Associations between alcohol use and sex-specific maturation of subcortical gray matter morphometry from adolescence to adulthood: Replication across two longitudinal samples.

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.

Alcohol-induced changes in mesostriatal resting-state functional connectivity are linked to sensation seeking in young adults.

BACKGROUND: Studies in animals and humans suggest that greater levels of sensation seeking and alcohol use are related to individual differences in drug-induced dopamine release. However, it remains unclear whether drug-induced alterations in the functional synchrony between mesostriatal regions are related to sensation seeking and alcohol use. METHODS: In this within-subject masked-design study, 21-year-old participants (n = 34) underwent functional magnetic resonance imaging to measure ventral tegmental area (VTA) resting-state functional connectivity to the striatum after receiving alcohol (target blood alcohol concentration 0.08 g/dL) or placebo. Participants also completed the UPPS-P Impulsive Behavior Scale to assess sensation seeking, the Young Adult Alcohol Consequences Questionnaire, and self-reported patterns of alcohol and drug use. RESULTS: Voxel-wise analyses within the striatum demonstrated that during the alcohol condition (compared with placebo) young adults had less connectivity between the VTA and bilateral caudate (p < 0.05 corrected). However, young adults exhibiting smaller alcohol-induced decreases or increases in VTA-left caudate connectivity reported greater sensation seeking. CONCLUSION: These findings provide novel information about how acute alcohol impacts resting-state connectivity, an effect that may be driven by the complex pre and postsynaptic effects of alcohol on various neurotransmitters including dopamine. Further, alcohol-induced differences in VTA connectivity represent a plausible mechanistic substrate underlying sensation seeking.

Recalibrating single-study effect sizes using hierarchical Bayesian models.

Introduction: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance. Methods: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method. Results: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. Discussion: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.

Adolescent novelty seeking is associated with greater ventral striatal and prefrontal brain response during evaluation of risk and reward.

Adolescence is a period during which reward sensitivity is heightened. Studies suggest that there are individual differences in adolescent reward-seeking behavior, attributable to a variety of factors, including temperament. This study investigated the neurobiological underpinnings of risk and reward evaluation as they relate to self-reported pleasure derived from novel experiences on the revised Early Adolescent Temperament Questionnaire (EATQ-R). Healthy participants (N = 265, ~50% male), aged 12-17 years, underwent functional magnetic resonance imaging during a modified Wheel of Fortune task, where they evaluated choices with varying probability of winning different monetary rewards. Across all participants, there was increased brain response in salience, reward, and cognitive control circuitry when evaluating choices with larger (compared with moderate) difference in risk/reward. Whole brain and a priori region-of-interest regression analyses revealed that individuals reporting higher novelty seeking had greater activation in bilateral ventral striatum, left middle frontal gyrus, and bilateral posterior cingulate cortex when evaluating the choices for largest difference in risk/reward. These novelty seeking associations with brain response were seen in the absence of temperament-related differences in decision-making behavior. Thus, while heightened novelty seeking in adolescents might be associated with greater neural sensitivity to risk/reward, accompanying increased activation in cognitive control regions might regulate reward-driven risk-taking behavior. More research is needed to determine whether individual differences in brain activation associated with novelty seeking are related to decision making in more ecologically valid settings.

Ventral striatal resting-state functional connectivity in adolescents is associated with earlier onset of binge drinking.

BACKGROUND: Earlier engagement in heavy drinking during adolescence is a risk factor for the development of alcohol use disorders later in life. Longitudinal studies in adolescents have linked brain structure and task-evoked function to future alcohol use; however, less is known about how intrinsic network-level interactions relate to future substance use during this developmental period. METHODS: In this prospective longitudinal study, resting-state functional connectivity of the ventral striatum, risky decision making, and sensation seeking were measured in 73 adolescents at baseline. Participants were between the ages of 14 and 15 and had no substantial history of substance use upon study entry. Follow-up interviews were conducted approximately every 3 months to assess the initiation of binge drinking (≥ 5 or ≥ 4 drinks per occasion for males or females, respectively). RESULTS: Adolescents who began binge drinking sooner exhibited greater connectivity of the ventral striatum to the left precuneus, left angular gyrus, and the left superior frontal gyrus. Greater connectivity of the ventral striatum to the right insula/putamen was associated with longer duration to the onset of binge drinking. Resting-state functional connectivity in these regions was not associated with baseline assessments of risky decision making or sensation seeking. CONCLUSIONS: Findings provide novel information about potential risk factors for early initiation of heavy alcohol use. Interventions that target relevant resting-state networks may enhance prevention efforts to decrease adolescent substance use by prolonging onset to heavier levels of alcohol consumption.

Prediction of suicidal ideation and attempt in 9 and 10 year-old children using transdiagnostic risk features.

The objective of the current study was to build predictive models for suicidal ideation in a sample of children aged 9-10 using features previously implicated in risk among older adolescent and adult populations. This case-control analysis utilized baseline data from the Adolescent Brain and Cognitive Development (ABCD) Study, collected from 21 research sites across the United States (N = 11,369). Several regression and ensemble learning models were compared on their ability to classify individuals with suicidal ideation and/or attempt from healthy controls, as assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. When comparing control participants (mean age: 9.92±0.62 years; 4944 girls [49%]) to participants with suicidal ideation (mean age: 9.89±0.63 years; 451 girls [40%]), both logistic regression with feature selection and elastic net without feature selection predicted suicidal ideation with an AUC of 0.70 (CI 95%: 0.70-0.71). The random forest with feature selection trained to predict suicidal ideation predicted a holdout set of children with a history of suicidal ideation and attempt (mean age: 9.96±0.62 years; 79 girls [41%]) from controls with an AUC of 0.77 (CI 95%: 0.76-0.77). Important features from these models included feelings of loneliness and worthlessness, impulsivity, prodromal psychosis symptoms, and behavioral problems. This investigation provided an unprecedented opportunity to identify suicide risk in youth. The use of machine learning to examine a large number of predictors spanning a variety of domains provides novel insight into transdiagnostic factors important for risk classification.

CYP2D6 genotype may moderate measures of brain structure in methamphetamine users.

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (ß = -0.254; p = 0.035), but not in control subjects (ß = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.

Adolescent alcohol use disrupts functional neurodevelopment in sensation seeking girls.

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.

Identifying Early Risk Factors for Addiction Later in Life: A Review of Prospective Longitudinal Studies.

PURPOSE OF REVIEW: To review prospective longitudinal studies that have identified risk factors for the development of substance use disorders in adulthood from individual differences during childhood and adolescence. RECENT FINDINGS: Risk factors during childhood and adolescence that have been consistently linked to increased risk for addiction include externalizing and internalizing symptoms, early substance use, and environmental influences, such as parental behavior and exposure to traumatic experiences. SUMMARY: Since the etiology of substance use disorders is complex and likely is attributable to many causal pathways, systematic examination of the associations between risk factors will be necessary to understand the mixed findings in the existing literature, to determine which individuals should be targeted for prevention efforts, and to design interventions that address risk factors that are most likely to improve outcomes.

Default mode network connectivity is related to pain frequency and intensity in adolescents.

Pain during adolescence is common and is associated with future pain chronicity and mental health in adulthood. However, understanding of the neural underpinnings of chronic pain has largely come from studies in adults, with recent studies in adolescents suggesting potentially unique neural features during this vulnerable developmental period. In addition to alterations in the pain network, resting state functional magnetic resonance imaging studies in adults suggest alterations in the default mode network (DMN), involved in internally-driven, self-referential thought, may underlie chronic pain; however, these findings have yet to be examined in adolescents. The current study sought to investigate associations between pain frequency and intensity, and disruptions in DMN connectivity, in adolescents. Adolescents (ages 12-20) with varying levels of pain frequency and intensity, recruited from a pediatric pain clinic and the local community (n = 86; 60% female), underwent resting state functional magnetic resonance imaging. Using independent components analysis, the DMN was identified and correlated voxel-wise to assess associations between pain frequency and intensity and DMN connectivity. Findings revealed that adolescents with greater pain frequency demonstrated greater DMN to superior frontal gyrus connectivity, while adolescents with greater pain intensity demonstrated lesser DMN to cerebellum (lobule VIII) connectivity, during rest. These findings suggest that increasing levels of pain are associated with potential desegregation of the DMN and the prefrontal cortex, important for cognitive control, and with novel patterns of DMN to cerebellum connectivity. These findings may prove beneficial as neurobiological targets for future treatment efforts in adolescents.

Associations between nucleus accumbens structural connectivity, brain function, and initiation of binge drinking.

Adolescent alcohol use is associated with increased risk for alcohol use disorders later in life; therefore, identifying biomarkers for initiation of heavy alcohol use, such as individual differences in the development of white-matter microstructure, may inform prevention strategies that improve public health. This prospective cohort study included 40 adolescents, ages 14 and 15, without substantial history of alcohol or drug use at baseline. Fractional anisotropy (FA), an index of white-matter microstructure, was assessed in pathways connecting the nucleus accumbens (NAcc) to the rest of the brain using diffusion tensor imaging. Path analyses were conducted voxel-wise within these pathways to examine direct effects of premorbid FA on number of months between baseline assessment and the onset of binge drinking and indirect effects mediated by NAcc activation during decision making assessed using functional magnetic resonance imaging. Adolescents with lower premorbid accumbofrontal FA began binge drinking sooner, an effect which was mediated by greater NAcc activation during decision making involving greater levels of risk and reward (P < .05 corrected). An additional direct effect of FA on duration to onset of binge drinking was observed in white matter near the ventral pallidum, as adolescents with lower premorbid FA in this region began binge drinking sooner (P < .05 corrected). Findings suggest that delayed maturation of prefrontal white matter is associated with less top-down control over striatal sensitivity to reward. These factors, along with individual differences in white matter proximal to ventral pallidum, may represent premorbid risk factors for earlier initiation of heavy alcohol use.

Sex Differences in the Effect of Nucleus Accumbens Volume on Adolescent Drinking: The Mediating Role of Sensation Seeking in the NCANDA Sample.

OBJECTIVE: In adolescence, sensation seeking is associated with earlier onset of alcohol use, which is a risk factor for a variety of negative consequences later in life. Individual differences in sensation seeking are related to brain function in the nucleus accumbens (NAcc), a brain region that undergoes considerable structural development during adolescence. Therefore, the goal of this study was to determine whether NAcc volume in alcohol-naive adolescents was associated with future sensation seeking and alcohol use and whether these associations differed by sex. METHOD: High-resolution magnetic resonance imaging was used to measure NAcc volume at baseline in 514 alcohol-naive adolescents (50.2% female) from the National Consortium on Alcohol & Neurodevelopment in Adolescence study. Direct effects of NAcc volume on adolescent drinking 2 years after baseline, and indirect effects mediated through sensation seeking 1 year after baseline, were assessed. RESULTS: An indirect effect of NAcc volume on subsequent drinking through sensation seeking was significant for males, but not females. This effect was driven by a positive association between NAcc volume and sensation seeking observed in male, but not female, participants. A direct effect of NAcc volume on subsequent alcohol use was detected in females, but not males. In females, no association between NAcc volume and sensation seeking was detected, but NAcc volume was positively associated with future alcohol use. CONCLUSIONS: These findings suggest that delayed structural maturation of the NAcc may be a risk factor for alcohol use in adolescence; however, the mechanism by which the structure of the NAcc confers risk differs by sex.

Effects of Naltrexone on Large-Scale Network Interactions in Methamphetamine Use Disorder.

Naltrexone attenuates craving, and the subjective effects of methamphetamine and extended-release naltrexone (XR-NTX) reduces functional connectivity between regions of the striatum and limbic cortex. Naltrexone modulates neural activity at dopaminergic synapses; however, it is unclear whether naltrexone has an effect on large-scale brain networks. Functional networks interact to coordinate behavior, and as substance-use disorders are associated with an imbalance between reward and cognitive control networks, treatment approaches that target interactive brain systems underlying addiction may be a useful adjunct for behavioral therapies. The objective of this study was to examine the effect of XR-NTX on large-scale brain networks and to determine whether changes in network relationships attenuate drug use, craving, and addiction severity. Thirty-nine participants in or seeking treatment for methamphetamine-use disorder were enrolled in a clinical trial of XR-NTX between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Functional magnetic resonance imaging (fMRI) and questionnaires were conducted before and after double-blinded randomization to a 4-week injection of XR-NTX or placebo. In the XR-NTX group, methamphetamine use was reduced along with a decrease in the coupling between executive control (ECN) and default mode (DMN) networks. As decoupling of ECN and DMN networks was associated with change in the severity of dependence, the results suggest that XR-NTX may modulate and enhance ECN attentional resources and suppress DMN self-referential and emotional processing. This study identifies the effect of naltrexone on changes in the intrinsic functional coupling of large-scale brain networks and provides a more systematic understanding of how large-scale networks interact to promote behavioral change in methamphetamine-use disorder.

Resilience to Risk for Psychopathology: The Role of White Matter Microstructural Development in Adolescence.

BACKGROUND: One major risk factor for the development of psychopathology is a family history of psychopathology (FHP). Cross-sectional studies have shown that FHP is associated with alterations in white matter microstructure in adolescents without current psychopathology; however, whether these associations persist throughout adolescence, particularly in those who remain resilient to developing psychopathology, is unclear. METHODS: Sixty-six adolescents underwent diffusion-weighted imaging at baseline (12-16 years of age) and at one or two follow-up visits (142 total scans). Adolescents' parents completed a modified Family History Assessment Module to calculate FHP density (FHPD) based on familial alcohol use, substance use, and major depressive, generalized anxiety, substance-induced mood, and antisocial personality disorders. The relationship between FHPD and white matter microstructural development was examined using multilevel modeling. RESULTS: FHPD was associated with significant alterations in white matter microstructure at baseline; in the bilateral superior corona radiata and left superior longitudinal fasciculus, these effects were transient (FHPD was associated with altered white matter microstructure only in early adolescence), while effects in the posterior limb of the internal capsule were persistent. Associations between FHPD and white matter microstructure in the body of the corpus callosum emerged later in adolescence. CONCLUSIONS: This prospective, longitudinal study provides novel information indicating that the association between FHP and white matter microstructure previously observed in adolescents is transient in most regions but may persist into late adolescence in other regions, despite current resilience to developing psychopathology. Future studies are necessary to determine if these persistent alterations are associated with onset of psychopathology later in life.

Ventral striatal response during decision making involving risk and reward is associated with future binge drinking in adolescents.

Beginning to engage in heavy alcohol use during adolescence, as opposed to later in life, is associated with elevated risk for a variety of negative consequences, including the development of an alcohol use disorder. Behavioral studies suggest that poor decision making predicts alcohol use during adolescence; however, more research is needed to determine the neurobiological risk factors that underlie this association. Using functional magnetic resonance imaging, brain activation during decision making involving risk and reward was assessed in 47 adolescents (14-15 years old) with no significant history or alcohol or drug use. After baseline assessment, participants completed follow-up interviews every 3 months to assess the duration to onset of binge drinking. Adolescents who made a greater number of risky selections and had greater activation in the nucleus accumbens, precuneus, and occipital cortex during decision making involving greater potential for risk and reward began binge drinking sooner. Findings suggest that heightened activation of reward circuitry during decision making under risk is a neurobiological risk factor for earlier onset of binge drinking. Furthermore, brain activation was a significant predictor of onset to binge drinking, even after controlling for decision-making behavior, suggesting that neurobiological markers may provide additional predictive validity over behavioral assessments. Interventions designed to modify these behavioral and neurobiological risk factors may be useful for curbing heavy alcohol use during adolescence.

Cognitive deficit in methamphetamine users relative to childhood academic performance: link to cortical thickness.

Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users' childhood grade point average was significantly lower than that of the control group (p < 0.05). Further, methamphetamine users' overall cognitive performance was lower than was predicted from their grade point average prior to methamphetamine use (p = 0.001), with specific deficits in attention/concentration and memory (ps < 0.01). Memory deficits were associated with lower whole-brain cortical thickness (p < 0.05). Thus, in addition to having an apparent premorbid weakness in cognition, methamphetamine users exhibit subsequent cognitive function that is significantly lower than premorbid estimates would predict. The results support the view that chronic methamphetamine use causes a decline in cognition and/or a failure to develop normative cognitive abilities, although aside from methamphetamine use per se, other drug use and unidentified factors likely contribute to the observed effects.

Convergent neurobiological predictors of emergent psychopathology during adolescence.

The adolescent brain undergoes significant structural and functional development. Through the use of magnetic resonance imaging in adolescents, it has been demonstrated that the prefrontal cortex, pertinent for executive control, demonstrates protracted development compared to limbic structures, active during emotion and reward processing. This asynchronous development creates a sensitive window during adolescence, in which many psychopathological disorders (i.e., mental health and substance use) emerge. This review outlines longitudinal studies that use magnetic resonance imaging to identify neurobiological predictors of emergent psychopathology (depression, anxiety, and substance use), during adolescence. Studies identifying neurobiological markers that predict onset and escalation of these disorders, as well as those that predict successful treatment outcomes are explored. An emphasis is placed on frontolimbic brain structures, a convergent neurobiological target for both emergent mental health issues and emergent substance use. The literature reviewed herein suggests that reduced volume and cortical thickness in frontolimbic regions, as well as reduced functional activation (particularly during task involving reward or emotional stimuli) in these regions, may serve as a neurobiological predictors of emergent psychopathology in adolescence. This knowledge is crucial, as it may be used to develop neurobiologically targeted prevention and intervention strategies for youth who are at-risk for developing these psychopathologies.

A neural network that links brain function, white-matter structure and risky behavior.

The ability to evaluate the balance between risk and reward and to adjust behavior accordingly is fundamental to adaptive decision-making. Although brain-imaging studies consistently have shown involvement of the dorsolateral prefrontal cortex, anterior insula and striatum during risky decision-making, activation in a neural network formed by these regions has not been linked to structural connectivity. Therefore, in this study, white-matter connectivity was measured with diffusion-weighted imaging in 40 healthy research participants who performed the Balloon Analogue Risk Task, a test of risky decision-making, during fMRI. Fractional anisotropy within a network that includes white-matter pathways connecting four regions (the prefrontal cortex, insula and midbrain to the striatum) was positively correlated with the number of risky choices and total amount earned on the task, and with the parametric modulation of activation in regions within the network to the level of risk during choice selection. Furthermore, analysis using a mixed model demonstrated how relationships of the parametric modulation of activation in each of the four aforementioned regions are related to risk probabilities, and how previous trial outcomes and task progression influence the choice to take risk. The present findings provide the first direct evidence that white-matter integrity is linked to function within previously identified components of a network that is activated during risky decision-making, and demonstrate that the integrity of white-matter tracts is critical in consolidating and processing signals between cortical and striatal circuits during the decision-making process.

Mixture models of delay discounting and smoking behavior.

BACKGROUND: Smokers exhibit an unusually high willingness to forgo a delayed reward of greater magnitude to receive a smaller, more immediate reward. The functional form of such "delay discounting" behavior is central to the discounting-based operationalization of impulsivity, and has implications for theories regarding the basis of steep discounting among smokers and treatment approaches to addiction. OBJECTIVES: We examined the discounting behavior of current smokers, ex-smokers, and never-smokers to determine whether the functional form of discounting differs between these groups. METHODS: Participants completed a 27-item delay discounting questionnaire (25). We used finite mixture modeling in analyzing data as the product of two simultaneous data-generating processes (DGPs), a hyperbolic function and an exponential function, and compared results to a quasi-hyperbolic (QH) approximation, in a relatively large sample (n = 1205). RESULTS: Consistent with prior reports, current smokers exhibited steeper discounting relative to never-smokers across exponential, hyperbolic, and QH models. A mixture model provided significant support for exponential and hyperbolic discounting in the data, and both accounted for roughly 50% of the participants' choices. This mixture model showed a statistically significantly better fit to the data than the exponential, hyperbolic, or QH functions alone. Contrary to the prevailing view, current smokers were not more likely to discount hyperbolically than nonsmokers, and, thus, were not more prone to time-inconsistent discounting. CONCLUSIONS: The results inform the interpretation of steep discounting among smokers and suggest that treatment approaches could be tailored to the type of discounting behavior that smokers exhibit.

Genetic imaging consortium for addiction medicine: From neuroimaging to genes.

Since the sample size of a typical neuroimaging study lacks sufficient statistical power to explore unknown genomic associations with brain phenotypes, several international genetic imaging consortia have been organized in recent years to pool data across sites. The challenges and achievements of these consortia are considered here with the goal of leveraging these resources to study addiction. The authors of this review have joined together to form an Addiction working group within the framework of the ENIGMA project, a meta-analytic approach to multisite genetic imaging data. Collectively, the Addiction working group possesses neuroimaging and genomic data obtained from over 10,000 subjects. The deadline for contributing data to the first round of analyses occurred at the beginning of May 2015. The studies performed on this data should significantly impact our understanding of the genetic and neurobiological basis of addiction.