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

We lack the fundamental information needed to understand how DNA damage in the brain is generated and how it is controlled over a lifetime in the absence of replication check points. To address these questions, here, we integrate cell-type and region-specific features of DNA repair activity in the normal brain. The brain has the same repair proteins as other tissues, but normal, canonical repair activity is unequal and is characterized by high base excision repair (BER) and low double strand break repair (DSBR). The natural imbalance creates conditions where single strand breaks (SSBs) can convert to double strand breaks (DSBs) and reversibly switch between states in response to oxidation both in vivo and in vitro. Our data suggest that, in a normal background of repair, SSBs and DSBs are in an equilibrium which is pushed or pulled by metabolic state. Interconversion of SSB to DSBs provides a physiological check point, which would allow the formation of unrepaired DSBs for productive functions, but would also restrict them from exceeding tolerable limits.

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

OBJECTIVES: To describe the utilization of early ketamine use among patients mechanically ventilated for COVID-19, and examine associations with in-hospital mortality and other clinical outcomes. DESIGN: Retrospective cohort study. SETTING: Six hundred ten hospitals contributing data to the Premier Healthcare Database between April 2020 and June 2021. PATIENTS: Adults with COVID-19 and greater than or equal to 2 consecutive days of mechanical ventilation within 5 days of hospitalization. INTERVENTION: The exposures were early ketamine use initiated within 2 days of intubation and continued for greater than 1 day. MEASUREMENTS: Primary was hospital mortality. Secondary outcomes included length of stay (LOS) in the hospital and ICUs, ventilator days, vasopressor days, renal replacement therapy (RRT), and total hospital cost. The propensity score matching analysis was used to adjust for confounders. MAIN RESULTS: Among 42,954 patients, 1,423 (3.3%) were exposed to early ketamine use. After propensity score matching including 1,390 patients in each group, recipients of ketamine infusions were associated with higher hospital mortality (52.5% vs. 45.9%, risk ratio: 1.14, [1.06-1.23]), longer median ICU stay (13 vs. 12 d, mean ratio [MR]: 1.15 [1.08-1.23]), and longer ventilator days (12 vs. 11 d, MR: 1.19 [1.12-1.27]). There were no associations for hospital LOS (17 [10-27] vs. 17 [9-28], MR: 1.05 [0.99-1.12]), vasopressor days (4 vs. 4, MR: 1.04 [0.95-1.14]), and RRT (22.9% vs. 21.7%, RR: 1.05 [0.92-1.21]). Total hospital cost was higher (median $72,481 vs. $65,584, MR: 1.11 [1.05-1.19]). CONCLUSIONS: In a diverse sample of U.S. hospitals, about one in 30 patients mechanically ventilated with COVID-19 received ketamine infusions. Early ketamine may have an association with higher hospital mortality, increased total cost, ICU stay, and ventilator days, but no associations for hospital LOS, vasopressor days, and RRT. However, confounding by the severity of illness might occur due to higher extracorporeal membrane oxygenation and RRT use in the ketamine group. Further randomized trials are needed to better understand the role of ketamine infusions in the management of critically ill patients.

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

Study objectivesAdolescence is characterized by significant brain development, accompanied by changes in sleep timing and architecture. It also is a period of profound psychosocial changes, including the initiation of alcohol use; however, it is unknown how alcohol use affects sleep architecture in the context of adolescent development. We tracked developmental changes in polysomnographic (PSG) and electroencephalographic (EEG) sleep measures and their relationship with emergent alcohol use in adolescents considering confounding effects (e.g. cannabis use).MethodsAdolescents (n = 94, 43% female, age: 12-21 years) in the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study had annual laboratory PSG recordings across 4-years. Participants were no/low drinkers at baseline.ResultsLinear mixed effect models showed developmental changes in sleep macrostructure and EEG, including a decrease in slow wave sleep and slow wave (delta) EEG activity with advancing age. Emergent moderate/heavy alcohol use across three follow-up years was associated with a decline in percentage rapid eye movement (REM) sleep over time, a longer sleep onset latency (SOL) and shorter total sleep time (TST) in older adolescents, and lower non-REM delta and theta power in males.ConclusionsThese longitudinal data show substantial developmental changes in sleep architecture. Emergent alcohol use during this period was associated with altered sleep continuity, architecture, and EEG measures, with some effects dependent on age and sex. These effects, in part, could be attributed to the effects of alcohol on underlying brain maturation processes involved in sleep-wake regulation.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has significantly increased depression rates, particularly in emerging adults. The aim of this study was to examine longitudinal changes in depression risk before and during COVID-19 in a cohort of emerging adults in the U.S. and to determine whether prior drinking or sleep habits could predict the severity of depressive symptoms during the pandemic.MethodsParticipants were 525 emerging adults from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a five-site community sample including moderate-to-heavy drinkers. Poisson mixed-effect models evaluated changes in the Center for Epidemiological Studies Depression Scale (CES-D-10) from before to during COVID-19, also testing for sex and age interactions. Additional analyses examined whether alcohol use frequency or sleep duration measured in the last pre-COVID assessment predicted pandemic-related increase in depressive symptoms.ResultsThe prevalence of risk for clinical depression tripled due to a substantial and sustained increase in depressive symptoms during COVID-19 relative to pre-COVID years. Effects were strongest for younger women. Frequent alcohol use and short sleep duration during the closest pre-COVID visit predicted a greater increase in COVID-19 depressive symptoms.ConclusionsThe sharp increase in depression risk among emerging adults heralds a public health crisis with alarming implications for their social and emotional functioning as this generation matures. In addition to the heightened risk for younger women, the role of alcohol use and sleep behavior should be tracked through preventive care aiming to mitigate this looming mental health crisis.

BackgroundAccurate measurement of trajectories in longitudinal studies, considered the gold standard method for tracking functional growth during adolescence, decline in aging, and change after head injury, is subject to confounding by testing experience.MethodsWe measured change in cognitive and motor abilities over four test sessions (baseline and three annual assessments) in 154 male and 165 female participants (baseline age 12-21 years) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. At each of the four test sessions, these participants were given a test battery using computerized administration and traditional pencil and paper tests that yielded accuracy and speed measures for multiple component cognitive (Abstraction, Attention, Emotion, Episodic memory, Working memory, and General Ability) and motor (Ataxia and Speed) functions. The analysis aim was to dissociate neurodevelopment from testing experience by using an adaptation of the twice-minus-once tested method, which calculated the difference between longitudinal change (comprising developmental plus practice effects) and practice-free initial cross-sectional performance for each consecutive pairs of test sessions. Accordingly, the first set of analyses quantified the effects of learning (i.e., prior test experience) on accuracy and after speed domain scores. Then developmental effects were  determined for each domain for accuracy and speed having removed the measured learning effects.ResultsThe greatest gains in performance occurred between the first and second sessions, especially in younger participants, regardless of sex, but practice gains continued to accrue thereafter for several functions. For all 8 accuracy composite scores, the developmental effect after accounting for learning was significant across age and was adequately described by linear fits. The learning-adjusted developmental effects for speed were adequately described by linear fits for Abstraction, Emotion, Episodic Memory, General Ability, and Motor scores, although a nonlinear fit was better for Attention, Working Memory, and Average Speed scores.ConclusionThus, what appeared as accelerated cognitive and motor development was, in most cases, attributable to learning. Recognition of the substantial influence of prior testing experience is critical for accurate characterization of normal development and for developing norms for clinical neuropsychological investigations of conditions affecting the brain.

ObjectiveIndividual differences in adolescent personality are related to a variety of long-term health outcomes. While previous studies have demonstrated sex differences and non-linear changes in personality development, these results remain equivocal. The current study utilized longitudinal data (n = 831) from the National Consortium on Alcohol and Neurodevelopment in Adolescence to examine sex differences in the development of personality and the association between substance use and personality.MethodParticipants (ages 12-21 at baseline) completed the Ten-Item Personality Inventory and self-reported past year alcohol and marijuana use at up to 7 yearly visits. Data were analyzed using generalized additive mixed-effects models and linear mixed-effects models.ResultsFindings support linear increases in agreeableness and conscientious and decreases in openness with age and inform on timing of sex-specific non-linear development of extraversion and emotional stability. Further, results provide novel information regarding the timing of the association between substance use and personality, and replicate past reporting of differential associations between alcohol and marijuana use and extraversion, and sex-dependent effects of marijuana use on emotional stability.ConclusionsThese findings highlight the importance of modeling sex differences in personality development using flexible non-linear modeling strategies, and accounting for sex- and age-specific effects of alcohol and marijuana use.

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

ObjectiveExecutive control continues to develop throughout adolescence and is vulnerable to alcohol use. Although longitudinal assessment is ideal for tracking executive function development and onset of alcohol use, prior testing experience must be distinguished from developmental trajectories.MethodWe used the Stroop Match-to-Sample task to examine the improvement of processing speed and specific cognitive and motor control over 4 years in 445 adolescents. The twice-minus-once-tested method was used and expanded to four test sessions to delineate prior experience (i.e., learning) from development. A General Additive Model evaluated the predictive value of age and sex on executive function development and potential influences of alcohol use on development.ResultsResults revealed strong learning between the first two assessments. Adolescents significantly improved their speed processing over 4 years. Compared with boys, girls enhanced ability to control cognitive interference and motor reactions. Finally, the influence of alcohol use initiation was tested over 4 years for development in 110 no/low, 110 moderate/heavy age- and sex-matched drinkers; alcohol effects were not detected in the matched groups.ConclusionsEstimation of learning effects is crucial for examining developmental changes longitudinally. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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

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

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

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

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

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

Head motion represents one of the greatest technical obstacles in magnetic resonance imaging (MRI) of the human brain. Accurate detection of artifacts induced by head motion requires precise estimation of movement. However, head motion estimates may be corrupted by artifacts due to magnetic main field fluctuations generated by body motion. In the current report, we examine head motion estimation in multiband resting state functional connectivity MRI (rs-fcMRI) data from the Adolescent Brain and Cognitive Development (ABCD) Study and comparison 'single-shot' datasets. We show that respirations contaminate movement estimates in functional MRI and that respiration generates apparent head motion not associated with functional MRI quality reductions. We have developed a novel approach using a band-stop filter that accurately removes these respiratory effects from motion estimates. Subsequently, we demonstrate that utilizing a band-stop filter improves post-processing fMRI data quality. Lastly, we demonstrate the real-time implementation of motion estimate filtering in our FIRMM (Framewise Integrated Real-Time MRI Monitoring) software package.

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

The 21-site Adolescent Brain Cognitive Development (ABCD) study provides an unparalleled opportunity to characterize functional brain development via resting-state functional connectivity (RSFC) and to quantify relationships between RSFC and behavior. This multi-site data set includes potentially confounding sources of variance, such as differences between data collection sites and/or scanner manufacturers, in addition to those inherent to RSFC (e.g., head motion). The ABCD project provides a framework for characterizing and reproducing RSFC and RSFC-behavior associations, while quantifying the extent to which sources of variability bias RSFC estimates. We quantified RSFC and functional network architecture in 2,188 9-10-year old children from the ABCD study, segregated into demographically-matched discovery (N = 1,166) and replication datasets (N = 1,022). We found RSFC and network architecture to be highly reproducible across children. We did not observe strong effects of site; however, scanner manufacturer effects were large, reproducible, and followed a "short-to-long" association with distance between regions. Accounting for potential confounding variables, we replicated that RSFC between several higher-order networks was related to general cognition. In sum, we provide a framework for how to characterize RSFC-behavior relationships in a rigorous and reproducible manner using the ABCD dataset and other large multi-site projects.

The Adolescent Brain Cognitive Development (ABCD) study is poised to be the largest single-cohort long-term longitudinal study of neurodevelopment and child health in the United States. Baseline data on N= 4521 children aged 9-10 were released for public access on November 2, 2018. In this paper we performed principal component analyses of the neurocognitive assessments administered to the baseline sample. The neurocognitive battery included seven measures from the NIH Toolbox as well as five other tasks. We implemented a Bayesian Probabilistic Principal Components Analysis (BPPCA) model that incorporated nesting of subjects within families and within data collection sites. We extracted varimax-rotated component scores from a three-component model and associated these scores with parent-rated Child Behavior Checklist (CBCL) internalizing, externalizing, and stress reactivity. We found evidence for three broad components that encompass general cognitive ability, executive function, and learning/memory. These were significantly associated with CBCL scores in a differential manner but with small effect sizes. These findings set the stage for longitudinal analysis of neurocognitive and psychopathological data from the ABCD cohort as they age into the period of maximal adolescent risk-taking.

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 and 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 with 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. (PsycINFO Database Record

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

ObjectiveThe 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.MethodThis 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.ResultsIn 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.ConclusionsInitiation 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.

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.

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.

Effective strategies are needed to address the health behaviors of older patients with diabetes. One approach is health coaching, the practice of health education and health promotion through a structured partnership designed to enhance well-being and facilitate the achievement of individuals' health-related goals. The aim of this study was to describe the development of a pilot health coaching curriculum, investigate its effects on geriatric patient outcomes, and examine qualitative feedback by older patients and medical students to the curriculum. This mixed-methods study involved 29 first-year medical students randomly paired with 29 older adults with uncontrolled Type 2 diabetes. Health-related quality of life (HRQoL), stage of change movement, diabetes knowledge, locus of control, Body Mass Index (BMI), and glycosylated hemoglobin (HbA1c) were assessed. Focus groups were used to evaluate patients' and medical students' experiences. Results showed significant increases in patients' HRQoL and stage of change for exercise improved significantly over time. There were no significant changes in stage of change for healthy diet and medication, diabetes knowledge, BMI, and HbA1c from baseline to end of study. Focus group data indicated positive responses by older patients and the medical students. A health coaching curriculum may improve patient outcomes and can provide medical students the skills needed to provide compassionate care for geriatric patients.

BackgroundAbundant 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.MethodsParticipants 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.ResultsAt 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.ConclusionsFindings 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.

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 1year 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.

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.

ObjectiveTo investigate development of cognitive and motor functions in healthy adolescents and to explore whether hazardous drinking affects the normal developmental course of those functions.MethodParticipants 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).ResultsOlder 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.ConclusionsHigher 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. (PsycINFO Database Record

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.

BackgroundNetrins are a family of extracellular proteins that function as chemotropic guidance cues for migrating cells and axons during neural development. In the visual system, netrin-1 has been shown to play a key role in retinal ganglion cell (RGC) axon growth and branching at the target, where presynaptic RGC axons form partnerships with the dendrites of tectal neurons. However, the signals that guide the connections between RGC axons and their postsynaptic partners are yet unknown. Here, we explored dynamic cellular mechanisms by which netrin-1 influences visual circuit formation, particularly those that impact postsynaptic neuronal morphology and connectivity during retinotectal wiring.ResultsTime-lapse in vivo imaging of individual Xenopus laevis optic tectal neurons co-expressing tdTomato and PSD95-GFP revealed rapid remodeling and reorganization of dendritic arbors following acute manipulations in netrin-1 levels. Effects of altered netrin signaling on developing dendritic arbors of tectal neurons were distinct from its effects on presynaptic RGC axons. Within 4 h of treatment, tectal injection of recombinant netrin-1 or sequestration of endogenous netrin with an UNC-5 receptor ectodomain induced significant changes in the directionality and orientation of dendrite growth and in the maintenance of already established dendrites, demonstrating that relative levels of netrin are important for these functions. In contrast, altering DCC-mediated netrin signaling with function-blocking antibodies induced postsynaptic specialization remodeling and changed growth directionality of already established dendrites. Reducing netrin signaling also decreased avoidance behavior in a visually guided task, suggesting that netrin is essential for emergent visual system function.ConclusionsThese in vivo findings together with the patterns of expression of netrin and its receptors reveal an important role for netrin in the early growth and guidance of vertebrate central neuron dendritic arbors. Collectively, our studies indicate that netrin shapes both pre- and postsynaptic arbor morphology directly and in multiple ways at stages critical for functional visual system development.

ObjectiveDuring 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.MethodA 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.ResultsThe 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.ConclusionsNCANDA 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.

ObjectiveThis study investigates salivary gland biopsies in living patients with Parkinson disease (PD).MethodsPatients with PD for ≥5 years underwent outpatient transcutaneous needle core biopsies (18-gauge or 16-gauge) of 1 submandibular gland. Minor salivary glands were removed via a small incision in the lower lip. Tissue was fixed in formalin and serial 6-µm paraffin sections were immunohistochemically stained for phosphorylated α-synuclein and reviewed for evidence of Lewy type α-synucleinopathy (LTS).ResultsFifteen patients with PD were biopsied: 9 female/6 male, mean age 68.7 years, mean PD duration 11.8 years. Twelve of the needle core biopsies had microscopically evident submandibular gland tissue to assess and 9/12 (75%) had LTS. Only 1/15 (6.7%) minor salivary gland biopsies were positive for LTS. Five patients had an adverse event; all were minor and transient.ConclusionsThis study demonstrates the feasibility of performing needle core biopsies of the submandibular gland in living patients with PD to assess LTS. Although this was a small study, this tissue biopsy method may be important for tissue confirmation of PD in patients being considered for invasive procedures and in research studies of other PD biomarkers.

BACKGROUND: The extent to which channels within scar are interconnected is not known. The objective of the study was to evaluate the impact of local ablation of late potentials (LPs) on adjacent and remote areas of slow conduction with simultaneous multipolar mapping. METHODS AND RESULTS: Analysis was performed on consecutive patients referred for ablation of scar-mediated ventricular tachycardia with double ventricular access. Ablation was performed targeting the earliest of LPs visualized on the multipolar catheter, and the impact on later LPs was recorded. In 21 patients, a multipolar catheter placed within scar visualized spatially distinct LPs. Among 39 radiofrequency applications, ablation at earlier LPs had an effect on neighboring and remote LPs in 31 (80%), with delay in 8 (21%), partial elimination in 9 (23%), and complete elimination in 14 (36%). The mean distance where an ablation impact was detected was 17.6±14.7 mm (range, 2-50 mm). Among all patients, 9.7±7.8 radiofrequency applications were delivered to homogenize the targeted scar region with a mean number of 23±12 LPs targeted. CONCLUSIONS: Ablation can eliminate neighboring and remote areas of slow conduction, suggesting that channels within scar are frequently interconnected. This is the first mechanistic demonstration to show that ablation can modify electrical activity in regions of scar outside of the known radius of an radiofrequency lesion. The targeting of relatively earlier LPs can expedite scar homogenization without the need for extensive ablation of all LPs.

Studies have suggested that teens with alcohol use disorder (AUD) can demonstrate memory deficits, but the underlying neuroanatomical substrates are unclear. The hippocampus is crucial to intact memory functioning, and it actively develops during adolescence. The current study attempted to replicate and extend previous findings suggesting that adolescents with AUD show smaller hippocampal volumes than healthy adolescents. Manual tracings of bilateral hippocampi were performed on structural magnetic resonance images of 14 adolescents (ages 15 to 17 years) with AUD and 17 healthy comparison teens. Intracranial, white, and gray matter volumes, as well as memory abilities, were also measured. Results revealed that adolescents with AUD had significantly smaller left hippocampal volumes than healthy teens, even after removal of teens with comorbid conduct disorder from the analyses. In contrast, the groups did not differ in right hippocampal, intracranial, gray or white matter volumes, or memory performance. Hippocampal volumes were not related to alcohol-consumption rates. These findings indicate that adolescents with AUD, but free from other psychiatric comorbidities, have reduced left hippocampal volume. Because hippocampal volume did not relate to alcohol use characteristics, it is possible that premorbid volumetric differences could account for some of the observed group differences in hippocampal volume. (c) 2005 Elsevier Ireland Ltd. All rights reserved.