation is harrowingly hard,” said Katsanis, who is also director of the Duke Center for Human Disease Modeling.

The reason is that a duplication of DNA or missing DNA usually involves several genes. “It is very difficult to go from ‘here is a region with many genes, sometimes over 50’ to ‘these are the genes that are driving this pathology,’” Katsanis said.

"There was a light bulb moment," Katsanis said. "The area of the genome we were exploring gave rise to reciprocal (opposite) defects in terms of brain cell growth, so we realized that overexpressing a gene in question might give one phenotype — a smaller head, while shutting down the same gene might yield the other, a larger head."

The researchers transplanted a common duplication area of human chromosome 16 known to contain 29 genes into zebrafish embryos and then systematically turned up the activity of each transplanted human gene to find which might cause a small head (microcephaly) in the fish. They then suppressed the same gene set and asked whether any of them caused the reciprocal defect: larger heads (macrocephaly).

The researchers knew that deletion of the region that contained these 29 genes occurred in 1.7% of children with autism.

It took the team a few months to dissect such a “copy number variant” — an alteration of the genome that results in an abnormal number of one or more sections of chromosomal DNA.

"Now we can go from a genetic finding that is dosage-sensitive and start asking reasonable questions about this gene as it pertains to neurocognitive traits, which is a big leap," Katsanis said. Neurocognitive refers to the ability to think, concentrate, reason, remember, process information, learn, understand and speak.

Many human conditions have anatomical features that are also related to genetics, he said. “There are major limitations in studying autistic or schizophrenic behavior in zebrafish, but we can measure head size, jaw size, or facial abnormalities.”

The single gene in question, KCTD13, is responsible for driving head size in zebrafish by regulating the creation and destruction of new neurons (brain cells). This discovery let the team focus on the analogous gene in humans. “This gene contributes to autism cases, and probably is associated with schizophrenia and also childhood obesity,” Katsanis said.

Once the gene has been uncovered, researchers can examine the protein it produces. “Once you have the protein, you can start asking valuable functional questions and learning what the gene does in the animal or human,” Katsanis said.

Copy number variants, such as the ones this team found on chromosome 16, are now thought to be one of the most common sources of genetic mutations. Hundreds, if not thousands, of such chromosomal deletions and duplications have been found in patients with a broad range of clinical problems, particularly neurodevelopmental disorders.

"Now we may have an efficient tool for dissecting them, which gives us the ability to improve both diagnosis and understanding of disease mechanisms," Katsanis said.

The current study suggests that KCTD13 is a major contributor to some cases of autism, but also points to the synergistic action of this gene with two other genes in the region, named MVP and MAPK3, Katsanis said.

Source: Science Daily

ScienceDaily (May 16, 2012) — In a new study analyzing Internet usage among college students, researchers at Missouri University of Science and Technology have found that students who show signs of depression tend to use the Internet differently than those who show no symptoms of depression.

Using actual Internet usage data collected from the university’s network, the researchers identified nine fine-grained patterns of Internet usage that may indicate depression. For example, students showing signs of depression tend to use file-sharing services more than their counterparts, and also use the Internet in a more random manner, frequently switching among several applications.

The researchers’ findings provide new insights on the association between Internet use and depression compared to existing studies, says Dr. Sriram Chellappan, an assistant professor of computer science at Missouri S&T and the lead researcher in the study.

"The study is believed to be the first that uses actual Internet data, collected unobtrusively and anonymously, to associate Internet usage with signs of depression," Chellappan says. Previous research on Internet usage has relied on surveys, which are "a far less accurate way" of assessing how people use the Internet, he says.

"This is because when students themselves reported their volume and type of Internet activity, the amount of Internet usage data is limited because people’s memories fade with time," Chellappan says. "There may be errors and social desirability bias when students report their own Internet usage." Social desirability bias refers to the tendency of survey respondents to answer questions in a manner that will be viewed favorably by others.

Chellappan and his fellow researchers collected a month’s worth of Internet data for 216 Missouri S&T undergraduate students. The data was collected anonymously and unobtrusively, and students involved in the study were assigned pseudonyms to keep their identities hidden from the researchers.

Before the researchers collected the usage data from the campus network, the students were tested to determine whether they showed signs of depression. The researchers then analyzed the usage data of the study participants. They found that students who showed signs of depression used the Internet much differently than the other study participants.

Chellappan and his colleagues found that depressed students tended to use file-sharing services, send email and chat online more than the other students. Depressed students also tended to use higher “packets per flow” applications, those high-bandwidth applications often associated with online videos and games, than their counterparts.

Students who showed signs of depression also tended to use the Internet in a more “random” manner — frequently switching among applications, perhaps from chat rooms to games to email. Chellappan thinks that randomness may indicate trouble concentrating, a characteristic associated with depression.

The randomness stood out to Chellappan after his graduate student, Raghavendra Kotikalapudi, examined the “flow duration entropy” of students’ online usage. Flow duration entropy refers to the consistency of Internet use during certain periods of time. The lower the flow duration entropy, the more consistent the Internet use.

"Students showing signs of depression had high flow duration entropy, which means that the duration of Internet flows of these students is highly inconsistent," Chellappan says.

At the beginning of the study, the 216 participating students were tested to determine whether they exhibited symptoms of depression. Based on the Center for Epidemiologic Studies-Depression (CES-D) scale, about 30 percent of the students in the study met the minimum criteria for depression. Nationally, previous studies show that between 10 percent and 40 percent of all American students suffer from depression.

To ensure that participants were not identified during the study, each participant was assigned a pseudonym. The campus information technology department then provided the on-campus Internet usage data for each participant from the month of February 2011.

The researchers’ analysis of the month’s worth of data led Chellappan and his colleagues to conclude that students who were identified as exhibiting symptoms of depression used the Internet differently than the other students in the study.

Chellappan’s research has been accepted for publication in a forthcoming issue of IEEE Technology and Society Magazine.

The chief author of the paper is Kotikalapudi, who received his master of science degree in computer science from Missouri S&T in December 2011. His co-authors are Chellappan; Dr. Frances Montgomery, Curators’ Teaching Professor of psychological science; Dr. Donald C. Wunsch, the M.K. Finley Missouri Distinguished Professor of Computer Engineering; and Karl F. Lutzen, information security officer for Missouri S&T’s IT department.

Chellappan is now interested in using these findings to develop software that could be installed on home computers to help individuals determine whether their Internet usage patterns may indicate depression. The software would unobtrusively monitor Internet usage and alert individuals if their usage patterns indicate symptoms of depression.

"The software would be a cost-effective and an in-home tool that could proactively prompt users to seek medical help if their Internet usage patterns indicate possible depression," Chellappan says. "The software could also be installed on campus networks to notify counselors of students whose Internet usage patterns are indicative of depressive behavior."

Chellappan also believes the method used to connect Internet use and depression could also help diagnose other mental disorders like anorexia, bulimia, attention deficit hyperactivity disorder or schizophrenia.

"We could also investigate associations between other Internet features like visits to social networking sites, late night Internet use and randomness in time of Internet use with depressive symptoms," he says. "Applications of this study to diagnose and treat mental disorders for other vulnerable groups like the elderly and military veterans are also significant."

Source: Science Daily

ScienceDaily (May 16, 2012) — A new study suggests that head impacts experienced during contact sports such as football and hockey may worsen some college athletes’ ability to acquire new information. The research is published in the May 16, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

A new study suggests that head impacts experienced during contact sports such as football and hockey may worsen some college athletes’ ability to acquire new information. (Credit: © modestil / Fotolia)

The study involved college athletes at three Division I schools and compared 214 athletes in contact sports to 45 athletes in non-contact sports such as track, crew and Nordic skiing at the beginning and at the end of their seasons. The contact sport athletes wore special helmets that recorded the acceleration speed and other data at the time of any head impact.

The contact sport athletes experienced an average of 469 head impacts during the season. Athletes were not included in the study if they were diagnosed with a concussion during the season.

All of the athletes took tests of thinking and memory skills before and after the season. A total of 45 contact sport athletes and 55 non-contact sport athletes from one of the schools also took an additional set of tests of concentration, working memory and other skills.

"The good news is that overall there were few differences in the test results between the athletes in contact sports and the athletes in non-contact sports," said study author Thomas W. McAllister, MD, of The Geisel School of Medicine at Dartmouth in Lebanon, N.H. "But we did find that a higher percentage of the contact sport athletes had lower scores than would have been predicted after the season on a measure of new learning than the non-contact sport athletes."

A total of 22 percent of the contact sport athletes performed worse than expected on the test of new learning, compared to four percent of the non-contact sport athletes.

McAllister noted that the study did not find differences in test results between the two groups of athletes at the beginning of the season, suggesting that the cumulative head impacts that contact athletes had incurred over many previous seasons did not result in reduced thinking and memory skills in the overall group.

"These results are somewhat reassuring, given the recent heightened concern about the potential negative effects of these sports," he said. "Nevertheless, the findings do suggest that repetitive head impacts may have a negative effect on some athletes."

McAllister said it’s possible that some people may be genetically more sensitive to head impacts.

Source: Science Daily

ScienceDaily (May 16, 2012) — Genes play a greater role in forming character traits — such as self-control, decision making or sociability — than was previously thought, new research suggests.

Identical twin boys. Genes play a greater role in forming character traits — such as self-control, decision making or sociability — than was previously thought, new research suggests. (Credit: © vgm6 / Fotolia)

A study of more than 800 sets of twins found that genetics were more influential in shaping key traits than a person’s home environment and surroundings.

Psychologists at the University of Edinburgh who carried out the study, say that genetically influenced characteristics could well be the key to how successful a person is in life.

The study of twins in the US — most aged 50 and over- used a series of questions to test how they perceived themselves and others. Questions included “Are you influenced by people with strong opinions?” and “Are you disappointed about your achievements in life?”

The results were then measured according to the Ryff Psychological Well-Being Scale which assesses and standardizes these characteristics.

By tracking their answers, the research team found that identical twins — whose DNA is [presumed to be] exactly the same — were twice as likely to share traits compared with non-identical twins.

Psychologists say the findings are significant because the stronger the genetic link, the more likely it is that these character traits are carried through a family.

Professor Timothy Bates, of the University of Edinburgh’s School of Philosophy, Psychology and Language Sciences, said that the genetic influence was strongest on a person’s sense of self-control.

Researchers found that genes affected a person’s sense of purpose, how well they get on with people and their ability to continue learning and developing.

Professor Bates added: “Ever since the ancient Greeks, people have debated the nature of a good life and the nature of a virtuous life. Why do some people seem to manage their lives, have good relationships and cooperate to achieve their goals while others do not? Previously, the role of family and the environment around the home often dominated people’s ideas about what affected psychological well-being. However, this work highlights a much more powerful influence from genetics.”

The study, which builds on previous research that found that happiness is underpinned by genes, is published online in the Journal of Personality.

Source: Science Daily

ScienceDaily (May 16, 2012) — Poor Phineas Gage. In 1848, the supervisor for the Rutland and Burlington Railroad in Vermont was using a 13-pound, 3-foot-7-inch rod to pack blasting powder into a rock when he triggered an explosion that drove the rod through his left cheek and out of the top of his head. As reported at the time, the rod was later found, “smeared with blood and brains.”

Recreation of Gage accident. (Credit: Copyright John Darrell Van Horn and the UCLA Laboratory of Neuro Imaging, 2012)

Miraculously, Gage lived, becoming the most famous case in the history of neuroscience — not only because he survived a horrific accident that led to the destruction of much of his left frontal lobe but also because of the injury’s reported effects on his personality and behavior, which were said to be profound. Gage went from being an affable 25-year-old to one that was fitful, irreverent and profane. His friends and acquaintances said he was “no longer Gage.”

Over the years, various scientists have studied and argued about the exact location and degree of damage to Gage’s cerebral cortex and the impact it had on his personality. Now, for the first time, researchers at UCLA, using brain-imaging data that was lost to science for a decade, have broadened the examination of Gage to look at the damage to the white matter “pathways” that connect various regions of the brain.

Reporting in the May 16 issue of the journal PLoS ONE, Jack Van Horn, a UCLA assistant professor of neurology, and colleagues note that while approximately 4 percent of the cerebral cortex was intersected by the rod’s passage, more than 10 percent of Gage’s total white matter was damaged. The passage of the tamping iron caused widespread damage to the white matter connections throughout Gage’s brain, which likely was a major contributor to the behavioral changes he experienced.

Because white matter and its myelin sheath — the fatty coating around the nerve fibers that form the basic wiring of the brain — connect the billions of neurons that allow us to reason and remember, the research not only adds to the lore of Phineas Gage but may eventually lead to a better understanding of multiple brain disorders that are caused in part by similar damage to these connections.

"What we found was a significant loss of white matter connecting the left frontal regions and the rest of the brain," said Van Horn, who is a member of UCLA’s Laboratory of Neuro Imaging (LONI). "We suggest that the disruption of the brain’s ‘network’ considerably compromised it. This may have had an even greater impact on Mr. Gage than the damage to the cortex alone in terms of his purported personality change."

LONI is part of an ambitious joint effort with Massachusetts General Hospital and the National Institutes of Health to document the trillions of microscopic links between every one of the brain’s 100 billion neurons — the so-called “connectome.” And because mapping the brain’s physical wiring eventually will lead to answers about what causes mental conditions that may be linked to the breakdown of these connections, it was appropriate, as well as historically interesting, to take a new look at the damage to Gage’s brain.

Since Gage’s 189-year-old skull, which is on display in the Warren Anatomical Museum at Harvard Medical School, is now fragile and unlikely to again be subjected to medical imaging, the researchers had to track down the last known imaging data, from 2001, which had been lost due to various circumstances at Brigham and Women’s Hospital, a teaching affiliate of Harvard, for some 10 years.

The authors were able to recover the computed tomographic data files and managed to reconstruct the scans, which revealed the highest-quality resolution available for modeling Gage’s skull. Next, they utilized advanced computational methods to model and determine the exact trajectory of the tamping iron that shot through his skull. Finally, because the original brain tissue was, of course, long gone, the researchers used modern-day brain images of males that matched Gage’s age and (right) handedness, then used software to position a composite of these 110 images into Gage’s virtual skull, the assumption being that Gage’s anatomy would have been similar.

Van Horn found that nearly 11 percent of Gage’s white matter was damaged, along with 4 percent of the cortex.

"Our work illustrates that while cortical damage was restricted to the left frontal lobe, the passage of the tamping iron resulted in the widespread interruption of white matter connectivity throughout his brain, so it likely was a major contributor to the behavioral changes he experienced," Van Horn said. "Connections were lost between the left frontal, left temporal and right frontal cortices and the left limbic structures of the brain, which likely had considerable impact on his executive as well as his emotional functions."

And while Gage’s personality changed, he eventually was able to travel and find employment as a stagecoach driver for several years in South America. Ultimately, he died in San Francisco, 12 years after the accident.

Van Horn noted a modern parallel.

"The extensive loss of white matter connectivity, affecting both hemispheres, plus the direct damage by the rod, which was limited to the left cerebral hemisphere, is not unlike modern patients who have suffered a traumatic brain injury," he said. "And it is analogous to certain forms of degenerative diseases, such as Alzheimer’s disease or frontal temporal dementia, in which neural pathways in the frontal lobes are degraded, which is known to result in profound behavioral changes."

Van Horn noted that the quantification of the changes to Gage’s brain’s pathways might well provide important insights for clinical assessment and outcome-monitoring in modern-day brain trauma patients.

Source: Science Daily

May 16, 2012

(Medical Xpress) — When an animal is born, its early experiences help map out the still-forming connections in its brain. As neurons in sensory areas of the brain fire in response to sights, smells, and sounds, synapses begin to form, laying the neuronal groundwork for activity later in life. Not all parts of the brain receive input directly from the external world, however, and researchers have wondered how these regions build their wiring early in development.

The output of this indirect-pathway neuron in the striatum of a mouse brain has been genetically silenced. The neuron has been filled through the attached electrode with a red fluorophore to measure its spine density and the number of active synapses. In the background, other indirect pathway neurons are seen in green and red. Credit: Bernardo Sabatini

New research from Howard Hughes Medical Institute investigator Bernardo Sabatini and colleagues on the basal ganglia, a region of the brain that controls motor planning, indicates that development here follows a different strategy. The new findings suggest that wiring of the basal ganglia during early development is driven not only by experience, but also by a self-reinforcing loop of neuronal signaling. As the loop strengthens, more synapses form.

“What we found is that silencing these neurons doesn’t really change their output patterns — of course they are silenced, but they still find their targets and survive — but instead drastically influences their inputs,” said Bernardo L. Sabatini.

The basal ganglia help an animal select its actions based on sensory and social context, as well as past experience. The new clues about how the basal ganglia gets wired shortly after birth, described in the May 13, 2012, issue of the journal Nature, may help scientists understand what happens when the area goes awry, such as in Parkinson’s disease, when degradation of neurons in the basal ganglia interferes with patients’ ability to initiate appropriate movements, or drug addiction, where overstimulation of the basal ganglia spurs inappropriate actions. Sabatini says his team’s findings also suggest that the process can be easily perturbed during development, and may contribute to human disorders such as cerebral palsy and attention deficit hyperactivity disorder.

Although the basal ganglia do not receive direct messages from the external world, this region of the brain is by no means anatomically isolated: it receives signals from all over the cortex, and its output eventually returns to the cortex. Sabatini, who is at Harvard Medical School, explains that to select a motor action, the brain likely signals through that whole loop. “The question is, how do you lay down the circuits for those patterns?”

The basal ganglia are complex, containing many clusters of cells, some of which send excitatory signals and others inhibitory. Sabatini’s group focused on the basal ganglia’s main input station, the striatum. The striatum uses the information it receives to help direct movement in two ways: a ‘direct’ pathway stimulates motor actions and an ‘indirect’ pathway inhibits them. To learn how striatal activity affects circuit development, Sabatini’s team studied mutant mice whose indirect or direct pathways were turned off (because they were unable to release the inhibitory chemical messenger, GABA).

The group expected that silencing these neurons would prevent them from forming connections with the neurons that should have been receiving their signals. To their surprise, the silenced neurons survived and wired themselves to their targets normally. Unexpectedly, however, silencing the striatum’s direct pathway seemed to prevent formation of the connections sending input to the striatum. Silencing the indirect pathway upped the number of inputs. “We went into this study thinking completely differently,” says Sabatini. “What we found is that silencing these neurons doesn’t really change their output patterns — of course they are silenced, but they still find their targets and survive — but instead drastically influences their inputs.”

To see whether individual cells help set up the basal ganglia circuit, Sabatini’s group turned off a select few striatal neurons, rather than whole pathways, in the mice. They found that silencing these neurons did not affect excitatory connections to the area, suggesting that circuit-level activity patterns set up the basal ganglia’s wiring, rather than individual genes or molecules within cells. “It’s hard to believe that there are molecular cues that specify these structures, because it would be way too complicated,” Sabatini says.

When the group dampened activity in neurons that project from the brain’s cortex to the striatum during development, then examined the brain when the mouse had reached early adulthood (25 days after birth) they saw fewer neuronal connections in the striatum compared to mice that had developed normally suggesting that early perturbations in development can have lasting effects. “That experiments is what told us that it’s the ongoing activity of cortical neurons that is driving this process in the striatum,” Sabatini says. The axons — the slender processes of the neuron that carry electrical impulses — stimulate striatal cells by releasing the excitatory neurotransmitter glutamate, telling them to make more synapses and stabilize them, he adds.

Sabatini believes that the basal ganglia tests random connection patterns after an animal is born and reinforces the correct ones. This type of plasticity of the basal ganglia probably lasts into adulthood, because animals are constantly learning to take new actions. Using genetically engineered mice that allow researchers to control exactly which neurons to inactivate and when, Sabatini’s group is now studying how perturbations affect the wiring later in life.

Sabatini expects that these results will get us a step closer to understanding human disease. “Maybe we will show that there’s hope for therapy,” he adds. “If it is plastic, maybe we can recover.”

Provided by Howard Hughes Medical Institute

Source: medicalxpress.com

May 16, 2012

(Medical Xpress) — Scientists at the University of Bristol have shed new light on one of the great unanswered questions of neuroscience: how the brain initiates rhythmic movements like walking, running and swimming.

The Xenopus frog tadpole is a small, simple vertebrate

While experiments in the 1970s using electrical brain stimulation identified areas of the brain responsible for starting locomotion, the precise neuron-by-neuron pathway has not been described in any vertebrate – until now. 

To find this pathway, Dr. Edgar Buhl and colleagues in Bristol’s School of Biological Sciences studied a small, simple vertebrate: the Xenopus frog tadpole.

They found that the pathway to initiate swimming consists of just four types of neurons.  By touching skin on the head of the tadpole and applying cellular neurophysiology and anatomy techniques, the scientists identified nerve cells that detect the touch on the skin, two types of brain nerve cells which pass on the signal, and the motor nerve cells that control the swimming muscles. 

Dr. Buhl said: “These findings address the longstanding question of how locomotion is initiated following sensory stimulation and, for the first time in any vertebrate, define in detail a direct pathway responsible.  They could thus be of great evolutionary interest and could also open the path to understanding initiation of locomotion in other vertebrates.”

When mechanisms in the brain that initiate locomotion break down – for example, in people with Parkinson’s disease – starting to walk becomes a real problem.  Therefore, understanding the initiation of swimming in tadpoles could be a first step towards understanding the initiation of locomotion in more complex vertebrates, including people, and may eventually have implications for treating movement disorders such as Parkinson’s.

The research is published today in the Journal of Physiology.

Provided by University of Bristol

Source: medicalxpress.com

May 15th, 2012

Technique could help those with C6, C7 spinal cord injuries.

Surgeons at Washington University School of Medicine in St. Louis have restored some hand function in a quadriplegic patient with a spinal cord injury at the C7 vertebra, the lowest bone in the neck. Instead of operating on the spine itself, the surgeons rerouted working nerves in the upper arms. These nerves still “talk” to the brain because they attach to the spine above the injury.

Following the surgery, performed at Barnes-Jewish Hospital, and one year of intensive physical therapy, the patient regained some hand function, specifically the ability to bend the thumb and index finger. He can now feed himself bite-size pieces of food and write with assistance.

The case study, published online May 15 in the Journal of Neurosurgery, is, to the authors’ knowledge, the first reported case of using nerve transfer to restore the ability to flex the thumb and index finger after a spinal cord injury.

“This procedure is unusual for treating quadriplegia because we do not attempt to go back into the spinal cord where the injury is,” says surgeon Ida K. Fox, MD, assistant professor of plastic and reconstructive surgery at Washington University, who treats patients at Barnes-Jewish Hospital. “Instead, we go out to where we know things work — in this case the elbow — so that we can borrow nerves there and reroute them to give hand function.”

To detour around the block in this patient’s C7 spinal cord injury and return hand function, Mackinnon operated in the upper arms. There, the working nerves that connect above the injury (green) and the non-working nerves that connect below the injury (red) run parallel to each other, making it possible to tap into a functional nerve and direct those signals to a non-functional neighbor (yellow arrow). Image adapted from Eric Young image available in press release mentioned.

Although patients with spinal cord injuries at the C6 and C7 vertebra have no hand function, they do have shoulder, elbow and some wrist function because the associated nerves attach to the spinal cord above the injury and connect to the brain. Since the surgeon must tap into these working nerves, the technique will not benefit patients who have lost all arm function due to higher injuries — in vertebrae C1 through C5.

The surgery was developed and performed by the study’s senior author Susan E. Mackinnon, MD, chief of the Division of Plastic and Reconstructive Surgery at Washington University School of Medicine. Specializing in injuries to peripheral nerves, she has pioneered similar surgeries to return function to injured arms and legs.

Mackinnon originally developed this procedure for patients with arm injuries specifically damaging the nerves that provide the ability to flex the thumb and index finger. This is the first time she has applied this peripheral nerve technique to return limb function after a spinal cord injury.

[Video: Surgeons restore some hand function to quadriplegic patient]
Surgeons at Washington University School of Medicine in St. Louis have restored some hand function in a quadriplegic patient with a spinal cord injury at the C7 vertebra, the lowest bone in the neck. Instead of operating on the spine itself, the surgeons rerouted working nerves in the upper arms. These nerves still “talk” to the brain because they attach to the spine above the injury. Following the surgery, performed at Barnes-Jewish Hospital, and one year of intensive physical therapy, the patient regained the ability to pinch and can now feed himself bite-size pieces of food and write with assistance.

“Many times these patients say they would like to be able to do very simple things,” Fox says. “They say they would like to be able to feed themselves or write without assistance. If we can restore the ability to pinch, between thumb and index finger, it can return some very basic independence.”

Mackinnon cautions that the hand function restored to the patient was not instantaneous and required intensive physical therapy. It takes time to retrain the brain to understand that nerves that used to bend the elbow now provide pinch, she says.

Though this study reports only one case, Mackinnon and her colleagues do not anticipate a limited window of time during which a patient with a similar spinal cord injury must be treated with this nerve transfer technique. This patient underwent the surgery almost two years after his injury. As long as the nerve remains connected to the support and nourishment of the spinal cord, even though it no longer “talks” to the brain, the nerve and its associated muscle remain healthy, even years after the injury.

“The spinal cord is the control center for the nerves, which run like spaghetti all the way out to the tips of the fingers and the tips of the toes,” says Mackinnon, the Sydney M. Shoenberg Jr. and Robert H. Shoenberg Professor and director of the School of Medicine’s Center for Nerve Injury and Paralysis. “Even nerves below the injury remain healthy because they are still connected to the spinal cord. The problem is that these nerves no longer ‘talk’ to the brain because the spinal cord injury blocks the signals.”

To detour around the block in this patient’s C7 spinal cord injury and return hand function below the level of the injury, Mackinnon operated in the upper arms. There, the working nerves that connect above the injury and the non-working nerves that connect below the injury run parallel to each other, making it possible to tap into a functional nerve and direct those signals to a non-functional neighbor.

In this case, Mackinnon took a non-working nerve that controls the ability to pinch and plugged it into a working nerve that drives one of two muscles that flex the elbow. After the surgery, the bicep still flexes the elbow, but a second muscle, called the brachialis, that used to also provide elbow flexion, now bends the thumb and index finger.

“This is not a particularly expensive or overly complex surgery,” Mackinnon says. “It’s not a hand or a face transplant, for example. It’s something we would like other surgeons around the country to do.”

By Julia Evangelou Strait

Source: Neuroscience News

ScienceDaily (May 15, 2012) — Attention, college students cramming between midterms and finals: Binging on soda and sweets for as little as six weeks may make you stupid.

New research suggests that binging on soda and sweets for as little as six weeks may make you stupid. (Credit: © RTimages / Fotolia)

A new UCLA rat study is the first to show how a diet steadily high in fructose slows the brain, hampering memory and learning — and how omega-3 fatty acids can counteract the disruption. The peer-reviewed Journal of Physiology publishes the findings in its May 15 edition.

"Our findings illustrate that what you eat affects how you think," said Fernando Gomez-Pinilla, a professor of neurosurgery at the David Geffen School of Medicine at UCLA and a professor of integrative biology and physiology in the UCLA College of Letters and Science. "Eating a high-fructose diet over the long term alters your brain’s ability to learn and remember information. But adding omega-3 fatty acids to your meals can help minimize the damage."

While earlier research has revealed how fructose harms the body through its role in diabetes, obesity and fatty liver, this study is the first to uncover how the sweetener influences the brain.

The UCLA team zeroed in on high-fructose corn syrup, an inexpensive liquid six times sweeter than cane sugar, that is commonly added to processed foods, including soft drinks, condiments, applesauce and baby food. The average American consumes more than 40 pounds of high-fructose corn syrup per year, according to the U.S. Department of Agriculture. “We’re not talking about naturally occurring fructose in fruits, which also contain important antioxidants,” explained Gomez-Pinilla, who is also a member of UCLA’s Brain Research Institute and Brain Injury Research Center. “We’re concerned about high-fructose corn syrup that is added to manufactured food products as a sweetener and preservative.”

Gomez-Pinilla and study co-author Rahul Agrawal, a UCLA visiting postdoctoral fellow from India, studied two groups of rats that each consumed a fructose solution as drinking water for six weeks. The second group also received omega-3 fatty acids in the form of flaxseed oil and docosahexaenoic acid (DHA), which protects against damage to the synapses — the chemical connections between brain cells that enable memory and learning.

"DHA is essential for synaptic function — brain cells’ ability to transmit signals to one another," Gomez-Pinilla said. "This is the mechanism that makes learning and memory possible. Our bodies can’t produce enough DHA, so it must be supplemented through our diet."

The animals were fed standard rat chow and trained on a maze twice daily for five days before starting the experimental diet. The UCLA team tested how well the rats were able to navigate the maze, which contained numerous holes but only one exit. The scientists placed visual landmarks in the maze to help the rats learn and remember the way.

Six weeks later, the researchers tested the rats’ ability to recall the route and escape the maze. What they saw surprised them.

"The second group of rats navigated the maze much faster than the rats that did not receive omega-3 fatty acids," Gomez-Pinilla said. "The DHA-deprived animals were slower, and their brains showed a decline in synaptic activity. Their brain cells had trouble signaling each other, disrupting the rats’ ability to think clearly and recall the route they’d learned six weeks earlier."

The DHA-deprived rats also developed signs of resistance to insulin, a hormone that controls blood sugar and regulates synaptic function in the brain. A closer look at the rats’ brain tissue suggested that insulin had lost much of its power to influence the brain cells.

"Because insulin can penetrate the blood-brain barrier, the hormone may signal neurons to trigger reactions that disrupt learning and cause memory loss," Gomez-Pinilla said.

He suspects that fructose is the culprit behind the DHA-deficient rats’ brain dysfunction. Eating too much fructose could block insulin’s ability to regulate how cells use and store sugar for the energy required for processing thoughts and emotions.

"Insulin is important in the body for controlling blood sugar, but it may play a different role in the brain, where insulin appears to disturb memory and learning," he said. "Our study shows that a high-fructose diet harms the brain as well as the body. This is something new."

Gomez-Pinilla, a native of Chile and an exercise enthusiast who practices what he preaches, advises people to keep fructose intake to a minimum and swap sugary desserts for fresh berries and Greek yogurt, which he keeps within arm’s reach in a small refrigerator in his office. An occasional bar of dark chocolate that hasn’t been processed with a lot of extra sweetener is fine too, he said.

Still planning to throw caution to the wind and indulge in a hot-fudge sundae? Then also eat foods rich in omega-3 fatty acids, like salmon, walnuts and flaxseeds, or take a daily DHA capsule. Gomez-Pinilla recommends one gram of DHA per day.

"Our findings suggest that consuming DHA regularly protects the brain against fructose’s harmful effects," said Gomez-Pinilla. "It’s like saving money in the bank. You want to build a reserve for your brain to tap when it requires extra fuel to fight off future diseases."

Source: Science Daily

ScienceDaily (May 15, 2012) — Child abuse or neglect are strong predictors of major health and emotional problems, but little is known about how the chronicity of the maltreatment may increase future harm apart from other risk factors in a child’s life.

This chart illustrates the individual childhood and adult outcomes according to the number of reports that occurred before the event of interest. Because it was possible for some children to enter the study period with a pre-existing condition, these are indicated as gray or black bars with the legend indicating the outcome occurred “before the study.” Chronicity is associated with increasing risk for all but child maltreatment perpetration, violent delinquency, and head or brain injury. In these cases, there is a slight decline in prevalence for the highest category compared with middle categories, but in all cases having reports was associated with higher rates of outcomes. (Credit: Image courtesy of Washington University in St. Louis)

In a new study published in the current issue of the journal Pediatrics, Melissa Jonson-Reid, PhD, child welfare expert and a professor at the Brown School at Washington University in St. Louis, looked at how chronic maltreatment impacted the future health and behavior of children and adults.

The study tracked children by number of child maltreatment reports (zero to four or more) and followed the children into early adulthood, by which time some of the children had become parents.

The study sought to determine how well the number of child maltreatment reports predicted poor outcomes in adolescence, such as delinquency, substance abuse in the teen years or getting a sexually transmitted disease.

"For every measure studied, a more chronic history of child maltreatment reports was powerfully predictive of worse outcomes," Jonson-Reid says.

"For most outcomes, having a single maltreatment report put children at a 20 percent to 50 percent higher risk than non-maltreated comparison children.

In addition, a series of adult outcomes were tracked to see if the chronicity of maltreatment still mattered after controlling for the poor outcomes in adolescence. Adult outcomes included adult substance abuse or growing up and having children whom they then maltreated.

"In models of adult outcomes, children with four or more reports were about least twice as likely to later abuse their own children and have contact with the mental health system, even when controlling for the negative outcomes during adolescence." Jonson-Reid says that there appears to be good reason to put resources into preventing ongoing maltreatment.

"Successfully interrupting chronic child maltreatment may well reduce risk of a wide range of other costly child and adolescent health and behavioral problems," she says.

Jonson-Reid cites a recently published Centers for Disease Control and Prevention study estimating lifetime costs for a single year’s worth of children reported for maltreatment at $242 billion.

"What our study illustrates is that these costs are even more likely to accrue for children who continue to be re-reported," she says.

The study also found that maltreatment predicts a range of negative adolescent outcomes, and those adolescent outcomes then predict poor adult outcomes.

"If the poor outcomes in adolescence can be dealt with effectively, then later adult outcomes may also be forestalled," Jonson-Reid says.

"Our findings could therefore be interpreted as supporting many current evidence-based interventions that seek to improve behavioral and social functioning among children and adolescents who have experienced trauma like abuse or neglect."

Source: Science Daily

ScienceDaily (May 15, 2012) — A novel mechanism for anxiety behaviors, including a previously unrecognized inhibitory brain signal, may inspire new strategies for treating psychiatric disorders, University of Chicago researchers report.

By testing the controversial role of a gene called Glo1 in anxiety, scientists uncovered a new inhibitory factor in the brain: the metabolic by-product methylglyoxal. The system offers a tantalizing new target for drugs designed to treat conditions such as anxiety disorder, epilepsy, and sleep disorders.

The study, published in the Journal of Clinical Investigation, found that animals with multiple copies of the Glo1 gene were more likely to exhibit anxiety-like behavior in laboratory tests. Further experiments showed that Glo1 increased anxiety-like behavior by lowering levels of methylglyoxal (MG). Conversely, inhibiting Glo1 or raising MG levels reduced anxiety behaviors.

"Animals transgenic for Glo1 had different levels of anxiety-like behavior, and more copies made them more anxious," said Abraham Palmer, PhD, assistant professor of human genetics at the University of Chicago Medicine and senior author of the study. "We showed that Glo1 was causally related to anxiety-like behavior, rather than merely correlated."

In 2005, a comparison of different mouse strains found a link between anxiety-like behaviors and Glo1, the gene encoding the metabolic enzyme glyoxylase 1. However, subsequent studies questioned the link, and the lack of an obvious connection between glyoxylase 1 and brain function or behavior made some scientists skeptical.

Read More →

May 15, 2012

A drug made from the saliva of the Gila monster lizard is effective in reducing the craving for food. Researchers at the Sahlgrenska Academy, University of Gothenburg, have tested the drug on rats, who after treatment ceased their cravings for both food and chocolate.

In a study with rats published in the Journal of Neuroscience, Assistant Professor Karolina Skibicka and her colleagues show that exendin-4 effectively reduces the cravings for food. Credit: Photo: University of Gothenburg

An increasing number of patients suffering from type 2 diabetes are offered a pharmaceutical preparation called Exenatide, which helps them to control their blood sugar. The drug is a synthetic version of a natural substance called exendin-4, which is obtained from a rather unusual source – the saliva of the Gila monster lizard (Heloderma suspectum), North America’s largest lizard.

Researchers at the Sahlgrenska Academy at the University of Gothenburg, have now found an entirely new and unexpected effect of the lizard substance.

In a study with rats published in the Journal of Neuroscience, Assistant Professor Karolina Skibicka and her colleagues show that exendin-4 effectively reduces the cravings for food.

"This is both unknown and quite unexpected effect," comments an enthusiastic Karolina Skibicka:

" Our decision to eat is linked to the same mechanisms in the brain which control addictive behaviours. We have shown that exendin-4 affects the reward and motivation regions of the brain"

The implications of the findings are significant” states Suzanne Dickson, Professor of Physiology at the Sahlgrenska Academy: “Most dieting fails because we are obsessed with the desire to eat, especially tempting foods like sweets. As exendin-4 suppresses the cravings for food, it can help obese people to take control of their weight,” suggests Professor Dickson.

Research on exendin-4 also gives hope for new ways to treat diseases related to eating disorders, for example, compulsive overeating.

Another hypothesis for the Gothenburg researchers’ continuing studies is that exendin-4 may be used to reduce the craving for alcohol.

"It is the same brain regions which are involved in food cravings and alcohol cravings, so it would be very interesting to test whether exendin-4 also reduces the cravings for alcohol,” suggests Assistant Professor Skibicka.

Provided by University of Gothenburg

Source: medicalxpress.com

May 15, 2012

(Medical Xpress) — New research from Uppsala University, Sweden, suggests that an active lifestyle in late life protects grey matter and cognitive functions in humans. The findings are now published in the scientific journal Neurobiology of Aging.

In a new study, a multidisciplinary research team from the Uppsala University has systematically studied 331 men and women at the age of 75 years. The researchers examined whether an active lifestyle is tied to brain health in seniors living in Uppsala, Sweden. The brain structure of each participant was measured using magnetic imaging technology, so-called MRT, and various memory tests were administered in order to monitor the seniors’ cognitive status.

“We found that those elderly who reported to be more active in daily routine had larger grey and white matter and showed better performances on various memory tests, compared to those who had a sedentary lifestyle. Interestingly, active elderly had also more grey matter in the precuneus, a brain region that typically shrinks at the beginning of Alzheimer’s disease. Our findings suggest that an active lifestyle is a promising strategy for counteracting cognitive aging late in life,” says Christian Benedict.

The data for the study were taken from the major epidemiological study Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). http://www.medsci.uu.se/pivus/

More information: Benedict C et al., Association between physical activity and brain health in older adults, Neurobiology of Aging, in press. http://www.sciencedirect.com/science/article/pii/S0197458012002618

Provided by Uppsala University

Source: medicalxpress.com

ScienceDaily (May 14, 2012) — A new study consisting of inducing cells to express telomerase, the enzyme which — metaphorically — slows down the biological clock — was successful. The research provides a “proof-of-principle” that this “feasible and safe” approach can effectively “improve health span.”

Pictured are Maria A. Blasco and Bruno M. Bernardes de Jesús (co-author) in the CNIO building in Madrid. (Credit: CNIO)

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals’ genes permanently from the embryonic stage — an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director María Blasco, have demonstrated that the mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal’s genes. And they have done so using gene therapy, a strategy never before employed to combat aging. The therapy has been found to be safe and effective in mice.

The results were recently published in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Eduard Ayuso and Fátima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autònoma de Barcelona (UAB), treated adult (one-­‐year-­‐old) and aged (two-­‐year-­‐old) mice, with the gene therapy delivering a “rejuvenating” effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals’ health, delaying the onset of age-­‐related diseases — like osteoporosis and insulin resistance — and achieving improved readings on aging indicators like neuromuscular coordination.

The gene therapy consisted of treating the animals with a DNA-­modified virus, the viral genes having been replaced by those of the telomerase enzyme, with a key role in aging. Telomerase repairs the extreme ends or tips of chromosomes, known as telomeres, and in doing so slows the cell’s and therefore the body’s biological clock. When the animal is infected, the virus acts as a vehicle depositing the telomerase gene in the cells.

This study “shows that it is possible to develop a telomerase-­based anti-­aging gene therapy without increasing the incidence of cancer,” the authors affirm. “Aged organisms accumulate damage in their DNA due to telomere shortening, [this study] finds that a gene therapy based on telomerase production can repair or delay this kind of damage,” they add.

'Resetting' the biological clock

Telomeres are the caps that protect the end of chromosomes, but they cannot do so indefinitely: each time the cell divides the telomeres get shorter, until they are so short that they lose all functionality. The cell, as a result, stops dividing and ages or dies. Telomerase gets around this by preventing telomeres from shortening or even rebuilding them. What it does, in essence, is stop or reset the cell’s biological clock.

But in most cells the telomerase gene is only active before birth; the cells of an adult organism, with few exceptions, have no telomerase. The exceptions in question are adult stem cells and cancer cells, which divide limitlessly and are therefore immortal — in fact several studies have shown that telomerase expression is the key to the immortality of tumour cells.

It is precisely this risk of promoting tumour development that has set back the investigation of telomerase-­‐based anti-­‐aging therapies.

In 2007, Blasco’s group demonstrated that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer-­‐resistant genes. These animals live 40% longer than is normal and do not develop cancer.

The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.

Also important is the kind of virus employed to carry the telomerase gene to the cells. The authors selected demonstrably safe viruses that have been successfully used in gene therapy treatment of hemophilia and eye disease. Specifically, they are non-­‐replicating viruses derived from others that are non-­‐pathogenic in humans.

This study is viewed primarily as “a proof-­‐of-­‐principle that telomerase gene therapy is a feasible and generally safe approach to improve healthspan and treat disorders associated with short telomeres,” state Virginia Boccardi (Second University of Naples) and Utz Herbig (New Jersey Medical School-­‐University Hospital Cancer Centre) in a commentary published in the same journal.

Although this therapy may not find application as an anti-­‐aging treatment in humans, in the short term at least, it could open up a new treatment option for ailments linked with the presence in tissue of abnormally short telomeres, as in some cases of human pulmonary fibrosis.

More healthy years

As Blasco says, “aging is not currently regarded as a disease, but researchers tend increasingly to view it as the common origin of conditions like insulin resistance or cardiovascular disease, whose incidence rises with age. In treating cell aging, we could prevent these diseases.”

With regard to the therapy under testing, Bosch explains: “Because the vector we use expresses the target gene (telomerase) over a long period, we were able to apply a single treatment. This might be the only practical solution for an anti-­‐aging therapy, since other strategies would require the drug to be administered over the patient’s lifetime, multiplying the risk of adverse effects.”

Source: Science Daily

May 14th, 2012

Controlled trial shows improved spasticity, reduced pain after smoking medical marijuana.

A clinical study of 30 adult patients with multiple sclerosis (MS) at the University of California, San Diego School of Medicine has shown that smoked cannabis may be an effective treatment for spasticity – a common and disabling symptom of this neurological disease.

The placebo-controlled trial also resulted in reduced perception of pain, although participants also reported short-term, adverse cognitive effects and increased fatigue. The study will be published in the Canadian Medical Association Journal on May 14.

Principal investigator Jody Corey-Bloom, MD, PhD, professor of neurosciences and director of the Multiple Sclerosis Center at UC San Diego, and colleagues randomly assigned participants to either the intervention group (which smoked cannabis once daily for three days) or the control group (which smoked identical placebo cigarettes, also once a day for three days). After an 11-day interval, the participants crossed over to the other group.

“We found that smoked cannabis was superior to placebo in reducing symptoms and pain in patients with treatment-resistant spasticity, or excessive muscle contractions,” said Corey-Bloom.

Earlier reports suggested that the active compounds of medical marijuana were potentially effective in treating neurologic conditions, but most studies focused on orally administered cannabinoids. There were also anecdotal reports of MS patients that endorsed smoking marijuana to relieve symptoms of spasticity.

However, this trial used a more objective measurement, a modified Ashford scale which graded the intensity of muscle tone by measuring such things as resistance in range of motion and rigidity. The secondary outcome, pain, was measured using a visual analogue scale. The researchers also looked at physical performance (using a timed walk) and cognitive function and – at the end of each visit – asked patients to assess their feeling of “highness.”

Although generally well tolerated, smoking cannabis did have mild effects on attention and concentration. The researchers noted that larger, long-terms studies are needed to confirm their findings and determine whether lower doses can result in beneficial effects with less cognitive impact.

The current study is the fifth clinical test of the possible efficacy of cannabis for clinical use reported by the University of California Center for Medicinal Cannabis Research (CMCR). Four other human studies on control of neuropathic pain also reported positive results.

Source: Neuroscience News

May 14th, 2012

Using tiny solar-panel-like cells surgically placed underneath the retina, scientists at the Stanford University School of Medicine have devised a system that may someday restore sight to people who have lost vision because of certain types of degenerative eye diseases.

This device — a new type of retinal prosthesis — involves a specially designed pair of goggles, which are equipped with a miniature camera and a pocket PC that is designed to process the visual data stream. The resulting images would be displayed on a liquid crystal microdisplay embedded in the goggles, similar to what’s used in video goggles for gaming. Unlike the regular video goggles, though, the images would be beamed from the LCD using laser pulses of near-infrared light to a photovoltaic silicon chip — one-third as thin as a strand of hair — implanted beneath the retina.

Electric currents from the photodiodes on the chip would then trigger signals in the retina, which then flow to the brain, enabling a patient to regain vision.

A study, to be published online May 13 in Nature Photonics, discusses how scientists tested the photovoltaic stimulation using the prosthetic device’s diode arrays in rat retinas in vitro and how they elicited electric responses, which are widely accepted indicators of visual activity, from retinal cells . The scientists are now testing the system in live rats, taking both physiological and behavioral measurements, and are hoping to find a sponsor to support tests in humans.

“It works like the solar panels on your roof, converting light into electric current,” said Daniel Palanker, PhD, associate professor of ophthalmology and one of the paper’s senior authors. “But instead of the current flowing to your refrigerator, it flows into your retina.” Palanker is also a member of the Hansen Experimental Physics Laboratory at Stanford and of the interdisciplinary Stanford research program, Bio-X. The study’s other senior author is Alexander Sher, PhD, of the Santa Cruz Institute of Particle Physics at UC Santa Cruz; its co-first authors are Keith Mathieson, PhD, a visiting scholar in Palanker’s lab, and James Loudin, PhD, a postdoctoral scholar. Palanker and Loudin jointly conceived and designed the prosthesis system and the photovoltaic arrays.

This pinpoint-sized photovoltaic chip (upper right corner) is implanted under the retina in a blind rat to restore sight. The center image shows how the chip is comprised of an array of photodiodes, which can be activated by pulsed near-infrared light to stimulate neural signals in the eye that propagate then to the brain. A higher magnification view (lower left corner) shows a single pixel of the implant, which has three diodes around the perimeter and an electrode in the center. The diodes turn light into an electric current which flows from the chip into the inner layer of retinal cells. Adapted from Stanford image courtesy of the Daniel Palanker lab.

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May 14, 2012

What goes bump in the night? In many U.S. households: people. That’s according to new Stanford University School of Medicine research, which found that about 3.6 percent of U.S. adults are prone to sleepwalking. The work also showed an association between nocturnal wanderings and certain psychiatric disorders, such as depression and anxiety.

The study, the researchers noted, “underscores the fact that sleepwalking is much more prevalent in adults than previously appreciated.”

Maurice Ohayon, MD, DSc, PhD, professor of psychiatry and behavioral sciences, is the lead author of the paper, which will appear in the May 15 issue of Neurology, the medical journal of the American Academy of Neurology.

Sleepwalking is a disorder “of arousal from non-REM sleep.” While wandering around at night can be harmless and is often played for laughs — anyone remember the Simpsons episode where Homer began wandering around and doing silly things in his sleep? — sleepwalking can have serious consequences. Episodes can result in injuries to the wanderer or others and lead to impaired psychosocial functioning.

It is thought that medication use and certain psychological and psychiatric conditions can trigger sleepwalking, but the exact causes are unknown. Also unclear to experts in the field is the prevalence.

"Apart from a study we did 10 years ago in the European general population, where we reported a prevalence of 2 percent of sleepwalking," the researchers wrote in their paper, "there are nearly no data regarding the prevalence of nocturnal wanderings in the adult general population. In the United States, the only prevalence rate was published 30 years ago."

For this study, the first to use a large, representative sample of the U.S. general population to demonstrate the number of sleepwalkers, the researchers also aimed to evaluate the importance of medication use and mental disorders associated with sleepwalking. Ohayon and his colleagues secured a sample of 19,136 individuals from 15 states and then used phone surveys to gather information on participants’ mental health, medical history and medication use.

Participants were asked specific questions related to sleepwalking, including frequency of episodes during sleep, duration of the sleep disorder and any inappropriate or potentially dangerous behaviors during sleep. Those who didn’t report any episodes in the last year were asked if they had sleepwalked during their childhood. Participants were also queried about whether there was a family history of sleepwalking and whether they had other parasomnia symptoms, such as sleep terrors and violent behaviors during sleep.

The researchers determined that as many as 3.6 percent of the sample reported at least one episode of sleepwalking in the previous year, with 1 percent saying they had two or more episodes in a month. Because of the number of respondents who reported having episodes during childhood or adolescence, lifetime prevalence of sleepwalking was found to be 29.2 percent.

The study also showed that people with depression were 3.5 times more likely to sleepwalk than those without, and people with alcohol abuse/dependence or obsessive-compulsive disorder were also significantly more likely to have sleepwalking episodes. In addition, individuals taking SSRI antidepressants were three times more likely to sleepwalk twice a month or more than those who didn’t.

"There is no doubt an association between nocturnal wanderings and certain conditions, but we don’t know the direction of the causality," said Ohayon. "Are the medical conditions provoking sleepwalking, or is it vice versa? Or perhaps it’s the treatment that is responsible."

Although more research is needed, the work could help raise awareness of this association among primary care physicians. “We’re not expecting them to diagnose sleepwalking, but they might detect symptoms that could be indices of sleepwalking,” said Ohayon.

Among the researchers’ other findings:

• The duration of sleepwalking was mostly chronic, with just over 80 percent of those who have sleepwalked reporting they’ve done so for more than five years.
• Sleepwalking was not associated with gender and seemed to decrease with age.
• Nearly one-third of individuals with nocturnal wandering had a family history of the disorder.
• People using over-the-counter sleeping pills had a higher likelihood of reporting sleepwalking episodes at least two times per month. (Indeed, a sleeping pill was the trigger for Homer Simpson’s middle-of-the-night shenanigans.)

D. Le’ger, MD, PhD, from the Universite Paris Descartes in France, was senior author of the study. Researchers from the University of Minnesota Medical School, the Hopital Gui-de-Chauliac in Montpellier, France, and Duke University School of Medicine were also involved.

Provided by Stanford University Medical Center

Source: medicalxpress.com

May 14, 2012

Why does one person become anorexic and another obese? A study recently published by a University of Colorado School of Medicine researcher shows that reward circuits in the brain are sensitized in anorexic women and desensitized in obese women. The findings also suggest that eating behavior is related to brain dopamine pathways involved in addictions.

Guido Frank, MD, assistant professor director of the Developmental Brain Research Program at the CU School of Medicine and his colleagues used functional magnetic resonance imaging (fMRI) to examine brain activity in 63 women who were either anorexic or obese. Scientists compared them to women considered “normal” weight. The participants were visually conditioned to associate certain shapes with either a sweet or a non-sweet solution and then received the taste solutions expectedly or unexpectedly. This task has been associated with brain dopamine function in the past.

The authors found that during these fMRI sessions, an unexpected sweet-tasting solution resulted in increased neural activation of reward systems in the anorexic patients and diminished activation in obese individuals. In rodents, food restriction and weight loss have been associated with greater dopamine-related reward responses in the brain.

"It is clear that in humans the brain’s reward system helps to regulate food intake" said Frank. "The specific role of these networks in eating disorders such as anorexia nervosa and, conversely, obesity, remains unclear.”

Scientists agree that more research is needed in this area. The study was published in Neuropsychopharmacology.

Provided by University of Colorado Denver

Source: medicalxpress.com

May 14, 2012

Following a stroke, factors as varied as blood sugar, body temperature and position in bed can affect patient outcomes, Loyola University Medical Center researchers report.

In a review article in the journal MedLink Neurology, first author Murray Flaster, MD, PhD and colleagues summarize the latest research on caring for ischemic stroke patients. (Most strokes are ischemic, meaning they are caused by blood clots.)

"The period immediately following an acute ischemic stroke is a time of significant risk,” the Loyola neurologists write. “Meticulous attention to the care of the stroke patient during this time can prevent further neurologic injury and minimize common complications, optimizing the chance of functional recovery.”

Stroke care has two main objectives – minimizing injury to brain tissue and preventing and treating the many neurologic and medical complications that can occur just after a stroke.

The authors discuss the many complex factors that affect outcomes. For example, there is considerable evidence of a link between hyperglycemia (high blood sugar) and poor outcomes after stroke. The authors recommend strict blood sugar control, using frequent finger-stick glucose checks and aggressive insulin treatment.

For each 1 degree C increase in the body temperature of stroke patients, the risk of death or severe disability more than doubles. Therapeutic cooling has been shown to help cardiac arrest patients, and clinical trials are underway to determine whether such cooling could also help stroke patients. Until those trials are completed, the goal should be to keep normal temperatures (between 95.9 and 99.5 degrees F).

Position in bed also is important, because sitting upright decreases blood flow in the brain. A common practice is to keep the patient lying flat for 24 hours. If a patient has orthopnea (difficulty breathing while lying flat), the head of the bed should be kept at the lowest elevation the patient can tolerate.

The authors discuss many other issues in stroke care, including blood pressure management; blood volume; statin therapy; management of complications such as pneumonia and sepsis; heart attack and other cardiac problems; blood clots; infection; malnutrition and aspiration; brain swelling; seizures; recurrent stroke; and brain hemorrhages.

Studies have shown that hospital units that specialize in stroke care decrease mortality, increase the likelihood of being discharged to home and improve functional status and quality of life.

All patients should receive supportive care — including those who suffer major strokes and the elderly. “Even in these populations, the majority of patients will survive their stroke,” the authors write. “The degree of functional recovery, however, may be dramatically impacted by the intensity and appropriateness of supportive care.”

Provided by Loyola University Health System

Source: medicalxpress.com

May 14, 2012

(Medical Xpress) — It has long been suspected that humans do not experience the world continuously, but rather in rapid snapshots.

Now, researchers at the University of Glasgow have demonstrated this is indeed the case. Just as the body goes through a 24-hour sleep-wake cycle controlled by a circadian clock, brain function undergoes such cyclic activity – albeit at a much faster rate.

Professor Gregor Thut of the Institute of Neuroscience and Psychology, said: “Rhythms are intrinsic to biological systems. The circadian rhythm, with its very slow periodicity of sleep and wake cycles every 24 hours has an obvious, periodic effect on bodily functions.

“Brain oscillations – the recurrent neural activity that we see in the brain – also show periodicity but cycle at much faster speeds. What we wanted to know was whether brain function was affected in a cyclic manner by these rapid oscillations.”

The researchers studied a prominent brain rhythm associated with visual cortex functioning that cycles at a rate of 10 times per second (10Hz).

They used a ‘simple trick’ to affect the oscillations of this rhythm which involved presenting a brief sound to ‘reset’ the oscillation.

Testing subsequent visual perception, by using transcranial magnetic stimulation of the visual cortex, revealed a cyclic pattern at the very rapid rate of brain oscillations, in time with the underlying brainwaves.

Prof Thut said: “Rhythmicity therefore is indeed omnipresent not only in brain activity but also brain function. For perception, this means that despite experiencing the world as a continuum, we do not sample our world continuously but in discrete snapshots determined by the cycles of brain rhythms.”

The research, ‘Sounds reset rhythms of visual cortex and corresponding human visual perception’ is published in the journal Current Biology.

Provided by University of Glasgow

Source: medicalxpress.com

May 14, 2012 By Sandy Evangelista

(Medical Xpress) — Swiss scientists have proven that light intensity influences our cognitive performance and how alert we feel, and that these positive effects last until early evening.

Credit: 2012 EPFL

Tests conducted in EPFL’s Solar Energy and Building Physics Laboratory (LESO) have confirmed the hypothesis that light influences our subjective feeling of sleepiness. The research team, led by Mirjam Münch, also showed that the effects of light exposure last until the early evening, and that light intensity has an impact on cognitive mechanisms. The results of this research were recently published in the journal Behavioral Neuroscience.

Light synchronizes our biological clocks. It is collected in the eye by photoreceptors that use photopigments (pigments that change when exposed to light), known as melanopsin. These cells, which differ from rods and cones, are considered a third class of photoreceptors in the retina and were discovered just ten years ago. They’re not there to form an image, but to perceive and absorb photons in the visible light spectrum. In addition, they are stimulated by blue light.

Exploring office lighting

Münch and her team wanted to know how our circadian rhythm could be influenced by our perception of light during the daytime. They created realistic office lighting conditions and recruited 29 young participants. “For this study, we took into account the intensity of natural and artificial light without specifically evaluating their spectra.”

From daytime to dusk

To synchronize their internal biological clocks, the volunteers had to maintain a regular sleep schedule during the seven days leading up to the test. They wore bracelets equipped with light sensors and accelerometers, so that the scientists could monitor their movements.

The study itself took place over two eight-hour sessions. The participants spent the first six hours in an experiment room, first in well-lighted conditions (1000-2000 lux, more or less equivalent to natural light in a room). In the second session, the light intensity was about 170 lux, which is what the eye perceives in a room without a window, lit with artificial light. For this experiment, light intensity was measured at eye-level. Every 30 minutes, the subjects were asked to assess how alert or sleepy they felt.

Finally, at the end of each session, the participants underwent two hours of supplemental memory tests in a darkened room – less than 6 lux. During these last two hours, the researchers took saliva samples in order to measure cortisol and melatonin concentrations. These two hormones are produced in a in a 24-hour cycle by the human body.

Boosted by the light

The volunteers who were subjected to higher light intensity during the afternoon were more alert all the way into the early evening. When they were subjected to light intensity ten times weaker, however, they showed signs of sleepiness and obtained lower scores on the memory tests.

These results were observed even in the absence of changes in cortisol and melatonin concentrations in their saliva. “With this study, we have discovered that light intensity has a direct effect on the subjective feeling of sleepiness as well as on objective cognitive performance, and that the benefits of more intense light during the daytime last long past the time of exposure,” concludes Münch.

Provided by Ecole Polytechnique Federale de Lausanne

Source: medicalxpress.com

ScienceDaily (May 13, 2012) — Scientists at Weill Cornell Medical College have discovered that the single protein — alpha 2 delta — exerts a spigot-like function, controlling the volume of neurotransmitters and other chemicals that flow between the synapses of brain neurons. The study, published online in Nature, shows how brain cells talk to each other through these signals, relaying thoughts, feelings and action, and this powerful molecule plays a crucial role in regulating effective communication.

In the study, the investigators also suggest how the widely used pain drug Lyrica might work. The alpha 2 delta protein is the target of this drug and the new work suggests an approach to how other drugs could be developed that effectively twist particular neurotransmitter spigots on and off to treat neurological disorders. The research findings surprised the research team, which includes scientists from University College London.

"We are amazed that any single protein has such power," says the study’s lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. "It is indeed rare to identify a biological molecule’s function that is so potent, that seems to be controlling the effectiveness of neurotransmission."

The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. “But if you add more alpha 2 delta, you can triple the number of channels at synapses,” Dr. Ryan says. “This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters.”

Before this study, it was known that Lyrica, which is used for neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but little was understood about how this protein works to control synapses.

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ScienceDaily (May 11, 2012) — Neuroscientist Patrik Verstreken, associated with VIB and KU Leuven, succeeded in undoing the effect of one of the genetic defects that leads to Parkinson’s using vitamin K2. His discovery gives hope to Parkinson’s patients.

Male fruit fly (Drosophila Melanogaster). Scientists have succeeded in undoing the effect of one of the genetic defects that leads to Parkinson’s using vitamin K2. The research was done in fruit flies. (Credit: © Studiotouch / Fotolia)

This research was done in collaboration with colleagues from Northern Illinois University (US) and was recently published in the journal Science.

"It appears from our research that administering vitamin K2 could possibly help patients with Parkinson’s. However, more work needs to be done to understand this better," says Patrik Verstreken.

Malfunctioning power plants are at the basis of Parkinson’s.

If we looked at cells as small factories, then mitochondria would be the power plants responsible for supplying the energy for their operation. They generate this energy by transporting electrons. In Parkinson’s patients, the activity of mitochondria and the transport of electrons have been disrupted, resulting in the mitochondria no longer producing sufficient energy for the cell. This has major consequences as the cells in certain parts of the brain will start dying off, disrupting communication between neurons. The results are the typical symptoms of Parkinson’s: lack of movement (akinesia), tremors and muscle stiffness.

The exact cause of this neurodegenerative disease is not known. In recent years, however, scientists have been able to describe several genetic defects (mutations) found in Parkinson’s patients, including the so-called PINK1 and Parkin mutations, which both lead to reduced mitochondrial activity. By studying these mutations, scientists hope to unravel the mechanisms underlying the disease process.

Paralyzed fruit flies

Fruit flies (Drosophila) are frequently used in lab experiments because of their short life spans and breeding cycles, among other things. Within two weeks of her emergence, every female is able to produce hundreds of offspring. By genetically modifying fruitflies, scientists can study the function of certain genes and proteins. Patrik Verstreken and his team used fruitflies with a genetic defect in PINK1 or Parkin that is similar to the one associated with Parkinson’s. They found that the flies with a PINK1 or Parkin mutation lost their ability to fly.

Upon closer examination, they discovered that the mitochondria in these flies were defective, just as in Parkinson’s patients. Because of this they generated less intracellular energy — energy the insects needed to fly. When the flies were given vitamin K2, the energy production in their mitochondria was restored and the insects’ ability to fly improved. The researchers were also able to determine that the energy production was restored because the vitamin K2 had improved electron transport in the mitochondria. This in turn led to improved energy production.

Conclusion

Vitamin K2 plays a role in the energy production of defective mitochondria. Because defective mitochondria are also found in Parkinson’s patients with a PINK1 or Parkin mutation, vitamin K2 potentially offers hope for a new treatment for Parkinson’s.

Source: Science Daily

May 11, 2012

Regenerating sensory hair cells, which produce electrical signals in response to vibrations within the inner ear, could form the basis for treating age- or trauma-related hearing loss. One way to do this could be with gene therapy that drives new sensory hair cells to grow.

Researchers at Emory University School of Medicine have shown that introducing a gene called Atoh1 into the cochleae of young mice can induce the formation of extra sensory hair cells.

Their results show the potential of a gene therapy approach, but also demonstrate its current limitations. The extra hair cells produce electrical signals like normal hair cells and connect with neurons. However, after the mice are two weeks old, which is before puberty, inducing Atoh1 has little effect. This suggests that an analogous treatment in adult humans would also not be effective by itself.

The findings were published May 9 in the Journal of Neuroscience.

"We’ve shown that hair cell regeneration is possible in principle," says Ping Chen, PhD, associate professor of cell biology at Emory University School of Medicine. “In this paper, we have identified which cells are capable of becoming hair cells under the influence of Atoh1, and we show that there are strong age-dependent limitations on the effects of Atoh1 by itself.”

The first author of the paper, Michael Kelly, now a postdoctoral fellow at the National Institute on Deafness and Other Communication Disorders, was a graduate student in Emory’s Neuroscience program.

Kelly and his coworkers engineered mice to turn on the Atoh1 gene in the inner ear in response to the antibiotic doxycycline. Previous experimenters had used a virus to introduce Atoh1 into the cochleae of animals. This approach resembles gene therapy, but has the disadvantage of being slightly different each time, Chen says. In contrast, the mice have the Atoh1 gene turned on in specific cells along the lining of the inner ear, called the cochlear epithelium, but only when fed doxycycline.

Young mice given doxycycline for two days had extra sensory hair cells, in parts of the cochlea where developing hair cells usually appear, and also additional locations (see accompanying image).

The extra hair cells could generate electrical signals, although those signals weren’t as strong as mature hair cells. Also, the extra hair cells appeared to attract neuronal fibers, which suggests that those signals could connect to the rest of the nervous system.

"They can generate electrical signals, but we don’t know if they can really function in the context of hearing.” Chen says. “For that to happen, the hair cells’ signals need to be coordinated and integrated.”

Although doxycycline could turn on Atoh1 all over the surface of the cochlea, extra sensory hair cells did not appear everywhere. When they removed cochleae from the mice and grew them in culture dishes, her team was able to provoke even more hair cells to grow when they added a drug that inhibits the Notch pathway.

Manipulating the Notch pathway affects several aspects of embryonic development and in some contexts appears to cause cancer, so the approach needs to be refined further. Chen says that it may be possible to unlock the age-related limits on hair cell regeneration by supplying additional genes or drugs in combination with Atoh1, and the results with the Notch drug provide an example.

"Our future goals are to develop approaches to stimulate hair cell formation in older animals, and to examine functional recovery after Atoh1 induction," she says.

Provided by Emory University

Source: medicalxpress.com

May 11, 2012

A brain study in infant rats demonstrates that the anti-epilepsy drug phenobarbital stunts neuronal growth, which could prompt new questions about using the first-line drug to treat epilepsy in human newborns.

In Annals of Neurology EarlyView posted online May 11, researchers at Georgetown University Medical Center (GUMC) report that the anti-epilepsy drug phenobarbital given to rat pups about a week old changed the way the animals’ brains were wired, causing cognitive abnormalities later in life.

The researchers say it has been known that some of the drugs used to treat epilepsy increase the amount of neurons that die shortly after birth in the rat brain, but, until this study, no one had shown whether this action had any adverse impact on subsequent brain development.

"Our study is the first to show that the exposure to these drugs — and just a single exposure — can prevent brain circuits from developing their normal connectivity, meaning they may not be wired correctly, which can have long-lasting effects on brain function,” says the study’s senior investigator, Karen Gale, Ph.D., a professor of pharmacology at GUMC. “These findings suggest that in the growing brain, these drugs are not as benign as one would like to believe.”

For their study, the Georgetown researchers studied four agents including phenobarbital.

"The good news is not all anti-epilepsy drugs have this disruptive effect in the animal studies," Gale says.

The researchers found that the anti-epilepsy drug levetiracetam did not stunt synaptic growth. Animals treated with a third drug, lamotrigine, showed neural maturation, but it was delayed. An additional finding involved melatonin. When added to phenobarbital, it appeared to prevent the persistent adverse neural effects in the rat pups. Melatonin has been used clinically to protect cells from injury in humans.

"Many clinicians have been advocating for a reexamination of the use of these drugs in infants, and our findings provide experimental data to support that need," says the study’s co-lead investigator, Patrick A. Forcelli, Ph.D., a postdoctoral fellow in the department of pharmacology and physiology at GUMC. "Phenobarbital has been used to treat seizures for over 100 years — well before a Food and Drug Administration approval process was established— and for more than 50 years, it has been the first drug of choice in the treatment of seizures in neonates."

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May 11, 2012

Neurons are arranged in periodic patterns that repeat over large distances in two areas of the cerebral cortex, suggesting that the entire cerebral cortex has a stereotyped organization, reports a team of researchers led by Toshihiko Hosoya of the RIKEN Brain Science Institute. The entire cortex has a stereotypical layered structure with the same cell types arranged in the same way, but how neurons are organized in the other orientation—parallel to the brain’s surface—is poorly understood.

Figure 1: In the mouse visual cortex, neurons expressing id2 mRNA (magenta) are found in regularly repeating clusters. Reproduced from Ref. 1 © 2011 Hisato Maruoka et al., RIKEN Brain Science Institute

Hosoya and his colleagues therefore examined layer V (5) of the mouse cortex, which contains two classes of large pyramidal neurons that look identical but differ in the connections they form. One projects axons straight down to regions beneath the cortex; the other projects to the cortex on the opposite side of the brain.

First, the researchers examined expression of the id2 gene in cells of the visual cortex, because these cells form clusters in that part of the brain. They found that id2 is expressed in nearly all cells that project axons downward, but not in those that cross over. Hosoya and colleagues verified this by visualizing the connections of cells using fluorescent cholera toxin, which binds to cell membranes and travels along the axons.

Further examination of gene expression patterns in tissue slices revealed that the cells are arranged in clusters aligned perpendicular to the brain’s surface, and that the clusters are organized in a regular pattern, with the same basic unit repeating every thirty micrometers (Fig. 1). They also observed the same pattern in layer V of the somatosensory cortex, suggesting that this organization is common to all other areas.

By generating a strain of mutant mice expressing green fluorescent protein in the progenitor cells that produce the cells in layer V during brain development, Hosoya and his colleagues investigated the embryonic origin of these cells. This revealed that each cluster contains neurons that are produced by different progenitor cells.

Finally, the researchers showed that the regular pattern persists in the adult visual cortex, and that neurons in each cluster show the same activity patterns in response to visual stimulation. “Our preliminary data suggest that at least several other areas in the cortex have the same structure,” says Hosoya. “It’s likely that the entire cortex has the same organization, and I expect that the human cortex has the same structure.”

Provided by RIKEN

Source: medicalxpress.com

May 11, 2012

Global network activity in the brain modulates local neural circuitry via calcium signaling in non-neuronal cells called astrocytes (Fig. 1), according to research led by Hajime Hirase of the RIKEN Brain Science Institute. The finding clarifies the link between two important processes in the brain.

Figure 1: Astrocytes are star-shaped cells with numerous fine projections that ensheath synapses in the brain. © 2012 Hajime Hirase

Activity in large-scale brain networks is thought to modulate changes in neuronal connectivity, so-called ‘synaptic plasticity’, in the cerebral cortex. The neurotransmitter acetylcholine regulates global brain activity associated with attention and awareness, and is involved in plasticity.

To investigate how these processes are linked, Hirase and his colleagues simultaneously stimulated the whiskers of mice and the nucleus basalis of Meynert (NBM), a basal forebrain structure containing neurons that synthesize acetylcholine and project widely to the cortex. Using electrodes and an imaging technique called two-photon microscopy, performed through a ‘cranial window’, they monitored the responses of cells in the barrel cortex, which receives inputs from the whiskers.

Recordings from the electrodes showed that repeated co-stimulation of the whiskers and NBM induced plasticity in the barrel cortex. This plasticity depended on two types of receptors—muscarinic acetylcholine receptors (mAChRs) and N-methyl-D-aspartic acid receptors (NMDARs). Two-photon imaging microscopy further revealed that activation of the mAChRs during co-stimulation elevated the concentration of calcium ions within astrocytes of the barrel cortex.

The researchers repeated these experiments in mutant mice lacking the receptor that controls the release of calcium ions in astrocytes. Since co-stimulation of whiskers and NBM did not induce plasticity in the mutants, Hirase and colleagues concluded that calcium signaling in astrocytes acts as a ‘gate’ linking the changes in global brain state induced by acetylcholine to activity in local cortical circuits.

Furthermore, the researchers found that stimulation of the NBM led to an increase in the extracellular concentration of the amino acid D-serine in the normal, but not the mutant, mice. D-serine is secreted by astrocytes and activates NMDARs. Hirase’s team had previously shown that astrocytes are electrically silent in living rodents even in the presence of neural activity2. The new findings showed that the biochemical, as opposed to electrical, activation of astrocytes induces them to release the transmitter that modulates synaptic plasticity in the neuronal circuitry.

“Our study is probably the first to show that calcium signaling in astrocytes is related to neuronal circuit plasticity in living animals,” says Hirase. “We are now studying if this type of calcium signaling occurs in all parts of an astrocyte or is restricted to some parts of the cell.”

Provided by RIKEN

Source: medicalxpress.com

May 11, 2012

Even mild head injuries can cause significant abnormalities in brain function that last for several days, which may explain the neurological symptoms experienced by some individuals who have experienced a head injury associated with sports, accidents or combat, according to a study by Virginia Commonwealth University School of Medicine researchers.

These findings, published in the May issue of the Journal of Neuroscience, advance research in the field of traumatic brain injury (TBI), enabling researchers to better understand what brain structural or functional changes underlie posttraumatic disorders – a question that until now has remained unclear.

Previous research has shown that even a mild case of TBI can result in long-lasting neurological issues that include slowing of cognitive processes, confusion, chronic headache, posttraumatic stress disorder and depression.

The VCU team, led by Kimberle M. Jacobs, Ph.D., associate professor in the Department of Anatomy and Neurobiology, demonstrated for the first time, using sophisticated bioimaging and electrophysiological approaches, that mild injury can cause structural disruption of axons in the brain while also changing the way the neurons fire in areas where they have not been structurally altered. Axons are nerve fibers in the brain responsible for conducting electrical impulses. The team used models of mild traumatic brain injury and followed morphologically identified neurons in live cortical slices.

“These findings should help move the field forward by providing a unique bioimaging and electrophysiological approach to assess the evolving changes evoked by mild TBI and their potential therapeutic modulation,” said co-investigator, John T. Povlishock, Ph.D., professor and chair of the VCU School of Medicine’s Department of Anatomy and Neurobiology and director of the Commonwealth Center for the Study of Brain Injury.

According to Povlishock, additional benefit may also derive from the use of this model system with repetitive injuries to determine if repeated insults exacerbate the observed abnormalities.

Provided by Virginia Commonwealth University

Source: medicalxpress.com

May 11th, 2012

Babies born to women with sensitivity to gluten appear to be at increased risk for certain psychiatric disorders later in life, according to research by scientists at Karolinska Institutet in Sweden and Johns Hopkins Children’s Center in Baltimore.

The team’s findings, published in The American Journal of Psychiatry, add to a growing body of evidence that many “adult” diseases may take root before and shortly after birth.

“Lifestyle and genes are not the only factors that shape disease risk, and factors and exposures before, during and after birth can help pre-program much of our adult health,” said investigator Robert Yolken, M.D., a neuro-virologist at Johns Hopkins Children’s Center. “Our study is an illustrative example suggesting that a dietary sensitivity before birth could be a catalyst in the development of schizophrenia or a similar condition 25 years later.”

Maternal infections and other inflammatory disorders during pregnancy have long been linked to greater risk for schizophrenia in the offspring but, the Swedish and U.S. investigators say, this is the first study that points to maternal food sensitivity as a possible culprit in the development of such disorders. The findings establish a strong link but do not mean that gluten sensitivity will invariably cause schizophrenia, the investigators caution. The research, however, does suggest an intriguing new mechanism that may drive up risk and illuminate possible prevention strategies.

“Our research not only underscores the importance of maternal nutrition during pregnancy and its lifelong effects on the offspring, but also suggests one potential cheap and easy way to reduce risk if we were to find further proof that gluten sensitivity exacerbates or drives up schizophrenia risk,” said study lead investigator Håkan Karlsson, M.D., Ph.D., a neuroscientist at Karolinska Institutet and former neuro-virology fellow at Johns Hopkins.

The team’s findings are based on an examination of 764 birth records and neonatal blood samples of Swedes born between 1975 and 1985. Some 211 of them subsequently developed non-affective psychoses, such as schizophrenia and delusional disorders.

Using stored neonatal blood samples, the investigators measured levels of IgG antibodies to milk and wheat. IgG antibodies are markers of immune system reaction triggered by the presence of certain proteins. Because a mother’s antibodies cross the placenta during pregnancy to confer immunity to the baby, a newborn’s elevated IgG levels are proof of protein sensitivity in the mother.

Children born to mothers with abnormally high levels of antibodies to the wheat protein gluten had nearly twice the risk of developing schizophrenia later in life, compared with children who had normal levels of gluten antibodies. The link persisted even after researchers accounted for other factors known to increase schizophrenia risk, including maternal age, gestational age, mode of delivery and the mother’s immigration status. The risk for psychiatric disorders was not increased among those with elevated levels of antibodies to milk protein.

The researchers say the suspicion that food sensitivity in the mother can affect her child’s risk for psychiatric disorders stems from an observation made in the wake of the World War II by U.S. Army researcher F. Curtis Dohan, M.D. Dohan noted that food scarcity in post-war Europe and wheat-poor diets led to notably fewer hospital admissions for schizophrenia.  The link was merely observational, but it has piqued the curiosity of scientists ever since.

Researchers in the past also have observed that people diagnosed with schizophrenia have disproportionately high rates celiac disease, a rare autoimmune disorder characterized by gluten sensitivity. Although it is a hallmark of the condition, gluten sensitivity alone is not enough to diagnose celiac disease. Other studies have found that some people with schizophrenia have gluten sensitivity without other signs of celiac disease, the researchers note.

Yolken and Karlsson say the team already is conducting follow-up studies to clarify how gluten or sensitivity to it increases schizophrenia risk and whether it does so only in those genetically predisposed.

Source: Neuroscience News

ScienceDaily (May 10, 2012) — Researchers at the Medical Research Council (MRC) Toxicology Unit at the University of Leicester have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice.

Scientists have identified a major pathway leading to brain cell death in mice with neurodegenerative disease. The team was able to block the pathway, preventing brain cell death and increasing survival in the mice. (Credit: © pressmaster / Fotolia)

In human neurodegenerative diseases, including Alzheimer’s, Parkinson’s and prion diseases, proteins “mis-fold” in a variety of different ways resulting in the build up of mis-shapen proteins. These form the plaques found in Alzheimer’s and the Lewy bodies found in Parkinson’s disease.

The researchers studied mice with neurodegeneration caused by prion disease. These mouse models currently provide the best animal representation of human neurodegenerative disorders, where it is known that the build up of mis-shapen proteins is linked with brain cell death.

They found that the build up of mis-folded proteins in the brains of these mice activates a natural defense mechanism in cells, which switches off the production of new proteins. This would normally switch back ‘on’ again, but in these mice the continued build-up of mis-shapen protein keeps the switch turned ‘off’. This is the trigger point leading to brain cell death, as those key proteins essential for nerve cell survival are not made.

By injecting a protein that blocks the ‘off’ switch of the pathway, the scientists were able to restore protein production, independently of the build up of mis-shapen proteins,and halt the neurodegeneration. The brain cells were protected, protein levels and synaptic transmission (the way in which brain cells signal to each other) were restored and the mice lived longer, even though only a very small part of their brain had been treated.

Mis-shapen proteins in human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, also over-activate this fundamental pathway controlling protein synthesis in the brains of patients, which represents a common target underlying these different clinical conditions. The scientists’ results suggest that treatments focused on this pathway could be protective in a range of neurodegenerative disease in which mis-shapen proteins are building up and causing neurons to die.

Professor Giovanna Mallucci, who led the team, said, “What’s exciting is the emergence of a common mechanism of brain cell death, across a range of different neurodegenerative disorders, activated by the different mis-folded proteins in each disease. The fact that, in mice with prion disease, we were able to manipulate this mechanism and protect the brain cells means we may have a way forward in how we treat other disorders. Instead of targeting individual mis-folded proteins in different neurodegenerative diseases, we may be able to target the shared pathways and rescue brain cell degeneration irrespective of the underlying disease.”

Professor Hugh Perry, chair of the MRC’s Neuroscience and Mental Health Board, said, “Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are debilitating and largely untreatable conditions. Alzheimer’s disease and related disorders affect over seven million people in Europe, and this figure is expected to double every 20 years as the population ages across Europe. The MRC believes that research such as this, which looks at the fundamental mechanisms of these devastating diseases, is absolutely vital. Understanding the mechanism that leads to neuronal dysfunction prior to neuronal loss is a critical step in finding ways to arrest disease progression.”

Source: Science Daily

May 10th, 2012

Glial cells pass on metabolites to neurons.

Around 100 billion neurons in the human brain enable us to think, feel and act. They transmit electrical impulses to remote parts of the brain and body via long nerve fibres known as axons. This communication requires enormous amounts of energy, which the neurons are thought to generate from sugar. Axons are closely associated with glial cells which, on the one hand, surround them with an electrically insulating myelin sheath and, on the other hand support their long-term function. Klaus Armin and his research group from the Max Planck Institute of Experimental Medicine in Göttingen have now discovered a possible mechanisms by which these glial cells in the brain can support their associated axons and keep them alive in the long term.

Oligodendrocytes are a group of highly specialised glial cells in the central nervous system. They are responsible for the formation of the fat-rich myelin sheath that surrounds the nerve fibres as an insulating layer. The comparison with the coating on electricity cables is an obvious one; however, myelin can do much more than act as the insulating layer on electricity cables: it increases the transmission speed of the axons and also reduces ongoing energy consumption. The extreme importance of myelin for a functioning nervous system is shown by the diseases that arise from a defective insulating layer, such as multiple sclerosis

Interestingly, the function of the oligodendrocytes goes far beyond the mere provision of myelin. Klaus-Armin Nave and his team at the Max Planck Institute in Göttingen already succeeded in demonstrating years ago that healthy glial cells are also essential for the long-term function and survival of the axons themselves, irrespective of myelination. “The way in which the oligodendrocytes functionally support their associated axons was not clear to us up to now,” says Nave. In a new study, the researchers were able to show that the glial cells are involved in, among other things, the replenishment of energy in the nerve fibres. “They could be described as the petrol stations on the data highway of the axons,” says Nave, explaining the results.

Electron microscope cross-section image of the nerve fibres (axons) of the optic nerve. Axons are surrounded by special glial cells, the oligodendrocytes, wrapping themselves around the axons in several layers. Between the axons, there are extensions of astrocytes, another type of glial cells. © K.-A.Nave/MPI f. Experimental Medicine

But how does the energy refuelling work? Is there a metabolic connection between the oligodendrocytes and axons? To find out, Ursula Fünfschilling generated genetically modified mice: the function of the mitochondria was deliberately disrupted in the oligodendrocytes through the inactivation of the Cox10 gene. This affects the final stages of sugar breakdown taking place in the mitochondria where energy is harnessed – a process known as the respiratory chain. If a link in this chain is missing, in this instance cytochrome oxidase, which is only functional when cells have the enzyme Cox10, the glial cells gradually lose the capacity for cell respiration in their mitochondria. “Without independent breathing, the manipulated glial cells of the nervous systems should have died,” explains the scientist. That is, unless the low level of energy harnessed from the splitting of the glucose to form pyruvate or milk acid, a process known as glycolysis, is sufficient for them.

And this is precisely what the scientists observed in their mice: the animals’ myelin was initially formed in the normal way. The loss of the mitochondrial respiratory chain, which started at this point, did not appear to affect the glial cells in the central nervous system. Even one year later, there were no neurodegenerative changes in the brain to be observed. The scientists assume that in the early weeks of life – a phase characterised by maximum energy requirement – the mutated oligodendrocytes still rely on many intact mitochondria. All of the more mature oligodendrocytes later appear to reduce the mitochondrial respiration and set it to energy generation through increased glycolysis. This has the advantage in healthy glial cells that the metabolic products which arise during the breaking down of glucose can be used as components for myelin synthesis. In addition, the lactic acid that arises in the oligodendrocytes can be given to the axons where it can be used to produce energy with the help of the axon’s own mitochondria.

“The complete loss of the respiratory chain in the deliberately modified oligodendrocytes probably elevates a developmental step that unfolds naturally,” explains Nave. Thus the loss of glial mitochondria does not result in the deterioration of the energy supply to the axons but, conversely, to an oversupply of exploitable lactic acid. The affected nerve pathways themselves have no problem demonstrably in metabolising the lactic acid from oligodendrocytes. Transport proteins ensure the rapid transfer of the lactic acid between the oligodendrocytes and their myelinated axons.

This finding provides a new understanding of the role of oligodendrocytes: in addition to their known significance for myelinisation [aka myelination], they can directly provide the axons with glucose products that can be used as fuel with the help of axonal mitochondria in periods of high activity. This coupling of glial cells could explain, among other things, why in many myelin diseases, for example multiple sclerosis, the affected demyelinised axons often suffer irreversible damage.

Source: Neuroscience News

ScienceDaily (May 10, 2012) — Research into hearing loss after exposure to loud noises could lead to the first drug treatments to prevent the development of tinnitus.

Researchers in the University of Leicester’s Department of Cell Physiology and Pharmacology have identified a cellular mechanism that could underlie the development of tinnitus following exposure to loud noises. The discovery could lead to novel tinnitus treatments, and investigations into potential drugs to prevent tinnitus are currently underway.

Tinnitus is a sensation of phantom sounds, usually ringing or buzzing, heard in the ears when no external noise is present. It commonly develops after exposure to loud noises (acoustic over-exposure), and scientists have speculated that it results from damage to nerve cells connected to the ears.

Although hearing loss and tinnitus affect around ten percent of the population, there are currently no drugs available to treat or prevent tinnitus.

University of Leicester researcher Dr Martine Hamann, who led the study published in the journal Hearing Research, said: “We need to know the implications of acoustic over exposure, not only in terms of hearing loss but also what’s happening in the brain and central nervous system. It’s believed that tinnitus results from changes in excitability in cells in the brain — cells become more reactive, in this case more reactive to an unknown sound.”

Dr Hamann and her team, including PhD student Nadia Pilati, looked at cells in an area of the brain called the dorsal cochlear nucleus — the relay carrying signals from nerve cells in the ear to the parts of the brain that decode and make sense of sounds. Following exposure to loud noises, some of the nerve cells (neurons) in the dorsal cochlear nucleus start to fire erratically, and this uncontrolled activity eventually leads to tinnitus.

Dr Hamann said “We showed that exposure to loud sound triggers hearing loss a few days after the exposure to the sound. It also triggers this uncontrolled activity in the neurons of the dorsal cochlear nucleus. This is all happening very quickly, in a matter of days”

In a key breakthrough in collaboration with GSK who sponsored Dr Pilati’s PhD, the team also discovered the specific cellular mechanism that leads to the neurons’ over-activity. Malfunctions in specific potassium channels that help regulate the nerve cell’s electrical activity mean the neurons cannot return to an equilibrium resting state.

Ordinarily, these cells only fire regularly and therefore regularly return to a rest state. However, if the potassium channels are not working properly, the cells cannot return to a rest state and instead fire continuously in random bursts, creating the sensation of constant noise when none exists.

Dr Hamann explained: “In normal conditions the channel helps to drag down the cellular electrical activity to its resting state and this allows the cell to function with a regular pattern. After exposure to loud sound, the channel is functioning less and therefore the cell is constantly active, being unable to reach its resting state and displaying those irregular bursts.”

Although many researchers have investigated the mechanisms underlying tinnitus, this is the first time that cellular bursting activity has been characterised and linked to specific potassium channels. Identifying the potassium channels involved in the early stages of tinnitus opens up new possibilities for preventing tinnitus with early drug treatments.

Dr Hamann’s team is currently investigating potential drugs that could regulate the damaged cells, preventing their erratic firing and returning them to a resting state. If suitable drug compounds are discovered, they could be given to patients who have been exposed to loud noises to protect them against the onset of tinnitus.

These investigations are still in the preliminary stages, and any drug treatment would still be years away.

Source: Science Daily