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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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(A and B) Coronal planes through an AC–PC aligned MPRAGE image showing striatal regions of interest. (A) Ventral striatum (2, 3), pre-commissural dorsal putamen (4, 5), pre-commissural dorsal caudate (6, 7); (B) post-commissural putamen (8, 9) and post-commissural caudate (10, 11). The red line helped to divide the pre-commissural caudate and putamen into ventral and dorsal. (C) Midbrain region of interest defined on a T2 scan co-registered to the MRAC-PC.
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awt263-F2: (A and B) Coronal planes through an AC–PC aligned MPRAGE image showing striatal regions of interest. (A) Ventral striatum (2, 3), pre-commissural dorsal putamen (4, 5), pre-commissural dorsal caudate (6, 7); (B) post-commissural putamen (8, 9) and post-commissural caudate (10, 11). The red line helped to divide the pre-commissural caudate and putamen into ventral and dorsal. (C) Midbrain region of interest defined on a T2 scan co-registered to the MRAC-PC.

Mentions: For each subject, regions of interest were manually drawn on coronal planes of the MRAC-PC with Analyze 7.0 (AnalyzeDirect) as previously described (Mawlawi et al., 2001; Martinez et al., 2003; Del Campo et al., 2011b). The following striatal subregions were defined bilaterally: ventral striatum, pre-commissural dorsal putamen, pre-commissural dorsal caudate, post-commissural putamen and post-commissural caudate (Fig. 2).Figure 2


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)

(A and B) Coronal planes through an AC–PC aligned MPRAGE image showing striatal regions of interest. (A) Ventral striatum (2, 3), pre-commissural dorsal putamen (4, 5), pre-commissural dorsal caudate (6, 7); (B) post-commissural putamen (8, 9) and post-commissural caudate (10, 11). The red line helped to divide the pre-commissural caudate and putamen into ventral and dorsal. (C) Midbrain region of interest defined on a T2 scan co-registered to the MRAC-PC.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

awt263-F2: (A and B) Coronal planes through an AC–PC aligned MPRAGE image showing striatal regions of interest. (A) Ventral striatum (2, 3), pre-commissural dorsal putamen (4, 5), pre-commissural dorsal caudate (6, 7); (B) post-commissural putamen (8, 9) and post-commissural caudate (10, 11). The red line helped to divide the pre-commissural caudate and putamen into ventral and dorsal. (C) Midbrain region of interest defined on a T2 scan co-registered to the MRAC-PC.
Mentions: For each subject, regions of interest were manually drawn on coronal planes of the MRAC-PC with Analyze 7.0 (AnalyzeDirect) as previously described (Mawlawi et al., 2001; Martinez et al., 2003; Del Campo et al., 2011b). The following striatal subregions were defined bilaterally: ventral striatum, pre-commissural dorsal putamen, pre-commissural dorsal caudate, post-commissural putamen and post-commissural caudate (Fig. 2).Figure 2

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