Two neurosubtypes of ADHD different from the clinical phenotypes

Clinical and etiological variability of attention deficit hyperactivity disorder (ADHD) presents an obstacle to understand the disorder. The aim of this study was to disentangle the heterogeneity of ADHD using neuroimaging and a semi-supervised machine learning algorithm. We collected brain structural and functional magnetic resonance imaging (MRI) data and clinical profiles of 183 children with ADHD and 396 neurotypical controls from 7 independent sites. We also used an external validation set with 750 subjects. We adopted a semi-supervised clustering method to subtype ADHD by regional volumetric measures of gray matter, white matter, and fractional amplitude of low frequency fluctuation (fALFF). In addition, split sample test, leave-one-site-out test and external validation were applied to evaluate the reproducibility and stability of ADHD subtypes. Two stable and reproducible neurosubtypes of ADHD were disclosed, which were proved by the split-sample test and leave-one-site-out validation. The structural and functional patterns of ADHD subtypes were also stable in the external validation set. The current two neurosubtypes differed in clinical manifestations and volumetric gray matter, white matter volume and fALFF patterns. The current neurosubtypes of ADHD which were different from clinical phenotypes could facilitate understanding the underlying neuropathological and neurobiological mechanism of the disorder.