Posts tagged autism
Posts tagged autism
A single dose of the hormone oxytocin, delivered via nasal spray, has been shown to enhance brain activity while processing social information in children with autism spectrum disorders, Yale School of Medicine researchers report in a new study published in the Dec. 2 issue of Proceedings of the National Academy of Sciences.
“This is the first study to evaluate the impact of oxytocin on brain function in children with autism spectrum disorders,” said first author Ilanit Gordon, a Yale Child Study Center adjunct assistant professor, whose colleagues on the study included senior author Kevin Pelphrey, the Harris Professor in the Child Study Center, and director of the Center for Translational Developmental Neuroscience at Yale.
Gordon, Pelphrey, and their colleagues conducted a double-blind, placebo-controlled study of 17 children and adolescents with autism spectrum disorders. The participants, between the ages of 8 and 16.5, were randomly given either oxytocin spray or a placebo nasal spray during a task involving social judgments. Oxytocin is naturally occurring hormone produced in the brain and throughout the body.
“We found that brain centers associated with reward and emotion recognition responded more during social tasks when children received oxytocin instead of the placebo,” said Gordon. “Oxytocin temporarily normalized brain regions responsible for the social deficits seen in children with autism.”
Gordon said oxytocin facilitated social attunement, a process that makes the brain regions involved in social behavior and social cognition activate more for social stimuli (such as faces) and activate less for non-social stimuli (such as cars).
“Our results are particularly important considering the urgent need for treatments to target social dysfunction in autism spectrum disorders,” Gordon added.
Exposure to air pollution appears to increase the risk for autism among people who carry a genetic disposition for the neurodevelopmental disorder, according to newly published research led by scientists at the Keck School of Medicine of the University of Southern California (USC).
"Our research shows that children with both the risk genotype and exposure to high air pollutant levels were at increased risk of autism spectrum disorder compared to those without the risk genotype and lower air pollution exposure," said the study’s first author, Heather E. Volk, Ph.D., M.P.H., assistant professor of research in preventive medicine and pediatrics at the Keck School of Medicine of USC and principal investigator at The Saban Research Institute of Children’s Hospital Los Angeles.
The study, “Autism spectrum disorder: Interaction of air pollution with the MET receptor tyrosine kinase gene,” is scheduled to appear in the January 2014 edition of Epidemiology.
Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disability characterized by problems with social interaction, communication and repetitive behaviors. The Centers for Disease Control and Prevention estimates that one in 88 children in the United States has an ASD.
ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder.
"Although gene-environment interactions are widely believed to contribute to autism risk, this is the first demonstration of a specific interaction between a well-established genetic risk factor and an environmental factor that independently contribute to autism risk," said Daniel B. Campbell, Ph.D., assistant professor of psychiatry and the behavioral sciences at the Keck School of Medicine of USC and the study’s senior author. "The MET gene variant has been associated with autism in multiple studies, controls expression of MET protein in both the brain and the immune system, and predicts altered brain structure and function. It will be important to replicate this finding and to determine the mechanisms by which these genetic and environmental factors interact to increase the risk for autism."
Independent studies by Volk and Campbell have previously reported associations between autism and air pollution exposure and between autism and a variant in the MET gene. The current study suggests that air pollution exposure and the genetic variant interact to augment the risk of ASD.
Campbell and Volk’s team studied 408 children between 2 and 5 years of age from the Childhood Autism Risks From Genetics and the Environment Study, a population-based, case-control study of preschool children from California. Of those, 252 met the criteria for autism or autism spectrum disorder. Air pollution exposure was determined based on the past residences of the children and their mothers, local traffic-related sources, and regional air quality measures. MET genotype was determined through blood sampling.
Campbell and Volk continue to study the interaction of air pollution exposure and the MET genotype in mothers during pregnancy.
Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication. The study is published in the journal Cell Reports.
The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.
Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.
The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.
Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: “These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.”
The research builds on the team’s earlier work that identified a group of proteins in the brain responsible for protecting nerve cells from damage and could be used in future for therapies for stroke and other brain diseases.
UCL scientists have shown that there are widespread differences in how genes, the basic building blocks of the human body, are expressed in men and women’s brains.
Based on post-mortem adult human brain and spinal cord samples from over 100 individuals, scientists at the UCL Institute of Neurology were able to study the expression of every gene in 12 brain regions. The results are published today in Nature Communications.
They found that the way that the genes are expressed in the brains of men and women were different in all major brain regions and these differences involved 2.5% of all the genes expressed in the brain.
Among the many results, the researchers specifically looked at the gene NRXN3, which has been implicated in autism. The gene is transcribed into two major forms and the study results show that although one form is expressed similarly in both men and women, the other is produced at lower levels in women in the area of the brain called the thalamus. This observation could be important in understanding the higher incidence of autism in males.
Overall, the study suggests that there is a sex-bias in the way that genes are expressed and regulated, leading to different functionality and differences in susceptibility to brain diseases observed by neurologists and psychiatrists.
Dr. Mina Ryten, UCL Institute of Neurology and senior author of the paper, said: “There is strong evidence to show that men and women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.
“Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the brain. We have released our data so that others can assess how any gene they are interested in is expressed differently between men and women.”
A team led by UC San Francisco scientists has identified the disruption of a single type of cell – in a particular brain region and at a particular time in brain development – as a significant factor in the emergence of autism.
The finding, reported in the Nov. 21 issue of Cell, was made with techniques developed only within the last few years, and marks a turning point in autism spectrum disorders (ASDs) research.
Large-scale gene sequencing projects are revealing hundreds of autism-associated genes, and scientists have begun to leverage new methods to decipher how mutations in these disparate genes might converge to exert their effects in the developing brain.
The new research focused on just nine genes, those most strongly associated with autism in recent sequencing studies, and investigated their effects using precise maps of gene expression during human brain development.
Led by Jeremy Willsey, a graduate student in the laboratory of senior author Matthew W. State, MD, PhD, chair of the UCSF Department of Psychiatry, the group showed that this set of genes contributes to abnormalities in brain cells known as cortical projection neurons in the deepest layers of the developing prefrontal cortex during the middle period of fetal development.
Though a range of developmental scenarios in multiple brain regions are surely at work in ASDs, the ability to place these specific genetic mutations in one specific set of cells – among hundreds of cell types in the brain, and at a specific time point in human development – is a critical step in beginning to understand how autism comes about.
“Given the small subset of autism genes we studied, I had no expectation that we would see the degree of spatiotemporal convergence that we saw,” said State, an international authority on the genetics of neurodevelopmental disorders.
“This strongly suggests that though there are hundreds of autism risk genes, the number of underlying biological mechanisms will be far fewer. This is a very important clue to advance precision medicine for autism toward the development of personalized and targeted therapies.”
Complex Genetic Architecture of ASDs
ASDs, marked by deficits in social interaction and language development, as well as by repetitive behaviors and/or restricted interests, are known to have a strong genetic component.
But these disorders are exceedingly complex, with considerable variation in symptoms and severity, and there does not appear to be a small collection of mutations widely shared among all affected individuals that always lead to ASDs.
Instead, with the rise of new sequencing methods over the past several years, researchers have identified many rare, non-inherited, spontaneous mutations that appear to act in combination with other genetic and non-genetic factors to cause ASDs. According to some estimates, mutations in as many as 1,000 genes could play a role in the development of these disorders.
While researchers have been heartened that specific genes are now rapidly being tied to ASDs, State said the complex genetic architecture of ASDs is also proving to be challenging.
“If there are 1,000 genes in the population that can contribute to risk in varying degrees and each has multiple developmental functions, it is not immediately obvious how to move forward to determine what is specifically related to autism. And without this, it is very difficult to think about how to develop new and better medications,” he said.
Focusing on Nine Genes
To begin to grapple with those questions, the researchers involved in the new study first selected as “seeds” the nine genes that have been most strongly tied to ASDs in recent sequencing research from their labs and others.
Importantly, these nine genes were chosen solely because of the statistical evidence for a relationship to ASDs, not because their function was known to fit a theory of the cause of ASDs. “We asked where the leads take us, without any preconceived idea about where they should take us,” said State.
The team then took advantage of BrainSpan, a digital atlas assembled by a large research consortium, including co-author Nenad Šestan, MD, PhD, and colleagues at Yale School of Medicine. Based on donated brain specimens, BrainSpan documents how and where genes are expressed in the human brain over the lifespan.
The scientists, who also included Bernie Devlin, PhD, of The University of Pittsburgh School of Medicine; Kathryn Roeder, PhD, of Carnegie-Mellon University; and James Noonan, PhD, of Yale School of Medicine, used this tool to investigate when and where the nine seed genes join up with other genes in “co-expression networks” to wire up the brain or maintain its function.
The resulting co-expression networks were then tested using a variety of pre-determined criteria to see if they showed additional evidence of being related to ASDs. Once this link was established, the authors were then able to home in on where in the brain and when in development these networks were localizing, which proved to be in cortical projection neurons found in layers 5 and 6 of the prefrontal cortex, and during a time period spanning 10 to 24 weeks after conception. Notably, a study using different methods and published in the same issue of Cell also implicates cortical projection neurons in ASDs.
“To see these gene networks as highly connected as they are, as convergent as they are, is quite amazing,” said Willsey “An important outcome of this study is that for the first time it gives us the ability to design targeted experiments based on a strong idea about when and where in the brain we should be looking at specific genes with specific mutations.”
In addition to its importance in ASD research, State sees the new work as a reflection of the tremendous value of “big science” efforts, such as large-scale collaborative genomic studies and the creation of foundational resources such as the BrainSpan atlas.
“We couldn’t have done this even two years ago,” State said, “because we didn’t have the key ingredients: a set of unbiased autism genes that we have confidence in, and a map of the landscape of the developing human brain. This work combines large-scale ‘-omics’ data sets to pivot into a deeper understanding of the relationship between complex genetics and biology.”
Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.
"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team’s findings. “We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally.”
The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.
By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.
"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."
"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.
To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.
"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.
A Michigan State University researcher has discovered the first anatomical evidence that the brains of children with a nonverbal learning disability – long considered a “pseudo” diagnosis – may develop differently than the brains of other children.
The finding, published in Child Neuropsychology, could ultimately help educators and clinicians better distinguish between – and treat – children with a nonverbal learning disability, or NLVD, and those with Asperger’s, or high functioning autism, which is often confused with NLVD.
“Children with nonverbal learning disabilities and Asperger’s can look very similar, but they can have very different reasons for why they behave the way they do,” said Jodene Fine, assistant professor of school psychology in MSU’s College of Education.
Understanding the biological differences in children with learning and behavioral challenges could help lead to more appropriate intervention strategies.
Children with nonverbal learning disability tend to have normal language skills but below average math skills and difficulty solving visual puzzles. Because many of these kids also show difficulty understanding social cues, some experts have argued that NVLD is related to high functioning autism – which this latest study suggests may not be so.
Fine and Kayla Musielak, an MSU doctoral student in school psychology, studied about 150 children ages 8 to 18. Using MRI scans of the participants’ brains, the researchers found that the children diagnosed with NVLD had smaller spleniums than children with other learning disorders such as Asperger’s and ADHD, and children who had no learning disorders.
The splenium is part of the corpus callosum, a thick band of fibers in the brain that connects the left and right hemispheres and facilitates communication between the two sides. Interestingly, this posterior part of the corpus callosum serves the areas of the brain related to visual and spatial functioning.
In a second part of the study, the participants’ brain activity was analyzed after they were shown videos in an MRI that portrayed both positive and negative examples of social interaction. (A typical example of a positive event was a child opening a desired birthday present with friend; a negative event included a child being teased by other children.)
The researchers found that the brains of children with nonverbal learning disability responded differently to the social interactions than the brains of children with high functioning autism, or HFA, suggesting the neural pathways that underlie those behaviors may be different.
“So what we have is evidence of a structural difference in the brains of children with NLVD and HFA, as well as evidence of a functional difference in the way their brains behave when they are presented with stimuli,” Fine said.
While more research is needed to better understand how nonverbal learning disability fits into the family of learning disorders, Fine said her findings present “an interesting piece of the puzzle.”
“I would say at this point we still don’t have enough evidence to say NVLD is a distinct diagnosis, but I do think our research supports the idea that it might be,” she said.
People with autism are more likely to also have synaesthesia, suggests new research in the journal Molecular Autism.
Synaesthesia involves people experiencing a ‘mixing of the senses’, for example, seeing colours when they hear sounds, or reporting that musical notes evoke different tastes. Autism is diagnosed when a person struggles with social relationships and communication, and shows unusually narrow interests and resistance to change. The team of scientists from Cambridge University found that whereas synaesthesia only occurred in 7.2% of typical individuals, it occurred in 18.9% of people with autism.
On the face of it, this is an unlikely result, as autism and synaesthesia seem as if they should not share anything. But at the level of the brain, synaesthesia involves atypical connections between brain areas that are not usually wired together (so that a sensation in one channel automatically triggers a perception in another). Autism has also been postulated to involve over-connectivity of neurons (so that the person over-focuses on small details but struggles to keep track of the big picture).
The scientists tested – and confirmed – the prediction that if both autism and synaesthesia involve neural over-connectivity, then synaesthesia might be disproportionately common in autism.
The team, led by Professor Simon Baron-Cohen at the Autism Research Centre at Cambridge University, tested 164 adults with an autism spectrum condition and 97 adults without autism. All volunteers were screened for synaesthesia. Among the 31 people with autism who also had synaesthesia, the most common forms of the latter were ‘grapheme-colour’ (18 of them reported black and white letters being seen as coloured) and ‘sound-colour’ (21 of them reported a sound triggering a visual experience of colour). Another 18 of them reported either tastes, pains, or smells triggering a visual experience of colour.
Professor Baron-Cohen said: “I have studied both autism and synaesthesia for over 25 years and I had assumed that one had nothing to do with the other. These findings will re-focus research to examine common factors that drive brain development in these traditionally very separate conditions. An example is the mechanism ‘apoptosis,’ the natural pruning that occurs in early development, where we are programmed to lose many of our infant neural connections. In both autism and synaesthesia apoptosis may not occur at the same rate, so that these connections are retained beyond infancy.”
Professor Simon Fisher, a member of the team, and Director of the Language and Genetics Department at Nijmegen’s Max Planck Institute, added: “Genes play a substantial role in autism and scientists have begun to pinpoint some of the individual genes involved. Synaesthesia is also thought to be strongly genetic, but the specific genes underlying this are still unknown. This new research gives us an exciting new lead, encouraging us to search for genes which are shared between these two conditions, and which might play a role in how the brain forms or loses neural connections.”
Donielle Johnson, who carried out the study as part of her Master’s degree in Cambridge, said: “People with autism report high levels of sensory hyper-sensitivity. This new study goes one step further in identifying synaesthesia as a sensory issue that has been overlooked in this population. This has major implications for educators and clinicians designing autism-friendly learning environments.”
The iPad you use to check email, watch episodes of Mad Men and play Words with Friends may hold the key to enabling children with autism spectrum disorders to express themselves through speech. New research indicates that children with autism who are minimally verbal can learn to speak later than previously thought, and iPads are playing an increasing role in making that happen, according to Ann Kaiser, a researcher at Vanderbilt Peabody College of education and human development.
In a study funded by Autism Speaks, Kaiser found that using speech-generating devices to encourage children ages 5 to 8 to develop speaking skills resulted in the subjects developing considerably more spoken words compared to other interventions. All of the children in the study learned new spoken words and several learned to produce short sentences as they moved through the training.
“For some parents, it was the first time they’d been able to converse with their children,” said Kaiser, Susan W. Gray Professor of Education and Human Development. “With the onset of iPads, that kind of communication may become possible for greater numbers of children with autism and their families.”
Augmentative and alternative communication devices—which employ symbols, gestures, pictures and speech output—have been used for decades by people who have difficulty speaking. Now, with the availability of apps that emulate those devices, the iPad offers a more accessible, cheaper and more user-friendly way to help minimally verbal children with autism to communicate. And, the iPad is far less stigmatizing for young people with autism who rely on them for communicating with fellow students, teachers and friends.
The reason speech-generating devices like the iPad are effective in promoting language development is simple. “When we say a word it sounds a little different every time, and words blend together and take on slightly different acoustic characteristics in different contexts,” Kaiser explained. “Every time the iPad says a word, it sounds exactly the same, which is important for children with autism, who generally need things to be as consistent as possible.”
As many as a third of children with autism have mastery of only a few words by the time they are school age. Previously, researchers thought that if children with autism had not begun to speak by age 5 or 6, they were unlikely to acquire spoken language. But Kaiser is encouraged by study results and believes that her iPad studies may help change that notion.
Building on findings from this research, Kaiser has begun a new five-year long study supported by the National Institutes of Health’s Autism Centers of Excellence with colleagues at UCLA, University of Rochester, and Cornell Weill Medical School. She and a team of researchers and therapists at the four sites are using iPads in two contrasting interventions (direct-teaching and naturalistic-teaching) to evaluate the effectiveness of the two communication interventions for children who have autism and use minimal spoken language.
In the direct-teaching approach, children are taught prerequisite skills for communication (such as matching objects, motor imitation and verbal imitation) and basic communication skills (such as requesting objects) in a massed trial format. For example, an adult partner may present five to 10 consecutive opportunities for a child to use the iPad to request preferred objects. During these opportunities, the child is prompted to use the iPad to request and may receive physical assistance if he cannot use the iPad independently.
In the naturalistic-teaching approach, the adult models the use of the iPad during play and conversation. She also teaches turn-taking, use of gestures to communicate, play with objects and social attention to partners during the play. She provides a limited number of prompts to use the iPad to make choices, to comment or make new requests.
In both approaches, children touch the symbols on the screen, listen to the device repeat the words, and sometimes say the words themselves. They are encouraged to use both words and the iPad to communicate, and the adult therapist uses both modes of communication throughout the instructional sessions.
Results from the Autism Speaks study will be available in Spring 2014; the NIH study will continue through Spring 2017; and more information can be found at Kidtalk.org.
The brains of children with autism show more connections than the brains of typically developing children do. What’s more, the brains of individuals with the most severe social symptoms are also the most hyper-connected. The findings reported in two independent studies published in the Cell Press journal Cell Reports (1, 2) on November 7th are challenge the prevailing notion in the field that autistic brains are lacking in neural connections.
The findings could lead to new treatment strategies and new ways to detect autism early, the researchers say. Autism spectrum disorder is a neurodevelopmental condition affecting nearly 1 in 88 children.
"Our study addresses one of the hottest open questions in autism research," said Kaustubh Supekar of Stanford University School of Medicine of his and his colleague Vinod Menon’s study aimed at characterizing whole-brain connectivity in children. "Using one of the largest and most heterogeneous pediatric functional neuroimaging datasets to date, we demonstrate that the brains of children with autism are hyper-connected in ways that are related to the severity of social impairment exhibited by these children."
In the second Cell Reports study, Ralph-Axel Müller and colleagues at San Diego State University focused specifically on neighboring brain regions to find an atypical increase in connections in adolescents with a diagnosis of autism spectrum disorder. That over-connection, which his team observed particularly in the regions of the brain that control vision, was also linked to symptom severity.
"Our findings support the special status of the visual system in children with heavier symptom load," Müller said, noting that all of the participants in his study were considered "high-functioning" with IQs above 70. He says measures of local connectivity in the cortex might be used as an aid to diagnosis, which today is based purely on behavioral criteria.
For Supekar and Menon, these new views of the autistic brain raise the intriguing possibility that epilepsy drugs might be used to treat autism.
"Our findings suggest that the imbalance of excitation and inhibition in the local brain circuits could engender cognitive and behavioral deficits observed in autism," Menon said. That imbalance is a hallmark of epilepsy as well, which might explain why children with autism so often suffer with epilepsy too.
"Drawing from these observations, it might not be too far fetched to speculate that the existing drugs used to treat epilepsy may be potentially useful in treating autism," Supekar said.