Full-length ArticleAberrant reward processing in Parkinson's disease is associated with dopamine cell loss
Introduction
Dopamine has long been implicated in reward motivation and impulsivity. However, the precise nature of the relationship between dopamine, reward and impulsivity remains unclear. Here we address this issue by assessing reward processing in Parkinson's disease (PD), a neurodegenerative disorder characterized by severe dopamine loss. PD can be accompanied by compulsive drug taking (i.e., dopamine dysregulation syndrome) and/or impulse control problems, such as pathological gambling, compulsive shopping, and hyper-sexuality (Evans et al., 2009, Voon et al., 2011, Weintraub et al., 2010). According to recent understanding, such impulsive–compulsive behavior may result from the common dopaminergic medication that is prescribed to treat the motor and cognitive symptoms of PD, such as the D2/3 receptor agonists and levodopa (Gallagher et al., 2007, Pontone et al., 2006, Weintraub et al., 2010). In particular, we and others have put forward the dopamine overdose hypothesis, stating that medication doses that are necessary to remedy severe dopamine depletion in the dorsal striatum might detrimentally overdose relatively intact dopamine levels in the ventral striatum (Cools et al., 2001a, Cools et al., 2003, Cools et al., 2007a, Swainson et al., 2000). Remediation of dorsal striatal dopamine would lead to restoration of motor and cognitive inflexibility, whereas overdosing of ventral striatal dopamine would contribute to aberrant reward sensitivity and impulsivity. This theory concurs with the implication of dopamine in reward and incentive motivation (Dagher and Robbins, 2009), and with the well-known dopamine-releasing properties of drugs and other rewards of abuse (Boileau et al., 2006, Di Chiara and Imperato, 1988, Leyton et al., 2002).
However, factors unrelated to medication have also been implicated in aberrant reward sensitivity and impulsivity in PD, for instance premorbid personality and genetic vulnerability (Dagher and Robbins, 2009, Evans et al., 2009). Furthermore, in apparent contradiction to the overdose hypothesis, trait impulsivity has been associated with low dopamine function (Buckholtz et al., 2010, Cools et al., 2007b, Dalley et al., 2007). Specifically, pathological gambling and other addictions have been hypothesized to reflect self-medication of a reward-deficient state (Blum et al., 2000, Reuter et al., 2005). If true, then the aberrant impact of reward in PD might be related, at least in part, to degeneration of dopamine cells. This implies that the dopamine-depleted state of PD should be accompanied not only by motor and cognitive inflexibility, but also by aberrant impact of reward.
Here we investigated associations between, on the one hand, cognitive inflexibility and reward impact, and on the other hand, the degree of dopamine cell loss of mild PD patients. Cognitive inflexibility was anticipated to be positively associated with dopamine cell loss. Furthermore, aberrant reward impact was hypothesized to be greatest in patients with the greatest dopamine cell loss. To test this hypothesis, dopamine cell loss was quantified using pre-synaptic dopamine transporter (DaT) imaging with 123I-FP-CIT Single Photon Emission Computed Tomography (SPECT). Patients performed a behavioral task that allowed us to quantify cognitive inflexibility as well as the impact of reward. Specifically, we used a task-switching paradigm where each trial was preceded by either a high or low reward cue (Aarts et al., 2010). Cognitive inflexibility was indexed by the ability to switch between tasks under low reward. Previous task-set switching studies in PD have found that switch deficits were restricted to switching between well-established sets, and did not extend to new, to-be-learned sets (Cools et al., 2001b, Lewis et al., 2005, Slabosz et al., 2006). Because the best established task (here, the arrow task) is known to evoke larger switch costs than the least established task (here, the word task) (Wylie and Allport, 2000), we expected cognitive inflexibility in PD to be most pronounced in the arrow task.
Section snippets
Participants
We included 32 early- to moderate-stage PD patients (withdrawn from their dopaminergic medication or never medicated) and 26 matched controls (Table 1). All participants gave written informed consent according to institutional guidelines of the local ethics committee (CMO region Arnhem-Nijmegen, The Netherlands). All participants were native Dutch speakers. They were paid for participation according to institutional guidelines. 31 PD patients were included in the SPECT analyses, because DaT
Patients: regional DaT binding
Consistent with prior evidence (Kish et al., 1988), analyses of DaT binding in the different striatal sub-regions demonstrated a spatial gradient, with DaT reduction being highest in the posterior putamen, followed by the anterior putamen, the caudate nucleus, and the nucleus accumbens (Fig. 2A–C and Supplement 2b). In line with these and previous results (Brooks and Piccini, 2006, Spiegel et al., 2007), we found that DaT binding in the posterior putamen predicted disease severity (Fig. 2D),
Discussion
The present data show that the impact of reward on cognitive performance in non-medicated PD patients is predicted by reduced DaT binding, likely reflecting severe dopamine cell loss. In particular, we demonstrate that lower DaT binding in the most affected striatal sub-region, posterior putamen, is associated not only with greater disease severity and greater cognitive inflexibility (for a review, see Cools, 2006), but also with greater (beneficial as well as detrimental) impact of reward.
Conclusions
Dopamine depletion in PD is accompanied by both cognitive inflexibility (on low reward trials) as well as aberrant impact of reward. The finding that aberrant reward processing in PD is proportional to dopamine cell loss suggests that a low baseline dopamine state contributes to impulsive–compulsive behavior. Here, reward-related impulsivity was associated with detrimental effects of anticipated reward on the persistence of current task representations, but beneficial effects on task-switching.
Acknowledgments
This work was supported by a fellowship of the Hersenstichting Nederland to support dementia research to R.C. (F2008 (1)-01), a VIDI grant of The Netherlands Organisation for Scientific Research (NWO) to R.C. (016.095.340), the Niels Stensen foundation to E.A., the Alkemade–Keuls foundation to B.R.B and a VIDI grant of The Netherlands Organisation for Scientific Research (NWO) to B.R.B. (91776352). The funding sources had no involvement in acquisition, analysis, interpretation, or reporting of
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Authors contributed equally to this work.