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Autism biomarkers found in infants

Using magnetic resonance imaging (MRI) to study brains of infant siblings of older children with autism, scientists were able to correctly identify 80 percent of babies who subsequently were diagnosed with autism at 2 years of age.

Researchers from the University of Washington (UW) were part of a North American effort led by the University of North Carolina to use MRI to measure brains of "low-risk" infants, with no family history of autism, compared with "high-risk" infants who had at least one older autistic sibling.

A computer algorithm then predicted autism before clinical diagnosis and autistic behaviors began. The study was announced Feb. 17 in a letter to the journal Nature (1).

This is the first study to show that it is possible to use brain biomarkers to identify which infants in a high-risk pool — in this case, those having an older sibling with autism — will be diagnosed with Autism Spectrum Disorder, or ASD, at 24 months of age.

"Typically, the earliest we can reliably diagnose autism in a child is age 2, when there are consistent behavioral symptoms. Due to health access disparities the average age of diagnosis in the U.S. is actually age 4. But in our study, brain imaging biomarkers at 6 and 12 months were able to identify babies who would be later diagnosed with ASD."

Annette Estes PhD, Professor, Department of Speech and Hearing Sciences, Center on Human Development and Disability (CHDD), Seattle, University of Washington, WA, USA and co-author.

The predictive power of the team's findings may inform the development of a diagnostic tool for ASD which could be used in the first year of life, before behavioral symptoms emerge.

"We don't have such a tool yet," adds Estes. "But if we did, parents of high-risk infants wouldn't need to wait for a diagnosis of ASD at 2, 3 or even 4 years and researchers could start developing interventions to prevent these children from falling behind in social and communication skills."

People with ASD — which includes 3 million people in the United States — have characteristic social communication deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors.

In the United States, it is estimated as frequently as 1 out of 68 babies develops autism. But, the risk for infants with an autistic older sibling may be as high as 1 out of 5.

This research project included hundreds of children from across the country and was led by researchers at four clinical sites across the United States: the University of North Carolina-Chapel Hill, UW, Washington University in St. Louis and The Children's Hospital of Philadelphia. Other key collaborators are at the Montreal Neurological Institute, and the University of Alberta and New York University.

"We have wonderful, dedicated families involved in this study," said Stephen Dager, a UW professor of radiology and associate director of the Center on Human Development and Disability (CHDD), who led the study at the UW. "They have been willing to travel long distances to our research site and then stay up until late at night so we can collect brain imaging data on their sleeping children. The families also return for follow-up visits so we can measure how their child's brain grows over time. We could not have made these discoveries without their wholehearted participation."

Researchers obtained MRI scans of children while they were sleeping at 6, 12 and 24 months of age. The study also assessed behavior and intellectual ability at each visit, using criteria developed by Estes and her team. They found that babies who develop autism experience a hyper-expansion of brain surface area from 6 to 12 months, as compared to babies with an older sibling with autism but who themselves, did not show evidence of autism at 24 months of age. Increased surface area growth rate in the first year of life was linked to increased growth rate of brain volume in the second year of life. Brain overgrowth is tied to emergence of autistic social deficits in the second year.

Researchers input their data — MRI calculations of brain volume, surface area, and cortical thickness at 6 and 12 months of age, as well as sex of the infants — into a computer program, asking it to classify babies most likely to meet ASD criteria at 24 months of age. The program developed the best algorithm to accomplish this, and then researchers applied that algorithm to a separate set of study participants.

Researchers found among infants with an older ASD sibling, brain differences at 6 and 12 months of age successfully identified 80 percent of those who would be clinically diagnosed with autism at 24 months.

If these findings could form the basis for a "pre-symptomatic" diagnosis of ASD, health care professionals could intervene even earlier.

"By the time ASD is diagnosed at 2 to 4 years, often children have already fallen behind their peers in terms of social skills, communication and language," said Estes, who directs behavioral evaluations for the network. "Once you've missed those developmental milestones, catching up is a struggle for many and nearly impossible for some."

Research could then begin to examine interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

"Our hope is that early intervention — before age 2 — can change the clinical course of those children whose brain development has gone awry and help them acquire skills that they would otherwise struggle to achieve," adds Dager.

The research team has gathered additional behavioral and brain imaging data on these infants and children — such as changes in blood flow in the brain and the movement of water along white matter networks — to understand how brain connectivity and neural activity may differ between high-risk children who do and don't develop autism.

In a separate study published Jan. 6 in Cerebral Cortex (2), researchers identified specific brain regions that may be important for acquiring an early social behavior called joint attention, which is orienting your attention toward an object after another person points it out to you.

"We hope these ongoing studies will lead to additional biomarkers which provide the basis for early, pre-symptomatic diagnosis. They could also serve to guide individualized interventions to help kids from falling behind their peers."

Stephen Dager, Professor, Department of Radiology, University of Washington, Seattle, WA, USA; Associate director of the CHDD.

Early brain development in infants at high risk for autism spectrum disorder (1)

Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development1, 2. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life3, 4. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6–12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging.

The research was funded by the National Institutes of Health, Autism Speaks and the Simons Foundation.

For more information, contact Estes at 206-543-1051 or estesa@uw.edu and Dager at 206-616-1558 or srd@uw.edu.

Contributors: Heather Cody Hazlett, Hongbin Gu, Brent C. Munsell, Sun Hyung Kim, Martin Styner, Jason J. Wolff, Jed T. Elison, Meghan R. Swanson, Hongtu Zhu, Kelly N. Botteron, D. Louis Collins, John N. Constantino, Stephen R. Dager, Annette M. Estes, Alan C. Evans, Vladimir S. Fonov, Guido Gerig, Penelope Kostopoulos, Robert C. McKinstry, Juhi Pandey, Sarah Paterson, John R. Pruett, Robert T. Schultz, Dennis W. Shaw, Lonnie Zwaigenbaum, Joseph Piven & The IBIS Network

Grant numbers: HD055741, HD003110, R01 MH093510, 6020, 140209.

Adapted from a release by the UNC news office.


Joint Attention and Brain Functional Connectivity in Infants and Toddlers (2)

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

Keywords: development, enrichment, fMRI, initiating joint attention, network
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Feb 22, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Cortical brain regions of 6 to 12 month olds, surface area measurements
contributing to reduction in deep learning. Males (left) and Females (right)
Image Credit: University of North Carolina-Chapel Hill, UW, Washington University in St. Louis
and The Children's Hospital of Philadelphia



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