The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans.

Ubiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naive Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared with wild-type flies. In contrast to wild-type flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G allele of single nucleotide polymorphism (SNP) rs13265422 in PSD3, as well as a haplotype containing rs13265422, was associated with an increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging revealed that the same PSD3 haplotype was also associated with a differential functional magnetic resonance imaging signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis, therefore, suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.

EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction.

In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with ß-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.

Combined universal and selective prevention for adolescent alcohol use: a cluster randomized controlled trial.

BACKGROUND: No existing models of alcohol prevention concurrently adopt universal and selective approaches. This study aims to evaluate the first combined universal and selective approach to alcohol prevention. METHOD: A total of 26 Australian schools with 2190 students (mean age: 13.3 years) were randomized to receive: universal prevention (Climate Schools); selective prevention (Preventure); combined prevention (Climate Schools and Preventure; CAP); or health education as usual (control). Primary outcomes were alcohol use, binge drinking and alcohol-related harms at 6, 12 and 24 months. RESULTS: Climate, Preventure and CAP students demonstrated significantly lower growth in their likelihood to drink and binge drink, relative to controls over 24 months. Preventure students displayed significantly lower growth in their likelihood to experience alcohol harms, relative to controls. While adolescents in both the CAP and Climate groups demonstrated slower growth in drinking compared with adolescents in the control group over the 2-year study period, CAP adolescents demonstrated faster growth in drinking compared with Climate adolescents. CONCLUSIONS: Findings support universal, selective and combined approaches to alcohol prevention. Particularly novel are the findings of no advantage of the combined approach over universal or selective prevention alone.

The structure of adolescent psychopathology: a symptom-level analysis.

BACKGROUND: Most empirical studies into the covariance structure of psychopathology have been confined to adults. This work is not developmentally informed as the meaning, age-of-onset, persistence and expression of disorders differ across the lifespan. This study investigates the underlying structure of adolescent psychopathology and associations between the psychopathological dimensions and sex and personality risk profiles for substance misuse and mental health problems. METHOD: This study analyzed data from 2175 adolescents aged 13.3 years. Five dimensional models were tested using confirmatory factor analysis and the external validity was examined using a multiple-indicators multiple-causes model. RESULTS: A modified bifactor model, with three correlated specific factors (internalizing, externalizing, thought disorder) and one general psychopathology factor, provided the best fit to the data. Females reported higher mean levels of internalizing, and males reported higher mean levels of externalizing. No significant sex differences emerged in liability to thought disorder or general psychopathology. Liability to internalizing, externalizing, thought disorder and general psychopathology was characterized by a number of differences in personality profiles. CONCLUSIONS: This study is the first to identify a bifactor model including a specific thought disorder factor. The findings highlight the utility of transdiagnostic treatment approaches and the importance of restructuring psychopathology in an empirically based manner.

Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Effectiveness of a brief school-based intervention on depression, anxiety, hyperactivity, and delinquency: a cluster randomized controlled trial.

Problematic substance use and mental health problems often co-occur in adolescents. Effective school-based interventions that are brief and target multiple problems are promising in the field of health promotion. Preventure is a brief, school-based, selective preventive intervention, tailored to four personality profiles. Preventure has already proved effective on alcohol outcomes. Previous trials also reveal effects on several mental health outcomes, yet the evidence for these outcomes is limited. This study presents the results of the Dutch Preventure Trial, on a range of mental health outcomes. In a cluster RCT, including 699 high risk students (mean age 14 years), the intervention effects on mental health problems at 2, 6, and 12 months post intervention were tested in the total high risk population and in four specific personality groups. No significant intervention effects were found on 22 from the 24 tests. A positive intervention effect on anxiety was found in the anxiety sensitivity personality group at 12-month follow-up, and a negative intervention effect on depression was found at 12-month follow-up in the negative thinking group. In post hoc growth curve analyses these effects were not found. This study found no convincing evidence for the effectiveness of Preventure in The Netherlands on mental health problems. This finding is not in line with the results of an earlier effectiveness study in the UK. This highlights the need for more research into the knowledge transfer model of interventions, to ensure that interventions are effective in a variety of circumstances.

Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence.

Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder).

Developmental trajectories of psychotic-like experiences across adolescence: impact of victimization and substance use.

BACKGROUND: Research suggests that psychotic-like experiences (PLEs) in the general population are common, but can reflect either transitory or persistent developmental phenomena. Using a general adolescent population it was examined whether different developmental subtypes of PLEs exist and whether different trajectories of PLEs are associated with certain environmental risk factors, such as victimization and substance use. METHOD: Self-reported PLEs were collected from 409 adolescents (mean age 14 years 7 months) at four time points, each 6 months apart. General growth mixture modelling was utilized to identify classes of adolescents who followed distinct trajectories of PLEs across this period. Predictors of class membership included demographics, personality, victimization, depression, anxiety and substance use. RESULTS: We identified the following three developmental subgroups of PLEs: (1) persistent; (2) increasing; (3) low. Adolescents on the persistent trajectory reported frequent victimization and consistent elevated scores in depression and anxiety. Adolescents on the increasing trajectory were engaging in cigarette use prior to any increases in PLEs and were engaging in cocaine, cannabis and other drug use as PLEs increased at later time points. CONCLUSIONS: The findings suggest that different developmental subgroups of PLEs exist in adolescence and are differentially related to victimization and substance use.

The IMAGEN study: reinforcement-related behaviour in normal brain function and psychopathology.

A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional reactivity, and determining their predictive value for the development of frequent psychiatric disorders. Comprehensive behavioural and neuropsychological characterization, functional and structural neuroimaging and genome-wide association analyses of 2000 14-year-old adolescents are combined with functional genetics in animal and human models. Results will be validated in 1000 adolescents from the Canadian Saguenay Youth Study. The sample will be followed up longitudinally at the age of 16 years to investigate the predictive value of genetics and intermediate phenotypes for the development of frequent psychiatric disorders. This review describes the strategies the IMAGEN consortium used to meet the challenges posed by large-scale multicentre imaging-genomics investigations. We provide detailed methods and Standard Operating Procedures that we hope will be helpful for the design of future studies. These include standardization of the clinical, psychometric and neuroimaging-acquisition protocols, development of a central database for efficient analyses of large multimodal data sets and new analytic approaches to large-scale genetic neuroimaging analyses.

Specificity of personality relationships to particular forms of concurrent substance use among methadone maintenance therapy clients.

OBJECTIVE: A mainstay treatment for opioid addiction in North America is methadone maintenance therapy (MMT) - a form of opiate agonist therapy (OAT). While efficacious for treating opioid addiction, MMT fails to address the concurrent polysubstance use that is common among opioid dependent clients. Moreover, psychosocial approaches for addressing polysubstance use during MMT are lacking. Our study's goals were to validate the use of the four-factor personality model of substance use vulnerability in MMT clients, and to demonstrate theoretically-relevant relationships of personality to concurrent substance use while receiving MMT. METHOD: Respondents included 138 daily-witnessed MMT clients (65.9% male, 79.7% Caucasian), mean age (SD) 40.18 (11.56), recruited across four Canadian MMT clinics. Bayesian confirmatory factor analysis was used to establish the structural validity of the four-factor personality model of substance use vulnerability (operationalized with the Substance Use Risk Profile Scale [SURPS]) in MMT clients. SURPS personality scores were then used as predictors for specific forms of recent (past 30-day) substance use. RESULTS: Using a latent hierarchal model, hopelessness was associated with recent opioid use; anxiety sensitivity with recent tranquilizer use; and sensation seeking with recent alcohol, cannabis, and stimulant use. CONCLUSION: Personality is associated with substance use patterns and may be an appropriate target for intervention for those undergoing MMT to reduce opioid use, and potentially dangerous concurrent use of other drugs, while receiving methadone.

Disentangling the autism-anxiety overlap: fMRI of reward processing in a community-based longitudinal study.

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.

BDNF Val66Met and reward-related brain function in adolescents: role for early alcohol consumption.

Changes in reward processing have been identified as one important pathogenetic mechanism in alcohol addiction. The nonsynonymous single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene (rs6265/Val66Met) modulates the central nervous system activity of neurotransmitters involved in reward processing such as serotonin, dopamine, and glutamate. It was identified as crucial for alcohol consumption in healthy adults and, in rats, specifically related to the function in the striatum, a region that is commonly involved in reward processing. However, studies in humans on the association of BDNF Val66Met and reward-related brain functions and its role for alcohol consumption, a significant predictor of later alcohol addiction, are missing. Based on an intermediate phenotype approach, we assessed the early orientation toward alcohol and alcohol consumption in 530 healthy adolescents that underwent a monetary incentive delay task during functional magnetic resonance imaging. We found a significantly lower response in the putamen to reward anticipation in adolescent Met carriers with high versus low levels of alcohol consumption. During reward feedback, Met carriers with low putamen reactivity were significantly more likely to orient toward alcohol and to drink alcohol 2 years later. This study indicates a possible effect of BDNF Val66Met on alcohol addiction-related phenotypes in adolescence.

Reliability and validity of alcohol-induced heart rate increase as a measure of sensitivity to the stimulant properties of alcohol.

RATIONALE: Alcohol-induced heart rate (HR) stimulation during the rising limb of the blood alcohol curve reliably discriminates between individuals at differential risk for alcoholism, and appears to be a potential psychophysiological index of psychomotor stimulation from alcohol. OBJECTIVES: Three studies are presented which explore the reliability and convergent and discriminant validity of this alcohol response index. METHODS: Young men with and without a multigenerational family history of alcoholism were administered a 1.0 ml/kg dose of 95% USP alcohol. Resting baseline cardiac and subjective measures were assessed before and after alcohol consumption. RESULTS: Study 1 demonstrated that alcohol-induced HR stimulation was significantly and positively related to alcohol-induced changes in mood. Study 2 demonstrated that alcohol-induced HR stimulation was reliable across two alcohol administration sessions (r=0.33-0.66, P<0.01). Study 3 explored the relationship between the proposed index and measures of sensitivity to alcohol previously linked to genetic predisposition to alcoholism. Multiple regression analysis indicated that alcohol-induced HR increase and reduced subjective intoxication (measured using the Subjective High Assessment Scale) were both positively associated with alcohol-induced changes in mood states that have previously been shown to be sensitive to the effects of stimulant drugs and the reinforcing effects of alcohol. CONCLUSIONS: Sensitivity to alcohol-induced heart-rate stimulation during the ascending limb of the blood alcohol curve may be a useful and informative marker for understanding susceptibility to alcoholism.

Validation of a system of classifying female substance abusers on the basis of personality and motivational risk factors for substance abuse.

This study explored the validity of classifying a community-recruited sample of substance-abusing women (N = 293) according to 4 personality risk factors for substance abuse (anxiety sensitivity, introversion-hopelessness, sensation seeking, and impulsivity). Cluster analyses reliably identified 5 subtypes of women who demonstrated differential lifetime risk for various addictive and nonaddictive disorders. An anxiety-sensitive subtype demonstrated greater lifetime risk for anxiolytic dependence, somatization disorder, and simple phobia, whereas an introverted-hopeless subtype evidenced a greater lifetime risk for opioid dependence, social phobia, and panic and depressive disorders. Sensation seeking was associated with exclusive alcohol dependence, and impulsivity was associated with higher rates of antisocial personality disorder and cocaine and alcohol dependence. Finally, a low personality risk subtype demonstrated lower lifetime rates of substance dependence and psychopathology.

Efficacy of brief coping skills interventions that match different personality profiles of female substance abusers.

Female substance abusers recruited from the community were randomly assigned to receive 1 of 3 brief interventions that differentially targeted their personality and reasons for drug use. The 90-min interventions were: (a) a motivation-matched intervention involving personality-specific motivational and coping skills training, (b) a motivational control intervention involving a motivational film and a supportive discussion with a therapist, and (c) a motivation-mismatched intervention targeting a theoretically different personality profile. Assessment 6 months later (N = 198) indicated that only the matched intervention proved to be more effective than the motivational control intervention in reducing frequency and severity of problematic alcohol and drug use and preventing use of multiple medical services. These findings indicate promise for a client-treatment matching strategy that focuses on personality-specific motives for substance abuse.

Functional associations among trauma, PTSD, and substance-related disorders.

This review article presents several potential functional pathways which may explain the frequent co-occurrence of PTSD and substance abuse disorders in traumatized individuals. Emerging empirical studies which have examined these potential pathways are reviewed, including studies on relative order of onset, PTSD patients' perceptions of various drug effects, comparisons of PTSD patients with and without comorbid substance use disorders, and correlational studies examining the relations between severity of specific PTSD symptom clusters and substance disorder symptoms. Research on the acute and chronic effects of alcohol and other drugs on cognitive and physiological variables relevant to PTSD intrusion and arousal symptoms is reviewed to highlight ways in which these two sets of PTSD symptoms might be functionally interrelated with substance abuse. Finally, based on these findings, recommendations are made for the treatment of individuals with comorbid PTSD-substance use disorders.

Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents.

Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.

The neural basis of video gaming.

Video game playing is a frequent recreational activity. Previous studies have reported an involvement of dopamine-related ventral striatum. However, structural brain correlates of video game playing have not been investigated. On magnetic resonance imaging scans of 154 14-year-olds, we computed voxel-based morphometry to explore differences between frequent and infrequent video game players. Moreover, we assessed the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging and the Cambridge Gambling Task (CGT). We found higher left striatal grey matter volume when comparing frequent against infrequent video game players that was negatively correlated with deliberation time in CGT. Within the same region, we found an activity difference in MID task: frequent compared with infrequent video game players showed enhanced activity during feedback of loss compared with no loss. This activity was likewise negatively correlated with deliberation time. The association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity.

Autonomic reactivity and alcohol-induced dampening in men at risk for alcoholism and men at risk for hypertension.

Both sons of male alcoholics with multigenerational family history of male alcoholism (MFH) and sons of essential hypertensives (HTs) exhibit elevated psychophysiological reactivity to stress when compared with male controls (FH-). MFHs also demonstrate a significant baseline heart rate increase and stress-response dampening following alcohol consumption. The present study investigates the specificity of this alcohol-induced psychophysiological response pattern by testing these two risk groups in a shock response paradigm, both sober and alcohol-intoxicated. A repeated measures analysis of variance on sober and alcohol-intoxicated heart rate reactivity yielded a significant risk by alcohol interaction, indicating that alcohol consumption led to a greater decrease in reactivity in the MFH group compared with the HT and FH- groups. Similar results were obtained for muscle tension measures. MFHs also displayed greater increases in resting baseline heart rate and muscle tension when alcohol intoxicated. The results may reflect a sensitivity to negatively and positively reinforcing effects of alcohol specific to individuals with multigenerational familial histories of alcoholism.