A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

Zoë W Hawks; Alexandre Todorov; Natasha Marrus; Tomoyuki Nishino; Muhamed Talovic; Mary Beth Nebel; Jessica B Girault; Savannah Davis; Scott Marek; Benjamin A Seitzman; Adam T Eggebrecht; Jed Elison; Stephen Dager; Matthew W Mosconi; Lawrence Tychsen; Abraham Z Snyder; Kelly Botteron; Annette Estes; Alan Evans; Guido Gerig; Heather C Hazlett; Robert C McKinstry; Juhi Pandey; Robert T Schultz; Martin Styner; Jason J Wolff; Lonnie Zwaigenbaum; Lori Markson; Steven E Petersen; John N Constantino; Desirée A White; Joseph Piven; John R Pruett Jr

doi:10.1016/j.bpsgos.2021.12.004

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

Biol Psychiatry Glob Open Sci. 2021 Dec 16;3(1):149-161. doi: 10.1016/j.bpsgos.2021.12.004. eCollection 2023 Jan.

Authors

Zoë W Hawks¹, Alexandre Todorov², Natasha Marrus², Tomoyuki Nishino², Muhamed Talovic², Mary Beth Nebel³, Jessica B Girault⁴, Savannah Davis², Scott Marek², Benjamin A Seitzman⁵, Adam T Eggebrecht⁶, Jed Elison⁷, Stephen Dager⁸, Matthew W Mosconi⁹, Lawrence Tychsen¹⁰, Abraham Z Snyder^{5

6}, Kelly Botteron², Annette Estes¹¹, Alan Evans¹², Guido Gerig¹³, Heather C Hazlett⁴, Robert C McKinstry⁶, Juhi Pandey¹⁴, Robert T Schultz¹⁴, Martin Styner⁴, Jason J Wolff¹⁵, Lonnie Zwaigenbaum¹⁶, Lori Markson¹, Steven E Petersen⁵, John N Constantino², Desirée A White¹, Joseph Piven⁴, John R Pruett Jr²

Affiliations

¹ Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri.
² Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁴ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁵ Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
⁶ Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
⁷ Institute of Child Development, University of Minnesota, Minneapolis, Minnesota.
⁸ Departments of Radiology, University of Washington, Seattle, Washington.
⁹ Life Span Institute and Clinical Child Psychology Program, University of Kansas, Lawrence, Kansas.
¹⁰ Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
¹¹ Speech and Hearing Sciences, University of Washington, Seattle, Washington.
¹² McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, Quebec, Canada.
¹³ Department of Computer Science and Engineering, Tandon School of Engineering, New York University, New York, New York.
¹⁴ Center for Autism Research, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁵ Department of Educational Psychology, University of Minnesota, Minneapolis, Minnesota.
¹⁶ Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.

Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection.

Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections.

Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections.

Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Keywords: Autism; Cerebellum; Development; Error-based learning; Functional connectivity; Infancy.

Abstract

Grants and funding