Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers

Extensive investigations spanning multiple levels of inquiry, from genetic to behavioural studies, have sought to unravel the mechanistic foundations of attention-deficit hyperactivity disorder (ADHD), with the aspiration of developing efficacious treatments for this condition. Despite these efforts, the pathogenesis of ADHD remains elusive. In this Review, we reflect on what has been learned about ADHD while also providing a framework that may serve as a roadmap for future investigations. We emphasize that ADHD is a highly heterogeneous disorder with multiple aetiologies that necessitates a multifactorial dimensional phenotype, rather than a fixed dichotomous conceptualization. We highlight new findings that suggest a more brain-wide, ‘global’ view of the disorder, rather than the traditional localizationist framework, which asserts that a limited set of brain regions or networks underlie ADHD. Last, we underscore how underpowered studies that have aimed to associate neurobiology with ADHD phenotypes have long precluded the field from making progress. However, a new age of ADHD research with refined phenotypes, advanced methods, creative study designs and adequately powered investigations is beginning to put the field on a good footing. Indeed, the field is at a promising juncture to advance the neurobiological understanding of ADHD and fulfil the promise of clinical utility.