PUBLICATIONS RESULTING FROM NCANDA DATA

2021

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

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). Frequent continuous mobile assessment of health behaviors in a multi-year study: Acceptability, validity, and engagement with mNCANDA.J Med Internet Res 9(2): e24472. doi: 10.2196/24472. PMCID: 7904399

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. doi: 10.1111/adb.12914

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. doi: 10.1038/s41398-021-01275-0.

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.

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. DOI: 10.1007/s40429-020-00303-1

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.

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 (2020) Association of heavy drinking with deviant fiber tract development in frontal brain systems in young adolescents. JAMA Psychiatry 78(4): 407-415. doi: 10.1001/jamapsychiatry.2020.4064. 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.

2020

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

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 (2020). Stress, sleep, and autonomic function in healthy adolescent girls and boys: Findings from the NCANDA study. Sleep Health Jul 27:S2352-7218(20)30174-1. DOI: 10.1016/j.sleh.2020.06.004.

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.

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 METHODS: 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.

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. DOI: 10.1080/10826084.2020.1768549

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

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

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.

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2019

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.

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 (2019). 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.

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.

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.

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.

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 (2019). Effects of age, sex, and puberty on neural efficiency of cognitive and motor control in adolescents. Brain Imaging and Behavior Mar 23. PMCID: PMC6756998

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.

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

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.

2018

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, Springer-Verlag, Lecture Notes in Computer Science.

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

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

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

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.

2017

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

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

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

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, 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

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

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

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

2016

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

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

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

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

2015

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

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

2014

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

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 N-CANDA’s data collection system helped reduce project start-up time by several months. Read more

Li W, Wu B, Batrachenko A, Bancroft-Wu V, Morey RA, Shashi V, Langkammer C, De Bellis MD, Ropele S, Song AW, Liu C. (2014). Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan. Human Brain Mapping. 35:2698-713. PMCID: PMC3954958

As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing. Read more

PRESENTATIONS RESULTING FROM NCANDA DATA


Harmonization of Multimodal Neuroimaging to Examine Age, Sex, and Alcohol-Related Changes in Brain Structure Through Adolescence and Young Adulthood

RSA 2017
June 26, 2017
Denver, CO

Adolf Pfefferbaum
SRI International & Stanford University

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Harnessing the Power of Mobile Technology to Monitor Alcohol Use and Behaviors in Daily Life

RSA 2017
June 26, 2017
Denver, CO

Ty Brumback
UC San Diego

» View Full Presentation (PDF)

The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA): Clinical & Neuropsychological Assessment Battery

RSA 2017
June 26, 2017
Denver, CO

Susan F. Tapert
UC San Diego

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Curating, Releasing, and Access NCANDA Data

RSA 2017
June 26, 2017
Denver, CO

Killian M. Pohl
SRI International

» View Full Presentation (PDF)

Executive Functioning Deficits and Problem Drinking

APA 2017
May 24, 2017
San Diego, CA

Duncan B. Clark
University of Pittsburgh

» View Full Presentation (PDF)

Sleep in the NCANDA Cohort

APA 2017
May 24, 2017
San Diego, CA

Fiona C. Baker
SRI International & University of the Witwatersrand, South Africa

» View Full Presentation (PDF)

Functional Brain Networks Related to Sex, Age, and Alcohol Use in Adolescence: Resting-State and Task-Activated fMRI Findings from NCANDA

APA 2017
May 24, 2017
San Diego, CA

Eva M. Muller-Oehring
SRI International & Stanford University

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Use of Multimodal Neuroimaging Techniques to Examine Age, Sex, and Alcohol-Related Changes in Brain Structure Through Adolescence and Young Adulthood

APA 2017
May 24, 2017
San Diego, CA

Adolf Pfefferbaum & Edith V. Sullivan
SRI International & Stanford University

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NCANDA-2 Innovations in Research Design and Assessments

APA 2017
May 24, 2017
San Diego, CA

Susan Tapert & Ty Brumback
UC San Diego

» View Full Presentation (PDF)

National Consortium on Alcohol and Neurodevelopment in Adolescence

APA 2017
May 24, 2017
San Diego, CA

Sandra A. Brown
UC San Diego

» View Full Presentation (PDF)

National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA): Adolescent Brain Structure and Function Linked to Risk for Heavy Drinking

RSA 2016
June 26, 2016
New Orleans, LA

Bonnie Nagel
Oregon Health & Science University

» View Full Presentation (PDF)

Sleep Composition and Sleep EEG: Age, Sex, Ethnicity and Alcohol Effects in NCANDA

RSA 2016
June 26, 2016
New Orleans, LA

Ian M. Colrain
SRI International

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Executive functioning and risks for alcohol use disorder: Baseline results from NCANDA

RSA 2016
June 26, 2016
New Orleans, LA

Duncan B. Clark
University of Pittsburgh

» View Full Presentation (PDF)

Adolescent Brain Function in Relation to Trauma and PTSD

RSA 2016
June 26, 2016
New Orleans, LA

Michael DeBellis and Kate Nooner
Duke University

» View Full Presentation (PDF)

Functional Brain Networks Related to Sex, Age, and Alcohol in Adolescence: Initial Resting-State fMRI Findings from NCANDA

RSA 2016
June 26, 2016
New Orleans, LA

Eva M. Müller-Oehring
Stanford University

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NCANDA: Testing the Boundaries

RSA 2016
June 26, 2016
New Orleans, LA

Sara J. Nixon
University of Florida

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The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA): A Framework Supporting Neuroimaging Data Integration and Analysis

NEUROINFORMATICS 2015
August 20, 2015
Cairns, Australia

Nolan Nichols, WeiWei Chu, & Kilian Pohl
Stanford University & SRI International

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» View Full Presentation (PDF)

NCANDA: Characterization of the Sample

RSA 2015
June 22, 2015
San Antonio, Texas

Susan Tapert
UC San Diego

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Age & Sex Differences in Cognitive, Motor, & Sleep Indices: Initial Findings of the National Consortium on Alcohol & NeuroDevelopment in Adolescence

RSA 2015
June 22, 2015
San Antonio, Texas

Edith Sullivan & Fiona Baker
Stanford University & SRI International

» View Full Presentation (PDF)

Differences in Adolescent Cortext Related to Age and Sex: Initial Findings from the National Consortium on Alcohol & NeuroDevelopment in Adolescence

RSA 2015
June 22, 2015
San Antonio, Texas

Adolf Pfefferbaum
Stanford University & SRI International

» View Full Presentation (PDF)

Age-Related Differences in Adolescent Brain Microstructures: Initial Findings from teh National Consortium on Alcohol & NeuroDevelopment in Adolescence

RSA 2015
June 22, 2015
San Antonio, Texas

Kilian M. Pohl
Stanford University & SRI International

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NCANDA: Baseline Findings Discussion

RSA 2015
June 22, 2015
San Antonio, Texas

Sandra A. Brown
UC San Diego

» View Full Presentation (PDF)

Machine Learning for MRI Phenotype Detection

RSA 2014
June 2014
Seattle Washington

Kilian Pohl, Ph.D.
SRI

» View Full Presentation (PDF)

NCANDA Introduction Presentation

RSA 2013
June 24, 2013
Orlando Florida

Sandra Brown, Ph.D.
UC San Diego

» View Full Presentation (PDF)

Consortium on Alcohol and Neurodevelopment in Adolescence: The Foundational Research

RSA 2013
June 24, 2013
Orlando Florida

Antonio Noronha, Ph.D.
Division of Neuroscience & Behavior

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Insights into the developing brain using the sleep EEG

RSA 2013
June 24, 2013
Orlando Florida

Fiona C. Baker, Ph.D.
SRI International

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Adolescent Substance Use Disorders, Psychological Regulation, and the Frontoparietal Network

RSA 2013
June 24, 2013
Orlando Florida

Duncan Clark M.D. Ph.D.
University of Pittsburgh

» View Full Presentation (PDF)

Using Functional Connectivity to Identify Risk For and Consequences of Alcohol Use During Adolescence

RSA 2013
June 24, 2013
Orlando Florida

Bonnie J. Nagel, Ph.D.
Oregon Health & Science University

» View Full Presentation (PDF)

Early Abstinence-Related Improvements Following Adolescent Heavy Episodic Drinking

RSA 2013
June 24, 2013
Orlando Florida

Susan Tapert, Ph.D.
UC San Diego

» View Full Presentation (PDF)

IN THE MEDIA

November 2017

Impact of Adolescent Drinking on the Brain

Drinking during adolescence interrupts normal brain development and results in gray matter loss, new research shows.

» READ MORE


May 2015

Youth and Addiction: Can There Be Freedom of Will? -- Degrees of Freedom with Sandra A. Brown

This program and other videos are available online on UCSD-TV's web site at www.ucsd.tv



October 2014

At a congressional briefing co-sponsored by APA, experts say it's critical to prevent substance abuse early on. » READ MORE

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