Theory of mind network and mirror neuron system dysconnectivity underlies social deficits in autism spectrum disorder

The theory of mind (ToM) and mirror neuron system (MNS) are known to be involved in social communication deficits in the autism spectrum disorder (ASD). While prior studies have examined the functional connectivity (FC) of the two systems, few have systematically investigated both the within and between network FC and the seed-based whole-brain FC of the two networks to elucidate the neuromechanism of the social deficit in ASD. The current study aims to investigate the abnormalities of FC of ToM and MNS, and their association with behavior indicators of ASD with a multi-center large-scale dataset. A total of 646 subjects (298 ASDs and 348 typically developing [TD] controls) from the Autism Brain Imaging Data Exchange (ABIDE) I were used in this study. Based on prior meta-analyses, four ToM and five MNS seed regions were selected for the within and between network FC and seed-based whole-brain FC analysis. Aberrant FCs were identified using two-sample t -tests, and their associations with clinical measures were evaluated via partial Pearson’s correlation. We also performed mediation analyses to examine potential pathways linking altered FC, social communicative deficits, and overall autism symptoms. Seed-based whole-brain analysis revealed a mixed pattern of hypo- and hyper-connectivity in ASD relative to TD controls. The severe social symptoms were significantly predicted by the increases in ToM-Overconnectivity and MNS-Overconnectivity, and by the decreases in ToM-Underconnectivity. For the within and between network analysis, we observed atypically decreased FC between the bilateral inferior parietal lobule (IPL) within MNS and increased FC between the precuneus (PC) and left IPL, which are associated with social deficits in ASD. Furthermore, ToM-Underconnectivity was associated with overall autism symptom severity, with social communication deficits as a mediator. Our findings highlight the aberrant FC of ToM and MNS in ASD, offering new insights into the neural basis of social communication deficits and supporting the development of more effective interventions.