Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis

Abstract

Background: Alterations in frontal and striatal function are hypothesized to underlie risky decision making in drug users, but how these regions interact to affect behavior is incompletely understood. We used mediation analysis to investigate how prefrontal cortex and ventral striatum together influence risk avoidance in abstinent drug users.

Method: Thirty-seven abstinent substance-dependent individuals (SDI) and 43 controls underwent fMRI while performing a decision-making task involving risk and reward. Analyses of a priori regions-of-interest tested whether activity in dorsolateral prefrontal cortex (DLPFC) and ventral striatum (VST) explained group differences in risk avoidance. Whole-brain analysis was conducted to identify brain regions influencing the negative VST-risk avoidance relationship.

Results: Right DLPFC (RDLPFC) positively mediated the group-risk avoidance relationship (p < 0.05); RDLPFC activity was higher in SDI and predicted higher risk avoidance across groups, controlling for SDI vs.

Controls: Conversely, VST activity negatively influenced risk avoidance (p < 0.05); it was higher in SDI, and predicted lower risk avoidance. Whole-brain analysis revealed that, across group, RDLPFC and left temporal-parietal junction positively (p ≤ 0.001) while right thalamus and left middle frontal gyrus negatively (p < 0.005) mediated the VST activity-risk avoidance relationship.

Conclusion: RDLPFC activity mediated less risky decision making while VST mediated more risky decision making across drug users and controls. These results suggest a dual pathway underlying decision making, which, if imbalanced, may adversely influence choices involving risk. Modeling contributions of multiple brain systems to behavior through mediation analysis could lead to a better understanding of mechanisms of behavior and suggest neuromodulatory treatments for addiction.

Keywords: Decision-making; Dorsolateral prefrontal cortex (DLPFC); Impulsivity; Mediation; Substance dependence; Ventral striatum (VST).

Figure 1. Single-level mediation model

Path a represents the relationship of X to M. Path b represents the relationship of M to Y while controlling for X, c’ represents the relationship of X to Y controlling for M, and c represents the indirect relationship of X to Y (not adjusted for any other factors).

Figure 2. Single-level mediation analysis

RDLPFC and VST oppositely mediate group differences in risk avoidance. Path coefficients are shown next to arrows with standard errors in parentheses. Path a is from the group (X) to the RDLPFC (M1). Path b is from RDLPFC (M1) to risk avoidance (Y). Path a2 is from the group (X) to the VST (M2). Path b2 is from VST (M2) to risk avoidance (Y). Paths b and b2 are calculated controlling for group (X). Paths a, b, and a*b control for VST (M2), and Paths a2, b2, and a2*b2 control for RDLPFC (M1). The direct path c’ is calculated controlling for both mediators. ****p<0.001, ***p<0.005, **p<0.01, *p<0.05, one-tailed; right dorsolateral prefrontal cortex (RDLPFC), ventral striatum (VST), mediator (M1, M2)

Figure 3. Mediation Effect Parametric Mapping (MEPM)

Across group, RDLPFC positively mediated and the right thalamus negatively mediated the VST-risk avoidance relationship. The a path is from the VST (X) to each mediating region. The b path is from the mediating region (M) to risk avoidance (Y). The b path is calculated controlling for VST (X) and for other mediators. Path coefficients are shown next to arrows with standard errors in parentheses. The direct path c’ is calculated controlling for the mediator. Coefficients and p values were calculated using maxstat. ***p<0.001, **p<0.005, two-tailed. Ventral striatum (VST), right dorsolateral prefrontal cortex (RDLPFC), right thalamus (R thalamus)

Figure 4. Impulsivity affects risk avoidance

a) Controls (blue) were less impulsive than SDI (red; p<0.001). b) Risk avoidance and impulsivity were negatively correlated across groups (r=-0.435, p<0.001). c) Mediation analysis results depicting the mediating effect of impulsivity on group differences in risk avoidance. After controlling for the mediating effect of impulsivity, the relationship between group and risk avoidance was no longer significant. ***p<0.001, **p<0.005, two-tailed