Tagrid Leménager

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

Decision Making of Heavy Cannabis Users on the Iowa Gambling Task: Stronger Association with THC of Hair Analysis than with Personality Traits of the Tridimensional Personality Questionnaire

Background: It is unclear whether impairment in decision making, measured by the Iowa Gambling Task (IGT), in addiction is substance-induced or the consequence of personality structure. Methods: Analysis of the IGT, the Tridimensional Personality Questionnaire (TPQ) and cannabinoids in hair and urine were performed in 13 cannabis users and matched controls. Results: Hair Δ9-tetrahydrocannabinol (THC) correlated negatively with the last subtrial (cards 80–100) of the IGT (R = –0.67). In all participants (n = 26) the TPQ dimension, harm avoidance, correlated negatively with the total IGT score (R = –0.46). The last IGT-subtrial correlated with adventure seeking (R = 0.43), harm avoidance (R = –0.39) and reward dependence (R = –0.44). The last subtrial gives information on whether a participant has learned the IGT strategy. Multiple regression confirmed the impact of THC on the last subtrial, whereas TPQ personality traits did not additionally explain variance. Conclusions: Former indications of the IGT performance depending on the amount of cannabis consumed were replicated with an objective measurement of chronic cannabis consumption (hair THC). Multiple regression analysis argues for a stronger impact of chronic THC consumption than personality traits, but does not provide a causal relationship. Other factors (e.g. genetic) may also play a role.

Abnormalities of functional brain networks in pathological gambling: a graph-theoretical approach

Functional neuroimaging studies of pathological gambling (PG) demonstrate alterations in frontal and subcortical regions of the mesolimbic reward system. However, most investigations were performed using tasks involving reward processing or executive functions. Little is known about brain network abnormalities during task-free resting state in PG. In the present study, graph-theoretical methods were used to investigate network properties of resting state functional magnetic resonance imaging data in PG. We compared 19 patients with PG to 19 healthy controls (HCs) using the Graph Analysis Toolbox (GAT). None of the examined global metrics differed between groups. At the nodal level, pathological gambler showed a reduced clustering coefficient in the left paracingulate cortex and the left juxtapositional lobe (supplementary motor area, SMA), reduced local efficiency in the left SMA, as well as an increased node betweenness for the left and right paracingulate cortex and the left SMA. At an uncorrected threshold level, the node betweenness in the left inferior frontal gyrus was decreased and increased in the caudate. Additionally, increased functional connectivity between fronto-striatal regions and within frontal regions has also been found for the gambling patients. These findings suggest that regions associated with the reward system demonstrate reduced segregation but enhanced integration while regions associated with executive functions demonstrate reduced integration. The present study makes evident that PG is also associated with abnormalities in the topological network structure of the brain during rest. Since alterations in PG cannot be explained by direct effects of abused substances on the brain, these findings will be of relevance for understanding functional connectivity in other addictive disorders.

Impaired decision making in opiate addiction correlates with anxiety and self-directedness but not substance use parameters.

Background:Despite a large number of empirical reports of impaired decision making in substance use disorders, the underlying factors contributing to such deficits remain to be elucidated. This study examined the potential influences of personality traits, affective symptoms, and pharmacological variables on decision making, as measured by the Iowa Gambling Task (IGT) in a sample of opioid-dependent patients. Methods:A total of 46 opioid-dependent patients taking part in an opiate maintenance outpatient program and 46 healthy control subjects performed the IGT. Personality traits and affective symptoms were examined by using Zuckerman Sensation-Seeking Scale, the State-Trait Anxiety Inventory and Beck Depression Inventory. In addition, Cloninger Temperament and Character Inventory was administered in the patient group. Information on current and life-time substance use was acquired with a standardized interview. Results:Opioid-dependent patients performed significantly worse on the IGT than controls. This difference disappeared after statistically controlling for trait anxiety, state anxiety, disinhibition, depressive symptoms, and lifetime alcohol consumption. Trait and state anxiety and self-directedness were significantly associated with the IGT final score. Hierarchical regression analyses suggested that self-directedness differentially moderated the relationships between the anxiety variables and IGT performance. Conclusions:The decision-making impairments observed in opioid-dependent patients are influenced by current levels of anxiety and the personality markers trait anxiety and self-directedness. Differences in decision making between opioid-dependent and healthy individuals may also be due to differences in other personality facets, affective symptoms, and alcohol consumption. Amount of opioid and other substance intake did not show any effects. These results indicate that psychological characteristics may have a higher impact on decision-making performance than drug-induced pharmacological effects.

Decision‐making deficits in patients diagnosed with disordered gambling using the Cambridge Gambling task: the effects of substance use disorder comorbidity

Disordered gambling (DG) has often been associated with impaired decision‐making abilities, suggesting a dysfunction in the ventromedial prefrontal cortex (vmPFC).

Insula and striatum activity in effort-related monetary reward processing in gambling disorder: the role of depressive symptomatology.

The neurobiological underpinnings of effort-related monetary reward processing of gambling disorder have not been previously studied. To date neuroimaging studies lack in large sample sizes and as a consequence less attention has been given to brain reward processing that could potentially be attributed to comorbid conditions such as depressive mood state. We assessed monetary reward processing using an effort-dependent task during 3 tesla functional magnetic resonance imaging. We investigated a large sample of male, right-handed, slot-machine-playing disordered gamblers (DGs; N = 80) as well as age- and smoking-matched male healthy controls (HCs; N = 89). Depressive symptoms were assessed using the Beck Depression Inventory (BDI). DGs and HCs were divided into subgroups (“high” and “low”) based on their BDI scores. Effort-related monetary reward processing did not differ between the complete groups of HCs and DGs. Brain activation during receipt of monetary reward though revealed a significant Group × BDI interaction: DGs with higher BDI scores compared to DGs with lower BDI scores showed greater brain activity in the right insula cortex and dorsal striatum while no differences were observed for HCs with higher versus lower BDI scores. Our results suggest that effort-related aspects of monetary motivation, i.e. when monetary output is tied to performance, are not altered in DG. Additionally, our findings strengthen the need for subgroup comparisons in future investigations of the disorder as part of a personalized medicine approach.

A model comparison of COMT effects on central processing of affective stimuli.

The number of studies on imaging genetics has risen considerably over the last few years, and haplotypes are being increasingly applied as a model to increase the explained variance in functional brain activation. Haplotypes, however, are not always the preferable approach. While such highly complex models have a greater capacity for fitting data, they might also lead to over-fitting. This study compares individual single nucleotide polymorphisms (SNPs) with haplotypes by applying both models to effects of catechol-O-methyltransferase (COMT), one of the most extensively studied genes in psychiatric research and imaging genetics, on the central processing of affective cues. To our knowledge, this is the first study to compare haplotypes and SNPs of the COMT gene in an imaging genetics study. The model comparison in this study is based on the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), introducing the novel concepts of posterior evidence ratio maps and best model maps. Findings reveal the simplest model, comprising only the well studied COMT Val(158)Met polymorphism, to be the most informative one. These results do not necessarily mean that haplotype models are in general inferior to individual SNP analysis. They do underline, however, that techniques for model comparison such as the ones used in this study need to be employed to establish whether the increase in likelihood provided by a more complex haplotype-based model is large enough to warrant the increase in model complexity.

Neurobiological correlates of physical self-concept and self-identification with avatars in addicted players of Massively Multiplayer Online Role-Playing Games (MMORPGs)

AIMS MMORPG addiction has been associated with self-concept impairments and increased identification with the own avatar. Yet, the underlying neurobiological mechanisms of self-identification with avatars, especially reflected in the left angular gyrus (AG), have only been assessed in regular gamers. Therefore, the study aims to examine neurobiological processes in addicted MMORPG players while evaluating their own and their personal avatars body image (physical self-concept). METHODS Sixteen addicted and seventeen non-addicted gamers underwent functional Magnetic Resonance Imaging (fMRI) while viewing images of themselves, their own avatar and unfamiliar persons. The Body Image Questionnaire (FKB-20) and Visual Analog Scales (VAS) assessing the degree of attractiveness, sympathy and gender identity of the self, of the avatar as well as of the unfamiliar persons were applied. RESULTS Addicts showed a significantly extended negative body image and lower gender identity levels as well as decreased bilateral brain activations in the AG and the middle occipital gyrus during self-perception. They further exhibited higher activations in the left AG during avatar-perception. Regression analyses in the overall group and in addicted gamers indicated a significant positive correlation between gender identity and brain activation in the left AG during self-perception. CONCLUSIONS Our results confirm addicted MMORPG players to have physical self-concept deficits which may be related to hypoactivations in the AG. The findings further indicate addicted gamers to have a tendency to identify themselves easier with their own avatar than with their real self. Lower gender identity levels might be associated with physical self-concept deficits in MMORPG addiction.

Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin

Background: Weight gain is a common but only a partially understood consequence of smoking cessation. Existing data suggest modulating effects of the orexigenic peptide ghrelin on food intake. The aim of the present study was to investigate the effect of tobacco withdrawal on plasma concentration of acetylated and total ghrelin. Methods: Fifty four normal-weighted smokers and 30 non-smoking healthy controls were enrolled in our study. Concentrations of acetylated and total ghrelin were measured in blood plasma drawn two hours after a standardized meal and three hours after the smokers smoked their last cigarette. The severity of tobacco addiction was assessed based on cotinine plasma concentration, the Fagerström Test for Nicotine Dependence (FTND) and the number of cigarettes smoked per day. Results: The plasma concentration of acetylated ghrelin, but not total ghrelin, was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence. Conclusions: Early abstinence from tobacco smoking seems to be associated with increased plasma concentration of the orexigenic peptide acetylated ghrelin. This could be one reason for increased food craving during nicotine withdrawal and subsequent weight gain. Smokers might compensate these effects by increasing tobacco intake.

Attention Shift towards Smoking Cues Relates to Severity of Dependence, Smoking Behavior and Breath Carbon Monoxide

The aim of this study was to assess the severity of dependence as a factor affecting the attentional bias of smokers towards smoking-related stimuli and to clarify contradictory results of previous studies. A visual dot probe task was administered to 51 smokers and 41 nonsmokers to assess the attentional bias. Smokers were classified into a group of less severely dependent and a group of more severely dependent smokers according to the Fagerström Test for Nicotine Dependence, the number of cigarettes smoked per day or the CO concentration in the expired air. Nicotine craving was assessed as well. The more severely dependent smokers displayed an attentional bias towards smoking-related stimuli, while smokers with less severe nicotine dependence showed a negative attentional bias which was also observed in nonsmokers. A multiple linear regression indicated that CO concentration was the only significant predictor of attentional bias. In the total group of smokers we found a positive association between attentional bias and craving for the rewarding effects of nicotine. Future studies are warranted to further enhance our understanding of factors that affect attentional bias as appetitive responses towards smoking-related stimuli might be an important target for therapeutic interventions.