Sex Differences in Resting-State Functional Connectivity of the Cerebellum in Autism Spectrum Disorder

Rachel E W Smith, Jason A Avery, Gregory L Wallace, Lauren Kenworthy, Stephen J Gotts, Alex Martin, Rachel E W Smith, Jason A Avery, Gregory L Wallace, Lauren Kenworthy, Stephen J Gotts, Alex Martin

Abstract

Autism spectrum disorder (ASD) is more prevalent in males than females, but the underlying neurobiology of this sex bias remains unclear. Given its involvement in ASD, its role in sensorimotor, cognitive, and socio-affective processes, and its developmental sensitivity to sex hormones, the cerebellum is a candidate for understanding this sex difference. The current study used resting-state functional magnetic resonance imaging (fMRI) to investigate sex-dependent differences in cortico-cerebellar organization in ASD. We collected resting-state fMRI scans from 47 females (23 ASD, 24 controls) and 120 males (56 ASD, 65 controls). Using a measure of global functional connectivity (FC), we ran a linear mixed effects analysis to determine whether there was a sex-by-diagnosis interaction in resting-state FC. Subsequent seed-based analyses from the resulting clusters were run to clarify the global connectivity effects. Two clusters in the bilateral cerebellum exhibited a diagnosis-by-sex interaction in global connectivity. These cerebellar clusters further showed a pattern of interaction with regions in the cortex, including bilateral fusiform, middle occipital, middle frontal, and precentral gyri, cingulate cortex, and precuneus. Post hoc tests revealed a pattern of cortico-cerebellar hyperconnectivity in ASD females and a pattern of hypoconnectivity in ASD males. Furthermore, cortico-cerebellar FC in females more closely resembled that of control males than that of control females. These results shed light on the sex-specific pathophysiology of ASD and are indicative of potentially divergent neurodevelopmental trajectories for each sex. This sex-dependent, aberrant cerebellar connectivity in ASD might also underlie some of the motor and/or socio-affective difficulties experienced by members of this population, but the symptomatic correlate(s) of these brain findings remain unknown. Clinical Trial Registration: www.ClinicalTrials.gov, NIH Clinical Study Protocol 10-M-0027 (ZIA MH002920-09) identifier #NCT01031407.

Keywords: autism; cerebellum; connectivity; fMRI; resting state; sex differences.

Figures

Figure 1
Figure 1
Cerebellar clusters exhibiting a diagnosis-by-sex interaction. Shown in standard Talairach Tournoux space. Left is shown on the left. Mode contrast = autism spectrum disorder (ASD males—ASD Females) × typically developing (TD males—TD females). Clusters shown were significant at p < 0.05 with small volume correction for the cerebellum.
Figure 2
Figure 2
Mean global connectedness values for left and right cerebellar clusters. The y-axis displays the average z-transformed correlation coefficient of the cluster’s mask with every other voxel in the brain. White bars denote standard error.
Figure 3
Figure 3
Regions resulting from seed-based analysis showing diagnosis-by-sex interaction. Cerebellar seeds are pictured in the lower right panel. Left is shown on the left, and results are in standard Talairach-Tournoux space. Refer to Table 2 for key of numeric region labels.
Figure 4
Figure 4
(A–C) Cerebellar-cortical region correlation matrices. (A)F-values for diagnosis-by-sex interaction (left), and surviving pairs at P < 0.0069 after false discovery rate (FDR) correction to q < 0.05 shown in white (right). (B) Z-values for ASD—TD contrast in females (left), and surviving pairs at P < 0.0216 (FDR-corrected to q < 0.05 within those combinations already FDR-corrected in the diagnosis-by-sex contrast) shown in red (right). (C) Z-values for ASD—TD contrast in males (left), and surviving pairs at P < 0.0216 (FDR-corrected to q < 0.05 within those combinations already FDR-corrected in the diagnosis-by-sex contrast) shown in blue (right).

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