A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

Patients with ADHD had equivalent D2/D3 receptor availability to healthy control subjects.

“they had equivalent D2/D3 receptor availability”

• Also stated in: § Placebo results · plain

  “The mean BPND values were not significantly different between patients with ADHD and control subjects across all regions (either unilaterally or bilaterally)”

Patients with ADHD as a group showed significant attentional deficits.

“Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits”

• Also stated in: § Sample characteristics and cognitive performance · plain

  “Patients with ADHD had significantly higher ADHD self-rating scale scores (P ≤ 0.01) and performed significantly worse on the RVP A’ signal detection parameter [main effect of group: F(1,29) = 8.31, P = 0.007; placebo data only: F(1,29) = 9.89, P = 0.004].”

Poor attentional performers drawn from both the ADHD and control groups had significantly reduced left caudate dopamine activity.

“poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity.”

Patients with ADHD had equivalent increases in endogenous dopamine after methylphenidate treatment to healthy control subjects.

“equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects”

Methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis.

“Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis.”

Methylphenidate significantly increased dopamine levels in all nigro-striatal regions.

“Methylphenidate significantly increased dopamine levels in all nigro-striatal regions”

Methylphenidate normalized dopamine levels in the left caudate in low performers.

“thereby normalizing dopamine levels in the left caudate in low performers.”

Patients with ADHD showed reduced grey matter volume in fronto-striato-cerebellar and limbic networks.

“reduced grey matter volume in fronto-striato-cerebellar and limbic networks”

• Also stated in: § Grey matter volume · plain

  “patients with ADHD showed significantly reduced grey matter volume in left prefrontal cortical areas (middle frontal cortex, inferior portions of the orbitofrontal cortex and gyrus rectus), and in bilateral putamen, amygdala, hippocampus, fusiform, insula and cerebellum”

In patients, low A' scores were associated with low BPND in left pre-commissural dorsal caudate.

“In patients, low A’ scores were associated with low BPND in left pre-commissural dorsal caudate (r = 0.48, P = 0.031) and right post-commissural caudate (r = 0.43, P = 0.048).”

There was no significant main effect of methylphenidate on A'.

“There was no significant main effect of methylphenidate on A’, nor was there an interaction of methylphenidate with group.”

Repeated measures ANOVA revealed lower BPND % change in low compared with high performers in substantia nigra/ventral tegmental area.

“Corroborating this finding, repeated measures ANOVA revealed lower BPND % change in low compared with high performers in substantia nigra/ventral tegmental area (Fig. 9) [F(1,28) = 9.351, P = 0.005; F(1,28) = 5.46, P = 0.027 and F(1,28) = 5.2, P = 0.030 for bilateral, left and right substantia nigra/ventral tegmental area, respectively], but not in any other region.”

Methylphenidate-induced % change in A' was positively correlated with BPND % change in substantia nigra/ventral tegmental area.

“Methylphenidate-induced % change in A’ was negatively correlated with BPND % change in ventral striatum (r = −0.29, P = 0.05) and positively with substantia nigra/ventral tegmental area (r = 0.5, P = 0.002), with the correlation coefficients being highly significantly different (z = 3.25, P < 0.001).”

Self-rated hyperactivity was not correlated with BPND in substantia nigra/ventral tegmental area in patients.

“Conversely, self-rated hyperactivity was not associated with BPND in total striatum but was negatively correlated with BPND in substantia nigra/ventral tegmental area in control subjects (r = −0.59, P = 0.010) although not in patients (r = −0.123, P = 0.33) (Fig. 5B).”

Self-rated hyperactivity was negatively correlated with BPND in substantia nigra/ventral tegmental area in control subjects.

“Conversely, self-rated hyperactivity was not associated with BPND in total striatum but was negatively correlated with BPND in substantia nigra/ventral tegmental area in control subjects (r = −0.59, P = 0.010) although not in patients (r = −0.123, P = 0.33) (Fig. 5B).”

Self-rated hyperactivity was not associated with BPND in total striatum.

“Conversely, self-rated hyperactivity was not associated with BPND in total striatum but was negatively correlated with BPND in substantia nigra/ventral tegmental area in control subjects (r = −0.59, P = 0.010) although not in patients (r = −0.123, P = 0.33) (Fig. 5B).”

Controlling for between-subject differences in A' scores had no impact on the correlation between methylphenidate-induced changes in A' scores and BPND % change in ventral striatum.

“Controlling for between-subject differences in A’ scores (in addition to methylphenidate plasma levels) had no impact on the correlation between methylphenidate-induced changes in A’ scores and BPND % change in ventral striatum (r = −0.348, P = 0.032 for bilateral ventral striatum; r = −0.247, P = 0.098 and r = −0.349, P = 0.033 for left and right ventral striatum, respectively).”

ADHD self-rating scale total and inattention sub-scores did not correlate with BPND in substantia nigra/ventral tegmental area for either patients or control subjects.

“ADHD self-rating scale total and inattention sub-scores correlated negatively with total striatum BPND both in patients (r = −0.48, P = 0.032; r = −0.51, P = 0.020) and control subjects (r = −0.47, P = 0.04; r = −0.54, P = 0.019) (Fig. 5A) but did not correlate with BPND in substantia nigra/ventral tegmental area for either subject group.”

In control subjects, ADHD self-rating scale total and inattention sub-scores correlated negatively with total striatum BPND.

“ADHD self-rating scale total and inattention sub-scores correlated negatively with total striatum BPND both in patients (r = −0.48, P = 0.032; r = −0.51, P = 0.020) and control subjects (r = −0.47, P = 0.04; r = −0.54, P = 0.019) (Fig. 5A) but did not correlate with BPND in substantia nigra/ventral tegmental area for either subject group.”

For patients and control subjects combined, inattention scores were negatively correlated with BPND in post-commissural caudate.

“For patients and control subjects combined, inattention scores were negatively correlated with BPND in the portions of the associative striatum corresponding to pre-commissural dorsal caudate and post-commissural caudate (r = −0.393, P = 0.014; r = −0.375, P = 0.019) and in sensorimotor striatum (r = −0.324, P = 0.038).”

Stepwise linear regression of all regional BPND values on attentional performance in all subjects revealed a significant best-fit model with the left pre-commissural dorsal caudate as independent variable.

“Stepwise linear regression of all regional BPND values on attentional performance (in all subjects) revealed a significant best-fit model with the left pre-commissural dorsal caudate as independent variable [β = 0.386, P = 0.029; F(1,30) = 5.26, adjusted R2 = 0.21].”

Methylphenidate produced significant increases in systolic blood pressure.

“Methylphenidate produced significant increases in systolic blood pressure [mean paired difference 5 mmHg; t(31) = 4.5; P < 0.001] and heart rate [mean paired difference 7 beats per min; t(31) = 4.4; P < 0.001] (Supplementary material).”

Methylphenidate improved A' scores in low performers.

“This analysis showed that methylphenidate affected cognition differentially in high and low performing subjects [drug by group interaction: F(1,28) = 10.94, P = 0.003], improving A’ scores in low [t(15) = −2.610, P = 0.02] but not in high performers [t(15) = 1.656, P = 0.119] (Fig. 6B).”

Mean methylphenidate plasma concentrations were similar in patients with ADHD and control subjects.

“Mean methylphenidate plasma concentrations were similar in patients with ADHD and control subjects (P > 0.05).”

The correlation coefficients for ventral striatum and substantia nigra/ventral tegmental area were highly significantly different.

“Methylphenidate-induced % change in A’ was negatively correlated with BPND % change in ventral striatum (r = −0.29, P = 0.05) and positively with substantia nigra/ventral tegmental area (r = 0.5, P = 0.002), with the correlation coefficients being highly significantly different (z = 3.25, P < 0.001).”

Across the entire subject group, low A' scores were associated with low BPND in right post-commissural caudate.

“Across the entire subject group, low A’ scores were associated with low BPND in left pre-commissural dorsal caudate (r = 0.314, P = 0.04) as well as in left and right post-commissural caudate (r = 0.308, P = 0.043 and r = 0.323, P = 0.036, respectively; mean: r = 0.33, P = 0.032).”

Covarying for medication status within the patient groups did not change the results on A'.

“Covarying for medication status within the patient groups did not change these results (interactions between treatment and group versus medication status all P > 0.05) (Fig. 6A).”

There was no significant interaction of methylphenidate with group on A'.

“There was no significant main effect of methylphenidate on A’, nor was there an interaction of methylphenidate with group.”

Correlation coefficients for left and right striatal subregions and substantia nigra/ventral tegmental area were similar in patients and control subjects.

“Correlation coefficients for left and right striatal subregions and substantia nigra/ventral tegmental area were similar in patients and control subjects (P > 0.1).”

In patients, low A' scores were associated with low BPND in right post-commissural caudate.

“In patients, low A’ scores were associated with low BPND in left pre-commissural dorsal caudate (r = 0.48, P = 0.031) and right post-commissural caudate (r = 0.43, P = 0.048).”

For patients and control subjects combined, inattention scores were negatively correlated with BPND in sensorimotor striatum.

“For patients and control subjects combined, inattention scores were negatively correlated with BPND in the portions of the associative striatum corresponding to pre-commissural dorsal caudate and post-commissural caudate (r = −0.393, P = 0.014; r = −0.375, P = 0.019) and in sensorimotor striatum (r = −0.324, P = 0.038).”

Hyperactivity scores for all subjects were associated with BPND in left substantia nigra/ventral tegmental area.

“Hyperactivity scores for all subjects on the other hand were associated with BPND in left substantia nigra/ventral tegmental area (r = −0.34, P = 0.032) but not in any other region.”

There was an overlap of performance between patients with ADHD and control subjects in about a third of all subjects.

“There was an overlap of performance between patients with ADHD and control subjects in about a third of all subjects.”

Methylphenidate reduced BPND differentially across ventral striatum, associative striatum and sensorimotor striatum.

“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.”

Patients with ADHD had significantly higher ADHD self-rating scale scores than controls.

“Patients with ADHD had significantly higher ADHD self-rating scale scores (P ≤ 0.01)”

There was a trend for decreased BPND % change in substantia nigra/ventral tegmental area in patients with ADHD compared to control subjects.

“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].”

Across the entire subject group, low A' scores were associated with low BPND in left post-commissural caudate.

“Across the entire subject group, low A’ scores were associated with low BPND in left pre-commissural dorsal caudate (r = 0.314, P = 0.04) as well as in left and right post-commissural caudate (r = 0.308, P = 0.043 and r = 0.323, P = 0.036, respectively; mean: r = 0.33, P = 0.032).”

Methylphenidate-induced % change in A' was negatively correlated with BPND % change in ventral striatum.

“Methylphenidate-induced % change in A’ was negatively correlated with BPND % change in ventral striatum (r = −0.29, P = 0.05) and positively with substantia nigra/ventral tegmental area (r = 0.5, P = 0.002), with the correlation coefficients being highly significantly different (z = 3.25, P < 0.001).”

Hyperactivity scores for all subjects were not associated with BPND in any other region.

“Hyperactivity scores for all subjects on the other hand were associated with BPND in left substantia nigra/ventral tegmental area (r = −0.34, P = 0.032) but not in any other region.”

The magnitude of regional BPND % change was similar in patients with ADHD and control subjects.

“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).”

The reduction in BPND by methylphenidate ranged from −4.0 to −7.8% depending on anatomical region.

“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 had a preferential effect in sensorimotor striatum.

“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.”

In patients with ADHD, ADHD self-rating scale total and inattention sub-scores correlated negatively with total striatum BPND.

“ADHD self-rating scale total and inattention sub-scores correlated negatively with total striatum BPND both in patients (r = −0.48, P = 0.032; r = −0.51, P = 0.020) and control subjects (r = −0.47, P = 0.04; r = −0.54, P = 0.019) (Fig. 5A) but did not correlate with BPND in substantia nigra/ventral tegmental area for either subject group.”

Methylphenidate affected cognition differentially in high and low performing subjects.

“This analysis showed that methylphenidate affected cognition differentially in high and low performing subjects [drug by group interaction: F(1,28) = 10.94, P = 0.003], improving A’ scores in low [t(15) = −2.610, P = 0.02] but not in high performers [t(15) = 1.656, P = 0.119] (Fig. 6B).”

Methylphenidate significantly reduced BPND.

“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).”

There were no between session practice effects on task performance.

“There were no between session practice effects on task performance (P > 0.1).”

For patients and control subjects combined, inattention scores were negatively correlated with BPND in pre-commissural dorsal caudate.

“For patients and control subjects combined, inattention scores were negatively correlated with BPND in the portions of the associative striatum corresponding to pre-commissural dorsal caudate and post-commissural caudate (r = −0.393, P = 0.014; r = −0.375, P = 0.019) and in sensorimotor striatum (r = −0.324, P = 0.038).”

Across the entire subject group, low A' scores were associated with low BPND in left pre-commissural dorsal caudate.

“Across the entire subject group, low A’ scores were associated with low BPND in left pre-commissural dorsal caudate (r = 0.314, P = 0.04) as well as in left and right post-commissural caudate (r = 0.308, P = 0.043 and r = 0.323, P = 0.036, respectively; mean: r = 0.33, P = 0.032).”

Methylphenidate did not improve A' scores in high performers.

“This analysis showed that methylphenidate affected cognition differentially in high and low performing subjects [drug by group interaction: F(1,28) = 10.94, P = 0.003], improving A’ scores in low [t(15) = −2.610, P = 0.02] but not in high performers [t(15) = 1.656, P = 0.119] (Fig. 6B).”

Methylphenidate increased dopamine levels across all striatal regions as well as the midbrain.

“Methylphenidate increased dopamine levels across all striatal regions as well as the midbrain similarly in patients with ADHD and control subjects, thereby normalizing D2/D3 receptor availability in low performers.”

Methylphenidate increased dopamine levels similarly in patients with ADHD and control subjects.

“Methylphenidate increased dopamine levels across all striatal regions as well as the midbrain similarly in patients with ADHD and control subjects, thereby normalizing D2/D3 receptor availability in low performers.”

The same group of adult patients with ADHD had significant brain tissue abnormalities in frontostriatal and limbic structures compared with control subjects.

“However, it is striking that although no group differences were found in terms of dopamine activity in our study, the same group of adult patients with ADHD had significant brain tissue abnormalities in frontostriatal and limbic structures compared with control subjects.”

Baseline performance levels on A' predicted BPND changes specifically in the left midbrain.

“A further regression model revealed that baseline performance levels on A’ predicted BPND changes specifically in the left midbrain [β = −0.471, P < 0.01; F(1,30) = 8.57, adjusted R2 = 0.20], confirming the above correlational results.”

Poor performance on the computerized sustained attention task across both patient and control groups was associated with low BPND values in the left caudate.

“No significant group differences in D2/D3 receptor availability were found; however, poor performance on the computerized sustained attention task across both patient and control groups was associated with low BPND values in the left caudate.”

The drug improved sustained attention in a baseline-dependent manner independently from diagnosis.

“The drug improved sustained attention in a baseline-dependent manner independently from diagnosis.”

The substantia nigra/ventral tegmental area showed high levels of BPND % change, comparable to those observed in sensorimotor striatum.

“Consistent with previous reports, the substantia nigra/ventral tegmental area showed high levels of BPND % change, which were comparable to those observed in sensorimotor striatum.”

Therapeutic doses of methylphenidate administered orally reduce 18F-fallypride binding.

“Thus, here we report, for the first time, that therapeutic doses of methylphenidate administered orally reduce 18F-fallypride binding, which can be attributed to methylphenidate-induced increases in synaptic dopamine levels.”

• AssumptionRests on an assumption: The single oral dose of methylphenidate used in this study is a therapeutic dose.

Adult patients with ADHD as a group showed reduced grey matter volume in distributed frontostriatal and limbic circuits relative to control subjects.

“Adult patients with ADHD as a group had marked deficits in sustained attention and showed reduced grey matter volume in distributed frontostriatal and limbic circuits relative to control subjects.”

On methylphenidate, the group difference in BPND in left pre-commissural dorsal caudate between low and high performers was no longer observed.

“As shown in Fig. 10B, on methylphenidate this group difference was no longer observed [F(1,28) = 2.97, P = 0.096].”

Low performing subjects drawn from both ADHD and control groups had significantly lower BPND in the left pre-commissural caudate than high-performing subjects, independent of diagnosis.

“However, it is possible that the apparent discrepancy can be resolved by the following consideration: low performing subjects drawn from both ADHD and control groups on the computerized test of sustained attention in fact had significantly lower BPND (attributed to lower D2/D3 receptor availability) in the left pre-commissural caudate than high-performing subjects, though independent of diagnosis.”

Repeated measures ANOVA revealed no lower BPND % change in low compared with high performers in any other region.

“Corroborating this finding, repeated measures ANOVA revealed lower BPND % change in low compared with high performers in substantia nigra/ventral tegmental area (Fig. 9) [F(1,28) = 9.351, P = 0.005; F(1,28) = 5.46, P = 0.027 and F(1,28) = 5.2, P = 0.030 for bilateral, left and right substantia nigra/ventral tegmental area, respectively], but not in any other region.”

Subjects performing poorly at baseline also had significantly smaller drug-induced dopamine release in the midbrain.

“Subjects performing poorly at baseline also had significantly smaller drug-induced dopamine release in the midbrain.”

A central finding of this study was that the drug-induced changes in performance correlated with changes in midbrain dopamine levels.

“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.”

Methylphenidate significantly improved sustained attention in a baseline-dependent manner in low performers from both groups.

“Methylphenidate significantly improved sustained attention in a baseline-dependent manner in low performers from both groups.”

No significant group differences in D2/D3 receptor availability were found.

“No significant group differences in D2/D3 receptor availability were found; however, poor performance on the computerized sustained attention task across both patient and control groups was associated with low BPND values in the left caudate.”

On placebo, low performers had reduced BPND in left pre-commissural dorsal caudate.

“On placebo, low performers had reduced BPND in left pre-commissural dorsal caudate (Fig. 10A) [F(1,28) = 4.63, P = 0.04].”

These findings replicate the preferential effect of methylphenidate in the sensorimotor striatum when administered orally using 11C-raclopride binding.

“These findings replicate the preferential effect of methylphenidate in the sensorimotor striatum when administered orally using 11C-raclopride binding (Clatworthy et al., 2009).”

• cites Clatworthy et al., 2009 sourceNot checked yet

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Stepwise linear regression confirmed the role of the right midbrain in predicting changes in attentional performance.

“Stepwise linear regression modelling to determine the relative impact of methylphenidate-induced BPND changes across regions and methylphenidate plasma levels on drug-induced A’ changes confirmed the role of the right midbrain in predicting changes in attentional performance [β = 0.39, P = 0.30; F(1,30) = 5.21, adjusted R2 = 0.12].”

Adult patients with ADHD as a group had marked deficits in sustained attention relative to control subjects.

“Adult patients with ADHD as a group had marked deficits in sustained attention and showed reduced grey matter volume in distributed frontostriatal and limbic circuits relative to control subjects.”

Signal recovery due to partial volume effect was similar in patients with ADHD and control subjects, independently from brain region and experimental condition.

“Importantly, signal recovery due to partial volume effect was similar in patients with ADHD and control subjects, independently from brain region and experimental condition”

Methylphenidate-induced midbrain dopamine increases were reduced in low performers (mostly patients with ADHD).

“The findings of reduced methylphenidate-induced midbrain dopamine increases and improved sustained attention in low performers (mostly patients with ADHD)”

We did not find any differences in PET measurements between patients with previous exposure to ADHD medication and medication-naïve patients (all P > 0.05).

“we did not find any differences in PET measurements between patients with previous exposure to ADHD medication and medication-naïve patients (all P > 0.05).”

Placebo 18F-fallypride BPND values were largely comparable in magnitude and rank order to estimates documented by other groups in the same regions of interest at baseline in fixed designs.

“Values were largely comparable in terms of both magnitude and rank order”

Sustained attention improved in low performers (mostly patients with ADHD).

“improved sustained attention in low performers (mostly patients with ADHD)”

Our finding of reduced grey matter volume in the putamen in patients with ADHD compared with control subjects.

“Moreover, our finding of reduced grey matter volume in the putamen in patients with ADHD compared with control subjects”

Stimulant-induced increases in endogenous dopamine levels trigger negative feedback mechanisms that inhibit dopamine neuron firing.

“According to preclinical evidence, stimulant-induced increases in endogenous dopamine levels trigger negative feedback mechanisms that inhibit dopamine neuron firing (Bunney and Achajanian, 1976).”

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In vivo nuclear imaging techniques such as PET and SPECT have often yielded inconsistent findings regarding the state of the dopamine system in ADHD.

“Indeed, in vivo nuclear imaging techniques such as PET and single photon emission computed tomography (SPECT) have often yielded inconsistent findings regarding the state of the dopamine system in this patient population (Del Campo et al., 2011a).”

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The findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of ADHD that extends into the healthy population.

“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.”

One study in adolescent patients with ADHD found that oral methylphenidate-induced increases in dopamine concentrations in the right striatum were greater in patients showing poor performance on a computerized continuous performance test relative to high performing patients.

“One study in adolescent patients with ADHD found that oral methylphenidate-induced increases in dopamine concentrations in the right striatum were greater in patients showing poor performance on a computerized continuous performance test relative to high performing patients (Rosa-Neto et al., 2005).”

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The clinical effectiveness of stimulants such as methylphenidate in the treatment of ADHD suggests a putative role for both dopamine and noradrenaline in the manifestation of the disorder.

“The clinical effectiveness of stimulants such as methylphenidate in the treatment of ADHD suggests a putative role for both dopamine and noradrenaline in the manifestation of the disorder (Castells et al., 2011).”

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One of the best replicated findings in ADHD is reduced grey matter volume in the catecholamine-rich fronto-striato-cerebellar circuits known to subserve top-down cognitive functions.

“Providing support to these theories, one of the best replicated findings in ADHD is that of reduced grey matter volume in the catecholamine-rich fronto-striato-cerebellar circuits known to subserve these cognitive functions (Seidman et al., 2005; Nakao et al., 2011).”

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• cites Nakao et al., 2011 sourceNot checked yet

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Dopamine dysregulation per se is unlikely to be the primary cause underlying ADHD pathology in adults.

“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.”

Midbrain dopamine autoreceptors have a hitherto neglected role in the therapeutic effects of oral methylphenidate in ADHD.

“Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder.”

• AssumptionRests on an assumption: The midbrain operates as an interface for the dynamic processing of striatal function.

The effects of methylphenidate on sustained attention associated with BPND % change in ventral striatum were not baseline-dependent.

“Therefore, these effects were not baseline-dependent.”

Both groups were matched for age and IQ.

“Both groups were matched for age and IQ.”

RVP A' is associated with activity in neural networks including frontal and striatal regions.

“The selection of RVP A’ to measure attentional performance in this study is supported by evidence that this parameter (i) is a suitable ADHD endophenotype (Gau and Huang, 2013); (ii) is associated with activity in neural networks including frontal and striatal regions (Lawrence et al., 2003)”

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Methylphenidate has been reported to augment several aspects of cognition in healthy subjects similar to those improved in ADHD.

“because methylphenidate has been reported to augment several aspects of cognition in healthy subjects (Rapoport et al., 1978, 1980; Strauss et al., 1984; Koelega, 1993; Elliott et al., 1997; Mehta et al., 2000) similar to those improved in ADHD (Mehta et al., 2004; Turner et al., 2005; Clark et al., 2007; Spencer et al., 2007).”

• cites Rapoport et al., 1978, 1980Not matched

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• cites Strauss et al., 1984 sourceNot checked yet

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• cites Koelega, 1993 sourceNot checked yet

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Effects of methylphenidate and related drugs on cognition are baseline performance-dependent.

“Based on accumulating evidence that effects of methylphenidate and related drugs on cognition are baseline performance-dependent (Kimberg et al., 1997; Mattay et al., 2000; Mehta et al., 2000; Gibbs and D’Esposito, 2005; Tipper et al., 2005; Finke et al., 2010), changes in sustained attention following methylphenidate were assessed as a function of baseline A’ scores, independent of group.”

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• cites Mattay et al., 2000 sourceNot checked yet

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• cites Mehta et al., 2000 sourceNot checked yet

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RVP A' is a suitable ADHD endophenotype.

“The selection of RVP A’ to measure attentional performance in this study is supported by evidence that this parameter (i) is a suitable ADHD endophenotype (Gau and Huang, 2013)”

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Findings for both juvenile and adult ADHD have implicated functional and structural midbrain abnormalities in the pathophysiology of the disorder.

“This question is particularly relevant because findings for both juvenile and adult ADHD have implicated functional and structural midbrain abnormalities in the pathophysiology of the disorder (Ernst et al., 1999; Jucaite et al., 2005; Volkow et al., 2009; Romanos et al., 2010), also consistent with experimental animal models of ADHD (Leo et al., 2003).”

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• cites Jucaite et al., 2005 sourceNot checked yet

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• cites Volkow et al., 2009 sourceNot checked yet

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The effects of methylphenidate and related stimulant drugs in healthy individuals have been shown to be baseline-dependent; i.e. those subjects with relatively low performance levels exhibit greater benefit after the drug.

“The effects of methylphenidate and related stimulant drugs in healthy individuals have been shown to be baseline-dependent; i.e. those subjects with relatively low performance levels exhibit greater benefit after the drug (Naylor et al., 1985; Rogers et al., 1999; Mehta et al., 2000; Turner et al., 2003; Clatworthy et al., 2009).”

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• cites Rogers et al., 1999 sourceNot checked yet

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• cites Mehta et al., 2000 sourceNot checked yet

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These results may reflect regional differences in the response of midbrain dopamine neurons following methylphenidate administration.

“These results may reflect regional differences in the response of midbrain dopamine neurons following methylphenidate administration.”

The effects of methylphenidate on midbrain dopamine levels play a hitherto unknown role in the modulation of attention.

“These findings suggest that the effects of methylphenidate on midbrain dopamine levels play a hitherto unknown role in the modulation of attention.”

The sensitivity of 18F-fallypride to the methylphenidate dose administered in the current design was arguably suboptimal for detecting robust changes in dopamine levels in regions with low D2/D3 receptor density such as the prefrontal cortex.

“However, the sensitivity of 18F-fallypride to the methylphenidate dose administered in the current design was arguably suboptimal for detecting robust changes in dopamine levels in regions with low D2/D3 receptor density such as the prefrontal cortex.”

The differences in regional patterns of methylphenidate-induced dopamine increase following oral versus intravenous methylphenidate administration suggest that the mechanisms underlying the effects of the drug to improve attention differ from those mediating its reinforcing actions.

“Overall, the differences in regional patterns of methylphenidate-induced dopamine increase following oral versus intravenous methylphenidate administration suggest that the mechanisms underlying the effects of the drug to improve attention differ from those mediating its reinforcing actions.”

The observed inverse correlation may reflect the inhibitory influences exerted by midbrain dopamine neurons to regulate dopamine levels in ventral striatum.

“The observed inverse correlation may thus reflect the inhibitory influences exerted by midbrain dopamine neurons to regulate dopamine levels in ventral striatum.”

Our findings define a role for D2/D3 receptor availability in the manifestation of attentional deficits.

“Our findings define a role for D2/D3 receptor availability in the manifestation of attentional deficits that can be explained in the light of the previously hypothesized continuum model of cognitive deficits and underlying dopaminergic dysregulation associated with ADHD (Sahakian and Robbins, 1977).”

• cites Sahakian and Robbins, 1977Not checked yet

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The lack of overall group differences in 18F-fallypride binding argues against a primary nigro-striatal-dependent dopamine dysfunction in adult ADHD.

“However, the lack of overall group differences in 18F-fallypride binding argue against a primary nigro-striatal-dependent dopamine dysfunction in adult ADHD.”

These robust neurobiological correlates argue against the behavioural baseline-dependent effects resulting simply from a statistical regression towards the mean.

“These robust neurobiological correlates argue against the behavioural baseline-dependent effects resulting simply from a statistical regression towards the mean.”

The pattern of dopamine changes observed along the ventral-dorsal gradient of the striatum following oral versus intravenous administration of methylphenidate and amphetamine may be explained by the different pharmacokinetics associated with each route of drug administration.

“The pattern of dopamine changes observed along the ventral–dorsal gradient of the striatum following oral versus intravenous administration of methylphenidate and amphetamine may be explained in light of the different pharmacokinetics associated with each route of drug administration.”

• AssumptionRests on an assumption: Oral methylphenidate penetrates the brain slowly, peaking 60–90 min after administration, whereas intravenous methylphenidate rapidly enters the brain, peaking in <15 min.

In healthy humans, amphetamine-induced dopamine changes in ventral but not dorsal striatum were found to predict hedonic responses.

“Consistent with these data, in healthy humans, amphetamine-induced dopamine changes in ventral but not dorsal striatum were found to predict hedonic responses (Drevets et al., 2001; Leyton et al., 2002; Martinez et al., 2003).”

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• cites Leyton et al., 2002 sourceNot checked yet

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• cites Martinez et al., 2003 sourceNot checked yet

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After administration of psychostimulants, including methylphenidate, the inhibitory effect prevails, leading to decreased responsiveness in dopaminergic neurons.

“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).”

• cites Bunney and Achajanian, 1976Not checked yet

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• cites Shi et al., 2004 sourceNot checked yet

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Methylphenidate normalized D2/D3 receptor availability in low performers.

“Methylphenidate increased dopamine levels across all striatal regions as well as the midbrain similarly in patients with ADHD and control subjects, thereby normalizing D2/D3 receptor availability in low performers.”

These findings possibly constitute the first direct evidence in humans supporting the notion that the doses used clinically to treat ADHD exert their therapeutic actions through presynaptic mechanisms.

“These findings possibly constitute the first direct evidence in humans supporting the notion that the doses used clinically to treat ADHD exert their therapeutic actions through presynaptic mechanisms.”

Previous evidence implicates the left caudate in inattentiveness in patients with ADHD and in healthy subjects.

“This result is consistent with previous evidence implicating the left caudate in inattentiveness, not only in patients with ADHD, but also in healthy subjects (Schrimsher et al., 2002; Volkow et al., 2007a, b, 2009) and is also congruent with reports that lesions in the left caudate produce attentional deficits (Benke et al., 2003).”

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• cites Volkow et al., 2007a, b, 2009 sourceNot checked yet

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• cites Benke et al., 2003 sourceNot checked yet

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Dopamine neurons located in the midbrain receive GABAergic projections from the same striatal subregion they project to through reciprocal connections, giving rise to topographically organized striato-nigro-striatal circuits.

“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).”

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The reduction in 18F-fallypride binding by oral methylphenidate can be attributed to methylphenidate-induced increases in synaptic dopamine levels.

“Thus, here we report, for the first time, that therapeutic doses of methylphenidate administered orally reduce 18F-fallypride binding, which can be attributed to methylphenidate-induced increases in synaptic dopamine levels.”

The attentional deficits observed in ADHD fall along a single normal continuum extending into the healthy population, with patients with ADHD predominantly representing the lower end of the distribution.

“Consistent with the model, the attentional deficits observed in ADHD fall along a single normal continuum extending into the healthy population, with patients with ADHD predominantly representing the lower end of the distribution.”

A further likely mechanism by which methylphenidate improved sustained attention in low performers is the observed normalization of dopamine levels in the left caudate.

“A further likely mechanism by which methylphenidate improved sustained attention in low performers is the observed normalization of dopamine levels in the left caudate.”

The drug is capable of improving sustained attention in low-performing individuals, regardless of ADHD diagnosis.

“Although the lack of methylphenidate effects on attention in high performers was possibly due to ceiling effects, this does not undermine the key finding that the drug is capable of improving sustained attention in low-performing individuals, regardless of ADHD diagnosis.”

The grey matter changes observed in patients did not confound the PET results here reported.

“and thus it can be concluded that the grey matter changes observed in patients did not confound the PET results here reported.”

This technique did not allow a distinction of the proportion of different D2/D3 receptor types (synaptic versus extra-synaptic, post versus presynaptic) or their state of affinity for dopamine.

“Moreover, this technique did not allow a distinction of the proportion of different D2/D3 receptor types (synaptic versus extra-synaptic, post versus presynaptic) or their state of affinity for dopamine.”

Using high-resolution co-registered MRI images to localize the PET signal was crucial to allow segmentation of the striatum into its functional subregions.

“An important innovation of this study relative to previous ADHD PET studies was the use of high resolution co-registered MRI images to help localize the PET signal.”

Striatal functional subregions have different tracer uptake due to heterogeneous D2/D3 receptor density.

“known to have different tracer uptake due to heterogeneous D2/D3 receptor density (Del Campo et al., 2011b).”

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PET evidence has shown that sensitization to amphetamine in humans leads to carry-over effects in subsequent sessions when placebo is administered.

“Indeed, PET evidence has shown that sensitization to amphetamine in humans leads to carry-over effects in subsequent sessions when placebo is administered (Boileau et al., 2007).”

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The regional BPND values reported here following placebo administration were within the expected baseline ranges.

“suggesting that the regional BPND values reported here following placebo administration were within the expected baseline ranges.”

Our findings are consistent with the modulation of attention by nigro-striatal dopamine.

“Although our findings are consistent with the modulation of attention by nigro-striatal dopamine”

There is no evidence to suggest that our design produced anomalous results.

“However, there is no evidence to suggest that our design produced anomalous results.”

Our data suggest that dopamine dysregulation per se is unlikely to be the primary cause underlying ADHD pathology in adults.

“our data also suggest that dopamine dysregulation per se is unlikely to be the primary cause underlying ADHD pathology in adults.”

PET evidence suggests that anticipation of stimulants such as caffeine can induce dopaminergic responses in humans.

“PET evidence suggests that anticipation of stimulants such as caffeine can induce dopaminergic responses in humans (Kaasinen et al., 2004).”

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Half of the patients in the current study had been previously exposed to ADHD medication.

“Finally, the medication history of the patients also needs discussing, as half of the patients in the current study had been previously exposed to ADHD medication.”

Our findings are consistent with poor attention being a key deficit in the clinical profile of ADHD.

“and with poor attention being a key deficit in the clinical profile of ADHD”

These findings implicate a hitherto neglected role of midbrain dopamine in the mediation of therapeutic effects of methylphenidate.

“implicate a hitherto neglected role of midbrain dopamine in the mediation of therapeutic effects of methylphenidate.”

This conclusion is reinforced by evidence of structural brain changes in the same set of patients with adult ADHD.

“This conclusion is reinforced by evidence of structural brain changes in the same set of patients with adult ADHD.”

In the absence of information regarding levels of endogenous dopamine, it was not possible to determine to what extent D2/D3 receptor availability reflected receptor density or basal occupancy.

“In the absence of information regarding levels of endogenous dopamine, it was not possible to determine to what extent D2/D3 receptor availability reflected receptor density or basal occupancy.”

Combining structural MRI and neuroreceptor PET imaging has considerable potential in identifying and characterizing cognitive endophenotypes of ADHD.

“We have shown the considerable potential of combining the complementary strengths of structural MRI and neuroreceptor PET imaging in identifying and characterizing cognitive endophenotypes of ADHD”