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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.

SUBMITTER: Kayser AS

PROVIDER: S-EPMC5200917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Individuals suffering from pathological gambling (PG) show impaired decision making, but it is still not clear how this impairment is related to other traits and neuroanatomical characteristics. In this study, we investigated how the influence of PG on decision making (1) is connected to different impulsivity facets and (2) how it is related to gray matter volume (GMV) in various brain regions. Twenty-eight diagnosed PG patients and 23 healthy controls completed the cups task to measure decision making. In this task, participants had to decide between safe and risky options, which varied in expected value (EV) between risk advantageous, equal EV, and risk disadvantageous choices. A delay discounting task and the Barrant Impulsiveness Scale were applied to assess multiple impulsivity facets. In addition, structural magnetic resonance images were acquired. In comparison to the control group PG patients demonstrated more deficits in decision making, indicated by less EV sensitivity, but there was no significant difference in number of overall risky choices. Also, PG patients showed increased impulsivity in nearly every dimension. Results revealed (1) a positive correlation between decision making impairments and non-planning impulsivity but no significant relation to other impulsivity facets. Although we found no GMV differences between PG patients and controls, (2) a regions of interest analysis showed a correlation between medial orbitofrontal GMV and EV sensitivity in PG patients. Our findings showed that (1) the association between decision making and impulsivity can also be found in PG patients, but only for certain impulsivity facets. This suggests that it is essential to consider measuring different dimensions, when investigating impulsivity in a PG sample. Secondly, our findings revealed that (2) dysfunctional decision making-particularly the component of risk evaluation-is related to decreased GMV in the medial orbitofrontal cortex, a brain region concerned with processing of rewards. Interestingly, we did not find more risky choices for PG patients, and thus, we assume that decision making deficits in PG are primarily related to risk evaluation, not risk seeking, which is in line with our GMV findings.

Project description:Attention Deficit/Hyperactivity Disorder (ADHD) is a self-regulation disorder, with impairments in error monitoring associated with underactivation of the related brain network(s). Psychostimulant medication improves ADHD symptoms and can upregulate brain function, but has side effects, with limited evidence for longer-term effects. Real-time functional magnetic resonance neurofeedback (fMRI-NF) has potential longer-term neuroplastic effects. We previously reported the effects of 11 runs of 8.5 min of fMRI-NF of the right inferior frontal cortex (rIFC) in adolescents with ADHD. This resulted in improvement of clinical symptom and enhanced rIFC activation post-pre treatment during response inhibition, when compared to a control group receiving fMRI-NF of the left parahippocampal gyrus (lPHG). In the current study we applied a novel analysis to the existing data by investigating the effects of fMRI-NF of rIFC in 16 adolescents with ADHD compared to fMRI-NF of lPHG in 11 adolescents with ADHD on the neurofunctional correlates of error monitoring during the same fMRI tracking stop task and potential associations with cognitive and clinical measures. We found stronger performance adjustment to errors in the rIFC-NF compared to the control lPHG-NF group. At the brain function level, fMRI-NF of rIFC compared to that of lPHG was associated with increased activation in error monitoring regions of the left IFC, premotor cortex, insula and putamen. The increased activation in left IFC-insular-striatal error monitoring regions in the rIFC-NF relative to the lPHG-NF group was furthermore trend-wise correlated with NF-induced ADHD symptom improvements. The findings of this study show, that during error monitoring, fMRI-NF training of rIFC upregulation elicited improvement in post-error behavioural adjustments and concomitant increased activation in left hemispheric fronto-insular-striatal and premotor regions mediating self-control and self-monitoring functions. This suggests that the administration of fMRI-NF of the rIFC may have had an impact on wider networks of self-regulation and self-monitoring in adolescents with ADHD.

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

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