Excitation/inhibition balance subtypes in autism and their genetic, neural, and clinical profiles

Excitation (E)/inhibition (I) imbalance is considered a key mechanism in Autism Spectrum Disorder (ASD). However, E/I imbalance can have different etiologies with increased E relative to I (E > I) and increased I relative to E (E < I). Both neural profiles can be associated with altered clinical phenotype, suggesting "bell"-shape brain-behavior relationships. We derived E/I balance measures from resting-state EEG in a large sex-balanced sample of youths with and without autism (N = 310; 164 youths with ASD and 146 typically developing (TD) youths) to address group discriminative power of neural markers, their relation to social skills, and the potential to define different neural subtypes within the autistic group. We also conducted genome-wide copy number variant (CNV) and gene expression analyses to provide additional insight into distinct neural subtypes in autism. A high-density 128-channel electroencephalography (EEG) was used to register neural activity of participants, blood samples were collected from the ASD youths to obtain genomic DNA, and rich behavioral phenotyping was provided for each participant. The results revealed three subgroups within the autistic cohort with the presence of "typical" E/I, E > I, and E < I neural profiles. The two subgroups with E/I imbalance had altered clinical phenotypes. In addition, these subgroups had different genetic profiles, showing that genes within identified CNVs had distinct expression patterns with the evidence of more prenatal (E < I) vs. postnatal (E > I) gene expression. The study suggests that the proposed clustering approach has relevance for the identification of clinically meaningful neural and genetic subtypes within a heterogeneous autistic cohort.