Autism excitation-inhibition imbalance linked to brain hyperconnectivity: An analysis based on 657 autistic subjects

The large heterogeneity in autism spectrum disorder (ASD) is a major drawback for the development of therapies. Here, we apply consensus-subtyping strategies based on functional connectivity patterns to a population of N=657 quality-assured autistic subjects. We found two major subtypes (each divided hierarchically into several minor subtypes): Subtype 1 exhibited hypoconnectivity (less average connectivity than typically developing controls) and subtype 2, hyperconnectivity. The two subtypes did not differ in structural imaging metrics in any of the regions analyzed (64 cortical and 14 subcortical), nor in any of the behavioral scores (including Intelligence Quotient, ADI and ADOS). Finally, we used the Allen Human Brain Atlas of gene transcription to show that subtype 2, corresponding with about 42% of all patients, had significant enrichment (after multiple comparisons correction) to excitation-inhibition (E/I) imbalance, a leading reported mechanism in the developmental pathophysiology of ASD. Altogether, our results support a link between E/I imbalance and brain hyperconnectivity in ASD, an association that does not exist in hypoconnected autistic subjects.