Atypical Cerebral Lateralization in Children with Autism Spectrum Disorder

Background: Autism Spectrum Disorder (ASD) affects 1 in 59 children, yet relatively little is known about its etiology or development before the emergence of symptoms. Recent research has focused on identifying biomarkers to understand how abnormalities in neural development lead to the ASD phenotype. Prior work has suggested that ASD is characterized by abnormal network connectivity (Wass, 2011). Similarly, previous work has identified abnormal lateralization of functional connectivity at rest in prematurely born individuals—a group at high risk for developmental delay—with greater lateralization associated with poorer language ability (Scheinost et al., 2015). This study utilized resting-state fMRI to investigate cerebral lateralization in children with ASD to elucidate potential mechanisms of aberrant neurodevelopment.

Objectives: Investigate whether children with ASD demonstrate atypical cerebral lateralization.

Methods: Using resting-state fMRI data from the Autism Brain Imaging Data Exchange, we examined connectivity lateralization in children with ASD aged 6-14 years compared to typically-developing (TD) peers. We used cross-hemisphere intrinsic connectivity distribution to correlate each voxel to every other time course in the series in the ipsilateral and contralateral hemispheres independently and then calculated ipsilateral connectivity minus contralateral connectivity. Functional connectivity was performed using linear regression while controlling for sex, age, site, and motion. Analyses included 309 children with ASD and 434 TD peers.Significance was assessed at p<0.05, corrected for multiple comparisons.

Results: Children with ASD compared to TD peers exhibited increased connectivity lateralization in right BA-22, right BA-19, and right BA-23/31, and decreased connectivity lateralization in right BA-10. To identify the functional connection most likely responsible for these cross-hemisphere connectivity differences, follow up seed connectivity analysis was performed with these regions as seeds. For children with ASD compared to TD peers, seed connectivity from right BA-22 revealed greater ipsilateral connectivity with right fusiform and middle temporal gyrus and greater contralateral connectivity with left medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and inferior frontal gyrus (IFG). Seed connectivity from right BA-19 revealed greater ipsilateral connectivity with right inferior and middle temporal gyrus. Seed connectivity from right BA-23/31 revealed greater contralateral connectivity with the left insula and weaker contralateral connectivity with the left mPFC, PCC, and IFG. Seed connectivity from right BA-10 revealed greater ipsilateral connectivity with right fusiform and angular gyrus, greater contralateral connectivity with the left precuneus, and weaker contralateral connectivity with the left putamen.

Conclusions: Findings suggest that children with ASD demonstrate increased right-hemisphere lateralization in temporal and parietal regions relative to their TD peers. However, children with ASD demonstrated reduced right-hemisphere lateralization in a frontal region relative to peers. This atypical lateralization is associated with multiple resting-state brain networks including the default mode (PCC, mPFC), fronto-parietal (fusiform), ventral-attention (middle temporal gyrus), cingular-oppercular (insula), and subcortical networks (putamen). These findings are consistent with prior work suggesting long-range under-connectivity and short-range over-connectivity in ASD (Lewis et al., 2014)and lend support to the hypothesis that ASD is associated with altered cerebral network development. Future work will investigate plasticity of this lateralization across development and its functional significance.