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Importance: Past studies have identified associations between brain macrostructure and alcohol use behaviors. However, identifying directional associations between these phenotypes is difficult due to the limitations of observational studies.Objective: To use mendelian randomization (MR) to identify directional associations between brain structure and alcohol use and elucidate the transcriptomic and cellular underpinnings of identified associations.Design, Setting, and Participants: The main source data comprised summary statistics from population-based and case-control genome-wide association studies (GWAS) of neuroimaging, behavioral, and clinical phenotypes (N = 763 874). Using these data, bidirectional and multivariable MR was performed analyzing associations between brain macrostructure and alcohol use. Downstream transcriptome-wide association studies (TWAS) and cell-type enrichment analyses investigated the biology underlying identified associations. The study approach was data driven and did not test any a priori hypotheses. Data were analyzed August 2021 to May 2022.Main Outcomes and Measures: Brain structure phenotypes (global cortical thickness [GCT] and global cortical surface area [GCSA] in 33 709 individuals and left-right subcortical volumes in 19 629 individuals) and alcohol use behaviors (alcoholic drinks per week [DPW] in 537 349 individuals, binge drinking frequency in 143 685 individuals, and alcohol use disorder in 8845 individuals vs 20 657 control individuals [total of 29 502]).Results: The main bidirectional MR analyses were performed in samples totaling 763 874 individuals, among whom more than 94% were of European ancestry, 52% to 54% were female, and the mean cohort ages were 40 to 63 years. Negative associations were identified between genetically predicted GCT and binge drinking (β, -2.52; 95% CI, -4.13 to -0.91) and DPW (β, -0.88; 95% CI, -1.37 to -0.40) at a false discovery rate (FDR) of 0.05. These associations remained significant in multivariable MR models that accounted for neuropsychiatric phenotypes, substance use, trauma, and neurodegeneration. TWAS of GCT and alcohol use behaviors identified 5 genes at the 17q21.31 locus oppositely associated with GCT and binge drinking or DPW (FDR = 0.05). Cell-type enrichment analyses implicated glutamatergic cortical neurons in alcohol use behaviors.Conclusions and Relevance: The findings in this study show that the associations between GCT and alcohol use may reflect a predispositional influence of GCT and that 17q21.31 genes and glutamatergic cortical neurons may play a role in this association. While replication studies are needed, these findings should enhance the understanding of associations between brain structure and alcohol use. [ABSTRACT FROM AUTHOR]

Importance: Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology.Objective: To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations.Design, Setting, and Participants: Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018.Main Outcomes and Measures: Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip.Results: The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87; P = 1.70 × 10-4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = -3.05; P = .002; n = 157) and unaffected siblings (z = -2.08; P = .04; n = 149).Conclusions and Relevance: Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation. [ABSTRACT FROM AUTHOR]

Key Points: Question: Are psychoticlike experiences in adolescents associated with altered prefrontal and striatal activation during reward processing? Findings: In this cohort study of 298 adolescents, those with an elevated rate of psychoticlike experiences at age 14 years demonstrated reduced activation in prefrontal and limbic cortical areas during reward processing compared with adolescents with no psychoticlike experiences. However, by age 19 years, the group with the elevated rate of psychoticlike experiences showed differentially increased activation of the right prefrontal cortex and reduced activation of dorsal striatum. Meaning: Adolescents with an elevated rate of psychoticlike experiences show differential activation in frontostriatal brain areas engaged during reward processing compared with control adolescents; given the nonclinical nature of the sample, the increase in prefrontal cortical activation from early to late adolescence may reflect a compensatory cognitive mechanism in the presence of abnormal striatal reward processing to contextualize these abnormal experiences. Importance: Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective: To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants: A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures: Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results: Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation (F1, 93 = 5.559; P =.02; F1, 93 = 5.009; P =.03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction (F1, 93 = 7.448; P =.01). Conclusion and Relevance: The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them. This cohort study examines the rate of psychoticlike experiences in adolescents. [ABSTRACT FROM AUTHOR]

The ABCD study is recruiting and following the brain development and health of over 10,000 9–10 year olds through adolescence. The imaging component of the study was developed by the ABCD Data Analysis and Informatics Center (DAIC) and the ABCD Imaging Acquisition Workgroup. Imaging methods and assessments were selected, optimized and harmonized across all 21 sites to measure brain structure and function relevant to adolescent development and addiction. This article provides an overview of the imaging procedures of the ABCD study, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature. [ABSTRACT FROM AUTHOR]

Previous research has suggested an association between living environment during the first 15 years of life and brain structure. More precisely, urbanicity during upbringing has been shown to be negatively related to prefrontal cortex grey matter. The present study focusses instead on the current living environment of 677 younger adults recruited from different cities across Europe. We observed a positive association between amount of tree cover density, in a radius of 500m around the current home address and grey matter volume in right orbitofrontal cortex (rOFC). Of note, the volume of the rOFC cluster identified, showed a positive association with cognitive performance in the Wechsler Adult Intelligence Scale, namely in the verbal and spatial ability domain (Vocabulary, Block Design), and a negative association with both, self-reported and behavioural markers of impulsivity (delay discounting). Moreover, rOFC volume showed a negative association with self-reported alcohol use problems. The data provide strong evidence in favour of a link between geographical features of the current living environment (particularly trees) and brain structure above and beyond childhood and upbringing. Interestingly, the respective brain correlates are associated with cognitive, behavioural and personality characteristics which have been considered as risk factors for several psychiatric disorders. Environmental neuroscience may in the long run provide a knowledge base for evidence-based urban landscape planning to facilitate mental health. • Urbanicity during upbringing is negatively associated with prefrontal cortex volume • We used data from 677 younger adults from different European cities • Current tree cover density at home was positively related to orbitofrontal cortex • The lOFC cluster was positively associated to cognitive performance • The lOFC cluster was negatively associated with markers of impulsivity [ABSTRACT FROM AUTHOR]

Although many studies of the adolescent brain identified positive associations between cognitive abilities and cortical thickness, little is known about mechanisms underlying such brain-behavior relationships. With experience-induced plasticity playing an important role in shaping the cerebral cortex throughout life, it is likely that some of the inter-individual variations in cortical thickness could be explained by genetic variations in relevant molecular processes, as indexed by a polygenic score of neuronal plasticity (PGS-NP). Here, we studied associations between PGS-NP, cognitive abilities, and thickness of the cerebral cortex, estimated from magnetic resonance images, in the Saguenay Youth Study (SYS, 533 females, 496 males: age=15.0 ± 1.8 years of age; cross-sectional), and the IMAGEN Study (566 females, 556 males; between 14 and 19 years; longitudinal). Using Gene Ontology, we first identified 199 genes implicated in neuronal plasticity, which mapped to 155,600 single nucleotide polymorphisms (SNPs). Second, we estimated their effect sizes from an educational attainment meta-GWAS to build a PGS-NP. Third, we examined a possible moderating role of PGS-NP in the relationship between performance intelligence quotient (PIQ), and its subtests, and the thickness of 34 cortical regions. In SYS, we observed a significant interaction between PGS-NP and object assembly vis-à-vis thickness in male adolescents (p = 0.026). A median-split analysis showed that, in males with a 'high' PGS-NP, stronger associations between object assembly and thickness were found in regions with larger age-related changes in thickness (r = 0.55, p = 0.00075). Although the interaction between PIQ and PGS-NP was non-significant (p = 0.064), we performed a similar median-split analysis. Again, in the high PGS-NP males, positive associations between PIQ and thickness were observed in regions with larger age-related changes in thickness (r = 0.40, p = 0.018). In the IMAGEN cohort, we did not replicate the first set of results (interaction between PGS-NP and cognitive abilities via-a-vis cortical thickness) while we did observe the same relationship between the brain-behaviour relationship and (longitudinal) changes in cortical thickness (Matrix reasoning: r = 0.63, p = 6.5e-05). No statistically significant results were observed in female adolescents in either cohort. Overall, these cross-sectional and longitudinal results suggest that molecular mechanisms involved in neuronal plasticity may contribute to inter-individual variations of cortical thickness related to cognitive abilities during adolescence in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Sleep is an important contributor for neural maturation and emotion regulation during adolescence, with long-term effects on a range of white matter tracts implicated in affective processing in at-risk populations. We investigated the effects of adolescent sleep patterns on longitudinal changes in white matter development and whether this is related to the emergence of emotional (internalizing) problems. Sleep patterns and internalizing problems were assessed using self-report questionnaires in adolescents recruited in the general population followed up from age 14–19 years (N = 111 White matter structure was measured using diffusion tensor imaging (DTI) and estimated using fractional anisotropy (FA). We found that longitudinal increases in time in bed (TIB) on weekends and increases in TIB-variability between weekdays to weekend, were associated with an increase in FA in various interhemispheric and cortico-striatal tracts. Extracted FA values from left superior longitudinal fasciculus mediated the relationship between increases in TIB on weekends and a decrease in internalizing problems. These results imply that while insufficient sleep might have potentially harmful effects on long-term white matter development and internalizing problems, longer sleep duration on weekends (catch-up sleep) might be a natural counteractive and protective strategy. [ABSTRACT FROM AUTHOR]

Importance: Psychotic disorders are characterized by attenuated activity in the brain's valuation system in key reward processing areas, such as the ventral striatum (VS), as measured with functional magnetic resonance imaging.Objective: To examine whether common risk variants for psychosis are associated with individual variation in the VS.Design, Setting, and Participants: A cross-sectional study of a large cohort of adolescents from the IMAGEN study (a European multicenter study of reinforcement sensitivity in adolescents) was performed from March 1, 2008, through December 31, 2011. Data analysis was conducted from October 1, 2015, to January 9, 2016. Polygenic risk profile scores (RPSs) for psychosis were generated for 1841 healthy adolescents. Sample size and characteristics varied across regression analyses, depending on mutual information available (N = 1524-1836).Main Outcomes and Measures: Reward-related brain function was assessed with blood oxygen level dependency (BOLD) in the VS using the monetary incentive delay (MID) task, distinguishing reward anticipation and receipt. Behavioral impulsivity, IQ, MID task performance, and VS BOLD were regressed against psychosis RPS at 4 progressive P thresholds (P < .01, P < .05, P < .10, and P < .50 for RPS models 1-4, respectively).Results: In a sample of 1841 healthy adolescents (mean age, 14.5 years; 906 boys and 935 girls), we replicated an association between increasing psychosis RPS and reduced IQ (matrix reasoning: corrected P = .003 for RPS model 2, 0.4% variance explained), supporting the validity of the psychosis RPS models. We also found a nominally significant association between increased psychosis RPS and reduced MID task performance (uncorrected P = .03 for RPS model 4, 0.2% variance explained). Our main finding was a positive association between psychosis RPS and VS BOLD during reward anticipation at all 4 psychosis RPS models and for 2 P thresholds for reward receipt (RPS models 1 and 3), correcting for the familywise error rate (0.8%-1.9% variance explained).Conclusions and Relevance: These findings support an association between psychosis RPS and VS BOLD in adolescents. Genetic risk for psychosis may shape an individual's response to rewarding stimuli. [ABSTRACT FROM AUTHOR]

To assess whether alcohol exposure was exacerbating the cannabis associations, we tested for an AUDIT-C score by cannabis use interaction on cortical thickness in the same regions of interest. Moreover, while the cannabis use association was significant, there were no significant AUDIT-C score by cannabis use interactions. Comment & Response B In Reply b We thank Kung et al for their thoughtful comments regarding the association of alcohol use with our findings.[1] The potential confounding or interactive associations of alcohol use when investigating cannabis associations is a perennial challenge with human research, but a number of analyses lead us to conclude that the cortical thinning we reported was most strongly associated with cannabis exposure. [Extracted from the article]

The Adolescent Brain Cognitive Development (ABCD)SM study aims to retain a demographically diverse sample of youth and one parent across 21 sites throughout its 10-year protocol while minimizing selective (systematic) attrition. To evaluate the effectiveness of these efforts, the ABCD Retention Workgroup (RW) has employed a data-driven approach to examine, track, and intervene via three key metrics: (1) which youth completed visits late; (2) which youth missed visits; and (3) which youth withdrew from the study. The RW actively examines demographic (race, education level, family income) and site factors (visit satisfaction, distance from site, and enrollment in ancillary studies) to strategize efforts that will minimize disengagement and loss of participating youth and parents. Data showed that the most robust primary correlates of late visits were distance from study site, race, and parental education level. Race, lower parental education level, parental employment status, and lower family income were associated with higher odds of missed visits, while being enrolled in one of the ancillary studies was associated with lower odds of missed visits. Additionally, parents who were primary Spanish speakers withdrew at slightly higher rates. These findings provide insight into future targets for proactive retention efforts by the ABCD RW. • Three metrics were used to track retention: late visits, missed visits, and study withdrawal. • Distance from study site, race, and parental education level were associated with late visits. • Race, parental education and parental employment were associated with missed visits. • Parental Spanish language preference was associated with study withdrawal. • Further retention efforts can be made to target and retain hard-to-reach families. [ABSTRACT FROM AUTHOR]

IMPORTANCE Higher rates of substance use and dependence have been observed in the offspring of mothers who smoked during pregnancy. Animal studies indicate that prenatal exposure to nicotine alters the development of brain areas related to reward processing, which might be a risk factor for substance use and addiction later in life. However, no study has examined the effect of maternal smoking on the offspring's brain response during reward processing. OBJECTIVE To determine whether adolescents with prenatal exposure to maternal cigarette smoking differ from their nonexposed peers in the response of the ventral striatum to the anticipation or the receipt of a reward. DESIGN An observational case-control study. SETTING Data were obtained from the IMAGEN Study, a European multicenter study of impulsivity, reinforcement sensitivity, and emotional reactivity in adolescents. The IMAGEN sample consists of 2078 healthy adolescents (age range, 13-15 years) recruited from March 1, 2008, through December 31, 2011, in local schools. PARTICIPANTS We assessed an IMAGEN subsample of 177 adolescents with prenatal exposure to maternal cigarette smoking and 177 nonexposed peers (age range, 13-15 years) matched by sex, maternal educational level, and imaging site. MAIN OUTCOME AND MEASURE Response to reward in the ventral striatum measured with functional magnetic resonance imaging. RESULTS In prenatally exposed adolescents, we observed a weaker response in the ventral striatum during reward anticipation (left side, F = 14.98 [P < .001]; right side, F = 15.95 [P < .001]) compared with their nonexposed peers. No differences were found regarding the responsivity of the ventral striatum to the receipt of a reward (left side, F = 0.21 [P = .65]; right side, F = 0.47 [P = .49]). CONCLUSIONS The weaker responsivity of the ventral striatum to reward anticipation in prenatally exposed adolescents may represent a risk factor for substance use and development of addiction later in life. This result highlights the need for education and preventive measures to reduce smoking during pregnancy. Future analyses should assess whether prenatally exposed adolescents develop an increased risk for substance use and addiction and which role the reported neuronal differences during reward anticipation plays in this development. [ABSTRACT FROM AUTHOR]

Abstract: Kelly C, Foxe JJ, Garavan H. Patterns of normal human brain plasticity after practice and their implications for neurorehabilitation. Objectives: To illustrate how our knowledge about normal patterns of experience-induced plasticity can provide insights into the mechanisms of neurorehabilitation; to provide an overview of the practice-effects literature in order to simplify and amalgamate a large number of heterogeneous findings and identify typical patterns of practice effects and their determining factors; and to concentrate on the impact of practice on higher cognitive functions, such as working memory, and present some preliminary but promising behavioral data that show how practice on a complex cognitive task can benefit cognitive functioning more generally. Data Sources: We performed a systematic search for peer-reviewed journal articles using computerized databases (PubMed, ISI Web of Science, PsycINFO). Data Selection: Neuroimaging studies using functional magnetic resonance imaging (fMRI) or positron-emission tomography (PET) to examine functional activation changes as a result of practice on sensory, motor, or cognitive tasks in normal (healthy) populations were included in the review. Further studies were identified that examined the effects of rehabilitative training on functional activations in clinical populations using fMRI or PET. Data Extraction: Important characteristics of the selected studies were summarized in a systematic manner so to enable the extraction of specific factors impacting on the pattern of practice effects observed. Data Synthesis: We identified a number of factors that impact on the patterns of practice effects observed and discuss how the insights gained from the study of healthy populations can by applied to rehabilitation of cognitive deficits in clinical populations. Conclusions: Progress in our understanding of neurorehabilitative plasticity will be enabled by neuroimaging examinations of cognitive rehabilitation training grounded in a knowledge of normal (healthy) patterns of brain activation and practice-induced plasticity. [Copyright &y& Elsevier]