Evaluating dopamine reward pathway in ADHD: clinical implications

Abstract

Context: Attention-deficit/hyperactivity disorder (ADHD)--characterized by symptoms of inattention and hyperactivity-impulsivity--is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder.

Objective: To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens).

Design, setting, and participants: We used positron emission tomography to measure dopamine synaptic markers (transporters and D(2)/D(3) receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory.

Main outcome measures: We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [(11)C]cocaine and for D(2)/D(3) receptors using [(11)C]raclopride, quantified as binding potential (distribution volume ratio -1).

Results: 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. Region-of-interest analyses corroborated these findings. 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) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P < or = .001); for D(2)/D(3) receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); 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). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D(2)/D(3) for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D(2)/D(3) 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). Ratings of attention correlated with D(2)/D(3) 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 and with DAT in the midbrain (r = 0.37; 95% CI, 0.16-0.53; P < or = .001).

Conclusion: A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.

Figure 1. Regions of Interest Used to Extract the D₂/D₃ Receptor and Dopamine Transporter Measures

The regions of interest for the midbrain are obtained in several planes, and the shadow is projected to the axial image shown in the figure, which explains why the third ventricle is covered by the region. The x coordinate maps the left-right position; they coordinate, the anterior-posterior position; and the z coordinate, the superior-inferior position.

Figure 2. Regions in the Brain in Which Dopamine Measures Were Lower in Participants With ADHD Than in Controls

A, Regions showed significantly lower dopamine D₂/D₃ receptor availability in participants with attention-deficit/hyperactivity disorder (ADHD) than in controls (obtained from [¹¹C]raclopride images). B, Regions showed significantly lower dopamine transporter availability in the participants with ADHD than in controls (obtained from [¹¹C]cocaine images). Significance corresponds to P<.005, cluster >100 voxels. The yellow regions identify the areas in the brain for which the measures differed between controls and participants with ADHD. The location of the region that differed was similar for the dopamine D₂/D₃ receptor and for the dopamine transporter and included the locations of the left ventral striatum (including accumbens and ventral caudate), left midbrain, and left hypothalamus. The z coordinate maps the superior-inferior position.

Figure 3. Regression Slopes Between Dopamine D₂/D₃ Receptor and Dopamine Transporter Availability and Scores on Attention

The Dimension of the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder (ADHD)–symptoms and Normal-behavior (SWAN) rating scale 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 below average” to “far above average.” The negative numbers in some of the regions show that the ratio of the specific to nonspecific binding of the radioligand is very low for these regions. The solid line in each scatter plot corresponds to the regression line (line of best fit).