Researchers explore links between learning disorders in children

New interdisciplinary research from Western University has uncovered fundamental links among three major learning difficulties in some school-age children.

Although many children have specific problems with dyslexia, specific language impairment and dyscalculia, this study is the first to show a significant portion of these children have overlapping deficits.

Importantly, the research team has also devised a 10-minute screening test that could be administered broadly in primary schools to identify children at risk for the different disorders.

The collaborative project includes findings from four researchers at Western's Brain and Mind Institute (BMI) and the Faculty of Health Sciences that independently specialize in the three key developmental disorders.

Dyslexia is a deficit in the development of reading while specific language impairment is a disorder related to poor development of spoken language skills. Dyscalculia is a severe difficulty in making mathematical calculations.

Past research in these disorders has focused on each of these as single impairments, despite the widespread recognition that they commonly overlap.

For a study published in the journal PLOS ONE, Lisa Archibald and Janis Oram Cardy from the Faculty of Health Sciences' School of Communication Sciences and Disorders and Marc Joanisse and Daniel Ansari from BMI collaborated across disciplines and examined – for the first time ever – the co-occurrence of difficulties in reading, spoken language, and mathematical calculations in a large sample of school-age children.

In the study, researchers tested learning profiles of a large sample of school children aged 4 to 10-years old in the region of London, Ontario.

The research team found that although some of the children showed specific deficits in reading, spoken language, or math, a significant number of children exhibited a mixed profile of a reading plus a math deficit, or an even wider-ranging weakness spanning math, reading, and spoken language.

"This is the first time researchers have looked at possible learning difficulties in different areas in a large sample of the same kids," says Archibald, the PLOS One paper's lead author.

"It's an important first step in trying to understand the large variability that is commonly reported for groups with learning disabilities."

The study has also uncovered some essential hints as to why different learning patterns might occur in different children.

For instance, children who showed weaknesses on all three types of abilities also scored very low on a working memory assessment.

NB: Working memory is the ability to hold multiple pieces of information in mind and perform simple operations on them, such as repeating a sequence of digits in the reverse order in which they were presented. 

According to the findings, such children may require a more targeted approach to remediation, due to the complex nature of their difficulties.

Children who have more specific deficits did not show the same difficulty with working memory and would require quite different interventions.

"Educators face significant challenges in identifying learning problems in children. With additional testing, we hope that a new tool that we have developed will someday provide educators with a quick and effective method for identifying which children need extra help, but also a way to develop more individualized remediation programs," says Joanisse.

More information: Original Article: Archibald LMD, Oram Cardy J, Joanisse MF, Ansari D (2013) Language, Reading, and Math Learning Profiles in an Epidemiological Sample of School Age Children. PLoS ONE 8(10): e77463. DOI: 10.1371/journal.pone.0077463

Researchers ferret out function of autism gene

The structure of the protein NHE9 is one piece of the puzzle of what causes autism. 

Credit: Kalyan Kondapalli and Rajini Rao

Researchers say it's clear that some cases of autism are hereditary, but have struggled to draw direct links between the condition and particular genes.

Now a team at the Johns Hopkins University School of Medicine, Tel Aviv University and Technion-Israel Institute of Technology has devised a process for connecting a suspect gene to its function in autism.

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

"Autism is considered one of the most inheritable neurological disorders, but it is also the most complex," says Rajini Rao, Ph.D., a professor of physiology in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

"There are hundreds of candidate genes to sort through, and a single genetic variant may have different effects even within the same family. This makes it difficult to separate the chaff from the grain, to distinguish harmless variations from disease-causing mutations. We were able to use a new process to screen variants in one candidate gene that has been linked to autism, and figure out how they might contribute to the disorder."

An estimated one in 88 children in the United States is affected by autism spectrum disorders, a group of neurological development conditions marked by varying degrees of social, communication and behavioral problems.

Scientists for years have looked for the biological roots of the problem using tools such as genome-wide association studies and gene-linkage analysis, which crunch genetic and health data from thousands of people in an effort to pinpoint disease-causing genetic variants.

But while such techniques have turned up a number of gene mutations that may be linked to autism, none of them appear in more than 1 percent of people with the condition. With numbers that low, researchers need a way to screen variants in order to make a definitive link, Rao says.

For the new study, Rao and her collaborators focused on NHE9, which other researchers had flagged as a suspect in attention-deficit hyperactivity disorder, addiction and epilepsy as well as autism spectrum disorders.

The gene was already known to be involved in transporting hydrogen, sodium and potassium ions in and out of cellular compartments called endosomes, and the team wondered how this function might be related to neurological conditions.

Rao's collaborators at Tel Aviv University and Technion-Israel Institute of Technology constructed a computer model of the NHE9 protein based on previous research on a distant relative in bacteria.

They then used the model to predict how autism-linked variants in the NHE9 gene would affect the protein's shape and function.

Some of them were predicted to cause dramatic changes, while other changes appeared to be more subtle.

Rao's team next tested how these variant forms of NHE9 would affect a relatively simple organism often used in genetic studies: yeast.

"Using yeast to screen the function of variants was a quick, easy and inexpensive way of figuring out which were worth further study, and which we could ignore because they didn't have any effect," Rao says.

To do that, the team engineered the yeast form of NHE9 to have the variants seen in autistic people.

For those mutations that did have a detectable effect on the yeast, the team moved on to a third and more challenging step, in mouse brains.

They homed in on astrocytes, a type of brain cell that clears the signaling molecule glutamate out of the way after it has performed its job of delivering a message across a synapse between two nerve cells.

Using lab-grown mouse astrocytes with variant forms of NHE9, the researchers found a change in the pH (acidity) inside cellular compartments called endosomes, which in turn altered the ability of cells to take up glutamate.

Because endosomes are the vehicles that deliver cargo essential for communication between brain cells, changing their pH alters traffic to and from the cell surface, which could affect learning and memory, Rao says.

"Elevated glutamate levels are known to trigger seizures, perhaps explaining why autistic patients with mutations in NHE9 and related genes also have seizures," she notes.

Rao and her team hope that pinpointing the importance of this trafficking mechanism in autism spectrum disorders may lead to the development of new drugs for autism that alter endosomal pH.

As the use of genomic data becomes increasingly commonplace in the future, the step-wise strategy devised by her team can be used to screen gene variants and identify at-risk patients, she says.

More information: www.nature.com/ncomms/2013/130925/ncomms3510/full/ncomms3510.html

Autism ASD: Researchers discover a potential cause

Topoisomerase inhibitors reduce the expression of long genes in neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders -- 200 kb is four times longer than the average gene. 

Credit: Concept: Mark Zylka. Illustration: Janet Iwasa.

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature.

Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder's genetic causes.

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC.

"Inhibiting these enzymes has the potential to profoundly affect neurodevelopment—perhaps even more so than having a mutation in any one of the genes that have been linked to autism."

The study could have important implications for ASD detection and prevention.

Mark Zylka

"This could point to an environmental component to autism," said Zylka.

"A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. "

This study could also explain why some people with mutations in topoisomerases develop autism and other neuro-developmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells.

"If there are additional compounds like this in the environment, then it becomes important to identify them," said Zylka.

"That's really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects—so that pregnant women can avoid being exposed to these compounds."

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy.

Investigating the drug's effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long—composed of many DNA base pairs.

The group then made the serendipitous connection that many autism-linked genes are extremely long.

"That's when we had the 'Eureka moment,'" said Zylka. "We realized that a lot of the genes that were suppressed were incredibly long autism genes."

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board—even to a small extent—means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study's findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses—the connections between brain cells.

Another 20 percent are related to gene transcription—the process of translating genetic information into biological functions.

Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person's ability to construct synapses.

"Our discovery has the potential to unite these two classes of genes—synaptic genes and transcriptional regulators," said Zylka.

"It could ultimately explain the biological mechanisms behind a large number of autism cases."

More information: Nature paper dx.doi.org/10.1038/nature12504

Children with fever: Researchers distinguish between bacterial from viral infections

Using microarray technology, researchers can distinguish between viral and bacterial infections in children with fever by profiling the activity of genes in a blood sample.

While more research is needed, the new technology could one day help to identify the cause of illness and ensure that children get the right treatment. 

Credit: Robert Boston, Washington University in St. Louis

In children with fever but no other symptoms of illness, it is difficult to know whether a child has a viral infection that will resolve on its own or a potentially serious bacterial infection that requires antibiotics.

Now, researchers at Washington University School of Medicine in St. Louis report that they can distinguish between viral and bacterial infections in children with fever by profiling the activity of genes in a blood sample.

In a small study, analyzing genes in white blood cells was more than 90 percent accurate, far better than the standard diagnostic test, which is only correct about 70 percent of the time.

The research is published July 15 in the Proceedings of the National Academy of Sciences Online Early Edition.

While more work is needed, the study's results support the notion that analyzing the activity of the body's genes in response to childhood infections could help to identify the cause of illness and ensure that children get the right treatment.

Gregory Storch

"It's a common problem that children develop a fever without any apparent cause," says senior author Gregory Storch, MD, the Ruth L. Siteman Professor of Pediatrics and chief of the Division of Pediatric Infectious Diseases at Washington University School of Medicine and St. Louis Children's Hospital.

"Some of these kids have serious bacterial infections that can be life threatening, but the largest number have viral infections. The trouble is, from a practical standpoint, it's hard to know which is which."

As a precaution, many children who have a fever without an apparent cause are treated with antibiotics even though the drugs don't work against viruses and overprescribing them contributes to antibiotic resistance.

The new study involved 30 children ages two months to 3 years who had fevers above 100.4° F but no obvious signs of illness, like a cough or diarrhea.

Twenty-two of the children were known to have viral infections based on previous extensive genomic testing that is not yet practical to use in a clinic setting, and eight others children had bacterial infections.

But Storch and his colleagues at the university's Genome Institute and the Genome Technology Access Center wanted to know whether a test called a gene expression microarray could identify patterns of gene activity in white blood cells that could discriminate children with viral infections from those with bacterial infections.

White blood cells are the immune system's first line of defense against foreign invaders, and the scientists theorized that they would respond differently to viruses than to bacteria.

The researchers also had access to results of a standard diagnostic test performed when the children initially were evaluated with fevers at St. Louis Children's Hospital.

That test involves analyzing the number of white blood cells in a blood sample. Generally, the counts are elevated for bacterial infections and either low or normal for viral infections.

More information: Storch GA, Crosby SD, Yu J, Hu X. Gene expression profiles in febrile children with defined viral and bacterial infection. Proceedings of the National Academy of Sciences. Online July 15, 2013. www.pnas.org/cgi/doi/10.1073/pnas.1302968110

Researchers identify emotions based on brain activity (fMRI Scans)

For the first time, scientists at Carnegie Mellon University have identified which emotion a person is experiencing based on brain activation. 

This image shows the average positions of brain regions used to identify emotional states. 

Credit: Carnegie Mellon University

For the first time, scientists at Carnegie Mellon University have identified which emotion a person is experiencing based on brain activity.

The study, which will be published in the June 19 issue of PLOS ONE, combines functional magnetic resonance imaging (fMRI) and machine learning to measure brain signals to accurately read emotions in individuals.

Led by researchers in CMU's Dietrich College of Humanities and Social Sciences, the findings illustrate how the brain categorizes feelings, giving researchers the first reliable process to analyze emotions.

Until now, research on emotions has been long stymied by the lack of reliable methods to evaluate them, mostly because people are often reluctant to honestly report their feelings.

Further complicating matters is that many emotional responses may not be consciously experienced.

Identifying emotions based on neural activity builds on previous discoveries by CMU's Marcel Just and Tom M. Mitchell, which used similar techniques to create a computational model that identifies individuals' thoughts of concrete objects, often dubbed "mind reading."

"This research introduces a new method with potential to identify emotions without relying on people's ability to self-report," said Karim Kassam, assistant professor of social and decision sciences and lead author of the study.

"It could be used to assess an individual's emotional response to almost any kind of stimulus, for example, a flag, a brand name or a political candidate."

One challenge for the research team was find a way to repeatedly and reliably evoke different emotional states from the participants.

Traditional approaches, such as showing subjects emotion-inducing film clips, would likely have been unsuccessful because the impact of film clips diminishes with repeated display.

The researchers solved the problem by recruiting actors from CMU's School of Drama.

Read the full article here

Researchers unravel genetics of dyslexia and language impairment

A new study of the genetic origins of dyslexia and other learning disabilities could allow for earlier diagnoses and more successful interventions, according to researchers at Yale School of Medicine.

Many students now are not diagnosed until high school, at which point treatments are less effective.

The study is published online and in the July print issue of the American Journal of Human Genetics.

Jeffrey R. Gruen

Senior author Jeffrey R. Gruen, M.D., professor of pediatrics, genetics, and investigative medicine at Yale, and colleagues analyzed data from more than 10,000 children born in 1991-1992 who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted by investigators at the University of Bristol (UK).

Gruen and his team used the ALSPAC data to unravel the genetic components of reading and verbal language.

In the process, they identified genetic variants that can predispose children to dyslexia and language impairment, increasing the likelihood of earlier diagnosis and more effective interventions.

Dyslexia and language impairment are common learning disabilities that make reading and verbal language skills difficult.

Both disorders have a substantial genetic component, but despite years of study, determining the root cause had been difficult.

In previous studies, Gruen and his team found that dopamine-related genes ANKK1 and DRD2 are involved in language processing.

In further non-genetic studies, they found that prenatal exposure to nicotine has a strong negative affect on both reading and language processing.

They had also previously found that a gene called DCDC2 was linked to dyslexia. In this new study, Gruen and colleagues looked deeper within the DCDC2 gene to pinpoint the specific parts of the gene that are responsible for dyslexia and language impairment.

They found that some variants of a gene regulator called READ1 (regulatory element associated with dyslexia1) within the DCDC2 gene are associated with problems in reading performance while other variants are strongly associated with problems in verbal language performance.

Gruen said these variants interact with a second dyslexia risk gene called KIAA0319. "When you have risk variants in both READ1 and KIAA0319, it can have a multiplier effect on measures of reading, language, and IQ," he said.

"People who have these variants have a substantially increased likelihood of developing dyslexia or language impairment."

"These findings are helping us to identify the pathways for fluent reading, the components of those pathways; and how they interact," said Gruen.

"We now hope to be able to offer a pre-symptomatic diagnostic panel, so we can identify children at risk before they get into trouble at school. Almost three-quarters of these children will be reading at grade level if they get early intervention, and we know that intervention can have a positive lasting effect."

More information: dx.doi.org/10.1016/j.ajhg.2013.05.008

Autism: Researchers shed light on role of genes

Research carried out by Medical Research Council (MRC) researchers at the University of Oxford (UK) has uncovered a chain of genetic events that are common in individuals with autism, and have examined for the first time how this chain may influence how messages are sent between nerve cells in the brain.

This knowledge will help researchers better understand the role that genetics plays in autism.

Autism Spectrum Disorders (ASD) affects around 1 per cent of the population and typically cause difficulties in social interaction, communication and repetitive behaviour.

While it's known that genes can play a strong role in the development of ASD, doctors are currently only able to identify the exact genetic cause in around one in five cases.

The team, based at the MRC Functional Genomics Unit (FGU), looked at 181 autism patients who had either additional copies of some genes, or fewer copies of other genes, than people without autism.

In around half of these patients, the genes whose copy count had changed were found to work together in a large biological network that plays a key role in the way in which information is passed between cells in the brain.

By changing the number of copies of genes within this network, the study highlighted disturbances in those with autism in the way the information was carried across synapses in the brain.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Notably, the study also found that while some genes had gained more copies while other genes had lost copies, the final effect was predicted to be the same.

Dr Caleb Webber, lead author on the study at the MRC FGU at the University of Oxford, says: "Think of a pipe that carries water. At some points along the pipe there are genes that act as taps to let more water into the pipe. At other points genes act as holes to let some of the water out. We found that in individuals with autism the mutations in all these different types of genes act in the same way to affect waterflow. This indicates the 'tap' genes are duplicated in some individuals with autism which increases flow into the pipe, while in other individuals with autism the 'hole' genes are deleted which decreases the amount of water leaving the pipe. Both of these events cause the same thing; too much water flowing through the pipe."

"Knowing not just which 'pipes' in the cell are affected in autism but also in what way they are affected helps us to know in which way we have to change the flow to restore the balance."

Professor Hugh Perry, chair of the MRC's Neurosciences and Mental Health Board, says: "Autism Spectrum Disorders are extremely complex in the way they can influence a person's ability to communicate or interact with their environment. Tracking down and understanding the functions of genes that regulate how information is passed around the brain is a crucial part of the story and will help to underpin the evidence with which diagnoses and treatments are given. This study is a clear example of how MRC-funding can use genetic studies to improve our understanding of the brain and its networks."

The research team's findings are published in Plos Genetics

Phelan-McDermid Syndrome (PMS): Researchers provide first prospective characterisation

In the first prospective study of its kind, Seaver Autism Center researchers at the Icahn School of Medicine at Mount Sinai provide new evidence of the severity of intellectual, motor, and speech impairments in a subtype of autism called Phelan-McDermid Syndrome (PMS).

The data are published online in the June 11 issue of the journal Molecular Autism.

Mutation or deletion of a gene known as SHANK3 is one of the more common single-gene causes of autism spectrum disorders and is critical to the development of PMS, a severe type of autism.

To date, clinicians have relied on case studies and retrospective reviews of medical records to understand the features of this disorder and how the clinical presentation relates to the extent of the genetic changes in the SHANK3 region.

In the first systematic and comprehensive prospective trial, researchers led by Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, under the direction of Joseph Buxbaum, PhD, Director of the Seaver Autism Center, enrolled 32 participants with SHANK3 deletions to comprehensively assess their clinical symptoms and examine how the size of the SHANK3 deletion correlated to those symptoms.

"Previous studies have not utilized prospective assessments to understand Phelan-McDermid Syndrome, and the prevalence of autism spectrum disorder has never been examined using gold-standard instruments" said Dr. Kolevzon.

"There is no established standard for assessing this type of autism, and our study provides important guidance in developing such a standard."

Of the 32 patients enrolled, 84 percent met criteria for an autism spectrum disorder. Seventy-seven percent of patients exhibited severe to profound intellectual disability, with 19 percent using some form of verbal communication.

Other common features included low muscle tone, gait disturbance, and seizures. The researchers also found that patients who had larger SHANK3 deletions had more severe disease.

"Our findings provide additional evidence of the significant impairment associated with SHANK3 deficiency," said Dr. Kolevzon.

"Also, knowing how large the deletion of the SHANK3 gene is may have important implications for medical monitoring and individualizing treatment plans. Results also provide much-needed guidance in developing a standardized methodology for evaluating the features of this disorder."

Read more of this article here

Down syndrome: Researchers target a particular aspect

The protrusion of a neuron without Dscam protein (green) and that of a neuron with an abnormally high level of Dscam protein (red). 

The protrusions are overlaid on the fruitfly's equivalent of the human spinal cord (blue). Credit: Xin Wang 

University of Michigan researchers have determined how a gene that is known to be defective in Down syndrome is regulated and how its dysregulation may lead to neurological defects, providing insights into potential therapeutic approaches to an aspect of the syndrome.

Normally, nerve cells called neurons undergo an intense period of extending and branching of neuronal protrusions around the time of birth.

During this period, the neurons produce the proteins of the gene called Down syndrome cell-adhesion molecule, or Dscam, at high levels.

After this phase, the growth and the levels of protein taper off. However, in the brains of patients with Down syndrome, epilepsy and several other neurological disorders, the amount of Dscam remains high.

The impact of the elevated Dscam amount on how neurons develop is unknown. Bing Ye, a faculty member at U-M's Life Sciences Institute, found that in the fruit fly Drosophila, the amount of Dscam proteins in a neuron determines the size to which a neuron extends its protrusions before it forms connections with other nerve cells.

An overproduction of Dscam proteins leads to abnormally large neuronal protrusions.

Ye also identified two molecular pathways that converge to regulate the abundance of Dscam. One, dual leucine zipper kinase (DLK), which is involved in nerve regeneration, promotes the synthesis of Dscam proteins.

Another, fragile X mental retardation protein (FMRP), which causes fragile X syndrome when defective, represses Dscam protein synthesis.

Because humans share these genes with Drosophila, the DLK-FMRP-Dscam relationship presents a possible target for therapeutic intervention, Ye said.

Many genes are involved in neurological disorders like Down syndrome, and how molecular defects cause the disease is complex.

"But because of the important roles of Dscam in the development of neurons, its related defect is very likely to be an aspect of Down syndrome and it may be an aspect of the syndrome that can be treated," said Ye, an assistant professor in the Department of Cell and Developmental Biology at the U-M Medical School.

Ye's next step is to test the effects of over-expression of Dscam in mice to see how it changes the development of the nervous system and the behavior of the animal.

Down syndrome occurs in about one in 830 newborns; an estimated 250,000 people in the U.S. have the condition, according to the National Library of Medicine's Genetics Home Reference.

Ye's study is scheduled to be published online June 5 in Neuron.

Autism-related disorder: Researchers have found new role for mTOR in Tuberous Sclerosis

Researchers have found a novel role for a protein that has been implicated in an autism-related disorder known as tuberous sclerosis complex (TSC). 

The disease, which affects 1 in about 8,000 children, manifests itself in the form of mental retardation in addition to severe epileptic episodes.

The disease is caused by mutations in two tumor-suppressing proteins, TSC1 and TSC2.

"Kids with this condition have benign tumors that grow all over the body," said Bernardo Sabatini  the Takeda Professor of Neurobiology at Harvard Medical School and senior author of the study, "but we wanted to know what happened in the brain."

The researchers found that when mutations in TSC1 and TSC2 adversely affected a third protein, mTOR, this mutation increased brain activity, which can result in epileptic seizures.

Bernardo Sabatini

The findings were published in the May 8 issue of Neuron. A protein kinase, mTOR is responsible for controlling cell growth in many parts of the body and has been widely implicated in epilepsy and autism.

TSC1 and TSC2 normally repress the activity of mTOR to keep cell growth in check.

In the case of TSC, there are mutations in TSC1 or TSC2, and mTOR's ability to promote cell growth goes unchecked, resulting in tumors in regularly dividing cells.

"But neurons don't divide," said Sabatini. "So it was important to note the changes in these non-dividing cells."

The researchers hypothesized that mTOR's function in the brain related to homeostasis, the brain's ability to maintain a controlled level of electrical activity.

When there's a lot of electrical activity, a negative feedback system switches on to suppress activity.

Conversely, when levels are too low, other positive feedback pathways are engaged that bring the activity level back up.

"We went into this study with the specific hypothesis that mTOR would be part of the homeostatic loop in the brain," explained Sabatini.

In the case of TSC patients, they thought that mTOR was incapable of maintaining homeostasis and kept adding to the level of electrical activity, leading to seizures. "But we were wrong," he added.

Helen Bateup

"What we actually found was that mTOR is part of a positive feedback pathway," said Helen Bateup, HMS research fellow in neurobiology and first author on the study.

"When a cell is active, mTOR gets turned on more frequently and makes the cell even more active by reducing the amount of inhibition that the neuron receives."

In cells where TSC proteins are mutated, this positive feedback gets out of control, and the neuronal circuit remains overactive despite all the pathways that normally shut down activity being turned on.

"It's like the circuit is trying to keep itself quiet, but it can't," said Sabatini. "The out-of-control mTOR causes some cells to loss all inhibition, something that can't be compensated for by turning down excitation."

The researchers think this key difference in how mTOR operates, in working to promote electrical activity, is important for the disease because patients end up with high levels of dysfunctional mTOR that makes for highly active circuits prone to epileptic fits.

Furthermore, "we know that once a person has one seizure, they're much more likely to have more, a concept known as kindling," said Sabatini.

These findings are among the first to show that contrary to scientific consensus, mTOR does not play a part in everything.

"We have shown that one of the few things that mTOR does not seem to partake in is this negative feedback pathway," said Sabatini.

Working in both in vitro and in vivo mouse models, the researchers think the next step would be tease out the molecular pathway of mTOR's involvement in this positive feedback loop.

"It's also important to compare how this pathway works in normal brains versus a diseased model," added Bateup.

"A huge challenge when studying the brain is that there are so many feedback pathways that a mutation in one gene can result in a hundred other secondary changes," said Sabatini.

Rapamycin (Sirolimus), a drug currently used to prevent organ rejection following transplants, targets mTOR and brings activity levels back to normal.

"We could use the drug to restore this excitatory-inhibitory balance in the brain," said Bateup. "

A lot of drugs that treat epilepsy try to make inhibition more powerful but given that the primary problem here is that a group of cells has lost inhibition, that approach won't work," she added.

"What we might need is to target the excitation side. Or find ways of changing the biochemistry of the cells to make inhibitory synapses again."

"For this disease, this is the right time to start looking at human cells," said Sabatini.

"We have really good data from the mouse model and it would be a really nice test to see if the mouse model is really predictive of human disorder and if it's worth being continued."

More information: www.sciencedirect.… 62731300264X

Koegel Researchers Claim to have successfully treat Autism in infants

Most infants respond to a game of peek-a-boo with smiles at the very least, and, for those who find the activity particularly entertaining, gales of laughter.

For infants with autism spectrum disorders (ASD), however, the game can be distressing rather than pleasant, and they'll do their best to tune out all aspects of it—and that includes the people playing with them.

That disengagement is a hallmark of ASD, and one of the characteristics that amplifies the disorder as infants develop into children and then adults.

A study conducted by researchers at the Koegel Autism Center at UC Santa Barbara has found that replacing such games in favour of those the infant prefers can actually lessen the severity of the infants' ASD symptoms, and, perhaps, alleviate the condition altogether.

Their work is highlighted the current issue of the Journal of Positive Behavioral Interventions. Lynn Koegel, clinical director of the center and the study's lead author, described the game-playing protocol as a modified Pivotal Response Treatment (PVT).

Developed at UCSB, PRT is based on principles of positive motivation. The researchers identified the activities that seemed to be more enjoyable to the infants and taught the respective parents to focus on those rather than on the typical games they might otherwise choose.

"We had them play with their infants for short periods, and then give them some kind of social reward," Koegel said.

"Over time, we conditioned the infants to enjoy all the activities that were presented by pairing the less desired activities with the highly desired ones."

The social reward is preferable to, say, a toy, Koegel noted, because it maintains the ever-crucial personal interaction.

"The idea is to get them more interested in people," she continued, "to focus on their socialisation. If they're avoiding people and avoiding interacting, that creates a whole host of other issues.

They don't form friendships, and then they don't get the social feedback that comes from interacting with friends."

According to Koegel, by the end of the relatively short one- to three-month intervention period, which included teaching the parents how to implement the procedures, all the infants in the study had normal reactions to stimuli.

"Two of the three have no disabilities at all, and the third is very social," she said. "The third does have a language delay, but that's more manageable than some of the other issues."

On a large scale, Koegel hopes to establish some benchmark for identifying social deficits in infants so parents and health care providers can intervene sooner rather than later.

"We have a grant from the Autism Science Foundation to look at lots of babies and try to really figure out which signs are red flags, and which aren't," she said.

"A number of the infants who show signs of autism will turn out to be perfectly fine; but we're saying, let's not take the risk if we can put an intervention in play that really works. Then we don't have to worry about whether or not these kids would develop the full-blown symptoms of autism."

Historically, ASD is diagnosed in children 18 months or older, and treatment generally begins around 4 years. "You can pretty reliably diagnose kids at 18 months, especially the more severe cases," said Koegel.

"The mild cases might be a little harder, especially if the child has some verbal communication. There are a few measures –– like the ones we used in our study –– that can diagnose kids pre-language, even as young as six months.

But ours was the first that worked with children under 12 months and found an effective intervention." Given the increasing number of children being diagnosed with ASD, Koegel's findings could be life altering.

"When you consider that the recommended intervention for preschoolers with autism is 30 to 40 hours per week of one-on-one therapy, this is a fairly easy fix," she said.

"We did a single one-hour session per week for four to 12 weeks until the symptoms improved, and some of these infants were only a few months old. We saw a lot of positive change."

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Neuromuscular diseases in Children: Dutch Researchers design new respirators

3D imaging system for the development of the breathing mask. TU Delft is developing a special respirator for children with a neuromuscular disease.

The Sporters in Actie foundation collected €100,000 for research on this breathing mask during the 'Greatest Golf Tournament in the World' in Zoetermeer on Saturday 6 April.

Many neuromuscular diseases damage respiratory muscles, so that artificial respiration becomes necessary in time.

As yet, there are no special respirators for small children (up to the age of six) who require artificial respiration for extended periods. These children often have to use masks designed for adults.

As the masks often do not fit properly this can lead to serious problems, such as eye infections caused by escaping air, facial and dental deformation, insufficient ventilation caused by leaking masks, pressure spots on the nose and forehead because the mask has to be tightened extra fast, and skin damage caused by the mask shifting due to the poor fit.

3D TU Delft is developing a special children's respirator. The project will cost €250,000 and the contribution by the 'Greatest Golf Tournament in the World' will help to complete the research so the mask can actually be produced.

Lyè Goto

PhD student Lyè Goto of TU Delft's Faculty of Industrial Design Engineering has been developing the new mask for over a year now.

'The first and most important step is the collection of what we call the anthropometric data. These data help describe the shape of an average child's face per age category and gender. '

'We build an inventory of 3D images of a large population of children's faces, paying particular attention to the level of diversity between the individual children. '

'To do this, we have a 3D imaging system made up of six digital cameras which record the faces from various angles.'

Prototypes Goto is presently photographing the faces of a few hundred healthy children aged between six months and six years.'

'This data will be supplemented with the data of patients with neuromuscular diseases, which is necessary because these children's faces may be malformed by the disease. '

'Next we have to analyse the anthropometric data, which can be a very complex operation,' explains Goto.

'Once we have completed the analysis we can deliberate on the design of the mask. We will have to decide whether to produce masks in different sizes or size categories, or to choose a modular design with a separate facepiece, or maybe another solution.'

'I will have working prototypes ready by the third year of my PhD research, after which we want to involve the industry in the project.'

TU Delft is collaborating on the research with Sophia Children's hospital in Rotterdam, Youth Healthcare and other scientists.

Johan Molenbroek

Dr Johan Molenbroek, TU Delft's project leader: 'The treatment of these children has been suboptimal for decades.

Thanks to this research, soon the youngest children will be able to have their own personal and comfortably fitting respirators as well.

The children and their parents and carers will sleep better at night and we will see fewer complications among these young patients.'  

Researchers 'read' words in brain signals

U.S. researchers say they've translated brain signals into words, a step toward allowing severely paralyzed people to use their thoughts to "talk."

University of Utah scientists translated signals generated by the brain into words using grids of micro-electrodes implanted beneath the skull but atop the brain, a university release said Monday.

"We have been able to decode spoken words using only signals from the brain with a device that has promise for long-term use in paralyzed patients who cannot now speak," Bradley Greger, an assistant professor of bioengineering, said.

The study used a new kind of non-penetrating micro-electrode that sits on the brain without poking into it. Because the micro-electrodes do not penetrate brain matter, they are considered safe to place on speech areas of the brain.

The scientists placed grids of tiny micro-electrodes over speech centers in the brain of a volunteer with severe epileptic seizures. Using the micro-electrodes, the scientists recorded brain signals as the patient repeatedly read each of 10 words that might be useful to a paralyzed person: yes, no, hot, cold, hungry, thirsty, hello, goodbye, more and less.

When they compared any two brain signals, such as those generated as the volunteer said the words "yes" and "no," they were able to distinguish brain signals for each word 76 percent to 90 percent of the time.

People who eventually could benefit from a wireless device that converts thoughts into computer-spoken spoken words include those paralyzed by stroke, Lou Gehrig's disease and trauma, Greger said.

Ambidextrous children more likely to have mental health, language and scholastic problems, say researchers

Mixed-handed children more likely to have mental health, language and scholastic problems, say Imperial College London researchers

Children who are mixed-handed, or ambidextrous, are more likely to have mental health, language and scholastic problems in childhood than right- or left-handed children, according to a new study published today in the journal Pediatrics.

The researchers behind the study, from Imperial College London and other European institutions, suggest that their findings may help teachers and health professionals to identify children who are particularly at risk of developing certain problems.

Around one in every 100 people is mixed-handed. The study looked at nearly 8,000 children, 87 of whom were mixed-handed, and found that mixed-handed 7 and 8-year old children were twice as likely as their right-handed peers to have difficulties with language and to perform poorly in school.

When they reached 15 or 16, mixed-handed adolescents were also at twice the risk of having symptoms of attention deficit/hyperactivity disorder (ADHD). They were also likely to have more severe symptoms of ADHD than their right-handed counterparts. It is estimated that ADHD affects between 3 to 9% of school-aged children and young people.

The adolescents also reported having greater difficulties with language than those who were left- or right-handed. This is in line with earlier studies that have linked mixed-handedness with dyslexia.

Little is known about what makes people mixed-handed but it is known that handedness is linked to the hemispheres in the brain. Previous research has shown that where a person's natural preference is for using their right hand, the left hemisphere of their brain is more dominant.

Some researchers have suggested that mixed-handedness indicates that the pattern of dominance is not that which is typically seen in most people, i.e. it is less clear that one hemisphere is dominant over the other. One study has suggested that ADHD is linked to having a weaker function in the right hemisphere of the brain, which could help explain why some of the mixed-handed students in today's study had symptoms of ADHD.

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