Differential links in 16p11.2 deletion carriers reveal aberrant connections between large-scale networks.

Qualitatively different topographical patterns of connections are thought to underlie individual differences in thought and behavior, particularly at heteromodal association areas. As such, we hypothesized that connections unique to 16p11.2 deletion carriers compared to controls, rather than hyper- or hypo-connectivity, would serve as a better model to explain the cognitive and behavioral changes observed in individuals carrying this autism-risk copy number variation. Using a spatially-unbiased, data-driven approach we found that differential links clustered non-uniformly across the cortex-particularly at the superior temporal gyrus and sulcus, posterior insula, cingulate sulcus, and inferior parietal lobule bilaterally. At these hotspots, altered local connectivity that spanned across the borders of cortical large-scale networks coincided with aberrant distant interconnectivity between large-scale networks. This was most evident between the auditory and the dorsomedial default (DNb) networks-such that greater between-network interconnectivity was associated with greater communication and social impairment. Entangled connectivity between large-scale networks may preclude each network from having the necessary fidelity to operate properly, particularly when the 2 networks have opposing organization principles-namely, local specialization (segregation) versus global coherency (integration).