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Sex differences in brain development in fetuses and infants who are at low or high likelihood for autism

By Luca M Villa, Sarah Hampton, Ezra Aydin, Roger Tait, Matthew J Leming, Alexandros Tsompanidis, Ilse Patterson, Carrie Allison, Topun Austin, John Suckling, Simon Baron-Cohen, Rosemary Holt

Posted 11 Mar 2021
medRxiv DOI: 10.1101/2021.03.08.21251862

Background: It is unknown whether the neural underpinnings of autism are present in utero. In addition, it is unclear whether typical neural sexual differentiation, which is associated with the development of autism, is evident in utero. We longitudinally investigated fetal and infant sex differences in brain structure and function, and differences in brain development in those at low and high likelihood for autism. Here, we use the term "typical" interchangeably with the term "low-autism likelihood". Methods: Participants were longitudinally studied in utero first at 30-33 weeks of gestation, and then as infants 8-12 weeks after birth. We compared total brain volumes and resting-state functional connectivity between 15 female and 15 male low-autism likelihood fetuses (defined as having no first degree autistic relative). We also compared the brain structure and function of these 30 fetuses to a rare group of 11 fetuses (5 females and 6 males) who had an autistic mother or sibling, and therefore a higher likelihood of developing autism. Although a small sample, the high-autism likelihood group are reported as they are challenging to recruit. Additionally, we correlated sex differences in functional connectivity with autism likelihood group differences across the fetal and infant brains. Results: There was a group-by-sex interaction in fetal total brain volume. Typical males, on average, showed faster total brain volume growth in the perinatal period than typical females. The high-autism likelihood group showed lower resting-state functional connectivity at both time-points compared to the typical group, and regions indicating sex differences overlapped with those associated with high-autism likelihood group differences in functional connectivity. Conclusions: In utero sexual differentiation of brain structure was more pronounced in fetuses with a high likelihood for autism. Moreover, sexual differentiation of the fetal and infant brain may overlap with the neural development of autism.

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