Posts tagged brain

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

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.

Read more …

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

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