Search

Previously, we studied the relationship between cannabis use and individuals with mood/anxiety disorders using cross-sectional data from the Tulsa 1000 study (Victor et al., 2018). Using that dataset, we found that individuals with mood/anxiety disorders and problematic cannabis use were characterized by (1) attenuated striatal activations during reward anticipation (Spechler et al., in press), and (2) higher impulsivity measures under periods of urgency (Spechler et al., in-preparation). As those findings were derived from cross-sectional data, we propose to reproduce these effects in children with prenatal cannabis exposure. In doing so, these findings would help inform causal mechanisms related to cannabis use and associated outcomes. Spechler et al., in press. "Attenuated Reward Activations Associated with Cannabis Use in Anxious/Depressed Individuals". Translational Psychiatry. Spechler et al., in preparation. "Multifaceted impulsivity differences in anxious/depressed cannabis users".

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.

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 nativeMR 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 less than< .001), and a positron emission tomography–assessed cannabinoid 1 receptor–binding map derived from a separate sample of participants (r = −0.189; P less than .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.

Contains fulltext : 200963.pdf (Publisher’s version ) (Closed access) Objective: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. Method: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. Results: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. Conclusions: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine. 10 p.

Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal / amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential ‘aberrant’ neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.

Objective: To characterize the structural and functional neurobiology of a large group of adolescents exhibiting a behaviorally and emotionally dysregulated phenotype.Methods: Age 14 adolescents from the IMAGEN study were investigated. Latent class analysis (LCA) on the Strengths and Difficulties Questionnaire (SDQ) was used to identify a class of individuals with elevated behavioral and emotional difficulties (“dysregulated”; N=233) who were compared to a matched sample from a low symptom class (controls, N=233). Whole-brain gray matter volume (GMV) images were compared using a general linear model with 10,000 random label permutations. Regional GMV findings were then probed for functional differences from three fMRI tasks. Significant brain features then informed mediation path models linking the likelihood of psychiatric disorders (DSM-IV) with dysregulation.Results: Whole-brain differences were found in the right orbitofrontal cortex (R.OFC; p less than .05; k=48), with dysregulated individuals exhibiting lower GMV. The dysregulated group also exhibited higher activity in this region during successful inhibitory control (F1,429=7.53, p less than .05). Path analyses indicated significant direct effects between the likelihood of psychopathologies and dysregulation. Modeling the R.OFC as a mediator returned modest partial effects, suggesting the path linking the likelihood of an anxiety or conduct disorder diagnoses to dysregulation is partially explained by this anatomical feature.Conclusion: A large sample of dysregulated adolescents exhibited lower GMV in the R.OFC relative to controls. Dysregulated individuals also exhibited higher regional activations when exercising inhibitory control at performance levels comparable to controls. These findings suggest a neurobiological marker of dysregulation, and highlight the role of the R.OFC in impaired emotional and behavioral control.

© 2019 Background: Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. Methods: Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. Results: Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. Conclusions: These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

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. 1,104 participants (M = 14.52 yrs, SD = 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 = -.274, p < .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.

OBJECTIVE: This study aimed to investigate the neural correlates of psychotic-like experiences in youth on measures of inhibitory control, reward anticipation and emotion processing. A secondary aim was to test whether these neuro-functional correlates of risk were predictive of psychotic symptoms 2 years later. METHOD: Functional imaging response to three paradigms: the Stop-Signal, Monetary Incentive Delay, and Faces tasks was collected in youth at age 14, as part of the IMAGEN study. At baseline, youth from London and Dublin sites were assessed on psychotic-like experiences and those reporting significant experiences were compared with matched controls. Significant brain activity differences between the groups were used to predict, with cross-validation, the presence of psychotic symptoms in the context of mood fluctuation at age 16, assessed in the full sample. These prediction analyses were conducted with the London-Dublin subsample (N=246) and the full sample (N=1196). RESULTS: Youth reporting psychotic-like experiences showed increased hippocampus/amygdala activity during neutral faces processing and reduced dorsolateral prefrontal activity during failed inhibition relative to controls. The most prominent region for classifying 16-year olds with mood fluctuation and psychotic symptoms relative to the control groups (those with mood fluctuations but no psychotic symptoms and those with no mood symptoms) included hyperactivation of the hippocampus/amygdala, when controlling for baseline psychotic-like experiences and cannabis use. CONCLUSIONS: The results stress the importance of the limbic network’s increased response to neutral facial stimuli as a marker of the extended psychosis phenotype. These findings might help to guide early intervention strategies for at-risk youth.

Epileptic seizures can initiate a neural circuit and lead to aberrant neural communication with brain areas outside the epileptogenic region. We focus on interictal activity in focal temporal lobe epilepsy and evaluate functional connectivity differences that emerge as function of bilateral versus strictly unilateral epileptiform activity. We assess the strength of functional connectivity at rest between the ictal and non-ictal temporal lobes, in addition to whole brain connectivity with the ictal temporal lobe. Results revealed strong connectivity between the temporal lobes for both patient groups, but this did not vary as a function of unilateral versus bilateral interictal status. Both the left and right unilateral temporal lobe groups showed significant anti-correlated activity in regions outside the epileptogenic temporal lobe, primarily involving the contralateral (non-ictal/non-pathologic) hemisphere, with precuneus involvement prominent. The bilateral groups did not show this contralateral anti-correlated activity. This anti-correlated connectivity may represent a form of protective and adaptive inhibition, helping to constrain epileptiform activity to the pathologic temporal lobe. The absence of this activity in the bilateral groups may be indicative of flawed inhibitory mechanisms, helping to explain their more widespread epileptiform activity. Our data suggest that the location and build up of epilepsy networks in the brain are not truly random, and are not limited to the formation of strictly epileptogenic networks. Functional networks may develop to take advantage of the regulatory function of structures such as the precuneus to instantiate an anti-correlated network, generating protective cortico-cortico inhibition for the purpose of limiting seizure spread or epileptogenesis.

OBJECTIVE: This study aimed to investigate the neural correlates of psychotic-like experiences in youth on measures of inhibitory control, reward anticipation and emotion processing. A secondary aim was to test whether these neuro-functional correlates of risk were predictive of psychotic symptoms 2 years later. METHOD: Functional imaging response to three paradigms: the Stop-Signal, Monetary Incentive Delay, and Faces tasks was collected in youth at age 14, as part of the IMAGEN study. At baseline, youth from London and Dublin sites were assessed on psychotic-like experiences and those reporting significant experiences were compared with matched controls. Significant brain activity differences between the groups were used to predict, with cross-validation, the presence of psychotic symptoms in the context of mood fluctuation at age 16, assessed in the full sample. These prediction analyses were conducted with the London-Dublin subsample (N=246) and the full sample (N=1196). RESULTS: Youth reporting psychotic-like experiences showed increased hippocampus/amygdala activity during neutral faces processing and reduced dorsolateral prefrontal activity during failed inhibition relative to controls. The most prominent region for classifying 16-year olds with mood fluctuation and psychotic symptoms relative to the control groups (those with mood fluctuations but no psychotic symptoms and those with no mood symptoms) included hyperactivation of the hippocampus/amygdala, when controlling for baseline psychotic-like experiences and cannabis use. CONCLUSIONS: The results stress the importance of the limbic network’s increased response to neutral facial stimuli as a marker of the extended psychosis phenotype. These findings might help to guide early intervention strategies for at-risk youth.