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Background: Previous studies have established a connection between adverse childhood experiences (ACE) and alcohol use disorder (AUD), both of which are associated with alterations in grey matter volume (GMV) and cortical thickness (CT). The current study aimed to assess the neurobiological impact of ACE specifically in the context of AUD, as well as the role of maltreatment type (i.e., abuse or neglect) and timing. Methods: Structural MRI data were collected from 35 adults with AUD (mean age: 40; 31% female) and 28 healthy controls (mean age: 36; 61% female). ACE were assessed retrospectively using the Childhood Trauma Questionnaire, and the Maltreatment and Abuse Chronology interview. Global and regional GMV and CT were estimated using voxel‐ and surface‐based morphometry. Results: Relative to the healthy controls, the AUD group had significantly reduced CT in the left inferior frontal gyrus, left circular sulcus of the insula and subcentral gyrus and sulci (cluster C1), and in the central sulcus and precentral gyrus (cluster C2). Within the AUD group, a reduction of CT in cluster C1 was significantly associated with higher severity of ACE and AUD. Type and timing analyses revealed a significant association between higher levels of abuse at ages 13 to 15 and reduced CT in cluster C1 within the AUD group. Conclusions: In adults with AUD, abuse experienced during early adolescence is associated with reduced CT in regions involved in inhibitory control, indicating the potential relevance of cognitive pathways in the association between ACE and AUD. Longitudinal studies are needed to confirm and expand upon current findings. [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute‐on‐chronic liver failure (ACLF). Infections with multidrug‐resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation. Aim: The aim of the study was to assess the influence of non‐antibiotic medication contributing to MDRO colonisation. Methods: Three hundred twenty‐four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi‐centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes. Results: A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%‐confidence interval (CI) 1.82–4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%‐CI 2.96–30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%‐CI 1.22–23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911–6.823, p = 0.075) and associated with risk of MDRO infection during follow‐up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001). Conclusions: Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non‐antibiotic co‐medications had negligible influence. Future prospective trials are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background and Aims: The addictive potential of electronic cigarettes (e‐cigarettes) remains to be fully understood. We identified patterns and correlates of perceived addiction to e‐cigarettes and perceived addictiveness of e‐cigarettes relative to tobacco cigarettes (relative addictiveness) in dual users as well as exclusive e‐cigarette users. Design, Setting and Participants: Observational study using cross‐sectional survey data from England (2016) from the International Tobacco Control Project (ITC) Four Country Smoking and Vaping (4CV) survey. The study comprised 832 current e‐cigarette users who had been vaping for at least 4 months. Measurements: Perceived addiction to e‐cigarettes and relative addictiveness of e‐cigarettes were examined. Socio‐demographic factors were age, gender and education; markers of addiction included urge to vape, time to first vape after waking and nicotine strength used; vaping and smoking characteristics included frequency and duration of e‐cigarette use, intention to quit, adjustable power or temperature, enjoyment, satisfaction relative to tobacco cigarettes and tobacco cigarette smoking status. Findings A total of 17% of participants reported feeling very addicted to e‐cigarettes, while 40% considered e‐cigarettes equally/more addictive than tobacco cigarettes. Those who felt very addicted had higher odds of regarding e‐cigarettes as more addictive than tobacco cigarettes (odds ratio 3.4, 95% confidence interval 2.3–5.1). All markers of addiction, daily use and enjoyment were associated with higher perceived addiction, whereas time to first vape after waking, daily vaping and perceiving vaping as less satisfying than smoking were associated with relative addictiveness. Conclusions: Markers of addiction to e‐cigarettes appear to correspond with perceived addiction to e‐cigarettes, suggesting that self‐reported perceived addiction might serve as an indicator of addiction. Prevalence both of markers of addiction and perceived addiction were comparatively low overall, suggesting a limited but relevant addictive potential of e‐cigarettes. Additionally, positive and negative reinforcement, reflected here by enjoyment and relative satisfaction, might play a role in e‐cigarette addiction. [ABSTRACT FROM AUTHOR]

Childhood trauma (CT) is frequent in patients with alcohol use disorder (AUD) and may impact on adult drinking behaviour and treatment outcome. This study aimed to investigate the structural correlates of CT in AUD, focusing on the amygdala, which plays a crucial role in the neurobiology of trauma. We hypothesized reduced amygdala volume and reduced structural connectivity as quantified by fractional anisotropy (FA) and by number of streamlines in those AUD patients with a history of moderate to severe CT (AUD-CT). T1-weighted MP2RAGE and diffusion-weighted imaging (DWI) 3-Tesla MRI-scans were acquired in 41 recently abstinent patients with AUD. We compared bilateral amygdala volume and structural connectivity (FA and number of streamlines) of pathways emanating from the amygdala between AUD-CT (n = 20) and AUD without CT (AUD-NT, n = 21) using a mixed model multivariate analysis of variance (MANCOVA) controlling for age and gender. AUD-CT displayed reduced FA and reduced number of streamlines of amygdalar tracts. There were no differences regarding amygdala volume. The severity of physical abuse, a subscale of the childhood trauma questionnaire, was negatively correlated with FA and with number of streamlines. AUD-CT and AUD-NT differ regarding structural connectivity of pathways projecting to and from the amygdala, but not regarding amygdala volume. Those alterations of structural connectivity in AUD-CT may represent a distinguishable neurobiological subtype of AUD, which might be associated with the complex clinical picture and poorer outcome that patients with CT and AUD often present. [ABSTRACT FROM AUTHOR]

Aberrant limbic circuit reactivity to negative stimuli might be related to alterations in emotion processing and regulation in alcohol use disorder (AUD). The current study tested for the first time in AUD the hypothesis of aberrant amygdala habituation to repeated aversive stimuli—a robust and reliable neuroimaging marker for emotion processing. We explored the link between deficits in habituation to adverse childhood experience (ACE), a common risk factor for impaired emotion regulation and AUD. AUD individuals (N = 36) and healthy controls (HC; N = 26) participated in an observational case–control functional magnetic resonance imaging (fMRI) study. An established habituation index was used to investigate processing of aversive emotional faces of the amygdala. AUD individuals showed an overall deficit in amygdala habituation (right: t = 4.26, pFWE = 0.004; left: t = 4.79, pFWE ≤ 0.001). Amygdala habituation was significantly related to increased exposure to ACE in HC (t = 3.88, pFWE = 0.012), whereas this association was not observed in AUD individuals (T = 1.80, pFWE = 0.662). Further, a significant association between higher alcohol consumption and reduced amygdala habituation (right: R2 = −0.356, F = 8.736, p = 0.004; left: R2 = −0.309, F = 6.332, p = 0.015) was observed. We found novel evidence for neural alterations in emotion processing in AUD individuals, indexed by deficient amygdala habituation to negative emotional content. We replicated a prior report on a link between ACE and amygdala habituation, a well‐established environmental risk factor for mental disorders and emotion dysregulation, in our control sample. Additionally, deficient amygdala habituation related to the amount of alcohol consumption in the overall sample might indicate a short‐term substance effect. [ABSTRACT FROM AUTHOR]

Lead isotope provenance studies of archaeological artefacts rely crucially on the availability of reference data from raw material sources. The OXALID database, a collection of Excel sheets with Pb isotope data of ores and artefacts, is still the most cited data source in archaeometry. However, OXALID has not been updated for several years and contains almost exclusively data from Europe, particularly from the Mediterranean area. Digitalisation and open science philosophy currently revolutionise the use of machine‐generated data by developing digital data infrastructures. A modernised Pb isotope reference database, which is tailored for, but not limited to archaeometric research, is hence overdue. Here, we introduce GlobaLID, a FAIR (findable, accessible, interoperable, reusable) and extendable database and a web application with interactive and statistical tools for user‐friendly data handling up to publication quality. GlobaLID aims to be a collection point for worldwide Pb isotope data. It is designed as research infrastructure for Pb isotope studies in (for example) archaeometry, ore deposit and environmental geochemistry. As a community engagement project, GlobaLID invites scientists around the world to become active contributors to enable GlobaLID's rapid growth. We released GlobaLID as a pilot study to showcase the infrastructure we build and provide a starting point for community discussion. [ABSTRACT FROM AUTHOR]

Alcohol Use Disorder has been associated with impairments of functional connectivity between neural networks underlying reward processing and cognitive control. Evidence for aberrant functional connectivity between the striatum, insula, and frontal cortex in alcohol users exists at rest, but not during cue-exposure. In this study, we investigated functional connectivity changes during a cue-reactivity task across different subgroups of alcohol consumers. Ninety-six participants (ranging from light social to heavy social drinkers and nonabstinent dependent to abstinent dependent drinkers) were examined. A functional magnetic resonance imaging cue-reactivity paradigm was administered, during which alcohol-related and neutral stimuli were presented. Applying psychophysiological interaction analyses, we found: (a) Abstinent alcohol-dependent patients compared with non-abstinent dependent drinkers showed a greater increase of functional connectivity of the ventral striatum and anterior insula with the anterior cingulate cortex and dorsolateral prefrontal cortex during the presentation of alcohol cues compared with neutral cues. (b) Subjective craving correlated positively with functional connectivity change between the posterior insula and the medial orbitofrontal cortex and negatively with functional connectivity change between the ventral striatum and the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex. (c) Compulsivity of alcohol use correlated positively with functional connectivity change between the dorsolateral prefrontal cortex and the ventral striatum, anterior insula, and posterior insula. Results suggest increased cognitive control over cue-processing in abstinent alcohol-dependent patients, compensating high levels of cue-provoked craving and compulsive use. Clinical trial registration details: ClinicalTrials.gov ID: NCT00926900. [ABSTRACT FROM AUTHOR]

Abnormal resting‐state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph‐theoretical analyses, enabling improved resolution and fine‐grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large‐scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region‐specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular–supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment. [ABSTRACT FROM AUTHOR]

Over the last decades, the assessment of alcohol cue‐reactivity gained popularity in addiction research, and efforts were undertaken to establish neural biomarkers. This attempt however depends on the reliability of cue‐induced brain activation. Thus, we assessed test–retest reliability of alcohol cue‐reactivity and its implications for imaging studies in addiction. We investigated test–retest reliability of alcohol cue‐induced brain activation in 144 alcohol‐dependent patients over 2 weeks. We computed established reliability estimates, such as intraclass correlation (ICC), Dice and Jaccard coefficients, for the three contrast conditions of interest: 'alcohol', 'neutral' and the 'alcohol versus neutral' difference contrast. We also investigated how test–retest reliability of the different contrasts affected the capacity to establishing associations with clinical data and determining effect size estimates. Whereas brain activation, indexed by the constituting contrast conditions 'alcohol' and 'neutral' separately, displayed overall moderate (ICC > 0.4) to good (ICC > 0.75) test–retest reliability in areas of the mesocorticolimbic system, the difference contrast 'alcohol versus neutral' showed poor overall reliability (ICC < 0.40), which was related to the intercorrelation between the constituting conditions. Data simulations and analyses of craving data confirmed that the low reliability of the difference contrast substantially limited the capacity to establish associations with clinical data and precisely estimate effect sizes. Future research on alcohol cue‐reactivity should be cautioned by the low reliability of the common 'alcohol versus neutral' difference contrast. We propose that this limitation can be overcome by using the constituent task conditions as an individual difference measure, when intending to longitudinally monitor brain responses. [ABSTRACT FROM AUTHOR]

Ghrelin has been shown to be involved in the pathophysiology of alcohol dependence, affecting alcohol self-administration and craving. However, the mechanism of action in alcohol dependence still has to be determined. We thus investigated whether ghrelin is associated with mesolimbic cue reactivity to alcohol cues and alcohol craving in recently detoxified alcohol-addicted subjects. We included 41 recently detoxified alcohol-dependent individuals. Functional magnetic resonance imaging (fMRI) was used to study mesolimbic cue reactivity during the presentation of alcohol-related pictures. Additionally, we assessed patients' alcohol craving using the Alcohol Urge Questionnaire and a visual analogue scale. Plasma concentrations of total and acylated (activated) ghrelin were measured in parallel to the fMRI session. The association between ghrelin plasma concentrations, mesolimbic cue reactivity and alcohol craving was assessed by performing correlation and mediation analyses. Alcohol-induced brain response in a network of brain clusters, including the right and left ventral striatum, showed a significant positive association with acylated ghrelin plasma concentration. Additionally, acylated ghrelin was significantly associated with craving. Mediation analyses showed that the association between acylated ghrelin plasma concentration and alcohol craving is mediated by a cue-induced brain response in the ventral striatum. Based on the finding that ghrelin modulates mesolimbic reactivity to alcohol cues, the following should be considered: If alcohol craving and the appetitive status were interrelated, this has to be taken into account when implementing fMRI studies for addictive disorders. Moreover, appetite regulation seems to represent a valid treatment target for reducing cue reactivity in addictive disorders. [ABSTRACT FROM AUTHOR]

Aim: Due to scarce available national data, this study assessed current attitudes of neonatal caregivers regarding decisions on life‐sustaining interventions, and their views on parents' aptitude to express their infant's best interest in shared decision‐making. Methods: Self‐administered web‐based quantitative empirical survey. All 552 experienced neonatal physicians and nurses from all Swiss NICUs were eligible. Results: There was a high degree of agreement between physicians and nurses (response rates 79% and 70%, respectively) that the ability for social interactions was a minimal criterion for an acceptable quality of life. A majority stated that the parents' interests are as important as the child's best interest in shared decision‐making. Only a minority considered the parents as the best judges of what is their child's best interest. Significant differences in attitudes and values emerged between neonatal physicians and nurses. The language area was very strongly associated with the attitudes of neonatal caregivers. Conclusion: Despite clear legal requirements and societal expectations for shared decision‐making, survey respondents demonstrated a gap between their expressed commitment to shared decision‐making and their view on parental aptitude to formulate their infant's best interest. National guidelines need to address these barriers to shared decision‐making to promote a more uniform nationwide practice. [ABSTRACT FROM AUTHOR]

Background: A link between attention‐deficit/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) has been widely demonstrated. In this study, we used neuroimaging to investigate the connectivity traits that may contribute to the comorbidity of these disorders. Methods: The study included an AUD group (N = 18), an ADHD group (N = 17), a group with AUD + ADHD comorbidity (N = 12) and a control group (N = 18). We used resting‐state functional connectivity in a seed‐based approach in the default mode networks, the dorsal attention network, and the salience network. Results: Within the default mode networks, all affected groups shared greater connectivity toward the temporal gyrus when compared to the control group. Regarding the dorsal attention network, the Brodmann area 6 presented greater connectivity for each affected group in comparison with the control group, displaying the strongest aberrations in the AUD + ADHD group. In the salience network, the prefrontal cortex showed decreased connectivity in each affected group compared to the control group. Conclusions: Despite the small and unequal sample sizes, our findings show evidence of common neurobiological alterations in AUD and ADHD, supporting the hypothesis that ADHD could be a risk factor for the development of AUD. The results highlight the importance of an early ADHD diagnosis and treatment to reduce the risk of a subsequent AUD. [ABSTRACT FROM AUTHOR]

Background & Aims: Phosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis. Methods: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot. Results: ED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects. Conclusions: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis. [ABSTRACT FROM AUTHOR]

Background & Aims: Acute‐on‐chronic liver failure (ACLF) is characterized by high short‐term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. Results: At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL‐33 receptor (sIL‐33R). Patients were divided according to CI (<3.2; 3.2‐4.2; >4.2 L/min/m2) in hypo‐ (n = 84), normo‐ (n = 69) and hyperdynamic group (n = 55). After a median follow‐up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P =.011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL‐6 was an independent predictor of fatal ACLF development. Conclusions: Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF. [ABSTRACT FROM AUTHOR]

Alcohol metabolizing enzymes, such as the alcohol dehydrogenases and the aldehyde dehydrogenases, regulate the levels of acetaldehyde in the blood and play an important role in the development and maintenance of alcohol addiction. Recent genome-wide systematic searches found associations between a single nucleotide polymorphism (rs1789891, risk allele: A, protective allele: C) in the alcohol dehydrogenase gene cluster and the risk of alcohol dependence. The current study investigated the effect of this single nucleotide polymorphism on alcohol consumption, craving for alcohol, relapse risk and brain gray matter volume. Alcohol-dependent patients (n = 74) and controls (n = 43) were screened, genotyped and underwent magnetic resonance imaging scanning, and relapse data were collected during 3 months following the experiment. Alcohol-dependent A allele carriers reported increased alcohol craving and higher alcohol consumption compared with the group of alcohol-dependent individuals homozygous for the C allele, which displayed craving values similar to the control group. Further, follow-up data indicated that A allele carriers relapsed earlier to heavy drinking compared with individuals with two C alleles. Analyses of gray matter volume indicated a significant genotype difference in the patient group: individuals with two C alleles had reduced gray matter volume in the left and right superior, middle and inferior temporal gyri. Findings of the current study further support the relevance of genetic variants in alcohol metabolizing enzymes to addictive behavior, brain tissue volume and relapse risk. Genotype-dependent differences in acetaldehyde formation, implicated by earlier studies, might be the biological substrate of the genotype differences. [ABSTRACT FROM AUTHOR]

The feature is a part of the series about medical library services in various countries. It gives an overview of medical library services to support research, education and clinical practice in Switzerland. Data were collected by means of an online survey and set in the wider context of the Swiss healthcare system. Key findings are that library services, including support by academic librarians, are provided to health care staff in hospitals – both university and others, while there is no information service infrastructure to serve the large number of GPs and specialists who mostly run their own practice. The authors recommend that – if the health authorities take EBM seriously – information services should be introduced for these small practices. J.M. [ABSTRACT FROM AUTHOR]

Background: Aspects of self‐control such as sensation seeking and impaired impulse control have been implicated in alcohol dependence (ALC). Conversely, sensation seeking has been ascribed a possible protective role in stress‐related psychopathologies. We therefore examined gray matter (GM) morphology in individuals with ALC, focusing on differences in prefrontal regions that have been associated with self‐control. Additionally, we accounted for differences in lifetime alcohol intake regarding self‐control measures and cortical structures in ALC patients. Methods: With voxel‐based morphometry (VBM) focusing on prefrontal a priori defined regions of interest, we assessed a group of 62 detoxified ALC patients and 62 healthy controls (HC). ALC patients were subsequently divided into high (n = 9) and low consumers (n = 53). Self‐control was assessed by use of the Barratt Impulsiveness Scale and the Sensation Seeking Scale. Results: Compared to HC, ALC had significantly less GM volume in bilateral middle frontal gyrus (MFG) and right medial prefrontal cortex as well as in the right anterior cingulate. High‐consuming ALC showed smaller GM in right orbitofrontal cortex as well as lower sensation seeking scores than low consumers. In low‐consuming ALC, right MFG‐GM was positively associated with magnitude of sensation seeking; particularly, larger MFG‐GM correlated with greater thrill and adventure seeking. Conclusion: Thus, our findings (i) indicate deficient GM volume in prefrontal areas related to self‐control and (ii) might accentuate the phenotypic divergence of ALC patients and emphasize the importance of the development of individual treatment options. [ABSTRACT FROM AUTHOR]

Hypnosis has been shown to have treatment effects on nicotine addiction. However, the neural basis of these effects is poorly understood. This preliminary study investigated the neural mechanisms of hypnosis‐based treatment on cigarette smoking, specifically, whether the hypnosis involves a top‐down or bottom‐up mechanism. Two groups of 45 smokers underwent a smoking aversion suggestion and viewed smoking‐related pictures and neutral pictures. One group underwent functional magnetic resonance imaging scanning twice (control and hypnotic states), whereas the other group underwent two electroencephalograph sessions. Our study found that self‐reported smoking craving decreased in both groups following hypnosis. Smoking cue‐elicited activations in the right dorsal lateral prefrontal cortex (rDLPFC) and left insula (lI) and the functional connectivity between the rDLPFC and lI were increased in the hypnotic state compared with the control state. The delta band source waveforms indicated the activation from 390 to 862 ms at the rDLPFC and from 490 to 900 ms at the lI was significantly different between the smoking and neutral conditions in the hypnotic state, suggesting the activation in the rDLPFC preceded that in the lI. These results suggest that the decreased smoking craving via hypnotic aversion suggestions may arise from the top‐down regulation of the rDLPFC to the lI. Our findings provide novel neurobiological evidence for understanding the therapeutic effects of hypnosis on nicotine addiction, and the prefrontal–insula circuit may serve as an imaging biomarker to monitor the treatment efficacy noninvasively. [ABSTRACT FROM AUTHOR]

The processes involved in value evaluation and self‐control are critical when making behavioral choices. However, the evidence linking these two types of processes to behavioral choices in intertemporal decision‐making remains elusive. As the ventromedial prefrontal cortex (vmPFC), striatum, and dorsolateral prefrontal cortex (dlPFC) have been associated with these two processes, we focused on these three regions. We employed functional magnetic resonance imaging during a delayed discounting task (DDT) using a relatively large sample size, three independent samples. We evaluated how much information about a specific choice could be decoded from local patterns in each brain area using multivoxel pattern analysis (MVPA). To investigate the relationship between the dlPFC and vmPFC/striatum regions, we performed a psychophysiological interaction (PPI) analysis. In Experiment I, we found that the vmPFC and dlPFC, but not the striatum, could determine choices in healthy participants. Furthermore, we found that the dlPFC showed significant functional connectivity with the vmPFC, but not the striatum, when making decisions. These results could be replicated in Experiment II with an independent sample of healthy participants. In Experiment III, the choice‐decoding accuracy in the vmPFC and dlPFC was lower in patients with addiction (smokers and participants with Internet gaming disorder) than in healthy participants, and decoding accuracy in the dlPFC was related to impulsivity in addicts. Taken together, our findings may provide neural evidence supporting the hypothesis that value evaluation and self‐control processes both guide the intertemporal choices, and might provide potential neural targets for the diagnosis and treatment of impulsivity‐related brain disorders. [ABSTRACT FROM AUTHOR]

Threshold-free cluster enhancement (TFCE) is a sensitive means to incorporate spatial neighborhood information in neuroimaging studies without using arbitrary thresholds. The majority of methods have applied TFCE to voxelwise data. The need to understand the relationship among multiple variables and imaging modalities has become critical. We propose a new method of applying TFCE to vertexwise statistical images as well as cortexwise (either voxel- or vertexwise) mediation analysis. Here we present TFCE_mediation, a toolbox that can be used for cortexwise multiple regression analysis with TFCE, and additionally cortexwise mediation using TFCE. The toolbox is open source and publicly available (). We validated TFCE_mediation in healthy controls from two independent multimodal neuroimaging samples ( N = 199 and N = 183). We found a consistent structure-function relationship between surface area and the first independent component (IC1) of the N-back task, that white matter fractional anisotropy is strongly associated with IC1 N-back, and that our voxel-based results are essentially identical to FSL randomise using TFCE (all PFWE<0.05). Using cortexwise mediation, we showed that the relationship between white matter FA and IC1 N-back is mediated by surface area in the right superior frontal cortex ( PFWE < 0.05). We also demonstrated that the same mediation model is present using vertexwise mediation ( PFWE < 0.05). In conclusion, cortexwise analysis with TFCE provides an effective analysis of multimodal neuroimaging data. Furthermore, cortexwise mediation analysis may identify or explain a mechanism that underlies an observed relationship among a predictor, intermediary, and dependent variables in which one of these variables is assessed at a whole-brain scale. Hum Brain Mapp 38:2795-2807, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non-comorbid (PGPURE ) and two comorbid (PGALCOHOL and PGPOLY ) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel-based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post-central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects. [ABSTRACT FROM AUTHOR]

Aim: Studies have provided insights into the different attitudes and values of healthcare professionals and parents towards extreme prematurity. This study explored societal attitudes and values in Switzerland with regard to this patient group.Methods: A nationwide trilingual telephone survey was conducted in the French-, German- and Italian-speaking regions of Switzerland to explore the general population's attitudes and values with regard to extreme prematurity. Swiss residents of 18 years or older were recruited from the official telephone registry using quota sampling and a logistic regression model assessed the influence of socio-demographic factors on end-of-life decision-making.Results: Of the 5112 people contacted, 1210 (23.7%) participated. Of these 5% were the parents of a premature infant and 26% knew parents with a premature infant. Most participants (77.8%) highlighted their strong preference for shared decision-making, and 64.6% said that if there was dissent then the parents should have the final word. Overall, our logistic regression model showed that regional differences were the most significant factors influencing decision-making.Conclusion: The majority of the Swiss population clearly favoured shared decision-making. The context of sociocultural demographics, especially the linguistic region in which the decision-making took place, strongly influenced attitudes towards extreme prematurity and decision-making. [ABSTRACT FROM AUTHOR]

Background Xenotransplantation is considered to be a promising solution to the growing demand for suitable donor organs for transplantation. Despite tremendous progress in the generation of pigs with multiple genetic modifications thought to be necessary to overcoming the severe rejection responses after pig-to-non-human primate xenotransplantation, the production of knockout pigs by somatic cell nuclear transfer ( SCNT) is still an inefficient process. Producing genetically modified pigs by intracytoplasmic microinjection of porcine zygotes is an alluring alternative. The porcine GGTA1 gene encodes for the α1,3-galactosyltransferase that synthesizes the Gal epitopes on porcine cells which constitute the major antigen in a xenotransplantation setting. GGTA1- KO pigs have successfully been produced by transfecting somatic cells with zinc-finger nucleases ( ZFNs), transcription activator-like effector nucleases ( TALENs), or CRISPR/Cas targeting GGTA1, followed by SCNT. Methods Here, we microinjected a CRISPR/Cas9 vector coding for a single-guide RNA (sg RNA) targeting exon 8 of the GGTA1 gene into the cytoplasm of 97 in vivo-derived porcine zygotes and transferred 86 of the microinjected embryos into three hormonally synchronized recipients. Fetuses and piglets were analyzed by flow cytometry for remaining Gal epitopes. DNA was sequenced to detect mutations at the GGTA1 locus. Results Two of the recipients remained pregnant as determined by ultrasound scanning on day 25 of gestation. One pregnancy was terminated on day 26, and six healthy fetuses were recovered. The second pregnancy was allowed to go to term and resulted in the birth of six healthy piglets. Flow cytometry analysis revealed the absence of Gal epitopes in four of six fetuses (66%), indicating a biallelic KO of GGTA1. Additionally, three of the six live-born piglets (50%) did not express Gal epitopes on their cell surface. Two fetuses and two piglets showed a mosaicism with a mixed population of Gal-free and Gal-expressing cells. Only a single piglet did not have any genomic modifications. Genomic sequencing revealed indel formation at the GGTA1 locus ranging from +17 bp to −20 bp. Conclusions These results demonstrate the efficacy of CRISPR/Cas to generate genetic modifications in pigs by simplified technology, such as intracytoplasmic microinjection into zygotes, which would significantly facilitate the production of genetically modified pigs suitable for xenotransplantation. Importantly, this simplified injection protocol avoids the penetration of the vulnerable pronuclear membrane, and is thus compatible with higher survival rates of microinjected embryos, which in turn facilitates production of genetically modified piglets. [ABSTRACT FROM AUTHOR]

The aim of the current study was to determine genotype effects of four single nucleotide polymorphisms (SNPs) in the genes of the N-Methyl-d-aspartate receptor (GRIN1, GRIN2A, GRIN2C) and kainate receptor (GRIK1), which have been previously associated with alcoholism, on behavior, neural cue-reactivity and drinking outcome. Eighty-six abstinent alcohol dependent patients were recruited from an in-patient setting. Neuropsychological tests, genotyping and functional magnetic resonance imaging (fMRI) were used to study genotype effects. GRIN2C risk allele carriers displayed increased alcohol cue-induced activation in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (dlPFC). Neural activation in the ACC positively correlated with craving for alcohol (r = 0.201, P = 0.032), whereas activation in the dlPFC showed a negative association (r = -0.215, P = 0.023). In addition, dlPFC activation predicted time to first relapse (HR = 2.701, 95%CI 1.244-5.864, P = 0.012). GRIK1 risk allele carriers showed increased cue-induced activation in the medial prefrontal (PFC) and orbitofrontal cortex (OFC) and in the lateral PFC and OFC. Activation in both clusters positively correlated with alcohol craving (rmedOFC, medPFC  = 0.403, P = 0.001, rlatOFC, latPFC  = 0.282, P = 0.008), and activation in the cluster that encompassed the medial OFC predicted time to first relapse (HR = 1.911, 95%CI 1.030-3.545, P = 0.040). Findings indicate that SNPs in the GRIN2C and GRIK1 genes are associated with altered cue-induced brain activation that is related to craving for alcohol and relapse risk. [ABSTRACT FROM AUTHOR]

Background & Aims Patients with cirrhosis display hypocontractility of splanchnic vessels because of dysregulation of vasoactive proteins, such as decreased effect of RhoA/ROCK and increased activity of β-Arrestin-2 and eNOS. However, it is unknown whether the dysregulation of vasoactive proteins is displayed in other vessels. We investigated whether expression of vasoactive proteins can be evaluated in gastric mucosa vessels. Methods Biopsies from the gastric mucosa of 111 patients with cirrhosis were collected at three different centres and from 13 controls. Forty-nine patients had received TIPS. Portal pressure gradient was measured in 49 patients with TIPS and in 16 patients without TIPS. Biopsies from the antrum were conserved in formaldehyde for immunohistochemistry or shock-frozen for PCR and Western blot. Results The mucosal transcription of vascular markers (αSMA, CD31) was higher in cirrhotic patients than controls, which was confirmed by immunohistochemistry. On average, relative mucosal levels of RhoA and ROCK were lower, while β-Arrestin-2 levels were higher in cirrhotic patients compared to controls. Transcriptional levels of eNOS increased with presence of ascites and grade of oesophageal varices. Patients with TIPS showed less pronounced markers of vascular dysfunction in gastric mucosa. Conclusion This is the first evidence that the expression of vasoactive proteins in mucosa from the gastric antrum of patients with cirrhosis reflects their vascular dysfunction and possibly changes after therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background Alcohol consumption has been suggested to be associated with a dysregulation in habit formation and execution in dependent patients. Although there are established craving questionnaires assessing various components of craving, to our knowledge, no questionnaire exists to assess habitual and automated substance intake. In this study, we present and validate the 'Craving Automated Scale for Alcohol' ( CAS-A), a newly developed questionnaire assessing craving and other components of automated addictive behavior. Methods Forty-three recently detoxified alcohol-dependent patients were examined in an inpatient setting using a cross-sectional design. The CAS-A, a self-report questionnaire, was applied. According to classical test theory, we conducted principal component analyses (PCAs) to identify the components of CAS-A, after which we validated it using established craving questionnaires. Thirty-two healthy participants served as a control group. Results Our first-order PCA identified a 5-factor solution. A second-order analysis then identified 2 general factors. These factors were partially associated with established craving measures and with the severity of dependence. Conclusions Our findings suggest that CAS-A assesses additional components of addictive behavior compared to established measures. We interpret the 5 CAS-A factors as 'only aware in hindsight,' 'no deliberate decision,' 'contrary to intention,' 'no perception,' and 'no control.' We suggest the 2 general factors be interpreted as 'unaware' and 'nonvolitional.' Our results indicate that the CAS-A indeed assesses some components of automated craving and automated drinking behavior in a more sophisticated way than established questionnaires. The CAS-A as a retrospective questionnaire can be considered to be a trait rather than a state measure. [ABSTRACT FROM AUTHOR]

Background Effect sizes of pharmacotherapy in alcoholism are modest. They might improve if subjects could be divided into more homogeneous subgroups and would then be treated targeted to their neurobiological profile. In such an effort, we tested neural cue reactivity as a potential predictor of treatment response to naltrexone. Alcohol-associated cues cause brain activations in mesocorticolimbic networks due to the positive reinforcing properties of alcohol. These activations were reported to be associated with relapse behavior. Naltrexone, an antagonist at the mu-opioid receptor, improves drinking behavior in some but not all patients probably by blocking the positive reinforcement of alcohol. Conversely, acamprosate is proposed to modulate negative reinforcement (withdrawal and cue-induced withdrawal). Identifying subjects with elevated cue reactivity and testing their response to medical treatment could thus improve our understanding of some of the mechanisms underlying pharmacotherapy response. Methods A picture-perception task featuring alcohol-related and neutral stimuli was presented to 64 recently detoxified alcohol-dependent patients. Patients came from 1 center of a larger double-blind randomized multicenter clinical trial (the 'PREDICT Study'). They were scanned prior to being randomized to either naltrexone or acamprosate. We examined the interaction between medication and functional magnetic resonance imaging ( fMRI) cue reactivity, as measured by the percentage of voxels activated, using the time to the first severe relapse as the outcome criterion. Our a priori formulated hypothesis was that naltrexone but not acamprosate should be efficacious in subjects with high cue reactivity. Results We observed an interaction effect between pretreatment brain activation induced by alcohol images and medication (acamprosate/naltrexone) on relapse behavior. In line with our hypothesis, this interaction was driven by treatment response to naltrexone in patients with elevated pretreatment cue reactivity in the ventral striatum. Conclusions fMRI has the potential for predicting treatment response to naltrexone in a subgroup of alcohol-dependent patients. However, this approach will be limited to researching the mechanisms and principles of treatment response. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated higher discount rates for delayed rewards in smokers than non-smokers. We performed this study to determine whether those differences in intertemporal choice are due to pharmacological effects of nicotine and to track related brain regions. Thirty-three non-smokers and 27 nicotine-dependent smokers underwent functional magnetic resonance imaging while performing an intertemporal choice task consisting of 40 sets of monetary reward options that varied by delay to delivery. Smokers were investigated in a state of nicotine satiation. Non-smokers were investigated twice, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Smokers displayed steeper temporal discounting than non-smokers. Those behavioural differences were reflected in the brain response during the decision between two alternative money/time pairs: smokers showed less activation in parietal and occipital areas (e.g. precuneus) than non-smokers under placebo. A single dose of nicotine in non-smokers led to a similar effect on brain activation but did not impact behaviour. Processing of the reward magnitude of money/time pairs differed between smokers and non-smokers: smokers showed decreased reactivity of the ventral striatum. Moreover, there was an acute nicotine effect in non-smokers on processing of the reward magnitude: nicotine increased the correlation of blood oxygen level-dependent response and mean amount in the left hippocampus, amygdala and anterior insula. We conclude that cross-sectional differences between smokers and non-smokers are only, in part, due to the acute pharmacological effects of nicotine. Longitudinal studies are needed to investigate pre-drug group characteristics as well as consequences of smoking on discounting behaviour and its neural correlates. [ABSTRACT FROM AUTHOR]

Working memory ( WM) impairments are often observed in alcohol-dependent individuals, especially in early abstinence, which may contribute to an increased relapse risk after detoxification. Brain imaging studies on visuospatial WM in alcohol-dependent patients compared to controls indicate that information processing requires compensatory increased neural activation to perform at a normal level. However, to date, no study tested whether such increased neural WM activation patterns or the lack thereof predict relapse behavior in alcohol-dependent individuals, and whether such differences persist when adequately correcting for individual grey matter differences. We combined analyses of neural activation during an n-back task and local grey matter volumes using Biological Parametric Mapping in 40 detoxified alcohol-dependent patients and 40 matched healthy controls ( HC), and assessed prospective relapse risk during a 7-month follow-up period. Despite equal task performance, we found increased functional activation during high versus low cognitive WM load ( 2-back-0-back) in bilateral rostral prefrontal cortex ( BA10) and bilateral ventrolateral prefrontal cortex ( BA45,47) in prospective abstainers versus relapsers, and further in left/right lateral/medial premotor cortex ( BA6,8) in abstainers versus HC. In prospective abstainers, but not relapsers, subtle cognitive impairment was associated with increased neural task activity in the premotor cortex. These findings suggest that in prospective abstainers, higher functional engagement of presumably less impaired neural resources in executive behavioral control brain areas ( BA10, 45, 47, 6, 8) may constitute a resilience factor associated with good treatment outcome. [ABSTRACT FROM AUTHOR]

Mast cells are abundantly situated at contact sites between the body and its environment, such as the skin and, especially during certain immune responses, at mucosal surfaces. They mediate allergic reactions and degrade toxins as well as venoms. However, their roles during innate and adaptive immune responses remain controversial and it is likely that major functions remain to be discovered. Recent developments in mast cell-specific conditional gene targeting in the mouse promise to enhance our understanding of these fascinating cells. To complete the genetic toolbox to study mast cell development, homeostasis and function, it is imperative to inducibly manipulate their gene expression. Here, we report the generation of a novel knock-in mouse line expressing a tamoxifen-inducible version of the Cre recombinase from within the endogenous c- Kit locus. We demonstrate highly efficient and specific inducible expression of a fluorescent reporter protein in mast cells both in vivo and in vitro. Furthermore, induction of diphtheria toxin A expression allowed selective and efficient ablation of mast cells at various anatomical locations, while other hematopoietic cells remain unaffected. This novel mouse strain will hence be very valuable to study mast cell homeostasis and how specific genes influence their functions in physiology and pathology. [ABSTRACT FROM AUTHOR]

Background The development and maintenance of alcohol use disorders ( AUD) have been hypothesized to be associated with an imbalance of glutamate (GLU) homeostasis. White matter ( WM) loss, especially in anterior brain regions, has been reported in alcohol dependence, which may involve disturbances in both myelin and axonal integrity. Frontal lobe dysfunction plays an important role in addiction, because it is suggested to be associated with the loss of control over substance use. This study investigated magnetic resonance spectroscopy (MRS)-detectable Glu levels in frontal WM of non-treatment-seeking heavy drinkers and its associations with AUD symptoms. Methods Single-voxel MR spectra optimized for Glu assessment ( TE 80 ms) were acquired at 3 T from a frontal WM voxel in a group of heavy drinking, non-treatment-seeking subjects in comparison with a group of subjects with only light alcohol consumption. Results The results corroborate previous findings of increased total choline in heavy drinking subjects. A negative association of Glu levels with severity of alcohol dependence and especially loss of control over time and amount of alcohol intake was observed. Conclusions In contrast to the rather unspecific rise in choline-containing compounds, low Glu in frontal WM may be specific for the shift from nondependent heavy drinking to dependence and does not reflect a simple effect of the amount of alcohol consumption alone. [ABSTRACT FROM AUTHOR]

Overweight and obesity pose serious challenges to public health and are promoted by our food-rich environment. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to food cues after overnight fasting and following a standardized caloric intake (i.e., a 75 g oral glucose tolerance test, OGTT) in 26 participants (body mass index, BMI between 18.5 and 24.9 kg m−2). They viewed pictures of palatable food and low-level control stimuli in a block design and rated their current appetite after each block. Compared to control pictures, food pictures activated a large bilateral network typically involved in homeostatically and hedonically motivated food processing. Glucose ingestion was followed by decreased activation in the basal ganglia and paralimbic regions and increased activation in parietal and occipital regions. Plasma level increases in insulin correlated with cue-induced appetite at the neural and behavioral level. High insulin increases were associated with reduced activation in various bilateral regions including the fusiform gyrus, the superior temporal gyrus, the medial frontal gyrus, and the limbic system in the right hemisphere. In addition, they were accompanied by lower subjective appetite ratings following food pictures and modulated the neural response associated with it (e.g., in the fusiform gyrus). We conclude that individual insulin reactivity is critical to reduce food-cue responsivity after an initial energy intake and thereby may help to counteract overeating. Hum Brain Mapp 34:2367-2380, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent ( BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis ( n = 848) and a functional magnetic resonance imaging ( fMRI) task ( n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory- Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task ( SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level. [ABSTRACT FROM AUTHOR]

Objectives Bipolar disorder is a severe mood disorder, which normally begins during adolescence or early adulthood and has a heritability of up to 80%. The largest genome-wide association analysis of bipolar disorder recently identified a new genome-wide associated variant in OZD4 (rs12576775). The aim of the present study was to further elucidate the role of this risk variant in the disease process using an imaging genetics approach. As increased amygdala and striatal responses during the processing of reward and emotion are characteristic for bipolar disorder patients, it was tested whether the risk variant has an influence on this endophenotype in healthy adolescents. Methods We examined the impact of the risk variant rs12576775 on functional magnetic resonance imaging data in an adolescent sample (N = 485). Differential activation between carriers of the risk allele (G-allele) and homozygous A-allele carriers in the amygdala and the striatum during a modification of the monetary incentive delay task (examining reward) and a face task (examining emotion) was analyzed. Results Carriers of the risk allele showed an increased blood oxygen level-dependent response in the amygdala during reward sensitivity (p = 0.05) and reward expectation (p < 0.05) but not during the face task. No significant group differences were found in the striatum during both reward and emotion processing. Conclusion Our results indicate that the ODZ4 risk variant influences reward processing in the amygdala. Alterations in the processing of emotion may have different underlying mechanisms and need to be further examined. [ABSTRACT FROM AUTHOR]

ABSTRACT Alcohol-associated cues are able to elicit brain activations in mesocorticolimbic networks that are related to the rewarding properties of the drug. Some authors hypothesize that the activation of the mesocorticolimbic reward system triggers an attention allocation to alcohol-associated cues. Yet, no functional magnetic resonance imaging (fMRI) studies examining this proposition are available. In this fMRI study we investigate the association between attentional bias and neural cue reactivity. Thirty-eight recently abstinent alcohol-dependent patients were examined. fMRI was used to study cue reactivity during the presentation of alcohol-related pictures. A modified visual dot-probe task was used to assess attentional bias. Alcohol-dependent patients showed an attentional bias to alcohol-associated cues as well as cue-induced fMRI activation in response to alcohol-related stimuli in limbic and reward-related brain regions and visual areas. We found a positive correlation between cue-induced brain activation and attentional bias score in a network including frontal, temporal and subcortical regions. This study is the first demonstrating that, in line with previous suggestions, cue induced activation of the mesocorticolimbic reward system triggers focusing attention to substance-associated cues. However, this association could also be bidirectional with the attentional bias enhancing cue-induced neural activity. [ABSTRACT FROM AUTHOR]

ABSTRACT Pre-clinical research indicates that opioids reduce extracellular glutamate in acute opioid treatment, whereas during withdrawal, glutamatergic neurotransmission is increased and withdrawal symptoms can be blocked by glutamate receptor antagonists. The glutamate hypothesis of addiction suggests that withdrawal-associated hyperglutamatergic states destabilize the glutamatergic system chronically and contribute to relapse. magnetic resonance spectroscopy at three tesla optimized for glutamate assessment (TE 80 ms) was performed in the anterior cingulate gyrus (ACC) and frontal white matter (fWM) of 17 opiate-dependent patients during opiate maintenance therapy and 20 healthy controls. Controlling for age and gray matter content, glutamate in the ACC was positively associated with the number of previous withdrawals. For glutamate + glutamine (Glx), a significant group-age interaction was found. Whereas Glx declines with age in healthy controls, Glx increases with age in opiate-dependent patients. The number of previous withdrawals did not correlate with age. In fWM spectra, increased Cho concentrations were observed in opiate-dependent patients. Both new findings, the positive correlation of glutamate and previous withdrawals and increasing Glx with age in contrast to an age-dependent Glx decrease in controls indicate a destabilization of the glutamate system in opiate-dependent patients and support the glutamate hypothesis of addiction. Increased Cho concentrations in fWM corroborate findings of WM abnormalities in opioid-dependent subjects. [ABSTRACT FROM AUTHOR]

Brief contact of the duodenal mucosa with luminal acid elicits a long-lasting bicarbonate (Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed.) secretory response, which is believed to be the primary protective mechanism against mucosal damage. Here, we show that cGMP-dependent protein kinase type I-knockout (cGKI-/-) mice are unable to respond to a physiological H stimulus with a Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. secretory response and spontaneously develop duodenal ulcerations. Smooth muscle-selective cGKI knock-in rescued the motility disturbance but not the defective Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. secretion. Proton-induced Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. secretion was not attenuated by selective inactivation of the cGKI gene in interstitial cells of Cajal or in enterocytes, but was abolished by inactivation of cGKI in neurons (ncGKI-/-). cGKI was expressed in the brainstem nucleus tractus solitarius that connects the afferent with the efferent N. vagus. Accordingly, truncation of the subdiaphragmal N. vagus significantly diminished proton-induced Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. secretion in wild-type mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar Due to image rights restrictions, multiple line equation(s) cannot be graphically displayed. secretory response in cGKI-/-, ncGKI-/- and wild-type mice. These findings show that protection of the duodenum from acid injury requires neuronal cGKI. [ABSTRACT FROM AUTHOR]

Alcohol is a common cause of hepatic liver injury with steatosis and fibrosis. Cannabinoid receptors (CB) modulate steatosis, inflammation and fibrogenesis. To investigate the differences between CB and CB in the hepatic response to chronic alcohol intake, we examined CB knockout mice (CB, CB). Eight- to 10-week-old CB, CB and wild-type mice received 16% ethanol for 35 weeks. Animals receiving water served as controls. We analysed triglyceride and hydroxyproline contents in liver homogenates. mRNA levels of CBs, pro-inflammatory cytokines [tumour necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1β] and profibrotic factors [α-smooth muscle actin (α-SMA), procollagen-Ia, platelet-derived growth factor β receptor (PDGFβ-R)] were analysed by reverse transcription-polymerase chain reaction (RT-PCR). Histology (hemalaun and eosin, oil-red O, CD3, CD45R, CD45, F4/80, Sirius red) characterized hepatic steatosis, inflammation and fibrosis. Activation of lipogenic pathways, activation and proliferation of hepatic stellate cell (HSC) were assessed by western blot [fatty acid synthase (FAS), sterol regulatory element binding protein 1c (SREBP-1c), α-SMA, proliferating cell nuclear antigen (PCNA), cathepsin D]. Hepatic mRNA levels of the respective CBs were increased in wild-type animals and in CB mice after ethanol intake. Ethanol intake in CB mice induced much higher steatosis (SREBP-1c mediated) and inflammation (B-cell predominant infiltrates) compared with wild-type animals and CB mice. HSC activation and collagen production were increased in all groups after forced ethanol intake, being most pronounced in CB mice and least pronounced in CB mice. The fact that CB receptor knockout mice exhibited the most pronounced liver damage after ethanol challenge indicates a protective role of CB receptor expression in chronic ethanol intake. By contrast, in CB knockouts, the effect of ethanol was attenuated, suggesting aggravation of fibrogenesis and SREBP-1c-mediated steatosis via CB receptor expression after ethanol intake. [ABSTRACT FROM AUTHOR]

Studies in smokers suggest that nicotine might exert anxiolytic, stress-dampening and mood-enhancing effects and beneficially influences neural processing of affective information. Regarding non-smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non-smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event-related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non-smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala-pACC circuit. Besides the possibility that reactions to nicotine may differ between non-smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non-smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity. [ABSTRACT FROM AUTHOR]

Smoking-related cues elicit craving and mesocorticolimbic brain activation in smokers. Severity of nicotine dependence seems to moderate cue reactivity, but the direction and mechanisms of its influence remains unclear. Although tobacco control policies demand a ban on tobacco advertising, cue reactivity studies in smokers so far have not employed tobacco advertisement as experimental stimuli. We investigated whether tobacco advertisement elicits cue reactivity at a behavioral (subjective craving) and a neural level (using functional magnetic resonance imaging) in 22 smokers and 21 never-smokers. Moreover, we studied the influence of severity of dependence on cue reactivity. In smokers, tobacco advertisement elicited substantially more craving than control advertisement whereas never-smokers reported no cue induced craving. Surprisingly, neuronal cue reactivity did not differ between smokers and never-smokers. Moderately dependent smokers' craving increased over the course of the experiment, whereas highly dependent smokers' craving was unaffected. Moderately dependent smokers' brain activity elicited by tobacco advertisement was higher in the amygdala, hippocampus, putamen and thalamus compared with highly dependent smokers. Furthermore, limbic brain activation predicted picture recognition rates after the scanning session, even in never-smokers. Our findings show that tobacco advertisement elicits cigarette craving and neuronal cue reactivity primarily in moderately dependent smokers, indicating that they might be particularly responsive towards external smoking-related cues. On the other hand, neuronal cue reactivity and cigarette craving in highly dependent smokers is more likely triggered by internal cues such as withdrawal symptoms. Tobacco advertisement seems to likewise appeal to smokers and non-smokers, clarifying the potential danger especially for young non-smokers. [ABSTRACT FROM AUTHOR]

Aims During the development of drug addiction, initial hedonic effects decrease when substance use becomes habitual and ultimately compulsive. Animal research suggests that these changes are represented by a transition from prefrontal cortical control to subcortical striatal control and within the striatum from ventral to dorsal domains of the striatum, but only limited evidence exists in humans. In this study we address this hypothesis in the context of alcohol dependence. Design, setting and participants Non-abstinent heavy social drinkers ( n = 21, 5.0 ± 1.5 drinks/day, 13 of them were alcohol-dependent according to DSM-IV) and light social drinkers ( n = 10, 0.4 ± 0.4 drinks/day) were examined. Measurements We used a cue-reactivity functional magnetic resonance imaging (fMRI) design during which pictures of alcoholic beverages and neutral control stimuli were presented. Findings In the dorsal striatum heavy drinkers showed significant higher activations compared to light drinkers, whereas light social drinkers showed higher cue-induced fMRI activations in the ventral striatum and in prefrontal areas compared to heavy social drinkers [region of interest analyses, P < 0.05 false discovery rate (FDR)-corrected]. Correspondingly, ventral striatal activation in heavy drinkers correlated negatively with obsessive-compulsive craving, and furthermore we found a positive association between cue-induced activation in the dorsal striatum and obsessive-compulsive craving in all participants. Conclusions In line with our hypothesis we found higher cue-induced activation of the ventral striatum in social compared to heavy drinkers, and higher dorsal striatal activation in heavy drinkers. Increased prefrontal activation may indicate that social drinkers activate cortical control when viewing alcohol cues, which may prevent the development of heavy drinking or alcohol dependence. Our results suggest differentiating treatment research depending on whether alcohol use is hedonic or compulsive. [ABSTRACT FROM AUTHOR]

Dopamine (DA) modulates the response of the amygdala. However, the relation between dopaminergic neurotransmission in striatal and extrastriatal brain regions and amygdala reactivity to affective stimuli has not yet been established. To address this issue, we measured DA D2/D3 receptor (DRD2/3) availability in twenty-eight healthy men (nicotine-dependent smokers and never-smokers) using positron emission tomography with [18F]fallypride. In the same group of participants, amygdala response to unpleasant visual stimuli was determined using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The effects of DRD2/3 availability in emotion-related brain regions and nicotine dependence on amygdala response to unpleasant stimuli were examined by multiple regression analysis. We observed enhanced prefrontal DRD2/3 availability in those individuals with higher amygdala response to unpleasant stimuli. As compared to never-smokers, smokers showed an attenuated amygdala BOLD response to unpleasant stimuli. Thus, individuals with high prefrontal DRD2/3 availability may be more responsive toward aversive and stressful information. Through this mechanism, dopaminergic neurotransmission might influence vulnerability for affective and anxiety disorders. Neuronal reactivity to unpleasant stimuli seems to be reduced by smoking. This observation could explain increased smoking rates in individuals with mental disorders. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Activation of the anterior cingulate cortex (ACC) in a spatial working memory task has been associated with risk factors for alcohol use disorders such as low alcohol effects and positive alcohol expectations in adolescents. To transfer these results into adults, we used the same task in adults. Methods: During functional magnetic resonance imaging, 12 light social, 7 heavy social, and 11 non-abstinent-dependent alcohol drinkers performed a spatial working memory task and completed measures of automatic alcohol-related thoughts and behavior (Obsessive–Compulsive Drinking Scale—OCDS), alcohol use of the last 90 days, and general intelligence. Results: Behavioral performance in the spatial working memory task was not significantly different in all 3 groups. Controlling for differences in general intelligence alcohol-dependent participants showed a higher task-related activation of the dorsal ACC (dACC) in comparison with light and heavy social drinkers. Measures of the OCDS were positively correlated with the activation in the left hippocampus and right thalamus in all participants. Conclusions: Our results support the findings of increased dACC activation during a spatial working memory task as a risk factor for alcohol dependence. Increased task-related activation in the dACC was only observed in alcohol-dependent participants and not in heavy social drinkers with comparable alcohol consumption. Furthermore, the absence of behavioral performance differences between groups as well as an association between dACC activation and working memory performance indicates subtle working memory deficits. Low capacity of working memory has been linked to more automatic and less self-regulated behavior in studies on natural reward processing. Therefore, additional neural activation during performance of the non-alcohol-related working memory task in participants with higher OCDS values in the left hippocampus and the right thalamus may be a consequence of decreased neural capacity because of distracting alcohol-related thoughts. [ABSTRACT FROM AUTHOR]

It has been suggested that the attention towards alcohol-related stimuli increases with the duration of drinking and alcohol dependence. The present study aimed to assess whether an attentional bias was present in detoxified alcohol-dependent patients, and if the magnitude of the attentional bias depended on the subject's drinking history and variables of executive functioning. Attentional bias was assessed in 30 alcohol-dependent patients using a visual dot-probe task with a picture presentation time of 50 ms. In addition, patients completed a variety of different cognitive tasks such as attention, continuous performance, working memory, set shifting and inhibitory control tests. Based on correlation analysis we split the patient sample on the median with regard to the duration of alcohol dependence and our results indicated a significant attentional bias towards alcohol-associated pictures in patients dependent for less than 9 years, but not in patients with a longer duration of dependence. The two patient samples differed significantly with regard to attention and working memory functioning with patients who were dependent for more than 9 years showing a greater impairment. When impairment of attention and working memory were controlled for, the group differences in attentional bias were no longer significant. Our results indicate that differences with regard to drinking-related variables as well as cognitive functioning seem to modulate attentional bias and need to be taken into account in models of drinking maintenance. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption is associated with neural damage that manifests in deficits in information processing. Previous studies evaluated higher cognitive functions such as working memory, but basic sensory information processing circuits have never been investigated before. Therefore, we applied a simple visual and acoustic stimulation paradigm in this functional magnetic resonance imaging (fMRI) pilot study. Nine recently detoxified male alcohol-dependent patients and nine healthy volunteers were presented a well-established 6-Hz checkerboard and auditory stimuli in the form of drumbeats in a block-design fMRI paradigm. During visual and acoustic stimulation, alcoholics and controls activated widespread occipital and temporal brain areas, as well as parts of the dorsolateral prefrontal cortex and thalamus. In a comparison of the stimulation-induced activation of alcoholics and controls, the alcoholics showed a significantly lower blood oxygen level dependent (BOLD) signal in an extended bilateral occipital area ( P < 0.001) as compared with healthy controls. In no region was the BOLD signal significantly higher in the alcohol-dependent subjects compared with controls. The reason for the new finding of a highly significant lower activation of the occipital cortex is unclear. It is in line with studies of neuropsychological tests in recently detoxified alcohol-dependent patients that also reported deficits in visual abilities. Attention deficits or a persisting neuronal alteration in the first weeks of alcohol abstinence may have contributed to this result. [ABSTRACT FROM AUTHOR]

Background: Once alcohol dependence is established, alcohol-associated cues may induce dopamine release in the reward system, which is accompanied by alcohol craving and may lead to relapse. In cocaine addicts, dopamine release in the thalamus was positively correlated with cocaine craving. We tested the effects of the atypical dopamine D2/3 blocker amisulpride on cue-induced brain activation in a functional magnetic resonance imaging (fMRI) paradigm. Methods: Alcohol-associated and neutral pictures were presented in a block design to 10 male abstinent alcoholics (1–3 weeks after detoxification) and 10 healthy men during fMRI. The fMRI scans were acquired before and 2 hours after the oral application of 400 mg amisulpride. Before and after each scan, alcohol craving was measured with visual analogue scales. Results: Before the application of amisulpride, alcohol versus control cues elicited a higher blood oxygen level–dependent (BOLD) signal in the left frontal and orbitofrontal lobe, left cingulate gyrus, bilateral parietal lobe, and bilateral hippocampus in alcoholics compared with healthy controls. After amisulpride, alcoholics showed a reduced activation in the right thalamus compared with the first scan. Alcoholics no longer showed significant differences in their cue-elicited BOLD response after amisulpride medication compared with medication-free controls. Self-reported craving was not affected by amisulpride medication. Conclusions: Amisulpride medication was associated with reduced cue-induced activation of the thalamus, a brain region closely connected with frontostriatal circuits that regulate behavior and may influence relapse risk. [ABSTRACT FROM AUTHOR]

Candida glabrata has emerged as one of the most common causes of candidosis. In order to identify factors that are necessary for viability and pathogenicity of this fungal pathogen, we analysed the role of the KEX2 gene, which codes for a regulatory endoproteinase that is known to process certain virulence factors in Candida albicans. The KEX2 gene from C. glabrata was cloned and found to have 51% and 62% identity and high structural similarities to the homologous counterparts in C. albicans and Saccharomyces cerevisiae. KEX2 was expressed at all time points investigated during growth in complex medium. In order to investigate the role of this putative regulatory proteinase, Kex2-deficient mutants were produced. In addition to known kex2 phenotypes, such as pH and calcium hypersensitivity, the mutants grew in cellular aggregates and were found to be hypersensitive to several antifungal drugs that target the cell membrane, including azoles, amorolfine and amphotericin B. Ultrastructural investigation after exposure to low doses of itraconazole showed azole-specific alterations such as enlarged vacuoles and proliferation of the cytoplasmatic membrane in the kex2 mutants, but not in the control strains. In contrast, antifungals such as 5-flucytosine and hydroxypyridones inhibited growth of the kex2 mutants and the control strains to the same extent. In an in vitro model of oral candidosis, kex2 mutants showed reduced tissue damage in the presence of itraconazole compared with the control infections. These data suggest that Kex2 is involved in the processing of proteins that are essential for cell surface integrity of C. glabrata. [ABSTRACT FROM AUTHOR]