This study provides evidence in favor of the predicted disruption in the mesoaccumbens dopamine pathway in ADHD. With PET imaging, lower D2
receptor and DAT availability in those with ADHD than in the control group was documented in 2 key brain regions for reward and motivation (accumbens and midbrain).29
It also corroborates disruption of synaptic dopamine markers in caudate in adults with ADHD and provides preliminary evidence that the hypothalamus may also be affected.
The lower than normal D2
receptor and DAT availability in the accumbens and midbrain regions supports the hypothesis of an impairment of the dopamine reward pathway in ADHD.30
Because measures of reward sensitivity were not measured, we can only infer that the impairment in the dopamine reward pathway could underlie the clinical evidence of abnormal responses to reward in ADHD. 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
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
In our study, the D2
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. This could provide an explanation of why the attentional deficits in individuals with ADHD are most evident in tasks that are considered boring, repetitive, and uninteresting (ie, tasks or assignments that are not intrinsically rewarding).32
Finally, because a low number of dopamine D2
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
receptor availability in the accumbens region in ADHD underlies the higher vulnerability for substance abuse in this population.34
The lower D2
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
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. 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.
Lower than normal D2
receptors and DAT availability in ADHD in the caudate was also demonstrated. Prior imaging studies had reported smaller caudate volumes36–40
and caudate functional under activation41,42
in ADHD participants compared with controls. 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
and others no differences.44
Reason(s) for the discrepancies have been outlined else where6
and could reflect differences in radiotracers, the methods used (radiotracers; PET vs single photon emission computed tomography), differences in patients characteristics (including prior medication histories; comorbidities, and age of participants), and sample sizes, which vary from 6 to 53 (in this study). These findings differ from those reported in adolescents with ADHD, which showed higher D2
receptor availability in the left striatum (including caudate) than in young adults, that was interpreted to reflect deficient dopamine occupancy of these receptors.7
In these adolescents with ADHD, the largest increases in striatal D2
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 reported herein of lower than normal dopamine D2
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 abnormal responses to stress.48
Multiple hypothalamic nuclei express dopamine D2
but the limited spatial resolution of a PET scan does not allow for localizing where the differences between the groups occurred. 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
Our findings of an association of the mesoaccumbens dopamine pathway with ADHD inattention symptoms may have clinical relevance. 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. Both motivational interventions and contingency management have been shown to improve performance in ADHD patients.52
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
C] Raclopride measures are influenced by extracellular dopamine (the higher the extracellular dopamine, the less the binding of [11
C]raclopride to D2
receptors), and thus low-binding potential could reflect low D2
receptor levels or increased dopamine release.54
However, the latter is unlikely since we had previously reported that dopamine release in a sub-group of our ADHD participants was lower than in controls.8
Also although [11
C]cocaine’s binding to DATs is minimally affected by competition with endogenous dopamine,55
DAT availability reflects not only the density of dopamine terminals but also synaptic dopamine tone, because DAT up-regulates when synaptic dopamine is high and down-regulates when dopamine is low.56
Thus low DAT availability could reflect fewer dopamine terminals or decreased DAT expression per dopamine terminal.
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. However, despite this limitation, significant differences in the latter regions between controls and participants with ADHD was shown.
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.
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
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
receptors rather than decreases secondary to partial volume effects.
The correlations with reflectivity or impulsivity and the PET dopamine measures were not significant, which could reflect that the scores were low and thus the sensitivity to observe such a correlation was lacking. Alternatively it could reflect the involvement of frontal regions in impulsivity,57
which could not be measured with current PET radioligands; D2
receptors and DAT levels in frontal regions are very low.
Although the significant findings in this study are restricted to the left hemisphere, low statistical power may have contributed to the lack of significant ADHD-normal differences in the right brain regions. Moreover, because an a priori laterality hypothesis was lacking and, to our knowledge, no solid evidence exists in the literature to support laterality for reward, the laterality effects should be interpreted as preliminary and in need of replication.
This study was not initially designed to evaluate hypothalamic dopamine involvement in ADHD. Thus, this finding is preliminary and in need of replication. Moreover, future studies designed to evaluate hypothalamic pathology in ADHD and its potential clinical significance should assess sleep pathology and should not exclude obese participants, as was the case for the current study.
In conclusion, these findings show a reduction in dopamine synaptic markers in the dopamine reward pathway midbrain and accumbens region of participants with ADHD that were associated with measures of attention. It also provides preliminary evidence of hypothalamic involvement in ADHD (lower than normal D2/D3 receptor availability).