Limits...
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.

Show MeSH

Related in: MedlinePlus

Schematic model of dopamine activity along striato-nigro-striatal circuits at baseline (A) and after oral methylphenidate (MPH) in high (B) and low performers (C). Ascending arrows represent projections from dopamine (DA) neurons located in the substantia nigra (SN)/ventral tegmental area (VTA) to the striatum and descending arrows represent GABA-ergic projections from the striatum to the substantia nigra/ventral tegmental area. Different colours represent different striatal functional circuits (red = limbic, green = associative, blue = sensorimotor). Methylphenidate administration (B) increased postsynaptic catecholamine stimulation (solid lines), leading to inhibition of dopamine neuron firing (dashed lines) by activation of synthesis- and release-regulating dopamine autoreceptors. It is suggested that the level of responsivity of dopamine neurons and subsequent striato-nigro-striatal neuromodulation following methylphenidate administration was dependent on baseline dopamine activity in the striatum. Adapted from Haber et al. (2000) and Martinez et al. (2003). CAU = caudate PUT = putamen; VST = ventral striatum.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4125626&req=5

awt263-F12: Schematic model of dopamine activity along striato-nigro-striatal circuits at baseline (A) and after oral methylphenidate (MPH) in high (B) and low performers (C). Ascending arrows represent projections from dopamine (DA) neurons located in the substantia nigra (SN)/ventral tegmental area (VTA) to the striatum and descending arrows represent GABA-ergic projections from the striatum to the substantia nigra/ventral tegmental area. Different colours represent different striatal functional circuits (red = limbic, green = associative, blue = sensorimotor). Methylphenidate administration (B) increased postsynaptic catecholamine stimulation (solid lines), leading to inhibition of dopamine neuron firing (dashed lines) by activation of synthesis- and release-regulating dopamine autoreceptors. It is suggested that the level of responsivity of dopamine neurons and subsequent striato-nigro-striatal neuromodulation following methylphenidate administration was dependent on baseline dopamine activity in the striatum. Adapted from Haber et al. (2000) and Martinez et al. (2003). CAU = caudate PUT = putamen; VST = ventral striatum.

Mentions: Methylphenidate-induced dopamine changes in substantia nigra/ventral tegmental area were negatively related to dopamine changes in ventral striatum but not associative striatum or sensorimotor striatum. These results may reflect regional differences in the response of midbrain dopamine neurons following methylphenidate administration. Dopamine neurons located in the midbrain receive γ-aminobutyric acid (GABA)-ergic projections from the same striatal subregion they project to through reciprocal connections, giving rise to topographically organized striato-nigro-striatal circuits (Haber et al., 2000). Additionally, this system provides non-reciprocal connections, facilitating dopamine transmission along a feed–forward spiral starting in the ventral striatum and finishing in the sensorimotor striatum, whose projections to the midbrain are confined to the regions from which it receives its dopamine input (Haber et al., 2000) (Fig. 12A). GABAergic neurons descending from the striatum to the midbrain can inhibit or stimulate dopamine cell firing depending on whether they contact dopamine neurons or GABAergic interneurons. After administration of psychostimulants (Bunney and Achajanian, 1976), including methylphenidate (Shi et al., 2004), the inhibitory effect prevails, leading to decreased responsiveness in dopaminergic neurons (Fig. 12B).Figure 12


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)

Schematic model of dopamine activity along striato-nigro-striatal circuits at baseline (A) and after oral methylphenidate (MPH) in high (B) and low performers (C). Ascending arrows represent projections from dopamine (DA) neurons located in the substantia nigra (SN)/ventral tegmental area (VTA) to the striatum and descending arrows represent GABA-ergic projections from the striatum to the substantia nigra/ventral tegmental area. Different colours represent different striatal functional circuits (red = limbic, green = associative, blue = sensorimotor). Methylphenidate administration (B) increased postsynaptic catecholamine stimulation (solid lines), leading to inhibition of dopamine neuron firing (dashed lines) by activation of synthesis- and release-regulating dopamine autoreceptors. It is suggested that the level of responsivity of dopamine neurons and subsequent striato-nigro-striatal neuromodulation following methylphenidate administration was dependent on baseline dopamine activity in the striatum. Adapted from Haber et al. (2000) and Martinez et al. (2003). CAU = caudate PUT = putamen; VST = ventral striatum.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

awt263-F12: Schematic model of dopamine activity along striato-nigro-striatal circuits at baseline (A) and after oral methylphenidate (MPH) in high (B) and low performers (C). Ascending arrows represent projections from dopamine (DA) neurons located in the substantia nigra (SN)/ventral tegmental area (VTA) to the striatum and descending arrows represent GABA-ergic projections from the striatum to the substantia nigra/ventral tegmental area. Different colours represent different striatal functional circuits (red = limbic, green = associative, blue = sensorimotor). Methylphenidate administration (B) increased postsynaptic catecholamine stimulation (solid lines), leading to inhibition of dopamine neuron firing (dashed lines) by activation of synthesis- and release-regulating dopamine autoreceptors. It is suggested that the level of responsivity of dopamine neurons and subsequent striato-nigro-striatal neuromodulation following methylphenidate administration was dependent on baseline dopamine activity in the striatum. Adapted from Haber et al. (2000) and Martinez et al. (2003). CAU = caudate PUT = putamen; VST = ventral striatum.
Mentions: Methylphenidate-induced dopamine changes in substantia nigra/ventral tegmental area were negatively related to dopamine changes in ventral striatum but not associative striatum or sensorimotor striatum. These results may reflect regional differences in the response of midbrain dopamine neurons following methylphenidate administration. Dopamine neurons located in the midbrain receive γ-aminobutyric acid (GABA)-ergic projections from the same striatal subregion they project to through reciprocal connections, giving rise to topographically organized striato-nigro-striatal circuits (Haber et al., 2000). Additionally, this system provides non-reciprocal connections, facilitating dopamine transmission along a feed–forward spiral starting in the ventral striatum and finishing in the sensorimotor striatum, whose projections to the midbrain are confined to the regions from which it receives its dopamine input (Haber et al., 2000) (Fig. 12A). GABAergic neurons descending from the striatum to the midbrain can inhibit or stimulate dopamine cell firing depending on whether they contact dopamine neurons or GABAergic interneurons. After administration of psychostimulants (Bunney and Achajanian, 1976), including methylphenidate (Shi et al., 2004), the inhibitory effect prevails, leading to decreased responsiveness in dopaminergic neurons (Fig. 12B).Figure 12

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