On the role of dopamine replacement therapy in decision-making, working memory, and reward in Parkinson’s disease: Does the therapy-dose matter?
Introduction
Parkinson’s disease (PD) is characterized by a loss of dopamine (DA) containing neurons in the substantia nigra (SN) pars compacta, which projects to the striatum. In early PD, DA depletion is restricted to the putamen and dorsal caudate nucleus, only later progressing to the more ventral parts of the striatum as well as the mesocorticolimbic DA system (Agid et al., 1993, Kish et al., 1988).
Dopamine replacement therapy (DRT) proved to ameliorate motor deficits in PD, but depending on the fronto-striatal circuit (dorsal or ventral), cognitive function, nature of the task, basal level of DA, evolution of the disease and motor response to levodopa, it can both improve and impair the performance (Cools et al., 2001, Cools et al., 2003, Kulisevsky, 2000, Kulisevsky et al., 1996, Kulisevsky et al., 2007, Robbins, 2005). In fact, DRT ameliorates the tasks associated with the dorsal fronto-striatal circuitry (Sohn, Ursu, Anderson, Stenger, & Carter, 2000) but impairs those relying on the ventral fronto-striatal pathways (Cools, Clark, Owen, & Robbins, 2002). The fact that DRT acts differentially on such circuits has been explained in terms of an “overdose theory”. Such “overdose theory” was originally advanced by Gotham, Brown, and Marsden (1988) to explain impairments in tests of conditional associative learning and self-ordered pointing in a memory paradigm when patients were On medication. In contrast, impaired performance Off medication on a verbal fluency task was normalized by the reintroduction of dopaminergic medication. Gotham and colleagues suggested that an imbalance of dopamine levels in different cognitive systems, relying on different areas of prefrontal cortex may underlie their results. Swainson et al. (2000) added evidence to the original hypothesis confirming the presence of the imbalance. In fact, as underlined by the authors, a dopamine depletion severe enough to produce functional deficits may be present in all regions of the putamen and only in the most dorsal, rostral aspects of the head of the caudate nucleus. This impairment would affect the motor and dorsolateral prefrontal loops. Medication would bring DA levels to the optimum resulting in beneficial effects to motor control and some cognitive abilities such as set-shifting. By contrast, introducing dopaminergic medication to the less affected ventromedial head and tail of the caudate nucleus (pars of the orbitofrontal and inferotemporal loops, respectively) may push the amount of dopaminergic activity above the optimal level impairing performance on tasks which utilize these circuits.
Cools and co-workers (2003) demonstrated in mild PD that such an effect was detectable in a task-switching paradigm (dorsal circuitry), which was improved by DRT and in a gambling task (ventral circuitry) where impulsivity augmented when patients were On medication (namely impaired by medication). Other studies (Czernecki et al., 2002) did not show a therapy effect on the Iowa Gambling Task (Bechara, Damasio, Damasio, & Anderson, 2000). The authors tested a group of advanced PD patients and, in a second session of the task, highlighted a pattern of behavior that was consistent with that of ventromedial prefrontal damaged patients, not different in the On and Off medication conditions and sub-optimal compared to normal volunteers. They interpreted such a lack of influence of DRT on the task, supported by the absence of differences in behavior from the On to the Off medication stage, as a failure of therapy in modifying the implicit learning of the prediction of rewarding events (guided by dopamine neurons) in a short-term period (Hollerman & Schultz, 1998). Furthermore, they suggested that the deleterious effect of the therapy on the mesocorticolimbic dopamine system could not account for the deficits in the Off medication state (Czernecki et al., 2002).
In the present study, we aimed to investigate the effects of therapy on decision-making and working memory tasks in a moderate to advanced PD population with motor fluctuations. Besides, in order to test whether the prospect of a monetary reward may enhance the cognitive performance, we introduced some rewarded trials in the working memory task.
The Cambridge Gamble Task (CGT) (Rogers et al., 1999) has been previously used in PD populations (Cools et al., 2003) and has proven to be sensitive to deficits produced by aneurysms of the anterior communicating artery which supplies blood to the medial and ventral prefrontal cortex (PFC) (Mavaddat, Kirkpatrick, Rogers, & Sahakian, 2000) to frontal lesions (Manes et al., 2002) and to insular and ventromedial prefrontal lesions (Clark et al., 2008). In addition, it has been employed to elucidate the decision-making behavior in patients with borderline personality disorders who show fronto-executive deficits (Bazanis et al., 2002, O’Leary et al., 1991).
Thus, our aim was threefold: it first concerned the possibility to investigate the effects of dopaminergic therapy on tasks investigating decision-making and working memory abilities in PD patients at a more severe stage of the illness as compared to those tested in the Cools’ and colleagues study (Cools et al., 2003) described before. Secondly, we aimed to investigate whether the beneficial or detrimental effects of therapy on the aforementioned tasks are dose-related. Finally, by introducing the prospect of an external monetary reward, we were interested in analyzing if dopaminergic therapy was able to sharpen the sensitivity to reward and, through this mechanism, to enhance thereby cognitive performance.
Section snippets
Subjects
The present study was carried out in accordance with the Declaration of Helsinki criteria and was approved by the Ethics Committee of the Department of Psychology, University of Turin. All of the participants gave their written informed consent.
Fifteen consecutive PD patients (13 men and 2 women) considered eligible for the deep brain stimulation of the subthalamic nucleus (DBS of STN) (Lanotte et al., 2002, Lopiano et al., 2002) and thirteen healthy volunteers (11 men and 2 women) fulfilled
Patients (On medication vs. Off medication condition)
A 2-way ANOVA using as between factors the “condition of task” (descending vs. ascending) and as a within factor the “treatment” (On vs. Off dopaminergic therapy) was carried out for the quality of the decision, impulsivity, risk adjustment, and deliberation times. A main effect of the treatment was noticed on the deliberation times (F(1, 13) = 5.037, p = 0.042), in that the patients were slower in selecting the color to choose when On medication. The quality of the decision, impulsivity, and risk
Discussion
This study was designed to address several issues: (1) to test the previous findings of a detrimental effect of therapy on some functions, such as impulsivity (Cools et al., 2003), at a more severe stage of illness, in fluctuating PD patients, (2) to investigate whether such an effect was present also in other cognitive domains, and (3) to elucidate whether the prospect of a reward was able to enhance cognitive performance, as demonstrated before in PD patients by means of reaction time tasks (
Acknowledgments
We would like to thank Dr. M. Rosso, Dr. A Cinquepalmi, and Dr. M. Pesare for their clinical help. The present study was funded by a CRT Foundation “Progetto Alfieri” Grant. All the authors state that they have no competing interests.
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