Dopaminergic medication reduces striatal sensitivity to negative outcomes in Parkinson’s disease

Abstract

Reduced levels of dopamine in Parkinson's disease (PD) contribute to changes in learning, resulting from the loss of midbrain dopamine neurons that transmit a teaching signal to the striatum. Dopamine medication used by PD patients has previously been linked to either behavioral changes during learning itself or adjustments in approach and avoidance behavior after learning. To date, however, very little is known about the specific relationship between dopaminergic medication-driven differences during learning and subsequent changes in approach/avoidance tendencies in individual patients. We assessed 24 PD patients on and off dopaminergic medication and 24 healthy controls (HC) performing a probabilistic reinforcement learning task, while undergoing functional magnetic resonance imaging.During learning, medication in PD reduced an overemphasis on negative outcomes. When patients were on medication, learning rates were lower for negative (but not positive) outcomes and concurrent striatal BOLD responses showed reduced prediction error sensitivity. Medication-induced shifts in negative learning rates were predictive of changes in approach/avoidance choice patterns after learning, and these changes were accompanied by striatal BOLD response alterations. These findings highlight dopaminedriven learning differences in PD and provide new insight into how changes in learning impact the transfer of learned value to approach/avoidance responses in novel contexts.

Attention and reinforcement learning in Parkinson’s disease

“…Full details are provided elsewhere (see Supplementary Materials in 37). One notable difference between the analysis described here and that described in [37] is that data were unsmoothed for the current MVPA procedure.…”

“…To quantify the distinct contribution of distractibility on learning, we carried out a mixed effects logistic regression on all trial-by-trial learning data. A similar analysis has previously been carried out on this data [37], however here we also include distractibility, along with stimulus pair (AB, CD, or EF), medication and disease status, to address our specific research questions (see Supplementary Eq. 2).…”

“…PD patients suffer from a depletion of dopaminergic neurons, leading not only to the motor deficits characteristic of the disease, but also to changes in cognitive functioning, such as learning from feedback [35,36,37]. Replacement dopamine medication in patients has proven beneficial for certain cognitive processes, such as attentional switching [4,38], but dopaminerelated impairments have been observed in learning contexts [35].…”

“…Replacement dopamine medication in patients has proven beneficial for certain cognitive processes, such as attentional switching [4,38], but dopaminerelated impairments have been observed in learning contexts [35]. Much research suggests that these impairments are driven by reduced learning from negative outcomes when patients are on compared to off medication [1,35,37,39,40], although other studies also report medicationrelated differences in learning from positive outcomes [41,42,43]. Overall, there is general consensus that increased dopamine levels by medication in PD leads to a positivity bias [37,44,45].…”

“…Much research suggests that these impairments are driven by reduced learning from negative outcomes when patients are on compared to off medication [1,35,37,39,40], although other studies also report medicationrelated differences in learning from positive outcomes [41,42,43]. Overall, there is general consensus that increased dopamine levels by medication in PD leads to a positivity bias [37,44,45]. A recent study in PD patients showed that when off dopaminergic medication, patients showed greater distractibility than healthy controls [46].…”