Differential associations of adolescent versus young adult cannabis initiation with longitudinal brain change and behavior.

Leveraging ~10 years of prospective longitudinal data on 704 participants, we examined the effects of adolescent versus young adult cannabis initiation on MRI-assessed cortical thickness development and behavior. Data were obtained from the IMAGEN study conducted across eight European sites. We identified IMAGEN participants who reported being cannabis-naïve at baseline and had data available at baseline, 5-year, and 9-year follow-up visits. Cannabis use was assessed with the European School Survey Project on Alcohol and Drugs. T1-weighted MR images were processed through the CIVET pipeline. Cannabis initiation occurring during adolescence (14-19 years) and young adulthood (19-22 years) was associated with differing patterns of longitudinal cortical thickness change. Associations between adolescent cannabis initiation and cortical thickness change were observed primarily in dorso- and ventrolateral portions of the prefrontal cortex. In contrast, cannabis initiation occurring between 19 and 22 years of age was associated with thickness change in temporal and cortical midline areas. Follow-up analysis revealed that longitudinal brain change related to adolescent initiation persisted into young adulthood and partially mediated the association between adolescent cannabis use and past-month cocaine, ecstasy, and cannabis use at age 22. Extent of cannabis initiation during young adulthood (from 19 to 22 years) had an indirect effect on psychotic symptoms at age 22 through thickness change in temporal areas. Results suggest that developmental timing of cannabis exposure may have a marked effect on neuroanatomical correlates of cannabis use as well as associated behavioral sequelae. Critically, this work provides a foundation for neurodevelopmentally informed models of cannabis exposure in humans.

Maturational trajectories of pericortical contrast in typical brain development.

In the last few years, a significant amount of work has aimed to characterize maturational trajectories of cortical development. The role of pericortical microstructure putatively characterized as the gray-white matter contrast (GWC) at the pericortical gray-white matter boundary and its relationship to more traditional morphological measures of cortical morphometry has emerged as a means to examine finer grained neuroanatomical underpinnings of cortical changes. In this work, we characterize the GWC developmental trajectories in a representative sample (n = 394) of children and adolescents (~4 to ~22 years of age), with repeated scans (1-3 scans per subject, total scans n = 819). We tested whether linear, quadratic, or cubic trajectories of contrast development best described changes in GWC. A best-fit model was identified vertex-wise across the whole cortex via the Akaike Information Criterion (AIC). GWC across nearly the whole brain was found to significantly change with age. Cubic trajectories were likeliest for 63% of vertices, quadratic trajectories were likeliest for 20% of vertices, and linear trajectories were likeliest for 16% of vertices. A main effect of sex was observed in some regions, where males had a higher GWC than females. However, no sex by age interactions were found on GWC. In summary, our results suggest a progressive decrease in GWC at the pericortical boundary throughout childhood and adolescence. This work contributes to efforts seeking to characterize typical, healthy brain development and, by extension, can help elucidate aberrant developmental trajectories.

Ventromedial Prefrontal Volume in Adolescence Predicts Hyperactive/Inattentive Symptoms in Adulthood.

Youths with attention-deficit/hyperactivity disorder symptomatology often exhibit residual inattention and/or hyperactivity in adulthood; however, this is not true for all individuals. We recently reported that dimensional, multi-informant ratings of hyperactive/inattentive symptoms are associated with ventromedial prefrontal cortex (vmPFC) structure. Herein, we investigate the degree to which vmPFC structure during adolescence predicts hyperactive/inattentive symptomatology at 5-year follow-up. Structural equation modeling was used to test the extent to which adolescent vmPFC volume predicts hyperactive/inattentive symptomatology 5 years later in early adulthood. 1104 participants (M = 14.52 years, standard deviation = 0.42; 583 females) possessed hyperactive/inattentive symptom data at 5-year follow-up, as well as quality controlled neuroimaging data and complete psychometric data at baseline. Self-reports of hyperactive/inattentive symptomatology were obtained during adolescence and at 5-year follow-up using the Strengths and Difficulties Questionnaire (SDQ). At baseline and 5-year follow-up, a hyperactive/inattentive latent variable was derived from items on the SDQ. Baseline vmPFC volume predicted adult hyperactive/inattentive symptomatology (standardized coefficient = -0.274, P < 0.001) while controlling for baseline hyperactive/inattentive symptomatology. These results are the first to reveal relations between adolescent brain structure and adult hyperactive/inattentive symptomatology, and suggest that early structural development of the vmPFC may be consequential for the subsequent expression of hyperactive/inattentive symptoms.

The initiation of cannabis use in adolescence is predicted by sex-specific psychosocial and neurobiological features.

Cannabis use initiated during adolescence might precipitate negative consequences in adulthood. Thus, predicting adolescent cannabis use prior to any exposure will inform the aetiology of substance abuse by disentangling predictors from consequences of use. In this prediction study, data were drawn from the IMAGEN sample, a longitudinal study of adolescence. All selected participants (n = 1,581) were cannabis-naïve at age 14. Those reporting any cannabis use (out of six ordinal use levels) by age 16 were included in the outcome group (N = 365, males n = 207). Cannabis-naïve participants at age 14 and 16 were included in the comparison group (N = 1,216, males n = 538). Psychosocial, brain and genetic features were measured at age 14 prior to any exposure. Cross-validated regularized logistic regressions for each use level by sex were used to perform feature selection and obtain prediction error statistics on independent observations. Predictors were probed for sex- and drug-specificity using post-hoc logistic regressions. Models reliably predicted use as indicated by satisfactory prediction error statistics, and contained psychosocial features common to both sexes. However, males and females exhibited distinct brain predictors that failed to predict use in the opposite sex or predict binge drinking in independent samples of same-sex participants. Collapsed across sex, genetic variation on catecholamine and opioid receptors marginally predicted use. Using machine learning techniques applied to a large multimodal dataset, we identified a risk profile containing psychosocial and sex-specific brain prognostic markers, which were likely to precede and influence cannabis initiation.

Neural circuitry underlying sustained attention in healthy adolescents and in ADHD symptomatology.

Moment-to-moment reaction time variability on tasks of attention, often quantified by intra-individual response variability (IRV), provides a good indication of the degree to which an individual is vulnerable to lapses in sustained attention. Increased IRV is a hallmark of several disorders of attention, including Attention-Deficit/Hyperactivity Disorder (ADHD). Here, task-based fMRI was used to provide the first examination of how average brain activation and functional connectivity patterns in adolescents are related to individual differences in sustained attention as measured by IRV. We computed IRV in a large sample of adolescents (n = 758) across 'Go' trials of a Stop Signal Task (SST). A data-driven, multi-step analysis approach was used to identify networks associated with low IRV (i.e., good sustained attention) and high IRV (i.e., poorer sustained attention). Low IRV was associated with greater functional segregation (i.e., stronger negative connectivity) amongst an array of brain networks, particularly between cerebellum and motor, cerebellum and prefrontal, and occipital and motor networks. In contrast, high IRV was associated with stronger positive connectivity within the motor network bilaterally and between motor and parietal, prefrontal, and limbic networks. Consistent with these observations, a separate sample of adolescents exhibiting elevated ADHD symptoms had increased fMRI activation and stronger positive connectivity within the same motor network denoting poorer sustained attention, compared to a matched asymptomatic control sample. With respect to the functional connectivity signature of low IRV, there were no statistically significant differences in networks denoting good sustained attention between the ADHD symptom group and asymptomatic control group. We propose that sustained attentional processes are facilitated by an array of neural networks working together, and provide an empirical account of how the functional role of the cerebellum extends to cognition in adolescents. This work highlights the involvement of motor cortex in the integrity of sustained attention, and suggests that atypically strong connectivity within motor networks characterizes poor attentional capacity in both typically developing and ADHD symptomatic adolescents.

Individual differences in stop-related activity are inflated by the adaptive algorithm in the stop signal task.

Research using the Stop Signal Task employing an adaptive algorithm to accommodate individual differences often report inferior performance on the task in individuals with ADHD, OCD, and substance use disorders compared to non-clinical controls. Furthermore, individuals with deficits in inhibitory control tend to show reduced neural activity in key inhibitory regions during successful stopping. However, the adaptive algorithm systematically introduces performance-related differences in objective task difficulty that may influence the estimation of individual differences in stop-related neural activity. This report examines the effect that these algorithm-related differences have on the measurement of neural activity during the stop signal task. We compared two groups of subjects (n = 210) who differed in inhibitory ability using both a standard fMRI analysis and an analysis that resampled trials to remove the objective task difficulty confound. The results show that objective task difficulty influences the magnitude of between-group differences and that controlling for difficulty attenuates stop-related activity differences between superior and poor inhibitors. Specifically, group differences in the right inferior frontal gyrus, right middle occipital gyrus, and left inferior frontal gyrus are diminished when differences in objective task difficulty are controlled for. Also, when objective task difficulty effects are exaggerated, group differences in stop related activity emerge in other regions of the stopping network. The implications of these effects for how we interpret individual differences in activity levels are discussed.

Anxious/depressed symptoms are related to microstructural maturation of white matter in typically developing youths.

There are multiple recent reports of an association between anxious/depressed (A/D) symptomatology and the rate of cerebral cortical thickness maturation in typically developing youths. We investigated the degree to which anxious/depressed symptoms are tied to age-related microstructural changes in cerebral fiber pathways. The participants were part of the NIH MRI Study of Normal Brain Development. Child Behavior Checklist A/D scores and diffusion imaging were available for 175 youths (84 males, 91 females; 241 magnetic resonance imagings) at up to three visits. The participants ranged from 5.7 to 18.4 years of age at the time of the scan. Alignment of fractional anisotropy data was implemented using FSL/Tract-Based Spatial Statistics, and linear mixed model regression was carried out using SPSS. Child Behavior Checklist A/D was associated with the rate of microstructural development in several white matter pathways, including the bilateral anterior thalamic radiation, bilateral inferior longitudinal fasciculus, left superior longitudinal fasciculus, and right cingulum. Across these pathways, greater age-related fractional anisotropy increases were observed at lower levels of A/D. The results suggest that subclinical A/D symptoms are associated with the rate of microstructural development within several white matter pathways that have been implicated in affect regulation, as well as mood and anxiety psychopathology.

Trajectories of cortical thickness maturation in normal brain development--The importance of quality control procedures.

Several reports have described cortical thickness (CTh) developmental trajectories, with conflicting results. Some studies have reported inverted-U shape curves with peaks of CTh in late childhood to adolescence, while others suggested predominant monotonic decline after age 6. In this study, we reviewed CTh developmental trajectories in the NIH MRI Study of Normal Brain Development, and in a second step, evaluated the impact of post-processing quality control (QC) procedures on identified trajectories. The quality-controlled sample included 384 individual subjects with repeated scanning (1-3 per subject, total scans n=753) from 4.9 to 22.3years of age. The best-fit model (cubic, quadratic, or first-order linear) was identified at each vertex using mixed-effects models. The majority of brain regions showed linear monotonic decline of CTh. There were few areas of cubic trajectories, mostly in bilateral temporo-parietal areas and the right prefrontal cortex, in which CTh peaks were at, or prior to, age 8. When controlling for total brain volume, CTh trajectories were even more uniformly linear. The only sex difference was faster thinning of occipital areas in boys compared to girls. The best-fit model for whole brain mean thickness was a monotonic decline of 0.027mm per year. QC procedures had a significant impact on identified trajectories, with a clear shift toward more complex trajectories (i.e., quadratic or cubic) when including all scans without QC (n=954). Trajectories were almost exclusively linear when using only scans that passed the most stringent QC (n=598). The impact of QC probably relates to decreasing the inclusion of scans with CTh underestimation secondary to movement artifacts, which are more common in younger subjects. In summary, our results suggest that CTh follows a simple linear decline in most cortical areas by age 5, and all areas by age 8. This study further supports the crucial importance of implementing post-processing QC in CTh studies of development, aging, and neuropsychiatric disorders.

Postconcussion symptoms are associated with cerebral cortical thickness in healthy collegiate and preparatory school ice hockey players.

OBJECTIVE: To investigate the degree to which concussion history and postconcussive symptoms are associated with cortical morphology among male hockey players. STUDY DESIGN: Male subjects (n = 29), ranging in age from 14 to 23 years (mean 17.8 years), were recruited from preparatory school and collegiate ice hockey teams and underwent neuroimaging and baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) testing. Cerebral cortical thickness was regressed against ImPACT Total Symptom Score (TSS), concussion history, as well as baseline measures of psychopathology. Reconstruction of surfaces and cortical thickness analysis were conducted with FreeSurfer (version 5.3.0). RESULTS: ImPACT TSS was inversely associated with local cortical thickness in widespread brain areas. Associations were revealed in a host of frontal as well as bilateral temporoparietal cortices. Conversely, concussion history was not associated with cortical thickness. An "Age by Concussion History" interaction was associated with thickness in the right ventrolateral and right parietal cortices. Post-hoc analysis revealed that concussed participants did not exhibit age-related cortical thinning in these regions. CONCLUSION: We have identified an association between brain structure and postconcussive symptoms among young, otherwise-healthy male athletes. Postconcussive symptoms and related reductions in cortical thickness may be tied to participation in a full-contact sport that involves frequent blows to the head.

Anxious/depressed symptoms are linked to right ventromedial prefrontal cortical thickness maturation in healthy children and young adults.

The relationship between anxious/depressed traits and neuromaturation remains largely unstudied. Characterizing this relationship during healthy neurodevelopment is critical to understanding processes associated with the emergence of child/adolescent onset mood/anxiety disorders. In this study, mixed-effects models were used to determine longitudinal cortical thickness correlates of Child Behavior Checklist (CBCL) and Young Adult Self Report Anxious/Depressed scores in healthy children. Analyses included 341 subjects from 4.9 to 22.3 year-old with repeated MRI at up to 3 time points, at 2-year intervals (586 MRI scans). There was a significant "CBCL Anxious/Depressed by Age" interaction on cortical thickness in the right ventromedial prefrontal cortex (vmPFC), including the medial orbito-frontal, gyrus rectus, and subgenual anterior cingulate areas. Anxious/Depressed scores were negatively associated with thickness at younger ages (<9 years), but positively associated with thickness at older ages (15-22 years), with the shift in polarity occurring around age 12. This was secondary to a slower rate of vmPFC cortical thinning in subjects with higher scores. In young adults (18-22 years), Anxious/Depressed scores were also positively associated with precuneus/posterior cingulate cortical thickness. Potential neurobiological mechanisms underlying this maturation pattern are proposed. These results demonstrate the dynamic impact of age on relations between vmPFC and negative affect in the developing brain.

Associations Between Family History of Alcohol and/or Substance Use Problems and Frontal Cortical Development From 9 to 13 Years of Age: A Longitudinal Analysis of the ABCD Study.

Background: Previous investigations that have examined associations between family history (FH) of alcohol/substance use and adolescent brain development have been primarily cross-sectional. Here, leveraging a large population-based sample of youths, we characterized frontal cortical trajectories among 9- to 13-year-olds with (FH+) versus without (FH-) an FH and examined sex as a potential moderator. Methods: We used data from 9710 participants in the Adolescent Brain Cognitive Development (ABCD) Study (release 4.0). FH+ was defined as having ≥1 biological parents and/or ≥2 biological grandparents with a history of alcohol/substance use problems (n = 2433). Our primary outcome was frontal cortical structural measures obtained at baseline (ages 9-11) and year 2 follow-up (ages 11-13). We used linear mixed-effects models to examine the extent to which FH status qualified frontal cortical development over the age span studied. Finally, we ran additional interactions with sex to test whether observed associations between FH and cortical development differed significantly between sexes. Results: For FH+ (vs. FH-) youths, we observed increased cortical thinning from 9 to 13 years across the frontal cortex as a whole. When we probed for sex differences, we observed significant declines in frontal cortical thickness among boys but not girls from ages 9 to 13 years. No associations were observed between FH and frontal cortical surface area or volume. Conclusions: Having a FH+ is associated with more rapid thinning of the frontal cortex across ages 9 to 13, with this effect driven primarily by male participants. Future studies will need to test whether the observed pattern of accelerated thinning predicts future substance use outcomes.

Brain structural covariance network features are robust markers of early heavy alcohol use.

BACKGROUND AND AIMS: Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies. DESIGN AND SETTING: Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14-22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17-22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22-37 years). CASES: Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected. MEASUREMENTS: Graph theory metrics of segregation and integration were used to summarize SCN. FINDINGS: Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = -0.029, P = 0.002], lower modularity (AUC = -0.14, P = 0.004), lower average shortest path length (AUC = -0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = -0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar. CONCLUSION: Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology.

Evidence for a cerebral cortical thickness network anti-correlated with amygdalar volume in healthy youths: implications for the neural substrates of emotion regulation.

Recent functional connectivity studies have demonstrated that, in resting humans, activity in a dorsally-situated neocortical network is inversely associated with activity in the amygdalae. Similarly, in human neuroimaging studies, aspects of emotion regulation have been associated with increased activity in dorsolateral, dorsomedial, orbital and ventromedial prefrontal regions, as well as concomitant decreases in amygdalar activity. These findings indicate the presence of two countervailing systems in the human brain that are reciprocally related: a dorsally-situated cognitive control network, and a ventrally-situated limbic network. We investigated the extent to which this functional reciprocity between limbic and dorsal neocortical regions is recapitulated from a purely structural standpoint. Specifically, we hypothesized that amygdalar volume would be related to cerebral cortical thickness in cortical regions implicated in aspects of emotion regulation. In 297 typically developing youths (162 females, 135 males; 572 MRIs), the relationship between cortical thickness and amygdalar volume was characterized. Amygdalar volume was found to be inversely associated with thickness in bilateral dorsolateral and dorsomedial prefrontal, inferior parietal, as well as bilateral orbital and ventromedial prefrontal cortices. Our findings are in line with previous work demonstrating that a predominantly dorsally-centered neocortical network is reciprocally related to core limbic structures such as the amygdalae. Future research may benefit from investigating the extent to which such cortical-limbic morphometric relations are qualified by the presence of mood and anxiety psychopathology.

Gender diversity associated with patterns of brain activation seen in populations that experience childhood stress.

Introduction: Stressful childhood experiences are associated with unique brain activity patterns during emotional processing. Specifically, pediatric stress is linked to activation in the insulae, superior temporal and parahippocampal gyri, and the amygdalae, as well as differential activation in the dorsal anterior cingulate cortex when viewing emotional faces. Gender diversity is broadly associated with higher victimization and mental health disparities in children aged 9/10, but whether it is associated with stress-like alterations in brain function (BOLD signal during task-based fMRI) remains unknown. We investigate the functional brain correlates of this relationship to determine if gender-diverse youth show patterns of functional activity during an emotional task consistent with those of other populations that experience heightened stress. Methods: We used data from the Adolescent Brain Cognitive Development (ABCD)® study. First, we identified a subset of 4,385 participants aged 10/11 years with gender diversity data and quality-controlled fMRI data from the EN-Back (emotional n-back) task. The EN-Back is a working memory task that presents emotion faces as well as pictures of places as control stimuli. We regressed BOLD signal associated with emotion faces (faces minus places contrast) on gender diversity. Next, we tested if parental acceptance or youth perceptions of their school environment moderated the relationship between gender diversity and activation in the insulae or fusiform gyrus. Finally, we used structural equation modeling to investigate gender diversity's association with parental acceptance, perceptions of school environments, internalizing and externalizing problems. Results: Gender diversity was associated with widespread increases in BOLD signal during the faces condition of the EN-Back task. Youth's report of parental acceptance and school environment did not moderate the relationship between gender diversity and BOLD signal in the insula or fusiform gyrus. Gender diversity was related to greater parent and school-related stress, which was associated with elevated mental health problems. Conclusion: Patterns of functional activity were consistent with those reported in prior literature on childhood stress. Gender diversity was associated with increased emotional and behavioral problems, as well as parent and school-related stress. These findings indicate the importance of the home and school environments for supporting the wellbeing of gender diverse youth.

Conduct problems are associated with accelerated thinning of emotion-related cortical regions in a community-based sample of adolescents.

Few studies have examined the association between conduct problems and cerebral cortical development. Herein, we characterize the association between age-related brain change and conduct problems in a large longitudinal, community-based sample of adolescents. 1,039 participants from the IMAGEN study possessed psychopathology and surface-based morphometric data at study baseline (M = 14.42 years, SD = 0.40; 559 females) and 5-year follow-up. Self-reports of conduct problems were obtained using the Strengths and Difficulties Questionnaire (SDQ). Vertex-level linear mixed effects models were implemented using the Matlab toolbox, SurfStat. To investigate the extent to which cortical thickness maturation was qualified by dimensional measures of conduct problems, we tested for an interaction between age and SDQ Conduct Problems (CP) score. There was no main effect of CP score on cortical thickness; however, a significant "Age by CP" interaction was revealed in bilateral insulae, left inferior frontal gyrus, left rostral anterior cingulate, left posterior cingulate, and bilateral inferior parietal cortices. Across regions, follow-up analysis revealed higher levels of CP were associated with accelerated age-related thinning. Findings were not meaningfully altered when controlling for alcohol use, co-occurring psychopathology, and socioeconomic status. Results may help to further elucidate neurodevelopmental patterns linking adolescent conduct problems with adverse adult outcomes.

Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning.

While there is substantial evidence that cannabis use is associated with differences in human brain development, most of this evidence is correlational in nature. Bayesian causal network (BCN) modeling attempts to identify probable causal relationships in correlational data using conditional probabilities to estimate directional associations between a set of interrelated variables. In this study, we employed BCN modeling in 637 adolescents from the IMAGEN study who were cannabis naïve at age 14 to provide evidence that the accelerated prefrontal cortical thinning found previously in adolescent cannabis users by Albaugh et al. [1] is a result of cannabis use causally affecting neurodevelopment. BCNs incorporated data on cannabis use, prefrontal cortical thickness, and other factors related to both brain development and cannabis use, including demographics, psychopathology, childhood adversity, and other substance use. All BCN algorithms strongly suggested a directional relationship from adolescent cannabis use to accelerated cortical thinning. While BCN modeling alone does not prove a causal relationship, these results are consistent with a body of animal and human research suggesting that adolescent cannabis use adversely affects brain development.

Demographic and mental health assessments in the adolescent brain and cognitive development study: Updates and age-related trajectories.

The Adolescent Brain Cognitive Development (ABCD) Study of 11,880 youth incorporates a comprehensive range of measures assessing predictors and outcomes related to mental health across childhood and adolescence in participating youth, as well as information about family mental health history. We have previously described the logic and content of the mental health assessment battery at Baseline and 1-year follow-up. Here, we describe changes to that battery and issues and clarifications that have emerged, as well as additions to the mental health battery at the 2-, 3-, 4-, and 5-year follow-ups. We capitalize on the recent release of longitudinal data for caregiver and youth report of mental health data to evaluate trajectories of dimensions of psychopathology as a function of demographic factors. For both caregiver and self-reported mental health symptoms, males showed age-related decreases in internalizing and externalizing symptoms, while females showed an increase in internalizing symptoms with age. Multiple indicators of socioeconomic status (caregiver education, family income, financial adversity, neighborhood poverty) accounted for unique variance in both caregiver and youth-reported externalizing and internalizing symptoms. These data highlight the importance of examining developmental trajectories of mental health as a function of key factors such as sex and socioeconomic environment.

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

OBJECTIVE: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences. METHOD: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting. RESULTS: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008). CONCLUSION: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

Association of Cannabis Use During Adolescence With Neurodevelopment.

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.

Social supports moderate the effects of child adversity on neural correlates of threat processing.

BACKGROUND: Child abuse and other forms of adversity are associated with alterations in threat processing and emotion regulation brain circuits. OBJECTIVE: The goal of the current investigation is to determine if the availability of positive social support can ameliorate the negative impact of adversity on these brain systems. PARTICIPANTS AND SETTING: Subjects included 55 children ages 7-16 (X = 11.8, SD = 2.0). Approximately one-third of the cohort had no significant history of adversity, one-third had a history of moderate adversity, and one-third had a history of severe adversity. Brain imaging was conducted at the University of Vermont using a 3.0 T Philips scanner. METHODS: The Emotional Go-NoGo task with fearful and calm facial stimuli was used to assess the neural correlates of threat processing and emotion regulation in children during functional magnetic resonance imaging (fMRI). Dimensional measures of anxiety, social supports, and children's adverse experiences were also obtained. RESULTS: A conjunction analysis was used to test if trauma-related brain activation in responding to fearful vs. calm targets was impacted by social support. This approach identified multiple activation foci, including a cluster extending from the left amygdala to several other key brain regions involved in emotion regulation, including the orbitofrontal cortex, anterior cingulate cortex (ACC), anterior insula, nucleus accumbens, and frontal pole (Family Wise Error (FWE) correction, p < 0.05). CONCLUSIONS: Greater social support may reduce the effect that adversity has on neural processing of threat stimuli, consistent with the protective role of positive supports in promoting resilience and recovery demonstrated in the literature.