Impulsive-compulsive Behaviors Research Articles

A Single-institution Study on Predictors of Short-term Progression from Mild Cognitive Impairment in Parkinson's Disease to Parkinson's Disease with Dementia.

Patients with non-demented Parkinson's disease (PD) sometime have mild cognitive impairment (MCI), and mild cognitive impairment in Parkinson's disease (PD-MCI) may convert to Parkinson's disease with dementia (PDD) within several years. Cognitive impairment also occurs in the early stages of the disease, gradually progressing to lower quality of life and instrumental activities of daily living. It is important to elucidate the predictors of progression from PD-MCI to PDD via longitudinal studies. This was a single center, case-control study. We analysed data from 49 patients with PD-MCI diagnosed as level I using the Movement Disorder Society PD-MCI criteria at baseline who had completed 1.5 years of follow-up. We defined patients who progressed to PDD as patients with progressive PD-MCI and patients who did not progress to PDD as patients with non-progressive PD-MCI. Depression, apathy, sleep disorders, constipation, light-headedness, hallucinations, impulse control disorders (ICDs) and impulsive-compulsive behaviors (ICBs) at baseline were statistically analysed as predictors of progression. Of the 49 PD-MCI patients, 33 did not convert to PDD (non-progressive PD-MCI), and 16 converted to PDD (progressive PD-MCI). The Mini-Mental State Examination (MMSE) score, light-headedness and ICDs were elucidated as predictors of progressive PD-MCI via a multivariate logistic regression model. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each item were MMSE score, OR 0.324, 95% CI 0.119-0.882, P = 0.027; light-headedness, OR 27.665, 95% CI 2.263-338.185, P= 0.009; and ICDs, OR 53.451, 95% CI 2.298-291.085, P = 0.010. Cognitive function, ICDs and light-headedness may be risk factors for the development of PDD in PD-MCI patients.

Association between REM sleep behavior disorder and impulsive-compulsive behaviors in Parkinson's disease: a systematic review and meta-analysis of observational studies.

Both REM sleep behavior disorder (RBD) and impulsive-compulsive behaviors (ICBs) are well-recognized non-motor features in patients with Parkinson's disease (PD). Studies have given contradictory results about the potential association between RBD and ICBs. PubMed, Embase (via Ovid), and the Cochrane Central Registry of Controlled Trials (CENTRAL) databases were systematically searched till August 20, 2019 to identify studies that explored the possible correlation between RBD and ICBs in patients with PD. Two authors independently screened records, extracted data and evaluated quality of included studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by employing a random or fixed-effects model. We performed subgroup and sensitivity analyses, and we assessed potential publication bias. A total of 134 references were screened and 10 studies involving 2781 PD patients were included. Overall, RBD was associated with a more than twofold higher risk of developing ICBs (OR 2.12, 95% CI 1.43-3.14, I2 = 56.7%, P < 0.01). Similar results were obtained in sensitivity analyses and in meta-analyses of subgroups stratified based on multivariable adjustment and methods for diagnosing RBD and ICBs. No significant risk of publication bias was found. RBD in PD is confirmed to be a risk factor for ICBs. Clinicians should be aware of this association to help them improve patient management.

Lower nucleus accumbens α-synuclein load and D3 receptor levels in Parkinson's disease with impulsive compulsive behaviours

Impulsive compulsive behaviours in Parkinson's disease have been linked to increased dopaminergic release in the ventral striatum and excessive stimulation of dopamine D3 receptors. Thirty-one patients with impulsive compulsive behaviours and Parkinson's disease who donated their brains to the Queen Square Brain Bank for Neurological Disorders were assessed for α-synuclein neuropathological load and tyrosine hydroxylase levels in the nucleus accumbens, dorsal putamen and caudate using immunohistochemistry. Dopamine D2 and dopamine D3 receptors protein levels in the nucleus accumbens, frontal cortex and putamen were determined using western blotting. Results were compared to 29 Parkinson's disease cases without impulsive compulsive behaviours matched by age, sex, disease duration, age at Parkinson's disease onset and disease duration. The majority of patients with impulsive compulsive behaviours had dopamine dysregulation syndrome. Patients with Parkinson's disease and impulsive compulsive behaviours had lower α-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. No differences were seen between groups in the other brain areas and in the analysis of tyrosine hydroxylase and dopamine D2 receptor levels. Lower α-synuclein load in the nucleus accumbens of individuals with Parkinson's disease and impulsive compulsive behaviours was confirmed on western blotting. Downregulation of the dopamine D3 receptor levels may have occurred either as a consequence of the degenerative process or of a pre-morbid trait. The lower levels of α-synuclein may have contributed to an excessive stimulation of the ventral striatum resulting in impulsive compulsive behaviours.

Deterioration of postural deformity in Parkinson’s disease patients with punding and hobbyism

This study aimed to examine whether worsening of postural deformities is seen in Parkinson’s disease (PD) patients who exhibit the behavioral disorders punding or hobbyism (P-H), which involve maintaining the same poor posture. The subjects were 80 patients with PD (aged 73.1 ± 8.8 years; duration of disease, 6.4 ± 5.5 years). Using the Japanese-language version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (J-QUIP), a group with P-H alone (P-H only group) and a group without impulsive-compulsive behaviors (non-ICB group) were compared with respect to the angles of forward and lateral trunk flexion while standing at rest. The group with ICBs (ICB group) identified by the J-QUIP consisted of 36 patients (45.0%). Of these, 25 (31.3%) were in the P-H only group. The non-ICB group, who were negative on all items of the J-QUIP, consisted of 44 patients (55.0%). Significantly higher values were seen in the P-H only group compared with non-ICB group for the angle of forward flexion of the trunk (FFT angle, p = 0.04), Unified Parkinson’s Disease Rating Scale (UPDRS) part II score (p = 0.002), and UPDRS total score (p = 0.007). The FFT angle was increased and activities of daily living decreased in PD patients with P-H.

Saccadic Direction Errors are Associated with Impulsive Compulsive Behaviours in Parkinson's Disease Patients.

Fifteen individuals with Parkinson's disease (PD) and impulsive compulsive behaviours (PD+ICB) were compared to 15 PD patients without ICBs (PD-ICB) and 15 healthy controls (HC) on a pro-saccades and an anti-saccades task to assess if ICBs are associated with distinct saccadic abnormalities. PD+ICB made shorter saccades than HC and more direction errors in the anti-saccades task than PD-ICB and HC, suggesting that patients with ICBs have greater difficulty in suppressing automatic saccades towards a given target. Saccadic assessment has the potential to evolve into a marker to guide therapeutic decisions in patients at risk of developing ICBs.

Impulsive-Compulsive Behaviours in Belgian-Flemish Parkinson's Disease Patients: A Questionnaire-Based Study.

Background Impulsive-compulsive behaviours (ICB) are a potentially harmful group of behavioural symptoms among the nonmotor aspects of Parkinson's disease (PD). Objective To develop and perform partial validation of a Belgian-Flemish version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) as a screening instrument for ICB in PD patients. Methods Using a translation-backtranslation method, we developed a Belgian-Flemish version of the QUIP, which was subsequently completed by 88 PD patients. QUIP-positive patients were invited for a semistructured diagnostic interview. Results A positive QUIP score for one or more ICB was observed in 37 patients (41%). In 15 patients (17%), a positive QUIP score for one or more impulse control disorders (ICD) was noted: pathological gambling in 1, hypersexuality in 8, compulsive shopping in 5, and compulsive eating in 8 patients. A positive QUIP score for punding, hobbyism, and/or walkabout was observed in 30 patients. The semistructured diagnostic interview was performed in 22 QUIP-positive patients. The diagnosis of ICB was confirmed in 6 patients, suggesting a positive predictive value of 27% for the Belgian-Flemish version of the QUIP. Conclusions We have developed a Belgian-Flemish version of the QUIP, which can be used as a screening questionnaire for ICB in PD patients. Our data suggest that sensitivity is high, specificity is low, and validity of the questionnaire is similar to the original version. We confirm the necessity of additional clinical assessment of QUIP-positive patients to ascertain a diagnosis of ICB.

A Systematic Meta-Review of Impulsivity and Compulsivity in Addictive Behaviors.

It is well established that poor inhibitory control confers both a vulnerability to, and maintenance of, addictive behaviors across the substance and behavioral spectrums. By comparison, the role of compulsivity in addictive behaviors has received less research focus. The neurocognitive literature to date is vast, and it is unclear whether there are any convincing lines of systematic evidence delineating whether and how aspects of impulsivity and compulsivity are shared and unique across different substance and behavioral addictive disorders. Such information has significant implications for our understanding of underlying mechanisms and clinical implications for assessing and treating neurocognitive deficits across addictions. Here, we conducted a systematic meta-review of the quantitative meta-analyses to date, specifically examining the neurocognitive functions central to impulsive-compulsive behaviors transdiagnostically across addictive behaviors. Out of 1186 empirical studies initially identified, six meta-analyses met inclusion criteria examining alcohol, cannabis, cocaine, MDMA, methamphetamine, opioid and tobacco use, as well as gambling and internet addiction. The pooled findings across the systematic meta-analyses suggest that impulsivity is a core process underpinning both substance and behavioral addictive disorders, although it is not equally implicated across all substances. Compulsivity-related neurocognition, by comparison, is important across alcohol and gambling disorders, but has yet to be examined systematically. The gestalt of findings to date suggests that both impulsivity and compulsivity are core constructs linked to addictive behaviors and may not be solely the secondary sequelae associated with the effects of prolonged substance exposure.

Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control.

Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density. Furthermore, previous studies have demonstrated a reduction of fronto-striatal connectivity to be associated with increased risk of impulsive-compulsive behaviour in Parkinson's disease. Therefore, another aim of this study was to investigate the relationship between severity of impulsive-compulsive behaviour, dopamine synthesis capacity and fronto-striatal connectivity. Eighty participants underwent resting state functional MRI and anatomical T1-weighted images [mean age: 68 ± 9.9 years, 67% male (patients)]. In 59 participants, 18F-DOPA-PET was obtained and voxel-wise Patlak slopes indicating dopamine synthesis capacity were calculated. All participants completed the QUIP-RS questionnaire, a well validated test to quantify severity of impulsive-compulsive behaviour in Parkinson's disease. A voxel-wise correlation analysis between dopamine synthesis capacity and QUIP-RS score was calculated for striatal regions. To investigate the relationship between symptom severity and functional connectivity, voxel-wise correlations were performed. A negative correlation was found between dopamine synthesis capacity and QUIP-RS score in the nucleus accumbens (r = -0.57, P = 0.001), a region functionally connected to the rostral anterior cingulate cortex. The connectivity strength was modulated by QUIP-RS, i.e. patients with more severe impulsive-compulsive behaviours had a weaker functional connectivity between rostral anterior cingulate cortex and the nucleus accumbens. In addition, cortical thickness and severity of impulsive-compulsive behaviour were positively correlated in the subgenual rostral anterior cingulate cortex. We found three factors to be associated with severity of impulsive-compulsive behaviour: (i) decreased dopamine synthesis capacity in the nucleus accumbens; (ii) decreased functional connectivity of the rostral anterior cingulate cortex with the nucleus accumbens; and (iii) increased cortical thickness of the subgenual rostral anterior cingulate cortex. Rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortex-a region known to play a key role in impulse control-could be the most crucial neurobiological risk factor for the development of impulsive-compulsive behaviours in patients with Parkinson's disease under dopamine replacement therapy.

The long-term outcome of impulsive compulsive behaviours in Parkinson’s disease

Impulsive compulsive behaviours (ICBs) such as dopamine dysregulation syndrome (DDS), pathological gambling, compulsive sexual behaviour, punding, compulsive shopping and binge eating are recognised complications of dopaminergic treatment that affect at...

The factors associated with impulse control behaviors in Parkinson's disease: A 2-year longitudinal retrospective cohort study.

IntroductionImpulse control behaviors (ICBs) are impulsive–compulsive behaviors often associated with dopamine replacement therapy in Parkinson's disease (PD). Although remission can occur in ICB, only four reports on the ratio of remission and the persistence of ICB have been published, and the associated factors with ICB remission or persistence have been little known. Therefore, we conducted a longitudinal assessment of the remission, persistence, and development of ICB and those associated factors in patients with PD.MethodsWe retrospectively investigated a PD database at Aomori Prefectural Central Hospital, Japan. One hundred and forty‐eight patients with PD who could be followed up for 2 years were enrolled. ICB was assessed using the Questionnaire for Impulsive–Compulsive Disorders in Parkinson's disease. Motor severity (Hoehn and Yahr scale and United Parkinson's Disease Rating Scale), cognitive function (Mini–Mental State Examination), and other clinical variables (sex, age, onset age, disease duration, olfactory dysfunction, and dyskinesia) and medications used to treat PD were assessed. Univariate analyses were performed.ResultsSeven patients were excluded because of the exclusion criteria, and 141 patients were analyzed. Thirty patients (21.3%) had ICB at baseline, and these patients also had significantly higher use of pergolide. The ICB remission rate was 60%, the ICB persistence ratio was 40%, and the ICB development ratio was 12.6% over 2 years. Statistically, younger age and pergolide use were associated with ICB persistence. Being male, having dyskinesia, and rotigotine, entacapone, zonisamide, and istradefylline use were associated with ICB development.ConclusionThis study suggests that younger age and pergolide use may be the new associated factors with ICB persistence and that entacapone, zonisamide, and istradefylline use may be associated with the development of ICB. Drug profiles and medication practices in Japan may explain the association of these factors with ICB.

Longitudinal Cortical Thickness Changes in Early Parkinson’s Disease Patients with Impulsive Compulsive Behaviors (P3.070)

Longitudinal Cortical Thickness Changes in Early Parkinson’s Disease Patients with Impulsive Compulsive Behaviors (P3.070)

Pathophysiology of dyskinesia and behavioral disorders in non-human primates: the role of serotonergic fibers.

The MPTP monkey model of Parkinson's disease (PD) has allowed huge advances regarding the understanding of the pathological mechanisms of PD and L-DOPA-induced adverse effects. Among the main findings were the imbalance between the efferent striatal pathways in opposite directions between the hypokinetic and hyperkinetic states of PD. In both normal and parkinsonian monkeys, the combination of behavioral and anatomical studies has allowed the deciphering of the cortico-basal ganglia circuits involved in both movement and behavioral disorders. A major breakthrough has then been made regarding the hypothesis of the involvement of serotonergic fibers in the conversion of L-DOPA to dopamine when dopaminergic neurons are dying and to release it, in an uncontrolled manner, as serotonergic neurons are deprived from the machinery required for buffering dopamine from the synaptic cleft. The crucial involvement of serotonergic fibers underlying L-DOPA-induced dyskinesia (LID) has been demonstrated in both rodent and monkey models of PD, in which dyskinesia induced by L-DOPA is abolished following lesion of the serotonergic system. Moreover, the role of serotonergic fibers goes well beyond dyskinesia, as lesioning of such serotonergic fibers by MDMA in the monkey also decreased other L-DOPA-induced adverse effects such as impulsive compulsive behaviors and visual hallucinations. The same pathological mechanism, i.e., an imbalance between serotonin and dopamine terminals may, therefore, favor L-DOPA-induced adverse effects according to the basal ganglia territory it inhabits. Further non-human primate studies will be needed to demonstrate the role of such a pathological mechanism in both movement and behavioral disorders driven by L-DOPA therapy but also to determine the causal link between serotonin lesions and the expression of non-motor symptoms like apathy, depression and anxiety, frequently observed in PD patients.

Nigrostriatal and Mesolimbic D2/3Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n = 17) and without (n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3 receptor BPND Group differences in regional D2/3 BPND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

Impulse control disorders in Parkinson's disease: Review of pathophysiology, epidemiology, clinical features, management, and future challenges.

Impulsive-compulsive behavior (ICB) in Parkinson's disease (PD) suggests a combination of impulse control disorders (ICDs), such as pathological gambling, hypersexuality, compulsive eating, excessive buying, and compulsive behaviors, such as punding, dopamine dysregulation syndrome (DDS), hoarding, and hobbyism. Hypersexuality and gambling are common in male patients while compulsive buying is common in women patients. Recent studies reveal the prevalence of ICB to be more than 25% among the PD patients. The nigrostriatal, mesocortical, and mesolimbic dopaminergic pathways play a crucial role in the pathogenesis of ICDs in PD patients. The greater tonic release of dopamine creates a state of relative dopamine deficit and reduced reward sensation and impulsive behaviors. The major risk factors for ICB are the use of dopamine agonist (DA), male gender, young patient, depression, smoking, drug abuse, Parkin mutation, and family history of ICDs. Single nucleotide polymorphism in dopamine receptors D1, D2, and D3 also acts as a major risk factor. Questionnaire for impulsive-compulsive disorders in PD is the most widely adopted screening tool for the detection of ICB in PD. The major treatment for PD is to discontinue DAs and use prolonged release formulation of the DAs. The role of deep brain stimulation (DBS) and apomorphine in the treatment of ICB is still uncertain. Though DBS can reduce the risk of DDS, it can precipitate new ICBs such as hypersexuality.

Can we predict development of impulsive–compulsive behaviours in Parkinson’s disease?

ObjectiveTo determine clinical and structural imaging predictors of impulsive–compulsive behaviour (ICB) in de novo Parkinson’s disease (PD).MethodsFrom a cohort of 1116 subjects from the Parkinson’s Progression Marker Initiative database, we...

Deterioration of postural deformity in Parkinson’s disease patients with punding and hobbyism

Abstract This study aimed to examine whether worsening of postural deformities is seen in Parkinson’s disease (PD) patients who exhibit the behavioral disorders punding or hobbyism (P-H), which involve maintaining the same poor posture. The subjects were 80 patients with PD (aged 73.1 ± 8.8 years; duration of disease, 6.4 ± 5.5 years). Using the Japanese-language version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (J-QUIP), a group with P-H alone (P-H only group) and a group without impulsive-compulsive behaviors (non-ICB group) were compared with respect to the angles of forward and lateral trunk flexion while standing at rest. The group with ICBs (ICB group) identified by the J-QUIP consisted of 36 patients (45.0%). Of these, 25 (31.3%) were in the P-H only group. The non-ICB group, who were negative on all items of the J-QUIP, consisted of 44 patients (55.0%). Significantly higher values were seen in the P-H only group compared with non-ICB group for the angle of forward flexion of the trunk (FFT angle, p = 0.04), Unified Parkinson’s Disease Rating Scale (UPDRS) part II score (p = 0.002), and UPDRS total score (p = 0.007). The FFT angle was increased and activities of daily living decreased in PD patients with P-H.

Association between REM sleep behaviour disorder and impulse control disorder in patients with Parkinson's disease

IntroductionThe relationship between impulse control disorder (ICD) and REM sleep behaviour disorder (RBD) has not yet been clarified, and the literature reports contradictory results. Our purpose is to analyse the association between these 2 disorders and their presence in patients under dopaminergic treatment. MethodsA total of 73 patients diagnosed with Parkinson's disease and treated with a single dopamine agonist were included in the study after undergoing clinical assessment and completing the single-question screen for REM sleep behaviour disorder and the short version of the questionnaire for impulsive–compulsive behaviours in Parkinson's disease. ResultsMean age was 68.88±7.758 years. Twenty-six patients (35.6%) were classified as probable-RBD. This group showed a significant association with ICD (P=.001) and had a higher prevalence of non-tremor akinetic rigid syndrome and longer duration of treatment with levodopa and dopamine agonists than the group without probable-RBD. We found a significant correlation between the use of oral dopamine agonists and ICD. Likewise, patients treated with oral dopamine agonists demonstrated a greater tendency towards presenting probable-RBD than patients taking dopamine agonists by other routes; the difference was non-significant. ConclusionsThe present study confirms the association between RBD and a higher risk of developing symptoms of ICD in Parkinson's disease.

White matter tract alterations in Parkinson's disease patients with punding

ObjectiveTo assess brain white matter tract alterations in patients with Parkinson's disease and punding (PD-punding) compared with controls and PD cases without any impulsive-compulsive behaviour. MethodsForty-nine PD patients (21 PD-punding and 28 PD with no impulsive-compulsive behaviours) and 28 controls were consecutively recruited. Clinical, cognitive and psychopathological evaluations were performed. Diffusion tensor MRI metrics of the main white matter tracts were assessed using a tractography approach. ResultsCompared with controls, both PD groups showed white matter microstructural alterations of the left pedunculopontine tract and splenium of the corpus callosum. PD-punding patients showed a further damage to the right pedunculopontine tract and uncinate fasciculus, genu of the corpus callosum, and left parahippocampal tract relative to controls. When adjusting for depression and/or apathy severity, a greater damage of the genu of the corpus callosum and the left pedunculopontine tract was found in PD-punding compared with patients with no impulsive-compulsive behaviours. ConclusionsPD-punding is associated with a disconnection between midbrain, limbic and white matter tracts projecting to the frontal cortices. These alterations are at least partially independent of their psychopathological changes. Diffusion tensor MRI is a powerful tool for understanding the neural substrates underlying punding in PD.

Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors.

PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors. Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity. Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions. These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.

Chronic pramipexole treatment induces compulsive behavior in rats with 6-OHDA lesions of the substantia nigra and ventral tegmental area.

Dopamine replacement therapy (DRT) reduces motor symptoms in Parkinson's disease (PD), but also induces impulsive-compulsive behavior (ICB) in up to 25% of PD patients. These non-motor side effects of DRT generally follow a gradual transition from impulsive to compulsive-like-i.e. repetitive, compelled, and non-pleasurable-behavior. Here, we investigated the effect of chronic pramipexole (PPX) treatment on the onset of compulsive-like behavior, measured via the post-training signal attenuation (PTSA) procedure, in rats with dopaminergic lesions. Accordingly, we aimed to mimic chronic DRT in a PD context, and obtain data on the brain regions that potentially sustain this type of compulsive behavior pattern in rats. We observed that the lesion or treatment alone did not induce compulsive lever pressing in rats. However, rats with lesions of the substantia nigra and ventral tegmental area as well as with chronic PPX treatment developed strong compulsive lever-pressing behavior, as measured via PTSA. Furthermore, when chronic PPX treatment was discontinued before the PTSA test, the lesioned rats showed the same level of compulsive behavior as sham-operated rats. In fact, lesioned, treated, and compulsive-like rats showed significantly higher Fos expression in the orbitofrontal cortex and dorsal striatum. Thus, chronic PPX treatment in PD rats induced a strong compulsive-like behavior. Furthermore, Fos expression mapping suggests that the behavior was sustained via the activation of the orbitofrontal cortex and dorsal striatum.