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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

Regression lines representing the relationship between methylphenidate (MPH) effects on RVP A’ scores and 18F-fallypride BPND % change in (A) right ventral striatum (VST) and (B) right substantia nigra/ventral tegmental area (SN/VTA). Correlation coefficients in these regions were significantly different (z = 2.43, P < 0.001). Note the x-axis scales are different.
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awt263-F8: Regression lines representing the relationship between methylphenidate (MPH) effects on RVP A’ scores and 18F-fallypride BPND % change in (A) right ventral striatum (VST) and (B) right substantia nigra/ventral tegmental area (SN/VTA). Correlation coefficients in these regions were significantly different (z = 2.43, P < 0.001). Note the x-axis scales are different.

Mentions: After controlling for between-subject differences in methylphenidate plasma levels, improvements in sustained attention were associated with greater BPND % change in right ventral striatum (r = −0.318, P = 0.043) and lower BPND % change in substantia nigra/ventral tegmental area [r = 0.32, P = 0.043; r = 0.309, 8 P = 0.048; r = 0.374, P = 0.021; in left, right and bilateral substantia nigra/ventral tegmental area, respectively (Fig. 8)]. Correlation coefficients for ventral striatum and substantia nigra/ventral tegmental area were significantly different from each other (P < 0.01), but similar in patients with ADHD and control subjects.Figure 8


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 lines representing the relationship between methylphenidate (MPH) effects on RVP A’ scores and 18F-fallypride BPND % change in (A) right ventral striatum (VST) and (B) right substantia nigra/ventral tegmental area (SN/VTA). Correlation coefficients in these regions were significantly different (z = 2.43, P < 0.001). Note the x-axis scales are different.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

awt263-F8: Regression lines representing the relationship between methylphenidate (MPH) effects on RVP A’ scores and 18F-fallypride BPND % change in (A) right ventral striatum (VST) and (B) right substantia nigra/ventral tegmental area (SN/VTA). Correlation coefficients in these regions were significantly different (z = 2.43, P < 0.001). Note the x-axis scales are different.
Mentions: After controlling for between-subject differences in methylphenidate plasma levels, improvements in sustained attention were associated with greater BPND % change in right ventral striatum (r = −0.318, P = 0.043) and lower BPND % change in substantia nigra/ventral tegmental area [r = 0.32, P = 0.043; r = 0.309, 8 P = 0.048; r = 0.374, P = 0.021; in left, right and bilateral substantia nigra/ventral tegmental area, respectively (Fig. 8)]. Correlation coefficients for ventral striatum and substantia nigra/ventral tegmental area were significantly different from each other (P < 0.01), but similar in patients with ADHD and control subjects.Figure 8

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