Scientists discover unique neuron density patterns in children with autism

Published in Autism Research, a recent study has uncovered how brain structure differs in children with autism compared to typically developing children. The study found lower total neurite density—an indicator of neuron structure and connectivity—in the right cerebellar cortex of children with autism. Additional changes in how neurons spread in different directions were observed across various brain regions, suggesting that structural differences in the brain could be key to understanding autism.

Autism is a complex neurodevelopmental condition characterized by difficulties with social communication, repetitive behaviors, and restricted interests. While previous research has shown that children with autism often have differences in brain size and structure, the exact nature of these differences is not fully understood.

Past studies have identified increased brain volume in young children with autism, but this enlargement tends to normalize by age four. These early changes in brain structure could play a crucial role in the development of autism-related symptoms, but understanding the specific cellular and structural changes has been challenging due to the heterogeneity of autism and the limitations of available imaging techniques.

The goal of this study was to gain a better understanding of the brain’s cytoarchitecture, or cellular structure, in children with autism. The researchers aimed to explore how neuron density and connectivity differ in children with autism compared to typically developing children and those with other psychiatric conditions, like anxiety or attention disorders.

“Our lab here at the Del Monte Institute for Neuroscience in Rochester is concentrated on shedding light on the neuropathological processes that give rise to intellectual and developmental disabilities,” said John Foxe, the senior author of the study, director of the Del Monte Institute for Neuroscience, and Kilian J. and Caroline F. Schmitt Chair in Neuroscience at the University of Rochester.

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“We’ve had a long-standing goal of uncovering the neural differences that underpin autism. Effective therapeutic approaches are fundamentally dependent on knowing what the issue is in the first place. Simply stated, it is very difficult to fix something if you don’t know how it is broken in the first place.

“The other important aspect of our work is that we are trying to discover neuromarkers that can provide better sensitivity and objectivity in clinical trials. Many, if not most, clinical trials in neurodevelopmental disorders have failed because the measures we have to assess success are so crude (e.g. observational symptom scales). Using objective neuroimaging measures has the promise to give us much greater sensitivity to detect real neural changes.”

For their study, the researchers used data from the Adolescent Brain and Cognitive Development (ABCD) study. This large sample size is one of the study’s strengths, allowing for a more robust analysis than many previous investigations with smaller participant pools.

“A key aspect of this study is that the data come from the ABCD study, which is a national effort to map brain development across childhood and adolescence in a very large cohort of youngsters. We at Rochester, and 20 other sites nationally, have been following over 11,000 children since they were 9 years of age. The size of this study is unprecedented, and could not be achieved without the concerted effort of the National Institutes of Health. By measuring so many children, the sensitivity of this study is massively better than anything we’ve been able to do previously.”

The researchers analyzed brain imaging data from 95 children with autism and 7,339 children without the condition. The key imaging technique used in the study was diffusion-weighted imaging, which measures how water molecules move within the brain. This method provides insights into neuron structure by capturing details about neurite density—the extensions of neurons that connect different brain regions. The team specifically measured two types of diffusion: isotropic diffusion, which represents neuron cell bodies, and directional diffusion, reflecting the neurite branches like axons and dendrites.

“We’ve spent many years describing the larger characteristics of brain regions, such as thickness, volume, and curvature,” said Zachary Christensen, MD/PhD candidate at the University of Rochester School of Medicine and Dentistry, and first author of the paper. “However, newer techniques in the field of neuroimaging for characterizing cells using MRI, unveil new levels of complexity throughout development.”

Through these imaging techniques, the researchers could evaluate neurite density in 87 different brain regions. They compared these measures across three groups: children with autism, typically developing children, and children with other psychiatric diagnoses. In addition, they analyzed behavioral data, including reports from parents on their children’s social and emotional functioning, to explore any links between brain structure and behavior.

The findings revealed significant differences in neurite density in several key brain regions. The most notable was a decrease in total neurite density in the right cerebellar cortex of children with autism. This region, located in the back of the brain, is involved in motor control and higher cognitive functions, such as social behavior. Lower neurite density in this area could be related to some of the motor and social challenges experienced by individuals with autism.

Beyond the cerebellum, the researchers found changes in both isotropic and directional diffusion in various parts of the brain. For example, children with autism had lower isotropic diffusion in posterior regions like the parietal and occipital lobes, indicating fewer neuron cell bodies in these areas. At the same time, they had increased directional diffusion in frontal and temporal lobes, suggesting more extensive neuron branching and connectivity in those regions. These patterns highlight how different parts of the brain are affected differently in autism.

“I think that the extent of the brain regions that were implicated was a bit of a surprise in retrospect,” Foxe told PsyPost. “We thought that the brain regions that would be implicated would be much more localized.”

To ensure that these findings were specific to autism and not other psychiatric conditions, the team compared the results from the autism group to those of children with anxiety, depression, and other disorders. They found that the differences in neurite density, particularly in the cerebellum, were unique to children with autism, reinforcing the link between these structural changes and the condition.

Lastly, the study explored how these brain structure differences related to behavior. The researchers found a connection between decreased neurite density in the right cerebellar cortex and somatization, a condition where individuals experience physical symptoms without an apparent medical cause. Children with autism and lower cerebellar neurite density were more likely to report somatic symptoms, providing an interesting clue about how brain structure could influence physical experiences in autism.

“People with a diagnosis of autism often have other things they have to deal with, such as anxiety, depression, and ADHD. But these findings mean we now have a new set of measurements that have shown unique promise in characterizing individuals with autism,” Christensen said. “If characterizing unique deviations in neuron structure in those with autism can be done reliably and with relative ease, that opens a lot of opportunities to characterize how autism develops, and these measures may be used to identify individuals with autism that could benefit from more specific therapeutic interventions.”

According to Foxe, the research highlights “that modern neuroimaging techniques are getting ever more sensitive and that these techniques hold out promise for better understanding of neurodevelopmental disorders.”

While this study provides valuable new insights, it also has some limitations. First, the autism diagnoses in this study were based on parental reports, which may not be as reliable as clinical evaluations.

“We are very confident in our determinations but these diagnoses should be confirmed using gold-standard assessments in future work,” Foxe said.

Additionally, the study focused on a narrow age range (9-12 years), meaning that it provides a snapshot of brain development during middle childhood. The findings may not capture changes that occur earlier or later in development, and future studies will be needed to track how these brain differences evolve over time.

“The ABCD study is designed to follow these children for a decade and hopefully beyond,” Foxe said. “Our study took advantage of the first two sets of neuroimaging data, so it is just covering the ages from about 9-12. It will be fascinating to follow up the study with later neuroimaging scans to see how the brain develops in these individuals, if the differences even out or persist.”

“It doesn’t get said as often as it should, but we in the research community owe so much to the families of the ABCD study who have stuck with us for nearly 8 years now,” Foxe added. “None of this is possible without them. Every year they show up for our tests and give of their time and patience with grace and good will. What we would like them to know is that they are truly changing the face of brain research and paving the way for better care for future generations.”

The study, “Autism is associated with in vivo changes in gray matter neurite architecture,” was authored by Zachary P. Christensen, Edward G. Freedman, and John J. Foxe.