Levodopa and the feedback process on set-shifting in Parkinson's disease

Abstract

Objective: To study the interaction between levodopa and the feedback process on set-shifting in Parkinson's disease (PD).

Methods: Functional magnetic resonance imaging (fMRI) studies were performed on 13 PD subjects and 17 age-matched healthy controls while they performed a modified card-sorting task. Experimental time periods were defined based on the types of feedback provided. PD subjects underwent the fMRI experiment twice, once during "off" medication (PDoff) and again after levodopa replacement (PDon).

Results: Compared with normal subjects, the cognitive processing times were prolonged in PDoff but not in PDon subjects during learning through positive outcomes. The ability to set-shift through negative outcomes was not affected in PD subjects, even when "off" medication. Intergroup comparisons showed the lateral prefrontal cortex was deactivated in PDoff subjects during positive feedback learning, especially following internal feedback cues. The cortical activations were increased in the posterior brain regions in PDoff subjects following external feedback learning, especially when negative feedback cues were provided. Levodopa replacement did not completely restore the activation patterns in PD subjects to normal although activations in the corticostriatal loops were restored.

Conclusion: PD subjects showed differential ability to set-shift, depending on the dopamine status as well as the types of feedback cues provided. PD subjects had difficulty performing set-shift tasks through positive outcomes when "off" medication, and showed improvement after levodopa replacement. The ability to set-shift through negative feedback was not affected in PD subjects even when "off" medication, possibly due to compensatory changes outside the nigrostriatal dopaminergic pathway.

Figure 1

Modified Card Sorting Task (MCST). Subjects were asked to match the stimulus card at the bottom of the computer screen to one of the four index cards displayed in the top half of the screen. The sorting principle was derived from a comparison of attributes (color, number, or shape) between the stimulus and index cards. Only the control condition blocks were shown in this figure, where an exact match existed between the stimulus and one of the index cards. In the continuous shift blocks (not shown in this figure), the stimulus card contained only one attribute shared with one of the four index cards. The matching attributes of consecutive trials varied in a random order, such that a shift was implicitly given by the task. In the MCST trials, external feedback was not provided after a response was made. Subjects had to perform the tasks through implicit or internal learning without external feedback guidance. In MCST‐F trials, external feedback was provided after each response. A green tick was displayed when the response was correct, and a red cross was shown when the response was incorrect. All error trials were removed from the fMRI analysis (e.g., trial number 3). Four experimental time periods were defined for the remaining correct trials: (1) MCST‐PF, correct trials just after receiving a positive external feedback, (2) MCST‐NF, correct trials just after receiving a negative external feedback, (3) MCST‐CR, correct trials just after a correct response was made in MCST trials, and (4) MCST‐IR, correct trials just after an incorrect response was made in MCST trials.

Figure 2

Age‐adjusted upper limb motor performance index amongst PD and healthy subjects. Normal, healthy subjects; PDoff, PD subjects during “off” medication, PDon, PD subjects after levodopa replacement. Error bar = Standard Error of Mean (SEM).

Figure 3

Response times to make a correct trial following (A) positive reinforcement (MCST‐CR, MCST‐PF), and (B) negative reinforcement (MCST‐IR, MCST‐NF). Asterisks (*, **, ***) denote significance level at P < 0.05, P < 0.01, and P < 0.001 respectively. Error bar = Standard Error of Mean (SEM).

Figure 4

Intergroup comparisons of fMRI activation patterns in (A) MCST‐CR, and (B) MCST‐NF. A: Deactivations were noted in the right DLPFC in the hypodopaminergic state during MCST‐CR. Compared with normal subjects, the deactivations were greater in PDoff (t = 4.16, P < 0.0001) than in PDon subjects (t = 3.71, P < 0.0001). B: In MCST‐NF, greater activations were observed in the PDoff group compared to normal subjects in the caudate nucleus and posterior brain regions, without activating the DLPFC. On the other hand, greater activations were observed in the PDon group compared to normal subjects in the DLPFC, without caudate activations. Both PDoff and PDon groups showed deactivations in the cingulate cortex, supramarginal gyrus, and inferior temporal gyrus, when compared with normal subjects. The significance values are given as color‐coded t‐statistics.