This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: Difficulty with response inhibition is a cardinal symptom of attention deficit hyperactivity disorder (ADHD), combined type. Prefrontal and cingulate brain regions are known to be involved in inhibitory control. Event-related functional magnetic imaging (fMRI) may be able to establish if these regions differ in their activity in ADHD children relative to healthy controls. Method: Fifteen healthy controls and 17 children with ADHD, combined type completed fMRI studies while performing the Stop Signal task. Eight of the ADHD subjects were treatment naive. The remainder of the ADHD subjects had a history of chronic stimulant treatment, but were medication free at the time of the fMRI. No subject had a learning disorder or comorbid psychiatric condition (other than oppositional defiant disorder in the ADHD subjects). Results: Both ADHD and controls activated the right dorsolateral prefrontal cortex (DLPFC) on STOP trials relative to GO trials, and this increase was greater in ADHD subjects. When inhibition was unsuccessful (relative to successful inhibition), healthy controls strongly activated the anterior cingulate cortex (ACC) and left ventrolateral prefrontal cortex (VLPFC). In contrast, ADHD subjects did not show these differences. Activations in treatment naive and chronically treated ADHD subjects did not differ significantly in any brain regions. Conclusions: Compared to healthy controls, ADHD subjects failed to activate the ACC and VLPFC after an unsuccessful inhibition. These findings appear in treatment naive ADHD individuals and, thus, are unlikely to be an artifact of chronic stimulant treatment or abrupt termination of stimulant prior to imaging. 2. Comparison of ADHD children and controls at baseline on ERP. Liotti et al., Developmental Neuropsychology, in submission Neural mechanisms underlying inhibitory processes were investigated in 36 ADHD-combined type and 30 healthy children using High-Density ERPs during the Stop Signal Task. The influence of age, gender and previous treatment history was evaluated. In the control group, a right inferior frontal-maximal N200 wave elicited by Successful Inhibitions was markedly greater than in the ADHD group; and it was larger for Success than Failed Inhibitions. In contrast, such modulation was absent in the ADHD group. The NoGo-P3 was reduced in size in the ADHD group over frontocentral scalp, and it was greater for Success than Failed Inhibitions, but independent of diagnosis. Finally, the Late Positive Wave (LPW) was greater for Failed than Success Stops in both groups over left posterior scalp. Importantly, the LPW was greater in Chronically Treated ADHD than Treatment Naive ADHD subjects. Age and Gender differentially affected the size of the NoGo-P3, but independent of diagnosis: it was greater in older than younger children for Successful Stops, and larger for females than males for Failed Stops. Right frontal N200 and frontocentral Nogo-P3 abnormalities differentiate ADHD-C from healthy children, independent of previous stimulant treatment, age and gender. LPW amplitude distinguishes ADHD-C with and without previous stimulant treatment, independent of acute stimulant withdrawal. 3. Volumetric MRI differences in treatment-naive and chronically-treated children with ADHD. Semrud-Clikeman et al. Neurology, in press Objective: To determine if there are differences in the volume of the caudate and anterior cingulate cortex (ACC) between children with attention deficit hyperactivity disorder (ADHD) and controls, and if such differences are related to the subjects' history of stimulant treatment. Methods: We performed a case-control study in an academic medical center. Twenty-one healthy controls, 16 children with ADHD, combined type with a history of stimulant treatment, and 14 children with ADHD, combined type treatment naive underwent structural MRI. All children with ADHD were medication-free at the time of the MRI. Regional hemispheric volumes (in cm3) of caudate and anterior cingulate cortex. Results: There were significant differences bilaterally on caudate volume for both ADHD groups vs. controls, with no difference between the ADHD groups on either side. In contrast, the right ACC was significantly smaller for the ADHD-Treatment Naive (ADHD/TN) group compared to the ADHD-Treated (ADHD/Rx) and control group. The volume of left ACC approached significance contrast between ADHD/RX and ADHD/TN. There were no differences found between the ADHD/Rx and controls on the ACC volumes bilaterally. Conclusions: The results from this study indicate a relationship of previous treatment history with caudate and anterior cingulate volumetric changes in children with ADHD-Combined type. 4. Electrophysiological Effects of Stimulant Treatment on Inhibitory Control in Children with Attention Deficit-Hyperactivity Disorder. Pliszka et al. J Am Acad Child and Adolescent Psychiatry, in submission Objective: To examine the electrophysiological effects of methylphenidate (MPH) on inhibitory control in children with Attention Deficit/Hyperactivity Disorder (ADHD). Method: Twelve children with ADHD performed the Stop Signal Task while event related potentials (ERP) were obtained. Each child completed two testing sessions, once on placebo and again on an individualized dose of MPH, with the order of medication administration counterbalanced. The following ERP parameters were studied: the N200, often seen as a measure of the activation of the inhibitory process, and the NoGo-P3, which may represent the degree of performance monitoring and/or error detection. Results: MPH significantly improved behavioral performance on the SST. During successful inhibitions, MPH also significantly increased the amplitude of the right frontal N200, while during unsuccessful inhibitions MPH increased the amplitude of the NoGo-P3. Conclusions: MPH may improve inhibitory control by enhancing brain mechanisms that trigger the inhibitory process and make stopping a motor act more probable (reflected by increased N200) and by increasing attentional resources to the task when unsuccessful inhibitions occur (as reflected by increased NoGo-P3). These results are consistent with functional imaging studies suggesting a role for the right frontal inferior cortex and the cingulate cortex in the pathophysiology of ADHD. An ongoing study is the comparison of ADHD subjects to controls using measures of inhibitory control in functional MRI in the new 3T magnet. We are also examining the effects of atomoxetine on the functional MRI measures of inhibitory control in children with ADHD.
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