Research report
Dopaminergic modulation of the updating of stimulus–response episodes in Parkinson's disease

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Abstract

Increasing evidence suggests that the control of retrieval of episodic feature bindings is modulated by the striatal dopaminergic pathway. The present study investigated whether this may reflect a contribution from the ventral or the dorsal part of the striatum. Along the lines of the overdose hypothesis in Parkinson's disease (PD), functions known to rely on the dorsal striatum are enhanced with dopaminergic medication, while operations relying on the ventral circuitry are impaired. We found that partial mismatches between present and previous stimulus–response relations are, compared to control participants, abnormally low OFF DA medication and normalized ON DA medication. The results suggest that the dorsal striatum, but not (or not so much) the ventral striatum, is driving the flexible control of retrieval of stimulus–response episodes.

Highlights

► Updating of stimulus–response bindings relies on dopamine. ► PD patients update more efficiently OFF medication than ON medication. ► Dorsal striatum drives the updating of stimulus–response bindings.

Introduction

The primate cortex represents the features of perceptual events as well as actions associated with these events in distinct, but tightly connected, brain regions [1], [2]. The temporal binding of neural codes associated with perceptual features and actions offers a mechanism for integrating distinct features into more meaningful and complex events [3]. Studies of repetition effects offer some of the most compelling empirical evidence for the existence of mechanisms that bind features into more complex events. For instance, participants respond faster to letters presented in a previous display than to novel letters (a standard priming or repetition effect), and reactions are even faster if the repeated letter also appears in the same location as in the previous display [4]. This suggests that processing a letter appearing in a particular location induces a binding between the codes that represent the letter's shape and location (an “object file” in the terms of Kahneman and colleagues), so that repeating this exact conjunction of features enhances the efficiency of processing the stimulus event. Binding as an essential mechanism for constructing perceptual events is also illustrated by repetition effects that impede performance. When a subsequent event consists of only a partial repetition of features from the previous display, conflict results from the mismatch between the previously bound features and the current novel combination of features. In this situation, the automatic retrieval of bound features from the initial display must be reconfigured and updated to accommodate the novel binding of features in the present display, a process that slows response times and increases the potential for decision errors [5], [6], [7].

Repetition effects attributable to feature binding have been observed within and across various sensory/perceptual modalities as well as for perceptual and action features [8], [9], [10], [11]. Regarding the latter, performance speed and accuracy are compromised if a stimulus feature repeats while the response changes, or if the response repeats while the stimulus feature changes, than if both stimulus and response repeat or if both alternate [11]. This suggests that the binding and integration of features spans codes representing perceived events, such as stimuli, and produced events, such as performed actions [12]. The present study focused on stimulus–response binding mechanisms that integrate stimulus and response features into complex events and on how the after-effects of stimulus–response binding affect performance.

Of particular relevance for the present study, there is evidence suggesting that the retrieval of stimulus–response bindings is mediated by dopaminergic pathways. Very recently we are able to demonstrate that genetic markers of striatal dopamine level, dopamine transporter gene (DAT1) gene, predict individual differences in the efficiency of updating stimulus-response episodes [13]. The performance of 9-repeat carriers of the DAT1 gene was more hampered by partial mismatches between present and previous stimulus–response relations compared to the performance of 10/10 homozygotes.

Section snippets

Purpose of study

The finding that the efficiency of updating stimulus–response bindings is predicted by genes related to striatal dopamine suggests that the striatum plays an important role in the control of the retrieval of such bindings. At the same time, however, it leaves open which particular subcomponent of the striatum is responsible. The present study aimed at distinguishing, even though in an indirect way, between two possible candidates: the ventral (i.e. nucleus accumbens, ventral putamen and

Participants

Eleven PD patients treated with anti-parkinsonian medication (l-DOPA and DA agonist) served as participants in the PD group, see Table 1 for the demographic characteristics. Patients with a mini-mental state examination (MMSE [24]) score lower than 25, history of major psychiatric disorders, psychoactive medication, alcoholism, stroke, neurosurgical operation or any other condition known to impair mental status other than PD were excluded. Fourteen healthy participants (9 males, 5 females),

Results

After excluding trials with missing (>2000 ms) or anticipatory responses (<200 ms), mean reaction times (RTs) and proportions of errors (PEs) for R2 were analyzed. Table 1 provides an overview of the ANOVA outcomes for RTs and PEs obtained for R2.

Conclusions

Our findings show that the after-effects of stimulus–response feature integration are modulated by dopaminergic medication in PD patients. This fits with previous suggestions that the control of retrieval of stimulus–response episodes is predicted by genetic predispositions related to striatal dopamine [13]. More specifically, the pattern of our findings are more consistent with predictions based on the hypothesized ameliorative effects of the dorsal striatum as a result of dopamine replacement

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