Striatal dopamine dissociates methylphenidate effects on value-based versus surprise-based reversal learning

Abstract

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.

Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity

“…Critically, the absence of correlations was not due to measurement error in the estimates of striatal dopamine synthesis capacity or a lack of behavioural relevance of these estimates. The striatal [ 18 F]-FDOPA uptake values are in the typical range (Supplementary Figure 1), and dopamine synthesis capacity in this dataset has been shown to account for (dopamine drug effects on) effort-based decision making, response vigour, reversal learning, and smartphone social activity in the expected direction (Hofmans et al, 2020, 2022; van den Bosch et al, 2022; Westbrook et al, 2020, 2021). More specifically, [ 18 F]-FDOPA uptake in the striatum was associated positively with the value of cognitive effort (Westbrook et al, 2020), with the impact of average reward value on response vigour (Hofmans et al, 2022) and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum (van den Bosch et al, 2022).…”

“…The striatal [ 18 F]-FDOPA uptake values are in the typical range (Supplementary Figure 1), and dopamine synthesis capacity in this dataset has been shown to account for (dopamine drug effects on) effort-based decision making, response vigour, reversal learning, and smartphone social activity in the expected direction (Hofmans et al, 2020, 2022; van den Bosch et al, 2022; Westbrook et al, 2020, 2021). More specifically, [ 18 F]-FDOPA uptake in the striatum was associated positively with the value of cognitive effort (Westbrook et al, 2020), with the impact of average reward value on response vigour (Hofmans et al, 2022) and with dopaminergic drug-related changes in prediction error-related BOLD signal in the striatum (van den Bosch et al, 2022). The implication of this body of work is that more sophisticated and quantitative indices of value-based learning, motivation, and even daily logs of participants’ social activity on their smartphone might be better proxy measures of striatal dopamine synthesis capacity than the simple trait measures reported here.…”

“…This is particularly pertinent, because while both [ 18 F]-FDOPA and [ 18 F]-FMT ligands are substrates for aromatic amino acid decarboxylase, [ 18 F]-FDOPA is subject to additional in vivo COMT metabolism, implying lower signal to noise ratio than [ 18 F]-FMT (DeJesus et al, 1997), and perhaps also to some degree dopamine turnover rather than synthesis capacity (Dejesus et al, 2001). Future work is required to reconcile the growing body of literature demonstrating differential, sometimes even contrasting effects of dopamine synthesis capacity measured with [ 18 F]-FMT and [ 18 F]-FDOPA (Berry et al, 2016, 2018; Cools et al, 2009; Ito et al, 2011; Kumakura et al, 2010; van den Bosch et al, 2022). While we cannot exclude the possibility that the present lack of correlations reflects the use of a tracer with insufficient signal to noise, we consider it unlikely that the use of different radiotracers can fully explain the extant discrepancy for the following reasons.…”

Effect of striatal dopamine on Pavlovian bias. A large [¹⁸F]-DOPA PET study.

“…On their first visit (day 1), participants were screened for eligibility, in part based on medical and psychiatric interviews, and completed assessments of WM capacity; listening span (Daneman & Carpenter, 1980; Salthouse & Babcock, 1991), digit span (Groth-Marnat et al, 2000), and crystallized intelligence (Crawford et al, 1989; Schmand et al, 1991), and also providing measures of spontaneous eye blink rate (electrooculography), and an anatomical brain scan. The screening session was followed by pharmacological-fMRI sessions on day 2–4, which are reported elsewhere (van den Bosch, Lambregts, et al, 2022). On the final visit, in addition to the PIT task, participants completed a second Digit Span Test and a fluid intelligence assessment; Wechsler Adult Intelligence Scale, 4th edition, Dutch edition (Wechsler, 2008), followed by an [ 18 F]-DOPA PET scan to establish participants’ K i .…”

“…The data reported here were acquired in the context of a larger pharmacological PET/fMRI study, components of which have been and will be reported separately (Hofmans et al, 2020(Hofmans et al, , 2022Määttä et al, 2021;van den Bosch, Hezemans, et al, 2022;van den Bosch, Lambregts, et al, 2022;Westbrook et al, 2020; an overview of the complete study at https://osf.io/d3h8e). For this study, participants paid five visits.…”