Action Reprogramming in Parkinson's Disease: Response to Prediction Error Is Modulated by Levels of Dopamine

Abstract

Humans are able to use knowledge of previous events to estimate the probability of future actions. Consequently, an unexpected event will elicit a prediction error as the prepared action has to be replaced by an unprepared option in a process known as "action reprogramming" (AR). Here we show that people with Parkinson's disease (PD) have a dopamine-sensitive deficit in AR that is proportional to the size of the prediction error. Participants performed a probabilistic reaction time (RT) task in the context of either a predictable or unpredictable environment. For an overall predictable sequence, PD patients, on and off dopamine medication, and healthy controls showed similar improvements in RT. However, in the context of a generally predictable sequence, PD patients off medication were impaired in reacting to unexpected events that elicit large prediction errors and require AR. Critically, this deficit in AR was modulated by the prediction error associated with the upcoming event. The prolongation of RT was not observed during an overall unpredictable sequence, in which relatively unexpected events evoke little prediction error and the requirement for AR should be minimal, given the context. The data are compatible with recent theoretical accounts suggesting that levels of dopamine encode the reliability, i.e., precision, of sensory information. In this scheme, PD patients off medication have low dopamine levels and may therefore be less confident about incoming sensory information and more reliant on top-down predictions. Consequently, when these internal predictions are incorrect, PD patients take longer to respond appropriately to unexpected sensory information.

Dopaminergic medication increases reliance on current information in Parkinson’s disease

“…This effect was strongest in early-stage PD patients, who have a more specific localized loss of dopaminergic neurons in the putamen. These results are in accordance with theories suggesting that dopamine affects the relative weight given to current bottom-up sensory evidence (likelihood) vs. top-down priors10,18,19, and indicate that dopaminergic medication (and potentially dopamine itself) can increase the relative weight given to current information.…”

Pharmacological Fingerprints of Contextual Uncertainty

“…The RT data were log transformed [58]. To assess the interaction between stimulus transition probability and drug, trials were binned according to three probability levels corresponding to the presented stimuli’s true conditional probabilities as existed in the TMs (High: 0.85 and 0.70; Mid: 0.25 and 0.20; Low: 0.05) [58,59]. Mean log(RTs) for each participant’s correct responses were compared across these three probability levels and between drug groups.…”

“…The first response model contained the following parameters: δ 1 (sensory PE), because of evidence that DA sensitises motor responses to low-level PE [58,59]; ε 3 (precision-weighted contingency PE), which has been shown to correlate with activity in the cholinergic basal forebrain [15]; and μ 3 (estimated phasic volatility), which is relevant to cognitive switching tasks for which there is a proposed role for DA. For each parameter, the quantity relates to the stimulus transition that actually occurred on each trial.…”

“…An additional mechanism is required to modify action selection based on one’s own beliefs about the latent changes in the environment and/or the occurrence of unexpected events. Indeed, when an unexpected event occurs, humans are capable of engaging resources to inhibit a prepared response and replace it with an alternative [56,57], albeit at the expense of a prolonged reaction time (RT) [58,59]. …”

“…Dopaminergic deficits due to Parkinson’s disease are associated with specific flexibility impairments in both motor [59,65] and cognitive domains [60,66], with performance restored by dopaminergic medication [59,67]. In healthy individuals, pharmacological DA depletions impair adaptive reactions to unexpected events occurring within a broadly predictable context [58].…”