Neurochemical modulation of response inhibition and probabilistic learning in humans

Abstract

Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and to learn from complex feedback (probabilistic learning), play critical roles in activities of daily life. To what extent do different neurochemical systems modulate these two cognitive functions? Here, using stop-signal and probabilistic learning tasks, we show a double dissociation for the involvement of noradrenaline and serotonin in human cognition. In healthy volunteers, inhibition of central noradrenaline reuptake improved response inhibition but had no effect on probabilistic learning, whereas inhibition of central serotonin reuptake impaired probabilistic learning with no effect on response inhibition.

Fig. 1

(A) On the computerized stop-signal task, subjects respond rapidly to left- or right-facing arrows on screen with corresponding motor responses, and they attempt to inhibit responses when an auditory stop-signal sounds. Over the course of the task, the time between stimulus onset and occurrence of the stop-signal is varied by means of a tracking algorithm. This permits calculation of the SSRT, which reflects an estimate of the time taken to internally suppress prepotent motor responses [for further details of calculation, see (18, 23)]. The average response time for Go trials is also recorded. (B) On the probabilistic learning task, volunteers make a two-alternative forced choice between two stimuli (one red, one green) on each trial. The “correct” stimulus (always the first stimulus touched) receives an 8:2 ratio of positive:negative feedback, and the opposite ratio is given for the “incorrect” stimulus. Feedback is provided in the form of “CORRECT” or “INCORRECT” appearing on screen after each choice. Ability to acquire the stimulus-reward association on the basis of this degraded feedback is assessed by the number of errors made before reaching criterion, defined as eight consecutive correct responses to the maximally rewarded stimulus. After 40 trials (stage 1), the contingencies reverse for the subsequent 40 trials (stage 2) (i.e., if “red” was previously correct, then “green” becomes correct). Ability to reverse the previously acquired stimulus-reward association is assessed by the number of perseverative errors to the previously maximally rewarded stimulus. Ability to acquire the new stimulus-reward association is again assessed by the number of errors made before reaching criterion. The detrimental effect of misleading negative feedback on learning is assessed by means of an overall “feedback sensitivity” score. This is defined as the overall likelihood that the volunteer inappropriately switched to choose the incorrect stimulus after misleadingly being informed that his or her correct response on the previous trial was not correct.

Fig. 2

Atomoxetine enhances response inhibition on the stop-signal task, whereas citalopram impairs performance on the probabilistic learning task. *P < 0.05 difference versus controls; **P < 0.01 difference versus controls. Error bars show SEM. In the stop-signal task, groups differed significantly on SSRTs (F_2,57 = 4.377, P = 0.017) but not on median Go response times (F_2,57 = 0.780, P = 0.463). The atomoxetine-treated group showed significantly shorter SSRTs relative to the citalopram-treated group (P = 0.013) and the placebo group (P = 0.014), whereas the citalopram-treated group did not differ from the placebo group (P = 0.973). In the probabilistic learning task, groups in stage 1 (graphs, second row) differed overall on number of errors made before attaining criterion (F_2,57 = 5.549, P = 0.006) and on response latency (F_2,57 = 5.588, P = 0.006). The citalopram-treated group made more errors before reaching criterion than did the atomoxetine-treated group (P = 0.012) and the placebo group (P = 0.002) and displayed longer mean response latencies than did the atomoxetine-treated group (P = 0.003) and the placebo group (P = 0.012). The atomoxetine-treated group did not differ from the placebo group on these measures (P = 0.379; P = 0.616). In stage 2, groups did not differ significantly in terms of perseverative errors made to the previously maximally rewarded stimulus (mean errors ± SD: atomoxetine, 2.95 ± 1.67; citalopram, 4.00 ± 6.54; placebo, 3.15 ± 1.73; F_2,57 = 0.390, P = 0.679). Groups differed overall (graphs, third row) on number of errors made before attaining criterion (F_2,57 = 5.019, P = 0.010) and on response latency (F_2,57 = 7.981, P = 0.001). The citalopram-treated group made more errors before reaching criterion than did the atomoxetine-treated group (P = 0.004) and the placebo group (P = 0.020) and displayed longer mean response latencies than did the atomoxetine-treated group (P = 0.001) and the placebo group (P = 0.001). The atomoxetine-treated group did not differ from the placebo group on these measures (P = 0.557; P = 0.885). Groups differed on feedback sensitivity scores (F_2,57 = 4.109, P = 0.022). The citalopram-treated group showed greater feedback sensitivity than did the atomoxetine-treated group (P = 0.037) and the placebo group (P = 0.009). The atomoxetine-treated group did not differ from the placebo group on this measure (P = 0.554).