Toward Understanding the Basis of ADHD

Difficulties in attention associated with impulsive behavior and overactivity are common presenting problems in both preschool and school-age children and are the cardinal features of attention deficit hyperactivity disorder. Over time there have been significant changes in definition that have helped to clarify important aspects of the condition (1). In turn, research on potential mechanisms has also become increasingly sophisticated. Although the etiology of the condition is likely heterogeneous, a substantial body of research has implicated a range of neurobiological factors, including genetic ones (2). Follow-up studies have demonstrated the persistence of difficulties into adulthood in many cases, and a body of work on the manifestations of the disorder in adults has now appeared (3).

Much research has focused on the neuropsychological and neurobiological substrates of this complex condition (3–5). Models of specific processes that potentially underlie the disorder, or important aspects of it, have become the focus of recent work. For example, early theoretical models emphasized abnormal arousal or sustained attention (6). Subsequent studies have shifted to a focus on impaired executive functions (processes involved in forward planning) (7) or to difficulties with response inhibition (4). Difficulties in the latter domains are consistent with neuroimaging research that has suggested structural and functional abnormalities in prefrontal structures and basal ganglia regions, which underlie motor response inhibition and executive functions (2, 8). Two papers in this issue of the Journal contribute to the growing body of work on this topic.

Rubia and colleagues compare brain activation patterns in medication-naive adolescents with ADHD to a group of age-, sex-, and IQ-matched subjects during a novel inhibition task. The task was specifically designed to force individuals to work “at the edge” of their own performance, thus allowing for a comparison of individual differences in brain activation in relation to inhibitory success and failure. Of additional interest is the study’s use of a medication-naive ADHD subject group. Relative to matched comparison subjects, adolescents with ADHD demonstrated significantly reduced activation in the right inferior prefrontal cortex during successful motor inhibition and in the precuneus and posterior cingulate gyrus during inhibitory failures; this activity was correlated with a measure of ADHD severity. The observation strengthens our confidence that functional brain abnormalities are observed in inhibitory tasks regardless of medication history.

Schachar and colleagues are concerned with familial aspects of motor response inhibition. They studied ADHD-concordant and ADHD-discordant sibling pairs as well as an unrelated group of normally developing individuals. As expected, the ADHD-concordant sibling pairs and the affected sibling of the discordant pairs exhibited difficulties in inhibitory control. Nonaffected siblings in the ADHD-discordant pairs exhibited intermediate levels of performance between the affected individuals and the healthy comparison subjects. In their study, group differences persisted even when age was controlled. The results suggest the important potential utility of impairment in inhibitory control as a potential marker, or endophenotype, of the disorder. As Schachar and Tannock (9) noted, it will be important to study other relevant processes in the attempt to derive more quantitative traits for genetic research.

These papers are a testament to the growing sophistication of work in ADHD. Both papers raise a number of questions for future research, including a clarification of the strength of the relationship between inhibitory processes and severity of attentional difficulties and the role for environmental factors in syndrome pathogenesis. Both studies underscore the importance of combing neuropsychological and neurobiological perspectives in the study of both genetic and brain mechanisms in the pathogenesis of ADHD.

Address reprint requests to Dr. Volkmar, Yale University Child Study Center, 230 South Frontage Rd., New Haven, CT 06520; [email protected] (email).