Development Of Impulse Control Disorders Research Articles

Predicting Impulse Control Disorders in Parkinson Disease through Incentive Biomarkers.

This study was undertaken to evaluate whether the feedback-related negativity (FRN)-a neurophysiological marker of incentive processing-can be used to predict the development of impulse control disorders (ICDs) in Parkinson disease (PD). The longitudinal cohort consisted of consecutive nondemented PD patients with no ICD history. We recorded FRN signals while they performed a gambling task. We calculated the mean amplitude difference between losses and gains (FRNdiff) to be used as a predictor of future ICD development. We performed prospective biannual follow-up assessments for 30months to detect incident ICDs. Finally, we evaluated how basal FRNdiff was associated with posterior development of ICDs using survival models. Between October 7, 2015 and December 16, 2016, we screened 120 patients. Among them, 94 patients performed the gambling and 92 completed the follow-up. Eighteen patients developed ICDs during follow-up, whereas 74 remained free of ICDs. Baseline FRNdiff was greater in patients who developed ICDs than in those who did not (-2.33μV vs -0.84μV, p= 0.001). No other significant baseline differences were found. The FRNdiff was significantly associated with ICD development in the survival models both when not adjusted (hazard ratio [HR]= 0.73, 95% confidence interval [CI]= 0.58-0.91, p= 0.006) and when controlling for dopamine replacement therapy, sex, and age (HR=0.74, 95% CI=0.55-0.97, p= 0.035). None of the impulsivity measures evaluated was related to ICD development. Reward-processing differences measured by FRN signals precede ICD development in PD. This neurophysiological marker permits identification of patients with high risk of ICD development. ANN NEUROL 2022;92:974-984.

Parkinson's Disease - What is New?

The prevalence of Parkinson's disease (PD) will double by 2030. PD is no longer regarded as a single disease entity. Monogenetic forms may appear clinically identical to sporadic PD. The corona pandemic has caused a deterioration in a great proportion of patients due to concerns of accessing medical care. During this time, teleconsultations emerged as a helpful service for many PD patients as they can reliably administer parts of the neurological examination remotely. New studies address the ongoing controversy about whether the use of levodopa should be delayed. The conclusion is that physicians should not be afraid of using levodopa to treat patients early in the course of PD. Furthermore, the role of dopamine agonists is changing. Besides their known high rates of edema, somnolence and hallucinations dopamine agonists are associated with the development of impulse control disorders in approx. half of the treated patients. During the last 10 years, only two new substances (safinamide, opicapone) have come onto the market in Germany, both with the indication as add on therapy to levodopa in patients with fluctuations. The use of deep brain stimulation and drug pumps in patients with levodopa effect fluctuations is growing, because at this point in the course of the disease, patients also accept invasive therapies that can prolong and optimize independence. Patients who need levodopa more than 5 times a day and who have severe, disturbing OFF phases (> 2 hours a day) despite optimal non-levodopa-based treatment can consider these options. PD stage and symptom-focused, guideline-based physiotherapy has a positive effect on the course of the disease, everyday performance and quality of life and reduces the risk of falling. Multidisciplinary networks are proving effective in reducing falls and hospital admissions.

Impulse control disorders in Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterised by typical motor symptoms and a range of non-motor symptoms, among which impulse control disorders, defined by an inability to resist temptations, impulses or urges, despite them being potentially harmful to the patient or caregivers, are gaining an increasing research interest. The most common compulsive activities include pathological gambling, hyper-sexuality, compulsive buying, and binge eating. The prevalence of impulse control disorders varies greatly depending on the country where the study was conducted, probably due to cultural and socioeconomic factors or the research methods used. Non-ergotamine dopamine agonists, and to a lesser extent highdose L-dopa and other antiparkinsonian drugs, are considered to be major risk factors for the development of impulse control disorders. Young age of patients, male gender, and early age of disease onset also increase the risk of developing this type of disorder. A probable cause of impulse control disorders is a state of dopaminergic overstimulation within the mesolimbic pathway and frontal-striatal circuit. The management of impulse control disorders is particularly challenging in view of the possible worsening of motor symptoms. The primary strategy remains dose reduction, discontinuation or switching from a dopamine agonist to another drug. If this type of intervention has failed, it is advisable to add atypical antipsychotics or antiepileptic drugs. Because of the low detection rate of impulse control disorders and their potentially devastating impact on patients’ personal and family lives, every clinician managing patients with Parkinson’s disease should be particularly vigilant for the presence of such disorders.

White matter microstructural changes preceding the development of impulse control disorders in patients with Parkinson's disease

Impulse control disorders (ICD) can be triggered by dopamine replacement therapies in patients with Parkinson's Disease (PD). Previous studies have identified several risk factors associated with ICD. In this study we investigated the presence of white matter (WM) microstructural changes at baseline in a cohort of drug-naïve PD patients who successively developed ICD over a 36-month follow-up period (ICD+) compared with patients who did not (ICD-).

Elevated Serum Ceruloplasmin Levels Are Associated with Higher Impulsivity in People with Parkinson's Disease.

Background Heightened impulsivity has been reported in a subset of people with Parkinson's disease (PwP) and is considered a risk factor for the development of impulse control disorders (ICDs). However, at present, there are no recognised biochemical markers of heightened impulsivity. Objectives To determine if ceruloplasmin, a serum marker involved in the regulation of iron and copper homeostasis, is associated with trait impulsivity in PwP. Methods The study measured serum ceruloplasmin and impulsivity using the Barratt Impulsiveness Scale (BIS-11) in an Australian cohort of 214 PwP. Multivariate general linear models (GLMs) were used to identify whether higher serum ceruloplasmin levels (>75th percentile) were significantly predictive of BIS-11 scores. Results Serum ceruloplasmin was higher in females with PD (p < 0.001) and associated with MDS-UPDRS III, Hoehn and Yahr, and ACE-R scores (p < 0.05). When correcting for covariates, higher serum ceruloplasmin concentrations were associated with the 2nd order nonplanning impulsivity and with the 1st order self-control and cognitive complexity impulsivity domains. Conclusions Higher serum ceruloplasmin levels are independently associated with heightened nonplanning impulsivity in PwP. Thus, serum ceruloplasmin levels may have clinical utility as a marker for heightened impulsivity in PD.

Dopamine and reward hypersensitivity in Parkinson's disease with impulse control disorder.

Impulse control disorders in Parkinson's disease are common neuropsychiatric complications associated with dopamine replacement therapy. Some patients treated with dopamine agonists develop pathological behaviours, such as gambling, compulsive eating, shopping, or disinhibited sexual behaviours, which can have a severe impact on their lives and that of their families. In this study we investigated whether hypersensitivity to reward might contribute to these pathological behaviours and how this is influenced by dopaminergic medication. We asked participants to shift their gaze to a visual target as quickly as possible, in order to obtain reward. Critically, the reward incentive on offer varied over trials. Motivational effects were indexed by pupillometry and saccadic velocity, and patients were tested ON and OFF dopaminergic medication, allowing us to measure the effect of dopaminergic medication changes on reward sensitivity. Twenty-three Parkinson's disease patients with a history of impulse control disorders were compared to 26 patients without such behaviours, and 31 elderly healthy controls. Intriguingly, behavioural apathy was reported alongside impulsivity in the majority of patients with impulse control disorders. Individuals with impulse control disorders also exhibited heightened sensitivity to exogenous monetary rewards cues both ON and OFF (overnight withdrawal) dopamine medication, as indexed by pupillary dilation in anticipation of reward. Being OFF dopaminergic medication overnight did not modulate pupillary reward sensitivity in impulse control disorder patients, whereas in control patients reward sensitivity was significantly reduced when OFF dopamine. These effects were independent of cognitive impairment or total levodopa equivalent dose. Although dopamine agonist dose did modulate pupillary responses to reward, the pattern of results was replicated even when patients with impulse control disorders on dopamine agonists were excluded from the analysis. The findings suggest that hypersensitivity to rewards might be a contributing factor to the development of impulse control disorders in Parkinson's disease. However, there was no difference in reward sensitivity between patient groups when ON dopamine medication, suggesting that impulse control disorders may not emerge simply because of a direct effect of dopaminergic drug level on reward sensitivity. The pupillary reward sensitivity measure described here provides a means to differentiate, using a physiological measure, Parkinson's disease patients with impulse control disorder from those who do not experience such symptoms. Moreover, follow-up of control patients indicated that increased pupillary modulation by reward can be predictive of the risk of future emergence of impulse control disorders and may thereby provide the potential for early identification of patients who are more likely to develop these symptoms.

MON-293 The Prevalence of Impulse Control Disorders in Patients with Acromegaly and Prolactinomas Treated with Dopamine Agonists

Objective: There is emerging evidence linking dopamine agonist (DA) use with the development of impulse control disorders (ICD) in patients with prolactinomas. On the other hand, no data exist whether DA use in acromegaly is associated with ICD. We aimed to evaluate the prevalence of ICD, psychiatric symptoms in patients with prolactinoma and acromegaly receiving DA in comparison to those with nonfunctioning pituitary adenomas (NFA) and healthy controls (HC). Material and Method: Forty patients with prolactinoma, 40 patients with acromegaly, 38 patients with NFA and 32 HC were included in this study. All patients and controls included in the study were evaluated with revised version of Minnesota Impulsive Disorders Interview (MIDI-R), Symptom Check List (SCL-90-R) questionnaire, Barratt Impulsiveness Scale (BIS-11), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). All of the patients with prolactinoma and acromegaly had been receiving cabergoline therapy but patients with NFA had not been receiving cabergoline therapy at the time of the study. Results: We detected DA associated with ICD in 3 patients (7.5%) with prolactinoma, and 2 patients with acromegaly (5%). All patients’ symptoms resolved after either discontinuation of the drug or surgical intervention. There was no significant difference between patients with acromegaly and prolactinoma in terms of ICD prevalence. On the other hand, ICD was not detected in non functional adenoma and HC. There was no correlation between BIS-11 scores and total dose, mean monthly dose and duration of DA.According to SCL-90-R, obsession and interpersonal sensitivity positivity was significantly higher in patients with prolactinoma than acromegaly (p: 0.040, p:0.010, respectively). There was no significant difference between the groups in terms of BAI, BDI and BIS-11’s subscales and total scores (p> 0.005). Scl-90 somatization and depression positivity was significantly higher in patients with NFA than acromegaly (p: 0.043, p: 0.024 respectively). Likewise, scl-90 depression, interpersonal sensitivity and additional items subscale positivity was significantly higher in patients with NFA than HC (p: 0.005, p: 0.045, p: 0.045 respectively). Conclusion: Although DA dose was significantly higher in patients with acromegaly compared to patients with prolactinoma, there was no significant difference in the prevalence of DA -related ICD. We have showed that there was no association between BIS-11 scores and total DA dose, mean monthly DA dose and duration of DA treatment. The higher prevalence of depression, interpersonal sensitivity in patients with NFA in comparison to HC supports the hypothesis the presence of a pituitary adenoma per se might cause a large psychiatric symptom burden.

Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease.

To longitudinally evaluate the role of depression in the development of impulse control disorders (ICDs) in Parkinson disease (PD) patients. Using data from the Parkinson's Progression Markers Initiative, we included PD patients without ICDs at baseline according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Patients were prospectively evaluated first quarterly and then biannually. Development of an ICD was defined as an increase in QUIP scores during follow-up. Using survival proportional hazard models, we studied the effect of baseline depression on ICD risk. We also evaluated this effect controlling for dopamine agonist use as a time-dependent variable and for other potential confounders. Among 354 patients, 68 were depressed at baseline. The median follow-up was 4.08 years. Depression at baseline was associated with higher ICD risk (hazard ratio [HR] = 1.96, 95% confidence interval [CI] = 1.32-2.9, p < 0.001). This risk remained significant after controlling for dopamine agonist use (HR = 1.97, 95% CI = 1.33-2.9, p < 0.001), which was also independently linked to ICD development (HR = 1.87, 95% CI = 1.3-2.7, p < 0.001). Therefore, depressed patients faced an even higher ICD risk when receiving dopamine agonists. Controlling for multiple potential confounders did not alter these results. Depression predisposes to the development of ICDs in PD. This risk is magnified by dopamine agonists. Dopamine agonists should thus be used cautiously in depressed PD patients. ANN NEUROL 2019;86:762-769.

Impulse control symptoms in patients with Parkinson's disease: The influence of dopaminergic agonist

BackgroundImpulse control disorders and punding are common in Parkinson's disease patients. Cross-sectional studies suggest an association between dopamine replacement therapy, especially dopaminergic agonists, and impulse control and related disorders in Parkinson's disease. However, some surveys suggest that Parkinson's disease itself does not confer an altered risk for impulse control disorders and related behavior, although these disturbances are more frequently reported in Parkinsonian patients than in healthy controls. ObjectiveTo ascertain the frequency of impulse control disorders and punding symptoms in Parkinson's disease patients and healthy controls and to determine the influence of dopamine agonist treatment on the prevalence of these disturbances. MethodsA case-control study was conducted on 207 Parkinson's disease patients (79 taking dopamine agonists) and 230 healthy controls. The outcome measures were the presence of current impulse control disorders and punding symptoms, based on clinical criteria after application of the Minnesota Impulsive Disorders Interview for screening. ResultsThe frequency of impulse control disorders in Parkinson's disease patients vs. Healthy controls was 16.9% vs. 15.2% (p = 0.631). Punding was more frequent in Parkinson's disease patients (p = 0.028); however, impulse control disorders were more frequent in medicated Parkinson's disease patients taking dopamine agonists than in medicated patients not taking dopamine agonists (p = 0.001) and healthy controls (p = 0.014). ConclusionsParkinson's disease itself does not lead to the development of impulse control disorders. Dopaminergic agonist treatment may trigger the disorder in susceptible individuals. Punding may be more prevalent in Parkinson's disease patients.

Pramipexole-induced impulsivity in mildparkinsonian rats: a model of impulse control disorders in Parkinson's disease

Treatment with dopaminergic agonists such as pramipexole (PPX) contributes to the development of impulse control disorders (ICDs) in patients with Parkinson's disease (PD). As such, animal models of abnormal impulse control in PD are needed to better study the pathophysiology of these behaviors. Thus, we investigated impulsivity and related behaviors using the 5-choice serial reaction time task, as well as FosB/ΔFosB expression, in rats with mild parkinsonism induced by viral-mediated substantia nigra overexpression of human A53T mutated α-synuclein, and following chronic PPX treatment (0.25 mg/kg/d) for 4 weeks. The bilateral loss of striatal dopamine transporters (64%) increased the premature response rate of these rats, indicating enhanced waiting impulsivity. This behavior persisted in the OFF state after the second week of PPX treatment and it was further exacerbated in the ON state throughout the treatment period. The enhanced rate of premature responses following dopaminergic denervation was positively correlated with the premature response rate following PPX treatment (both in the ON and OFF states). Moreover, the striatal dopaminergic deficit was negatively correlated with the premature response rate at all times (pretreatment, ON and OFF states) and it was positively correlated with the striatal FosB/ΔFosB expression. By contrast, PPX treatment was not associated with changes in compulsivity (perseverative responses rate). This model recapitulates some features of PD with ICD, namely the dopaminergic deficit of early PD and the impulsivity traits provoked by dopaminergic loss in association with PPX treatment, making this model a useful tool to study the pathophysiology of ICDs.

Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson's disease.

Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). Our findings demonstrated that abnormal brain connectivity in the three large-scale networks characterizes drug-naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society.

Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease?

Apathy and impulsivity are two major comorbid syndromes of Parkinson’s disease (PD) that may represent two extremes of a behavioral spectrum modulated by dopamine-dependent processes. PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta to which are attributed the cardinal motor symptoms of the disorder. Dopamine replacement therapy (DRT), used widely to treat these motor symptoms, is often associated with deficits in hedonic processing and motivation, including apathy and depression, as well as impulse control disorders (ICDs). ICDs comprise pathological gambling, hypersexuality, compulsive shopping, binge eating, compulsive overuse of dopaminergic medication, and punding. More frequently observed in males with early onset PD, ICDs are associated not only with comorbid affective symptoms, such as depression and anxiety, but also with behavioral traits, such as novelty seeking and impulsivity, as well as with personal or familial history of alcohol use. This constellation of associated risk factors highlights the importance of inter-individual differences in the vulnerability to develop comorbid psychiatric disorders in PD patients. Additionally, withdrawal from DRT in patients with ICDs frequently unmasks a severe apathetic state, suggesting that apathy and ICDs may be caused by overlapping neurobiological mechanisms within the cortico-striato-thalamo-cortical networks. We suggest that altered hedonic and impulse control processes represent distinct prodromal substrates for the development of these psychiatric symptoms, the etiopathogenic mechanisms of which remain unknown. Specifically, we argue that deficits in hedonic and motivational states and impulse control are mediated by overlapping, yet dissociable, neural mechanisms that differentially interact with DRT to promote the emergence of ICDs in vulnerable individuals. Thus, we provide a novel heuristic framework for basic and clinical research to better define and treat comorbid ICDs in PD.

Treating prolactinomas with dopamine agonists: always worth the gamble?

Dopamine agonists are the treatment of choice for all patients with prolactinomas. They are generally safe, effective, and well-tolerated. However, a link between their use and the development of impulse control disorders has been well recognized in the field of neurology for some time, and evidence for a similar effect in endocrine patients is emerging. This has mainly been revealed through clinical case reports, plus a small number of comparative studies of varying robustness. We review the current available literature and discuss the implications for clinical practice, in particular emphasizing the need for clinicians to be alert to these uncommon but serious adverse effects.

Infusion Therapies and Development of Impulse Control Disorders in Advanced Parkinson Disease: Clinical Experience After 3 Years' Follow-up.

In Parkinson disease (PD), compulsive behaviors, cumulatively termed impulse control disorders (ICDs), are known to develop in patients receiving dopamine-replacement therapy with oral dopamine agonists being particularly implicated. However, the effects of continuous infusion therapies have not been explored. We report data from a 3-year clinical observational screening of our active cohort of patients receiving apomorphine (Apo) infusion and intrajejunal levodopa infusion (IJLI) for development or attenuation of ICDs. Forty-one patients (24 male/17 female, mean age 61.9 ± 10.9 years; PD duration 14.2 ± 4.5 years) on Apo (mean dose 106 ± 24 mg; mean duration of infusion 16 h/d) and 19 patients (13 male/6 female, mean age 58.6 ± 8.2 years; PD duration 16.2 ± 5.7 years) on IJLI (mean dose 1990 ± 807 mg; mean duration of infusion 16 h/d) were screened and observed prospectively for development of nonmotor symptoms and ICD at 3 monthly follow-ups for up to 3 years. In Apo group, 4 patients had preexisting ICD, and in 1 patient, ICD (binge eating) completely resolved after being started on Apo. In 3 others, ICDs continue but attenuated after Apo. However, 7 new cases of ICDs developed in the Apo group, but in only 1 (2.4%), Apo had to be discontinued. Furthermore, in 3 with binge eating, the ICDs resolved after 2 months with Apo infusion being continued. In the IJLI group, 8 patients with active ICDs showed attenuation of the behavior after IJLI initiation. At 3 years, 2 of these patients continue to have ICD. No new ICDs have developed. Strategies utilizing continuous drug delivery appear to have a relatively low risk of development of ICD. Apomorphine and IJLI can be used in cases with ICD if clinically indicated, with IJLI therapy possibly emerging as the most advantageous in this setting.

1.: Levodopa-carbidopa intestinal gel infusion improves motor performance and quality of life in patients with advanced Parkinson’s disease

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from the largest case series in an Australian movement disorder center at Westmead Hospital. An open-label, 12 months prospective study (Clinicaltrials.gov identifier: NCT00335153) of treatment with LCIG in patients with advanced Parkinson's disease was conducted. Patients with motor fluctuations despite optimal pharmacological treatment were included. Patients were given a16 hour daily infusion of LCIG for mean of 22±10 months. Minnesota Impulse Disorders Interview (MIDI), complications, the total levodopa daily equivalent dose, Unified Parkinson's Disease Rating Scale (UPDRS) part III, daily hours "off", daily hours "on" without dyskinesia, daily total hours "on" and pre-existing psychiatric diagnosis or impulse control disorder (ICD) was collected at baseline, 3, 6 and 12 months. The study was approved by the Human Research Ethic Committee at Western Sydney Area Health Service. Fifteen patients participated. Mean improvement in UPDRS part III was 37±11%. Mean daily "off" period reduced from 6.3±2 to 1.9±2 hours; total daily "on" time increased from 10.2±3 to 13.7±2 hours; "on" period without dyskinesia increased from 4.5±3 to 7.5±5 hours; 39-item Parkinson's Disease Questionnaire Summary Index improved by 32.5±35%. The most common adverse event was peripheral neuropathy secondary to vitamin B12±vitamin B6 deficiency (67%), local tube problems (60%), impulse control disorder (47%), and stoma infection (30%). No patient had stoma bleeding or peritonitis. All patients with impulse control disorder had a past psychiatric diagnosis and a higher daily levodopa intake at 6 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily "on" period. Our rate of intestinal tube problem or infection was similar to reported literature. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. Our study suggests that an increased daily levodopa dose compared to baseline is associated with a later development of impulse control disorders, but larger sample studies are needed to confirm this finding.

Failure of stop and go in de novo Parkinson's disease—a functional magnetic resonance imaging study

Behavioral impairments in response inhibition and initiation are common in Parkinson's disease (PD) and are associated with reduced impulse control. No prior study, however, has investigated the functional correlates of response inhibition in de novo PD. Twenty-one de novo PD patients and 37 matched healthy controls performed a stop-signal task during functional magnetic resonance imaging. The results showed that PD patients, compared with healthy controls, were slower on response initiation but not inhibition. Task-related activation of the response inhibition network, including the inferior frontal gyrus, was reduced in PD patients, and the activity in the inferior frontal gyrus correlated negatively with motor symptom severity. These findings show that de novo PD patients exhibit functional deficits in the response inhibition network, which are partly related to disease pathology and already evident before commencing dopamine replacement therapy. This study provides insights into the neural underpinnings of impulse control deficits, relevant for the study of the neural vulnerability factors involved in the development of impulse control disorders in PD.

Decision-Making, Reward-Seeking Behaviors and Dopamine Agonist Therapy in Restless Legs Syndrome

To assess whether the frequency of impulse control disorders (ICDs), addictive behaviors, impulsivity, and impairment of decision-making task performance under ambiguous and risky conditions were present in patients with restless legs syndrome (RLS) and whether changes could be related to dopaminergic medications. Case-control prospective study. Academic Sleep Disorders Center. Of the 149 participants, there were 39 who were drug free with primary RLS, 50 who were taking dopamine agonists (DA), and 60 control subjects. Participants were assessed with a clinical interview screening for ICDs, augmentation syndrome, impulsivity, depression, and addictive behaviors. All participants completed two decision-making tasks, one under an ambiguous condition (Iowa Gambling Task) and the other under a risky condition (Game of Dice Task). Drug-free patients with RLS underwent 1 night of polysomnography recording. Seventy percent of patients were treated with pramipexole (median dose, 0.36 mg), and 30% with ropinirole (median dose, 0.75 mg). Median duration of DA intake was 11 mo (range, 1-72 mo). No differences were found on impulsivity scores, ICDs, and substance addiction between drug-free patients or those taking DA, or control subjects. Patients with RLS reported more depressive symptoms than control subjects, but without differences between patients taking or not taking DA. Drug-free and treated patients demonstrated reduced performances on the Iowa Gambling Task but not on the Game of Dice Task compared to control subjects, with no differences between patients taking medications and those who were not. No association was found between decision-making task performances, or polysomnographic and clinical variables. Impulse control disorders, impulsivity, and substance addiction were infrequent in drug-free patients with restless legs syndrome or those treated with a low dose of dopamine agonists. However, patients with restless legs syndrome, either drug free or taking dopamine agonists, had preferences toward risky choices on the Iowa Gambling Task, which led to negative consequences in the long run, a condition potentially leading to further development of impulse control disorders.

Dopaminergic influences on executive function and impulsive behaviour in impulse control disorders in Parkinson's disease

The development of impulse control disorders (ICDs) in Parkinson's disease (PD) may arise from an interaction among cognitive impairment, impulsive responding and dopaminergic state. Dopaminergic state may be influenced by pharmacologic or genotypic (catechol-O-methyltransferase; COMT) factors. We sought to investigate this interaction further by comparing those with (n=35) and without (n=55) ICDs on delay-discounting in different pharmacologic conditions (ON or OFF dopaminergic medication) and on response inhibition as well as aspects of executive functioning in the ON state. We then undertook an exploratory sub-group analysis of these same tasks when the overall PD group was divided into different allelic variants of COMT (val/val vs. met/met). A healthy control group (HC; n=20) was also included. We found that in those with PD and ICDs, 'cognitive flexibility' (set shifting, verbal fluency, and attention) in the ON medication state was not impaired compared with those without ICDs. In contrast, our working memory, or 'cognitive focus', task was impaired in both PD groups compared with the HC group when ON. During the delay-discounting task, the PD with ICDs group expressed greater impulsive choice compared with the PD group without ICDs, when in the ON, but not the OFF, medication state. However, no group difference on the response inhibition task was seen when ON. Finally, the met homozygous group performed differently on tests of executive function compared with the val homozygous group. We concluded that the disparity in levels of impairment among different domains of executive function and impulsive decision-making distinguishes those with ICD in PD from those without ICD, and may in part be affected by dopaminergic status. Both pharmacologic and genotypic influences on dopaminergic state may be important in ICD.

Risky choices link the subthalamic nucleus with pathological gambling in Parkinson's disease

A commonly recognized feature of Parkinson’s disease (PD) is a deficit in movement initiation and execution, which is considered a problem of “energization.” However, excessive inhibition (eg freezing of gait) or disinhibition (eg levodopa [L-dopa]-induced dyskinesias) are also frequent manifestations. Moreover, in a sense, bradykinesia and akinesia could be considered as representing excessive inhibition of movement initiation/execution. Impulsivity, which is one of the symptoms associated with inhibitory deficits, can take many forms. Responding fast without taking time for reflection (reflection impulsivity), a preference for immediate small rewards rather than delayed larger rewards (aversion to delayed gratification), delayed inhibition of responses to a prepotent stimulus (delayed motor inhibition), and engaging in more risky decision making (risk taking) are some of the characteristics of impulsive individuals. 1,2 Until recently, there have been two separate strands of research on failure of inhibitory control and impulsivity in relation to PD. The first has been related to the development of impulse control disorders (ICDs), including hypersexuality, pathological gambling (PG) and shopping, overeating, hobbyism, and punding. Together, these ICDs occur in about 14% of patients with PD and are associated with dopamine agonist therapy, particularly ropinirole and pramipexole as well as L-dopa. 3 ICDs have been related to dysfunction of the mesolimbic dopamine pathways with their reward-related functions. For PG, which is a behavioral addiction associated with monetary risk taking, this was supported by evidence from a raclopride imaging study in which, during performance of a gambling task, there was greater release of dopamine in the ventral striatum in patients with PG versus those without PG. 4 Furthermore, during a gambling task, dopamine induced a reduction of activation in brain areas implicated in impulse control and response inhibition, namely, the lateral orbitofrontal cortex (OFC), rostral cingulate area, amygdala, and external segment of the pallidum, in patients who had PD with PG, which was not observed in those without PG. 5 A previous functional magnetic resonance imaging study by the same group established that, on a probabilistic reward task, the dopamine agonist pramipexole, similar to L-dopa, reduced reward processing in the ventral striatum compared with off medication but resulted in higher outcome-induced activation of the lateral OFC compared with L-dopa or off medication, a change that was associated with greater risk taking on a balloon analogue

Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra

Parkinson's disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive individuals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1-D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control.