Neurology of Deficient Response Control in ADHD

Principal Investigator: Stewart Mostofsky

Building on evidence established in the initial grant period, the overall goals of the proposed study, “Neurology of Deficient Response Control in ADHD,” are to apply advanced neuroimaging and experimental behavioral methods to understanding the biological basis of ADHD and, as a critical next step, to identify neural mechanisms facilitating effective compensation.
Motivated by observations of adult lesions, initial models of ADHD emphasized prefrontal abnormalities (and associated executive dysfunction). However, this is inconsistent with recognized patterns of brain development and the fact that early prefrontal lesions present a clinical picture (with late childhood onset and worsening through adolescence) very different from ADHD. Findings established in the initial funded project provide a basis for a shift towards a more developmental model, in which dysfunction in neural systems critical to motor response control, established early in development, contribute to the pathophysiology of ADHD, while function of later-developing prefrontal systems facilitate compensation. Motor response control, mediated by the basal ganglia and, at the cortical level, the supplementary motor area (SMA), is crucial for selecting to withhold unwanted responses and thereby necessary for effective inhibition of impulsive, hyperactive and off-task behavior that characterizes ADHD. Several laboratories, including our own, have found that individuals with ADHD show increased intrasubject response variability (ISV), reflecting inefficient motor response control. Furthermore, neuroimaging findings, from our laboratory and others, indicate that ADHD is associated with abnormalities in the SMA and interconnected regions of the basal ganglia. A goal of the current proposal is to use novel imaging analysis methods to investigate the hypothesis that abnormalities in a neural circuit involving the SMA and basal ganglia contribute to ADHD-associated impairments in response control (Aim 1).
Preliminary evidence from the initial grant period also revealed that for children with ADHD, but not typically developing (TD) children, recruitment of the prefrontal cortex (PFC) was associated with lower ISV, reflecting improved response control. We therefore propose to investigate the hypothesis that, in some children with ADHD, successful response control depends on prefrontal recruitment (Aims 2 and 3). As an alternative, we will investigate whether a presentation format that increases vigilance can also result in improved response control (Aim 4). The proposed studies will not only help to identify relevant intermediate endophenotypes of ADHD but also might point to potentially effective treatment strategies.