Dopamine controls the neural dynamics of memory signals and retrieval accuracy

Abstract

The human brain is capable of differentiating between new and already stored information rapidly to allow optimal behavior and decision-making. Although the neural mechanisms of novelty discrimination were often described as temporally constant (ie, with specific latencies), recent electrophysiological studies have demonstrated that the onset of neural novelty signals (ie, differences in event-related responses to new and old items) can be accelerated by reward motivation. While the precise physiological mechanisms underlying this acceleration remain unclear, the involvement of the neurotransmitter dopamine in both novelty and reward processing suggests that enhanced dopamine levels in the context of reward prospect may have a role. To investigate this hypothesis, we used magnetoencephalography (MEG) in combination with an old/new recognition memory task in which correct discrimination between old and new items was rewarded. Importantly, before the task, human subjects received either 150 mg of the dopamine precursor levodopa or placebo. For the placebo group, old/new signals peaked at ∼100 ms after stimulus onset over left temporal/occipital sensors. In contrast, after levodopa administration earliest old/new effects only emerged after ∼400 ms and retrieval accuracy was reduced as expressed in lower d' values. As such, our results point towards a previously unreported role of dopamine in controlling the chronometry of neural processes underlying the distinction between old and new information. They also suggest that this relationship follows a nonlinear function whereby slightly enhanced dopamine levels accelerate neural/cognitive processes and excessive dopamine levels impair them.

Figure 1

Experimental design. Subjects were first familiarized with a set of indoor and outdoor scene images (not shown) and then performed a reward-based old/new discrimination task. See Materials and methods section for further details. CS, conditioned stimulus; ISI, interstimulus interval.

Figure 2

Interaction between novelty processing and drug group. Analyses of event-related magnetic fields were limited to a priori defined sensors of interest (red dots in (a), see text). Interactions between novelty status (old images, new images) and drug group (levodopa, placebo) were observed for an early (60–140 ms) and a later (500–800 ms) time-window (b). The early effect was driven by significant old/new responses in the placebo but not drug group; in the later time-window, the opposite pattern emerged. (c and d) Topographical maps of these effects (ie, differences between new vs old items). Asterisks represent statistically significant interactions (p<0.05). For a full depiction of all eight conditions see Supplementary Figure S1.

Figure 3

Main effect of drug group. Statistical Parametric Mapping-based analysis across all sensors and time-points revealed a main effect of drug group (levodopa, placebo) over left occipital sensors (peak at 267 ms; nearest sensor: MLO43) (a). It was driven by more positive event-related magnetic fields across all conditions in the levodopa group ranging from ∼100 to 800 ms (b). Asterisk indicates the statistically significant main effect (p<0.05).

Figure 4

Inverted u-shaped relationship between dopamine (DA) levels and the chronometry of novelty processing. We suggest that slightly enhanced dopamine levels, for example, in the context of reward prospect (middle), accelerate the onset of neural novelty signals. If dopamine levels exceed an optimal range, for example, in the context of reward together with levodopa administration (right), the onset latency returns to baseline or even delays.