A longitudinal mediation study of peer victimization and resting-state functional connectivity as predictors of development of adolescent psychopathology.

Background: Peer victimization (PV) is associated with alterations in neural responses in regions subserving emotional regulatory processes and with increased risk of psychopathology during adolescence. The present study examined the longitudinal mediating effects of resting-state functional connectivity (rsFC) between adolescent PV and subsequent internalizing (depression and anxiety), and externalizing (conduct and hyperactivity/inattention) symptoms. Methods: 151 adolescents (baseline mean age 12-14; 54% males) were assessed and imaged three times during a five-year period. We focused on rsFC of a priori determined Regions-of-Interest (ROIs) guided by the literature (i.e., amygdala, anterior and posterior insula, anterior cingulate cortex, and medial prefrontal cortex). Multilevel mediation (MLM) analyses simultaneously examined the between-person, concurrent within-person, and lagged within-person associations between PV and internalizing/externalizing symptoms through changes in couplings of the amygdala with the other four ROIs. All models controlled for the effects of self-reported childhood maltreatment and sex differences. Results: An increased rsFC of the amygdala-posterior insula significantly mediated the lagged within-person association of PV and internalizing symptoms (ß = 0.144; 95% CI [0.018, 0.332]). This effect was significant regardless of childhood maltreatment, concurrent externalizing symptoms, and sex differences. The rsFC did not mediate the relationship between PV and externalizing symptoms. Conclusions: Results of this study suggest that adolescent PV may lead to long-lasting maladaptive neural communication between emotional response and sensory perception of pain (i.e., bottom-up emotion regulation) and that these neural responses may serve as unique markers for increased internalizing symptoms that appear in later adolescence in peer-victimized youth. These findings have implications for interventions targeting internalizing symptoms in victimized adolescents.

Sleep as a Mediator Between Cannabis Use and Psychosis Vulnerability: A Longitudinal Cohort Study.

Objectives: Increasing evidence implicates cannabis consumption as a key risk factor in the development of psychosis, but the mechanisms underpinning this relationship remain understudied. This study proposes to determine whether sleep disruption acts as a mediator of the cannabis-to-psychosis relationship. Study Design: This longitudinal study assessed measures of cannabis use frequency, sleep quality (SQ), and psychotic-like experiences (PLEs) were collected using self-reported questionnaires. Data were collected from September 2012 to September 2018. Data were collected from a general population sample of adolescents who entered the seventh grade in 31 schools in the Greater Montreal area. The study uses data collected on an annual basis from 3801 high school students from grades 7 to 11. The aforementioned measures were measured using the Detection of Alcohol and Drug Problems in Adolescents questionnaire, a SQ Likert scale, and measures the Psychotic-Like Experiences Questionnaire for Children. Study Results: Results show a reciprocal 1-year cross-lagged effect of cannabis use and sleep (ß = -0.076, 95% CI = -0.037 to -0.018, P = .000), of sleep on cannabis use (ß = -.016, 95% CI = -0.025 to -0.006, P = .007), of sleep on PLEs (ß = -0.077, 95%CI = -0.014 to -0.051, P = .000), and of PLEs on sleep (ß = -0.027, 95% CI = -0.037 to -0.018, P = .000). We additionally found a 2 years indirect lagged-effect of cannabis use on PLEs (ß = 0.068, 95% CI = 0.024 to 0.113, P = .011) mediated by 1-year sleep (ß = 0.006, 95% CI = 0.003 to 0.009, P = .001). Conclusions: Our results suggest sleep disruptions simultaneously aggravate, and are aggravated by, cannabis addiction and PLEs. The longitudinal sleep-mediated effect of cannabis use on PLEs encourages further research into the role of sleep as a potential therapeutic target in the prevention of cannabis-related psychosis.

Cross-lagged Relationships Between Depressive Symptoms and Altered Default Mode Network Connectivity Over the Course of Adolescence.

BACKGROUND: Although the peak onset of depressive symptoms occurs during adolescence, very few studies have directly examined depression-related changes in resting-state (RS) default mode network activity during adolescence, controlling for potential neural markers of risk. METHODS: This study used data from a longitudinal adolescent cohort to investigate age-specific, persistent (i.e., lagged), and dynamic associations between RS functional connectivity within the default mode network and depressive symptoms during adolescence using a random intercept cross-lagged panel framework. The Neuroventure sample consisted of 151 adolescents ages 12-14 at study entry without any neurological illness who were assessed three times during a 5-year follow-up with 97% follow-up across the three assessments. Depressive symptoms were measured using the depression subscale of the Brief Symptoms Inventory. RS functional magnetic resonance imaging data were collected using a 3T Siemens Magnetom Trio scanner in a single 6-minute sequence. RESULTS: After controlling for relationships between random intercepts, future depression risk was predicted by RS couplings in the perigenual anterior cingulate cortex and anterior dorsomedial prefrontal cortex (ß = -0.69, p = .014) and in the left inferior parietal lobule and anterior superior frontal gyrus (ß = -0.43, p = .035). Increases in depressive symptoms at previous time points significantly predicted changes in functional connectivity between the posterior cingulate cortex and the precuneus and posterior middle temporal gyrus (ß = 0.37, p = .039) and between the dorsal precuneus and posterior middle temporal gyrus (ß = 0.47, p = .036). CONCLUSIONS: This study was able to disassociate the RS brain markers of depression from those that appear to follow early-onset depression.

Endocannabinoid Gene × Gene Interaction Association to Alcohol Use Disorder in Two Adolescent Cohorts.

Genetic markers of the endocannabinoid system have been linked to a variety of addiction-related behaviors that extend beyond cannabis use. In the current study we investigate the relationship between endocannabinoid (eCB) genetic markers and alcohol use disorder (AUD) in European adolescents (14-18 years old) followed in the IMAGEN study (n = 2,051) and explore replication in a cohort of North American adolescents from Canadian Saguenay Youth Study (SYS) (n = 772). Case-control status is represented by a score of more than 7 on the Alcohol Use Disorder Identification Test (AUDIT). First a set-based test method was used to examine if a relationship between the eCB system and AUDIT case/control status exists at the gene level. Using only SNPs that are both independent and significantly associated to case-control status, we perform Fisher's exact test to determine SNP level odds ratios in relation to case-control status and then perform logistic regressions as post-hoc analysis, while considering various covariates. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the most robust SNP×SNP interaction of the five eCB genes with positive AUDIT screen. While no gene-sets were significantly associated to AUDIT scores after correction for multiple tests, in the case/control analysis, 7 SNPs were significantly associated with AUDIT scores of > 7 (p < 0.05; OR<1). Two SNPs remain significant after correction by false discovery rate (FDR): rs9343525 in CNR1 (pcorrected =0.042, OR = 0.73) and rs507961 in MGLL (pcorrected = 0.043, OR = 0.78). Logistic regression showed that both rs9353525 (CNR1) and rs507961 (MGLL) remained significantly associated with positive AUDIT screens (p < 0.01; OR < 1) after correction for multiple covariables and interaction of covariable × SNP. This result was not replicated in the SYS cohort. The GMDR model revealed a significant three-SNP interaction (p = 0.006) involving rs484061 (MGLL), rs4963307 (DAGLA), and rs7766029 (CNR1) predicted case-control status, after correcting for multiple covariables in the IMAGEN sample. A binomial logistic regression of the combination of these three SNPs by phenotype in the SYS cohort showed a result in the same direction as seen in the IMAGEN cohort (BETA = 0.501, p = 0.06). While preliminary, the present study suggests that the eCB system may play a role in the development of AUD in adolescents.

Adolescent Resting-State Brain Networks and Unique Variability of Conduct Problems Within the Externalizing Dimension.

The externalizing psychopathological dimension is associated with alterations in adolescents' functional brain connectivity. The current study aims to identify the functional correlates of the unique variability in conduct problems within the context of the broad externalizing dimension. The broad externalizing dimension and unique variability in conduct problems were estimated using a bifactor model. Resting-state data were available for a sample of 125 adolescents. Based on multiresolution parcellation of functional brain networks atlas, major resting-state functional brain networks and the connectivity correlates of unique conduct problems and the broad externalizing dimension were established. The broad externalizing dimension was related to connectivity alterations in the ventral attention/salience network, while unique variability in conduct problems dimension was related to connectivity alterations in the cerebellum crusi as well as the mesolimbic network. The current study is a first step toward the identification of functional resting-state network correlates of broad and specific variability in the externalizing dimension.