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1.  Fronto-striatal dysregulation in drug addiction and pathological gambling: Consistent inconsistencies?☆ 
NeuroImage : Clinical  2013;2:385-393.
Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a ‘toxicity free’ addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.
Highlights
•We outline the current psychological theories of addiction and their predictions.•We review recent fMRI literature of substance addictions and appetitive processing.•Reasons for opposing results (hyper- vs hypo-active reward regions) are discussed.•Recent fMRI findings of appetitive processing in pathological gambling are reviewed.•Pathological gambling is suggested as a prototypical addiction for imaging research.
doi:10.1016/j.nicl.2013.02.005
PMCID: PMC3777686  PMID: 24179792
Addiction; Pathological gambling; fMRI; Ventral striatum; Appetitive processing
2.  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
3.  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
4.  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
5.  Elucidating Poor Decision-Making in a Rat Gambling Task 
PLoS ONE  2013;8(12):e82052.
Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task – the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms.
doi:10.1371/journal.pone.0082052
PMCID: PMC3855331  PMID: 24339988
6.  The Iowa Gambling Task and the three fallacies of dopamine in gambling disorder 
Gambling disorder sufferers prefer immediately larger rewards despite long term losses on the Iowa Gambling Task (IGT), and these impairments are associated with dopamine dysfunctions. Dopamine is a neurotransmitter linked with temporal and structural dysfunctions in substance use disorder, which has supported the idea of impaired decision-making and dopamine dysfunctions in gambling disorder. However, evidence from substance use disorders cannot be directly transferred to gambling disorder. This article focuses on three hypotheses of dopamine dysfunctions in gambling disorder, which appear to be “fallacies,” i.e., have not been supported in a series of positron emission tomography (PET) studies. The first “fallacy” suggests that gambling disorder sufferers have lower dopamine receptor availability, as seen in substance use disorders. However, no evidence supported this hypothesis. The second “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during gambling. No evidence supported the hypothesis, and the literature on substance use disorders offers limited support for this hypothesis. The third “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during winning. The evidence did not support this hypothesis either. Instead, dopaminergic coding of reward prediction and uncertainty might better account for dopamine dysfunctions in gambling disorder. Studies of reward prediction and reward uncertainty show a sustained dopamine response toward stimuli with maximum uncertainty, which may explain the continued dopamine release and gambling despite losses in gambling disorder. The findings from the studies presented here are consistent with the notion of dopaminergic dysfunctions of reward prediction and reward uncertainty signals in gambling disorder.
doi:10.3389/fpsyg.2013.00709
PMCID: PMC3792697  PMID: 24115941
gambling disorder; Iowa Gambling Task (IGT); dopamine; addiction; positron-emission tomography
7.  Increased Functional Connectivity between Prefrontal Cortex and Reward System in Pathological Gambling 
PLoS ONE  2013;8(12):e84565.
Pathological gambling (PG) shares clinical characteristics with substance-use disorders and is thus discussed as a behavioral addiction. Recent neuroimaging studies on PG report functional changes in prefrontal structures and the mesolimbic reward system. While an imbalance between these structures has been related to addictive behavior, whether their dysfunction in PG is reflected in the interaction between them remains unclear. We addressed this question using functional connectivity resting-state fMRI in male subjects with PG and controls. Seed-based functional connectivity was computed using two regions-of-interest, based on the results of a previous voxel-based morphometry study, located in the prefrontal cortex and the mesolimbic reward system (right middle frontal gyrus and right ventral striatum). PG patients demonstrated increased connectivity from the right middle frontal gyrus to the right striatum as compared to controls, which was also positively correlated with nonplanning aspect of impulsiveness, smoking and craving scores in the PG group. Moreover, PG patients demonstrated decreased connectivity from the right middle frontal gyrus to other prefrontal areas as compared to controls. The right ventral striatum demonstrated increased connectivity to the right superior and middle frontal gyrus and left cerebellum in PG patients as compared to controls. The increased connectivity to the cerebellum was positively correlated with smoking in the PG group. Our results provide further evidence for alterations in functional connectivity in PG with increased connectivity between prefrontal regions and the reward system, similar to connectivity changes reported in substance use disorder.
doi:10.1371/journal.pone.0084565
PMCID: PMC3868704  PMID: 24367675
8.  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
9.  Effect of executive functioning, decision-making and self-reported impulsivity on the treatment outcome of pathologic gambling 
Background
Impairments in self-regulatory behaviour reflect a deficit in executive functioning and decision-making, as well as higher levels of self-reported impulsivity, and may be involved in the development and maintenance of addictive disorders. We sought to explore the association between self-reported impulsivity and neurocognitive measures, and their association with treatment outcome in pathologic gambling.
Methods
We assessed patients with pathologic gambling using executive functioning and decision-making tests and self-report measures of impulsivity. Patients underwent cognitive–behavioural therapy (CBT) for pathologic gambling.
Results
We included 88 patients (8% women) in our study. High self-reported extravagance was associated with poor performance in the Iowa Gambling Task (IGT)-ABCD version. High impulsiveness, low disorderliness, high exploratory excitability (trend), poor backward block span and poor IGT-EFGH scores (trend) predicted dropout. We observed no self-reported or neurocognitive predictors of relapse or number of treatment sessions attended.
Limitations
Most participants were slot-machine gamblers seeking treatment. No follow-up data and no control group were included in the study. The missing sample (i.e., individuals who were recruited and assessed in the pretreatment stage but who chose not to begin treatment) had higher extravagance scores than the final sample.
Conclusion
Neurocognitive reward sensitivity was related to self-reported overspending behaviour. Self-regulatory impairments (especially rash impulsiveness and punishment sensitivity) and executive dysfunction predicted only dropout of CBT in participants with pathologic gambling. Different neurocognitive processes and personality traits might mediate treatment response to psychological therapy of pathologic gambling according to the specific target variable assessed.
doi:10.1503/jpn.090095
PMCID: PMC3080512  PMID: 21138656
10.  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
11.  A new approach to assess gambling-like behavior in laboratory rats: using intracranial self-stimulation as a positive reinforcer 
Pathological gambling is one manifestation of impulse control disorders. The biological underpinnings of these disorders remain elusive and treatment is far from ideal. Animal models of impulse control disorders are a critical research tool for understanding this condition and for medication development. Modeling such complex behaviors is daunting, but by its deconstruction, scientists have recapitulated in animals critical aspects of gambling. One aspect of gambling is cost/benefit decision-making wherein one weighs the anticipated costs and expected benefits of a course of action. Risk/reward, delay-based and effort-based decision-making all represent cost/benefit choices. These features are studied in humans and have been translated to animal protocols to measure decision-making processes. Traditionally, the positive reinforcer used in animal studies is food. Here, we describe how intracranial self-stimulation can be used for cost/benefit decision-making tasks and overview our recent studies showing how pharmacological therapies alter these behaviors in laboratory rats. We propose that these models may have value in screening new compounds for the ability to promote and prevent aspects of gambling behavior.
doi:10.3389/fnbeh.2014.00215
PMCID: PMC4052818  PMID: 24966822
cost/benefit decision-making; discounting; effort-based decision-making; gambling; intracranial self-stimulation
12.  The Neurobiology of Impulse Control Disorders 
Objective
To review the neurobiological substrates of impulse control disorders (ICDs). Pathological gambling (PG) is a main focus of the review in that most biological studies of the formal ICDs have examined this disorder.
Methods
The medical database MedLine from 1966 to present was searched to identify relevant articles that were subsequently reviewed to generate this manuscript.
Results
Preclinical studies suggest that differential brain monoamine neuromodulation is associated with impulsive decision-making and risk-taking behaviors. Clinical studies implicate multiple neurotransmitter systems (serotonergic, dopaminergic, adrenergic, and opioidergic) in the pathophysiology of PG and other ICDs. Initial neuroimaging studies have implicated the ventromedial prefrontal cortex and ventral striatum in the pathophysiology of PG and other ICDs. Genetic contributions to PG seem substantial and initial studies have implicated specific allelic polymorphisms, although genome-wide analyses have yet to be published.
Conclusion
Although significant advances have been made in our understanding of the neurobiology of ICDs, more research is needed to extend existing knowledge and translate these findings into clinical advances.
PMCID: PMC3676928  PMID: 18278382
Pathological Gambling; Serotonin; Norepinephrine; Dopamine; Opioids; Impulsivity; Stress; Genetics; Brain Imaging; Biochemistry
13.  Dissociable Neural Processes Underlying Risky Decisions for Self Versus Other 
Previous neuroimaging studies on decision making have mainly focused on decisions on behalf of oneself. Considering that people often make decisions on behalf of others, it is intriguing that there is little neurobiological evidence on how decisions for others differ from those for oneself. The present study directly compared risky decisions for self with those for another person using functional magnetic resonance imaging (fMRI). Participants were asked to perform a gambling task on behalf of themselves (decision-for-self condition) or another person (decision-for-other condition) while in the scanner. Their task was to choose between a low-risk option (i.e., win or lose 10 points) and a high-risk option (i.e., win or lose 90 points) with variable levels of winning probability. Compared with choices regarding others, those regarding oneself were more risk-averse at lower winning probabilities and more risk-seeking at higher winning probabilities, perhaps due to stronger affective process during risky decisions for oneself compared with those for other. The brain-activation pattern changed according to the target, such that reward-related regions were more active in the decision-for-self condition than in the decision-for-other condition, whereas brain regions related to the theory of mind (ToM) showed greater activation in the decision-for-other condition than in the decision-for-self condition. Parametric modulation analysis using individual decision models revealed that activation of the amygdala and the dorsomedial prefrontal cortex (DMPFC) were associated with value computations for oneself and for another, respectively, during risky financial decisions. The results of the present study suggest that decisions for oneself and for other may recruit fundamentally distinct neural processes, which can be mainly characterized as dominant affective/impulsive and cognitive/regulatory processes, respectively.
doi:10.3389/fnins.2013.00015
PMCID: PMC3602668  PMID: 23519016
fMRI; self–other decision; amygdala; dorsomedial prefrontal cortex; risky decision; prosocial behavior; social neuroscience
14.  Neurobiology of Gambling Behaviors 
Current opinion in neurobiology  2013;23(4):660-667.
For many, gambling is a recreational activity that is performed periodically without ill effects, but for some, gambling may interfere with life functioning. A diagnostic entity, pathological gambling, is currently used to define a condition marked by excessive and problematic gambling. In this review, the current status of understanding of the neurobiologies of gambling and pathological gambling is described. Multiple neurotransmitter systems (norepinephrine, serotonin, dopamine, opioid and glutamate) and brain regions (ventral striatum, ventromedial prefrontal cortex, insula, among others) have been implicated in gambling and pathological gambling. Considerations for future directions in gambling research, with a view towards translating neurobiological advances into more effective prevention and treatment strategies, are discussed.
doi:10.1016/j.conb.2013.03.004
PMCID: PMC3803105  PMID: 23541597
Gambling; neuroimaging; neurobiology; treatment development
15.  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
16.  Reward Signals, Attempted Suicide, and Impulsivity in Late-Life Depression 
JAMA psychiatry (Chicago, Ill.)  2013;70(10):10.1001/jamapsychiatry.2013.75.
IMPORTANCE
Suicide can be viewed as an escape from unendurable punishment at the cost of any future rewards. Could faulty estimation of these outcomes predispose to suicidal behavior? In behavioral studies, many of those who have attempted suicide misestimate expected rewards on gambling and probabilistic learning tasks.
OBJECTIVES
To describe the neural circuit abnormalities that underlie disadvantageous choices in people at risk for suicide and to relate these abnormalities to impulsivity, which is one of the components of vulnerability to suicide.
DESIGN
Case-control functional magnetic resonance imaging study of reward learning using a reinforcement learning model.
SETTING
University hospital and outpatient clinic.
PATIENTS
Fifty-three participants 60 years or older, including 15 depressed patients who had attempted suicide, 18 depressed patients who had never attempted suicide (depressed control subjects), and 20 psychiatrically healthy controls.
MAIN OUTCOMES AND MEASURES
Components of the cortical blood oxygenation level–dependent response tracking expected and unpredicted rewards.
RESULTS
Depressed elderly participants displayed 2 distinct disruptions of control over reward-guided behavior. First, impulsivity and a history of suicide attempts (particularly poorly planned ones) were associated with a weakened expected reward signal in the paralimbic cortex, which in turn predicted the behavioral insensitivity to contingency change. Second, depression was associated with disrupted corticostriatothalamic encoding of unpredicted rewards, which in turn predicted the behavioral oversensitivity to punishment. These results were robust to the effects of possible brain damage from suicide attempts, depressive severity, co-occurring substance use and anxiety disorders, antidepressant and anticholinergic exposure, lifetime exposure to electroconvulsive therapy, vascular illness, and incipient dementia.
CONCLUSIONS AND RELEVANCE
Altered paralimbic reward signals and impulsivity and/or carelessness may facilitate unplanned suicidal acts. This pattern, also seen in gambling and cocaine use, may reflect a primary deficit in the paralimbic cortex or in its mesolimbic input. The overreactivity to punishment in depression may be caused in part by a disruption of appetitive learning in the corticostriatothalamic circuits.
doi:10.1001/jamapsychiatry.2013.75
PMCID: PMC3859132  PMID: 23925710
17.  Neural mechanisms of economic commitment in the human medial prefrontal cortex 
eLife  2014;3:e03701.
Neurobiologists have studied decisions by offering successive, independent choices between goods or gambles. However, choices often have lasting consequences, as when investing in a house or choosing a partner. Here, humans decided whether to commit (by acceptance or rejection) to prospects that provided sustained financial return. BOLD signals in the rostral medial prefrontal cortex (rmPFC) encoded stimulus value only when acceptance or rejection was deferred into the future, suggesting a role in integrating value signals over time. By contrast, the dorsal anterior cingulate cortex (dACC) encoded stimulus value only when participants rejected (or deferred accepting) a prospect. dACC BOLD signals reflected two decision biases–to defer commitments to later, and to weight potential losses more heavily than gains–that (paradoxically) maximised reward in this task. These findings offer fresh insights into the pressures that shape economic decisions, and the computation of value in the medial prefrontal cortex.
DOI: http://dx.doi.org/10.7554/eLife.03701.001
eLife digest
Humans, in general, are not particularly good at making economic decisions. People can be influenced by unhelpful biases: such as ‘loss aversion’ where a person views losses as more significant than gains. Sometimes these biases stop us making the decisions that offer the best reward, as such, they raise the question: why do these biases exist at all?
One way to examine this question is by looking at the brain activity of people making economic decisions. Two regions near the front of the brain are known to be involved in human decision-making in response to rewards. However, many researchers disagree as to what these two regions are actually doing when we make economic decisions.
Much of the research in this area has asked participants to essentially gamble on a series of independent events, which typically provide a one-off instant reward with no further positive consequences. However, these tasks do not accurately reflect real economic decisions. In real life situations, people tend to take time to make a decision, and weigh up the potential long-term costs and benefits of an investment. Indeed the decision itself may be deferred until enough information is gathered; for example, very few people would choose to buy a house on the spur of the moment.
Now Tsetsos et al. have attempted to bridge the gap between previous studies and everyday experiences by designing a task that encompasses many of the factors involved in real life decision-making. In this task, participants were given the option of deciding whether to commit to, or reject, an investment opportunity immediately; or to choose to defer making the decision until later—similar to how a person might wait to view different properties before deciding which house to buy. Using brain imaging, Tsetsos et al. found that one of the two brain regions (called the dorsal ACC for short) was involved in weighing up the cost of rejecting an offer, but not accepting it. The other region (called the rostromedial prefrontal cortex or rmPFC) was involved in assessing the value of an offer only when the participant decided to defer making a decision, and not when they decided to commit.
Furthermore, by using computer simulations, Tsetsos et al. found that, with this more realistic task, biases such as loss aversion were in fact beneficial and helped participants to make decisions that increased their financial payoff. This suggests that the ‘unhelpful biases’ often seen in traditional decision making tasks may be a result of participants’ real life strategies failing to work when applied to an artificial situation. In other words, perhaps humans are not so bad at economic decision-making after all.
DOI: http://dx.doi.org/10.7554/eLife.03701.002
doi:10.7554/eLife.03701
PMCID: PMC4227044  PMID: 25333687
decision-making; neuroeconomics; prefrontal cortex; human
18.  The Functional Anatomy of Impulse Control Disorders 
Impulsive–compulsive disorders such as pathological gambling, hypersexuality, compulsive eating, and shopping are side effects of the dopaminergic therapy for Parkinson’s disease. With a lower prevalence, these disorders also appear in the general population. Research in the last few years has discovered that these pathological behaviors share features similar to those of substance use disorders (SUD), which has led to the term “behavioral addictions”. As in SUDs, the behaviors are marked by a compulsive drive toward and impaired control over the behavior. Furthermore, animal and medication studies, research in the Parkinson’s disease population, and neuroimaging findings indicate a common neurobiology of addictive behaviors. Changes associated with addictions are mainly seen in the dopaminergic system of a mesocorticolimbic circuit, the so-called reward system. Here we outline neurobiological findings regarding behavioral addictions with a focus on dopaminergic systems, relate them to SUD theories, and try to build a tentative concept integrating genetics, neuroimaging, and behavioral results.
doi:10.1007/s11910-013-0386-8
PMCID: PMC3779310  PMID: 23963609
Behavioral addictions; Pathological gambling; Binge eating; Compulsive buying; Hypersexuality; Substance use disorders; Mesocorticolimbic circuit; Reward system; Dopamine; Parkinson; Parkinson’s disease; Neurobiology; Risk factors; Impulse control disorders; Functional anatomy
19.  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
20.  Diminished fronto-striatal activity during processing of monetary rewards and losses in pathological gambling 
Biological psychiatry  2012;71(8):749-757.
Background
Mesocorticolimbic neurocircuitry and impulsivity have both been implicated in pathological gambling (PG) and in reward processing. However, the neural underpinnings of specific phases of reward and loss processing in PG and their relationships to impulsivity remain only partially understood. The present functional magnetic resonance imaging study examined brain activity associated with different phases of reward and loss processing in PG. Given an inverse relationship between ventral striatal recruitment during anticipation of monetary rewards and impulsivity in alcohol dependence, the current study explored whether a similar association might also be present in PG.
Methods
Fourteen adults with PG and 14 control comparison (CC) participants performed the Monetary Incentive Delay Task (MIDT) to identify brain activation changes associated with reward/loss prospect, reward/loss anticipation and reward/loss notification. Impulsivity was assessed separately using the Barratt Impulsiveness Scale.
Results
Relative to the CC group, the PG group exhibited significantly reduced activity in the ventromedial prefrontal cortex, insula and ventral striatum during several phases, including the prospect and anticipation phases of both gain and losses. Activity in the ventral striatum correlated inversely with levels of impulsivity in PG participants, consistent with prior findings in alcohol dependence.
Conclusions
Relatively decreased activity in cortico-striatal neurocircuitry during multiple phases of reward processing suggests consistent alterations in neurocircuitry underlying incentive valuation and loss prediction. Together with findings in alcohol dependence, these results suggest that impulsive tendencies in addictions may be reflected in diminished ventral striatal activations to reward anticipation and may represent targets for treatment development in addictions.
doi:10.1016/j.biopsych.2012.01.006
PMCID: PMC3460522  PMID: 22336565
fMRI; vmPFC; ventral striatum; insula; incentive; gambling
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.  Gambling 
Over the past several decades, and particularly during the last 10 to 15 years, there has been a rapid increase in the accessibility of legalized gambling in the United States and other parts of the world. Few studies have systematically explored the relationships between patterns of gambling and health status. Existing data support the notion that some gambling behaviors, particularly problem and pathological gambling, are associated with nongambling health problems. The purpose of this article is to provide a perspective on the relationship between gambling behaviors and substance use disorders, review the data regarding health associations and screening and treatment options for problem and pathological gambling, and suggest a role for generalist physicians in assessing problem and pathological gambling. A rationale for conceptualization of pathological gambling as an addictive disorder and a model proposing stress as a possible mediating factor in the relationship between gambling and health status are presented. More research is needed to investigate directly the biological and health correlates associated with specific types of gambling behaviors and to define the role for generalist physicians in the prevention and treatment of problem and pathological gambling.
doi:10.1046/j.1525-1497.2002.10812.x
PMCID: PMC1495100  PMID: 12220370
addiction; pathological gambling; treatment; prevention; substance abuse
23.  Similarities and Differences between Pathological Gambling and Substance Use Disorders: A Focus on Impulsivity and Compulsivity 
Psychopharmacology  2011;219(2):469-490.
Rationale
Pathological gambling (PG) has recently been considered as a “behavioral” or non-substance addiction. A comparison of characteristics of PG and substance use disorders (SUDs) has clinical ramifications and could help advance future research on these conditions. Specific relationships with impulsivity and compulsivity may be central to understanding PG and SUDs.
Objectives
To compare and contrast research findings in PG and SUDs pertaining to neurocogntive tasks, brain function and neurochemistry, with a focus on impulsivity and compulsivity.
Results
Multiple similarities were found between PG and SUDs, including poor performance on neurocognitive tasks, specifically with respect to impulsive choice and response tendencies and compulsive features (e.g., response perseveration and action with diminished relationship to goals or reward). Findings suggest dysfunction involving similar brain regions, including the ventromedial prefrontal cortex (PFC) and striatum and similar neurotransmitter systems, including dopaminergic and serotonergic. Unique features exist which may in part reflect influences of acute or chronic exposures to specific substances.
Conclusions
Both similarities and differences exist between PG and SUDs. Understanding these similarities more precisely may facilitate treatment development across addictions, whereas understanding differences may provide insight into treatment development for specific disorders. Individual differences in features of impulsivity and compulsivity may represent important endophenotypic targets for prevention and treatment strategies.
doi:10.1007/s00213-011-2550-7
PMCID: PMC3249521  PMID: 22057662
Iowa Gambling Task; delay discounting; neuroimaging; alcohol; cocaine; dopamine; serotonin; glutamate; frontal cortex; striatum
24.  Proactive Motor Control Reduces Monetary Risk Taking in Gambling 
Psychological Science  2012;23(7):805-815.
Less supervision by the executive system after disruption of the right prefrontal cortex leads to increased risk taking in gambling because superficially attractive—but risky—choices are not suppressed. Similarly, people might gamble more in multitask situations than in single-task situations because concurrent executive processes usually interfere with each other. In the study reported here, we used a novel monetary decision-making paradigm to investigate whether multitasking could reduce rather than increase risk taking in gambling. We found that performing a task that induced cautious motor responding reduced gambling in a multitask situation (Experiment 1). We then found that a short period of inhibitory training lessened risk taking in gambling at least 2 hr later (Experiments 2 and 3). Our findings indicate that proactive motor control strongly affects monetary risk taking in gambling. The link between control systems at different cognitive levels might be exploited to develop new methods for rehabilitation of addiction and impulse-control disorders.
doi:10.1177/0956797611434538
PMCID: PMC3724270  PMID: 22692336
gambling; impulse control; executive functions; stop signal; training; response inhibition; self-control
25.  Endogenous cortisol levels are associated with an imbalanced striatal sensitivity to monetary versus non-monetary cues in pathological gamblers 
Pathological gambling is a behavioral addiction characterized by a chronic failure to resist the urge to gamble. It shares many similarities with drug addiction. Glucocorticoid hormones including cortisol are thought to play a key role in the vulnerability to addictive behaviors, by acting on the mesolimbic reward pathway. Based on our previous report of an imbalanced sensitivity to monetary versus non-monetary incentives in the ventral striatum of pathological gamblers (PGs), we investigated whether this imbalance was mediated by individual differences in endogenous cortisol levels. We used functional magnetic resonance imaging (fMRI) and examined the relationship between cortisol levels and the neural responses to monetary versus non-monetary cues, while PGs and healthy controls were engaged in an incentive delay task manipulating both monetary and erotic rewards. We found a positive correlation between cortisol levels and ventral striatal responses to monetary versus erotic cues in PGs, but not in healthy controls. This indicates that the ventral striatum is a key region where cortisol modulates incentive motivation for gambling versus non-gambling related stimuli in PGs. Our results extend the proposed role of glucocorticoid hormones in drug addiction to behavioral addiction, and help understand the impact of cortisol on reward incentive processing in PGs.
doi:10.3389/fnbeh.2014.00083
PMCID: PMC3971166  PMID: 24723862
cortisol; reward; pathological gambling; fMRI; ventral striatum; addiction; incentive; glucocorticoid hormones

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