n-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2-3-dimethoxybenzamide and Attention-Deficit-Disorder-with-Hyperactivity

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the sam

Topics: Adult; Attention Deficit Disorder with Hyperactivity; Benzamides; Corpus Striatum; Cross-Over Studies; Dopamine Uptake Inhibitors; Double-Blind Method; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Mesencephalon; Methylphenidate; Multimodal Imaging; Positron-Emission Tomography; Psychiatric Status Rating Scales; Radiopharmaceuticals; Young Adult

Sub-striatal regions of interest (ROIs) are widely used in PET studies to investigate the role of dopamine in the modulation of neural networks implicated in emotion, cognition and motor function. One common approach is that of Mawlawi et al. (2001) and Martinez et al. (2003), where each striatum is divided into five sub-regions. This study focuses on the use of two spatial normalization-based alternatives to manual sub-striatal ROI delineation per subject: manual ROI delineation on a template brain and the production of probabilistic ROIs from a set of subject-specific manually delineated ROIs. Two spatial normalization algorithms were compared: SPM5 unified segmentation and ART. The ability of these methods to quantify sub-striatal regional non-displaceable binding potential (BP(ND)) and BP(ND) % change (following methylphenidate) was tested on 32 subjects (16 controls and 16 ADHD patients) scanned with the dopamine D(2)/D(3) ligand [(18)F]fallypride. Probabilistic ROIs produced by ART provided the best results, with similarity index values against subject-specific manual ROIs of 0.75-0.89 (mean 0.84) compared to 0.70-0.85 (mean 0.79) for template ROIs. Correlations (r) for BP(ND) and BP(ND) % change between subject-specific manual ROIs and these probabilistic ROIs of 0.90-0.98 (mean 0.95) and 0.98-1.00 (mean 0.99) respectively were superior overall to those obtained with template ROIs, although only marginally so for BP(ND) % change. The significance of relationships between BP(ND) measures and both behavioural tasks and methylphenidate plasma levels was preserved with ART combined with both probabilistic and template ROIs. SPM5 virtually matched the performance of ART for BP(ND) % change estimation but was inferior for BP(ND) estimation in caudate sub-regions. ART spatial normalization combined with probabilistic ROIs and to a lesser extent template ROIs provides an efficient and accurate alternative to time-consuming manual sub-striatal ROI delineation per subject, especially when the parameter of interest is BP(ND) % change.

Topics: Adult; Attention Deficit Disorder with Hyperactivity; Benzamides; Computer Simulation; Corpus Striatum; Data Interpretation, Statistical; Female; Humans; Male; Models, Neurological; Models, Statistical; Positron-Emission Tomography; Pyrrolidines; Radiopharmaceuticals; Receptors, Dopamine; Tissue Distribution