Neuroscience

ScienceDaily (June 7, 2012) — Degeneration of the axon and synapse, the slender projection through which neurons transmit electrical impulses to neighboring cells, is a hallmark of some of the most crippling neurodegenerative and brain diseases such as amyotrophic lateral sclerosis (ALS), Huntington’s disease and peripheral neuropathy. Scientists have worked for decades to understand axonal degeneration and its relation to these diseases. Now, researchers at the University of Massachusetts Medical School are the first to describe a gene — dSarm/Sarm1 — responsible for actively promoting axon destruction after injury. The research, published June 7 online by Science, provides evidence of an exciting new therapeutic target that could be used to delay or even stop axon decay.

"This discovery has the potential to have a profound impact on our understanding of neurodegenerative diseases, much like the discovery of apoptosis (programmed cell death) fundamentally changed our understanding of cancer," said Marc R. Freeman, PhD, associate professor of neurobiology at the University of Massachusetts Medical School and lead investigator on the study. "Identification of this gene allows us to start asking exciting new questions about the role of axon death in neurodegenerative diseases. For example, is it possible that these pathways are being inappropriately activated to cause premature axon death?"

For more than a century, scientists believed that injured axons severed from the neuron cell body passively wasted away due to a lack of nutrients. However, a mouse mutation identified in the early 1990s — called slow Wallerian degeneration (Wlds) — was able to suppress axon degeneration for weeks. This finding forced scientists to reassess Wallerian degeneration, the process through which an injured axon degenerates, as a passive process and consider the possibility that an active program of axon auto-destruction, akin to apoptotic death, was at work instead.

If Wallerian degeneration was an active process, hypothesized Dr. Freeman, a Howard Hughes Medical Institute Early Career Scientist, then it should be possible through forward genetic screens in Drosophila to identify mutants exhibiting Wlds-like axon protection. Freeman and colleagues screened more than 2,000 Drosophila mutants for ones that exhibited long-term survival of severed axons. Freeman says this was a heroic effort on the part of his colleagues. The screen took place over the next two and a half years, and involved seven students and post-docs in the Freeman lab — Jeannette M. Osterloh, A. Nicole Fox, PhD, Michelle A. Avery, PhD, Rachel Hackett, Mary A. Logan, PhD, Jennifer M. MacDonald, Jennifer S. Zeigenfuss — who performed the painstaking and labor-intensive experiments needed on each Drosophila mutant to identify flies that suppressed axonal degeneration after nerve injury.

Through these tests, they identified three mutants (out of the 2,000 screened) where severed axons survived for the lifespan of the fly. Next generation sequencing and chromosome deficiency mapping techniques were then used to isolate the single gene affected in all three — dSarm. These were loss-of-function alleles, meaning that Drosophila unable to produce the dSarm/Sarm1 molecule exhibited prolonged axon survival for as many as 30 days after injury. Freeman and colleagues went on to show that mice lacking Sarm1, the mammalian homolog of dSarm, also displayed remarkable preservation of injured axons. These findings provided the first direct evidence that Wallerian degeneration was driven by a conserved axonal death program and not a passive response to axon injury.

"For 20 years people have been looking for a gene whose normal function is to promote axon degeneration," said Osterloh, first author on the study. "Identification of the dSarm/Sarm1 gene has enormous therapeutic potential, for example as a knockdown target for patients suffering from diseases involving axonal loss."

The next step for Freeman and colleagues is to identify additional genes in the axon death pathway and investigate whether any have links with specific neurodegenerative diseases. “We’re already working with scientists at UMMS to understand the role axon death plays in ALS and Huntington’s disease,” said Freeman. “We are very excited about the possibility that these findings could have broad therapeutic potential in many neurodegenerative diseases.”

Source: Science Daily

ScienceDaily (June 7, 2012) — Scientists have discovered a new function for a protein that protects cells during injury and could eventually translate into treatment for conditions ranging from cardiovascular disease to Alzheimer’s.

Researchers report online June 7 in the journal Cell that a type of protein called thrombospondin activates a protective pathway that prevents heart cell damage in mice undergoing simulated extreme hypertension, cardiac pressure overload and heart attack.

"Our results suggest that medically this protein could be targeted as a way to help people with many different disease states where various organs are under stress,” said Jeffery Molkentin, PhD, lead investigator and a researcher at Cincinnati Children’s Hospital Medical Center and the Howard Hughes Medical Institute. "Although more study is needed to determine how our findings might be applied clinically, a possible therapeutic strategy could include a drug or gene therapy that induces overexpression of the protein in tissues or organs undergoing injury."

Thrombospondin (Thbs) proteins are produced by the body in cells where tissues are being injured, reconfigured or remodeled, such as in chronic cardiac disease. They appear in part of the cell’s internal machinery called the endoplasmic reticulum. There, Thbs triggers a stress response process to regulate production of other proteins and help correct or rid cells of proteins that misfold and lose their form and intended function. Misfolded proteins help drive tissue damage and organ dysfunction.

The researchers zeroed in on how one thrombospondin protein (Thbs4) activates cellular stress responses in mice bred to overexpress the protein in heart cells. They compared how the hearts of the Thbs4-positive mice responded to simulated stress and injury to mice not bred to overexpress cardiac-specific Thbs4.

Overexpression of Thbs4 had no effect on the animals prior to cardiac stress — although during simulated hypertension and cardiac infarction the protein reduced injury and protected them from death. Mice not bred for Thbs4 overexpression were extremely sensitive to cardiac injury, according to Molkentin, a member of the Division of Molecular Cardiovascular Biology and Cincinnati Children’s Heart Institute.

The researchers reported that overexpressed Thbs4 enhanced the ability of heart cells to secrete helpful proteins, resolve misfolded proteins and properly reconstruct extracellular matrix — connective tissues that help give the heart functional form and structural integrity.

Critical to the stress response process was Thbs4 activating and regulating a transcription factor called Aft6alpha. Transcription factors help decode genetic instructions of other genes to control their expression. In the case of Aft6alpha in the heart, it helps mediate repair processes. When Aft6alpha is activated by Thbs4, the endoplasmic reticulum in cells expands and the production of chaperone molecules and other repair proteins is enhanced.

Mice bred not to overexpress cardiac Thbs4 did not exhibit activated Aft6alpha or robust repair processes following cardiac injury, leading to their poor outcomes.

Molkentin said the research team continues to examine the Thbs-dependent stress response pathway to better understand the involved processes. This includes seeing how the pathway affects laboratory models of neurodegenerative diseases like Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis.

Source: Science Daily

June 7, 2012

The Huntington Study Group (HSG), under the leadership of Ray Dorsey, M.D. with Johns Hopkins Medical and Diana Rosas, M.D. with Massachusetts General Hospital, is conducting a clinical trial in Huntington’s disease (HD) throughout the United States and Australia, “A randomized, double-blind, placebo-controlled, study to assess the safety and tolerability, and efficacy of PBT2 in patients with early to mid-stage Huntington’s disease” comparing a 100 mg dose or 250 mg dose versus placebo. The HSG is a not-for-profit group of physicians and other clinical researchers who are experienced in the care of HD patients and dedicated to clinical research of the disease. This trial is sponsored by Prana Biotechnology Limited (Melbourne, Australia) and is being managed by the University of Rochester Medical Center.

Huntington’s disease is an inherited neurodegenerative disease which affects over 30,000 people in both the United States and Australia. HD is characterized by brain cell death that usually begins between the ages of 30 to 50, and results in motor, cognitive and behavioral signs and symptoms. While there are medications to help relieve some of the disease symptoms, there is no known treatment to address the cognitive impairment associated with HD.

Research has shown that normally occurring metals in the brain play a significant role in diseases such as Alzheimer’s disease and more recently, HD. Researchers at Prana Biotechnology are identifying drugs designed to interrupt interactions between these biological metals and target proteins in the brain, to prevent deterioration of brain cells. One of the chemical compounds, called PBT2, has shown in animal models, and as well as in a small group of patients with Alzheimer’s disease, that it may improve cognition. There is some indication in animal models of HD, that the drug may improve motor function and control, increase life span and reduce the amount of brain cell degeneration. Based on these results, Prana is investigating whether the drug will have similar effects with HD patients.

Reach2HD will evaluate how safe and well tolerated PBT2 is at a dose of 100 mg or 250 mg a day compared to a placebo over six months. The trial will also measure whether there is an effect on cognitive abilities as well as other HD symptoms including motor and overall functioning of individuals with HD.

"We are excited to work with Prana to investigate the safety and tolerability of an interesting and innovative experimental treatment for Huntington’s disease, PBT2," said Dorsey. "We have few treatment options for Huntington disease, and none for cognition. We hope this is a step to addressing this large unmet need for patients and their families."

Provided by University of Rochester Medical Center

Source: medicalxpress.com

June 7, 2012

The Allen Institute for Brain Science announced today its latest public data release, enhancing online resources available via the Allen Brain Atlas data portal and expanding its application programming interface (API).

With this release, the Allen Institute has expanded access to its data and services via the Allen Brain Atlas API and added new data and feature enhancements to four atlas resources: the Allen Human Brain Atlas, the Allen Mouse Brain Connectivity Atlas, the Allen Developing Mouse Brain Atlas, and the Allen Mouse Brain Atlas. In addition, two new video tutorials have been added to the Institute’s tutorial library.

The Allen Human Brain Atlas, a multi-modal, three-dimensional map of the human brain that integrates anatomical and gene expression data throughout the adult human brain, has been expanded to include gene expression data from brains of autistic individuals, allowing scientists to compare disease and control states. In addition, the Atlas contains new features to facilitate search, navigation, and download of data.

The Allen Mouse Brain Connectivity Atlas is a three-dimensional, high-resolution map of neural connections throughout the mouse brain. Today’s data release expands the set of available high-resolution images of axonal projections and adds multiplanar viewing capabilities, offering a first step towards three-dimensional visualization of neural connectivity throughout the mouse brain. This foundational map will help scientists understand how the brain is wired, offering new insights into how the brain works and what goes awry in brain diseases and disorders.

Additionally, the Allen Mouse Brain Atlas and the Allen Developing Mouse Brain Atlas have been updated with new search capabilities based on additional data annotation, allowing users to explore the gene expression data in new ways.

Application Programming Interface (API)

To broaden the user community and enable further innovation, the Allen Institute has expanded access to its data and services via the Allen Brain Atlas API, now offering access to data from across the suite of Allen Brain Atlas resources. The Allen Brain Atlas API provides the programming community with under-the-hood access to the Allen Institute’s vast datasets, sample applications and programming solutions for data searches and download, as well as opportunities for discovery and creation of new applications or data representations. This release coincides with the Allen Brain Atlas Hackathon, an elite programming event to be held later this month.

Available data in the Allen Brain Atlas API includes high-resolution images, 3-D expression summaries, primary microarray and RNA-sequencing results, and MRI and DTI files from across the Institute’s suite of atlas resources. Services offered by the Allen Brain Atlas API include RESTful model access to retrieve all experimental information; image download service for all gene expression, connectivity, histology and atlas data; as well as API access to various integrated search services.

Provided by Allen Institute for Brain Science

Source: medicalxpress.com

ScienceDaily (June 7, 2012) — Scientists at the Gladstone Institutes have for the first time transformed skin cells — with a single genetic factor — into cells that develop on their own into an interconnected, functional network of brain cells. The research offers new hope in the fight against many neurological conditions because scientists expect that such a transformation — or reprogramming — of cells may lead to better models for testing drugs for devastating neurodegenerative conditions such as Alzheimer’s disease.

Rendering of neural network. Scientists at the Gladstone Institutes have for the first time transformed skin cells — with a single genetic factor — into cells that develop on their own into an interconnected, functional network of brain cells. (Credit: © nobeastsofierce / Fotolia)

This research comes at a time of renewed focus on Alzheimer’s disease, which currently afflicts 5.4 million people in the United States alone — a figure expected to nearly triple by 2050. Yet there are no approved medications to prevent or reverse the progression of this debilitating disease.

In findings appearing online June 7 in Cell Stem Cell, researchers in the laboratory of Gladstone Investigator Yadong Huang, MD, PhD, describe how they transferred a single gene called Sox2 into both mouse and human skin cells. Within days the skin cells transformed into early-stage brain stem cells, also called induced neural stem cells (iNSCs). These iNSCs began to self-renew, soon maturing into neurons capable of transmitting electrical signals. Within a month, the neurons had developed into neural networks.

"Many drug candidates — especially those developed for neurodegenerative diseases — fail in clinical trials because current models don’t accurately predict the drug’s effects on the human brain," said Dr. Huang, who is also an associate professor of neurology at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "Human neurons — derived from reengineered skin cells — could help assess the efficacy and safety of these drugs, thereby reducing risks and resources associated with human trials."

Dr. Huang’s findings build on the work of other Gladstone scientists, starting with Gladstone Investigator, Shinya Yamanaka, MD, PhD. In 2007, Dr. Yamanaka used four genetic factors to turn adult human skin cells into cells that act like embryonic stem cells — called induced pluripotent stem cells.

Also known as iPS cells, these cells can become virtually any cell type in the human body — just like embryonic stem cells. Then last year, Gladstone Senior Investigator Sheng Ding, PhD, announced that he had used a combination of small molecules and genetic factors to transform skin cells directly into neural stem cells. Today, Dr. Huang takes a new tack by using one genetic factor — Sox2 — to directly reprogram one cell type into another without reverting to the pluripotent state.

Avoiding the pluripotent state as Drs. Ding and Huang have done is one approach to avoiding the potential danger that “rogue” iPS cells might develop into a tumor if used to replace or repair damaged organs or tissue.

"We wanted to see whether these newly generated neurons could result in tumor growth after transplanting them into mouse brains," said Karen Ring, UCSF Biomedical Sciences graduate student and the paper’s lead author. "Instead we saw the reprogrammed cells integrate into the mouse’s brain — and not a single tumor developed."

This research, which was performed at the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, has also revealed the precise role of Sox2 as a master regulator that controls the identity of neural stem cells. In the future, Dr. Huang and his team hope to identify similar regulators that guide the development of specific neural progenitors and subtypes of neurons in the brain.

"If we can pinpoint which genes control the development of each neuron type, we can generate them in the petri dish from a single sample of human skin cells," said Dr. Huang. "We could then test drugs that affect different neuron types — such as those involved in Parkinson’s disease — helping us to put drug development for neurodegenerative diseases on the fast track."

Source: Science Daily

ScienceDaily (June 7, 2012) — A study led by Karolinska Institutet in Sweden reports for the first time the positive effects of an active vaccine against Alzheimer’s disease. The new vaccine, CAD106, can prove a breakthrough in the search for a cure for this seriously debilitating dementia disease. The study is published in the scientific journal Lancet Neurology.

A study led by Karolinska Institutet in Sweden reports for the first time the positive effects of an active vaccine against Alzheimer’s disease. (Credit: © Tyler Olson / Fotolia)

Alzheimer’s disease is a complex neurological dementia disease that is the cause of much human suffering and a great cost to society. According to the World Health Organisation, dementia is the fastest growing global health epidemic of our age. The prevailing hypothesis about its cause involves APP (amyloid precursor protein), a protein that resides in the outer membrane of nerve cells and that, instead of being broken down, form a harmful substance called beta-amyloid, which accumulates as plaques and kills brain cells.

There is currently no cure for Alzheimer’s disease, and the medicines in use can only mitigate the symptoms. In the hunt for a cure, scientists are following several avenues of attack, of which vaccination is currently the most popular. The first human vaccination study, which was done almost a decade ago, revealed too many adverse reactions and was discontinued. The vaccine used in that study activated certain white blood cells (T cells), which started to attack the body’s own brain tissue.

The new treatment, which is presented in Lancet Neurology, involves active immunisation, using a type of vaccine designed to trigger the body’s immune defence against beta-amyloid. In this second clinical trial on humans, the vaccine was modified to affect only the harmful beta-amyloid. The researchers found that 80 per cent of the patients involved in the trials developed their own protective antibodies against beta-amyloid without suffering any side-effects over the three years of the study. The researchers believe that this suggests that the CAD106 vaccine is a tolerable treatment for patients with mild to moderate Alzheimer’s. Larger trials must now be conducted to confirm the CAD106 vaccine’s efficacy.

Source: Science Daily

ScienceDaily (June 7, 2012) — Researchers at Columbia University Medical Center (CUMC) have identified a brain receptor that appears to play a central role in regulating appetite. The findings, published June 7 in the online edition of Cell, could lead to new drugs for preventing or treating obesity.

"We’ve identified a receptor that is intimately involved in regulating food intake," said study leader Domenico Accili, MD, professor of Medicine at CUMC. "What is especially encouraging is that this receptor is belongs to a class of receptors that turn out to be good targets for drug development, making it a highly ‘druggable’ target. In fact, several existing medications already seem to interact with this receptor. So, it’s possible that we could have new drugs for obesity sooner rather than later."

In their search for new targets for obesity therapies, scientists have focused on the hypothalamus, a tiny brain structure that regulates appetite. Numerous studies suggest that the regulatory mechanism is concentrated in neurons that express a neuropeptide, or brain modulator, called AgRP. But the specific factors that influence AgRP expression are not known.

The CUMC researchers found new clues to appetite control by tracing the actions of insulin and leptin. Both hormones are involved in maintaining the body’s energy balance, and both are known to inhibit AgRP. “Surprisingly, blocking either the insulin or leptin signaling pathway has little effect on appetite,” says Dr. Accili. “We hypothesized that both pathways have to be blocked simultaneously in order to influence feeding behavior.”

To test their hypothesis, the researchers created a strain of mice whose AgRP neurons lack a protein that is integral to both insulin and leptin signaling. As the researchers hypothesized, removing this protein — Fox01 — had a profound effect on the animals’ appetite. “Mice that lack Fox01 ate less and were leaner than normal mice,” said lead author Hongxia Ren, PhD, associate research scientist in Medicine. “In addition, the Fox01-deficient mice had better glucose balance and leptin and insulin sensitivity — all signs of a healthier metabolism.”

Since Fox01 is a poor drug target, the researchers searched for other ways to inhibit the action of this protein. Using gene-expression profiling, they found a gene that is highly expressed in mice with normal AgRP neurons but is effectively silenced in mice with Fox01-deficient neurons. That gene is Gpr17 (for G-protein coupled receptor 17), which produces a cell-surface receptor called Gpr17.

To confirm that the receptor is involved in appetite control, the researchers injected a Gpr17 activator into normal mice, and their appetite increased. Conversely, when the mice were given a Gpr17 inhibitor, their appetite decreased. Similar injections had no effect on Fox01-deficient mice.

According to Dr. Accili, there are several reasons why Gpr17, which is also found in humans, would be a good target for anti-obesity medications. Since Grp17 is part of the so-called G-protein-coupled receptor family, it is highly druggable. About a third of all existing drugs work through G-protein-coupled receptors. In addition, the receptor is abundant in AgRP neurons but not in other neurons, which should limit unwanted drug side effects.

Source: Science Daily

ScienceDaily (June 7, 2012) — Increasing the spacing between characters and words in a text improves the speed and quality of dyslexic children’s reading, without prior training. They read 20% faster on average and make half as many errors. This is the conclusion reached by a French-Italian research team, jointly headed by Johannes Ziegler of the Laboratoire de Psychologie Cognitive (CNRS/Aix-Marseille Université).

Increasing the spacing between characters and words in a text improves the speed and quality of dyslexic children’s reading, without prior training. (Credit: © Johannes Ziegler, courtesy CNRS)

These results were published 4 June 2012 in the Proceedings of the National Academy of Science (PNAS). In parallel, the team has developed an iPad/iPhone application, available under the name “DYS.” It allows both parents and children to modify the spacing between letters and thus test the benefits of these changes on reading. This will enable researchers to collect large-scale, real time data, which they will then analyze and study.

Dyslexia is a learning disability that impairs an individual’s capacity to read and is linked to difficulty in identifying letters, syllables and words — despite suitable schooling and in the absence of intellectual or sensorial deficiencies. Dyslexia, which often causes writing problems, affects on average one child in every class and 5% of the world’s population.

In this study, the researchers tested the effects of letter spacing on the reading ability of 54 dyslexic Italian and 40 dyslexic French children aged between 8 and 14 years. The children had to read a text composed of 24 sentences, in which the spacing was either normal or wider than usual. The results showed that wider spacing enabled the children to improve their reading both in terms of speed and precision. On average, they read 20% faster and made half as many errors. This progress could stem from the fact that dyslexic children are particularly sensitive to “perceptual crowding,” in other words the visual masking of each individual letter by those surrounding it. The results of this study show that this crowding effect may be reduced by spacing letters apart.

This finding opens interesting perspectives in the field of dyslexia treatment techniques. Indeed, reading better means reading more — yet it takes one year for a dyslexic child to read what a “normal reader” reads in two days. This is because reading can be “torture” for dyslexic children, whose decoding difficulties cause to stumble, putting them off reading on a regular basis. The researchers have found a simple and efficient “trick” that helps these children break the vicious circle and correctly read more words in less time.

An iPad/iPhone application known as “DYS” has been developed in parallel with these research results by Stéphane Dufau, CNRS research engineer at the Laboratoire de Psychologie Cognitive. Available initially in French and English and downloadable free of charge from Apple Store, it enables both parents and children to adjust the spacing between letters and to test the benefits of such modifications on reading. The researchers for their part hope to be able to collect large-scale data that will allow them to quantify and analyze whether optimal spacing exists as a function of the subject’s age and reading level.

Download available: http://itunes.apple.com/us/app/dys-help-people-with-dyslexia/id529867852?mt=8

Source: Science Daily

ScienceDaily (June 6, 2012) — Even when brain injury is so subtle that it can only be detected by an ultra-sensitive imaging test, the injury might predispose soldiers in combat to post-traumatic stress disorder, according to a University of Rochester Medical Center study.

The research is important for physicians who are caring for troops in the years following deployment, as they try to untangle the symptom overlap between PTSD and mild traumatic brain injury (mild TBI) and provide the appropriate treatment. Until now, the nature of the interaction between TBI and PTSD was unclear. URMC researchers believe they are the first to find an association that can be demonstrated with advanced imaging techniques.

The study is published online by the Journal of Head Trauma Rehabilitation.

"Most people believe that, to a large extent, chronic stress from intense combat experiences triggers PTSD. Our study adds more information by suggesting that a physical force such as exposure to a bomb blast also may play a role in the genesis the syndrome," said lead author Jeffrey J. Bazarian, M.D., M.P.H., associate professor of Emergency Medicine at URMC, and a member of the 2007 Institute of Medicine committee that investigated brain injuries among war veterans.

By 2008 it was estimated that 320,000 troops suffered concussions in Iraq and Afghanistan. Bazarian’s research involved 52 war veterans from western New York who served in combat areas between 2001 and 2008. Approximately four years after their final tour of duty, researchers asked each veteran about PTSD symptoms, blast exposures, mild concussions, and combat experiences.

Researchers measured combat stress in the study participants with a standard Walter Reed Institute of Research Combat Experiences Survey, which asks about the intensity of deployment duties (such as handling or uncovering remains), exposure to explosive devices, vehicle accidents, falls or assaults, and events such as being ambushed or knowing someone who was seriously injured or killed. The investigators also performed standard MRI testing, as well as a more sensitive test called diffusion tensor imaging, or DTI. The latter has been used to detect axonal injury, a type of neuronal damage that occurs during a concussion.

Results showed that 30 of the 52 New York veterans suffered at least one mild traumatic brain injury, and seven reported having more than one. Sixty percent of the veterans were exposed to one or more explosive blasts.

All 52 veterans had one or more PTSD symptoms, and 15 met the formal criteria for PTSD, which is a devastating psychiatric illness. The severity of veterans’ PTSD symptoms correlated with the amount of axonal injury seen on the DTI scans.

In addition, five of the 52 veterans showed abnormalities on standard MRI scans, and their PTSD severity was much worse than the 46 veterans with normal MRIs.

Interestingly, PTSD severity did not correlate with the clinical diagnosis of mild TBI. This suggests that subtle brain injury can occur without producing the loss of consciousness or amnesia that is typically associated with diagnosis of mild TBI, and that this injury may make a person more vulnerable to psychiatric illness when coupled with extreme chronic stress.

"Based on our results, it looks like the only way to detect this injury is with DTI/MRI," Bazarian said. "While it may not be feasible due to costs and limited availability of some neuro-imaging tests to screen thousands of service members for brain injury, our study highlights the pressing need to develop simpler tests that are accurate and practical, that correlate with brain injury."

Source: Science Daily

ScienceDaily (June 6, 2012) — Psychoactive medications in water affect the gene expression profiles of fathead minnows in a way that mimics the gene expression patterns associated with autism spectrum disorder in genetically susceptible humans, according to research published June 6 in the open access journal PLoS ONE. These results suggest a potential environmental trigger for autism spectrum disorder in this vulnerable population, the authors write.

The researchers, led by Michael A. Thomas of Idaho State University, exposed the fish to three psychoactive pharmaceuticals — fluoxetine, a selective serotonin reuptake inhibitor, or SSR1; venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and carbamazepine, used to control seizures — at concentrations comparable to the highest estimated environmental levels.

They found that the only gene expression patterns affected were those associated with idiopathic autism spectrum disorders, caused by genetic susceptibility interacting with unknown environmental triggers. These results suggest that exposure to environmental psychoactive pharmaceuticals may play a role in the development of autism spectrum disorder in genetically predisposed individuals.

Lead researcher Michael A. Thomas remarks, “While others have envisioned a causal role for psychotropic drugs in idiopathic autism, we were astonished to find evidence that this might occur at very low dosages, such as those found in aquatic systems.”

Source: Science Daily

ScienceDaily (June 6, 2012) — An Indiana University biologist has shown that natural variation in measures of the brain’s ability to process steroid hormones predicts functional variation in aggressive behavior.

Researchers studied the behaviors of free-living dark-eyed juncos during breeding season to measure variations in aggressiveness. (Credit: Image courtesy of Indiana University)

The new work led by Kimberly A. Rosvall, a postdoctoral fellow and assistant research scientist in the IU Bloomington College of Arts and Sciences’ Department of Biology, has found strong and significant relationships between aggressive behavior in free-living birds and the abundance of messenger RNA in behaviorally relevant brain areas for three major sex steroid processing molecules: androgen receptor, estrogen receptor and aromatase.

"Individual variation is the raw material of evolution, and in this study we report that free-living birds vary in aggression and that more aggressive individuals express higher levels of genes related to testosterone processing in the brain," she said. "We’ve long hypothesized that the brain’s ability to process steroids may account for individual differences in hormone-mediated behaviors, but direct demonstrations are rare, particularly in unmanipulated or free-living animals."

Rosvall said the study shows that aggression is strongly predicted by individual variation in gene expression of the molecules that initiate the genomic effects of testosterone. The new work, “Neural sensitivity to sex steroids predicts individual differences in aggression: implications for behavioral evolution,” was published June 6 in Proceedings of The Royal Society B.

The findings are among the first to show that individual variation in neural gene expression for three major sex steroid processing molecules predicts individual variation in aggressiveness in both sexes in nature, results that should have broad implications for understanding the mechanisms by which aggressive behavior may evolve.

"On the one hand, we have lots of evidence to suggest that testosterone is important in the evolution of all kinds of traits," Rosvall noted. "On the other hand, we know that individual variation is a requirement for natural selection, but individual variation in testosterone does not always predict behavior. This conundrum has led to debate among researchers about how hormone-mediated traits evolve."

To find such strong relationships between behavior and individual variation in the expression of genes related to hormone-processing is exciting because it tells scientists that evolution could shape behavior via changes in the expression of these genes, as well as via changes in testosterone levels themselves.

The team measured natural variation in aggressiveness toward the same sexes in male and female free-living dark-eyed juncos (Junco hyemalis) early in the breeding season. The dark-eyed junco is a North American sparrow that is well studied with respect to hormones, behavior and sex differences. By comparing individual differences in aggressiveness (flyovers or songs directed at intruders) to circulating levels of testosterone and to neural gene expression for the three major sex steroid processing molecules, the researchers were able to quantify measures of sensitivity to testosterone in socially relevant brain areas: the hypothalamus, the ventromedial telencephalon and the right posterior telencephalon.

Their results suggest selection could shape the evolution of aggression through changes in the expression of androgen receptor, estrogen receptor and aromatase in both males and females, to some degree independently of circulating levels of testosterone. They found, for example, that males that sing more songs at an intruder have more mRNA for aromatase and estrogen receptor in the posterior telencephalon, and also that males and females that dive-bomb an intruder more frequently have more androgen receptor, estrogen receptor and aromatase mRNA in brain tissues including the medial amygdala, an area of the brain that’s known to control aggression in rodents and other birds. mRNA are single-stranded copies of genes that are translated into protein molecules.

The work reveals there is ample variation in hormone signal and in gene expression on which selection may act to affect aggressiveness. It also establishes a prerequisite for the evolution of testosterone-mediated characteristics through changes in localized gene expression for the key molecules that process sex steroids, and suggests that trait evolution can occur with some degree of independence from circulating testosterone levels.

"Researchers have thought this was probably the case for about a hundred years, based on a lot of really important work that uses experimental manipulations like castration or hormone replacement," Rosvall said. "But very few people have looked to see if individuals actually do vary in expression of these genes, and whether this individual variation means anything, in terms of an animal’s behavior. Our work shows that it does."

The new insights into how neuroendocrine mechanisms of aggression may be modified as populations diverge into species also offer opportunities for future research, including trying to determine whether genes that are up- or down-regulated in response to environmental stimuli may be the same genes that contribute to the evolution of certain traits and characteristics.

Source: Science Daily

ScienceDaily (June 6, 2012) — New pictures from the University of Iowa show what it looks like when a person runs out of patience and loses self-control.

Brain activity when people exert self-control. (Credit: Image courtesy of University of Iowa)

A study by University of Iowa neuroscientist and neuro-marketing expert William Hedgcock confirms previous studies that show self-control is a finite commodity that is depleted by use. Once the pool has dried up, we’re less likely to keep our cool the next time we’re faced with a situation that requires self-control.

But Hedgcock’s study is the first to actually show it happening in the brain using fMRI images that scan people as they perform self-control tasks. The images show the anterior cingulate cortex (ACC) — the part of the brain that recognizes a situation in which self-control is needed and says, “Heads up, there are multiple responses to this situation and some might not be good” — fires with equal intensity throughout the task.

However, the dorsolateral prefrontal cortex (DLPFC) — the part of the brain that manages self-control and says, “I really want to do the dumb thing, but I should overcome that impulse and do the smart thing” — fires with less intensity after prior exertion of self-control.

He said that loss of activity in the DLPFC might be the person’s self-control draining away. The stable activity in the ACC suggests people have no problem recognizing a temptation. Although they keep fighting, they have a harder and harder time not giving in.

Which would explain why someone who works very hard not to take seconds of lasagna at dinner winds up taking two pieces of cake at desert. The study could also modify previous thinking that considered self-control to be like a muscle. Hedgcock says his images seem to suggest that it’s like a pool that can be drained by use then replenished through time in a lower conflict environment, away from temptations that require its use.

The researchers gathered their images by placing subjects in an MRI scanner and then had them perform two self-control tasks — the first involved ignoring words that flashed on a computer screen, while the second involved choosing preferred options. The study found the subjects had a harder time exerting self-control on the second task, a phenomenon called “regulatory depletion.” Hedgcock says that the subjects’ DLPFCs were less active during the second self-control task, suggesting it was harder for the subjects to overcome their initial response.

Hedgcock says the study is an important step in trying to determine a clearer definition of self-control and to figure out why people do things they know aren’t good for them. One possible implication is crafting better programs to help people who are trying to break addictions to things like food, shopping, drugs, or alcohol. Some therapies now help people break addictions by focusing at the conflict recognition stage and encouraging the person to avoid situations where that conflict arises. For instance, an alcoholic should stay away from places where alcohol is served.

But Hedgcock says his study suggests new therapies might be designed by focusing on the implementation stage instead. For instance, he says dieters sometimes offer to pay a friend if they fail to implement control by eating too much food, or the wrong kind of food. That penalty adds a real consequence to their failure to implement control and increases their odds of choosing a healthier alternative.

The study might also help people who suffer from a loss of self-control due to birth defect or brain injury.

"If we know why people are losing self-control, it helps us design better interventions to help them maintain control," says Hedgcock, an assistant professor in the Tippie College of Business marketing department and the UI Graduate College’s Interdisciplinary Graduate Program in Neuroscience.

Source: Science Daily

June 6, 2012 by Chris Barncard

Stress may affect brain development in children — altering growth of a specific piece of the brain and abilities associated with it — according to researchers at the University of Wisconsin–Madison.

"There has been a lot of work in animals linking both acute and chronic stress to changes in a part of the brain called the prefrontal cortex, which is involved in complex cognitive abilities like holding on to important information for quick recall and use,” says Jamie Hanson, a UW–Madison psychology graduate student. “We have now found similar associations in humans, and found that more exposure to stress is related to more issues with certain kinds of cognitive processes.”

Children who had experienced more intense and lasting stressful events in their lives posted lower scores on tests of what the researchers refer to as spatial working memory. They had more trouble navigating tests of short-term memory such as finding a token in a series of boxes, according to the study, which will be published in the June 6 issue of the Journal of Neuroscience.

Brain scans revealed that the anterior cingulate, a portion of the prefrontal cortex believed to play key roles in spatial working memory, takes up less space in children with greater exposure to very stressful situations.

"These are subtle differences, but differences related to important cognitive abilities" Hanson says.

But they maybe not irreversible differences.

"We’re not trying to argue that stress permanently scars your brain. We don’t know if and how it is that stress affects the brain," Hanson says. "We only have a snapshot — one MRI scan of each subject — and at this point we don’t understand whether this is just a delay in development or a lasting difference. It could be that, because the brains is very plastic, very able to change, that children who have experienced a great deal of stress catch up in these areas."

The researchers determined stress levels through interviews with children ages 9 to 14 and their parents. The research team, which included UW–Madison psychology professors Richard Davidson and Seth Pollak and their labs, collected expansive biographies of stressful events from slight to severe.

"Instead of focusing in on one specific type of stress, we tried to look at a range of stressors," Hanson says. "We wanted to know as much as we could, and then use all this information to later to get an idea of how challenging and chronic and intense each experience was for the child."

Interestingly, there was little correlation between cumulative life stress and age. That is, children who had several more years of life in which to experience stressful episodes were no more likely than their younger peers to have accumulated a length stress resume. Puberty, on the other hand, typically went hand-in-hand with heavier doses of stress.

The researchers, whose work was funded by the National Institutes of Health, also took note of changes in brain tissue known as white matter and gray matter. In the important brain areas that varied in volume with stress, the white and gray matter volumes were lower in tandem.

White matter, Hanson explained, is like the long-distance wiring of the brain. It connects separated parts of the brain so that they can share information. Gray matter “does the math,” Hanson says. “It takes care of the processing, using the information that gets shared along the white matter connections.”

Gray matter early in development appears to enable flexibility; children can play and excel at many different activities. But as kids age and specialize, gray matter thins. It begins to be “pruned” after puberty, while the amount of white matter grows into adulthood.

"For both gray and white matter, we actually see smaller volumes associated with high stress," Hanson says. "Those kinds of effects across different kinds of tissue, those are the things we would like to study over longer periods of time. Understanding how these areas change can give you a better picture of whether this is just a delay in development or more lasting."

More study could also show the researchers how to help children who have experienced an inordinate amount of stress.

"There are groups around the country doing working memory interventions to try to train or retrain people on this particular cognitive ability and improve performance," Hanson says. "Understanding if and how stress affects these processes could help us know whether there may be similar interventions that could aid children living in stressful conditions, and how this may affect the brain.”

Provided by University of Wisconsin-Madison

Source: medicalxpress.com

June 6, 2012

New research by scientists at the University of North Carolina School of Medicine may have pinpointed an underlying cause of the seizures that affect 90 percent of people with Angelman syndrome (AS), a neurodevelopmental disorder.

This image shows inhibitory neurons (red) and cell bodies (blue) in the cerebral cortex of an Angelman syndrome model mouse. Credit: Philpot Lab, UNC School of Medicine

Published online Thursday June 7, 2012 in the journal Neuron, researchers led by Benjamin D. Philpot, PhD, professor of cell and molecular physiology at UNC, describe how seizures in individuals with AS could be linked to an imbalance in the activity of specific types of brain cells.

"Our study indicates that a common abnormality that may apply to many neurodevelopmental disorders is an imbalance between neuronal excitation and inhibition," Philpot said. This imbalance has been observed in several genetic disorders including Fragile X and Rett syndromes, both of these, like AS, can be associated with autism.

Angelman syndrome occurs in one in 15,000 live births. The syndrome often is misdiagnosed as cerebral palsy or autism. Its characteristics, along with seizures, include cognitive delay, severe intellectual disability, lack of speech (minimal or no use of words), sleep disturbance, hand flapping and motor and balance disorders.

The most common genetic defect of the syndrome is the lack of expression of the maternally inherited allele of gene UBE3A on chromosome 15.

This loss of gene function in AS animal models has been linked to decreased release of an excitatory neurotransmitter which increases the activity of other neurons. But that seems at odds with the high seizure activity observed in AS patients. The new study may clarify this issue.

In his lab in UNC’s Neuroscience Research Center, Philpot and graduate student Michael L. Wallace, the study’s first author, explored the neurocircuitry of an Angelman syndrome mouse model. These mice show behavioral features similar to humans with AS, including seizures.

The researchers used electrophysiological methods to record excitatory and inhibitory activity from individual neurons. These involved highly precise recording electrodes, microscopic tips attached to individual neurons. “In this way you can record from precise neuron types and tell which neuron you’re recording from and what its activity is,” explained Philpot.

"You can stimulate it to drive other neurons and also record the activity on other neurons onto it."

The researchers found that neurotransmitters sent from inhibitory neurons and carrying chemical messages meant to stop excitatory neurons from increasing their activity were defective.

In addition, they found that AS model mice have a defect in their inhibitory neurons which decreases their ability to recover from high levels of activity. “One of the reasons why inhibition is so important is that it’s needed to ensure that brain activity is regulated,” Philpot said. “Inhibition plays an important role in timing of information transfer between neurons, and if the timing is messed up, as you might observe if you had a decrease in inhibition, then a lot of information is lost in that transfer.”

"We found a disproportionately large decrease in inhibition to excitation," Wallace said. "We think that the circuit we investigated is in a hyperexcitable state and may be underlying some of the epileptic problems observed in the AS animal model. This improperly regulated brain activity might also underlie cognitive impairments in AS.”

Philpot says one of their goals is to understand exactly how these changes in the connections between neurons underlie seizures in AS. “A very long term goal is to try to get better treatments for these individuals because their epilepsy is very hard to treat.”

Provided by University of North Carolina Health Care

Source: medicalxpress.com

ScienceDaily (June 6, 2012) — Cutting the amount we drink to just over half a unit a day could save 4,600 lives a year in England, according to a modelling study by Oxford University researchers published in the journal BMJ Open.

Half a unit of alcohol is as little as a quarter of a glass of wine, or a quarter of a pint. (Credit: © G.G. Lattek / Fotolia)

Scientists have carried out a complex analysis in an attempt to determine the “optimal” level of alcohol consumption that is associated with the lowest rates of chronic disease in the UK. They conclude that the intake of about one-half of a typical drink per day would result in the healthiest outcomes, and the authors conclude that the recommended alcohol intake for the UK should be reduced from the current advised level of drinking.

Half a unit of alcohol is as little as a quarter of a glass of wine, or a quarter of a pint. That’s much lower than current government recommendations of between 3 to 4 units a day for men and 2-3 units for women.

The researchers set out to find the optimum daily amount of alcohol that would see fewest deaths across England from a whole range of diseases connected to drink. Previous studies have often looked at the separate effects of alcohol on heart disease, liver disease or cancers in isolation.

'Although there is good evidence that moderate alcohol consumption protects against heart disease, when all of the chronic disease risks are balanced against each other, the optimal consumption level is much lower than many people believe,' says lead author Dr Melanie Nichols of the BHF Health Promotion Research Group in the Department of Public Health at Oxford University.

The team used a mathematical model to assess what impact changing average alcohol consumption would have on deaths from 11 conditions known to be at least partially linked to drink.

These included coronary heart disease, stroke, high blood pressure, diabetes, cirrhosis of the liver, epilepsy, and five cancers. Over 170,000 people in England died from these 11 conditions in 2006, and ill health linked to alcohol is estimated to cost the NHS in England £3.3 billion every year.

The researchers used information from the 2006 General Household Survey on levels of alcohol consumption among adults in England. They combined this with the disease risks for differing levels of alcohol consumption as established in large analyses of published research.

They found that just over half a unit of alcohol a day was the optimal level of consumption among current drinkers.

They calculate this level of drinking would prevent around 4,579 premature deaths, or around 3% of all deaths from the 11 conditions.

The number of deaths from heart disease would increase by 843, but this would be more than offset by around 2,600 fewer cancer deaths and almost 3,000 fewer liver cirrhosis deaths.

'Moderating your alcohol consumption overall, and avoiding heavy-drinking episodes, is one of several things, alongside a healthy diet and regular physical activity, that you can do to reduce your risk of dying early of chronic diseases,' says Dr Nichols.

She adds: ‘We are not telling people what to do, we are just giving them the best balanced information about the different health effects of alcohol consumption, so that they can make an informed decision about how much to drink.

'People who justify their drinking with the idea that it is good for heart disease should also consider how alcohol is increasing their risk of other chronic diseases. A couple of pints or a couple of glasses of wine per day is not a healthy option.'

Although this study in BMJ Open did not look at patterns of drinking, Dr Nichols says: ‘Regardless of your average intake, if you want to have the best possible health, it is also very important to avoid episodes of heavy drinking (“binge drinking”) as there is very clear evidence that this will increase your risks of many diseases, as well as your risk of injuries.’

Source: Science Daily

June 6, 2012

A genetically-modified version of the rabies virus is helping scientists at Harvard to trace neural pathways in the brain, a research effort that could one day lead to treatments for Parkinson’s disease and addiction.

As described in a paper published on June 7 in the journal Neuron, a team of researchers led by Associate Professor of Molecular and Cellular Biology Naoshige Uchida used the virus to create the first-ever comprehensive list of inputs that connect directly to dopamine neurons in two regions of the brain, the ventral tegmental area (VTA), known for processing reward, and the substantia nigra (SNc), known for motor control.

"You may be familiar with the term connectome," Uchida explained. "The basic idea is we want to understand the brain in terms of connectivity and the various cell types. In this case, we’re examining long-range connections; that is, how other parts of the brain connect directly to dopamine neurons.

Dopamine neurons are thought to be important for processing reward and regulating motor output.

"By understanding their inputs, we might be able to better understand how the function of dopamine neurons is regulated, and, in turn, how addiction happens, and how Parkinson’s disease and other motor-control disorders are affected by problems with dopamine neurons,” Uchida continued. “And because this application provides us with very quantitative data, it’s possible that this is a technique that might be useful in attacking the causes of those diseases.”

Creating that connectivity diagram, however, is anything but easy.

While both the VTA and SNc are known to have high concentrations of dopamine neurons, Uchida chose to examine both areas because the cells in the two regions fire differently.

"We wanted to know what the difference was, generally," Uchida said. "That’s why we compared the inputs to both structures. Based on how other neurons are connected there, we can start to explain why these two regions of the brain do different things."

The challenge, however, is that dopamine neurons are packed into relatively small regions with several other cell types. To ensure they were only observing dopamine neurons, researchers turned to an organism more typically known for damaging neurons – the rabies virus.

Before they infect genetically-engineered mice with the rabies virus, however, they first inject the animals with a pair of “helper” viruses. The first causes dopamine neurons to produce a receptor protein, meaning the rabies virus can only infect dopamine neurons, while the second restores the virus’ ability to “hop” from one neuron to another.

The mice are then infected with a version of the rabies virus that has been genetically-modified to produce a fluorescent protein, allowing researchers to track the virus as it binds with dopamine neurons, and then jumps to the cells that link directly to those neurons.

The results, as depicted in images of a mouse’s brain showing the wealth of connections to dopamine neurons, show that a number of brain regions – including some previously unknown areas – are connected to dopamine neurons.

"We found some new connections, and we found some that we suspected were there, but that were not well understood," Uchida said. "For example, we found that there are connection between the motor cortex and the SNc, which may be related to SNc dopamine neurons’ role in motor control.

"Other connections, though, were more intriguing," he continued. "We found that the subthalmic nucleus preferentially connects to SNc neurons – that’s particularly important because that region is a popular target for deep brain stimulation as a treatment for Parkinson’s."

Often used as a treatment for Parkinson’s and a variety of other disorders, deep brain stimulation involves implanting a device, called a brain pacemaker, into a patient’s brain. The device then electrically stimulates specific regions of the brain, helping to mitigate symptoms of the disease.

"The mechanism for why deep brain stimulation works is not completely understood," Uchida said. "There was speculation that it might have been inhibiting neurons in the subthalmic nucleus, but our findings suggest, because there is a direct connection between those neurons and dopamine neurons in the SNc, that it is actually activating those neurons. I don’t think this explains the entire mechanism for why deep brain stimulation works, but this may be part of it.”

"This work also offers us a roadmap for other areas we might investigate, so now we can target those areas and record from them," Uchida added. "This is a critical step for future investigations."

Provided by Harvard University

Source: medicalxpress.com

June 6, 2012

Ask the average person the street how the brain develops, and they’ll likely tell you that the brain’s wiring is built as newborns first begin to experience the world. With more experience, those connections are strengthened, and new branches are built as they learn and grow.

A new study conducted in a Harvard lab, however, suggests that just the opposite is true.

As reported on June 7 in the journal Neuron, a team of researchers led by Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology, has found that just days before birth mice undergo an explosion of neuromuscular branching. At birth, the research showed, some muscle fibers are contacted by as many as 10 nerve cells. Within days, however, all but one of those connections had been pruned away.

"By the time mammals – and humans would certainly be included – are first coming into the world, when they can do almost nothing, the brain is probably very wired up," Lichtman said. "Through experience, the brain works to select, out of this mass of possible circuits, a very small subset…and everything else that could have been there is gone.

"I don’t think anyone suspected that this was taking place – I certainly didn’t," he continued. "In some simple muscles, every nerve cell branches out and contacts every muscle fiber. That is, the wiring diagram is as diffuse as possible. But by the end, only two weeks later, every muscle fiber is the lifelong partner of a single nerve cell, and 90 percent of the wires have disappeared."

Though researchers, including Lichtman, had shown as early as the 1970’s that mice undergo an early developmental period in which target cells including muscle fibers and some neurons are contacted by multiple nerve cells before being reduced to a single connection, those early studies and his current work were hampered by the same problem – technological challenges make it difficult to identify individual nerve cells in earlier and earlier stages of life.

And though the use of mice that have been genetically-engineered to express fluorescent protein molecules in nerve cells has made it easier for researchers to identify nerve cells, it remains challenging to study early stages of development because the fluorescent labeling in the finest nerve cell wires often becomes so weak as to be invisible.

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ScienceDaily (June 6, 2012) — One of the top suspects behind killer vascular diseases is the victim of mistaken identity, according to researchers from the University of California, Berkeley, who used genetic tracing to help hunt down the real culprit.

Within the walls of blood vessels are smooth muscle cells and newly discovered vascular stem cells. The stem cells are multipotent and are not only able to differentiate into smooth muscle cells, but also into fat, cartilage and bone cells. UC Berkeley researchers provide evidence that the stem cells are contributing to clogged and hardened arteries. (Credit: Song Li illustration)

The guilty party is not the smooth muscle cells within blood vessel walls, which for decades was thought to combine with cholesterol and fat that can clog arteries. Blocked vessels can eventually lead to heart attacks and strokes, which account for one in three deaths in the United States.

Instead, a previously unknown type of stem cell — a multipotent vascular stem cell — is to blame, and it should now be the focus in the search for new treatments, the scientists report in a new study appearing June 6 in the journal Nature Communications.

"For the first time, we are showing evidence that vascular diseases are actually a kind of stem cell disease," said principal investigator Song Li, professor of bioengineering and a researcher at the Berkeley Stem Cell Center. "This work should revolutionize therapies for vascular diseases because we now know that stem cells rather than smooth muscle cells are the correct therapeutic target."

The finding that a stem cell population contributes to artery-hardening diseases, such as atherosclerosis, provides a promising new direction for future research, the study authors said.

"This is groundbreaking and provocative work, as it challenges existing dogma," said Dr. Deepak Srivastava, who directs cardiovascular and stem cell research at the Gladstone Institutes in San Francisco, and who provided some of the mouse vascular tissues used by the researchers. "Targeting the vascular stem cells rather than the existing smooth muscle in the vessel wall might be much more effective in treating vascular disease."

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ScienceDaily (June 6, 2012) — Swiss researchers have succeeded in generating detailed three-dimensional images of the spatial distribution of amyloid plaques in the brains of mice afflicted with Alzheimer’s disease. These plaques are accumulations of small pieces of protein in the brain and are a typical characteristic of Alzheimer’s. The new technique used in the investigations provides an extremely precise research tool for a better understanding of the disease. In the future, scientists hope that it will also provide the basis for a new and reliable diagnosis method.

Virtual cut. (Credit: Image courtesy of Paul Scherrer Institut (PSI))

The results were achieved within a joint project of two teams of researchers — one from the Paul Scherrer Institute (PSI) and ETH Zurich, the other from the École Polytechnique Fédérale de Lausanne (EPFL). They have been published in the journal Neuroimage.

Alzheimer’s disease is responsible for about 60% to 80% of all cases of dementia. This disease affects people differently, but the most common initial symptom is the difficulty in remembering new information, because the disease first affects brain regions involved in the formation of new memories. Alzheimer’s dementia is characterized by typical brain lesions that spread to other brain regions as the disease progresses. One of these lesions, the so-called amyloid plaque, is composed of the accumulation of extracellular protein aggregates. These lesions appear early in the course of the disease and there is a high interest in detecting them in patients to diagnose or evaluate the progression of the disease. Recently, medical imaging methods have been developed and validated for this purpose. These allow regional amount of amyloid deposits to be measured, but individual plaques cannot be quantified.

The latest results obtained by researchers from the Paul Scherrer Institute (PSI), ETH Zurich and the École Polytechnique Fédérale de Lausanne (EPFL) show that imaging single plaques is feasible under certain conditions. “This achievement could help to advance the development and evaluation of new imaging diagnostic markers for ultimately improving the diagnosis of Alzheimer’s disease,” explains Matthias Cacquevel, one of the authors at EPFL.

Precise plaque distribution in 3D

Using a method known as Phase Contrast Imaging, the researchers were able, within a short time, to make visible the exact three-dimensional distribution of amyloid plaques in the brains of mice with Alzheimer’s. Before this achievement, the only possibility of studying the distribution of amyloid plaques at the single-plaque level was to perform time-consuming studies. “Until now, for such an investigation, the brain had to be cut into slices and the slices coloured so that the plaques became visible,” explains Bernd Pinzer, from the Paul Scherrer Institute, who carried out the investigations. “This process is the gold standard amongst such investigations. It is, however, very time-consuming, as everything has to be done by hand. At the same time, it provides much less information than our new method. Naturally, we compared the results from our new method with those obtained using this traditional method, and they showed excellent agreement.”

As a first concrete result, the researchers determined the distribution of plaques in the brains of a number of mice with different stages of the disease. For each brain, the scientists obtained a three-dimensional image of the overall plaque distribution so that the development of the disease could be followed in detail. With conventional processes, it would hardly have been possible to gather such comprehensive information.

Developments for reliable diagnostic techniques

"One goal is to use the phase contrast technique to help improve imaging methods which make visible the plaques in the brain of a living patient, and thereby allow a reliable diagnosis of Alzheimer’s disease to be made," explains Pinzer. "These methods are under constant development and it is important to compare their results with those achieved using a known and reliable method. Now it will be possible to directly compare the two sets of 3D images of a mouse brain produced both by a diagnostic method and by our phase contrast technique. One of the diagnostic methods available is Positron Emission Tomography (PET), in which special molecules are attached to the plaques and, after some time, emit gamma radiation, which can be ascertained externally."

Although the deposited radiation dose required — which is high, in order to generate the necessary high resolution — prevents measurements being made on living animals at the moment, the method is already an outstanding research tool, which will lead to a better understanding of Alzheimer’s disease. “This tool will allow much more precise studies on how amyloid plaques are distributed,” explains Matthias Cacquevel, one of the authors at EPFL. “The relationship between plaques and the symptoms of the disease are still unclear, and information on how these plaques spread throughout the brain is also missing.”

Comprehensive information from changes in the light

These investigations were carried out at the Swiss Light Source (SLS) at PSI. The SLS generates synchrotron light — X-rays that are very intensive and well focused. The investigation is similar to a conventional X-ray examination — the scientists pass the X-rays through the object under investigation and determine how they have changed on their way. A normal X-ray picture, however, only shows how strongly the light is attenuated by the object; in a sense, it shows the shadow of the object. The problem is that various kinds of soft tissue attenuate X-rays in approximately the same way, which makes it difficult to distinguish between them.

"With the phase contrast method that we are using here, we also take into consideration the fact that different tissues deviate the light slightly from its original direction by a different amount. In physics, this effect is known to generate a so-called X-ray phase shift," explains Marco Stampanoni, Professor of X-Ray Microscopy at the Institute of Biomedical Technology at the ETH Zürich and Project Manager at PSI. The team he is leading built up the measuring station and designed the experiment. "Our instrument is able to measure such subtle shifts very precisely and transform this information into understandable images."

Phase Contrast Imaging for various medical applications

"While we cannot carry out an investigation on patients using the phase contrast method to detect Alzheimer’s disease, we are close to developing diagnostic tools for other diseases," emphasises Stampanoni. "We have already shown, in a pilot study on the imaging of tumours in the female breast, how useful the additional information can be. A first step in the direction of the hospital is the development of a mammography facility, the first prototype of which can be used in a doctor’s practice."

Source: Science Daily

June 6, 2012

A 25-year follow-up study reveals that 68% of patients with juvenile myoclonic epilepsy (JME) became seizure-free, with nearly 30% no longer needing antiepileptic drug (AED) treatment. Findings published today in Epilepsia, a journal of the International League Against Epilepsy (ILAE), report that the occurrence of generalized tonic-clonic seizures preceded by bilateral myoclonic seizures, and AED polytherapy significantly predicted poor long-term seizure outcome.

Patients with JME experience “jerking” of the arms, shoulders, and sometimes the legs. Previous evidence suggests that JME is a common type of epilepsy (in up to 11% of people with epilepsy), occurring more frequently in females than in males, and with onset typically in adolescence.. There is still much debate among experts over the long-term outcome of JME, and about which factors predict seizure outcome.

To further investigate JME outcomes and predictive factors, Dr. Felix Schneider and colleagues from the Epilepsy Center at the University of Greifswald in Germany studied data from 12 male and 19 female patients with JME. All participants had a minimum of 25 years follow-up which included review of medical records, and telephone or in-person interviews.

Sixty-eight percent of the 31 JME patients became free of seizures, and 28% discontinued AED treatment due to seizure-freedom. Significant predictors of poor long-term seizure outcome included: occurrence of generalized tonic-clonic seizures (GTCS - formerly known as grand mal seizures) that affect the entire brain and which are preceded by bilateral myoclonic seizures (abnormal movements on both sides of the body and a regimen of AED polytherapy.

Researchers also determined that remission of GTCS using AED therapy significantly increased the possibility of complete seizure-freedom. However, once AED therapy is discontinued, the occurrence of photoparoxysmal responses (brain discharges in response to brief flashes of light) significantly predicted an increased risk of seizure recurrence.

"Our findings confirm the feasibility of personalized treatment of the individual JME patient," concludes Dr. Schneider. "Life-long AED therapy is not necessarily required in many patients to maintain seizure freedom. Understanding the predictors for successful long-term seizure outcome will aid clinicians in their treatment options for those with JME.”

Provided by Wiley

Source: medicalxpress.com

ScienceDaily (June 5, 2012) — In a discovery that could help in the identification and treatment of anxiety disorders, Michigan State University scientists say the brains of anxious girls work much harder than those of boys.

This electrode cap was worn by participants in an MSU experiment that measured how people responded to mistakes. Female subjects who identified themselves as big worriers recorded the highest brain activity. (Credit: G.L. Kohuth)

The finding stems from an experiment in which college students performed a relatively simple task while their brain activity was measured by an electrode cap. Only girls who identified themselves as particularly anxious or big worriers recorded high brain activity when they made mistakes during the task.

Jason Moser, lead investigator on the project, said the findings may ultimately help mental health professionals determine which girls may be prone to anxiety problems such as obsessive compulsive disorder or generalized anxiety disorder.

"This may help predict the development of anxiety issues later in life for girls," said Moser, assistant professor of psychology. "It’s one more piece of the puzzle for us to figure out why women in general have more anxiety disorders."

The study, reported in the International Journal of Psychophysiology, is the first to measure the correlation between worrying and error-related brain responses in the sexes using a scientifically viable sample (79 female students, 70 males).

Participants were asked to identify the middle letter in a series of five-letter groups on a computer screen. Sometimes the middle letter was the same as the other four (“FFFFF”) while sometimes it was different (“EEFEE”). Afterward they filled out questionnaires about how much they worry.

Although the worrisome female subjects performed about the same as the males on simple portions of the task, their brains had to work harder at it. Then, as the test became more difficult, the anxious females performed worse, suggesting worrying got in the way of completing the task, Moser said.

"Anxious girls’ brains have to work harder to perform tasks because they have distracting thoughts and worries," Moser said. "As a result their brains are being kind of burned out by thinking so much, which might set them up for difficulties in school. We already know that anxious kids — and especially anxious girls — have a harder time in some academic subjects such as math."

Currently Moser and other MSU researchers are investigating whether estrogen, a hormone more common in women, may be responsible for the increased brain response. Estrogen is known to affect the release of dopamine, a neurotransmitter that plays a key role in learning and processing mistakes in the front part of the brain.

"This may end up reflecting hormone differences between men and women," Moser said.

In addition to traditional therapies for anxiety, Moser said other ways to potentially reduce worry and improve focus include journaling — or “writing your worries down in a journal rather than letting them stick in your head” — and doing “brain games” designed to improve memory and concentration.

Source: Science Daily

ScienceDaily (June 5, 2012) — Mothers who use marijuana as teens — long before having children — may put their future children at a higher risk of drug abuse, new research suggests.

Researchers in the Neuroscience and Reproductive Biology section at the Cummings School of Veterinary Medicine conducted a study to determine the transgenerational effects of cannabinoid exposure in adolescent female rats. For three days, adolescent rats were administered the cannabinoid receptor agonist WIN-55, 212-2, a drug that has similar effects in the brain as THC, the active ingredient in marijuana. After this brief exposure, they remained untreated until being mated in adulthood.

The male offspring of the female rats were then measured against a control group for a preference between chambers that were paired with either saline or morphine. The rats with mothers who had adolescent exposure to WIN-55,212-2 were significantly more likely to opt for the morphine-paired chamber than those with mothers who abstained. The results suggest that these animals had an increased preference for opiate drugs.

The study was published in the Journal of Psychopharmocology and funded by the National Institutes of Health.

"Our main interest lies in determining whether substances commonly used during adolescence can induce behavioral and neurochemical changes that may then influence the development of future generations," said Research Assistant Professor John J. Byrnes, the study’s lead author, "We acknowledge that we are using rodent models, which may not fully translate to the human condition. Nevertheless, the results suggest that maternal drug use, even prior to pregnancy, can impact future offspring."

Byrnes added that much research is needed before a definitive connection is made between adolescent drug use and possible effects on future children.

The study builds on earlier findings by the Tufts group, most notably a study published last year in Behavioral Brain Research by Assistant Professor Elizabeth Byrnes that morphine use as adolescent rats induces changes similar to those observed in the present study.

Other investigators in the field have previously reported that cannabinoid exposure during pregnancy (in both rats and humans) can affect offspring development, including impairment of cognitive function, and increased risk of depression and anxiety.

Source: Science Daily

ScienceDaily (June 5, 2012) — Using a noninvasive test on maternal blood that deploys a novel biochemical assay and a new algorithm for analysis, scientists can detect, with a high degree of accuracy, the risk that a fetus has the chromosomal abnormalities that cause Down syndrome and a genetic disorder known as Edwards syndrome. The new approach is more scalable than other recently developed genetic screening tests and has the potential to reduce unnecessary amniocentesis or CVS.

Two studies evaluating this approach are available online in advance of publication in the April issue of the American Journal of Obstetrics & Gynecology (AJOG).

Diagnosis of fetal chromosomal abnormalities, or aneuploidies, relies on invasive testing by chorionic villous sampling or amniocentesis in pregnancies identified as high-risk. Although accurate, the tests are expensive and carry a risk of miscarriage. A technique known as massively parallel shotgun sequencing (MPSS) that analyzes cell-free DNA (cfDNA) from the mother’s plasma for fetal conditions has been used to detect trisomy 21 (T21) pregnancies, those with an extra copy of chromosome 21 that leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. MPSS accurately identifies the conditions by analyzing the entire genome, but it requires a large amount of DNA sequencing, limiting its clinical usefulness.

Scientists at Aria Diagnostics in San Jose, CA developed a novel assay, Digital Analysis of Selected Regions (DANSR™), which sequences loci from only the chromosomes under investigation. The assay requires 10 times less DNA sequencing than MPSS approaches.

In the current study, the researchers report on a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. Explains author Ken Song, MD, “The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk.”

To test the performance of the DANSR/FORTE assay, Dr. Song and his colleagues evaluated a set of subjects consisting of 123 normal, 36 T21, and 8 T18 pregnancies. All samples were assigned FORTE odd scores for chromosome 18 and chromosome 21. The combination of DANSR and FORTE correctly identified all 36 cases of T21 and 8 cases of T18 as having a greater than 99% risk for each trisomy in a blinded analysis. There was at least a 1,000 fold magnitude separation in the risk score between trisomic and disomic samples.

In a related study, researchers from the Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, University of London and the University College London Hospital, University College London, provided 400 maternal plasma samples to Aria for analysis using the DANSR assay with the FORTE algorithm. The subjects were all at risk for aneuploidies, and they had been tested by chorionic villous sampling. The analysis distinguished all cases of T21 and 98% of T18 cases from euploid pregnancies. In all cases of T21, the estimated risk for this aneuploidy was greater than or equal to 99%, whereas in all normal pregnancies and those with T18, the risk score for T21 was less than or equal to 0.01%.

"Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk," says Dr. Song. "Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation."

Kypros H. Nicolaides, MD, senior author of the University of London study, suggests that fetal trisomy evaluation with cfDNA testing will inevitably be introduced into clinical practice. “It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing.”

Dr. Nicolaides also notes that the plasma samples were obtained from high-risk pregnancies where there is some evidence of impaired placental function. It would also be necessary to demonstrate that the observed accuracy with cfDNA testing obtained from the investigation of pregnancies at high-risk for aneuploidies is applicable to the general population where the prevalence of fetal trisomy 21 is much lower. “This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population,” he concludes.

Source: Science Daily

ScienceDaily (June 5, 2012) — In an early study, UCLA researchers found that the immune cells of patients with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, may play a role in damaging the neurons in the spinal cord. ALS is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement.

In the ALS spinal cord, a patient’s own immune cells called macrophages (green) impact neurons (live neurons =red, which are also marked by an asterisk (*), and dead neurons = magenta that are marked by an arrow. (Credit: University of California, Los Angeles)

Specifically, the team found that inflammation instigated by the immune system in ALS can trigger macrophages — cells responsible for gobbling up waste products in the brain and body — to also ingest healthy neurons. During the inflammation process, motor neurons, whether healthy or not, are marked for clean-up by the macrophages.

In addition, the team found that a lipid mediator called resolvin D1, which is made in the body from the omega-3 fatty acid DHA, was able to “turn off” the inflammatory response that made the macrophages so dangerous to the neurons. Resolvin D1 blocked the inflammatory proteins being produced by the macrophages, curbing the inflammation process that marked the neurons for clean-up. It inhibited key inflammatory proteins like IL-6 with a potency 1,100 times greater than the parent molecule, DHA. DHA has been shown in studies to be neuroprotective in a number of conditions, including stroke and Alzheimer’s disease.

For the study, the team isolated macrophages from blood samples taken from both ALS patients and controls and spinal cord cells from deceased donors.

The study findings on resolvin D1 may offer a new approach to attenuating the inflammation in ALS. Currently, there is no effective way of administering resolvins to patients, so clinical research with resolvin D1 is still several years away. The parent molecule, DHA, is available in stores, although it has not been tested in clinical trials for ALS. Studies with DHA are in progress for Alzheimer’s disease, stroke and brain injury and have been mostly positive.

Source: Science Daily

June 5, 2012

The brain receives information from the ear in a surprisingly orderly fashion, according to a University at Buffalo study scheduled to appear June 6 in the Journal of Neuroscience.

Light microscope image of a bushy neuron in the cochlear nucleus, with a glass microelectrode for recording electrical activity inside the cell. The cell is about 12 micrometers in diameter. New research, published in the Journal of Neuroscience, shows that the synapses onto these cells are sorted according to their plasticity. Credit: Dr. L. Pliss

The research focuses on a section of the brain called the cochlear nucleus, the first way-station in the brain for information coming from the ear. In particular, the study examined tiny biological structures called synapses that transmit signals from the auditory nerve to the cochlear nucleus.

The major finding: The synapses in question are not grouped randomly. Instead, like orchestra musicians sitting in their own sections, the synapses are bundled together by a key trait: plasticity.

Plasticity relates to how quickly a synapse runs down the supply of neurotransmitter it uses to send signals, and plasticity can affect a synapse’s sensitivity to different qualities of sound. Synapses that unleash supplies rapidly may provide good information on when a sound began, while synapses that release neurotransmitter at a more frugal pace may provide better clues on traits like timbre that persist over the duration of a sound.

UB Associate Professor Matthew Xu-Friedman, who led the study, said the findings raise new questions about the physiology of hearing. The research shows that synapses in the cochlear nucleus are arranged by plasticity, but doesn’t yet explain why this arrangement is beneficial, he said.

"It’s clearly important, because the synapses are sorted based on this. What we don’t know is why," said Xu-Friedman, a member of UB’s Department of Biological Sciences. "If you look inside a file cabinet and find all these pieces of paper together, you know it’s important that they’re together, but you may not know why."

In the study, Xu-Friedman and Research Assistant Professor Hua Yang used brain slices from mice to study about 20 cells in the cochlear nucleus called bushy cells, which receive information from synapses attached to auditory nerve fibers.

The experiments revealed that each bushy cell was linked to a network of synapses with similar plasticity. This means that bushy cells themselves may become specialized, developing unique sensitivities to particular characteristics of a sound, Xu-Friedman said.

The study hints that the cochlear nucleus may not be the only part of the brain where synapses are organized by plasticity. The researchers observed the phenomenon in the excitatory synapses of the cerebellum as well.

"One reason this may not have been noticed before is that measuring the plasticity of two different synapses onto one cell is technically quite difficult," Xu-Friedman said.

Provided by University at Buffalo

Source: medicalxpress.com

June 5, 2012

(Medical Xpress) — Using transcranial magnetic stimulation (TMS), an international team led by French researchers from the Centre de Recherche de l’Institut du Cerveau (CNRS) has succeeded in enhancing the visual abilities of a group of healthy subjects. Following stimulation of an area of the brain’s right hemisphere involved in perceptual awareness and in orienting spatial attention, the subjects appeared more likely to perceive a target appearing on a screen. This work, published in the journal PLoS ONE, could lead to the development of novel rehabilitation techniques for certain visual disorders. In addition, it could help improve the performance of individuals whose tasks require very high precision.

TMS is a non-invasive technique that consists in sending a magnetic pulse into a given area of the brain. This results in an activation of the cortical neurons located within the range of the magnetic field, which modifies their activity in a painless and temporary manner. For several years, scientists have been looking at the possibility of using this technique to enhance certain brain functions in healthy subjects.

In this respect, the team led by Antoni Valero-Cabré has carried out research involving the stimulation of a region of the right cerebral hemisphere known as the frontal eye field. Strictly speaking, this is not a primary visual area but it participates in the planning of ocular movements and the orientation of each individual’s attention in the visual space. In a first experiment, a group of healthy subjects tried to distinguish a very low contrast target appearing on a screen for just 30 ms. In some of the tests, the subjects received a magnetic pulse lasting between 80 and 140 ms on this frontal region before the target appeared. The researchers found that the success rate was higher when using TMS. The visual sensitivity of healthy subjects was temporarily increased by around 12%. In a second experiment, the subjects were shown a fleeting visual cue indicating the spot where the target could appear. In this configuration, the enhancement of visual sensitivity, which remained of the same order, was only apparent when the cue indicated the correct location of the target.

Although cerebral functions such as conscious vision are highly optimized in healthy adults, these results show that there is a significant margin for improvement, which can be “enhanced” by TMS. This technique could be tested for the rehabilitation of patients suffering from cortical damage, due for example to a cardiovascular accident, and for that of patients with retinal disorders. The second experiment suggests that rehabilitation based on both TMS and visual cues could be more selective than the use of stimulation alone. The researchers want to further explore this possibility using repetitive TMS, which, in this case, could make it possible to obtain long-lasting modification of cerebral activity.

Furthermore, according to the researchers, TMS could be used in the near future to increase the attentional abilities of individuals performing tasks that require good visual skills.

Provided by CNRS

Source: medicalxpress.com

June 5, 2012

Researchers studying stroke patients have found a strong association between impairments in a network of the brain involved in emotional regulation and the severity of post-stroke depression. Results of the study are published online in the journal Radiology.

"A third of patients surviving a stroke experience post-stroke depression (PSD),” said lead researcher Igor Sibon, M.D., Ph.D., professor of neurology at the University of Bordeaux in Bordeaux, France. “However, studies have failed to identify a link between lesions in the brain caused by ischemia during a stroke and subsequent depression.”

Instead of looking for dysfunction in a specific area of the brain following a stroke, Dr. Sibon’s study was designed to assess a group of brain structures organized in a functional network called the default-mode network (DMN). Modifications of connectivity in the DMN, which is associated with internally generated thought processes, has been observed in depressive patients.

"The default-mode network is activated when the brain is at rest," Dr. Sibon said. "When the brain is not actively involved in a task, this area of the brain is engaged in internal thoughts involving self-related memory retrieval and processing.”

In the study, 24 patients between the ages of 18 and 80 underwent resting-state functional magnetic resonance imaging (fMRI) 10 days after having mild to moderate ischemic stroke. An fMRI imaging study measures metabolic changes in specific areas of the brain. Although many fMRI exams are designed to measure brain changes while a patient performs a specific task, during a resting-state fMRI exam, patients lie motionless.

The patients, which included 19 men and five women, were also clinically evaluated 10 days and three months post-stroke to determine the presence and severity of depression and anxiety symptoms. At three months post-stroke, patients were evaluated for depression using the DSM-IV diagnostic classification system.

Using the DSM-IV criteria, 10 patients had minor to moderate depression, and 14 patients had no depression. Results of the fMRI exams revealed an association between modifications of connectivity in the DMN 10 days after stroke and the severity of depression three months post-stroke.

"We found a strong association between early resting-state network modifications and the risk of post-stroke mood disorders," Dr. Sibon said. "These results support the theory that functional brain impairment following a stroke may be more critical than structural lesions."

According to Dr. Sibon, the widespread chemical changes that result from a stroke may lead to the modification of connectivity in brain networks such as the DMN. He said results of his study may contribute to the clinical management of stroke patients by providing an opportunity to investigate the effects of a variety of treatments on patients whose fMRI results immediately post-stroke indicate impaired connectivity in the DMN.

Provided by Radiological Society of North America

Source: medicalxpress.com

June 4, 2012

A nuzzle of the neck, a stroke of the wrist, a brush of the knee—these caresses often signal a loving touch, but can also feel highly aversive, depending on who is delivering the touch, and to whom. Interested in how the brain makes connections between touch and emotion, neuroscientists at the California Institute of Technology (Caltech) have discovered that the association begins in the brain’s primary somatosensory cortex, a region that, until now, was thought only to respond to basic touch, not to its emotional quality.

The new finding is described in this week’s issue of the Proceedings of the National Academy of Sciences (PNAS).

The team measured brain activation while self-identified heterosexual male subjects lay in a functional MRI scanner and were each caressed on the leg under two different conditions. In the first condition, they saw a video of an attractive female bending down to caress them; in the second, they saw a video of a masculine man doing the same thing. The men reported the experience as pleasurable when they thought the touch came from the woman, and aversive when they thought it came from the man. And their brains backed them up: this difference in experience was reflected in the activity measured in each man’s primary somatosensory cortex.

"We demonstrated for the first time that the primary somatosensory cortex—the brain region encoding basic touch properties such as how rough or smooth an object is—also is sensitive to the social meaning of a touch," explains Michael Spezio, a visiting associate at Caltech who is also an assistant professor of psychology at Scripps College in Claremont, California. "It was generally thought that there are separate brain pathways for how we process the physical aspects of touch on the skin and for how we interpret that touch emotionally—that is, whether we feel it as pleasant, unpleasant, desired, or repulsive. Our study shows that, to the contrary, emotion is involved at the primary stages of social touch."

Unbeknownst to the subjects, the actual touches on their leg were always exactly the same—and always from a woman. Yet, it felt different to them when they believed a man versus a woman was doing the touching.

"The primary somatosensory cortex responded more to the ‘female’ touch than to the ‘male’ touch condition, even while subjects were only viewing a video showing a person approach their leg," says Ralph Adolphs, Bren Professor of Psychology and Neuroscience at Caltech and director of the Caltech Brain Imaging Center, where the research was done. "We see responses in a part of the brain thought to process only basic touch that were elicited entirely by the emotional significance of social touch prior to the touch itself, simply in anticipation of the caress that our participants would receive."

The study was carried out in collaboration with the husband-and-wife team of Valeria Gazzola and Christian Keysers, who were visiting Caltech from the University of Groningen in the Netherlands.

"Intuitively, we all believe that when we are touched by someone, we first objectively perceive the physical properties of the touch—its speed, its gentleness, the roughness of the skin," says Gazzola. "Only thereafter, in a separable second step based on who touched us, do we believe we value this touch more or less."

The experiment showed that this two-step vision is incorrect, at least in terms of separation between brain regions, she says, and who we believe is touching us distorts even the supposedly objective representation of what the touch was like on the skin.

"Nothing in our brain is truly objective," adds Keysers. "Our perception is deeply and pervasively shaped by how we feel about the things we perceive."

One possible practical implication of the work is to help reshape social responses to touch in people with autism.

"Now that we have clear evidence that primary somatosensory cortex encodes emotional significance of touch, it may be possible to work with early sensory pathways to help children with autism respond more positively to the gentle touch of their parents and siblings," says Spezio.

The work also suggests that it may be possible to use film clips or virtual reality to reestablish positive responses to gentle touch in victims of sexual and physical abuse, and torture.

Next, the researchers hope to test whether the effect is as robust in women as in men, and in both sexes across sexual orientation. They also plan to explore how these sensory pathways might develop in infants or children.

Provided by California Institute of Technology

Source: medicalxpress.com

ScienceDaily (June 4, 2012) — Those cups of coffee that you drink every day to keep alert appear to have an extra perk — especially if you’re an older adult. A recent study monitoring the memory and thinking processes of people older than 65 found that all those with higher blood caffeine levels avoided the onset of Alzheimer’s disease in the two-to-four years of study follow-up. Moreover, coffee appeared to be the major or only source of caffeine for these individuals.

Those cups of coffee that you drink every day to keep alert appear to have an extra perk — especially if you’re an older adult. A recent study monitoring the memory and thinking processes of people older than 65 found that all those with higher blood caffeine levels avoided the onset of Alzheimer’s disease in the two-to-four years of study follow-up. (Credit: © Yuri Arcurs / Fotolia)

Researchers from the University of South Florida and the University of Miami say the case control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset. Their findings will appear in the online version of an article to be published June 5 in the Journal of Alzheimer’s Disease. The collaborative study involved 124 people, ages 65 to 88, in Tampa and Miami.

"These intriguing results suggest that older adults with mild memory impairment who drink moderate levels of coffee — about 3 cups a day — will not convert to Alzheimer’s disease — or at least will experience a substantial delay before converting to Alzheimer’s," said study lead author Dr. Chuanhai Cao, a neuroscientist at the USF College of Pharmacy and the USF Health Byrd Alzheimer’s Institute. "The results from this study, along with our earlier studies in Alzheimer’s mice, are very consistent in indicating that moderate daily caffeine/coffee intake throughout adulthood should appreciably protect against Alzheimer’s disease later in life."

The study shows this protection probably occurs even in older people with early signs of the disease, called mild cognitive impairment, or MCI. Patients with MCI already experience some short-term memory loss and initial Alzheimer’s pathology in their brains. Each year, about 15 percent of MCI patients progress to full-blown Alzheimer’s disease. The researchers focused on study participants with MCI, because many were destined to develop Alzheimer’s within a few years.

Blood caffeine levels at the study’s onset were substantially lower (51 percent less) in participants diagnosed with MCI who progressed to dementia during the two-to-four year follow-up than in those whose mild cognitive impairment remained stable over the same period.

No one with MCI who later developed Alzheimer’s had initial blood caffeine levels above a critical level of 1200 ng/ml — equivalent to drinking several cups of coffee a few hours before the blood sample was drawn. In contrast, many with stable MCI had blood caffeine levels higher than this critical level.

"We found that 100 percent of the MCI patients with plasma caffeine levels above the critical level experienced no conversion to Alzheimer’s disease during the two-to-four year follow-up period," said study co-author Dr. Gary Arendash.

The researchers believe higher blood caffeine levels indicate habitually higher caffeine intake, most probably through coffee. Caffeinated coffee appeared to be the main, if not exclusive, source of caffeine in the memory-protected MCI patients, because they had the same profile of blood immune markers as Alzheimer’s mice given caffeinated coffee. Alzheimer’s mice given caffeine alone or decaffeinated coffee had a very different immune marker profile.

Since 2006, USF’s Dr. Cao and Dr. Arendash have published several studies investigating the effects of caffeine/coffee administered to Alzheimer’s mice. Most recently, they reported that caffeine interacts with a yet unidentified component of coffee to boost blood levels of a critical growth factor that seems to fight off the Alzheimer’s disease process.

"We are not saying that moderate coffee consumption will completely protect people from Alzheimer’s disease," Dr. Cao cautioned. "However, we firmly believe that moderate coffee consumption can appreciably reduce your risk of Alzheimer’s or delay its onset."

Alzheimer’s pathology is a process in which plaques and tangles accumulate in the brain, killing nerve cells, destroying neural connections, and ultimately leading to progressive and irreversible memory loss. Since the neurodegenerative disease starts one or two decades before cognitive decline becomes apparent, the study authors point out, any intervention to cut the risk of Alzheimer’s should ideally begin that far in advance of symptoms.

"Moderate daily consumption of caffeinated coffee appears to be the best dietary option for long-term protection against Alzheimer’s memory loss," Dr. Arendash said. "Coffee is inexpensive, readily available, easily gets into the brain, and has few side-effects for most of us. Moreover, our studies show that caffeine and coffee appear to directly attack the Alzheimer’s disease process."

In addition to Alzheimer’s disease, moderate caffeine/coffee intake appears to reduce the risk of several other diseases of aging, including Parkinson’s disease, stroke, Type II diabetes, and breast cancer. However, supporting studies for these benefits have all been observational (uncontrolled), and controlled clinical trials are needed to definitively demonstrate therapeutic value.

A study tracking the health and coffee consumption of more than 400,000 older adults for 13 years, and published earlier this year in the New England Journal of Medicine, found that coffee drinkers reduced their risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, and even injuries and accidents.

With new Alzheimer’s diagnostic guidelines encompassing the full continuum of the disease, approximately 10 million Americans now fall within one of three developmental stages of Alzheimer’s disease — Alzheimer’s disease brain pathology only, MCI, or diagnosed Alzheimer’s disease. That number is expected to climb even higher as the baby-boomer generation continues to enter older age, unless an effective and proven preventive measure is identified.

"If we could conduct a large cohort study to look into the mechanisms of how and why coffee and caffeine can delay or prevent Alzheimer’s disease, it might result in billions of dollars in savings each year in addition to improved quality of life," Dr. Cao said.

Source: Science Daily

June 4, 2012

In a new study of the effects of soy supplements for postmenopausal women, researchers at the Stanford University School of Medicine and the USC Keck School of Medicine found no significant differences — positive or negative — in overall mental abilities between those who took supplements and those who didn’t.

While questions have swirled for years around a possible link between soy consumption and changes in cognition, this research offers no evidence to support such claims. “There were no large effects on overall cognition one way or another,” said the study’s lead author, Victor Henderson, MD, professor of health research and policy and of neurology and neurological sciences at Stanford.

The findings from the 2.5-year study in middle-aged and older women, which was larger and longer than any previous trials on soy use, will appear in the June 5 issue of Neurology, the medical journal of the American Academy of Neurology. The results are in line with the largest previous study in this area: a 12-month trial of Dutch women during which daily soy intake showed “no significant effect on cognitive endpoints.” That work was published in a 2004 issue of the Journal of the American Medical Association.

Still, there are a number of randomized clinical trials on soy’s effect on cognition and memory in women that have presented conflicting takes about its benefits and harms. While improved cognition was seen in some findings, other research suggested that soy could have an adverse effect on memory.

Soy and soy-based products contain an estrogen-like compound called isoflavones, and some women choose to take soy supplements as an alternative to estrogen. It has been thought that isoflavones might be able to boost memory and perhaps overall brain function. The hippocampus, the part of the brain that controls memory, is rich in estrogen beta receptors, and isoflavones are known to activate these receptors.

Henderson’s interest in the matter is part of his broader research agenda on finding new strategies to improve cognitive function in aging.

For this work, he and his colleagues conducted the National Institutes of Health-sponsored Women’s Isoflavone Soy Health Trial, which was done between 2004 and 2008 to determine the effect of soy isoflavones on the progression of atherosclerosis and, secondarily, the effect on cognition. During this study, 350 healthy women ages 45-92 were randomized to receive daily 25 grams of isoflavone-rich soy protein (a dose comparable to that of traditional Asian diets) or a placebo. A battery of neuropsychological tests was given to the participants at the start of the study and again 2.5 years later.

Henderson and his colleagues examined changes to the composite of 14 scores and found no significant differences in global cognition — that is, overall mental abilities — from baseline to study-end between women who took the supplements and those on placebo. During a planned secondary analysis, they did identify a statistically significant difference in one of the identified cognitive factors: Women in the supplement group showed a greater improvement in visual memory (memory for faces). Henderson said this could be important, but “the finding needs to be replicated in future studies.”

According to Henderson, this research “helps provide a firm answer” about soy and overall cognition, and he and his co-authors note in the paper that postmenopausal women shouldn’t pursue a high-soy diet or take supplements for the primary goal of global cognitive benefit.

At the same time, Henderson said the work is not meant discourage women who consume soy for other purposes. “I don’t think they should be disappointed at all,” he said. “They should be pleased that there aren’t negative effects on overall cognitive function and that there are potential gains in aspects of memory. If a woman enjoys eating soy and if there may be other health benefits, she should keep doing what she’s doing.”

The researchers note that while these results are reasonably definitive — Henderson said the sample size was large enough that if there were major effects, the researchers would have likely seen them — the cognitive effects of soy isoflavones might differ for women of reproductive age and for men. More study is needed in these populations, he said. He also emphasized the need for researchers to continue studying a variety of interventions to improve cognition among older adults, including nutritional approaches, physical and mental activities, and pharmaceutical approaches.

Journal reference: Neurology

Source: medicalxpress.com

ScienceDaily (June 4, 2012) — A pair of new studies by computer scientists, biologists, and cognitive psychologists at Harvard, Northwestern, Wellesley, and Tufts suggest that collaborative touch-screen games have value beyond just play.

Multi-touch tables can recognize and accommodate several users at once, allowing students to collaborate and learn while they play an engaging game. (Credit: Michael Horn, Northwestern University)

Two games, developed with the goal of teaching important evolutionary concepts, were tested on families in a busy museum environment and on pairs of college students. In both cases, the educational games succeeded at making the process of learning difficult material engaging and collaborative.

The findings were presented at the Association for Computing Machinery (ACM) Special Interest Group on Computer-Human Interaction (SIGCHI) conference in May.

The games take advantage of the multi-touch-screen tabletop, which is essentially a desk-sized tablet computer. In a classroom or a museum, several users can gather around the table and use it simultaneously, either working on independent problems in the same space, or collaborating on a single project. The table accommodates multiple users and can also interact with physical objects like cards or blocks that are placed onto its surface.

The new research moves beyond the novelty of the system, however, and investigates the actual learning outcomes of educational games in both formal and informal settings.

"Do we know what the users are actually learning from this? That question is a step beyond the research of the past 10 years, where we’ve been seeing research publications that assess how well the system is performing, but not addressing how well it’s accomplishing what it’s really designed for," says principal investigator Chia Shen, a Senior Research Fellow in Computer Science at the Harvard School of Engineering and Applied Sciences (SEAS) and Director of the Scientists’ Discovery Room Lab.

The two collaborative games that have been developed for the system, Phylo-Genie and Build-a-Tree, are designed to help people understand phylogeny — specifically, the tree diagrams that evolutionary biologists use to indicate the evolutionary history of related species. Learners new to the discipline sometimes think of evolution as a linear progression, from the simple to the complex, with humans as the end point.

"What people are used to typically is geospatial data, like a map," explains Shen. "In phylogeny, however, the students need to understand that the relationship between species really depends on when they diverged. That’s represented by the position of the internal nodes of the tree, not by counting across the top of the tree, which is how many people intuitively do it."

The Phylo-Genie game, developed by researchers at Harvard, Wellesley, and Tufts, attempts to address the misconceptions that students hold even at the college level. Designed for a formal classroom setting, the game walks students through a scenario in which they have been bitten by an unusual species of snake and must identify its closest relatives in order to choose the correct anti-venom.

The researchers tested Phylo-Genie on pairs of undergraduate students who had not yet taken a course in evolutionary biology. Other pairs of students were given the same exercise, but in a pen-and-paper format. In comparison to the paper version, the electronic game produced statistically significantly higher scores on a post-test (an exam borrowed from a Harvard course), as well as higher participant ratings for engagement and collaboration.

Both of the phylogeny games were designed and evaluated in accordance with accepted principles of cognitive psychology and learning sciences.

The Build-a-Tree game was designed with an informal museum environment in mind. Researchers on this project, directed by lead author Michael S. Horn at Northwestern University and Shen at Harvard, observed 80 families and other social groups interacting with the Build-a-Tree game at the Harvard Museum of Natural History.

The game asks users to construct phylogenetic trees by dragging icons — for example, a bat, a bird, and a butterfly — toward one another in the correct order. As the user progresses through several levels, the problems become more challenging.

The idea, Shen says, is to encourage what museum science educators call “active prolonged engagement,” as opposed to “planned discovery.” The former allows learners to explore information independently and to interact with it in an open-ended manner; the latter approach, common in natural history museums, guides the user toward a particular set of facts.

"Natural history museums have always been a place where the exhibits are behind glass in the gallery," explains Shen. "You come here to see things that you just don’t see anywhere else — fossils millions of years old — and you come here to learn. You see school groups and parents coming in with a serious mind, and we’re breaking into that culture."

The Build-a-Tree game performed well against established measures of active prolonged engagement and social learning.

Even in the most high-tech exhibit hall, where visitors are engaged at every turn, it takes a great deal of creative thinking to demonstrate a phenomenon that is essentially imperceptible in real time.

"Evolution is a process that takes millions of years, whereas in chemistry or physics there are all sorts of phenomena that you can experiment with, like the tornado exhibit where you can go in and interrupt the air," says Shen. "This is our experiment: can we build something that is not as phenomenon-driven but can still engage them? I think we’ve succeeded in that."

Source: Science Daily

June 4, 2012

(Medical Xpress) — Ever been stuck in traffic when a feel-good song comes on the radio and suddenly your mood lightens?

Our emotions and feelings are typically associated with the right side of the brain. For example, processing the emotion in human facial expressions is done in the right hemisphere.

However, new Australian research is challenging the widely-held view that emotions and feelings are the domain of the right hemisphere only.

Dr. Sharpley Hsieh and colleagues from Neuroscience Research Australia (NeuRA) found that people with semantic dementia, a disease where parts of the left hemisphere are severely affected, have difficulty recognising emotion in music.

These findings have exciting implications for our understanding of how music, language and emotions are handled by the brain.

“It’s known that processing whether a face is happy or sad is impaired in people who lose key regions of the right hemisphere, as happens in people with Alzheimer’s and semantic dementia”, says Dr. Hsieh.

“What we have now learnt from looking at people with semantic dementia is that understanding emotions in music involves key parts of the other side of the brain as well”, she says.

“Ours is the first study from patients with dementia to show that language-based areas of the brain, primarily on the left, are important for extracting emotional meaning from music. Our findings suggest that the brain considers melodies and speech to be similar and that overlapping parts of the brain are required for both”, says Hsieh.

This paper is published in the journal Neuropsychologia.

How was this study done?

• People with Alzheimer’s disease lose episodic memory (‘What did I do yesterday?’); people with semantic dementia lose semantic memory (‘What is a zebra?’).
• Dr. Hsieh studied people with Alzheimer’s disease, semantic dementia and healthy people without either disease. Participants were played new pieces of music and had to indicate whether the song was happy, sad, peaceful or scary.
• Images were then taken of the patients’ brains using MRI so that diseased parts of the brain could be compared statistically to the answers provided in the musical test.
• Patients with Alzheimer’s and semantic dementia have problems deciding whether a human face looks happy or sad because the amygdala in the right hemisphere is diseased.
• Patients with semantic dementia have additional problems labelling whether a piece of music is happy or sad because the anterior temporal lobe in the left hemisphere is diseased.

Provided by Neuroscience Research Australia

Source: medicalxpress.com

June 3, 2012

Unlike their visual cousins, the neurons that control movement are not a predictable bunch. Scientists working to decode how such neurons convey information to muscles have been stymied when trying to establish a one-to-one relationship between a neuron’s behavior and external factors such as muscle activity or movement velocity.

The 19th century mathematician Joseph Fourier showed that two rhythms could be summed to produce a third rhythm. Researchers at Stanford have shown that this principle is behind the brain activity that produces arm movements. Credit: Mark Churchland, Stanford School of Engineering

In an article published online June 3rd by the journal Nature, a team of electrical engineers and neuroscientists working at Stanford University propose a new theory of the brain activity behind arm movements. Their theory is a significant departure from existing understanding and helps to explain, in relatively simple and elegant terms, some of the more perplexing aspects of the activity of neurons in motor cortex.

In their paper, electrical engineering Associate Professor Krishna Shenoy and post-doctoral researchers Mark Churchland, now a professor at Columbia, and John Cunningham of Cambridge University, now a professor at Washington University in Saint Louis, have shown that the brain activity controlling arm movement does not encode external spatial information—such as direction, distance and speed—but is instead rhythmic in nature.

Understanding the brain

Neuroscientists have long known that the neurons responsible for vision encode specific, external-world information—the parameters of sight. It had been theorized and widely suggested that motor cortex neurons function similarly, conveying specifics of movement such as direction, distance and speed, in the same way the visual cortex records color, intensity and form.

"Visual neurons encode things in the world. They are a map, a representation," said Churchland, who is first author of the paper. "It’s not a leap to imagine that neurons in the motor cortex should behave like neurons in the visual cortex, relating in a faithful way to external parameters, but things aren’t so concrete for movement."

Scientists have disagreed about which movement parameters are being represented by individual neurons. They could not look at a particular neuron firing in the motor cortex and determine with confidence what information it was encoding.

"Many experiments have sought such lawfulness and yet none have found it. Our findings indicate an alternative principle is at play," said co-first author Cunningham.

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ScienceDaily (June 1, 2012) — Neuroscientists at Cold Spring Harbor Laboratory (CSHL) just reached an important milestone, publicly releasing the first installment of data from the 500 terabytes so far collected in their pathbreaking project to construct the first whole-brain wiring diagram of a vertebrate brain, that of the mouse.

Composite image generated with Mouse Brain Architecture project data. Injections of two fluorescently marked (red and green) adeno-associated viral (AAV) tracers indicate neural pathways, superimposed upon a whole-brain image stained to reveal the protective sheathing around myelinated axons. Axonal paths leaving the injection site are seen, including horizontal ones crossing over to the other side of the brain along the Corpus Callosum. (Credit: Image courtesy of Cold Spring Harbor Laboratory)

The data consist of gigapixel images (each close to 1 billion pixels) of whole-brain sections that can be zoomed to show individual neurons and their processes, providing a “virtual microscope.” The images are integrated with other data sources from the web, and are being made fully accessible to neuroscientists as well as interested members of the general public (http://mouse.brainarchitecture.org). The data are being released pre-publication in the spirit of open science initiatives that have become familiar in digital astronomy (e.g., Sloan Digital Sky Survey) but are not yet as widespread in neurobiology.

Each sampled brain is represented in about 500 images, each image showing an optical section through a 20 micron-thick slice of brain tissue. A multi-resolution viewer permits users to journey through each brain from “front” to “back,” and thus enables them to follow the pathways taken through three-dimensional brain space by tracer-labeled neuronal pathways. The tracers were picked to follow neuronal inputs and outputs of given brain regions.

"We’re executing a grid-based "shotgun" strategy for neuronal tract tracing that we first proposed a few years ago, and which I am pleased to note has gained acceptance elsewhere within the neuroscience community," says Partha P. Mitra, Ph.D., the Crick-Clay Professor of Biomathematics at CSHL and director of the Mouse Brain Architecture (MBA) Project. After the initial June 1 release, project data will be made public continuously on a monthly basis, Mitra says.

Project addresses a large gap in knowledge

"Our project seeks to address a remarkable gap in our knowledge of the brain," Mitra explains. "Our knowledge of how the brain is wired remains piecemeal and partial after a century of intense activity. Francis Crick and Ted Jones emphasized this in an article published in Nature nearly 20 years ago. Yet to understand how the brain works (or fails to work in neurological or neuropsychiatric disease), it is critical that we understand this wiring diagram more fully. Further, there remain fundamental questions about brain evolution that cannot be addressed without obtaining such wiring diagrams for the brains of different species.”

The MBA Project, which has received critical funding from the Keck Foundation and from the National Institutes of Health, is distinguished by the approach advocated by Mitra and colleagues in a position paper published in 2009. Mitra there proposed mapping vertebrate brains at what he calls the “mesoscopic” scale, a middle-range amenable to light microscopy, providing far more detail than, for instance, MRI-based methods, and yet considerably less detail than is achievable via electron microscopy (EM). The latter approach, while useful for mapping synaptic connections between individual neurons, is feasible on a whole-brain basis only for very small brains (e.g. that of the fruitfly) or very small portions of the mouse brain.

The pragmatic approach Mitra advocated and which is realized in this first data release, is to image whole mouse brains in a semi-automated, quality-controlled process using light microscopy and injected neural tracers (both viruses and classically used tracer substances). While the basic methodology has been available for some time, systematically applying it to a grid of locations spanning the entire brain, and digitizing and re-assembling the resulting collection of brains, is a new approach made feasible by the rapidly falling costs of computer storage. A single mouse brain at light-microscope resolution produces about a terabyte (1 trillion bytes, or 1000 GB) of data; thus, generating and storing the data set currently being gathered would have been prohibitively expensive a decade or so ago.

Assembling the circuit diagram at a mesoscopic scale using ‘shotgun approach’

A key point is that at the mesoscopic scale, the team expects to assemble a picture of connections that are stereotypical — that is, essentially the same in different individuals, and probably genetically determined in a species-specific manner. By dividing the volume of a hemisphere of the mouse brain into 250 equidistant, predefined grid-points, and administering four different kinds of tracer injections at each grid point — in different animals of the same sex and age — the eight-member team at CSHL assisted by collaborating scientists at Boston University, MIT and the University of California, San Diego seeks to assemble a complete wiring diagram that will be stitched together from the full dataset.

The project in this sense is analogous to the Human Genome Project’s “shotgun” approach, in that its final product — a comprehensive wiring diagram — will be the product of many individually obtained data components, woven together thanks to the power of advanced computing and informatics. Indeed, Mitra says one of the genome project’s early advocates, Dr. James D. Watson (now CSHL Chancellor Emeritus), provided him with motivation and encouragement to pursue the project.

"We will never understand how the brain works until we have the wiring diagram," Dr. Watson comments today. "Mitra is on the right track and I’m impressed he’s gone from conception to putting out data in a couple of years on a quite modest budget. His approach deserves strong funding support."

The MBA Project was also inspired by early efforts of the Allen Institute, funded by Microsoft co-founder and philanthropist Paul Allen, which resulted in assembly of a comprehensive map of gene expression across the mouse brain. That effort was the product of standard molecular biology procedures iterated in a quasi-industrialized process. The resulting whole-brain gene-expression map, while a triumph, was not designed to shed light on connections in the brain, which became a point of departure for Mitra.

Since the 2009 publication of Mitra and colleagues’ proposal for meso-scale circuit-mapping projects for whole vertebrate brains, the approach has not only spawned Mitra’s CSHL project, but also other meso-scale circuit-mapping projects for the mouse at the Allen Institute and at UCLA. Each differs in aim and technical detail.

A number of features distinguish the “meso-scale” circuit project at CSHL. The 20-micron spacing between brain “slices” gives the CSHL results a particularly rich sense of three-dimensional depth and detail. The team’s use of four tracers including both classical tracer substances as well as neurotropic viruses (attenuated or disabled viruses that infect nerve cells), provides redundancy and helps control for differing efficacies of the different tracer substances. The images one sees on the MBA Project website begininng today provide hard data on actual neuronal processes — the “ground truth” of neuroanatomy, in Mitra’s words — and do not rely on inferential methodologies such as functional MRI scans and diffusion tensor imaging to suggest areas in which connections occur. Finally, it is noteworthy that the slides generated by the project are being physically stored, to permit re-examination at a later date, using more refined imaging methods if necessary or as new methods become available.

"Our project is what I’d call a necessary first step in a much larger enterprise, that of understanding both structure and dynamics of the vertebrate, and ultimately, the human brain," says Mitra. "While facile comparisons with Genome projects should be avoided, the data sets generated by the MBA and similar projects will provide a useful framework — not unlike a reference genome — on which we can ‘hang’ all kinds of neuroscience knowledge, the body of which has always been notably fragmentary."

Source: Science Daily

ScienceDaily (June 1, 2012) — Exercise helps to alleviate pain related to nerve damage (neuropathic pain) by reducing levels of certain inflammation-promoting factors, suggests an experimental study in the June issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).

The results support exercise as a potentially useful nondrug treatment for neuropathic pain, and suggest that it may work by reducing inflammation-promoting substances called cytokines. The lead author was Yu-Wen Chen, PhD, of China Medical University, Taichung, Taiwan.

Exercise Reduces Nerve Pain and Cytokine Expression in Rats Neuropathic pain is a common and difficult-to-treat type of pain caused by nerve damage, seen in patients with trauma, diabetes, and other conditions. Phantom limb pain after amputation is an example of neuropathic pain.

Dr Chen and colleagues examined the effects of exercise on neuropathic pain induced by sciatic nerve injury in rats. After nerve injury, some animals performed progressive exercise — either swimming or treadmill running — over a few weeks. The researchers assessed the effects of exercise on neuropathic pain severity by monitoring observable pain behaviors.

The results suggested significant reductions in neuropathic pain in rats assigned to swimming or treadmill running. Exercise reduced abnormal responses to temperature and pressure — both characteristic of neuropathic pain.

Exercise also led to reduced expression of inflammation-promoting cytokines in sciatic nerve tissue — specifically, tumor necrosis factor-alpha and interleukin-1-beta. That was consistent with previous studies suggesting that inflammation and pro-inflammatory cytokines play a role in the development of neuropathic pain in response to nerve injury.

Exercise also led to increased expression of a protein, called heat shock protein-27, which may have contributed to the reductions in cytokine expression.

Neuropathic pain causes burning pain and numbness that is not controlled by conventional pain medications. Antidepressant and antiepileptic drugs may be helpful, but have significant side effects. Exercise is commonly recommended for patients with various types of chronic pain, but there are conflicting data as to whether it is helpful in neuropathic pain.

The new results support the benefits of exercise in reducing neuropathic pain, though not eliminating it completely. In the experiments, exercise reduced abnormal pain responses by 30 to 50 percent.

The study also adds new evidence that inflammation contributes to the development of neuropathic pain, including the possible roles of pro-inflammatory cytokines. The results provide support for exercise as a helpful, nondrug therapy for neuropathic pain — potentially reducing the need for medications and resulting side effects.

Source: Science Daily

ScienceDaily (June 1, 2012) — Too often, communication barriers exist between those who can hear and those who cannot. Sign language has helped bridge such gaps, but many people are still not fluent in its motions and hand shapes.

During the past semester, students in UH’s engineering technology and industrial design programs teamed up to develop the concept and prototype for MyVoice, a device that reads sign language and translates its motions into audible words. (Credit: Image courtesy of University of Houston)

Thanks to a group of University of Houston students, the hearing impaired may soon have an easier time communicating with those who do not understand sign language. During the past semester, students in UH’s engineering technology and industrial design programs teamed up to develop the concept and prototype for MyVoice, a device that reads sign language and translates its motions into audible words. Recently, MyVoice earned first place among student projects at the American Society of Engineering Education (ASEE) — Gulf Southwest Annual Conference.

The development of MyVoice was through a collaborative senior capstone project for engineering technology students (Anthony Tran, Jeffrey Seto, Omar Gonzalez and Alan Tran) and industrial design students (Rick Salinas, Sergio Aleman and Ya-Han Chen). Overseeing the student teams were Farrokh Attarzadeh, associate professor of engineering technology, and EunSook Kwon, director of UH’s industrial design program.

MyVoice’s concept focuses on a handheld tool with a built-in microphone, speaker, soundboard, video camera and monitor. It would be placed on a hard surface where it reads a user’s sign language movements. Once MyVoice processes the motions, it then translates sign language into space through an electronic voice. Likewise, it would capture a person’s voice and can translate words into sign language, which is projected on its monitor.

The industrial designers researched the application of MyVoice by reaching out to the deaf community to understand the challenges associated with others not understanding sign language. They then designed MyVoice, while the engineering technology students had the arduous task of programming the device to translate motion into sound.

"The biggest difficulty was sampling together a databases of images of the sign languages. It involved 200-300 images per sign," Seto said. "The team was ecstatic when the prototype came together."

From its conceptual stage, MyVoice evolved into a prototype that could translate a single phrase: “A good job, Cougars.”

"This wasn’t just a project we did for a grade," said Aleman, who just graduated from UH. "While designing and developing it, it turned into something very personal. When we got to know members of the deaf community and really understood their challenges, it made this MyVoice very important to all of us."

Since MyVoice’s creation and first place prize at the ASEE conference, all of the team members have graduated. Still, Aleman said that the project is not history.

"We got it to work, but we hope to work with someone to implement this as a product," Aleman said. "We want to prove to the community that this will work for the hearing impaired."

"We are proud of such a contribution to society through MyVoice, which breaks the barrier between deaf community and common society," added Attarzadeh.

Source: Science Daily

June 1, 2012

In a step towards improving rehabilitation for patients with walking impairments, researchers from the Kennedy Krieger Institute found that non-invasive stimulation of the cerebellum, an area of the brain known to be essential in adaptive learning, helped healthy individuals learn a new walking pattern more rapidly. The findings suggest that cerebellar transcranial direct current stimulation (tDCS) may be a valuable therapy tool to aid people relearning how to walk following a stroke or other brain injury.

Previous studies in the lab of Amy Bastian, PhD, PT, director of the Motion Analysis Laboratory at Kennedy Krieger Institute, have shown that the cerebellum, a part of the brain involved in movement coordination, is essential for walking adaptation. In this new study, Dr. Bastian and her colleagues explored the impact of stimulation over the cerebellum on adaptive learning of a new walking pattern. Specifically, her team tested how anode (positive), cathode (negative) or sham (none) stimulation affected this learning process.

"We’ve known that the cerebellum is essential to adaptive learning mechanisms like reaching, walking, balance and eye movements,” says Dr. Bastian. “In this study, we wanted to examine the effects of direct stimulation of the cerebellum on locomotor learning utilizing a split-belt treadmill that separately controls the legs.”

The study, published today in the Journal of Neurophysiology, found that by placing electrodes on the scalp over the cerebellum and applying very low levels of current, the rate of walking adaptation could be increased or decreased. Dr. Bastian’s team studied 53 healthy adults in a series of split-belt treadmill walking tests. Rather than a single belt, a split-belt treadmill consists of two belts that can move at different speeds. During split-belt walking, one leg is set to move faster than the other. This initially disrupts coordination between the legs so the user is not walking symmetrically, however over time the user learns to adapt to the disturbance.

The main experiment consisted of a two-minute baseline period of walking with both belts at the same slow speed, followed by a 15-minute period with the belts at two separate speeds. While people were on the treadmill, researchers stimulated one side of the cerebellum to assess the impact on the rate of re-adjustment to a symmetric walking pattern.

Dr. Bastian’s team found not only that cerebellar tDCS can change the rate of cerebellum-dependent locomotor learning, but specifically that the anode speeds up learning and the cathode slows it down. It was also surprising that the side of the cerebellum that was stimulated mattered; only stimulation of the side that controls the leg walking on the faster treadmill belt changed adaptation rate.

"It is important to demonstrate that we can make learning faster or slower, as it suggests that we are not merely interfering with brain function," says Dr. Bastian. "Our findings also suggest that tDCS can be selectively used to assess and understand motor learning."

The results from this study present an exciting opportunity to test cerebellar tDCS as a rehabilitation tool. Dr. Bastian says, “If anodal tDCS prompts faster learning, this may help reduce the amount of time needed for stroke patients to relearn to walk evenly. It may also be possible to use tDCS to help sustain gains made in therapy, so patients can retain and practice improved walking patterns for a longer period of time. We are currently testing these ideas in individuals who have had a stroke.”

Provided by Kennedy Krieger Institute

Source: medicalxpress.com

ScienceDaily (May 31, 2012) — When flies are made to lose a gene with links to Restless Legs Syndrome (RLS), they suffer the same sleep disturbances and restlessness that human patients do. The findings reported online on May 31 in Current Biology, a Cell Press publication, strongly suggest a genetic basis for RLS, a condition in which patients complain of an irresistible urge to move that gets worse as they try to rest.

"Although widely prevalent, RLS is a disorder whose pathophysiological basis remains very poorly understood," said Subhabrata Sanyal of Emory University School of Medicine. "The major significance of our study is to highlight the fact that there might be a genetic basis for RLS. Understanding the function of these genes also helps to understand and diagnose the disease and may offer more focused therapeutic options that are currently limited to very general approaches."

Sanyal’s team recognized that a number of genome-wide association studies in humans had suggested connections between RLS and variation in a single gene (BTBD9).

"BTBD9 function or its relationship to RLS and sleep were a complete mystery," Sanyal said.

His team realized that there might be a way to shed some light on that mystery in fruit flies. Flies have a single, highly conserved version of the human BTBD9. They decided to test whether the gene that had turned up in those human studies would have any effect on sleep in the insects. In fact, flies need sleep just like humans do, and their sleep patterns are influenced by the same kinds of brain chemistry.

The researchers now report that flies lacking their version of the RLS-associated gene do lose sleep as they move more. When those flies were treated with a drug used for RLS, they showed improvements in their sleep.

The studies also yielded evidence about how the RLS gene works by controlling dopamine levels in the brain as well as iron balance in cells. Sanyal said his team will continue to explore other RLS-related genes that have been identified in human studies in search of more details of their interaction and function.

"Our results support the idea that genetic regulation of dopamine and iron metabolism constitute the core pathophysiology of at least some forms of RLS," the researchers write.

More broadly, they say, the study emphasizes the utility of simple animals such as fruit flies in unraveling the genetics of sleep and sleep disorders.

Source: Science Daily

ScienceDaily (May 31, 2012) — Rats with spinal cord injuries and severe paralysis are now walking (and running) thanks to researchers at EPFL. Published in the June 1, 2012 issue of Science, the results show that a severed section of the spinal cord can make a comeback when its own innate intelligence and regenerative capacity is awakened. The study, begun five years ago at the University of Zurich, points to a profound change in our understanding of the central nervous system. According to lead author Grégoire Courtine, it is yet unclear if similar rehabilitation techniques could work for humans, but the observed nerve growth hints at new methods for treating paralysis.

Test subject takes first steps up stairs after neurorehabilitation with a combination of robotic harness and electrical-chemical stimulation. (Credit: EPFL/Grégoire Courtine)

"After a couple of weeks of neurorehabilitation with a combination of a robotic harness and electrical-chemical stimulation, our rats are not only voluntarily initiating a walking gait, but they are soon sprinting, climbing up stairs and avoiding obstacles when stimulated," explains Courtine, who holds the International Paraplegic Foundation (IRP) Chair in Spinal Cord Repair at EPFL.

Waking up the spinal cord

It is well known that the brain and spinal cord can adapt and recover from moderate injury, a quality known as neuroplasticity. But until now the spinal cord expressed so little plasticity after severe injury that recovery was impossible. Courtine’s research proves that, under certain conditions, plasticity and recovery can take place in these severe cases — but only if the dormant spinal column is first woken up.

To do this, Courtine and his team injected a chemical solution of monoamine agonists into the rats. These chemicals trigger cell responses by binding to specific dopamine, adrenaline, and serotonin receptors located on the spinal neurons. This cocktail replaces neurotransmitters released by brainstem pathways in healthy subjects and acts to excite neurons and ready them to coordinate lower body movement when the time is right.

Five to 10 minutes after the injection, the scientists electrically stimulated the spinal cord with electrodes implanted in the outermost layer of the spinal canal, called the epidural space. “This localized epidural stimulation sends continuous electrical signals through nerve fibers to the chemically excited neurons that control leg movement. All that is left was to initiate that movement,” explains Rubia van den Brand, contributing author to the study.

The innate intelligence of the spinal column

In 2009, Courtine already reported on restoring movement, albeit involuntary. He discovered that a stimulated rat spinal column — physically isolated from the brain from the lesion down — developed in a surprising way: It started taking over the task of modulating leg movement, allowing previously paralyzed animals to walk over treadmills. These experiments revealed that the movement of the treadmill created sensory feedback that initiated walking — the innate intelligence of the spinal column took over, and walking essentially occurred without any input from the rat’s actual brain. This surprised the researchers and led them to believe that only a very weak signal from the brain was needed for the animals to initiate movement of their own volition.

To test this theory, Courtine replaced the treadmill with a device that vertically supported the subjects, a mechanical harness did not facilitate forward movement and only came into play when they lost balance, giving them the impression of having a healthy and working spinal column. This encouraged the rats to will themselves toward a chocolate reward on the other end of the platform. “What they deemed willpower-based training translated into a fourfold increase in nerve fibers throughout the brain and spine — a regrowth that proves the tremendous potential for neuroplasticity even after severe central nervous system injury,” says Janine Heutschi, co-author in the study.

First human rehabilitation on the horizon

Courtine calls this regrowth “new ontogeny,” a sort of duplication of an infant’s growth phase. The researchers found that the newly formed fibers bypassed the original spinal lesion and allowed signals from the brain to reach the electrochemically-awakened spine. And the signal was sufficiently strong to initiate movement over ground — without the treadmill — meaning the rats began to walk voluntarily towards the reward, entirely supporting their own weight with their hind legs.

"This is the world-cup of neurorehabilitation," exclaims Courtine. "Our rats have become athletes when just weeks before they were completely paralyzed. I am talking about 100% recuperation of voluntary movement."

In principle, the radical reaction of the rat spinal cord to treatment offers reason to believe that people with spinal cord injury will soon have some options on the horizon. Courtine is optimistic that human, phase-two trials will begin in a year or two at Balgrist University Hospital Spinal Cord Injury Centre in Zurich, Switzerland. Meanwhile, researchers at EPFL are coordinating a nine million Euro project called NeuWalk that aims at designing a fully operative spinal neuroprosthetic system, much like the one used here with rats, for implanting into humans.

Source: Science Daily

ScienceDaily (May 31, 2012) — The molecular structure of a protein involved in Alzheimer’s disease — and the surprising discovery that it binds cholesterol — could lead to new therapeutics for the disease, Vanderbilt University investigators report in the June 1 issue of the journal Science.

Vanderbilt Center for Structural Biology investigators determined the structure of the C99 protein (shown in green and blue), which participates in triggering Alzheimer’s disease. Their discovery that C99 binds to cholesterol (shown in black, white and red) suggests a mechanism for cholesterol’s recognized role in promoting the memory-robbing disease and may lead to new therapeutics. (Credit: Charles Sanders and colleagues/Vanderbilt University)

Charles Sanders, Ph.D., professor of Biochemistry, and colleagues in the Center for Structural Biology determined the structure of part of the amyloid precursor protein (APP) — the source of amyloid-beta, which is believed to trigger Alzheimer’s disease. Amyloid-beta clumps together into oligomers that kill neurons, causing dementia and memory loss. The amyloid-beta oligomers eventually form plaques in the brain — one of the hallmarks of the disease.

"Anything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer’s disease," Sanders said.

Amyloid-beta production requires two “cuts” of the APP protein. The first cut, by the enzyme beta-secretase, generates the C99 protein, which is then cut by gamma-secretase to release amyloid-beta. The Vanderbilt researchers used nuclear magnetic resonance and electron paragmagnetic resonance spectroscopy to determine the structure of C99, which has one membrane-spanning region.

They were surprised to discover what appeared to be a “binding” domain in the protein. Based on previously reported evidence that cholesterol promotes Alzheimer’s disease, they suspected that cholesterol might be the binding partner. The researchers used a model membrane system called “bicelles” (that Sanders developed as a postdoctoral fellow) to demonstrate that C99 binds cholesterol.

"It has long been thought that cholesterol somehow promotes Alzheimer’s disease, but the mechanisms haven’t been clear," Sanders said. "Cholesterol binding to APP and its C99 fragment is probably one of the ways it makes the disease more likely."

Sanders and his team propose that cholesterol binding moves APP to special regions of the cell membrane called “lipid rafts,” which contain “cliques of molecules that like to hang out together,” he said.

Beta- and gamma-secretase are part of the lipid raft clique.

"We think that when APP doesn’t have cholesterol around, it doesn’t care what part of the membrane it’s in," Sanders said. "But when it binds cholesterol, that drives it to lipid rafts, where these ‘bad’ secretases are waiting to clip it and produce amyloid-beta."

The findings suggest a new therapeutic strategy to reduce amyloid-beta production, he said.

"If you could develop a drug that blocks cholesterol from binding to APP, then you would keep the protein from going to lipid rafts. Instead it would be cleaved by alpha-secretase — a ‘good’ secretase that isn’t in rafts and doesn’t generate amyloid-beta."

Drugs that inhibit beta- or gamma-secretase — to directly limit amyloid-beta production — have been developed and tested, but they have toxic side effects. A drug that blocks cholesterol binding to APP may be more specific and effective in reducing amyloid-beta levels and in preventing, or treating, Alzheimer’s disease.

The C99 structure had some other interesting details, Sanders said.

The membrane domain of C99 is curved, which was unexpected but fits perfectly into the predicted active site of gamma-secretase. Also, a certain sequence of amino acids (GXXXG) that usually promotes membrane protein dimerization (two of the same proteins interacting with each other) turned out to be central to the cholesterol-binding domain. This is a completely new function for GXXXG motifs, Sanders said.

"This revealing new information on the structure of the amyloid precursor protein and its interaction with cholesterol is a perfect example of the power of team science," said Janna Wehrle, Ph.D., who oversees grants focused on the biophysical properties of proteins at the National Institutes of Health’s National Institute of General Medical Sciences (NIGMS), which partially funded the work. "The researchers at Vanderbilt brought together biological and medical insight, cutting-edge physical techniques and powerful instruments, each providing a valuable tool for piecing together the puzzle."

"When we were developing bicelles 20 years ago, no one was saying, ‘someday these things are going to lead to discoveries in Alzheimer’s disease,’" he said. "It was interesting basic science research that is now paying off."

Source: Science Daily

ScienceDaily (May 31, 2012) — Working memory training is unlikely to be an effective treatment for children suffering from disorders such as attention-deficit/hyperactivity or dyslexia, according to a research analysis published by the American Psychological Association. In addition, memory training tasks appear to have limited effect on healthy adults and children looking to do better in school or improve their cognitive skills.

"The success of working memory training programs is often based on the idea that you can train your brain to perform better, using repetitive memory trials, much like lifting weights builds muscle mass," said the study’s lead author, Monica Melby-Lervåg, PhD, of the University of Oslo. "However, this analysis shows that simply loading up the brain with training exercises will not lead to better performance outside of the tasks presented within these tests." The article was published online in Developmental Psychology.

Working memory enables people to complete tasks at hand by allowing the brain to retain pertinent information temporarily. Working memory enhancing tasks usually involve trying to get people to remember information presented to them while they are performing distracting activities. For example, participants may be presented with a series of numbers one at a time on a computer screen. The computer presents a new digit and then prompts participants to recall the number immediately preceding. More difficult versions might ask participants to recall what number appeared two, three or four digits ago.

In this meta-analysis, researchers from the University of Oslo and University College London examined 23 peer-reviewed studies with 30 different comparisons of groups that met their criteria. The studies were randomized controlled trials or experiments, had some sort of working memory treatment and a control group. The studies comprised a wide range of participants, including young children, children with cognitive impairments, such as ADHD, and healthy adults. Most of the studies had been published within the last 10 years.

Overall, working memory training improved performance on tasks related to the training itself but did not have an impact on more general cognitive performance such as verbal skills, attention, reading or arithmetic. “In other words, the training may help you improve your short-term memory when it’s related to the task implemented in training but it won’t improve reading difficulties or help you pay more attention in school,” said Melby-Lervåg.

In recent years, several commercial, computer-based working memory training programs have been developed and purport to benefit students suffering from ADHD, dyslexia, language disorders, poor academic performance or other issues. Some even claim to boost people’s IQs. These programs are widely used around the world in schools and clinics, and most involve tasks in which participants are given many memory tests that are designed to be challenging, the study said.

"In the light of such evidence, it seems very difficult to justify the use of working memory training programs in relation to the treatment of reading and language disorders," said Melby-Lervåg. "Our findings also cast strong doubt on claims that working memory training is effective in improving cognitive ability and scholastic attainment."

Source: Science Daily

ScienceDaily (May 31, 2012) — Summer vacation time is upon us. If you have been saving up for your dream vacation for years, you may want to make sure your dream spot is still the best place to go. A new study has found that when we fantasize about such trips before they are possible, we tend to overlook the negatives — thus influencing our decision-making down the line.

Summer vacation time is upon us. If you have been saving up for your dream vacation for years, you may want to make sure your dream spot is still the best place to go. A new study has found that when we fantasize about such trips before they are possible, we tend to overlook the negatives — thus influencing our decision-making down the line. (Credit: © XtravaganT / Fotolia)

"We were interested in the effects of positive fantasies — what happens when people imagine an idealized, best-case-scenario version of the future, compared to when they imagine a less idealized version," says Heather Barry Kappes of New York University, co-author of the study published online this week in Personality and Social Psychology Bulletin. “This is one of the first papers to examine selective information acquisition at this early stage, before people are seriously considering a possibility.”

Say, for example, that you would like to take a trip to Australia this year but think you are very unlikely to do so — you have no more vacation time left, cannot afford it, or would rather save up for a new car. But you still daydream about how nice it would be to see the Australian Outback and lie on the white sand beaches, perhaps without thinking about the long plane ride there or the poisonous animals. Those daydreams, Kappes says, have powerful effects.

To test those effects, Kappes and co-author Gabriele Oettingen asked people to imagine a particular future about one of three topics: wearing glamorous high-heeled shoes, making money in the stock market, or taking a vacation. To induce positive fantasies for each topic, the study participants were prompted to think about how great it would be to do each activity. In the control condition, participants also imagined experiencing the future, but were prompted to think about the negatives as well, with questions like “Would it really be so great?” In both conditions, participants wrote down what they were thinking, for the researchers to ensure they were engaged in the imagery.

After that exercise, the researchers offered the participants a choice of different types of information. For example, participants could browse a website describing the positive and negative health consequences of wearing high heels, and researchers noted how much more time they spent reading about positive versus negative consequences. Or, they could choose which of five (fictitious) tripadvisor.com reviews they wanted to read, and researchers recorded whether they chose one that was more pro-trip (i.e., five stars) or con-trip (i.e., one star).

Kappes’ team found that for each topic, imagining the idealized version made people prefer to learn about the pros rather than the cons of the future event. “These effects are pronounced when people are not seriously considering pursuing a given future,” Kappes says.

The work has important implications for even the most deliberate of decision-makers. “When people are seriously considering implementing a decision like taking a trip, they often engage in careful deliberations about the pros versus cons,” Kappes says. “Our work suggests that before getting to this point, positive fantasies might lead people to acquire biased information — to learn more about the pros rather than the cons. Thus, even if people deliberate very carefully on the information they’ve acquired, they could still make poor decisions.”

People need to be aware of these effects to ensure that they acquire balanced information before it is time to make a decision, she says. The study also contributes to a larger body of research about the powerful consequences of mental imagery — and shows that positive thinking may not always be best. “Although there are benefits to imagining a positive future, there are also drawbacks, and it’s important to recognize them in order to most effectively pursue our goals.”

Source: Science Daily

ScienceDaily (May 30, 2012) — New findings from the Monell Center reveal that humans can identify the age of other humans based on differences in body odor. Much of this ability is based on the capacity to identify odors of elderly individuals, and contrary to popular supposition, the so-called ‘old-person smell’ is rated as less intense and less unpleasant than body odors of middle-aged and young individuals.

Baby-smell. Humans can identify the age of other humans based on differences in body odor. (Credit: © S.Kobold / Fotolia)

"Similar to other animals, humans can extract signals from body odors that allow us to identify biological age, avoid sick individuals, pick a suitable partner, and distinguish kin from non-kin," said senior author Johan Lundström, a sensory neuroscientist at Monell.

Like non-human animals, human body odors contain a rich array of chemical components that can transmit various types of social information. The perceptual characteristics of these odors are reported to change across the lifespan, as are concentrations of the underlying chemicals.

Scientists theorize that age-related odors may help animals select suitable mates: older males might be desirable because they contribute genes that enable offspring to live longer, while older females might be avoided because their reproductive systems are more fragile.

In humans, a unique ‘old person smell’ is recognized across cultures. This phenomenon is so acknowledged in Japan that there is a special word to describe this odor, kareishū.

Because studies with non-human animals at Monell and other institutions have demonstrated the ability to identify age via body odor, Lundström’s team examined whether humans are able to do the same.

In the study, published in the journal PLoS ONE, body odors were collected from three age groups, with 12-16 individuals in each group: Young (20-30 years old), Middle-age (45-55), and Old-age (75-95). Each donor slept for five nights in unscented t-shirts containing underarm pads, which were then cut into quadrants and placed in glass jars.

Odors were assessed by 41 young (20-30 years old) evaluators, who were given two body odor glass jars in nine combinations and asked to identify which came from the older donors. Evaluators also rated the intensity and pleasantness of each odor. Finally evaluators were asked to estimate the donor’s age for each odor sample.

Evaluators were able to discriminate the three donor age categories based on odor cues. Statistical analyses revealed that odors from the old-age group were driving the ability to differentiate age. Interestingly, evaluators rated body odors from the old-age group as less intense and less unpleasant than odors from the other two age groups.

"Elderly people have a discernible underarm odor that younger people consider to be fairly neutral and not very unpleasant," said Lundström. "This was surprising given the popular conception of old age odor as disagreeable. However, it is possible that other sources of body odors, such as skin or breath, may have different qualities."

Future studies will both attempt to identify the underlying biomarkers that evaluators use to identify age-related odors and also determine how the brain is able to identify and evaluate this information.

Source: Science Daily

ScienceDaily (May 30, 2012) — Children today may be busier than ever, but Case Western Reserve University psychologists have found that their imagination hasn’t suffered — in fact, it appears to have increased.

Children today may be busier than ever, but Case Western Reserve University psychologists have found that their imagination hasn’t suffered — in fact, it appears to have increased. (Credit: © BeTa-Artworks / Fotolia)

Psychologists Jessica Dillon and Sandra Russ expected the opposite outcome when they analyzed 14 play studies that Russ conducted between 1985 and 2008.

But as they report in “Changes in Children’s Play Over Two Decades,” an article in the Creativity Research Journal, the data told a story contrary to common assumptions. First, children’s use of imagination in play and their overall comfort and engagement with play activities actually increased over time. In addition, the results suggested that children today expressed less negative feelings in play. Finally, their capacity to express a wide range of positive emotions, to tell stories and to organize thoughts stayed consistent.

Dillon, a fifth-year doctoral student, and Russ, a professor in psychological sciences at Case Western Reserve, decided to revisit the play data after a 2007 report from the American Academy of Pediatrics showed children played less.

They set out to see if having less time for unstructured play affected the processes in play that influence cognition and emotional development, a focus of the play research.

The pretend play studies focused on children between the ages of 6 and 10. The children’s play was measured for comfort, imagination, the range and amount of positive to negative emotions used and expressed, and the quality of storytelling by using Russ’ Affect in Play Scale (APS).

The APS is a five-minute, unstructured play session. Children are asked to play freely with three wooden blocks and two human hand puppets. The play is videotaped, and later reviewed and scored for imagination, expression of emotions, actions and storytelling.

Russ explains that children who exhibit good play skills with imaginative and emotional play situations have shown better skills at coping, creativity and problem solving. She stresses there is no link between being a good player and intelligence.

The APS data provided a consistent measurement and research structure over the 23-year period. Russ said the consistency of having the same tool to measure play provided this unique opportunity to track changes in play.

"We were surprised that outside of imagination and comfort, play was consistent over time," said Dillon.

Russ did voice concern about the decrease in displayed negative emotions and actions. “Past studies have linked negative emotions in play with creativity,” she said.

But even with the lack of time to play, Russ said, children, like some other forms of higher mammals, have a drive to play and always will find ways to do it.

As new stimuli, like video games and the Internet, have crept into everyday life, Russ explains that children might gain cognitive skills from using technology where they once got it from acting out situations in play. Skills might also develop from daydreaming.

Russ said future research will need to focus on whether acting out emotions and creating stories in play is as important as it once was in helping children to be creative.

Even though children have less time these days for play, Russ still advises giving children time for it, adding that it helps children develop emotional and cognitive abilities.

Video: Studying imagination in children’s play

Source: Science Daily

ScienceDaily (May 30, 2012) — In a new paper, the researchers describe a mathematical model they created that helps predict pragmatic reasoning and may eventually lead to the manufacture of machines that can better understand inference, context and social rules.

Noah Goodman, right, and Michael Frank, both assistant professors of psychology, discuss their research at the white board that covers the wall in Goodman’s office. (Credit: L.A. Cicero)

Language is so much more than a string of words. To understand what someone means, you need context.

Consider the phrase, “Man on first.” It doesn’t make much sense unless you’re at a baseball game. Or imagine a sign outside a children’s boutique that reads, “Baby sale — One week only!” You easily infer from the situation that the store isn’t selling babies but advertising bargains on gear for them.

Present these widely quoted scenarios to a computer, however, and there would likely be a communication breakdown. Computers aren’t very good at pragmatics — how language is used in social situations.

But a pair of Stanford psychologists has taken the first steps toward changing that.

In a new paper published recently in the journal Science, Assistant Professors Michael Frank and Noah Goodman describe a quantitative theory of pragmatics that promises to help open the door to more human-like computer systems, ones that use language as flexibly as we do.

The mathematical model they created helps predict pragmatic reasoning and may eventually lead to the manufacture of machines that can better understand inference, context and social rules. The work could help researchers understand language better and treat people with language disorders.

It also could make speaking to a computerized customer service attendant a little less frustrating.

"If you’ve ever called an airline, you know the computer voice recognizes words but it doesn’t necessarily understand what you mean," Frank said. "That’s the key feature of human language. In some sense it’s all about what the other person is trying to tell you, not what they’re actually saying."

Frank and Goodman’s work is part of a broader trend to try to understand language using mathematical tools. That trend has led to technologies like Siri, the iPhone’s speech recognition personal assistant.

But turning speech and language into numbers has its obstacles, mainly the difficulty of formalizing notions such as “common knowledge” or “informativeness.”

That is what Frank and Goodman sought to address.

The researchers enlisted 745 participants to take part in an online experiment. The participants saw a set of objects and were asked to bet which one was being referred to by a particular word.

For example, one group of participants saw a blue square, a blue circle and a red square. The question for that group was: Imagine you are talking to someone and you want to refer to the middle object. Which word would you use, “blue” or “circle”?

The other group was asked: Imagine someone is talking to you and uses the word “blue” to refer to one of these objects. Which object are they talking about?

"We modeled how a listener understands a speaker and how a speaker decides what to say," Goodman explained.

The results allowed Frank and Goodman to create a mathematical equation to predict human behavior and determine the likelihood of referring to a particular object.

"Before, you couldn’t take these informal theories of linguistics and put them into a computer. Now we’re starting to be able to do that," Goodman said.

The researchers are already applying the model to studies on hyperbole, sarcasm and other aspects of language.

"It will take years of work but the dream is of a computer that really is thinking about what you want and what you mean rather than just what you said," Frank said.

Source: Science Daily

ScienceDaily (May 30, 2012) — The same gene variations that make it difficult to stop smoking also increase the likelihood that heavy smokers will respond to nicotine-replacement therapy and drugs that thwart cravings, a new study shows.

High-risk genetic variations can increase the risk for nicotine dependence, but the same gene variants predict a more robust response to anti-smoking medications. (Credit: Li-Shiun Chen)

The research, led by investigators at Washington University School of Medicine in St. Louis, will appear online May 30 in the American Journal of Psychiatry.

The study suggests it may one day be possible to predict which patients are most likely to benefit from drug treatments for nicotine addiction.

"Smokers whose genetic makeup puts them at the greatest risk for heavy smoking, nicotine addiction and problems kicking the habit also appear to be the same people who respond most robustly to pharmacologic therapy for smoking cessation," says senior investigator Laura Jean Bierut, MD, professor of psychiatry. "Our research suggests that a person’s genetic makeup can help us better predict who is most likely to respond to drug therapy so we can make sure those individuals are treated with medication in addition to counseling or other interventions."

For the new study, the researchers analyzed data from more than 5,000 smokers who participated in community-based studies and more than 1,000 smokers in a clinical treatment study. The scientists focused on the relationship between their ability to quit smoking successfully and genetic variations that have been associated with risk for heavy smoking and nicotine dependence.

"People with the high-risk genetic markers smoked an average of two years longer than those without these high-risk genes, and they were less likely to quit smoking without medication," says first author Li-Shiun Chen, MD, assistant professor of psychiatry at Washington University. "The same gene variants can predict a person’s response to smoking-cessation medication, and those with the high-risk genes are more likely to respond to the medication."

In the clinical treatment trial, individuals with the high-risk variants were three times more likely to respond to drug therapy, such as nicotine gum, nicotine patches, the antidepressant buproprion and other drugs used to help people quit.

Tobacco use is the leading cause of preventable illness and death in the United States and a major public health problem worldwide. Cigarette smoking contributes to the deaths of an estimated 443,000 Americans each year. Although lung cancer is the leading cause of smoking-related cancer death among both men and women, tobacco also contributes to other lung problems, many other cancers and heart attacks.

Bierut and Chen say that the gene variations they studied are not the only ones involved in whether a person smokes, becomes addicted to nicotine or has difficulty quitting. But they contend that because the same genes can predict both heavy smoking and enhanced response to drug treatment, the genetic variants are important to the addiction puzzle.

"It’s almost like we have a ‘corner piece’ here," Bierut says. "It’s a key piece of the puzzle, and now we can build on it. Clearly these genes aren’t the entire story — other genes play a role, and environmental factors also are important. But we’ve identified a group that’s responding to pharmacologic treatment and a group that’s not responding, and that’s a key step in improving, and eventually tailoring, treatments to help people quit smoking."

Since people without the risky genetic variants aren’t as likely to respond to drugs, Bierut says they should get counseling or other non-drug therapies.

"This is an actionable genetic finding," Chen says. "Scientific journals publish genetic findings every day, but this one is actionable because treatment could be based on a person’s genetic makeup. I think this study is moving us closer to personalized medicine, which is where we want to go."

And Bierut says that although earlier studies suggested the genes had only a modest influence on smoking and addiction, the new clinical findings indicate the genetic variations are having a big effect on treatment response.

"These variants make a very modest contribution to the development of nicotine addiction, but they have a much greater effect on the response to treatment. That’s a huge finding," she says.

Source: Science Daily

ScienceDaily (May 30, 2012) — Changes to just three genetic letters among billions contributed to the evolution and development of the mammalian motor sensory circuits and laid the groundwork for the defining characteristics of the human brain, Yale University researchers report.

Illustration of neurons. Changes to just three genetic letters among billions contributed to the evolution and development of the mammalian motor sensory circuits and laid the groundwork for the defining characteristics of the human brain. (Credit: © nobeastsofierce / Fotolia)

In a study published in the May 31 issue of the journal Nature, Yale researchers found that a small, simple change in the mammalian genome was critical to the evolution of the corticospinal neural circuits. This circuitry directly connects the cerebral cortex, the conscious part of the human brain, with the brainstem and the spinal cord to make possible the fine, skilled movements necessary for functions such as tool use and speech. The evolutionary mechanisms that drive the formation of the corticospinal circuit, which is a mammalian-specific advance, had remained largely mysterious.

"What we found is a small genetic element that is part of the gene regulatory network directing neurons in the cerebral cortex to form the motor sensory circuits," said Nenad Sestan, professor of neurobiology, researcher for the Kavli Institute for Neuroscience, and senior author of the paper.

Most mammalian genomes contain approximately 22,000 protein-encoding genes. The critical drivers of evolution and development, however, are thought to reside in the non-coding portions of the genome that regulate when and where genes are active. These so-called cis-regulatory elements control the activation of genes that carry out the formation of basic body plans in all organisms.

Sungbo Shim, the first author, and other members of Sestan’s lab identified one such regulatory DNA region they named E4, which specifically drives the development of the corticospinal system by controlling the dynamic activity of a gene called Fezf2 — which, in turn, directs the formation of the corticospinal circuits. E4 is conserved in all mammals but divergent in other craniates, suggesting that it is important to both the emergence and survival of mammalian species. The species differences within E4 are tiny, but crucially drive the regulation of E4 activity by a group of regulatory proteins, or transcription factors, that include SOX4, SOX11, and SOX5. In cooperation, they control the dynamic activation and repression of E4 to shape the development of the corticospinal circuits in the developing embryo.

Source: Science Daily

ScienceDaily (May 30, 2012) — A new method for rapidly solving the three-dimensional structures of a special group of proteins, known as integral membrane proteins, may speed drug discovery by providing scientists with precise targets for new therapies, according to a paper published May 20 in Nature Methods.

Using their new rapid technique, Choe’s team generated the structure of a hIMP known as TMEM14A, shown here in multiple three-dimensional conformations. (Credit: Courtesy of the Salk Institute for Biological Studies)

The technique, developed by scientists at the Salk Institute for Biological Studies, provides a shortcut for determining the structure of human integral membrane proteins (hIMPs), molecules found on the surface of cells that serve as the targets for about half of all current drugs.

Knowing the exact three-dimensional shape of hIMPs allows drug developers to understand the precise biochemical mechanisms by which current drugs work and to develop new drugs that target the proteins.

"Our cells contain around 8,000 of these proteins, but structural biologists have known the three-dimensional structure of only 30 hIMPs reported by the entire field over many years," says Senyon Choe, a professor in Salk’s Structural Biology Laboratory and lead author on the paper. "We solved six more in a matter of months using this new technique. The very limited information on the shape of human membrane proteins hampers structure-driven drug design, but our method should help address this by dramatically increasing the library of known hIMP structures."

Integral membrane proteins are attached to the membrane surrounding each cell, serving as gateways for absorbing nutrients, hormones and drugs, removing waste products, and allowing cells to communicate with their environment. Many diseases, including Alzheimer’s, heart disease and cancer have been linked to malfunctioning hIMPs, and many drugs, ranging from aspirin to schizophrenia medications, target these proteins.

Most of the existing drugs were discovered through brute force methods that required screening thousands of potential molecules in laboratory studies to determine if they had a therapeutic effect. Given a blueprint of the 3D structure of a hIMP involved in a specific disease, however, drug developers could focus only on molecules that are most likely to interact with the target hIMP, saving time and expense.

In the past, it was extremely difficult to solve the structure of hIMPs, due to the difficulty of harvesting them from cells and the difficulty of labeling the amino acids that compose the proteins, a key step in determining their three-dimensional configuration.

"One problem was that hIMPs serve many functions in a cell, so if you tried to engineer cells with many copies of the proteins on their membrane, they would die before you could harvest the hIMPs," says Christian Klammt, a postdoctoral researcher in Choe’s lab and a first author on the paper.

To get around this, the scientists created an outside-the-cell environment, called cell-free expression system, to synthesize the proteins. They used a plexiglass chamber that contained all the biochemical elements necessary to manufacture hIMPs as if they were inside the cell. This system provided the researchers with enough of the proteins to conduct structural analysis.

The cell-free method also allowed them to easily add labeled amino acids into the biochemical stew, which were then incorporated into the proteins. These amino acids gave off telltale structural clues when analyzed with nuclear magnetic resonance spectroscopy, a method for using the magnetic properties of atoms to determine a molecule’s physical and chemical properties.

"It was very difficult and inefficient to introduce labeled amino acids selectively into the protein produced in live cells," says Innokentiy Maslennikov, a Salk staff scientist and co-first author on the paper. "With a cell-free system, we can precisely control what amino acids are available for protein production, giving us isotope-labeled hIMPs in large quantities. Using a proprietary labeling strategy we devised a means to minimize the number of samples to prepare."

Prior methods might take up to a year to determine a single protein structure, but using their new method, the Salk scientists determined the structure of six hIMPs within just 18 months. They have already identified 38 more hIMPs that are suitable for analysis with their technique, and expect it will be used to solve the structure for many more.

Source: Science Daily