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Trends Cogn Sci. 2014 August ; 18(8): 429–438. doi:10.1016/j.tics.2014.03.007.

The neural bases of cognitive processes in gambling disorder

Marc N. Potenza
Departments of Psychiatry, Neurobiology, and Child Study Center, Yale University School of
Medicine, New Haven, Connecticut

Abstract
Functional imaging is offering powerful new tools to investigate the neurobiology of cognitive
functioning in people with and without psychiatric conditions like gambling disorder. Based on
similarities between gambling and substance-use disorders in neurocognitive and other domains,
gambling disorder has recently been classified in DSM-5 as a behavioral addiction. Despite the
advances in understanding, there exist multiple unanswered questions about the pathophysiology
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underlying gambling disorder and the promise for translating the neurobiological understanding
into treatment advances remains largely unrealized. Here we review the neurocognitive
underpinnings of gambling disorder with an eye towards improving prevention, treatment and
policy efforts.

Keywords
Gambling; neuroimaging; neurobiology; cognition

Introduction
Evidence of gambling extends back to the earliest recorded cultures in human history [1].
Gambling may take many forms including lotteries, electronic gambling machines (i.e., slot
machines), cards, and sports, and may occur in multiple venues (e.g., in casinos,
convenience stores or bars or on the Internet), either legally or illegally [2]. Most adults
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gamble, as do most adolescents, making gambling a normative behavior for these groups [3,
4]. Although most people gamble without experiencing problems, a minority develops
gambling problems with lifetime estimates amongst adults typically cited in the range of
0.2%–5.3%, with precise estimates depending on the threshold used for considering
gambling problematic [2].

© 2014 Elsevier Ltd. All rights reserved.

Correspondence concerning this article should be addressed to Marc N. Potenza, MD, PhD, Yale University School of Medicine,
CMHC, 34 Park Street, New Haven, CT, 06519, USA. marc.potenza@yale.edu.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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 Potenza Page 2

The diagnostic entity in the fifth edition of the Diagnostic and Statistical Manual (DSM-5)
relating to gambling is gambling disorder (previously termed “pathological gambling” in the
third and fourth editions of the DSM [5, 6]). The inclusionary criteria for pathological
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gambling and gambling disorder (Box 1) share similarities with those for substance abuse,
dependence and use disorders across DSM-IV and DSM-5. For example, the inclusionary
criteria for gambling disorder, like those for substance use disorders, include criteria
targeting tolerance, withdrawal, repeated unsuccessful attempts to cut back or quit and
interference in major areas of life functioning. Although certain criteria are specifically
listed for gambling and substance-use disorders, they often have applicability to both. For
example, cravings (strong desires or urges to use substances) are listed in the inclusionary
criteria for substance-use but not gambling disorders, although gambling urges are present in
people with gambling disorder and a target of clinical interventions [7]. On the other hand,
gambling when feeling distressed is an inclusionary criterion for gambling but not
substance-use disorders, although negative-reinforcement motivations are clinically relevant
for substance addictions, particularly women [8].

Based on existing data from epidemiological, clinical, genetic, and neurobiological domains
[9], pathological gambling was reclassified from the category of “Impulse Control Disorders
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Not Elsewhere Classified” in DSM-IV to the category of “Addictive and Related Disorders”
in DSM-5 [10]. Although gambling and substance-use disorders are now classified together,
the DSM-5 applies a threshold of relatively greater stringency for the diagnosis of gambling
disorder (meeting 4 of 9 inclusionary criteria) compared to substance-use disorders (meeting
2 of 11 inclusionary criteria) [10]. This situation has the potential to underestimate the
societal impact of gambling relative to substance-use disorders. As levels of gambling not
meeting the threshold for gambling disorder have been associated with adverse measures of
functioning (e.g., psychopathology [11]), consideration of both risky and disordered
gambling is warranted from neurobiological and public health perspectives [12].

Unlike many other psychiatric disorders, there are no medications with indications for
treating gambling disorder (i.e., no drug with an indication approval from the US Food and
Drug Administration for treating the disorder) [13]. Thus, there is a significant need for
medications development efforts to help advance the treatment of gambling disorder. In
order to facilitate these efforts, an improved understanding of the biological underpinnings
of gambling disorder is needed. Additionally, an improved understanding of the neural
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features underlying gambling disorder will generate an improved understanding of the

mechanisms underlying effective behavioral therapies for gambling disorder and may lead to
improved or better targeted therapies [14]. In this article, a current understanding of the
neurobiology of gambling disorder will be presented. The term gambling disorder will be
used in place of pathological gambling given the changes in DSM-5, albeit with the
understanding that most neurobiological investigations to date have studied populations with
pathological gambling. When relevant, findings described will be placed within the context
of other psychiatric conditions (most notably substance-use disorders) given biological
similarities across the conditions [15]. Given recent reviews into the neurobiology of
gambling disorder [12, 15–18], an emphasis will be placed on recent data published over the
past several years, with a focus on current controversies like whether gambling disorder is
associated with hyper-or hypo-responsive reward systems and the extent to which dopamine

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dysfunction exists and predominates in gambling disorder. The review will cover cognitive/
behavioral, neuroimaging and neurochemistry domains, and a schematic is included
describing key components in these areas (Figure 1). A glossary with definitions for some
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terms relevant to gambling disorder, including less widely used gambling-related terms, is
provided.

Cognitions and Gambling Behaviors in Gambling Disorder

Cognitive Processes
Cognitive factors (e.g., relating to decision-making) may contribute importantly to gambling
behaviors and gambling disorder. Individuals with gambling disorder have shown
differences in multiple cognitive processes. Early studies indicated that individuals with
gambling disorder showed differences from healthy comparison subjects on measures of
executive function relating to attention, learning and reversal learning, and planning,
attending and decision-making [19]. More recent studies have identified cognitive
differences that seem particularly related to ventral prefrontal cortical function. For example,
in a study comparing individuals with gambling problems to those with alcohol-use
problems and those with neither, those with gambling problems performed similar to healthy
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comparison subjects (who both performed better than those with alcoholuse problems) on
tasks assessing visuospatial working memory and the maintenance and manipulation of
verbal information in working memory [20]. However, both the problem gambling and
alcohol-abusing groups performed worse than the non-addicted comparison group on
measures of reflection impulsivity and gamblingrelated decision-making [20]. These
findings resonate with those of independent investigations that have identified
disadvantageous patterns of decision-making in individuals with gambling disorders [21], as
well as other studies that have compared individuals with gambling problems, alcohol-use
problems and healthy comparison subjects [22]. However, in some of these studies between-
group differences extended to a broader range of cognitive functions relating to inhibition
(including aspects of cognitive control and stopping an ongoing action when rapidly
responding), time estimation, cognitive flexibility, and planning [22]. In general, in each of
these domains with the possible exception of cognitive flexibility, individuals with gambling
problems and those with alcohol-use problems performed more poorly than did non-addicted
comparison subjects [22]. Although findings and their interpretations are not entirely
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consistent across studies [23], the extant literature suggests similarities across gambling and
substance-use disorders, consistent with the reclassification of gambling disorder together
with substance-use disorders in DSM-5 [10]. They also suggest that multiple cognitive
domains contribute to gambling disorder and that understanding the clinical and
neurobiological correlates may help in guiding treatment development efforts. However, the
most consistently identified cognitive disturbances in gambling disorder appear related to
risk-reward decision-making, cognitive processes linked to functioning of ventromedial
prefrontal cortex (vmPFC) rather than dorsolateral PFC (dlPFC), consistent with findings
from neuroimaging studies (discussed later in this article).

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Gambling-related Cognitions
In addition to the “traditional” cognitive domains described above, gambling behaviors may
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be associated with more unique cognitive features that may contribute importantly to
gambling disorder. For example, irrational cognitions relating to gambling behaviors have
been observed in people who gamble, including those with and without gambling problems.
These cognitions may relate to superstitions, gambler’s fallacy, illusion of control,
inaccurate processing of wins, losses or near-wins (so-called “near-miss” effect), persistence
of gambling despite often recurrent losses (so-called “chasing”) or other gambling-related
domains [24]. Given that studies have found that non-problematic gamblers experience
irrational gambling-related cognitions [25], behavioral measures of gambling seem not to be
substantially influenced by cognitive biases [26], and cognition-related information alone
(e.g., relating to odds of winning) may not influence gambling behaviors significantly [27],
the centrality of irrational cognitions to gambling disorders has been questioned [28].
However, structured assessments of irrational gambling-related cognitions are now
permitting more nuanced and systematic investigations into the relationships between
irrational gambling-related cognitions, gambling behaviors and gambling problems.

A widely used scale to assess irrational cognitions related to gambling is the gambling
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related cognitions scale (GRCS) [29]. The GRCS is a 23-item measure with good
psychometric properties [29]. It has been found to identify and assess five factors relating to
interpretative control/bias (e.g., “Relating my winnings to my skill and ability makes me
continue gambling”), illusion of control (e.g., “I have specific rituals and behaviors that
increase my chances of winning”), predictive control (e.g., “Losses when gambling, are
bound to be followed by a series of wins”), gambling-related expectancies (e.g., “Gambling
makes things seem better”), and a perceived inability to stop (e.g., “It is difficult to stop
gambling as I am so out of control”) [29], although there is considerable correlation between
the factors (mean =0.55), raising questions about a one-factor or five factor model [30].
Amongst non-problem gamblers, there exist individual differences that relate to gender, with
men scoring higher overall and on all subscales except for the illusion-of-control subscale
[29]. Among adolescents, boys scored higher than girls on the GRCS; additionally, GRCS
scores were associated with disordered gambling across gender groups, with the GRCS
scores (particularly subscales relating to perceived inability to stop, gambling-related
expectancies, and illusion of control) statistically predicting problem-gambling severity [30].
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Amongst adults, the subscale of the GRCS relating to perceived inability to stop was related
to persistence of slot-machine gambling behavior, and gambling-related cognitions more
broadly were related to subjective effects of desires to continuing to gamble following
multiple types of outcomes including near-misses [31]. Together, these findings indicate
important relationships between gambling-related cognitions and persistence and severity of
gambling across different developmental epochs, and more research is needed into the
neural factors that relate to these cognitions in groups with and without gambling disorders.

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Neuroimaging
Neural Underpinnings
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Functional neuroimaging has provided insight into the regional brain activation patterns
underlying specific cognitive processes in gambling disorder. These studies have identified
in individuals with and without gambling disorder differences in corticostriatal-limbic
activations. In multiple cases, relatively blunted activation of corticostriatal-limbic regions,
in particular the vmPFC and ventral striatum (VS), has been observed in individuals with
gambling disorder [15]. For example, relatively diminished activation of the vmPFC and/or
VS has been observed during task performance interrogating cognitive control (Stroop) [32],
gambling urges [33, 34], simulated gambling [35], decision-making (Iowa gambling task)
[36], and the processing of monetary rewards and losses (monetary incentive delay task) [37,
38]. These findings show similarities to those involving individuals with or at-risk for
substance-use disorders. For example, like individuals with gambling disorder during the
anticipatory phase of reward processing on the monetary incentive delay task [37, 38],
individuals with alcohol-use disorder [39, 40], tobacco-use disorder [41], or a familial
history of alcoholism [42] show relatively blunted VS activation as compared to those
without or at lower risk for addictions. These findings appear to extend to other groups
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characterized by impaired impulse control (e.g., individuals with binge-eating disorder [43]),
relate to impulsivity in gambling and alcohol-use disorders (e.g., with less VS activation
during reward anticipation linked to greater impulsivity [37]), and relate prospectively to
treatment outcome in preliminary studies (e.g., with individuals with binge-eating disorder
who continued to binge following treatment as compared to those who ceased bingeing
following treatment demonstrating at treatment onset relatively blunted VS activation during
reward anticipation [44]). Additionally, problem-gambling severity amongst individuals
with gambling disorders has been associated inversely with activation of the VS and/or
vmPFC during simulated gambling [35, 45] and the encoding of value signals for delayed
rewards in the vmPFC, VS and substantia nigra during performance of an intertemporal
choice task [46]. Together, these findings suggest that blunted activation of VS, vmPFC and
other neural regions linked to reward processing contribute importantly to a range of
cognitive processes in gambling disorder and other conditions characterized by impaired
impulse control. These findings suggest that gambling disorder might be conceptualized as a
reward-processing disorder; alternatively, alterations in function of vmPFC, VS and/or other
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brain regions contributing to ventral-prefrontal/subcortical circuits may give rise to key

features (abnormalities in reward processing, craving, decision-making, delay discounting,
cognitive control) of gambling disorder. These possibilities warrant further examination,
with longitudinal and translational studies (across species) offering possible avenues of
further study.

Despite these data, there is debate as to the extent to which blunted neuronal sensitivity to
rewards may underlie gambling disorder. Several studies investigating gambling urges [47,
48] and monetary processing [49] have identified relatively increased neuronal activations of
corticostriatal circuitry in individuals with, as compared to those without, gambling disorder.
Although seemingly contradictory to findings described in the prior paragraph, differences
in task designs, participants, and other features like context may contribute to differences in

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findings [50–53]. Specifically, different contexts may exert important influences, with
situations or cues that are more closely related to the addiction (i.e., to gambling in gambling
disorder) more likely to elicit increased activation of the VS and other reward-related brain
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regions [51–53]. Additionally, the risk associated with the gambling may influence brain
activations as individuals who gambled problematically and those who gambled
occasionally demonstrated opposite patterns of regional brain activations to high- and
lowrisk conditions [54]. Given that gambling-related contexts may be more physiologically
arousing for individuals with gambling problems as compared to those without [55], the
effect of context on neuroendocrine response and brain function should be examined further.
Further supporting the relevance of these lines of research are data suggesting greater
functional connectivity between ventral affective and dorsal executive systems during
affective processing in an emotional/motivational Go/No-Go task in individuals with
gambling problems as compared to those without [56]. The findings from this study resonate
with those from a study of cocaine dependence in which greater connectivity with ventral
cortical and subcortical regions were identified during a cognitive control task in the
cocaine-dependent as compared to the control group [57].

Future studies are needed to investigate systematically context, not only relating to the
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object of addiction (i.e., gambling for gambling disorder), but also to mood, stress and other
possible factors that might relate to or influence motivational tendencies to engage in
addictive behaviors [58, 59]. For example, negative mood states or stress might promote
gambling behaviors in certain individuals with gambling disorders, consistent with negative
reinforcement models of addiction and findings linking gambling disorder and related
cognitive processes (e.g., gambling urges) to stress and trauma [58, 60]. These relationships
may be particularly relevant to women given their greater acknowledgement of gambling to
escape negative affective states and links between gambling disorder in trauma in women as
compared with men [60, 61]. Subjective responses to emotional or gambling-related cues
may also provide additional insight; for example, activation of the temporal pole, a brain
region implicated in the recollection of personally relevant events, was related to the
magnitude of gambling urges in response to gambling cues during the onset of subjective
awareness of these feelings [62]. As personalized cues relating to stress more strongly
elicited corticostriatal-limbic activations in cocaine-dependent women and cocaine cues
more strongly elicited corticostriatal-limbic activations in cocainedependent women [8],
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similar studies of gambling-disordered women and men are needed to investigate the extent
to which similar neurobiological processes might underlie sex differences in gambling
disorder. While stress might operate through increasing urges to gamble in individuals with
gambling disorder, it might also operate by comprising prefrontal control mechanisms in
individuals with addictions [63], mechanisms that have been linked to regulation of craving
states amongst drug-dependent individuals [64], and direct examination of these possibilities
is warranted.

Other contexts also warrant examination. For example, peer influence might promote risk-
taking behaviors particularly amongst adolescents, and certain adolescents might be
particularly prone to risk-taking behaviors under peer influence. For example, adolescent
smokers but not non-smokers increased risk-taking on a laboratory task under peer
influence, and this peer-related increase in risk-taking was linked to self-reported impulsive

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tendencies [65]. The extent to which such contexts may increase gambling behaviors,
particularly adolescents with gambling disorders, warrants direct examination. Additionally,
other cognitive constructs underlying aspects of reward processing and related behaviors
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(near-miss effects [66], loss-chasing [67]) that have been investigated in people without
gambling problems warrant further study in individuals with gambling disorder, both
amongst adolescents and adults.

Neurochemistry
Neurochemical Contributions to Gambling Disorder
Recent reviews has described in detail neurochemical contributions to gambling disorder
[15, 17, 18, 52]. For decades, biogenic amines and other neurochemicals have been
implicated in the pathophysiology of gambling disorder [15]. Noradrenergic, serotonergic,
dopaminergic, and opioidergic contributions have been proposed to contribute to arousal/
excitement, impulse control, reward/reinforcement and urges/cravings, respectively [15].
Recently communicated data suggest more extensive contributions to cognit ive factors
underlying gambling behaviors; e.g., with respect to dopamine and executive functioning
[68]. Additionally roles for alpha-adrenergic mechanisms, particularly in relationship to
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stress responsiveness [69], and glutamatergic mechanisms that may relate to compulsive
engagement in gambling [70, 71] have been suggested and supported, although other
pathways may also contribute to identified findings [72]. Given the importance of dopamine
in substance addictions, dopaminergic systems have been an important focus of recent
neurochemical investigations of gambling disorder.

Dopamine in Gambling Disorder

Debate exists regarding the centrality of dopamine to gambling disorder [73]. Although
multiple lines of evidence associate dopamine with gambling, gambling disorder, substance
use and substance-use disorders, the precise relationships between dopamine and these
behaviors and disorders remain incompletely understood. For example, dopamine
replacement therapies (including dopamine agonists acting upon dopamine D2-like
receptors, which include D2, D3 and D4) have been associated with gambling disorder and
other “behavioral” addictions [74], dopamine agonists influence impulsive choices
differentially in people with Parkinson’s disease with and without gambling disorder and
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other behavioral addictions [75], and amphetamine administration has been found to prime/
promote gambling urges in individuals with gambling problems [76]. These findings suggest
that pro-dopaminergic agents or states may promote problematic gambling and underlie the
pathophysiology observed in gambling disorder. However, drugs antagonizing dopamine
D2-like receptors (e.g., haloperidol) have been associated with increasing the rewarding and
priming effects of a gambling in people with gambling problems but not in those without
[77]. Furthermore, drugs that antagonize dopamine D2-like receptors like olanzapine have
not shown clinical utility in randomized clinical trials involving people with gambling
disorder [78, 79].

There may be multiple reasons for the seemingly conflicting results regarding a role for
dopamine in gambling disorder. Among these is the homology between D2, D3 and D4

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dopamine receptors that translate into overlapping affinities for drugs, and this situation has
important research and clinical implications. Specifically, each dopamine receptor may play
a role in gambling behaviors and gambling disorder. For example, in animal studies for
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which drugs with greater specificity are available, the D4 dopamine receptor has been
implicated in slot-machine gambling behaviors in rodents [80]. In humans, positron
emission tomography (PET) studies have used [11C]raclopride in preliminary studies to
investigate D2/D3 receptors in relationship to gambling behaviors and gambling disorder. In
one study of individuals with Parkinson’s disease, less [11C]raclopride availability in the VS
at baseline and greater [11C]raclopride displacement following performance of a gambling
task was observed in individuals with gambling disorder as compared to those without,
suggesting greater VS dopamine release in the group with gambling disorder [81]. However,
the extent to which dopaminergic or other brain pathology associated with Parkinson’s
disease may have contributed to these findings is unclear. In studies of individuals without
Parkinson’s disease, between-group differences in individuals with and without gambling
disorder in [11C]raclopride binding have typically not been identified [82–85]. However,
individual differences in VS [11C]raclopride binding have correlated inversely with negative
urgency [82] and money lost and other aspects of Iowa gambling task performance [83, 84]
in preliminary studies. These findings suggest potential roles for dopamine
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neurotransmission in the VS as related to specific cognitive aspects of gambling disorder.

An important advancement with respect to dissecting dopamine D2 and D3 receptor

contributions to cognitive aspects of gambling disorder relates to the availability of [11C]-
(+)-propyl-hexahydro-naphtho-oxazin ([11C]PHNO) as a radio-ligand available for use in
humans. [11C]PHNO is a dopamine-D3-receptor-preferring radioligand. In regions like the
substantia nigra, where the D2-like dopamine signal is primarily attributable to dopamine
D3 receptors, [11C]PHNO can provide specific insight into a role for D3 versus D2
dopamine receptors. In individuals with gambling disorder, binding values of [11C]PHNO
did not differ between individuals with or without gambling disorder; however, among
individuals with gambling disorder, [11C]PHNO binding values in the substantia nigra
correlated positively with problem-gambling severity and impulsiveness [85]. Furthermore,
following amphetamine administration, the individuals with gambling disorder exhibited
findings consistent with greater dopamine release in the dorsal striatum, with the
dopaminergic response to amphetamine relating positively to [11C]PHNO binding (or
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dopamine D3 receptor levels) in the substantia nigra [86]. These findings suggest in
gambling disorder a hyper-dopaminergic state involving the substantia nigra and dorsal
striatum, and suggest possible differences between gambling and drug addictions. The extent
to which these findings relate to specific cognitive functions in gambling disorders,
represent potential vulnerability factors, or relate importantly to clinical outcomes requires
additional investigation.

Intermediate Phenotypes and Trans-diagnostic Considerations

An important approach to understanding psychiatric conditions involves the identification
and characterization of relevant intermediate phenotypes or endophenotypes [87]. Such
constructs may link more closely to underlying biological factors than do heterogeneous

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psychiatric disorders. NIH initiatives like the Research Domain Criteria (RDoC) and Phen-X
(https://www.phenxtoolkit.org) reflect current efforts related to this line of research [88].
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Among the most widely studied intermediary phenotypes in gambling disorder is

impulsivity, a construct that has been related to multiple psychiatric conditions [89–92].
Impulsivity has been found to factor into multiple domains (e.g., choice and motor or
response forms), and behavioral and self-report measures may factor separately or not
correlate with one another, even within the same domain [90]. Compulsivity has historically
received less research attention but may also relate importantly to gambling disorder,
particularly as behavior becomes more engrained or habitual [90]. Although early models
conceptualized impulsivity and compulsivity as lying along a continuous linear spectrum
[93], data indicate that certain groups like those with gambling disorder may score high both
on measures relating to impulsivity and compulsivit y [94]. As measures of impulsivity and
compulsivity have been linked to treatment outcomes in gambling disorder [95, 96], both
constructs warrant further investigation into how they may relate to specific biological
measures in gambling disorder. Additional intermediate phenotypes (e.g., relating to
emotional regulation and stress responsiveness) also warrant investigation [58, 59, 62].
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Future Directions
Although significant advances have been made with respect to understanding the cognitive
processes underlying gambling behaviors and gambling disorder, there remain many
unanswered questions and clinical needs. Among the clinical needs is the identification of
effective treatments for people with gambling disorder. Although multiple behavioral
therapies have shown promise and are used in clinical settings, little is known about the
biological mechanisms of action underlying these therapies or the extent to which specific
therapies might best help specific groups of people with gambling problems [14]. For
example, opioid antagonists in the treatment of gambling disorder have received support
from multiple randomized clinical trials [13]. However, human studies into their biological
mechanisms of action are lacking. Unlike many other psychiatric conditions, there is no
medication with an approved indication from the US Food and Drug Administration for
gambling disorder. As such, there is a distinct need for medications development efforts.

Technologies currently available afford great opportunities for investigating the

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neurobiological underpinnings of cognitive processes in gambling disorder. While much of

the current article has focused on functional neuroimaging, other approaches, such as
magnetization-prepared rapid gradient-echo (MPRAGE) and diffusion tensor imaging (DTI)
that can be used to assess regional brain volume and white matter integrity, respectively, are
available. These have been used to identify differences between individuals with and
without gambling disorder and relate the biological measures to individual differences
related to avoidance and approach tendencies [97–99]. Additionally, PET studies using non-
dopaminergic radioligands in individuals with and without gambling disorder have
implicated other neurochemical systems (e.g., the serotonin 1B receptor system [100], one
also implicated in alcohol and cocaine-use disorders [101, 102]). While few studies to date
have used multiple radioligand probes in the same individuals, such approaches have
significant potential to advance our understanding of how neurochemical systems may

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interact in psychiatric conditions [103]. Given data implicating dopaminergic, serotonergic,

noradrenergic, opioidergic, glutamatergic and other neurochemical systems in gambling
disorder, the investigation of these systems and how they interact and relate to specific
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aspects of gambling disorder (e.g., reward processing, urges/cravings, risk/reward decision-

making) warrants direct examination. Along a similar line of reasoning, employing multiple
imaging modalities concurrently (functional magnetic resonance imaging, MPRAGE, DTI,
PET and others) may offer complementary insight into brain biology and promote an
understanding of how these multiple domains (brain activation patterns, gray-matter
structure, white-matter integrity, and neurochemical processes) interact and underlie
individual differences in clinically relevant phenomena (e.g., impulsivity, treatment
outcomes) in gambling disorder, as is currently the case for substance-use disorders [104].
Integrating information from functional neuroimaging with that from other domains
(molecular genetic, clinical outcomes) is in early stages, with preliminary studies in
gambling disorder suggesting promise and providing insight into future lines of investigation
[14, 68, 105]. Additionally, utilizing alternative analytic strategies (e.g., independent
component analysis or intrinsic connectivity distributions) may help to identify brain
networks underlying cognitive constructs and relate them to clinically relevant measures like
treatment outcome as is being done for substanceuse disorders [57, 106, 107]. In these
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efforts, longitudinal studies may help identify biological factors that may predispose people
to developing gambling problems, as well as biological changes that occur during the
progression of developing and recovering from the disorder. “Deep phenotyping” using both
valid, reliable assessments of psychiatric conditions, detailed gambling information and
assessments of intermediate phenotypes used in studies of other psychiatric conditions (e.g.,
measures of impulsivity or other research RDoC constructs [88, 90]) will ultimately help to
understand gambling disorder and how it relates to other disorders, identify and intervene to
assist people at risk, and help best those currently suffering from the disorder.

Concluding Remarks
While gambling and gambling problems have long been recognized, there has been a recent
shift in the classification of the disorder based in considerable part on neurobiological
similarities between gambling and substance-use disorders. Despite the advances over the
past dozen years (prior to which no brain imaging study of people with gambling disorder
had been published), there exist significant gaps in our understanding of the biological
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underpinnings of gambling disorder, how they are similar to and distinct from those
underlying other psychiatric disorders, how they relate to specific cognitive functions in
gambling disorder and how they mat be targeted therapeutically. In addition to the future
directions cited above for research in people with gambling disorder, the field would benefit
from additional translational research. Over the past five years, important inroads have been
made with respect to generating rodent models of slot-machine and other gambling
behaviors [108, 109]. These tasks have allowed for the initial investigation of dopaminergic
and serotonergic systems involved in specific aspects of gambling behaviors and gambling-
related decision-making and provide complementary data to human investigations. For
example, studies in rats suggest that the D4 dopamine receptor may contribute importantly
to slot-machine behaviors, shedding additional insight into potential roles for dopamine in

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gambling disorder and providing potential novel targets for drug development [80].
Similarly, development of tasks for use in other species might generate important knowledge
regarding gambling behaviors in humans; for example, development of analogous tasks for
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use in mice might capitalize on knowledge about and experimental capacities relating to
murine genetics. Additional technologies (involving targeted gene regulation via
optogenetics, viral mediation and other techniques) could be used to understand gambling-
related behaviors.

Additionally, studies of gambling behaviors in non-human primates might offer insight into
electrophysiological brain function and how such brain function might be targeted
therapeutically to influence gambling behaviors. For example, gambling-related tasks in
which specific manipulation of risk and uncertainty have been developed for use in non-
human primates, and an alpha-2 adrenergic agonist (guanfacine) was found to influence
choice of larger later rewards only when the reward was certain, and that guanfacine
influenced time preference (selecting of larger later rewards) but not risk preference [110].
These behaviors were accompanied by guanfacine-related changes in prefrontal cortical
function that suggested the drug may enhance top-down control over subcortical regions that
may promote impulsive choices [110]. These findings complement human studies
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suggesting a role for alpha-2 adrenergic involvement in gambling disorder [69] and suggest
the potential utility of guanfacine in the treatment of gambling disorder. While in these
rodent and nonhuman- primate examples gambling-related behaviors and not gambling
disorder per se is being studied, the findings have important implications for the study of
gambling disorder in humans.

As a behavioral addiction, gambling disorder has the potential to provide important insight
into substance addictions (e.g., the effects that chronic or recent exposure to drugs may have
on brain structure and function and behavior). The concurrent study of individuals with
substance-use disorders and those with gambling disorders thus is likely to provide
important insight into substance addictions, as well as into gambling disorder. The improved
understanding should thus diminish the currently large impact that addictions have on
individuals, their families and society in general.

Acknowledgments
NIH-PA Author Manuscript

This research was funded in part by NIH grants from NIDA (P20 DA027844, R01 DA018647, R01 DA035058,
P50 DA09241), the National Center for Responsible Gaming, the Connecticut State Department of Mental Health
and Addictions Services, and the Connecticut Mental Health Center. The funding agencies did not provide input or
comment on the content of the manuscript, and the content of the manuscript reflects the contributions and thoughts
of the author and not necessarily reflect the views of the funding agencies.

Dr. Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and
advised Lundbeck and Ironwood pharmaceuticals; has received research support from the Mohegan Sun Casino and
the National Center for Responsible Gaming; has participated in surveys, mailings or telephone consultations
related to drug addiction, impulse control disorders or other health topics; has consulted for legal and gambling
entities on issues related to gambling behaviors and disorders; provides clinical care in a Problem Gambling
Services Program; has performed grant reviews for the National Institutes of Health and other agencies; has edited
journals and journal sections; has given academic lectures in grand rounds, CME events and other clinical or
scientific venues; and has generated books or book chapters for publishers of mental health texts.

Trends Cogn Sci. Author manuscript; available in PMC 2015 August 01.
 Potenza Page 12

Glossary

Compulsivity relating to tendencies to engage in repetitive and functionally

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impairing overt or covert behaviors without apparent adaptive

function; may involve perseverative or stereotypic features
Craving a strong desire or urge to engage in a behavior; typically applied to
substance-use disorders and may motivate an individual to engage in
the addictive behavior; frequently a therapeutic target in the treatment
of addictions
Decision- a cognitive process considered by some to be a core element of
making addictions in which decisions to engage in addictive behaviors take
precedent over ones that may be more adaptive (e.g., engaging in
work, family functions or other pro-social roles)
Delay Also termed temporal discounting; refers to preferences for smaller,
Discounting sooner as compared to larger, later rewards; greater or steeper delay
discounting is often seen in individuals with addictions; reflecting a
greater tendency to prefer or select smaller, sooner as opposed to
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larger, later rewards

Executive a term applied to a broad range of cognitive processes that includes
Functioning working memory, attention monitoring, reasoning, and flexibility
Gambling placing something of value (usually money) at risk in the hopes of
gaining something of greater value
Gambler’s the belief that an independent event is more or less likely on the basis
Fallacy of prior independent events; e.g., that the odds of a coin-flip outcome
is not 50% heads or 50% tails if three consecutive heads outcomes
were observed
Illusion of a tendency to believe that one has control over events over which he
Control or she has no influence
Impulsivity a predisposition to rapid, unplanned reactions to internal or external
stimuli with diminished regard to the negative consequences of the
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reactions to the impulsive individual or others

Loss-chasing the behavior of trying to win back money recently lost gambling by
engaging in more gambling; for example, “double or nothing” bets
Near-miss the occurrence of a nearly winning event, usually on a slot machine
(or other electronic gambling machine); for example, when the first
two reels of a slot machine stop on the same symbol and the third ends
on a different symbol

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Box 1. A) DSM-IV Diagnostic Criteria for 312.31 Pathological Gambling

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A. Persistent and the current maladaptive gambling behavior as indicated by five (or
more) of the following:

1. is preoccupied with gambling (e.g., preoccupied with reliving past gambling

experiences, handicapping or planning the next venture, or thinking of ways to
get money with which to gamble)

2. needs to gamble with increasing amounts of money in order to achieve the

desired excitement

3. has repeated unsuccessful efforts to control, cut back, or stop gambling

4. is restless or irritable when attempting to cut down or stop gambling

5. gambles as a way of escaping from problems or of relieving a dysphoric mood

(e.g., feelings of helplessness, guilt, anxiety, depression)

6. after losing money gambling, often returns another day to get even (“chasing”
one’s losses)
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7. lies to family members, therapist, or others to conceal the extent of involvement

with gambling

8. has committed illegal acts such as forgery, fraud, theft, or embezzlement to

finance gambling

9. has jeopardized or lost a significant relationship, job, or education or career

opportunity because of gambling

10. relies on others to provide money to relieve a desperate financial situat ion
caused by gambling

B. The gambling behavior is not better accounted for by a Manic Episode.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric
Association
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Box 1. B) DSM-5 Diagnostic Criteria for 312.31 Gambling Disorder

A. Persistent and recurrent problematic gambling behavior leading to clinically
significant impairment or distress, as indicated by the individual exhibiting four (or
more) of the following in a 12-month period:

1. Needs to gamble with increasing amounts of money in order to achieve the

desired excitement.

2. Is restless or irritable when attempting to cut down or stop gambling.

3. Has made repeated unsuccessful efforts to control, cutback, or stop gambling.

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4. Is often preoccupied with gambling (e.g., having persistent thoughts of reliving

past gambling experiences, handicapping or planning the next venture, thinking
of ways to get money with which to gamble).
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5. Often gambles when feeling distressed (e.g., helpless, guilty, anxious,

depressed).

6. After losing money gambling, often returns another day to get even (“chasing”
one’s losses).

7. Lies to conceal the extent of involvement with gambling.

8. Has jeopardized or lost a significant relationship, job, or educational or career

opportunity because of gambling.

9. Relies on others to provide money to relieve desperate financial situations

caused by gambling.
B. Gambling behavior is not better explained by a manic episode

Specify if:
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Episodic: Meeting diagnostic criteria at more than one time point, with symptoms
subsiding between periods of gambling disorder for at least several months.

Persistent: Experiencing continuous symptoms, to meet diagnostic criteria for

multiple years.

Specify if:

In early remission: After full criteria for gambling disorder were previously met,
none of the criteria for gambling disorder have been met for at least 3 months but for
less than 12 months.

In sustained remission: After full criteria for gambling disorder were previously
met, none of the criteria for gambling disorder have been met during a period of 12
months or longer.

Specify current severity:

Mild: 4–5 criteria met.

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Moderate: 6–7 criteria met.

Severe: 8–9 criteria met.

Note: Although some behavioral conditions that do not involve ingestion of substances
have similarities to substance-related disorders, only one disorder – gambling disorder –
sufficient data to be included in this section.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association

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Highlights
Debate exists regarding the extent to which blunted or exaggerated reward
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responsiveness underlies gambling disorder.

Seemingly conflicting data exist for a role for dopamine in gambling disorder and its
related cognitive processes.

Further examination of intermediate phenotypes like impulsivity and compulsivity

will help understand gambling disorder and other addictions.
There exists a need to translate a neurocognitive understanding of gambling disorder
into improved prevention, treatment and policy initiatives.
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NIH-PA Author Manuscript

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Figure 1.
Schematic Diagram Relating Biological Measures to Cognitions and Behaviors in Gambling
Disorder. A diagram linking the domains of “Neurochemical Systems” and “Brain Regions
and Circuits” to “Cognitions” which then influence the domain of “Excessive Gambling
Behaviors” is presented. Salient representative factors within each domain are presented.
Each domain has potential as targets for possible prevention and treatment interventions.

Trends Cogn Sci. Author manuscript; available in PMC 2015 August 01.