Long‐term follow‐up of impulse control disorders in Parkinson's disease

Recent studies have linked dopamine agonist (DA) usage with the development of impulse control disorders (ICDs) in Parkinson's disease (PD). Little is known about optimal management strategies or the long‐term outcomes of affected patients. To report on the clinical interventions and long‐term outcomes of PD patients who developed an ICD after DA initiation. Subjects contacted by telephone for a follow‐up interview after a mean time period of 29.2 months. They were administered a modified Minnesota Impulse Disorder Interview for compulsive buying, gambling, and sexuality, and also self‐rated changes in their ICD symptomatology. Baseline and follow‐up dopamine replacement therapy use was recorded and verified by chart review. Of 18 subjects, 15 (83.3%) participated in the follow‐up interview. At follow‐up, patients were receiving a significantly lower DA levodopa equivalent daily dosage (LEDD) (Z = ?3.1, P = 0.002) and a higher daily levodopa dosage (Z = ?1.9, P = 0.05), but a similar total LEDD dosage (Z = ?0.47, P = 0.64) with no changes in Unified Parkinson's Disease Rating Scale motor score (Z = ?1.3, P = 0.19). As part of ICD management, 12 (80.0%) patients discontinued or significantly decreased DA treatment, all of whom experienced full or partial remission of ICD symptoms by self‐report, and 10 (83.3%) of whom no longer met diagnostic criteria for an ICD. For PD patients who develop an ICD in the context of DA treatment, discontinuing or significantly decreasing DA exposure, even when offset by an increase in levodopa treatment, is associated with remission of or significant reduction in ICD behaviors without worsening in motor symptoms. © 2007 Movement Disorder Society     

Long‐term cognitive follow‐up of Parkinson's disease patients with impulse control disorders

This study investigated cognitive functions in Parkinson's disease (PD) patients with impulse control disorders (ICDs) and aimed to identify possible predictors of behavioral outcome. In this longitudinal cohort study, 40 PD outpatients with ICDs and 40 without, were matched for sex, age at PD onset, age and disease duration at cognitive assessment. All patients had two neuropsychological assessments at least 2 years apart (mean, 3.5 years). Multivariate logistic regression analysis was performed to identify predictors of ICDs remission at follow‐up. The PD patients with and without ICDs had overall comparable cognitive performance at baseline. When evaluating changes between baseline and follow‐up, we found significant group × time interactions in several frontal lobe–related tests, with the ICDs group showing a less pronounced worsening over time. ICDs remission was associated with better performance at baseline in working memory–related tasks, such as digit span (odds ratio [OR] = 2.69 [95% confidence interval (CI), 1.09‐6.66]) and attentive matrices (OR=1.19 [95%CI, 1.03‐1.37]). ICDs remitters and non‐remitters had no remarkable differences in baseline PD‐related features and therapy management strategies (including the extent of dopamine agonist dose reduction). In conclusion, ICDs in PD patients are not related to greater cognitive impairment or executive dysfunction, but rather show relatively lower cognitive decline over time. The impaired top‐down inhibitory control characterizing ICDs is likely attributable to a drug‐induced overstimulation of relatively preserved prefrontal cognitive functions. Full behavioral remission in the long term was predicted by better working memory abilities. © 2015 International Parkinson and Movement Disorder Society     

Decreased ventral striatal activity with impulse control disorders in Parkinson's disease

A range of impulse control disorders (ICDs) are reported to occur in Parkinson's disease (PD). However, alterations in brain activity at rest and during risk taking occurring with ICDs in PD are not well understood. We used both arterial spin labeling perfusion functional magnetic resonance imaging (fMRI) to directly quantify resting cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) fMRI to measure neural responses to risk taking during performance on the Balloon Analogue Risk Task (BART). Eighteen PD patients, either with a diagnosis of one or more ICDs (N = 9) or no lifetime ICD history (N = 9), participated. BOLD fMRI data demonstrated that PD patients without an ICD activate the mesocorticolimbic pathway during risk taking. Compared with non‐ICD patients, ICD patients demonstrated significantly diminished BOLD activity in the right ventral striatum during risk taking and significantly reduced resting CBF in the right ventral striatum. ICDs in PD are associated with reduced right ventral striatal activity at rest and diminished striatal activation during risk taking, suggesting that a common neural mechanism may underlie ICDs in individuals with PD and those without PD. Thus, treatments for ICDs in non‐PD patients warrant consideration in PD patients with ICDs. © 2010 Movement Disorder Society     

Brain PET substrate of impulse control disorders in Parkinson's disease: A metabolic connectivity study

Impulse control disorders (ICDs) have received increased attention in Parkinson's disease (PD) because of potentially dramatic consequences. Their physiopathology, however, remains incompletely understood. An overstimulation of the mesocorticolimbic system has been reported, while a larger network has recently been suggested. The aim of this study is to specifically describe the metabolic PET substrate and related connectivity changes in PD patients with ICDs. Eighteen PD patients with ICDs and 18 PD patients without ICDs were evaluated using cerebral 18F‐fluorodeoxyglucose positron emission tomography. SPM‐T maps comparisons were performed between groups and metabolic connectivity was evaluated by interregional correlation analysis (IRCA; p < .005, uncorrected; k > 130) and by graph theory (p < .05). PD patients with ICDs had relative increased metabolism in the right middle and inferior temporal gyri compared to those without ICDs. The connectivity of this area was increased mostly with the mesocorticolimbic system, positively with the orbitofrontal region, and negatively with both the right parahippocampus and the left caudate (IRCA). Moreover, the betweenness centrality of this area with the mesocorticolimbic system was lost in patients with ICDs (graph analysis). ICDs are associated in PD with the dysfunction of a network exceeding the mesocorticolimbic system, and especially the caudate, the parahippocampus, and the orbitofrontal cortex, remotely including the right middle and inferior temporal gyri. This latest area loses its central place with the mesocorticolimbic system through a connectivity dysregulation.     

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

Background: 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. Methods: 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. Results: 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). Conclusions: 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     

Reduced dopamine transporter binding predates impulse control disorders in Parkinson's disease

Impulse control disorders (ICD) are relatively common in Parkinson's disease (PD) and generally are regarded as adverse effects of dopamine replacement therapy, although certain demographic and clinical risk factors are also involved. Previous single‐photon emission computed tomography (SPECT) studies showed reduced ventral striatal dopamine transporter binding in Parkinson patients with ICD compared with patients without. Nevertheless, these studies were performed in patients with preexisting impulse control impairments, which impedes clear‐cut interpretation of these findings. We retrospectively procured follow‐up data from 31 medication‐naïve PD patients who underwent dopamine transporter SPECT imaging at baseline and were subsequently treated with dopamine replacement therapy. We used questionnaires and a telephone interview to assess medication status and ICD symptom development during the follow‐up period (31.5 ± 12.0 months). Eleven patients developed ICD symptoms during the follow‐up period, eight of which were taking dopamine agonists. The PD patients with ICD symptoms at follow‐up had higher baseline depressive scores and lower baseline dopamine transporter availability in the right ventral striatum, anterior‐dorsal striatum, and posterior putamen compared with PD patients without ICD symptoms. No baseline between‐group differences in age and disease stage or duration were found. The ICD symptom severity correlated negatively with baseline dopamine transporter availability in the right ventral and anterior‐dorsal striatum. The results of this preliminary study show that reduced striatal dopamine transporter availability predates the development of ICD symptoms after dopamine replacement therapy and may constitute a neurobiological risk factor related to a lower premorbid dopamine transporter availability or a more pronounced dopamine denervation in PD patients susceptible to ICD. © 2014 International Parkinson and Movement Disorder Society     

Prospective cohort study of impulse control disorders in Parkinson's disease

Impulse control disorders (ICDs) are potentially serious side effects of dopamine agonist therapy in Parkinson's disease (PD), but prospective data are lacking about their incidence, time course, and risk factors. This work was a 4‐year, prospective cohort study of outpatients with PD and no previous ICDs (N = 164). All subjects treated with a dopamine agonist during the study were followed longitudinally for new‐onset ICDs. Baseline characteristics were compared in groups with (ICD+) and without (ICD?) subsequent ICDs. Forty‐six subjects were treated with a dopamine agonist, including 25 who were newly treated and 21 who received ongoing dopamine agonist therapy. Of these 46 subjects, 18 (39.1%) developed new‐onset ICDs. The timing of ICD onset varied from 3.0 to 114.0 months (median, 23.0) after initiation of dopamine agonist therapy. Baseline demographic characteristics were similar in ICD+ and ICD? groups. At baseline, ICD+ subjects had a greater prevalence of motor complications (61.1% versus 25.0%; P = 0.01) than ICD? subjects, despite comparable total dopaminergic medication usage in both groups (median, 150.0 versus 150.0 levodopa equivalents; P = 0.61). Compared with ICD? subjects, ICD+ subjects had a greater baseline prevalence of caffeine use (100% versus 66.7%; P = 0.007) and higher lifetime prevalence of cigarette smoking (44.4% versus 14.3%; P = 0.04). Peak dopamine agonist doses were higher in ICD+ than ICD? subjects (median 300.0 versus 165.0 L ‐dopa equivalents; P = 0.03), but cumulative dopamine agonist exposure was similar in both groups. In summary, the timing of new‐onset ICDs in PD is highly variable. Risk factors include cigarette smoking, caffeine use, motor complications, and higher peak dopamine agonist dosage. © 2013 Movement Disorder Society     

Patterns of cortical thickness associated with impulse control disorders in Parkinson's disease

Previous functional neuroimaging studies in Parkinson's disease (PD) patients with impulse control disorders (ICDs) demonstrated dysfunction of the reward network, although the extent of anatomical changes is unclear. The aim of this study was to measure brain cortical thickness and subcortical volumes, and to assess their relationship with presence and severity of symptoms, in PD patients with and without ICDs. We studied 110 PD patients (N = 58 with ICDs) and 33 healthy controls (all negative for ICDs) who underwent an extensive neurological, neuropsychological, and behavioral assessment as well as structural 1.5 Tesla magnetic resonance imaging (MRI). Between‐group differences in brain cortical thickness and subcortical volumes, assessed with the FreeSurfer 5.1 tool, were analyzed. In patients with ICDs, we found significant cortical thinning in fronto‐striatal circuitry, specifically in the right superior orbitofrontal, left rostral middle frontal, bilateral caudal middle frontal region, and corpus callosum, as well as volume reduction in the right accumbens and increase in the left amygdala. Finally, we observed a positive association relationship between severity of impulsive symptoms and left rostral middle frontal, inferior parietal, and supramarginal areas. These results support the involvement of both reward and response inhibition networks in PD patients with ICDs. Moreover, their severity is associated with alterations in brain regions linked with reward and top‐down control networks. Increased understanding of the mechanisms underlying impulsive and compulsive behaviors might help improve therapeutic strategies for these important disorders. © 2015 International Parkinson and Movement Disorder Society     

Exploratory analysis of the genetics of impulse control disorders in Parkinson's disease using genetic risk scores

ObjectiveTo study the association between impulse control disorders (ICDs) in Parkinson's disease (PD) and genetic risk scores (GRS) for 40 known or putative risk factors (e.g. depression, personality traits).BackgroundIn absence of published genome-wide association studies (GWAS), little is known about the genetics of ICDs in PD. GRS of related phenotypes, for which large GWAS are available, may help shed light on the genetic contributors of ICDs in PD.MethodsWe searched for GWAS on European ancestry populations with summary statistics publicly available for a broad range of phenotypes, including other psychiatric disorders, personality traits, and simple phenotypes. We separately tested their predictive ability in two of the largest PD cohorts with clinical and genetic available: the Parkinson's Progression Markers Initiative database (N = 368, 33% female, age range = [33–84]) and the Drug Interaction With Genes in Parkinson's Disease study (N = 373, 40% female, age range = [29–85]).ResultsWe considered 40 known or putative risk factors for ICDs in PD for which large GWAS had been published. After Bonferroni correction for multiple comparisons, no GRS or the combination of the 40 GRS were significantly associated with ICDs from the analyses in each cohort separately and from the meta-analysis.ConclusionAlbeit unsuccessful, our approach will gain power in the coming years with increasing availability of genotypes in clinical cohorts of PD, but also from future increase in GWAS sample sizes of the phenotypes we considered. Our approach may be applied to other complex disorders, for which GWAS are not available or limited.     

Disrupted salience network dynamics in Parkinson's disease patients with impulse control disorders

BackgroundDynamic functional network analysis may add relevant information about the temporal nature of the neurocognitive alterations in PD patients with impulse control disorders (PD-ICD). Our aim was to investigate changes in dynamic functional network connectivity (dFNC) in PD-ICD patients, and topological properties of such networks.MethodsResting state fMRI was performed on 16 PD PD-ICD patients, 20 PD patients without ICD and 17 healthy controls, whose demographic, clinical and behavioral scores were assessed. We conducted a group spatial independent component analysis, sliding window and graph-theory analyses.ResultsPD-ICD patients, in contrast to PD-noICD and HC subjects, were engaged across time in a brain configuration pattern characterized by a lack of between-network connections at the expense of strong within-network connections (State III) in temporal, frontoinsular and cingulate cortices, all key nodes of the salience network. Moreover, this increased maintenance of State III in PD-ICD patients was positively correlated with the severity of impulsivity and novelty seeking as measured by specific scales. While in State III, these patients also exhibited increased local efficiency in all the aforementioned areas.ConclusionsOur findings show for the first time that PD-ICD patients have a dynamic functional engagement of local connectivity involving the limbic circuit, leading to the inefficient modulation in emotional processing and reward-related decision-making. These results provide new insights into the pathophysiology of ICD in PD patients and indicate that the dFC study of fMRI could be a useful biomarker to identify patients at risk to develop ICD.     

REM sleep behavior disorder: Association with motor complications and impulse control disorders in Parkinson's disease

ObjectiveClinical phenotypes such as old age, longer disease duration, motor disability, akineto-rigid type, dementia and hallucinations are known to be associated with REM sleep behavior disorder (RBD) in Parkinson's disease (PD). However, the relationship between motor fluctuations/impulse control and related behaviors (ICRB) and RBD is not clear. We designed this study to elucidate the clinical manifestations associated with RBD to determine the implications of RBD in PD.DesignIn a cross-sectional study, a total of 994 patients with PD were interviewed to determine the presence of RBD and their associated clinical features including motor complications and ICRB.ResultsOf the 944 patients, 578 (61.2%) had clinical RBD. When comparing the clinical features between patients with RBD (RBD group) and without RBD (non-RBD group), older age, longer disease duration, higher Hoehn and Yahr stage (H&Y stage), higher levodopa equivalent daily dose (LEDD), and the existence of wearing off, dyskinesia, freezing, and ICRB, especially punding, were associated with the RBD group compared to the non-RBD group (P < .05 in all). Multivariate analysis showed that motor complications including wearing off, peak dose dyskinesia, and diphasic dyskinesia were the only relevant factors for RBD after adjusting for age and disease duration.ConclusionMotor complications and ICRB are more frequent in patients with RBD than in patients without RBD. In addition, motor complications are related to RBD even after adjusting for age and disease duration.     

The relationship between balance confidence and control in individuals with Parkinson's disease

IntroductionA broad range of subjective and objective assessments have been used to assess balance confidence and balance control in persons with Parkinson's disease (PD). However, little is known about the relationship between self-perceived balance confidence and actual balance control in PD. The purpose of this investigation was to determine the relationship between self-perceived balance confidence and objectively measured static/dynamic balance control abilities.MethodsForty-four individuals with PD participated in the study. Patients were stratified into 2 groups based on the modified Hoehn and Yahr (H&Y) disability score: early stage, H&Y ≤ 2.0 and moderate stage, H&Y ≥ 2.5. All participants completed the activities-specific balance confidence (ABC) scale and performed standing balance and gait initiation tasks to assess static and dynamic balance control. The center of pressure (COP) sway (CE95%Sway) during static balance and the peak distance between the projections of the COP and the center of mass (COM) in the transverse plane (COPCOM) during gait initiation were calculated. Pearson correlation analyses were conducted relating the ABC score and CE95%Sway and COPCOM.ResultsFor early stage PD, there was a moderate correlation between ABC score and CE95%Sway (r = −0.56, R² = 0.32, p = 0.002), while no significant correlation was found between ABC score and COPCOM (r = −0.24, R² = 0.06, p = 0.227). For moderate stage PD, there was a moderate correlation between ABC score and COPCOM (r = 0.49, R² = 0.24, p = 0.044), while no correlation was found between ABC score and CE95%Sway (r = −0.19, R² = 0.04, p = 0.478).ConclusionIndividuals with different disease severities showed different relationships between balance confidence and actual static/dynamic balance control.     

Past smoking and current dopamine agonist use show an independent and dose-dependent association with impulse control disorders in Parkinson's disease

BackgroundPrevious studies have described the association between dopamine replacement therapy in Parkinson's disease and impulse control disorders.MethodsA case–control study was performed to establish the prevalence of four of these behaviors in Brazilian patients with Parkinson's disease on stable dopamine replacement therapy and the possible associated risk factors. We investigated 152 patients and 212 healthy controls for pathological gambling, compulsive sexual behavior and compulsive buying and eating.ResultsOverall, patients had more impulsive control disorders than controls (18.4% vs. 4.2%, P < 0.001). Impulse control disorders were more common in younger patients (P = 0.008) and in those taking dopamine agonist (P < 0.001) and levodopa (P = 0.02). Higher Unified Parkinson's Disease Rating Scale motor score (P = 0.03) and past smoking (P = 0.02) were also associated in the univariate analysis. Variables independently associated with impulse control disorders were history of smoking (odds ratio = 1.059 for each year of smoking, P = 0.010) and current use of pramipexole (odds ratio = 2.551 for each increase in 1 mg, P < 0.001).ConclusionsDopaminergic stimulation and previous exposure to smoking are independently associated with impulse control disorders in a dose-dependent manner.     

Cognitive impulsivity in Parkinson's disease patients: Assessment and pathophysiology

Impulsivity may be induced by therapeutic interventions (dopamine replacement therapies and sub‐thalamic nucleus (STN) stimulation) in patients with Parkinson's disease (PD). The present review has two goals. First, to describe the most frequently encountered facets of cognitive impulsivity and to stress the links between cognitive impulsivity and aspects such as reward‐related decision making, risk‐taking, and time‐processing in healthy population. The most widely used related cognitive impulsivity paradigms are presented. Second, to review the results of studies on cognitive impulsivity in healthy volunteers and in patients with PD, the latter support the applicability and clinical relevance of this construct in PD population. Data show that PD treatments may favor impulsivity via different mechanisms. Suggestions on the roles of dopamine and STN in the pathophysiology of cognitive impulsivity are proposed. © 2009 Movement Disorder Society     

Dopamine‐agonists and impulsivity in Parkinson's disease: Impulsive choices vs. impulsive actions

The control of impulse behavior is a multidimensional concept subdivided into separate subcomponents, which are thought to represent different underlying mechanisms due to either disinhibitory processes or poor decision‐making. In patients with Parkinson's disease (PD), dopamine‐agonist (DA) therapy has been associated with increased impulsive behavior. However, the relationship among these different components in the disease and the role of DA is not well understood. In this imaging study, we investigated in PD patients the effects of DA medication on patterns of brain activation during tasks testing impulsive choices and actions. Following overnight withdrawal of antiparkinsonian medication, PD patients were studied with a H₂ ⁽¹⁵⁾O PET before and after administration of DA (1 mg of pramipexole), while they were performing the delay discounting task (DDT) and the GoNoGo Task (GNG). We observed that pramipexole augmented impulsivity during DDT, depending on reward magnitude and activated the medial prefrontal cortex and posterior cingulate cortex and deactivated ventral striatum. In contrast, the effect of pramipexole during the GNG task was not significant on behavioral performance and involved different areas (i.e., lateral prefrontal cortex). A voxel‐based correlation analysis revealed a significant negative correlation between the discounting value (k) and the activation of medial prefrontal cortex and posterior cingulate suggesting that more impulsive patients had less activation in those cortical areas. Here we report how these different subcomponents of inhibition/impulsivity are differentially sensitive to DA treatment with pramipexole influencing mainly the neural network underlying impulsive choices but not impulsive action. Hum Brain Mapp 35:2499–2506, 2014. © 2013 Wiley Periodicals, Inc.     

Paraphilias and paraphilic disorders in Parkinson's disease: A systematic review of the literature

Paraphilias are intense urges or behaviors involving non‐normative sexual interests. The newly approved diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) have established that, although paraphilias should not be regarded as inherently pathological, they ought to be qualified as paraphilic disorders if resulting in distress, impairment, or harm to the affected individual or others. Recent evidence documents that both phenomena can emerge as relatively uncommon iatrogenic consequences in Parkinson's disease (PD) patients. To outline the clinical characteristics of paraphilias and paraphilic disorders in PD patients, we summarized the available evidence on these phenomena. The review encompasses all studies on paraphilias in PD patients identified by a search on the Pubmed and Scopus online databases through May 2014. Twenty‐two case reports on a total of 31 PD patients with paraphilias or paraphilic disorders were identified. These phenomena were typically associated with dopaminomimetic treatment (with a mean levodopa‐equivalent daily dose of 1,303 ± 823 mg/d) in male patients with motor complications, young age at PD onset, and long disease duration. Paraphilias were highly concomitant with impulse‐control disorders or dopamine dysregulation syndrome. Although evidence on paraphilias and paraphilic disorders in PD patients remains anecdotal, available data point to these phenomena as likely sequelae of high‐dose dopaminomimetic treatment. Accordingly, the intensity of paraphilic urges is typically attenuated by the reduction of dopaminomimetic doses, sometimes in association with atypical antipsychotics. Failure to recognize paraphilic disorders may significantly impair the relational functioning of the affected PD patients. Practitioners should routinely inquire about paraphilias during their clinical assessment of PD patients. © 2015 International Parkinson and Movement Disorder Society