Transdiagnostic symptom subtypes across autism spectrum disorders and attention deficit hyperactivity disorder: validated by measures of neurocognition and structural connectivity

Abstract

Backgrounds: Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are neurodevelopmental disorders that exhibit within-disorder heterogeneity and cross-disorder phenotypic overlap, thus suggesting that the current disease categories may not fully represent the etiologic essence of the disorders, especially for highly comorbid neurodevelopmental disorders. In this study, we explored the subtypes of a combined sample of ASD and ADHD by integrating measurements of behavior, cognition and brain imaging. Methods: A total of 164 participants, including 65 with ASD, 47 with ADHD, and 52 controls, were recruited. Unsupervised machine learning with an agglomerative hierarchical clustering algorithm was used to identify transdiagnostic symptom clusters. Neurocognition and brain structural connectivity measurements were used to assess symptom clusters. Mediation analysis was used to explore the relationship between transdiagnostic symptoms, neurocognition and brain structural connectivity. Results: We identified three symptom clusters that did not fall within the diagnostic boundaries of DSM. External measurements from neurocognition and neuroimaging domains supported distinct profiles, including fine motor function, verbal fluency, and structural connectivity in the corpus callosum between these symptom clusters, highlighting possible biomarkers for ASD and ADHD. Additionally, fine motor function was shown to mediate the relationship between the corpus callosum and perseveration symptoms. Conclusions: In this transdiagnostic study on ASD and ADHD, we identified three subtypes showing meaningful associations between symptoms, neurocognition and brain white matter structural connectivity. The fine motor function and structural connectivity of corpus callosum might be used as biomarkers for neurodevelopmental disorders with social skill symptoms. The results of this study highlighted the importance of precise phenotyping and further supported the effects of fine motor intervention on ASD and ADHD.