You may think of video games as a waste of time — and in many cases, you may be right. But some researchers are using multiplayer games to measure how social and other factors influence an individual’s decision-making process. The games, these researchers say, could help assess social deficits in people with autism.

Some studies have already yielded insights into autism, as outlined in a review published 12 May in Biological Psychiatry.

In a 2010 study, participants played a game in which they could either hunt rabbits alone for a few points or cooperate to hunt stags for more points. Cooperation requires the player to infer the other player’s strategy: To hunt the stag, player A must believe that player B believes player A will cooperate.

People with autism tend to use strategies with fewer inferences, the study found. The results provide one of the first demonstrations that computational models can identify social impairments, the researchers say.

In another study, published last year, participants played a game in which they decided how much money to donate to a charity. People with autism donated the same amount, regardless of whether anyone was watching, whereas controls donated more when they knew they were being observed.

Some teams are using brain imaging during gaming to try to develop biomarkers for autism. In one example, researchers analyzed a brain area known as the cingulate cortex while participants played a trust game, in which players invest money or other virtual goods with another player with the hopes of getting a return on the investment.

Brain activity in people with autism differed from controls for only the part of the game in which the player decides how much to invest, called the ‘me’ or ‘self’ response.

Moreover, the level of activity in the cingulate cortex correlated with the severity of social deficits in people with autism. Taken together, the studies highlight how multiplayer games can be used to identify patterns of social behavior that characterize autism and other disorders.

Researchers are beginning to use brain imaging in conjunction with potential treatments. Oxytocin, for example, a hormone that has been shown to increase trust, also improves emotion recognition when given to people with autism. Research presented last week at the International Meeting for Autism Research in Toronto showed that oxytocin treatment increases activity in parts of the brain linked to the processing of social information.

Perhaps these two approaches will soon come together, allowing researchers to study how oxytocin affects both brain activity and behavior while children are playing these games.

Mice that are unable to produce a carbohydrate molecule that regulates cell growth show behaviors that resemble the core deficits of autism, according to a study published 27 March in the Proceedings of the National Academy of Sciences¹.

Heparan sulfate forms complexes with proteins that sit on the cell surface, and mediates cell signaling by linking them to other proteins, such as growth factors. The compound is also present at synapses, the junctions between neurons.

Studies have shown that animal models lacking genes necessary for the production of heparan sulfate develop abnormally shaped brains. To investigate whether heparan sulfate is also involved in maintaining neuronal signaling, the researchers looked at its role in the mature brain.

They engineered mice to lose the EXT1 gene — which is required for heparan sulfate synthesis — three weeks after birth, and only in neurons of the forebrain. The forebrain is an important cognitive region that includes the hippocampus, which is required for learning and memory, and the amygdala, which helps process emotions.

Unexpectedly, these mice show features that resemble the core deficits in autism, the study found. The mice are less interested than controls in reuniting with siblings after a separation, more likely to avoid than to challenge intruder mice in their cages, and more likely than controls to back down when confronted with another mouse in a small tube, all of which suggest social deficits. Male mice lacking EXT1 also produce fewer and shorter vocalizations compared with controls when interacting with females.

When placed in a cage with holes in the floor, the mice lacking EXT1 tend to repeatedly poke their noses into the same hole, a behavior reminiscent of the restricted interests seen in people with autism, whereas controls explore different holes, the study found.

The mice also show sensory sensitivity, which is often associated with autism. However, they are less anxious than controls, freely exploring elevated or bright corridors and running around open spaces.

These mice also produce weaker signals from neurons in the amygdala. These neurons have fewer receptors that bind to glutamate, which mediates excitatory signaling in the brain.

Two autism-associated genes, CNTNAP2 and NRXN1, contain regions that could bind to carbohydrates such as heparan sulfate, the researchers say.

References:

1: Irie F. et al. Proc. Natl. Acad. Sci. USA 109, 5052-5056 (2012) PubMed

Size matters: Large, population-based studies are needed to determine how head size varies in children who develop autism.

Girls diagnosed with autism have slower brain growth in the first year of their life than controls, whereas boys’ brains grow at the same rate as those of controls, according to a population-based study in Norway. The results were presented Saturday at the International Meeting for Autism Research in Toronto.

Exactly how head size varies in children with autism has been a matter of debate, depending on where the study took place and the age of the participants.

Researchers from the Norwegian Institute of Public Health, analyzed data from 90,000 children born between 1999 and 2007, including 249 diagnosed with autism at age 3. The male to female ratio of those with autism in the study is 4.2 to 1, in line with average rates. (The overall prevalence rate is low because at 3 years of age, not all children with autism in the group have been detected.)

All infants had their head size measured six times in the first year of life, and weight and length measured regularly from birth to 36 months as part of well-baby clinics that are a standard of healthcare in Norway.

The researchers found little difference in head growth between the 203 boys who were later diagnosed with autism and those who were not. But the 46 girls who were later diagnosed with autism started out with smaller heads and had slower head growth throughout the first year of life than did typically developing girls. At 12 months, head size of girls in the autism group was an average of 7 millimeters smaller than that of typically developing infants.

The researchers also looked at the incidence of macrocephaly, or a larger-than-normal head, when the infants were 1 year old. About 12 percent of boys later diagnosed with autism had a head size in the highest 3 percent, compared with only 3 percent of the typically developing group. Only one girl in the autism group had macrocephaly at 1 year.

Conversely, 27 percent of girls in the autism group had a smaller-than-average head, or microcephaly, at 8 months compared with 3 percent of the controls. Among boys, there was no difference in the incidence of microcephaly between those who later developed autism and those who did not.

In terms of weight and length, boys in the autism group were a bit taller and heavier than other boys. Girls in the autism group were similar in height to controls, but weighed less.

Well-baby clinics in Norway do not typically measure head size beyond 1 year of age, so it’s not clear how head size varies in toddlers.

The study is significant both for its scale and because it analyzed data from the general population. Most studies of head size have focused on children recruited through a clinic. Because children with more severe symptoms are the most likely to visit clinics, those studies are potentially subject to greater bias.

Several studies have found accelerated head growth in the first year of life, and brain imaging studies have implicated specific parts of the brain. One study of postmortem brain tissue found that the brains of people with autism seem to have more neurons than the brains of controls.

Those studies had serious limitations, however, including small numbers and the inclusion of few girls.

For more reports from the 2012 International Meeting for Autism Research, please click here.

Doubtful diagnosis: Some researchers question how the proposed diagnostic criteria for autism will affect those who have profound social communication deficits but few repetitive behaviors. 

Earlier this year, Susan Swedo, chief of the Pediatrics & Developmental Neuroscience Branch at the National Institute of Mental Health in Bethesda, Maryland, found herself at the center of an unexpected maelstrom.

The New York Times had published a damning report of the proposed criteria for diagnosing autism in the upcoming fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The article quoted a preliminary study predicting it would exclude many from an autism diagnosis and make it difficult for them to access services. Some states, for example, are required to provide services for people diagnosed with autistic disorder but not other disorders in the same class.

“The thing that hurt like hell is that newspapers were accusing us of trying to hurt kids by denying them services,” Swedo said Friday at the International Meeting for Autism Research in Toronto. “We never expected to make headlines with the DSM-5. It’s actually kind of boring.”

As chair of the Neurodevelopmental Disorders Work Group — which was charged with rewriting the DSM’s autism diagnostic criteria — Swedo came under fire from parents, advocacy groups and even a misguided state legislator in New York, who proposed banning the DSM-5 from the entire state.

Preliminary data from the field trials of the DSM-5, which Swedo presented at the conference, suggest these concerns are unfounded. 

“We were accused of trying to fudge numbers to make the epidemic go away, but that was never our intent,” she said, addressing a packed conference hall. “We wanted to improve the criteria.” 

New spectrum:

The controversy was triggered by a handful of studies suggesting that the new criteria are too strict and will leave out a number of people currently diagnosed with autism or a related disorder, most notably Asperger syndrome and pervasive developmental disorder-not otherwise specified (PDD-NOS)^1,2.

Two new studies also presented at the conference indicate that the DSM-5 might miss people with PDD-NOS, but is unlikely to affect diagnoses of Asperger syndrome.

Expected to be released in May 2013, the DSM-5 reduces the traditional triad of autism symptoms — deficits in communication, problems with social reciprocity, and rigid thoughts and behavior — into just two classes: social communication and interaction, and repetitive and restricted behavior.

The most controversial change is that it brings several different diagnoses, including Asperger syndrome and PDD-NOS, under the single heading of autism.

To meet the new criteria, individuals must have deficits in three different types of social communication and exhibit two of four repetitive and restricted behaviors. A full outline of the DSM-5 criteria can be found here.

Most studies of the DSM-5 to date have been retrospective, using data collected using the DSM-IV or other surveys and trying to match that to the DSM-5 criteria.

But Swedo said this is a flawed approach.

“There is no point in using DSM-IV data to assess the DSM-5,” she said. “Our criteria are different, so you’re not going to find the information you need.”

Swedo also pointed out that the DSM-IV is not the gold standard for diagnosing autism. “If it were, we wouldn’t have been asked to fix it,” she said.

For example, the DSM-IV is notoriously bad at detecting autism at different ages and in different groups, including females, blacks and Hispanics, she noted. If the DSM-5 can accurately detect autism in those groups, “it might actually increase the numbers.”

Field trials of the new criteria, which use newly collected data to assess each child using both the DSM-IV and the DSM-5, are ongoing. Early results suggest that fears that many children will be left out are unfounded. According to studies of almost 300 children at two sites, the DSM-5 missed a handful of cases that were picked up by the DSM-IV, but the reverse was also true, said Swedo.

The DSM-5 criteria also proved highly reliable, meaning that two different clinicians using them were likely to diagnose the same child with the same disorder. (Because ratings for psychiatric disorders are subjective, responses among different clinicians can often vary.)

Diverse results:

Preliminary results from the two other studies also presented at the conference are somewhat different.

William Mandy, who led one of the two studies, had previously expressed concern that the DSM-5 might miss people with Asperger syndrome. He says his new analysis allays that fear.

“We didn’t find evidence that when you carefully implement the DSM-5, it will discriminate against people with Asperger syndrome,” said Mandy, a physician and lecturer in clinical health psychology at University College London. “But we do find that some people with PDD-NOS will move out of [autism] and into social communication disorder,” a new category in the DSM-5.

Using rich clinical information to deduce whether an individual meets the DSM-5 criteria, his team found marked differences in scores between those with autism and those with PDD-NOS, specifically on the repetitive and restricted behaviors.

“In our experience, people with a PDD-NOS diagnosis often miss out on a full diagnosis due to a lack of restrictive and repetitive behaviors,” said Mandy. “But I think a lot of them have profound communication difficulties on level with autism.”

The precise definition of social communication disorder is not yet clear, nor is it clear how those who mediate access to services, including insurance companies, state governments and schools, will regard that diagnosis.

The second study also found that the DSM-5 does not detect some children, primarily those with PDD-NOS. Kristen D’Eramo, director of clinical services at the Center for Children with Special Needs in Glastonbury, Connecticut, and collaborators analyzed data collected from 117 children referred to the clinic because of suspected autism. Clinicians assessed the children using a number of tools and then filled out two questionnaires, one with DSM-IV criteria and the other with DSM-5 criteria.

Of the 107 children ultimately diagnosed with an autism spectrum disorder, about 16 percent (17 children) do not meet the DSM-5 criteria. All meet the DSM-IV criteria. Of the 17, 16 qualify for a PDD-NOS diagnosis under the DSM-IV, and 1 for Asperger syndrome.

D’Eramo told SFARI.org she is surprised by the field trials’ findings that the DSM-IV misses some children who meet the DSM-5 criteria. “We did not have any of those cases, so it’s hard to imagine that kind of profile,” she says.

History counts:

During her talk at the conference, Swedo pointed out that children don’t necessarily have to meet each DSM-5 criterion at the time of diagnosis, but rather at any point in their lifetime.

For example, a child who had serious repetitive behaviors earlier in development but has since outgrown them would still meet that particular requirement. She said this will be written explicitly into the DSM-5 criteria.

D’Eramo says the guidelines must also clarify exactly how to apply this in clinical practice. The DSM-5 criteria listed online suggest that historical data must be supported by both parent and clinician reports, which can be hard to find. “We need to understand how to apply these codes,” she says.

Fred Volkmar, professor of psychiatry and psychology at Yale University, whose study sparked the New York Times report, says he is concerned about how the DSM-5 criteria will fare outside research studies.

“The findings applied in a real-world setting may be different than with a well-done diagnostic interview,” he says. For example, researchers often use tools such as the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised to assess children. But not all clinicians use these tools, and no specific tools are required by the DSM-5.

One thing all of these experts agree on is that more research is needed to clarify the true impact of the DSM-5.

The research and advocacy organization Autism Speaks, along with the Centers for Disease Control and Prevention, is funding research on how the DSM-5 affects prevalence, according to Geraldine Dawson, chief scientific officer of the organization.

At the end of her talk, Swedo pointed out that the guidelines are still open to comment. “We would be happy to get another 6,000 emails.”

For more reports from the 2012 International Meeting for Autism Research, please click here.

References:

1: McPartland J.C. et al. J. Am. Acad. Child Adolesc. Psychiatry. 51, 368-383 (2012) PubMed

2: Matson J.L. et al. Dev. Neurorehabil. 15, 185-190 (2012) PubMed

Sputnik Animation, McGovern Institute

Clear results: A glass pipette carefully placed next to the cell wall of a neuron can record the strength of its signals.

A robot can replace researchers in performing a painstaking technique that records neuronal signals in live animal brains, according to a study published 6 May in Nature Methods¹.

In 1991, Erwin Neher and Bert Sakmann received the Nobel Prize for a technique dubbed patch clamping, in which scientists record the activity of a neuron using a miniature glass pipette. Researchers carefully insert the pipette adjacent to a cell wall, covering one of many channels that release ions when neurons fire. A cable inserted into the pipette records these electrical changes.

The technique revolutionized neurobiology, but is extremely difficult to perform in the brains of live, anesthetized animals, and takes scientists months to master. 

In the new study, researchers engineered a robotic arm controlled by an algorithm designed to search and find neurons in the mouse brain.

First, the arm moves the glass pipette carefully into the brain up to a set distance, positioned near the neurons of interest. Next, the arm carefully advances the pipette two micrometers at a time, sampling electrical currents ten times per second. When the robot detects a neuron through a change in electrical current, it stops immediately. It then creates suction to form a seal with the cell wall, and sends a zap through the tube to open up a passage into the cell.

Using the arm, researchers were able to seek and successfully record signals from neurons approximately 33 percent of the time, equivalent to the success rate for a skilled researcher.

They plan to use the robot to sample from multiple neurons simultaneously; for example, neurons in distant regions of the brain. Some studies have suggested that deficits in long-range brain connections underlie autism.

The researchers can also modify the robot to perform other tasks. For example, it could inject neurons with dyes that outline their shape, extract genetic information to provide a picture of gene expression, or it could be trained to detect specific subsets of cells.

References:

1: Kodandaramaiah S.B. et al. Nat. Methods Epub ahead of print (2012) PubMed

Social rules: Knowing that their behavior is not socially acceptable, but being unable to control it, could make children with autism anxious.

A high intelligence quotient (IQ), a good understanding of social skills, and aggressiveness may all contribute to anxiety in children with autism, according to a study published 14 March in The Journal of Clinical Child and Adolescent Psychiatry¹.

Although anxiety is not one of the core deficits of the disorder, many individuals with autism are highly anxious, typically in social situations. Studies have shown that children with autism who have higher IQs are more anxious than those with lower scores², but the reasons for this association are not well understood.

In the new study, researchers investigated the links between IQ, autism diagnosis, awareness of acceptable social behavior, aggressiveness and age. They looked at 231 children between 2 and 9 years of age and assessed their IQ using one of five questionnaires, based on the age and abilities of the child. They also used the Parent Rating Scales of the Behavior Assessment System for Children to measure the children’s anxiety, social skills and aggression.

Children who have a diagnosis of Asperger syndrome have the most anxiety, followed by those who have pervasive developmental disorder–not otherwise specified, and those with autism have the least anxiety, the study found. Controlling for IQ scores made these associations insignificant, suggesting that the higher intelligence is connected to the anxiety, the researchers say.

Toddlers who have autism and high IQ scores are more anxious if they also have a greater understanding of social skills and are aggressive compared with those who are less aggressive and have poor social skills, the study found. This could be because knowing that one’s behaviors are not socially acceptable, but being unable to control this, could be anxiety-provoking, the researchers suggest.

The relationship between these factors is more nuanced for preschool and elementary school children than it is for toddlers, the study also found. In each case, aggressiveness and understanding of social skills are associated with elevated anxiety. However, children who have low IQs and show little aggression show no difference in their anxiety regardless of their social understanding.

The results suggest that measuring the severity of autism is complicated and cannot be done in isolation by individual factors such as IQ scores.

References:

1: Niditch L.A. et al. J. Clin. Child Adolesc. Psychol. 41, 127-137 (2012) PubMed

2: Sukhodolsky D.G. et al. J. Abnorm. Child Psychol. 36, 117-128 (2008) PubMed

You’ve probably heard the axiom about autism’s infamous variability: If you’ve met one child with autism, you’ve met one child with autism — meaning that every child shows a unique combination of atypical behaviors. The same could be said for a mouse carrying an autism-linked genetic glitch.

Mice may all look alike but, like people, they carry different combinations of background genes that may interact with a given mutated gene. They also have variable exposures in utero and experiences after birth that may influence the expression of genes. Even if all of these variables were the same, no two mice, like no two people, will respond to a given situation in exactly the same way.

And yet, most studies are designed as if mice were all the same.  

Researchers typically use only one ‘cohort,’ a group of about three dozen mice, for a given set of experiments. In the handful of studies that have used more than one cohort — the latest of which came out 9 May in the Journal of Neuroscience — sometimes the results hold up, and sometimes they don’t.

In a study published last year, researchers made two cohorts of mice carrying extra copies of UBE3A, an autism candidate gene. Both groups of mice showed little interest in social interactions.

By contrast, consider a 2007 study of mice lacking the receptor for vasopressin, the 'fight or flight' hormone linked to autism. The researchers, led by Jacqueline Crawley, made five cohorts of mice. They found that social behavior is abnormal in one group but normal in the other four.

“From my reading of the literature, the field has been seriously muddied by the current lack of required standards for at least one replication before publication — and before press releases,” says Crawley, chief of behavioral neuroscience at the National Institute of Mental Health, and lead investigator of the new report.

The report gives a perfect example of the many flavors of variability in mouse models. Crawley and her colleagues looked at mice carrying a mutation in one copy of SHANK3, a gene that’s strongly linked to autism.

The mice debuted in 2010 (with Crawley as one of the authors), and the new study validates some previous findings. For example, it confirms that these mice show normal social behaviors as adults and mild deficits during juvenile social interactions.

The new study also looked at a wide range of behaviors in three independent cohorts. The researchers found that, although object recognition and motor performance are consistent among the groups, repetitive self-grooming, abnormal ultrasonic vocalizations and water-maze learning are not.

Addressing variability can’t stop with adding cohorts. The precise nature of a mutation matters, as does the strain of the mice used. Mice carrying a glitch in a different piece of SHANK3, for example, show severe social problems and compulsive grooming. And the same NLGN3 mutation causes social deficits in one strain of mice but not in another.

Last year, a study of six mouse strains lacking the gene for fragile X syndrome, found that each strain has its own distinct set of abnormal behaviors.

It’s pretty clear, then, that mouse studies need to be repeated — in multiple cohorts and strains. Crawley’s lab routinely creates two cohorts of mice for each experiment. If the results don’t match, the researchers make a third.

These extra steps are no doubt more time-consuming and expensive, but without them, the data don’t mean much. If you study one mouse cohort of autism, you study one mouse cohort of autism.

Lost linker: Neurons carrying either of two new mutations in neurexin-1 (red), an autism-linked protein, have less of the protein (above and middle) than controls do (top).

Researchers have identified four new mutations in the autism-linked gene neurexin-1 (NRXN1) in individuals who have autism and severe intellectual disability, they reported 3 April in Neurobiology of Disease¹.

Neurexins are linker molecules that jut out on the signal-transmitting ends of synapses, the junctions between neurons. They form connections with neuroligins, which sit at the neurons’ signal-receiving ends. A 2003 study first identified mutations in neuroligins in two brothers with autism, implicating dysfunction at the synapse in the disorder.  

Since then, several studies have linked both neuroligins and neurexins to autism, and identified duplications and deletions of regions of the NRXN1 gene in individuals with the disorder.

In the new study, researchers sequenced NRXN1 in 86 individuals who have autism and intellectual disability and 200 controls. They identified four individuals, each of whom has a different NRXN1 mutation that alters a single DNA base pair. None of these mutations is present in any of the controls.

Two of the mutations overlap with the start of the gene and would be expected to interfere with gene expression. But cells expressing these mutations produce a shortened version of NRXN1 protein that uses an alternative site at which to initiate expression, the study found. The other two mutations disrupt the protein in a region that extends through the cell membrane.

One mutation in each region — M1G at the start site and R375Q in the part that extends through the membrane — lowers the amount of NRXN1 present at the synapse by 30 percent and 60 percent respectively, compared with control protein.

The mutations are all inherited and each is present in affected family members, unaffected family members and those with related symptoms.

For example, the M1G mutation is also present in two sisters who have depression, a nephew with attention deficit hyperactivity disorder and antisocial personality disorder, and an unaffected niece. The individual with the R375Q mutation inherited the mutation from her unaffected mother and shares it with her brother who also has autism.

References:

1: Camacho-Garcia R.J. et al. Neurobiol. Dis. Epub ahead of print (2012) PubMed

Cohesive unit: A unique partnership brings together researchers from different European countries, in different phases of research, and from both academia and the pharmaceutical industry.

A $38.7 million project in the European Union — the largest single grant for autism research in the world — aims to bring together academic labs and pharmaceutical companies, including Roche, Eli Lilly and Pfizer, to speed the move from basic to clinical research.

The effort, called European Autism Interventions – A Multicentre Study for Developing New Medications, or EU-AIMS, focuses on improving translational research, including developing stem cells, animal models and a European network for running clinical trials. Launched in April, it is led by Roche and researchers at King's College London.

“If we want to find new medicines, we need to lower the barrier for investment,” says Luca Santarelli, head of neuroscience at Roche. “That means we need to collectively progress the science, translational research and clinical trial technology.”

Half the funding for the five-year project comes from the Innovative Medicines Initiative, a European public-private initiative designed to help develop better and safer medicines, and half from the European Federation of Pharmaceutical Industry Associations. Autism Speaks, a U.S.-based research and advocacy organization that contributed $1 million to the project, is another collaborator.

“I think it’s a great first effort and will dramatically contribute to the understanding, treatment and de-stigmatization of autism in Europe,” says Randall Carpenter, president of Seaside Therapeutics, a Massachusetts-based biotech company testing drugs for autism and fragile X syndrome, and head of the grant review committee. “They have been visionary in their thought process and tried to integrate and learn from everyone else who has tried these projects.”

For example, the researchers plan to make the resources that emerge from the project, such as databases and a collection of biological samples, able to link with existing autism repositories. 

The products of the project are also considered ‘pre-competitive,’ meaning the information can be shared freely. “Pre-competitive applies to areas where the field is young and needs to progress to a critical point where companies can invest in proprietary research,” says Santarelli.

Trial training:

A central thrust of the EU-AIMS project is to create a network of centers of expertise for the various components of autism research.

“We want to develop better animal models, better understanding of the biology of disease, and better clinical scales and endpoints,” says Santarelli. “If you do that in isolation, you have less power than doing it as a team.”

One group aims to generate induced pluripotent stem (iPS) cells from people with autism to try to identify cellular abnormalities, and to develop new technology for drug discovery assays.

Researchers specializing in animal models plan to generate new strains that robustly show the core symptoms of autism: social deficits and repetitive and restricted behaviors. They also aim to develop reproducible behavioral assays and anatomical and functional biomarkers, such as differences in brain structure or behavior, that can ultimately be used to test drugs. 

The animals will be housed in a central animal repository, and breeding pairs can be shared with other researchers.

Part of the translational effort will be to develop new molecular imaging techniques that can be used across different species.

“We want to put everything together and try to come up with a holistic view,” says Declan Murphy, professor of neurodevelopmental sciences at King’s College London, and the academic lead on the effort.

For example, he says, the researchers don’t just want to measure glutamate and GABA, two chemical messengers in the brain, in live animals. They instead hope to understand how these markers relate to autism-linked mutations and how they are modulated by different drugs.

On the clinical side, researchers plan to work closely with families, for example by studying infants who have siblings with autism and are therefore at higher-than-average risk of developing the disorder. They plan to follow approximately 300 of these so-called ‘baby sibs’, as well as 500 children with autism, in search of early biomarkers that can predict autism, and to assess whether those biomarkers change over time. 

“What they are doing is very comprehensive and commendable in terms of trying to integrate investigators and bringing in pharma to the table,” says Antonio Hardan, assistant professor of psychiatry and behavioral science at Stanford University in California, who is not involved in the project. Forty million dollars, he points out, “is a great catalyzer.”

One of the most important aspects of the project is the development of six clinical centers — with more planned — across Europe. “If we identify new treatments, we can roll them out to clinical populations immediately,” says Murphy.

The researchers also plan to work with Europe’s drug regulatory body, the European Medicines Agency, to determine the best outcome measures.

For a disorder as diverse as autism, it’s especially important to have access to large numbers of people for clinical trials. Most clinical trials in autism have been comparatively small, with 50 or fewer participants. That makes it difficult to identify subgroups that might respond to the treatment, says Hardan.

Given that the effort spans at least seven different countries and intends to include individuals who speak as many languages, the researchers face the unique challenge of developing and validating tools that work across the various languages and cultures. 

The U.S. has its own autism clinical trials network, known as the Research Units on Pediatric Psychopharmacology Autism Network, but it has few sites and does not incorporate a basic science component.

“No other effort [in the autism field] is bringing basic science and clinical trials under one umbrella,” says Hardan. “These countries have done it before politically, so they can probably [work] together here also.”

Preliminary results from a placebo-controlled trial of the antibiotic minocycline in children with fragile X syndrome suggest the drug alleviates some aspects of the disorder, according to research presented Friday at the International Meeting for Autism Research in Toronto.

In the study, researchers analyzed data from 48 children and teens, ages 3 to 16, with fragile X syndrome, one of the most common forms of inherited intellectual disability. Participants took either the drug or the placebo for three months, and then switched to the other arm of the study, a design known as a double-blind cross-over clinical trial.

Minocycline significantly improved scores on the Clinical Global Impression rating scale, a seven-point measure used to assess symptom severity and response to treatment, lead investigator Randi Hagerman, medical director of the MIND Institute at the University of California, Davis, reported at the conference.

The researchers also saw improvement on the anxiety and mood subscales of the Visual Analog Scale, which is designed to measure conditions such as pain. Because it is a subjective test, it is typically used to measure changes in an individual.

In the trial, the researchers did not see significant differences between placebo and drug treatments in the language or aggression scales of this test, nor in the Aberrant Behavior Checklist, another test used to assess treatment effects. The drug seems to be safe and well tolerated, Hagerman says.

Previous research in animal models of fragile X has shown that minocycline improves some symptoms of the disorder, including anxiety. It also helps to mature neural connections between hippocampal cells grown in culture, says Hagerman. Mouse models of fragile X have an abundance of immature neural connections.

The drug may act through a variety of mechanisms. It is an anti-inflammatory and also slows protein synthesis, which is thought to be overactive in fragile X.

It also lowers levels of matrix metalloproteinase 9 or MMP9, an enzyme that has several functions, including breaking down the extracellular matrix MMP9 levels are elevated in many people with fragile X and some people with autism, Hagerman says.

The researchers hope to do a longer-term clinical trial, as well as to test the drug in children with autism, she adds. They have applied for funding to study levels of MMP9 as a biomarker in children with fragile X and in those with autism, as well as how these children respond to minocycline.

For more reports from the 2012 International Meeting for Autism Research, please click here.

Autism researchers need to build a culture of data-sharing. That’s the message that Thomas Insel, director of the National Institute of Mental Health (NIMH), wanted to convey Friday at the International Meeting for Autism Research (IMFAR) in Toronto.

Grants from the National Institutes of Health (NIH) already require that researchers add their data to the National Database of Autism Research (NDAR) within a year of publication. That’s important so that data can be reused in new ways, for example to create larger datasets with greater statistical power, said Susan Daniels, acting director of the NIMH’s Office of Autism Research Coordination, who filled in for Insel as a speaker at the conference.

Given shrinking research budgets, data-sharing is likely to become even more important. In Insel’s words, presented by Daniels at the conference, “Share data to protect the future of your funding and funding for autism research as a whole."

After growing steadily for most of the past decade, funding for autism research has plateaued, a trend Insel pointed to at IMFAR last year.

However, autism funding is growing faster than that for other neurological disorders, such as multiple sclerosis, as well as for neuroscience in general.

In 2010, a combination of 18 public (82 percent) and private (18 percent) organizations gave out a total of $408 million. The Simons Foundation, SFARI.org’s parent organization, is the second largest funder after the NIH.

Research on lifespan issues, including functioning of adults with autism and treatments tailored to this group, get the smallest chunk of funding, less than two percent. This issue used to be lumped together with research into autism services, but it is now its own category because it is considered so important, said Daniels. Services garner 16 percent of overall funding.

For more reports from the 2012 International Meeting for Autism Research, please click here.

Children and teens with autism — or the related disorders schizophrenia and attention deficit hyperactivity disorder, among others — are often prescribed antipsychotic drugs from an early age.

But little is known about the long-term effects these drugs may have on the brain.

Research on schizophrenia suggests that many of these drugs affect brain volume: Antipsychotics appear to shrink the brain and the mood stabilizer lithium seems to enlarge it. What has been unclear so far is whether these changes result from the treatment or are a normal part of the disease course.

A new study confirms that the observed changes in brain size are the result of drug treatment. Researchers treated rats with either the antipsychotic haloperidol or with lithium every day for eight weeks, roughly equivalent to five years for humans.

According to brain scans taken before and after treatment, haloperidol shrank the volume of gray matter, which contains neuronal cell bodies, by six percent, and lithium increased gray matter volume by three percent. The findings were published 8 May in Biological Psychiatry.

The study leaves many questions unanswered. It’s not clear, for example, whether these changes reflect part of the benefits of the drugs, or whether they are a negative side effect. Also, the researchers used normal rats rather than those engineered to mimic the symptoms of schizophrenia or autism, so they can't say whether the drugs would have different structural effects in those animals.

Still, the findings could be relevant for children with autism. About one in three people with autism are treated with antipsychotics to relieve irritability, aggression and sleeplessness. In fact, the only two drugs approved by the Food and Drug Administration to treat autism, risperidone and aripiprazole, are both antipsychotics. (Other drugs, including antidepressants and stimulants, are commonly prescribed as well.)

Although neither risperidone nor aripiprazole was tested in the current study, they share some molecular mechanisms with haloperidol. Risperidone binds to receptors for brain-derived neurotrophic factor, a protein that stimulates the growth of new neurons and neural connections.

Lithium has been shown to reverse some of the signs of fragile X syndrome, an autism-related disorder, in animal models. Preliminary evidence suggests it can improve irritability in people with the syndrome. 

Given that autism is thought to be a disorder of brain connectivity, and that changes in brain size are associated with the disorder, it seems crucial to understand the long-term effects of drugs used to treat it. 

Methyl marks: A study of pregnant women could help clarify the gene-environment interactions that raise autism risk.

By studying pregnant women who already have a child with autism, researchers hope to understand how epigenetic changes — those that affect gene expression but don’t directly alter DNA — during pregnancy influence risk of the disorder.

One group is using a method called CHARM, or comprehensive high-throughput arrays for relative methylation, to assess methylation, the addition of a methyl group to DNA that typically turns off gene expression. The researchers are studying how methylation changes during pregnancy and in young children over time, as well as in response to specific environmental exposures.

A second group is measuring ‘methylation capacity,’ an indirect measure of how well a cell can methylate genes, in pregnant women to determine whether abnormal levels can predict a later autism diagnosis for the child.

Both projects, presented yesterday at the International Meeting for Autism Research in Toronto, are part of the Early Autism Risk Longitudinal Investigation (EARLI), which aims to sort out the genetic and environmental factors that contribute to autism.

EARLI results:

Launched in 2009, EARLI is focused on pregnant women who already have a child with autism and have a higher-than-normal risk of having another. About 10 to 25 percent of siblings of a child with autism will go on to develop the disorder, compared with an average risk of about 1 percent. (One of EARLI’s goals is to get a better handle on that number.)

Researchers at a number of sites across the U.S. are collecting blood and other biological samples from these women and their children as well as data on their diet, medication use, medical conditions, pesticide exposure, vaccine use, occupational history and additional factors. The children get behavioral assessments beginning at 6 months of age and through 36 months, when they can be tested for autism. EARLI ultimately aims to enroll 1,200 mothers.

Because the study is prospective, meaning that data are collected over time, the researchers say they hope it will help clarify how genetic and environmental factors interact to raise autism risk. Epigenetics, which can be influenced by the environment, is one way to examine this interaction. (Retrospective studies rely on participants to recall information about the past and so are more subject to bias.)

One of the two EARLI projects presented yesterday aims to link methylation data from women during and after pregnancy with environmental exposure. Preliminary findings show that methylation appears to be stable throughout pregnancy.

The second looked at metabolic biomarkers in pregnant women. The researchers had previously found that women who have children with autism have an abnormal methylation capacity, defined as the ratio of S-adenosyl methionine (SAM) to S-adenosylhomocysteine (SAH) SAM is a critical ingredient of methylation. The methylation process, in turn, produces SAH.

EARLI gave the team the opportunity to determine whether this pattern is present in pregnancy and, if so, whether it predicts the child’s risk of autism.

The researchers found that about 15 percent of the 60 women have low methylation capacity compared with 100 controls. However, they won't know for about three years, when the children can reliably be diagnosed with autism, whether this is predictive of the disorder.

Still, the 15 percent figure is interesting because it aligns with the risk for siblings of children with autism, notes lead investigator Jill James, director of the Metabolic Genomics Laboratory at Arkansas Children’s Hospital Research Institute.

For more reports from the 2012 International Meeting for Autism Research, please click here.

Simon says: Children who have autism struggle with joint attention, the ability to engage others’ attention. 

Toddlers with autism who receive behavioral interventions that improve joint attention — engaging and following others’ focus — have better language ability five years later than do controls, according to a study published in May in the Journal of the American Academy of Child and Adolescent Psychiatry¹.

Studies have shown that early behavioral interventions may be among the best available treatments for autism, but they are not effective for all children. Few studies have documented the long-term outcomes of this type of intervention.

In a 2006 study, researchers enrolled 58 children with autism in behavioral interventions for 30 hours a week, for five to six weeks.

The researchers divided the children into three groups². In one group, the intervention focused on joint attention, for example by repeating back to the child whatever he or she said. In the second, researchers encouraged the children to participate in symbolic play, such as pretending that a doll can drive a car. The third group of children represented controls, and received standard treatment with no particular emphasis on joint attention or play skills.

After the intervention, the children who learned joint attention skills were more likely to engage the attention of their mothers, and those who learned play skills were more likely to engage in unprompted symbolic play.

In the new study, researchers followed up on 40 of these 58 children. Overall, regardless of the treatment group, the children who spontaneously engaged in symbolic play at 3 years of age have better language ability five years later, the study found.

Toddlers who participated in one of the two interventions also developed a better vocabulary compared with controls. Those who were closer to 3 years of age when they began the intervention improved more than those who were closer to 4, the study found.

References:

1: Kasari C. et al. J. Am. Acad. Child Adolesc. Psychiatry 51, 487-495 (2012) PubMed

2: Kasari C. et al. J. Child Psychol. Psychiatry 47, 611-620 (2006) PubMed

Love hormone: After a single dose of oxytocin, fathers were less willing to stop gazing at their babies.

Two new studies on the so-called ‘trust hormone’ oxytocin, presented today at the International Meeting for Autism Research in Toronto, suggest new avenues for using the drug to treat autism.

One study found that treating fathers with the hormone boosts levels in their infants. The second showed that when children with autism play with a parent, their oxytocin levels rise to those of controls.

Oxytocin, a hormone first discovered for its role in childbirth, governs social bonding and is released both in the brain and peripherally in the body.

Mutations in genes that regulate oxytocin release are thought to raise the risk of autism or autism-like traits, although some findings are contradictory. Some studies suggest that when people with autism sniff oxytocin, their performance on social tasks improves.

Ruth Feldman, professor of psychology at Bar-Ilan University in Israel, studies the development of the parent-child bond, and the role that oxytocin plays.

Feldman’s previous research has shown that mothers and fathers both have an increase in oxytocin levels in saliva when holding and playing with their babies. Her team is studying how treatment with oxytocin in parents affects hormone levels in their children, as well as how the drug might be used to treat autism and other disorders.

In one study, Feldman and her team gave 35 fathers a single dose of oxytocin by nasal puff before playing with their babies. (They didn't study mothers because they had not yet been given approval to give the hormone to breastfeeding women.)

These fathers showed a significant increase in saliva oxytocin levels after playing with their infants, from an average concentration of 1,000 picomoles at baseline to 6,000 after play. The fathers were less willing to stop gazing at the infants, and the infants held the gaze longer, says Feldman. Fathers given a placebo didn’t show a significant rise in oxytocin or change in behavior.

Strikingly, infants showed a similar increase in hormone levels, even though they hadn’t been given any drugs, notes Feldman. That may prove relevant for treating children at risk of developing autism.

“Giving oxytocin to a parent has a parallel effect on the child, which may open a new direction for intervention for young high-risk infants,” says Feldman.

In the second study, her team analyzed oxytocin levels in parents, and in preschool-aged children with high-functioning autism, before and after a play session.

Mothers of children with autism showed no difference in oxytocin levels compared with controls, before or after play, the study found.

As might be expected, the children with autism spent less time gazing at parents and engaging in joint attention — when the parent gestures for the child to pay attention to something — compared with controls.

The children with autism had lower baseline levels of oxytocin compared with controls, a finding in line with previous research showing that adults with the disorder have low levels of the hormone.

After playing with a parent for 20 minutes, oxytocin levels in the children with autism rose to levels similar to those of controls, and remained elevated for about 40 minutes before falling back down.

“This is the first result we know of in peripheral oxytocin of young children with autism,” says Feldman. “These findings, if replicated and further understood, can serve as a baseline of intervention, maybe pharmacological or behavioral, to maintain a high level of oxytocin.”

For more reports from the 2012 International Meeting for Autism Research, please click here.