Dopamine is associated with prioritization of reward-associated memories in Parkinson's disease

Abstract

Patients with Parkinson's disease have reduced reward sensitivity related to dopaminergic neuron loss, which is associated with impairments in reinforcement learning. Increasingly, however, dopamine-dependent reward signals are recognized to play an important role beyond reinforcement learning. In particular, it has been shown that reward signals mediated by dopamine help guide the prioritization of events for long-term memory consolidation. Meanwhile, studies of memory in patients with Parkinson's disease have focused on overall memory capacity rather than what is versus what isn't remembered, leaving open questions about the effect of dopamine replacement on the prioritization of memories by reward and the time-dependence of this effect. The current study sought to fill this gap by testing the effect of reward and dopamine on memory in patients with Parkinson's disease. We tested the effect of dopamine modulation and reward on two forms of long-term memory: episodic memory for neutral objects and memory for stimulus-value associations. We measured both forms of memory in a single task, adapting a standard task of reinforcement learning with incidental episodic encoding events of trial-unique objects. Objects were presented on each trial at the time of feedback, which was either rewarding or not. Memory for the trial-unique images and for the stimulus-value associations, and the influence of reward on both, was tested immediately after learning and 2 days later. We measured performance in Parkinson's disease patients tested either ON or OFF their dopaminergic medications and in healthy older control subjects. We found that dopamine was associated with a selective enhancement of memory for reward-associated images, but that it did not influence overall memory capacity. Contrary to predictions, this effect did not differ between the immediate and delayed memory tests. We also found that while dopamine had an effect on reward-modulated episodic memory, there was no effect of dopamine on memory for stimulus-value associations. Our results suggest that impaired prioritization of cognitive resource allocation may contribute to the early cognitive deficits of Parkinson's disease.

Keywords: Parkinson’s disease; dopamine; episodic memory; reinforcement learning; reward.

Figure 1

Experimental design: testing the effect of feedback on episodic memory and stimulus-value memory. Trial sequence of learning task. (A) Participants had to choose one of two abstract stimuli presented in pairs. Each stimulus had a different probability of leading to rewarding feedback ranging from 0.14 to 0.86. To incorporate trial-unique object images presented at the time of feedback meaningfully, we used a task narrative. Participants were told they were going shopping, that the abstract stimuli represented store logos, and that their goal was to accumulate as many objects as possible from a given category (e.g. food). Over time, they would learn which stores were most likely to yield the desired items. At the time of feedback, we presented a trial-unique object from the given category if they were correct, or an object from a different category (e.g. sporting good) if they were incorrect. The object was briefly presented alone, and then positive or negative verbal feedback was additionally presented. No object was presented twice. (B) Both training pairs and novel pairs were presented during the reinforcement learning memory test. Novel pairs were constructed by pairing the best stimulus (0.86) and the worst stimulus (0.14) with all others. (C) During the object recognition memory test, memory for all the trial-unique objects presented during the learning task was tested allowing us to compare memory performance for images encoded in the presence of positive versus negative feedback. (D) During the reinforcement learning memory test participants were presented with the same six stimuli either arranged in the original training pairs or in novel pairs. Performance on ‘Choose the best’ trials reflected memory for learning from positive feedback whereas performance on ‘Avoid the worst’ trials reflected memory for learning from negative feedback.

Figure 2

Overall study design: testing the effects of dopamine and reward on memory. To compare memory after a short (immediate) and long (2 day) delay, participants performed the reinforcement learning and object encoding task twice, 2 days apart, using non-overlapping ‘store logo’ and object image sets. Memory testing for both learning sessions, and for both the stimulus value memory and the recognition memory, was conducted only in Session 2. This order ensured the surprise element of the test and provided measures of stimulus value and recognition memory after both a short delay and a long delay. During the memory test phase, memory for the reinforcement learning was performed first, with presentation of the short delay store logos (set B) followed by the long delay store logos (set A). This was followed by the object recognition memory test where images belonging to set B (short delay) and set A (long delay) were mixed randomly. Patients in the OFF group were tested OFF for both sessions, and patients in the ON group were tested ON for both sessions.

Figure 3

Effect of reward on object recognition memory is dopamine dependent but not time dependent. (A) Recognition memory for objects encoded on trials where either rewarding or negative feedback was delivered, shown collapsed across the short-delay and long-delay memory tests, for participants who reached the learning criterion on the reinforcement learning task (see Supplementary material for similar pattern in full sample). Lines represent data for individual participants. Memory was better for reward-associated images in patients ON dopaminergic medication compared to patients OFF dopaminergic medications (ON versus OFF difference estimate = 0.16, P = 0.03). There were no differences between groups in overall recognition memory. (B) Recognition memory shown separately for the short and the long-delay memory tests to illustrate the decay across the delay, and grouped according to whether the images were associated with rewarding versus negative feedback, shown for participants who reached the learning criterion. Thick lines represent group averages and thin lines represent individual participants. There was no effect of reward on decay of memory, nor any differences between groups for the effect of reward on memory decay. Error bars represent ±1 standard error of the within group differences. Asterix indicates significant difference (*P < 0.05). HC = healthy controls.

Figure 4

Memory for stimulus-value associations did not differ based on reward, Parkinson’s disease or dopamine medications. (A) Memory for stimulus-value associations, taken as the performance on the novel pairs, stratified according to whether novel pairs represented learning from rewarding (‘Choose best’) versus non-rewarding feedback (‘Avoid worst’), presented here collapsed across both time-points for participants who reached the learning criterion. Lines represent data for individual participants. There was no significant effect of reward at the time of learning on later memory for stimulus-value associations in any of the groups. (B) Decay in memory for stimulus-value associations across the 2-day delay, presented for stimuli learned from rewarding versus those learned from non-rewarding feedback, for participants who reached the learning criterion. Thick lines represent group averages and thin lines represent individual participants. There was a trend for better maintenance of reward-associated memory in the PD-ON compared to PD-OFF (difference estimate = 0.60 P = 0.072). Error bars represent ±1 standard error of the within group (A), and within group and within condition (B) differences. HC = healthy controls.