A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

• Published in: Brain (London, England : 1878) Vol. 136; no. 11; pp. 3252 - 3270
• Main Authors: del Campo, Natalia, Fryer, Tim D., Hong, Young T., Smith, Rob, Brichard, Laurent, Acosta-Cabronero, Julio, Chamberlain, Samuel R., Tait, Roger, Izquierdo, David, Regenthal, Ralf, Dowson, Jonathan, Suckling, John, Baron, Jean-Claude, Aigbirhio, Franklin I., Robbins, Trevor W., Sahakian, Barbara J., Müller, Ulrich
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2013
• Subjects: Adult; Anatomy; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - metabolism; Attention Deficit Disorder with Hyperactivity - pathology; Attention Deficit Disorder with Hyperactivity - physiopathology; Benzamides; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Corpus Striatum - physiopathology; Cross-Over Studies; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - pharmacology; Double-Blind Method; Fluorodeoxyglucose F18; Humans; Investigative techniques, diagnostic techniques (general aspects); Magnetic Resonance Imaging - instrumentation; Magnetic Resonance Imaging - methods; Male; Medical sciences; Mesencephalon - drug effects; Mesencephalon - metabolism; Mesencephalon - pathology; Mesencephalon - physiopathology; Methylphenidate - administration & dosage; Methylphenidate - pharmacology; Multimodal Imaging - instrumentation; Multimodal Imaging - methods; Nervous system; Neurology; Original; Positron-Emission Tomography - instrumentation; Positron-Emission Tomography - methods; Psychiatric Status Rating Scales; Radionuclide investigations; Radiopharmaceuticals; Young Adult; Radionuclide study; Nervous system diseases; Dopamine; sustained attention; Attention; Catecholamine; attention deficit/hyperactivity disorder; Treatment; F-fallypride PET; Neurotransmitter; Attention disorder with hyperactivity; Positron emission tomography; Methylphenidate; Emission tomography; methylphenidate; dopamine; 18F-fallypride PET
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awt263

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.