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1.  Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study 
Addiction Biology  2010;15(4):491-503.
Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerström Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores.
doi:10.1111/j.1369-1600.2010.00242.x
PMCID: PMC3014110  PMID: 20840335
Addiction; cue reactivity; fMRI; impulse control disorder; nicotine dependence; pathological gambling
2.  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
3.  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
4.  Response Inhibition during Cue Reactivity in Problem Gamblers: An fMRI Study 
PLoS ONE  2012;7(3):e30909.
Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).
Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.
PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.
This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.
doi:10.1371/journal.pone.0030909
PMCID: PMC3316530  PMID: 22479305
5.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study 
Brain : a journal of neurology  2009;132(Pt 5):1376-1385.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
doi:10.1093/brain/awp054
PMCID: PMC3479148  PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
6.  Getting a grip on problem gambling: what can neuroscience tell us? 
In problem gamblers, diminished cognitive control and increased impulsivity is present compared to healthy controls. Moreover, impulsivity has been found to be a vulnerability marker for the development of pathological gambling (PG) and problem gambling (PrG) and to be a predictor of relapse. In this review, the most recent findings on functioning of the brain circuitry relating to impulsivity and cognitive control in PG and PrG are discussed. Diminished functioning of several prefrontal areas and of the anterior cingulate cortex (ACC) indicate that cognitive-control related brain circuitry functions are diminished in PG and PrG compared to healthy controls. From the available cue reactivity studies on PG and PrG, increased responsiveness towards gambling stimuli in fronto-striatal reward circuitry and brain areas related to attentional processing is present compared to healthy controls. At this point it is unresolved whether PG is associated with hyper- or hypo-activity in the reward circuitry in response to monetary cues. More research is needed to elucidate the complex interactions for reward responsivity in different stages of gambling and across different types of reward. Conflicting findings from basic neuroscience studies are integrated in the context of recent neurobiological addiction models. Neuroscience studies on the interface between cognitive control and motivational processing are discussed in light of current addiction theories.
Clinical implications: We suggest that innovation in PG therapy should focus on improvement of dysfunctional cognitive control and/or motivational functions. The implementation of novel treatment methods like neuromodulation, cognitive training and pharmacological interventions as add-on therapies to standard treatment in PG and PrG, in combination with the study of their effects on brain-behavior mechanisms could prove an important clinical step forward towards personalizing and improving treatment results in PG.
doi:10.3389/fnbeh.2014.00141
PMCID: PMC4033022  PMID: 24904328
pathological gambling; disordered gambling; reward sensitivity; impulsivity; cue reactivity; response inhibition; review; addictive behaviors
7.  Gambling severity predicts midbrain response to near-miss outcomes 
Gambling is a common recreational activity that becomes dysfunctional in a subset of individuals, with DSM ‘pathological gambling’ regarded as the most severe form. During gambling, players experience a range of cognitive distortions that promote an over-estimation of the chances of winning. Near-miss outcomes are thought to fuel these distortions. We observed previously that near-misses recruited overlapping circuitry to monetary wins in a study in healthy volunteers (Clark et al. 2009). The present study sought to extend these observations in regular gamblers and relate brain responses to an index of gambling severity. Twenty regular gamblers, who varied in their involvement from recreational players to probable pathological gamblers, were scanned whilst performing a simplified slot-machine task that delivered occasional monetary wins, as well as near-miss and full-miss non-win outcomes. In the overall group, near-miss outcomes were associated with a significant response in the ventral striatum, which was also recruited by monetary wins. Gambling severity, measured with the South Oaks Gambling Screen, predicted a greater response in the dopaminergic midbrain to near-miss outcomes. This effect survived controlling for clinical co-morbidities that were present in the regular gamblers. Gambling severity did not predict win-related responses in the midbrain or elsewhere. These results demonstrate that near-miss events during gambling recruit reward-related brain circuitry in regular players. An association with gambling severity in the midbrain suggests that near-miss outcomes may enhance dopamine transmission in disordered gambling, which extends neurobiological similarities between pathological gambling and drug addiction.
doi:10.1523/JNEUROSCI.5758-09.2010
PMCID: PMC2929454  PMID: 20445043
Gambling; Cognitive; Addiction; Dopamine; Striatum; Midbrain
8.  Study protocol: the JEU cohort study – transversal multiaxial evaluation and 5-year follow-up of a cohort of French gamblers 
BMC Psychiatry  2014;14(1):226.
Background
There is abundant literature on how to distinguish problem gambling (PG) from social gambling, but there are very few studies of the long-term evolution of gambling practice. As a consequence, the correlates of key state changes in the gambling trajectory are still unknown. The objective of the JEU cohort study is to identify the determinants of key state changes in the gambling practice, such as the emergence of a gambling problem, natural recovery from a gambling problem, resolution of a gambling problem with intermediate care intervention, relapses or care recourse.
Methods/design
The present study was designed to overcome the limitations of previous cohort study on PG. Indeed, this longitudinal case–control cohort is the first which plans to recruit enough participants from different initial gambling severity levels to observe these rare changes. In particular, we plan to recruit three groups of gamblers: non-problem gamblers, problem gamblers without treatment and problem gamblers seeking treatment.
Recruitment takes place in various gambling places, through the press and in care centers.
Cohort participants are gamblers of both sexes who reported gambling on at least one occasion in the previous year and who were aged between 18 and 65. They were assessed through a structured clinical interview and self-assessment questionnaires at baseline and then once a year for five years. Data collection comprises sociodemographic characteristics, gambling habits (including gambling trajectory), the PG section of the DSM-IV, the South Oaks Gambling Screen, the Gambling Attitudes and Beliefs Survey – 23, the Mini International Neuropsychiatric Interview, the Wender-Utah Rating Scale-Child, the Adult ADHD Self-report Scale, somatic comorbidities (especially current treatment and Parkinson disease) and the Temperament and Character Inventory – 125.
Discussion
The JEU cohort study is the first study which proposes to identify the predictive factors of key state changes in gambling practice. This is the first case–control cohort on gambling which mixes non-problem gamblers, problem gamblers without treatment and problem gamblers seeking treatment in almost equal proportions. This work may help providing a fresh perspective on the etiology of pathological gambling, which may provide support for future research, care and preventive actions.
Trial Registration
(ClinicalTrials.gov): NCT01207674.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0226-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-014-0226-7
PMCID: PMC4147162  PMID: 25141820
Gambling; State changes; Cohort; Problem gambling; Recourse to treatment; Predictive factors
9.  Risk-taking and pathological gambling behavior in Huntington’s disease 
Huntington’s disease (HD) is a genetic, neurodegenerative disorder, which specifically affects striatal neurons of the indirect pathway, resulting in a progressive decline in muscle coordination and loss of emotional and cognitive control. Interestingly, predisposition to pathological gambling and other addictions involves disturbances in the same cortico-striatal circuits that are affected in HD, and display similar disinhibition-related symptoms, including changed sensitivity to punishments and rewards, impulsivity, and inability to consider long-term advantages over short-term rewards. Both HD patients and pathological gamblers also show similar performance deficits on risky decision-making tasks, such as the Iowa Gambling Task (IGT). These similarities suggest that HD patients are a likely risk group for gambling problems. However, such problems have only incidentally been observed in HD patients. In this review, we aim to characterize the risk of pathological gambling in HD, as well as the underlying neurobiological mechanisms. Especially with the current rise of easily accessible Internet gambling opportunities, it is important to understand these risks and provide appropriate patient support accordingly. Based on neuropathological and behavioral findings, we propose that HD patients may not have an increased tendency to seek risks and start gambling, but that they do have an increased chance of developing an addiction once they engage in gambling activities. Therefore, current and future developments of Internet gambling possibilities and related addictions should be regarded with care, especially for vulnerable groups like HD patients.
doi:10.3389/fnbeh.2014.00103
PMCID: PMC3980094  PMID: 24765067
Huntington’s disease; risk-taking; gambling; prefrontal cortex; basal ganglia; disinhibtion
10.  Problem gamblers share deficits in impulsive decision-making with alcohol-dependent individuals 
Addiction (Abingdon, England)  2009;104(6):1006-1015.
Aims
Problem gambling has been proposed to represent a ‘behavioural addiction’ that may provide key insights into vulnerability mechanisms underlying addiction in brains that are not affected by the damaging effects of drugs. Our aim was to investigate the neurocognitive profile of problem gambling in comparison with alcohol dependence. We reasoned that shared deficits across the two conditions may reflect underlying vulnerability mechanisms, whereas impairments specific to alcohol dependence may reflect cumulative effects of alcohol consumption.
Design
Cross-sectional study.
Setting
Out-patient addiction treatment centres and university behavioural testing facilities.
Participants
A naturalistic sample of 21 male problem and pathological gamblers, 21 male alcohol-dependent out-patients and 21 healthy male control participants.
Measurements
Neurocognitive battery assessing decision-making, impulsivity and working memory.
Findings
The problem gamblers and alcohol-dependent groups displayed impairments in risky decision-making and cognitive impulsivity relative to controls. Working memory deficits and slowed deliberation times were specific to the alcohol-dependent group.
Conclusions
Gambling and alcohol-dependent groups shared deficits in tasks linked to ventral prefrontal cortical dysfunction. Tasks loading on dorsolateral prefrontal cortex were selectively impaired in the alcohol-dependent group, presumably as a consequence of long-term alcohol use.
doi:10.1111/j.1360-0443.2009.02533.x
PMCID: PMC2773538  PMID: 19466924
Addiction; alcohol; decision-making; impulsivity; pathological gambling; prefrontal cortex; risk-taking; vulnerability
11.  Dopamine Agonists Diminish Value Sensitivity of the Orbitofrontal Cortex: A Trigger for Pathological Gambling in Parkinson’s Disease? 
The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson’s disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences.
doi:10.1038/sj.npp.npp2009124
PMCID: PMC2972251  PMID: 19741594 CAMSID: cams1534
fMRI; impulse control disorder; dopamine agonist; reward; addiction; reinforcement
12.  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
13.  Decision-making during gambling: an integration of cognitive and psychobiological approaches 
Gambling is a widespread form of entertainment that may afford unique insights into the interaction between cognition and emotion in human decision-making. It is also a behaviour that can become harmful, and potentially addictive, in a minority of individuals. This article considers the status of two dominant approaches to gambling behaviour. The cognitive approach has identified a number of erroneous beliefs held by gamblers, which cause them to over-estimate their chances of winning. The psychobiological approach has examined case-control differences between groups of pathological gamblers and healthy controls, and has identified dysregulation of brain areas linked to reward and emotion, including the ventromedial prefrontal cortex (vmPFC) and striatum, as well as alterations in dopamine neurotransmission. In integrating these two approaches, recent data are discussed that reveal anomalous recruitment of the brain reward system (including the vmPFC and ventral striatum) during two common cognitive distortions in gambling games: the near-miss effect and the effect of personal control. In games of chance, near-misses and the presence of control have no objective influence on the likelihood of winning. These manipulations appear to harness a reward system that evolved to learn skill-oriented behaviours, and by modulating activity in this system, these cognitive distortions may promote continued, and potentially excessive, gambling.
doi:10.1098/rstb.2009.0147
PMCID: PMC2827449  PMID: 20026469
gambling; addiction; risk; reward; cognition; emotion
14.  Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity 
NeuroImage : Clinical  2014;5:232-239.
Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. ‘Near-miss’ events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the ‘illusion of control’).
Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression.
For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex.
These findings corroborate the ‘non-categorical’ nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.
doi:10.1016/j.nicl.2014.06.008
PMCID: PMC4110887  PMID: 25068112
Gambling; Connectivity; fMRI; Reward; Near-miss; Addiction
15.  A neurocognitive comparison of cognitive flexibility and response inhibition in gamblers with varying degrees of clinical severity 
Psychological Medicine  2011;41(10):2111-2119.
Background
As a behavioral addiction with clinical and phenomenological similarities to substance addiction, recreational and pathological gambling represent models for studying the neurobiology of addiction, without the confounding deleterious brain effects which may occur from chronic substance abuse.
Method
A community sample of individuals aged 18–65 years who gamble was solicited through newspaper advertising. Subjects were grouped a priori into three groups (no-risk, at-risk, and pathological gamblers) based on a diagnostic interview. All subjects underwent a psychiatric clinical interview and neurocognitive tests assessing motor impulsivity and cognitive flexibility. Subjects with a current axis I disorder, history of brain injury/trauma, or implementation or dose changes of psychoactive medication within 6 weeks of study enrollment were excluded.
Results
A total of 135 no-risk, 69 at-risk and 46 pathological gambling subjects were assessed. Pathological gamblers were significantly older, and exhibited significant deficiencies in motor impulse control (stop-signal reaction times), response speed (median ‘go’ trial response latency) and cognitive flexibility [total intra-dimensional/extra-dimensional (IDED) errors] versus controls. The finding of impaired impulse control and cognitive flexibility was robust in an age-matched subgroup analysis of pathological gamblers. The no-risk and at-risk gambling groups did not significantly differ from each other on task performance.
Conclusions
Impaired response inhibition and cognitive flexibility exist in people with pathological gambling compared with no-risk and at-risk gamblers. The early identification of such illness in adolescence or young adulthood may aid in the prevention of addiction onset of such disabling disorders.
doi:10.1017/S0033291711000316
PMCID: PMC3381334  PMID: 21426627
Cognition; gambling; impulsivity
16.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Background
Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.
Methods
We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.
Results
Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.
Conclusions
During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.
doi:10.1371/journal.pone.0049923
PMCID: PMC3509135  PMID: 23209619
17.  Neurocognitive Dysfunction in Strategic and Non-Strategic Gamblers 
Objective
It has been theorized that there may be subtypes of pathological gambling, particularly in relation to the main type of gambling activities undertaken. Whether or not putative pathological gambling subtypes differ in terms of their clinical and cognitive profiles has received little attention.
Method
Subjects meeting DSM-IV criteria for pathological gambling were grouped into two categories of preferred forms of gambling – strategic (e.g., cards, dice, sports betting, stock market) and non-strategic (e.g., slots, video poker, pull tabs). Groups were compared on clinical characteristics (gambling severity, and time and money spent gambling), psychiatric comorbidity, and neurocognitive tests assessing motor impulsivity and cognitive flexibility.
Results
Seventy-seven subjects were included in this sample (45.5% females; mean age: 42.7±14.9) which consisted of the following groups: strategic (n=22; 28.6%) and non-strategic (n=55; 71.4%). Non-strategic gamblers were significantly more likely to be older, female, and divorced. Money spent gambling did not differ significantly between groups although one measure of gambling severity reflected more severe problems for strategic gamblers. Strategic and non-strategic gamblers did not differ in terms of cognitive function; both groups showed impairments in cognitive flexibility and inhibitory control relative to matched healthy volunteers.
Conclusion
These preliminary results suggest that preferred form of gambling may be associated with specific clinical characteristics but are not associated dissociable in terms of cognitive inflexibility and motor impulsivity.
doi:10.1016/j.pnpbp.2012.05.006
PMCID: PMC3389298  PMID: 22613186
cognition; impulsivity; gambling
18.  An analysis of problem gambling among the Finnish working-age population: a population survey 
BMC Public Health  2013;13:519.
Background
Gambling problems currently affect approximately 100 000 Finns. In order to prevent and reduce gambling-related harms it is crucial for the Finnish public health authorities to gain a stronger understanding of the association between gambling problems and related socio-demographic factors, other commonly co-occurring dependencies (e.g. alcohol and nicotine) and the type of games gambled. In this article the prevalence of problem gambling in Finland and the socio-demographic profiles of problem gamblers are studied.
Method
An annual postal survey entitled Health Behaviour and Health among the Finnish Adult Population AVTK was sent to a random sample of Finnish adults (N=5000) aged between 15 and 64. The sample was derived from the Finnish Population Register. The survey was mailed to the participants in April 2010. Gender differences in socio-demographic variables and Problem Gambling Severity Index PGSI were assessed. A multinomial regression model was created in order to explore the association between socio-demographic factors and the severity of gambling.
Results
A total of 2826 individuals (1243 males and 1583 females) replied to the survey. Of the respondents, 1.1% (2.1% of males, 0.3% of females) were identified as problem gamblers. Those who were of younger age, gender, had less than twelve years of education, consumed alcohol at risk level and smoked had higher odds of having low or moderate levels of gambling problems. Whereas, unemployment and smoking predicted significantly for problem gambling. Females gambled Lotto and slot machines less frequently than males and had more low level gambling problems. Males gambled more with a higher frequency and had a more severe level of gambling problems. Females were more attracted to scratch card gambling and daily Keno lotteries compared to males. In comparison, males gambled more on internet poker sites than females. Overall, a high frequency of gambling in Lotto, daily lotteries, slot machines, horse race betting and internet gambling was significantly associated with a more severe level of problem gambling.
Conclusion
Gambling problems affect tens of thousands of individuals annually, therefore certain vulnerabilities should be noted. Comorbid dependencies, smoking in particular, ought to be screened for and recognised in the public health sector. Regulating the availability of slot machine gambling and enforcement of the age limit should be acknowledged. In establishing new gambling venues, prevalence rates in those particular areas should be actively monitored.
doi:10.1186/1471-2458-13-519
PMCID: PMC3673882  PMID: 23714573
19.  Yohimbine-Induced Amygdala Activation in Pathological Gamblers: A Pilot Study 
PLoS ONE  2012;7(2):e31118.
Rationale and Objectives
There is evidence that drug addiction is associated with increased physiological and psychological responses to stress. In this pilot functional magnetic resonance imaging (fMRI) study we assessed whether a prototype behavioral addiction, pathological gambling (PG), is likewise associated with an enhanced response to stress.
Methods
We induced stress by injecting yohimbine (0.2–0.3 mg/kg, IV), an alpha-2 adrenoceptor antagonist that elicits stress-like physiological and psychological effects in humans and in laboratory animals, to four subjects with PG and to five non-gamblers mentally healthy control subjects. Their fMRI brain responses were assessed along with subjective stress and gambling urges ratings.
Results
Voxelwise analyses of data sets from individual subjects, utilizing generalized linear model approach, revealed significant left amygdala activation in response to yohimbine across all PG subjects. This amygdala effect was not observed in the five control individuals. Yohimbine elicited subjective stress ratings in both groups with greater (albeit not statically significantly) average response in the PG subjects. On the other hand, yohimbine did not induce urges to gamble.
Conclusions
The present data support the hypothesis of brain sensitization to pharmacologically-induced stress in PG.
doi:10.1371/journal.pone.0031118
PMCID: PMC3271103  PMID: 22319607
20.  Longitudinal patterns of gambling activities and associated risk factors in college students 
Addiction (Abingdon, England)  2009;104(7):1219.
Aims
To investigate which clusters of gambling activities exist within a longitudinal study of college health, how membership in gambling clusters change over time and whether particular clusters of gambling are associated with unhealthy risk behaviour.
Design
Four-year longitudinal study (2002–2006).
Setting
Large, public university.
Participants
Undergraduate college students.
Measurements
Ten common gambling activities were measured during 4 consecutive college years (years 1–4). Clusters of gambling activities were examined using latent class analyses. Relations between gambling clusters and gender, Greek membership, alcohol use, drug use, personality indicators of behavioural undercontrol and psychological distress were examined.
Findings
Four latent gambling classes were identified: (1) a low-gambling class, (2) a card gambling class, (3) a casino/slots gambling class and (4) an extensive gambling class. Over the first college years a high probability of transitioning from the low-gambling class and the card gambling class into the casino/slots gambling class was present. Membership in the card, casino/slots and extensive gambling classes were associated with higher scores on alcohol/drug use, novelty seeking and self-identified gambling problems compared to the low-gambling class. The extensive gambling class scored higher than the other gambling classes on risk factors.
Conclusions
Extensive gamblers and card gamblers are at higher risk for problem gambling and other risky health behaviours. Prospective examinations of class membership suggested that being in the extensive and the low gambling classes was highly stable across the 4 years of college.
doi:10.1111/j.1360-0443.2009.02573.x
PMCID: PMC2818490  PMID: 19438422
College student population; gambling; gambling activities; longitudinal; risk factors
21.  Risk assessment and reward processing in problem gambling investigated by event-related potentials and fMRI-constrained source analysis 
BMC Psychiatry  2014;14(1):229.
Background
The temporo-spatial dynamics of risk assessment and reward processing in problem gamblers with a focus on an ecologically valid design has not been examined previously.
Methods
We investigated risk assessment and reward processing in 12 healthy male occasional gamblers (OG) and in 12 male problem gamblers (PG) with a combined EEG and fMRI approach to identify group-differences in successively activated brain regions during two stages within a quasi-realistic blackjack game.
Results
Both groups did not differ in reaction times but event-related potentials in PG and OG produced significantly different amplitudes in middle and late time-windows during high-risk vs. low-risk decisions. Applying an fMRI-constrained regional source model during risk assessment resulted in larger source moments in PG in the high-risk vs. low-risk comparison in thalamic, orbitofrontal and superior frontal activations within the 600-800 ms time window. During reward processing, PG showed a trend to enhanced negativity in an early time window (100-150 ms) potentially related to higher rostral anterior cingulate activity and a trend to centro-parietal group-differences in a later time window (390-440 ms) accompanied by increased superior-frontal (i.e., premotor-related) source moments in PG vs. OG.
Conclusions
We suggest that problem gambling is characterized by stronger cue-related craving during risk assessment. Reward processing is associated with early affective modulation followed by increased action preparation for ongoing gambling in PG.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-014-0229-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-014-0229-4
PMCID: PMC4149195  PMID: 25108447
EEG; Addiction; Decision-making
22.  Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease 
Mayo Clinic Proceedings  2009;84(4):310-316.
OBJECTIVE: To determine the frequency of new-onset compulsive gambling or hypersexuality among regional patients with Parkinson disease (PD), ascertaining the relationship of these behaviors to PD drug use.
PATIENTS AND METHODS: We retrospectively reviewed the medical records of patients from 7 rural southeastern Minnesota counties who had at least 1 neurology appointment for PD between July 1, 2004, and June 30, 2006. The main outcome measure was compulsive gambling or hypersexuality developing after parkinsonism onset, including the temporal relationship to PD drug use.
RESULTS: Of 267 patients with PD who met the study inclusion criteria, new-onset gambling or hypersexuality was documented in 7 (2.6%). All were among the 66 patients (10.6%) taking a dopamine agonist. Moreover, all 7 (18.4%) were among 38 patients taking therapeutic doses (defined as ≥2 mg of pramipexole or 6 mg of ropinirole daily). Behaviors were clearly pathologic and disabling in 5: 7.6% of all patients taking an agonist and 13.2% of those taking therapeutic doses. Of the 5 patients, 2 had extensive treatment for what was considered a primary psychiatric problem before the agonist connection was recognized.
CONCLUSION: Among the study patients with PD, new-onset compulsive gambling or hypersexuality was documented in 7 (18.4%) of 38 patients taking therapeutic doses of dopamine agonists but was not found among untreated patients, those taking subtherapeutic agonist doses, or those taking carbidopa/levodopa alone. Behaviors abated with discontinuation of agonist therapy or dose reduction. Because this is a retrospective study, cases may have been missed, and hence this study may reflect an underestimation of the true frequency. Physicians who care for patients taking these drugs should recognize the drug's potential to induce pathologic syndromes that sometimes masquerade as primary psychiatric disease.
In patients with Parkinson disease, new-onset compulsive gambling or hypersexuality was documented in 7 of 38 patients taking therapeutic doses of dopamine agonists but was not found among untreated patients, those taking subtherapeutic agonist doses, or those taking carbidopa/levodopa alone.
PMCID: PMC2665974  PMID: 19339647
23.  Cue Reactivity in Active Pathological, Abstinent Pathological, and Regular Gamblers 
Journal of Gambling Studies  2009;26(1):53-65.
Twenty-one treatment-seeking pathological gamblers, 21 pathological gamblers in recovery, and 21 recreational gamblers watched two video-taped exciting gambling scenarios and an exciting roller-coaster control scenario while their arousal (heart rate and subjective excitement) and urge to gamble were being measured. The gamblers did not differ significantly in cue-elicited heart rate elevations or excitement. However, the active pathological gamblers reported significantly greater urges to gamble across all cues compared to the abstinent pathological gamblers and, with marginal significance (p = 0.06), also compared to the social gamblers. Further exploration of these findings revealed that active pathological gamblers experience urges to gamble in response to exciting situations, whether or not they are gambling related, whereas abstinent and social gamblers only report urges to an exciting gambling-related cue. This suggests that for pathological gamblers excitement itself, irrespective of its source, may become a conditioned stimulus capable of triggering gambling behavior. Implications for treatment and future research are discussed.
doi:10.1007/s10899-009-9146-8
PMCID: PMC2822908  PMID: 19662519
Pathological gambling; Cue reactivity; Urge; Excitement; Addiction
24.  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
25.  Impulsivity and cognitive distortions in pathological gamblers attending the UK National Problem Gambling Clinic: a preliminary report 
Psychological Medicine  2011;41(12):2625-2635.
Background
Pathological gambling (PG) is a form of behavioural addiction that has been associated with elevated impulsivity and also cognitive distortions in the processing of chance, probability and skill. We sought to assess the relationship between the level of cognitive distortions and state and trait measures of impulsivity in treatment-seeking pathological gamblers.
Method
Thirty pathological gamblers attending the National Problem Gambling Clinic, the first National Health Service clinic for gambling problems in the UK, were compared with 30 healthy controls in a case-control design. Cognitive distortions were assessed using the Gambling-Related Cognitions Scale (GRCS). Trait impulsivity was assessed using the UPPS-P, which includes scales of urgency, the tendency to be impulsive in positive or negative mood states. Delay discounting rates were taken as a state measure of impulsive choice.
Results
Pathological gamblers had elevated impulsivity on several UPPS-P subscales but effect sizes were largest (Cohen's d>1.4) for positive and negative urgency. The pathological gamblers also displayed higher levels of gambling distortions, and elevated preference for immediate rewards, compared to controls. Within the pathological gamblers, there was a strong relationship between the preference for immediate rewards and the level of cognitive distortions (R2=0.41).
Conclusions
Impulsive choice in the gamblers was correlated with the level of gambling distortions, and we hypothesize that an impulsive decision-making style may increase the acceptance of erroneous beliefs during gambling play.
doi:10.1017/S003329171100095X
PMCID: PMC3206226  PMID: 21733207
Behavioural addiction; decision making; delay discounting; problem gambling; risk taking

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