Dopamine, corticostriatal connectivity, and intertemporal choice

Abstract

Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.

Figures

Figure 1.

Task structure. 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 latter two trial types comprised the control (“Con”) condition. The pie chart at right illustrates the relative proportions of each of the trial types.

Figure 2.

Behavioral results. a, Shown are the differences between the variance-stabilized impulsive choice ratios [ΔICR = ICR (tolcapone) − ICR (placebo)], ordered by magnitude across the 23 subjects (left), as well as the actual ICR values for both placebo and tolcapone (right). There was a significant decline in ICR across the group in the tolcapone condition: ΔICR = −0.04, p = 0.025. b, The effect of tolcapone varied with an independent measure of baseline impulsivity (r = −0.45; p = 0.032). Specifically, ΔICR was negatively correlated with the score on the BIS, where higher BIS scores indicate greater impulsivity.

Figure 3.

Main effect of task and drug. Tolcapone produced significant differences in BOLD activity during task performance relative to placebo, as assessed by the main effect of task (p < 0.05, corrected for multiple comparisons). Significant increases in BOLD signal could be seen in the dorsomedial prefrontal cortex and bilateral dorsolateral frontal cortices (slices Z = 50 and Z = 28), as well as the bilateral fusiform cortex (slice Z = −20) and the dorsal midbrain (sagittal slice X = −2). Areas with significant decreases in BOLD signal were also present (Table 1).

Figure 4.

Brain–behavior correlations. a, Three brain regions demonstrated significant negative correlations between ΔICR and the change in BOLD activity during the Want condition on tolcapone versus placebo (p < 0.05, corrected for multiple comparisons): left anterior insula, left putamen (slice Z = −2), and left precentral gyrus (coronal slice Y = 26; Table 1). Thus, greater BOLD increases in these regions on tolcapone versus placebo covaried with greater declines in ICR. b, Shown are the parameter estimates across subjects for the left insula and the left putamen, demonstrating that these effects were not driven by outlier values.

Figure 5.

Insula and putamen function/connectivity. a, Shown is the contrast between all Want (Later) and all Want (Now) choices (p < 0.05, corrected for multiple comparisons). This contrast revealed a significant increase in BOLD signal in the left anterior insula, overlapping the anterior insula region identified in Figure 4 (Table 1). b, In the resting state, the correlation between the putamen region identified in Figure 4 and the pregenual anterior cingulate cortex (pgACC) declined (p < 0.05, corrected for multiple comparisons; sagittal slice X = 4). c, During task performance, the difference in coherence between the pgACC and left putamen on tolcapone versus placebo correlated positively with the change in ICR (r = 0.64; p = 0.0017). Specifically, greater declines in pgACC ⇆ putamen coherence correlated with greater declines in ICR.