Toward individual heterogeneity and neurobiological subtypes in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a biologically and clinically heterogeneous neurodevelopmental condition, which hinders the identification of biologically rooted evidence for treatment choices and clinical predictions. Identifying brain-based homogenous ADHD subtypes with neuroimaging data to reduce this heterogeneity is promising for elucidating specific neural mechanisms underlying complex clinical presentations, which may enable the development of personalized treatments and the identification of precise therapeutic targets. In this review, we first discuss the large individual differences among ADHD patients indicated by neuroimaging findings from both large-scale group-level studies and individual-level studies, which motivated new efforts to discover neurobiological subtypes. Next, we review recent research on neuroimaging-based ADHD subtypes in terms of three aspects: sample selection, subtyping methodology (i.e., neuroimaging features, subtyping algorithms, and validation strategies), and subtype findings. Eleven studies utilizing multiple single neuroimaging modalities or multimodal neuroimaging were identified. Through diverse features and approaches, current studies have revealed a range of different ADHD neurobiological subtypes characterized by distinct neural and clinical profiles, providing important insight into the heterogeneous nature of ADHD. Despite the current progress, most ADHD subtypes still have little biological relevance, limited clinical utility, and generalizability, slowing down the pace of their clinical translation. We highlight several crucial considerations to overcome these challenges and contribute to more useful and reproducible subtype identification. With the increasing access to large datasets, deliberate features/methods selection, and adequate validation strategies, we believe that ADHD neurobiological subtypes could be used to inform the development of personalized treatments, thereby advancing ADHD clinical practice towards precision psychiatry.