title: A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment.
abstract: 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 same set of patients with attention deficit/hyperactivity disorder.
authors.affiliation: 1 Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: del Campo
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.forename: Rob
authors.initials: R
authors.lastname: Smith
authors.forename: Laurent
authors.initials: L
authors.lastname: Brichard
authors.forename: Julio
authors.initials: J
authors.lastname: Acosta-Cabronero
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Chamberlain
authors.forename: Roger
authors.initials: R
authors.lastname: Tait
authors.forename: David
authors.initials: D
authors.lastname: Izquierdo
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.forename: Jonathan
authors.initials: J
authors.lastname: Dowson
authors.forename: John
authors.initials: J
authors.lastname: Suckling
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Baron
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aigbirhio
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001549:Benzamides; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018592:Cross-Over Studies; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008774:Methylphenidate / Q000008:administration & dosage / Q000494:pharmacology*; D064847:Multimodal Imaging / Q000295:instrumentation / Q000379:methods; D049268:Positron-Emission Tomography / Q000295:instrumentation / Q000379:methods; D011569:Psychiatric Status Rating Scales; D019275:Radiopharmaceuticals; D055815:Young Adult
chemical_list: D001549:Benzamides; D018765:Dopamine Uptake Inhibitors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D008774:Methylphenidate; C574003:fallypride
keywords: 18F-fallypride PET; attention deficit/hyperactivity disorder; dopamine; methylphenidate; sustained attention