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Single dose of a dopamine agonist impairs reinforcement learning in humans: evidence from event-related potentials and computational modeling of striatal-cortical function - PubMed

Randomized Controlled Trial

. 2009 Jul;30(7):1963-76.

doi: 10.1002/hbm.20642.

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Randomized Controlled Trial

Single dose of a dopamine agonist impairs reinforcement learning in humans: evidence from event-related potentials and computational modeling of striatal-cortical function

Diane L Santesso et al. Hum Brain Mapp. 2009 Jul.

Abstract

Animal findings have highlighted the modulatory role of phasic dopamine (DA) signaling in incentive learning, particularly in the acquisition of reward-related behavior. In humans, these processes remain largely unknown. In a recent study, we demonstrated that a single low dose of a D2/D3 agonist (pramipexole)-assumed to activate DA autoreceptors and thus reduce phasic DA bursts-impaired reward learning in healthy subjects performing a probabilistic reward task. The purpose of this study was to extend these behavioral findings using event-related potentials and computational modeling. Compared with the placebo group, participants receiving pramipexole showed increased feedback-related negativity to probabilistic rewards and decreased activation in dorsal anterior cingulate regions previously implicated in integrating reinforcement history over time. Additionally, findings of blunted reward learning in participants receiving pramipexole were simulated by reduced presynaptic DA signaling in response to reward in a neural network model of striatal-cortical function. These preliminary findings offer important insights on the role of phasic DA signals on reinforcement learning in humans and provide initial evidence regarding the spatiotemporal dynamics of brain mechanisms underlying these processes.

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Figures

Figure 1
Figure 1

Neural network model of cortico‐striatal circuitry (squares represent units, with height and color reflecting neural activity; yellow, most active; red, less active; gray, not active). The model includes the direct (Go) and indirect (NoGo) pathways of the basal ganglia [Frank,2005,2006]. The Go cells disinhibit the thalamus via the internal segment of globus pallidus (GPi) and thereby facilitate the execution of an action represented in cortex. The NoGo cells have an opposing effect by increasing inhibition of the thalamus, which suppresses actions and thereby keeps them from being executed. Dopamine from the substantia nigra pars compacta (SNc) projects to the dorsal striatum. A tonic level of dopamine is shown in SNc; a burst or dip ensues in a subsequent error feedback phase, causing corresponding changes in Go/NoGo unit activations, which drive learning, via simulated D1 and D2 receptors. Pramipexole was simulated by reducing the size of DA bursts during rewards to simulate presynaptic autoreceptor effects induced by the low dose. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 2
Figure 2

Left panel: Summary of (a) response bias; (b) discriminability; (c) accuracy for the more frequently rewarded (rich) stimulus; and (d) accuracy for the less frequently rewarded (lean) stimulus. Figures modified from Pizzagalli et al. [2008] with permission. Right panel: Corresponding variables for the intact neural network of cortico‐striatal circuitry (“placebo groups”) and the neural network simulating reduced presynaptic DA bursts in response to rewards (“pramipexole group”). Error bars refer to standard errors.

Figure 3
Figure 3

(a) Averaged ERP waveforms from 200 ms before to 600 ms after the presentation of correct feedback during the probabilistic reward task for the pramipexole (heavy line) and placebo (light line) group averaged across Fz, FCz, and Cz; (b) Topographic map of the FRN difference wave between the pramipexole and placebo group (pramipexole minus placebo); and (c) Results of voxel‐by‐voxel independent t‐tests contrasting current density for the placebo and pramipexole group in response to reward feedback. Red: relatively higher activity for placebo subjects. Blue: relatively higher activity for pramipexole subjects. Statistical map is thresholded at P < 0.005 and displayed on the MNI template.

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