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1.  Response Inhibition during Cue Reactivity in Problem Gamblers: An fMRI Study 
PLoS ONE  2012;7(3):e30909.
Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).
Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.
PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.
This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.
doi:10.1371/journal.pone.0030909
PMCID: PMC3316530  PMID: 22479305
2.  Time course of attentional bias for gambling information in problem gambling 
There is a wealth of evidence showing enhanced attention towards drug-related information (i.e. attentional bias) in substance abusers. However, little is known about attentional bias in deregulated behaviors without substance use such as abnormal gambling. This study examined whether problem gamblers (PrG, as assessed through self-reported gambling-related craving and gambling dependence severity) exhibit attentional bias for gambling-related cues.
Forty PrG and 35 control participants performed a change detection task using the flicker paradigm, in which two images differing in only one aspect are repeatedly flashed on the screen until the participant is able to report the changing item. In our study, the changing item was either neutral or related to gambling. Eye movements were recorded, which made it possible to measure both initial orienting of attention as well as its maintenance on gambling information.
Direct (eye-movements) and indirect (change in detection latency) measures of attention in individuals with problematic gambling behaviors suggested the occurrence of both engagement and of maintenance attentional biases towards gambling-related visual cues. Compared to non-problematic gamblers, PrG exhibited (1) faster reaction times to gambling-cues as compared to neutral cues, (2) higher percentage of initial saccades directed toward gambling pictures; (3) an increased fixation duration and fixation count on gambling pictures. In the PrG group, measures of gambling-related attentional bias were not associated with craving for gambling and gambling dependence severity. Theoretical and clinical implications of these results are discussed.
doi:10.1037/a0024201
PMCID: PMC3792789  PMID: 21688874
Gambling; Attentional bias; Dependence; Eye-tracking; Craving
3.  Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study 
PLoS ONE  2012;7(11):e49923.
Background
Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations.
Methods
We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions.
Results
Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition.
Conclusions
During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.
doi:10.1371/journal.pone.0049923
PMCID: PMC3509135  PMID: 23209619
4.  Cue Reactivity in Active Pathological, Abstinent Pathological, and Regular Gamblers 
Journal of Gambling Studies  2009;26(1):53-65.
Twenty-one treatment-seeking pathological gamblers, 21 pathological gamblers in recovery, and 21 recreational gamblers watched two video-taped exciting gambling scenarios and an exciting roller-coaster control scenario while their arousal (heart rate and subjective excitement) and urge to gamble were being measured. The gamblers did not differ significantly in cue-elicited heart rate elevations or excitement. However, the active pathological gamblers reported significantly greater urges to gamble across all cues compared to the abstinent pathological gamblers and, with marginal significance (p = 0.06), also compared to the social gamblers. Further exploration of these findings revealed that active pathological gamblers experience urges to gamble in response to exciting situations, whether or not they are gambling related, whereas abstinent and social gamblers only report urges to an exciting gambling-related cue. This suggests that for pathological gamblers excitement itself, irrespective of its source, may become a conditioned stimulus capable of triggering gambling behavior. Implications for treatment and future research are discussed.
doi:10.1007/s10899-009-9146-8
PMCID: PMC2822908  PMID: 19662519
Pathological gambling; Cue reactivity; Urge; Excitement; Addiction
5.  Neural Substrates of Resisting Craving during Cigarette Cue Exposure 
Biological psychiatry  2007;62(6):642-651.
Background
In cigarette smokers, the most commonly-reported areas of brain activation during visual cigarette cue exposure are: the prefrontal, anterior cingulate, and visual cortices. We sought to determine changes in brain activity in response to cigarette cues when smokers actively resist craving.
Methods
Forty-two tobacco dependent smokers underwent functional magnetic resonance imaging, during which they were presented with videotaped cues. Three cue presentation conditions were tested: cigarette cues with subjects allowing themselves to crave (cigarette cue crave), cigarette cues with the instruction to resist craving (cigarette cue resist), and matched neutral cues.
Results
Activation was found in the cigarette cue resist (compared to the cigarette cue crave) condition in the left dorsal anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus. Lower MR signal for the cigarette cue resist condition was found in the cuneus bilaterally, left lateral occipital gyrus, and right post-central gyrus. These relative activations and deactivations were more robust when the cigarette cue resist condition was compared to the neutral cue condition.
Conclusions
Suppressing craving during cigarette cue exposure involves activation of limbic (and related) brain regions and deactivation of primary sensory and motor cortices.
doi:10.1016/j.biopsych.2006.10.026
PMCID: PMC1992815  PMID: 17217932
Nicotine Dependence; functional magnetic resonance imaging; cue-induced cigarette craving; cingulate cortex; visual cortex
6.  Effects of Acute Nicotine Abstinence on Cue-elicited Ventral Striatum/Nucleus Accumbens Activation in Female Cigarette Smokers: A Functional Magnetic Resonance Imaging Study 
Brain imaging and behavior  2007;1(3-4):43-57.
To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs—suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.
doi:10.1007/s11682-007-9004-1
PMCID: PMC2367252  PMID: 18458752
fMRI; Smoking; Tobacco; Cue reactivity; Ventral striatum; Nucleus accumbens
7.  Cue-Specific Reactivity in Experienced Gamblers 
To examine whether gambling cue reactivity is cue-specific, 47 scratch-off lottery players and 47 horse race gamblers were presented with video clips of their preferred and non-preferred modes of gambling, and two control stimuli including an exciting car race and a mental stressor task while heart rates, excitement, and urge to gamble were being measured. Heart rates for both groups of gamblers were highest to the mental stressor and did not differ in response to the other three cues. Excitement for both groups was highest in response to the action cues (horse race and car chase). Urge to gamble was significantly higher for each group to their preferred mode of gambling. A post-hoc exploratory analysis comparing social gamblers (n=54) and probable pathological gamblers (n=40) revealed a similar pattern of responses. However, pathological gamblers reported overall significantly higher urges to gamble than social gamblers. As urges have been shown to play a pivotal role in addictive behaviors and relapse, the current findings may have implications for the development of gambling problems and relapse after successful treatment.
doi:10.1037/a0017134
PMCID: PMC2804265  PMID: 20025381
cue-reactivity; gambling; heart rate; excitement; urge
8.  Neural substrates of smoking cue reactivity: A meta-analysis of fMRI studies 
Neuroimage  2011;60(1):252-262.
Reactivity to smoking-related cues may be an important factor that precipitates relapse in smokers who are trying to quit. The neurobiology of smoking cue reactivity has been investigated in several fMRI studies. We combined the results of these studies using activation likelihood estimation, a meta-analytic technique for fMRI data. Results of the meta-analysis indicated that smoking cues reliably evoke larger fMRI responses than neutral cues in the extended visual system, precuneus, posterior cingulate gyrus, anterior cingulate gyrus, dorsal and medial prefrontal cortex, insula, and dorsal striatum. Subtraction meta-analyses revealed that parts of the extended visual system and dorsal prefrontal cortex are more reliably responsive to smoking cues in deprived smokers than in non-deprived smokers, and that short-duration cues presented in event-related designs produce larger responses in the extended visual system than long-duration cues presented in blocked designs. The areas that were found to be responsive to smoking cues agree with theories of the neurobiology of cue reactivity, with two exceptions. First, there was a reliable cue reactivity effect in the precuneus, which is not typically considered a brain region important to addiction. Second, we found no significant effect in the nucleus accumbens, an area that plays a critical role in addiction, but this effect may have been due to technical difficulties associated with measuring fMRI data in that region. The results of this meta-analysis suggest that the extended visual system should receive more attention in future studies of smoking cue reactivity.
doi:10.1016/j.neuroimage.2011.12.024
PMCID: PMC3288122  PMID: 22206965
smoking; cue reactivity; fMRI; meta-analysis; tobacco; addiction
9.  Cue Reactivity in Non-Daily Smokers: Effects on Craving and Smoking Behavior 
Psychopharmacology  2012;226(2):321-333.
Rationale
Non-daily, or intermittent smokers (ITS), are increasingly prevalent. Their smoking may be more situational than that of daily smokers (DS), and thus is hypothesized to be more influenced by cues.
Objectives
To assess ITS’ response to cues, and compare it to that of DS.
Methods
Samples of 239 ITS and 207 DS (previously reported in (Shiffman et al., in press-a) were studied in 2,586 laboratory cue-reactivity sessions. Craving (Questionnaire of Smoking Urges) and smoking (probability, latency, puff parameters, and carbon monoxide increases) in response to cues was assessed following exposure to neutral cues and cues related to smoking, alcohol, negative affect, positive affect, and smoking prohibitions. Mixed effects models, GEE and random-effects survival analyses were used to assess response to cues and differences between DS and ITS.
Results
ITS’ craving increased following exposure to smoking and alcohol cues and decreased following positive affect cues, but cues had little effect on smoking behaviors. Cue reactivity was similar in ITS and DS. Among ITS, craving intensity predicted smoking probability, latency, and intensity, and the effects on latency were stronger among ITS than DS.
Conclusions
Contrary to hypotheses, ITS were not more responsive to laboratory cues than DS. Results show that ITS do experience craving and craving increases that are then associated with smoking.
doi:10.1007/s00213-012-2909-4
PMCID: PMC3581749  PMID: 23142992
smoking; non-daily smoking; craving; cue reactivity; smoking topography
10.  Laboratory-based, Cue-Elicited Craving and Cue Reactivity as Predictors of Naturally Occurring Smoking Behavior 
Addictive behaviors  2009;34(6-7):536-541.
Cigarette craving, one hallmark sign of nicotine dependence, is often measured in laboratory settings using cue reactivity methods. How lab measures of cue reactivity relate to real world smoking behavior is unclear, particularly among non-treatment seeking smokers. Within a larger study of hormonal effects on cue reactivity (N=78), we examined the predictive relationship of cue reactivity to smoking, each measured in several ways. Results indicated that cue-evoked craving in response to stressful imagery, and to a lesser extent, in vivo smoking cues, significantly predicted smoking behavior during the week following testing. However, this predictive relationship was absent upon controlling for reactivity to neutral cues. Nicotine dependence may moderate the relationship between cue reactivity and actual smoking, such that this predictive relationship is less robust among highly dependent smokers than among smokers low in nicotine dependence. The question of whether cue-elicited craving predicts smoking among smokers not in treatment is best answered with a qualified yes, depending on how craving is manipulated and measured. Our findings highlight important methodological and theoretical considerations for cue reactivity research.
doi:10.1016/j.addbeh.2009.03.022
PMCID: PMC2685198  PMID: 19395178
cue reactivity; craving; dependence; smoking
11.  Anatomical differences and network characteristics underlying smoking cue reactivity 
NeuroImage  2010;54(1):131-141.
A distributed network of brain regions is linked to drug-related cue responding. However, the relationships between smoking cue-induced phasic activity and possible underlying differences in brain structure, tonic neuronal activity and connectivity between these brain areas are as yet unclear. Twenty-two smokers and 22 controls viewed smoking-related and neutral pictures during a functional arterial spin labeling scanning session. T1, resting functional, and diffusion tensor imaging data were also collected. Six brain areas, dorsal lateral prefrontal cortex (dlPFC), dorsal medial prefrontal cortex (dmPFC), dorsal anterior cingulate cortex/cingulate cortex, rostral anterior cingulate cortex (rACC), occipital cortex, and insula/operculum, showed significant smoking cue-elicited activity in smokers when compared with controls and were subjected to secondary analysis for resting state functional connectivity (rsFC), structural, and tonic neuronal activity. rsFC strength between rACC and dlPFC was positively correlated with the cue-elicited activity in dlPFC. Similarly, rsFC strength between dlPFC and dmPFC was positively correlated with the cue-elicited activity in dmPFC while rsFC strength between dmPFC and insula/operculum was negatively correlated with the cue-elicited activity in both dmPFC and insula/operculum, suggesting these brain circuits may facilitate the response to the salient smoking cues. Further, the gray matter density in dlPFC was decreased in smokers and correlated with cue-elicited activity in the same brain area, suggesting a neurobiological mechanism for the impaired cognitive control associated with drug use. Taken together, these results begin to address the underlying neurobiology of smoking cue salience, and may speak to novel treatment strategies and targets for therapeutic interventions.
doi:10.1016/j.neuroimage.2010.07.063
PMCID: PMC2962771  PMID: 20688176
Smoking cue; anatomical; ASL; DTI; VBM; resting state functional connectivity
12.  “Bringing the real world into the laboratory: Personal smoking and nonsmoking environments” 
Drug and alcohol dependence  2010;111(1-2):58-63.
Pictorial representations of specific environments related to smoking can evoke robust craving to smoke, even in the absence of any proximal cues to smoke (e.g., cigarettes, lighters.) To evaluate the salience of smoking environment cues, we developed a novel procedure for bringing smokers’ real world smoking and nonsmoking environments into the laboratory to compare them with standard (i.e. not personalized) environments within a cue-reactivity paradigm. Seventy-two smokers used digital cameras to take pictures of the environments in which they do and do not smoke. They then completed a cue-reactivity session during which they viewed and rated pictures of smoking and nonsmoking environments, half personal and half standard, all devoid of proximal smoking cues. As hypothesized, personal environments led to a significantly larger smoking-nonsmoking difference in craving, compared with the standard environments. Personalization also enhanced stimuli vividness, relevance, positive affect, and excitement, as well as heart rate changes from baseline. Implications of these findings for exposure-based research and treatment for addiction, as well as other psychological disorders, are discussed.
doi:10.1016/j.drugalcdep.2010.03.017
PMCID: PMC2930143  PMID: 20510552
tobacco; cue reactivity; context; conditioning
13.  fMRI BOLD Response in High-risk College Students (Part 1): During Exposure to Alcohol, Marijuana, Polydrug and Emotional Picture Cues† 
Aim: This functional magnetic resonance imaging (fMRI) study examined reactivity to alcohol, polydrug, marijuana and emotional picture cues in students who were referred to a college alcohol and drug assistance program. Methods: The fMRI data of 10 participants (5 females; 5 males) were collected while they viewed standardized emotional and appetitive cues. Results: Positive and negative emotional cues produced greater activity than neutral cues in the expected brain areas. Compared with neutral cues, alcohol cues produced greater brain activation in the right insula, left anterior cingulate, left caudate and left prefrontal cortex (Z = 2.01, 1.86, 1.82, 1.81, respectively; P < 0.05). Drug cues produced significantly greater left prefrontal activity compared with neutral cues, with polydrug cues activating the right insula and marijuana cues activating left anterior cingulate. Conclusions: Students at-risk for alcohol abuse showed neural reactivity to alcohol cues in four brain regions, which is consistent with their greater use of alcohol. Insula activation to appetitive cues may be an early marker of risk for progression to alcohol/drug abuse.
doi:10.1093/alcalc/agq042
PMCID: PMC2930251  PMID: 20729530
14.  Correlates of at-risk/problem internet gambling in adolescents 
Objective
The internet represents a new and widely available forum for gambling. However, relatively few studies have examined internet gambling in adolescents. This study sought to investigate the correlates of at-risk or problem gambling amongst adolescents acknowledging or denying gambling on the internet.
Method
Survey data from 2,006 Connecticut high-school-student gamblers were analyzed using chi-square and logistic regression analyses.
Results
At-risk/problem gambling was found more frequently in adolescent internet gamblers than in non-internet gamblers. As compared to at-risk/problem gambling in the non-internet gambling group, at-risk/problem gambling in the internet gambling group was more strongly associated with poor academic performance and substance use (particularly current heavy alcohol use; odds ratio=2.99; p=0.03) and less strongly associated with gambling with friends (odds ratio=0.32; p=0.0003). At-risk/problem gambling in both the internet and non-internet gambling groups, respectively, was associated at p<0.05 each with multiple adverse measures including dysphoria/depression (odds ratios=1.76, 1.96), getting into serious fights (odds ratios=2.50, 1.93), carrying weapons (odds ratios=2.11, 1.90), and use of tobacco (odds ratios=2.05, 1.88 for regular use), marijuana (odds ratios=2.02, 1.39) and other drugs (odds ratios=3.24, 1.67).
Conclusions
Clinically, it is important to assess for teenagers’ involvement in internet gambling, particularly as adolescent at-risk/problem internet gambling appears specifically associated with non-peer involvement, heavy alcohol use and poor academic functioning.
doi:10.1016/j.jaac.2010.11.006
PMCID: PMC3190180  PMID: 21241952
gambling; adolescence; internet; risk behaviors; substance use
15.  Factors associated with disordered gambling in Finland 
Background
The purpose of this study was to compare the socio-demographic characteristics of non-problem gamblers, problem gamblers and pathological gamblers, to investigate the association between gambling related factors and perceived health and well-being among the three subgroups of gamblers, and to analyse simultaneously socio-demographic characteristics, gambling related factors and perceived health and well-being and the severity of disordered gambling (problem gamblers and pathological gamblers).
Methods
The data were collected through a nationwide telephone survey in 2011. Participants were selected through a random population sample of 15-74-year-old Finns. From that sample, persons with any past-year gambling involvement (N = 3451) were selected for a subsample for the descriptive and inferential analysis in the present paper. Gambling was assessed using the South Oaks Gambling Screen. Statistical significance was determined by chi-squared tests. The odds ratio and effect size were computed by using multivariate-adjusted multinomial logistic regression analysis.
Results
The most significant socio-demographic characteristics (male gender, young age, education ≤12 years), gambling related factors (slot machine gambling, internet gambling) and perceived health and well-being (feeling lonely, smoking daily, risky alcohol consumption, mental health problems) explained 22.9 per cent of the variation in the severity of disordered gambling.
Conclusion
Male gender and loneliness were found to be associated with problem gambling in particular, along with smoking and risky alcohol consumption. Mental health problems and risky alcohol consumption were associated with pathological gambling. These identified associations between disordered gambling, mental health problems and risky alcohol consumption should be taken into consideration when implementing screenings of disordered gambling.
doi:10.1186/1747-597X-8-24
PMCID: PMC3706208  PMID: 23816162
Disordered gambling; Pathological gambling; Population survey; Problem gambling; Public health; South Oaks Gambling Screen
16.  Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study 
Psychiatry research  2004;130(3):269-281.
In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two 18F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order—one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.
doi:10.1016/j.pscychresns.2003.12.006
PMCID: PMC2773650  PMID: 15135160
Positron emission tomography; Nicotine dependence; Brain metabolism; Anterior cingulate cortex; Orbitofrontal cortex; Bupropion hydrochloride
17.  Gender Differences in Craving and Cue Reactivity to Smoking and Negative Affect/Stress Cues 
There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking-and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n=37) and men (n=53) smokers to two active cue types, each with an associated control cue: 1) in vivo smoking cues and in vivo neutral control cues, and 2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking vs. neutral cues and greater subjective stress in response to the negative affect/stress vs. neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.
doi:10.1111/j.1521-0391.2012.00232.x
PMCID: PMC3325498  PMID: 22494223
18.  Gambling severity predicts midbrain response to near-miss outcomes 
Gambling is a common recreational activity that becomes dysfunctional in a subset of individuals, with DSM ‘pathological gambling’ regarded as the most severe form. During gambling, players experience a range of cognitive distortions that promote an over-estimation of the chances of winning. Near-miss outcomes are thought to fuel these distortions. We observed previously that near-misses recruited overlapping circuitry to monetary wins in a study in healthy volunteers (Clark et al. 2009). The present study sought to extend these observations in regular gamblers and relate brain responses to an index of gambling severity. Twenty regular gamblers, who varied in their involvement from recreational players to probable pathological gamblers, were scanned whilst performing a simplified slot-machine task that delivered occasional monetary wins, as well as near-miss and full-miss non-win outcomes. In the overall group, near-miss outcomes were associated with a significant response in the ventral striatum, which was also recruited by monetary wins. Gambling severity, measured with the South Oaks Gambling Screen, predicted a greater response in the dopaminergic midbrain to near-miss outcomes. This effect survived controlling for clinical co-morbidities that were present in the regular gamblers. Gambling severity did not predict win-related responses in the midbrain or elsewhere. These results demonstrate that near-miss events during gambling recruit reward-related brain circuitry in regular players. An association with gambling severity in the midbrain suggests that near-miss outcomes may enhance dopamine transmission in disordered gambling, which extends neurobiological similarities between pathological gambling and drug addiction.
doi:10.1523/JNEUROSCI.5758-09.2010
PMCID: PMC2929454  PMID: 20445043
Gambling; Cognitive; Addiction; Dopamine; Striatum; Midbrain
19.  Neural Responses to BEGIN- and END-Stimuli of the Smoking Ritual in Nonsmokers, Nondeprived Smokers, and Deprived Smokers 
Neuropsychopharmacology  2010;35(5):1209-1225.
Drug-associated stimuli (cues) have a prominent role in addiction research because they are able to provoke craving and relapses. Generally, drug cues are seen as conditioned excitatory stimuli, which elicit drug seeking and usage. However, newer data suggest differential effects for smoking stimuli depending on their stage in the smoking ritual. Specifically, stimuli associated with the terminal stage of smoke consumption (END-stimuli) may evoke reactivity opposite to the reactivity evoked by stimuli associated with the beginning of smoke consumption (BEGIN-stimuli). This fMRI study compared 20 nondeprived smokers with 20 nonsmokers to unravel the influence of smoking-related pictures displaying the beginning (BEGIN-stimuli) and termination (END-stimuli) of the smoking ritual on neural activity in the addiction network. In addition, 20 deprived smokers (12 h deprivation) were investigated to explore the effects of deprivation on the processing of these stimuli. In nondeprived smokers, BEGIN-stimuli reliably activated the addiction network (for example, the ventral striatum, orbitofrontal cortex, and anterior cingulate cortex (ACC)). In contrast, END-stimuli triggered a differential pattern of activations as well as deactivations; deactivations were found in the ventral striatum and the ACC. Deprivation had no clear effect on the responses triggered by BEGIN-stimuli, but affected the reactivity to END-stimuli. Our data clearly suggest that stimuli associated with different stages of the smoking ritual trigger differential neuronal responses. While BEGIN-stimuli generally seem to activate the addiction network, END-stimuli presumably have some inhibitory properties. This new finding might add to a more differentiated understanding of cue reactivity and addiction.
doi:10.1038/npp.2009.227
PMCID: PMC3055400  PMID: 20090671
addiction; smoking; cue reactivity; fMRI; deprivation; terminal stimuli; Addiction & Substance Abuse; Biological Psychiatry; Learning & Memory; Imaging; Clinical or Preclinical; addiction; smoking; cue-reactivity; fMRI; deprivation; terminal stimuli
20.  Instructed smoking expectancy modulates cue-elicited neural activity: A preliminary study 
In recent years, research applying functional neuroimaging to the study of cue-elicited drug craving has emerged. This research has begun to identify a distributed system of brain activity during drug craving. A review of this literature suggested that expectations regarding the opportunity to use a drug affected the pattern of neural responses elicited by drug cues. Using functional magnetic resonance imaging (fMRI), we examined the effects of smoking expectancy on the neural response to neutral (e.g., roll of tape) and smoking-related (a cigarette) stimuli in male cigarette smokers deprived of nicotine for 8 hr. As predicted, several brain regions (e.g., the anterior cingulate cortex) exhibited differential activation during cigarette versus neutral cue exposure. Moreover, we found that subregions of the prefrontal cortex (i.e., ventromedial, ventrolateral, and dorsolateral prefrontal cortices) showed cue-elicited activation that was modulated by smoking expectancy. These results highlight the importance of perceived drug use opportunity in the neurobiological response to drug cues.
doi:10.1080/14622200500185520
PMCID: PMC2633119  PMID: 16085533
21.  Neural Circuitry of Impulsivity in a Cigarette Craving Paradigm 
Impulsivity has been shown to play a pivotal role in the onset, pattern of consumption, relapse and, most notably, craving of illicit and licit drugs such as cigarette smoking. The goal of this study was to examine the neurobiological influence of trait impulsivity during cue-induced cigarette craving. Thirty-one chronic smokers passively viewed appetitive smoking-related and neutral images while being scanned and reported their feelings of craving. They completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. We conducted functional connectivity analyses using the psycho-physiological interaction method. During the processing of smoking stimuli, participants presented increased activations in the cingulate and prefrontal cortices. We observed a significant positive relationship between impulsivity scores and reported craving. A negative correlation was observed between the impulsivity score and activity in the posterior cingulate cortex (PCC). The insula, dorsal anterior cingulate cortex (dACC) as well as the dorsolateral prefrontal cortex (DLPFC) presented a negative connectivity with the PCC. Consistent with the view that the PCC is related to the ability to resist cigarette craving, our results suggest that high impulsive smokers have greater difficulty in controlling their cravings, and that this weakness may be mediated by lower PCC activity. Moreover, we argue that the less PCC activity, the greater the probability of a stronger emotional, physiological, and biased attentional response to smoking cues mediated by insula, dACC, and DLPFC activity. This is the first study on this topic, and so, results will need to be replicated in both licit and illicit drug abusers. Our findings also highlight a need for more emphasis on the PCC in drug addiction research, as it is one of the most consistently activated regions in functional magnetic resonance imaging studies examining the neural correlates of cue-induced alcohol, drug, and tobacco cravings.
doi:10.3389/fpsyt.2013.00067
PMCID: PMC3712893  PMID: 23874307
craving; impulsivity; cigarette smoking; neural correlates; fMRI
22.  Intentional Modulation of the Late Positive Potential in Response to Smoking Cues by Cognitive Strategies in Smokers 
PLoS ONE  2011;6(11):e27519.
Attentional bias is considered an important concept in addiction since it has been found to correlate with subjective craving and is strongly associated with relapse after periods of abstinence. Hence, investigating in ways to regulate attention for drug cues would be of major clinical relevance. The present study examined deliberate, cognitive modulation of motivated attention for smoking cues in smokers. The effects of three different reappraisal strategies on an electrophysiological measure of attentive processing were investigated. Early and late LPP components in response to passively viewed neutral and smoking pictures were compared with LPPs in response to smoking pictures that were reappraised with three different reappraisal strategies. Results show that when smokers actively imagine how pleasant it would be to smoke (pleasant condition), their early LPP in response to smoking cues increases, but when smokers actively focus on an alternative stimulus (distraction condition) or think of a rational, uninvolved interpretation of the situation (rational condition), smoking-related late LPP amplitude decreases to the processing level of neutral stimuli. Present results are the first to indicate that smoking cue-elicited LPP amplitudes can be modulated by cognitive strategies, suggesting that attentive processing of smoking cues can be intentionally regulated by smokers with various levels of dependence. Although cognitive strategies can lead to enhanced processing of smoking cues, it is not completely clear whether cognitive strategies are also successful in reducing smoking-related motivated attention. Although findings do point in this direction, present study is best considered preliminary and a starting point for other research on this topic. A focus on the distraction strategy is proposed, as there are indications that this strategy is more successful than the rational strategy in decreasing LPP amplitude.
doi:10.1371/journal.pone.0027519
PMCID: PMC3210181  PMID: 22087333
23.  Evidence for greater cue reactivity among low dependent vs. high dependent smokers 
Addictive behaviors  2010;35(7):673-677.
Introduction
Cue reactivity paradigms are well-established laboratory procedures used to examine subjective craving in response to substance-related cues. For smokers, the relationship between nicotine dependence and cue reactivity has not been clearly established. The main aim of the present study was to further examine this relationship.
Methods
Participants (N=90) were between the ages 18–40 and smoked ≥10 cigarettes per day. Average nicotine dependence (Fagerström Test for Nicotine Dependence; FTND) at baseline was 4.9 (SD=2.1). Participants completed four cue reactivity sessions consisting of two in vivo cues (smoking, neutral) and two affective imagery cues (stressful, relaxed), all counterbalanced. Craving in response to cues was assessed following each cue exposure using the Questionnaire of Smoking Urges—Brief (QSU-B). Differential cue reactivity was operationally defined as the difference in QSU scores between the smoking and neutral cues, and between the stressful and relaxed cues.
Results
Nicotine dependence was significantly and negatively associated with differential cue reactivity scores in regards to hedonic craving (QSU factor 1) for both in vivo and imagery cues, such that those who had low FTND scores demonstrated greater differential cue reactivity than those with higher FTND scores (β = −.082; p = .037; β = −.101; p = .023, respectively). Similar trends were found for the total QSU and for negative reinforcement craving (QSU factor 2), but did not reach statistical significance.
Discussion
Under partially sated conditions, less dependent smokers may be more differentially cue reactive to smoking cues as compared to heavily dependent smokers. These findings offer methodological and interpretative implications for cue reactivity studies.
doi:10.1016/j.addbeh.2010.02.010
PMCID: PMC2856788  PMID: 20206451
cue reactivity; craving; dependence; smoking; nicotine
24.  Personalized smoking environment cue reactivity in smokers with schizophrenia and controls: a pilot study 
Psychiatry research  2011;188(2):286-288.
Exposure to smoking cues increases craving to smoke and negatively changes mood in smokers with schizophrenia (SWS). This pilot study compared reactivity to real-world smoking environments versus neutral environments in SWS (n = 10) and non-psychiatric control smokers (CON; n = 10). Results indicate that both SWS and CON experienced increases in smoking urges when viewing images of their smoking environments and that SWS tended to report greater increases in withdrawal-related negative mood than CON when viewing images of their smoking environments. These findings signify that personalized smoking environments trigger smoking urges in SWS and suggest that extinguishing this reactivity may aid cessation efforts in this population.
doi:10.1016/j.psychres.2011.04.005
PMCID: PMC3114290  PMID: 21550670
cigarette smoking; schizophrenia; nicotine
25.  Virtual harm reduction efforts for Internet gambling: effects of deposit limits on actual Internet sports gambling behavior 
Background
In an attempt to reduce harm related to gambling problems, an Internet sports betting service provider, bwin Interactive Entertainment, AG (bwin), imposes limits on the amount of money that users can deposit into their online gambling accounts. We examined the effects of these limits on gambling behavior.
Methods
We compared (1) gambling behavior of those who exceeded deposit limits with those who did not, and (2) gambling behavior before and after exceeding deposit limits. We analyzed 2 years of the actual sports gambling behavior records of 47000 subscribers to bwin.
Results
Only 160 (0.3%) exceeded deposit limits at least once. Gamblers who exceeded deposit limits evidenced higher average number of bets per active betting day and higher average size of bets than gamblers who did not exceed deposit limits. Comparing the gambling behavior before and after exceeding deposit limits revealed slightly more unfavorable gambling behavior after exceeding deposit limits.
Conclusion
Our findings indicate that Internet gamblers who exceed deposit limits constitute a group of bettors willing to take high risks; yet, surprisingly, they appear to do this rather successfully because their percentage of losses is lower than others in the sample. However, some of these gamblers exhibit some poor outcomes. Deposit limits might be necessary harm reduction measures to prevent the loss of extremely large amounts of money and cases of bankruptcy. We discuss how these limits might be modified based on our findings.
doi:10.1186/1477-7517-5-27
PMCID: PMC2519063  PMID: 18684323

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