Evaluating Dopamine Reward Pathway in ADHD: Clinical Implications
Open accessAbstract
We used positron emission tomography to measure dopamine synaptic markers (transporters and D2/D3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls. For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls in regions of the dopamine reward pathway in the left side of the brain. The mean for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD. For D2/D3 receptors, the mean in the caudate for controls was 2.80 vs 2.67 for those with ADHD; and in the accumbens for controls was 2.85 vs 2.68 for those with ADHD.
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- Findingown data
Mean D2/D3 receptor availability in nucleus accumbens was lower in ADHD (2.68) than controls (2.85), 95% CI 0.06-0.30, P=.004.
“for D2/D3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06–0.30, P=.004)”
Quote in the paperSubstantial claim - Findingown data
Mean D2/D3 receptor availability in hypothalamic region was lower in ADHD (0.05) than controls (0.12), 95% CI 0.02-0.12, P=.004.
“differences in D2/D3 in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02–0.12; P=.004)”
Quote in the paperSubstantial claim - Findingown data
DAT reductions in left hypothalamic region were not significantly different between groups.
“but the reductions in left hypothalamic region were not significantly different (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
Mean DAT availability in midbrain was lower in ADHD (0.09) than controls (0.16), 95% CI 0.03-0.12, P≤.001.
“and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03–0.12; P ≤ .001)”
Quote in the paperSubstantial claim - Findingown data
Mean D2/D3 receptor availability in midbrain was lower in ADHD (0.18) than controls (0.28), 95% CI 0.02-0.17, P=.01.
“and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02–0.17, P=.01)”
Quote in the paperSubstantial claim
- Findingown data
The correlations with reflectivity or impulsivity and PET dopamine measures were not significant.
“The correlations with reflectivity or impulsivity and the PET dopamine measures were not significant”
Quote in the paperNot a substantial claim - Findingown data
Despite the low affinity limitation, significant differences in hypothalamus and midbrain were shown.
“However, despite this limitation, significant differences in the latter regions between controls and participants with ADHD was shown.”
Quote in the paperSubstantial claim - Findingown data
In adults with ADHD compared with healthy controls, PET measures of DAT and D2/D3 receptor specific binding were lower in left-hemisphere regions of the dopamine reward pathway.
“For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P<.005) in regions of the dopamine reward pathway in the left side of the brain.”
- Also stated in: § Dopamine D2/D3 Receptors · plain
“Statistical parametric mapping analysis of the [11C]raclopride distribution volume ratio images revealed 1 cluster with lower D2/D3 availability in ADHD participants than controls in the left hemisphere.”
- Also stated in: § Dopamine Transporters · plain
“Statistical parametric mapping analysis of the [11C]cocaine distribution volume ratio images revealed a cluster in the same location as manifested in the [11C]raclopride images.”
Quote in the paperSubstantial claim - Also stated in: § Dopamine D2/D3 Receptors · plain
- Findingown data
K1 measures for [11C]cocaine did not differ between groups in left caudate or left accumbens.
“The mean (95% CI for mean difference) of the K1 measures for [11C]cocaine did not differ in the left caudate with 0.49 among the controls vs 0.48 among those with ADHD (95% CI, −0.05 to 0.03) or in left accumbens region with a respective difference of 0.49 vs 0.51 among those with ADHD (95% CI, −0.02 to 0.07).”
Quote in the paperNot a substantial claim - Findingown data
K1 measures for [11C]raclopride did not differ between groups in left caudate or left accumbens.
“In contrast the K1 measures for [11C]raclopride (transport of radioligand from plasma to tissue) did not differ either in left caudate with the both groups having a mean 0.11 (95% confidence interval [CI], −0.01 to 0.006 mean difference) or in left accumbens region with the controls having a mean of 0.12 vs a mean of 0.11 for those with ADHD (95% CI, −0.01 to 0.005).”
Quote in the paperNot a substantial claim - Findingown data
The significant findings are restricted to the left hemisphere.
“Although the significant findings in this study are restricted to the left hemisphere”
Quote in the paperNot a substantial claim - Findingown data
Mean D2/D3 receptor availability in left caudate was lower in ADHD (2.47) than controls (2.80), 95% CI 0.10-0.56, P=.005.
“the mean D2/D3 for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10–0.56; P=.005)”
Quote in the paperSubstantial claim - Findingown data
Attention ratings were negatively correlated with D2/D3 receptor availability in left accumbens, midbrain, caudate, and hypothalamic regions.
“Ratings of attention correlated with D2/D3 in the accumbens (r =0.35; 95% CI, 0.15–0.52; P =.001), midbrain (r=0.35; 95% CI, 0.14–0.52; P=.001), caudate (r=0.32; 95% CI, 0.11–0.50; P=.003), and hypothalamic (r=0.31; CI, 0.10–0.49; P=.003) regions”
Quote in the paperSubstantial claim - Findingown data
Mean DAT availability in nucleus accumbens was lower in ADHD (0.63) than controls (0.71), with 95% CI for mean difference 0.03-0.13, P=.004.
“The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03–0.13, P=.004)”
Quote in the paperSubstantial claim - Findingown data
Mean DAT availability in left caudate was lower in ADHD (0.53) than controls (0.66), 95% CI 0.04-0.22, P=.003.
“the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04–0.22; P=.003)”
Quote in the paperSubstantial claim - Study design and conductnone given
The relatively low affinity of [11C]raclopride and [11C]cocaine makes them better suited to measure high-density regions and less sensitive to low-density regions like hypothalamus and midbrain.
“The relatively low affinity of [11C]raclopride and [11C]cocaine for their targets makes them better suited to measure regions with high D2/D3 receptor or DAT density (ie, caudate, putamen, and accumbens) and less sensitive to regions with lower levels such as the hypothalamus and midbrain.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The lower D2/D3 and DAT availability in midbrain could underlie the decreased dopamine release reported in adults with ADHD.
“This could underlie the decreased dopamine release reported in adults with ADHD8 because firing of dopamine neurons in the midbrain is responsible for release of dopamine in striatum.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Recent fMRI studies showed decreased nucleus accumbens activation with processing of reward in participants with ADHD.
“Indeed recent functional magnetic resonance imaging (fMRI) studies showed decreased nucleus accumbens activation with processing of reward in participants with ADHD.16,17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The negative correlation between dopamine markers in midbrain and attention suggests impaired signaling from dopamine cells may contribute to severity of inattention in ADHD.
“Moreover, the negative correlation between dopamine markers in the midbrain and the dimension of attention (DAT and D2 receptors) suggests that impaired signaling from dopamine cells may contribute to severity of symptoms of inattention in ADHD.”
Quote in the paperSubstantial claim - Study design and conductreasoning
Sample-size calculation based on preliminary studies indicated at least 40 participants per group were needed to achieve at least 80% power.
“Sample-size calculation for this study was based on our preliminary studies (with smaller sample sizes) on DAT6 and D2/D3 receptors,8 which revealed a difference in caudate between groups at an effect size (ratio between the mean difference and the pooled standard deviation) between 0.65 and 0.80. For such effect sizes, to achieve a power of at least 80% using the independent samples t test with a”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The study corroborates disruption of synaptic dopamine markers in caudate in adults with ADHD.
“It also corroborates disruption of synaptic dopamine markers in caudate in adults with ADHD”
Quote in the paperSubstantial claim - Premisecitation
A recent fMRI study reported decreased activation of the ventral striatum for both immediate and delayed rewards in adult participants with ADHD compared with controls.
“Consistent with this important clinical feature of the ADHD syndrome, a recent fMRI study reported decreased activation of the ventral striatum (wherein nucleus accumbens is located) for both immediate and delayed rewards in adult participants with ADHD compared with controls.17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The study provides preliminary evidence that the hypothalamus may also be affected in ADHD.
“and provides preliminary evidence that the hypothalamus may also be affected.”
Quote in the paperNot a substantial claim - Interpretationown data
The association of the mesoaccumbens dopamine pathway with ADHD inattention symptoms may have clinical relevance.
“Our findings of an association of the mesoaccumbens dopamine pathway with ADHD inattention symptoms may have clinical relevance.”
Quote in the paperSubstantial claim - Study design and conductown data
Region-of-interest analyses independently confirmed the SPM finding of lower ligand binding in ADHD.
“Region-of-interest analyses corroborated these findings.”
- Also stated in: § Dopamine D2/D3 Receptors · plain
“These findings were confirmed by independently drawn region of interest, which also showed ADHD-control differences in left accumbens, midbrain, caudate, and in hypothalamic regions(Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Dopamine D2/D3 Receptors · plain
- Study design and conductreasoning
The eventual sample sizes of 53 ADHD and 44 controls allowed detection of estimated mean differences with power between 88% and 97%.
“The eventual sample sizes of 53 in the ADHD and 44 in the control groups allowed the detection of the estimated mean differences with a power between 88% and 97% via the independent samples t test at the significance level of .05 (2 sided).”
Quote in the paperSubstantial claim - Study design and conductreasoning
Exclusion criteria minimized confounding from prior drug exposures or comorbidity.
“To minimize confounding from prior drug exposures or comorbidity, participants were excluded if they had a prior history of substance abuse (other than nicotine) or with positive urine drug screen results, prior or current treatment with psychotropic medications (including stimulants), psychiatric comorbidities (axis I or II diagnosis other than ADHD), neurological disease, medical conditions that”
Quote in the paperSubstantial claim - Interpretationown data
The lower D2/D3 and DAT availability in accumbens and midbrain supports the hypothesis of an impairment of the dopamine reward pathway in ADHD.
“The lower than normal D2/D3 receptor and DAT availability in the accumbens and midbrain regions supports the hypothesis of an impairment of the dopamine reward pathway in ADHD.”
Quote in the paperSubstantial claim - Premisecitation
These findings differ from those reported in adolescents with ADHD, which showed higher D2/D3 receptor availability in the left striatum than in young adults.
“These findings differ from those reported in adolescents with ADHD, which showed higher D2/D3 receptor availability in the left striatum (including caudate) than in young adults, that was interpreted to reflect deficient dopamine occupancy of these receptors.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
The study provides evidence in favor of the predicted disruption in the mesoaccumbens dopamine pathway in ADHD.
“This study provides evidence in favor of the predicted disruption in the mesoaccumbens dopamine pathway in ADHD.”
Quote in the paperSubstantial claim - Interpretationcitation
The lower D2/D3 and DAT availability in midbrain is consistent with findings from prior imaging studies of children and adolescents with ADHD documenting midbrain abnormalities.
“The lower D2/D3 receptor and DAT availability in the midbrain, which contains most of the dopamine neurons in the brain, is consistent with findings from prior imaging studies of children and adolescents with ADHD documenting midbrain abnormalities.5,35”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
The lack of group differences in K1 measures indicates that findings reflect decreased availability of DAT and D2/D3 receptors rather than decreases secondary to partial volume effects.
“However, that there were no group differences in measures of K1 (transport of radiotracer from plasma to tissue) in striatum, which would have also been affected by volumetric changes, indicates that these findings reflect decreased availability of DAT and D2/D3 receptors rather than decreases secondary to partial volume effects.”
Quote in the paperSubstantial claim - Premisecitation
DAT findings in striatum have been inconsistent in studies of ADHD vs controls, with some reporting high, some low, and others no differences.
“In contrast, DAT findings in striatum (including caudate) have been inconsistent in studies of participants with ADHD vs controls, with some studies reporting high,43 others low,6 and others no differences.44”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [6]
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- cites [44]
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- Premisecitation
Stimulant medications have been shown to increase the saliency of a cognitive task in proportion to drug-induced dopamine increases in striatum.
“Also stimulant medications have been shown to increase the saliency of a cognitive task (motivation, interest) in proportion to the drug-induced dopamine increases in striatum.53”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
A mutation in the melanocortin-4-receptor (MC4R) gene, expressed in several hypothalamic nuclei that results in obesity, is associated with ADHD.
“Relevant to the role of the hypothalamus in ADHD is the association of a mutation in the melanocortin-4-receptor (MC4R) gene, expressed in several hypothalamic nuclei that results in obesity, with ADHD.50”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 18
- May combine two claims. 12
The quote only partly states this claim.
Findingown dataNo brain regions showed higher D2/D3 or DAT availability in ADHD participants than in controls.
“There were no regions that were higher in ADHD participants than in controls.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Findingown dataAttention ratings were negatively correlated with DAT availability in left midbrain.
“and with DAT in the midbrain (r=0.37; 95% CI, 0.16–0.53; P ≤ .001).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenLower than normal D2/D3 receptors and DAT availability in caudate was demonstrated in ADHD.
“Lower than normal D2/D3 receptors and DAT availability in ADHD in the caudate was also demonstrated.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGenetic and environmental etiologies implicating dopamine have been proposed for ADHD.
“Genetic and environmental etiologies that implicate the neurotransmitter dopamine have been proposed for ADHD.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3]
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Study design and conductcitationThe SWAN rating scale has psychometric properties superior to truncated symptom-severity rating scales.
“The psychometric properties of the SWAN rating scale are superior to those of truncated symptom-severity ratings scales.22”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningThe finding of hypothalamic involvement is preliminary and in need of replication.
“Thus, this finding is preliminary and in need of replication.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe lack of significant correlations with reflectivity/impulsivity could reflect low scores and thus lack of sensitivity.
“which could reflect that the scores were low and thus the sensitivity to observe such a correlation was lacking.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationown dataThe preliminary finding of lower D2/D3 receptor availability in hypothalamic region could provide a neurobiological basis for the high comorbidity of ADHD with signs and symptoms suggestive of hypothalamic pathology.
“The preliminary finding reported herein of lower than normal dopamine D2/D3 receptor availability in the hypothalamic region of ADHD participants is intriguing because if replicated, it could hypothetically provide a neurobiological basis for the high co-morbidity of ADHD with signs and symptoms suggestive of hypothalamic pathology45 such as sleep disturbances,46 overweight or obesity,47 and abnor”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Study design and conductreasoningThe laterality effects should be interpreted as preliminary and in need of replication.
“the laterality effects should be interpreted as preliminary and in need of replication.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThis study was not initially designed to evaluate hypothalamic dopamine involvement in ADHD.
“This study was not initially designed to evaluate hypothalamic dopamine involvement in ADHD.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationEvidence from brain imaging studies have shown that brain dopamine neurotransmission is disrupted in ADHD and that these deficits may underlie core symptoms of inattention and impulsivity.
“Evidence from brain imaging studies have shown that brain dopamine neurotransmission is disrupted in ADHD5–9 and that these deficits may underlie core symptoms of inattention8 and impulsivity.9”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [5]
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- cites [6]
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- cites [7]
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- cites [8]
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- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown dataMorphological MRI images were not obtained, so volumetric differences in striatum could not be ascertained.
“Morphological MRI images were not obtained and thus whether volumetric differences in striatum in those with ADHD that could account for these findings could not be ascertained since volumetric differences in striatum have been reported in ADHD.36–40”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [36]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [37]
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- cites [38]
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- cites [39]
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- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataThe D2/D3 receptor measures in accumbens correlated with attention, implicating the dopamine reward pathway in symptoms of inattention in ADHD.
“In our study, the D2/D3 receptor measures in accumbens were correlated with the dimension of attention, which would implicate the dopamine reward pathway in the symptoms of inattention in ADHD.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe mesoaccumbens dopamine pathway plays a key role in reinforcement-motivation and in learning stimuli-reward associations.
“This pathway plays a key role in reinforcement-motivation and in learning stimuli-reward associations,51 and its involvement in ADHD supports the use of interventions to enhance the saliency of school and work tasks to improve performance.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationThe Conners Adult ADHD Rating Scale has well-established factor structure, reliability, and validity.
“This rating system has been widely used in clinical and research settings and has well-established factor structure, reliability, and validity (Table 1).24”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationThe reward deficits in ADHD are characterized by a failure to delay gratification, impaired response to partial schedules of reinforcement, and preference for small immediate rewards over larger delayed rewards.
“The reward deficits in ADHD are characterized by a failure to delay gratification, impaired response to partial schedules of reinforcement, and preference for small immediate rewards over larger delayed rewards.31”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
PremisecitationLow number of dopamine D2/D3 receptors in the nucleus accumbens have been associated with a greater risk for drug abuse.
“Finally, because a low number of dopamine D2/D3 receptors in the nucleus accumbens have been associated with a greater risk for drug abuse,33 future work should determine if the lower than normal D2/D3 receptor availability in the accumbens region in ADHD underlies the higher vulnerability for substance abuse in this population.34”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationBoth motivational interventions and contingency management have been shown to improve performance in ADHD patients.
“Both motivational interventions and contingency management have been shown to improve performance in ADHD patients.52”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown dataMeasures of reward sensitivity were not performed, so the inference that dopamine marker decreases underlie reward deficits is limited.
“Another study limitation was that measures of reward sensitivity were not performed. Thus, we can only infer that the decreases in the dopamine markers in the accumbens region could underlie the reward deficits that have been reported in patients with ADHD.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMultiple hypothalamic nuclei express dopamine D2 receptors.
“Multiple hypothalamic nuclei express dopamine D2 receptors,49 but the limited spatial resolution of a PET scan does not allow for localizing where the differences between the groups occurred.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLow statistical power may have contributed to the lack of significant ADHD-normal differences in the right brain regions.
“low statistical power may have contributed to the lack of significant ADHD-normal differences in the right brain regions.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataThe analysis used a significance threshold of P<.005 (cluster corrected >100 voxels) for SPM, corroborated by ROI at P<.05, and Bonferroni correction for correlations.
“Definitions for significant difference for the outcome measures1 were that statistical parametric mapping comparisons for the DAT and the D2/D3 images had to be significant at P<.005 (cluster corrected > 100 voxels) and the regional findings had to be corroborated by independently drawn region of interests2; comparisons for these corroborative measures had to be significant at P<.053; correlations”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe mesoaccumbens dopamine pathway is critically involved in reward and motivation and has been hypothesized to underlie the reward and motivational deficits observed in ADHD.
“The mesoaccumbens dopamine pathway, which projects from the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens is critically involved in reward and motivation14 and has been hypothesized to underlie the reward and motivational deficits observed in ADHD.11,15”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [14]
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- cites [11]
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- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationAlternatively, the lack of significant correlations could reflect involvement of frontal regions in impulsivity, which could not be measured with current PET radioligands.
“Alternatively it could reflect the involvement of frontal regions in impulsivity,57 which could not be measured with current PET radioligands; D2/D3 receptors and DAT levels in frontal regions are very low.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: D2/D3 receptors and DAT levels in frontal regions are very low.
Classified as probably not a substantial claim.
PremisecitationThere is increased awareness that patients with ADHD may have reward and motivation deficits.
“There is also increased awareness that patients with ADHD may have reward and motivation deficits.10–12”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
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- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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Study design and conductnone givenThe limited spatial resolution of a PET scan does not allow localizing where the differences between groups occurred.
“but the limited spatial resolution of a PET scan does not allow for localizing where the differences between the groups occurred.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
No prior study has directly measured synaptic dopamine markers in the accumbens region of individuals with ADHD.
“However, to our knowledge no study has directly measured synaptic dopamine markers in the accumbens region of individuals with ADHD.”
The paper relies on this without support.
D2/D3 receptors and DAT levels in frontal regions are very low.
“D2/D3 receptors and DAT levels in frontal regions are very low.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ADHD participants had lower D2/D3 receptor and DAT availability in NAcc and midbrain compared to controls.
“using positron emission tomography (PET) we showed lower than normal availability of DA D2/D3 receptors (measured with [ 11 C]raclopride) and of DA transporters (measured with [ 11 C]cocaine) in the midbrain and in NAcc in drug naïve ADHD participants compared to non-ADHD control subjects 10 .”
From Motivation Deficit in ADHD is Associated with Dysfunction of the Dopamine Reward Pathway (2011) · cites this paper as [10]
Substance-use disorders are typically accompanied by decreased reward motivation for typical and non-pathological rewards, termed motivational toxicity or reward-deficiency syndrome.
“As a number of researchers have described [106,149], substance-use disorders are typically accompanied by decreased reward motivation for typical and non-pathological rewards, a phenomenon that has been variously termed ‘motivational toxicity’ [150] and ‘reward-deficiency syndrome’ [151].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [149]
Immediate and marked response of ADHD symptoms to stimulant medications suggests main underlying pathophysiological process may involve deficits or imbalances in catecholaminergic, dopaminergic, and nicotinergic functioning.
“The immediate and marked response of ADHD symptoms to stimulant medications such as amphetamines and methylphenidate, which increase levels of synaptic dopamine, suggests that the main underlying pathophysiological process may involve deficits or imbalances in catecholaminergic, dopaminergic, and nicotinergic functioning [109-111].”
From European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD (2010) · cites this paper as [111]
Both addiction and ADHD have been strongly associated with dysfunction in ascending dopaminergic systems that relate to reward response.
“It readily applies to ADHD because children with ADHD are at elevated risk of addiction, and both addiction and ADHD have been strongly associated with dysfunction in ascending dopaminergic systems that relate to reward response (Volkow et al., 2009, Volkow et al., 2011a, Volkow et al., 2011b).”
From Characterizing heterogeneity in children with and without ADHD based on reward system connectivity (2015) · cites this paper as Volkow et al., 2009
Children with ADHD are at elevated risk of addiction.
“It readily applies to ADHD because children with ADHD are at elevated risk of addiction, and both addiction and ADHD have been strongly associated with dysfunction in ascending dopaminergic systems that relate to reward response (Volkow et al., 2009, Volkow et al., 2011a, Volkow et al., 2011b).”
From Characterizing heterogeneity in children with and without ADHD based on reward system connectivity (2015) · cites this paper as Volkow et al., 2009
Methylphenidate and similar stimulants act on dopamine reward circuitry that is disrupted in ADHD and may explain the broad effects of stimulant treatment.
“Stimulant treatment, such as methylphenidate, is known to act directly on brain regions associated with disrupted dopamine reward pathways in ADHD [62,63] and may be responsible for the global effects seen with stimulant treatment in ADHD.”
From Will Working Memory Training Generalize to Improve Off-Task Behavior in Children with Attention-Deficit/Hyperactivity Disorder? (2012) · cites this paper as [63]
ADHD subjects show reduced D2 receptor binding in the ventral striatum and caudate, which correlates inversely with attention.
“A subsequent study of ADHD subjects showed the same finding of reduced D2 receptor binding in the ventral striatum and caudate (Volkow et al., 2009), which correlated inversely with attention.”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Volkow et al., 2009
Decreased dopamine transmission may contribute to motivation and reward deficits in ADHD, which are characterized by poor response inhibition and preference for small immediate rewards over larger delayed rewards.
“Based on these results, this group hypothesized that decreased dopamine transmission plays a role in the motivation and reward deficits seen in ADHD, which are characterized by poor response inhibition and preference for small immediate rewards over larger delayed rewards (Volkow et al., 2009).”
From Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity (2014) · cites this paper as Volkow et al., 2009
A number of studies have shown that ADHD is associated with a motivational deficit due to a dopamine dysfunction in the basal ganglia.
“A number of studies have shown that ADHD is associated with a motivational deficit due to a dopamine dysfunction in the basal ganglia [71–73].”
From The brain anatomy of attention-deficit/hyperactivity disorder in young adults—a magnetic resonance imaging study (2017) · cites this paper as [71]
Recent studies have indicated deficits in the dopamine reward circuitry in ADHD, as predicted by developmental neurobiological models of the disorder.
“Recent studies have further indicated deficits in the dopamine reward circuitry,3–5 as predicted by developmental neurobiological models of the disorder.6–8”
From Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder (2012) · cites this paper as [5]
Neurochemical studies have demonstrated alterations in dopaminergic signaling in the striatum and midbrain in ADHD, and linked such alterations with inattention symptoms and motivation problems in children and adults with ADHD.
“Neurochemical studies have demonstrated alterations in dopaminergic signaling in the striatum and the midbrain in ADHD, and linked such alterations with inattention symptoms and motivation problems in children and adults with ADHD.5,27–29”
From Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder (2012) · cites this paper as [5]
A recent set of case-control PET studies in adult medication-naïve patients found that ADHD is associated with reduced dopamine transporter and dopamine D2/D3 receptor availability in selected brain regions of the left hemisphere, including the nucleus accumbens, caudate and midbrain.
“A recent set of case–control PET studies in adult medication-naïve patients found that ADHD is associated with reduced dopamine transporter and dopamine D2/D3 receptor availability in selected brain regions of the left hemisphere, including the nucleus accumbens, caudate and midbrain (Volkow et al., 2007a, b, 2009).”
From A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment (2013) · cites this paper as Volkow et al., 2007a, b, 2009
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).”
From A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment (2013) · cites this paper as Volkow et al., 2009
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).”
From A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment (2013) · cites this paper as Volkow et al., 2007a, b, 2009
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Reported correlation sign conflicts with the stated interpretation
MajorThe results call the association with attention negative, but the reported coefficient is positive (r=0.35), as are the other reported attention correlations. Because the paper says higher SWAN scores indicate more symptoms, the reported sign reverses the stated interpretation that lower dopamine measures accompany greater inattention.
“The dimension of attention (from the SWAN) was negatively correlated with D2/D3 receptor availability in the left accumbens region (r=0.35; 95% CI, 0.15–0.52; P=.001)”
“Because the SWAN scale rates symptoms with a positive scale (from 1 to 3) and the opposite of symptoms with a negative scales (from −1 to −3) the negative correlation indicates that the lower the dopamine measures, the greater the symptoms of inattention.”
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Origins of altered reinforcement effects in ADHD
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InfluentialGenes and attention-deficit hyperactivity disorder
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Self-citationAttention deficit disorder with hyperactivity.
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Genes and attention deficit hyperactivity disorder
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“The DSM-IV ADHD items were assessed using the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN) rating scale, which uses a positive scale for symptoms (1 to 3) and a negative scale for the opposite of the symptoms (−1 to −3) ranging from far belowaverage to faraboveaverage.(21) This allowsonetoasses…”
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“In these adolescents with ADHD, the largest increases in striatal D2/D3 receptor availability were seen in those patients who at birth had the lowest cerebral blood flow measures, which was interpreted to reflect the adverse consequences of neonatal distress on dopamine brain function.(9) The preliminary finding repor…”
Attention Deficit Hyperactivity Disorder: A Rasch Analysis of the SWAN Rating Scale
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“[(11)C]Raclopridemeasuresare influenced byextracellulardopamine(thehigherthe extracellulardopamine, theless thebindingof[(11)C]raclopridetoD2/D3 receptors), andthus low-bindingpotential couldreflectlowD2/D3receptorlevelsorincreased dopamine release.(54) However, the latter is unlikely since we had previously reported…”
Carbon-11-cocaine binding compared at subpharmacological and pharmacological doses: a PET study.
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Self-citationAttention Deficit Disorder with Hyperactivity
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Sensitivity of striatal [11C]cocaine binding to decreases in synaptic dopamine
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Self-citationAttention Deficit Disorder with Hyperactivity
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Quantitative Brain Magnetic Resonance Imaging in Girls With Attention-Deficit/Hyperactivity Disorder
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BackgroundHeart rate variability as a transdiagnostic biomarker of psychopathology
Beauchaine, T. P., & Thayer, J. F. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.08.004 · Cited by 870 · see citing works
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“There is also growing evidence that the brain’s dopaminedependent reward system is dysfunctional in ADHD (Volkow et al., 2009).”
Backgrounddel Campo, N., Chamberlain, S. R., Sahakian, B. J., & Robbins, T. W. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.02.036 · Cited by 685 · see citing works
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BackgroundMethodInfluentialSevere Mood Dysregulation, Irritability, and the Diagnostic Boundaries of Bipolar Disorder in Youths
Leibenluft, E. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.10050766 · Cited by 565 · see citing works
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“In sum, from amongst these neurobiologically testable predictions, there is mixed evidence that ADHD is related to a lower level of tonic DA in the fronto-limbic circuitry (prediction 10; e.g., Dougherty et al., 1999; Volkow et al., 2009), and some evidence of an attenuated DA response to anticipated rewards (predicti…”
BackgroundNorman, L. J., Carlisi, C., Lukito, S., Hart, H., Mataix-Cols, D., Radua, J., & Rubia, K. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0700 · Cited by 426 · see citing works
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“Moreover, recent positron emission tomography studies that carefully selected noncomorbid adults with ADHD observed abnormal dopamine transporter levels relative to healthy adults in areas of the limbic system including nucleus accumbens and midbrain, amygdala, and hippocampus that furthermore correlated with inattent…”
BackgroundCardiac vagal control and children's adaptive functioning: A meta-analysis
Graziano, P., & Derefinko, K. (2013) · Biological Psychology · doi:10.1016/j.biopsycho.2013.04.011 · Cited by 439 · see citing works
“…dysfunctional structural and neurochemical functioning implicated with such disorders (e.g., abnormalities in the mesoaccumbens dopamine pathway; Volkow et al., 2009) blunts the PNS’s response to stress via a lack of reciprocity with the SNS's response, which has recently been shown to…”
BackgroundMotivation Deficit in ADHD is Associated with Dysfunction of the Dopamine Reward Pathway
Volkow, N. D., Wang, G.-J., Newcorn, J. H., Kollins, S. H., Wigal, T. L., Telang, F., Fowler, J. S., Goldstein, R. Z., Klein, N., Logan, J., et al. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.97 · Cited by 429 · see citing works
Self-citationAbnormal Functional Connectivity in Children with Attention-Deficit/Hyperactivity Disorder
Tomasi, D., & Volkow, N. D. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.003 · Cited by 363 · see citing works
“Thus, lower dopaminergic function in ADHD patients (8) could impair brain activity and the long-range connectivity in SPC, a region that includes prominent long-range functional connectivity hubs (29).”
BackgroundSelf-citationLuman, M., Tripp, G., & Scheres, A. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.11.021 · Cited by 335 · see citing works
“In sum, from amongst these neurobiologically testable predictions, there is mixed evidence that ADHD is related to a lower level of tonic DA in the fronto-limbic circuitry (prediction 10; e.g., Dougherty et al., 1999; Volkow et al., 2009), and some evidence of an attenuated DA response to anticipated rewards (predicti…”
BackgroundInfluentialMartel, M. M. (2013) · Psychological Bulletin · doi:10.1037/a0032247 · Cited by 329 · see citing works
Reward processing and mood-related symptoms: An RDoC and translational neuroscience perspective
Nusslock, R., & Alloy, L. B. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.02.001 · Cited by 322 · see citing works
SLC6 transporters: Structure, function, regulation, disease association and therapeutics
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Neuroinflammation as a risk factor for attention deficit hyperactivity disorder
Dunn, G. A., Nigg, J. T., & Sullivan, E. L. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.05.005 · Cited by 299 · see citing works
“The role of dopamine and catecholamines in ADHD has been previously and extensively reviewed (Del Campo et al., 2011; Volkow et al., 2009).”
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Dopamine, Immunity, and Disease
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Treatment strategies for ADHD: an evidence-based guide to select optimal treatment
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Self-citationMolecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress
Ahmadinejad, F., Møller, S. G., Chaleshtori, M. H., Bidkhori, G., & Jami, M. (2017) · Antioxidants · doi:10.3390/antiox6030051 · Cited by 299 · see citing works
“PD, Schizophrenia and attention deficit hyperactivity disorder (ADHD) are some of examples of these diseases [98,99].”
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“The severity of ADHD symptoms also correlated with striatal dopamine receptor density (Volkow et al., 2009).”
BackgroundThe C factor: cognitive dysfunction as a transdiagnostic dimension in psychopathology
Abramovitch, A., Short, T., & Schweiger, A. (2021) · Clinical Psychology Review · doi:10.1016/j.cpr.2021.102007 · Cited by 269 · see citing works
“…et al., 2016), SCZ (Strauss, Waltz, & Gold, 2014), social anxiety (Richey et al., 2014) BD (Alloy, Olino, Freed, & Nusslock, 2016), personality disorders, (Murray, Waller, & Hyde, 2018; V ¨ ollm et al., 2007), ADHD (Volkow et al., 2009), and substance abuse (Cooper, Robison, & Mazei-Robison, 2017).”
InfluentialFusar-Poli, P., Rubia, K., Rossi, G., Sartori, G., & Balottin, U. (2012) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.11060940 · Cited by 260 · see citing works
Swanson, J., Baler, R. D., & Volkow, N. D. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.160 · Cited by 252 · see citing works
Self-citationVolkow, N. D., Wang, G.-J., Tomasi, D., Kollins, S. H., Wigal, T. L., Newcorn, J. H., Telang, F. W., Fowler, J. S., Logan, J., Wong, C. T., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.4461-11.2012 · Cited by 237 · see citing works
“Historically, the core feature of ADHD has been characterized as one of an attention deficit, but increasing evidence suggests that a reward and motivation deficit may be of equal importance (Haenlein and Caul, 1987; Sonuga-Barke, 2003; Tripp and Wickens, 2008; Castellanos, 2009; Volkow et al., 2009).”
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Caffeine, Mental Health, and Psychiatric Disorders
Lara, D. R. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1378 · Cited by 236 · see citing works
“Interestingly, caffeine improves cognitive performance in an animal model of ADHD [121] and promotes effortrelated behavior in animals treated with dopamine antagonists [122].”
BackgroundInfluentialTrait Impulsivity and the Externalizing Spectrum
Beauchaine, T. P., Zisner, A. R., & Sauder, C. L. (2017) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-021815-093253 · Cited by 230 · see citing works
“2012); (b) reduced mesolimbic DA transporter function, and reduced D2 receptor or D3 receptor binding (or both) among adults with ADHD (Volkow et al. 2009) and alcoholism (e.”
BackgroundAdult Attention Deficit–Hyperactivity Disorder
Volkow, N. D., & Swanson, J. M. (2013) · New England Journal of Medicine · doi:10.1056/nejmcp1212625 · Cited by 227 · see citing works
Self-citationPoelmans, G., Pauls, D. L., Buitelaar, J. K., & Franke, B. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.10070948 · Cited by 223 · see citing works
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The Potential for Misuse and Abuse of Medications in ADHD: A Review
Clemow, D. B., & Walker, D. J. (2014) · Postgraduate Medicine · doi:10.3810/pgm.2014.09.2801 · Cited by 198 · see citing works
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Beauchaine, T. P., Hinshaw, S. P., & Pang, K. (2010) · Clinical Psychology Science and Practice · doi:10.1111/j.1468-2850.2010.01224.x · Cited by 189 · see citing works
McClernon, F. J., & Kollins, S. H. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1441.016 · Cited by 188 · see citing works
Self-citationCosta Dias, T. G., Wilson, V. B., Bathula, D. R., Iyer, S. P., Mills, K. L., Thurlow, B. L., Stevens, C. A., Musser, E. D., Carpenter, S. D., Grayson, D. S., et al. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2012.10.015 · Cited by 180 · see citing works
“This may indicate involvement of NAcc with cognitive and attention processes and is consistent with studies that found correlation between NAcc alterations and inattentive symptoms (Depue et al., 2010; Volkow et al., 2009).”
ResultPaloyelis, Y., Asherson, P., Mehta, M. A., Faraone, S. V., & Kuntsi, J. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.124 · Cited by 180 · see citing works
Top-Down Dysregulation—From ADHD to Emotional Instability
Petrovic, P., & Castellanos, F. X. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00070 · Cited by 179 · see citing works
“This neuromodulatory system is implicated in ADHD (Swanson et al., 2007; Volkow et al., 2009) and may affect both emotional and non-emotional processing.”
BackgroundGreen, C. T., Long, D. L., Green, D., Iosif, A.-M., Dixon, J. F., Miller, M. R., Fassbender, C., & Schweitzer, J. B. (2012) · Neurotherapeutics · doi:10.1007/s13311-012-0124-y · Cited by 176 · see citing works
“Stimulant treatment, such as methylphenidate, is known to act directly on brain regions associated with disrupted dopamine reward pathways in ADHD [62, 63] and may be responsible for the global effects seen with stimulant treatment in ADHD.”
BackgroundGilbert, D. L., Isaacs, K. M., Augusta, M., MacNeil, L. K., & Mostofsky, S. H. (2011) · Neurology · doi:10.1212/wnl.0b013e31820c2ebd · Cited by 173 · see citing works
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Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity
Trifilieff, P., & Martinez, D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.031 · Cited by 171 · see citing works
Decision Making: From Neuroscience to Psychiatry
Lee, D. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.008 · Cited by 169 · see citing works
“Neurochemically, ADHD might result from lower levels of dopamine and/or norepinephrine in the brain (Volkow et al., 2009; Arnsten and Pliszka, 2011).”
Hauser, T. U., Iannaccone, R., Ball, J., Mathys, C., Brandeis, D., Walitza, S., & Brem, S. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.1093 · Cited by 168 · see citing works
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“Importantly, other incentive-processing research has linked alterations in reward–punishment responsivity to a variety of psychopathologies, including schizophrenia (Dowd & Barch, 2010), major depressive disorder (Eshel & Roiser, 2010), bipolar disorder (Urošević, Abramson, Harmon-Jones, & Alloy, 2008), anxiety disord…”
Structural and functional neuroimaging in attention-deficit/hyperactivity disorder
Albajara Sáenz, A., Villemonteix, T., & Massat, I. (2019) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14050 · Cited by 154 · see citing works
Imaging Functional and Structural Brain Connectomics in Attention-Deficit/Hyperactivity Disorder
Cao, M., Shu, N., Cao, Q., Wang, Y., & Yong He, A. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8685-x · Cited by 153 · see citing works
Beauchaine, T. P., Gatzke‐Kopp, L. M., Neuhaus, E., Chipman, J., Reid, M. J., & Webster-Stratton, C. H. (2013) · Journal of Consulting and Clinical Psychology · doi:10.1037/a0032302 · Cited by 153 · see citing works
“Although full articulation of the neurobiological substrates of ADHD is well beyond the scope of this article, most theories of impulsivity focus at least in part on deficient responding in mesolimbic structures rich in dopamine (DA) neurons (see Volkow et al., 2009).”
BackgroundSonuga‐Barke, E. J. S., Becker, S. P., Bölte, S., Castellanos, F. X., Franke, B., Newcorn, J. H., Nigg, J. T., Rohde, L. A., & Simonoff, E. (2023) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.13696 · Cited by 157 · see citing works
Self-citationWang, G.-J., Volkow, N. D., Wigal, T., Kollins, S. H., Newcorn, J. H., Telang, F., Logan, J., Jayne, M., Wong, C. T., Han, H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063023 · Cited by 144 · see citing works
“Full characteristics of the subjects have been described previously [5], so only a summary will be presented here.”
BackgroundSelf-citationEagle, D. M., Wong, J. C. K., Allan, M. E., Mar, A. C., Theobald, D. E., & Robbins, T. W. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6182-10.2011 · Cited by 145 · see citing works
“These deficits arise from dysregulation within frontal/basal ganglia circuitry that is often linked with dopamine dysfunction (Volkow et al., 2009; Pine et al., 2010).”
BackgroundCharacterizing heterogeneity in children with and without ADHD based on reward system connectivity
Costa Dias, T. G., Iyer, S. P., Carpenter, S. D., Cary, R. P., Wilson, V. B., Mitchell, S. H., Nigg, J. T., & Fair, D. A. (2015) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2014.12.005 · Cited by 130 · see citing works
“It readily applies to ADHD because children with ADHD are at elevated risk of addiction, and both addiction and ADHD have been strongly associated with dysfunction in ascending dopaminergic systems that relate to reward response (Volkow et al., 2009, 2011a, 2011b).”
BackgroundTomasi, D. G., & Volkow, N. D. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs382 · Cited by 144 · see citing works
“Disruption of these DA pathways are implicated in several psychiatric disorders including schizophrenia, ADHD, and addiction (Volkow et al. 2009), which are disorders that emerge between childhood and young adulthood (Kessler et al.”
BackgroundSelf-citationThe screens culture: impact on ADHD
Weiss, M. D., BAER, S., Allan, B. A., Saran, K., & Schibuk, H. (2011) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-011-0065-z · Cited by 140 · see citing works
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“2000), and decreased DA D2/ D3 receptor availability (Volkow et al. 2009).”
BackgroundHinshaw, S. P., Arnold, L. E., & For the MTA Cooperative Group (2014) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1324 · Cited by 138 · see citing works
Attention-Deficit/Hyperactivity Disorder and Substance Abuse
Harstad, E., Levy, S., COMMITTEE ON SUBSTANCE ABUSE, Levy, S., Ammerman, S. D., Gonzalez, P. K., Ryan, S. A., Siqueira, L. M., & Smith, V. C. (2014) · Pediatrics · doi:10.1542/peds.2014-0992 · Cited by 131 · see citing works
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Attention-deficit/hyperactivity disorder and the dopaminergic hypotheses
Genro, J. P., Kieling, C., Rohde, L. A., & Hutz, M. H. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.17 · Cited by 133 · see citing works
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“For example, among those with ADHD, both with and without comorbid conduct disorder (CD), blunted neural activation in mesolimbic structures is observed during reward tasks (e.g., Durston, 2003; Durston et al., 2003; Vaidya et al., 1998; Volkow et al., 2009).”
BackgroundYen, C., Chou, W., Liu, T., Yang, P., & Hu, H. (2014) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2014.05.025 · Cited by 125 · see citing works
“Meanwhile, people with ADHD tend to seek enhanced stimulation of the reward pathway [6].”
BackgroundFuemmeler, B. F., Østbye, T., Yang, C., McClernon, F. J., & Kollins, S. H. (2011) · International Journal of Obesity · doi:10.1038/ijo.2010.214 · Cited by 128 · see citing works
Self-citationGriffiths, K. R., Morris, R. W., & Balleine, B. W. (2014) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2014.00101 · Cited by 118 · see citing works
“Attention was found to be negatively correlated with D2/D3 receptor availability in the left NAc and caudate (Volkow et al., 2009), regions key to reward valuation and contingency awareness in goal-directed action.”
BackgroundSonuga-Barke, E. J. S., & Fairchild, G. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.04.004 · Cited by 124 · see citing works
Aguiar, A., Eubig, P. A., & Schantz, S. L. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.1002326 · Cited by 125 · see citing works
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“Moreover, there are several nondepressive disorders that are also associated with impairments in PA and reward processing (Bernat, Nelson, Steele, Gehring, & Patrick, 2011; Bjork, Chen, Smith, & Hommer, 2010; Gatzke-Kopp et al., 2009; Volkow et al., 2009; Volkow et al., 2011).”
BackgroundEarly life protein restriction alters dopamine circuitry
Vucetic, Z., Totoki, K., Schoch, H., Whitaker, K. W., Hill‐Smith, T. E., Lucki, I., & Reyes, T. M. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.04.010 · Cited by 119 · see citing works
“However, decreases in DAT (and D2/D3) in the left midbrain and accumbens have been linked to measures of inattention in ADHD patients (Volkow et al., 2009), highlighting the difficulty of replicating the totality and heterogeneity of ADHD symptoms in any one animal model.”
Backgrounddel Campo, N., Fryer, T. D., Hong, Y. T., Smith, R., Brichard, L., Acosta-Cabronero, J., Chamberlain, S. R., Tait, R., Izquierdo, D., Regenthal, R., et al. (2013) · Brain · doi:10.1093/brain/awt263 · Cited by 113 · see citing works
“BRAIN”
Blum, K., Chen, A. L., Oscar‐Berman, M., Chen, T. J. H., Lubar, J. F., WHITE, N. V., Lubar, J. O., Bowirrat, A., Braverman, E. R., Schoolfield, J. D., et al. (2011) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph8124425 · Cited by 121 · see citing works
“Only a handful of treatment centers have utilized the neurobiology of addiction as an integral part of patient education with explicit integration of RDS into all treatment content especially as it relates ADHD, Posttraumatic stress disorder and drug dependence [207-213].”
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Proof-of-concept study of an at-home, engaging, digital intervention for pediatric ADHD
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Self-citationPerinatal Exposure to Phthalates: From Endocrine to Neurodevelopment Effects
Lucaccioni, L., Trevisani, V., Passini, E., Righi, B., Plessi, C., Predieri, B., & Iughetti, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084063 · Cited by 119 · see citing works
“It has been known for a long time how dopamine system dysfunction could have a key role in ADHD genesis [78,79].”
BackgroundRole for the Membrane Receptor Guanylyl Cyclase-C in Attention Deficiency and Hyperactive Behavior
Gong, R., Ding, C., Hu, J., Lu, Y., Liu, F., Mann, E. A., Xu, F., Cohen, M. B., & Luo, M. (2011) · Science · doi:10.1126/science.1207675 · Cited by 112 · see citing works
Jupp, B., Caprioli, D., Saigal, N., Reverte, I., Shrestha, S., Cumming, P., Everitt, B. J., Robbins, T. W., & Dalley, J. W. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12146 · Cited by 109 · see citing works
“We investigated possible lateralised modulation of impulsivity on the basis of the reported hemispheric imbalance of D2/D3 receptor binding in attention deficit/hyperactive disorder (ADHD; Volkow et al., 2009) and the apparent left–right asymmetry in other tests of impulsivity (Aron et al., 2003).”
BackgroundShock – Classification and Pathophysiological Principles of Therapeutics
Kislitsina, O. N., Rich, J. D., Wilcox, J. E., Pham, D. T., Churyla, A., Vorovich, E. B., Ghafourian, K., & Yancy, C. W. (2018) · Current Cardiology Reviews · doi:10.2174/1573403x15666181212125024 · Cited by 109 · see citing works
Cognitive Neurostimulation: Learning to Volitionally Sustain Ventral Tegmental Area Activation
MacInnes, J., Dickerson, K. C., Chen, N., & Adcock, R. A. (2016) · Neuron · doi:10.1016/j.neuron.2016.02.002 · Cited by 98 · see citing works
“…(Lou et al., 2011; Pessoa and Engelmann , 2010), invigoration of motor responses (Beierholm et al., 2013; Niv et al., 2007), improved attention (Volkow et al., 2009), working memory (Cools and D'Esposito, 2011; Goldman-Rakic, 1997), and long-term memory encoding (Lisman et al., 2011; Shohamy…”
Neural Substrates of Impaired Sensorimotor Timing in Adult Attention-Deficit/Hyperactivity Disorder
Valera, E. M., Spencer, R. M. C., Zeffiro, T. A., Makris, N., Spencer, T. J., Faraone, S. V., Biederman, J., & Seidman, L. J. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.05.012 · Cited by 104 · see citing works
“The neural signature of ADHD has been conceptualized in terms of abnormalities in networks of response inhibition (35), attention (36) and reward (37), among others.”
Using chaotic artificial neural networks to model memory in the brain
Aram, Z., Jafari, S., Ma, J., Sprott, J. C., Zendehrouh, S., & Pham, V. (2016) · Communications in Nonlinear Science and Numerical Simulation · doi:10.1016/j.cnsns.2016.08.025 · Cited by 104 · see citing works
Singer, H. S. (2019) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000000752 · Cited by 122 · see citing works
Gehricke, J.-G., Kruggel, F., Thampipop, T., Alejo, S. D., Tatos, E., Fallon, J., & Muftuler, L. T. (2017) · PLOS ONE · doi:10.1371/journal.pone.0175433 · Cited by 103 · see citing works
Di Nisio, A., Pannella, M., Vogiatzis, S., Sut, S., Dall'Acqua, S., Rocca, M. S., Antonini, A., Porzionato, A., De Caro, R., Bortolozzi, M., et al. (2022) · Environment International · doi:10.1016/j.envint.2021.106982 · Cited by 103 · see citing works
Genetic Characterization of Dog Personality Traits
Ilska, J. J., Haskell, M. J., Blott, S. C., Sánchez-Molano, E., Polgár, Z., Lofgren, S. E., Clements, D. N., & Wiener, P. (2017) · Genetics · doi:10.1534/genetics.116.192674 · Cited by 100 · see citing works
“Furthermore, conditions in humans involving inattention and impulsivity, such as attention deficit hyperactivity disorder (ADHD), are associated with decreased dopamine activity (Volkow et al. 2009).”
BackgroundNusslock, R., Walden, K., & Harmon-Jones, E. (2015) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2015.06.004 · Cited by 95 · see citing works
“The fronto-striatal circuit is central to the Positive Valence Systems domain of the RDoC initiative, and implicated in the pathophysiology of unipolar depression (Forbes et al., 2009; Heller et al., 2009; Smoski et al., 2009), bipolar disorder (Bermpohl et al., 2010; Caseras et al., 2013; Nusslock et al., 2012a, 2014…”
BackgroundInfluentialKim, P., Choi, C. S., Park, J. H., Joo, S. H., Kim, S. Y., Ko, H. M., Kim, K. C., Jeon, S. J., Park, S. H., Han, S., et al. (2014) · Journal of Neuroscience Research · doi:10.1002/jnr.23275 · Cited by 100 · see citing works
“Positron emission tomography (PET) studies also suggested the relationship of inattention with reduced dopaminergic activity in the dopamine reward pathway of participants with ADHD (Volkow et al., 2009).”
BackgroundFranke, A., Gränsmark, P., Agricola, A., Schühle, K., Rommel, T., Sebastian, A., Balló, H. E., Gorbulev, S., Gerdes, C., Frank, B., et al. (2017) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.01.006 · Cited by 73 · see citing works
Molecular Imaging of the Dopamine Transporter
Varrone, A., & Halldin, C. (2010) · Journal of Nuclear Medicine · doi:10.2967/jnumed.109.065656 · Cited by 96 · see citing works
Ganjali, M. R., Beitollahi, H., Zaimbashi, R., et al. (2018) · International Journal of Electrochemical Science · doi:10.20964/2018.03.11 · Cited by 96 · see citing works
Kollins, S. H., & Adcock, R. A. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.02.002 · Cited by 95 · see citing works
“One of themore recently published PET studies of dopamine receptor density in ADHD sought to address some of these difficulties by enrolling a relatively large sample of adults with (n= 53) and without (n= 44) ADHD, who had no previous history of medication treatment (Volkow et al., 2009).”
BackgroundInfluentialSelf-citationStriatal sensitivity during reward processing in attention-deficit/hyperactivity disorder
Paloyelis, Y., Mehta, M. A., Faraone, S. V., Asherson, P., & Kuntsi, J. (2012) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2012.05.006 · Cited by 94 · see citing works
Stoy, M., Schlagenhauf, F., Schlochtermeier, L., Wrase, J., Knutson, B., Lehmkuhl, U., Huss, M., Heinz, A., & Ströhle, A. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2166-y · Cited by 91 · see citing works
“There is evidence from positron emission tomography studies for a disruption in the mesodopaminergic pathway in ADHD, in the nucleus accumbens and midbrain regions (Volkow et al. 2009).”
BackgroundZisner, A. R., & Beauchaine, T. P. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000754 · Cited by 92 · see citing works
“…studies implicate compromised mesolimbic and/or mesocortical DA function in ADHD (e.g., Ludolph et al., 2008; Vles, Feron, & Hendrikson, 2003; Volkow et al., 2007, 2009), CD (e.g., Rubia, Smith, et al., 2009), SUDs (e.g., Martin-Soelch et al., 2001; Volkow, Fowler, & Wang, 2004), and…”
Abnormal striatal BOLD responses to reward anticipation and reward delivery in ADHD
Furukawa, E., Bado, P., Tripp, G., Mattos, P., Wickens, J. R., Bramati, I. E., Alsop, B., Ferreira, F. M., Lima, D., Tovar-Moll, F., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089129 · Cited by 90 · see citing works
“A reduction in dopamine synaptic markers including DAT1 has also been shown in the dopamine reward pathway [8].”
Background
- Authors
- Volkow, N. D., Wang, G.-J., Kollins, S. H., Wigal, T. L., Newcorn, J. H., Telang, F., Fowler, J. S., Zhu, W., Logan, J., Ma, Y., Pradhan, K., Wong, C., & Swanson, J. M.
- Affiliations
- National Institute on Drug Abuse (US)
- Corresponding author
- Volkow, Nora D.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2009-09-09
- Volume
- 302
- Issue
- 10
- Pages
- 1084
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC2958516
- OpenAlex
- W2071411087
- Semantic Scholar
- 73303180da9a733fdf01dc78501b5769db289660
- Cited by
- 728
- References
- 69
- Citations by year
- 2026: 67 · 2025: 46 · 2024: 36 · 2023: 27 · 2022: 35 · 2021: 37 · 2020: 37 · 2019: 29 · 2018: 29 · 2017: 40 · 2016: 29 · 2015: 39 · 2014: 62 · 2013: 52 · 2012: 61
- FWCI
- 33.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000550)
- National Institute of Mental Health (R01MH066961)
- National Institute on Drug Abuse (K24DA023464)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- attention deficit hyperactivity disorder, dopamine reward pathway, dopamine transporter, D2/D3 receptors, nucleus accumbens, caudate nucleus, adult ADHD, neuroimaging biomarkers, cocaine binding, left hemisphere lateralization, inattention, hyperactivity/impulsivity
- MeSH terms
- Adult, Attention Deficit Disorder with Hyperactivity, Brain, Brain Mapping, Carbon Radioisotopes, Cocaine, Dopamine, Female, Humans, Male, Mesencephalon, Synaptic Transmission, Reward, Dopamine Agents, Receptors, Dopamine D2, Raclopride, Positron-Emission Tomography, Dopamine Plasma Membrane Transport Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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