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Parkinson's disease is characterized by the degeneration of dopaminergic pathways projecting to the striatum. These pathways are implicated in reward prediction. In this study, we investigated reward and punishment processing in young, never-medicated Parkinson's disease patients, recently medicated patients receiving the dopamine receptor agonists pramipexole and ropinirole and healthy controls. The never-medicated patients were also re-evaluated after 12 weeks of treatment with dopamine agonists. Reward and punishment processing was assessed by a feedback-based probabilistic classification task. Personality characteristics were measured by the temperament and character inventory. Results revealed that never-medicated patients with Parkinson's disease showed selective deficits on reward processing and novelty seeking, which were remediated by dopamine agonists. These medications disrupted punishment processing. In addition, dopamine agonists increased the correlation between reward processing and novelty seeking, whereas these drugs decreased the correlation between punishment processing and harm avoidance. Our finding that dopamine agonist administration in young patients with Parkinson's disease resulted in increased novelty seeking, enhanced reward processing, and decreased punishment processing may shed light on the cognitive and personality bases of the impulse control disorders, which arise as side-effects of dopamine agonist therapy in some Parkinson's disease patients.

Clinical reports, primarily with Parkinson’s patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats’ impulsive choices where impulsivity was defined as selecting a smaller-sooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats’ choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 & 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2; i.e., multiple discriminations between changing delays within each session.

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.

Objective:

Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls).

Methods:

Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2 15O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback.

Results:

We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity.

Conclusions:

We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions—outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)—together with restricted access of those areas to executive control (external pallidum)—may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.

GLOSSARY

= analysis of variance;

= dopamine agonist;

= Gambling Symptom Assessment Scale;

= external pallidum;

= Montréal Neurological Institute;

= orbitofrontal cortex;

= Parkinson disease;

= regional cerebral blood flow;

= rostral cingulated zone;

= Unified Parkinson's Disease Rating Scale.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

The use of D2/D3 dopaminergic agonists in Parkinson's disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system.

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.

The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson's disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Rationale

The dopaminergic system, particularly D2-like dopamine receptors, has been strongly implicated in reward processing. Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans.

Objectives

To evaluate the effect of a single, low dose of a D2/D3 agonist—pramipexole—on reinforcement learning in healthy adults. Based on prior evidence indicating that low doses of DA agonists decrease phasic DA release through autoreceptor stimulation, we hypothesized that 0.5 mg of pramipexole would impair reward learning due to presynaptic mechanisms.

Methods

Using a double-blind design, a single 0.5 mg dose of pramipexole or placebo was administered to 32 healthy volunteers, who performed a probabilistic reward task involving a differential reinforcement schedule as well as various control tasks.

Results

As hypothesized, response bias toward the more frequently rewarded stimulus was impaired in the pramipexole group, even after adjusting for transient adverse effects. In addition, the pramipexole group showed reaction time and motor speed slowing and increased negative affect; however, when adverse physical side effects were considered, group differences in motor speed and negative affect disappeared.

Conclusions

These findings show that a single low dose of pramipexole impaired the acquisition of reward-related behavior in healthy participants, and they are consistent with prior evidence suggesting that phasic DA signaling is required to reinforce actions leading to reward. The potential implications of the present findings to psychiatric conditions, including depression and impulse control disorders related to addiction, are discussed.

Background

Reward value and uncertainty are represented by dopamine neurons in monkeys by distinct phasic and tonic firing rates. Knowledge about the underlying differential dopaminergic pathways is crucial for a better understanding of dopamine-related processes. Using functional magnetic resonance blood-oxygen level dependent (BOLD) imaging we analyzed brain activation in 15 healthy, male subjects performing a gambling task, upon expectation of potential monetary rewards at different reward values and levels of uncertainty.

Results

Consistent with previous studies, ventral striatal activation was related to both reward magnitudes and values. Activation in medial and lateral orbitofrontal brain areas was best predicted by reward uncertainty. Moreover, late BOLD responses relative to trial onset were due to expectation of different reward values and likely to represent phasic dopaminergic signaling. Early BOLD responses were due to different levels of reward uncertainty and likely to represent tonic dopaminergic signals.

Conclusions

We conclude that differential dopaminergic signaling as revealed in animal studies is not only represented locally by involvement of distinct brain regions but also by distinct BOLD signal characteristics.

Background

The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward and pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A(GABAA)-mediated inhibition in motor cortex, measured by paired transcranial magnetic stimulation (TMS), changes with expectation and uncertainty of money rewards generated by a slot machine simulation.

Methods

We examined the role of dopamine in this phenomenon by testing 13 mildly affected Parkinson disease patients, off and on dopaminergic medications, and 13 healthy, age-matched controls.

Results

Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired TMS in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired TMS response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired TMS response amplitude during low expectation.

Conclusions

These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that physiological states in the motor cortex are associated with levels of risk-taking behavior in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment.

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus–reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus–reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus–reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's Disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly Dopamine Agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n=22) and without (n=19) active ICD symptoms. Patients performed the task both ‘on’ and ‘off’ DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their ability to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients.

This article reviews the role of an extended-release formulation of pramipexole in the treatment of Parkinson’s disease at an early stage. Pramipexole is a nonergot D2/D3 synthetic aminobenzothiazole derivative that is effective as monotherapy in early disease and as an adjunct to levodopa in patients with motor fluctuations. Although levodopa is the current “gold standard” for treatment of Parkinson’s disease, its effectiveness fades rapidly and its use results in serious motor fluctuations (on-off, wearing-off, freezing, involuntary movements) for most patients with the disease. Pramipexole has selective actions at dopamine receptors belonging to the D2 subfamily, where it possesses full activity similar to dopamine itself. Its preferential affinity for the D3 receptor subtype could contribute to its efficacy in the treatment of both the motor and psychiatric symptoms of Parkinson’s disease. The best approach to medical management of early Parkinson’s disease remains controversial. While enormous progress has been made in the treatment of the disease, challenges still remain. A variety of treatment-related and patient-related factors must be taken into account when making these decisions. The current approach to treatment of early Parkinson’s disease depends in part on individual patient factors, including age, severity and nature of symptoms and their impact, presence of cognitive dysfunction, possible underlying behavioral factors predisposing to impulse control disorders, and other comorbidities. Today, the once-daily extended-release formulation of pramipexole offers the advantages of easy continuous delivery of drug and convenience to patients, particularly early in the disease when monotherapy is the rule. Thus, a new “levodopa-sparing” paradigm for treating Parkinson’s disease may now be possible, whereby patients are initially treated with pramipexole and levodopa is added only as necessary.

Animal findings have highlighted the modulatory role of phasic dopamine (DA) signaling in incentive learning, particularly in the acquisition of reward-related behavior. In humans, these processes remain largely unknown. In a recent study we demonstrated that a single low dose of a D2/D3 agonist (pramipexole) – assumed to activate DA autoreceptors and thus reduce phasic DA bursts – impaired reward learning in healthy subjects performing a probabilistic reward task. The purpose of the present study was to extend these behavioral findings using event-related potentials and computational modeling. Compared to the placebo group, participants receiving pramipexole showed increased feedback-related negativity to probabilistic rewards and decreased activation in dorsal anterior cingulate regions previously implicated in integrating reinforcement history over time. Additionally, findings of blunted reward learning in participants receiving pramipexole were simulated by reduced presynaptic DA signaling in response to reward in a neural network model of striatal-cortical function. These preliminary findings offer important insights on the role of phasic DA signals on reinforcement learning in humans, and provide initial evidence regarding the spatio-temporal dynamics of brain mechanisms underlying these processes.

Background

Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood.

Objective

To examine the effects of a dopamine agonist on the motor response to levodopa.

Design

Double-blind, randomized, placebo-controlled, crossover clinical trial.

Setting

Ambulatory academic referral center.

Patients

Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia.

Interventions

Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment.

Main Outcome Measures

Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to “ON” (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC.

Results

Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute×minutes (P=.006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P=.02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P=.004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion.

Conclusions

Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.

Trial Registration

clinicaltrials.gov Identifier: NCT00666653

The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the “overdose hypothesis” which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients’ actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks.

Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.

Immediate-release (IR) pramipexole is indicated for the symptomatic treatment of idiopathic Parkinson’s disease (PD), either alone (without levodopa) or in combination with levodopa, that is, during the entire progress of disease up to the advanced stage. It is also currently indicated for the treatment of moderate-to-severe primary restless legs syndrome (RLS). An extended-release (ER) formulation of pramipexole has been developed to allow a once-daily formulation and to provide more stable dopaminergic stimulation. This review summarized the pharmacokinetic profile of pramipexole for both the IR and ER formulations, and discussed the role of pramipexole in the management of early and advanced PD. The introduction of a once-daily formulation of pramipexole poses significant potential advantages for patients and this is reflected by relatively stable plasma levels. The most obvious benefit is convenience of use and better adherence to treatment schedule. Additional advantages may be represented by the opportunity to provide continuous drug delivery in a fashion that could potentially help minimize dyskinesia risk if the drug is used early in the disease course.

Objective: High frequency stimulation of the subthalamic nucleus (STN) dramatically decreases motor disability in patients with Parkinson"s disease (PD), but has been reported to aggravate apathy. The aim of this study was to analyse the effect of STN stimulation on motivation and reward sensitivity in a consecutive series of PD patients.

Methods: Apathy and reward sensitivity (Apathy Scale, Stimulus-Reward Learning, Reversal, Extinction, and Gambling tasks) were assessed in 18 PD patients treated by bilateral STN stimulation ("on" and "off" conditions) compared with 23 matched patients undergoing long term treatment with levodopa ("on" and "off" conditions).

Results: Apathy decreased under both STN stimulation and levodopa treatment, whereas explicit and implicit stimulus reward learning was unchanged.

Conclusions: Bilateral STN stimulation in PD patients does not necessarily have a negative effect on motivation and reward sensitivity and can even improve apathy provided patients have been appropriately selected for neurosurgery.

Making appropriate choices often requires the ability to learn the value of available options from experience. Parkinson’s disease is characterized by a loss of dopamine neurons in the substantia nigra, neurons hypothesized to play a role in reinforcement learning. Although previous studies have shown that Parkinson’s patients are impaired in tasks involving learning from feedback, they have not directly tested the widely held hypothesis that dopamine neuron activity specifically encodes the reward prediction error signal used in reinforcement learning models. To test a key prediction of this hypothesis, we fit choice behavior from a dynamic foraging task with reinforcement learning models and show that treatment with dopaminergic drugs alters choice behavior in a manner consistent with the theory. More specifically, we found that dopaminergic drugs selectively modulate learning from positive outcomes. We observed no effect of dopaminergic drugs on learning from negative outcomes. We also found a novel dopamine-dependent effect on decision making that is not accounted for by reinforcement learning models: perseveration in choice, independent of reward history, increases with Parkinson’s disease and decreases with dopamine therapy.

Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.

Disordered dopamine neurotransmission is implicated in mediating impulsiveness across a range of behaviors and disorders including addiction, compulsive gambling, attention-deficit/hyperactivity disorder, and dopamine dysregulation syndrome. Whereas existing theories of dopamine function highlight mechanisms based on aberrant reward learning or behavioral disinhibition, they do not offer an adequate account of the pathological hypersensitivity to temporal delay that forms a crucial behavioral phenotype seen in these disorders. Here we provide evidence that a role for dopamine in controlling the relationship between the timing of future rewards and their subjective value can bridge this explanatory gap. Using an intertemporal choice task, we demonstrate that pharmacologically enhancing dopamine activity increases impulsivity by enhancing the diminutive influence of increasing delay on reward value (temporal discounting) and its corresponding neural representation in the striatum. This leads to a state of excessive discounting of temporally distant, relative to sooner, rewards. Thus our findings reveal a novel mechanism by which dopamine influences human decision-making that can account for behavioral aberrations associated with a hyperfunctioning dopamine system.

We describe a patient with advanced Parkinson's disease who developed pathological gambling within a month after successful bilateral subthalamic nucleus (STN) stimulation. There was no history of gambling. On neuropsychological testing, slight cognitive decline was evident 1 year after surgery. Stimulation of the most dorsal contact with and without medication induced worse performances on decision making tests compared with the more ventral contact. Pathological gambling disappeared after discontinuation of pergolide and changing the stimulation parameters. Pathological gambling does not seem to be associated with decision making but appears to be related to a combination of bilateral STN stimulation and treatment with dopamine agonists.

Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.