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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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Methylphenidate (MPH)-induced BPND % change in healthy control subjects and ADHD patients across regions of interest. Reductions in BPND were significant in all regions and similar in both groups. There was a trend for decreased BPND % change in substantia nigra/ventral tegmental area in patients with ADHD compared to control subjects [t(30) = −1.65, P = 0.055]. Error bars denote standard error of the mean.VST = ventral striatum; AST = associative striatum; prePUT = pre-commissural putamen; preCAU = pre-commissural caudate; postCAU = post-commissural caudate; SMST = sensorimotor striatum; SN/VTA = substantia nigra/ventral tegmental area.
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awt263-F7: Methylphenidate (MPH)-induced BPND % change in healthy control subjects and ADHD patients across regions of interest. Reductions in BPND were significant in all regions and similar in both groups. There was a trend for decreased BPND % change in substantia nigra/ventral tegmental area in patients with ADHD compared to control subjects [t(30) = −1.65, P = 0.055]. Error bars denote standard error of the mean.VST = ventral striatum; AST = associative striatum; prePUT = pre-commissural putamen; preCAU = pre-commissural caudate; postCAU = post-commissural caudate; SMST = sensorimotor striatum; SN/VTA = substantia nigra/ventral tegmental area.

Mentions: Methylphenidate significantly reduced BPND [main effect of treatment: F(1,29) = 30.51, P < 0.001], ranging from −4.0 to −7.8% depending on anatomical region {region of interest by treatment interaction [F(3,87) = 10.31, P < 0.001]}, being greatest in substantia nigra/ventral tegmental area and least in ventral striatum (Table 3 and Fig. 7). Methylphenidate also reduced BPND differentially across ventral striatum, associative striatum and sensorimotor striatum [region of interest by treatment interaction: F(2,42) = 8.34, P = 0.002], revealing a preferential effect in sensorimotor striatum. The magnitude of regional BPND % change was similar in patients with ADHD and control subjects (main effect of group and group by drug interaction: P > 0.05).Figure 7


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)

Methylphenidate (MPH)-induced BPND % change in healthy control subjects and ADHD patients across regions of interest. Reductions in BPND were significant in all regions and similar in both groups. There was a trend for decreased BPND % change in substantia nigra/ventral tegmental area in patients with ADHD compared to control subjects [t(30) = −1.65, P = 0.055]. Error bars denote standard error of the mean.VST = ventral striatum; AST = associative striatum; prePUT = pre-commissural putamen; preCAU = pre-commissural caudate; postCAU = post-commissural caudate; SMST = sensorimotor striatum; 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-F7: Methylphenidate (MPH)-induced BPND % change in healthy control subjects and ADHD patients across regions of interest. Reductions in BPND were significant in all regions and similar in both groups. There was a trend for decreased BPND % change in substantia nigra/ventral tegmental area in patients with ADHD compared to control subjects [t(30) = −1.65, P = 0.055]. Error bars denote standard error of the mean.VST = ventral striatum; AST = associative striatum; prePUT = pre-commissural putamen; preCAU = pre-commissural caudate; postCAU = post-commissural caudate; SMST = sensorimotor striatum; SN/VTA = substantia nigra/ventral tegmental area.
Mentions: Methylphenidate significantly reduced BPND [main effect of treatment: F(1,29) = 30.51, P < 0.001], ranging from −4.0 to −7.8% depending on anatomical region {region of interest by treatment interaction [F(3,87) = 10.31, P < 0.001]}, being greatest in substantia nigra/ventral tegmental area and least in ventral striatum (Table 3 and Fig. 7). Methylphenidate also reduced BPND differentially across ventral striatum, associative striatum and sensorimotor striatum [region of interest by treatment interaction: F(2,42) = 8.34, P = 0.002], revealing a preferential effect in sensorimotor striatum. The magnitude of regional BPND % change was similar in patients with ADHD and control subjects (main effect of group and group by drug interaction: P > 0.05).Figure 7

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