Right inferior frontal cortex activity correlates with tolcapone responsivity in problem and pathological gamblers

Abstract

Failures of self-regulation in problem and pathological gambling (PPG) are thought to emerge from failures of top-down control, reflected neurophysiologically in a reduced capacity of prefrontal cortex to influence activity within subcortical structures. In patients with addictions, these impairments have been argued to alter evaluation of reward within dopaminergic neuromodulatory systems. Previously we demonstrated that augmenting dopamine tone in frontal cortex via use of tolcapone, an inhibitor of the dopamine-degrading enzyme catechol-O-methyltransferase (COMT), reduced delay discounting, a measure of impulsivity, in healthy subjects. To evaluate this potentially translational approach to augmenting prefrontal inhibitory control, here we hypothesized that increasing cortical dopamine tone would reduce delay discounting in PPG subjects in proportion to its ability to augment top-down control. To causally test this hypothesis, we administered the COMT inhibitor tolcapone in a randomized, double-blind, placebo-controlled, within-subject study of 17 PPG subjects who performed a delay discounting task while functional MRI images were obtained. In this subject population, we found that greater BOLD activity during the placebo condition within the right inferior frontal cortex (RIFC), a region thought to be important for inhibitory control, correlated with greater declines in impulsivity on tolcapone versus placebo. Intriguingly, connectivity between RIFC and the right striatum, and not the level of activity within RIFC itself, increased on tolcapone versus placebo. Together, these findings support the hypothesis that tolcapone-mediated increases in top-down control may reduce impulsivity in PPG subjects, a finding with potential translational relevance for gambling disorders, and for behavioral addictions in general.

Trial registration: ClinicalTrials.gov NCT02772978.

Keywords: Dopamine; Frontostriatal; Gambling; Prefrontal cortex; Tolcapone; Ventral striatum.

Figures

Fig. 1

Study Flow Diagram. As documented in Materials and methods, 39 subjects were screened, of whom 19 met criteria for study participation and were allocated to the intervention. During participation in the randomized, double-blind, placebo-controlled, within-subject portion of the study, two additional subjects were excluded: one after he failed a urine toxicology screen at his first MRI visit, and another after she fell asleep during her second fMRI session.

Fig. 2

Task Design. A. Each trial of the delay discounting task began with fixation, followed by a cue to the trial type. After a brief jittered delay, subjects were prompted to make a decision (in this case, a “Want” decision). B. Illustrated are the four trial types: Want, Don't Want, Sooner, and Larger (see Materials and methods). The pie chart at right illustrates the relative proportions of each of the trial types.

Fig. 3

Behavioral Results. A. Shown are the variance-stabilized impulsive choice ratios for each subject in the placebo (dark gray) and tolcapone (light gray) conditions, ordered by magnitude of the difference within the 17 subjects. Subjects whose ICR values decreased on tolcapone are to the left. B. The change in ICR on tolcapone versus placebo was significantly correlated with subjects' scores on the non-planning subscale of the Barratt Impulsiveness Scale (BIS).

Fig. 4

Brain-Behavior Correlation. A. Two brain regions demonstrated significant negative correlations between ΔICR and BOLD activity during the Want condition on placebo at a significance level of p 2 = 0.59)). A similar result was seen for the right premotor cortex (data not shown). B. This finding was replicated in the tolcapone condition. The same two brain regions demonstrated significant negative correlations between ΔICR and BOLD activity during Want trials at a significance level of p < 0.05, corrected (left panel); and greater BOLD signal in these regions again covaried with greater declines in ICR on tolcapone versus placebo (right panel, shown for the RIFC region; for reference, the equivalent Pearson's r = − 0.89 (r2 = 0.79)).

Fig. 5

Connectivity-Behavior Correlation. A psychophysiological interaction (PPI) analysis was performed in which the right inferior frontal cortex (RIFC) served as the seed region and the right striatum as the search volume of interest. Shown is the correlation between connectivity with the RIFC during the Want condition (tolcapone versus placebo) and the change in ICR (tolcapone versus placebo), thresholded at a significance level of p 2 = 0.58)). Specifically, greater increases in RIFC ↔ right putamen connection strength on tolcapone versus placebo correlated with greater declines in ICR on tolcapone versus placebo (left panel). When the search was expanded to the rest of the brain, no other regions of this cluster size or greater were found (data not shown).