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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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Regression line representing the relationship between methylphenidate (MPH) effects on sustained attention and on 18F-fallypride BPND in the midbrain (r = 0.502; P = 0.002, two-tailed). SN/VTA = substantia nigra/ventral tegmental area.
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awt263-F11: Regression line representing the relationship between methylphenidate (MPH) effects on sustained attention and on 18F-fallypride BPND in the midbrain (r = 0.502; P = 0.002, two-tailed). SN/VTA = substantia nigra/ventral tegmental area.

Mentions: A central finding of this study was that the drug-induced changes in performance correlated with changes in midbrain dopamine levels (Fig. 11), a result that remained unchanged after excluding ceiling performers. Changes in midbrain dopamine levels mirrored the behavioural baseline-dependent effect: low performers had reduced methylphenidate-induced BPND reductions in the midbrain compared with high performers, with smaller dopamine changes being associated with greater improvements on the sustained attention task. These robust neurobiological correlates argue against the behavioural baseline-dependent effects resulting simply from a statistical regression towards the mean.Figure 11


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)

Regression line representing the relationship between methylphenidate (MPH) effects on sustained attention and on 18F-fallypride BPND in the midbrain (r = 0.502; P = 0.002, two-tailed). SN/VTA = substantia nigra/ventral tegmental area.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

awt263-F11: Regression line representing the relationship between methylphenidate (MPH) effects on sustained attention and on 18F-fallypride BPND in the midbrain (r = 0.502; P = 0.002, two-tailed). SN/VTA = substantia nigra/ventral tegmental area.
Mentions: A central finding of this study was that the drug-induced changes in performance correlated with changes in midbrain dopamine levels (Fig. 11), a result that remained unchanged after excluding ceiling performers. Changes in midbrain dopamine levels mirrored the behavioural baseline-dependent effect: low performers had reduced methylphenidate-induced BPND reductions in the midbrain compared with high performers, with smaller dopamine changes being associated with greater improvements on the sustained attention task. These robust neurobiological correlates argue against the behavioural baseline-dependent effects resulting simply from a statistical regression towards the mean.Figure 11

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