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
Highlights
Autism spectrum disorder (ASD) is a heterogeneous, neurodevelopmental condition characterized by socialcommunicative impairments and restricted/repetitive or stereotyped behaviors (American Psychiatric Association, 2013)
Both clusters exhibited a similar crossover interaction pattern of mean connectedness with the rest of the cortex, whereby males with ASD displayed significantly reduced functional connectivity (FC) compared to their typically developing (TD) male counterparts, and females with ASD displayed significantly increased connectivity compared to TD females (Figure 2)
Given the modest differences in the subscales of the Autism Diagnostic Interview (ADI) and Autism Diagnostic Observation Schedule (ADOS) shown in Table 1, we examined whether there might be a correspondence between the ASD male/female subscale scores and the diagnosis-by-sex interactions observed in FC
Summary
Autism spectrum disorder (ASD) is a heterogeneous, neurodevelopmental condition characterized by socialcommunicative impairments and restricted/repetitive or stereotyped behaviors (American Psychiatric Association, 2013). ASD has a strong male preponderance, with only one female diagnosed for every three to four males (Lai et al, 2015a; Centers for Disease Control and Prevention, 2017). This uneven sex ratio has resulted in decades of ASD research that focuses almost exclusively on males, thereby limiting the generalizability of published findings, and leaving females with this disorder underrepresented and poorly understood. Certain neurodevelopmental mechanisms may put males at a heightened risk of being diagnosed with ASD. Other mechanisms may play a protective role for females, thereby putting them at a comparatively lower risk (Robinson et al, 2013, or for review see Lai et al, 2015a, 2017; McCarthy and Wright, 2017)
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