A new study has uncovered a key factor behind the disparate outcomes seen in children with autism. Researchers from the University of California San Diego found that differences in the biological development of the brain during the first weeks and months of embryonic growth play a significant role in the severity of autism symptoms later in life.
This discovery, published in the journal Molecular autismprovides a deeper understanding of why some children with autism develop serious, lifelong problems, while others experience milder symptoms that improve over time.
The research team wanted to solve a long-standing mystery: why do symptoms of autism spectrum disorder (ASD) vary so much between children? Some children with autism struggle with severe problems in social, language and cognitive skills and may be nonverbal, while others show significant improvements as they grow older.
Understanding the biological roots of these differences is essential for developing more effective, tailored treatments and interventions for autism. Previous studies have suggested that autism has prenatal origins, but no study has yet definitively linked early brain development to the severity of autism symptoms.
To investigate, the researchers used a groundbreaking approach involving inducible pluripotent stem cells (iPSCs). These stem cells, which can be reprogrammed to become any type of human cell, were derived from blood samples from 10 toddlers diagnosed with autism and six neurotypical toddlers as controls. The iPSCs were then used to create brain cortical organoids (BCOs), three-dimensional models that mimic the cerebral cortex during early embryonic development. These “mini-brains” allowed the researchers to study developmental processes in a controlled environment.
This method allowed the researchers to observe and measure brain development as it might occur in the first weeks and months of embryogenesis. A key finding was that BCOs from toddlers with ASD grew significantly larger—about 40 percent larger—than those from neurotypical toddlers.
One of the most critical findings of the study was the correlation between the size of the BCOs and the severity of autism symptoms observed in the children. Toddlers with the most severe form of autism, called profound autism, showed the largest BCOs.
On the other hand, toddlers with milder autism symptoms had only moderately enlarged BCOs. This relationship suggested that the degree of brain overgrowth during embryonic development might be predictive of the severity of autism symptoms later in life.
“We found that the larger the embryonic BCO size, the more severe the child’s later social autism symptoms,” said Eric Courchesne of UC San Diego, the study’s lead investigator and co-director of the Autism Center of Excellence. “Toddlers with severe autism, which is the most severe form of autism, had the greatest BCO overgrowth during embryonic development. Those with mild social autism symptoms had only mild overgrowth.”
The study also included brain imaging to further understand the differences in brain development between children with autism spectrum disorder (ASD) and neurotypical children. The imaging was performed on a subset of the toddlers using magnetic resonance imaging (MRI). This advanced imaging technique allowed researchers to capture detailed structural images of the brain, focusing on regions critical for social and language development.
The MRI scan results showed significant differences in brain structure between the toddlers with ASD and the neurotypical controls. The children with ASD, particularly those with severe autism, showed a striking overgrowth in several brain areas. For example, the primary sensory cortices, which are involved in processing auditory, visual, and tactile information, were significantly larger in the children with severe autism compared to the controls. This overgrowth was also clearly visible in the social and language-related cortices.
In addition to overgrowth, the imaging data highlighted specific areas of the brain where growth was reduced. Notably, the visual cortex in children with severe autism was found to be smaller than that of neurotypical children. This reduction in size may contribute to the sensory and social attention deficits often observed in children with severe ASD.
The imaging results were consistent with the findings from the cerebral cortical organoids (BCOs) developed from the iPSCs. The correlation between the size of the BCOs and the structural abnormalities observed in the brain scans provided compelling evidence that the overgrowth observed during embryonic development persisted into early childhood. Furthermore, the imaging data confirmed the behavioral observations, linking larger brain size and overgrowth to more severe social and cognitive symptoms.
“The bigger the brain, the better” isn’t necessarily true, says Alysson Muotri, director of the Integrated Space Stem Cell Orbital Research Center at the Sanford Stem Cell Institute and lead author of the study.
Further analysis revealed a potential mechanism underlying this excessive growth. The researchers found that the protein and enzyme NDEL1, which plays a key role in regulating brain growth, was reduced in the BCOs of children with ASD. Specifically, lower expression levels of NDEL1 were associated with larger BCO sizes. This finding indicated that the disruption of NDEL1 could be an important factor contributing to the abnormal brain growth observed in ASD-derived organoids.
“Finding that NDEL1 was not functioning properly was an important discovery,” Muotri said.
Despite the groundbreaking insights, the study has some limitations. The sample size was relatively small, with only 10 toddlers with ASD and six neurotypical controls. Larger studies are needed to confirm these findings and explore the full spectrum of ASD severity. Further research is also needed to understand the precise mechanisms by which NDEL1 and other factors influence brain development in ASD.
The research team plans to further investigate the genetic and molecular basis of brain overgrowth in autism. By identifying the exact causes, they hope to develop interventions that can mitigate the developmental abnormalities seen in children with severe autism.
The study, “Embryonic origins of two ASD subtypes of social symptom severity: The larger the brain cortical organoid, the more severe the social symptoms,” was authored by Eric Courchesne, Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Joao V. Nani, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo, Janaina S. de Souza, Mirian A. F. Hayashi, and Alysson R. Muotri.