Brain function distinguishes female carriers and non-carriers of familial risk for autism

Abstract

Background Autism spectrum disorder (ASD) is characterized by high population-level heritability and a three-to-one male-to-female ratio that occurs independent of sex linkage. Prior research in a mixed-sex pediatric sample identified neural signatures of familial risk elicited by passive viewing of point light motion displays, suggesting the possibility that both resilience and risk of autism might be associated with brain responses to biological motion. To confirm a relationship between these signatures and inherited risk of autism, we tested them in families enriched for genetic loading through undiagnosed (“carrier”) females. Methods Using functional magnetic resonance imaging, we examined brain responses to passive viewing of point light displays—depicting biological versus non-biological motion—in a sample of undiagnosed adult females enriched for inherited susceptibility to ASD on the basis of affectation in their respective family pedigrees. Brain responses in carrier females were compared to responses in age-, SRS-, and IQ-matched non-carrier-females—i.e., females unrelated to individuals with ASD. We conducted a hypothesis-driven analysis focused on previously published regions of interest as well as exploratory, brain-wide analyses designed to characterize more fully the rich responses to this paradigm. Results We observed robust responses to biological motion. Notwithstanding, the 12 regions implicated by prior research did not exhibit the hypothesized interaction between group (carriers vs. controls) and point light displays (biological vs. non-biological motion). Exploratory, brain-wide analyses identified this interaction in three novel regions. Post hoc analyses additionally revealed significant variations in the time course of brain activation in 20 regions spanning occipital and temporal cortex, indicating group differences in response to point light displays (irrespective of the nature of motion) for exploration in future studies. Limitations We were unable to successfully eye-track all participants, which prevented us from being able to control for potential differences in eye gaze position. Conclusions These methods confirmed pronounced neural signatures that differentiate brain responses to biological and scrambled motion. Our sample of undiagnosed females enriched for family genetic loading enabled discovery of numerous contrasts between carriers and non-carriers of risk of ASD that may index variations in visual attention and motion processing related to genetic susceptibility and inform our understanding of mechanisms incurred by inherited liability for ASD.

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

“…The testing arena (black open field box, 60 × 60 cm with 35 cm walls) was divided into 16 squares with white lines (15 × 15 cm). The four squares located in the center of the box were defined as the central zone, and the others (12) were defined as the peripheral arena. The experimental room was dark, and only the center of the open field was illuminated by a 75 W incandescent lamp placed 70 cm above the apparatus floor.…”

“…2021, 22, 9662 2 of 19 life in society and to have a reduced quality of life [11]. In the 21st century, the number of people diagnosed with ASD is still growing, and the sex ratio is three to one (boys to girls) [12]. Therefore, the search for the pathogenic mechanisms and risk factors for this complex disease, as well as understanding the sex differences that lead to a significantly more frequent diagnosis of ASD in boys, is very important.…”

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk

“…Study procedures were approved by the Washington University in Saint Louis Institutional Review Board (#201508067), as well as the Institutional Review Boards for the John Hopkins Medicine IRB (IAN), TKI, and University of North Carolina (TEACCH). Washington University Genomic Dataset: We assembled results of microarray-based genomic characterization (see below) acquired among ASD-affected children and their mothers through routine clinical care at the WUSTL Autism Clinical Center or by virtue of coenrollment in HD 087011, which recruited women from the community enriched for asymptomatic transmission of ASD risk [32]. For mothers of ASD-affected children from the clinical service, microarray testing was performed if a chromosomal variant was first identified in the proband, given the testing was conducted as part of the child's medical work-up.…”

Attentional influences on neural processing of biological motion in typically developing children and those on the autism spectrum

“…For example, hypoactivation of the superior temporal sulcus (STS), inferior frontal gyrus and cerebellum during biological motion processing have been linked with higher ASD symptom severity [ 35 , 36 ] and impaired gesture production [ 37 ], and pre-treatment STS activation selectivity to biological over scrambled motion predicts improvement in ASD symptoms with pivotal response therapy [ 38 ]. Furthermore, STS activation during biological motion processing is one functional region that can distinguish aspects of familial risk for ASD [ 39 , 40 ]. While the STS has repeatedly been implicated in fMRI studies of biological motion processing in ASD, our understanding of associated temporal dynamics is somewhat more limited as fewer electrophysiologic studies have been conducted to date.…”