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1.  Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study 
PLoS ONE  2014;9(1):e84560.
Introduction
With the progression of substance dependence, drug cue-related brain activation is thought to shift from motivational towards habit pathways. However, a direct association between cue-induced brain activation and dependence duration has not yet been shown. We therefore examined the relationship between alcohol cue-reactivity in the brain, cue-induced subjective craving and alcohol dependence duration and severity. Since alcohol dependence is highly comorbid with depression/anxiety, which may modulate brain responses to alcohol cues, we also examined the relation between comorbid depression/anxiety and cue-reactivity.
Methods
We compared 30 alcohol dependent patients with 15 healthy controls and 15 depression/anxiety patients during a visual alcohol cue-reactivity task using functional magnetic resonance imaging blood oxygenated level-dependent responses and subjective craving as outcomes. Within the alcohol dependent group we correlated cue-reactivity with alcohol dependence severity and duration, with cue-induced craving and with depression/anxiety levels.
Results
Alcohol dependent patients showed greater cue-reactivity in motivational brain pathways and stronger subjective craving than depression/anxiety patients and healthy controls. Depression/anxiety was not associated with cue-reactivity, but depression severity in alcohol dependent patients was positively associated with craving. Within alcohol dependence, longer duration of alcohol dependence was associated with stronger cue-related activation of the posterior putamen, a structure involved in habits, whereas higher alcohol dependence severity was associated with lower cue-reactivity in the anterior putamen, an area implicated in goal-directed behavior preceding habit formation.
Conclusion
Cue-reactivity in alcohol dependence is not modulated by comorbid depression or anxiety. More importantly, the current data confirm the hypothesis of a ventral to dorsal striatal shift of learning processes with longer dependence duration, which could underlie increasingly habitual substance use with progressing substance dependence.
doi:10.1371/journal.pone.0084560
PMCID: PMC3882248  PMID: 24400099
2.  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
3.  Approach-Bias Predicts Development of Cannabis Problem Severity in Heavy Cannabis Users: Results from a Prospective FMRI Study 
PLoS ONE  2012;7(9):e42394.
A potentially powerful predictor for the course of drug (ab)use is the approach-bias, that is, the pre-reflective tendency to approach rather than avoid drug-related stimuli. Here we investigated the neural underpinnings of cannabis approach and avoidance tendencies. By elucidating the predictive power of neural approach-bias activations for future cannabis use and problem severity, we aimed at identifying new intervention targets. Using functional Magnetic Resonance Imaging (fMRI), neural approach-bias activations were measured with a Stimulus Response Compatibility task (SRC) and compared between 33 heavy cannabis users and 36 matched controls. In addition, associations were examined between approach-bias activations and cannabis use and problem severity at baseline and at six-month follow-up. Approach-bias activations did not differ between heavy cannabis users and controls. However, within the group of heavy cannabis users, a positive relation was observed between total lifetime cannabis use and approach-bias activations in various fronto-limbic areas. Moreover, approach-bias activations in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) independently predicted cannabis problem severity after six months over and beyond session-induced subjective measures of craving. Higher DLPFC/ACC activity during cannabis approach trials, but lower activity during cannabis avoidance trials were associated with decreases in cannabis problem severity. These findings suggest that cannabis users with deficient control over cannabis action tendencies are more likely to develop cannabis related problems. Moreover, the balance between cannabis approach and avoidance responses in the DLPFC and ACC may help identify individuals at-risk for cannabis use disorders and may be new targets for prevention and treatment.
doi:10.1371/journal.pone.0042394
PMCID: PMC3434213  PMID: 22957019
4.  The Relationship between Impulsive Choice and Impulsive Action: A Cross-Species Translational Study 
PLoS ONE  2012;7(5):e36781.
Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.
doi:10.1371/journal.pone.0036781
PMCID: PMC3344935  PMID: 22574225
5.  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

Results 1-5 (5)