The neurobiology of pathological gambling and drug addiction an overview and new findings (2008)

Abstract

1. Recreational, problem and pathological gambling

Gambling can be defined as placing something of value at risk in the hopes of gaining something of greater value (Potenza 2006). A majority of adults gamble, and most do so without encountering significant problems. Nonetheless, gambling problems among adults have been estimated as high as 5%, with certain groups (young adults, people with mental health disorders and incarcerated individuals) having estimates several fold higher (Shaffer et al. 1999). Pathological gambling (PG), representing the most severe form of problem gambling (see below), has prevalence estimates of approximately 0.5–1% (Petry et al. 2005). Given the increased availability of legalized gambling and its popularity over the past several decades, increased attention to the health impacts of specific levels of gambling behaviours is warranted (Shaffer & Korn 2002).

It was not until 1980 that the Diagnostic and statistical manual (DSM) defined criteria for a gambling disorder (American Psychiatric Association 1980). The term ‘PG’ was selected in favour of other terms (e.g. compulsive gambling) that were arguably more widely used at the time, perhaps in an effort to distinguish the disorder from obsessive-compulsive disorder. Along with pyromania, kleptomania, trichotillomania and intermittent explosive disorder, PG is currently classified as an ‘impulse control disorder (ICD) not elsewhere categorized’ in the DSM. Similarly, in the International Classification of Disorders, the disorder is classified under ‘Habit and impulse disorders’ along with pyromania, kleptomania and trichotillomania. Many of the current diagnostic criteria for PG share features with those for drug dependence (DD). For example, criteria targeting tolerance, withdrawal, repeated unsuccessful attempts to cut back or quit, and interference in major areas of life functioning are contained in the criteria for both PG and DD. Similarities extend to phenomenological, epidemiological, clinical, genetic and other biological domains (Goudriaan et al. 2004; Potenza 2006; Brewer & Potenza 2008), raising questions about whether PG might best be characterized as a ‘behavioural’ addiction.

2. PG as an addiction

If PG represents an addiction, it should share with DD core features. Core components of addictions have been proposed including (i) continued engagement in a behaviour despite adverse consequences, (ii) diminished self-control over engagement in the behaviour, (iii) compulsive engagement in the behaviour, and (iv) an appetitive urge or craving state prior to the engagement in the behaviour (Potenza 2006). Many of these features, as well as others, such as tolerance and withdrawal, appear relevant to PG and DD (Potenza 2006). Concurrent studies of both PG and DD should help define aspects that are related to drugs. That is, drugs may influence brain structure and function in ways that are central or unrelated to the addiction process. In that PG may be conceptualized as an addiction without the drug, direct comparison of both disorders may provide insight into the core neurobiological features of addiction and guide the development and testing of effective treatments.

3. Neurotransmitter systems and PG

Specific neurotransmitters have been hypothesized to relate to different aspects of PG. Based on studies of PG and/or other disorders, noradrenaline has been hypothesized in ICDs to be particularly relevant to aspects of arousal and excitement, serotonin to behavioural initiation and cessation, dopamine to reward and reinforcement, and opioids to pleasure or urges. These and other systems are considered below.

4. Neural systems

Relatively few investigations have examined how brain activities differ in individuals with PG or other ICDs as compared to those without. One initial functional magnetic resonance imaging (fMRI) study investigated urge or craving states in men with PG (Potenza et al. 2003b). When viewing gambling tapes and prior to the onset of subjective motivational or emotional response, the pathological gamblers (PGers) as compared to recreational ones showed relatively less blood oxygen level-dependent (BOLD) signal change in frontal cortical, basal ganglionic and thalamic brain regions. These between-group differences were not observed during the happy or sad videotape conditions during the comparable epochs of viewing, and the findings are distinct from studies of individuals with obsessive-compulsive disorder, who typically show relatively increased activation of these regions during symptom provocation studies (Breiter & Rauch 1996). During the final period of tape viewing, the time at which the most robust gambling stimuli were presented, men with PG as compared to those without were most distinguished by showing relatively diminished BOLD signal change in vmPFC. These findings appear consistent with those from studies of impaired impulse control in other behavioural domains, notably aggression (Siever et al. 1999; New et al. 2002) and decision making (Bechara 2003).

Although other imaging studies have implicated frontal regions in PG (Crockford et al. 2005), multiple investigations have observed differences in vmPFC function in PG. A study of cognitive control using an event-related version of the Stroop colour-word interference task found that men with PG as compared to those without were most distinguished by a relatively diminished BOLD signal change in left vmPFC following the presentation of incongruent stimuli (Potenza et al. 2003a). When performing the same fMRI Stroop paradigm, individuals with bipolar disorder were distinguished most from control subjects in a similar region of vmPFC (Blumberg et al. 2003), suggesting that some elements common to the disorders (e.g. impaired impulse control, poor emotional regulation) share neural substrates across diagnostic boundaries. Analogously, individuals with substance dependence with or without PG showed less activation of vmPFC than did control subjects in a ‘gambling’ task assessing decision making (Tanabe et al. 2007).

In another fMRI study, individuals with PG as compared to those without showed less activation of vmPFC during simulated gambling in contrasts comparing winning and losing conditions, and BOLD signal change in vmPFC correlated inversely with gambling severity among PGers (Reuter et al. 2005). In the same study and using the same contrasts, a similar pattern of diminished activation was observed in PGers in the ventral striatum, a brain region with dopaminergic innervation and which is widely implicated in drug addiction and reward processing (Everitt & Robbins 2005). Based on work in primates (Schultz et al. 2000), studies of reward processing in humans have associated activation of the ventral striatum with anticipation of working for monetary reward and activation of vmPFC with receipt of monetary rewards (Knutson et al. 2003). This circuitry appears particularly relevant to the processing of immediate rewards as the selection of larger delayed reward involves more dorsal cortical networks (McClure et al. 2004). Blackjack gambling as compared to playing blackjack for points is associated with greater corticostriatal activations in PGers (Hollander et al. 2005). However, this study did not include subjects without PG and thus did not investigate how PG subjects differed from those without the disorder. The finding of relatively diminished activation of ventral striatum in PGers in the simulated gambling paradigm (Reuter et al. 2005) is consistent with the findings from studies of reward anticipation in individuals with addictions or seemingly at risk for such disorders. For example, relatively diminished activation of ventral striatum during anticipation of monetary rewards has been reported in individuals with alcohol dependence (Hommer 2004; Wrase et al. 2007) or cocaine dependence (CD; Pearlson et al. 2007) as well as in adolescents as compared to adults (Bjork et al. 2004) and those with a family history of alcoholism as compared to those without (Hommer et al. 2004). Together, these findings suggest that relatively diminished activation of ventral striatum during anticipation phases of reward processing might represent an important intermediary phenotype for substance addiction and ICDs.

5. Appetitive urge states in PG and CD

Appetitive urge or craving states often immediately precede engagement in problematic behaviours such as gambling for PGers or drug use in drug addiction. As such, an understanding of the neural correlates of these states has important clinical implications (Kosten et al. 2006). From a scientific perspective, studies of similar processes, such as craving states in individuals with PG or those with DD, may clarify aspects that are central to the underlying motivational processes across disorders, independent of the effects of acute or chronic drug exposure.

To investigate, we employed data from our published studies of gambling urges in PG (Potenza et al. 2003b) and drug craving in CD (Wexler et al. 2001). As our gambling study involved only male subjects, we restricted analyses to men, yielding a sample including 10 PG subjects and 11 recreational gamblers (C_PG subjects) who viewed the gambling, sad and happy videotapes during fMRI, and 9 CD subjects and 6 non-cocaine-using control comparison men (C_CD subjects) who viewed the cocaine, sad and happy scenarios, as described previously. We investigated in the following manner the extent to which brain activations in motivational and emotional processing were similar or distinct in a behavioural addiction like PG as compared to the drug addiction CD. We hypothesized that brain regions whose function was influenced by cocaine exposure, such as frontal and anterior cingulate cortex, would be differentially involved in cocaine cravings in CD and gambling urges in PG.

We used a voxel-based randomization procedure to assign statistical significance in the generation of p-maps that identify differences in the manner in which affected subjects’ brain function differs from that of controls across the gambling and cocaine groups during viewing of the addiction, happy and sad videotapes (Wexler et al. 2001; Potenza et al. 2003b). For each subject group viewing each tape type, we generated a t-map comparing the period of scenario viewing as compared to the average pre- and post-tape grey screen baselines. Next, for each tape type, we generated t-maps contrasting the manners in which the affected subjects (e.g. PG) differed from their respective controls (e.g. C_PG), generating a PG–C_PG contrast. Next, we contrasted the manner in which the affected groups differed from controls across the addictions ((PG–C_PG)−(CD–C_CD); table 1a, see figure 1A in the electronic supplementary material). At p<0.005 and using a cluster of 25 to increase stringency (Friston et al. 1994), disorder-related differences in the contrasts between affected and non-affected subject groups were observed during viewing of the addiction tapes (table 1a; see figure 1A in the electronic supplementary material) but not the sad or happy scenarios (not shown). The regions of ventral and dorsal anterior cingulate and right inferior parietal lobule were identified during viewing of the addiction scenarios, with relatively decreased activity in the (PG–C_PG) contrast as compared to the (CD–C_CD) comparison. Within-subject group contributions to these differences are tabulated (table 1a). The anterior cingulate cortex, a brain region implicated in emotional processing and cognitive control in healthy (Bush et al. 2000) and CD subjects (Goldstein et al. 2007), has been shown to activate during cocaine craving (Childress et al. 1999). Cocaine administration activates the anterior cingulate (Febo et al. 2005), and the timing and the pattern of cocaine administration influence anterior cingulate function (Harvey 2004). The difference in inferior parietal lobule activation across subject groups reflects mainly a difference in the neural responses of the control groups to the gambling and cocaine videotapes. The inferior parietal lobule has been implicated in response inhibition components of impulse regulation (Menon et al. 2001; Garavan et al. 2006). Thus, the findings indicate that viewing tapes of different content (e.g. descriptions of a socially sanctioned behaviour (gambling) as compared to an illegal activity (simulated cocaine use)) is associated with differential activation in control subjects of a brain region involved in mediating response inhibition.

Table 1

Brain activations in PG and CD as compared to control subjects.

We next investigated brain regions common to cocaine cravings and gambling urges, hypothesizing that we would identify brain regions that have been similarly implicated in CD and PG, such as diminished activation of the ventral striatum in reward processing in affected as compared to control subjects (Reuter et al. 2005; Pearlson et al. 2007). For each subject group viewing each tape type, we generated a t-map comparing the period of scenario viewing to the average pre- and post-tape baselines. Next, for each tape type, we created t-maps showing activation abnormalities in the patient groups by contrasting each patient group with its respective control, generating PG–C_PG and CD–C_CD contrasts. Computer-generated comparisons at successive significance thresholds (p<0.005, p<0.01, p<0.02 and p<0.05) were made to identify regions in which the PG–C_PG and CD–C_CD contrasts demonstrated similar findings. Individual group p-maps were used to identify brain regions contributing to these findings. No brain regions were identified using this procedure for the addiction, happy and sad tapes. As our prior studies demonstrated that the initial period of tape viewing, prior to the reported onset of motivational/emotional response, was associated with significant between-group differences in responses to the addiction videotapes (Wexler et al. 2001; Potenza et al. 2003b), we performed similar analyses focusing on the initial period of tape viewing as compared to the pre-tape baseline. This procedure identified multiple brain regions (table 1b; see figure 1B in the electronic supplementary material) showing similar activity changes in the contrasts between addicted and control subjects during viewing of the respective addiction tapes, and no regions were identified in comparisons involving the sad or happy tapes (not shown).

The brain regions identified as showing common activation patterns in the addicted versus non-addicted subject groups include regions that contribute to emotional and motivational processing, reward evaluation and decision making, response inhibition, and outcome in addiction treatment. In most cases, these regions were activated in control subjects but not in addicted ones. Relatively diminished activation of ventral striatum was observed in the addicted subjects as compared to control subjects, consistent with the findings on tasks involving reward processing in PG and CD subject groups (Reuter et al. 2005; Pearlson et al. 2007). Ventral components of prefrontal cortex, notably the orbitofrontal cortex, have been implicated in the processing of rewards (Schultz et al. 2000; Knutson et al. 2003; McClure et al. 2004), and the lateral region is thought to activate when additional information is needed to guide behavioural actions or when decision making involves the suppression of previously rewarded responses (Elliott et al. 2000). Lateral regions of ventral prefrontal cortex, such as the inferior frontal gyrus, are also considered to be of significant importance in response inhibition and impulse control (Chamberlain & Sahakian 2007). Other brain regions whose activation patterns distinguished addicted and non-addicted subjects in the present study have also been implicated in mediating impulse control. For example, in a Go/NoGo paradigm involving healthy subjects, the insula, precuneus and posterior cingulate were activated during error processing and orbitofrontal cortex and lingual gyrus during response inhibition (Menon et al. 2001). Insular activation also contributes to conscious urges and thus may influence decision-making processes in addiction (Craig 2002; Naqvi et al. 2007). The failure of addicted subjects to activate these regions in the early stages of response to cues that serve as triggers could contribute to poor self-control and subsequent drug use. These findings have implications for treatment outcome for both PG and drug addiction. For example, insula damage has been associated with impaired betting behaviour as evidenced by a failure to adjust bets with respect to odds of winning, and thus impaired activation might be particularly relevant to PG (Clark et al. 2008). Posterior cingulate activation during viewing of cocaine videotapes was associated with treatment outcome in CD subjects, with those who were able to abstain showing greater activation of this brain region (Kosten et al. 2006). Thus, although these results should be considered preliminary given the relatively small samples of each group of subjects, the findings complement the larger literature on PG, drug addiction, impulse control and the neural correlates of treatment outcome for drug addiction. Additional investigations involving larger and more diverse samples are needed to substantiate and extend these findings.

6. Conclusions and future directions

Although significant advances have been made in our understanding of PG over the past decade, substantial gaps remain in our understanding of the disorder. Most biological studies to date have involved small samples of predominantly or exclusively men, raising concerns regarding the generalizability of the findings, particularly to women. Sex differences in gambling behaviours have been reported both with respect to types of gambling problematic for women as compared to men as well as for patterns of development of gambling problems (Potenza et al. 2001). For example, the ‘telescoping’ phenomenon, a process referring to the foreshortened time frame between initiation and problematic levels of behavioural engagement, was first described for alcoholism, more recently for DD, and most recently for problem and PG (Potenza et al. 2001). Given such clinically relevant differences, examinations into the underlying biology of PG should consider potential influences of sex. Similarly, different stages of gambling pathology should be considered in biological investigations, given the data suggesting differential involvements of neurocircuitry (e.g. ventral versus dorsal striatum) as behaviours progress from more novel or impulsive to habitual or compulsive (Everitt & Robbins 2005; Chambers et al. 2007; Belin & Everitt 2008; Brewer & Potenza 2008). Additional considerations include the nature of impulsivity and its relationship to ICDs and substance addictions. That is, it is possible that substance use may lead to more gambling, more gambling may lead to substance use, or that common factors like impulsivity may contribute to excessive engagement in each domain. Clarifying these possibilities in animal and real-life settings represents a clinically and scientifically relevant goal (Dalley et al. 2007). Given that impulsivity is a complex multifaceted construct (Moeller et al. 2001), understanding how specific aspects relate to pathophysiologies of and treatments for PG and drug addictions is important. Finally, PG is arguably the best studied of a group of ICDs that are currently categorized together in diagnostic manuals. Additional research is needed into other ICDs and their neurobiology, prevention and treatment, particularly as these disorders are associated with markers of greater psychopathology and appear currently to go frequently undiagnosed in clinical settings (Grant et al. 2005).

Acknowledgments

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