Pathological gambling is characterized by persistent and recurrent maladaptive gambling behaviour (American Psychiatric Association 2003). Up to 50% of problem gamblers report that direct presentation of gambling stimuli is a trigger to gamble (Grant and Kim 2001). However, the mechanisms underlying this recurrent maladaptive gambling behaviour are still unclear.
An influential and empirically grounded neurobiological model for substance dependence, the Impaired Response Inhibition and Salience Attribution (I-RISA) model, postulates that repeated drug use triggers a series of adaptations in neuronal circuits involved in memory, motivation, and cognitive control. If an individual has used drugs, memories of this event are stored as associations between the stimulus and the elicited positive (pleasant) or negative (aversive) experiences, facilitated by dopaminergic activation caused by the drug of abuse. This results in an enhanced (and long-lasting) salience for the drug and its associated cues at the expense of decreased salience for natural reinforcers 
. In addition, the I-RISA model assumes loss of control (disinhibition) over drugs due to enhanced salience and pre-existing deficiencies, which renders individuals suffering from addictive disorders vulnerable to relapse into addictive behaviour. Although the I-RISA model is based on findings in substance dependent subjects, converging evidence suggests that this model could also explain the development and course of pathological gambling 
Enhanced salience attribution towards gambling cues has consistently been reported in problem gamblers. Functional magnetic resonance imaging (fMRI) studies in problem gamblers compared to controls investigating salience attribution (i.e. cue reactivity) towards gambling pictures have found enhanced Blood Oxygen Level-Dependent (BOLD) responses in the amygdala, cingulate cortex, dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) 
, similar to the enhanced BOLD responses to drug-related pictures or movies in alcohol and drug dependent subjects 
. Diminished sensitivity towards monetary wins and losses as observed in substance dependent disorders 
has also been reported in problem gamblers. For example, in fMRI paradigms where participants experienced small monetary gains and losses, problem gamblers showed attenuated responses in the ventral striatum, and ventromedial and ventral lateral prefrontal cortex compared to controls 
. However, the majority of problem gamblers are used to play with large amounts of money, which could also explain the attenuated response to winning or losing small amounts of money. Evidence of diminished sensitivity towards non-monetary cues in gamblers should therefore be tested, for example with positive or negative affective pictures which are also known to recruit salience/motivational circuitry, including amygdala, striatum, and orbitofrontal cortex 
Cognitive control and impulse regulation are critically dependent on intact prefrontal cortex functioning, in particular the inferior frontal cortex (IFC), anterior cingulate (ACC) and DLPFC 
. Diminished IFC, ACC and DLPFC activity associated with impaired response inhibition has been reported in individuals with a substance use disorder 
. In contrast, some other studies found similar response inhibition performance in substance dependent groups and healthy controls, together with increased activity in IFC, ACC and DLPFC in the substance dependent groups 
. These latter findings have been interpreted as indicative of a compensatory brain response in substance dependent individuals to achieve a similar level of performance as controls.
Impaired response inhibition has been reported in behavioural studies in problem gamblers, e.g., increased cognitive interference on the Stroop task, and diminished inhibition in stop-signal tasks 
. However, similar to the literature in substance use disorders, some studies failed to observe behavioural differences between problem gamblers and healthy controls 
. The mixed results in studies on response inhibition in problem gamblers may be explained by the presence of comorbid conditions or differences in gambling problem severity in these studies [e.g., 30]
. Alternatively, the distributed cortical and subcortical network supporting efficient response inhibition, such as the DLPFC, may be functionally intact, with impaired error processing being responsible for diminished response inhibition 
. The two neuroimaging studies on this topic to date, indicate diminished ventral lateral prefrontal cortex activity in PRGs compared to controls during response inhibition on a Stroop task between problem gamblers and controls 
and diminished responsiveness of the dorsomedial prefrontal cortex during a stop-signal response inhibition task in problem gamblers, compared to healthy controls 
To date, impaired inhibition and enhanced salience attribution in substance dependent disorders has only been studied in separate designs, i.e. neutral Go/Nogo tasks in inhibition studies 
and cue-reactivity tasks in salience attribution studies 
. Functional MRI studies examining the interaction between cognitive control (IFC, DLPFC, ACC) and salience attribution (amygdala, striatum, VLPFC) in substance dependent individuals or problem gamblers are currently lacking. We therefore employed a modified Go/Nogo task by including affective stimulus blocks (gambling, positive and negative), in addition to the standard affectively neutral block in problem gamblers (PRGs) and healthy controls (HCs). Subjects were requested to respond or withhold a response to specific types of pictures with a different affective loading, allowing the investigation of the interaction between motor inhibition and salience attribution.
Based on the attenuated BOLD response to affective stimuli in problem gamblers 
and SUDs 
, we hypothesized that PRGs would show a decreased BOLD response to positive and negative pictures compared to HCs in salience/motivational brain circuitry. Based on the findings of an enhanced neuronal response to gambling-related cues in PRGs 
, we also hypothesized that PRGs compared to HCs would show enhanced brain activity during gambling related pictures in the salience/motivational circuitry (e.g. amygdala, striatum, VLPFC). Based on the I-RISA model, we hypothesized that compared to HCs, PRGs would show impaired response inhibition and diminished DLPFC, ACC and IFC activity in the context of neutral, positive and negative stimuli and even more so when confronted with an inhibition task in the context of gambling-related pictures compared to HCs.