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    Article from: Spring-Summer 2017

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    By Tony Fitzpatrick

    Case In Point

    Detecting Autism Earlier

    CaseInPoint-Toddler

    Above: An infant’s or toddler’sability to engage others, such as by pointing at something that grabs their attention, is a behavior that children with autism spectrum disorder don’t often or ever initiate.

    CaseInPoint-LimitedInterests

    Above: Limited interests and repetitive activities in a very young child can be a symptom of autism, whereas the joy of discovery is not.

    A key developmental behavior occurring around the first year of life — one that most parents or caregivers give barely a thought to — is the event called initiation of joint attention. This is where a toddler will see something of interest and point at it or otherwise acknowledge its existence by a shifting eye gaze or a non-linguistic babble in the presence of another toddler or person.

    It's a non-verbal action that implies: 'Hey, isn’t this neat?' And it draws others into the joy of discovery. However, those who a) don't often or ever initiate joint attention, b) keep focus on a restricted set of interests and activities, and c) exhibit repetitive behaviors (like arm flapping) may be considered at risk for developing autism spectrum disorder (ASD). The severity of ASD, a neurological disorder most commonly diagnosed between the ages of two and four, can vary greatly. At its more extreme levels it can make social engagement difficult and achievement challenging.

    The Sooner the Better

    Researchers studying autism and related neurological disorders agree that diagnosis at a younger age provides an opportunity for an earlier introduction of helpful treatment therapies, which can lead to a better outcome for the autistic child. Now those researchers are encouraged by the findings from a massive, multi-institutional study that features the analysis of functional magnetic resonance imaging data by the Mallinckrodt Institute of Radiology.

    Published in the journal Cerebral Cortex, the data gathered in the study from the brains of 177 children, ages 12- and 24-months, reveals a fingerprint of brain function that highlights two sets of interacting functional networks. The brain function was imaged with MRI as the children slept quietly, and the tendency to initiate joint attention was assessed in a laboratory setting the day following their scans.

    In the brain fingerprint of the initiators, there was a very strong positive coupling between the visual network and the posterior cingulate areas of the default mode network. The default mode network is active uring quiet rest or daydreaming but tends to shut down while a person focuses on a challenging task. In those less likely to initiate, there was a strong connection between the brain’s visual and dorsal networks. The dorsal attention network helps one to maintain focus on something while allowing the brain to respond to other potentially important sensory information.

    May I Have Your Attention?

    Linking this functional connectivity data out of a pool of 26,000 functional connections in the brain was an enormous undertaking.

    "We were interested in understanding the associations between this behavior and the way the brain is wired together using this model of functional connectivity," says Adam T. Eggebrecht, PhD, instructor in radiology, and the paper’s first author. They used the Communication and Social Symbolic Behavior Scale to assess how much kids were spontaneously initiating joint attention.

    "Initiation of joint attention is such a fundamental stepping stone to get to extraneous high-level and dynamic social interaction behaviors. This is an absolutely unique and amazing data set as far as having clean, functional connectivity MRI data," says Eggebrecht. "Also, having the behavioral MRI data in this age group is a very special thing.

    You can apply these analyses that we’ve developed to a wide range of behaviors to better understand typical and altered early childhood development relating to autism spectrum disorder and neurodevelopmental disorders in general."

    PruettandEggebrecht

    Above: John R. Pruett, Jr., MD, PhD, associate professor of child psychiatry (left), is co-senior author, and Adam T. Eggebrecht, PhD, instructor in radiology, is first author of a massive study involving dozens of researchers from other institutions in the multicenter Infant Brain Imaging Study.

    A Team Effort

    John R. Pruett, Jr., MD, PhD, associate professor of child psychiatry at Washington University, is cosenior author on the paper. "We think this is the first demonstration of brain-based correlates for initiation of joint attention using MRI, and we’re very excited about that," says Pruett. "Our hope is that we can identify brain-based changes that are predictive of autism outcome before behavioral symptoms manifest, and then we can get children into treatment earlier, which could mean great improvements in managing autism."

    In addition to Eggebrecht, Pruett and their MIR colleagues, who are funded by National Institute of Mental Health programs, the study involved dozens of researchers from other institutions in the multicenter Infant Brain Imaging Study (IBIS). IBIS is funded by the National Institutes of Health and headquartered at the University of North Carolina, Chapel Hill. The IBIS network principal investigator is Joseph Piven, MD, co-senior author on the paper, and a professor of psychiatry, pediatrics and psychology at the University of North Carolina. Piven is the principal investigator of a National Institute of Child Health and Human Development grant called Autism Centers of Excellence.

    JohnRPruettJrMDPhd

    Above: "You can apply these analyses that we’ve developed to a wide range of behaviors to better understand typical and altered early childhood development relating to autism spectrum disorder and neurodevelopmental disorders in general," says Adam Eggebrecht, PhD.

    "This research lays the groundwork for understanding how fundamentally aberrant processes develop in the brain as autism is first emerging in infants," says Piven. "Future work relating signatures of brain function to brain structure and behavior as children progress to school age may help illuminate the neurobiology underlying autism, and help us design more effective therapies."

    According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorders not otherwise specified (PDD-NOS) all fall under the autism umbrella. And the National Institute of Neurological Disorders and Stroke (NINDS) says ASD occurs in every racial and ethnic group, and across every socioeconomic level. It’s estimated that one out of every 100 babies born in the U.S. develops autism. Furthermore, the risk may be as high as 20 out of every 100 births for infants with older siblings who have the disorder. (See sidebar.)

    ASD is now defined by two categories of disruption. The first is disruption of social communication, including language and non-verbal communication. The second is repetitive and restricted behaviors. For instance, according to NINDS, some early suspicious childhood behaviors that might require an expert's evaluation include no babbling or pointing by age one, no response to name, no single words by 16 months or two-word phrases by age two, poor eye contact, no smiling, and excessive lining up of toys or objects. For children beyond age two, indicators include an inability to make friends, impaired ability to initiate or sustain a conversation, repetitive or unusual use of language, and abnormally intense or focused interest.

    "There is no known specific biological basis for autism today," says Eggebrecht. "Moreover, with few exceptions, a person’s genetic predisposition is not a ‘smoking gun’ for developing autism at a certain severity level."

    Evaluating Familial Risk

    Researchers evaluated 116 young children at 12 months of age and 98 children at 24 months. Some kids were imaged at both time frames and about 75% of all subjects had an older sibling with ASD. The latter makes the child high-risk, which the researchers knew going into the study.

    "One of the fundamental characteristics of the study is to try to understand what effect this familial risk has on exhibition of behaviors, as well as receiving a full-blown diagnosis,” Eggebrecht says. “Kids with an older sibling who has autism have a much higher likelihood of either developing autism or going on to exhibit disrupted behaviors, generally associated with autism, but at a level too low for a full-blown diagnosis."

    Children the age of the study participants are notoriously restive, adding to the difficulty of the study. The preference is to bring them into laboratories at night and "train" them so that they can sleep with the noise of the MRI machine, which can reach 120 decibels.

    "You basically bundle them up, so they’re very cozy and snug, and put on noise-cancelling earphones and headphones to deaden the sound," Eggebrecht says.

    "Many kids will sleep comfortably for at least two hours."

    Next Generation of Diffuse Optical Tomography (DOT)

    Eggebrecht and MIR colleagues are striving hard to develop the next generation of DOT, an optical imaging alternative to f-MRI. They are making improvements on the DOT hardware, which is literally a cap a patient wears. The cap holds dozens of wires that are optical fibers that shine infrared light to measure a host of brain responses. The researchers are making the hardware lighter, more wearable and more portable, enabling them to use this technology on infants in the first few weeks of life. They’re more compliant than 12- and 24-month-olds because they sleep most of the time. “The data set we’ve gathered in this study is very informative to the optical tools we are developing,” Eggebrecht says. "The regions and connections of the brain we’ve found vital in this study can help us optimize the design of our DOT caps for these kids."