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The impulse control disorders associated with dopaminergic medication in Parkinson’s disease provide a clear and unequivocal demonstration of the biological basis of behavioural addiction. These behaviours can be dramatic, resulting in significant financial and social consequences, with functional impairments, and include pathological gambling, compulsive shopping, hypersexuality, binge eating, punding (complex prolonged, purposeless, and stereotyped behaviour) and compulsive medication use.

The impulse control disorders (ICDs) associated with dopaminergic medication in Parkinson's disease (PD) provide a clear and unequivocal demonstration of the biological basis of behavioural addiction. These behaviours can be dramatic, resulting in significant financial and social consequences, with functional impairments [1], and include pathological gambling, compulsive shopping, hypersexuality, binge eating, punding (complex prolonged, purposeless, and stereotyped behaviour) and compulsive medication use.

The recent multicentre cross-sectional DOMINION study surveying 3,090 PD patients demonstrated that the ICDs are common, occurring in 13.6% of patients with behaviours in descending frequency as follows: compulsive shopping (5.7%), problem gambling (5.0%), binge eating disorder (4.3%) and compulsive sexual behaviour (3.5%) [2]. Patients reporting single ICDs were common, with multiple ICDs occurring in >25%. More recently, behaviours such as hoarding [3], kleptomania [4] and impulsive smoking [5] have been reported.

The DOMINION study confirmed a class effect of dopamine agonist (DA) and an association with higher levodopa, but not DA, dose [2]. A follow-up of the DOMINION study also highlighted a potential association between ICDs and amantadine [6], commonly used in the treatment of dyskinesia. However, this remains to be clarified, given the results of the randomised crossover amantadine study, which demonstrated efficacy of amantadine in the treatment of pathological gambling in PD [7].

Untreated PD appears not to be protective or causative, but may still interact with medication, thereby provoking the development of an ICD. Treated PD patients were more likely to have pathological gambling than general hospital controls [8]. Untreated PD patients did not differ in their frequency of ICDs compared with non-PD controls [9]. Furthermore, ICDs have been reported in other neurological disorders requiring dopaminergic medication, including restless legs syndrome [10], progressive supranuclear palsy [11] and multiple sclerosis [12]. Larger and prospective studies are required to determine the exact role of PD and the nature of its relationship with ICDs.

Younger PD patients are consistently demonstrated to be at greater risk, consistent with observations in the general population, but also raising the possibility of specific PD genotypic or phenotypic influences. The association with current or former smoking highlights the overlap with other substances of abuse. An association with a family history of gambling, and that demonstration of gender differences, with males expressing hypersexuality and females compulsive shopping, may speak towards either biological or social influences. Social factors are likely to be at play, given the association with being single, and living in the United States rather than in Canada [2]. The case-control arm of the DOMINION study compared 564 PD patients with and without ICDs and confirmed an association with depression, anxiety and obsessive compulsive symptoms, as previously observed [1]. Novelty seeking and impulsivity, both previously demonstrated to be elevated in PD patients with ICDs, appear differentially associated with behavioural subtype. Pathological gamblers and compulsive shoppers have higher novelty seeking and make more impulsive choices relative to binge eating and hypersexuality, emphasizing pathophysiological differences and the need to study subtype differences in the ICDs [1].

There are several pointers towards a specific relevance of dopaminergic medication in ICDs in PD that are outlined in the following section.

On a broader level, converging evidence suggests a mechanistic overlap between levodopa-induced behavioural ICDs and motor dyskinesias. The overlap reflects the engagement of the different behavioural and motor domains of corticostriatal circuitry [reviewed in 13]. ICDs in PD are associated with an oscillatory theta-alpha activity (mean frequency 6.71 Hz) in the ventral subthalamic nucleus, and there is electroencephalographic coherence with non-motor prefrontal regions that is distinct from that observed with dyskinesias; these are in contrast associated with a higher theta-alpha peak frequency (mean 8.38 Hz), dorsal localisation and coherence with motor regions [14]. Dyskinesias are also more common in patients with punding [15] and multiple ICDs [1]. On another level, the behaviours of ICDs, punding and compulsive medication use, together with dyskinesia, have also been postulated to reflect hyper-dopaminergic activity and apathy, whereas the symptom of depression has been thought to reflect hypo-dopaminergic activity. Patients with ICDs or compulsive medication use (21/63) presumably with hyper-dopaminergic activity had a complete resolution of symptoms with marked decreases in the dose of dopaminergic medication following subthalamic deep brain stimulation surgery. Furthermore, depression (17/63) and apathy (34/63) were very common in the larger group of postoperative patients with markedly low dopaminergic tone, and apathy correlated with mesolimbic dopaminergic denervation [16]. That the DA, pramipexole, is effective for depression in PD [17] is consistent with this concept. This links with the ‘overdose’ theory, stating that behavioural function has a U-shaped relationship with dopaminergic activity, where optimal function follows a mid-level, eudopaminergic, tone, and impaired function is associated with both low and high tone [18]. Dopaminergic medication targeted at ameliorating the extensively degenerated motor dorsal striatal function in PD may result in an overdose of the relatively preserved ventral corticostriatal function.

The effects of acute versus chronic DA administration and subsequent neuroadaptations are likely also to be of great relevance. In rodents, acute DA challenge decreases dopaminergic firing in a dose-dependent manner, due to D2 autoreceptor stimulation, yet dopaminergic firing normalises with chronic DA administration, likely to be secondary to D2/D3 autoreceptor downregulation [19]. Furthermore, chronic administration of DAs enhances serotonergic firing, probably via 5HT1A autoreceptor downregulation. The effects of the dopamine agonist withdrawal syndrome are also enhanced in PD patients with ICDs [20], emphasising the role of neuronal supersensitivity. The effects of exogenous dopamine may also influence function via tonic stimulation or interference with phasic endogenous signalling.

On this background, we discuss the emerging evidence on reward, incentive, behavioural regulation and risk. PD patients on medication engaged in a gambling type task have greater striatal dopamine release [21]. More specifically, two studies have demonstrated that PD patients with ICDs appear to learn faster from rewards [22, 23], possibly related to enhanced ventral striatal phasic prediction error and reward prediction activity. This may be of relevance to an early acquisition stage and is also relevant to forming learned associations with cues. The evidence for impaired learning from loss outcomes is more equivocal [22, 23]. PD patients with ICDs have greater striatal dopamine release [24] and greater striatal activity [25] to heterogeneous visual reward-related cues as compared with levodopa or neutral cues, supporting an incentive salience process. However, another study did not demonstrate any motivational differences, as measured by reaction time, in a reward incentive task [26]. These studies provide evidence to support enhanced ‘bottom-up’ striatal engagement. Some evidence for impaired ‘top-down’ prefrontal regulation is beginning to emerge. Apomorphine decreases activity in the orbitofrontal and rostral cingulate cortices in PD patients with pathological gambling [27], and patients have decreased functional connectivity between the striatum and anterior cingulate [28].

PD patients with ICDs have greater risk-taking biases [23, 29] relative to PD controls, associated with lower ventral striatal [30], orbitofrontal and anterior cingulate activity [29]. This is consistent with the expression of pathological behaviours, which represent a choice with both positive rewarding, and financially and socially negative, outcomes. DAs have differential effects on the different facets of impulsivity in PD patients with ICDs. DAs increase impulsive choice in PD patients with ICDs [1, 26, 31], shifting the preference towards small, immediate rewards and away from larger, delayed rewards. This effect has been suggested to be related to an impairment in waiting [26], but may also reflect the effect of DA on the subjective valuation of larger rewards [1]. DAs appear to enhance the rapidity of decision making or reflection impulsivity in PD patients with ICDs [31], thus decreasing the evaluation of conflicting or difficult choices. However, there have been no differences reported in the Stroop task [32], which probes inhibition of a verbal pre-potent response and response selection and engages the anterior cingulate cortex.

Recent evidence implicates impairments in working memory, including both visuospatial working memory [31] and memory for digit span [23]. That digit span was impaired both on and off medication suggests a potential overdosing of the dorsolateral corticostriatal circuitry when on medication, and from endogenous dopamine activity when off medication.

Vulnerability towards these disorders may also be associated with genetic polymorphisms. The D3 dopamine receptor p.S9G and GRIN2B c.366C > G was recently identified as a risk factor for ICDs [33]. This is consistent with the role of D3 receptors, expressed predominantly in the ventral striatum, in reward and emotional processes. In primate studies, levodopa administration results in aberrant D3 receptor expression in the dorsal striatum [34]. Similarly, levodopa with concurrent DA administration increases the risk for ICDs [2].

Patients and caregivers should be warned about the risk of ICDs at treatment onset and actively questioned on follow-up. Patients with a premorbid history of substance or behavioural addiction may be at a greater risk for the development of these disorders. A 5-min questionnaire, the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease, has been validated for screening of ICDs in PD [35]. Observational follow-up studies suggest that a decrease or discontinuation of the DA, if tolerated, may be helpful for some patients [36]. A recent randomised crossover trial demonstrated the efficacy of amantadine [7]; however, a contradicting report of increased risk of ICDs associated with amantadine suggests that its role is not yet fully established [6]. The efficacy of subthalamic stimulation in ICD patients, which allows for a decrease in the total dopaminergic dose and the discontinuation of the offending DA, is not yet resolved, given the contradictory published reports. However, the recent demonstration of a complete resolution of ICDs in a prospective study, in which dopaminergic medication was dramatically decreased [16], suggests that retrospective studies showing a post-operative worsening of symptoms [37] may represent inadequate post-operative titration of medication. Notably, ICD patients with PD may be at greater risk of post-operative suicidal behaviour [29]; careful pre-operative selection and post-operative follow-up are indicated.

Recent advances in the understanding of ICDs in PD provide greater insight into the mechanisms underlying this disorder and into basic questions about human behaviour. Such work brings us closer towards developing better preventative and treatment strategies.

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