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A groundbreaking study led by researchers at UC Davis has uncovered significant differences in brain development between autistic boys and girls, shedding light on the biological underpinnings that contribute to autism spectrum disorder (ASD). The study, recently published in Molecular Psychiatry, highlights sex-specific changes in the thickness of the brain’s outer layer, the cortex, in children aged 2 to 13.
This research addresses a critical gap in the understanding of ASD, particularly in girls, who are diagnosed with autism far less frequently than boys. Statistics show nearly four boys are diagnosed with autism for every one girl. However, Christine Wu Nordahl, a professor at the Department of Psychiatry and Behavioral Sciences and the UC Davis MIND Institute, asserts that this disparity is partially due to underdiagnosis in females.
“It is clear that this sex bias is due, in part, to underdiagnosis of autism in females,” Nordahl said. “But this study suggests that differences in diagnosis are not the full story—biological differences also exist.”
The cortex, composed of millions of neurons, is vital for cognitive functions such as thinking, learning, and experiencing emotions. During early childhood, the cortex thickens as neurons proliferate, but this process reverses post-2 years, with the cortical layer gradually thinning. Previous research has indicated that this thinning process differs in autistic children compared to their non-autistic peers. However, whether these differences manifest similarly in autistic boys and girls had remained unexplored until now.
Derek Andrews, the study’s lead author and an assistant project scientist at UC Davis, emphasized the importance of understanding how sex differences in brain development intersect with autism. “It’s important to learn more about how sex differences in brain development may interact with autistic development and lead to different developmental outcomes in boys and girls,” he explained.
The research involved brain scans of 290 autistic children (202 boys and 88 girls) and 139 typically developing children (79 boys and 60 girls), all participants in the MIND Institute’s Autism Phenome Project (APP). This project includes the Girls with Autism Imaging of Neurodevelopment (GAIN) study, which aims to increase female representation in autism research. Using MRI scans taken at up to four intervals between ages 2 and 13, the researchers discovered distinct patterns in cortical development.
At age 3, autistic girls exhibited a thicker cortex than their non-autistic counterparts, with these differences covering about 9% of the total cortical surface. In contrast, differences in cortical thickness between autistic and non-autistic boys were less widespread. Furthermore, autistic girls experienced faster cortical thinning into middle childhood compared to autistic boys. These cortical differences spanned multiple neural networks.
“We found differences in the brain associated with autism across nearly all networks in the brain,” Andrews noted.
Surprisingly, the most significant differences appeared at younger ages. By middle childhood, the rapid cortical thinning in autistic girls resulted in less pronounced differences between autistic boys and girls. Andrews explained, “We typically think of sex differences as being larger after puberty. However, brain development around the ages of 2-4 is highly dynamic, so small changes in timing of development between the sexes could result in large differences that then converge later.”
Nordahl underscored the necessity of longitudinal studies that include both sexes to capture the complete picture of cortical development. “If we had only looked at boys at age 3, we may have concluded that there were no differences. If we had both boys and girls, but only investigated differences at 11 years of age, we may have concluded that there were very few sex differences in the cortex,” she explained.
To address the lack of female representation, Nordahl launched the GAIN study in 2014. “The APP had a wonderfully large sample of about 150 autistic boys, but only about 30 autistic girls. This was too few autistic girls to really examine how they might be similar or different to boys, so we worked to increase the representation of autistic females in our research,” she said.
The findings from the GAIN study are unique and pave the way for more inclusive autism research. Andrews expressed hope that other researchers will follow suit, emphasizing that autistic females represent about 20% of the autistic population. “Any successful effort to understand autism will need to include autistic females,” he said.
The study’s co-authors include Kersten Diers and Martin Reuter of the German Center for Neurodegenerative Diseases; Devani Cordero of Massachusetts General Hospital; and Joshua K. Lee, Danielle J. Harvey, Brianna Heath, Sally J. Rogers, Marjorie Solomon, David Amaral, and Christine Wu Nordahl of UC Davis.
For more information, see the full study: Derek S. Andrews et al, Sex differences in trajectories of cortical development in autistic children from 2–13 years of age, Molecular Psychiatry (2024).
