Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

The long-term effectiveness of a personality-targeted substance use prevention program on aggression from adolescence to early adulthood.

BACKGROUND: Addressing aggressive behavior in adolescence is a key step toward preventing violence and associated social and economic costs in adulthood. This study examined the secondary effects of the personality-targeted substance use preventive program Preventure on aggressive behavior from ages 13 to 20. METHODS: In total, 339 young people from nine independent schools (M age = 13.03 years, s.d. = 0.47, range = 12-15) who rated highly on one of the four personality traits associated with increased substance use and other emotional/behavioral symptoms (i.e. impulsivity, anxiety sensitivity, sensation seeking, and negative thinking) were included in the analyses (n = 145 in Preventure, n = 194 in control). Self-report assessments were administered at baseline and follow-up (6 months, 1, 2, 3, 5.5, and 7 years). Overall aggression and subtypes of aggressive behaviors (proactive, reactive) were examined using multilevel mixed-effects analysis accounting for school-level clustering. RESULTS: Across the 7-year follow-up period, the average yearly reduction in the frequency of aggressive behaviors (b = -0.42; 95% confidence interval [CI] -0.64 to -0.20; p < 0.001), reactive aggression (b = -0.22; 95% CI 0.35 to -0.10; p = 0.001), and proactive aggression (b = -0.14; 95% CI -0.23 to -0.05; p = 0.002) was greater for the Preventure group compared to the control group. CONCLUSIONS: The study suggests a brief personality-targeted intervention may have long-term impacts on aggression among young people; however, this interpretation is limited by imbalance of sex ratios between study groups.

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: testing gene × environment moderation and mediation.

BACKGROUND: It has not yet been determined if the commonly reported cannabis-psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders. METHODS: We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort. RESULTS: PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects. CONCLUSIONS: These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.

The 3-year effects of a personality-targeted prevention program on general and specific dimensions of psychopathology.

This study aimed to examine the effect of a personality-targeted prevention program (Preventure) on trajectories of general and specific dimensions of psychopathology from early- to mid-adolescence. Australian adolescents (N = 2190) from 26 schools participated in a cluster randomized controlled substance use prevention trial. This study compared schools allocated to deliver Preventure (n = 13 schools; n = 466 students; Mage = 13.42 years), a personality-targeted selective intervention, with a control group (n = 7 schools; n = 235 students, Mage = 13.47 years). All participants were assessed for psychopathology symptoms at baseline, 6-, 12-, 24- and 36-months post-baseline. Outcomes were a general psychopathology factor and four specific factors: fear, distress, alcohol use/harms and conduct/inattention), extracted from a higher-order model. Participants who screened as 'high-risk' on at least one of four personality traits (negative thinking, anxiety sensitivity, impulsivity and sensation seeking) were included in intention-to-treat analyses. Intervention effects were examined using multi-level mixed models accounting for school-level clustering. Among high-risk adolescents, growth in general psychopathology was slower in the Preventure group compared to the control group (b = -0.07, p = 0.038) across the three years. After controlling for effects on general psychopathology, there were no significant, additional effects on the lower order factors. This study provides evidence for the effectiveness of a selective personality-targeted intervention in altering trajectories of general psychopathology during adolescence. This finding represents impacts on multiple symptom domains and highlights the potential for general psychopathology as an intervention target.

Personality-specific pathways from bullying victimization to adolescent alcohol use: a multilevel longitudinal moderated mediation analysis.

Bullying victimization is common in adolescence and has been associated with a broad variety of psychopathology and alcohol use. The present study assessed time-varying associations between bullying victimization and alcohol use through internalizing and externalizing symptoms and whether this indirect association throughout time is moderated by personality. This 5-year longitudinal study (3,800 grade 7 adolescents) used Bayesian multilevel moderated mediation models: independent variable was bullying victimization; moderators were four personality dimensions (anxiety sensitivity, hopelessness, impulsivity, and sensation seeking); internalizing symptoms (anxiety, depressive symptoms) and externalizing symptoms (conduct, hyperactivity problems) were the mediators; and alcohol use, the outcome. Results indicated significant between, within, and lagged effects on alcohol use through internalizing and externalizing symptoms. There were significant between and within effects on alcohol use through internalizing symptoms for adolescents with high anxiety sensitivity and hopelessness, and significant between, within, and lagged effects on alcohol use through externalizing symptoms for adolescents with high impulsivity and sensation seeking. These findings implicate two risk pathways that account for how bullying victimization enhances alcohol use risk and emphasize the importance of personality profiles that can shape the immediate and long-term consequences of victimization.

Do Anxiety Symptoms Mediate the Association Between Cannabis Use Frequency and Psychotic-Like Experiences in Emerging Adult Undergraduates?

OBJECTIVE: Cannabis is commonly used by Canadian emerging adults (ages 18-25 years), many of whom attend post-secondary institutions. Frequent cannabis use is linked with psychotic-like experiences (PLEs); however, the exact nature of this association remains unclear. Anxiety symptoms may mediate this association, as they are prevalent in emerging adults and have been independently linked with both cannabis use and PLEs. Past work found that anxiety mediated the association between cannabis use frequency and attenuated positive psychotic symptoms (further along the psychosis continuum than PLEs), however this research had yet to be validated in the Canadian population, and trait rather than state anxiety (frequency of anxiety symptoms) was studied. Thus, our primary objective was to examine if anxiety symptoms mediated the association between cannabis use frequency and PLEs in Canadian emerging adult undergraduates. Despite known sex differences in cannabis use, expression of anxiety, and PLEs, past work did not evaluate the potential impact of biological sex on the anxiety-mediated model, and thus is the secondary objective of the present study. METHODS: 1,266 first-/second-year emerging adult undergraduates from five Canadian universities provided cross-sectional, self-report survey data in fall 2021 semester. Validated measures of cannabis use frequency, anxiety, and PLEs were administered. RESULTS: Path analyses supported mediation from cannabis use to PLEs through anxiety (b = 0.07, P < 0.001, 95% bootstrap CI [0.03, 0.10]). No direct effect was found (P = 0.457), suggesting that the cannabis-to-PLEs association was mediated by anxiety. Mediation did not depend on biological sex (i.e., bootstrapped 95% CIs crossed zero). CONCLUSIONS: Anxiety symptoms mediated the association between cannabis use and PLEs in emerging adults regardless of their biological sex. Assuming replication in prospective research, results highlight anxiety as an important intervention target in frequent cannabis-using emerging adults, to potentially prevent development/worsening of PLEs, and in turn psychotic illness.

How do substance use disorders compare to other psychiatric conditions on structural brain abnormalities? A cross-disorder meta-analytic comparison using the ENIGMA consortium findings.

Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto-cerebellar and meso-cortico-limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions, and until recently there has been few large-scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case-control differences and to compare brain-correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta-analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age- and sex-matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case-control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co-variates . After correcting for multiple comparisons, AUD case-control meta-analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta-analysis of CUD case-control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross-disorder comparison of brain correlates of substance use disorders and showed alcohol-related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Neuropsychosocial profiles of current and future adolescent alcohol misusers.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Ventromedial Prefrontal Volume in Adolescence Predicts Hyperactive/Inattentive Symptoms in Adulthood.

Youths with attention-deficit/hyperactivity disorder symptomatology often exhibit residual inattention and/or hyperactivity in adulthood; however, this is not true for all individuals. We recently reported that dimensional, multi-informant ratings of hyperactive/inattentive symptoms are associated with ventromedial prefrontal cortex (vmPFC) structure. Herein, we investigate the degree to which vmPFC structure during adolescence predicts hyperactive/inattentive symptomatology at 5-year follow-up. Structural equation modeling was used to test the extent to which adolescent vmPFC volume predicts hyperactive/inattentive symptomatology 5 years later in early adulthood. 1104 participants (M = 14.52 years, standard deviation = 0.42; 583 females) possessed hyperactive/inattentive symptom data at 5-year follow-up, as well as quality controlled neuroimaging data and complete psychometric data at baseline. Self-reports of hyperactive/inattentive symptomatology were obtained during adolescence and at 5-year follow-up using the Strengths and Difficulties Questionnaire (SDQ). At baseline and 5-year follow-up, a hyperactive/inattentive latent variable was derived from items on the SDQ. Baseline vmPFC volume predicted adult hyperactive/inattentive symptomatology (standardized coefficient = -0.274, P < 0.001) while controlling for baseline hyperactive/inattentive symptomatology. These results are the first to reveal relations between adolescent brain structure and adult hyperactive/inattentive symptomatology, and suggest that early structural development of the vmPFC may be consequential for the subsequent expression of hyperactive/inattentive symptoms.

Evaluating the differential effectiveness of social influence and personality-targeted alcohol prevention on mental health outcomes among high-risk youth: A novel cluster randomised controlled factorial design trial.

OBJECTIVE: This study examined the secondary mental health outcomes of two contrasting alcohol prevention approaches, whereby one intervention targets common underlying personality risk for alcohol use and mental health problems (Preventure) and the other targets alcohol- and drug-related behaviours and cognitions (Climate Schools). METHODS: A 2 × 2 cluster randomised controlled factorial design trial was conducted in 26 Australian schools randomised to the following 4 conditions: Climate Schools (n = 6), Preventure (n = 7), combined Climate Schools and Preventure (CAP; n = 6) or treatment as usual (TAU; n = 7). Participants completed questionnaires at baseline, 6, 12, 24 and 36 months post-baseline including the Brief Symptom Inventory anxiety and depression scales and hyperactivity and conduct scales of the Strengths and Difficulties Questionnaire. Analyses focused on students who were at high-risk based on personality traits (n = 947; Mage = 13.3). The effectiveness of each approach in reducing symptoms of internalising and externalising problems was assessed using multi-level mixed effects analysis. RESULTS: Main effects for each intervention relative to not receiving that intervention revealed significant main effects of Preventure in reducing anxiety symptoms (d = -0.27, 95% confidence interval [CI] = [-0.53, -0.01], p < 0.05) and a marginal effect in reducing depressive symptoms (d = -0.24, 95% CI = [-0.49, 0.01], p = 0.06) over 3 years. Interaction effects revealed that when delivered alone, Preventure significantly reduced conduct problems (d = -0.45, 95% CI = [-0.78, -0.11], p < 0.05) and hyperactivity symptoms (d = -0.38, 95% CI = [-0.70,-0.07], p < 0.05) compared to TAU. CONCLUSION: This study is the first to report the effectiveness of personality-targeted alcohol prevention in reducing internalising and externalising symptoms relative to an active control, providing evidence in favour of its specificity in preventing concurrent substance use and mental health problems among high-risk youth.

The initiation of cannabis use in adolescence is predicted by sex-specific psychosocial and neurobiological features.

Cannabis use initiated during adolescence might precipitate negative consequences in adulthood. Thus, predicting adolescent cannabis use prior to any exposure will inform the aetiology of substance abuse by disentangling predictors from consequences of use. In this prediction study, data were drawn from the IMAGEN sample, a longitudinal study of adolescence. All selected participants (n = 1,581) were cannabis-naïve at age 14. Those reporting any cannabis use (out of six ordinal use levels) by age 16 were included in the outcome group (N = 365, males n = 207). Cannabis-naïve participants at age 14 and 16 were included in the comparison group (N = 1,216, males n = 538). Psychosocial, brain and genetic features were measured at age 14 prior to any exposure. Cross-validated regularized logistic regressions for each use level by sex were used to perform feature selection and obtain prediction error statistics on independent observations. Predictors were probed for sex- and drug-specificity using post-hoc logistic regressions. Models reliably predicted use as indicated by satisfactory prediction error statistics, and contained psychosocial features common to both sexes. However, males and females exhibited distinct brain predictors that failed to predict use in the opposite sex or predict binge drinking in independent samples of same-sex participants. Collapsed across sex, genetic variation on catecholamine and opioid receptors marginally predicted use. Using machine learning techniques applied to a large multimodal dataset, we identified a risk profile containing psychosocial and sex-specific brain prognostic markers, which were likely to precede and influence cannabis initiation.

The Effect of Contextual Risk Factors on the Effectiveness of Brief Personality-Targeted Interventions for Adolescent Alcohol Use and Misuse: A Cluster-Randomized Trial.

BACKGROUND: A range of school-based prevention programs has been developed and used to prevent, delay, or reduce alcohol use among adolescents. Most of these programs have been evaluated at the community-level impact. However, the effect of contextual risk factors has rarely been considered in the evaluation of these programs. The aim of this study was to investigate the potential moderating effects of 2 important contextual risk factors (i.e., socioeconomic status [SES] and peer victimization) on the effectiveness of the school-based personality-targeted interventions (Preventure program) in reducing adolescent alcohol use over a 2-year period using a cluster-randomized trial. METHODS: High-risk adolescents were identified using personality scores on the Substance Use Risk Profile Scale and randomized to intervention and control groups. Two 90-minute cognitive behavioral therapy-based group sessions targeted 1 of 4 personality risk profiles: Anxiety Sensitivity, Hopelessness, Impulsivity, or Sensation Seeking. Multilevel linear modeling of alcohol use, binge drinking, and drinking-related harm was conducted to assess the moderating effect of baseline peer victimization and SES. RESULTS: Results indicated that the Preventure program was equally beneficial to all adolescents, regardless of SES and victimization history, in terms of their alcohol outcomes and related harm. Receiving the intervention was additionally beneficial for adolescents reporting peer victimization regarding their alcohol-related harm compared to nonvictimized youth (ß = -0.29, SE = 0.11, p = 0.014). CONCLUSIONS: Findings suggest that the content of personality-targeted interventions is beneficial for all high-risk youth regardless of their SES or experience of peer victimization. The current study suggests that using targeted approaches, such as targeting underlying personality risk factors, may be the most appropriate substance use prevention strategy for high-risk youth, as it is beneficial for all high-risk youth regardless of their contextual risk factors.

Neural basis of reward anticipation and its genetic determinants.

Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature.

Individual differences in stop-related activity are inflated by the adaptive algorithm in the stop signal task.

Research using the Stop Signal Task employing an adaptive algorithm to accommodate individual differences often report inferior performance on the task in individuals with ADHD, OCD, and substance use disorders compared to non-clinical controls. Furthermore, individuals with deficits in inhibitory control tend to show reduced neural activity in key inhibitory regions during successful stopping. However, the adaptive algorithm systematically introduces performance-related differences in objective task difficulty that may influence the estimation of individual differences in stop-related neural activity. This report examines the effect that these algorithm-related differences have on the measurement of neural activity during the stop signal task. We compared two groups of subjects (n = 210) who differed in inhibitory ability using both a standard fMRI analysis and an analysis that resampled trials to remove the objective task difficulty confound. The results show that objective task difficulty influences the magnitude of between-group differences and that controlling for difficulty attenuates stop-related activity differences between superior and poor inhibitors. Specifically, group differences in the right inferior frontal gyrus, right middle occipital gyrus, and left inferior frontal gyrus are diminished when differences in objective task difficulty are controlled for. Also, when objective task difficulty effects are exaggerated, group differences in stop related activity emerge in other regions of the stopping network. The implications of these effects for how we interpret individual differences in activity levels are discussed.

Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents.

BACKGROUND: Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders. METHODS: Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity. RESULTS: We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens. CONCLUSIONS: Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

Pathways to prevention: protocol for the CAP (Climate and Preventure) study to evaluate the long-term effectiveness of school-based universal, selective and combined alcohol misuse prevention into early adulthood.

BACKGROUND: Alcohol use and associated harms are among the leading causes of burden of disease among young people, highlighting the need for effective prevention. The Climate and Preventure (CAP) study was the first trial of a combined universal and selective school-based approach to preventing alcohol misuse among adolescents. Initial results indicate that universal, selective and combined prevention were all effective in delaying the uptake of alcohol use and binge drinking for up to 3 years following the interventions. However, little is known about the sustainability of prevention effects across the transition to early adulthood, a period of increased exposure to alcohol and other drug use. This paper describes the protocol for the CAP long-term follow-up study which will determine the effectiveness of universal, selective and combined alcohol misuse prevention up to 7 years post intervention, and across the transition from adolescence into early adulthood. METHODS: A cluster randomized controlled trial was conducted between 2012 and 2015 with 2190 students (mean age: 13.3 yrs) from 26 Australian high schools. Participants were randomized to receive one of four conditions; universal prevention for all students (Climate); selective prevention for high-risk students (Preventure); combined universal and selective prevention (Climate and Preventure; CAP); or health education as usual (Control). The positive effect of the interventions on alcohol use at 12-, 24- and 36-month post baseline have previously been reported. This study will follow up the CAP study cohort approximately 5- and 7-years post baseline. The primary outcome will be alcohol use and related harms. Secondary outcomes will be cannabis use, alcohol and other drug harms including violent behavior, and mental health symptomatology. Analyses will be conducted using multi-level, mixed effects models within an intention-to-treat framework. DISCUSSION: This study will provide the first ever evaluation of the long-term effectiveness of combining universal and selective approaches to alcohol prevention and will examine the durability of intervention effects into the longer-term, over a 7-year period from adolescence to early adulthood. TRIAL REGISTRATION: This trial was registered in the Australian New Zealand Clinical Trials Registry ( ACTRN12612000026820 ) on January 6th 2012.

Rsu1 regulates ethanol consumption in Drosophila and humans.

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide.

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

Identifying disordered eating behaviours in adolescents: how do parent and adolescent reports differ by sex and age?

This study investigated the prevalence of disordered eating cognitions and behaviours across mid-adolescence in a large European sample, and explored the extent to which prevalence ratings were affected by informant (parent/adolescent), or the sex or age of the adolescent. The Development and Well-Being Assessment was completed by parent-adolescent dyads at age 14 (n = 2225) and again at age 16 (n = 1607) to explore the prevalence of 7 eating disorder symptoms (binge eating, purging, fear of weight gain, distress over shape/weight, avoidance of fattening foods, food restriction, and exercise for weight loss). Informant agreement was assessed using kappa coefficients. Generalised estimating equations were performed to explore the impact of age, sex and informant on symptom prevalence. Slight to fair agreement was observed between parent and adolescent reports (kappa estimates between 0.045 and 0.318); however, this was largely driven by agreement on the absence of behaviours. Disordered eating behaviours were more consistently endorsed amongst girls compared to boys (odds ratios: 2.96-5.90) and by adolescents compared to their parents (odds ratios: 2.71-9.05). Our data are consistent with previous findings in epidemiological studies. The findings suggest that sex-related differences in the prevalence of disordered eating behaviour are established by mid-adolescence. The greater prevalence rates obtained from adolescent compared to parent reports may be due to the secretive nature of the behaviours and/or lack of awareness by parents. If adolescent reports are overlooked, the disordered behaviour may have a greater opportunity to become more entrenched.