Motivation, reward, and Parkinson’s disease: influence of dopatherapy

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Abstract

“Orbitofrontal” and “cingulate” striatofrontal loops and the mesolimbic dopaminergic system that modulates their function have been implicated in motivation and sensitivity to reinforcement in animals. Parkinson’s disease (PD) provides a model to assess their implications in humans. The aims of the study were to investigate motivation and sensitivity to reinforcement in non-demented and -depressed PD patients and to evaluate the influence of dopaminergic therapy by comparing patients in “on” (with l-Dopa) and “off” (without l-Dopa) states. Twenty-three PD patients were compared, in both the “on” and “off” states, to 28 controls, using: (1) an Apathy Scale; (2) Stimulus–Reward Learning, Reversal, and Extinction tasks; and (3) a Gambling task. PD patients were found: (1) mildly apathetic; (2) impaired on Stimulus–Reward Learning and Reversal, but not on Extinction; and (3) able to progress in the Gambling task during the first, but not the second assessment. There was no significant correlation between these various deficits. l-Dopa treatment clearly improved motivation, but had more limited and contrasting effects on other variables, decreasing the number of omission errors in Reversal, but increasing the number of perseveration errors in Extinction. These results suggest: (1) an implication of striatofrontal loops in human motivation and explicit and implicit sensitivity to reinforcement; (2) a positive influence of l-Dopa treatment on the subjective evaluation of motivation, but contrasting effects on reward sensitivity.

Introduction

Motivation is a conscious or unconscious internal state, which incites the subject to act [28]. It influences all stages of behavioural planning: determination of aim, selection and elaboration of responses, and evaluation of consequences of action. Conversely, motivation and planning are affected by the ability to identify the behavioural relevance and the reinforcing value of environmental stimuli and to take into account the difference between the anticipated and the obtained reward. Motivation and sensitivity to reinforcement are therefore central processes for adaptive orientation of behaviour. According to Rolls [40], “computing the reward and punishment value of sensory stimuli, and then using selection between different rewards and avoidance of punishments in a common reward-based currency appears to be the fundamental solution that the brain uses in order to produce appropriate behaviour”.

This computation may be explicit when the rule is clear and the same reward is regularly associated to the same stimulus, as in Stimulus–Reward Learning. When subjects have explicitly learned the stimulus–reward association, the reward contingencies may be unexpectedly reversed (Reversal), or extinguished (Extinction) [41]. The ability to reverse the stimulus–reward–response association suggests a form of “sensitivity to reward” flexibility [11], whereas the ability to withhold a response is related to control of impulsiveness [41].

In real life, however, outcomes in terms of reward or punishment are more uncertain. Bechara et al. [3], [4] designed a task, so called the Gambling task, which resembles the decisions made in real life. The task includes four decks of cards, two of them being disadvantageous (high gains and unpredictable higher penalties), whereas the other two are advantageous (small immediate gains and lower penalties). Normal subjects progressively learn to choose the advantageous decks. This behaviour is largely implicit, since bias toward the selection of advantageous choices occurs before the subject becomes aware of the goodness or badness of his or her choice, and a great proportion of normal controls do not reach awareness [6].

Animal studies implicate limbic structures (amygdala and orbitofrontal cortex) in motivation, reinforcement associated learning, “sensitivity to reward” flexibility, and control of impulsiveness [40], [48]. The ventral striatum, which connects the limbic and frontal executive systems via the “orbitofrontal” and “cingulate” loops, [2] is also involved. In addition, the mesolimbic and the nigrostriatal dopaminergic systems, which modulate the activity of these loops, intervene in signalling changes or errors in the prediction of rewarding events [43]. In humans, reinforcement associated learning, “sensitivity to reward” flexibility, and control of impulsiveness have been shown to be impaired by orbitofrontal lesions [3], [41], whereas apathy or loss of motivation, in the absence of depression, has been observed in cases of lesions of basal ganglia [16], [24], [26]. Is apathy related to decreased sensitivity to reinforcement? Are the striatofrontal loops involved in reinforcement associated learning in humans? Does dopamine intervene in “sensitivity to reward” flexibility? Parkinson’s disease (PD), which alters the mesocorticolimbic dopaminergic system [21], [33] and consequently impairs the function of “orbitofrontal” and “cingulate” loops [1], [10], may help to answer these questions. Indeed, apathy has been observed in PD and might worsen the cognitive and behavioural difficulties of these patients [25], [45].

The aims of the study were to investigate motivation and sensitivity to reinforcement in non-demented and -depressed PD patients and to evaluate the influence of dopaminergic therapy comparing patients in “on” (with l-Dopa) and “off” (without l-Dopa) states.

Section snippets

Subjects

Thirty patients hospitalised in the Neurology Department of the Salpetriere Hospital for therapeutic equilibration or for candidature for subthalamic nucleus deep brain stimulation were recruited for the study. Inclusion criteria were idiopathic PD [20], persistence of a good reactivity to l-Dopa, lack of dementia (score >130 on the Mattis Dementia Rating Scale) [29] or depression (score <20 on the Montgomery and Asberg Depression Rating Scale (MADRS)) [30], ability to be tested not only in the

Motivation

Global ANOVA showed no repetition effect on the Apathy Scale [F(1,48)=0.025; P=0.88], but did show a group effect [F(2,48)=5.65; P=0.006] and an interaction between group and repetition [F(2,48)=8.32; P=0.0008]. Post-hoc analysis of the group effect showed that “On-first” patients (P=0.027) and “Off-first” patients (P<0.0001) differed from controls, but not one from another (P=0.13). Apathy was therefore similar in both groups of patients and more severe in patients than in controls. Post-hoc

Discussion

Several experimental variables were impaired in patients with PD. Their score on the Apathy Scale was higher than in control subjects, confirming that apathy may be observed in PD, even in non-demented and -depressed patients. Apathy was mild, since the mean score for patients was lower than the cut-off pathological score of 14. However, three patients in the “On-first” subgroup and six patients in the “Off-first” subgroup had pathological scores, comprising 39% of patients. This percentage is

Acknowledgements

INSERM and Assistance Publique supported the study. Dr. A. Bechara kindly provided us with the computerised version of his Gambling task. Dr. A.M. Bonnet and the nurses of the Centre d’Investigation Clinique and Federation de Neurologie are thanked for their contribution. Leon Tremblay gave us helpful comments. Nikki Horne revised the English.

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