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.

Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder.

In light of the upcoming eleventh edition of the International Classification of Diseases (ICD-11), the question arises as to the most appropriate classification of 'Pathological Gambling' ('PG'). Some academic opinion favors leaving PG in the 'Impulse Control Disorder' ('ICD') category, as in ICD-10, whereas others argue that new data especially from the neurobiological area favor allocating it to the category of 'Substance-related and Addictive Disorders' ('SADs'), following the decision in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders. The current review examines important findings in relation to PG, with the aim of enabling a well-informed decision to be made with respect to the classification of PG as a SAD or ICD in ICD-11. Particular attention is given to cognitive deficits and underlying neurobiological mechanisms that play a role in SADs and ICDs. These processes are impulsivity, compulsivity, reward/punishment processing and decision-making. In summary, the strongest arguments for subsuming PG under a larger SAD category relate to the existence of similar diagnostic characteristics; the high co-morbidity rates between the disorders; their common core features including reward-related aspects (positive reinforcement: behaviors are pleasurable at the beginning which is not the case for ICDs); the findings that the same brain structures are involved in PG and SADs, including the ventral striatum. Research on compulsivity suggests a relationship with PG and SAD, particularly in later stages of the disorders. Although research is limited for ICDs, current data do not support continuing to classify PG as an ICD.

Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder.

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

German Guidelines on Screening, Diagnosis and Treatment of Alcohol Use Disorders.

Evidence-based strategies for screening, diagnosing and treating alcohol use disorders (AUD) are instrumental in the early and better management of individuals at risk for or suffering from AUD. However, existing guidelines vary and may be biased by conflicts of interests. Unbiased recommendations can be achieved only if sufficient detail is provided on the composition and representativeness of author groups, methodological rigor, handling of potential conflicts of interest and financing. This paper presents the first evidence-based guidelines for AUD from German-speaking countries. These guidelines are based on the work of delegates from a representative sample of 46 scientific societies (mostly medical) from Austria, Germany and Switzerland dealing with AUD. It also included patients and relatives. Recommendations were derived from a standardised hierarchical process involving quality controls drawn from existing guidelines, de novo literature searches and/or expert experience. Potential conflicts of interest were assessed yearly and led to exclusion from voting in specific areas. An overall cost of more than 400,000€ (for alcohol and tobacco guidelines) were exclusively covered by the participating societies and academic institutions. More than 100 recommendations on screening, diagnostics and treatment of AUD are outlined in this paper, and their scientific background is given in the online supplementary material. Tables of aggregated study synopses (in English) and the full version of guidelines (in German) are available (see "Links").

Structural brain correlates of adolescent resilience.

BACKGROUND: Despite calls for integration of neurobiological methods into research on youth resilience (high competence despite high adversity), we know little about structural brain correlates of resilient functioning. The aim of the current study was to test for brain regions uniquely associated with positive functioning in the context of adversity, using detailed phenotypic classification. METHODS: 1,870 European adolescents (Mage  = 14.56 years, SDage  = 0.44 years, 51.5% female) underwent MRI scanning and completed behavioral and psychological measures of stressful life events, academic competence, social competence, rule-abiding conduct, personality, and alcohol use. RESULTS: The interaction of competence and adversity identified two regions centered on the right middle and superior frontal gyri; grey matter volumes in these regions were larger in adolescents experiencing adversity who showed positive adaptation. Differences in these regions among competence/adversity subgroups were maintained after controlling for several covariates and were robust to alternative operationalization decisions for key constructs. CONCLUSIONS: We demonstrate structural brain correlates of adolescent resilience, and suggest that right prefrontal structures are implicated in adaptive functioning for youth who have experienced adversity.

Personality and substance use: psychometric evaluation and validation of the Substance Use Risk Profile Scale (SURPS) in English, Irish, French, and German adolescents.

BACKGROUND: The aim of the present longitudinal study was the psychometric evaluation of the Substance Use Risk Profile Scale (SURPS). METHODS: We analyzed data from N = 2,022 adolescents aged 13 to 15 at baseline assessment and 2 years later (mean interval 2.11 years). Missing data at follow-up were imputed (N = 522). Psychometric properties of the SURPS were analyzed using confirmatory factor analysis. We examined structural as well as convergent validity with other personality measurements and drinking motives, and predictive validity for substance use at follow-up. RESULTS: The hypothesized 4-factorial structure (i.e., anxiety sensitivity, hopelessness, impulsivity [IMP], and sensation seeking [SS]) based on all 23 items resulted in acceptable fit to empirical data, acceptable internal consistencies, low to moderate test-retest reliability coefficients, as well as evidence for factorial and convergent validity. The proposed factor structure was stable for both males and females and, to lesser degree, across languages. However, only the SS and the IMP subscales of the SURPS predicted substance use outcomes at 16 years of age. CONCLUSIONS: The SURPS is unique in its specific assessment of traits related to substance use disorders as well as the resulting shortened administration time. Test-retest reliability was low to moderate and comparable to other personality scales. However, its relation to future substance use was limited to the SS and IMP subscales, which may be due to the relatively low-risk substance use pattern in the present sample.

No differences in ventral striatum responsivity between adolescents with a positive family history of alcoholism and controls.

Individuals with alcohol-dependent parents show an elevated risk of developing alcohol-related problems themselves. Modulations of the mesolimbic reward circuit have been postulated as a pre-existing marker of alcoholism. We tested whether a positive family history of alcoholism is correlated with ventral striatum functionality during a reward task. All participants performed a modified version of the monetary incentive delay task while their brain responses were measured with functional magnetic resonance imaging. We compared 206 healthy adolescents (aged 13-15) who had any first- or second-degree relative with alcoholism to 206 matched controls with no biological relative with alcoholism. Reward anticipation as well as feedback of win recruited the ventral striatum in all participants, but adolescents with a positive family history of alcoholism did not differ from their matched peers. Also we did not find any correlation between family history density and reward anticipation or feedback of win. This finding of no differences did not change when we analyzed a subsample of 77 adolescents with at least one parent with alcohol use disorder and their matched controls. Because this result is in line with another study reporting no differences between children with alcohol-dependent parents and controls at young age, but contrasts with studies of older individuals, one might conclude that at younger age the effect of family history has not yet exerted its influence on the still developing mesolimbic reward circuit.

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Dimensions of manic symptoms in youth: psychosocial impairment and cognitive performance in the IMAGEN sample.

BACKGROUND: It has been reported that mania may be associated with superior cognitive performance. In this study, we test the hypothesis that manic symptoms in youth separate along two correlated dimensions and that a symptom constellation of high energy and cheerfulness is associated with superior cognitive performance. METHOD: We studied 1755 participants of the IMAGEN study, of average age 14.4 years (SD = 0.43), 50.7% girls. Manic symptoms were assessed using the Development and Wellbeing Assessment by interviewing parents and young people. Cognition was assessed using the Wechsler Intelligence Scale For Children (WISC-IV) and a response inhibition task. RESULTS: Manic symptoms in youth formed two correlated dimensions: one termed exuberance, characterized by high energy and cheerfulness and one of undercontrol with distractibility, irritability and risk-taking behavior. Only the undercontrol, but not the exuberant dimension, was independently associated with measures of psychosocial impairment. In multivariate regression models, the exuberant, but not the undercontrolled, dimension was positively and significantly associated with verbal IQ by both parent- and self-report; conversely, the undercontrolled, but not the exuberant, dimension was associated with poor performance in a response inhibition task. CONCLUSIONS: Our findings suggest that manic symptoms in youth may form dimensions with distinct correlates. The results are in keeping with previous findings about superior performance associated with mania. Further research is required to study etiological differences between these symptom dimensions and their implications for clinical practice.

Predicting naltrexone response in alcohol-dependent patients: the contribution of functional magnetic resonance imaging.

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

From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits.

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

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.

Gaming disorder: Its delineation as an important condition for diagnosis, management, and prevention.

Online gaming has greatly increased in popularity in recent years, and with this has come a multiplicity of problems due to excessive involvement in gaming. Gaming disorder, both online and offline, has been defined for the first time in the draft of 11th revision of the International Classification of Diseases (ICD-11). National surveys have shown prevalence rates of gaming disorder/addiction of 10%-15% among young people in several Asian countries and of 1%-10% in their counterparts in some Western countries. Several diseases related to excessive gaming are now recognized, and clinics are being established to respond to individual, family, and community concerns, but many cases remain hidden. Gaming disorder shares many features with addictions due to psychoactive substances and with gambling disorder, and functional neuroimaging shows that similar areas of the brain are activated. Governments and health agencies worldwide are seeking for the effects of online gaming to be addressed, and for preventive approaches to be developed. Central to this effort is a need to delineate the nature of the problem, which is the purpose of the definitions in the draft of ICD-11.

Prediction of alcohol drinking in adolescents: Personality-traits, behavior, brain responses, and genetic variations in the context of reward sensitivity.

Adolescence is a time that can set the course of alcohol abuse later in life. Sensitivity to reward on multiple levels is a major factor in this development. We examined 736 adolescents from the IMAGEN longitudinal study for alcohol drinking during early (mean age=14.37) and again later (mean age=16.45) adolescence. Conducting structural equation modeling we evaluated the contribution of reward-related personality traits, behavior, brain responses and candidate genes. Personality seems to be most important in explaining alcohol drinking in early adolescence. However, genetic variations in ANKK1 (rs1800497) and HOMER1 (rs7713917) play an equal role in predicting alcohol drinking two years later and are most important in predicting the increase in alcohol consumption. We hypothesize that the initiation of alcohol use may be driven more strongly by personality while the transition to increased alcohol use is more genetically influenced.

BRAIN NETWORKS. Correlated gene expression supports synchronous activity in brain networks.

During rest, brain activity is synchronized between different regions widely distributed throughout the brain, forming functional networks. However, the molecular mechanisms supporting functional connectivity remain undefined. We show that functional brain networks defined with resting-state functional magnetic resonance imaging can be recapitulated by using measures of correlated gene expression in a post mortem brain tissue data set. The set of 136 genes we identify is significantly enriched for ion channels. Polymorphisms in this set of genes significantly affect resting-state functional connectivity in a large sample of healthy adolescents. Expression levels of these genes are also significantly associated with axonal connectivity in the mouse. The results provide convergent, multimodal evidence that resting-state functional networks correlate with the orchestrated activity of dozens of genes linked to ion channel activity and synaptic function.

Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis.

OBJECTIVE: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. METHOD: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. RESULTS: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. CONCLUSIONS: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

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

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

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

BACKGROUND: Disordered gambling (DG) has often been associated with impaired decision-making abilities, suggesting a dysfunction in the ventromedial prefrontal cortex (vmPFC). AIMS: To our knowledge, no previous study has accurately considered the effect of substance use disorder (SUD) comorbidity (including nicotine dependence) on decision-making impairments in DG. METHODS AND MATERIALS: We employed the Cambridge Gambling Task (CGT) to assess a big cohort of patients diagnosed with DG (N = 80) against matched healthy controls (HCs) (N = 108). The cohort included DG patients with nicotine and alcohol dependence, alcohol dependence only and 12 "pure" nonsmokers with only DG diagnosis. RESULTS: Pure nonsmoking, nicotine dependent as well as alcoholic DGs with current nicotine dependence, demonstrated a decision making profile, characterized by poor decision-making abilities and failure to make right choices (rational), closely resembling that of patients with vmPFC damage. DISCUSSION: This suggests that DGs with and without SUD comorbidity are equally affected in that domain of decision making abilities. Additionally, gambling diagnosis combined with alcohol and nicotine dependence involves a group of gambling patients with a relatively riskier decision making profile, showing that these patients apart from making irrational decisions take also more risks. Our findings highlight the importance of accounting for SUD comorbidities with useful implications for future research and therapy. Limitations of the current investigation are discussed.

Neural and cognitive correlates of the common and specific variance across externalizing problems in young adolescence.

Longitudinal and family-based research suggests that conduct disorder, substance misuse, and ADHD involve both unique forms of dysfunction as well as more specific dysfunctions unique to each condition. Using direct measures of brain function, this study also found evidence in both unique and disorder-specific perturbations.

Sex differences in COMT polymorphism effects on prefrontal inhibitory control in adolescence.

Catecholamine-0-methyl-transferase (COMT) gene variation effects on prefrontal blood oxygenation-level-dependent (BOLD) activation are robust; however, despite observations that COMT is estrogenically catabolized, sex differences in its prefrontal repercussions remain unclear. Here, in a large sample of healthy adolescents stratified by sex and Val(158)Met genotype (n=1133), we examine BOLD responses during performance of the stop-signal task in right-hemispheric prefrontal regions fundamental to inhibitory control. A significant sex-by-genotype interaction was observed in pre-SMA during successful-inhibition trials and in both pre-SMA and inferior frontal cortex during failed-inhibition trials with Val homozygotes displaying elevated activation compared with other genotypes in males but not in females. BOLD activation in the same regions significantly mediated the relationship between COMT genotype and inhibitory proficiency as indexed by stop-signal reaction time in males alone. These sexually dimorphic effects of COMT on inhibitory brain activation have important implications for our understanding of the contrasting patterns of prefrontally governed psychopathology observed in males and females.