Neuroscience of Attention-Deficit/Hyperactivity Disorder: The Search for Endophenotypes

Research title: Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes

Researchers: F. Xavier Castellanos, Rosemary Tannock

Published: Nature Neuroscience

The focus of this article is to describe a new approach for identifying genetic and environmental risk factors for ADHD that is intended to move the field beyond primarily descriptive research on the disorder to a richer conceptual understanding of how and why ADHD develops.

They argue that the most promising way to identify genetic and environmental risk factors for ADHD will begin by identifying ‘endophenotypes’ for the disorder. By endophenotypes they mean specific aspects of cognitive functioning that can be measured, that are clearly associated with the behavioral symptoms of ADHD, and that are less removed from environmental and genetic risk factors than the diagnostic category itself. They also argue that the endophenotypes to be studied should be ones for which the neuroscience underpinnings are reasonably well-established. For example, rather than searching for genes that increase the risk for ADHD, they argue that greater success will be attained by searching for genes associated with variability in an aspect of cognitive functioning that is compromised in individuals with ADHD. Focusing on endophenotypes will be more fruitful because they reflect actual cognitive processes that give rise to ADHD behaviors, while ADHD per se is a diagnostic category whose definition has changed over time.

The authors identify 3 potential endophenotypes for ADHD to be studied: “a specific abnormality in reward circuitry that leads to shortened delay gradients, deficits in temporal processing that results in high intrasubject intertrial variability, and deficits in working memory.” Shortened delay gradients refer to the well-established tendency for children with ADHD to prefer an immediate but smaller reward to a larger reward in the future. By temporal processing, they refer to the relative difficulties individuals with ADHD have in reproducing temporal durations, i.e. accurately tracking the passage of time. By working memory they refer to “…processes and mechanisms that that allow task-relevant information to be maintained temporarily in an active state for further processing and recall…” and that “…controls attention and guides decision making and behavior moment by moment during an activity.”

This is not a data-based paper in which the authors report the results of their own investigation. Instead, it presents a theoretically-driven discussion that is grounded in prior research and that articulates a new framework for guiding research on ADHD. It is noteworthy that the authors’ suggestion for working memory to be considered as an important endophenotype for ADHD has clearly been supported by the growing number of studies linking working memory deficits to ADHD that have appeared subsequent to the publication of this paper.