Marco Pagani, Valerio Zerbi, Silvia Gini, Filomena Grazia Alvino, Abhishek Banerjee, Andrea Barberis, M. Albert Basson, Yuri Bozzi, Alberto Galbusera, Jacob Ellegood, Michela Fagiolini, Jason P. Lerch, Michela Matteoli, Caterina Montani, Davide Pozzi, Giovanni Provenzano, María Luisa Scattoni, Nicole Wenderoth, Ting Xu, Michael V. Lombardo, Michael P. Milham, Adriana Di Martino, Alessandro Gozzi
It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking. Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes. Specifically, we found that functional magnetic resonance imaging (fMRI) connectivity alterations in 20 distinct genetic mouse models of autism cluster into hypoconnectivity-dominant and hyperconnectivity-dominant subtypes. These subtypes are linked to distinct biological pathways, with hypoconnectivity being associated with synaptic dysfunction and hyperconnectivity reflecting transcriptional and immune-related alterations. Here we identified analogous hypoconnectivity and hyperconnectivity subtypes in a multicenter human fMRI dataset of n = 940 individuals with idiopathic autism and n = 1,036 neurotypical individuals. The human autism subtypes are highly replicable, are associated with distinct functional network architectures and behavioral profiles and recapitulate the synaptic and immune-related pathways identified in the rodent dataset. Our work provides a new empirical framework for targeted subtyping of the autism spectrum.