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. ### Competing Interest Statement The authors have declared no competing interest. * ABIDE : Autism Brain Imaging Data Exchange ADI-R : Autism Diagnostic Interview-Revised ADOS-G : Autism Diagnostic Observation Schedule-Generic AHBA : Allen Human Brain Atlas ASD : Autism Spectrum Disorder CSF : cerebrospinal fluid Des : Desikan-Killiany DSM-5 : The Diagnostic and Statistical Manual of Mental Disorders V E/I : Excitation/Inhibition FC : Functional Connectivity FDR : False Discovery Rate FIQ : Full Intelligence Quotient GO : Gene Ontology GSEA : Gene Set Enrichment Analysis GWAS : Genome-Wide Association Studies MDMR : Multivariate Distance Matrix Regression MRI : Magnetic Resonance Imaging NIMH : National Institute of Mental Health NEG : Negative Associated OLS : Ordinary Least Squares PIQ : Performance Intelligence Quotient POS : Positive Associated QC : Quality Checks SFARI : Simons Foundation Autism Research Initiative TDC : Typically Developing Control VIQ : Verbal Intelligence Quotient