Big investment: Unlike the U.S., the U.K. spends more than half of its autism funds on understanding the biology underlying the disorder.
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Autism researchers presented the report during a government reception for Research Autism, a private U.K.-based charity that raises money for studies of the disorder.

Autism publications by researchers in the U.K. rose from 90 in 2001 to 186 in 2011. That’s a healthy increase, but worldwide, English-language publications on autism over the same time period nearly quadrupled from 548 to 2,101. 

Most of the U.K. studies are on children with the disorder, even though the majority of people with autism in the country are aged 18 or older. Of the 74 studies published from 2007 to 2011 that look at a specific age group, for instance, only 11 focused exclusively on adults.

Overall, in 2010 the U.K. spent £2.6 million ($4.08 million) on autism from both public and private sources, compared with $357 million in the U.S. In terms of per capita research dollars, the U.S. spends 18 times more per person with autism than the U.K. does.

About 80 percent of the autism funding in both countries comes from the government. However, they spend their money differently. In the U.K., 56 percent of the funds go toward studying the biology underlying the disorder, with the remainder split among studies on diagnosis, causes, treatments, services and societal issues.

In contrast, the U.S. spends its autism money more evenly across these categories, although neither country spends much on societal issues.

The researchers surveyed 1,600 people with autism, their families, their doctors and autism researchers on the U.K. funding priorities.

About two-thirds of those surveyed said they were dissatisfied with the U.K.'s emphasis on biology, brain and cognition. Instead, they said, they would like more money spent on publicly funded services for people with the disorder.

Although basic research is valuable, it's important to find treatments and services for people with autism, notes Tony Charman, chair of clinical child psychology at King's College London, one of the three investigators who led the study.

"I don't think it's right for people with autism and those who care for them to wait decades before they get better services, support and understanding," he says.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

Vision loss: The protein expressed by a mutant form of the fragile X gene severely damages fly eyes (left).

A mild form of the fragile X mutation produces an unusual protein that may trigger fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder, according to a study published 8 May in Neuron¹.

Fragile X syndrome is caused by more than 200 repeats of three nucleotides (CGG) located just before the coding region of the FMR1 gene. These repeats shut off FMR1’s expression, preventing its translation into messenger RNA (mRNA) and then into protein.

Unexpectedly, a premutation of FMR1, which has 55 to 200 repeats, boosts production of FMR1 mRNA. This can lead to FXTAS, which is characterized by memory loss and tremors. Researchers have speculated that in people with FXTAS, this mRNA may itself be toxic. Postmortem studies have also found clumps of protein in the brains of individuals who had FXTAS, although it was not clear how these clumps were related to the FMR1 mutation².

In the new study, researchers found that in people with the premutation, CGG repeats of various sizes themselves are translated. When large enough, the resulting protein, called FMRpolyG, may accumulate into toxic, insoluble clumps that the cell’s disposal machinery has difficulty clearing away.

The researchers found clumps that contain this protein in postmortem brains from three people who had FXTAS but none of five controls.

They also engineered fruit flies and cultured mammalian cells that express this CGG repeat region. The resulting clumps cause the flies’ eyes to degenerate, and they kill mammalian cells.

Stimulating production of this protein in fruit flies boosts the toxic effects, and dampening its production does the opposite. This confirms that it is the protein and not the untranslated mRNA that does the damage, the researchers say. 

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Todd P.K. et al. Neuron 78, 440-455 (2013) PubMed

2: Iwahashi C.K. et al. Brain 129, 256-271 (2006) PubMed

A. Kramer, Texas Children's Hospital

Delayed onset: Jeffrey Neul studies Rett syndrome, which is characterized by a loss of language and motor ability around 1 year of age.

There seem to be two broad patterns of disease progression in autism. Many individuals with the disorder show features within the first year of life, with gradually developing impairments in social and language development^{1, 2}.

However, a significant minority displays another distinct course, marked by loss of previously acquired skills around age 1 or 2, notably in language and social interaction. The prevalence of this ‘regressive' form of autism is not known, ranging from 12 to 50 percent of people with autism. (A meta-analysis published this year found the prevalence of regression in autism to be 32.1 percent³.) Part of the reason for this wide range is differences in the way these studies define regression in autism.  

Regression is better understood in Rett syndrome — a neurodevelopmental disorder that resembles autism — in which regression is a defining feature⁴. The syndrome predominantly affects girls, who appear to have normal motor, cognitive and social development until 6 months of age. These girls may show some developmental delay, but then at 1 or 2 years of age they undergo a severe developmental regression and lose the ability to speak and use their hands. 

Intriguingly, regression in Rett syndrome occurs at the same time as in regressive autism, and includes many of the same features, suggesting a common biological process.

Regression progression:

A fundamental question is: What is the biological basis of regression in autism? Loss of skills is seen in only a handful of other disorders. In some situations, loss of previously acquired skills is the first indication of a progressive, relentless disease process, as in some forms of childhood neurodegeneration, such as Batten disease.

However, the overall course in these conditions is distinct from that seen in regressive autism. In most neurodegenerative disorders, skills are progressively and continuously lost. In contrast, regression in autism occurs over a defined time period. Skills may ultimately stabilize and, potentially, be partially or even fully restored. Some studies have indicated that the presence of regression in autism correlates with poor social, intellectual and language function later in life. However, other reports did not find this relationship.

A small number of other disorders, such as childhood disintegrative disorder (CDD), do show the time-delimited regression seen in some cases of autism. There are many similarities between CDD and autism, with the notable distinction that the onset of symptoms and regression in CDD is seen later (older than 3 years) than in autism.

Severe seizures can also lead to loss of skills, for example in a condition known as epileptic encephalopathy. Although there is some relationship between seizures and autism, the rate of seizures in regressive versus non-regressive autism is not different, suggesting that the underlying cause of loss of skills is distinct between epileptic encephalopathy and regressive autism.

In the case of Rett syndrome, girls undergoing regression may have diminished eye contact and become socially withdrawn, indifferent to their surroundings and irritable. They have difficulty walking or lose the ability entirely, and display relentless, repetitive hand movements.

After this regression, they enter a period of developmental stabilization. During this time, they no longer lose skills and may show some improvement in hand skills and language, although most affected girls remain markedly impaired in these domains.

In contrast, social skills, especially gaze, dramatically improve after the regression period, and most girls with the syndrome show intense eye contact and use their gaze to communicate. Even so, they continue to show abnormal social behavior throughout life⁵, and more mildly affected individuals show distinct features of autism⁶.

Rett relationship:

What can Rett syndrome tell us about regression in autism? In both disorders, loss of spoken language and social skills are the key features. Also, the vast majority (95 percent) of Rett syndrome cases are caused by mutations in a single gene, MeCP2, which encodes a protein that regulates the expression of other genes.

Researchers can identify people who have MeCP2 mutations at a young age and then characterize clinical, physiological and molecular changes that occur during regression. For example, researchers could look at molecular changes in gene expression or metabolites in the blood, or at neuronal activity with electroencephalography or functional magnetic resonance imaging, as children undergo regression.

Understanding the genetic basis for Rett syndrome provides other distinct advantages. First, we know the underlying etiology of the clinical condition in essentially all affected individuals. Second, we can use the genetic information to create animal models, which can help us understand the disease process and allow testing of potential therapeutics. 

Animal models of Rett syndrome show many, if not all, of the clinical problems seen in people with this disorder. We have used these models to understand the function of the gene and the effect of its loss on the nervous system. 

We can also use animal models of Rett syndrome to understand molecular, cellular and circuit-level changes that occur during regression. 

However, demonstrating that regression occurs in the animal model has been a challenge. The major regression that occurs in Rett syndrome is loss of hand skills and loss of language, neither of which are present in the same way in rodents.

One approach is to look at other clinical features present both in people and in the animal model. My lab has focused one such feature: breathing abnormalities.

We recently determined that breathing in Rett syndrome mouse models is normal early in life, but becomes abnormal over time. Rett syndrome model mice breathe at a faster rate and hold their breaths more than controls, and have an abnormal breathing response to a low-oxygen environment⁷.

By focusing on the neural circuit controlling breathing and looking at changes that occur in its cells and connections, we hope to understand the molecular, cellular and circuit-level problems that lead to loss of correct breath control. 

Another way to expand our understanding of regression is to use animal models to explore molecular, cellular and circuit-level changes that occur both as the disorder progresses and in the face of regression. We hope that the insights we gain from this particular circuit will shed light on the circuit-level dysfunction underlying regression in Rett syndrome and potentially in autism.

One of the most exciting findings that has emerged in Rett syndrome is that the disease is reversible in mice⁸. Restoring MeCP2 function reverses the disease process, even in sick animals. This has provided great hope that researchers can develop similar treatments for both Rett syndrome and other neurodevelopmental disorders in people.

In fact, researchers have used these animal models to determine that treatments that modulate brain-derived neurotrophic factor can treat Rett syndrome in mice. Also, a tripeptide derived from insulin-like growth factor-1 has been shown to alter the course of the disease in animals⁹. This finding has lead to two clinical trials in Rett syndrome and one in Phelan-McDermid syndrome, an autism-related genetic syndrome.

Ultimately, detailed characterization of genetically defined disorders such as Rett syndrome, which have excellent animal models, is likely to provide insight into many of the biological processes involved in related neurodevelopmental disorders such as autism. This is especially true with regard to regression, as this is a feature shared by Rett syndrome and autism, but found in few other disorders.

Jeffrey Neul is associate professor of molecular and human genetics at the Baylor College of Medicine in Houston, Texas.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Ozonoff, S., Heung, K. and Thompson, M. (2011). Regression and other patterns of onset. In D. Amaral, D. Geschwind and G. Dawson (Eds.), Autism spectrum disorders (pp. 60-74). New York, NY: Oxford University Press.

2. Stefanatos G.A. Neuropsychol. Rev. 18, 305-319 (2008) PubMed

3. Barger B.D. et al. J. Autism Dev. Disord. 43, 817-828 (2013) PubMed

4. Neul J.L. et al. Ann. Neurol. 68, 944-950 (2010) PubMed

5. Kaufmann W.E. et al. J. Intellect. Disabil. Res. 56, 233-247 (2012) PubMed

6. Renieri A. et al. Brain Dev. 31, 208-216 (2009)  PubMed

7. Ward C.S. et al. J. Neurosci. 31, 10359-10370 (2011) PubMed

8. Guy J. et al. Science 315, 1143-1147 (2007) PubMed

9. Tropea D. et al. Proc. Natl. Acad. Sci. USA 106, 2029-2034 (2009) PubMed

Brain boost: Deleting one of the genes that leads to tuberous sclerosis (left, green) elevates mTOR levels (red) compared with control neurons (right), and may lead to seizures.

The mutation that causes tuberous sclerosis complex, an autism-related disorder, may disable calming signals in the brain, leading to hyperactive neurons, according to a study published 8 May in Neuron¹.

Tuberous sclerosis is caused by mutations in either TSC1 or TSC2 and is characterized by benign tumors, called tubers, throughout the body. One of its predominant symptoms is severe seizures, seen in as much as 90 percent of people with the disorder. The new study relies on mice lacking both copies of TSC1.

Studies have shown that mouse models of the disorder have elevated brain activity, which may be the cause of these seizures. But researchers were not clear on how exactly the TSC mutations trigger the changes.

“That is the frontier we know jack about,” says Gordon Fishell, professor of neuroscience at New York University, who was not involved in the study. “Despite the overt example of the tubers, I don’t think anyone really had any clear idea of what was happening.”

The popular theory for what causes seizures in tuberous sclerosis is that excitatory neurons, which initiate brain activity, are inherently hyperactive in people with the disorder.

The new study instead found that in the mouse model, the excitatory neurons don’t respond to signals from inhibitory neurons, which dampen their activity. Although the two sets of neurons form connections, or synapses, just as they do in controls, excitatory activity in the mutant mice remains unchecked.

This may be because the mutant excitatory neurons are missing some of the receptors that respond to gamma-aminobutyric acid (GABA), the chemical messenger released by the inhibitory neurons, the researchers say.

“It shows how wrong our intuition was about the system,” says senior investigator Bernardo Sabatini, professor of neurobiology at Harvard Medical School. “We kept going through one thing or the other until we finally had to face the fact that it was inhibition.”

Secondary changes:

The researchers first looked for signs of hyperactivity in cultured neurons lacking both copies of TSC1. They found that the excitatory neurons have altered patterns of signaling and gene expression.

But many of these changes would be expected to dampen, not boost, excitatory activity — for example, the mutant neurons have lower-than-normal levels of GLUA1 and GLUA2, components of a receptor that responds to excitatory signals. Levels of ARC, a protein that helps keep excitatory activity in check, are elevated in these neurons.

These alterations may be an attempt to compensate for the lack of inhibition, the researchers say. “[The excitatory neurons] are actively trying to restore balance to the system, but for some reason it isn’t working,” says Helen Bateup, assistant professor of neurobiology at the University of California, Berkeley. Bateup did the research as a postdoctoral fellow in Sabatini’s lab.

To separate the primary effect of lack of TSC1 from its ultimate influence on brain circuits, the researchers then deleted the gene in a small number of cells in the hippocampus. They activated this mutation in 14- to 17-day-old mature mice after brain circuits had already formed.

In these mice, the mutant excitatory neurons show a weaker response to inhibition than control neurons do, the researchers found.

“This is a novel finding that will open up new avenues for research,” says Mustafa Sahin, assistant professor of neurology at Boston Children’s Hospital, who is not involved in the study. “Why do inhibitory synapses change in those neurons?”

The results also help elucidate how rapamycin, a drug that is in clinical trials for tuberous sclerosis, works to quell seizures. Rapamycin corrects both the deficit in inhibition as well as the gene expression and other changes in the excitatory neurons.

Rapamycin inhibits the activity of mTOR, a protein involved in cell growth that is kept in check by TSC1 and TSC2. The study suggests that mTOR, which is elevated in the mouse model, leads to deficits in inhibition, although how it does this is still unknown.

Rapamycin may also be useful for seizure disorders that are unrelated to mTOR regulation but which show a similar block in inhibition, says Sabatini.

If the hyperactive signaling is the result of missing GABA receptors, as the study suggests, a commonly prescribed group of anti-seizure medications that activate GABA signals would be ineffective, notes Sabatini. Researchers should look for new compounds that may restore these receptors, he says.

About half of individuals with tuberous sclerosis have autism, and researchers have posited that a similar imbalance between excitatory and inhibitory signaling may underlie autism symptoms.

“We are getting to the point where we need to focus on cellular mechanisms,” says Fishell. “That makes this study an important step forward for autism, even if the genetics [of autism and tuberous sclerosis] aren’t tightly associated.”

References:

1: Bateup H.S. et al. Neuron 78, 510-522 (2013) PubMed

CONNECTIONS

SFARI.org's columnist Jon Brock explores the connections between the brain, social skills and autism.
Read more columns »

These are fast-moving times for autism research. Every week brings a new swath of research findings that promise fresh insights into the causes of autism, its diagnosis and treatment. Yet, beneath the flurry of publications, the reality is that progress has been painstakingly slow.

One reason, unfortunately, is that many published studies contain results that turn out not to be true. This isn’t because scientists are lying or fabricating their data. It is a consequence of the way science is done and the pressures on researchers to produce results.

The scientific approach is meant to guard against erroneous findings. Statistical analyses are used to indicate how likely it would be to get similar results just by chance. By convention, a result is only considered to be statistically significant if there’s less than a five percent chance of it being a fluke. So, naively, we might expect 95 percent of published research findings to be true.

The problem is that, as researchers, we are under pressure to find and report significant results. It’s much harder to get results published — particularly in high-profile journals — if they’re not statistically significant. And often, we have a vested interest in the hypothesis we’re testing. We’re testing our own ideas and, naturally, we want our ideas to be right.

We also have a lot of freedom in the analyses we choose to conduct and the outcomes we choose to report. If the data don’t quite come out as significant, we can always try a slightly different analysis, collect a few more data points, or find a reason to throw out data that don’t fit the general pattern. And we can keep going until we get a statistically significant result.

The more we poke around, the more likely we are to find a significant effect — and the more likely that the effect we end up reporting is just a fluke.

Research plans:

Awareness of this problem is growing. Last week, in a letter to the British newspaper The Guardian, U.K. neuroscientists Chris Chambers and Marcus Munafo called for the widespread introduction of a new form of journal article, the ‘registered report,’ which they hope will address the issue.

The journal Cortex, where Chambers is an associate editor, is already trying out registered reports. Before they even begin to collect their data, researchers have to submit a proposal to the journal, detailing exactly what they are going to do. This includes the analyses they plan to conduct, as well as the methods they will use to collect the data. 

Bastian - statistically-funny.blogspot.com

It was getting harder and harder to find a truly meaningful relationship at the medical journal happy hour.

Once the data are in, the paper is accepted not based on the results, but on whether the researchers did exactly what they said they would. 

There’s no room for fudging. Whatever the results turn out to be (significant or otherwise), we will know exactly how much we can trust them.

A similar approach is already standard practice in medical research. Before testing a new drug in a clinical trial, researchers have to state exactly what outcomes they are looking for.

However, trials of other forms of treatment or intervention often go unregistered. Researchers don’t want to commit to a single outcome measure, presumably because they’re not sure from the outset what the best measure might be. But if they’re allowed to pick and choose their outcome measures after the event, there’s a good chance of there being at least one measure that appears to support the treatment — even if the treatment is completely ineffective.

The proposal for registered reports is a recognition that we need to apply the same standards to all research, not just clinical trials.

Of course, it’s often the case that the most interesting findings are the ones we least expect. Many important scientific findings were discovered by accident. And there’s nothing intrinsically wrong with reporting findings that weren’t predicted.

Still, we should always be skeptical about findings that weren’t predicted. And of course, if the effects are real, then further studies should replicate the results.

Registered reports should be seen as the gold standard for research. They’re not the solution to all of the challenges facing autism research — or science in general. But they may be a way of identifying those findings in which we can have a high degree of confidence.

Jon Brock is a research fellow at Macquarie University in Sydney, Australia. He also blogs regularly on his website, Cracking the Enigma. Read more Connections columns at SFARI.org/connections »

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

Network hub: People who have many traits of autism, such as restricted interests and clumsy movements, have weaker connections between certain brain regions (bottom) compared with those who have only a few of the traits (top).

People who show strong autism traits tend to have weak connections between the posterior cingulate cortex and other areas of the brain, according to a study published 5 April in PLoS One¹.

The posterior cingulate cortex is involved in introspection and social memories, and has been shown to have abnormal activity in people with autism².

The ‘connectivity theory’ of autism contends that people with the disorder show abnormally weak connections between the frontal cortex and more posterior areas of the brain. But some studies have contradicted this idea, generating a lively debate among researchers.

In the new study, scientists in Hungary analyzed brain connectivity in 127 adult participants from the International Neuroimaging Data-Sharing Initiative, a large, free repository of data from brain scans and psychological tests.

The researchers compared participants’ brain activity at rest with their scores on two tests of autism traits: the Autism Spectrum Screening Questionnaire (ASSQ) and the Social Responsiveness Scale. For both tests, scores rise with increasing social impairment.

The researchers analyzed the brain scans with a technique based on graph theory, a mathematical approach that describes relationships between objects using nodes of a graph connected by lines. Each brain region, or node, is connected to many others. The method determines the strength of each connection based on the synchrony of their firing patterns during the brain scan.

Participants with high scores on the ASSQ show weak synchrony between the left posterior cingulate cortex and the rest of the brain, the study found. When the researchers merged data from high-scoring participants, they found that the left posterior cingulate cortex in these participants is strongly connected to 6 other regions compared with 75 in low-scoring participants.

The posterior cingulate cortex and many of its connections belong to the 'default mode network.' This network of brain connections is active when people are not engaged in any particular cognitive task, and has been implicated in autism and related disorders.

The researchers also looked at participants’ brain scans using diffusion tensor imaging, which indirectly gauges the strength of connections by tracking the movement of water molecules.

Participants with strong autism traits have weaker nerve fibers linked to the parahippocampal gyrus, which is involved in memory, and the nearby fusiform gyrus, which is important for recognizing faces, the study found.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Jakab A. et al. PLoS One 8, e60982 (2013) PubMed

2. Kana R.K. et al. Biol. Psychiatry 62, 198-206 (2007) PubMed

Neural wrinkles: Young men with autism have more folds in their brains (left) than typically developing males do (right).

The brains of people with autism are structurally different from those of controls, with more folds and a thicker cortex in certain regions, according to two studies published in the past few months.

One study, led by Greg Wallace at the National Institute of Mental Health, found that adolescents and young men with autism have more folds, or gyri, than controls do¹. The study, published 28 May in Brain, also suggests that as people age, they have fewer folds in their brains.

The researchers also found that a brain region associated with vocabulary has significantly more folds in controls with better vocabulary scores. However, this link is absent in people with autism.

In a study published in January in Research in Autism Spectrum Disorders, Evdokia Anagnostou and her colleagues linked more thickness in certain regions of the cortex with greater social impairment in people with autism².

The participants in that study span a large age range, allowing the researchers to assess the cortex across different ages.

In typical development, the cortex thins over the lifespan. "What we are seeing in kids with autism is that they fail to thin appropriately," says Anagnostou, assistant professor of pediatrics at the University of Toronto.

Scientists began measuring the thickness of the brain a decade ago. Before that, they could only compare volumes of brain structures using magnetic resonance imaging and other techniques. But volume is composed of multiple factors, such as thickness and surface area, which are difficult to tease apart unless they are measured separately.

Advances in software technology now allow researchers to measure these components individually. That’s important because each is regulated by a different set of genes and grows independently of the other, says Anagnostou.

Revealing scans:

For their study, Wallace and his colleagues scanned the brains of 41 boys and young men with high-functioning autism — defined as an intelligence quotient (IQ) of 85 or higher — and 39 controls matched for age, IQ and handedness. Both groups were between the ages of 12 and 24 years.

The researchers saw more folds in three areas in the brains of people with autism compared with controls. All three regions are at the back of the brain: the left lateral occipital cortex, right temporal-occipital cortex and left precuneus.

The researchers also found that a better vocabulary score is associated with more folding in the left inferior parietal cortex, a region known for its relationship with vocabulary. However, the brains of participants with autism do not show this association.

The results suggest that cognitive abilities disrupted in people with autism are related to differences in brain structure.

"They're making the argument that once you get abnormalities in gyrification, the normal association between vocabulary performance and gyrification goes away," Anagnostou says.

However, the study is small and did not include females or people with low IQs, she notes.

She and her colleagues looked at a different aspect of brain structure — thickness of the cortex — in 28 people with autism and 25 controls, all ranging in age from 7 to 39 years.

They found that several regions of the cortex, including the frontal cortex, the superior parietal lobules and the superior temporal gyrus, are thicker in the brains of those with autism than in controls.

"This further highlights the frontal, temporal and parietal regions as being important for autism," says Armin Raznahan, staff scientist at the Child Psychiatry Branch of the National Institute of Mental Health, who was not involved in either new study. "Their findings add strength to the idea that autism is accompanied by abnormal brain maturation that extends beyond the first few years of life.”

The study also shows that differences in cortical thickness may begin early in life, and points to which areas and ages researchers should look at next, adds Cynthia Schumann, assistant professor of psychiatry and behavioral sciences at the University of California, Davis MIND Institute, who was not involved in the studies.

The researchers looked at a single point in time, but the age range allowed them to make some observations about the relationship between age and cortical thickness. 

For example, although the cortex in both people with autism and controls thins with age, they saw that among people with autism, only the inferior frontal gyrus, the inferior temporal gyrus and the posterior cingulate gyrus are significantly thinner with increasing age.

"You still see some cortical thinning, but it is much less than in the typically developing group," Anagnostou says.

The researchers then looked at several regions involved in social behavior and communication, including the anterior cingulate cortex and the fusiform gyrus.

They found that a thicker rostral anterior cingulate cortex and a thinner orbital frontal cortex are both associated with social impairment.

“At this point it's hard to interpret,” says Anagnostou. “It's intriguing, if it's real."

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Wallace G.L. et al. Brain 36, 1956-1967 (2013) PubMed

2: Doyle-Thomas K.A. et al. Res. Autism Spectr. Disord. 7, 141-150 (2013) PubMed

Animated audience: Children with autism tend to look mainly at the avatar directly in front of them.

To study attention in people with autism during complex social situations, researchers have developed a virtual reality version of public speaking, according to a study published 20 May in Autism Research¹.

The computerized system allows researchers to repeat the experiment under the same conditions in different labs.

Preschool-aged children with autism often show deficits in joint attention, the ability to follow others’ focus. Unlike typically developing children, for example, children with autism may not look in the direction that a researcher is pointing. But there are few ways to study how older, high-functioning children continue to develop these skills.

The researchers designed the new system to study how 8- to 16-year-old children handle a situation that requires them to pay attention to themselves and others while also accomplishing a task.

In the virtual reality setup, the participants watch a monitor that shows seven avatars representing their peers. The researchers ask the participants personal questions and urge them to direct their answers to all of the avatars.

One avatar is directly in front of the participant, and others are seated farther away or to the side. The avatars all blink and nod to simulate interest. In some of the experiments, the avatars begin to fade until the participants look in their direction; in others they remain solid.

The participants wear headgear that allows the researchers to track which of the avatars they are looking at and for how long.

The 37 children with autism and 54 controls both paid better attention to the fading avatars than to those that remained solid. Both groups also looked more at the avatar in the center than at the others. The children with autism spent even less time looking at the avatars in the back and the sides than controls did, however.

The participants with autism who have symptoms of social anxiety or attention deficit hyperactivity disorder, or have relatively low intelligence quotients, perform worse on the test than the other participants, the study found.

When the researchers replaced the avatars with spheres, all the participants spent less time looking at them than they had at the avatars. This suggests that children with autism don’t have an aversion to talking to people, the researchers say.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Jarrold W. et al. Autism Res. Epub ahead of print (2013) PubMed

Cultural factors may explain why attention deficit hyperactivity disorder (ADHD) is diagnosed less frequently in the U.K. than in the U.S., and autism, which has genetic links to ADHD, is diagnosed more frequently, suggests a new study published 30 May in the Journal of Autism and Developmental Disorders.

About 1 in 58 children in the U.K. have been diagnosed with autism, 1 in 71 with ADHD and 1 in 300 with both conditions, according to a U.K. survey of more than 13,500 children at age 7. The survey is part of the Millennium Cohort Study, which has followed about 19,000 children from different socioeconomic groups since their birth.

This rate of autism, 1.7 percent, is higher than the 1.1 percent prevalence reported by a 2012 study of children in the U.S. The prevalence of ADHD, on the other hand, 1.4 percent, is far lower than the 6 percent in American children reported in other studies.

The numbers add to a debate on whether the divergence is due to cultural differences between the U.S. and the U.K., differences in diagnostic criteria, a true difference in prevalence or measurement error. For example, some scientists have suggested that doctors and parents in the U.K. are more loath to diagnose ADHD and medicate children for it than those in the U.S.

In their new study, the researchers note that because the diagnostic criteria for ADHD are “more stringent” in the U.K. than in the U.S., children with hyperactive behavior and social problems may be more likely to be diagnosed with autism than with ADHD, potentially explaining their results.

Measurement error is also a real possibility: The survey relied on parents' recollection of their children’s diagnoses, rather than on medical records. Other factors may include growing awareness of autism in the U.K., broader diagnostic criteria for autism, and diagnosis of children at younger ages than before.

Ultimately, any study can provide only a rough estimate of the prevalence of these disorders. Scandinavian countries that track their citizens’ health from birth are providing some of the most reliable analyses of prevalence and risk factors for autism.

It’s important to clarify whether the U.K.'s lower rate of ADHD diagnoses stems from cultural differences or from real differences in risk factors, the researchers say, in order to avoid missing children who need care.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

Gene profile: The gene expression pattern in autism gut cells (pink) is distinct from that in controls (green) and gut disorders (blue, yellow).

Autism is frequently accompanied by GI problems such as stomach pain, constipation or diarrhea. But there is conflicting evidence over whether these are merely side effects of other features of the disorder, such as picky eating.

Certain chronic GI conditions are caused by a hyperactive immune system, which has also been linked to autism, suggesting a possible connection between the GI symptoms in autism and immune dysfunction. 

The new study looked at the relationship between gut symptoms in autism and two inflammatory GI disorders: Crohn’s disease and ulcerative colitis. Studies have shown that cells taken from the intestines of people with either of these disorders have distinct gene expression patterns².

The researchers collected cells from the large and small intestines of 25 people with autism who have GI symptoms, 8 people with Crohn’s disease, 5 people with ulcerative colitis and 15 controls.

Overall gene expression patterns in the autism cells are distinct from those in controls, the researchers found. They are more similar to cells from people with one of the two inflammatory disorders, but are not a perfect match with either.

For example, small intestine cells from people with autism share 1,381 altered genes with Crohn’s disease and 1,071 with ulcerative colitis; 587 genes overlap with both disorders.

However, as many as 1,231 genes from cells in the small intestine and 1,011 from cells in the large intestine are abnormally expressed only in people with autism. The results suggest that people with autism may have a unique, immune-related GI disorder, the researchers say.  

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Walker S.J. et al. PLoS One 8, e58058 (2013) PubMed

2: von Stein P. et al. Gastroenterology 134, 1869-1881 (2008) PubMed

Big data: Powerful machines that scan the brain’s connections at high resolution are producing intricate pictures.

For five years in the late 1990s, Van Wedeen studied the structure of the heart, even though what he really wanted to explore was the wiring of the brain.

Wedeen was biding his time because he knew that existing imaging techniques couldn’t render an accurate picture of the brain’s white matter, which contains the long cellular fibers that connect neurons.

“So there the matter stayed for five or so years, while I turned to other organs and simpler questions,” says Wedeen, assistant professor of radiology at Massachusetts General Hospital.

By the mid-2000s, better scanners and advanced mathematical algorithms allowed Wedeen and others to distinguish tightly packed neuronal wires, or axons, running in different directions. That part of the picture had long been elusive; other techniques show only one direction of travel at a given point in the brain.

Wedeen is using those techniques as he co-leads a team of researchers working on the Human Connectome Project (HCP). Launched in 2010, the project is a five-year effort to describe the structure and function of connections between different regions of the brain in 1,200 healthy adults.

Defining the brain’s wiring diagram can help researchers understand what goes awry in brain disorders such as autism. The popular 'connectivity theory' of autism holds that long-range connections are impaired in the brains of people with the disorder.

Wedeen is not alone in pursuing this goal. Another team of HCP investigators has a somewhat different approach, favoring another imaging technique and way of calculating white-matter trajectories.

“It will probably turn out in the end that one method is modestly better than the other, and it will be valuable to sort that out,” says David Van Essen, professor of anatomy and neurobiology at Washington University in St. Louis, a leader of the second team.

Drawing straws:

As part of the $40 million project, both HCP teams have built customized brain scanners, and spent two years refining the methodology for acquiring and processing the images. The first data from the project went online in October.

The results of their methodological debates are likely to have wider significance.

“We’re watching with interest,” says David Edwards, director of the Centre for the Developing Brain at King’s College, London. Edwards is leading the Developing Human Connectome Project, a €15-million European effort to track how brain connectivity develops between 20 and 44 weeks after conception. His team is in close contact with leaders of the HCP, though the two projects are independent.

White matter is tricky to scan because its fibers are only a few micrometers wide, but often ten or more centimeters long.

“You have a three-dimensional (3D) trajectory that you have to be able to trace in the brain over what are fairly long distances,” says Pratik Mukherjee, associate professor of radiology at the University of California, San Francisco. Mukherjee is not involved in either connectome project, but has mapped white matter connections in people lacking a corpus callosum, a birth defect linked to autism.

The only way to trace white matter connectivity — at least, in a living person — is with diffusion imaging, a type of magnetic resonance imaging (MRI) based on the movement, or diffusion, of water inside the brain. White matter fibers act like drinking straws, constraining the movement of water along their length.

“We became aware, 20 years ago or so, that the diffusion signal provided information about the direction of cellular fibers inside the brain,” says Wedeen, who helped develop a technique called diffusion tensor imaging (DTI).

DTI studies have shown differences in particular regions of the brain in people with autism compared with controls¹, and in infants at high risk for autism who later develop the disorder compared with those who do not².

But Wedeen and others say DTI is a relatively crude method that isn’t well suited to mapping the fine-scale detail of the brain’s wiring. That’s because the images carve up the brain into 3D pixels, or voxels — imaginary cubes stacked together to build an image of the brain. In images from standard scanners, these cubes measure a few millimeters or so on a side. And DTI can only indicate one direction of water movement per voxel.

“In many areas of the brain, there are multiple fiber orientations within a voxel,” Mukherjee says. White matter fibers can cross over each other, fan out, converge, or turn sharply. “You cannot get adequate information from DTI in those areas.”

Sharp turns:

Researchers have had to develop new scanning protocols and mathematical models for processing MRI images. Faster scanners now yield higher-resolution images, which means that researchers can divide the brain into smaller voxels. The best resolution comes from state-of-the-art scanners built for the HCP by the engineering and electronics firm Siemens.

But even voxels that measure just over a millimeter per side from these scanners still contain many thousands of nerve fibers running in different directions.

“We have to obtain images where we monitor water molecules diffusing in different directions,” says Kamil Ugurbil, professor of radiology and neuroscience at the University of Minnesota and co-leader of Van Essen’s team.

Two new techniques, diffusion spectrum imaging (DSI) and high angular resolution diffusion imaging (HARDI), accomplish this, each capable of capturing the movement of water in hundreds of directions within every voxel.

These improvements in diffusion imaging are beginning to radically reshape our view of white matter’s architecture.

Last year, Wedeen reported data suggesting that white matter fibers traverse the brain by making a series of sharp 90-degree turns in a 3D grid, rather than in long, swooping arcs as researchers had initially assumed³.

Wedeen says he has unpublished microscopy data validating the existence of these ‘micro-turns.’ Others aren’t yet convinced that his proposal represents a fundamental insight into the structure of white matter.

“This is one where I would say I hope it’s true, but to me the jury’s still out,” says Van Essen. “And if it’s true in some places, it may not be true everywhere.”

Van Essen and Wedeen plan to conduct a side-by-side comparison of their techniques to work out which approach yields more useful results.

Meanwhile, researchers working on the European project have also been refining their methods. They plan to include brain images of fetuses in utero and preterm infants, and have developed mathematical methods to correct for movement during the fetal scans, which would normally wreck an MRI image.

The team plans to scan at least 1,200 participants, beginning in September 2014. The data will be made freely available online and compatible with HCP data as much as possible. “They’re a couple of years ahead of us, so we’ll be taking advantage of what they’ve learned,” Edwards says.

Image courtesy of the Laboratory of Neuro Imaging at UCLA and Martinos Center for Biomedical Imaging at MGH, Consortium of the Human Connectome Project.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Lange N. et al. Autism Res. 3, 350-358 (2010) PubMed

2: Wolff J.J. et al. Am. J. Psychiatry 169, 589-600 (2012) PubMed

3: Wedeen V.J. et al. Science 335, 1628-1634 (2012) PubMed

Placenta’s prophecy: Babies at high risk of autism tend to have multiple abnormal cells (arrows) in their placenta. 

Abnormal cells in the placenta, usually discarded at birth, may be early indicators of autism, suggests a study published 22 April in Biological Psychiatry¹. The study found that trophoblastic inclusions, abnormal folds in the placenta, are more common in babies at risk of developing autism than in controls.

This characteristic abnormality could serve as an early biomarker of autism, which is normally diagnosed only once children reach 3 years of age. Early behavioral interventions may give children the best chance of improving their symptoms.

The researchers initially discovered that preserved placentas from 5 of 13 babies who went on to develop autism have these abnormal cells, compared with 8 of 61 controls².

In the new study, they looked at 217 placentas: 117 from siblings of children with autism and 100 from controls. About 20 percent of siblings of children with autism develop the disorder.

Among the high-risk babies, 77 of the placentas have at least one inclusion, and 48 have more than one. In contrast, 32 of the 100 controls have more than one inclusion, and 8 have more than one. Only high-risk placentas, 28 in total, have three or more inclusions, and 4 of them have more than ten. 

The researchers intend to follow up with both sets of babies in a few years so that they can confirm a link between the abnormal cells and an eventual autism diagnosis.

The trophoblast inclusions are a sign that cells multiplied too quickly during early development. Similar abnormalities may develop in other structures in the fetus.

The results are not necessarily specific to autism, however. Studies have shown that babies with chromosomal abnormalities visible under a microscope are more likely than controls to have trophoblast inclusions³.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Walker C.K. et al. Biol. Psychiatry Epub ahead of print (2013) PubMed

2: Anderson G.M. et al. Biol. Psychiatry 15, 487-491 (2007) PubMed

3: Kliman H.J. et al. Fertil. Steril. 80, 88 (2003) Full text

Following the suspension in early May of two clinical trials of arbaclofen, a candidate drug for treating autism and fragile X syndrome, parents are appealing to the U.S. government and several pharmaceutical companies to continue testing the drug.

Parents are collecting signatures in two different petitions to continue the trials, conducted by Massachusetts-based company Seaside Therapeutics.

One petition, on the government website We the People, has so far amassed 600 signatures of the 100,000 required for the government to respond. The other, at change.org, an online platform for raising awareness of various causes, has been somewhat more successful, with 4,000 signatures to date.

Seaside canceled the two long-term trials for autism and fragile X after the results from one of their clinical trials turned out to be disappointing. In May, Seaside announced that its largest arbaclofen trial in people with autism had shown that the drug did not, as had been hoped, reduce social withdrawal more than placebo did.

The results led Switzerland-based Roche, Seaside's collaborator and funder, to pull funding for the remaining clinical trials.

“At this point, unfortunately, we had to halt the studies because of resource limitations," says Paul Wang, vice president of clinical development at Seaside Therapeutics. "But we are hopeful we will continue to move this forward."

Meanwhile, Roche plans to continue research into RG7314 and RG7090, two compounds that its researchers are testing for autism and fragile X treatment, respectively.

Seaside has worked on arbaclofen for several years. The drug is designed to stimulate the receptors of GABA-B, a neurotransmitter that inhibits nerve cells. Studies suggest that people with autism have an excitatory and inhibitory imbalance.

A 2012 trial conducted by Seaside showed that arbaclofen reduces social impairment in people with fragile X. But the trial did not meet its goal of reducing irritability, which Roche says was also a factor in the decision to pull funding.

Interestingly, some participants with autism showed significant improvements on tests of daily functioning and communication. Parents petitioning for the drug also report these improvements in their children.

"That is what we have found very promising," says Wang. But, because the trial didn’t set out to test these measures, he says, the company needs to redo the study — provided they find the money.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

RORA, an autism candidate gene, encodes a protein that binds to more than 2,500 other genes and alters the expression of some of those genes, according to a study published 22 May in Molecular Autism¹.

That long list is chock-full of genes that are involved in autism-related biology. For example, dozens of the genes are related to the development of the cerebellum, a brain region important for motor coordination that has been linked to autism. Others are involved in the birth of new synapses, the junctions between neurons, and in the transmission of messages between synapses.

Most exciting, the researchers say, is that 426 of RORA’s gene targets are listed in AutismKB, a database of autism candidates maintained by scientists at Peking University in Beijing, and 49 in SFARI Gene. (The latter is funded by the Simons Foundation, SFARI.org’s parent organization.)

“The list was so highly enriched, it was just amazing to us,” says lead investigator Valerie Hu, professor of biochemistry and molecular biology at George Washington University in Washington, D.C. “What it tells me is that any mechanism that will lead to dysfunctional RORA expression will impact a whole bunch of pathways relevant to autism.”

Other researchers say they are intrigued by the findings because previous studies have shown that RORA interacts with sex hormones.

“The exciting work coming out of Valerie Hu’s lab is providing important evidence consistent with the fetal testosterone theory of autism,” says Simon Baron-Cohen, director of the Autism Research Centre at the University of Cambridge in the U.K, who was not involved in the study.

Baron-Cohen first proposed that theory, which holds that individuals with autism have an ‘extreme male brain’ caused by high levels of testosterone in the womb. If true, this may help explain why the disorder is four times more common in boys than in girls.

ROR-ing ahead:

Neuroscientists have been interested in RORA for decades. A 1962 study first described the so-called ‘staggerer’ mice, an inbred strain with a tottering gait, muscle tremors and an underdeveloped cerebellum². In 1996 researchers pinpointed the gene responsible for the animals’ problems: retinoic acid-related orphan nuclear receptor alpha, or RORA. The gene encodes a transcription factor, a protein that turns other genes on and off.

The new study analyzed the genome of cultured human neurons and found that RORA binds to 2,544 unique genes. Just because RORA binds to a gene doesn’t mean it will influence its expression, however.

Hu’s team has so far chosen six of the autism-linked targets — ITPR1, CYP19A1, A2BP1, HSD17B10, NLGN1 and NTRK2 — for in-depth study.  The researchers confirmed RORA’s effect on these genes by showing that when they cut RORA levels by half, all six genes also go down in their expression.

CYP19A1 encodes aromatase, an enzyme that converts testosterone to estrogen, and also seems to be involved in synaptic activity. NLGN1 codes for neuroligin-1, an autism-linked protein that can strengthen or weaken synapses.

RORA didn’t catch the attention of autism researchers until 2010, when Hu’s team published a study on the characteristic chemical changes to DNA in people with autism, the so-called ‘epigenetic’ signature. She showed that identical twins who are discordant for autism — meaning that one twin has the disorder and the other does not — carry different levels of methylation in their DNA. RORA turned out to be one of the genes that is methylated differently in the twin with autism than in the twin without³.

In later experiments, Hu’s group showed that cultured neurons exposed to estrogen produce more RORA⁴. Conversely, they dial down RORA production when exposed to testosterone. This makes sense because RORA is known to dampen levels of aromatase.

Hu also found lower levels of RORA in the frontal cortex and cerebellum in postmortem brain samples from children with autism than in controls.

These results fit in nicely with the fetal testosterone theory, Baron-Cohen says. A lack of RORA might mean that testosterone cannot efficiently be converted to estrogen, leading to an overall increase in testosterone. But the opposite could also be true: An increase in testosterone could lead to lower levels of RORA.

Of the six genes confirmed as RORA targets so far, Baron-Cohen is particularly intrigued by CYP19A1. In 2009, his group reported common variants in this gene that increase the risk of autism⁵.  “Are RORA levels low in autism because of genetic differences in CYP19A1?” he asks.

The list of RORA’s targets is also interesting for neuroscientists working on sleep, which is disrupted in many children with autism. Take John Hogenesch, an expert on the mammalian circadian clock, the biological mechanism that allows us to coordinate sleep-wake cycles, metabolism and other behaviors with a 24-hour day. Hogenesch has been interested in RORA since 2004, when his team reported that RORA regulates the expression of BMAL1, a gene that’s crucial for clock function⁶.

Given that RORA has been linked to the cerebellum, sex hormones and the circadian clock, “it makes you wonder, via what pathway is the autism arising?” says Hogenesch, professor of pharmacology at the University of Pennsylvania.

Hogenesch notes that another gene in the ROR family, called RORB, might also have links to autism. “RORB is definitely in the central nervous system, so that would be worth investigating,” he says.

Perhaps most interestingly, there are drugs that selectively target ROR genes and can effectively boost their expression, Hogenesch says. “There could be potential there for [autism] therapeutics.”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Sarachana T. and V. Hu Mol. Autism 4, 14 (2013) PubMed

2. Sidman R.L. et al. Science 137, 610-612 (1962) PubMed

3. Nguyen A. et al. FASEB J. 24, 3036-3051 (2010) PubMed

4. Sarachana T. et al. PLoS One 6, e17116 (2011) PubMed

5. Chakrabarti et al. Autism Res. 2, 157-177 (2009) PubMed

6. Sato T.K. et al. Neuron 43, 527-537 (2004) PubMed

Relative risk: Studies that consider both common and rare variants may require fewer participants.

A new statistical method for linking genes to a disorder analyzes both rare and common variants of a gene at the same time, according to a study published 14 May in the American Journal of Human Genetics¹. This makes it possible to confirm associations that other techniques might overlook.

Some rare mutations, typically present in less than one percent of the population, are strongly linked to autism. Evidence is weaker for common variants’ link to the disorder, but some studies suggest that many common variants may together contribute to autism, or act with environmental factors to raise risk.

Genome-wide association studies, or GWAS, investigate whether variations in a gene are found more often in individuals with autism than in the general population. But this method requires large numbers of participants (on the order of tens of thousands of people) in order to confirm a statistically significant link between a gene and a disorder. Also, for statistical reasons, most GWAS methods downplay the contribution of common variants.

In the new study, the researchers developed an analysis that separately calculates the contributions of rare and common variants for a given gene, then combines the results into one measure. 

Using this method, they assessed the link between the LRP2 gene and autism. Studies sequencing the coding portion of the genome have found both rare and common variants in LRP2 in people with autism. Across a group of 430 people with autism and 379 controls, the new GWAS method, but not traditional ones, finds a significant link between this gene and autism.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Ionita-Laza I. et al. Am. J. Hum. Genet. Epub ahead of print (2013) PubMed