Electrophysiologically-defined excitation-inhibition autism neurosubtypes

Excitation-inhibition (E:I) imbalance has long been considered one of the primary neurobiological theories explaining autism. However, the theory has been bolstered heavily by research on high-penetrance genetic mechanisms which are only found in a small proportion of the autism population. Thus, how well does E:I imbalance explain idiopathic autism? Here we find that idiopathic autistic males can be split into two distinct E:I-defined ‘neurosubtypes’. These E:I neurosubtypes can be identified in EEG data via an E:I-sensitive metric known as the Hurst exponent (H). Half of autistic individuals fall into the first E:I neurosubtype and can be described as having elevated E:I ratio relative to typically-developing (TD) comparison group. The remaining other half of autistic males fall into a second E:I neurosubtype with the opposite pattern of reduced E:I ratio relative to TD. Finally, E:I neurosubtypes show differential relationships between H and behavioral and demographic variables consisting of age, intelligence, and autism symptomatology. This work suggests that different types of E:I imbalance can manifest in idiopathic autistic males. Such differential E:I biomarkers may be indicative of distinctive etiological or compensatory mechanisms and differential underlying micro- and macroscale neural organization with differential phenotypic impact. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This project was supported by funding from the Simons Foundation for Autism Research Initiative (SFARI; grant number 982347) to MVL and from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 755816; AUTISMS) to MVL. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study used publicly available data from the CMI-HBN dataset. The CMI-HBN initiative received ethical approval by the Chesapeake Institutional Review Board, and written informed consent was obtained from all participants or their legal guardians (for participants < 18 years). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes CMI-HBN data can be found at [http://fcon\_1000.projects.nitrc.org/indi/cmi\_healthy\_brain\_network/][1]. [1]: http://fcon_1000.projects.nitrc.org/indi/cmi_healthy_brain_network/