Summary
Summary ... 1
INTRODUCTION ... 2
Pathological gambling: definition and clinical features ... 2
Pathophysiology of PG ... 5
Biochemistry ... 5
Neuroimaging ... 12
Neurocognitive assessment, executive functions and frontal lobe ... 14
Relationship between impulsivity and PG ... 17
MATERIALS AND METHODS ... 21
Patients ... 21 Impulsivity assessment ... 22 Statistical analyses ... 22 RESULTS ... 23 DISCUSSION ... 24 REFERENCES ... 26 TABLE I. ... 46
INTRODUCTION
Pathological gambling: definition and clinical features
The American Psychiatric Association introduced the term ‘pathological gambling’ (PG) in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) (APA, 1980) to describe excessive gambling behavior. The essential features of this disorder are a chronic and progressive failure to resist impulses to gamble and gambling behavior that compromises, disrupts or damages personal, family, or vocational pursuits. These diagnostic criteria were criticized as they overestimated the ‘external’ consequences of the subject’s behavior that can result in loss of job, divorce and deterioration of patrimony or even criminal behavior (Lesieur, 1984). For this reason, in the revised version of DSM (APA, 1987), more emphasis was given to the similarities that PG shared with substance abuse disorder, such as craving, loss of control, tolerance, withdrawal syndromes and frequent relapses (Rosenthal, 1990). The current definition of DSM-IV-R (APA, 1994) outlines the PG as an impulse-control disorder, characterized by persistent and maladaptive gambling behaviors, with disruptive consequences for familial, occupational and social functions. The diagnostic features of PG, therefore, show not only similarities with impulse-control disorders but also with substance dependence, as all these disorders seem to be characterized by behavioral deficit in self-regulation (Blum et al., 2000; Koob and Le Moal, 2001; Blaszczynski and Nower, 2002; Goldstein and Volkow, 2002; Sharpe, 2002). Nevertheless, an alternative model of PG is that it constitutes a heterogeneous disorder with some subtypes being closer to substance abuse disorders, and other subtypes resembling obsessive-compulsive disorder (Blanco et al., 2001).
Recently, a great scientific interest on PG is emerging, after the evidence of its growing incidence, probably related to the high availability of legalized gambling. However, it is a
disorder poorly understood, so that psychological assistance and medical/social support to affected individuals are presently merely empirical. Meta-analysis studies carried out in USA and Canada concerning the last decades of publications demonstrated a PG prevalence ranging between the 1-3% of the adult population (Shaffer and Hall, 2001). The first onset of the symptoms occurs during adolescence with a prevalence of 4-7%, significantly higher than in the adulthood (Gerstein et al., 1999; Shaffer et al., 1999; Shaffer and Hall, 2001; Cunningham-Williams and Cottler, 2001). In addition, the prevalence is higher in social groups as refugee and migrant communities (Volberg, 1994; Volberg et al., 2001). Moreover, PG seems to spread rapidly also amongst women and teenagers (Pietrzak et al., 2003; Lynch et al., 2004). Other risk factors are represented by social welfare status (receiving social welfare payments), residence (living in a large city), marital status (being single), early exposure to gambling opportunities (offered by the family, peer and internet) and cognitive disturbances (Volberg et al., 2001). The PG is often accompanied by comorbid psychiatric conditions, such as obsessive-compulsive disorder (OCD), attention-deficit/hyper-activity disorders (ADHD) (Rugle and Melamed, 2001) and depression (McCormick , 1984; Specker et al., 1996; Cunningham-Williams et al., 1998). Up to 50% of pathological gamblers show substance addictions, such as alcohol, smoking and drug abuse (Lesieur et al., 1986; Steinberg et al., 1992; McCormick, 1993; Spunt et al., 1995; Smart and Ferris, 1996; Crockford and el-Guebaly, 1998; Lesieur and Rosenthal, 1998).
The clinical course of PG is characterized by three different phases: the winning phase, the losing phase and the desperation phase (Lesieur and Rosenthal, 1991).
The winning phase. The gambler begins to win. The winnings are big and exert a rewarding action, while giving him an omnipotence feeling. He’s sure he can influence his
luck through his skills and continue to win. This irrational optimism leads to play even more despite an inevitable series of losses.
The losing phase. The subject spend even more time and money in gaming, he begins to borrow, to lie to his family, going down to the so called "run-up to the loss". He remains convinced to be a skilled player and that he can recover the lost money through a 'last' play that he feels the good one. He will soon be trapped in this spiral with no way out, showing the symptomatology of addiction: his thoughts are completely focused on the game, he neglects his family, work, hobbies, and so on, until, indebted, commits illegal actions; if unabled to gamble he becomes anxious, irritable and even aggressive (symptoms comparable to those of withdrawal in substance addiction); he realizes that he should play more and invest higher sums of money to seek the previous sensations (symptoms comparable to the tolerance in the process of addiction). The convincement/hope that a big win could resolve all problems persists.
The desperation phase. The optimism and the awareness to repair all damages are replaced by the consciousness regarding the disastrous financial, legal and family situation; nevertheless the patient realizes that he could not stop playing and develops feelings of helplessness, anxiety, intense dysphoria, unto major depression. Ideation and suicide attempts are very common at this stage (the latter is the only way out). Women take a mean of 3-5 years to reach this phase, while men about 8-9 years.
Once developed, PG tends to have a chronic, worsen course. Generally, an increase of both frequency of play and sums of money put into play is observed. This aspect represents an equivalent of tolerance: the longer is the course and the higher is the sum of money spent in each bet in order to experience the same excitement.
During the progressive worsening of the disease, sudden exacerbations may occur, usually due to periods of intense stress or depression.
PG is associated with high rates of suicide: scientific literature unanimously reports a 17-24% of lifetime attempt suicide (Phillips et al., 1997).
Pathophysiology of PG
Biochemistry
Although the pathophysiology of PG is unclear, this disorder is interpreted as belonging to the group of impulsive, compulsive or addictive behaviors which may share common aetiological mechanisms (Comings, 1998) and could be dependent on the interplay between individual and environmental factors. The main hypotheses about PG disorder involve an altered activity in different brain areas (Bechara et al., 1994; Fellows and Farah, 2005; Wiederkehr et al., 2005), and/or biochemical dysfunctions mainly at the level of the dopamine (DA), serotonin (5-HT), norepinephrine (NE) and opioids.
Dopamine
The main location of dopaminergic neurons is represented by the ventral tegmental area (VTA). The mesolimbic system stems from VTA and projects to several components of the limbic system, such as the amygdala, the orbitofrontal cortex (OFC), the anterior cingulated cortex (ACC), and the nucleus accumbens (NAcc). This pathway is supposed to be involved in the activation of motivated behaviors with the function of producing subjective feelings of pleasure. Alterations of the dopaminergic pathways may underlie the seeking of rewards (such as gambling or drugs) that triggers the release of DA and generate pleasurable feelings.
It has been hypothesized that PG disorder can be explained by the so-called ‘reward deficiency syndrome’. A dysfunction in the brain reward system, provoked by certain genetic variants (polygenic), could lead to a hypodopaminergic trait (Blum et al., 2000). Indeed, an alteration of gene expression of the D2 receptor has been implicated in a range of addictive, impulsive and compulsive disorders (ICD) including drug abuse, smoking, ADHD and even PG (Blum et al., 1995; Comings et al., 1996). Moreover, an association has been hypothesized between the expression of a variant allele of the DA receptor (D4) gene that leads to a lower functioning of the receptor gene and PG (Perez de Castro et al., 1997; Comings et al., 1999).
At biochemical level, PG subjects showed lower DA concentration, but an increased level of its metabolites (mainly 3,4-dihydroxyphenylacetic acid, DOPAC, and homovanillic acid, HVA) in the cerebrospinal fluid (CSF), as compared with healthy subjects. Although differences in enzymatic activity cannot be excluded, this finding would suggest an increased release of DA in the brain of PG since DA-CSF turnover is considered a reliable marker of that occurring in the brain (Bergh et al., 1997). Moreover, higher blood DA levels have been observed in problem gamblers during casino session of blackjack (Meyer et al., 2004) and in people playing Pachinko (a form of gaming combining elements of pinball and slot machine (Shinohara et al., 1999), with respect to healthy subjects.
Therefore, it is not surprising that PG has been observed in disorders originally characterized by dopaminergic dysfunctions, such as the Parkinson’s disease (PD). In fact, some reports revealed a relationship between the use of DA agonists, normally employed in PD treatment, and PG, as well as other ICDs including compulsive sexual and eating behaviors (Driver-Dunckley et al., 2003; Weintraub and Potenza, 2006). Excessive gambling behavior was observed in PD patients when DA agonists were increased, while it disappeared with dosage reduction (Weintraub et al., 2006; Mamikonyan et al., 2008).
Similarly, a survey on 272 PD patients screened and assessed for ICDs found strong relations between different DA agonists (pramipexole, ropinirole, and pergolide), PG and other ICDs (Weintraub et al., 2006). In particular, 6.6% of subjects during the treatment experienced an ICD associated with the higher DA agonist dosage, regardless of the nature of the DA agonist. In the same way, 297 PD patients screened for PG showed an association between the use of DA agonists and the increase in PG symptoms, probably related to the increased dopaminergic effectiveness (Voon et al., 2006).
Serotonin
The 5-HT system originates in the raphe nuclei that project to almost all brain areas, through different efferents. A large bulk of data shows that the 5-HT system is involved in the regulation of a wide range of functions and behaviors, such as of mood, anxiety and impulsivity. In particular, abnormalities of the 5-HT system have been linked to an increased vulnerability towards impulsive behaviors, such as aggression and suicide (Coccaro et al., 1989; Siever et al., 1993; Clark et al., 2005; Ryding et al., 2006). Therefore, it has been hypothesized that PG could be related to 5-HT alterations.
Some authors reported a lower activity of the platelet monoamine-oxidase (MAO), an enzyme functionally reflecting the state of the 5-HT system (Oreland, 2004). Interestingly, a decreased MAO activity has been related to impulsivity since a long time (Carrasco et al., 1994; Blanco et al., 1996). Other findings were obtained by means of drug-challenge tests with m-chlorophenylpiperazine (m-CPP), a compound which behaves as a high-affinity agonist at the level of 5-HT1A, 5-HT 1B/D, 5-HT2C and 5-HT3 receptors, as an antagonist at the level of 5-HT2 receptors and as an inhibitor of the 5-HT reuptake. The oral administration of m-CPP in PG patients produced an enhanced prolactin response and euphoriant effects, while did not provoke any change in healthy subjects (DeCaria and
Hollander, 1998; Pallanti, 2006). These findings would suggest the presence of hypersensitive post-synaptic 5-HT2C receptors in PG, a condition comparable to that reported in OCD (Zohar and Insel, 1987; Hollander, 1993). Recently, the direct measurement of serotonergic parameters in the CSF of PG patients showed the presence of lower levels of HT and tryptophan, related to an increased concentration of 5-hydroxyindoleaceticacid (5-HIAA), the major 5-HT metabolite. This finding would indicate an increased consumption of tryptophan associated with a rapid turnover of the neurotransmitter (Nordin and Sjodin, 2006).
On the other hand, some studies failed to support a central role for 5-HT, finding out with similar paradigms that the 5-HIAA in the CSF of PG patients were unchanged (Roy et al., 1988, 1989; Bergh et al., 1997).
Another possibility to explore the 5-HT system in periphery is provided by the investigation of the platelet 5-HT transporter (SERT), which is considered a reliable mirror of the same transporter present in the brain (Lesch et al., 1993; Uebelhack et al., 2006). The SERT is demonstrated to play a key role in the regulation of the extracellular 5-HT concentration through the reuptake mechanism (Amara and Kuhar, 1993; Blakely et al., 1994; Rudnick, 2006). Several reports demonstrated alterations of the platelet SERT in different neuropsychiatric disorders and conditions, irrespective of the diagnosis (Marazziti et al., 1999; Murphy et al., 2003; Hesse et al., 2004). Moreover, there are indications of changes of SERT in healthy subjects (Marazziti et al., 1999, 2003), which have been hypothesized to be linked both to particular psychological states, such as anxiety or impulsivity (Marazziti et al., 1999, 2003; Mazzanti et al., 1998; Brocke et al., 2006; Lesch et al., 2007) and to antidepressant response (Serretti et al., 2006). In particular, only two reports indicated a decreased density of SERT in PG patients. The first study estimated SERT levels by the means of tritiated clomipramine (Moreno and Lopez-Ibor, 1991), but
this is not a specific ligand for SERT (Rotondo et al., 1996), while the second one highlighted the same abnormality by using a more specific ligand, the [³H]-Paroxetine (Marazziti et al., 2008b).
Norepinephrine
The largest collection of noradrenergic neurons is in the pons in the locus coeruleus that projects to every major region of the brain and spinal cord. The locus coeruleus maintains vigilance and responsiveness to novel stimuli while influencing both arousal at the level of the forebrain and sensory perception and motor tone in the brain stem and spinal cord. The NE, therefore, may play an important role in the arousal and novelty-seeking behaviors associated with PG. Roy et al. (1988, 1989) measured NE and NE metabolites 3-metossi-4-idrossifenilglicol (MHPG) and observed that PG subjects had a higher CSF levels of MHPG and higher urinary values of NE, as confirmed subsequently (Bergh et al., 1997). In addition, the scores of ‘extraversion’ of the Eysenck Personality scale of the PG subjects correlated positively and significantly with both the CSF and plasma levels of MHPG and the NE urinary concentrations (Roy et al., 1988, 1989).
The blood NE levels were found to increase from baseline during Pachinko playing, with statistically significant changes at the ‘Fever-start’, at the ‘Fever-end’ and 30 minutes after the ending of the gaming session. Alterations in heart rate, a physiological measurement associated with arousal, with a presence of peaks measured at the ‘Fever-start’ were also observed (Shinohara et al., 1999). Moreover, PG individuals, as compared with healthy subjects, showed a higher growth hormone (GH) peak response to the clonidine, an adrenergic agonist used to assess central NE function (Hollander et al., 1998), with a correlation between the severity of PG and the magnitude of the response.
Opioids
Different opioids modulate mesolimbic DA pathways in the VTA by activating µ-opioid receptors present on the postsynaptic interneurons, while causing its hyperpolarization and the inhibition of GABA release on the presinaptic dopaminergic neurons, with a resulting increased DA release (Johnson and North, 1992). Moreover, the activation of κ-opioid receptors on presinaptic neurons provokes their direct inhibition (Margolis et al., 2003). Recently, it has been also shown that opioid receptor activation (κ- VS µ-) differentially inhibits the mesolimbic neurons depending on their target projections (respectively, the nucleus accumbens, NAcc, VS the basolateral amygdala, BLA) (Ford et al., 2006). The endogenous opioid system, via both µ- and κ-opioid receptors, tonically inhibits the HPA axis, while suggesting that atypical responsivity contributes to the addiction (Kreek et al., 2005).
PG subjects during playing sessions of Pachinko showed higher blood levels of β-endorphins than control individuals at the start of ‘high-pitched’ play (Shinohara et al., 1999). However, the β-endorphin levels did not change during casino gambling sessions in both problem and non-problem gamblers, but the formers tended to show lower levels than the latters (Meyer et al., 2004). The involvement of opiods in PG is supported also by clinical studies demonstrating the efficacy of both opioid antagonists naltrexone and nalmefene in the treatment of ICDs (Grant et al., 2006). Taken as a whole, these findings implicate that opioids are intervening factors in PG, although the precise nature of their involvement remains not yet completely understood.
Stress response system
The hypothalamus-pituitary-adrenal (HPA) axis is a key element in the stress. Corticotropin releasing hormone (CRH) produced in the paraventricular nucleus (PVN)
and released into the median eminence and hypophysial portal system promotes the release of adrenocorticotropin (ACTH) from the anterior pituitary gland, which initiates the release of glucocorticoids from adrenals (like cortisol in humans). The NE inputs from medullary nuclei provide the primary stimulus for CRH synthesis and release from PVN. In addition, CRH inputs act as a neurotransmitter to initiate the autonomic nervous system response to stress, while CRH inputs from the central nucleus of the amygdala (CnAmy) to the locus coeruleus induce a release of NE and epinephrine which modulate physiological functions, such as respiratory and heart rate.
Heart rate and salivary cortisol levels were investigated in problem gamblers wagering their own money in "real-life" casino game sessions of blackjack, and resulted increased after, respectively, 30 and 60 minutes the onset of the experimental session with respect to the control condition (no-money task). In addition, at the onset of game session, both problem gamblers and control subjects showed a higher HPA-axis and sympathoadrenergic system activation and cortisol production with respect to baseline values, but the former group also showed a significantly higher heart rate, DA and NE levels with respect to the control one during the entire gambling session (Meyer et al., 2004).
In addition, high impulsivity gamblers show significantly higher heart rate and cortisol levels with respect to low impulsivity ones and impulsivity scores are reported to correlate positively with the severity of PG (Krueger et al., 2005).
These results suggest that the activation of the stress response pathway could be implicated in PG of gambling stronger than in normal subjects.
Neuroimaging
Gambling (Breiter et al., 2001) and responses to monetary consequences (Delgado et al., 2000; Elliott et al., 2000, 2003; O'Doherty et al., 2001) in healthy volunteers are reported to activate the orbitofrontal cortex (OFC), striatum and limbic areas which are believed to be part of the extended DA pathway (Kalivas, 2001; Goldstein and Volkow, 2002). Salience of a monetary reward was shown to correlate with the activation of caudate and nucleus accumbens, involved in the dopaminergic transmission (Spanagel and Weiss, 1999; Drevets, 2001; Zink et al., 2004) and into the extrapolation of cues for reward expectancy from sensory stimuli, via direct mediation of the cortex (Hikosaka and Watanabe, 2000). The prefrontal cortex seems to have two partially overlapping and interconnected neural networks: one involving the OFC, believed to play a role in emotional and motivational aspects of reward expectancy, and another involving the dorsolateral prefrontal cortex (DLPFC) hypothesized to subserve working memory and related cognitive processing of reward expectancy (Hikosaka and Watanabe, 2000; Mesulam, 2002). DLPFC is also involved in the attentional shift towards sudden stimuli (Corbetta and Shulman, 2002). Functional imagings in substance abuse patients showed increased activation in both OFC and DLPFC during exposure to substance-related cues (Maas et al., 1998; Wexler et al., 2001; Goldstein and Volkow, 2002; Volkow et al., 2003; Heinz et al., 2004). Other fMRI studies with healthy volunteers responding to monetary consequences showed activation of prefrontal and premotor cortical pathways whenever the cognitive elaboration and the decision making related to the reward choice take place (Elliott et al., 2000; Ramnani and Miall, 2003; Potenza et al., 2003). The fMRI studies carried out in PG subjects (Potenza et al., 2003; Potenza and Winters, 2003; Reuter et al., 2005) have identified significant activation decreases, with respect to healthy control subjects, relative to OFC and ventromedial prefrontal cortex (VMPFC). In one study (Potenza and Winters, 2003), 10
PG subjects were compared with 11 control subjects over extended periods of time, while viewing videotapes designed to simulate interpersonal interactions as potential emotional and motivational factors for gambling craving. Results showed temporally dynamic changes during the viewing of gambling videotapes compared with happy or sad ones. The authors found decreased activation in OFC, basal ganglionic and thalamic regions prior to the reported onset of an emotional/motivational response. Decreased ventral anterior cingulate activation was described during presentation of the most provocative gambling stimuli. The findings were consistent with those reported about decreased impulse regulation, but the cue presentation would have been expected to result in an increased activity of the OFC, rather than a decreased one. Potential insufficient or compensatory processes could be involved in task resolution by PG subjects and underlie these findings. The second fMRI study, carried out on 13 PG and 11 healthy subjects, employed the Stroop Test (Potenza et al., 2003), which requires subjects to ignore distractors during the target detection. In healthy subjects, medial prefrontal, anterior cingulate and lateral prefrontal cortices were activated, while in PG subjects there was a significant decrease of activity in the VMPFC. The third study involved 12 PG and 12 matched healthy control subjects, who performed a guessing task previously found to activate the ventral striatum (Reuter et al., 2005). A reduction of ventral striatal and VMPFC activation in these subjects negatively correlated to gambling severity. The VMPFC activity appears to be more closely related to that of OFC, as deficits in this region have been reported to be associated with decreased response inhibition and a tendency to seek immediate gratification (Bechara et al., 1997, 1998).
Therefore, it can be concluded that a combination of both OFC and VMPFC dysfunctions in PG may affect three distinct behavioral aspects: the expectancy, which is based on the predictions of reward and observed probabilities or reinforcement associated with a stimulus; the compulsion, which involves the repetitive application of a behavioral strategy
despite the lack of the association of reward with the stimulus; and the decision-making, which is involved in the balancing of expectations with stimulus-associated rewards or reinforcing probabilities.
The compulsive feature of gambling, the obvious lack of inhibitory control and the impaired ability to integrate information on adverse outcomes into behavioral choice, such as lack of self-regulation, may be assigned to a pathological motivation related to gambling abuse.
Neurocognitive assessment, executive functions and frontal lobe
Through administration of several psychological tests it is possible to identify a neuropsychological background similar to that observed in subjects with neurological damage of the frontal lobe. In particular, PG subjects display impairments of the high cognitive executive functions (EFs). In the last decade, an increasing number of studies have focused on disrupted EFs of PG improving the neurocognitive assessment of this disorder.
Planning, judgment, decision-making, set-shifting, anticipation and reasoning are the cognitive processes subserving the higher EFs required during the resolution of any complex behavioral or cognitive task (Roberts, 1998; Miyake and Shah, 1999; Shah and Miyake, 1999). A key point of this resolution is the suppression of unnecessary input/output and the inhibition of inappropriate responses. The EFs were first described as ‘central executive’ by Baddeley and Hitch (1974) and according to the description of Lezak (1983), they constitute ‘the dimension of human behavior that deals with how behavior is expressed’.
From the observation of soldiers wounded in war who exhibited altered behavior, as well as an impaired ability to engage in appropriate actions towards the completion of a goal, it was possible to describe the main neural correlates of EFs, identifying the frontal lobes as ‘the essential apparatus for organizing intellectual activity as a whole...' (Luria, 1973; Stuss, 1986). The body of behavioral and cognitive alterations found in patients with frontal lobe damage is described as ‘dysexecutive syndrome’ (Baddeley and Wilson, 1988), which includes problems in planning, organization, abstract reasoning, problem-solving and decision-making (Norris and Tate, 2000; Hobson and Leeds, 2001; Ardila and Surloff, 2004). Although early observations suggested a homogenous involvement of the frontal lobes, and specifically of the prefrontal cortex, now it is accepted that EFs are modulated in different regions of the frontal lobes (Koechlin et al., 2000; Stuss, 2000; Stuss et al., 2002), as well as they are distributed over a wide cerebral network which includes subcortical structures and thalamic pathways (Lewis et al., 2004; Kassubek et al., 2005, Monchi et al., 2006). Several studies (Stuss and Benson, 1986; Cummings, 1995; Duke and Kaszniak, 2000; Sbordone et al., 2000) suggested that there are three main prefrontal cortical-subcortical circuits, localized in dorsolateral, ventromedial and orbitofrontal cortical areas, involved in cognitive, emotional and motivational processes. The dorsolateral prefrontal cortex (DLPFC) projection to the dorsolateral head of the caudate nucleus has been linked to EFs, including verbal and design fluency, ability to maintain and shift set (cognitive flexibility), planning, response inhibition, working memory, organizational skills, reasoning, problem-solving and abstract thinking (Milner, 1971; Ettlinger et al., 1975; Cummings, 1993; Jonides et al., 1993; Grafman and Litvan, 1999; Duke and Kaszniak, 2000; Stuss, 2000; Malloy and Richardson, 2001). The ventromedial circuit, involved in motivation, originates in the ACC and projects to the NACC. Lesions to this region often produce apathy, decreased social interaction and psychomotor retardation (Sbordone et al., 2000; for a complete review see also Fellow, 2007). The OFC
projects to the ventromedial caudate nucleus and is linked to socially appropriate behavior. Lesions to this area induce disinhibition, impulsivity and antisocial behavior (Blumer and Benson, 1975; Cummings, 1995).
Studies of patients with damage to the VMPFC largely contributed to the recent advances in this field (Bechara et al., 2000). Converging evidence suggests that the VMPFC is involved in representing the current relative value of stimuli, in other words this structure is crucially involved to indicate, amongst potential choices, the best that is worth to be made at the moment of decision (Kringelbachet, 2005; Clark et al., 2008). This set of valuable informations aims decision-making by determining the goals towards which behavior is directed and providing a context to judge decision outcomes. Therefore, VMPFC supports the execution of complex behavior, incorporating information about factors such as risk, delay, and ambiguity (Surgue and Newsome, 2005). The cognitive assessment of these factors may be reflected in (or affected by) emotional and automatic responses to potential choices, biased by the outcomes of previous decisions, and it shortly maintains in working memory all the decisional trees interrupted after evaluation.
For the neurocognitive and neuropsychological assessment in PG disorder, the use in patients of specific tests demonstrated how the neuropsychological background was similar to that observed in subjects with neurological damage of the frontal lobe. In particular, PG subjects display impairments of the high cognitive EFs. The cognitive and the neuropsychological approaches have found erroneous beliefs in gamblers which causes an over-estimation of their chances of winning. This cognitive distortion may contribute to the continued and excessive gambling in PG.
Impulsivity
Impulsivity has been variously definedas swift action without forethought or conscious judgment (Hinslie and Shatzky, 1940),behavior without adequate thought (Smith, 1952), and the tendency to actwith less forethought than do most individuals of equal abilityand knowledge (Dickman, 1993).
An exhaustive definition of impulsivity is that given by the International Society for Research on Impulsivity (ISRI), which considers it as “a human behaviour without adequate thought, the tendency to act with less forethought than do most individuals of equal ability and knowledge, or a predisposition toward rapid, unplanned reactions to internal or external stimuli without regard to negative consequences of these reactions”. One of the most used and validated instruments for the assessment of impulsivity is the so-called “Barratt Impulsivity Scale”, which is the results of decades of efforts and modifications until the latest version 11 (BIS-11) (Patton et al., 1995) and considers impulsivity as a trait influenced by temperament and, as such, heritable and widely distributed in the population (Coccaro et al., 1993; Livesley et al., 1998).
Relationship between impulsivity and PG
At neuropsychological level, impulsivity is thought to arise from an impairment of inhibitory control. This is a core component of EFs that are implemented by a network of cortical and subcortical structures including the lateral prefrontal cortex (PFC) (Aron et al. 2004; Jentsch and Taylor 1999; Lyvers 2000; Patterson et al., 2006).
Neuropsychological studies of pathological gamblers have demonstrated that these subjects have deficits in the frontal lobe/reward system, leading investigators to hypothesize that impairment of EFs may play an important role in the aetiology of PG (Nutt, 1996;
Hollander, 1998; Steel and Blaszczynski 1998; Blaszczynski, 1999; Frost et al., 2001; Spinella, 2003; Petry, 2006; Tamminga and Nestler, 2006). A recent study using a comprehensive neuropsychological battery measuring EFs, demonstrated that PG and alcohol-dependent patients showed a reduction of executive functioning performance on inhibition, time estimation, cognitive flexibility and planning tasks (Goudriaan et al., 2006). Moreover, neurocognitive indicators of decision-making and disinhibition, such as the Card Playing Task and Stop Signal Reaction Time respectively, seem to be powerful predictors of relapse in PG (Goudriaan et al., 2007). The impairement of decision-making observed in PG might be explained by the inability to inhibit irrelevant information: in a recent study, the performances on the reverse Stroop task, which highly discriminates the ability to inhibit interferences, were significantly impaired in PG patients than in healthy subjects (Kertzman et al., 2006). More recently, Marazziti et al. (2008a) reported that 20 PG patients had alterations at a neuropsychological test, the Wisconsin Card Sorting Test: in particular, they had a great difficulty in finding alternative methods of problem-solving and showed a decrease, rather than an increase, in efficiency, as they progressed through the consecutive phases of the test. These abnormalities would seem to confirm an altered functioning of the prefrontal areas which might provoke a sort of cognitive "rigidity" that might predispose to the development of impulsive and/or compulsive behaviors, such as those typical of PG.
A great bulk of evidence suggests that impulsivity is widely implicated in the development and maintenance of addictive behaviours (Verdejo-Garcia et al. 2008). However, the association between impulsivity and PG remains a matter of debate: some researchers find high levels of impulsivity within pathological gamblers, while others report no difference compared to controls, and yet others suggest that it is lower (Dannon et al., 2010). PG has been associated to impulsivity and attention deficit: PG patients were found to perform
childhood behaviors related to attention deficits (Rugle and Melamed, 2003). Gambling severity has been considered the best single predictor of impulsive behavior in a delay discounting task in a sample of pathological gamblers (Alessi and Petry, 2003). In gambling situations, a paradoxical reinforcing effect of high-risk decision-making after repeated big monetary losses was relevated. The gap between explicit deliberation and implicit impulsivity drew them into PG (Takano et al., 2010). In a recent study, neuropsychological measures of impulsivity, such as the reaction time and number of errors at Go/No-go tasks, as well as the scores at the BIS-11, were higher in PG patients than healthy control subjects, while highlighting the importance of this dimension in the clinical picture of PG. In particular, impulsivity seems to be a multi-dimensional phenomenon, and PG a heterogeneous population in which different types of impulsivity are present (Fuentes et al., 2006). More recently, 1171 PG patients were subtypized, by means of neuropsychological tests, in 4 clusters but only two were characterized by high levels of impulsivity (Alvarez-Moya et al., 2010).
At biological level an alterated SERT density, as measured by means of the specific binding of 3H-paroxetine to platelet membranes, was found both in 17 PG patients, as compared with healthy controls (Marazziti et al., 2008b), and associated with impulsivity, as measured by the BIS-11 questionnaire, in 32 healthy subjects (Marazziti et al., 2010).
Objectives
Since the diagnostic features of PG show similarities not only with substance dependence, but also with impulse control disorders and impulsivity is considered a core element in both impulsive and addictive behaviours from both clinical and biological points of view, this study aimed at measuring impulsivity, by means of the BIS-11, in a group of drug-free PG patients, as compared with a similar group of healthy control subjects, in order to provide a further contribution on this topic and better understand which characeristics of impulsivity are involved in PG.
MATERIALS AND METHODS
Patients
Twenty-six outpatients of both sexes (25 men and 1 woman, mean age ± standard deviation [SD]: 46.23 ± 11.6) with a diagnosis of PG, as assessed by the structured clinical interview for DSM-IV Patient Version 2.0 (First et al., 1997) were recruited at they first psychiatric interview at the Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy. None suffered from any severe physical illness nor had ever taken psychotropic drugs, except for six patients who had occasionally taken benzodiazepines for difficulty with sleeping (2) or panic attacks (4). The severity of PG was assessed by means of the South Oaks Gambling Screen (Lesieur and Blume, 1987).
The patients were compared with a similar group of healthy control subjects (24 men and 2 women, mean age ± standard deviation [SD]: 47.19 ± 13.4), who had no family or personal history of any major psychiatric disorder, as assessed by a psychiatric interview, carried out by a senior psychiatrist (DM) by means of the SCID. They were recruited amongst medical and nursing staff at the Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy. These subjects were also free of any physical illness, as documented by a general check-up and by the normal blood and urine tests and were completely psychotropic drug-free for about 12 months. None of them were heavy cigarette smokers; none of the participants belonged to a high-risk HIV group, and none took any regular medication. All gave their informed consent to participation in this study, which was approved by the Ethics Committee of Pisa University.
Impulsivity assessment
Impulsivity was assessed by means of the BIS-11 questionnaire, validated into Italian (Fossati et al., 2001). The BIS-11 is a self-report scale developed to measure impulsivity as a stable characteristic, composed by 30 items, which are answered on a four-point scale; items are scored 1, 2, 3, 4 where 4 indicates the most impulsive response: the higher the total scores for all items, the higher the level of impulsivity. The total score ranges between 30 and 120, with no established cut-off point and is the result of the sum of three different subscales: attentional (rapid shifts of attention and impatience with complexity), motor (impetuous action), and nonplanning (lack of future orientation) impulsivity. In addition, the 30 items form six factors determined by principal component analyses: attention, motor impulsivity, self-control, cognitive complexity, perseverance, and cognitive instability.
Statistical analyses
Parametric and non-parametric data of the two groups were compared by means of the Student t-test or chi-square analysis, respectively. The comparisons between two independent samples were assessed by the Mann-Whitney test, and the relationships between variables by the Spearman’s coefficient. All analyses were carried out using the SPSS version 14.0, by means of personal computer programs.
RESULTS
Sixteen patients were single or divorced, 8 were married and 2 was widowed. 18 patients had completed the secondary school, 4 had high school diplomas and 4 had completed the primary school.
Six patients were suffering also from simple phobia, 5 from substance abuse (cocaine and cannabis), 4 from panic disorder, 4 from bipolar disorder (2 of type II and 2 of type I), 2 from major depressive episode, 2 from generalized anxiety disorder, 2 from alcohol abuse, 1 from social anxiety disorder and 1 from schizoaffective disorder.
The South Oaks Gambling Screen total score (mean ± SD) was 28.9 ± 6.7. The age of onset of the disorder (mean ± SD) was 30.8 ± 13.2 years.
The BIS total score was significantly higher in PG patients than in control subjects. The “motor impulsivity” and “cognitive complexity” factor scores were significantly higher in PG patients than in control subjects. The same was true for “motor” and “nonplanning” impulsivity subscale scores (Table I). The comparison of the “self-control” factor scores showed a similar trend close to significance.
DISCUSSION
PG patients showed higher levels of impulsivity than control subjects, as measured by the BIS-11 total score. This result confirms the association between impulsivity and PG and is in line with the theory of impulsivity as a core element in PG, not only related with the severity of gambling, but also as a personality trait or a part of a general personality disorder structure that may predict the development of addictive and impusive behaviors, typical of PG (Blaszczynski et al., 1997; Steel and Blaszczynski, 1998; Chambers and Potenza, 2003; Alessi and Petry, 2003).
While comparing the results obtained on each BIS-11 subscale and factor, we observed significant differences in the motor and cognitive impulsivity and a trend in self-control, while no differences were found neither in the attentional impulsivity subscale nor in the attention factor. These data are in agreement with the involvement in PG of impulsivity as originated by EFs’ deficits (Nutt, 1996; Hollander, 1998; Steel and Blaszczynski 1998; Blaszczynski, 1999; Frost et al., 2001; Alessi and Petry, 2003; Spinella, 2003; Petry, 2006; Goudriaan et al., 2006, 2007; Kertzman et al., 2006; Tamminga and Nestler, 2006; Marazziti et al. 2008a; Takano et al., 2010), rather than attention ones (Rugle and Melamed, 2003). Moreover, the perseverance factor was no significantly different between the groups. This last aspect could be interpreted as consistent with some authors substaining that no link was seen with neither obsessive-compulsive disorder (Black et al., 2006) nor obsessional personality (Steel and Blaszczynski,1998). Also Blanco et al. (2009) observed that, although PG patients exhibits features of both obsessionality/compulsivity and impulsivity, impulsivity predominates and changes in gambling severity are most associated with changes in impulsivity.
The results of the present study should be interpreted keeping in mind some limitations. First, we utilized only one instrument, the BIS-11 questionnaire, to evaluate levels of impulsivity. It’s noteworthy to remind that the BIS-11 is a self-report scale and that it is developed to measure impulsivity as a stable characteristic. A second limitation is the limited sample size, that did not allow us to perform subgroup analyses finalized at investigating, for example, a possible correlation between the BIS-11 factors and the severity of PG. Third, a rilevant bias is represented by the fact that 11 patients had comorbid psychiatric disorders characterized by high levels of impulsivity (von Diemen et al., 2008; Di Nicola et al., 2010). Finally, our sample was composed almost entirely by men and this aspect could influence the results, since a recent study demonstrated, although in contrast with the most part of the literature, that women are generally more impulsive than men, at least when considering impulsivity as a trait, construct at the basis of the BIS questionnaire (Marazziti et al., 2010).
Further studies, conducted in larger samples of PG patients without comorbid impulsive disorders, of both sex and contempling the use of multiple neurocognitive tests, will be necessary to confirm these data and explore the possible relationships between impulsivity characteristics and PG severity.
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