Cummins K, Brumback T, Corrales C, Nooner KB, Brown SA, & Clark DB (2024). Patterns of depression symptoms in relation to stressors and social behaviors during the COVID-19 pandemic among older youth and emerging adults in the United States. PLOS Global Public Health 4(10): e0003545. doi.org/10.1371/journal.pgph.0003545

Abstract: Substantial increases in depression at the outset of the pandemic were previously reported in NCANDA, a longitudinal sample of adolescents and young adults. The current NCANDA study examined depression symptoms before and during the COVID-19 pandemic. It evaluated the influence of stressors and social behavior (e.g., in-person and online socializing) with linear mixed effects models. A strong, positive association between COVID-19-related stressors and depression symptoms was observed. The frequency of in-person socializing did not account for the totality of the changes in depression observed during the early COVID-19 pandemic. It may be that pandemic-related stressors counteracted the benefits of in-person interactions during the early stages of the COVID-19 pandemic. Future studies can continue to elucidate the interactions among psychosocial, genetic, and behavioral factors contributing to depression symptoms in the unprecedented context of the COVID-19 pandemic. Read more.

Nguyen-Louie TT, Thompson WK, Sullivan EV, Pfefferbaum A, Gonzalez C, Eberson-Shumate SC, Wade NE, Clark DB, Nagel BJ, Baker FC, Luna B, Nooner KB, de Zambotti M, Goldston DB, Knutson B, Pohl KM*, Tapert SF (2024). Multi-dimensional predictors of first drinking initiation and regular drinking onset in adolescence: A prospective longitudinal study. Developmental Cognitive Neuroscience 69: 101424. doi:10.1016/j.dcn.2024.101424

*Corresponding author

Abstract: Early adolescent drinking onset is linked to myriad negative consequences. Using the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) baseline to year 8 data, this study (1) leveraged best subsets selection and Cox Proportional Hazards regressions to identify the most robust predictors of adolescent first and regular drinking onset, and (2) examined the clinical utility of drinking onset in forecasting later binge drinking and withdrawal effects. Baseline predictors included youth psychodevelopmental characteristics, cognition, brain structure, family, peer, and neighborhood domains. Participants (N=538) were alcohol-naïve at baseline. The strongest predictors of first and regular drinking onset were positive alcohol expectancies (Hazard Ratios [HRs]=1.67–1.87), easy home alcohol access (HRs=1.62–1.67), more parental solicitation (e.g., inquiring about activities; HRs=1.72–1.76), and less parental control and knowledge (HRs=.72–.73). Robust linear regressions showed earlier first and regular drinking onset predicted earlier transition into binge and regular binge drinking (βs=0.57–0.95). Zero-inflated Poisson regressions revealed that delayed first and regular drinking increased the likelihood (Incidence Rate Ratios [IRR]=1.62 and IRR=1.29, respectively) of never experiencing withdrawal. Findings identified behavioral and environmental factors predicting temporal paths to youthful drinking, dissociated first from regular drinking initiation, and revealed adverse sequelae of younger drinking initiation, supporting efforts to delay drinking onset. Read more.

Patel H, Nooner KB, Reich JC, Woodley MM, Cummins K, & Brown SA (2024). Trauma's distinctive and combined effects on subsequent substance use, mental health, and neurocognitive functioning with the NCANDA sample. Developmental Cognitive Neuroscience 69: 101427. doi: 10.1016/j.dcn.2024.101427

Purpose. Traumatic brain injury (TBI) and potentially traumatic events (PTEs) contribute to increased substance use, mental health issues, and cognitive impairments. However, there's not enough research on how TBI and PTEs combined impact mental heath, substance use, and neurocognition.

Methods. This study leverages a subset of The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) multi-site dataset with 551 adolescents to assess the combined and distinctive impacts of TBI, PTEs, and TBI+PTEs (prior to age 18) on substance use, mental health, and neurocognitive outcomes at age 18.

Results. TBI, PTEs, and TBI+PTEs predicted greater lifetime substance use and past-year alcohol and cannabis use. PTEs predicted greater internalizing symptoms, while TBI+PTEs predicted greater externalizing symptoms. Varying effects on neurocognitive outcomes included PTEs influencing attention accuracy and TBI+PTEs predicting faster speed in emotion tasks. PTEs predicted greater accuracy in abstraction-related tasks. Associations with working memory were not detected.

Conclusions. This exploratory study contributes to the growing literature on the complex interplay between TBI, PTEs, and adolescent mental health, substance use, and neurocognition. The developmental implications of trauma via TBIs and/or PTEs during adolescence are considerable and worthy of further investigation. Read more.

Zhao Q, Paschali M, Dehoney J, Baker FC, de Zambotti M, De Bellis MD, Goldston DB, Nooner KB, Clark DB, Luna B, Nagel BJ, Brown SA, Tapert SF, Eberson S, Thompson WK, Pfefferbaum A, Sullivan EV, & Pohl, KM (2024). Identifying high school risk factors that forecast heavy drinking onset in understudied young adults. Developmental Cognitive Neuroscience 68: 101413. doi: 10.1016/j.dcn.2024.101413

Abstract: Heavy alcohol drinking is a major, preventable problem that adversely impacts the physical and mental health of US young adults. Studies seeking drinking risk factors typically focus on young adults who enrolled in 4-year residential college programs (4YCP) even though most high school graduates join the workforce, military, or community colleges. We examined 106 of these understudied young adults (USYA) and 453 4YCPs from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) by longitudinally following their drinking patterns for 8 years from adolescence to young adulthood. All participants were no-to-low drinkers during high school. Whereas 4YCP individuals were more likely to initiate heavy drinking during college years, USYA participants did so later. Using mental health metrics recorded during high school, machine learning forecasted individual-level risk for initiating heavy drinking after leaving high school. The risk factors differed between demographically matched USYA and 4YCP individuals and between sexes. Predictors for USYA drinkers were sexual abuse, physical abuse for girls, and extraversion for boys, whereas 4YCP drinkers were predicted by the ability to recognize facial emotion and, for boys, greater openness. Thus, alcohol prevention programs need to give special consideration to those joining the workforce, military, or community colleges, who make up the majority of this age group. Read more.

Meruelo AD, Brumback T, Pelham WE 3rd, Wade NE, Thomas ML, Coccaro EF, Nooner KB, Brown SA, Tapert SF, & Mrug S (2024). How Do Anger and Impulsivity Impact Fast-Food Consumption in Transitional Age Youth? AJPM Focus 3(3), 100208. doi: 10.1016/j.focus.2024.100208

Introduction. Consumption of fast food has been linked to psychiatric distress, violent behaviors, and impulsivity in adolescents. The relationship between eating fast food, anger, and impulsivity has not been widely investigated. The National Consortium on Alcohol and Neurodevelopment in Adolescence community-based cohort consists of 831 youth, half at elevated risk factors for substance use disorders during adolescence, followed annually.

Methods. Impulsivity using Urgency, Premeditation, Perseverance, and Sensation Seeking Impulsive Behavior scale from annual assessments was examined in relation to self-reported fast-food consumption frequency and mobile application questions of anger. This study tested the hypotheses that youth anger may be predicted by fast-food consumption frequency and impulsivity using multiple regression, in addition to whether adolescent fast-food consumption frequency may be predicted by anger and impulsivity.

Results. Among youth, higher anger levels and impulsivity predicted greater frequency of fast-food consumption, and greater fast-food consumption frequency and impulsivity predicted higher anger levels.

Conclusions. This study's longitudinal findings are consistent with those of other studies that have found fast-food consumption and anger associated with impulsivity and also reveal a bidirectional link between anger and fast-food consumption. These results may point attention to food selection considerations for those at risk of anger and poorer psychiatric outcomes. Read more.

Ottino-González J, Cupertino RB, Cao Z, Hahn S, Pancholi D, Albaugh MD, Brumback T, Baker FC, Brown SA, Clark DB, de Zambotti M, Goldston DB, Luna B, Nagel BJ, Nooner KB, Pohl KM, Tapert SF, Thompson WK, Jernigan TL, Conrod P, Mackey S, Garavan H (2024). Brain structural covariance network features are robust markers of early heavy alcohol use. Addiction 119(1): 113-124. doi: 10.1111/add.16330

Background and Aims. Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies.

Design and Setting. Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14–22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17–22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22–37 years).

Cases. Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected.

Methods. Graph theory metrics of segregation and integration were used to summarize SCN.

Findings. Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = −0.029, P = 0.002], lower modularity (AUC = −0.14, P = 0.004), lower average shortest path length (AUC = −0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = −0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar.

Conclusions. Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology. Read more.

Jones SA, Morales AM, Harman G, Dominguez-Savage KA, Gilbert S, Baker FC, de Zambotti M, Goldston DB, Nooner KB, Clark DB, Luna B, Thompson WK, Brown SA, Tapert SF, Nagel BJ (2023). Associations between alcohol use and sex-specific maturation of subcortical gray matter morphometry from adolescence to adulthood: Replication across two longitudinal samples. Developmental Cognitive Neuroscience 63: 101294. doi: 10.1016/j.dcn.2023.101294

Abstract: 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. Read more.

Alzuetta E, Podhajsky S, Zhao Q, Tapert SF, Thompson WK, de Zambotti M, Yuksel D, Kiss O, Wang R, Volpe L, Prouty D, Colrain IM, Clark DB, Goldston DB, Nooner KB, Brown, De Bellis MD, Brown SA, Nagel BJ, Pfefferbaum A, Sullivan EV, Baker FC, Pohl, KM (2023). Risk for depression tripled during COVID-19 pandemic in emerging adults followed for the last 8 years. Psychological Medicine 53(5), 2156–2163. doi:10.1017/S0033291721004062

Background. The coronavirus disease 2019 (COVID-19) pandemic has significantly increased depression rates, particularly in emerging adults. The aim of this study was to examine longitudinal changes in depression risk before and during COVID-19 in a cohort of emerging adults in the U.S. and to determine whether prior drinking or sleep habits could predict the severity of depressive symptoms during the pandemic.

Methods. Participants were 525 emerging adults from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a five-site community sample including moderate-to-heavy drinkers. Poisson mixed-effect models evaluated changes in the Center for Epidemiological Studies Depression Scale (CES-D-10) from before to during COVID-19, also testing for sex and age interactions. Additional analyses examined whether alcohol use frequency or sleep duration measured in the last pre-COVID assessment predicted pandemicrelated increase in depressive symptoms.

Results. The prevalence of risk for clinical depression tripled due to a substantial and sustained increase in depressive symptoms during COVID-19 relative to pre-COVID years. Effects were strongest for younger women. Frequent alcohol use and short sleep duration during the closest pre-COVID visit predicted a greater increase in COVID-19 depressive symptoms.

Conclusions. The sharp increase in depression risk among emerging adults heralds a public health crisis with alarming implications for their social and emotional functioning as this generation matures. In addition to the heightened risk for younger women, the role of alcohol use and sleep behavior should be tracked through preventive care aiming to mitigate this looming mental health crisis. Read more.

Tervo-Clemmens B, Calabro FJ, Parr AC, Fedor J, Foran W, Luna B. (2023). A canonical trajectory of executive function maturation from adolescence to adulthood. Nature Communications 14: 6922. doi: 10.1038/s41467-023-42540-8

Abstract: Theories of human neurobehavioral development suggest executive functions mature from childhood through adolescence, underlying adolescent risk-taking and the emergence of psychopathology. Investigations with relatively small datasets or narrow subsets of measures have identified general executive function development, but the specific maturational timing and independence of potential executive function subcomponents remain unknown. Integrating four independent datasets (N = 10,766; 8–35 years old) with twenty-three measures from seventeen tasks, we provide a precise charting, multi-assessment investigation, and replication of executive function development from adolescence to adulthood. Across assessments and datasets, executive functions follow a canonical non-linear trajectory, with rapid and statistically significant development in late childhood to mid-adolescence (10–15 years old), before stabilizing to adult-levels in late adolescence (18–20 years old). Age effects are well captured by domain-general processes that generate reproducible developmental templates across assessments and datasets. Results provide a canonical trajectory of executive function maturation that demarcates the boundaries of adolescence and can be integrated into future studies. Read more.

Piekarski DJ, Zahr NM, Zhao Q, Ferizi U, Pohl KM, Sullivan EV, Pfefferbaum A. (2023). White matter microstructural integrity continues to develop from adolescence to young adulthood in mice and humans: Same phenotype, different mechanism. Neuroimage: Reports 3(3): 100179. doi: 10.1016/j.ynirp.2023.100179

Abstract: As direct evaluation of a mouse model of human neurodevelopment, adolescent and young adult mice and humans underwent MR diffusion tensor imaging to quantify age-related differences in microstructural integrity of brain white matter fibers. Fractional anisotropy (FA) was greater in older than younger mice and humans. Despite the cross-species commonality, the underlying developmental mechanism differed: whereas evidence for greater axonal extension contributed to higher FA in older mice, evidence for continuing myelination contributed to higher FA in human adolescent development. These differences occurred in the context of species distinctions in overall brain growth: whereas the continued growth of the brain and skull in the murine model can accommodate volume expansion into adulthood, human white matter volume and myelination continue growth into adulthood within a fixed intracranial volume. Appreciation of the similarities and differences in developmental mechanism can enhance the utility of animal models of brain white matter structure, function, and response to exogenous manipulation. Read more.

Benedetti D, Frati E, Kiss O, Yuksel D, Faraguana U, Hasler B, Franzen PL, Clark DB, Baker FC, de Zambotti M. (2023). Performance evaluation of the open-source Yet Another Spindle Algorithm (YASA) sleep staging algorithm against gold standard manual evaluation of polysomnographic records in adolescence. Sleep Health 9(6):910-924. doi: 10.1016/j.sleh.2023.07.019

Goals and Aims. To evaluate an automatic sleep scoring algorithm against manual polysomnography sleep scoring.

Focus Method/Technology. Yet Another Spindle Algorithm automatic sleep staging algorithm.

Reference Method/Technology. Manual sleep scoring.

Sample. 327 nights (151 healthy adolescents), from the NCANDA study.

Design. Participants underwent one-to-three overnight polysomnography recordings, one consisting of an event-related-potential paradigm.

Core Analytics. Epoch by Epoch and discrepancy analyses (Bland Altman plots) were conducted on the overall sample.

Additional Analytics and Exploratory Analysis. Epoch by Epoch and discrepancy analysis were repeated separately on standard polysomnography nights and event-related potential nights. Regression models were estimated on age, sex, scorer, and site of recording, separately on standard polysomnography nights and event-related potential nights.

Core Outcomes. The Yet Another Spindle Algorithm sleep scoring algorithm’s average sensitivity of 93.04% for Wake, 87.67% for N2, 84.46% for N3, 86.02% for rapid-eye-movement, and 40.39% for N1. Specificity was 96.75% for Wake, 97.31% for N1, 88.87% for N2, 97.99% for N3, and 97.70% for rapid-eye-movement. The Matthews Correlation Coefficient was highest in rapid-eye-movement sleep (0.85) while lowest in N1 (0.39). Cohen’s Kappa mirrored Matthews Correlation Coefficient results. In Bland-Altman plots, the bias between Yet Another Spindle Algorithm and human scoring showed proportionality to the manual scoring measurement size.

Important Additional Outcomes. Yet Another Spindle Algorithm performance was reduced in event-related-potential/polysomnography nights for N3 and rapid-eye-movement. According to the Matthews Correlation Coefficient, the Yet Another Spindle Algorithm performance was affected by younger age, male sex, recording sites, and scorers.

Core Conclusion. Results support the use of Yet Another Spindle Algorithm to score adolescents' polysomnography sleep records, possibly with classification outcomes supervised by an expert scorer. Read more.

Kiss O, Goldstone A, de Zambotti M, Yüksel D, Hasler BP, Franzen PL, Brown SA, De Bellis MD, Nagel BJ, Nooner KB, Tapert SF, Colrain IM, Clark DC & Baker FC (2023). Effects of emerging alcohol use on developmental trajectories of functional sleep measures in adolescents. Sleep Volume 46, Issue 9, zsad113. doi:10.1093/sleep/zsad113.

Study Objectives. Adolescence is characterized by significant brain development, accompanied by changes in sleep timing and architecture. It also is a period of profound psychosocial changes, including the initiation of alcohol use; however, it is unknown how alcohol use affects sleep architecture in the context of adolescent development. We tracked developmental changes in polysomnographic (PSG) and electroencephalographic (EEG) sleep measures and their relationship with emergent alcohol use in adolescents considering confounding effects (e.g. cannabis use).

Methods. Adolescents (n = 94, 43% female, age: 12–21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study had annual laboratory PSG recordings across 4-years. Participants were no/low drinkers at baseline.

Results. Linear mixed effect models showed developmental changes in sleep macrostructure and EEG, including a decrease in slow wave sleep and slow wave (delta) EEG activity with advancing age. Emergent moderate/heavy alcohol use across three follow-up years was associated with a decline in percentage rapid eye movement (REM) sleep over time, a longer sleep onset latency (SOL) and shorter total sleep time (TST) in older adolescents, and lower non-REM delta and theta power in males.

Conclusions. These longitudinal data show substantial developmental changes in sleep architecture. Emergent alcohol use during this period was associated with altered sleep continuity, architecture, and EEG measures, with some effects dependent on age and sex. These effects, in part, could be attributed to the effects of alcohol on underlying brain maturation processes involved in sleep–wake regulation. Read more.

Lydiard JB, Patel H, Strugatsky Y, Thompson WK, Pelham WE 3rd, & Brown SA. (2023). Prospective associations between cannabis use and depressive symptoms across adolescence and early adulthood. Psychiatry Research 325, 115190. doi: 10.1016/j.psychres.2023.115190

Abstract: Cannabis use and occurrences of depression during adolescence are common. However, the temporal relationship between the two is less understood. Does depression lead to cannabis use, or does cannabis use lead to depression, or is it a combination of both? Furthermore, this directionality is confounded by other substance use, specifically binge drinking, which is common during adolescence. This study aimed to examine the temporal directionality of cannabis use and depression among a prospective, longitudinal, sequential cohort of 15 to 24-year-olds. Data were drawn from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The final sample included 767 participants. Multilevel regression models were run to assess concurrent (at the same time point) and prospective (1 year later) associations between cannabis use and depression. When measured concurrently, depressive symptoms did not significantly predict past-month cannabis use but did significantly predict more days of use among cannabis users. Prospective associations indicated that depressive symptoms significantly predicted cannabis use 1 year later and cannabis use significantly predicted depressive symptoms 1 year later. We found no evidence that these associations varied by age or binge drinking. Overall, the relationship between cannabis use and depression appears to be complex and not unidirectional. Read more.

Albinni B, Baker FC, Javitz H, Hasler BP, Franzen PL, Clark DB, de Zambotti M. (2023). Morning perception of sleep, stress, and mood, and its relationship with overnight physiological sleep: Findings from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. Journal of Sleep Research e13886. doi: 10.1111/jsr.13886

Abstract: This cross-sectional study investigated objective-subjective sleep discrepancies and the physiological basis for morning perceptions of sleep, mood, and readiness, in adolescents. Data collected during a single in-laboratory polysomnographic assessment from 137 healthy adolescents (61 girls; age range: 12-21 years) in the United States National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study were analysed. Upon awakening, participants completed questionnaires assessing sleep quality, mood, and readiness. We evaluated the relationship between overnight polysomnographic, electroencephalographic, sleep autonomic nervous system functioning measures, and next morning self-reported indices. Results showed that older adolescents reported more awakenings, yet they perceived their sleep to be deeper and less restless than younger adolescents. Prediction models including sleep physiology measures (polysomnographic, electroencephalographic, and sleep autonomic nervous system) explained between 3% and 29% of morning sleep perception, mood, and readiness indices. The subjective experience of sleep is a complex phenomenon with multiple components. Distinct physiological sleep processes contribute to the morning perception of sleep and related measures of mood and readiness. More than 70% of the variance (based on a single observation per person) in the perception of sleep, mood, and morning readiness is not explained by overnight sleep-related physiological measures, suggesting that other factors are important for the subjective sleep experience. Read more.

McCabe CJ, Brumback T, Brown SA, Meruelo AD (2023). Assessing cross-lagged associations between depression, anxiety, and binge drinking in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. Drug Alcohol Depend. 243:109761. doi: 10.1016/j.drugalcdep.2022.109761

Background. Between 20 and 30 percent of teens suffer from depression or anxiety before reaching adulthood, and up to half also use or misuse alcohol. Although theories suggest bidirectional links between harmful alcohol use (e.g., binge drinking) and internalizing symptoms (i.e., depression and anxiety), empirical evidence to-date has been mixed. Systematic reviews have attributed mixed findings to limitations in study design, such as the utilization of between-person analyses and the focus on unidirectional effects. The goal of this study was to address these limitations by assessing bidirectional within-person associations between internalizing symptoms and binge drinking over the course of 5 years in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) sample, a large cohort recruited at ages 12-21 and followed annually on substance use and psychiatric functioning.

Methods. We used latent curve models with structured residuals to examine within-person lagged associations between depression, anxiety, and past month counts of binge drinking using NCANDA data (N=831). Analyses were supplemented with post-hoc power simulations.

Results. We found marginal evidence linking binge drinking with subsequent depression symptoms one year later among females. We found no evidence that depression or anxiety predicted subsequent binge drinking despite sufficient power.

Conclusions. Social and cognitive consequences of binge drinking may predict later depression symptoms in adolescence and young adulthood for young women, though there was little evidence favoring self-medication models for binge drinking. We note several moderating variables and common factor mechanisms that may better explain this link. Read more.

Arwood, Z., Nooner, K.B. Adverse Childhood Experiences and Binge Drinking in Adolescence: the Role of Impulsivity and PTSD Symptoms. Journal of Pediatric Neuropsychology doi: 10.1007/s40817-022-00135-z

Background. The present study examines impulsivity and posttraumatic stress disorder (PTSD) symptoms as factors that may help understand the relationship between adverse childhood experiences (ACEs) and adolescent binge drinking.

Methods. Data were drawn from a subset of adolescents (N = 285) ages 12–22 from the National Consortium on Alcohol & Neurodevelopment in Adolescence (NCANDA). Impulsivity and PTSD symptoms were each predicted to moderate the relationship between ACEs and binge drinking.

Results. The positive relationship between PTSD symptoms and binge drinking was stronger when impulsivity was included. The positive relationship between ACEs and binge drinking was also strengthened when accounting for PTSD symptoms.

Conclusions. Our results provide evidence that impulsivity and PTSD symptoms may increase the risk for binge drinking during adolescence, including following ACEs. Interventions targeting PTSD symptoms and impulsivity could be valuable tools in preventing adolescent binge drinking. Read more.

Sun D, Adduru V, Phillips R, Bouchard H, Sotiras A, Michael A, Baker F, Tapert S, Brown S, Clark D, Goldston D, Nooner K, Nagel K, Nagel B, Thompson W, De Bellis MD, Morey R (2023). Adolescent alcohol use is linked to disruptions in age-appropriate cortical thinning: An unsupervised machine learning approach. Neuropsychopharmacology 48(2):317-326. doi: 10.1038/s41386-022-01457-4.

Abstract: 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. Read more.

Li Y, Wei Q, Adeli E, Pohl K, Zhao Q (2022). Joint graph convolution for analyzing brain structural and functional connectome. In: Wang L, Dou Q, Fletcher PT, Speidel S, Li S (Eds), Medical Image Computing and Computer Assisted Intervention – MICCAI 2022. MICCAI 2022. Lecture Notes in Computer Science pg 231-240. doi: 10.1007/978-3-031-16431-6_22

Abstract: The white-matter (micro-)structural architecture of the brain promotes synchrony among neuronal populations, giving rise to richly patterned functional connections. A fundamental problem for systems neuroscience is determining the best way to relate structural and functional networks quantified by diffusion tensor imaging and resting-state functional MRI. As one of the state-of-the-art approaches for network analysis, graph convolutional networks (GCN) have been separately used to analyze functional and structural networks, but have not been applied to explore inter-network relationships. In this work, we propose to couple the two networks of an individual by adding inter-network edges between corresponding brain regions, so that the joint structure-function graph can be directly analyzed by a single GCN. The weights of inter-network edges are learnable, reflecting non-uniform structure-function coupling strength across the brain. We apply our Joint-GCN to predict age and sex of 662 participants from the public dataset of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) based on their functional and micro-structural white-matter networks. Our results support that the proposed Joint-GCN outperforms existing multi-modal graph learning approaches for analyzing structural and functional networks. Read more.

Paschali M, Zhao Q, Adeli E, Pohl KM (2022). Bridging the gap between deep learning and hypothesis-driven analysis via permutation testing. In: Rekik I, Adeli E, Park SH, Cintas C (eds) Predictive Intelligence in Medicine. PRIME 2022: Predictive Intelligence in Medicine pp 13–23. doi: 10.1007/978-3-031-16919-9_2.

Abstract: A fundamental approach in neuroscience research is to test hypotheses based on neuropsychological and behavioral measures, i.e., whether certain factors (e.g., related to life events) are associated with an outcome (e.g., depression). In recent years, deep learning has become a potential alternative approach for conducting such analyses by predicting an outcome from a collection of factors and identifying the most “informative” ones driving the prediction. However, this approach has had limited impact as its findings are not linked to statistical significance of factors supporting hypotheses. In this article, we proposed a flexible and scalable approach based on the concept of permutation testing that integrates hypothesis testing into the data-driven deep learning analysis. We apply our approach to the yearly self-reported assessments of 621 adolescent participants of the National Consortium of Alcohol and Neurodevelopment in Adolescence (NCANDA) to predict negative valence, a symptom of major depressive disorder according to the NIMH Research Domain Criteria (RDoC). Our method successfully identifies categories of risk factors that further explain the symptom. Read more.

Zhao Q, Wang K, Kiss O, Yuksel D, de Zambotti M, Clark DB, Goldston DB, Nooner KB, Brown SA, Tapert SF, Thompson WK, Nagel BJ, Pfefferbaum A, Sullivan EV, Pohl KM, Baker FC (2022). Earlier bedtime and effective coping skills predict a return to low-risk of depression in young adults during the COVID-19 pandemic. Int. J. Environ. Res. Public Health 19(16): 10300. doi: 10.3390/ijerph191610300

Abstract: To determine the persistent effects of the pandemic on mental health in young adults, we categorized depressive symptom trajectories and sought factors that promoted a reduction in depressive symptoms in high-risk individuals. Specifically, longitudinal analysis investigated changes in the risk for depression before and during the pandemic until December 2021 in 399 young adults (57% female; age range: 22.8 ± 2.6 years) in the United States (U.S.) participating in the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. The Center for Epidemiologic Studies Depression Scale (CES-D-10) was administered multiple times before and during the pandemic. A score ≥10 identified individuals at high-risk for depression. Self-reported sleep behavior, substance use, and coping skills at the start of the pandemic were assessed as predictors for returning to low-risk levels while controlling for demographic factors. The analysis identified four trajectory groups regarding depression risk, with 38% being at low-risk pre-pandemic through 2021, 14% showing persistent high-risk pre-pandemic through 2021, and the remainder converting to high-risk either in June 2020 (30%) or later (18%). Of those who became high-risk in June 2020, 51% were no longer at high-risk in 2021. Logistic regression revealed that earlier bedtime and, for the older participants (mid to late twenties), better coping skills were associated with this declining risk. Results indicate divergence in trajectories of depressive symptoms, with a considerable number of young adults developing persistent depressive symptoms. Healthy sleep behavior and specific coping skills have the potential to promote remittance from depressive symptoms in the context of the pandemic. Read more.

Paschali M, Kiss O, Zhao Q, Adeli E, Podhajsky S, Muller-Oehring EM, Gotlib IH, Pohl KM, Fiona Baker FC (2022). Detecting negative valence symptoms in adolescents based on longitudinal self-reports and behavioral assessments. Journal of Affective Disorders 312: 30-38. doi: 10.1016/j.jad.2022.06.002

Background. Given the high prevalence of depressive symptoms reported by adolescents and associated risk of experiencing psychiatric disorders as adults, differentiating the trajectories of the symptoms related to negative valence at an individual level could be crucial in gaining a better understanding of their effects later in life.

Methods. A longitudinal deep learning framework is presented, identifying self-reported and behavioral measurements that detect the depressive symptoms associated with the Negative Valence System domain of the NIMH Research Domain Criteria (RDoC).

Results. Applied to the annual records of 621 participants (age range: 12 to 17 years) of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), the deep learning framework identifies predictors of negative valence symptoms, which include lower extraversion, poorer sleep quality, impaired executive control function and factors related to substance use.

Limitations. The results rely mainly on self-reported measures and do not provide information about the underlying neural correlates. Also, a larger sample is required to understand the role of sex and other demographics related to the risk of experiencing symptoms of negative valence.

Conclusions. These results provide new information about predictors of negative valence symptoms in individuals during adolescence that could be critical in understanding the development of depression and identifying targets for intervention. Importantly, findings can inform preventive and treatment approaches for depression in adolescents, focusing on a unique predictor set of modifiable modulators to include factors such as sleep hygiene training, cognitive-emotional therapy enhancing coping and controllability experience and/or substance use interventions. Read more.

Sullivan EV, Thompson WK, Brumback T, Prouty D, Tapert SF, Brown SA, De Bellis MD, Nooner KB, Baker FC, Colrain IM, Clark DB, Nagel BJ, Pohl KM, Pfefferbaum A (2022). Prior test experience confounds longitudinal tracking of adolescent cognitive and motor development. BMC Medical Research Methodology 22(1): 177. doi: 10.1186/s12874-022-01606-9

Background. Accurate measurement of trajectories in longitudinal studies, considered the gold standard method for tracking functional growth during adolescence, decline in aging, and change after head injury, is subject to confounding by testing experience.

Methods. We measured change in cognitive and motor abilities over four test sessions (baseline and three annual assessments) in 154 male and 165 female participants (baseline age 12-21 years) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. At each of the four test sessions, these participants were given a test battery using computerized administration and traditional pencil and paper tests that yielded accuracy and speed measures for multiple component cognitive (Abstraction, Attention, Emotion, Episodic memory, Working memory, and General Ability) and motor (Ataxia and Speed) functions. The analysis aim was to dissociate neurodevelopment from testing experience by using an adaptation of the twice-minus-once tested method, which calculated the difference between longitudinal change (comprising developmental plus practice effects) and practice-free initial cross-sectional performance for each consecutive pairs of test sessions. Accordingly, the first set of analyses quantified the effects of learning (i.e., prior test experience) on accuracy and after speed domain scores. Then developmental effects were determined for each domain for accuracy and speed having removed the measured learning effects.

Results. The greatest gains in performance occurred between the first and second sessions, especially in younger participants, regardless of sex, but practice gains continued to accrue thereafter for several functions. For all 8 accuracy composite scores, the developmental effect after accounting for learning was significant across age and was adequately described by linear fits. The learning-adjusted developmental effects for speed were adequately described by linear fits for Abstraction, Emotion, Episodic Memory, General Ability, and Motor scores, although a nonlinear fit was better for Attention, Working Memory, and Average Speed scores.

Conclusions. Thus, what appeared as accelerated cognitive and motor development was, in most cases, attributable to learning. Recognition of the substantial influence of prior testing experience is critical for accurate characterization of normal development and for developing norms for clinical neuropsychological investigations of conditions affecting the brain. Read more.

Lorkiewicz SA, Baker FC, Müller-Oehring EM, Haas A, Wickham R, Sassoon SA, Clark DB, Nooner KB, Tapert SF, Brown SA, Schulte T (2022). A longitudinal examination of alcohol-related blackouts as a predictor of changes in learning, memory, and executive function in adolescents. Frontiers in Psychiatry 13: 866051. doi: 10.3389/fpsyt.2022.866051

Introduction. In adolescents, the relationship between alcohol-related blackouts (ARBs) and distinct cognitive changes lasting beyond intoxication is unclear. We examined ARBs as a predictor of persistent changes in the development of learning, memory, and executive function in participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study.

Methods. Descriptive analyses of the NCANDA sample (N = 831, 50.9% female, 12-21 years at baseline) identified ARB patterns within participants with an ARB history (n = 106). Latent growth curve modeling evaluated ARB-related performance changes on four neuropsychological measures across five years, excluding baseline data to reduce the magnitude of practice effects over time (n = 790). Measures included the Penn Conditional Exclusion Test (PCET), Penn Letter N-back Test (PLBT), Penn Facial Memory Test immediate (PFMTi), and delayed (PFMTd) recognition trials, and the Rey Complex Figure Test copy (RCFTc), immediate recall (RCFTi), and delayed recall (RCFTd) trials. Multivariate models were fit for raw accuracy scores from each measure, with ARB history (i.e., presence of past-year ARBs) as the main independent variable. Age, sex, race, socioeconomic status, assessment site, and alcohol use (i.e., past-year frequency) were included as covariates. Interaction effects between ARB history and alcohol use frequency were tested.

Results. By year five, 16% of participants had experienced at least one ARB (59% of whom reported > 1 ARB and 57% of whom had an ARB lasting > 1 h). After controlling for demographics and alcohol use, ARB history predicted attenuated PFMTd performance growth at year one. Interaction effects between ARB history and alcohol use frequency predicted attenuated PFMTd performance growth at years one and two. ARB history predicted attenuated RCFTi and RCFTd performance growth by year four, but not PCET or PLBT performance over time. By contrast, greater past-year alcohol use predicted attenuated PFMTi and PFMTd performance growth between years two and four in adolescents without an ARB history.

Conclusions. We found that ARBs predict distinct, lasting changes in learning and memory for visual information, with results suggesting that the developing brain is vulnerable to ARBs during adolescence and emerging adulthood. Read more.

Pelham WE, Yuksel D, Baker FC, Tapert SF, Pohl KM, Thompson WK, Podhajsky S, Reuter C, Zhao Q, Eberson-Shumate SC, Clark DB, Goldston DB, Nagel BJ, Nooner KB, & Brown SA (2022). Did the acute impact of the COVID-19 pandemic on drinking or nicotine use persist? Evidence from a cohort of emerging adults followed for up to nine years. Addictive Behaviors 131: 107313. doi.org/10.1016/j.addbeh.2022.107313

Objective. This study examined the impact of the COVID-19 pandemic on drinking and nicotine use through June of 2021 in a community-based sample of young adults.

Methods. Data were from 348 individuals (49% female) enrolled in a long-term longitudinal study with an accelerated longitudinal design: the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) Study. Individuals completed pre-pandemic assessments biannually from 2016 to early 2020, then completed up to three web-based, during-pandemic surveys in June 2020, December 2020, and June 2021. Assessments when individuals were 18.8-22.4 years old (N = 1,458) were used to compare drinking and nicotine use pre-pandemic vs. at each of the three during-pandemic timepoints, adjusting for the age-related increases expected over time.

Results. Compared to pre-pandemic, participants were less likely to report past-month drinking in June or December 2020, but there was an increase in drinking days among drinkers in June 2020. By June 2021, both the prevalence of past-month drinking and number of drinking days among drinks were similar to pre-pandemic levels. On average, there were no statistically significant differences between pre-pandemic and during-pandemic time points for binge drinking, typical drinking quantity, or nicotine use. Young adults who reported an adverse financial impact of the pandemic showed increased nicotine use while their peers showed stable or decreased nicotine use.

Conclusions. Initial effects of the pandemic on alcohol use faded by June 2021, and on average there was little effect of the pandemic on nicotine use. Read more.

Hasler BP, Graves JL, Wallace ML, Claudatos S, Franzen PL, Nooner KB, Brown SA, Tapert SF, Baker FC, Clark DB (2022). Self-Reported sleep and circadian characteristics predict alcohol and cannabis use: A longitudinal analysis of the National Consortium on Alcohol and Neurodevelopment in Adolescence Study. ACER 46(5): 848-860. doi.org/10.1111/acer.14808.

Background. Growing evidence indicates that sleep characteristics predict future substance use and related problems. However, most prior studies assessed a limited range of sleep characteristics, studied a narrow age span, and included few follow-up assessments. Here, we used six annual assessments from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study, which spans adolescence and young adulthood with an accelerated longitudinal design, to examine whether multiple sleep characteristics in any year predict alcohol and cannabis use the following year.

Methods. The sample included 831 NCANDA participants (423 females; baseline age 12-21 years). Sleep variables included circadian preference, sleep quality, daytime sleepiness, the timing of midsleep (weekday/weekend), and sleep duration (weekday/weekend). Using generalized linear mixed models (logistic for cannabis; ordinal for binge severity), we tested whether each repeatedly measured sleep characteristic (years 0-4) predicted substance use (alcohol binge severity or cannabis use) the following year (years 1-5), covarying for age, sex, race, visit, parental education, and previous year's substance use.

Results. Greater eveningness, more daytime sleepiness, later weekend sleep timing, and shorter sleep duration (weekday/weekend) all predicted more severe alcohol binge drinking the following year. Only greater eveningness predicted a greater likelihood of any cannabis use the following year. Post-hoc stratified exploratory analyses indicated that some associations (e.g., greater eveningness and shorter weekend sleep duration) predicted binge severity only in female participants, and that middle/high school versus post-high school adolescents were more vulnerable to sleep-related risk for cannabis use.

Conclusions. Our findings support the relevance of multiple sleep/circadian characteristics in the risk for future alcohol binge severity and cannabis use. Preliminary findings suggest that these risk factors vary based on developmental stage and sex. Results underscore a need for greater attention to sleep/circadian characteristics as potential risk factors for substance use in youth and may inform new avenues to prevention and intervention. Read more.

Ren J, Tapert S, Fan CC, Thompson WK (2022). A Semi-parametric Bayesian model for semi-continuous longitudinal data. Statistics in Medicine 41(13): pgs 2354-2374. doi: 10.1002/sim.9359.

Abstract: Semi-continuous data present challenges in both model fitting and interpretation. Parametric distributions may be inappropriate for extreme long right tails of the data. Mean effects of covariates, susceptible to extreme values, may fail to capture relevant information for most of the sample. We propose a two-component semi-parametric Bayesian mixture model, with the discrete component captured by a probability mass (typically at zero) and the continuous component of the density modeled by a mixture of B-spline densities that can be flexibly fit to any data distribution. The model includes random effects of subjects to allow for application to longitudinal data. We specify prior distributions on parameters and perform model inference using a Markov Chain Monte Carlo (MCMC) Gibbs-sampling algorithm programmed in R. Statistical inference can be made for multiple quantiles of the covariate effects simultaneously providing a comprehensive view. Various MCMC sampling techniques are used to facilitate convergence. We demonstrate the performance and the interpretability of the model via simulations and analyses on the National Consortium on Alcohol and Neurodevelopment in Adolescence study (NCANDA) data on alcohol binge drinking. Read more.

Cummins KM, Pitpitan EV, Brumback T, Moore TM, Trim RS, Clark DB, Brown SA, Tapert SF (2022). Comparison of factor analysis models applied to the NCANDA neuropsychological test battery. PLoS ONE 17(2). doi.org/10.1371/journal.pone.0263174

Abstract: The factor structure of neuropsychological functioning among a large sample (N = 831) of American youth (ages 12–21 at baseline) was investigated in order to identify an optimal model. Candidate models were selected based on their potential to provide service to the study of adolescent development and the effects of heavy episodic alcohol consumption. Data on neuropsychological functioning were obtained from the NCANDA study. This is a longitudinal community study of the effects of alcohol exposure on neurodevelopment. Three conceptually motivated and one empirically motivated factor analysis model of neuropsychological domains were compared based on penalized-likelihood selection criteria and model fit statistics. Two conceptually-motivated models were found to have adequate fit and pattern invariance to function as a measurement model for the Penn Computerized Neurocognitive Battery (Penn CNB) anchored neuropsychological battery in NCANDA. Corroboration of previous factor analysis models was obtained, in addition to the identification of an alternative factor model that has higher discriminant capacity for neuropsychological domains hypothesized to be most sensitive to alcohol exposure in human adolescents. The findings support the use of a factor model developed originally for the Penn CNB and a model developed specifically for the NCANDA project. The NCANDA 8-Factor Model has conceptual and empirical advantages that were identified in the current and prior studies. These advantages are particularly valuable when applied in alcohol research settings. Read more.

Lannoy S, Pfefferbaum A, Le Berre AP, Thompson WK, Brumback T, Schulte T, Pohl KM, De Bellis MD, Nooner KB, Baker FC, Prouty D, Colrain IM, Nagel BJ, Brown SA, Clark DB, Tapert SF, Sullivan EV, Müller-Oehring EM (2022). Growth trajectories of cognitive and motor control in adolescence: How much is development and how much is practice? Neuropsychology 36(1): 44-54. doi:10.1037/neu0000771.

Objective. Executive control continues to develop throughout adolescence and is vulnerable to alcohol use. Although longitudinal assessment is ideal for tracking executive function development and onset of alcohol use, prior testing experience must be distinguished from developmental trajectories.

Method. We used the Stroop Match-to-Sample task to examine the improvement of processing speed and specific cognitive and motor control over 4 years in 445 adolescents.

The twice-minus-once-tested method was used and expanded to 4 test sessions to delineate prior experience (i.e., learning) from development. A General Additive Model evaluated the predictive value of age and sex on executive function development and potential influences of alcohol use on development.

Results. Results revealed strong learning between the first two assessments. Adolescents significantly improved their speeded processing over 4 years. Compared with boys, girls enhanced ability to control cognitive interference and motor reactions. Finally, the influence of alcohol use initiation was tested over 4 years for development in 110 no/low, 110 moderate/heavy age- and sex-matched drinkers; alcohol effects were not detected in the matched groups.

Conclusions. Estimation of learning effects is crucial for examining developmental changes longitudinally. Read more.

M A Infante, S C Eberson, Y Zhang, T Brumback, S A Brown, I M Colrain, F C Baker, D B Clark, M D De Bellis, D Goldston, B J Nagel, K B Nooner, Q Zhao, K M Pohl, E V Sullivan, A Pfefferbaum, S F Tapert, W K Thompson (2021). Adolescent Binge Drinking Is Associated With Accelerated Decline of Gray Matter Volume. Cerebral Cortex 32(12): 2611-2620. doi.org/10.1093/cercor/bhab368.

Abstract: The age- and time-dependent effects of binge drinking on adolescent brain development have not been well characterized even though binge drinking is a health crisis among adolescents. The impact of binge drinking on gray matter volume (GMV) development was examined using 5 waves of longitudinal data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study. Binge drinkers (n=166) were compared with non-binge drinkers (n=82 after matching on potential confounders). Number of binge drinking episodes in the past year was linked to decreased GMVs in bilateral Desikan–Killiany cortical parcellations (26 of 34 with P<0.05/34) with the strongest effects observed in frontal regions. Interactions of binge drinking episodes and baseline age demonstrated stronger effects in younger participants. Statistical models sensitive to number of binge episodes and their temporal proximity to brain volumes provided the best fits. Consistent with prior research, results of this study highlight the negative effects of binge drinking on the developing brain. Our results present novel findings that cortical GMV decreases were greater in closer proximity to binge drinking episodes in a dose–response manner. This relation suggests a causal effect and raises the possibility that normal growth trajectories may be reinstated with alcohol abstinence. Read more.

Jones SA, Van Fossen RP, Thompson WK, Baker FC, Clark DB, Nagel BJ (2021). Developmental trajectories of Big Five personality traits among adolescents and young adults: Differences by sex, alcohol use, and marijuana use. Journal of Personality Dec 17. doi: 10.1111/jopy.12694.

Objective: Individual differences in adolescent personality are related to a variety of long-term health outcomes. While previous studies have demonstrated sex differences and non-linear changes in personality development, these results remain equivocal. The current study utilized longitudinal data (n = 831) from the National Consortium on Alcohol and Neurodevelopment in Adolescence to examine sex differences in the development of personality and the association between substance use and personality.

Method: Participants (ages 12-21 at baseline) completed the Ten-Item Personality Inventory and self-reported past year alcohol and marijuana use at up to 7 yearly visits. Data were analyzed using generalized additive mixed-effects models and linear mixed-effects models.

Results: Findings support linear increases in agreeableness and conscientious and decreases in openness with age and inform on timing of sex-specific non-linear development of extraversion and emotional stability. Further, results provide novel information regarding the timing of the association between substance use and personality, and replicate past reporting of differential associations between alcohol and marijuana use and extraversion, and sex-dependent effects of marijuana use on emotional stability.

Conclusions: These findings highlight the importance of modeling sex differences in personality development using flexible non-linear modeling strategies, and accounting for sex- and age-specific effects of alcohol and marijuana use. Read more.

Butskova A, Juhl R, Zukić D, Chaudhary A, Pohl KM, Zhao Q (2021) Adversarial Bayesian Optimization for Quantifying Motion Artifact Within MRI. Predictive Intelligence in Medicine. PRIME 2021. Lecture Notes in Computer Science, vol 12928, pp 83-92,. doi: 10.1007/978-3-030-87602-9_8.

Abstract: Subject motion during an MRI sequence can cause ghosting effects or diffuse image noise in the phase-encoding direction and hence is likely to bias findings in neuroimaging studies. Detecting motion artifacts often relies on experts visually inspecting MRIs, which is subjective and expensive. To improve this detection, we develop a framework to automatically quantify the severity of motion artifact within a brain MRI. We formulate this task as a regression problem and train the regressor from a data set of MRIs with various amounts of motion artifacts. To resolve the issue of missing fine-grained ground-truth labels (level of artifacts), we propose Adversarial Bayesian Optimization (ABO) to infer the distribution of motion parameters (i.e., rotation and translation) underlying the acquired MRI data and then inject synthetic motion artifacts sampled from that estimated distribution into motion-free MRIs. After training the regressor on the synthetic data, we applied the model to quantify the motion level in 990 MRIs collected by the National Consortium on Alcohol and Neurodevelopment in Adolescence. Results show that the motion level derived by our approach is more reliable than the traditional metric based on Entropy Focus Criterion and manually defined binary labels. Read more.

Kliamovich D, Jones SA, Chiapuzio AM, Baker FC, Clark DB, Nagel BJ (2021). Sex-specific patterns of white matter microstructure predict emerging depression during adolescence. Psychiatry Research: Neuroimaging.315: 111324. PMCID: PMC8387429

Abstract: Prior research has demonstrated associations between adolescent depression and alterations in the white matter microstructure of fiber tracts implicated in emotion regulation. Using diffusion tensor imaging, this study explored premorbid, sex-specific white matter microstructural features that related to future emergence major depressive disorder (MDD) during adolescence and young adulthood. Adolescents from the National Consortium on Alcohol and Neurodevelopment in Adolescence study, who were 12-21 years old at study entry and had not experienced major depression as of the baseline assessment, were selected for inclusion (N = 462, n = 223 female adolescents). Over five years of annual follow-up, 63 participants developed a diagnosis of MDD, as determined by the Computerized Semi-Structured Assessment for the Genetics of Alcoholism (n = 39 female adolescents). A whole-brain multivariate modeling approach was used to examine the relationship between fractional anisotropy (FA) at baseline and emergence into MDD, as a function of sex, controlling for age at baseline. Among female adolescents, those who developed MDD had significantly lower baseline FA in a portion of left precentral gyrus white matter, while male adolescents exhibited the opposite pattern. Such results may serve as indirect microstructural markers of risk and targets for the prevention of depression during adolescence. Read more.

Brumback T, Thompson W, Cummins K, Brown S, Tapert S (2021). Psychosocial predictors of substance use in adolescents and young adults: Longitudinal risk and protective factors. Addictive Behaviors 121: 106985. 10.1016/j.addbeh.2021.106985

Abstract: Many psychosocial factors have been implicated in the onset and escalation of substance use in adolescence and young adulthood. Typically, each factor explains a small amount of the variance in substance use outcomes, and effects are typically applied across a broad range of ages or computed from cross-sectional data. The current study evaluated the association of factors including social influence (e.g., peer substance use), cognitive features (e.g., alcohol expectancies), and personality and emotional characteristics (e.g., impulsivity and typical responses to stress) in substance use throughout adolescence and emerging adulthood (ages 13-25; N = 798). Mixed-effects models tailored for the accelerated longitudinal design employed in this study were constructed with psychosocial and developmental factors predicting alcohol and cannabis use. As most participants in the sample exhibited little or no substance use at baseline by design, we excluded baseline assessments and examined data from follow-up years 1, 2, 3, and 4. Interactions between age cohort, change in age, and psychosocial predictors of substance use revealed differing associations over the developmental window for alcohol and cannabis use. For example, positive alcohol expectancies and sensation seeking were most strongly associated with greater drinking after age 18, whereas sensation seeking was associated with increased cannabis use as early as age 15. Higher emotion regulation skills led to less cannabis use in younger ages (i.e., shallower slopes below age 17), but this protective effect diminished after age 17. Results highlight developmentally important factors that differentially contribute to substance use in adolescence and young adulthood. We also demonstrate the importance of developmentally sensitive analyses that maximize the value of data from accelerated longitudinal designs. Read more.

McCabe CJ, Wall TL, Gonzalez MR, Meruelo AD, Eberson-Shumate SC, Clark DB, Nooner KB, Brown SA, and Tapert SF (2021). Associations of developmental imbalance between sensation seeking and premeditation in adolescence and heavy episodic drinking in emerging adulthood. Alcoholism: Clinical and Experimental Research 45(6): 1249-1264.

Background: Dual systems theories suggest that greater imbalance between higher reward sensitivity and lower cognitive control across adolescence conveys risk for behaviors such as heavy episodic drinking (HED). Prior research demonstrated that psychological analogues of these systems, sensation seeking and premeditation, change from childhood through emerging adulthood, and each has been independently linked with HED. However, few studies have assessed whether change over time in these developing analogues is prospectively associated with HED. Moreover, we know of no research that has shown whether within‐person differences between higher sensation seeking and relatively lower premeditation across the adolescent period predict HED in emerging adulthood.

Methods: Prospective data from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study (n = 715) were used to examine the association of sensation seeking and premeditation with HED among adolescents ages 16 to 20 years. We used novel applications of latent difference score modeling and growth curve analysis to test whether increasing sensation seeking, premeditation, and their imbalance over time are associated with HED across the study period, and whether these associations differed by sex.

Results: Whereas premeditation increased linearly from adolescence through emerging adulthood across sexes, males reported growth and females reported decline in sensation seeking. Sensation seeking in adolescence (and not premeditation) was associated with higher levels of HED by emerging adulthood. Importantly, greater imbalance between sensation seeking and premeditation was associated with higher levels of HED by emerging adulthood though we note that variability capturing this imbalance correlated highly (r = 0.86) with baseline levels of sensation seeking.

Conclusions: Developmental imbalance between higher sensation seeking and lower premeditation in late adolescence may be a risk factor for greater HED in emerging adulthood. Read more.

Silveira S, Boney S, Tapert SF, Mishra J (2021). Developing functional network connectivity of the dorsal anterior cingulate cortex mediates externalizing psychopathology in adolescents with child neglect. Developmental Cognitive Neuroscience Vol:49

Abstract: 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. Read more.

Meruelo AD, Brumback T, Nagel BJ, Baker FC, Brown SA, Tapert SF (2021). Neuroimaging markers of adolescent depression in the NCANDA study. Journal of Affective Disorders 287: 380-386.

Background: Adolescents 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.

Methods: 692 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 < 0.01).

Results: Those who transitioned in the next year to MDD had, at baseline, thinner cortices in the superior frontal cortex, precentral and postcentral regions, and superior temporal cortex, above and beyond effects attributable to age and sex. No cortical thickness sex differences or sex-by-depression interactions were observed.

Limitations: A larger sample size could improve statistical power and future investigations will be needed to confirm our results.

Conclusions: Thinner cortices over frontal and temporal regions may be linked to enhanced vulnerability for future depression during the adolescent–young adulthood transition. Read more.

Nooner KB, Chung T, Feldstein-Ewing SW, Brumback T, Arwood-Wenke Z, Tapert SF, Brown SA, Cottler L (2021). Retaining adolescent & young adult participants in research during a pandemic: Best practices from two large-scale developmental neuroimaging studies (NCANDA and ABCD). Frontiers in Neuroscience 14: 597902. PMCID: PMC7848221

Abstract: The novel coronavirus pandemic that emerged in late 2019 (COVID-19) has created challenges not previously experienced in human research. This paper discusses two large-scale NIH-funded multi-site longitudinal studies of adolescents and young adults – the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) and the Adolescent Brain Cognitive Development (ABCD) Study – and valuable approaches to learn about adaptive processes for conducting developmentally sensitive research with neuroimaging and neurocognitive testing across consortia during a global pandemic. We focus on challenges experienced during the pandemic and modifications that may guide other projects, such as implementing adapted protocols that protect the safety of participants and research staff, and addressing assessment challenges through the use of strategies such as remote and mobile assessments. Given the pandemic’s disproportionate impacts on participants typically underrepresented in research, we describe efforts to retain these individuals. The pandemic provides an opportunity to develop adaptive processes that can facilitate future studies’ ability to mobilize effectively and rapidly. Read more.

Cummins K, Brumback T, Chung T, Moore R, Henthorn T, Eberson S, Lopez A, Sarkissyan T, Nooner K, Brown SA, Tapert SF (2021). Acceptability, validity, and engagement with a mobile app for frequent, continuous multiyear assessment of youth health behaviors (mNCANDA): Mixed methods study. UMIR Mhealth Uhealth 2021 9(2): e24472. PMCID: PMC7904399

Background. Longitudinal studies of many health behaviors often rely on infrequent self-report assessments. The measurement of psychoactive substance use among youth is expected to improve with more frequent mobile assessments, which can reduce recall bias. Researchers have used mobile devices for longitudinal research, but studies that last years and assess youth continuously at a fine-grained, temporal level (eg, weekly) are rare. A tailored mobile app (mNCANDA [mobile National Consortium on Alcohol and Neurodevelopment in Adolescence]) and a brief assessment protocol were designed specifically to provide a feasible platform to elicit responses to health behavior assessments in longitudinal studies, including NCANDA (National Consortium on Alcohol and Neurodevelopment in Adolescence).

Objective. This study aimed to determine whether an acceptable mobile app system could provide repeatable and valid assessment of youth’s health behaviors in different developmental stages over extended follow-up.

Methods. Participants were recruited (n=534; aged 17-28 years) from a larger longitudinal study of neurodevelopment. Participants used mNCANDA to register reports of their behaviors for up to 18 months. Response rates as a function of time measured using mNCANDA and participant age were modeled using generalized estimating equations to evaluate response rate stability and age effects. Substance use reports captured using mNCANDA were compared with responses from standardized interviews to assess concurrent validity. Reactivity was assessed by evaluating patterns of change in substance use after participants initiated weekly reports via mNCANDA. Quantitative feedback about the app was obtained from the participants. Qualitative interviews were conducted with a subset of participants who used the app for at least one month to obtain feedback on user experience, user-derived explanations of some quantitative results, and suggestions for system improvements.

Results. The mNCANDA protocol adherence was high (mean response rate 82%, SD 27%) and stable over time across all age groups. The median time to complete each assessment was 51 s (mean response time 1.14, SD 1.03 min). Comparisons between mNCANDA and interview self-reports on recent (previous 30 days) alcohol and cannabis use days demonstrate close agreement (eg, within 1 day of reported use) for most observations. Models used to identify reactivity failed to detect changes in substance use patterns subsequent to enrolling in mNCANDA app assessments (P>.39). Most participants (64/76, 84%) across the age range reported finding the mNCANDA system acceptable. Participants provided recommendations for improving the system (eg, tailoring signaling times).

Conclusions. mNCANDA provides a feasible, multi-year, continuous, fine-grained (eg, weekly) assessment of health behaviors designed to minimize respondent burden and provides acceptable regimes for long-term self-reporting of health behaviors. Fine-grained characterization of variability in behaviors over relatively long periods (eg, up to 18 months) may, through the use of mNCANDA, improve our understanding of the relationship between substance use exposure and neurocognitive development. Read more.

Zhao Q, Sullivan EV, Müller-Oehring EM, Honnorat N, Adeli E, Podhajsky S, Baker F, Colrain I, Prouty D, Tapert S, Brown S, Meloy MJ, Brumback T, Nagel B, Morales A, Clark D, Luna B, De Bellis M, Voyvodic J, Pfefferbaum A, Pohl K (2021). Adolescent alcohol use disrupts functional neurodevelopment in sensation seeking girls. Addiction Biology March 26(2): e12914.

Abstract: 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. Read more.

Phillips RD, De Bellis MD, Brumback T, Clausen AN, Clarke-Rubright EK, Haswell CC, & Morey RA (2021). Volumetric trajectories of hippocampal subfields and amygdala nuclei influenced by adolescent alcohol use and lifetime trauma. Translational Psychiatry 11(1): 154.

Abstract: Alcohol use and exposure to psychological trauma frequently co-occur in adolescence and share many risk factors. Both exposures have deleterious effects on the brain during this sensitive developmental period, particularly on the hippocampus and amygdala. However, very little is known about the individual and interactive effects of trauma and alcohol exposure and their specific effects on functionally distinct substructures within the adolescent hippocampus and amygdala. Adolescents from a large longitudinal sample (N = 803, 2684 scans, 51% female, and 75% White/Caucasian) ranging in age from 12 to 21 years were interviewed about exposure to traumatic events at their baseline evaluation. Assessments for alcohol use and structural magnetic resonance imaging scans were completed at baseline and repeated annually to examine neurodevelopmental trajectories. Hippocampal and amygdala subregions were segmented using Freesurfer v6.0 tools, followed by volumetric analysis with generalized additive mixed models. Longitudinal statistical models examined the effects of cumulative lifetime trauma measured at baseline and alcohol use measured annually on trajectories of hippocampal and amygdala subregions, while controlling for covariates known to impact brain development. Greater alcohol use, quantified using the Cahalan scale and measured annually, was associated with smaller whole hippocampus (β = −12.0, pFDR = 0.009) and left hippocampus tail volumes (β = −1.2, pFDR = 0.048), and larger right CA3 head (β = 0.4, pFDR = 0.027) and left subiculum (β = 0.7, pFDR = 0.046) volumes of the hippocampus. In the amygdala, greater alcohol use was associated with larger right basal nucleus volume (β = 1.3, pFDR = 0.040). The effect of traumatic life events measured at baseline was associated with larger right CA3 head volume (β = 1.3, pFDR = 0.041) in the hippocampus. We observed an interaction between baseline trauma and within-person age change where younger adolescents with greater trauma exposure at baseline had smaller left hippocampal subfield volumes in the subiculum (β = 0.3, pFDR = 0.029) and molecular layer HP head (β = 0.3, pFDR = 0.041). The interaction also revealed that older adolescents with greater trauma exposure at baseline had larger right amygdala nucleus volume in the paralaminar nucleus (β = 0.1, pFDR = 0.045), yet smaller whole amygdala volume overall (β = −3.7, pFDR = 0.003). Lastly, we observed an interaction between alcohol use and baseline trauma such that adolescents who reported greater alcohol use with greater baseline trauma showed smaller right hippocampal subfield volumes in the CA1 head (β = −1.1, pFDR = 0.011) and hippocampal head (β = −2.6, pFDR = 0.025), yet larger whole hippocampus volume overall (β = 10.0, pFDR = 0.032). Cumulative lifetime trauma measured at baseline and alcohol use measured annually interact to affect the volume and trajectory of hippocampal and amygdala substructures (measured via structural MRI annually), regions that are essential for emotion regulation and memory. Our findings demonstrate the value of examining these substructures and support the hypothesis that the amygdala and hippocampus are not homogeneous brain regions. Read more.

Zhao Q, Sullivan EV, Honnorat N, Adeli E, Podhajsky S, De Bellis MD, Nooner KB, Voyvodic J, Baker FC, Colrain IM, Tapert SF, Brown SA, Thompson WK, Nagel BJ, Clark DB, Pfefferbaum A, Pohl KM (2021) Association of heavy drinking with deviant fiber tract development in frontal brain systems in young adolescents. JAMA Psychiatry 78(4): 407-415. PMCID: PMC7774050

Importance. Maturation of white matter fiber systems subserves cognitive, behavioral, emotional, and motor development during adolescence. Hazardous drinking during this active neurodevelopmental period may alter the trajectory of white matter microstructural development, potentially increasing risk for developing alcohol-related dysfunction and alcohol use disorder in adulthood.

Objective. To identify disrupted adolescent microstructural brain development linked to drinking onset and to assess whether the disruption is more pronounced in younger rather than older adolescents.

Design, Setting, and Participants: This case-control study, conducted from January 13, 2013, to January 15, 2019, consisted of an analysis of 451 participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence cohort. Participants were aged 12 to 21 years at baseline and had at least 2 usable magnetic resonance diffusion tensor imaging (DTI) scans and up to 5 examination visits spanning 4 years. Participants with a youth-adjusted Cahalan score of 0 were labeled as no-to-low drinkers; those with a score of greater than 1 for at least 2 consecutive visits were labeled as heavy drinkers. Exploratory analysis was conducted between no-to-low and heavy drinkers. A between-group analysis was conducted between age- and sex-matched youths, and a within-participant analysis was performed before and after drinking.

Exposures. Self-reported alcohol consumption in the past year summarized by categorical drinking levels.

Main Outcomes and Measures. Diffusion tensor imaging measurement of fractional anisotropy (FA) in the whole brain and fiber systems quantifying the developmental change of each participant as a slope.

Results. Analysis of whole-brain FA of 451 adolescents included 291 (64.5%) no-to-low drinkers and 160 (35.5%) heavy drinkers who indicated the potential for a deleterious association of alcohol with microstructural development. Among the no-to-low drinkers, 142 (48.4%) were boys with mean (SD) age of 16.5 (2.2) years and 149 (51.2%) were girls with mean (SD) age of 16.5 (2.1) years and 192 (66.0%) were White participants. Among the heavy drinkers, 86 (53.8%) were boys with mean (SD) age of 20.1 (1.5) years and 74 (46.3%) were girls with mean (SD) age of 20.5 (2.0) years and 142 (88.8%) were White participants. A group analysis revealed FA reduction in heavy-drinking youth compared with age- and sex-matched controls (t154 = –2.7, P = .008). The slope of this reduction correlated with log of days of drinking since the baseline visit (r156 = –0.21, 2-tailed P = .008). A within-participant analysis contrasting developmental trajectories of youths before and after they initiated heavy drinking supported the prediction that drinking onset was associated with and potentially preceded disrupted white matter integrity. Age-alcohol interactions (t152 = 3.0, P = .004) observed for the FA slopes indicated that the alcohol-associated disruption was greater in younger than older adolescents and was most pronounced in the genu and body of the corpus callosum, regions known to continue developing throughout adolescence.

Conclusions and Relevance. This case-control study of adolescents found a deleterious association of alcohol use with white matter microstructural integrity. These findings support the concept of heightened vulnerability to environmental agents, including alcohol, associated with attenuated development of major white matter tracts in early adolescence. Read more.

Ouyang J, Zhao Q, Sullivan EV, Pfefferbaum A, Tapert SF, Adeli E, Pohl KM (2021). Longitudinal pooling and consistency regularization to model disease progression from MRIs. IEEE Journal of Biomedical Health and Informatics 25(6): 2082-2092

Abstract: Many neurological diseases are characterized by gradual deterioration of brain structure and function. Largelongitudinal MRI datasets have revealed such deterioration, inpart, 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 all three 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 here.

Yuksel D, Baker FC, Goldstone A, Claudatos SA, Forouzanfar M, Prouty DE, Colrain IM, de Zambotti M (2021). Stress, sleep, and autonomic function in healthy adolescent girls and boys: Findings from the NCANDA study. Sleep Health 7(1): 72-78. PMCID: PMC7854842

Objectives. Starting in adolescence, female sex is a strong risk factor for the development of insomnia. Reasons for this are unclear but could involve altered stress reactivity and/or autonomic nervous system (ANS) dysregulation, which are strongly associated with the pathophysiology of insomnia. We investigated sex differences in the effect of stress on sleep and ANS activity in adolescents, using the first night in the laboratory as an experimental sleep-related stressor.

Design. Repeated measures (first night vs. a subsequent night) with age (older/younger) and sex (males/females) as between factors.

Setting. Recordings were performed at the human sleep laboratory at SRI International. Participants: One hundred six healthy adolescents (Age, mean ± SD: 15.2 ± 2.0 years; 57 boys).

Measures. Polysomnographic sleep, nocturnal heart rate (HR), and frequency-domain spectral ANS HR variability (HRV) indices.

Results. Boys and girls showed a first-night effect, characterized by lower sleep efficiency, lower %N1 and %N2 sleep, more wake after sleep onset and %N3 sleep, altered sleep microstructure (increased high-frequency sigma and Beta1 electroencephalographic activity), and reduced vagal activity (P < .05) on the first laboratory night compared to a subsequent night. The first night ANS stress effect (increases in HR and suppression in vagal HRV during rapid eye movement sleep) was greater in girls than boys (P < .05). Conclusions: Sleep and ANS activity were altered during the first laboratory night in adolescents, with girls exhibiting greater ANS alterations than boys. Findings suggest that girls may be more vulnerable than boys to sleep-specific stressors, which could contribute to their increased risk for developing stress-related sleep disturbances. Read more.

de Zambotti M, Goldstone A, Forouzanfar M, Javitz H, Claudatos S, Colrain IM, Baker FC (2020). The falling asleep process in adolescents. Sleep 43(6): zsz312. PMCID: PMC7294410

Study Objectives. To investigate the pre-sleep psychophysiological state and the arousal deactivation process across the sleep onset (SO) transition in adolescents.

Methods. Data were collected from a laboratory overnight recording in 102 healthy adolescents (48 girls, 12-20 years old). Measures included pre-sleep self-reported cognitive/somatic arousal, and cortical electroencephalographic (EEG) and electrocardiographic activity across the SO transition.

Results. Adolescent girls, compared with boys, reported higher pre-sleep cognitive activation (p = 0.025) and took longer to fall asleep (p < 0.05), as defined with polysomnography. Girls also showed a less smooth progression from wake-to-sleep compared with boys (p = 0.022). In both sexes, heart rate (HR) dropped at a rate of ~0.52 beats per minute in the 5 minutes preceding SO, and continued to drop, at a slower rate, during the 5 minutes following SO (p < 0.05). Older girls had a higher HR overall in the pre-sleep period and across SO, compared to younger girls and boys (p < 0.05). The EEG showed a progressive cortical synchronization, with increases in Delta relative power and reductions in Alpha, Sigma, Beta1, and Beta2 relative powers (p < 0.05) in the approach to sleep, in both sexes. Delta relative power was lower and Theta, Alpha, and Sigma relative powers were higher in older compared to younger adolescents at bedtime and across SO (p < 0.05).

Conclusions. Our findings show the dynamics of the cortical-cardiac de-arousing process across the SO transition in a non-clinical sample of healthy adolescents. Findings suggest a female-specific vulnerability to inefficient sleep initiation, which may contribute to their greater risk for developing insomnia. Read more.

Zhao Q, Adeli E, Pohl KM (2020). Training confounder-free deep learning models for medical applications. Nature Communications Nov 11: 6010

Abstract: The presence of confounding effects (or biases) is one of the most critical challenges in using deep learning to advance discovery in medical imaging studies. Confounders affect the relationship between input data (e.g., brain MRIs) and output variables (e.g., diagnosis). Improper modeling of those relationships often results in spurious and biased associations. Traditional machine learning and statistical models minimize the impact of confounders by, for example, matching data sets, stratifying data, or residualizing imaging measurements. Alternative strategies are needed for state-of-the-art deep learning models that use end-to-end training to automatically extract informative features from large set of images. In this article, we introduce an end-to-end approach for deriving features invariant to confounding factors while accounting for intrinsic correlations between the confounder(s) and prediction outcome. The method does so by exploiting concepts from traditional statistical methods and recent fair machine learning schemes. We evaluate the method on predicting the diagnosis of HIV solely from Magnetic Resonance Images (MRIs), identifying morphological sex differences in adolescence from those of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), and determining the bone age from X-ray images of children. The results show that our method can accurately predict while reducing biases associated with confounders. The code is available here. Read more.

De Bellis MD, Nooner KB, Brumback T, Clark DB, Tapert SF, Brown SA (2020). Posttraumatic stress symptoms predicts transition to future adolescent and young adult moderate to heavy drinking in the NCANDA sample. Current Addiction Reports 7: 99-107.

Purpose of Study. Approximately two-thirds of youth report experiencing or witnessing a trauma. It is not known whether trauma or the posttraumatic stress symptoms (PTSS) following trauma increases adolescent drinking risk.

Recent Findings. We described trauma experienced by the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) longitudinal sample (N = 831) participants and examined drinking over 4 years. We hypothesize that more traumatic events and PTSS will predict transition to moderate/heavy drinking.

Summary. A total of 658 no/low drinkers at baseline were followed yearly for 4 years for transition to moderate/heavy drinking using logistic regression models. Youth were grouped by no trauma (n = 257), trauma (n = 348), and trauma with PTSS (n = 53). Those with trauma and PTSS showed escalation to moderate/heavy drinking compared with the no trauma group in follow-up years 2, 3, and 4. Number of traumatic events did not predict moderate/heavy drinking. Interventions targeting PTSS may prevent transition to moderate/heavy drinking. Read more.

Piantino J, Boespflug EL, Schwartz DL, Luther M, Morales AM, Lin A, Fossen RV, Silbert L, Nagel BJ (2020). Characterization of MR Imaging-visible perivascular spaces in the white matter of healthy adolescents at 3T. American Journal of Neuroradiology Oct 8, 10.3174/ajnr.A6789.

Background and Purpose. Perivascular spaces play a role in cerebral waste removal and neuroinflammation. Our aim was to provide data regarding the burden of MR imaging–visible perivascular spaces in white matter in healthy adolescents using an automated segmentation method and to establish relationships between common demographic characteristics and perivascular space burden.

Materials and Method. One hundred eighteen 12- to 21-year-old subjects underwent T1- and T2-weighted 3T MR imaging as part of the National Consortium on Alcohol and Neurodevelopment in Adolescence. Perivascular spaces were identified in WM on T2-weighted imaging using a local heterogeneity approach coupled with morphologic constraints, and their spatial distribution and geometric characteristics were assessed.

Results. MR imaging–visible perivascular spaces were identified in all subjects (range, 16–287). Males had a significantly higher number of perivascular spaces than females: males, mean, 98.4 ± 50.5, versus females, 70.7 ± 36.1, (P < .01). Perivascular space burden was bilaterally symmetric (r > 0.4, P < .01), and perivascular spaces were more common in the frontal and parietal lobes than in the temporal and occipital lobes (P < .01). Age and pubertal status were not significantly associated with perivascular space burden.

Conclusions. Despite a wide range of burden, perivascular spaces are present in all healthy adolescents. Perivascular space burden is higher in adolescent males than in females, regardless of age and pubertal status. In this population, perivascular spaces are highly symmetric. Although widely reported as a feature of the aging brain, awareness of the presence of perivascular spaces in a cohort of healthy adolescents provides the foundation for further research regarding the role of these structural variants in health and disease Read more.

Gadgil S, Zhao Q, Pfefferbaum A, Sullivan EV, Adeli E, Pohl KM (2020). Spatio-temporal graph convolution for resting-state fMRI Analysis. Medical Image Computing and Computer Assisted Intervention, Lecture Notes in Computer Science 12267. Springer, Cham. PMCID: PMC7700758

Abstract: The Blood-Oxygen-Level-Dependent (BOLD) signal of resting-state fMRI (rs-fMRI) records the temporal dynamics of intrinsic functional networks in the brain. However, existing deep learning methods applied to rs-fMRI either neglect the functional dependency between different brain regions in a network or discard the information in the temporal dynamics of brain activity. To overcome those shortcomings, we propose to formulate functional connectivity networks within the context of spatio-temporal graphs. We train a spatio-temporal graph convolutional network (ST-GCN) on short sub-sequences of the BOLD time series to model the non-stationary nature of functional connectivity. Simultaneously, the model learns the importance of graph edges within ST-GCN to gain insight into the functional connectivities contributing to the prediction. In analyzing the rs-fMRI of the Human Connectome Project (HCP, N = 1,091) and the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N = 773), ST-GCN is significantly more accurate than common approaches in predicting gender and age based on BOLD signals. Furthermore, the brain regions and functional connections significantly contributing to the predictions of our model are important markers according to the neuroscience literature. Read more.

Ayub R, Zhao Q, Meloy MJ, Sullivan EV, Pfefferbaum A, Adeli E, Pohl KM (2020). Inpainting cropped diffusion MRI using deep generative models. Predictive Intelligence in Medicine Lecture Notes in Computer Science, vol 12329. Springer, Cham. PMCID: PMC8123091

Abstract: Minor artifacts introduced during image acquisition are often negligible to the human eye, such as a confined field of view resulting in MRI missing the top of the head. This cropping artifact, however, can cause suboptimal processing of the MRI resulting in data omission or decreasing the power of subsequent analyses. We propose to avoid data or quality loss by restoring these missing regions of the head via variational autoencoders (VAE), a deep generative model that has been previously applied to high resolution image reconstruction. Based on diffusion weighted images (DWI) acquired by the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), we evaluate the accuracy of inpainting the top of the head by common autoencoder models (U-Net, VQVAE, and VAE-GAN) and a custom model proposed herein called U-VQVAE. Our results show that U-VQVAE not only achieved the highest accuracy, but also resulted in MRI processing producing lower fractional anisotropy (FA) in the supplementary motor area than FA derived from the original MRIs. Lower FA implies that inpainting reduces noise in processing DWI and thus increases the quality of the generated results. The code is available here. Read more.

Nooner K, De Bellis MD, Clark D, Thomson W, Brumback T (2020). Longitudinal impact of life events on adolescent binge drinking in National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). Substance Use & Misuse 55 (11): 1846-1855.

Background. Life events experienced during adolescence are associated with risk and resilience to heavy episodic drinking (HED; i.e. binge drinking). The current study builds on prior research using latent class analysis (LCA) to examine heterogeneity in patterns of adolescent life events at baseline to HED over the course of three years (4 timepoints) as part of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA).

Methods. Life event classes were modeled using LCA that characterized NCANDA participants based upon their responses to the Life Events Questionnaire (N = 467, age: M = 14.98, SD = 1.69, 49.7% female). These baseline latent life event classes were then compared to HED at baseline and years 1, 2 and 3 using multinomial logistic regression.

Results. At baseline, the LCA characterized four classes of adolescents based on endorsement of life events: negative-relational conflict (n = 65, 13.9%), negative-financial problems (n = 49, 10.5%), low life events (n = 130, 27.8%), and positive life events (n = 223, 47.8%). Life event trajectories differed for the negative life event classes compared to the other two classes, with greater odds of HED in the negative-financial problems class at year 1.

Conclusion. The four latent classes derived from the life events of NCANDA youth yielded a characterization of adolescents that could aid in understanding HED over the subsequent three years, suggesting that everyday life events may inform adolescent binge drinking. Read more.

Quach A, Tervo-Clemmens B, Foran W, Calabro FJ, Chung T, Clark DB, Luna B (2020). Adolescent development of inhibitory control and substance use vulnerability: A longitudinal neuroimaging study. Developmental Cognitive Neuroscience Feb 42: 100771. PMCID: PMC7038454

Abstract: Previous research indicates that risk for substance use is associated with poor inhibitory control. However, it remains unclear whether at-risk youth follow divergent patterns of inhibitory control development. As part of the longitudinal National Consortium on Adolescent Neurodevelopment and Alcohol study, participants (N = 113, baseline age: 12–21) completed a rewarded antisaccade task during fMRI, with up to three time points. We examined whether substance use risk factors, including psychopathology (externalizing, internalizing) and family history of substance use disorder, were associated with developmental differences in inhibitory control performance and BOLD activation. Among the examined substance use risk factors, only externalizing psychopathology exhibited developmental differences in inhibitory control performance, where higher scores were associated with lower correct response rates (p = .013) and shorter latencies (p < .001) in early adolescence that normalized by late adolescence. Neuroimaging results revealed higher externalizing scores were associated with developmentally-stable hypo-activation in the left middle frontal gyrus (p < .05 corrected), but divergent developmental patterns of posterior parietal cortex activation (p < .05 corrected). These findings suggest that early adolescence may be a unique period of substance use vulnerability via cognitive and phenotypic disinhibition. Read more.

Silveira SJ, Nooner K, Nagel B, Tapert S, De Bellis M, Mishra J (2020). Impact of childhood trauma on executive function in adolescence - mediating functional brain networks and prediction of high-risk drinking. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

Background. Childhood trauma is known to impart risk to several adverse life outcomes. Yet, its impact during adolescent development is not well understood. Here, we aimed to investigate the relationship between childhood trauma, functional brain connectivity, executive dysfunction (ED), and the development of high-risk drinking in adolescence.

Methods. Data from the National Consortium on Alcohol & Neurodevelopment in Adolescence (NCANDA, n=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 four annual follow-ups. We used longitudinal regression analyses to confirm the relationship between childhood trauma and ED, identified the mediating functional brain networks hubs, and used these linkages to predict future high-risk drinking in adolescence.

Results. Childhood trauma severity 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 post-central gyri mediated the relationship between childhood trauma and ED. Further, high-risk drinking in follow-up years 1-4 could be predicted with high accuracy from the trauma-impacted functional brain networks that mediated ED at baseline, together with age, childhood trauma severity and extent of ED.

Discussion. Functional brain networks, particularly from hub regions important for cognitive and sensory-motor 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. Read more.

Kwon D, Pfefferbaum A, Sullivan EV, Pohl KM (2020). Regional growth trajectories of cortical myelination in adolescents and young adults: Longitudinal validation and functional correlates. Brain Imaging & Behavior 14(1): 242-266. PMCID: PMC6506406

Abstract: Adolescence is a time of continued cognitive and emotional evolution occurring with continuing brain development involving synaptic pruning and cortical myelination. The hypothesis of this study is that heavy myelination occurs in cortical regions with relatively direct, predetermined circuitry supporting unimodal sensory or motor functions and shows a steep developmental slope during adolescence (12-21 years) until young adulthood (22-35 years) when further myelination decelerates. By contrast, light myelination occurs in regions with highly plastic circuitry supporting complex functions and follows a delayed developmental trajectory. In support of this hypothesis, cortical myelin content was estimated and harmonized across publicly available datasets provided by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) and the Human Connectome Project (HCP). The cross-sectional analysis of 226 no-to-low alcohol drinking NCANDA adolescents revealed relatively steeper age-dependent trajectories of myelin growth in unimodal primary motor cortex and flatter age-dependent trajectories in multimodal mid/posterior cingulate cortices. This pattern of continued myelination showed smaller gains when the same analyses were performed on 686 young adults of the HCP cohort free of neuropsychiatric diagnoses. Critically, a predicted correlation between a motor task and myelin content in motor or cingulate cortices was found in the NCANDA adolescents, supporting the functional relevance of this imaging neurometric. Furthermore, the regional trajectory slopes were confirmed by performing longitudinally consistent analysis of cortical myelin. In conclusion, coordination of myelin content and circuit complexity continues to develop throughout adolescence, contributes to performance maturation, and may represent active cortical development climaxing in young adulthood. Read more.

Meruelo AD (2020). Adolescent cerebellar development: An underexplored frontier. Biological Psychiatry 87(7): e19-e20.

Read more.

Sullivan EV, Brumback T, Tapert SF, Brown SA, Baker FC, Colrain IM, Prouty D, De Bellis MD, Clark DB, Nagel BJ, Pohl KM, Pfefferbaum A (2020). Disturbed cerebellar growth trajectories in adolescents who initiate alcohol drinking. Biological Psychiatry 87(7): 632-644. PMCID: PMC7061065.

Background. The 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.

Methods. Magnetic 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.

Results. Normal 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.

Conclusions. Alcohol 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. Read more.

Schulte T, Hong G, Sullivan EV, Pfefferbaum A, Chu W, Prouty D, Kwon D, Meloy MJ, Brumback T, Tapert SF, Baker F, Colrain I, Muller-Oehring E (2020). Effects of age, sex, and puberty on neural efficiency of cognitive and motor control in adolescents. Brain Imaging and Behavior 14(4) 1089-1107. doi: 10.1007/s11682-019-00075-x.

Abstract: 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. Read more.

de Zambotti M, Cellini N, Goldstone A, Colrain IM, Baker FC (2019). Wearable sleep technology in clinical and research settings. Med Sci Sports Exerc 51(7): 1538-57. PMCID: PMC6579636

Abstract: The accurate assessment of sleep is critical to better understand and evaluate its role in health and disease. The boom in wearable technology is part of the digital health revolution and is producing many novel, highly sophisticated and relatively inexpensive consumer devices collecting data from multiple sensors and claiming to extract information about users' behaviors, including sleep. These devices are now able to capture different biosignals for determining, for example, HR and its variability, skin conductance, and temperature, in addition to activity. They perform 24/7, generating overwhelmingly large data sets (big data), with the potential of offering an unprecedented window on users' health. Unfortunately, little guidance exists within and outside the scientific sleep community for their use, leading to confusion and controversy about their validity and application. The current state-of-the-art review aims to highlight use, validation and utility of consumer wearable sleep-trackers in clinical practice and research. Guidelines for a standardized assessment of device performance is deemed necessary, and several critical factors (proprietary algorithms, device malfunction, firmware updates) need to be considered before using these devices in clinical and sleep research protocols. Ultimately, wearable sleep technology holds promise for advancing understanding of sleep health; however, a careful path forward needs to be navigated, understanding the benefits and pitfalls of this technology as applied in sleep research and clinical sleep medicine. Read more.

Leng T, Zhao Q, Yang C, Lu Z, Adeli E, Pohl KM (2019). Data augmentation based on substituting regional MRI volume scores, large-scale annotation of biomedical data and expert label synthesis. Large-scale Annotation of Biomedical data and Expert Label Synthesis, Springer, Lecture Notes in Computer Science, 11851: 32-41. PMCID: PMC7486010

Abstract: Due to difficulties in collecting sufficient training data, recent advances in neural-network-based methods have not been fully explored in the analysis of brain Magnetic Resonance Imaging (MRI). A possible solution to the limited-data issue is to augment the training set with synthetically generated data. In this paper, we propose a data augmentation strategy based on regional feature substitution. We demonstrate the advantages of this strategy with respect to training a simple neural-network-based classifier in predicting when individual youth transition from no-to-low to medium-to-heavy alcohol drinkers solely based on their volumetric MRI measurements. Based on 20-fold cross-validation, we generate more than one million synthetic samples from less than 500 subjects for each training run. The classifier achieves an accuracy of 74.1% in correctly distinguishing non-drinkers from drinkers at baseline and a 43.2% weighted accuracy in predicting the transition over a three year period (5-group classification task). Both accuracy scores are significantly better than training the classifier on the original dataset. Read more.

Morales AM, Boyd SJ, Mackiewicz Seghete KL, Johnson AJ, De Bellis MD, Nagel BJ (2019). Sex differences in effect of nucleus accumbens volume on adolescent drinking: Mediating role of sensation seeking in NCANDA sample. Journal of Studies on Alcohol and Drugs Nov 80(6): 594-601. PMCID: PMC6900990.

Objective. In adolescence, sensation seeking is associated with earlier onset of alcohol use, which is a risk factor for a variety of negative consequences later in life. Individual differences in sensation seeking are related to brain function in the nucleus accumbens (NAcc), a brain region that undergoes considerable structural development during adolescence. Therefore, the goal of this study was to determine whether NAcc volume in alcohol-naive adolescents was associated with future sensation seeking and alcohol use and whether these associations differed by sex.

Method. High-resolution magnetic resonance imaging was used to measure NAcc volume at baseline in 514 alcohol-naive adolescents (50.2% female) from the National Consortium on Alcohol & Neurodevelopment in Adolescence study. Direct effects of NAcc volume on adolescent drinking 2 years after baseline, and indirect effects mediated through sensation seeking 1 year after baseline, were assessed.

Results. An indirect effect of NAcc volume on subsequent drinking through sensation seeking was significant for males, but not females. This effect was driven by a positive association between NAcc volume and sensation seeking observed in male, but not female, participants. A direct effect of NAcc volume on subsequent alcohol use was detected in females, but not males. In females, no association between NAcc volume and sensation seeking was detected, but NAcc volume was positively associated with future alcohol use.

Conclusions. These findings suggest that delayed structural maturation of the NAcc may be a risk factor for alcohol use in adolescence; however, the mechanism by which the structure of the NAcc confers risk differs by sex. Read more.

Zhao Q, Adeli E, Pfefferbaum A, Sullivan EV, Pohl KM (2019). Confounder-aware visualization of convNets. International Workshop on Machine Learning and Medical Imaging, Springer, Lecture Notes in Computer Science. ArXiv abs/1907.12727.

Abstract: With recent advances in deep learning, neuroimaging studies increasingly rely on convolutional networks (ConvNets) to predict diagnosis based on MR images. To gain a better understanding of how a disease impacts the brain, the studies visualize the salience maps of the ConvNet highlighting voxels within the brain majorly contributing to the prediction. However, these salience maps are generally confounded, i.e., some salient regions are more predictive of confounding variables (such as age) than the diagnosis. To avoid such misinterpretation, we propose in this paper an approach that aims to visualize confounder-free saliency maps that only highlight voxels predictive of the diagnosis. The approach incorporates univariate statistical tests to identify confounding effects within the intermediate features learned by ConvNet. The influence from the subset of confounded features is then removed by a novel partial back-propagation procedure. We use this two-step approach to visualize confounder-free saliency maps extracted from synthetic and two real datasets. These experiments reveal the potential of our visualization in producing unbiased model-interpretation. Read more.

Zhao Q, Honnorat N, Adeli E, Pfefferbaum A, Sullivan EV, Pohl KM (2019). Variational autoencoder with truncated mixture of gaussians for functional connectivity analysis. Information Processing in Medical Imaging, Springer Lecture Notes Computer Science 11492: 867-879.

Abstract: Resting-state functional connectivity states are often identified as clusters of dynamic connectivity patterns. However, existing clustering approaches do not distinguish major states from rarely occurring minor states and hence are sensitive to noise. To address this issue, we propose to model major states using a non-linear generative process guided by a Gaussian-mixture distribution in a low-dimensional latent space, while separately modeling the connectivity patterns of minor states by a non-informative uniform distribution. We embed this truncated Gaussian-Mixture model in a Variational Autoencoder framework to obtain a general joint clustering and outlier detection approach, called tGM-VAE. When applied to synthetic data with known ground-truth, tGM-VAE is more accurate in clustering connectivity patterns than existing approaches. On the rs-fMRI of 593 healthy adolescents of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study, tGM-VAE identified meaningful major connectivity states. The dwell time of these states significantly correlated with age. Read more.

Goldstone A, Willoughby AR, de Zambotti M, Clark DB, Sullivan EV, Hasler BP, Franzen PL, Prouty DE, Colrain IM, Baker FC (2019). Sleep spindle characteristics in adolescents. Clinical Neurophysiology Jun 130(6): 893-902. PMCID: PMC6684236

Objective. Sleep changes substantially during adolescence; however, our understanding of age-related differences in specific electroencephalographic waveforms during this developmental period is limited.

Method. Sigma power, spindle characteristics and cognitive data were calculated for fast (~13Hz) central and slow (~11Hz) frontal sleep spindles for a large cross-sectional sample of adolescents (N=134, aged 12-21 years, from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study).

Results. Older age (and advanced pubertal development) was associated with lower absolute sigma power and greater fast spindle density, with spindles having a shorter duration and smaller amplitude and occurring at a faster average frequency than at a younger age. Spindle characteristics were not directly associated with cognition. An indirect relationship (age*density) provided some evidence for an association between better episodic memory performance and greater spindle density only for younger adolescents.

Conclusion. Spindle characteristics in adolescents differed according to age, possibly reflecting underlying differences in thalamo-cortical connectivity, and may play a role in episodic memory early in adolescence.

Significance. Sleep spindles may serve as a marker of adolescent development, likely reflecting brain maturational status. Investigating specific spindle characteristics, in addition to sigma power, is necessary to fully characterize spindles during adolescence. Read more.

Zhao Q, Kwon D, Müller-Oehring EM, Le Berre AP, Pfefferbaum A, Sullivan EV (2019). Longitudinally consistent estimates of intrinsic functional networks. Human Brain Mapping 40(8): 2511-2528. PMCID: PMC6497087

Abstract: Increasing numbers of neuroimaging studies are acquiring data to examine changes in brain architecture by investigating intrinsic functional networks (IFN) from longitudinal resting-state functional MRI (rs-fMRI). At the subject level, these IFNs are determined by cross-sectional procedures, which neglect intra-subject dependencies and result in suboptimal estimates of the networks. Here, a novel longitudinal approach simultaneously extracts subject-specific IFNs across multiple visits by explicitly modeling functional brain development as an essential context for seeking change. On data generated by an innovative simulation based on real rs-fMRI, the method was more accurate in estimating subject-specific IFNs than cross-sectional approaches. Furthermore, only group-analysis based on longitudinally consistent estimates identified significant developmental effects within IFNs of 246 adolescents from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. The findings were confirmed by the cross-sectional estimates when the corresponding group analysis was confined to the developmental effects. Those effects also converged with current concepts of neurodevelopment. Read more.

Peterson ET, Kwon D, Luna B, Larsen B, Prouty D, De Bellis MD, Voyvodic J, Liu C, Li W, Pohl KM, Sullivan EV, Pfefferbaum A (2019). Distribution of brain iron accrual in adolescence: Evidence from cross-sectional and longitudinal analysis. Human Brain Mapping Apr 40(5):1480-95. PMCID: PMC6397094

Purpose. To track iron accumulation and location in the brain across adolescence, we repurposed diffusion tensor imaging (DTI) and functional Magnetic Resonance Imaging (fMRI) data acquired in 513 adolescents and validated iron estimates with quantitative susceptibility mapping (QSM) in 104 of these subjects.

Methods. DTI and fMRI data were acquired longitudinally over 1 year in 245 male and 268 female, no-to-low alcohol-consuming adolescents (12-21 years at baseline) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Brain region average signal values were calculated for susceptibility to non-heme iron deposition: pallidum, putamen, dentate nucleus, red nucleus, and substantia nigra. To estimate non-heme iron, the corpus callosum signal (robust to iron effects) was divided by regional signals to generate estimated R2 (edwR2 for DTI) and R2* (eR2* for fMRI). Longitudinal iron deposition was measured using the normalized signal change across time for each subject. Validation using baseline QSM, derived from susceptibility-weighted imaging, was performed on 46 male and 58 female participants.

Results. Normalized iron deposition estimates from DTI and fMRI correlated with age in most regions; both estimates indicated less iron in boys than girls. QSM results correlated highly with DTI and fMRI results (adjusted R2=0.643 for DTI, 0.578 for fMRI). Cross-sectional and longitudinal analyses indicated an initial rapid increase in iron, notably in the putamen and red nucleus, that slowed with age.

Conclusion. DTI and fMRI data can be repurposed for identifying regional brain iron deposition in developing adolescents as validated with high correspondence with QSM. Read more.

Müller-Oehring EM, Kwon D, Nagel BJ, Sullivan EV, Chu W, Rohlfing T, Prouty D, Nichols BN, Poline JB, Tapert SF, Brown SA, Cummins K, Brumback T, Colrain IM, Baker FC, De Bellis MD, Voyvodic JT, Clark DB, Pfefferbaum A, Pohl KM. (2018). Influences of age, sex, and moderate alcohol drinking on the intrinsic functional architecture of adolescent brains. Cerebral Cortex. 1-15. PMCID: PMC6059181

Abstract: The transition from adolescent to adult cognition and emotional control requires neurodevelopmental maturation likely involving intrinsic functional networks (IFNs). Normal neurodevelopment may be vulnerable to disruption from environmental insult such as alcohol consumption commonly initiated during adolescence. To test potential disruption to IFN maturation, we used resting-state functional magnetic resonance imaging (rs-fMRI) in 581 no-to-low alcohol-consuming and 117 moderate-to-high-drinking youth. Functional seed-to-voxel connectivity analysis assessed age, sex, and moderate alcohol drinking on default-mode, executive-control, salience, reward, and emotion networks and tested cognitive and motor coordination correlates of network connectivity. Among no-to-low alcohol-consuming adolescents, executive-control frontolimbicstriatal connectivity was stronger in older than younger adolescents, particularly boys, and predicted better ability in balance, memory, and impulse control. Connectivity patterns in moderate-to-high-drinking youth were tested mainly in late adolescence when drinking was initiated. Implicated was the emotion network with attenuated connectivity to default-mode network regions. Our cross-sectional rs-fMRI findings from this large cohort of adolescents show sexual dimorphism in connectivity and suggest neurodevelopmental rewiring toward stronger and spatially more distributed executive-control networking in older than younger adolescents. Functional network rewiring in moderate-to-high-drinking adolescents may impede maturation of affective and self-reflection systems and obscure maturation of complex social and emotional behaviors. Read more.

de Zambotti M, Trinder J, Silvani A, Colrain IM, Baker FC (2018). Dynamic coupling between the central and autonomic nervous systems during sleep: A review. Neurosci Biobehav Rev 90: 84-103. PMCID: PMC5993613

Abstract: Sleep is characterized by coordinated cortical and cardiac oscillations reflecting communication between the central (CNS) and autonomic (ANS) nervous systems. Here, we review fluctuations in ANS activity in association with CNS-defined sleep stages and cycles, and with phasic cortical events during sleep (e.g., arousals, K-complexes). Recent novel analytic methods reveal a dynamic organization of integrated physiological networks during sleep and indicate how multiple factors (e.g., sleep structure, age, sleep disorders) affect “CNS-ANS coupling”. However, these data are mostly correlational and there is a lack of clarity of the underlying physiology, making it challenging to interpret causality and direction of coupling. Experimental manipulations (e.g., evoking K-complexes or arousals) provide information on the precise temporal sequence of cortical-cardiac activity, and are useful for investigating physiological pathways underlying CNS-ANS coupling. With the emergence of new analytical approaches and a renewed interest in ANS and CNS communication during sleep, future work may reveal novel insights into sleep and cardiovascular interactions during health and disease, in which coupling could be adversely impacted. Read more.

de Zambotti M, Goldstone A, Colrain IM, Baker FC (2018). Insomnia disorder in adolescence: Diagnosis, impact, and treatment. Sleep Med Rev 39: 12-24. PMCID: PMC5931364

Abstract: Insomnia disorder is very common in adolescents; it is particularly manifest in older adolescents and girls, with a prevalence comparable to that of other major psychiatric disorders (e.g., depressive disorders). However, insomnia disorder in adolescence is poorly characterized, under-recognized, under-diagnosed, and under-treated, and the reason for the female preponderance for insomnia that emerges after puberty is largely unknown. Insomnia disorder goes beyond an individual complaint of poor sleep or a sleep state misperception, and there is emerging evidence supporting the association of insomnia symptoms in adolescents with alterations in several bio-systems including functional cortical alterations and systemic inflammation. Insomnia disorder is associated with depression and other psychiatric disorders, and is an independent risk factor for suicidality and substance use in adolescents, raising the possibility that treating insomnia symptoms in early adolescence may reduce risk for these adverse outcomes. Cognitive behavioral treatments have proven efficacy for adolescent insomnia and online methods seem to offer promising cost-effective options. Current evidence indicates that insomnia in adolescence is an independent entity that warrants attention as a public health concern in its own right. Read more.

Zhao Q, Kwon D, Pohl KM (2018). A Riemannian framework for longitudinal analysis of resting-state functional connectivity. Medical Image Computing and Computer-Assisted Intervention 11072: 145-153. PMCID: PMC7526985

Abstract: Even though the number of longitudinal resting-state-fMRI studies is increasing, accurately characterizing the changes in functional connectivity across visits is a largely unexplored topic. To improve characterization, we design a Riemannian framework that represents the functional connectivity pattern of a subject at a visit as a point on a Riemannian manifold. Geodesic regression across the ‘sample' points of a subject on that manifold then defines the longitudinal trajectory of their connectivity pattern. To identify group differences specific to regions of interest (ROI), we map the resulting trajectories of all subjects to a common tangent space via the Lie group action. We account for the uncertainty in choosing the common tangent space by proposing a test procedure based on the theory of latent p-values. Unlike existing methods, our proposed approach identifies sex differences across 246 subjects, each of them being characterized by three rs-fMRI scans. Read more.

Park SH, Zhang Y, Kwon D, Pfefferbaum A, Sullivan EV, Pohl KM (2018). Alcohol use effect on adolescent brain development revealed by simultaneously removing confounding factors, identifying morphometric patterns, and classifying individuals. Scientific Reports 8: 8297. PMCID: PMC5974423

Abstract: Group analysis of brain magnetic resonance imaging (MRI) metrics frequently employs generalized additive models (GAM) to remove contributions of confounding factors before identifying cohort specific characteristics. For example, the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) used such an approach to identify effects of alcohol misuse on the developing brain. Here, we hypothesized that considering confounding factors before group analysis removes information relevant for distinguishing adolescents with drinking history from those without. To test this hypothesis, we introduce a machine-learning model that identifies cohort-specific, neuromorphometric patterns by simultaneously training a GAM and generic classifier on macrostructural MRI and microstructural diffusion tensor imaging (DTI) metrics and compare it to more traditional group analysis and machine-learning approaches. Using a baseline NCANDA MR dataset (N = 705), the proposed machine learning approach identified a pattern of eight brain regions unique to adolescents who misuse alcohol. Classifying high-drinking adolescents was more accurate with that pattern than using regions identified with alternative approaches. The findings of the joint model approach thus were (1) impartial to confounding factors; (2) relevant to drinking behaviors; and (3) in concurrence with the alcohol literature. Read more

Boyd SJ, Sceeles EM, Tapert SF, Brown SA, Nagel B (2018). Reciprocal relations between positive alcohol expectancies and peer use on adolescent drinking: An accelerated autoregressive cross-lagged model using the NCANDA sample. Psychology of Addictive Behaviors Jul 2. PMCID: PMC6519438

Abstract:Positive alcohol expectancies (PAE) and associating with drinking peers are reliable predictors of adolescent alcohol use. Knowledge of when, and for whom these risk factors are most influential could enhance intervention effectiveness. Reciprocal relations between PAE, and adolescent and peer alcohol use were examined between the ages of 13-18 in a sample (N=566; 50% female) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), as well as sex differences in these associations. Associating with drinking peers prospectively predicted more frequent alcohol use for both sexes, although peer socialization was evident earlier for girls compared to boys. Higher PAE influenced later drinking in mid-adolescence, from age 14 to 16, for boys only. PAE influenced peer group selection for both sexes, although the influence was evident earlier in boys than girls. The relative impact of environmental risk factors for problematic alcohol use may vary over time and across developmental periods. These results suggest that prevention and treatment efforts for adolescent drinking can be improved by targeting age-appropriate risk factors. Early adolescent interventions may be best served by minimizing involvement with drinking peers and correcting normative beliefs of peer use. Among adolescent girls, early interventions focused on reducing peer influence may be most effective. Prevention and treatment programs aimed at addressing PAE would likely prove more effective for boys in mid- to late-adolescence. Read more.

Pfefferbaum A, Kwon D, Brumback T, Thompson WK, Cummins K, Tapert SF, Brown SA, Colrain IM, Baker FC, Prouty D, De Bellis MD, Clark DB, Nagel BJ, Chu W, Park SH, Sullivan EV.(2018). Altered brain development trajectories in adolescents after initiating drinking. American Journal of Psychiatry. Apr 175(4): 370-380. PMCID: PMC6504929

Objective. The authors sought evidence for altered adolescent brain growth trajectory associated with moderate and heavy alcohol use in a large national, multisite, prospective study of adolescents before and after initiation of appreciable alcohol use.

Method. This study examined 483 adolescents (ages 12-21) before initiation of drinking and 1 and 2 years later. At the 2-year assessment, 356 participants continued to meet the study's no/low alcohol consumption entry criteria, 65 had initiated moderate drinking, and 62 had initiated heavy drinking. MRI was used to quantify regional cortical and white matter volumes. Percent change per year (slopes) in adolescents who continued to meet no/low criteria served as developmental control trajectories against which to compare those who initiated moderate or heavy drinking.

Results. In no/low drinkers, gray matter volume declined throughout adolescence and slowed in many regions in later adolescence. Complementing gray matter declines, white matter regions grew at faster rates at younger ages and slowed toward young adulthood. Youths who initiated heavy drinking exhibited an accelerated frontal cortical gray matter trajectory, divergent from the norm. Although significant effects on trajectories were not observed in moderate drinkers, their intermediate position between no/low and heavy drinkers suggests a dose effect. Neither marijuana co-use nor baseline volumes contributed significantly to the alcohol effect.

Conclusions. Initiation of drinking during adolescence, with or without marijuana co-use, disordered normal brain growth trajectories. Factors possibly contributing to abnormal cortical volume trajectories include peak consumption in the past year and family history of alcoholism. Read more.

Goldstone A, Willoughby AR, de Zambotti M, Franzen PL, Kwon D, Pohl KM, Pfefferbaum A, Sullivan EV, Müller-Oehring EM, Prouty D, Hasler BP, Clark DB, Colrain IM, Baker FC (2018). The mediating role of cortical thickness and gray matter volume on sleep slow wave activity during adolescence. Brain Structure & Function. Mar 223(2): 669-685. PMCID: PMC5828920

Abstract: During the course of adolescence, reductions occur in cortical thickness and gray matter (GM) volume, along with a 65% reduction in slow-wave (delta) activity during sleep (SWA) but empirical data linking these structural brain and functional sleep differences, is lacking. Here, we investigated specifically whether age-related differences in cortical thickness and GM volume and cortical thickness accounted for the typical age-related difference in slow-wave (delta) activity (SWA) during sleep. 132 healthy participants (age 12-21 years) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence study were included in this cross-sectional analysis of baseline polysomnographic, electroencephalographic, and magnetic resonance imaging data. By applying mediation models, we identified a large, direct effect of age on SWA in adolescents, which explained 45% of the variance in ultra-SWA (0.3-1 Hz) and 52% of the variance in delta-SWA (1 to <4 Hz), where SWA was lower in older adolescents, as has been reported previously. In addition, we provide evidence that the structure of several, predominantly frontal, and parietal brain regions, partially mediated this direct age effect, models including measures of brain structure explained an additional 3-9% of the variance in ultra-SWA and 4-5% of the variance in delta-SWA, with no differences between sexes. Replacing age with pubertal status in models produced similar results. As reductions in GM volume and cortical thickness likely indicate synaptic pruning and myelination, these results suggest that diminished SWA in older, more mature adolescents may largely be driven by such processes within a number of frontal and parietal brain regions. Read more.

de Zambotti M, Javitz H, Franzen P, Brumback T, Clark D, Colrain I, Baker F (2018). Sex- and age-dependent differences in autonomic nervous system functioning in adolescents. Journal of Adolescent Health. Feb 62(2): 184-190. PMCID: PMC6415527

Purpose. We assessed sex- and age-dependent differences in a cross-sectional analysis of cardiac autonomic nervous system (ANS) regulation during sleep in adolescents.

Methods. Nocturnal heart rate (HR) and heart rate variability (HRV) metrics, reflecting ANS functioning, were analyzed across the night and within undisturbed rapid eye movement (REM) and non-REM sleep in 149 healthy adolescents (12-22 years; 67 female) from the National Consortium on Alcohol and Neurodevelopment in Adolescence.

Results. Nocturnal HR was slower in older, more pubertally advanced boys than in younger boys. In girls, HR did not vary according to age or maturity, although overall HRV and vagal modulation declined with age. Although younger boys and girls had similar HR, the male-female HR difference increased by ~2.4 bpm every year (p < .01, higher in older girls). Boys and girls showed expected increases in total HRV across the night but this within-night "recovery" was blunted in girls compared with boys (p < .05). Also, the non-REM and REM difference in HR was greater in girls (p < .01). Models exploring a role of covariates (sleep, mood, reproductive hormones, activity) in influencing HR and HRV showed few significant effects, apart from sedentary activity (higher in older girls), which partially mediated the sex × age interaction in HR.

Conclusions. Sex-related differences in cardiac ANS function emerge during adolescence. The extent to which sex-age divergences in ANS function are adaptive or reflect underlying sex-specific vulnerability for the development of psychopathology and other health conditions in adolescence needs to be determined. Read more.

Sullivan EV, Brumback T, Tapert SF, Prouty D, Fama R, Thompson WK, Brown SA, Cummins K, Colrain IM, Baker FC, Clark D, Chung T, De Bellis MD, Hooper SR, Nagel BJ, Nichols BN, Chu W, Kwon D, Pohl KM, Pfefferbaum A. (2017). Effects of prior testing lasting a full year in NCANDA adolescents: Contributions from age, sex, socioeconomic status, ethnicity, site, family history of alcohol or drug abuse, and baseline performance. Developmental Cognitive Neuroscience. 24:72-83. PMCID: PMC5429199

Abstract: Longitudinal study provides a robust method for tracking developmental trajectories. Yet inherent problems of retesting pose challenges in distinguishing biological developmental change from prior testing experience. We examined factors potentially influencing change scores on 16 neuropsychological test composites over 1 year in 568 adolescents in the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) project. The twice-minus-once-tested method revealed that performance gain was mainly attributable to testing experience (practice) with little contribution from predicted developmental effects. Group mean practice slopes for 13 composites indicated that 60% to∼100% variance was attributable to test experience; General Ability accuracy showed the least practice effect (29%). Lower baseline performance, especially in younger participants, was a strong predictor of greater gain. Contributions from age, sex, ethnicity, examination site, socioeconomic status, or family history of alcohol/ substance abuse were nil to small, even where statistically significant. Recognizing that a substantial proportion of change in longitudinal testing, even over 1-year, is attributable to testing experience indicates caution against assuming that performance gain observed during periods of maturation necessarily reflects development. Estimates of testing experience, a form of learning, may be a relevant metric for detecting interim influences, such as alcohol use or traumatic episodes, on behavior. Read more

de Zambotti M, Rosas L, Colrain IM, Baker FC. (2017). The sleep of the ring: Comparison of the ŌURA sleep tracker against polysomnography. Behavioral Sleep Medicine. PMCID: PMC6095823

Objective/Background. To evaluate the performance of a multisensor sleep-tracker (ŌURA ring) against polysomnography (PSG) in measuring sleep and sleep stages.

Participants. Forty-one healthy adolescents and young adults (13 females; Age: 17.2 ± 2.4 years).

Methods. Sleep data were recorded using the ŌURA ring and standard PSG on a single laboratory overnight. Metrics were compared using Bland-Altman plots and epoch-by-epoch (EBE) analysis.

Results. Summary variables for sleep onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) were not different between ŌURA ring and PSG. PSG-ŌURA discrepancies for WASO were greater in participants with more PSG-defined WASO (p < .001). Compared with PSG, ŌURA ring underestimated PSG N3 (~20 min) and overestimated PSG REM (~17 min; p < .05). PSG-ŌURA differences for TST and WASO lay within the ≤ 30 min a-priori-set clinically satisfactory ranges for 87.8% and 85.4% of the sample, respectively. From EBE analysis, ŌURA ring had a 96% sensitivity to detect sleep, and agreement of 65%, 51%, and 61%, in detecting “light sleep” (N1), “deep sleep” (N2 + N3), and REM sleep, respectively. Specificity in detecting wake was 48%. Similarly to PSG-N3 (p < .001), “deep sleep” detected with the ŌURA ring was negatively correlated with advancing age (p = .001). ŌURA ring correctly categorized 90.9%, 81.3%, and 92.9% into PSG-defined TST ranges of < 6 hr, 6–7 hr, > 7 hr, respectively.

Conclusions. Multisensor sleep trackers, such as the ŌURA ring have the potential for detecting outcomes beyond binary sleep–wake using sources of information in addition to motion. While these first results could be viewed as promising, future development and validation are needed. Read more

Clark DB, Chung T, Martin CS, Hasler BP, Fitzgerald DH, Luna B, Brown SA, Tapert SF, Brumback T, Cummins K, Pfefferbaum A, Sullivan EV, Pohl KM, Colrain IM, Baker FC, De Bellis MD, Nooner KB and Nagel BJ.(2017). Adolescent executive dysfunction in daily Life: Relationships to risks, brain structure and substance use. Frontiers in Behavioral Neuroscience. 11:223. PMCID: PMC5694208

Abstract: During adolescence, problems reflecting cognitive, behavioral and affective dysregulation, such as inattention and emotional dyscontrol, have been observed to be associated with substance use disorder (SUD) risks and outcomes. Prior studies have typically been with small samples, and have typically not included comprehensive measurement of executive dysfunction domains. The relationships of executive dysfunction in daily life with performance based testing of cognitive skills and structural brain characteristics, thought to be the basis for executive functioning, have not been definitively determined. The aims of this study were to determine the relationships between executive dysfunction in daily life, measured by the Behavior Rating Inventory of Executive Function (BRIEF), cognitive skills and structural brain characteristics, and SUD risks, including a global SUD risk indicator, sleep quality, and risky alcohol and cannabis use. In addition to bivariate relationships, multivariate models were tested. The subjects (n = 817; ages 12 through 21) were participants in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study. The results indicated that executive dysfunction was significantly related to SUD risks, poor sleep quality, risky alcohol use and cannabis use, and was not significantly related to cognitive skills or structural brain characteristics. In multivariate models, the relationship between poor sleep quality and risky substance use was mediated by executive dysfunction. While these cross-sectional relationships need to be further examined in longitudinal analyses, the results suggest that poor sleep quality and executive dysfunction may be viable preventive intervention targets to reduce adolescent substance use. Read more

Hasler BP, Franzen PL, de Zambotti M, Prouty D, Brown, SA, Tapert SF, Pfefferbaum A, Pohl KM, Sullivan EV, De Bellis MD, Nagel BJ, Baker FC, Colrain IM, Clark DB.(2017) Eveningness and later sleep timing are associated with greater risk for alcohol and marijuana use in adolescence: Initial findings from the National Consortium on Alcohol and Neurodevelopment in Adolescence study. Alcohol Clin Exp Res. 41(6):1154-1165. PMCID: PMC5488322

Background. Abundant cross-sectional evidence links eveningness (a preference for later sleep-wake timing) and increased alcohol and drug use among adolescents and young adults. However, longitudinal studies are needed to examine whether eveningness is a risk factor for subsequent alcohol and drug use, particularly during adolescence, which is marked by parallel peaks in eveningness and risk for the onset of alcohol use disorders. This study examined whether eveningness and other sleep characteristics were associated with concurrent or subsequent substance involvement in a longitudinal study of adolescents.

Methods. Participants were 729 adolescents (368 females; age 12 to 21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence study. Associations between the sleep variables (circadian preference, sleep quality, daytime sleepiness, sleep timing, and sleep duration) and 3 categorical substance variables (at-risk alcohol use, alcohol bingeing, and past-year marijuana use [y/n]) were examined using ordinal and logistic regression with baseline age, sex, race, ethnicity, socioeconomic status, and psychiatric problems as covariates.

Results. At baseline, greater eveningness was associated with greater at-risk alcohol use, greater bingeing, and past-year use of marijuana. Later weekday and weekend bedtimes, but not weekday or weekend sleep duration, showed similar associations across the 3 substance outcomes at baseline. Greater baseline eveningness was also prospectively associated with greater bingeing and past-year use of marijuana at the 1-year follow-up, after covarying for baseline bingeing and marijuana use. Later baseline weekday and weekend bedtimes, and shorter baseline weekday sleep duration, were similarly associated with greater bingeing and past-year use of marijuana at the 1-year follow-up after covarying for baseline values.

Conclusions. Findings suggest that eveningness and sleep timing may be under recognized risk factors and future areas of intervention for adolescent involvement in alcohol and marijuana that should be considered along with other previously identified sleep factors such as insomnia and insufficient sleep. Read more

Sullivan EV, Lane B, Kwon D, Meloy MJ, Tapert SF, Brown SA, Colrain IM, Baker FC, De Bellis MD, Clark DB, Nagel BJ, Pohl KM, Pfefferbaum A. (2017). Structural brain anomalies in healthy adolescents in the NCANDA cohort: Relation to neuropsychological test performance, sex, and ethnicity. Brain Imaging and Behavior. 11:1302-1315 . PMCID:PMC5656437

Abstract: 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. Read more

Tervo-Clemmens B, Quach A, Luna B, Foran W, Chung T, DeBellis MD, Clark DB.(2017). Neural correlates of rewarded response inhibition in youth at risk for problematic alcohol use. Frontiers in Behavioral Neuroscience. 11:205. PMCID: PMC5675888

Abstract: Risk for substance use disorder (SUD) is associated with poor response inhibition and heightened reward sensitivity. During adolescence, incentives improve performance on response inhibition tasks and increase recruitment of cortical control areas (Geier et al., 2010) associated with SUD (Chung et al., 2011). However, it is unknown whether incentives moderate the relationship between response inhibition and trait-level psychopathology and personality features of substance use risk. We examined these associations in the current project using a rewarded antisaccade (AS) task (Geier et al., 2010) in youth at risk for substance use. Participants were 116 adolescents and young adults (ages 12-21) from the University of Pittsburgh site of the National Consortium on Adolescent Neurodevelopment and Alcohol [NCANDA] study, with neuroimaging data collected at baseline and 1 year follow up visits. Building upon previous work using this task in normative developmental samples (Geier et al., 2010) and adolescents with SUD (Chung et al., 2011), we examined both trial-wise BOLD responses and those associated with individual task-epochs (cue presentation, response preparation, and response) and associated them with multiple substance use risk factors (externalizing and internalizing psychopathology, family history of substance use, and trait impulsivity). Results showed that externalizing psychopathology and high levels of trait impulsivity (positive urgency, SUPPS-P) were associated with general decreases in antisaccade performance. Accompanying this main effect of poor performance, positive urgency was associated with reduced recruitment of the frontal eye fields (FEF) and inferior frontal gyrus (IFG) in both a priori regions of interest and at the voxelwise level. Consistent with previous work, monetary incentive improved antisaccade behavioral performance and was associated with increased activation in the striatum and cortical control areas. However, incentives did not moderate the association between response inhibition behavioral performance and any trait-level psychopathology and personality factor of substance use risk. Reward interactions were observed for BOLD responses at the task-epoch level, however, they were inconsistent across substance use risk types. The results from this study may suggest poor response inhibition and heightened reward sensitivity are not overlapping neurocognitive features of substance use risk. Alternatively, more subtle, common longitudinal processes might jointly explain reward sensitivity and response inhibition deficits in substance use risk. Read more

Pohl KM, Sullivan EV, Rohlfing T, Chu W, Kwon D, Nichols BN, Zhang Y, Brown SA, Tapert SF, Cummins K, Thompson WK, Brumback T, Colrain IM, Baker FC, Prouty D, De Bellis MD, Voyvodic JT, Clark DB, Schrida C, Nagel BJ, Pfefferbaum A. (2016). Harmonizing DTI measurements across scanners to examine the development of white matter microstructure in 803 adolescents of the NCANDA study. NeuroImage. 130:194-213. PMCID: PMC4808415

Abstract: Neurodevelopment continues through adolescence, with notable maturation of white matter tracts comprising regional fiber systems progressing at different rates. To identify factors that could contribute to regional differences in white matter microstructure development, large samples of youth spanning adolescence to young adulthood are essential to parse these factors. Recruitment of adequate samples generally relies on multi-site consortia but comes with the challenge of merging data acquired on different platforms. In the current study, diffusion tensor imaging (DTI) data were acquired on GE and Siemens systems through the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a multi-site study designed to track the trajectories of regional brain development during a time of high risk for initiating alcohol consumption. This cross-sectional analysis reports baseline Tract-Based Spatial Statistic (TBSS) of regional fractional anisotropy (FA), mean diffusivity(MD), axial diffusivity (L1), and radial diffusivity (LT) from the five consortium sites on 671 adolescents who met no/low alcohol or drug consumption criteria and 132 adolescents with a history of exceeding consumption criteria. Harmonization of DTI metrics across manufacturers entailed the use of human-phantom data, acquired multiple times on each of three non-NCANDA participants at each site's MR system, to determine a manufacturer-specific correction factor. Application of the correction factor derived from human phantom data measured on MR systems from different manufacturers reduced the standard deviation of the DTI metrics for FA by almost a half, enabling harmonization of data that would have otherwise carried systematic error. Permutation testing supported the hypothesis of higher FA and lower diffusivity measures in older adolescents and indicated that, overall, the FA, MD, and L1 of the boys were higher than those of the girls, suggesting continued microstructural development notable in the boys. The contribution of demographic and clinical differences to DTI metrics was assessed with General Additive Models (GAM) testing for age, sex, and ethnicity differences in regional skeleton mean values. The results supported the primary study hypothesis that FA skeleton mean values in the no/low-drinking group were highest at different ages. When differences in intracranial volume were covaried, FA skeleton mean reached a maximum at younger ages in girls than boys and varied in magnitude with ethnicity. Our results, however, did not support the hypothesis that youth who exceeded exposure criteria would have lower FA or higher diffusivity measures than the no/low-drinking group; detecting the effects of excessive alcohol consumption during adolescence on DTI metrics may require longitudinal study. Read more

de Zambotti M, Baker FC, Willoughby AR, Godino JG, Wing D, Patrick K, Colrain IM. (2016). Measures of sleep and cardiac functioning during sleep using a multi-sensory commercially-available wristband in adolescents. Physiology & Behavior. 158:143-9. PMCID: PMC5498752

Abstract: To validate measures of sleep and heart rate (HR) during sleep generated by a commercially-available activity tracker against those derived from polysomnography (PSG) in healthy adolescents. Sleep data were concurrently recorded using FitbitChargeHR™ and PSG, including electrocardiography (ECG), during an overnight laboratory sleep recording in 32 healthy adolescents (15 females; age, mean±SD: 17.3±2.5years). Sleep and HR measures were compared between FitbitChargeHR™ and PSG using paired t-tests and Bland-Altman plots. Epoch-by-epoch analysis showed that FitbitChargeHR™ had high overall accuracy (91%), high sensitivity (97%) in detecting sleep, and poor specificity (42%) in detecting wake on a min-to-min basis. On average, FitbitChargeHR™ significantly but negligibly overestimated total sleep time by 8min and sleep efficiency by 1.8%, and underestimated wake after sleep onset by 5.6min (p<0.05). Within FitbitChargeHR™ epochs of sleep, the average HR was 59.3±7.5bpm, which was significantly but negligibly lower than that calculated from ECG (60.2±7.6bpm, p<0.001), with no change in mean discrepancies throughout the night. FitbitChargeHR™ showed good agreement with PSG and ECG in measuring sleep and HR during sleep, supporting its use in assessing sleep and cardiac function in healthy adolescents. Further validation is needed to assess its reliability over prolonged periods of time in ecological settings and in clinical populations. Read more

de Zambotti M, Willoughby AR, Franzen PL, Clark DB, Baker FC, Colrain IM. (2016) K-complexes: Interaction between the central and autonomic nervous systems during sleep. Sleep. 39:1129-37. PMCID: PMC4835312

Study Objectives. To investigate the relationship between K-complexes (KCs) and cardiac functioning.

Methods. Forty healthy adolescents aged 16-22 y (19 females) participated in the study. Heart rate (HR) fluctuations associated with spontaneous and evoked KCs were investigated on two nights, one with (event-related potential night) and one without auditory tones presented across the night.

Results. There was a clear biphasic cardiac response to evoked and spontaneous KCs, with an initial acceleration in HR followed by a deceleration (P < 0.001). HR acceleration occurred immediately to KCs in response to tones presented in the first third of the interbeat interval, but was delayed a beat when the tone occurred later in the cardiac cycle (P < 0.05). Sex differences were also evident. Pretone baseline HR was higher, and the magnitude of the HR response was blunted and delayed, in female compared to male adolescents (P < 0.001). Also, pretone baseline HR was lower when a tone elicited a KC compared to when it did not (P < 0.001), suggesting that KCs are possibly more likely to be elicited by external stimuli in states of reduced cardiac activation.

Conclusions. The strict dependency observed between KCs and cardiac control indicates a potential role of KCs in modulating the cardiovascular system during sleep. Sex differences in the KC-cardiac response indicate the sensitivity of this measure in capturing sex differences in cardiac regulatory physiology. Read more

Sullivan EV, Brumback T, Tapert SF, Fama R, Prouty D, Brown SA, Cummins K, Thompson WK, Colrain IM, Baker FC, De Bellis MD, Hooper SR, Clark DB, Chung T, Nagel BJ, Nichols BN, Rohlfing T, Chu W, Pohl KM, Pfefferbaum A. (2016) Cognitive, emotion control, and motor performance of adolescents in the NCANDA study: Contributions from alcohol consumption, age, sex, ethnicity, and family history of addiction. Neuropsychology. 30:449-73. PMCID: PMC4840074

Objective. To investigate development of cognitive and motor functions in healthy adolescents and to explore whether hazardous drinking affects the normal developmental course of those functions.

Method. Participants were 831 adolescents recruited across 5 United States sites of the National Consortium on Alcohol and NeuroDevelopment in Adolescence 692 met criteria for no/low alcohol exposure, and 139 exceeded drinking thresholds. Cross-sectional, baseline data were collected with computerized and traditional neuropsychological tests assessing 8 functional domains expressed as composite scores. General additive modeling evaluated factors potentially modulating performance (age, sex, ethnicity, socioeconomic status, and pubertal developmental stage).

Results. Older no/low-drinking participants achieved better scores than younger ones on 5 accuracy composites (general ability, abstraction, attention, emotion, and balance). Speeded responses for attention, motor speed, and general ability were sensitive to age and pubertal development. The exceeds-threshold group (accounting for age, sex, and other demographic factors) performed significantly below the no/low-drinking group on balance accuracy and on general ability, attention, episodic memory, emotion, and motor speed scores and showed evidence for faster speed at the expense of accuracy. Delay Discounting performance was consistent with poor impulse control in the younger no/low drinkers and in exceeds-threshold drinkers regardless of age.

Conclusions. Higher achievement with older age and pubertal stage in general ability, abstraction, attention, emotion, and balance suggests continued functional development through adolescence, possibly supported by concurrently maturing frontal, limbic, and cerebellar brain systems. Determination of whether low scores by the exceeds-threshold group resulted from drinking or from other preexisting factors requires longitudinal study. Read more

Baker FC, Willoughby AR, de Zambotti M, Franzen PL, Prouty D, Javitz H, Hasler B, Clark DB, Colrain IM. (2016). Age-related differences in sleep architecture and electroencephalogram in adolescents in the NCANDA sample. Sleep. 39:1429-39. PMCID: PMC4909625

Study Objectives. To investigate age-related differences in polysomnographic and sleep electroencephalographic (EEG) measures, considering sex, pubertal stage, ethnicity, and scalp topography in a large group of adolescents in the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA).

Methods. Following an adaptation/clinical screening night, 141 healthy adolescents (12-21 y, 64 girls) had polysomnographic recordings, from which sleep staging and EEG measures were derived. The setting was the SRI International Human Sleep Laboratory and University of Pittsburgh Pediatric Sleep Laboratory. Results. Older age was associated with a lower percentage of N3 sleep, accompanied by higher percentages of N2, N1, and rapid eye movement (REM) sleep. Older boys compared with younger boys had more frequent awakenings and wakefulness after sleep onset, effects that were absent in girls. Delta (0.3-4 Hz) EEG power in nonrapid eye movement NREM sleep was lower in older than younger adolescents at all electrode sites, with steeper slopes of decline over the occipital scalp. EEG power in higher frequency bands was also lower in older adolescents than younger adolescents, with equal effects across electrodes. Percent delta power in the first NREM period was similar across age. African Americans had lower EEG power across frequency bands (delta to sigma) compared with Caucasians. Finally, replacing age with pubertal status in the models showed similar relationships.

Conclusions. Substantial differences in sleep architecture and EEG were evident across adolescence in this large group, with sex modifying some relationships. Establishment and follow-up of this cohort allows the investigation of sleep EEG-brain structural relationships and the effect of behaviors, such as alcohol and substance use, on sleep EEG maturation. Read more

Pfefferbaum A, Rohlfing T, Pohl KM, Lane B, Chu W, Kwon D, Brown SA, Tapert SF, Cummins K, Thompson WK, Brumback T, Meloy MJ, Jernigan TJ, Dale A, Colrain IM, Baker FC, Prouty D, De Bellis MD, Voyvodic JT, Clark DB, Luna B, Chung T, Nagel BJ, Sullivan EV. (2016). Adolescent development of cortical and white matter structure in the NCANDA sample: Role of sex, ethnicity, puberty, and alcohol drinking. Cerebral Cortex. 26:4101-21. PMCID: PMC5027999

Abstract: Brain structural development continues throughout adolescence, when experimentation with alcohol is often initiated. To parse contributions from biological and environmental factors on neurodevelopment, this study used baseline National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) magnetic resonance imaging (MRI) data, acquired in 674 adolescents meeting no/low alcohol or drug use criteria and 134 adolescents exceeding criteria. Spatial integrity of images across the 5 recruitment sites was assured by morphological scaling using Alzheimer's disease neuroimaging initiative phantom-derived volume scalar metrics. Clinical MRI readings identified structural anomalies in 11.4%. Cortical volume and thickness were smaller and white matter volumes were larger in older than in younger adolescents. Effects of sex (male > female) and ethnicity (majority > minority) were significant for volume and surface but minimal for cortical thickness. Adjusting volume and area for supratentorial volume attenuated or removed sex and ethnicity effects. That cortical thickness showed age-related decline and was unrelated to supratentorial volume is consistent with the radial unit hypothesis, suggesting a universal neural development characteristic robust to sex and ethnicity. Comparison of NCANDA with PING data revealed similar but flatter, age-related declines in cortical volumes and thickness. Smaller, thinner frontal, and temporal cortices in the exceeds-criteria than no/low-drinking group suggested untoward effects of excessive alcohol consumption on brain structural development. Read more

Nichols BN & Pohl KM. (2015). Neuroinformatics software applications supporting electronic data capture, management, and sharing for the neuroimaging community. Neuropsychology Review. 25:356-68. PMCID: PMC5400666

Abstract: Accelerating insight into the relation between brain and behavior entails conducting small and large-scale research endeavors that lead to reproducible results. Consensus is emerging between funding agencies, publishers, and the research community that data sharing is a fundamental requirement to ensure all such endeavors foster data reuse and fuel reproducible discoveries. Funding agency and publisher man-dates to share data are bolstered by a growing number of data sharing efforts that demonstrate how information technologies can enable meaningful data reuse. Neuroinformatics evaluates scientific needs and develops solutions to facilitate the use of data across the cognitive and neurosciences. For example, electronic data capture and management tools designed to facilitate human neurocognitive research can decrease the set-up time of studies, improve quality control, and streamline the process of harmonizing, curating, and sharing data across data repositories. In this article we outline the advantages and disadvantages of adopting software applications that support these features by reviewing the tools available and then presenting two contrasting neuroimaging study scenarios in the context of conducting a cross-sectional and a multisite longitudinal study. Read more

de Zambotti M, Baker FC, Colrain IM. (2015). Validation of sleep-tracking technology compared with polysomnography in adolescents. Sleep. 38:1461-8. PMCID: PMC4531414

Study Objectives. To evaluate the accuracy in measuring nighttime sleep of a fitness tracker (Jawbone UP) compared to polysomnography (PSG).

Design. Jawbone UP and PSG data were simultaneously collected from adolescents during an overnight laboratory recording. Agreements between Jawbone UP and PSG sleep outcomes were analyzed using paired t tests and Bland-Altman plots. Multiple regressions were used to investigate which PSG sleep measures predicted Jawbone UP "Sound sleep" and "Light sleep."

Setting. SRI International Human Sleep Laboratory.

Participants. Sixty-five healthy adolescents (28 females, mean age ± standard deviation [SD]: 15.8 ± 2.5 y).

Interventions. N/A.

Measurements and Results. Outcomes showed good agreements between Jawbone UP and PSG for total sleep time (mean differences ± SD: -10.0 ± 20.5 min), sleep efficiency (mean differences ± SD: -1.9 ± 4.2 %), and wake after sleep onset (WASO) (mean differences ± SD: 10.6 ± 14.7 min). Overall, Jawbone UP overestimated PSG total sleep time and sleep efficiency and underestimated WASO but differences were small and, on average, did not exceed clinically meaningful cutoffs of > 30 min for total sleep time and > 5% for sleep efficiency. Multiple regression models showed that Jawbone UP "Sound sleep" measure was predicted by PSG time in N2 (β = 0.25), time in rapid eye movement (β = 0.29), and arousal index (β = -0.34). Jawbone UP "Light sleep" measure was predicted by PSG time in N2 (β = 0.48), time in N3 (β = 0.49), arousal index (β = 0.38) and awakening index (β = 0.28). Jawbone UP showed a progression from slight overestimation to underestimation of total sleep time and sleep efficiency with advancing age. All relationships were similar in boys and girls.

Conclusions. Jawbone UP shows good agreement with polysomnography in measures of total sleep time and wake after sleep onset in adolescent boys and girls. Further validation is needed in other age groups and clinical populations before advocating use of these inexpensive and easy-to-use devices in clinical sleep medicine and research. Read more

Brown SA, Brumback T, Tomlinson K, Cummins K, Thompson WK, Nagel BJ, De Bellis MD, Hooper SR, Clark DB, Chung T, Hasler BP, Colrain IM, Baker FB, Prouty D, Pfefferbaum A, Sullivan EV, Pohl KM, Rohlfing T, Nichols BN, Chu W & Tapert SF. (2015). The National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA): A multi-site study of adolescent development and substance use. Journal of Studies on Alcohol and Drugs. 76:895-908. PMCID: PMC4712659

Objective. During adolescence, neurobiological maturation occurs concurrently with social and interpersonal changes, including the initiation of alcohol and other substance use. The National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) is designed to disentangle the complex relationships between onset, escalation, and desistance of alcohol use and changes in neurocognitive functioning and neuromaturation.

Method. A sample of 831 youth, ages 12–21 years, was recruited at five sites across the United States, oversampling those at risk for alcohol use problems. Most (83%) had limited or no history of alcohol or other drug use, and a smaller portion (17%) exceeded drinking thresholds. A comprehensive assessment of biological development, family background, psychiatric symptomatology ,and neuropsychological functioning—in addition to anatomical, diffusion, and functional brain magnetic resonance imaging—was completed at baseline.

Results. The NCANDA sample of youth is nationally representative of sex and racial/ethnic groups. More than 50% have at least one risk characteristic for subsequent heavy drinking (e.g., family history ,internalizing or externalizing symptoms). As expected, those who exceeded drinking thresholds (n= 139) differ from those who did not(n=692) on identified factors associated with early alcohol use and problems.

Conclusions. NCANDA successfully recruited a large sample of adolescents and comprehensively assessed psychosocial functioning across multiple domains. Based on the sample’s risk profile, NCANDA is well positioned to capture the transition into drinking and alcohol problems in a large portion of the cohort, as well as to help disentangle the associations between alcohol use, neurobiological maturation, and neurocognitive development and functioning. Read more

Rohlfing T, Cummins K, Henthorn T, Chu W, Nichols BN. (2014). N-CANDA data integration: Anatomy of an asynchronous infrastructure for multi-site, multi-instrument longitudinal data capture. Journal of American Medical Informatics Association. 21:758-62. PMCID: PMC4078281

Abstract: The infrastructure for data collection implemented by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (N-CANDA) for data collection comprises several innovative features: (a) secure, asynchronous transfer and persistent storage of collected data via a revision control system; (b) two-stage import into a longitudinal database; and (c) use of a script-controlled web browser for data retrieval from a third-party, web based neuropsychological test battery. The asynchronous operation of data transmission and import is of particular benefit, as it has allowed the consortium sites to begin data collection before the receiving database infrastructure had been deployed. Records were collected within 86 days of funding, 35 days after finalizing the collected instruments. Final instruments were added to the database import 225 days after instrument selection, with up to 173 records already collected at that time. Thus, the concepts implemented in NCANDA’s data collection system helped reduce project start-up time by several months. Read more

Lorkiewicz SA, Müller-Oehring EM, Baker FC, Elkins BV, Schulte T (2024). A longitudinal study of the relationship between alcohol-related blackouts and attenuated structural brain development. Developmental Cognitive Neuroscience 69:101448. doi: 10.1016/j.dcn.2024.101448

Purpose. Alcohol-related blackouts (ARBs) are common in adolescents and emerging adults. ARBs may also be indicative of persistent, alcohol-related neurocognitive changes. This study explored ARBs as a predictor of altered structural brain development and associated cognitive correlates.

Method. Longitudinal growth curve modeling estimated trajectories of brain volume across 6 years in participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study (n = 800, 213 with lifetime ARB history). While controlling for demographics and overall alcohol use, ARB history was analyzed as a predictor of brain volume growth in regions associated with alcohol-related cognitive change. Post hoc analyses examined whether ARBs moderated relationships between brain morphology and cognition.

Results. ARBs significantly predicted attenuated development of fusiform gyrus and hippocampal volume at unique timepoints compared to overall alcohol use. Alcohol use without ARBs significantly predicted attenuated fusiform and hippocampal growth at earlier and later timepoints, respectively. Despite altered development in regions associated with memory, ARBs did not significantly moderate relationships between brain volume and cognitive performance.

Conclusions. ARBs and overall alcohol use predicted altered brain development in the fusiform gyrus and hippocampus at different timepoints, suggesting ARBs represent a unique marker of neurocognitive risk in younger drinkers. Read more.

Norman LJ, Sudre G, Price J, Shaw P (2024). Subcortico-cortical dysconnectivity in ADHD: A voxel-wise mega-analysis across multiple cohorts. Am J Psychiatry 181:553-562. doi: 10.1176/appi.ajp.20230026

Objective. A large body of functional MRI research has examined a potential role for subcortico-cortical loops in the pathogenesis of attention deficit hyperactivity disorder (ADHD), but has produced inconsistent findings. The authors performed a mega-analysis of six neuroimaging data sets to examine associations between ADHD diagnosis and traits and subcortico-cortical connectivity.

Method. Group differences were examined in the functional connectivity of four subcortical seeds in 1,696 youths with ADHD diagnoses (66.39% males; mean age, 10.83 years [SD=2.17]) and 6,737 unaffected control subjects (47.05% males; mean age, 10.33 years [SD=1.30]). The authors examined associations between functional connectivity and ADHD traits (total N=9,890; 50.3% males; mean age, 10.77 years [SD=1.96]). Sensitivity analyses were used to examine specificity relative to commonly comorbid internalizing and non-ADHD externalizing problems. The authors further examined results within motion-matched subsamples, and after adjusting for estimated intelligence.

Results. In the group comparison, youths with ADHD showed greater connectivity between striatal seeds and temporal, fronto-insular, and supplementary motor regions, as well as between the amygdala and dorsal anterior cingulate cortex, compared with control subjects. Similar findings emerged when ADHD traits were considered and when alternative seed definitions were adopted. Dominant associations centered on the connectivity of the caudate bilaterally. Findings were not driven by in-scanner motion and were not shared with commonly comorbid internalizing and externalizing problems. Effect sizes were small (largest peak d, 0.15).

Conclusions. The findings from this large-scale megaanalysis support established links with subcortico-cortical circuits, which were robust to potential confounders. However, effect sizes were small, and it seems likely that resting-state subcortico-cortical connectivity can capture only a fraction of the complex pathophysiology of ADHD. Read more.

Kirse HA, Bahrami M, Lyday RG, Simpson SL, Peterson-Sockwell H, Burdette JH, Laurienti PJ (2023). Differences in Brain Network Topology Based on Alcohol Use History in Adolescents. Brain Sciences 13(12), 1676. doi: 10.3390/brainsci13121676

Abstract: Approximately 6 million youth aged 12 to 20 consume alcohol monthly in the United States. The effect of alcohol consumption in adolescence on behavior and cognition is heavily researched; however, little is known about how alcohol consumption in adolescence may alter brain function, leading to long-term developmental detriments. In order to investigate differences in brain connectivity associated with alcohol use in adolescents, brain networks were constructed using resting-state functional magnetic resonance imaging data collected by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) from 698 youth (12-21 years; 117 hazardous drinkers and 581 no/low drinkers). Analyses assessed differences in brain network topology based on alcohol consumption in eight predefined brain networks, as well as in whole-brain connectivity. Within the central executive network (CEN), basal ganglia network (BGN), and sensorimotor network (SMN), no/low drinkers demonstrated stronger and more frequent connections between highly globally efficient nodes, with fewer and weaker connections between highly clustered nodes. Inverse results were observed within the dorsal attention network (DAN), visual network (VN), and frontotemporal network (FTN), with no/low drinkers demonstrating weaker connections between nodes with high efficiency and increased frequency of clustered nodes compared to hazardous drinkers. Cross-sectional results from this study show clear organizational differences between adolescents with no/low or hazardous alcohol use, suggesting that aberrant connectivity in these brain networks is associated with risky drinking behaviors. Read more.

Norman LJ, Sudre G, Price J, Shastri GG, Shaw P (2023). Evidence from "big data" for the default-mode hypothesis of ADHD: A mega-analysis of multiple large samples. Neuropsychopharmacology 48(2): 281-289. doi: 10.1038/s41386-022-01408-z

Abstract: We sought to identify resting-state characteristics related to attention deficit/hyperactivity disorder, both as a categorical diagnosis and as a trait feature, using large-scale samples which were processed according to a standardized pipeline. In categorical analyses, we considered 1301 subjects with diagnosed ADHD, contrasted against 1301 unaffected controls (total N = 2602; 1710 males (65.72%); mean age = 10.86 years, sd = 2.05). Cases and controls were 1:1 nearest neighbor matched on in-scanner motion and key demographic variables and drawn from multiple large cohorts. Associations between ADHD-traits and resting-state connectivity were also assessed in a large multi-cohort sample (N = 10,113). ADHD diagnosis was associated with less anticorrelation between the default mode and salience/ventral attention (B = 0.009, t = 3.45, p-FDR = 0.004, d = 0.14, 95% CI = 0.004, 0.014), somatomotor (B = 0.008, t = 3.49, p-FDR = 0.004, d = 0.14, 95% CI = 0.004, 0.013), and dorsal attention networks (B = 0.01, t = 4.28, p-FDR < 0.001, d = 0.17, 95% CI = 0.006, 0.015). These results were robust to sensitivity analyses considering comorbid internalizing problems, externalizing problems and psychostimulant medication. Similar findings were observed when examining ADHD traits, with the largest effect size observed for connectivity between the default mode network and the dorsal attention network (B = 0.0006, t = 5.57, p-FDR < 0.001, partial-r = 0.06, 95% CI = 0.0004, 0.0008). We report significant ADHD-related differences in interactions between the default mode network and task-positive networks, in line with default mode interference models of ADHD. Effect sizes (Cohen's d and partial-r, estimated from the mega-analytic models) were small, indicating subtle group differences. The overlap between the affected brain networks in the clinical and general population samples supports the notion of brain phenotypes operating along an ADHD continuum. Read more.

Sudre G, Norman L, Bouyssi-Kobar M, Price J, Ganesh Shastri G, Shaw P (2022). A mega-analytic study of white matter microstructural differences across 5 cohorts of youths with attention-deficit/hyperactivity disorder. Biological Psychiatry S0006-3223(22)01629-8. doi: 10.1016/j.biopsych.2022.09.021

Background. While attention-deficit/hyperactivity disorder (ADHD) has been associated with differences in the structural connections formed by the brain’s white matter tracts, studies of such differences have yielded inconsistent findings, likely reflecting small sample sizes. Thus, we conducted a mega-analysis on in vivo measures of white matter microstructure obtained through diffusion tensor imaging of more than 6000 participants from 5 cohorts.

Methods. In a mega-analysis, linear mixed models were used to test for associations between the fractional anisotropy of 42 white matter tracts and ADHD traits and diagnosis. Contrasts were made against measures of mood, anxiety, and other externalizing problems.

Results. Overall, 6993 participants (ages 6–18 years, mean age 10.62 years [SD 1.99]; 3368 girls, 3625 boys; 764 African American, 4146 non-Hispanic White, and 2083 other race/ethnicities) had measures of ADHD and other emotional/behavioral symptoms (N = 6933) and/or enough clinical data to allow a diagnosis of ADHD (n = 951) or its absence (n = 4884). Both the diagnosis and symptoms of ADHD were associated with lower fractional anisotropy of the inferior longitudinal and left uncinate fasciculi (at a false discovery rate–adjusted p < .05). Associated effect sizes were small (the strongest association with ADHD traits had an effect size of partial r = −0.14, while the largest case-control difference was associated with an effect size of d = −0.3). Similar microstructural anomalies were not present for anxiety, mood, or externalizing problems. Findings held when ADHD cases and control subjects were matched on in-scanner motion.

Conclusions. While present across cohorts, ADHD-associated microstructural differences had small effects, underscoring the limited clinical utility of this imaging modality used in isolation. Read more.

Luo X, Yang JJ, Buu A, Trucco EM, Li C-SR (2022). Alcohol and cannabis co-use and longitudinal gray matter volumetric changes in early and late adolescence. Addiction Biology 27(5): e13208. doi:10.1111/adb.13208

Background. Previous studies have characterized the impact of substance use on cerebral structure and function in adolescents. Yet, the great majority of prior studies employed a small sample, presented cross-sectional findings, and omitted potential sex differences.

Methods. Using data based on 724 adolescents (370 females) curated from the NCANDA study, we investigated how gray matter volumes (GMVs) decline longitudinally as a result of alcohol and cannabis use. The impacts of alcohol and cannabis co-use and how these vary across assigned sex at birth and age were examined. Brain imaging data comprised the GMVs of 34 regions of interest and the results were evaluated with a Bonferroni correction.

Results. Mixed-effects modeling showed faster volumetric declines in the caudal middle frontal cortex, fusiform, inferior frontal, superior temporal (STG), and supramarginal (SMG) gyri, at -0.046 to -0.138 cm3/year in individuals with prior-year alcohol and cannabis co-use, but not those engaged in alcohol or cannabis use only. These findings cannot be explained by more severe alcohol use among co-users. Further, alcohol and cannabis co-use in early versus late adolescence predicted faster volumetric decline in the STG and SMG across assigned sex at birth.

Conclusions. Findings highlight the longitudinal impact of alcohol and cannabis co-use on brain development, especially among youth reporting early adolescent onset of use. The volumetric decline was noted in cortical regions in support of attention, memory, executive control, and social cognition, suggesting the pervasive effect of alcohol and cannabis co-use on brain development. Read more.