Adult attention-deficit/hyperactivity disorder is associated with reduced norepinephrine transporter availability in right attention networks: a (S,S)-O-[11C]methylreboxetine positron emission tomography study

Abstract

The norepinephrine transporter (NET) has been suggested to play a critical role in attention-deficit/hyperactivity disorder (ADHD). In this prospective controlled study we tested the a-priori-hypothesis that central NET availability is altered in adult ADHD patients compared to healthy controls. Study participants underwent single positron emission tomography-magnetic resonance imaging (PET-MRI). MRI sequences included high resolution T1-MPRAGE data for regions of interest (ROI) delineation and voxel-based morphometry (VBM) and T2-weighted fluid-attenuated inversion-recovery for detection and exclusion of pathological abnormalities. NET availability was assessed by NET-selective (S,S)-O-[¹¹C]methylreboxetine; regional distribution volume ratios (DVR) were calculated based on individual PET-MRI data co-registration and a multi-linear reference tissue model with two constraints (MRTM2; reference region: occipital cortex). VBM analysis revealed no difference in local distribution of gray matter between the 20 ADHD patients (9 females, age 31.8 ± 7.9 years, 488 ± 8 MBq injected activity) and the 20 age-matched and sex-matched control participants (9 females, age 32.3 ± 7.9 years, 472 ± 72 MBq). In mixed-model repeated-measures analysis with NET availability as dependent and ROI as repeated measure we found a significant main effect group in fronto-parietal-thalamic-cerebellar regions (regions on the right: F_1,25 = 12.30, p = .002; regions on the left: F_1,41 = 6.80, p = .013) indicating a reduced NET availability in ADHD patients. None of the other investigated brain regions yielded significant differences in NET availability between groups after applying a Benjamini-Hochberg correction at a significance level of 0.05. Overall our findings demonstrate the pathophysiological involvement of NET availability in adult ADHD.

Fig. 1. Parametric images of the distribution volume ratio (DVR) in axial and sagittal view after spatial normalization to the MNI-space.

a An exemplary healthy control and ADHD together with their corresponding T1-MPRAGE image. b Group mean of all healthy controls and ADHD patients. ADHD attention-deficit/hyperactivity disorder, MNI Montreal neurological institute, R right, L left.

Fig. 2. Distribution, mean and error bars of DVR values in selected regions of interest for both, healthy controls (cyan) and ADHD patients (red).

a Right hemisphere. b Left hemisphere. ADHD attention-deficit/hyperactivity disorder, DVR distribution volume ratio, R right, L left.

Fig. 3. The sustained attention subtest of the computerized test of attentional performance (TAP, Zimmermann and Fimm, 2012).

a Experimental design. Stimulus onset asynchrony = 2 s. b Mean omission errors during the 15-min test in adult ADHD patients (n = 20), and age- and sex-matched healthy controls (n = 20). c Mean commission errors during the 15-min test in adult ADHD patients (n = 20) and healthy controls (n = 20).

Fig. 4. Scatterplots of mean distributed volume ratios (DVR) in right fronto-parietal-thalamic-cerebellar regions of interest versus measures of inattention and EEG extracted theta current density.

a Inattention assessed with the DSM-IV subscale inattention (total T-score) of the Conners’ Adult ADHD Rating Scale Self-Report (CAARS-SR–long version). b Inattention assessed with the 15-min subtest of the computerized test of attentional performance (TAP; Zimmermann and Fimm, 2012). T-scores of omission errors (number of targets that were presented but not responded to) were used as a measure of sustained attention. c Mean absolute right BA9 theta (6.5–8.0 Hz) current density. Red circles: adult ADHD patients (n = 20); cyan circles: sex-matched and age-matched healthy controls (n = 20). BA Brodmann area.