Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Implementing Approach-Bias Modification as Add-On to Varieties of Clinical Treatment for Alcohol Use Disorders: Results of a Multicenter RCT.

INTRODUCTION: Abstinence rates after inpatient treatment for alcohol use disorder (AUD) are modest (1-year rate around 50%). One promising approach is to re-train the automatically activated action tendency to approach alcohol-related stimuli (alcohol-approach bias) in AUD patients, as add-on to regular treatment. As efficacy has been demonstrated in well-controlled randomized controlled trials, the important next step is to add alcohol-approach-bias modification (alcohol-ApBM) to varieties of existing treatments for AUD. Therefore, this prospective, multicenter implementation-RCT examined whether adding alcohol-ApBM to regular treatments (various abstinence-oriented treatments including both individual and group-based interventions) would significantly increase abstinence rates compared to receiving regular treatment only, in a variety of naturalistic settings with different therapeutic approaches. METHODS: A total of 1,586 AUD inpatients from 9 German rehabilitation clinics were randomly assigned to receive either ApBM in addition to regular treatment or not. Training satisfaction of patients and therapists was measured after training. Success rates were determined at 3, 6, and 12 months post-treatment. RESULTS: Return rates of the post-treatment assessments varied greatly between clinics, often being low (18-76%). Nevertheless, ApBM significantly increased success rates after 3 months. After 6 and 12 months, the differences were not significant. ApBM was evaluated mostly positively by patients and therapists. DISCUSSION/CONCLUSION: ApBM was an effective add-on to regular treatment of AUD at 3 months follow-up, across a variety of AUD treatment settings. However, low return rates for the clinical outcomes reduced the effect size of ApBM considerably. The application of ApBM proved feasible in varying clinical settings, offering the opportunity to modify automatic processes and to promote abstinence.

Effectiveness and Acceptability of Conversational Agents for Smoking Cessation: A Systematic Review and Meta-analysis.

INTRODUCTION: Conversational agents (CAs; computer programs that use artificial intelligence to simulate a conversation with users through natural language) have evolved considerably in recent years to support healthcare by providing autonomous, interactive, and accessible services, making them potentially useful for supporting smoking cessation. We performed a systematic review and meta-analysis to provide an overarching evaluation of their effectiveness and acceptability to inform future development and adoption. AIMS AND METHODS: PsycInfo, Web of Science, ACM Digital Library, IEEE Xplore, Medline, EMBASE, Communication and Mass Media Complete, and CINAHL Complete were searched for studies examining the use of CAs for smoking cessation. Data from eligible studies were extracted and used for random-effects meta-analyses. RESULTS: The search yielded 1245 publications with 13 studies eligible for systematic review (total N = 8236) and six studies for random-effects meta-analyses. All studies reported positive effects on cessation-related outcomes. A meta-analysis with randomized controlled trials reporting on abstinence yielded a sample-weighted odds ratio of 1.66 (95% CI = 1.33% to 2.07%, p < .001), favoring CAs over comparison groups. A narrative synthesis of all included studies showed overall high acceptability, while some barriers were identified from user feedback. Overall, included studies were diverse in design with mixed quality, and evidence of publication bias was identified. A lack of theoretical foundations was noted, as well as a clear need for relational communication in future designs. CONCLUSIONS: The effectiveness and acceptability of CAs for smoking cessation are promising. However, standardization of reporting and designing of the agents is warranted for a more comprehensive evaluation. IMPLICATIONS: This is the first systematic review to provide insight into the use of CAs to support smoking cessation. Our findings demonstrated initial promise in the effectiveness and user acceptability of these agents. We also identified a lack of theoretical and methodological limitations to improve future study design and intervention delivery.

Goal-directedness enhances letter-speech sound learning and consolidation in an unknown orthography.

This study examined how top-down control influenced letter-speech sound (L-SS) learning, the initial phase of learning to read. In 2020, 107 Dutch children (53 boys, Mage  = 106.845 months) learned eight L-SS correspondences, either preceded by goal-directed or implicit instructions. Symbol knowledge and artificial word-reading ability were assessed immediately after learning and on the subsequent day to examine the effect of sleep. Goal-directed children were faster and more efficient in learning a new script and had better learning outcomes compared to children who were not instructed about the goal of the task. This study demonstrates that directing children toward the goal can promote L-SS learning and consolidation, giving insights into how top-down control influences the initial phase of reading acquisition.

A network approach to dyslexia: Mapping the reading network.

Research on the etiology of dyslexia typically uses an approach based on a single core deficit, failing to understand how variations in combinations of factors contribute to reading development and how this combination relates to intervention outcome. To fill this gap, this study explored links between 28 cognitive, environmental, and demographic variables related to dyslexia by employing a network analysis using a large clinical database of 1,257 elementary school children. We found two highly connected subparts in the network: one comprising reading fluency and accuracy measures, and one comprising intelligence-related measures. Interestingly, phoneme awareness was functionally related to the controlled and accurate processing of letter-speech sound mappings, whereas rapid automatized naming was more functionally related to the automated convergence of visual and speech information. We found evidence for the contribution of a variety of factors to (a)typical reading development, though associated with different aspects of the reading process. As such, our results contradict prevailing claims that dyslexia is caused by a single core deficit. This study shows how the network approach to psychopathology can be used to study complex interactions within the reading network and discusses future directions for more personalized interventions.

How We Lost 90% of Participants on a Bad Bet: Results from a Pilot Randomized Controlled Trial on Cognitive Bias Modification in Problem Gamblers.

Whilst opportunities to participate in gambling have increased, access to support for problem gamblers is lacking behind. This lack of balance calls for improved and accessible intervention methods. The present double-blind randomized controlled trial (RCT) explored the effectiveness of two interventions targeting automatic cognitive processes, known as Attentional Bias Modification (AtBM) and Approach Bias Modification (ApBM). It was hypothesized these interventions would reduce gambling behavior and reduce or reverse targeted biases. Participants (N = 331) were community-recruited Flemish (35%) and Dutch (65%) adult problem gamblers motivated to reduce or stop their gambling who received either six sessions of active training (AtBM or ApBM) or of the corresponding sham-training (sham-AtBM or sham-ApBM). Due to high attrition rates (90.1% up to the intervention phase) the study was terminated before completion, since it would greatly limit the validity of any results. A post hoc qualitative study was performed on a subset of participants to gain insight into contributing factors for the high attrition rate. Issues negatively impacting participants' motivation to complete the program were identified, as well as elements of the program that received approval. The results from this study provide a first insight into the potential of the use of online cognitive bias modification (CBM) interventions in problem gambling (PG). Suggestions and directions for future studies are discussed.

Can we measure individual differences in cognitive measures reliably via smartphones? A comparison of the flanker effect across device types and samples.

Research deployed via the internet and administered via smartphones could have access to more diverse samples than lab-based research. Diverse samples could have relatively high variation in their traits and so yield relatively reliable measurements of individual differences in these traits. Several cognitive tasks that originated from the experimental research tradition have been reported to yield relatively low reliabilities (Hedge et al., 2018) in samples with restricted variance (students). This issue could potentially be addressed by smartphone-mediated administration in diverse samples. We formulate several criteria to determine whether a cognitive task is suitable for individual differences research on commodity smartphones: no very brief or precise stimulus timing, relative response times (RTs), a maximum of two response options, and a small number of graphical stimuli. The flanker task meets these criteria. We compared the reliability of individual differences in the flanker effect across samples and devices in a preregistered study. We found no evidence that a more diverse sample yields higher reliabilities. We also found no evidence that commodity smartphones yield lower reliabilities than commodity laptops. Hence, diverse samples might not improve reliability above student samples, but smartphones may well measure individual differences with cognitive tasks reliably. Exploratively, we examined different reliability coefficients, split-half reliabilities, and the development of reliability estimates as a function of task length.

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

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

Predicting alcohol dependence from multi-site brain structural measures.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.

Can chatbots help to motivate smoking cessation? A study on the effectiveness of motivational interviewing on engagement and therapeutic alliance.

BACKGROUND: Cigarette smoking poses a major threat to public health. While cessation support provided by healthcare professionals is effective, its use remains low. Chatbots have the potential to serve as a useful addition. The objective of this study is to explore the possibility of using a motivational interviewing style chatbot to enhance engagement, therapeutic alliance, and perceived empathy in the context of smoking cessation. METHODS: A preregistered web-based experiment was conducted in which smokers (n = 153) were randomly assigned to either the motivational interviewing (MI)-style chatbot condition (n = 78) or the neutral chatbot condition (n = 75) and interacted with the chatbot in two sessions. In the assessment session, typical intake questions in smoking cessation interventions were administered by the chatbot, such as smoking history, nicotine dependence level, and intention to quit. In the feedback session, the chatbot provided personalized normative feedback and discussed with participants potential reasons to quit. Engagement with the chatbot, therapeutic alliance, and perceived empathy were the primary outcomes and were assessed after both sessions. Secondary outcomes were motivation to quit and perceived communication competence and were assessed after the two sessions. RESULTS: No significant effects of the experimental manipulation (MI-style or neutral chatbot) were found on engagement, therapeutic alliance, or perceived empathy. A significant increase in therapeutic alliance over two sessions emerged in both conditions, with participants reporting significantly increased motivation to quit. The chatbot was perceived as highly competent, and communication competence was positively associated with engagement, therapeutic alliance, and perceived empathy. CONCLUSION: The results of this preregistered study suggest that talking with a chatbot about smoking cessation can help to motivate smokers to quit and that the effect of conversation has the potential to build up over time. We did not find support for an extra motivating effect of the MI-style chatbot, for which we discuss possible reasons. These findings highlight the promise of using chatbots to motivate smoking cessation. Implications for future research are discussed.

A Pilot Study on Approach Bias Modification in Smoking Cessation: Activating Personalized Alternative Activities for Smoking in the Context of Increased Craving.

BACKGROUND: The act of smoking has been associated with the automatic activation of approach biases towards smoking-related stimuli. However, previous research has produced mixed findings when smokers are trained to avoid such smoking-related stimuli through the application of Approach Bias Modification (ApBM). As such, this study aimed to test an improved ApBM (ApBM +), where smokers were trained to approach personalized alternative activities for smoking in the context of increased craving, in addition to training smoking-avoidance responses. METHODS: Sixty-seven daily smokers motivated to quit (M age = 29.27, 58.2% female) were randomly assigned to seven sessions of either ApBM + (n = 26), standard-ApBM (n = 19), or sham-ApBM (n = 22), after a brief motivational smoking intervention. Primary outcomes of approach biases for smoking and for alternative activities and secondary outcomes of smoking-related behaviors were assessed at pre-test, post-test, and 1-month follow-up. RESULTS: Overall, no group differences by condition were demonstrated in changing approach biases or smoking-related behaviors at post-test and 1-month follow-up. A trend level indication for differences in changes of smoking-approach biases between sham-ApBM and ApBM + for relatively heavy smokers was found at post-test. This was primarily driven by a significant increase in smoking-approach biases within the sham-ApBM condition and a trend decrease in smoking-approach biases within the ApBM + condition. CONCLUSIONS: Our findings did not provide support for the current ApBM + concerning improved effects across the whole sample. Diverging training effects on approach biases for smoking in relatively heavy smokers warrants further research, for which we provide some suggestions.

Challenges in Recruiting University Students for Web-Based Indicated Prevention of Depression and Anxiety: Results From a Randomized Controlled Trial (ICare Prevent).

BACKGROUND: Depression and anxiety are common mental health conditions in college and university student populations. Offering transdiagnostic, web-based prevention programs such as ICare Prevent to those with subclinical complaints has the potential to reduce some barriers to receiving help (eg, availability of services, privacy considerations, and students' desire for autonomy). However, uptake of these interventions is often low, and accounts of recruitment challenges are needed to complement available effectiveness research in student populations. OBJECTIVE: The aims of this study were to describe recruitment challenges together with effective recruitment strategies for ICare Prevent and provide basic information on the intervention's effectiveness. METHODS: A 3-arm randomized controlled trial was conducted in a student sample with subclinical symptoms of depression and anxiety on the effectiveness of an individually guided (human support and feedback on exercises provided after each session, tailored to each participant) and automatically guided (computer-generated messages provided after each session, geared toward motivation) version of ICare Prevent, a web-based intervention with transdiagnostic components for the indicated prevention of depression and anxiety. The intervention was compared with care as usual. Descriptive statistics were used to outline recruitment challenges and effective web-based and offline strategies as well as students' use of the intervention. A basic analysis of intervention effects was conducted using a Bayesian linear mixed model, with Bayes factors reported as the effect size. RESULTS: Direct recruitment through students' email addresses via the central student administration was the most effective strategy. Data from 35 participants were analyzed (individually guided: n=14, 40%; automatically guided: n=8, 23%; care as usual: n=13, 37%). Use of the intervention was low, with an average of 3 out of 7 sessions (SD 2.9) completed. The analyses did not suggest any intervention effects other than anecdotal evidence (all Bayes factors10≤2.7). CONCLUSIONS: This report adds to the existing literature on recruitment challenges specific to the student population. Testing the feasibility of recruitment measures and the greater involvement of the target population in their design, as well as shifting from direct to indirect prevention, can potentially help future studies in the field. In addition, this report demonstrates an alternative basic analytical strategy for underpowered randomized controlled trials. TRIAL REGISTRATION: International Clinical Trials Registry Platform NTR6562; https://tinyurl.com/4rbexzrk. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-018-2477-y.

Effectiveness and acceptability of conversational agents for sexual health promotion: a systematic review and meta-analysis.

Digital health interventions for sexual health promotion have evolved considerably alongside innovations in technology. Despite these efforts, studies have shown that they do not consistently result in the desired sexual health outcomes. This could be attributed to low levels of user engagement, which can hinder digital health intervention effectiveness, as users do not engage with the system enough to be exposed to the intervention components. It has been suggested that conversational agents (automated two-way communication systems e.g. Alexa) have the potential to overcome the limitations of prior systems and promote user engagement through the increased interactivity offered by bidirectional, natural language-based interactions. The present review, therefore, provides an overview of the effectiveness and user acceptability of conversational agents for sexual health promotion. A systematic search of seven databases provided 4534 records, and after screening, 31 articles were included in this review. A narrative synthesis of results was conducted for effectiveness and acceptability outcomes, with the former supplemented by a meta-analysis conducted on a subset of studies. Findings provide preliminary support for the effectiveness of conversational agents for promoting sexual health, particularly treatment adherence. These conversational agents were found to be easy to use and useful, and importantly, resulted in high levels of satisfaction, use and intentions to reuse, whereas user evaluations regarding the quality of information left room for improvement. The results can inform subsequent efforts to design and evaluate these interventions, and offer insight into additional user experience constructs identified outside of current technology acceptance models, which can be incorporated into future theoretical developments.

Best research practices for using the Implicit Association Test.

Interest in unintended discrimination that can result from implicit attitudes and stereotypes (implicit biases) has stimulated many research investigations. Much of this research has used the Implicit Association Test (IAT) to measure association strengths that are presumed to underlie implicit biases. It had been more than a decade since the last published treatment of recommended best practices for research using IAT measures. After an initial draft by the first author, and continuing through three subsequent drafts, the 22 authors and 14 commenters contributed extensively to refining the selection and description of recommendation-worthy research practices. Individual judgments of agreement or disagreement were provided by 29 of the 36 authors and commenters. Of the 21 recommended practices for conducting research with IAT measures presented in this article, all but two were endorsed by 90% or more of those who felt knowledgeable enough to express agreement or disagreement; only 4% of the totality of judgments expressed disagreement. For two practices that were retained despite more than two judgments of disagreement (four for one, five for the other), the bases for those disagreements are described in presenting the recommendations. The article additionally provides recommendations for how to report procedures of IAT measures in empirical articles.

Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: a systematic review.

BACKGROUND: Poor mental health has consistently been associated with substance use (smoking, alcohol drinking, cannabis use, and consumption of caffeinated drinks). To properly inform public health policy it is crucial to understand the mechanisms underlying these associations, and most importantly, whether or not they are causal. METHODS: In this pre-registered systematic review, we assessed the evidence for causal relationships between mental health and substance use from Mendelian randomization (MR) studies, following PRISMA. We rated the quality of included studies using a scoring system that incorporates important indices of quality, such as the quality of phenotype measurement, instrument strength, and use of sensitivity methods. RESULTS: Sixty-three studies were included for qualitative synthesis. The final quality rating was '-' for 16 studies, '- +' for 37 studies, and '+'for 10 studies. There was robust evidence that higher educational attainment decreases smoking and that there is a bi-directional, increasing relationship between smoking and (symptoms of) mental disorders. Another robust finding was that higher educational attainment increases alcohol use frequency, but decreases binge-drinking and alcohol use problems, and that mental disorders causally lead to more alcohol drinking without evidence for the reverse. CONCLUSIONS: The current MR literature increases our understanding of the relationship between mental health and substance use. Bi-directional causal relationships are indicated, especially for smoking, providing further incentive to strengthen public health efforts to decrease substance use. Future MR studies should make use of large(r) samples in combination with detailed phenotypes, a wide range of sensitivity methods, and triangulate with other research methods.

A computational network perspective on pediatric anxiety symptoms.

BACKGROUND: While taxonomy segregates anxiety symptoms into diagnoses, patients typically present with multiple diagnoses; this poses major challenges, particularly for youth, where mixed presentation is particularly common. Anxiety comorbidity could reflect multivariate, cross-domain interactions insufficiently emphasized in current taxonomy. We utilize network analytic approaches that model these interactions by characterizing pediatric anxiety as involving distinct, inter-connected, symptom domains. Quantifying this network structure could inform views of pediatric anxiety that shape clinical practice and research. METHODS: Participants were 4964 youths (ages 5-17 years) from seven international sites. Participants completed standard symptom inventory assessing severity along distinct domains that follow pediatric anxiety diagnostic categories. We first applied network analytic tools to quantify the anxiety domain network structure. We then examined whether variation in the network structure related to age (3-year longitudinal assessments) and sex, key moderators of pediatric anxiety expression. RESULTS: The anxiety network featured a highly inter-connected structure; all domains correlated positively but to varying degrees. Anxiety patients and healthy youth differed in severity but demonstrated a comparable network structure. We noted specific sex differences in the network structure; longitudinal data indicated additional structural changes during childhood. Generalized-anxiety and panic symptoms consistently emerged as central domains. CONCLUSIONS: Pediatric anxiety manifests along multiple, inter-connected symptom domains. By quantifying cross-domain associations and related moderation effects, the current study might shape views on the diagnosis, treatment, and study of pediatric anxiety.

Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization.

Attention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance use, but the nature of this association is not fully understood. To inform intervention development and public health messages, a vital question is whether there are causal pathways from ADHD to substance use and/or vice versa. We applied bidirectional Mendelian randomization, using summary-level data from the largest available genome-wide association studies (GWAS) on ADHD, smoking (initiation, cigarettes per day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks per week, alcohol problems, and alcohol dependence), cannabis use (initiation), and coffee consumption (cups per day). Genetic variants robustly associated with the "exposure" were selected as instruments and identified in the "outcome" GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses (weighted median, weighted mode, MR-Egger, generalized summary data-based MR, and Steiger filtering). We found evidence that liability to ADHD increases likelihood of smoking initiation and heaviness of smoking among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation. There was weak evidence that liability to ADHD increases alcohol dependence risk but not drinks per week or alcohol problems. In the other direction, there was weak evidence that smoking initiation increases ADHD risk, but follow-up analyses suggested a high probability of horizontal pleiotropy. There was no clear evidence of causal pathways between ADHD and coffee consumption. Our findings corroborate epidemiological evidence, suggesting causal pathways from liability to ADHD to smoking, cannabis use, and, tentatively, alcohol dependence. Further work is needed to explore the exact mechanisms mediating these causal effects.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Moderate acute alcohol use impairs intentional inhibition rather than stimulus-driven inhibition.

Moderate alcohol intake may impair stimulus-driven inhibition of motor actions in go/no-go and stop-signal tasks. Exposure to alcohol-related cues has been found to exacerbate this impairment. By contrast, the effect of alcohol use on intentional inhibition, or the capacity to voluntarily suspend an action, has rarely been investigated. We examined whether and how moderate alcohol intake affects stimulus-driven inhibition (stop-signal task) and intentional inhibition (chasing bottles task), during exposure to alcohol-related stimuli. One hundred and eleven participants were randomly assigned to an alcohol (male: 0.55 g/kg, female: 0.45 g/kg), placebo, or control group. For the stop-signal task, ANOVAs were performed on stop-signal reaction time (SSRT) and go RT with Pharmacological and Expectancy Effects of Alcohol, Stimulus Category (alcohol-related or neutral), and Sex as factors. For the chasing bottles task, multilevel survival analysis was performed to predict whether and when intentional inhibition was initiated, with the same factors. For the stop-signal task, Sex moderated the Pharmacological Effect of Alcohol on SSRT: only for females, alcohol consumption shortened SSRT. In the non-alcohol groups, males had shorter SSRT than females. Concerning intentional inhibition, the alcohol group initiated intentional inhibition less often, especially when stimuli were non-alcohol related. These findings indicate that (1) stimulus-driven inhibition and intentional inhibition reflect different aspects of response inhibition; (2) moderate alcohol intake negatively affects intentional inhibition (but not stimulus-driven inhibition). Speculatively, the observed impairment in intentional inhibition might underlie the lack of control over alcohol drinking behavior after a priming dose. This study highlights the potential role of intentional inhibition in the development of addiction.

(No) escape from reality? Cigarette craving in virtual smoking environments.

Cue-Exposure Therapy (CET) is considered an effective strategy to combat cigarette cravings and smoking relapses, but evidence is mixed. In this lab-based experimental study, we manipulated levels of realism for smoking scenarios in Virtual Environments (VE) and randomly exposed smokers and recent-quitters to one of two versions (low versus high realism) of these scenarios. Prior and after scenario exposure, valid measures of cigarette craving were obtained. Prior to exposure, we assessed nicotine dependence and smoking status (current smokers versus recent-quitter). Within-subject repeated measures analysis of covariance showed that there was an interaction of experimental condition with smoking status on cigarette craving. Amongst recent-quitters, high realistic scenarios produced stronger increases in craving than low realistic scenarios, but this effect was reversed in current smokers. It is concluded that VE technologies are a potentially relevant tool for smoking CET that warrant further exploration.