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This report describes details of developing a volcano forcing reconstruction (Crowley et al., 2008) for climate models that is based primarily on sulphate records in Antarctic and Greenland ice cores. The chronology of eruptions is considered accurate to within 1 yr for the interval AD 1104–2000 and about 2 yr for AD 800–1103. The reconstruction involves (1) calibration against satellite aerosol optical depth (AOD) estimates of the 1991 Pinatubo/Hudson eruptions; (2) partial validation against independent lunar estimates of AOD and global sulphate emissions; (3) partial assessment of uncertainties in AOD estimates; (4) assessment of possible tropical "false positives" in ice core reconstructions due to simultaneous occurrence of mid/high-latitude eruptions in each hemisphere; (5) identification of a new category of eruptions, termed "unipolar" tropical eruptions, in which the eruption plume penetrates mainly to polar regions in only the hemisphere of its eruption; (6) use of different growth curves for high- and low-latitude eruptions; (7) specification of 2/3 power shortwave scaling for eruptions larger than the 1991 Pinatubo eruption; (8) introduction of an estimate of effective particle size that affects lifetime and scattering properties of stratospheric aerosols; and (9) utilization of bimonthly-resolution electrical conductivity measurements to estimate the eruption date of the 1258/1259 eruption as 1257.7±0.2. The data, and a high-temporal resolution reconstruction for climate models, are available at: http://hurricane.ncdc.noaa.gov/pls/paleox/f?p=519:1:::::P1_STUDY_ID:14168.

High resolution animations of the ice age surface have been developed as a tool for in-depth analysis of "paleometeorological" features. Synoptic-scale weather conditions of the Last Glacial Maximum (LGM) are simulated using the National Center for Atmospheric Research (NCAR) Community Climate Model version 3 (CCM3.6) on a globally resolved T170 (~75 km) grid domain. Model outputs have been saved at hourly intervals in order to better resolve diurnal features. The simulation has been run in tandem with a lower temporally resolved simulation of Kim et al. (2008) to enable a first-pass assessment of significance of features in the shorter run. Both simulations were forced with modified CLIMAP sea ice and sea surface temperatures (SSTs), reduced global CO2, ice sheet topography, lower sea level, and 21 000 BP orbital parameters. Results from the North Pacific show continued high storm activity during the LGM, whereas the North Atlantic tends to be more quiescent. Plots of storm tracks indicate that all North Pacific storms were steered northward into the Gulf of Alaska, bringing relatively warm air and precipitation into the region. This result is consistent with increased poleward heat transport into the region in the LGM climatological run as well as the absence of evidence for glaciation in middle Alaska. Storm-track trajectories should also have decreased upwelling along the northwest American coast – a response consistent with some geological data. The storms and other atmospheric features are illustrated in a high-resolution animation, which may also be useful as a teaching tool. Further investigation of these runs may provide additional insight into features such as wave-wave interactions, which have previously been unavailable to the research community for an alternate-Earth climate that has been at least as common as the present one over the last 500 000 years.

© 2015, Springer Science+Business Media New York. Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10−6). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD.

Marine and lacustrine sediment-based paleoclimate records are often not comparable within the early to middle portion of the last glacial cycle. This is due in part to significant revisions over the past 15 years to the Greenland ice core chronologies commonly used to assign ages outside of the range of radiocarbon dating. Therefore, creation of a compatible chronology is required prior to analysis of the spatial and temporal nature of climate variability at multiple locations. Here we present an automated mathematical function that updates GISP2-based chronologies to the newer, NGRIP GICC05 age scale between 8.24 and 103.74 ka b2k. The script uses, to the extent currently available, climate-independent volcanic synchronization of these two ice cores, supplemented by oxygen isotope alignment. The modular design of the script allows substitution for a more comprehensive volcanic matching, once it becomes available. Usage of this function highlights on the GICC05 chronology, for the first time for the entire last glaciation, the proposed global climate relationships during the series of large and rapid millennial stadial-interstadial events.

a b s t r a c t Background: Adolescents with conduct disorder (CD) and substance use disorders (SUD) experience dif- ficulty evaluating and regulating their behavior in anticipation of future consequences. Given the role of the brain's default mode network (DMN) in self-reflection and future thought, this study investigates whether DMN is altered in adolescents with CD and SUD, relative to controls. Methods: Twenty adolescent males with CD and SUD and 20 male controls of similar ages underwent functional magnetic resonance imaging as they completed a risk-taking decision task. We used indepen- dent component analysis as a data-driven approach to identify the DMN spatial component in individual subjects. DMN activity was then compared between groups. Results: Compared to controls, patients showed reduced activity in superior, medial and middle frontal gyrus (Brodmann area (BA) 10), retrosplenial cortex (BA 30) and lingual gyrus (BA 18), and bilateral middle temporal gryus (BA 21/22) - DMN regions thought to support self-referential evaluation, memory, foresight, and perspective taking. Furthermore, this pattern of reduced activity in patients remained robust after adjusting for the effects of depression and attention-deficit hyperactivity disorder (ADHD). Conversely, when not adjusting for effects of depression and ADHD, patients demonstrated greater DMN activity than controls solely in the cuneus (BA 19). Conclusions: Collectively, these results suggest that comorbid CD and SUD in adolescents is characterized by atypical activity in brain regions thought to play an important role in introspective processing. These functional imbalances in brain networks may provide further insight into the neural underpinnings of conduct and substance use disorders.

Background and Objectives The longitudinal risk for human immunodeficiency virus (HIV) infection following adolescent substance treatment is not known. Therefore, it is not known if adolescent substance treatment should include HIV prevention interventions. To address this important research gap, this study evaluates the longitudinal prevalence and predictors of injection drug use (IDU) and sex risk behaviors among adolescents in substance treatment. Methods Participants were 260 adolescents (13–18 years) in substance treatment and 201 community control adolescents (11–19 years). Participants were assessed at baseline and follow-up (mean time between assessments = 6.9 years for the clinical sample and 5.6 years for the community control sample). Outcomes included self-report lifetime history of IDU, number of lifetime sex partners and frequency of unprotected sexual intercourse. Results At baseline, 7.5% of the clinical sample, compared to 1.0% of the community control sample had a lifetime history of IDU (, p = .001). At follow-up, 17.4% of the clinical sample compared to 0% of the community control sample had a lifetime history of IDU (, p = .0005). The number of baseline substance use disorders and onset age of marijuana use significantly predicted the presence of lifetime IDU at follow-up, after adjusting for baseline age, race, and sex. The clinical sample reported more lifetime sex partners and more frequent unprotected sex than the community control sample at baseline and follow-up. Conclusions Many adolescents in substance treatment develop IDU and report persistent risky sex. Effective risk reduction interventions for adolescents in substance treatment are needed that address both IDU and risky sex. (Am J Addict 2013;22:558–565)

Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4β2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the β2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and β2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family-based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P-value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.

We sought to identify brain activation differences in conduct-problem youth with limited prosocial emotions (LPE) compared to conduct-problem youth without LPE and community adolescents, and to test associations between brain activation and severity of callous-unemotional traits. We utilized a novel task, which asks subjects to repeatedly decide whether to accept offers where they will benefit but a beneficent other will be harmed. Behavior on this task has been previously associated with levels of prosocial emotions and severity of callous-unemotional traits, and is related to empathic concern. During fMRI acquisition, 66 male adolescents (21 conduct-problem patients with LPE, 21 without, and 24 typically-developing controls) played this novel game. Within typically-developing controls, we identified a network engaged during decision involving bilateral insula, and inferior parietal and medial frontal cortices, among other regions. Group comparisons using non-parametric (distribution-free) permutation tests demonstrated LPE patients had lower activation estimates than typically-developing adolescents in right anterior insula. Additional significant group differences emerged with our a priori parametric cluster-wise inference threshold. These results suggest measurable functional brain activation differences in conduct-problem adolescents with LPE compared to typically-developing adolescents. Such differences may underscore differential treatment needs for conduct-problem males with and without LPE.

Some youths develop multiple substance use disorders early in adolescence and have severe, persistent courses. Such youths often exhibit impulsivity, risk-taking, and problems of inhibition. However, relatively little is known about the possible brain bases of these behavioral traits, especially among females. Methods We recruited right-handed female patients, 14–19 years of age, from a university-based treatment program for youths with substance use disorders and community controls similar for age, race and zip code of residence. We obtained 43 T1-weighted structural brain images (22 patients and 21 controls) to examine group differences in cortical thickness across the entire brain as well as six a priori regions-of-interest: 1) medial orbitofrontal cortex; 2) rostral anterior cingulate cortex; and 3) middle frontal cortex, in each hemisphere. Age and IQ were entered as nuisance factors for all analyses. Results A priori region-of-interest analyses yielded no significant differences. However, whole-brain group comparisons revealed that the left pregenual rostral anterior cingulate cortex extending into the left medial orbitofrontal region (355.84 mm2 in size), a subset of two of our a priori regions-of-interest, was significantly thinner in patients compared to controls (vertex-level threshold p = 0.005 and cluster-level family wise error corrected threshold p = 0.05). The whole-brain group differences did not survive after adjusting for depression or externalizing scores. Whole-brain within-patient analyses demonstrated a positive association between cortical thickness in the left precuneus and behavioral disinhibition scores (458.23 mm2 in size). Conclusions Adolescent females with substance use disorders have significant differences in brain cortical thickness in regions engaged by the default mode network and that have been associated with problems of emotional dysregulation, inhibition, and behavioral control in past studies.

Ice-rafting evidence for a “1500-year cycle” sparked considerable debate on millennial-scale climate change and the role of solar variability. Here, we reinterpret the last 70,000 years of the subpolar North Atlantic record, focusing on classic DSDP Site 609, in the context of newly available raw data, the latest radiocarbon calibration (Marine09) and ice core chronology (GICC05), and a wider range of statistical methodologies. A w1500-year oscillation is primarily limited to the short glacial Stage 4, the age of which is derived solely from an ice flow model (ss09sea), subject to uncertainty, and offset most from the original chronology. Results from the most well-dated, younger interval suggest that the original 1500 � 500 year cycle may actually be an admixture of the w1000 and w2000 cycles that are observed within the Holocene at multiple locations. In Holocene sections these variations are coherent with 14 C and 10 Be estimates of solar variability. Our new results suggest that the “1500-year cycle” may be a transient phenomenon whose origin could be due, for example, to ice sheet boundary conditions for the interval in which it is observed. We therefore question whether it is necessary to invoke such exotic explanations as heterodyne frequencies or combination tones to explain a phenomenon of such fleeting occurrence that is potentially an artifact of arithmetic averaging.

Methods The cross-drug relationship of subjective experiences between alcohol, tobacco, and marijuana and problem drug use behaviors were examined. Data were drawn from 3853 individuals between the ages of 11 and 30 years of age participating in the Colorado Center on Antisocial Drug Dependence [CADD]. Subjective experiences were assessed using a 13-item questionnaire that included positive and negative responses for alcohol, tobacco, and marijuana. Lifetime abuse and dependence on these three drugs was assessed using the Composite International Diagnostic Interview, Substance Abuse Module [CIDI-SAM]. Results Positive and negative subjective experience scales were similar for alcohol, tobacco, and marijuana, although the hierarchical ordering of items differed by drug. Subjective experience scales for each of the three drugs examined correlated significantly, with the strongest relationship being for alcohol and marijuana experiences. Significant associations were identified between how a person experienced a drug and abuse and dependence status for the same or different drug. Conclusion Cross-drug relationships provide evidence for a common liability or sensitivity towards responding in a similar manner to drugs of abuse within and across different pharmacological classes.

a b s t r a c t Boys with serious conduct and substance problems (Antisocial Substance Dependence (ASD)) repeat- edly make impulsive and risky decisions in spite of possible negative consequences. Because prefrontal cortex (PFC) is involved in planning behavior in accord with prior rewards and punishments, structural abnormalities in PFC could contribute to a person's propensity to make risky decisions. Methods: We acquired high-resolution structural images of 25 male ASD patients (ages 14-18 years) and 19 controls of similar ages using a 3 T MR system. We conducted whole-brain voxel-based morphome- tric analysis (p < 0.05, corrected for multiple comparisons at whole-brain cluster-level) using Statistical Parametric Mapping version-5 and tested group differences in regional gray matter (GM) volume with analyses of covariance, adjusting for total GM volume, age, and IQ; we further adjusted between-group analyses for ADHD and depression. As secondary analyses, we tested for negative associations between GM volume and impulsivity within groups and separately, GM volume and symptom severity within patients using whole-brain regression analyses. Results: ASD boys had significantly lower GM volume than controls in left dorsolateral PFC (DLPFC), right lingual gyrus and bilateral cerebellum, and significantly higher GM volume in right precuneus. Left DLPFC GM volume showed negative association with impulsivity within controls and negative association with substance dependence severity within patients. Conclusions: ASD boys show reduced GM volumes in several regions including DLPFC, a region highly rele- vant to impulsivity, disinhibition, and decision-making, and cerebellum, a region important for behavioral regulation, while they showed increased GM in precuneus, a region associated with self-referential and self-centered thinking. © 2011 Elsevier Ireland Ltd. All rights reserved.

Simulations of climate over the Last Millennium (850–1850 CE) have been incorporated into the third phase of the Paleoclimate Modelling Intercomparison Project (PMIP3). The drivers of climate over this period are chiefly orbital, solar, volcanic, changes in land use/land cover and some variation in greenhouse gas levels. While some of these effects can be easily defined, the reconstructions of solar, volcanic and land use-related forcing are more uncertain. We describe here the approach taken in defining the scenarios used in PMIP3, document the forcing reconstructions and discuss likely implications.

The impact of external influences on European temperatures before 1900 has been thought to be negligible. An analysis of reconstructions of seasonal European land temperatures and simulations from three global climate models instead suggests that external forcing is responsible for a best guess of 75% of the observed winter warming since the late seventeenth century. It is the regional and seasonal expression of climate change that determines the effect of greenhouse warming on ecosystemsand society1. Whereas anthropogenic influences on European temperatures have been detected over the twentieth century2,3, it has been suggested that the impact of external influences on European temperatures before 1900 is negligible4. Here we use reconstructions of seasonal European land temperature5,6 and simulations with three global climate models7,8,9 to show that external influences on climate—such as the concentrations of stratospheric volcanic aerosols or greenhouse gases, other anthropogenic effects and possibly changes in total solar irradiance—have had a discernible influence on European temperatures throughout the past five centuries. In particular, we find that external forcing contributes significantly (p

Marijuana is the most commonly used illicit drug among adolescents. Marijuana use induces both psychological and physiological responses, which can be interpreted by an individual in a variety of ways (i.e. subjective effects). We have examined subjective effects in adolescent, young adult community, and clinical populations to determine how patterns of use may be predicted by an individual's subjective experiences with the drug.Participants were community and clinical sample subjects drawn from the Colorado Center of Antisocial Drug Dependence (CADD) and a sample of adjudicated youth from the Denver metropolitan area (aged 11-30). They were evaluated with the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM) and the Lyons battery for subjective effects. Scales for subjective effects were created using Mokken scale analysis. Multivariate linear and logistic regression was used to examine associations between the subjective scales and marijuana outcomes.Mokken scaling revealed two subjective effects scales, positive and negative. Both scales were significantly positively associated with marijuana abuse or dependence in both the community and clinical sample and regular use in the community sample. The negative scale was negatively associated with past six-month use in the community sample (p0.05) and clinical sample, after controlling for age and gender effects.These findings suggest that diverse subjective experiences with marijuana can be ordered hierarchically and that the resulting short scales can be used in either clinical or community settings. Further, they suggest that the potential for marijuana use problems is related to the type of subjective experience from marijuana exposure.

Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.

Chronic exposure to drugs of addiction induces cellular adaptations in orbitofrontal cortex (OFC) and associated limbic-prefrontal pathways that might underlie abuse-related behavior. A propensity to make risky decisions in spite of substantial negative consequences might be mediated by medial OFC dysfunction in substance-dependent individuals (SDI). We tested the hypothesis that medial OFC gray matter (GM) volume would be lower in SDI compared with control subjects.Nineteen SDI and 20 control subjects participated. The SDI were dependent on two or more substances, most often cocaine, amphetamine, and alcohol, with mean duration of abstinence 4.7, 2.4, and 3.2 years, respectively. High-resolution T1-weighted images were acquired on a 3-T magnetic resonance system. Image processing and analyses were conducted with voxel-based morphometry (VBM) implemented in Statistical Parametric Mapping (SPM) 5. Differences in regional GM volume were tested with an analysis of covariance model, co-varying for global GM and age. Statistical maps were set at p.05, corrected for multiple comparisons. Medial OFC GM volume was correlated with behavioral performance on a modified gambling task.There was lower GM volume specifically in bilateral medial OFC in SDI compared with control subjects. There was a small but significant correlation between medial OFC GM and persistence of playing high-risk decks on a modified gambling task.This is the first study to use VBM with whole brain correction for multiple comparisons in SDI after prolonged abstinence. Reduced medial OFC GM might reflect long-term adaptations within the reward-learning circuit underlying pathological decision-making in substance dependence.

The past three million years have seen dramatic climate fluctuation, with conditions swinging between cold glacial and warm interglacial extremes. These changes are usually interpreted as nonlinear responses of the climate system to subtle cyclical changes in Earth's orbit or gradual reduction in the Earth's background CO2 level. Thomas Crowley and William Hyde offer an alternative view, proposing that these increasingly pronounced fluctuations, though driven by orbital variations, are indicative of transient behaviour of a system approaching a branching point. That is, a point at which the system will undergo a transition to a new stable climate state of permanent midlatitude Northern Hemisphere glaciation. Modelling results predict that such a transition could occur in the geologically near future (10,000–100,000 years), but only in the unlikely event that background atmospheric CO2 falls to levels lower than at during the past 10,000 years. Climate in the early Pleistocene1 varied with a period of 41 kyr and was related to variations in Earth's obliquity. About 900 kyr ago, variability increased and oscillated primarily at a period of ∼100 kyr, suggesting that the link was then with the eccentricity of Earth's orbit. This transition has often2,3,4,5 been attributed to a nonlinear response to small changes in external boundary conditions. Here we propose that increasing variablility within the past million years may indicate that the climate system was approaching a second climate bifurcation point, after which it would transition again to a new stable state characterized by permanent mid-latitude Northern Hemisphere glaciation. From this perspective the past million years can be viewed as a transient interval in the evolution of Earth's climate. We support our hypothesis using a coupled energy-balance/ice-sheet model, which furthermore predicts that the future transition would involve a large expansion of the Eurasian ice sheet. The process responsible for the abrupt change seems to be the albedo discontinuity at the snow–ice edge. The best-fit model run, which explains almost 60% of the variance in global ice volume6 during the past 400 kyr, predicts a rapid transition in the geologically near future to the proposed glacial state. Should it be attained, this state would be more ‘symmetric’ than the present climate, with comparable areas of ice/sea-ice cover in each hemisphere, and would represent the culmination of 50 million years of evolution from bipolar nonglacial climates to bipolar glacial climates.

Substance use and antisocial behavior are complex, interrelated behaviors. The current study identified model trajectory classes defined by concurrent substance use and antisocial behavior and examined trajectory associations with emerging adult outcomes. Participants from a high-risk sample of youth (n=536; 73% male) completed interviews at baseline (mean age= 16.1 years) and followup (mean age= 22.6 years). Latent class growth analyses identified five trajectory classes based on alcohol/drug use (AOD) and antisocial behavior (ASB): Dual Chronic, Increasing AOD/Persistent ASB, Persistent AOD/Adolescent ASB, Decreasing Drugs/Persistent ASB, and Resolved. Many individuals (56%) exhibited elevated/increasing AOD, and most (91%) reported ASB decreases. Those associated with the Dual Chronic class had the highest rates of substance dependence, antisocial personality disorder (ASPD), and negative psychosocial outcomes. There were no differences in adult role attainment across classes. Conjoint examination of these behaviors provides greater detail regarding clinical course and can inform secondary prevention and intervention efforts.

BACKGROUND: Some conduct-disordered youths have high levels of callous unemotional traits and meet the DSM-5's "with limited prosocial emotions" (LPE) specifier. These youths often do aggressive, self-benefitting acts that cost others. We previously developed a task, the AlAn's game, which asks participants to repeatedly decide whether to accept or reject offers in which they will receive money but a planned charity donation will be reduced. In our prior work, more "costly helping" (i.e., rejecting the offered money and protecting the donation) was associated with lower callous unemotional traits. Here we extend that prior work in a larger sample of adolescent male patients with serious conduct problems and controls, and test whether this association is mediated specifically by a Moral Elevation response (i.e., a positive emotional response to another's act of virtue). METHODS: The adolescent male participants were: 45 patients (23 with LPE) and 26 controls, who underwent an extensive phenotypic assessment including a measure of Moral Elevation. About 1 week later participants played the AlAn's game. RESULTS: All AlAn's game outcomes demonstrated significant group effects: (1) money taken for self (p = 0.02); (2) money left in the charitable donation (p = 0.03); and, (3) costly helping (p = 0.047). Controls took the least money and did the most costly helping, while patients with LPE took the most money and did the least costly helping. Groups also significantly differed in post-stimulus Moral Elevation scores (p = 0.005). Exploratory analyses supported that the relationship between callous unemotional traits and costly helping on the AlAn's game may be mediated in part by differences in Moral Elevation. CONCLUSIONS: The AlAn's game provides a standardized behavioral measure associated with callous unemotional traits. Adolescents with high levels of callous unemotional traits engage in fewer costly helping behaviors, and those differences may be related to blunting of positive emotional responses. Language: en

Neuronal nicotinic acetylcholine receptors have been implicated in various measures of nicotine dependence. In this paper, we present findings from an exploratory study of single nucleotide polymorphisms (SNPs) in the CHRNB3 and CHRNA6 genes with tobacco and alcohol phenotypes, including frequency of use and three subjective response factors occurring shortly after initiation of use. Subjects were 1056 ethnically diverse adolescents ascertained from clinical and community settings. The most significant associations were found between two CHRNB3 SNPs (rs4950 and rs13280604) and the three subjective response factors to initial tobacco use. These findings were replicated in a separate community sample of 1524 families participating in the National Longitudinal Study of Adolescent Health. Both CHRNB3 SNPs were found to be associated with similar measures of subjective response to tobacco. These results indicate that early subjective response to nicotine may be a valuable endophenotype for genetic studies aimed at uncovering genes contributing to nicotine use and addiction.

The climate of the last glacial maximum (LGM) is simulated with a high-resolution atmospheric general circulation model, the NCAR CCM3 at spectral truncation of T170, corresponding to a grid cell size of roughly 75 km. The purpose of the study is to assess whether there are significant benefits from the higher resolution simulation compared to the lower resolution simulation associated with the role of topography. The LGM simulations were forced with modified CLIMAP sea ice distribution and sea surface temperatures (SST) reduced by 1°C, ice sheet topography, reduced CO2, and 21,000 BP orbital parameters. The high-resolution model captures modern climate reasonably well, in particular the distribution of heavy precipitation in the tropical Pacific. For the ice age case, surface temperature simulated by the high-resolution model agrees better with those of proxy estimates than does the low-resolution model. Despite the fact that tropical SSTs were only 2.1°C less than the control run, there are many lowland tropical land areas 4–6°C colder than present. Comparison of T170 model results with the best constrained proxy temperature estimates (noble gas concentrations in groundwater) now yield no significant differences between model and observations. There are also significant upland temperature changes in the best resolved tropical mountain belt (the Andes). We provisionally attribute this result in part as resulting from decreased lateral mixing between ocean and land in a model with more model grid cells. A longstanding model-data discrepancy therefore appears to be resolved without invoking any unusual model physics. The response of the Asian summer monsoon can also be more clearly linked to local geography in the high-resolution model than in the low-resolution model; this distinction should enable more confident validation of climate proxy data with the high-resolution model. Elsewhere, an inferred salinity increase in the subtropical North Atlantic may have significant implications for ocean circulation changes during the LGM. A large part of the Amazon and Congo Basins are simulated to be substantially drier in the ice age—consistent with many (but not all) paleo data. These results suggest that there are considerable benefits derived from high-resolution model regarding regional climate responses, and that observationalists can now compare their results with models that resolve geography at a resolution comparable to that which the proxy data represent.

Conduct disorder (CD) is a disorder of childhood and adolescence defined by rule-breaking, aggressive, and destructive behaviors. For some individuals, CD signals the beginning of a lifelong persistent pattern of antisocial behavior (antisocial personality disorder [ASPD]), whereas for other people, these behaviors either desist or persist at a subclinical level. It has generally been accepted that about 40% of individuals with CD persist. This study examined the rate of persistence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) CD into ASPD and the utility of individual DSM-IV CD symptom criteria for predicting this progression. We used the nationally representative sample from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Approximately 75% of those with CD also met criteria for ASPD. Individual CD criteria differentially predicted severity and persistence of antisocial behavior with victim-oriented, aggressive behaviors generally being more predictive of persistence. Contrary to previous estimates, progression from CD to ASPD was the norm and not the exception in this sample. Relationships between individual DSM-IV CD symptom criteria and persistent antisocial outcomes are discussed. These findings may be relevant to the development of DSM-V.

The five factor model of personality is a useful metric to describe personality profiles associated with maladaptive functioning. Using the NEO-Five Factor Inventory (NEO-FFI), we examined a conceptually based profile of high neuroticism, low agreeableness and low conscientiousness among 243 youth (aged 13-18 years) with varying degrees of conduct disorder (CD) and substance use disorders (SUD). Comparisons of the NEO-FFI personality dimensions between CD/SUD youth and adolescent siblings (N=173), and relations between the personality dimensions and behavioral indicators of conduct disorder and substance involvement were examined. Youth with CD and SUD had greater neuroticism, lower agreeableness, and lower conscientiousness than siblings of a similar age. The NEO-FFI scales predicted aggression and substance involvement for both probands and siblings in this cross-sectional investigation. These findings support the role for personality in models of the etiology and persistence of conduct disorder and substance use disorders.

This study explores the association between a highly heritable behavioral disinhibition phenotype and the protein kinase C gamma (PRKCG) gene in an ethnically diverse youth sample from Colorado, USA. The rationale for this study was based on the impulsive behavior and increased ethanol consumption observed in the protein kinase C gamma (PKC-gamma)-deficient mouse model. Two composite behavioral disinhibition phenotypes and their component behavioral scores [conduct disorder, attention-deficit hyperactivity disorder (ADHD), substance experimentation (SUB) and novelty-seeking] were examined for association with five independent PRKCG single nucleotide polymorphisms (SNPs). Association analysis for the five individual SNPs revealed modest genetic association of Exon 14 (rs2242244) and Upstream (rs307941) markers with the behavioral disinhibition composite variables in the combined, Hispanic and African-American samples. Additionally, haplotype-based association analysis for two SNPs located in Intron 3 (rs402691) and Exon 6 (rs3745406) indicated a significant overall association of the PRKCG locus with the ADHD-hyperactive subscale scores in the combined and Caucasian samples, supporting the relation between impulsive behaviors and the PRKCG gene. A significant haplotype association was also observed with SUB scores but only in the Hispanic ethnic group, highlighting the marker variability for each ethnic group. In conclusion, our results support the role of the PKC-gamma enzyme in behavioral impulsivity previously observed in mice. This study provides the first exploration of the PRKCG gene and its association with behavioral disinhibition and warrants further study in other larger population samples.

Neural mechanisms underlying the reinforcing effects of nicotine and other drugs have been widely studied and are known to involve the ventral striatum, which is part of the mesocorticolimbic dopamine system. In contrast, mechanisms of nicotine withdrawal have received less attention although subjective withdrawal likely contributes to the difficulty of quitting. The goal of this study was to determine if nicotine withdrawal was associated with alterations of cerebral blood flow (CBF) in ventral striatum. Twelve smokers, moderately dependent on nicotine, underwent MR dynamic susceptibility contrast (DSC) imaging at baseline, after overnight withdrawal from nicotine, and after nicotine replacement. DSC images were used to calculate CBF in three regions of interest: ventral striatum, thalamus, and medial frontal cortex. Subjective withdrawal symptoms were measured at each time point. In spite of significant subjective withdrawal symptoms, there was no main effect of withdrawal on CBF in the three regions. However, there was a significant correlation between the increase in withdrawal symptoms and a reduction in thalamic CBF. In contrast to withdrawal, nicotine replacement significantly increased CBF in ventral striatum. Our findings are consistent with the known role of ventral striatum in drug reward. The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state.

Climate records over the last millennium place the twentieth-century warming in a longer historical context. Reconstructions of millennial temperatures show a wide range of variability, raising questions about the reliability of currently available reconstruction techniques and the uniqueness of late-twentieth-century warming. A calibration method is suggested that avoids the loss of low-frequency variance. A new reconstruction using this method shows substantial variability over the last 1500 yr. This record is consistent with independent temperature change estimates from borehole geothermal records, compared over the same spatial and temporal domain. The record is also broadly consistent with other recent reconstructions that attempt to fully recover low-frequency climate variability in their central estimate. High variability in reconstructions does not hamper the detection of greenhouse gas–induced climate change, since a substantial fraction of the variance in these reconstructions from the beginning of the analysis in the late thirteenth century to the end of the records can be attributed to external forcing. Results from a detection and attribution analysis show that greenhouse warming is detectable in all analyzed high-variance reconstructions (with the possible exception of one ending in 1925), and that about a third of the warming in the first half of the twentieth century can be attributed to anthropogenic greenhouse gas emissions. The estimated magnitude of the anthropogenic signal is consistent with most of the warming in the second half of the twentieth century being anthropogenic.

Objective Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed-sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. Hypotheses: Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum). Methods We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p

A climate simulation of an ocean/atmosphere general circulation model driven with natural forcings alone (constant “pre-industrial” land-cover and well-mixed greenhouse gases, changing orbital, solar and volcanic forcing) has been carried out from 1492 to 2000. Another simulation driven with natural and anthropogenic forcings (changes in greenhouse gases, ozone, the direct and first indirect effect of anthropogenic sulphate aerosol and land-cover) from 1750 to 2000 has also been carried out. These simulations suggest that since 1550, in the absence of anthropogenic forcings, climate would have warmed by about 0.1 K. Simulated response is not in equilibrium with the external forcings suggesting that both climate sensitivity and the rate at which the ocean takes up heat determine the magnitude of the response to forcings since 1550. In the simulation with natural forcings climate sensitivity is similar to other simulations of HadCM3 driven with CO2 alone. Climate sensitivity increases when anthropogenic forcings are included. The natural forcing used in our experiment increases decadal–centennial time-scale and large spatial scale climate variability, relative to internal variability, as diagnosed from a control simulation. Mean conditions in the natural simulation are cooler than in our control simulation reflecting the reduction in forcing. However, over certain regions there is significant warming, relative to control, due to an increase in forest cover. Comparing the simulation driven by anthropogenic and natural forcings with the natural-only simulation suggests that anthropogenic forcings have had a significant impact on, particularly tropical, climate since the early nineteenth century. Thus the entire instrumental temperature record may be “contaminated” by anthropogenic influences. Both the hydrological cycle and cryosphere are also affected by anthropogenic forcings. Changes in tree-cover appear to be responsible for some of the local and hydrological changes as well as an increase in northern hemisphere spring snow cover.

Aims Since the publication of the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), many studies have addressed substance use disorders (SUD) in adolescents. Based on that adolescent literature, this paper suggests further research to help guide decisions about revising for DSM-V the SUD criteria in DSM-IV. Method The author has reviewed the ‘Substance Related Disorders’ section of DSM-IV-TR, recalled his experience in helping to draft that section, accessed relevant articles in PubMed and reviewed his own extensive file of literature citations. Results This paper suggests six questions for adolescent research to help guide the framers of DSM-V’s ‘Substance Related Disorders’ section: (a) DSM-IV did not provide a diagnosis of cannabis withdrawal; should DSM-V continue that position? (b) Should SUD be included or referenced among ‘Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence’? (c) Can inter-rater reliability of the substance abuse (SA) criteria be improved with altered example situations, text descriptions or phrasing of the current criteria? (d) Between ages 14 and 18 years is earlier onset of SUD a severity marker that could be incorporated into DSM-V as a predictor of worse course? (e) In DSM-V could a phenotypic descriptor of pathological multi-substance involvement document severity and predict course of SUD? (f) Could clinicians and patients benefit from DSM-V-related postpublication procedures for classifying emerging new drugs into DSM-V’s categories? Conclusion Without substantive changes in SA or substance dependence diagnostic criteria, research may improve the usefulness of those criteria for adolescents.

This study examines the familial transmission of alcohol abuse and dependence to adolescents.Male adolescents recruited from a treatment program for substance problems, matched controls, and all available biological parents and siblings were assessed with a structured psychiatric interview assessing Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, based diagnoses of alcohol abuse and alcohol dependence. A total of 2,612 individuals from 911 families were interviewed. Structural equation modeling estimated tetrachoric correlations among family members, the proportion of variance in abuse and dependence attributable to parent-offspring transmission, and the effects of assortative mating and horizontal transmission among siblings.Tetrachoric correlations among siblings and parent-offspring ranged from .19 to .34 for abuse and dependence. Mother-father correlations were .14 and .37 for abuse and dependence, respectively. Modeling of familial transmission showed that 33% of the variance in abuse and 56% of the variance in dependence was accounted for by factors transmitted from parents. The effects of assortative mating could not be dropped from the abuse model without significant loss of model fit but could be dropped from the dependence model. Horizontal transmission among siblings could be dropped from both models without significant loss of fit.These results suggest that aggregation of alcohol abuse and alcohol dependence in families of male probands is significantly influenced by parental transmission of risk but is not reliably influenced by horizontal sibling effects such as sibling interactions or cohort effects. Spousal resemblance was found to be an important source of familial aggregation for alcohol abuse but not alcohol dependence.

Objective: Childhood maltreatment is a potent risk factor for subsequent aggressive and criminal behavior. A recent study suggested that the relationship between maltreatment and antisocial behavior may be moderated by a genetic vulnerability conferred by a functional polymorphism in the MAO-A gene. The authors investigated whether these findings would generalize to a clinical cohort of adolescents, examining whether there was a stronger association between maltreatment and conduct disorder severity in patients carrying the low MAO-A activity allele. Method: Male adolescent patients (N= 247) entering residential or intensive day treatment for persistent conduct and substance use problems were examined. Conduct disorder severity was indexed by a lifetime count of DSM–IV criteria obtained through structured psychiatric interviews. Maltreatment scores were derived from summing neglect and abuse events reported to have occurred before age 11. Results: Neglect, verbal/psychological abuse, physical abuse, and sexual abuse were prevalent among patients. Although level of maltreatment and lifetime conduct disorder symptoms were significantly correlated, no genetic-environmental interaction with genotype for maltreatment was found. Conclusion: The results of the current study do not support the hypothesis that a polymorphism in the gene encoding MAO-A contributes to the genetic risk for conduct disorder.

Adolescents with substance use and conduct disorders have high rates of aggression and attention deficit hyperactivity disorder (ADHD), all of which have been characterized in part by impulsivity. Developing measures that capture impulsivity behaviorally and correlate with self-reported impulsivity has been difficult. One promising behavioral measure, however, is a variant of the continuous performance test, the Immediate Memory Test/Delayed Memory Test (IMT/DMT). The authors showed significant group differences between adolescents in treatment for serious substance and conduct problems and community controls on impulsivity measures, both behavioral and self-report, as well as on aggression and problem behavior measures. Furthermore, the IMT/DMT correlated significantly with selfreported impulsivity. In summary, the IMT/DMT may be an effective behavioral measure of impulsivity in adolescents.

OBJECTIVE:: Adolescent patients' conduct disorder and substance use disorder symptoms are "risky behaviors" with unpredictable rewards and punishments. The authors asked whether such youths also take excessive risks in new situations without prior learning, peer pressure, or intoxication. METHOD:: Subjects were 20 adolescent patients in a program treating conduct disorder and substance use disorder and 20 controls. All were substance free >/=7 days; underwent substance-related, psychological, and social assessments; and performed the Balloon Analogue Risk Task: mouse presses inflated a computerized "balloon" image, each press earning 1 cent. The 30 balloons "popped" at unpredictable sizes; earnings from popped balloons were lost. A "Collect" response saved current earnings and advanced to the next balloon. RESULTS:: Mean number of inflating presses: patients, 1021 and controls, 705 (p = .001); group differences were stable from the task's beginning. Mean inflating presses before a "collect" response: patients, 38.6 and controls, 24.0 (p = .0005). Mean balloons popped: patients, 9.8 and controls, 6.3 (p = .001). Patients (versus controls) reported more aggressiveness and substance use and perceived less risk from substances. Patients' responses were significantly slower than those of controls. CONCLUSIONS:: From the beginning of this novel task, conduct disorder and substance use disorder patients (compared with controls) took more risks, indicating an initial risk-taking propensity, although patients' slower responses argued against "impulsive, thoughtless" behavior.

Several lines of research have suggested that serotonin dysfunction is associated with aggression, impulsivity, and antisocial behavior. A functional polymorphism in the promoter region (s, short and l, long allele variant) of the serotonin transporter gene (SLC6A4) that results in decreased transcription of the serotonin transporter gene has been linked with such serotonin dysfunction. To test for an association between 5HTTLPR genotype and conduct disorder diagnosis/aggression. Analysis for association between 5HTTLPR and conduct disorder/aggression using a case-control design and the transmission disequilibrium test. Conduct-disordered adolescents, who were drawn from admissions to a program that treats adolescents with serious substance and behavior problems, and conduct-disordered siblings of these patients (n, 297) were compared with non-conduct-disordered control adolescents and non-conduct-disordered siblings of these controls (n, 93). Second, using patient families where parental DNA was available, transmission disequilibrium tests were conducted for two phenotypes: (1) conduct disorder (74 trios), and (2) conduct disorder with at least one aggressive symptom (57 trios). Case-control analyses suggested a strong association between the ss genotype and conduct disorder (chi2(2) = 14.3; P < 0.01). Within-family analyses for conduct disorder with at least one aggressive symptom significantly favored greater transmission of the s-allele to affected offspring (chi(tdt)(2) = 4.13; P = 0.04); for conduct disorder, without aggressive symptoms, however, results were non-significant (chi(tdt)(2) = 1.61; P = 0.20). These data suggest that the s-allele may confer some risk for aggressive behavior or may be in linkage disequilibrium with such an allele.

Objective Little is known about adolescents with DSM-IV–defined inhalant abuse and dependence. The aim of this study was to compare comorbidity among (1) adolescents with inhalant use disorders, (2) adolescents who reported using inhalants without inhalant use disorder, and (3) other adolescent patients drawn from an adolescent drug and alcohol treatment program. Method The authors examined 847 admissions of patients who had completed structured diagnostic assessments. The three groups were compared for noninhalant substance use disorders, posttraumatic stress disorder, conduct disorder, major depression, previous suicide attempts, and physical/sexual abuse and neglect. Results Adolescents with inhalant abuse or dependence (group 1; n = 28) were significantly more likely to meet lifetime criteria for abuse or dependence on alcohol, hallucinogens, nicotine, cocaine, and amphetamines, to have had major depression, and to have attempted suicide compared with other adolescent patients who reported never using inhalants (group 3); adolescents with inhalant use disorders also reported significantly more abuse and neglect. Adolescents with inhalant abuse or dependence (group 1) did not differ significantly on any measure compared with adolescents who reported using inhalants without an inhalant use disorder (group 2). Conclusions Adolescent patients with a history of inhalant use, abuse, or dependence entering treatment should be carefully screened for noninhalant substance use disorders, major depression, suicidality, and abuse and neglect.

Substance dependence (SD) and antisocial personality disorder (ASPD) are highly comorbid and aggregate in families. Mating assortment may be an important process contributing to this familial aggregation. Hypothesis: Symptom counts of substance dependence, antisocial personality disorder, and retrospectively assessed conduct disorder (CD) will be correlated significantly among parents of youth in treatment for substance use and conduct problems and, separately, among parents of community controls. Methods: We examined SD, ASPD, and CD among 151 pairs of parents of adolescents in treatment for substance use and conduct problems, and in 206 pairs of parents of control subjects. Results: For average dependence symptoms (ADS) (the sum of across-drug substance dependence symptoms divided by the number of substance categories meeting minimum threshold use) mother–father correlations were 0.40 for patients and 0.28 for controls. Mother–father correlations for ASPD symptom count were 0.33 for patients and 0.26 for controls and for CD symptom count were 0.31 for patients (all P P =0.14). Conclusions: Spousal correlations for ADS and ASPD, suggest substantial non-random mating. Results support gender differences in homogamy for SD. Behavior genetic studies of these disorders need to account for assortment to avoid biases in estimates of genetic and environmental effects.

Centennial climate variability during the Holocene has been simulated in two 10,000 year experiments using the intermediate-complexity ECBilt model. ECBilt contains a dynamic atmosphere, a global 3-D ocean model and a thermodynamic sea-ice model. One experiment uses orbital forcing and solar irradiance forcing, which is based on the Stuiver et al. residual 14C record spliced into the Lean et al. reconstruction. The other experiment uses orbital forcing alone. A glacier model is coupled off-line to the climate model. A time scale analysis shows that the response in atmospheric parameters to the irradiance forcing can be characterised as the direct response of a system with a large thermal inertia. This is evident in parameters like surface air temperature, monsoon precipitation and glacier length, which show a stronger response for longer time scales. The oceanic response, on the other hand, is strongly modified by internal feedback processes. The solar irradiance forcing excites a (damped) mode of the thermohaline circulation (THC) in the North Atlantic Ocean, similar to the loop-oscillator modes associated with random-noise freshwater forcing. This results in a significant peak (at time scales 200–250 year) in the THC spectrum which is absent in the reference run. The THC response diminishes the sea surface temperature response at high latitudes, while it gives rise to a signal in the sea surface salinity. A comparison of the model results with observations shows a number of encouraging similarities.

Many youths with conduct and substance use problems experience abuse and neglect. A valid measure of the severity of abuse-neglect events could facilitate research and clinical care. The authors' goal was to examine the discriminative validity, clinical utility, and severity correlations of the Colorado Adolescent Rearing Inventory, a structured, 20-45-minute abuse-neglect interview in the assessment of adolescents with conduct and substance use problems.Ninety-eight adolescent patients with conduct and substance use problems and 102 comparison subjects (about 40% of the subjects in each group were female) completed the Colorado Adolescent Rearing Inventory, the Diagnostic Interview Schedule for Children, and the Composite International Diagnostic Interview-Substance Abuse Module.Although the subjects were advised that reports of abuse-neglect would be communicated to child welfare agencies, nearly two-thirds of the patients with conduct and substance use problems endorsed items indicating probable abuse-neglect, compared with about a third of the comparison subjects, a highly significant difference. Clinicians judged that 68%-80% of the cases of the patients and comparison subjects who endorsed such items warranted reporting to child welfare agencies. Scores on the Colorado Adolescent Rearing Inventory correlated significantly with severity of substance involvement, conduct disorder, and major depression. Compared to males, significantly more females (including 15% of comparison females) reported sexual abuse. Patients were significantly more likely than comparison subjects to attribute adverse life effects to their reported abuse-neglect experiences.Colorado Adolescent Rearing Inventory scores revealed many cases of serious abuse-neglect, generated many reports to child welfare agencies, demonstrated discriminative validity, correlated with clinical measures, and reflected important gender differences. The Colorado Adolescent Rearing Inventory can contribute to clinical evaluation and research involving youths with conduct and substance use problems.

Objective To review studies of adolescent substance use and abuse with genetically informative designs. Method Twin and adoption studies of adolescent substance use were searched in Medline using keywords. Results Of 19 studies that used adolescent samples, 18 examined initiation or use of substances and 1 examined abuse. Of the 7 retrospective studies using adult samples, 6 examined problematic behaviors such as substance dependence. Genetic and shared environmental influences on adolescent substance use are moderated by the specific substance, age, gender, specific contexts, religiousness, and region. There is some evidence for a common genetic influence on substance use across substances. Genetic influences on adolescent substance use may act through an influence on disinhibited behavior. Shared environment contributed to adolescent substance use consistently across all adolescent samples and common shared environmental influences influenced initiation into tobacco and alcohol use. While parental alcohol use had a small influence on adolescent shared environment, sibling influences were substantial. Conclusions Twin and adoption studies have increased our understanding of genetic and environmental influences on adolescent substance use and its initiation; however, more studies focusing on clinical syndromes of abuse and dependence are needed.

The cosinor model, used for variables governed by circadian and other biological rhythms, is a nonlinear model in the amplitude and acrophase parameters that has a linear representation upon transformation. With linear cosinor analysis, amplitude and acrophase for each harmonic can be computed as nonlinear functions of the estimated linear regression coefficients. Here a flexible mixed model approach to cosinor analysis is considered, where the fixed effect parameters may enter nonlinearly as acrophase and amplitude for each harmonic or linearly after transformation to regression coefficients. In addition, the random effects may enter nonlinearly as subject-specific deviations from the acrophases and amplitudes or linearly as subject-specific deviations from the regression coefficients. It is also possible for the fixed effects to enter nonlinearly while the random effects enter linearly. Additionally, we evaluate whether including higher order linear harmonic terms as random effects, that is, Rao-Khatri 'covariance adjustment', improves precision. Applying the delta method to nonlinear functions of the parameters from linear mixed cosinor models to obtain approximate variances produces results that are often identical to results from nonlinear mixed models. Consequently, traditional linear cosinor analysis can often be used to estimate and compare the nonlinear parameters of interest, that is, amplitudes and acrophases, via the delta method. This is advantageous since the nonlinear mixed model may have convergence difficulties for more complex models. However, for some multiple-group analyses, the linear cosinor transformation should not be used and we clarify when the two methods are equivalent and when they differ.

BackgroundAccidental injury and homicide, relatively common among adolescents, often follow risky behaviors; those are done more by boys and by adolescents with greater behavioral disinhibition (BD).HypothesisNeural processing during adolescents' risky decision-making will differ in youths with greater BD severity, and in males vs. females, both before cautious behaviors and before risky behaviors.Methodology/principal findings81 adolescents (PATIENTS with substance and conduct problems, and comparison youths (Comparisons)), assessed in a 2 x 2 design (PatientsComparisons x Male:Female) repeatedly decided between doing a cautious behavior that earned 1 cent, or a risky one that either won 5 or lost 10 cents. Odds of winning after risky responses gradually decreased. Functional magnetic resonance imaging captured brain activity during 4-sec deliberation periods preceding responses. Most neural activation appeared in known decision-making structures. PATIENTS, who had more severe BD scores and clinical problems than Comparisons, also had extensive neural hypoactivity. Comparisons' greater activation before cautious responses included frontal pole, medial prefrontal cortex, striatum, and other regions; and before risky responses, insula, temporal, and parietal regions. Males made more risky and fewer cautious responses than females, but before cautious responses males activated numerous regions more than females. Before risky behaviors female-greater activation was more posterior, and male-greater more anterior.Conclusions/significanceNeural processing differences during risky-cautious decision-making may underlie group differences in adolescents' substance-related and antisocial risk-taking. Patients reported harmful real-life decisions and showed extensive neural hypoactivity during risky-or-cautious decision-making. Males made more risky responses than females; apparently biased toward risky decisions, males (compared with females) utilized many more neural resources to make and maintain cautious decisions, indicating an important risk-related brain sexual dimorphism. The results suggest new possibilities for prevention and management of excessive, dangerous adolescent risk-taking.