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.

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.

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.

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.

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.

Resilience and corpus callosum microstructure in adolescence.

BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

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.

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.

Genomic architecture of human neuroanatomical diversity.

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms.

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.

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.

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.

Adolescent bullying, cannabis use and emerging psychotic experiences: a longitudinal general population study.

BACKGROUND: Using longitudinal and prospective measures of psychotic experiences during adolescence, we assessed the risk of developing psychosis in three groups showing low, increasing and elevated psychotic experiences associated with bullying by peers and cannabis use in a UK sample of adolescents. Method Data were collected by self-report from 1098 adolescents (mean age 13.6 years; 60.9% boys) at five separate time points, equally separated by 6 months, across a 24-month period. General growth mixture modelling identified three distinct trajectories of adolescents reporting psychotic experiences: elevated, increasing and low. RESULTS: Controlling for cannabis use, bullying by peers significantly predicted change in psychotic experiences between Time 2 and Time 5 in adolescents belonging to the increasing group. No effect was found for the elevated or low groups. Controlling for bullying, an earlier age of cannabis use and cannabis use more than twice significantly predicted change in psychotic experiences in adolescents belonging to the increasing group. Cannabis use at any age was significantly associated with subsequent change in psychotic experiences in the low group. Reverse causal associations were examined and there was no evidence for psychotic experiences at Time 1 predicting a subsequent change in cannabis use between Times 2 and 5 in any trajectory group. CONCLUSIONS: Bullying by peers and cannabis use are associated with adolescents' reports of increasing psychotic experiences over time. Further research into the longitudinal development of psychosis in adolescence and the associated risk factors would allow for early intervention programmes to be targeted more precisely.

Maternal interpersonal affiliation is associated with adolescents' brain structure and reward processing.

Considerable animal and human research has been dedicated to the effects of parenting on structural brain development, focusing on hippocampal and prefrontal areas. Conversely, although functional imaging studies suggest that the neural reward circuitry is involved in parental affection, little is known about mothers' interpersonal qualities in relation to their children's brain structure and function. Moreover, gender differences concerning the effect of maternal qualities have rarely been investigated systematically. In 63 adolescents, we assessed structural and functional magnetic resonance imaging as well as interpersonal affiliation in their mothers. This allowed us to associate maternal affiliation with gray matter density and neural responses during different phases of the well-established Monetary Incentive Delay task. Maternal affiliation was positively associated with hippocampal and orbitofrontal gray matter density. Moreover, in the feedback of reward hit as compared with reward miss, an association with caudate activation was found. Although no significant gender effects were observed in these associations, during reward feedback as compared with baseline, maternal affiliation was significantly associated with ventral striatal and caudate activation only in females. Our findings demonstrate that maternal interpersonal affiliation is related to alterations in both the brain structure and reward-related activation in healthy adolescents. Importantly, the pattern is in line with typical findings in depression and post-traumatic stress disorder, suggesting that a lack of maternal affiliation might have a role in the genesis of mental disorders.

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 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.

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.