Social Symptoms in Autistic Children May be Caused by Hyper-Connected Neurons

The brains of children with autism show more connections than the brains of typically developing children do. What’s more, the brains of individuals with the most severe social symptoms are also the most hyper-connected. The findings reported in two independent studies published in the Cell Press journal Cell Reports on November 7th are challenge the prevailing notion in the field that autistic brains are lacking in neural connections.

The findings could lead to new treatment strategies and new ways to detect autism early, the researchers say. Autism spectrum disorder is a neurodevelopmental condition affecting nearly 1 in 88 children.

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Caption: The brains of children with autism show more connections than the brains of typically developing children do. What’s more, the brains of individuals with the most severe social symptoms are also the most hyper-connected. The findings reported in two independent studies published in the Cell Press journal Cell Reports on Nov. 7 are challenge the prevailing notion in the field that autistic brains are lacking in neural connections. Credit: Cell Reports, Keown et al

“Our study addresses one of the hottest open questions in autism research,” said Kaustubh Supekar of Stanford University School of Medicine of his and his colleague Vinod Menon’s study aimed at characterizing whole-brain connectivity in children. “Using one of the largest and most heterogeneous pediatric functional neuroimaging datasets to date, we demonstrate that the brains of children with autism are hyper-connected in ways that are related to the severity of social impairment exhibited by these children.”

In the second Cell Reports study, Ralph-Axel Müller and colleagues at San Diego State University focused specifically on neighboring brain regions to find an atypical increase in connections in adolescents with a diagnosis of autism spectrum disorder. That over-connection, which his team observed particularly in the regions of the brain that control vision, was also linked to symptom severity.

“Our findings support the special status of the visual system in children with heavier symptom load,” Müller said, noting that all of the participants in his study were considered “high-functioning” with IQs above 70. He says measures of local connectivity in the cortex might be used as an aid to diagnosis, which today is based purely on behavioral criteria.

For Supekar and Menon, these new views of the autistic brain raise the intriguing possibility that epilepsy drugs might be used to treat autism.

“Our findings suggest that the imbalance of excitation and inhibition in the local brain circuits could engender cognitive and behavioral deficits observed in autism,” Menon said. That imbalance is a hallmark of epilepsy as well, which might explain why children with autism so often suffer with epilepsy too.

“Drawing from these observations, it might not be too far fetched to speculate that the existing drugs used to treat epilepsy may be potentially useful in treating autism,” Supekar said.

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NIH-funded Study Finds Attention to Others’ Eyes Declines in 2 to 6-month-old Infants Later Diagnosed with Autism

Eye contact during early infancy may be a key to early identification of autism, according to a study funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. Published this week in the journal Nature, the study reveals the earliest sign of developing autism ever observed—a steady decline in attention to others’ eyes within the first two to six months of life.

“Autism isn’t usually diagnosed until after age 2, when delays in a child’s social behavior and language skills become apparent. This study shows that children exhibit clear signs of autism at a much younger age,” said Thomas R. Insel, M.D., director of NIMH. “The sooner we are able to identify early markers for autism, the more effective our treatment interventions can be.”

Typically developing children begin to focus on human faces within the first few hours of life, and they learn to pick up social cues by paying special attention to other people’s eyes. Children with autism, however, do not exhibit this sort of interest in eye-looking. In fact, a lack of eye contact is one of the diagnostic features of the disorder.

To find out how this deficit in eye-looking emerges in children with autism, Warren Jones, Ph.D., and Ami Klin, Ph.D., of the Marcus Autism Center, Children’s Healthcare of Atlanta, and Emory University School of Medicine followed infants from birth to age 3. The infants were divided into two groups, based on their risk for developing an autism spectrum disorder. Those in the high risk group had an older sibling already diagnosed with autism; those in the low risk group did not.

Jones and Klin used eye-tracking equipment to measure each child’s eye movements as they watched video scenes of a caregiver. The researchers calculated the percentage of time each child fixated on the caregiver’s eyes, mouth, and body, as well as the non-human spaces in the images. Children were tested at 10 different times between 2 and 24 months of age.

By age 3, some of the children—nearly all from the high risk group—had received a clinical diagnosis of an autism spectrum disorder. The researchers then reviewed the eye-tracking data to determine what factors differed between those children who received an autism diagnosis and those who did not.

“In infants later diagnosed with autism, we see a steady decline in how much they look at mom’s eyes,” said Jones. This drop in eye-looking began between two and six months and continued throughout the course of the study. By 24 months, the children later diagnosed with autism focused on the caregiver’s eyes only about half as long as did their typically developing counterparts.

This decline in attention to others’ eyes was somewhat surprising to the researchers. In opposition to a long-standing theory in the field—that social behaviors are entirely absent in children with autism—these results suggest that social engagement skills are intact shortly after birth in children with autism. If clinicians can identify this sort of marker for autism in a young infant, interventions may be better able to keep the child’s social development on track.

“This insight, the preservation of some early eye-looking, is important,” explained Jones. “In the future, if we were able to use similar technologies to identify early signs of social disability, we could then consider interventions to build on that early eye-looking and help reduce some of the associated disabilities that often accompany autism.”

The next step for Jones and Klin is to translate this finding into a viable tool for use in the clinic. With support from the NIH Autism Centers of Excellence program, the research team has already started to extend this research by enrolling many more babies and their families into related long-term studies. They also plan to examine additional markers for autism in infancy in order to give clinicians more tools for the early identification and treatment of autism.


Decline in eye fixation reveals signs of autism present already within the first 6 months of life. Data from a 6-month-old infant later diagnosed with autism are plotted in red. Data from a typically developing 6-month-old are plotted in blue. The data show where the infants were looking while watching a video of a caregiver.
Source: Warren Jones, Ph.D., Marcus Autism Center, Children’s Healthcare of Atlanta, and Emory University School of Medicine
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This article is created from press materials provided by NIH/National Institute of Mental Health.

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Autistic Kids Have Poorer Sleep Quality Than Their Peers Right Up to Their Teens

Sleep duration is shorter and they are more prone to frequent waking at night

Children with autistic spectrum disorders have poorer sleep quality than their peers right up to their teens, reveals research published online in the Archives of Disease in Childhood.

Total sleep duration is shorter and punctuated by more frequent waking at night, the research shows. Poor quality sleep may affect daytime learning and behaviour, say the authors.

Disrupted sleep patterns have been linked to autism before, but the quality of the evidence accumulated to date has often been compromised by small sample size, lack of agreed definitions, and poor comparability of study participants.

The authors of this study instead base their findings on long term data derived from the Avon Longitudinal Study of Parents and Children (ALSPAC), which has been tracking the health and development of more than 14,000 children born in 1991-2 in South West England.

All the parents were quizzed about their children’s sleeping patterns when their kids were 6, 18, 30, 42, 69, 81, 115 and 140 months old, including when their children routinely went to bed and woke up on week days, and how much time they spent sleeping during the daytime.

The researchers also took account of other key information, including the results of validated questionnaires on social and communication skills (SCDC) and intelligence (WISC-III) when the children were 7 years old.

Eighty six of the children had been diagnosed with autistic spectrum disorders by the time they were 11 years old. Thirty had classic autism; 15 had atypical autism; and 23 had Asperger’s syndrome.

The final analysis was based on 39 children with autistic spectrum disorders and 7043 typical children for whom complete data across all time points were available.

This showed that before the age of 30 months, there was no major difference in sleeping patterns between the two groups of children. But from 30 months onwards, children with autistic spectrum disorders tended to sleep less in total, with the greatest discrepancy (43 minutes) persisting up to 140 months of age.

Although the gap in total sleep narrowed after this point, autistic children still slept around 20 fewer minutes each day than their typical peers by the time they reached their teens.

These differences remained even after taking account of influential factors, such as prematurity, low birthweight, maternal education, and social class.

These differences were wholly due to the length of night-time sleep, which was shortened by frequent bouts of wakefulness.

From the age of 30 months onwards, children with autistic spectrum disorders were significantly more likely to wake three or more times a night than their typical peers, a difference that became even more noticeable the older the children became.

By the time the children were 81 months old, more than one in 10 of those with autistic spectrum disorders were waking three or more times a night compared with just 0.5% of their peers.

An increasing body of data also suggests that production of the sleep hormone melatonin may be impaired in some children with autistic spectrum disorders, which may explain disturbed sleep patterns, suggest the authors.

But it’s unclear just what impact this shortened sleep pattern may have, they acknowledge. But they point out that other researchers have suggested that sleep loss may have impact on neuronal development.

“If this hypothesis of cumulative sleep reduction resulting in neuronal loss is confirmed, then clinically [children with autism] might gain from even a small consistent increase in total sleep time,” they write.

This article is reprinted from press materials provided by BMJ Group. The materials may have been edited for content.

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Whole Genome Sequencing Opens Way for Diagnosis, Medical Therapy for Autism

An international consortium, consisting of Autism Speaks, Duke University School of Medicine, The Hospital for Sick Children of Toronto, BGI and other institutes, has investigated the genetic variants in 32 families with Autism Spectrum Disorder (ASD). The results show that whole genome sequencing and analysis promise great value to identify de novo or rare inherited mutations that give rise to autism in ASD groups. The findings were published online today in American Journal of Human Genetics.

Autism is the fastest growing developmental disorder in the United States, or even the whole world. It is estimated that 1 in every 88 children in the United States is diagnosed with autism, which is greater than the prevalence of pediatric AIDS, cancer, and diabetes combined. It can rob the individual of typical development from childhood to adolescence to adulthood, and bring huge burden on the families. Continue reading

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Research Finds Brain Scans May Help in Diagnosing Autism

Joint research from the University of Alabama at Birmingham Department of Psychology and Auburn University indicates that brain scans show signs of autism that could eventually support behavior-based diagnosis of autism and effective early intervention therapies. The findings appear online today in Frontiers in Human Neuroscience as part of a special issue on brain connectivity in autism.

This brain scan from Kana’s study shows weaker neural connectivity in participants with autism compared with participants without autism.

This brain scan from Kana’s study shows weaker neural connectivity in participants with autism compared with participants without autism.

“This research suggests brain connectivity as a neural signature of autism and may eventually support clinical testing for autism,” said Rajesh Kana, Ph.D., associate professor of psychology and the project’s senior researcher. “We found the information transfer between brain areas, causal influence of one brain area on another, to be weaker in autism.”

The investigators found that brain connectivity data from 19 paths in brain scans predicted whether the participants had autism, with an accuracy rate of 95.9 percent. Continue reading

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Sleep Education Helps Families of Children with Autism

Parent sleep education is beneficial in improving sleep and aspects of daytime behavior and family functioning in children with autism spectrum disorders (ASD), according to a Vanderbilt study published in the Journal of Autism and Developmental Disorders.

Vanderbilt joined with the University of Colorado Denver and the University of Toronto to carry out a study of 80 children with ASD, ages 2-10 years, primarily focused on teaching parents the basics of sleep education.

“We found that one hour of one-on-one sleep education or four hours of group sleep education delivered to parents, combined with two brief follow-up phone calls, improved sleep as well as anxiety, attention, repetitive behavior and quality of life in children with ASD who had difficulty falling asleep,” said study author Beth Malow, M.D., professor of Neurology and Pediatrics, and the Burry Professor of Cognitive Childhood Development.

“The parents also benefited; they reported a higher level of parenting competence after completing the education sessions. The one-on-one and group sessions showed similar levels of success. In contrast, an earlier study that simply gave parents a pamphlet without guidance on how to use it did not provide the same level of improvement in child sleep.”

Before entering the study, all children were examined for medical conditions that could cause sleep problems, such as gastrointestinal disorders or seizures. In the instructional sessions, parents learned about daytime and evening habits that promote sleep, including the importance of increasing exercise, limiting caffeine during the day and minimizing use of video games and computers close to bedtime.

Sleep educators helped parents put together a visual schedule for their children to help them establish a bedtime routine and discussed ways to help children get back to sleep if they woke up at night.

Malow, also a Vanderbilt Kennedy Center investigator, said future studies are needed to determine the best approaches for providing sleep education to families, including those related to telemedicine and Internet-based technologies. Malow and her colleagues within the Autism Speaks Autism Treatment Network are also developing partnerships with local pediatric practices to provide training on sleep education.

Content from the sessions is available to download for free on the Autism Speaks website. A toolkit, “Strategies to Improve Sleep in Children with Autism Spectrum Disorders,” and three Quick Tips sheets are currently posted here.

“We are grateful to Autism Speaks for all of their support with our research and our toolkit materials. With their support, we have been able to help many children with ASD and their families get the rest they need to be at their best during the day,” Malow said. “We are also appreciative to all of the families who participated in this research.”

Research in ASD and sleep in young children, as well as adolescents and young adults, is continuing. For more information, please contact autismsleepresearch@vanderbilt.edu.
The study was supported by the Autism Speaks Autism Treatment Network and the Autism Intervention Research Network on Physical Health.

This article is reprinted from materials provided by Vanderbilt University Medical Center. The materials may have been edited for content.

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Viral Infections During Pregnancy May Increase Risk of Autism

Activating a mother’s immune system during her pregnancy disrupts the development of neural cells in the brain of her offspring and damages the cells’ ability to transmit signals and communicate with one another, researchers with the UC Davis Center for Neuroscience and Department of Neurology have found. They said the finding suggests how maternal viral infection might increase the risk of having a child with autism spectrum disorder or schizophrenia.

The study’s senior author is Kimberley McAllister, professor in the Center for Neuroscience with appointments in the departments of Neurology and Neurobiology, Physiology and Behavior, and a researcher with the UC Davis MIND Institute.

“This is the first evidence that neurons in the developing brain of newborn offspring are altered by maternal immune activation,” McAllister said. “Until now, very little has been known about how maternal immune activation leads to autism spectrum disorder and schizophrenia-like pathophysiology and behaviors in the offspring.”

The study was conducted in mice and rats and compared the brains of the offspring of rodents whose immune systems had been activated and those of animals whose immune systems had not been activated. The pups of animals that were exposed to viral infection had much higher brain levels of immune molecules known as the major histocompatibility complex I (MHCI) molecules.

“This is the first evidence that MHCI levels on the surface of young cortical neurons in offspring are altered by maternal immune activation,” McAllister said.

The researchers found that the high MHCI levels impaired the ability of the neurons from the newborn mice’s brains to form synapses, the tiny gaps separating brain cells through which signals are transmitted. Earlier research has suggested that ASD and schizophrenia may be caused by changes in the development of connections in the brain, especially the cerebral cortex.

The researchers experimentally reduced MHCI to normal levels in neurons from offspring following maternal immune activation.

“Remarkably, synapse density returned to normal levels in those neurons,” McAllister said.

“These results indicate that maternal immune activation does indeed alter connectivity during prenatal development, causing a profound deficit in the ability of cortical neurons to form synapses that is caused by changes in levels of MHCI on the neurons,” she said.

MHCI did not work alone to limit the development of synapses. In a series of experiments, the UC Davis researchers determined that MHCI interacted with calcineurin and myocyte enhancer factor-2 (Mef2), a protein that is a critical determinant of neuronal specialization.

MHCI, calcineurin and Mef2 form a biological signaling pathway that had not been previously identified. McAllister’s team showed that in the offspring of the maternal immune activation mothers, this novel signaling pathway was much more active than it was in the offspring of non-MIA animals.

“This finding provides a potential mechanism linking maternal immune activation to disease-linked behaviors,” McAllister said.

It also is a mechanism that may help McAllister and other scientists to develop diagnostic tests and eventually therapies to improve the lives of individuals with these neurodevelopmental disorders.

The research, “MHCI Requires MEF2 Transcription Factors to Negatively Regulate Synapse Density during Development and in Disease,” is published in the Journal of Neuroscience. Other study authors are Bradford M. Elmer, Myka L. Estes and Stephanie L. Barrow, all of UC Davis.

This article is based on press materials provided by University of California – Davis Health System. The materials may have been edited for content.

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