Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers

Abstract

Background: Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC.

Objective: In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task.

Study design: We performed a double-blinded, placebo-controlled, counter-balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083).

Setting: The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009.

Patients: Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated.

Intervention: Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH.

Main outcome measure: Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors.

Results: There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing).

Conclusion: Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance.

Fig. 1

Variable Attentional Control (VAC) task. The task is aimed to assess the effects of an increasing demand in attention. There were three levels of attention: (1) low level (LOW), when all three sizes of arrows were congruent in direction with each other, and subjects were cued to attend to the big arrow; (2) intermediate level (INT), when the big arrow was incongruent in direction to the small and the medium arrows, and subjects were cued to attend to either big or small arrows; and (3) high level (HIGH), when the medium arrows were incongruent in direction to the big and the small arrows, and subjects were cued to attend to either small or medium arrows

Fig. 2

Group statistical parametric maps showing a main effect of increasing level of attention (HIGH > INT > LOW) on brain activation (p <0.001; FWE whole-brain corrected) in regions including the dorsal cingulate, parietal, and prefrontal cortices. FWE-corr, whole brain familywise error correction at whole brain level, INT intermediate

Fig. 3

Group statistical parametric map illustrating a drug by task-load interaction, with relatively greater attentional load-related changes in the dorsal cingulate on placebo when compared with tolcapone. There was no significant difference in the inverse contrast (placebo < tolcapone). FWE-corr, dCC ROI familywise error correction in dorsal cingulate cortex (dCC) region of interest (ROI)

Fig. 4

Simple regression analyses illustrating a significant correlation between COMT activity and attentional load-related changes in the dorsal cingulate. There was no significant difference in the inverse contrast (negative correlation). COMT catechol-O-methyltransferase, FWE-corr, dCC ROI familywise error correction in dorsal cingulate cortex (dCC) region of interest (ROI)