The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

A robust brain network for sustained attention from adolescence to adulthood that predicts later substance use.

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance-use or a marker of the inclination to engage in such behaviour. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1,000 participants. Behaviours and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

Early-Life Adversities Are Associated With Lower Expected Value Signaling in the Adult Brain.

BACKGROUND: Early adverse experiences are assumed to affect fundamental processes of reward learning and decision making. However, computational neuroimaging studies investigating these circuits in the context of adversity are sparse and limited to studies conducted in adolescent samples, leaving the long-term effects unexplored. METHODS: Using data from a longitudinal birth cohort study (n = 156; 87 female), we investigated associations between adversities and computational markers of reward learning (i.e., expected value, prediction errors). At age 33 years, all participants completed a functional magnetic resonance imaging-based passive avoidance task. Psychopathology measures were collected at the time of functional magnetic resonance imaging investigation and during the COVID-19 pandemic. We applied a principal component analysis to capture common variations across 7 adversity measures. The resulting adversity factors (factor 1: postnatal psychosocial adversities and prenatal maternal smoking; factor 2: prenatal maternal stress and obstetric adversity; factor 3: lower maternal stimulation) were linked with psychopathology and neural responses in the core reward network using multiple regression analysis. RESULTS: We found that the adversity dimension primarily informed by lower maternal stimulation was linked to lower expected value representation in the right putamen, right nucleus accumbens, and anterior cingulate cortex. Expected value encoding in the right nucleus accumbens further mediated the relationship between this adversity dimension and psychopathology and predicted higher withdrawn symptoms during the COVID-19 pandemic. CONCLUSIONS: Our results suggested that early adverse experiences in caregiver context might have a long-term disruptive effect on reward learning in reward-related brain regions, which can be associated with suboptimal decision making and thereby may increase the vulnerability of developing psychopathology.

Lifespan adversities affect neural correlates of behavioral inhibition in adults.

Introduction: Growing evidence suggests that adverse experiences have long-term effects on executive functioning and underlying neural circuits. Previous work has identified functional abnormalities during inhibitory control in frontal brain regions in individuals exposed to adversities. However, these findings were mostly limited to specific adversity types such as maltreatment and prenatal substance abuse. Methods: We used data from a longitudinal birth cohort study (n = 121, 70 females) to investigate the association between adversities and brain responses during inhibitory control. At the age of 33 years, all participants completed a stop-signal task during fMRI and an Adult Self-Report scale. We collected seven prenatal and postnatal adversity measures across development and performed a principal component analysis to capture common variations across those adversities, which resulted in a three-factor solution. Multiple regression analysis was performed to identify links between adversities and brain responses during inhibitory control using the identified adversity factors to show the common effect and single adversity measures to show the specific contribution of each adversity. To find neural correlates of current psychopathology during inhibitory control, we performed additional regression analyses using Adult Self-Report subscales. Results: The first adversity factor reflecting prenatal maternal smoking and postnatal psychosocial adversities was related to higher activation during inhibitory control in bilateral inferior frontal gyri, insula, anterior cingulate cortex, and middle temporal gyri. Similar results were found for the specific contribution of the adversities linked to the first adversity factor. In contrast, we did not identify any significant association between brain responses during inhibitory control and the second adversity factor reflecting prenatal maternal stress and obstetric risk or the third adversity factor reflecting lower maternal sensitivity. Higher current depressive symptoms were associated with higher activation in the bilateral insula and anterior cingulate cortex during inhibitory control. Conclusion: Our findings extended previous work and showed that early adverse experiences have a long-term effect on the neural circuitry of inhibitory control in adulthood. Furthermore, the overlap between neural correlates of adversity and depressive symptomatology suggests that adverse experiences might increase vulnerability via neural alterations, which needs to be investigated by future longitudinal research.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Brain Networks and Adolescent Alcohol Use.

Importance: Alcohol misuse in adolescence is a leading cause of disability and mortality in youth and is associated with higher risk for alcohol use disorder. Brain mechanisms underlying risk of alcohol misuse may inform prevention and intervention efforts. Objective: To identify neuromarkers of alcohol misuse using a data-driven approach, with specific consideration of neurodevelopmental sex differences. Design, Setting, and Participants: Longitudinal multisite functional magnetic resonance imaging (fMRI) data collected at ages 14 and 19 years were used to assess whole-brain patterns of functional organization associated with current and future alcohol use risk as measured by the Alcohol Use Disorder Identification Test (AUDIT). Primary data were collected by the IMAGEN consortium, a European multisite study of adolescent neurodevelopment. Model generalizability was further tested using data acquired in a single-site study of college alcohol consumption conducted in the US. The primary sample was a developmental cohort of 1359 adolescents with neuroimaging, phenotyping, and alcohol use data. Model generalizability was further assessed in a separate cohort of 114 individuals. Main Outcomes and Measures: Brain-behavior model accuracy, as defined by the correspondence between model-predicted and actual AUDIT scores in held-out testing data, Bonferroni corrected across the number of models run at each time point, 2-tailed α < .008, as determined via permutation testing. Results: Among 1359 individuals in the study, the mean (SD) age was 14.42 (0.40) years, and 729 individuals (54%) were female. The data-driven, whole-brain connectivity approach identified networks associated with vulnerability for future and current AUDIT-defined alcohol use risk (primary outcome, as specified above, future: ρ, 0.22; P < .001 and present: ρ, 0.27; P < .001). Results further indicated sex divergence in the accuracies of brain-behavior models, such that female-only models consistently outperformed male-only models. Specifically, female-only models identified networks conferring vulnerability for future and current severity using data acquired during both reward and inhibitory fMRI tasks. In contrast, male-only models were successful in accurately identifying networks using data acquired during the inhibitory control-but not reward-task, indicating domain specificity of alcohol use risk networks in male adolescents only. Conclusions and Relevance: These data suggest that interventions focusing on inhibitory control processes may be effective in combating alcohol use risk in male adolescents but that both inhibitory and reward-related processes are likely of relevance to alcohol use behaviors in female adolescents. They further identify novel networks of alcohol use risk in youth, which may be used to identify adolescents who are at risk and inform intervention efforts.

Association of Maternal Smoking during Pregnancy with Neurophysiological and ADHD-Related Outcomes in School-Aged Children.

Data of a longitudinal cohort study were analyzed to investigate the association between prenatal tobacco exposure and electroencephalographical (EEG) power spectrum in healthy, school-aged children as well as its relationship with attention deficit hyperactivity disorder (ADHD)-related symptoms. Group comparisons (exposed, non-exposed) were performed to test whether prenatal tobacco exposure was associated with brain activity and ADHD symptoms, with adjustments made for covariates including child's sex, child's age, maternal age, maternal smoking habit before pregnancy, alcohol consumption during pregnancy, gestation age, and maternal psychopathology. Tobacco-exposed children showed higher brain activity in the delta and theta frequency bands. This effect was independent of the considered covariates. However, the effects on hyperactivity were found to significantly depend on maternal age and alcohol consumption during pregnancy, but not on the amount of exposure. In summary, smoking during pregnancy significantly affected the resting-state brain activity in children, independent of socio-demographic factors, indicating potential long-lasting effects on brain development. Its impact on ADHD-related behavior was shown to be influenced by socio-demographic confounding factors, such as maternal alcohol consumption and the age of the mother.

Federated Analysis in COINSTAC Reveals Functional Network Connectivity and Spectral Links to Smoking and Alcohol Consumption in Nearly 2,000 Adolescent Brains.

With the growth of decentralized/federated analysis approaches in neuroimaging, the opportunities to study brain disorders using data from multiple sites has grown multi-fold. One such initiative is the Neuromark, a fully automated spatially constrained independent component analysis (ICA) that is used to link brain network abnormalities among different datasets, studies, and disorders while leveraging subject-specific networks. In this study, we implement the neuromark pipeline in COINSTAC, an open-source neuroimaging framework for collaborative/decentralized analysis. Decentralized exploratory analysis of nearly 2000 resting-state functional magnetic resonance imaging datasets collected at different sites across two cohorts and co-located in different countries was performed to study the resting brain functional network connectivity changes in adolescents who smoke and consume alcohol. Results showed hypoconnectivity across the majority of networks including sensory, default mode, and subcortical domains, more for alcohol than smoking, and decreased low frequency power. These findings suggest that global reduced synchronization is associated with both tobacco and alcohol use. This proof-of-concept work demonstrates the utility and incentives associated with large-scale decentralized collaborations spanning multiple sites.

Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study.

BACKGROUND: Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs. METHODS: To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs. RESULTS: No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10-8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors. CONCLUSIONS: Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.

A Developmental Perspective on Facets of Impulsivity and Brain Activity Correlates From Adolescence to Adulthood.

BACKGROUND: On a theoretical level, impulsivity represents a multidimensional construct associated with acting without foresight, inefficient inhibitory response control, and alterations in reward processing. On an empirical level, relationships and changes in associations between different measures of impulsivity from adolescence into young adulthood and their relation to neural activity during inhibitory control and reward anticipation have not been fully understood. METHODS: We used data from IMAGEN, a longitudinal multicenter, population-based cohort study in which 2034 healthy adolescents were investigated at age 14, and 1383 were reassessed as young adults at age 19. We measured the construct of trait impulsivity using self-report questionnaires and neurocognitive indices of decisional impulsivity. With functional magnetic resonance imaging, we assessed brain activity during inhibition error processing using the stop signal task and during reward anticipation in the monetary incentive delay task. Correlations were analyzed, and mixed-effect models were fitted to explore developmental and predictive effects. RESULTS: All self-report and neurocognitive measures of impulsivity proved to be correlated during adolescence and young adulthood. Further, pre-supplementary motor area and inferior frontal gyrus activity during inhibition error processing was associated with trait impulsivity in adolescence, whereas in young adulthood, a trend-level association with reward anticipation activity in the ventral striatum was found. For adult delay discounting, a trend-level predictive effect of adolescent neural activity during inhibition error processing emerged. CONCLUSIONS: Our findings help to inform theories of impulsivity about the development of its multidimensional nature and associated brain activity patterns and highlight the need for taking functional brain development into account when evaluating neuromarker candidates.

Systematic Review and Meta-analysis: Screening Tools for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.

OBJECTIVE: This systematic review and meta-analysis aimed to determine the accuracies of a broad range of screening tools for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents, and to compare the diagnostic accuracy of tools between population-based and clinical/high-risk samples, and across reporters. METHOD: MEDLINE, PsycINFO, EMBASE, and PubMed were searched up until February 20, 2020, with no language restrictions. Studies reporting diagnostic accuracy of a screening tool against a diagnosis of ADHD in children and adolescents <18 years of age were eligible for inclusion. Meta-analyses were undertaken to provide pooled estimates of the area under the curve (AUC), and sensitivity and specificity of groups of measures. RESULTS: A total of 75 studies published between 1985 and 2021 reporting on 41 screening tools that were grouped into 4 categories (Achenbach System of Empirically Based Assessment [ASEBA], DSM-IV symptom scales, SDQ, and Other Scales) were retained. The pooled AUC for studies using a combined ADHD symptoms score was 0.82 (95% CI = 0.78-0.86), although this varied considerably across reporters (0.67-0.92) and populations (CI = 0.60-0.95). None of the measures met minimal standards for acceptable sensitivity (0.8) and specificity (0.8). CONCLUSION: Most tools have excellent overall diagnostic accuracy as indicated by the AUC. However, a single measure completed by a single reporter is unlikely to have sufficient sensitivity and specificity for clinical use or population screening.

Practice Tools for Screening and Monitoring Insomnia in Children and Adolescents with Autism Spectrum Disorder.

Between 50-80% of children with autism spectrum disorder (ASD) have insomnia, which adversely affects their mental and physical health. However, there is no consensus to-date on suitable tools for insomnia screening and monitoring in daily clinical practice. An expert panel of child neuropsychiatry and sleep specialists, with expertise in children with neurodevelopmental disabilities, recommends: (1) performing insomnia screening of all children with ASD; (2) considering discussion or referral to a sleep specialist when comorbid sleep disorders are suspected. The panel further developed structured, brief screening and monitoring tools to facilitate insomnia screening and management in daily practice, monitor treatment effectiveness and standardize and compare outcomes across clinical settings to improve care and well-being of children with ASD and their families.

Orbitofrontal cortex volume links polygenic risk for smoking with tobacco use in healthy adolescents.

BACKGROUND: Tobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood. METHODS: Genomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use. RESULTS: A higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use. CONCLUSIONS: Our data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.

Disentangling symptoms of externalizing disorders in children using multiple measures and informants.

The trait impulsivity theory suggests that a single, highly heritable externalizing liability factor, expressed as temperamental trait impulsivity, represents the core vulnerability for externalizing disorders. The present study sought to test the application of latent factor models derived from this theory to a clinical sample of children. Participants were 474 German children (age 6-12 years, 81% male) with symptoms of attention-deficit/hyperactivity disorder and externalizing behavior problems participating in an ongoing multicenter intervention study. Using confirmatory factor analyses (CFA) and exploratory structural equation modeling (ESEM), we evaluated several factor models of externalizing spectrum disorders (unidimensional; first-order correlated factors; higher-order factor; fully symmetrical bifactor; bifactor S-1 model). Furthermore, we assessed our prevailing factor models for measurement invariance across raters (clinicians, parents, teachers) and assessment modes (interview, questionnaires). While both CFA and ESEM approaches provided valuable insights into the multidimensionality, ESEM solutions were generally superior since they showed a substantially better model fit and less biased factor loadings. Among the models tested, the bifactor S-1 CFA/ESEM models, with a general hyperactivity-impulsivity reference factor, displayed a statistically sound factor structure and allowed for straightforward interpretability. Furthermore, these models showed the same organization of factors and loading patterns, but not equivalent item thresholds across raters and assessment modes, highlighting cross-situational variability in child behavior. Our findings are consistent with the assumption of the trait impulsivity theory that a common trait, presented as hyperactivity-impulsivity symptoms, underlies all externalizing disorders. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

[International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder]. / Internationale Konsenserklärung zu Screening, Diagnostik und Behandlung von Jugendlichen und Heranwachsenden mit Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung und gleichzeitigen Störungen durch Substanzgebrauch.

International Consensus Statement for the Screening, Diagnosis, and Treatment of Adolescents with Concurrent Attention-Deficit/Hyperactivity Disorder and Substance Use Disorder Abstract. Background: Childhood attention-deficit/hyperactivity disorder (ADHD) is a risk factor for substance misuse and substance use disorder (SUD) in adolescence and (early) adulthood. ADHD and SUD also frequently co-occur in treatment-seeking adolescents, which complicates diagnosis and treatment and is associated with poor treatment outcomes. Research on the effect of treatment of childhood ADHD on the prevention of adolescent SUD is inconclusive, and studies on the diagnosis and treatment of adolescents with ADHD and SUD are scarce. Thus, the available evidence is generally not sufficient to justify robust treatment recommendations. Objective: The aim of the study was to obtain a consensus statement based on a combination of scientific data and clinical experience. Method: A modified Delphi study to reach consensus based upon the combination of scientific data and clinical experience with a multidisciplinary group of 55 experts from 17 countries. The experts were asked to rate a set of statements on the effect of treatment of childhood ADHD on adolescent SUD and on the screening, diagnosis, and treatment of adolescents with comorbid ADHD and SUD. Results: After 3 iterative rounds of rating and adapting 37 statements, consensus was reached on 36 of these statements representing 6 domains: general (n = 4), risk of developing SUD (n = 3), screening and diagnosis (n = 7), psychosocial treatment (n = 5), pharmacological treatment (n = 11), and complementary treatments (n = 7). Routine screening is recommended for ADHD in adolescent patients in substance abuse treatment and for SUD in adolescent patients with ADHD in mental healthcare settings. Long-acting stimulants are recommended as the first-line treatment of ADHD in adolescents with concurrent ADHD and SUD, and pharmacotherapy should preferably be embedded in psychosocial treatment. The only remaining no-consensus statement concerned the requirement of abstinence before starting pharmacological treatment in adolescents with ADHD and concurrent SUD. In contrast to the majority, some experts required full abstinence before starting any pharmacological treatment, some were against the use of stimulants in the treatment of these patients (independent of abstinence), while some were against the alternative use of bupropion. Conclusion: This international consensus statement can be used by clinicians and patients together in a shared decision-making process to select the best interventions and to reach optimal outcomes in adolescent patients with concurrent ADHD and SUD.

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

BACKGROUND: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues. METHODS: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels. RESULTS: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%. CONCLUSIONS: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

Neuroimaging evidence for structural correlates in adolescents resilient to polysubstance use: A five-year follow-up study.

Early initiation of polysubstance use (PSU) is a strong predictor of subsequent addiction, however scarce individuals present resilience capacity. This neuroimaging study aimed to investigate structural correlates associated with cessation or reduction of PSU and determine the extent to which brain structural features accounted for this resilient outcome. Participants from a European community-based cohort self-reported their alcohol, tobacco and cannabis use frequency at ages 14, 16 and 19 and had neuroimaging sessions at ages 14 and 19. We included three groups in the study: the resilient-to-PSU participants showed PSU at 16 and/or 14 but no more at 19 (n = 18), the enduring polysubstance users at 19 displayed PSU continuation from 14 or 16 (n = 193) and the controls were abstinent or low drinking participants (n = 460). We conducted between-group comparisons of grey matter volumes on whole brain using voxel-based morphometry and regional fractional anisotropy using tract-based spatial statistics. Random-forests machine-learning approach generated individual-level PSU-behavior predictions based on personality and neuroimaging features. Adolescents resilient to PSU showed significant larger grey matter volumes in the bilateral cingulate gyrus compared with enduring polysubstance users and controls at ages 19 and 14 (p<0.05 corrected) but no difference in fractional anisotropy. The larger cingulate volumes and personality trait "openness to experience" were the best precursors of resilience to PSU. Early in adolescence, a larger cingulate gyrus differentiated adolescents resilient to PSU, and this feature was critical in predicting this outcome. This study encourages further research into the neurobiological bases of resilience to addictive behaviors.

Linked patterns of biological and environmental covariation with brain structure in adolescence: a population-based longitudinal study.

Adolescence is a period of major brain reorganization shaped by biologically timed and by environmental factors. We sought to discover linked patterns of covariation between brain structural development and a wide array of these factors by leveraging data from the IMAGEN study, a longitudinal population-based cohort of adolescents. Brain structural measures and a comprehensive array of non-imaging features (relating to demographic, anthropometric, and psychosocial characteristics) were available on 1476 IMAGEN participants aged 14 years and from a subsample reassessed at age 19 years (n = 714). We applied sparse canonical correlation analyses (sCCA) to the cross-sectional and longitudinal data to extract modes with maximum covariation between neuroimaging and non-imaging measures. Separate sCCAs for cortical thickness, cortical surface area and subcortical volumes confirmed that each imaging phenotype was correlated with non-imaging features (sCCA r range: 0.30-0.65, all PFDR < 0.001). Total intracranial volume and global measures of cortical thickness and surface area had the highest canonical cross-loadings (|ρ| = 0.31-0.61). Age, physical growth and sex had the highest association with adolescent brain structure (|ρ| = 0.24-0.62); at baseline, further significant positive associations were noted for cognitive measures while negative associations were observed at both time points for prenatal parental smoking, life events, and negative affect and substance use in youth (|ρ| = 0.10-0.23). Sex, physical growth and age are the dominant influences on adolescent brain development. We highlight the persistent negative influences of prenatal parental smoking and youth substance use as they are modifiable and of relevance for public health initiatives.

Association of Genetic and Phenotypic Assessments With Onset of Disordered Eating Behaviors and Comorbid Mental Health Problems Among Adolescents.

Importance: Eating disorders are serious mental disorders with increasing prevalence. Without early identification and treatment, eating disorders may run a long-term course. Objective: To characterize any associations among disordered eating behaviors (DEBs) and other mental health disorders and to identify early associations with the development of symptoms over time. Design, Setting, and Participants: This multicenter, population-based, longitudinal cohort study used data from baseline (collected in 2010), follow-up 1 (collected in 2012), and follow-up 2 (collected in 2015) of the IMAGEN Study, which included adolescents recruited from 8 European sites. The present study assessed data from 1623 healthy adolescents, aged 14 years at baseline, recruited from high schools. Data analyses were performed from January 2018 to September 2019. Main Outcomes and Measures: Body mass index (BMI), mental health symptoms, substance use behaviors, and personality variables were investigated as time-varying associations of DEBs (dieting, binge eating, and purging) or change in BMI over time. Polygenic risk scores were calculated to investigate genetic contributions associated with BMI, attention-deficit/hyperactivity disorder (ADHD) and neuroticism to DEBs. Results: In this cohort study of 1623 adolescents (829 girls [51.1%]) recruited at a mean (SD) age of 14.5 (0.4) years and followed up at ages 16 and 19 years, 278 adolescents (17.1%) reported binge eating, 334 adolescents (20.6%) reported purging, and 356 adolescents (21.9%) reported dieting at 14, 16, or 19 years. Among the precursors of DEBs, high BMI was associated with future dieting (OR, 3.44; 95% CI, 2.09-5.65). High levels of neuroticism (OR, 1.04; 95% CI, 1.01-1.06), conduct problems (OR, 1.41; 95% CI, 1.17-1.69), and deliberate self-harm (OR, 2.18; 95% CI, 1.37-3.45) were associated with future binge eating. Low agreeableness (OR, 0.95; 95% CI, 0.92-0.97), deliberate self-harm (OR, 2.59; 95% CI, 1.69-3.95), conduct problems (OR, 1.42; 95% CI, 1.20-1.68), alcohol misuse (OR, 1.31; 95% CI, 1.10-1.54), and drug abuse (OR, 2.91; 95% CI, 1.78-4.74) were associated with future purging. Polygenetic risk scores for BMI were associated with dieting (at 14 years: OR, 1.27; lower bound 95% CI, 1.08; at 16 years: OR, 1.38; lower bound 95% CI, 1.17); ADHD, with purging (at 16 years: OR, 1.25; lower bound 95% CI, 1.08; at 19 years, OR, 1.23; lower bound 95% CI, 1.06); and neuroticism, with binge eating (at 14 years: OR, 1.32; lower bound 95% CI, 1.11; at 16 years: OR, 1.24; lower bound 95% CI, 1.06), highlighting distinct etiologic overlaps between these traits. The DEBs predated other mental health problems, with dieting at 14 years associated with future symptoms of depression (OR, 2.53; 95% CI, 1.56-4.10), generalized anxiety (OR, 2.27; 95% CI, 1.14-4.51), deliberate self-harm (OR, 2.10; 95% CI, 1.51-4.24), emotional problems (OR, 1.24; 95% CI, 1.08-1.43), and smoking (OR, 2.16; 95% CI, 1.36-3.48). Purging at 14 years was also associated with future depression (OR, 2.87; 95% CI, 1.69-5.01) and anxiety (OR, 2.48; 95% CI, 1.49-4.12) symptoms. Conclusions and Relevance: The findings of this study delineate temporal associations and shared etiologies among DEBs and other mental health disorders and emphasize the potential of genetic and phenotypical assessments of obesity, behavioral disorders, and neuroticism to improve early and differential diagnosis of eating disorders.