Methylphenidate boosts choices of mental labor over leisure depending on striatal dopamine synthesis capacity

Abstract

The cognitive enhancing effects of methylphenidate are well established, but the mechanisms remain unclear. We recently demonstrated that methylphenidate boosts cognitive motivation by enhancing the weight on the benefits of a cognitive task in a manner that depended on striatal dopamine. Here, we considered the complementary hypothesis that methylphenidate might also act by changing the weight on the opportunity cost of a cognitive task, that is, the cost of foregoing alternative opportunity. To this end, 50 healthy participants (25 women) completed a novel cognitive effort-discounting task that required choices between task and leisure. They were tested on methylphenidate, placebo, as well as the selective D2-receptor agent sulpiride, the latter to strengthen inference about dopamine receptor selectivity of methylphenidate's effects. Furthermore, they also underwent an [¹⁸F]DOPA PET scan to quantify striatal dopamine synthesis capacity. Methylphenidate boosted choices of cognitive effort over leisure across the group, and this effect was greatest in participants with more striatal dopamine synthesis capacity. The effects of sulpiride did not reach significance. This study strengthens the motivational account of methylphenidate's effects on cognition, and suggests that methylphenidate reduces the cost of mental labor by increasing striatal dopamine.

Fig. 1. Schematic of data acquisition.

a Schematic of the color wheel working memory task. I = “ignore”: participants have to ignore the new squares, while still remembering the previous set of squares. U = “update”: participants have to remember the new set of squares and forget the previous set. b Example trial sequence of the cognitive effort discounting choice task. c Coronal view of our regions of interest, including the nucleus accumbens (blue), putamen (green), and caudate nucleus (red).

Fig. 2. Behavioral results.

a Median absolute deviance, b median response times, and c the proportion of trials on which participants chose the redo option across drug sessions plotted as a function of set size, separately for each task type. d Drug effect on the proportion of trials on which participants chose the redo option (methylphenidate or sulpiride minus placebo). The methylphenidate-induced effect on proportion redo choices is still significant without the participant showing the greatest effect: F_(2,86) = 4.0, p = 0.022. Error bars represent 95% confidence interval around the mean. MPH methylphenidate, SUL sulpiride, PBO placebo.

Fig. 3. Proportion redo choices as a function of dopamine synthesis capacity in the nucleus accumbens (upper panels), putamen (middle panels), and caudate nucleus (bottom panels).

P-values < 0.017 were considered significant. a Correlation between dopamine synthesis capacity and proportion redo choices under placebo. b Correlation between dopamine synthesis capacity and drug-induced changes in proportion redo choices. Correlation coefficients and p-values without the participant showing the greatest methylphenidate-induced effect on proportion redo choices: r_{nucleus accumbens} = 0.36, p = 0.014; r_putamen = 0.41, p = 0.005; r_{caudate nucleus} = 0.29, p = 0.056. c Median split on dopamine synthesis capacity for visualization purposes. Shaded areas and error bars represent 95% confidence interval around the mean. PBO placebo, MPH methylphenidate, SUL sulpiride, K_i [¹⁸F]DOPA uptake.

Fig. 4. Choice latency as a function of dopamine synthesis capacity in the nucleus accumbens (upper panels), putamen (middle panels), and caudate nucleus (bottom panels).

p-Values < 0.017 were considered significant. a Correlation between dopamine synthesis capacity and choice latency under placebo. b Correlation between dopamine synthesis capacity and drug-induced changes in choice latency. c Median split on dopamine synthesis capacity for visualization purposes. Shaded areas and error bars represent 95% confidence interval around the mean. PBO placebo, MPH methylphenidate, SUL sulpiride, K_i [¹⁸F]DOPA uptake.