Date of Award
Doctor of Philosophy (PhD)
Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed on the basis of social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar-mediated error signaling impairments contribute to the causation of ASD. However, the relationship between infant cerebellar functional connectivity (fcMRI) and later ASD behaviors and outcomes has not been investigated. Such work is critical to establish early (presymptomatic) cerebellar correlates of ASD. Methods: Data from the Infant Brain Imaging Study (n=94, 68 male) were used to evaluate cerebellar fcMRI as a presymptomatic biomarker for ASD. Specifically, brain-behavior associations were analyzed for 6-month cerebellar connections in relation to later (12- and 24-month) ASD behaviors and outcomes using univariate tests of association, multivariate machine learning prediction, and fcMRI enrichment. Univariate and multivariate approaches focused on cerebellar-frontoparietal network (FPN is implicated in error-signaling) and cerebellar-default mode network (DMN is implicated in adult studies of ASD) connections, while enrichment afforded a data-driven test of whole-brain connectivity. Results: Univariate tests of cerebellar-FPN and cerebellar-DMN connections failed to implicate the cerebellum in ASD, despite > 80% power to detect medium-sized effects. Multivariate tests in high-risk infants using cerebellar-FPN and cerebellar-DMN connections similarly failed to achieve above-chance classification accuracy for ASD diagnosis, despite replicating procedures that achieved > 80% positive predictive value in whole-brain data. FcMRI enrichment identified correlates of ASD-associated behaviors in brain networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (CO) and medial visual (mVis) networks. However, post-hoc tests did not support a unique role for cerebellar connectivity within these networks. Conclusions: Contrary to contemporary theories, we failed to observe a relationship between infant cerebellar fcMRI and ASD. Instead—in the first-known application of fcMRI enrichment to temporally lagged, early developmental brain-behavior associations—we identified infant control (FPN, CO), visual, and default mode correlates of later ASD behaviors. Future work may investigate whether connectivity involving these networks prospectively predicts ASD diagnosis, thereby expediting intervention and furthering etiologic understanding.
Chair and Committee
Lori Markson Desiree White
Richard Abrams, John Pruett, John Constantino,
Hawks, Zoe Wilson, "Testing Candidate Cerebellar Presymptomatic Biomarkers for Autism Spectrum Disorder" (2021). Arts & Sciences Electronic Theses and Dissertations. 2496.