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Importance: Animal studies have shown that the adolescent brain is sensitive to disruptions in endocannabinoid signaling, resulting in altered neurodevelopment and lasting behavioral effects. However, few studies have investigated ties between cannabis use and adolescent brain development in humans.Objective: To examine the degree to which magnetic resonance (MR) imaging-assessed cerebral cortical thickness development is associated with cannabis use in a longitudinal sample of adolescents.Design, Setting, and Participants: Data were obtained from the community-based IMAGEN cohort study, conducted across 8 European sites. Baseline data used in the present study were acquired from March 1, 2008, to December 31, 2011, and follow-up data were acquired from January 1, 2013, to December 31, 2016. A total of 799 IMAGEN participants were identified who reported being cannabis naive at study baseline and had behavioral and neuroimaging data available at baseline and 5-year follow-up. Statistical analysis was performed from October 1, 2019, to August 31, 2020.Main Outcomes and Measures: Cannabis use was assessed at baseline and 5-year follow-up with the European School Survey Project on Alcohol and Other Drugs. Anatomical MR images were acquired with a 3-dimensional T1-weighted magnetization prepared gradient echo sequence. Quality-controlled native MR images were processed through the CIVET pipeline, version 2.1.0.Results: The study evaluated 1598 MR images from 799 participants (450 female participants [56.3%]; mean [SD] age, 14.4 [0.4] years at baseline and 19.0 [0.7] years at follow-up). At 5-year follow-up, cannabis use (from 0 to >40 uses) was negatively associated with thickness in left prefrontal (peak: t785 = -4.87, cluster size = 1558 vertices; P = 1.10 × 10-6, random field theory cluster corrected) and right prefrontal (peak: t785 = -4.27, cluster size = 1551 vertices; P = 2.81 × 10-5, random field theory cluster corrected) cortices. There were no significant associations between lifetime cannabis use at 5-year follow-up and baseline cortical thickness, suggesting that the observed neuroanatomical differences did not precede initiation of cannabis use. Longitudinal analysis revealed that age-related cortical thinning was qualified by cannabis use in a dose-dependent fashion such that greater use, from baseline to follow-up, was associated with increased thinning in left prefrontal (peak: t815.27 = -4.24, cluster size = 3643 vertices; P = 2.28 × 10-8, random field theory cluster corrected) and right prefrontal (peak: t813.30 = -4.71, cluster size = 2675 vertices; P = 3.72 × 10-8, random field theory cluster corrected) cortices. The spatial pattern of cannabis-related thinning was associated with age-related thinning in this sample (r = 0.540; P < .001), and a positron emission tomography-assessed cannabinoid 1 receptor-binding map derived from a separate sample of participants (r = -0.189; P < .001). Analysis revealed that thinning in right prefrontal cortices, from baseline to follow-up, was associated with attentional impulsiveness at follow-up.Conclusions and Relevance: Results suggest that cannabis use during adolescence is associated with altered neurodevelopment, particularly in cortices rich in cannabinoid 1 receptors and undergoing the greatest age-related thickness change in middle to late adolescence. [ABSTRACT FROM AUTHOR]

Importance: Alcohol abuse correlates with gray matter development in adolescents, but the directionality of this association remains unknown.Objective: To investigate the directionality of the association between gray matter development and increase in frequency of drunkenness among adolescents.Design, Setting, and Participants: This cohort study analyzed participants of IMAGEN, a multicenter brain imaging study of healthy adolescents in 8 European sites in Germany (Mannheim, Dresden, Berlin, and Hamburg), the United Kingdom (London and Nottingham), Ireland (Dublin), and France (Paris). Data from the second follow-up used in the present study were acquired from January 1, 2013, to December 31, 2016, and these data were analyzed from January 1, 2016, to March 31, 2018. Analyses were controlled for sex, site, socioeconomic status, family history of alcohol dependency, puberty score, negative life events, personality, cognition, and polygenic risk scores. Personality and frequency of drunkenness were assessed at age 14 years (baseline), 16 years (first follow-up), and 19 years (second follow-up). Structural brain imaging scans were acquired at baseline and second follow-up time points.Main Outcomes and Measures: Increases in drunkenness frequency were measured by latent growth modeling, a voxelwise hierarchical linear model was used to observe gray matter volume, and tensor-based morphometry was used for gray matter development. The hypotheses were formulated before the data analyses.Results: A total of 726 adolescents (mean [SD] age at baseline, 14.4 [0.38] years; 418 [58%] female) were included. The increase in drunkenness frequency was associated with accelerated gray matter atrophy in the left posterior temporal cortex (peak: t1,710 = -5.8; familywise error (FWE)-corrected P = 7.2 × 10-5; cluster: 6297 voxels; P = 2.7 × 10-5), right posterior temporal cortex (cluster: 2070 voxels; FWE-corrected P = .01), and left prefrontal cortex (peak: t1,710 = -5.2; FWE-corrected P = 2 × 10-3; cluster: 10 624 voxels; P = 1.9 × 10-7). According to causal bayesian network analyses, 73% of the networks showed directionality from gray matter development to drunkenness increase as confirmed by accelerated gray matter atrophy in late bingers compared with sober controls (n = 20 vs 60; β = 1.25; 95% CI, -2.15 to -0.46; t1,70 = 0.3; P = .004), the association of drunkenness increase with gray matter volume at age 14 years (β = 0.23; 95% CI, 0.01-0.46; t1,584 = 2; P = .04), the association between gray matter atrophy and alcohol drinking units (β = -0.0033; 95% CI, -6 × 10-3 to -5 × 10-4; t1,509 = -2.4; P = .02) and drunkenness frequency at age 23 years (β = -0.16; 95% CI, -0.28 to -0.03; t1,533 = -2.5; P = .01), and the linear exposure-response curve stratified by gray matter atrophy and not by increase in frequency of drunkenness.Conclusions and Relevance: This study found that gray matter development and impulsivity were associated with increased frequency of drunkenness by sex. These results suggest that neurotoxicity-related gray matter atrophy should be interpreted with caution. [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]

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group ( n = 70) of 14-year olds with a history of cannabis use to a group ( n = 70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]