In other recent studies, fMRI was used to assess mean regional task-related signal change in 16 children and adolescents with ADHD, both on and off psychostimulants (e.g., methylphenidate), and 20 healthy controls (Potenza et al., unpublished data). Participants performed the Stroop task--an experimental conflict task requiring proficient readers to name the ink color of a displayed word. Individuals are usually slower and less accurate indicating the ink color of an incompatible color word (e.g., responding "blue" when the word red is inked in blue) than identifying the ink color of a congruent color name (e.g., responding "red" when the word red is inked in red). This difference in performance constitutes the Stroop conflict and is one of the most robust and well-studied phenomena in attentional research (MacLeod, 1991; MacLeod and MacDonald, 2000).

Potenza et al. (unpublished data) found that participants with ADHD were significantly less hyperactive and more attentive on clinical measures of ADHD symptoms when taking psychostimulants than they were when not taking psychostimulants, although they remained more hyperactive and inattentive than controls. They did not differ significantly from controls in measures of performance on the Stroop or other attentional measures, either on or off stimulants, although their performance when taking psychostimulants was consistently intermediate between their off-psychostimulant performance and that of the control group. A brain-region-by-diagnosis interaction was significant in comparing participants with ADHD who were off psychostimulants versus controls, as was a brain-region-by-stimulant interaction when comparing participants with ADHD on versus off psychostimulants. The brain-region-by-diagnosis effect comparing participants with ADHD and controls was no longer significant when the ADHD group was taking psychostimulants. Brain regions previously implicated in the regulation of attention and impulse control contributed to these interactions. In conclusion, using psychostimulants in children with ADHD was associated with improvement in attention and hyperactivity, and concurrently normalized activity in neural systems subserving attention and impulse control.

Neuroimaging data indicated, in addition to smaller prefrontal and basal ganglia structures, a decreased volume of the posterior-inferior vermis of the cerebellum (Berquin et al., 1998; Castellanos et al., 2001; Mostofsky et al., 1998), a region that is thought to be important in attentional processing (Middleton and Strick, 1994). Furthermore, the interpretation of some data proposes increased density of striatal dopamine transporters in adults with ADHD (Dougherty et al., 1999; Dresel et al., 2000). One study, however, reported no significant difference in striatal dopamine transporter density (van Dyck et al., 2002).

Compared to healthy controls, children with ADHD had less striatal activation during a cognitive inhibition task (Vaidya et al., 1998). Methylphenidate increased striatal activation in patients with ADHD but decreased striatal activation in controls. During another inhibitory task, adolescents with ADHD showed reduced activation of the medial prefrontal cortex, right inferior prefrontal cortex and left caudate nucleus, compared to controls (Rubia et al., 1999).

An inverse index of regional cerebral blood flow, T2 relaxometry (an fMRI procedure), was used to indirectly assess blood volume in the striatum (caudate and putamen) of boys ages 6 to 12 in steady-state conditions (Teicher et al., 2000). Boys with ADHD had higher T2 relaxation times bilaterally in the putamen than controls. Relaxation times strongly correlated with both the individual's capacity to sit still and error performance on an attentional task. Daily treatment with methylphenidate significantly changed T2 relaxation times in the putamen of boys with ADHD, although the magnitude and direction of the effect was strongly dependent on unmedicated baseline activity.

Similarly, Anderson et al. (2002) found that methylphenidate decreased steady-state blood flow to the cerebellar vermis of objectively hyperactive boys with ADHD and had the opposite effect on boys with ADHD who were not objectively hyperactive. Objective measures of activity and attention were quantified in children with ADHD on different doses of methylphenidate and placebo (Teicher et al., 2003). Data showed that higher doses altered activity and attentiveness in a rate-dependent manner. These findings illustrate an inverse association between symptom severity and degree of therapeutic response.

Genetic assays of executive attention (e.g., examining the gene that codes for catechol-O-methyltransferase [COMT]) have been few but with intriguing results (Fan et al., 2003, 2001; Fossella et al., 2003, 2002a, 2002b). For example, control participants with the valine/valine genotype showed somewhat more efficient conflict resolution (i.e., lower Stroop conflict) than participants with the valine/methionine genotype (Sommer et al., 2004). The valine allele of COMT, which confers relatively higher levels of enzyme activity and thus lower relative amounts of extrasynaptic dopamine, has been examined in the context of neuroimaging studies in which it was correlated with lower activity of the dorsolateral prefrontal cortex (Egan et al., 2001). Frontal attentional networks may provide insights into pathologies of higher cognition, but there is already compelling evidence relating these networks to ADHD (Berger and Posner, 2000).

In conclusion, the hypothesis that ADHD is a syndrome with multiple distinct endophenotypes and several different etiological mechanisms (Castellanos and Tannock, 2002) must be constrained by neuroimaging findings and behavioral results. Measures of cognitive inhibition, working memory and temporal processing will likely illuminate the neural bases of ADHD and further operationalize the roles of attention, impulsivity and disinhibition in the formulation of ADHD pathophysiology.
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