A new study has revealed an important factor behind the different outcomes seen in children with autism. Researchers at the University of California, San Diego have 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 severe lifelong problems, while others exhibit milder symptoms that improve over time.
The research team aimed to solve a long-standing puzzle: why do symptoms of autism spectrum disorder (ASD) vary so widely among children? Some children with autism experience severe difficulties in social, language and cognitive skills and may be non-verbal, while others show significant improvement with age.
Understanding the biological roots of these differences is essential to developing more effective, tailored treatments and interventions for autism. Previous studies have suggested that autism has a prenatal origin, but no study until now has definitively linked early brain development to the severity of autism symptoms.
To investigate, the researchers used a breakthrough approach involving inducible pluripotent stem cells (iPSCs). These stem cells, which can be reprogrammed to become any type of human cell, were obtained from blood samples of 10 toddlers diagnosed with autism and six neurotypical toddlers as controls. The iPSCs were then used to create cerebral cortical organoids (BCOs), which are three-dimensional models mimicking the cerebral cortex during early embryonic development. These “mini-brains” allowed researchers to study developmental processes in a controlled environment.
This method allowed scientists to observe and measure brain development as it may occur in the first weeks and months of embryogenesis. A significant finding was that BCOs derived from toddlers with ASD were substantially larger—about 40% larger—than those derived from neurotypical toddlers.
One of the most critical findings of the study was the correlation between the size of the BCO and the severity of autism symptoms observed in the children. Toddlers with the most severe form of autism, called profound autism, showed the greatest BCO.
On the other hand, toddlers with milder autism symptoms had only slightly increased BCO. This relationship suggested that the extent of brain overgrowth during embryonic development could predict the severity of autism symptoms later in life.
“We found that the larger the size of the embryonic BCO, the more severe the later social symptoms of autism in the child,” said Eric Courchesne of UC San Diego, the study’s principal investigator and co-director of the Autism Center of Excellence. “In toddlers who had profound autism, which is the most severe type of autism, there was the greatest overgrowth of BCO during embryonic development. Those with mild social symptoms of autism had only a slight increase.
The study also incorporated brain imaging to further understand differences in brain development between children with autism spectrum disorder (ASD) and neurotypical children. Imaging was performed on a subset of toddlers using magnetic resonance imaging (MRI). This advanced imaging technique allowed researchers to capture detailed structural images of the brain, focusing on areas critical to social and language development.
Magnetic resonance imaging results revealed significant differences in brain structure between toddlers with ASD and neurotypical controls. Children with ASD, especially those with profound autism, showed significant overgrowth in several brain regions. For example, the primary sensory cortices involved in processing auditory, visual and tactile information were significantly larger in children with profound autism compared to controls. This overgrowth was also evident in the social and linguistic cortex.
In addition to overgrowth, the imaging data highlighted specific areas of the brain where growth was reduced. Remarkably, the visual cortex of children with profound autism was found to be smaller than that of neurotypical children. This reduction in size may contribute to the sensory and social attention problems commonly seen in children with severe ASD.
The imaging results were consistent with findings from brain cortical organoids (BCOs) developed from iPSCs. The correlation between BCO size and structural abnormalities seen on brain scans provided compelling evidence that the overgrowth seen during embryonic development persisted into early childhood. In addition, imaging data confirmed behavioral observations, linking larger brain size and overgrowth with more severe social and cognitive symptoms.
“The bigger the brain, the better,” said Alysson Muotri, director of the Sanford Stem Cell Institute’s Center for Integrated Space Orbital Cell Research and lead author of the study.
Further analysis revealed a potential mechanism underlying this excess growth. The researchers found that the protein and enzyme NDEL1, which plays a key role in regulating brain growth, were reduced in the BCO of children with ASD. Specifically, lower levels of NDEL1 expression were associated with larger BCO sizes. This finding indicated that NDEL1 malfunction may be a key factor contributing to the abnormal brain growth observed in ASD-derived organoids.
“Finding that NDEL1 was not working properly was a key discovery,” Muotri said.
Despite its groundbreaking findings, 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 exact mechanisms by which NDEL1 and other factors influence brain development in ASD.
The research team plans to continue investigating the genetic and molecular basis of brain overgrowth in autism. By determining the exact causes, they hope to develop interventions that can alleviate the developmental abnormalities seen in children with profound autism.
The study, “Embryonic origins of two ASD subtypes of social symptom severity: larger cortical organoid size, more severe social symptoms,” was written 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, Jana V. Sombardo, Jana de Souza, Mirian AF Hayashi, and Alysson R. Muotri.