Effect of Tolcapone on Brain Activity During a Variable Attentional Control Task: A Double-Blind, Placebo-Controlled, Counter-Balanced Trial in Healthy Volunteers

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. 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. 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). The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009. Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated. 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. Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors. 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). 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.