Posts tagged brain

April 26, 2012 by Stuart Mason Dambrot

(Medical Xpress) — Remarkably, cortical maps show that neurons in the primary visual cortex have specific preferences for the location and orientation of a given visual field stimulus – but how these maps develop and what function they play in visual processing remains a mystery. Evidence suggests that the retinotopic map is established by molecular gradients, but little is known about how orientation maps are wired. One hypothesis: at their inception, these orientation maps are seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics. Recently, scientists in the Departments of Neurobiology and Psychology at the University of California, Los Angeles have shown that this proposed mechanism predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map, and have confirmed this prediction in the tree shrew primary visual cortex. The researchers say their findings support the idea that spatially structured retinal input may provide a blueprint of sorts for the early development of cortical maps and receptive fields – and that the same may hold true for other senses as well.

Moiré interference of retinal mosaics predicts a link between retinotopic and orientation maps. (A) (Upper) Two hexagonal lattices representing ON- (red) and OFF-center (blue) ganglion cell receptive fields/ (Lower) A cortical cell with input dominated by a dipole has a receptive field with side-by-side subregions of opposite sign and can be tuned for orientation. (B) (Upper) The orientation of dipoles in the interference pattern, indicated by the orientation of short line segments, changes over space, generating a blueprint for an orientation map. (Lower) The organization of orientation preferences around negative (Left) and positive (Right) singularities. Image Courtesy PNAS, doi: 10.1073/pnas.1118926109

Professor of Neurobiology and Psychology Dario L. Ringach articulates the primary elements of showing that the hypothesis that orientation maps are initially seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics corresponds to a mechanism that predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map. “The cerebral cortex of higher mammals contains diverse maps,” he tells Medical Xpress, “where information about sensory input or motor planning is laid out systematically across the surface of a given cortical area. Some scientists have postulated that these computational maps are key to cortical function. However, we still do not know exactly what role cortical maps play in normal sensory and motor processes.” Their importance, he stresses, is that understanding how cortical maps are wired during development, and what types of pathology may arise from their faulty wiring, are fundamental questions of brain function.

Ringach also notes that neurons in primary visual cortex are selective to the orientation of a stimulus in visual space, and their preference changes systematically across the cortical surface in a periodic fashion. “We know these maps are present at the earliest stages of life,” he continues, “and do not require normal sensory experience to develop – but how do they wire themselves? We’ve postulated that the initial structure of these maps is biased by the spatial organization of the periphery.” In the visual system this is represented by the signals the retina within the eye conveys to the brain.

The researchers’ model postulates that at each location in the visual field, the input from the retina constraints the range of orientation preferences that the cortex can implement at that location. “We show that, given what is known about the organization of retinal signals, that such constraints would be quasi-periodic, thereby potentially providing the blueprint for an orientation map in the cortex.” One prediction of this theory is that groups of neurons preferring the same orientation should be arranged on an approximate hexagonal lattice on the cortical surface – a prediction the researchers confirmed in a previous study¹. 

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April 26, 2012 by Larry Hardesty

In this week’s issue of the journal Neurology, researchers at MIT and two Boston hospitals provide early evidence that a simple, unobtrusive wrist sensor could gauge the severity of epileptic seizures as accurately as electroencephalograms (EEGs) do — but without the ungainly scalp electrodes and electrical leads. The device could make it possible to collect clinically useful data from epilepsy patients as they go about their daily lives, rather than requiring them to come to the hospital for observation. And if early results are borne out, it could even alert patients when their seizures are severe enough that they need to seek immediate medical attention.

Rosalind Picard, a professor of media arts and sciences at MIT, and her group originally designed the sensors to gauge the emotional states of children with autism, whose outward behavior can be at odds with what they’re feeling. The sensor measures the electrical conductance of the skin, an indicator of the state of the sympathetic nervous system, which controls the human fight-or-flight response.

In a study conducted at Children’s Hospital Boston, the research team — Picard, her student Ming-Zher Poh, neurologist Tobias Loddenkemper and four colleagues from MIT, Children’s Hospital and Brigham and Women’s Hospital — discovered that the higher a patient’s skin conductance during a seizure, the longer it took for the patient’s brain to resume the neural oscillations known as brain waves, which EEG measures.

At least one clinical study has shown a correlation between the duration of brain-wave suppression after seizures and the incidence of sudden unexplained death in epilepsy (SUDEP), a condition that claims thousands of lives each year in the United States alone. With SUDEP, death can occur hours after a seizure.

Currently, patients might use a range of criteria to determine whether a seizure is severe enough to warrant immediate medical attention. One of them is duration. But during the study at Children’s Hospital, Picard says, “what we found was that this severity measure had nothing to do with the length of the seizure.” Ultimately, data from wrist sensors could provide crucial information to patients deciding whether to roll over and go back to sleep or get to the emergency room.

Surprising signals

The realization that the wrist sensors might be of use in treating epilepsy was something of a fluke. “We’d been working with kids on the autism spectrum, and I didn’t realize, but a lot of them have seizures,” Picard says. In reviewing data from their autism studies, Picard and her group found that seizures were sometimes preceded by huge spikes in skin conductance. It seemed that their sensors might actually be able to predict the onset of seizures.

At the time, several MIT students were working in Picard’s lab through MIT’s Undergraduate Research Opportunities Program (UROP); one of them happened to be the daughter of Joseph Madsen, director of the Epilepsy Surgery Program at Children’s Hospital. “I decided it was time to meet my UROP’s dad,” Picard says.

In a project that would serve as the basis of Poh’s doctoral dissertation, Madsen agreed to let the MIT researchers test the sensors on patients with severe epilepsy, who were in the hospital for as much as a week of constant EEG monitoring. Poh and Picard considered several off-the-shelf sensors for the project, but “at the time, there was nothing we could buy that did what we needed,” Picard says. “Finally, we just built our own.”

"It’s a big challenge to make a device robust enough to withstand long hours of recording," Poh says. "We were recording days or weeks in a row." In early versions of the sensors, some fairly common gestures could produce false signals. Eliminating the sensors’ susceptibility to such sources of noise was largely a process of trial and error, Picard says.

Blending in

Additionally, Poh says, “I put a lot of thought into how to make it really comfortable and as nonintrusive as possible. So I packaged it all into typical sweatbands.” Since the patients in the study were children, “I allowed them to choose their favorite character on their wristband — for example, Superman, or Dora the Explorer, whatever they like,” Poh says. “To them, they were wearing a wristband. But there was a lot of complicated sensing going on inside the wristband.” Indeed, Picard says, the researchers actually lost five of their homemade sensors because hospital cleaning staff saw what they thought were ratty sweatbands lying around recently vacated rooms and simply threw them out.

Picard is continuing to investigate the possibility that initially intrigued her — that the devices could predict seizures. In the meantime, however, her collaborators at Children’s Hospital are conducting a study that will follow up on the one reported in Neurology, and a similar study is beginning at Brigham and Women’s Hospital. Rather than sweatbands with TV and comic-book characters, however, the new studies will use sensors produced by Affectiva, a company that Picard started in order to commercialize her lab’s work.

Provided by Massachusetts Institute of Technology 

Source: medicalxpress.com

April 26, 2012

(Medical Xpress) — The progression of the debilitating disease Multiple Sclerosis (MS) could be slowed or even halted by blocking a protein that contributes to nerve damage, according to a new study.

Professor Claude Bernard and Dr Steven Petratos

In research published today in the journal Brain, scientists from the Monash Immunology and Stem Cell Laboratories (MISCL), the University of Toronto, Yale and the University of Western Australia, have demonstrated the key role played by the collapsin response mediator protein 2 (CRMP-2) in the development of MS.

Led by MISCL’s Dr Steven Petratos, also of RMIT University, and Professor Claude Bernard, the research team found that a modified version of CRMP-2 is present in active MS lesions, which indicate damage to the nervous system, in a laboratory model of MS.

The modified CRMP-2 interacts with another protein to cause nerve fibre damage that can result in numbness, blindness, difficulties with speech and motor skills, and cognitive impairments in sufferers.

When either the modified CRMP-2 or the interaction between the two proteins was blocked, using a method already approved in both the US and Australia, the progression of the disease was halted.

Director of MISCL, Professor Richard Boyd said the discovery could lead to new treatments for MS.

“Blocking the same protein in people with MS could provide a ‘handbrake’ to the progression of the disease,” Professor Boyd said.

Dr Petratos said the method used to block the protein was approved for the treatment of other disease conditions by both the US Food and Drug Administration and Australia’s Therapeutic Goods Administration.

“This should mean that clinical trials – once they start – will be fast tracked as the form of administration has already been approved,” Dr Petratos said.

MS Australia estimates that the disease affects more than 20,000 people in Australia, and up to 2.5 million worldwide. The disease tends to strike early in adulthood, with women three times more likely than men to be diagnosed. The total cost to the Australian community of the disease is estimated at $1 billion annually.

The research received major funding from the National Multiple Sclerosis Society of the United States of America and partial funding from MS Research Australia.

Provided by Monash University

Source: medicalxpress.com

April 26, 2012

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a defect on chromosome four where, within the Huntingtin gene, a CAG repeat occurs too many times. Most individuals begin experiencing symptoms in their 40s or 50s, but studies have shown that significant brain atrophy occurs several years prior to an official HD diagnosis. As a result, the field has sought a preventive treatment that could be administered prior to the development of actual symptoms that might delay the onset of illness.

Using data from the ongoing PREDICT-HD study and led by Dr. Elizabeth Aylward, author and Associate Director at the Center for Integrative Brain Research, Seattle Children’s Research Institute, researchers examined whether neuroimaging measures can improve the accuracy of prediction of disease onset.

The PREDICT- HD study is an international, multi-site, long-term study of individuals who carry the gene mutation for Huntington disease but entered the study prior to onset of diagnosable motor impairment. Participants underwent structural magnetic resonance imaging (MRI) scans, which allowed for the comparison of individuals who developed HD during the course of the study and those who had not yet been diagnosed with HD.

They found that striatum and white matter volumes in the brain were significantly smaller in individuals diagnosed 1 to 4 years following the initial scan, suggesting that these volumetric measures can assist in determining which individuals are closest to disease onset.

"We believe that the results of this study will be important in designing future clinical trials for individuals who have the Huntington disease gene mutation, but who are not yet showing symptoms. We also believe this group of individuals is well suited for drug intervention studies, as their brain involvement is not as severe as those who have already been diagnosed," said Dr. Aylward.

"Huntington disease can be considered a model neuropsychiatric disorder, since it is caused by a single gene and has such predictable and well-characterized brain changes. It may guide thinking about other disorders with genetic contribution, such as schizophrenia," commented Dr. Christopher A. Ross, co-author and Professor of Psychiatry, Neurology and Neuroscience, Johns Hopkins University. "If we could better understand the natural history of brain changes in schizophrenia, for instance, we may be able to identify genetically vulnerable individuals, and intervene therapeutically, not just to treat symptoms, but to alter the biology and course of the disease."

Dr. John Krystal, Editor of Biological Psychiatry, agreed, noting that “biomarkers of illness progress are critical for all neuropsychiatric disorders.”

For now, these results may enhance the formulas used to calculate age of onset and help aid in the planning of future clinical trials aimed at delaying disease onset.

"Identifying individuals who are close to onset of diagnosable symptoms will allow feasible studies that use onset of symptoms as the primary outcome measure to determine if a drug intervention is effective," Dr. Aylward added. "Although it would be unreasonable to suggest that all potential clinical trial participants receive MRI scans one to four years prior to taking part in a trial, there are many individuals who have participated in pre-HD observational studies who already have such data available."

Perhaps more importantly, Dr. Krystal concluded that “the development of good disease staging using MRI in Huntington disease could assist investigators studying novel treatments and affected individuals and family members anxious to learn about disease progress.”

Provided by Elsevier

Source: medicalxpress.com

ScienceDaily (Apr. 26, 2012) — A team led by psychology professor Ian Spence at the University of Toronto reveals that playing an action videogame, even for a relatively short time, causes differences in brain activity and improvements in visual attention.

Playing an action videogame, even for a relatively short time, causes differences in brain activity and improvements in visual attention. (Credit: © j0yce / Fotolia)

Previous studies have found differences in brain activity between action videogame players and non-players, but these could have been attributed to pre-existing differences in the brains of those predisposed to playing videogames and those who avoid them. This is the first time research has attributed these differences directly to playing video games.

Twenty-five subjects — who had not previously played videogames — played a game for a total of 10 hours in one to two hour sessions. Sixteen of the subjects played a first-person shooter game and, as a control, nine subjects played a three-dimensional puzzle game.

Before and after playing the games, the subjects’ brain waves were recorded while they tried to detect a target object among other distractions over a wide visual field. Subjects who played the shooter videogame and also showed the greatest improvement on the visual attention task showed significant changes in their brain waves. The remaining subjects — including those who had played the puzzle game — did not.

"After playing the shooter game, the changes in electrical activity were consistent with brain processes that enhance visual attention and suppress distracting information," said Sijing Wu, a PhD student in Spence’s lab in U of T’s Department of Psychology and lead author of the study.

"Studies in different labs, including here at the University of Toronto, have shown that action videogames can improve selective visual attention, such as the ability to quickly detect and identify a target in a cluttered background," said Spence. "But nobody has previously demonstrated that there are differences in brain activity which are a direct result of playing the videogame."

"Superior visual attention is crucial in many important everyday activities," added Spence. "It’s necessary for things such as driving a car, monitoring changes on a computer display, or even avoiding tripping while walking through a room with children’s toys scattered on the floor."

Source: Science Daily

April 25th, 2012

National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say.

GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance, according to the researchers.

“Our findings suggest a strategy for developing a single treatment that could target multiple diagnostic symptoms,” explained Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). “Many cases of autism are caused by mutations in genes that control an ongoing process – the formation and maturation of synapses, the connections between neurons. If defects in these connections are not hard-wired, the core symptoms of autism may be treatable with medications.”

Crawley, Jill Silverman, Ph.D., and colleagues at NIMH and Pfizer Worldwide Research and Development, Groton, CT, report on their discovery April 25th, 2012 in the journal Science Translational Medicine.

“These new results in mice support NIMH-funded research in humans to create treatments for the core symptoms of autism,” said NIMH director Thomas R. Insel, M.D. “While autism has been often considered only as a disability in need of rehabilitation, we can now address autism as a disorder responding to biomedical treatments.”

(Video: Agent Reduces Repetitive Behavior in Mice)
Autism-like behaviors in mice have been reduced, using an experimental agent being tested in patients for a related disorder. Here, a mouse is absorbed in repetitive self-grooming. The experimental agent reduced this repetitive behavior in a strain of mice that is prone to it, and almost stopped repetitive vertical jumping in another strain of mice. Credit: MuYang, Ph.D., Adam Katz, and Jacqueline Crawley, Ph.D., NIMH Laboratory of Behavioral Neuroscience. 

Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs.

To test their hunch, the researchers examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves.

Crawley’s team found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-to-nose with – a strange mouse.

(Video: Agent Boosts Sociability in Mice)
Autism-like behaviors in mice have been reduced, using an experimental agent being tested in patients for a related disorder. Here, a mouse pays a social visit to a strange animal. The experimental agent increased such sociability, which is impaired in autism. Credit: MuYang, Ph.D., and Jacqueline Crawley, Ph.D., NIMH Laboratory of Behavioral Neuroscience.

Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice.

“These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.” 

Source: Neuroscience News  

ScienceDaily (Apr. 25, 2012) — New research from UC Davis and Washington State University shows that PCBs, or polychlorinated biphenyls, launch a cellular chain of events that leads to an overabundance of dendrites — the filament-like projections that conduct electrochemical signals between neurons — and disrupts normal patterns of neuronal connections in the brain.

New findings underscore the developing brain’s vulnerability to environmental exposures and demonstrate how PCBs could add to autism risk. (Credit: © yalayama / Fotolia)

"Dendrite growth and branching during early development is a finely orchestrated process, and the presence of certain PCBs confuses the conductor of that process," said Pamela Lein, a developmental neurobiologist and professor of molecular biosciences in the UC Davis School of Veterinary Medicine. "Impaired neuronal connectivity is a common feature of a number of conditions, including autism spectrum disorders."

Reported April 24 in two related studies in the journal Environmental Health Perspectives, the findings underscore the developing brain’s vulnerability to environmental exposures and demonstrate how PCBs could add to autism risk.

"We don’t think PCB exposure causes autism," Lein said, "but it may increase the likelihood of autism in children whose genetic makeup already compromises the processes by which neurons form connections."

The senior authors of the studies were Lein and Isaac Pessah, chair of molecular biosciences in the School of Veterinary Medicine and director of the Center for Children’s Environmental Health at UC Davis. Both are researchers with the UC Davis MIND Institute, which is dedicated to finding answers to autism and other neurodevelopmental disorders. The lead author was Gary Wayman of Washington State University’s Program in Neuroscience, who first described the molecular pathway that controls the calcium signaling in the brain that guides normal dendrite growth.

Wayman found that key cellular players, called calcium and calmodulin kinases, are activated by increased calcium levels. Activated calmodulin kinase then turns on the protein known as CREB that regulates genes that produce Wnt2, a potent molecule and the final arbiter of whether and how dendrites grow. Wnt2 directs structural proteins to construct scaffolding that supports dendrite growth and branching.

"Orderly choreography of the calmodulin kinase-to-Wnt2 pathway translates normal increases in calcium levels into normal levels of dendrite production," said Wayman. "The wiring of billions of neurons is dependent on the health of this cellular process and is crucial to proper development of virtually all complex behaviors, learning, memories and language."

For the current studies, the team set out to determine if that pathway was altered by exposure to PCBs, focusing on neurons of the hippocampus — the brain region linked with learning and memory and known to suffer impaired connectivity in many neurodevelopmental disorders.

The scientists also focused on the effects of an understudied PCB subset known as non-dioxin-like PCBs, which have been shown to increase calcium levels in neurons. Both non-dioxin-like PCBs and the more familiar dioxin-like subset were widely used in electrical equipment in the 1950s and 1960s. Banned in the 1970s because of the potential for dioxin-like PCBs to cause cancer, all PCBs are stable compounds that persist throughout the environment today.

One of the current UC Davis studies examined dendrite growth in rat pups born to and nursed by PCB-exposed mothers. Another study analyzed how PCBs affect rat neurons in cell cultures at developmental stages similar to those in the third trimester of pregnancy in humans. In both studies, PCB exposure levels were similar to those found in the human diet and in human tissues, including the placenta and breast milk.

Evaluation of the brains of the rats exposed to PCBs early in life showed significant overproduction of dendrites. The cellular studies showed that PCBs triggered the calcium pathway that led to the aberrant brain architecture, and that dendrite production was normal when that cellular pathway was blocked.

"We are the first to show that non-dioxin-like PCBs alter how the developing brain gets wired by hijacking the calcium signaling pathway and greatly expanding dendrite growth," said Lein.

The experiments also helped identify for the first time the specific trigger for this cellular chain of events as the ryanodine receptor (RyR) calcium channel. Pessah, a recognized leader in calcium-channel dysfunction and neurodevelopment, previously showed that RyR is selectively activated by non-dioxin-like PCBs. The new studies prove that RyR is a necessary component in the pathway that controls dendritic growth.

"These same calcium pathways are implicated in some forms of autism and, while environmental exposures alone do not cause autism, these new findings provide good evidence that PCBs could add to autism risk in genetically predisposed children," said Pessah. "Understanding the fundamental mechanisms by which PCBs alter neural networks sets the stage for research on environmental contaminants that are structurally related to PCBs, including flame retardants, and their risks to susceptible populations."

Source: Science Daily

April 25th, 2012

Second U-M stem cell line now publicly available to help researchers find treatments for nerve condition.
Charcot-Marie-Tooth disease line made from a never-frozen donated embryo.

The University of Michigan’s second human embryonic stem cell line has just been placed on the U.S. National Institutes of Health’s registry, making the cells available for federally-funded research. It is the second of the stem cell lines derived at U-M to be placed on the registry.

The line, known as UM11-1PGD, was derived from a cluster of about 30 cells removed from a donated five-day-old embryo roughly the size of the period at the end of this sentence. That embryo was created for reproductive purposes, tested and found to be affected with a genetic disorder, deemed not suitable for implantation, and would therefore have otherwise been discarded when it was donated in 2011.

It carries the gene defect responsible for Charcot-Marie-Tooth disease, a hereditary neurological disorder characterized by a slowly progressive degeneration of the muscles in the foot, lower leg and hand. CMT, as it is known, is one of the most common inherited neurological disorders, affecting one in 2,500 people in the United States. People with CMT usually begin to experience symptoms in adolescence or early adulthood.

The embryo used to create the cell line was never frozen, but rather was transported from another IVF laboratory in the state of Michigan to the U-M in a special container. This may mean that these stem cells will have unique characteristics and utilities in understanding CMT disease progression or screening therapies in comparison to other human embryonic stem cells.

“We are proud to provide this cell line to the scientific community, in hopes that it may aid the search for new treatments and even a cure for CMT,” says Gary Smith, Ph.D., who derived the line and also is co-director of the U-M Consortium for Stem Cell Therapies, part of the A. Alfred Taubman Medical Research Institute. “Once again, the acceptance of these cells to the registry demonstrates our attention to details of proper oversight, consenting, and following of NIH guidelines.”

U-M is one of only four institutions – including two other universities and one private company – to have disease-specific stem cell lines listed in the national registry. U-M has several other disease-specific hESC lines submitted to NIH and awaiting approval, says Smith, who is a professor in the Department of Obstetrics and Gynecology at the University of Michigan Medical School. The first line, a genetically normal one, was accepted to the registry in February.

“Stem cell lines that carry genetic traits linked to specific diseases are a model system to investigate what causes these diseases and come up with treatments,” says Sue O’Shea, Ph.D., professor of Cell and Developmental Biology at the U-M Medical School, and co-director of the Consortium for Stem Cell Therapies.

Each line is the culmination of years of preparation and cooperation between U-M and Genesis Genetics, a Michigan-based genetic diagnostic company. This work was made possible by Michigan voters’ November 2008 approval of a state constitutional amendment permitting scientists to derive embryonic stem cell lines using surplus embryos from fertility clinics or embryos with genetic abnormalities and not suitable for implantation.

The amendment also made possible an unusual collaboration that has blossomed between the University of Michigan and molecular research scientists at Genesis Genetics, a company that has grown in only eight years to become the leading global provider of pre-implantation genetic diagnosis (PGD) testing. PGD is a testing method used to identify days-old embryos carrying the genetic mutations responsible for serious inherited diseases. During a PGD test, a single cell is removed from an eight-celled embryo. The other seven cells continue to multiply and on the fifth day form a cluster of roughly 100 cells known as a blastocyst.

Genesis Genetics performs nearly 7,500 PGD tests annually. Under the arrangement between the company and U-M, patients with embryos that test positive for a genetic disease now have the option of donating those embryos to U-M if they have decided not to use them for reproductive purposes and the embryos would otherwise be discarded.

The agreement was worked out between U-M’s Smith and Mark Hughes, M.D., Ph.D., founder and president of Genesis Genetics and a pioneer in the field of pre-implantation genetic diagnosis. “These are very precious cells, and it would be unconscionable not to take advantage of such an opportunity for medical science and the cure of disease,” Hughes says.

“This is another major step forward for medical science in Michigan. It opens up another avenue for researchers to really begin exploring the causes and progression of those diseases, with the ultimate goal of finding new therapies for patients,” says Eva Feldman, M.D., Ph.D., F.A.A.N., director of the A. Alfred Taubman Medical Research Institute and the Russell N. DeJong professor of neurology at the U-M Medical School. Feldman sees patients with CMT as part of her clinical practice.

Contributors to the A. Alfred Taubman Medical Research Institute’s Consortium for Stem Cell Therapies include the Taubman Institute; the Office of the Executive Vice President for Medical Affairs; the Office of the Medical School Dean; the Comprehensive Cancer Center; the Department of Pediatrics and Communicable Diseases; the Office of the Vice President for Research; the School of Dentistry; the Department of Pathology; the Department of Cell and Developmental Biology; the College of Engineering; the Life Sciences Institute; the Department of Neurology; and U-M’s Michigan Institute for Clinical and Health Research.

A. Alfred Taubman, founder and chair of U-M’s Taubman Institute, called the second registry placement a tremendous step for stem cell research. “I consider stem cells to be a modern medical miracle – the most exciting advance in medicine since antibiotics. The progress we have made throughout the state in stem cell research has been nothing short of remarkable,” he says.

“This new milestone means much to the University and the state of Michigan, but also to the world. It offers another route for researchers to move ahead in studying these horrible diseases. We hope it is the first of many lines that we can contribute to the global efforts to improve human health.”

Written by Kara Gavin

Source: Neuroscience News

ScienceDaily (Apr. 25, 2012) — University of California, San Diego scientists have used powerful computational tools and laboratory tests to discover new support for a once-marginalized theory about the underlying cause of Parkinson’s disease.

This image shows a construction of a possible ring oligomer position in the cell membrane after four nanoseconds of molecular dynamics simulations. Image courtesy of Igor Tsigelny, San Diego Supercomputer Center and Department of Neurosciences, UC San Diego. (Credit: Image courtesy of University of California, San Diego)

The new results conflict with an older theory that insoluble intracellular fibrils called amyloids cause Parkinson’s disease and other neurodegenerative diseases. Instead, the new findings provide a step-by-step explanation of how a “protein-run-amok” aggregates within the membranes of neurons and punctures holes in them to cause the symptoms of Parkinson’s disease.

The discovery, published in the March 2012 issue of the FEBS Journal, describes how α-synuclein (a-syn), can turn against us, particularly as we age. Modeling results explain how α-syn monomers penetrate cell membranes, become coiled and aggregate in a matter of nanoseconds into dangerous ring structures that spell trouble for neurons.

"The main point is that we think we can create drugs to give us an anti-Parkinson’s effect by slowing the formation and growth of these ring structures," said Igor Tsigelny, lead author of the study and a research scientist at the San Diego Supercomputer Center and Department of Neurosciences, both at UC San Diego.

Familial Parkinson’s disease is caused in many cases by a limited number of protein mutations. One of the most toxic is A53T. Tsigelny’s team showed that the mutant form of α-syn not only penetrates neuronal membranes faster than normal α-syn, but the mutant protein also accelerates ring formation.

"The most dangerous assault on the neurons of Parkinson’s patients appears to be the relatively small α-syn ring structures themselves," said Tsigelny. "It was once heretical to suggest that these ring structures, rather than long fibrils found in neurons of people having Parkinson’s disease, were responsible for the symptoms of the disease; however, the ring theory is becoming more and more accepted for this neurodegenerative disease and others such as Alzheimer’s disease. Our results support this shift in thinking."

The modeling results also are consistent with the electron microscopy images of neurons in Parkinson’s disease patients; the damaged neurons are riddled with ring structures.

Wasting no time, the modeling discoveries have spawned an intense hunt at UC San Diego for drug candidates that block ring formation in neuron membranes. The sophisticated modeling required involves a complex realm of science at the intersection of chemistry, physics, and statistical probabilities. A kaleidoscope of interacting forces in this realm makes α-syn proteins bump and tremble like they’re in an earthquake, coil and uncoil, and join together in pairs or larger groups of inventive ballroom dancers.

The modeling is creating a much better understanding of the mysterious a-syn protein itself, according to Tsigelny. A few years ago it was shown to accumulate in the central nervous system of patients with Parkinson’s disease and a related disorder called dementia with Lewy bodies.

The new modeling study has revealed precisely how two α-syn proteins insert their molecular toes into the membrane of a neuron, wiggle into it in only a few nanoseconds and immediately join together as a pair. The pair isn’t itself toxic; however, when more α-syn proteins join the dance, a key threshold is eventually crossed; polymerization accelerates into a ring structure that perforates the membrane, damaging the cell.

Tsigelny said many ring structures may be required to actually kill neurons, which are known for their durability. The nerve cells may be able to repair dozens of ring-induced perforations, keeping pace with a-syn assault. But at some point, the rate of perforations surpasses the ability of neurons to repair them. As a result, symptoms of Parkinson’s disease gradually appear and worsen.

"We think we can create a drug that stops the α-syn polymerization at the point of non-propagating dimers," Tsigelny said. "By interrupting the polymerization at this crucial step, we may be able to slow the disease significantly."

Tsigelny’s research team included Yuriy Sharikov, with SDSC and UC San Diego’s Department of Neurosciences; Wolfgang Wrasidlo, with the university’s Moores Cancer Center; and Tania Gonzalez, Paula A. Desplats, Leslie Crews, and Brian Spencer, all with UC San Diego’s Department of Neurosciences. The experimental validation studies were performed by Eliezer Masliah, a professor in the UC San Diego departments of Neurosciences and Pathology, and his associates. They relied on 3-D models of proteins, plus molecular dynamics simulations of the proteins, other modeling techniques and cell-culture experiments.

Given their deeper understanding of α-syn polymerization in neurons, they are now focused on understanding how monomers of α-syn stick to one another. Their search for drug candidates will include molecules that induce different conformations of α-syn proteins that are less inclined to stick together. Tsigelny said this effect, even if small, could reduce symptoms.

This computationally intensive approach includes an examination of the many possible three-dimensional arrangements of α-syn dimers, trimmers and tetramers. Pharmaceutical companies have used versions of the approach to develop drug candidates designed to bind to ‘anchor residues’ or ‘hot spots’ within target proteins. Algorithms assess in virtual experiments the theoretical ability of thousands of candidate drugs to bind to human proteins in the ever-expanding database of known 3-D structures of those proteins.

However, attempts to find drugs this way have generated promising candidates that fail in clinical trials with expensive regularity.

"Out of these failures we’ve come to appreciate that proteins change their shapes so often that what would appear to be a primary drug target may be present one nanosecond, gone the next, or it wasn’t relevant in the first place," said Tsigelny, a physicist-turned-drug-designer.

Tsigelny’s approach takes advantage of classical drug-discovery algorithms, but adds additional analytical techniques to expand the search to include how a target protein’s conformations change in response to the forces operating on the scale of molecules.

"Sometimes, the drug-discovery models, despite being ‘nice looking,’ can be completely wrong," Tsigelny said. "Scientists involved in drug discovery need to know when and to what extent to trust them. Even a slight shift in a cell’s environment can profoundly change the interactions of proteins with neighboring molecules. We think it’s realistically possible to design a drug to treat neurodegenerative diseases such as Parkinson’s disease and other diseases like diabetes with a more fundamental understanding of the proteins involved in those diseases."

Source: Science Daily

ScienceDaily (Apr. 25, 2012) — Advertisers and public health officials may be able to access hidden wisdom in the brain to more effectively sell their products and promote health and safety, UCLA neuroscientists report in the first study to use brain data to predict how large populations will respond to advertisements.

The brain, with the medial prefrontal cortex highlighted in green. (Credit: Image courtesy of University of California - Los Angeles)

Thirty smokers who were trying to quit watched television commercials from three advertising campaigns, which all ended by showing the phone number of the National Cancer Institute’s smoking-cessation hotline. They were asked which commercials they thought would be most effective; they responded that advertising campaigns “A” and “B” would be the best and “C” would be the worst.

The UCLA researchers also consulted experts who work in the anti-smoking field and who have been involved in creating anti-smoking advertisements. These experts agreed that campaigns “A” and “B” were the best and “C” was the worst.

While the smokers watched the advertisements, they underwent functional magnetic resonance imaging (fMRI) brain scans at UCLA’s Ahmanson-Lovelace Brain Mapping Center, and the neuroscientists focused on part of the medial prefrontal cortex — located in the front of the brain, between the eyebrows — a region that they have found to be especially important in previous persuasion studies.

The researchers found that activity in the medial prefrontal cortex increased much more during advertising campaign “C” than it did during campaign “A,” and somewhat more than it did during campaign “B.”

"The medial prefrontal cortex predicted ‘C’ would be the best, ‘B’ would be second best and ‘A’ would be the worst — essentially the opposite of what the experts and the participants told us they thought would happen," said the study’s senior author, Matthew Lieberman, a UCLA professor of psychology and of psychiatry and biobehavioral sciences.

"We didn’t expect how radically different people’s predictions would be from the predictions we made based on their brain activity," said Lieberman, one of the founders of social cognitive neuroscience. "We had people telling us one thing and this brain region telling us something diametrically opposed."

Initially, Lieberman and first author Emily Falk, an assistant professor of communication studies and psychology at the University of Michigan-Ann Arbor, were concerned when they saw the results from the medial prefrontal cortex.

"We were hoping the brain data would add something to the self-reports of our participants," Lieberman said. "Given how different they were from one another, we were afraid our brain data might not end up predicting the real-world outcomes at all."

A few months later, after the advertisements had been broadcast, the authors received the call-volume data from the National Cancer Institute’s 1-800-QUIT-NOW hotline. They compared the number of people who called the hotline the month before and the month after each of the advertising campaigns was run. All three advertising campaigns were successful in increasing the number of phone calls to the hotline. Campaign “A” more than doubled the number of calls, “B” increased the number of calls more than ten-fold and “C” boosted the number of calls a remarkable thirty-fold. (The advertisements were shown in Michigan, Massachusetts and Louisiana.)

Activity in the medial prefrontal cortex predicted which ads persuaded more people to call the hotline significantly better than the smokers’ own thoughts about how successful the ads would be.

The research is published this month in the online edition of the journal Psychological Science.

What are the implications for the advertising industry, which often relies, at least partly, on unscientific focus groups?

"If people are making decisions based on what focus groups tell them, here’s an important brain region saying, ‘No, spend your money a different way,’" Lieberman said. "If I were deciding on an advertising campaign, I would want to know which ads are activating this region the most — that is where I would want to spend my money."

This new research represents “the first thing you could call a neural focus group,” Lieberman said.

One reason focus groups can be misleading, he said, is that people often do not know what motivates their own behavior.

"Our brain is built to generate reasons for our actions," Lieberman said, "and we think the reasons we come up with must be true. We believe our own reasons with an intensity that is out of proportion to their accuracy. In this study, we are bypassing people’s self-reports and getting at a form of hidden wisdom in the brain.

"We wanted to determine what kind of brain activity serves as the catalyst between people seeing a message and whether they actually change their behavior," he said. "This is the region we identified. We have tested it multiple times, and each time, it has been successful."

John Wanamaker, a 19th-century U.S. department store pioneer, famously said he wasted half the money he spent on advertising, but “the trouble is I don’t know which half.” Many people since Wanamaker have hoped to predict which advertising campaigns will succeed or fail before committing their advertising dollars.

"We’re too late for Wanamaker, but now we have a method for figuring out which ads will succeed," Lieberman said.

The 30 smokers in the study were between the ages of 28 and 69; half were female.

Brain regions associated with thinking analytically have not been consistently associated with whether people change their behavior in these studies, Lieberman said. The medial prefrontal cortex is associated not with analytical thinking but with self-reflection — thinking about our own identity as well as what we like and do not like.

"Persuasive advertising seems to be about getting to people’s hearts and their identity," Lieberman said. "We are just at the beginning of this line of research. There are many more questions than answers, but the initial results have been promising."

In research Lieberman and Falk published in the Journal of Neuroscience in 2010, greater activity in the same medial prefrontal region was predictive of who would increase their sunscreen usage after seeing persuasive messages about daily sunscreen use.

"We knew from prior studies that this brain region predicted people’s behavior change in response to a persuasive message," Lieberman said.

With the new study, Lieberman and his colleagues wanted to know whether they could predict not only people’s own behavior but use these brain responses to predict how effective advertisements would be throughout the country.

Source: Science Daily