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Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers., Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts., Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders., Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes., Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Subcortical brain morphometry matures across adolescence and young adulthood, a time when many youth engage in escalating levels of alcohol use. Initial cross-sectional studies have shown alcohol use is associated with altered subcortical morphometry. However, longitudinal evidence of sex-specific neuromaturation and associations with alcohol use remains limited. This project used generalized additive mixed models to examine sex-specific development of subcortical volumes and associations with recent alcohol use, using 7 longitudinal waves (n = 804, 51% female, ages 12-21 at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). A second, independent, longitudinal dataset, with up to four waves of data (n = 467, 43% female, ages 10-18 at baseline), was used to assess replicability. Significant, replicable non-linear normative volumetric changes with age were evident in the caudate, putamen, thalamus, pallidum, amygdala and hippocampus. Significant, replicable negative associations between subcortical volume and alcohol use were found in the hippocampus in all youth, and the caudate and thalamus in female but not male youth, with significant interactions present in the caudate, thalamus and putamen. Findings suggest a structural vulnerability to alcohol use, or a predisposition to drink alcohol based on brain structure, with female youth potentially showing heightened risk, compared to male youth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: While identifying risk factors for adolescent depression is critical for early prevention and intervention, most studies have sought to understand the role of isolated factors rather than across a broad set of factors. Here, we sought to examine multi-level factors that maximize the prediction of depression symptoms in US children participating in the Adolescent Brain and Cognitive Development (ABCD) study., Methods: A total of 7,995 participants from ABCD (version 3.0 release) provided complete data at baseline and 1-year follow-up data. Depression symptoms were measured with the Child Behavior Checklist. Predictive features included child demographic, environmental, and structural and resting-state fMRI variables, parental depression history and demographic characteristics. We used linear (elastic net regression, EN) and non-linear (gradient-boosted trees, GBT) predictive models to identify which set of features maximized prediction of depression symptoms at baseline and, separately, at 1-year follow-up., Results: Both linear and non-linear models achieved comparable results for predicting baseline (EN: MAE = 3.757; R 2  = 0.156; GBT: MAE = 3.761; R 2  = 0.147) and 1-year follow-up (EN: MAE = 4.255; R 2  = 0.103; GBT: MAE = 4.262; R 2  = 0.089) depression. Parental history of depression, greater family conflict, and shorter child sleep duration were among the top predictors of concurrent and future child depression symptoms across both models. Although resting-state fMRI features were relatively weaker predictors, functional connectivity of the caudate was consistently the strongest neural feature associated with depression symptoms at both timepoints., Conclusions: Consistent with prior research, parental mental health, family environment, and child sleep quality are important risk factors for youth depression. Functional connectivity of the caudate is a relatively weaker predictor of depression symptoms but may represent a biomarker for depression risk., (© 2022 Association for Child and Adolescent Mental Health.)

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Many neurological diseases are characterized by gradual deterioration of brain structure andfunction. Large longitudinal MRI datasets have revealed such deterioration, in part, by applying machine and deep learning to predict diagnosis. A popular approach is to apply Convolutional Neural Networks (CNN) to extract informative features from each visit of the longitudinal MRI and then use those features to classify each visit via Recurrent Neural Networks (RNNs). Such modeling neglects the progressive nature of the disease, which may result in clinically implausible classifications across visits. To avoid this issue, we propose to combine features across visits by coupling feature extraction with a novel longitudinal pooling layer and enforce consistency of the classification across visits in line with disease progression. We evaluate the proposed method on the longitudinal structural MRIs from three neuroimaging datasets: Alzheimer's Disease Neuroimaging Initiative (ADNI, N=404), a dataset composed of 274 normal controls and 329 patients with Alcohol Use Disorder (AUD), and 255 youths from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). In allthree experiments our method is superior to other widely used approaches for longitudinal classification thus making a unique contribution towards more accurate tracking of the impact of conditions on the brain. The code is available at https://github.com/ouyangjiahong/longitudinal-pooling.

Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings., Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended., Design, Setting, and Participants: This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020., Main Outcomes and Measures: Percentage of children with IFs in each category and prevalence of specific IFs., Results: A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387)., Conclusions and Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Critical changes in adolescence involve brain cognitive maturation of inhibitory control processes that are essential for a myriad of adult functions. Cognitive control advances into adulthood as there is more flexible integration of component processes, including inhibitory control of conflicting information, overwriting inappropriate response tendencies, and amplifying relevant responses for accurate execution. Using a modified Stroop task with fMRI, we investigated the effects of age, sex, and puberty on brain functional correlates of cognitive and motor control in 87 boys and 91 girls across the adolescent age range. Results revealed dissociable brain systems for cognitive and motor control processes, whereby adolescents flexibly adapted neural responses to control demands. Specifically, when response repetitions facilitated planning-based action selection, frontoparietal-insular regions associated with cognitive control operations were less activated, whereas cortical-pallidal-cerebellar motor regions associated with motor skill acquisition, were more activated. Attenuated middle cingulate cortex activation occurred with older adolescent age for both motor control and cognitive control with automaticity from repetition learning. Sexual dimorphism for control operations occurred in extrastriate cortices involved in visuo-attentional selection: While boys enhanced extrastriate selection processes for motor control, girls activated these regions more for cognitive control. These sex differences were attenuated with more advanced pubertal stage. Together, our findings show that brain cognitive and motor control processes are segregated, demand-specific, more efficient in older adolescents, and differ between sexes relative to pubertal development. Our findings advance our understanding of how distributed brain activity and the neurodevelopment of automaticity enhances cognitive and motor control ability in adolescence.

Academic performance in adolescence strongly influences adult prospects. Intelligence quotient (IQ) has historically been considered a strong predictor of academic performance. Less objectively explored have been morphometric features. We analyzed brain MRI morphometry metrics in early adolescence (age 12-14 years) as quantitative predictors of academic performance over high school using a naïve Bayesian classifier approach with n = 170 subjects. Based on the mean GPA, subjects were divided into high (GPA ≥3.54; n = 87) and low (GPA <3.54; n = 83) academic performers. Covariance analysis was performed to look at the influence of subject demographics. We examined predictive features from the 343 available regions (surface areas, cortical thickness, and subcortical volumes) and applied 4 algorithms for selection and reduction of attributes using Weka. Cortical thickness measures performed better than surface areas or subcortical volumes as predictors of academic performance. We identified 15 cortical thickness regions most predictive of academic performance, three of which have not been described in the literature predictive of academic performance. These were in the left hemisphere fusiform, bilateral insula, and left hemisphere paracentral regions. Prediction had a sensitivity of 0.65 and specificity of 0.73 with independent validation. Follow-up independent t-test analyses between high and low academic achievers on 10 of 15 regions showed between-group significance at the p < 0.05 level. High achievers demonstrated thicker cortices than low achievers. These newly identified regions may help pinpoint new targets for further study in understanding the developing adolescent brain in the classroom setting.

Background: Cognitive Bias Modification (CBM) has garnered interest as a potential addiction treatment. CBM interventions such as Approach Avoidance Training (AAT) are designed to alter automatic tendencies to approach drugs or drug-related cues. In our previous work, the cannabis AAT (CAAT) reduced cannabis approach bias, which was related to reduced cannabis use, among 80 non-treatment-seeking cannabis-using youth (Jacobus et al., 2018). In this preliminary examination, a subsample of these youth underwent neuroimaging to explore CAAT's effect on cannabis cue-related neural activation., Methods: Sub-study participants were 41 cannabis-using youth ages 17-21 (mean age = 18.83; 47.5% female). Participants completed a cannabis cue-reactivity task during a functional MRI scan pre- and post CAAT-training or CAAT-sham to examine CAAT-related neural changes., Results: Thirty-seven youth completed all six CAAT (n = 19) or CAAT-sham (n = 18) training sessions and had usable neuroimaging data. The group*time interaction on cannabis approach bias reached trend-level significance (p = .055). Change in approach bias slopes from pre-to post-treatment was positive for CAAT-sham (increased approach bias) and negative for CAAT-training (change to avoidance bias), consistent with the larger study. No significant changes emerged for cannabis cue-induced activation following CAAT-training or CAAT-sham in whole brain or region of interest analyses. However, active CAAT-training was associated with small-to-medium decreases in amygdala (Cohen's d z  = 0.36) and medial prefrontal cortex (Cohen's d z  = 0.48) activation to cannabis cues., Conclusions: Despite reducing cannabis use in the larger sample, CAAT-training did not alter neural cannabis cue-reactivity in the sub-study compared to CAAT-sham. More research is needed to understand neural mechanisms underlying AAT-related changes in substance use., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Acute alcohol consumption is associated with temporarily increased regional cerebral blood flow (CBF). The extent of this increase appears to be moderated by individual differences in the level of response (LR) to alcohol's subjective effects. The low LR phenotype is a known risk factor for the development of alcohol problems. This study investigates how the low LR phenotype relates to the relationship between alcohol-related changes in CBF and alcohol problems 5 years later., Methods: Young adults (ages 18 to 25) were selected based on their LR to alcohol and underwent a neuroimaging protocol including arterial spin labeling and functional scans. These participants were recontacted ~5 years later and assessed on alcohol outcomes. A final sample of 107 subjects (54 low and 53 high LR subjects) was included in the analyses. Whole-brain analysis revealed 5 clusters of significant alcohol-induced, versus placebo-induced, CBF changes that were consistent with a previous report. Peak alcohol-placebo CBF response was extracted from these regions and, along with the LR group, submitted to a hierarchical linear regression predicting alcohol problems. Analyses controlled for age, sex, and baseline alcohol problems., Results: In the regression analysis, greater alcohol-placebo CBF difference in the right middle/superior/inferior frontal gyri and bilateral anterior cingulate gyri clusters predicted greater future alcohol problems for the low LR group, whereas this relationship was not found to be significant in the high LR group., Conclusions: This study demonstrates a clinically important relationship between CBF and future alcohol problems, particularly in individuals with a low LR phenotype. These initial results help to elucidate the neurobiological pathways involved in the development of alcohol use disorders for individuals with low LR., (© 2019 by the Research Society on Alcoholism.)

Objective: Adult and adolescent studies suggest increased motivational responses to cannabis cues among regular cannabis users. However, functional magnetic resonance imaging (fMRI) studies have not explored neural activation in response to visual cannabis cues among adolescents in the United States. Gaining a better understanding of the neural circuits related to cue-elicited craving during adolescence may shed light on the neural basis for the development of problematic cannabis use that could ultimately be targeted for interventions., Methods: 41 non-treatment-seeking youth (ages 17-21; mean age = 18.83; 46.3% female) who reported regular cannabis use underwent fMRI scanning involving a visual cannabis cue task and completed self-report and biological measures. Whole-brain activation was examined for cannabis cues compared to non-cannabis cues, and for active versus passive cannabis cues. Associations between self-reported substance use and task activation were examined., Results: Cannabis images were identifiable to adolescents and were rated as more rewarding than matched non-cannabis images (p < .05). Greater activation was found for the cannabis cues compared to non-cannabis cues in bilateral posterior cingulate, cuneus, fusiform, precuneus, inferior temporal and parahippocampal gyri, as well as left thalamus, medial frontal and superior frontal gyri. Cue-elicited activation was not significantly associated with self-reported cannabis use (ps > 0.05). No differences were observed for the active versus passive cue contrast., Conclusions: Cannabis-using youth show more activation to cannabis cues than non-cannabis cues in brain regions underlying incentive salience, reward, and visual attention. This task could be useful for future studies examining neural underpinnings of reward processes in adolescent cannabis users., (Copyright © 2018. Published by Elsevier Ltd.)

Structural MRI of volunteers deemed "normal" following clinical interview provides a window into normal brain developmental morphology but also reveals unexpected dysmorphology, commonly known as "incidental findings." Although unanticipated, these anatomical findings raise questions regarding possible treatment that could even ultimately require neurosurgical intervention, which itself carries significant risk but may not be indicated if the anomaly is nonprogressive or of no functional consequence. Neuroradiological readings of 833 structural MRI from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) cohort found an 11.8 % incidence of brain structural anomalies, represented proportionately across the five collection sites and ethnic groups. Anomalies included 26 mega cisterna magna, 15 subarachnoid cysts, 12 pineal cysts, 12 white matter dysmorphologies, 5 tonsillar ectopias, 5 prominent perivascular spaces, 5 gray matter heterotopias, 4 pituitary masses, 4 excessively large or asymmetrical ventricles, 4 cavum septum pellucidum, 3 developmental venous anomalies, 1 exceptionally large midsagittal vein, and single cases requiring clinical followup: cranio-cervical junction stenosis, parietal cortical mass, and Chiari I malformation. A case of possible demyelinating disorder (e.g., neuromyelitis optica or multiple sclerosis) newly emerged at the 1-year NCANDA followup, requiring clinical referral. Comparing test performance of the 98 anomalous cases with 619 anomaly-free no-to-low alcohol consuming adolescents revealed significantly lower scores on speed measures of attention and motor functions; these differences were not attributed to any one anomaly subgroup. Further, we devised an automated approach for quantifying posterior fossa CSF volumes for detection of mega cisterna magna, which represented 26.5 % of clinically identified anomalies. Automated quantification fit a Gaussian distribution with a rightward skew. Using a 3SD cut-off, quantification identified 22 of the 26 clinically-identified cases, indicating that cases with percent of CSF in the posterior-inferior-middle aspect of the posterior fossa ≥3SD merit further review, and support complementing clinical readings with objective quantitative analysis. Discovery of asymptomatic brain structural anomalies, even when no clinical action is indicated, can be disconcerting to the individual and responsible family members, raising a disclosure dilemma: refrain from relating the incidental findings to avoid unnecessary alarm or anxiety; or alternatively, relate the neuroradiological findings as "normal variants" to the study volunteers and family, thereby equipping them with knowledge for the future should they have the occasion for a brain scan following an illness or accident that the incidental findings predated the later event.

Adolescence is a period marked by increases in risk taking, sensation seeking, and emotion dysregulation. Neurobiological models of adolescent development propose that lagging development in brain regions associated with affect and behavior control compared to regions associated with reward and emotion processing may underlie these behavioral manifestations. Cross-sectional studies have identified several functional brain networks that may contribute to risk for substance use and psychopathology in adolescents. Determining brain structure measures that prospectively predict substance use and psychopathology could refine our understanding of the mechanisms that contribute to these problems, and lead to improved prevention efforts. Participants (N = 265) were healthy substance-naïve adolescents (ages 12-14) who underwent magnetic resonance imaging and then were followed annually for up to 13 years. Cortical thickness and surface area measures for three prefrontal regions (dorsolateral prefrontal cortex, inferior frontal gyrus, and orbitofrontal cortex) and three cortical regions from identified functional networks (anterior cingulate cortex, insular cortex, and parietal cortex) were used to predict subsequent binge drinking, externalizing symptoms, and internalizing symptoms. Thinner dorsolateral prefrontal cortex and inferior frontal cortex in early adolescence predicted more binge drinking and externalizing symptoms, respectively, in late adolescence (ps < .05). Having a family history of alcohol use disorder predicted more subsequent binge drinking and externalizing symptoms. Thinner parietal cortex, but not family history, predicted more subsequent internalizing symptoms (p < .05). This study emphasizes the temporal association between maturation of the salience, inhibition, and executive control networks in early adolescence and late adolescent behavior outcomes. Our findings indicate that developmental variations in these brain regions predate behavioral outcomes of substance use and psychopathology, and may therefore serve as prospective biomarkers of vulnerability.

Background: Although the interaction of brain volume with amphetamine-type stimulants (ATS) and cocaine has been investigated in chronically dependent individuals, little is known about structural differences that might exist in individuals who consume ATS and cocaine occasionally but are not dependent on these drugs., Methods: Regional brain volumes in 165 college aged occasional users of ATS (namely: amphetamine, methamphetamine, methylphenidate, and 3,4-methylenedioxymethamphetamine; MDMA) and cocaine were compared by voxel-based morphometry with 48 ATS/cocaine-naive controls., Results: Grey matter volume was significantly higher in the left ventral anterior putamen of occasional users, and lower in the right dorsolateral cerebellum and right inferior parietal cortex. A regression in users alone on lifetime consumption of combined ATS (namely: amphetamine, methamphetamine, methylphenidate and MDMA) and cocaine use revealed that individuals who used more ATS/cocaine had greater volume in the right ventromedial frontal cortex. A second regression on lifetime consumption of ATS with cocaine as a covariate revealed that individuals with a greater history of ATS use alone had more grey matter volume in the left mid-insula. Interestingly, structural changes in the ventromedial prefrontal cortex, insula and striatum have been consistently observed in volumetric studies of chronic ATS and cocaine dependence., Conclusion: The present results suggest that these three brain regions may play a role in stimulant use even in early occasional users., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: A positive family history (FHP) of alcohol use disorders (AUD) is linked to increased risk for personal AUD, but the mechanisms behind this risk are unclear. Previous research suggests that a subtle neurodevelopmental lag in FHP adolescents may contribute to risk for future AUD., Methods: Functional magnetic resonance imaging (fMRI) response to a spatial working memory (SWM) task was examined for markers of neuromaturational delay in 85 youth with and without FHP. It was hypothesized that FHP adolescents (n = 24, ages 12-14 years), as compared to matched FHN youth (n = 26, ages 12-14 years), would show less similarity to brain connectivity observed in older adolescents (n = 35, ages 16-20 years) and that statistical comparison of SWM functional connectivity models would differentiate FHN and FHP youth. Structural equation modeling tested the fit of brain response connectivity between FH groups and against the older-adolescent model., Results: Patterns of connectivity were more similar between older adolescent and FHN than FHP adolescents; FHP youth demonstrated higher association between right posterior and left frontal brain regions than FHN and older adolescent youth. Comparison of FH groups indicated a significant difference on the pathway from the right superior parietal lobule to the left middle frontal gyrus., Conclusions: These findings provide additional support for the notion of a neuromaturational lag in FHP youth. Protracted neuromaturation may be a mechanism by which FH increases risk for alcohol dependence, and this less mature neural connectivity pattern may provide a novel endophenotype for identifying youth at risk for drinking problems.

Objective: Although substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL)., Method: A total of 25 medication-naive adolescents (13-17 years of age) diagnosed with major depressive disorder (MDD) and 26 well-matched control subjects underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency., Results: Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p < .05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p < .05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p < .05, corrected)., Conclusions: Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments, and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations., (Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Rationale: Adolescent binge drinking is concerning, as important neurodevelopments occur during this stage. Previous research suggests that binge drinking may disrupt typical brain development, and females may be particularly vulnerable., Objectives: We used magnetic resonance imaging (MRI) to examine cortical thickness in adolescent females and males with and without histories of binge drinking., Methods: Participants (N = 59) were 16-19-year-old adolescents recruited from local schools. Recent binge drinkers (n = 29, 48% female) were matched to non-drinkers (n = 30, 50% female) on age, gender, pubertal development, and familial alcoholism. Participants completed a neuropsychological battery and MRI session. Cortical surfaces were reconstructed with FreeSurfer., Results: Binge × gender interactions (p < .05) were seen for cortical thickness in four left frontal regions: frontal pole, pars orbitalis, medial orbital frontal, and rostral anterior cingulate. For all interactions, female bingers had thicker cortices than female controls, while male bingers had thinner cortices than male controls. Thicker left frontal cortices corresponded with poorer visuospatial, inhibition, and attention performances for female bingers (r = -0.69 to 0.50, p < 0.05) and worse attention for male bingers (r = -0.69, p = 0.005)., Conclusions: Adolescent females with recent binge drinking showed ~8% thicker cortices in left frontal regions than demographically similar female non-drinkers, which was linked to worse visuospatial, inhibition, and attention performances. In contrast, adolescent binge-drinking males showed ~7% thinner cortices in these areas than non-drinking males. These cross-sectional data suggest either different gray matter risk factors for males as for females toward developing heavy drinking, or differential adverse sequelae.

Background: A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed., Methods: Forty-nine drinking but not yet alcoholic matched pairs of 18- to 25-year-old subjects (N = 98; 53% women) with low and high LRs as established in separate alcohol challenges were evaluated in 2 event-related functional magnetic resonance imaging (fMRI) sessions (placebo and approximately 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session., Results: Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level-dependent (BOLD) signal during error and inhibitory processing, despite similar LR group performance on the task. In most clusters with significant (corrected p < 0.05, clusters > 1,344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared with placebo., Conclusions: This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks of a future life-threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk of future heavy drinking and alcohol dependence., (Copyright © 2011 by the Research Society on Alcoholism.)

Some neurocognitive recovery occurs within a month of abstinence from heavy marijuana use, yet functional magnetic resonance imaging (fMRI) has revealed altered activation among recent and abstinent adult users. We compared fMRI response during a spatial working memory (SWM) task between adolescent marijuana users with brief and sustained durations of abstinence. Participants were 13 recent users (two to seven days abstinent), 13 abstinent users (27 to 60 days abstinent), and 18 nonusing controls, all ages 15 to 18. Groups were similar on demographics, had no psychiatric or medical disorders, and user groups were similar on substance histories. Teens performed a two-back SWM task during fMRI. Recent users showed greater fMRI response in medial and left superior prefrontal cortices, as well as bilateral insula. Abstinent users had increased response in the right precentral gyrus (clusters > or = 1328 microl, p < .05). Results suggest that adolescents who recently used marijuana show increased brain activity in regions associated with working memory updating and inhibition. This study preliminarily suggests that (1) recent marijuana use may disrupt neural connections associated with SWM and result in compensatory brain response, and (2) sustained abstinence from marijuana may be associated with improvements in SWM response among adolescents.

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied. Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers. Participants recruited from local high schools were of ages 16-18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning. Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P=.07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps<.05, clusters >1,512microL). In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns., (2010 Elsevier Inc. All rights reserved.)

Objective: Functional neuroimaging studies have led to a significantly deeper understanding of the underlying neural correlates and the development of several mature models of depression in adults. In contrast, our current understanding of the underlying neural substrates of adolescent depression is very limited. Although numerous studies have consistently demonstrated a hyperactive amygdala in depressed adults, the few published pediatric studies have reported opposite results in the amygdala. Thus, the main purpose of this study was to further our knowledge of the underlying neural substrates of adolescent depression by examining the bilateral amygdala specifically and the whole brain in depressed adolescents compared to healthy controls., Method: Twelve unmedicated adolescents diagnosed with current major depressive disorder without a comorbid psychiatric disorder and 12 well-matched controls ages 13 to 17 years performed a facial-emotion matching task during functional magnetic resonance imaging at 3 T., Results: Region-of-interest analyses demonstrated: (1) significant bilateral amygdala activation in depressed and healthy adolescents, and (2) significantly greater left amygdala activation in depressed adolescents compared to controls. Whole-brain analysis revealed areas of significantly different brain activity in depressed adolescents compared to controls., Conclusions: These results suggest that (1) depressed adolescents without a comorbid psychiatric disorder exhibit an abnormally hyperactive amygdala compared to healthy controls; (2) models of adult depression might be extended to include depressed adolescents; and (3) neuropsychiatric interventions that have been developed in depressed adults should be further examined in adolescents.

Marijuana is the most widely used illicit substance among teenagers, yet little is known about the possible neural influence of heavy marijuana use during adolescence. We previously demonstrated an altered functional magnetic resonance imaging (fMRI) activity related to spatial working memory (SWM) among adolescents who were heavy users of after an average of 8 days of abstinence, but the persisting neural effects remain unclear. To characterize the potentially persisting neurocognitive effects of heavy marijuana use in adolescence, we examined fMRI response during SWM among abstinent marijuana-using teens. Participants were 15 MJ teens and 17 demographically similar non-using controls, ages 16-18. Teens underwent biweekly urine toxicology screens to ensure abstinence for 28 days before fMRI acquisition. Groups performed similarly on the SWM task, but MJ teens demonstrated lower activity in right dorsolateral prefrontal and occipital cortices, yet significantly more activation in right posterior parietal cortex. MJ teens showed abnormalities in brain response during a SWM task compared with controls, even after 1 month of abstinence. The activation pattern among MJ teens may reflect different patterns of utilization of spatial rehearsal and attention strategies, and could indicate altered neurodevelopment or persisting abnormalities associated with heavy marijuana use in adolescence.

Previous studies have suggested neural disruption and reorganization in adult marijuana users. However, it remains unclear whether these effects persist in adolescents after 28 days of abstinence and, if they do, what Performance x Brain Response interactions occur. Adolescent marijuana users (n=17) and controls (n=17) aged 16-18 years were recruited from local schools. Functional magnetic resonance imaging data were collected after 28 days' monitored abstinence as participants performed a spatial working memory task. Marijuana users show Performance x Brain Response interactions in the bilateral temporal lobes, left anterior cingulate, left parahippocampal gyrus, and right thalamus (clusters >/=1358 microl; p<.05), although groups do not differ on behavioral measures of task performance. Marijuana users show differences in brain response to a spatial working memory task despite adequate performance, suggesting a different approach to the task via altered neural pathways.

Background: Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence., Methods: Adolescents with (n = 16) and without (n = 17) histories of marijuana use were compared on blood oxygen level dependent (BOLD) response to a go/no-go task during functional magnetic resonance imaging (fMRI) after 28 days of monitored abstinence. Participants had no neurological problems or Axis I diagnoses other than cannabis abuse/dependence., Results: Marijuana users did not differ from non-users on task performance but showed more BOLD response than non-users during inhibition trials in right dorsolateral prefrontal, bilateral medial frontal, bilateral inferior and superior parietal lobules, and right occipital gyri, as well as during "go" trials in right prefrontal, insular, and parietal cortices (p < 0.05, clusters > 943 microl). Differences remained significant even after controlling for lifetime and recent alcohol use., Conclusions: Adolescent marijuana users relative to non-users showed increased brain processing effort during an inhibition task in the presence of similar task performance, even after 28 days of abstinence. Thus, increased brain processing effort to achieve inhibition may predate the onset of regular use or result from it. Future investigations will need to determine whether increased brain processing effort is associated with risk to use.

Aim: To use the superior spatial resolution of magnetic resonance imaging (MRI) to examine differences in cerebral perfusion between young alcohol dependent and normal women., Methods: Eight alcohol dependent women and 8 controls (all ages 18-25) received single-slice resting perfusion-weighted MRI (directly proportional to brain blood flow), with slices located above the corpus callosum., Results: Alcohol-dependent women had decreased perfusion in prefrontal and left parietal regions., Conclusions: Reduced perfusion has not previously been reported in young, physically healthy alcohol dependent females, yet is consistent with previously reported decreased cerebral activity in alcohol dependence.

The relationship between standardized neuropsychological test performance and functional magnetic resonance imaging (fMRI) response during cognitive tasks is largely unknown. This exploratory investigation examined the relationship between neuropsychological test performance and fMRI response to a spatial working memory (SWM) task among 49 typically developing adolescents. Participants were administered a variety of neuropsychological tests in the domains of working memory, visuospatial skills, executive functioning, attention, learning and memory, visuomotor skills and processing speed, and language functioning. Neuropsychological domain scores were used to predict fMRI response during a SWM task. Results suggest that in many brain regions, neuropsychological performance negatively predicts fMRI response, suggesting that those teens with better neuropsychological abilities required fewer neural resources to adequately perform the task. This study provides further understanding of how neuropsychological abilities relate to neural activity during fMRI tasks, and provides an important link between neuropsychological and fMRI research.

Recent studies have described neuromaturation and cognitive development across the lifespan, yet few neuroimaging studies have investigated task-related alterations in brain activity during adolescence. We used functional magnetic resonance imaging (fMRI) to examine brain response to a spatial working memory (SWM) task in 49 typically developing adolescents (25 females and 24 males; ages 12-17). No gender or age differences were found for task performance during SWM. However, age was positively associated with SWM brain response in left prefrontal and bilateral inferior posterior parietal regions. Age was negatively associated with SWM activation in bilateral superior parietal cortex. Gender was significantly associated with SWM response; females demonstrated diminished anterior cingulate activation and males demonstrated greater response in frontopolar cortex than females. Our findings indicate that the frontal and parietal neural networks involved in spatial working memory change over the adolescent age range and are further influenced by gender. These changes may represent evolving mnemonic strategies subserved by ongoing adolescent brain development.

Alcohol and marijuana use are prevalent in adolescence, yet the neural impact of concomitant use remains unclear. We previously demonstrated functional magnetic resonance imaging (fMRI) response to spatial working memory (SWM) among teens with alcohol use disorders (AUD) compared to controls, and predicted that adolescents with marijuana and alcohol use disorders would show additional abnormalities. Participants were three groups of 15-17-year-olds: 19 non-abusing controls, 15 AUD teens with limited exposure to drugs, and 15 teens with comorbid marijuana and alcohol use disorders (MAUD) and minimal other drug experience. After >2 days' abstinence, participants performed a SWM task during fMRI acquisition. fMRI brain response patterns differed between groups, despite similar performance on the task. MAUD youths showed less activation in inferior frontal and temporal regions than controls, and more response in other prefrontal regions. Compared to AUD teens, MAUD youths also showed less inferior frontal and temporal activation, but more medial frontal response. Overall, MAUD youths showed different brain response abnormalities than teens with AUD alone, despite relatively short histories of substance involvement. This pattern could suggest compensation for marijuana-related attention and working memory deficits. However, relatively recent use and premorbid features may influence results, and should be examined in future studies.

Context: Relapse is a common clinical problem in individuals with substance dependence. Previous studies have implicated a multifactorial process underlying relapse; however, the contribution of specific neural substrates has not yet been examined., Objective: To determine whether results from functional magnetic resonance imaging (fMRI) shortly after drug cessation could predict relapse in stimulant-dependent individuals., Participants and Design: Treatment-seeking methamphetamine-dependent males (N = 46) underwent fMRI 3 to 4 weeks after cessation of drug use. Of the 40 subjects who were followed up a median of 370 days, 18 relapsed and 22 did not., Main Outcome Measure: Blood oxygen level-dependent fMRI activation during a simple 2-choice prediction task., Results: The fMRI activation patterns in right insular, posterior cingulate, and temporal cortex obtained early in recovery correctly predicted 20 of 22 subjects who did not relapse and 17 of 18 subjects who did. A Cox regression analysis revealed that the combination of right middle frontal gyrus, middle temporal gyrus, and posterior cingulate activation best predicted the time to relapse., Conclusion: To our knowledge, this is the first investigation to show that fMRI can be used to predict relapse in substance-dependent individuals.

Objective: Personality and alcohol expectancies have been examined as risk factors for the initiation and maintenance of alcohol use in adolescents and young adults. Differences in processing appetitive stimuli are seen as a mechanism for personality's influence on behavior, and that mechanism predisposes individuals to form more positive expectancies for alcohol. The go/no-go task has been used to show how personality differences influence responding to appetitive stimuli in adolescents and adults, and functional magnetic resonance imaging (fMRI) has been used to examine the relation of go/no-go responding to personality in adult males. However, no study to date has examined the relation between fMRI responding, personality and alcohol expectancies in adolescents., Method: Forty-six adolescents (ages 12-14 years; 61% male) with minimal substance use histories completed measures of neuroticism, extraversion, and alcohol expectancies, and performed a go/no-go task during fMRI acquisition., Results: Greater blood oxygen level-dependent (BOLD) response to inhibition predicted fewer expectancies of cognitive and motor improvements but more expectancies of cognitive and motor impairment from alcohol. In addition, extraverted youths reported more positive alcohol expectancies. However, BOLD response did not predict neuroticism or extraversion., Conclusions: These preliminary results suggest that decreased inhibitory neural processing may contribute to more positive and less negative expectancies, which can eventually lead to problem drinking. Further, extraversion may also yield more positive expectancies and could underlie a vulnerability to disordered alcohol use.

Disinhibition among alcoholics may precede or result from alcohol use disorders (AUDs). It remains unclear how disinhibition might contribute to AUD risk among youths with a family history of alcoholism (FHP). We used functional magnetic resonance imaging (fMRI) to explore inhibition-related neural risk factors for AUD. Participants were 12- to 14-year-old nondrinkers, including 12 FHP youths and 14 youths with no family history of alcoholism (FHN). Youths performed a go/no-go task during fMRI acquisition. At a conservative threshold, FHN youths showed less inhibitory response than FHP youths in the left middle frontal gyrus, despite similar task performance between groups. Using a more liberal threshold, FHP youths also demonstrated less response in additional frontal regions. These preliminary findings suggest that FHP youths show less inhibitory frontal response than FHN youths. Altered neural activation among FHP youths may underlie subsequent disinhibition and could be related to the AUD risk.

The process of accurately predicting which actions are associated with advantageous versus disadvantageous outcomes is an important function of daily life. An integral part of this process is being able to detect when the association between an action and an outcome changes. This investigation examined the hypothesis that the inferior prefrontal cortex is critical for the detection of trends and that a trend process derived from the temporal difference model accomplishes this detection. Nineteen normal right-handed volunteers completed 120 4-s trials of a Rock Paper Scissors (RPS) task during functional magnetic resonance imaging. Subjects acquired the selection of advantageous actions during the RPS task. Activations in the medial frontal gyrus (BA 10), left ventrolateral frontal gyrus (BA 11/47), and left pallidum were significantly higher during trials in which subjects acquired the advantageous action. The time course of individually derived trend detection functions was found to be time-locked to the hemodynamic changes in the inferior frontal gyrus. These findings are consistent with the hypothesis that the inferior prefrontal cortex computes a trend from previously experienced action-outcome sequences based on a value function derived from the temporal difference model.

Background and aimsThe precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation.MethodsThis study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined.ResultsParticipants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (β = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (β = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (β = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (β = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (β = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable.ConclusionWe found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

Background and aimsRecently, 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 settingCross-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).CasesCases 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.MeasurementsGraph theory metrics of segregation and integration were used to summarize SCN.FindingsMirroring 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.ConclusionStructural 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.

Subcortical brain morphometry matures across adolescence and young adulthood, a time when many youth engage in escalating levels of alcohol use. Initial cross-sectional studies have shown alcohol use is associated with altered subcortical morphometry. However, longitudinal evidence of sex-specific neuromaturation and associations with alcohol use remains limited. This project used generalized additive mixed models to examine sex-specific development of subcortical volumes and associations with recent alcohol use, using 7 longitudinal waves (n = 804, 51% female, ages 12-21 at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). A second, independent, longitudinal dataset, with up to four waves of data (n = 467, 43% female, ages 10-18 at baseline), was used to assess replicability. Significant, replicable non-linear normative volumetric changes with age were evident in the caudate, putamen, thalamus, pallidum, amygdala and hippocampus. Significant, replicable negative associations between subcortical volume and alcohol use were found in the hippocampus in all youth, and the caudate and thalamus in female but not male youth, with significant interactions present in the caudate, thalamus and putamen. Findings suggest a structural vulnerability to alcohol use, or a predisposition to drink alcohol based on brain structure, with female youth potentially showing heightened risk, compared to male youth.

Cortical thickness changes dramatically during development and is associated with adolescent drinking. However, previous findings have been inconsistent and limited by region-of-interest approaches that are underpowered because they do not conform to the underlying spatially heterogeneous effects of alcohol. In this study, adolescents (n = 657; 12-22 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study who endorsed little to no alcohol use at baseline were assessed with structural magnetic resonance imaging and followed longitudinally at four yearly intervals. Seven unique spatial patterns of covarying cortical thickness were obtained from the baseline scans by applying an unsupervised machine learning method called non-negative matrix factorization (NMF). The cortical thickness maps of all participants' longitudinal scans were projected onto vertex-level cortical patterns to obtain participant-specific coefficients for each pattern. Linear mixed-effects models were fit to each pattern to investigate longitudinal effects of alcohol consumption on cortical thickness. We found in six NMF-derived cortical thickness patterns, the longitudinal rate of decline in no/low drinkers was similar for all age cohorts. Among moderate drinkers the decline was faster in the younger adolescent cohort and slower in the older cohort. Among heavy drinkers the decline was fastest in the younger cohort and slowest in the older cohort. The findings suggested that unsupervised machine learning successfully delineated spatially coordinated patterns of vertex-level cortical thickness variation that are unconstrained by neuroanatomical features. Age-appropriate cortical thinning is more rapid in younger adolescent drinkers and slower in older adolescent drinkers, an effect that is strongest among heavy drinkers.

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Tapert's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.

BackgroundSubstance use research has focused on family history of alcohol use disorders but less on other addictions in biological family members. We examined how parental substance use history relates to reward system functioning, specifically nucleus accumbens (NAcc) and putamen activation at age 9-10 in the Adolescent Brain Cognitive Development (ABCD) Study. This research hopes to address limitations in prior literature by focusing analyses on a large, substance-naïve sample.MethodWe included ABCD participants with valid Monetary Incentive Delay task fMRI Baseline data and parent substance use history at project baseline from Data Release 2.0 (N = 10,622). Parent-history-positive (PH+) participants had one or both biological parents with a history of two+problems with alcohol (n = 741; PH+A) and/or other drugs (n = 638; PH+D). Of participants who were parent-history-negative (PH-) for alcohol and/or drugs, a stratified random sample based on six sociodemographic variables was created and matched to the PH+group (PH-A n = 699; PH-D n = 615). The contrast of interest was anticipation of a large reward vs. neutral response.ResultsPH+A youth had more activation in the right NAcc during large reward anticipation than PH-A. PH+D youth showed enhanced left putamen activation during large reward anticipation than PH-D youth. Bayesian hypothesis testing showed moderate evidence (BF > 3) in favor of the null hypothesis.ConclusionThese findings suggest that pre-adolescents whose biological parents had a history of substance-related problems show small differences in reward processing compared to their PH- peers.

The human toll of disasters extends beyond death, injury and loss. Post-traumatic stress (PTS) can be common among directly exposed individuals, and children are particularly vulnerable. Even children far removed from harm's way report PTS, and media-based exposure may partially account for this phenomenon. In this study, we examine this issue using data from nearly 400 9- to 11-year-old children collected before and after Hurricane Irma, evaluating whether pre-existing neural patterns moderate associations between hurricane experiences and later PTS. The 'dose' of both self-reported objective exposure and media exposure predicted PTS, the latter even among children far from the hurricane. Furthermore, neural responses in brain regions associated with anxiety and stress conferred particular vulnerability. For example, heightened amygdala reactivity to fearful stimuli moderated the association between self-reported media exposure and PTS. Collectively, these findings show that for some youth with measurable vulnerability, consuming extensive disaster-related media may offer an alternative pathway to disaster exposure that transcends geography and objective risk.

Childhood adversity has been associated with elevated risk for psychopathology. We investigated whether development of functional brain networks important for executive function (EF) could serve as potential mediators of this association. We analyzed data of 475 adolescents, a subsample of the multisite longitudinal NCANDA (National Consortium on Alcohol and Neurodevelopment in Adolescence) cohort with completed measures of childhood trauma, resting-state functional brain connectivity data, and symptoms of internalizing and externalizing psychopathology at baseline and follow-up years 1-4. Using parallel process latent growth models, we found that childhood adversity was associated with increased risk for externalizing/internalizing behaviors. We specifically investigated whether functional connectivity of the dorsal anterior cingulate cortex (dACC) to brain regions within the cingulo-opercular (CO) network, a well-known EF network that underlies control of attention and self-regulation, mediates the association between adversity and symptoms of psychopathology. We found that childhood adversity, specifically child neglect was negatively associated with functional connectivity of the dACC within the CO network, and that this connectivity mediated the association between neglect and externalizing behaviors. Our study advances a mechanistic understanding of how childhood adversity may impact the development of psychopathology, highlighting the relevance of dACC functional networks particularly for externalizing psychopathology.

BackgroundAdolescents are at increased risk of developing major depressive disorder (MDD) than many other age groups. Although the neural correlates of MDD in adults have been studied prospectively, such adolescent depression studies are mainly cross-sectional. We extracted data regarding the relationship between cortical thickness and later development of adolescent MDD from a national community study that uses an accelerated longitudinal design to examine the psychological, environmental, and neural differences related to drinking and brain development.Methods692 subjects (age 12-21 years; 50% female) without a history of MDD were assessed with structural neuroimaging at baseline. We compared those 101 subjects who transitioned to MDD by 1-year follow-up to those who remained non-depressed over the same time period. FreeSurfer's autosegmentation process estimated vertex-wide cortical thicknesses and its Query, Design, Estimate, Contrast (Qdec) application investigated cortical thickness between those who later developed MDD and those who remained without MDD (Monte Carlo corrected for multiple comparisons, vertex-wise cluster threshold of 1.3, p

Exogenous causes, such as alcohol use, and endogenous factors, such as temperament and sex, can modulate developmental trajectories of adolescent neurofunctional maturation. We examined how these factors affect sexual dimorphism in brain functional networks in youth drinking below diagnostic threshold for alcohol use disorder (AUD). Based on the 3-year, annually acquired, longitudinal resting-state functional magnetic resonance imaging (MRI) data of 526 adolescents (12-21 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) cohort, developmental trajectories of 23 intrinsic functional networks (IFNs) were analyzed for (1) sexual dimorphism in 259 participants who were no-to-low drinkers throughout this period; (2) sex-alcohol interactions in two age- and sex-matched NCANDA subgroups (N = 76 each), half no-to-low, and half moderate-to-heavy drinkers; and (3) moderating effects of gender-specific alcohol dose effects and a multifactorial impulsivity measure on IFN connectivity in all NCANDA participants. Results showed that sex differences in no-to-low drinkers diminished with age in the inferior-occipital network, yet girls had weaker within-network connectivity than boys in six other networks. Effects of adolescent alcohol use were more pronounced in girls than boys in three IFNs. In particular, girls showed greater within-network connectivity in two motor networks with more alcohol consumption, and these effects were mediated by sensation-seeking only in girls. Our results implied that drinking might attenuate the naturally diminishing sexual differences by disrupting the maturation of network efficiency more severely in girls. The sex-alcohol-dose effect might explain why women are at higher risk of alcohol-related health and psychosocial consequences than men.

IntroductionInteroception, defined as the sense of the internal state of one's body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing.MethodsEighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing.ResultsOverall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls.ConclusionsOur findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Academic performance significantly influences educational advancement, career opportunities, and life outcomes. The extent to which adolescent substance use and brain morphology predict academic achievement has not been extensively explored. We examined grade point average (GPA) at the time alcohol and cannabis use often starts (7th - 9th grade) and subsequently during 11th and 12th grade in a 170 physically healthy adolescents in a longitudinal study. Covariance analysis examined predictive features from 36 metrics of middle school academic performance and initiation of alcohol and cannabis use. Using a machine learning approach, GPA from 7th, 8th, and 9th grade strongly predicted 11th and 12th grade GPA, followed in predictive power by alcohol use age of onset. A machine learning approach determined 16 (from 336) baseline neuroimaging features that reflected lower thickness, area, or volume in average high school GPA drinkers compared to nondrinkers. Features that distinguished average performing drinkers from nondrinkers suggested accelerated gray matter loss during adolescence for drinkers, while high performing drinkers compared to nondrinkers may have attenuated gray matter maturation. Additional possibilities are discussed.

ObjectiveData on the neurodevelopmental and associated behavioral effects of light to moderate in utero alcohol exposure are limited. This retrospective investigation tested for associations between reported maternal prenatal alcohol use and psychological, behavioral, and neurodevelopmental outcomes in substance-naive youths.MethodsParticipants were 9,719 youths (ages 9.0 to 10.9 years) from the Adolescent Brain Cognitive Development Study. Based on parental reports, 2,518 (25.9%) had been exposed to alcohol in utero. Generalized additive mixed models and multilevel cross-sectional and longitudinal mediation models were used to test whether prenatal alcohol exposure was associated with psychological, behavioral, and cognitive outcomes, and whether differences in brain structure and resting-state functional connectivity partially explained these associations at baseline and 1-year follow-up, after controlling for possible confounding factors.ResultsPrenatal alcohol exposure of any severity was associated with greater psychopathology, attention deficits, and impulsiveness, with some effects showing a dose-dependent response. Children with prenatal alcohol exposure, compared with those without, displayed greater cerebral and regional volume and greater regional surface area. Resting-state functional connectivity was largely unaltered in children with in utero exposure. Some of the psychological and behavioral outcomes at baseline and at the 1-year follow-up were partially explained by differences in brain structure among youths who had been exposed to alcohol in utero.ConclusionsAny alcohol use during pregnancy is associated with subtle yet significant psychological and behavioral effects in children. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy.

BackgroundChildhood trauma is known to impart risk for several adverse life outcomes. Yet, its impact during adolescent development is not well understood. We aimed to investigate the relationships among childhood trauma, functional brain connectivity, executive dysfunction (ED), and the development of high-risk drinking in adolescence.MethodsData from the National Consortium on Alcohol and Neurodevelopment in Adolescence (sample size = 392, 55% female) cohort were used. This included resting-state functional magnetic resonance imaging at baseline, childhood trauma and ED self-reports, and detailed interviews on alcohol and substance use collected at baseline and at 4 annual follow-ups. We used longitudinal regression analyses to confirm the relationship between childhood trauma and ED, identified the mediating functional brain network hubs, and used these linkages to predict future high-risk drinking in adolescence.ResultsChildhood trauma severity was significantly related to ED in all years. At baseline, distributed functional connectivity from hub regions in the bilateral dorsal anterior cingulate cortex, right anterior insula, right intraparietal sulcus, and bilateral pre- and postcentral gyri mediated the relationship between childhood trauma and ED. Furthermore, high-risk drinking in follow-up years 1-4 could be predicted with high accuracy from the trauma-affected functional brain networks that mediated ED at baseline, together with age, childhood trauma severity, and extent of ED.DiscussionFunctional brain networks, particularly from hub regions important for cognitive and sensorimotor control, explain the relationship between childhood trauma and ED and are important for predicting future high-risk drinking. These findings are relevant for the prognosis of alcohol use disorders.

BackgroundThe cerebellum is a target of alcoholism-related brain damage in adults, yet no study has prospectively tracked deviations from normal cerebellar growth trajectories in adolescents before and after initiating drinking.MethodsMagnetic resonance imaging tracked developmental volume trajectories of 10 cerebellar lobule and vermis tissue constituents in 548 no/low drinking youths age 12 to 21 years at induction into this 5-site, NCANDA (National Consortium on Alcohol and NeuroDevelopment in Adolescence) study. Over the 3- to 4-year longitudinal examination yielding 2043 magnetic resonance imaging scans, 328 youths remained no/low drinkers, whereas 220 initiated substantial drinking after initial neuroimaging.ResultsNormal growth trajectories derived from no/low drinkers indicated that gray matter volumes of lobules V and VI, crus II, lobule VIIB, and lobule X declined faster with age in male youths than in female youths, whereas white matter volumes in crus I and crus II and lobules VIIIA and VIIIB expanded faster in female youths than in male youths; cerebrospinal fluid volume expanded faster in most cerebellar regions of male youths than female youths. Drinkers exhibited accelerated gray matter decline in anterior lobules and vermis, accelerated vermian white matter expansion, and accelerated cerebrospinal fluid volumes expansion of anterior lobules relative to youths who remained no/low drinkers. Analyses including both alcohol and marijuana did not support an independent role for marijuana in alcohol effects on cerebellar gray matter trajectories.ConclusionsAlcohol use-related cerebellar growth trajectory differences from normal involved anterior lobules and vermis of youths who initiated substantial drinking. These regions are commonly affected in alcohol-dependent adults, raising the possibility that cerebellar structures affected by youthful drinking may be vulnerable to age-alcohol interactions in later adulthood.

BackgroundAltered brain activation during response inhibition has been linked to a greater risk for alcohol and other substance use behaviors in late adolescence. However, the ability of neural markers of response inhibition, acquired during adolescence, to temporally predict the transition from less frequent and lower quantity alcohol use to high-risk, frequent (≥ weekly) binge drinking behavior remains unclear.MethodsAdolescents (N = 29; 9 females) were selected from a larger ongoing longitudinal study to include those who transitioned to at least weekly binge drinking (≥5/4 alcoholic drinks for males/females per occasion) over a 15-year follow-up period. Prior to the onset of weekly binge drinking (mean age = 18.0), participants underwent a functional MRI including a go/no-go task. Whole-brain activation from the no-go correct rejection versus no-go false alarm contrast was used to predict time to transition to frequent binge drinking.ResultsLess no-go correct rejection versus no-go false alarm activation in a cluster including the precentral gyri, insula, and inferior frontal gyri predicted a more rapid transition into frequent binge drinking (voxel-wise alpha

The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing, nationwide study of the effects of environmental influences on behavioral and brain development in adolescents. The main objective of the study is to recruit and assess over eleven thousand 9-10-year-olds and follow them over the course of 10 years to characterize normative brain and cognitive development, the many factors that influence brain development, and the effects of those factors on mental health and other outcomes. The study employs state-of-the-art multimodal brain imaging, cognitive and clinical assessments, bioassays, and careful assessment of substance use, environment, psychopathological symptoms, and social functioning. The data is a resource of unprecedented scale and depth for studying typical and atypical development. The aim of this manuscript is to describe the baseline neuroimaging processing and subject-level analysis methods used by ABCD. Processing and analyses include modality-specific corrections for distortions and motion, brain segmentation and cortical surface reconstruction derived from structural magnetic resonance imaging (sMRI), analysis of brain microstructure using diffusion MRI (dMRI), task-related analysis of functional MRI (fMRI), and functional connectivity analysis of resting-state fMRI. This manuscript serves as a methodological reference for users of publicly shared neuroimaging data from the ABCD Study.

BackgroundCognitive Bias Modification (CBM) has garnered interest as a potential addiction treatment. CBM interventions such as Approach Avoidance Training (AAT) are designed to alter automatic tendencies to approach drugs or drug-related cues. In our previous work, the cannabis AAT (CAAT) reduced cannabis approach bias, which was related to reduced cannabis use, among 80 non-treatment-seeking cannabis-using youth (Jacobus et al., 2018). In this preliminary examination, a subsample of these youth underwent neuroimaging to explore CAAT's effect on cannabis cue-related neural activation.MethodsSub-study participants were 41 cannabis-using youth ages 17-21 (mean age = 18.83; 47.5% female). Participants completed a cannabis cue-reactivity task during a functional MRI scan pre- and post CAAT-training or CAAT-sham to examine CAAT-related neural changes.ResultsThirty-seven youth completed all six CAAT (n = 19) or CAAT-sham (n = 18) training sessions and had usable neuroimaging data. The group*time interaction on cannabis approach bias reached trend-level significance (p = .055). Change in approach bias slopes from pre-to post-treatment was positive for CAAT-sham (increased approach bias) and negative for CAAT-training (change to avoidance bias), consistent with the larger study. No significant changes emerged for cannabis cue-induced activation following CAAT-training or CAAT-sham in whole brain or region of interest analyses. However, active CAAT-training was associated with small-to-medium decreases in amygdala (Cohen's dz = 0.36) and medial prefrontal cortex (Cohen's dz = 0.48) activation to cannabis cues.ConclusionsDespite reducing cannabis use in the larger sample, CAAT-training did not alter neural cannabis cue-reactivity in the sub-study compared to CAAT-sham. More research is needed to understand neural mechanisms underlying AAT-related changes in substance use.