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1.  Subthalamic nucleus stimulation influences expression and suppression of impulsive behaviour in Parkinson’s disease 
Brain  2010;133(12):3611-3624.
Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinson’s disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinson’s disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinson’s disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus.
doi:10.1093/brain/awq239
PMCID: PMC2995881  PMID: 20861152
Parkinson’s disease; deep-brain stimulation; response inhibition; impulsivity; subthalamic nucleus
2.  Impulsive and Compulsive Behaviors in Parkinson’s Disease 
Background: Impulsive and compulsive behaviors (ICBs) are a heterogeneous group of conditions that may be caused by long-term dopaminergic replacement therapy (DRT) of Parkinson’s disease (PD). The spectrum of ICBs includes dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs).
Contents: We made a detailed review regarding the epidemiology, pathology, clinical characteristics, risk factors, diagnosis as well as treatment of ICBs.
Results: The prevalence of ICBs in PD patients is approximately 3–4% for DDS, 0.34–4.2% for punding, and 6–14% for ICDs, with higher prevalence in Western populations than in Asian. Those who take high dose of levodopa are more prone to have DDS, whereas, ICDs are markedly associated with dopamine agonists. Different subtypes of ICBs share many risk factors such as male gender, higher levodopa equivalent daily dose, younger age at PD onset, history of alcoholism, impulsive, or novelty-seeking personality. The Questionnaire for Impulsive–Compulsive Disorder in Parkinson’s Disease-Rating Scale seems to be a rather efficacious instrument to obtain relevant information from patients and caregivers. Treatment of ICBs is still a great challenge for clinicians. Readjustment of DRT remains the primary method. Atypical antipsychotics, antidepressants, amantadine, and psychosocial interventions are also prescribed in controlling episodes of psychosis caused by compulsive DRT, but attention should be drawn to balance ICBs symptoms and motor disorders. Moreover, deep brain stimulation of the subthalamic nucleus might be a potential method in controlling ICBs.
Conclusion: The exact pathophysiological mechanisms of ICBs in PD remains poorly understood. Further researches are needed not only to study the pathogenesis, prevalence, features, and risk factors of ICBs, but to find efficacious therapy for patients with these devastating consequences.
doi:10.3389/fnagi.2014.00318
PMCID: PMC4231987  PMID: 25452726
Parkinson disease; impulsive control disorders; dopamine dysregulation syndrome; review; dopaminergic replacement therapy
3.  Multiple Modes of Impulsivity in Parkinson's Disease 
PLoS ONE  2014;9(1):e85747.
Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I–III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity.
doi:10.1371/journal.pone.0085747
PMCID: PMC3897514  PMID: 24465678
4.  Dopamine agonists and risk: impulse control disorders in Parkinson's; disease 
Brain  2011;134(5):1438-1446.
Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.
doi:10.1093/brain/awr080
PMCID: PMC3097893  PMID: 21596771
Parkinson's; disease; dopamine; gambling; decision making; risk
5.  Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease 
Brain  2014;137(4):1145-1155.
Impulsivity is common in Parkinson’s disease. In a double-blind, placebo-controlled study with multi-modal imaging, Ye et al. reveal improved response inhibition in some patients receiving the SSRI citalopram, including those with advanced disease. Improvements correlated with preserved frontostriatal structural connectivity and drug-induced prefrontal activity, highlighting the need for patient stratification in trials.
Impulsivity is common in Parkinson’s disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic ‘overdose’ and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson’s disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46–76 years old, 11 male, Hoehn and Yahr stage 1.5–3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54–74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson’s disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson’s Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson’s disease.
doi:10.1093/brain/awu032
PMCID: PMC3959561  PMID: 24578545
Parkinson’s disease; response inhibition; serotonin; citalopram; functional MRI
6.  Ventral Striatal Dopamine Synthesis Capacity Predicts Financial Extravagance in Parkinson’s Disease 
Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
doi:10.3389/fpsyg.2013.00090
PMCID: PMC3583186  PMID: 23450713
dopa decarboxylase; dopamine; disordered gambling; externalizing; impulse control disorders; impulsivity; reward; ventral striatum
7.  Impulse control disorders in Parkinson’s disease: recent advances 
Current opinion in neurology  2011;24(4):324-330.
Purpose of review
To review the recent advances in the epidemiology and pathophysiology of impulse control disorders (ICD) in Parkinson’s disease (PD).
Recent findings
Large cross-sectional and case-control multicentre studies show that ICDs in PD are common with a frequency of 13.6%. These behaviours are associated with impaired functioning and with depressive, anxiety and obsessive symptoms, novelty seeking and impulsivity. Behavioural subtypes demonstrate differences in novelty seeking and impulsivity suggesting pathophysiological differences. Observational and neurophysiological studies point towards a potential mechanistic overlap between the behavioural (ICDs) and motor (dyskinesias) dopaminergic sequelae. Converging data suggest dopamine agonists in ICDs appear to enhance learning from rewarding outcomes and impulsive choice. ICD patients also have enhanced risk preference and impaired working memory. Neuroimaging data points towards enhanced bottom-up ventral striatal dopamine release to incentive cues, gambling tasks and reward prediction, and possibly inhibition of top-down orbitofrontal influences. Dopamine agonist-related ventral striatal hypoactivity to risk is consistent with impaired risk evaluation.
Summary
Recent large scale studies and converging findings are beginning to provide an understanding of mechanisms underlying ICDs in PD which can guide prevention of these behaviours and optimize therapeutic approaches.
doi:10.1097/WCO.0b013e3283489687
PMCID: PMC3154756  PMID: 21725242
Impulse control disorders; Parkinson’s disease; dopamine agonists; pathological gambling; impulsivity
8.  Dopamine agonists rather than deep brain stimulation cause reflection impulsivity in Parkinson’s disease 
Journal of Parkinson's disease  2013;3(2):139-144.
Objectives
To assess the role of dopamine agonist therapy and deep brain stimulation on reflection impulsivity in non-demented patients with Parkinson’s disease (PD).
Methods
We recruited 61 PD patients, 20 treated with L-dopa in combination with a dopamine agonist, 14 taking L-dopa monotherapy, a further 16 PD patients with bilateral subthalamic nucleus deep brain stimulation treated with L-dopa in combination with a dopamine agonist, and 11 PD patients with bilateral subthalamic nucleus deep brain stimulation taking L-dopa but not a dopamine agonist. Results were compared with 18 healthy controls. Patients who had evidence of impulsive compulsive behaviour were excluded.
Reflection impulsivity was assessed with the beads task, which is a validated information sampling task.
Results
All patients treated with a dopamine agonist gathered significantly less information and made more irrational decisions than all other groups regardless of whether they had surgical treatment.
Conclusions
Our results imply that dopamine agonist therapy but not deep brain stimulation lead to “reflection impulsivity“ in PD.
doi:10.3233/JPD-130178
PMCID: PMC4205962  PMID: 23938343
Parkinson’s disease [165]; deep brain stimulation [292]; neuropsychology [199]
9.  Investigation of impulsivity in patients on dopamine agonist therapy for hyperprolactinemia: a pilot study 
Pituitary  2014;17(2):150-156.
The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson’s disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross—sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r2 = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.
doi:10.1007/s11102-013-0480-6
PMCID: PMC4109390  PMID: 23504371
Cabergoline; Dopamine agonist; Hyperprolactinemia; Impulsivity; Pituitary adenoma
10.  Stimulation of the Subthalamic Nucleus and Impulsivity 
Annals of neurology  2009;66(6):817-824.
Objective
In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a “hold your horses” signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect.
Methods
We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD.
Results
Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition.
Interpretation
The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.
doi:10.1002/ana.21795
PMCID: PMC2972250  PMID: 20035509 CAMSID: cams1535
11.  Stroop test performance in impulsive and non impulsive patients with Parkinson’s disease 
Parkinsonism & related disorders  2011;17(3):212-214.
Impulsive personalities are considered to have a general impairment in cognitive flexibility and cortical inhibition. To examine this hypothesis we used a trial by trial Stroop task in impulsive and non impulsive patients with Parkinson’s disease (PD) and recorded errors and reaction times (RT). We tested 28 impulsive PD (PD+ICB) and 24 non impulsive PD (PD-ICB) patients prior to and after dopaminergic medication. These results were compared with 24 age matched normal controls. We found an increased error rate in all PD patients prior to their usual medication which resolved after medication. Furthermore patients on medication showed enhanced cognitive flexibility and shorter RT. There was no difference between non impulsive and impulsive PD patients. This suggests that the impulsive behaviours may not affect response inhibition tasks and the response inhibition required in the Stroop test does not engage the same processes that differentiate impulsive and non-impulsive PD patients, which likely involve mesolimbic dopamine.
doi:10.1016/j.parkreldis.2010.12.014
PMCID: PMC3042030  PMID: 21247790
12.  Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making 
Brain  2012;135(12):3721-3734.
Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus–response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the ‘normalization term’ in Bayes’ theorem). Here, we test these theories by investigating 22 patients with Parkinson’s disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions—information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their plan, a pattern of behaviour that mirrors the impulsivity described clinically in some patients with subthalamic nucleus deep brain stimulation. Thus, we demonstrate distinct mechanisms for two important facets of human decision making: first, a role for dopamine in memory consolidation, and second, the critical importance of the subthalamic nucleus in successful decision making when multiple pieces of information must be combined.
doi:10.1093/brain/aws273
PMCID: PMC3525052  PMID: 23114368
decision making; Parkinson’s disease; mathematical modelling; reasoning; memory
13.  Diagnosis and treatment of impulse control disorders in patients with movement disorders 
Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson’s disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson’s disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease has been developed specifically for Parkinson’s disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine.
doi:10.1177/1756285613476127
PMCID: PMC3625015  PMID: 23634190
Impulse control disorders; Parkinson’s disease; restless leg syndrome; parkinsonism; dopamine agonist; non-motor complication; neurobehavioural
14.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical psychology review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine
15.  Behavioral models of impulsivity in relation to ADHD: Translation between clinical and preclinical studies 
Clinical Psychology Review  2006;26(4):379-395.
Impulsivity, broadly defined as action without foresight, is a component of numerous psychiatric illnesses including attention deficit/hyperactivity disorder (ADHD), mania and substance abuse. In order to investigate the mechanisms underpinning impulsive behavior, the nature of impulsivity itself needs to be defined in operational terms that can be used as the basis for empirical investigation. Due to the range of behaviors that the term impulsivity describes, it has been suggested that impulsivity is not a unitary construct, but encompasses a variety of related phenomena that may differ in their biological basis. Through fractionating impulsivity into these component parts, it has proved possible to devise different behavioral paradigms to measure various aspects of impulsivity in both humans and laboratory animals. This review describes and evaluates some of the current behavioral models of impulsivity developed for use with rodents based on human neuropsychological tests, focusing on the five-choice serial reaction time task, the stop-signal reaction time task and delay-discounting paradigms. Furthermore, the contributions made by preclinical studies using such methodology to improve our understanding of the neural and neurochemical basis of impulsivity and ADHD are discussed, with particular reference to the involvement of both the serotonergic and dopaminergic systems, and frontostriatal circuitry.
doi:10.1016/j.cpr.2006.01.001
PMCID: PMC1892795  PMID: 16504359
ADHD; Impulsivity; Frontal cortex; Inhibition; Serotonin; Dopamine
16.  Unidirectional relationship between heroin self-administration and impulsive decision-making in rats 
Psychopharmacology  2011;219(2):443-452.
Rationale
There is growing clinical evidence for a strong relationship between drug addiction and impulsivity. However, it is not fully clear whether impulsivity is a pre-existing trait or a consequence of drug abuse. Recent observations in the animal models show that pre-existing levels of impulsivity predict cocaine and nicotine seeking. Whether such relationships also exist with respect to non-stimulant drugs is largely unknown.
Objective
We studied the relationship between impulsive choice and vulnerability to heroin taking and seeking.
Materials and methods
Rats were selected in the delayed reward task based on individual differences in impulsive choice. Subsequently, heroin intravenous self-administration behaviour was analysed, including acquisition of heroin intake, motivation, extinction and drug- and cue-induced reinstatement. Throughout the entire experiment, changes in impulsive choice were monitored weekly.
Results and discussion
High impulsivity did not predict measures of heroin taking. Moreover, high impulsive rats did not differ from low impulsive rats in extinction rates or heroin- and cue-induced reinstatement. However, both groups became more impulsive as heroin self-administration continued. During abstinence, impulsivity levels returned towards baseline (pre-heroin) levels. Our results indicate that, in contrast to psychostimulants, impulsive choice does not predict vulnerability to heroin seeking and taking.
Conclusion
These data implicate that different neural mechanisms may underlie the vulnerability to opiate and psychostimulant dependence. Moreover, our data suggest that elevated impulsivity levels as observed in heroin-dependent subjects are a consequence of heroin intake rather than a pre-existing vulnerability trait.
doi:10.1007/s00213-011-2444-8
PMCID: PMC3249213  PMID: 21887498
Impulsivity; Heroin; Opiate; Addiction; Delayed reward task; Self-administration
17.  Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review 
Neuropsychopharmacology  2009;35(3):591-604.
Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
doi:10.1038/npp.2009.185
PMCID: PMC3055606  PMID: 19940844
impulsive; compulsive; endophenotypes; serotonin; dopamine; Cognition; Psychiatry & Behavioral Sciences; Animal models; Biological Psychiatry; OCD; impulsivity; compulsivity; translational
18.  Impulsivity and apathy in Parkinson’s disease 
Journal of neuropsychology  2013;7(2):10.1111/jnp.12013.
Impulse control disorders (ICDs) and apathy are recognized as two important neuropsychiatric syndromes associated with Parkinson’s disease (PD), but as yet we understand very little about the cognitive mechanisms underlying them. Here, we review emerging findings, from both human and animal studies, that suggest that impulsivity and apathy are opposite extremes of a dopamine-dependent spectrum of motivated decision making. We first argue that there is strong support for a hypodopaminergic state in PD patients with apathy, as well as for an association between dopamine therapy and development of ICDs. However, there is little evidence for a clear dose-response relationship, and great heterogeneity of findings. We argue that dopaminergic state on its own is an insufficient explanation, and suggest instead that there is now substantial evidence that both apathy and impulsivity are in fact multi-dimensional syndromes, with separate, dissociable mechanisms underlying their ‘surface’ manifestations. Some of these mechanisms might be dopamine-dependent. According to this view, individuals diagnosed as impulsive or apathetic may have very different mechanisms underlying their clinical states. We propose that impulsivity and apathy can arise from dissociable deficits in option generation, option selection, action initiation or inhibition and learning. Review of the behavioural and neurobiological evidence leads us to a new conceptual framework that might help understand the variety of functional deficits seen in PD.
doi:10.1111/jnp.12013
PMCID: PMC3836240  PMID: 23621377
19.  Investigating the behavioral and self-report constructs of impulsivity domains using principal component analysis 
Behavioural Pharmacology  2009;20(5-6):390-399.
Impulsivity, often defined as a human behavior characterized by the inclination of an individual to act on urge rather than thought, with diminished regard to consequences, encompasses a range of maladaptive behaviors which are in turn affected by distinct neural systems. Congruent with the above definition, behavioral studies have consistently shown that the underlying construct of impulsivity is multidimensional in nature. However, research to date has been inconclusive regarding the different domains or constructs that constitute this behavior. In addition there is also no clear consensus as to whether self-report and laboratory based measures of impulsivity measure the same or different domains. The current study aimed to: 1) characterize the underlying multidimensional construct of impulsivity using a sample with varying degrees of putative impulsivity related to substance misuse, including subjects who were at-risk of substance use or addicted (ARA), and 2) assess relationships between self-report and laboratory measures of impulsivity, using a principal component-based factor analysis. In addition, our supplementary goal was to evaluate the structural constructs of impulsivity within each group separately (healthy and ARA). We used five self-report measures (Behavioral Inhibition System/Behavioral Activation System (BIS/BAS), Barratt Impulsivity Scale-11, Padua Inventory, Zuckerman Sensation Seeking Scale (SSS), and Sensitivity to Punishment and Sensitivity to Reward Questionnaire) and two computer based laboratory tasks (Balloon Analog Risk Task and the Experiential Delay Task) to measure aspects of impulsivity in a total of 176 adult subjects. Subjects included healthy controls (N=89), non-alcoholic subjects with family histories of alcoholism (FHP; N=36) and both former (N=20) and current (N=31) cocaine users. Subjects with a family history of alcoholism and cocaine abusers were grouped together as “at-risk/addicted” (ARA) to evaluate our supplementary goal. Our overall results revealed the multidimensional nature of the impulsivity construct as captured optimally through a five factor solution that accounted for nearly 70% of the total variance. The five factors/components were imputed as follows “Self-Reported Behavioral Activation”, “Self-Reported Compulsivity and Reward/Punishment”, “Self-Reported Impulsivity”, “Behavioral Temporal Discounting” and “Behavioral Risk-Taking.” We also found that contrary to previously published reports, there was significant overlap between certain laboratory and self-report measures, indicating that they might be measuring the same impulsivity domain. In addition, our supplemental analysis also suggested that the impulsivity constructs were largely, but not entirely the same within the healthy and ARA groups.
doi:10.1097/FBP.0b013e32833113a3
PMCID: PMC3268653  PMID: 19724194
impulsivity; behavior; substance abuse; cocaine; alcohol; factor analysis; PCA; BIS-BAS; BIS-11; EDT; BART; Zuckerman; SPSRQ; human
20.  Mu and Delta Opioid Receptors Oppositely Regulate Motor Impulsivity in the Signaled Nose Poke Task 
PLoS ONE  2009;4(2):e4410.
Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1) or delta- (Oprd1) opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6) or a hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB) background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue) and motor impulsivity (premature responses). Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders.
doi:10.1371/journal.pone.0004410
PMCID: PMC2635474  PMID: 19198656
21.  The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling 
An influential model suggests that dopamine signals the difference between predicted and experienced reward. In this way, dopamine can act as a learning signal that can shape behaviors to maximize rewards and avoid punishments. Dopamine is also thought to invigorate reward seeking behavior. Loss of dopamine signaling is the major abnormality in Parkinson’s disease. Dopamine agonists have been implicated in the occurrence of impulse control disorders in Parkinson’s disease patients, the most common being pathological gambling, compulsive sexual behavior, and compulsive buying. Recently, a number of functional imaging studies investigating impulse control disorders in Parkinson’s disease have been published. Here we review this literature, and attempt to place it within a decision-making framework in which potential gains and losses are evaluated to arrive at optimum choices. We also provide a hypothetical but still incomplete model on the effect of dopamine agonist treatment on these value and risk assessments. Two of the main brain structures thought to be involved in computing aspects of reward and loss are the ventral striatum (VStr) and the insula, both dopamine projection sites. Both structures are consistently implicated in functional brain imaging studies of pathological gambling in Parkinson’s disease.
doi:10.3389/fnbeh.2014.00196
PMCID: PMC4038955  PMID: 24910600
impulse control disorders; impulsivity; reward; loss aversion; insula; ventral striatum
22.  Deletion of alpha-synuclein decreases impulsivity in mice 
Genes, Brain, and Behavior  2011;11(2):137-146.
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
doi:10.1111/j.1601-183X.2011.00758.x
PMCID: PMC3380554  PMID: 22142176
Alpha-synuclein; impulse control disorders; impulsivity; Parkinson's disease
23.  The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study 
PLoS ONE  2012;7(5):e36781.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
doi:10.1371/journal.pone.0036781
PMCID: PMC3344935  PMID: 22574225
24.  Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study 
Neurobiology of disease  2012;48(3):519-525.
Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.
doi:10.1016/j.nbd.2012.06.021
PMCID: PMC3465363  PMID: 22766031 CAMSID: cams2373
Parkinson’s disease; Dopamine agonists; Pathological gambling; Impulsivity
25.  Decision-making, impulsivity and addictions: Do Parkinson’s disease patients jump to conclusions? 
Links between impulsive compulsive behaviors in treated Parkinson’s disease, behavioral addictions and substance abuse have been postulated, but no direct comparisons have been carried out so far.
We directly compared patients with Parkinson’s disease with and without impulsive compulsive behaviors with illicit drug abusers, pathological gamblers and age-matched healthy controls using the beads task, a test of reflection impulsivity and a working memory task.
We found that all patients with Parkinson’s disease made more impulsive and irrational choices than the control group. Parkinson’s disease patients who had an impulsive compulsive behavior showed similar behavior to illicit substance abusers whereas patients without impulsive compulsive behaviors more closely resembled pathological gamblers. In contrast we found no difference in working memory performance within the Parkinson’s disease groups. However Parkinson’s disease patients without impulsive compulsive behaviors remembered distractors significantly less than all other patients during working memory tests.
We were able to correctly classify 96% of the Parkinson’s disease patients with respect to whether or not they had an impulsive compulsive behavior by analyzing 3 trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3% and we propose that this task may prove to be a powerful screening tool to detect an impulsive compulsive behavior in Parkinson’s disease. Our results also suggest that intact cortical processing and less distractibility in Parkinson’s disease patients without impulsive compulsive behaviors may protect them from developing behavioral addictions.
doi:10.1002/mds.25105
PMCID: PMC3412901  PMID: 22821557
Impulsive compulsive behavior; Parkinson’s disease; reflection impulsivity; pathological gambling; substance abuse; beads task

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