Focused stimulation of dorsal versus ventral subthalamic nucleus enhances action-outcome learning in patients with Parkinson's disease

Abstract

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the clinical motor symptoms of Parkinson's disease, but may alter the ability to learn contingencies between stimuli, actions and outcomes. We investigated how stimulation of the functional subregions in the subthalamic nucleus (motor and cognitive regions) modulates stimulus-action-outcome learning in Parkinson's disease patients. Twelve Parkinson's disease patients with deep brain stimulation of the subthalamic nucleus completed a probabilistic stimulus-action-outcome task while undergoing ventral and dorsal subthalamic nucleus stimulation (within subjects, order counterbalanced). The task orthogonalized action choice and outcome valence, which created four action-outcome learning conditions: action-reward, inhibit-reward, action-punishment avoidance and inhibit-punishment avoidance. We compared the effects of deep brain stimulation on learning rates across these conditions as well as on computed Pavlovian learning biases. Dorsal stimulation was associated with higher overall learning proficiency relative to ventral subthalamic nucleus stimulation. Compared to ventral stimulation, stimulating the dorsal subthalamic nucleus led to a particular advantage in learning to inhibit action to produce desired outcomes (gain reward or avoid punishment) as well as better learning proficiency across all conditions providing reward opportunities. The Pavlovian reward bias was reduced with dorsal relative to ventral subthalamic nucleus stimulation, which was reflected by improved inhibit-reward learning. Our results show that focused stimulation in the dorsal compared to the ventral subthalamic nucleus is relatively more favourable for learning action-outcome contingencies and reduces the Pavlovian bias that could lead to reward-driven behaviour. Considering the effects of deep brain stimulation of the subthalamic nucleus on learning and behaviour could be important when optimizing stimulation parameters to avoid side effects like impulsive reward-driven behaviour.

Keywords: action–outcome learning; deep brain stimulation; subthalamic nucleus.

Graphical Abstract

Figure 1

Individual electrode positions in subthalamic nucleus (STN) used for dorsal (blue) and ventral (red) stimulation in (A) sagittal (enlarged and overview), (B) coronal planes (enlarged and overview) and (C) average electrode position in coronal plane and (D) individual electrodes in axial plane. Substantia nigra (structure below STN) and thalamus (structure above STN) are displayed for reference. Electrode volumes represent the estimated VTA radius, i.e. based on Butson and McIntyre, the projected volume of tissue activation with 0.4 mA, 130 Hz and 60 ms (with an average clinical impedance of 1 kΩ) would result in a VTA radius of ∼1.3 mm.

Figure 2

(A) Estimated probability of a correct response by learning condition and DBS. Lines within the bars reflect 95% confidence intervals. Connected dots next to the bars show individual variability in performance with dorsal and ventral stimulation for each condition. (B) Estimated probability of a correct response between conditions with significant differences (action, STN subregion, valence and interaction effects between action and STN subregion and between valence and STN subregion) based on GLM (OR > 1.65, ts > 2.38, ps < 0.05). *P < 0.05; **P < 0.01.

Figure 3

Trial-by-trial probability that a participant responds with an action for each action–valence condition separated by DBS of the STN site. (A) Action–reward. (B) Action–avoid punishment. (C) Inhibition–reward. The GLM showed improved inhibition–reward with dorsal versus ventral DBS (OR = 2.49, t = 2.6, P < 0.05). (D) Inhibition–avoid punishment. Note that when learning takes place, the probability to act across trials is expected be high at the end of the 40 trials for the action conditions (A and B) and expected to be low at the end of the 40 trials for the inhibition learning conditions (C and D).

Figure 4

Average RTs (ms) for action trials separated by stimulation site and outcome. Overall, performance was faster with the trials that had a rewarding outcome, as shown by the RM-ANOVA [F(1,11) = 11.33, P < 0.01]. Connected dots next to the bars show individual variability in performance with dorsal and ventral stimulation for each condition. **P < 0.01.

Figure 5

Average Pavlovian bias separated by stimulation site and outcome. Ventral stimulation resulted in a larger Pavlovian reward bias relative to dorsal stimulation. Connected dots next to the bars show individual variability in performance with dorsal and ventral stimulation for each bias. Note that removal of the outlier in the ventral reward bias does not change the effect of subregion stimulation, i.e. the reward bias remains significantly larger with ventral than the dorsal DBS (Wilcoxon signed rank = 2.43, P = 0.02). *P < 0.05.