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

del Campo N, Fryer TD, Hong YT, Smith R, Brichard L, Acosta-Cabronero J, Chamberlain SR, Tait R, Izquierdo D, Regenthal R, Dowson J, Suckling J, Baron JC, Aigbirhio FI, Robbins TW, Sahakian BJ, Müller U - Brain (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

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.

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Related in: MedlinePlus

Time line for PET and RVP data acquisition after capsule administration. Grey boxes indicate 15 min transmission scans.
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awt263-F1: Time line for PET and RVP data acquisition after capsule administration. Grey boxes indicate 15 min transmission scans.

Mentions: Participants were enrolled into a randomized, double-blind placebo-controlled cross-over design, consisting of two 18F-fallypride PET scans at least a week apart and one MRI scan. On each PET session, subjects were administered a capsule containing either 0.5 mg/kg of methylphenidate or placebo 75 min before the 18F-fallypride injection (Fig. 1). The dose of 0.5 mg/kg was chosen to be within the therapeutic range used in the clinic: according to the NICE 2008 guidelines regarding the diagnosis and treatment of patients with ADHD, starting methylphenidate doses of 3 × 5 mg or 3 × 10 mg and a dose limit of 100 mg per day are recommended. A dose of 0.5 mg/kg equals 40 mg for an 80 kg patient, representing thus a medium dose for a single dose study. At 0, 2 and 4 h after capsule administration, blood samples were collected for determination of methylphenidate plasma concentrations (Supplementary material) to assess compliance with drug discontinuation in medicated patients and account for between-subject differences in methylphenidate plasma levels. Cardiovascular measures were regularly monitored throughout the study.Figure 1


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

del Campo N, Fryer TD, Hong YT, Smith R, Brichard L, Acosta-Cabronero J, Chamberlain SR, Tait R, Izquierdo D, Regenthal R, Dowson J, Suckling J, Baron JC, Aigbirhio FI, Robbins TW, Sahakian BJ, Müller U - Brain (2013)

Time line for PET and RVP data acquisition after capsule administration. Grey boxes indicate 15 min transmission scans.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125626&req=5

awt263-F1: Time line for PET and RVP data acquisition after capsule administration. Grey boxes indicate 15 min transmission scans.
Mentions: Participants were enrolled into a randomized, double-blind placebo-controlled cross-over design, consisting of two 18F-fallypride PET scans at least a week apart and one MRI scan. On each PET session, subjects were administered a capsule containing either 0.5 mg/kg of methylphenidate or placebo 75 min before the 18F-fallypride injection (Fig. 1). The dose of 0.5 mg/kg was chosen to be within the therapeutic range used in the clinic: according to the NICE 2008 guidelines regarding the diagnosis and treatment of patients with ADHD, starting methylphenidate doses of 3 × 5 mg or 3 × 10 mg and a dose limit of 100 mg per day are recommended. A dose of 0.5 mg/kg equals 40 mg for an 80 kg patient, representing thus a medium dose for a single dose study. At 0, 2 and 4 h after capsule administration, blood samples were collected for determination of methylphenidate plasma concentrations (Supplementary material) to assess compliance with drug discontinuation in medicated patients and account for between-subject differences in methylphenidate plasma levels. Cardiovascular measures were regularly monitored throughout the study.Figure 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1 Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

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.

Show MeSH
Related in: MedlinePlus