Task-based functional connectivity in striato-motor-cortical system in autism: Associations with sex and executive function

Abstract Previously we found that female autistic youth (Aut-F) showed reduced brain response in dorsal striatum (putamen) when viewing human motion, alongside larger rare copy number variants that included genes expressed in early striatal development. Thus, striatal differences may characterize Aut-F, but broader systems-level and behavioral implications of these differences remain unexplored. We conducted secondary data analysis of the sex-balanced cohort (8-17y) in which we first discovered these patterns, in order to: 1) understand how functional connectivity between putamen and frontal targets might vary from the non-autistic population, and differ by sex; and 2) explore which brain connectivity and phenotypic features best predicted executive function. Using psychophysiological interaction analysis (N=184), we found that Aut-F youth (n=45) showed reduced functional connectivity between left anterior putamen (Pa) and dorsal premotor cortex/pre-supplementary motor area versus matched non-autistic female peers (NAut-F; n=45), suggesting reduced engagement of a typical Pa-frontal pathway for attentional regulation. Best subsets regression (N=200) indicated that left Pa-left dorsolateral prefrontal functional connectivity explained significant variance in executive functioning across all participants, controlling for neurotype. These results suggest that striatal differences in Aut-F may have adaptive consequences in part due to impacts on connectivity between Pa and frontal regions important for attentional control. Lay summary We previously found that female autistic people show differences in a part of the brain called the striatum. Some parts of the striatum connect to the frontal lobe of the brain, and may help people control their attention and behavior. We studied how the striatum “talked to” the frontal lobe in autistic girls. We found out that this communication is lower in autistic than non-autistic girls. We also found out that how much striatum “talks to” frontal lobe helps explain differences in how well both autistic and non-autistic youth of both sexes control their attention and behavior. Competing Interest Statement The authors have declared no competing interest. Footnotes Acknowledgments Funding. This work was supported by a National Institute of Mental Health Autism Center of Excellence Network Award (R01MH100028; MPIs: Pelphrey, Kenworthy, & Jack) and a grant from the Eunice Kennedy Shriver National Institute of Child Health and Development (R03HD100771; PI: Jack). The high performance computing cluster (“Argo”) used to run fMRI analyses for this project is supported by resources provided by the Office of Research Computing at George Mason University and funded in part by grants from the National Science Foundation (Awards # 1625039 and 2018631). NIMH, NICHD, and NSF had no role in the design of the study or collection, analysis, and interpretation of the data, or writing of the manuscript. The opinions expressed in the manuscript are solely the authors’ own and do not necessarily represent those of the National Institutes of Health, National Science Foundation, or US federal government. https://osf.io/wekd9/overview?view_only=0ff1800f1d95453d8f98b942d4204679