DRD2 methylation is associated with executive control network connectivity and severity of alcohol problems among a sample of polysubstance users.

Chronic exposure to alcohol and other drugs of abuse has been associated with deleterious consequences, including functional connectivity deficits within neural networks associated with executive control. Altered functional connectivity within the executive control network (ECN) might underlie the progressive inability to control consumption of alcohol and other drugs as substance use disorders progress. Genetic and epigenetic factors have been associated with substance use disorders (SUDs). For example, dopamine receptor 2 (DRD2) functioning has been associated with alcohol use disorder (AUD) and related phenotypes, including correlates of executive functioning. The present study aims to explore the relationship between a continuous measure of alcohol-related problems, epigenetic markers (methylation) within the DRD2 gene, and functional connectivity within the ECN among a sample of polysubstance users. A community sample of 658 subjects, whose consumption of alcohol, nicotine, and cannabis span across a spectrum of quantity and frequency of use, were obtained across previous studies in polysubstance using populations. Resting state functional magnetic resonance imaging was analyzed to identify intrinsic connectivity networks using a priori regions of interest. Methylation measurement of functionally relevant sites within the DRD2 gene was achieved via pyrosequencing. Regression-based models, including mediation and moderation models, tested the association between DRD2 methylation, functional connectivity within intrinsic neural networks (including the ECN), and severity of alcohol problems. Results suggest that average DRD2 methylation was negatively associated with right ECN (RECN) and left ECN (LECN) connectivity, but not associated with other networks tested, and DRD2 methylation was significantly associated with alcohol problems severity. Mediation models were not supported, although moderation models suggested that connectivity between edges within the RECN moderated the relationship between DRD2 methylation and AUD severity. Results support a theoretical model in which epigenetic factors are associated with neurobiological correlates of alcohol consumption among a sample of polysubstance users.

Neural activation during delay discounting is associated with 6-month change in risky sexual behavior in adolescents.

Background: Identifying cognitive and neural mechanisms of decision making in adolescence can enhance understanding of, and interventions to reduce, risky health behaviors in adolescence. Delay discounting, or the propensity to discount the magnitude of temporally distal rewards, has been associated with diverse health risk behaviors, including risky sex. This cognitive process involves recruitment of reward and cognitive control brain regions, which develop on different trajectories in adolescence and are also implicated in real-world risky decision making. However, no extant research has examined how neural activation during delay discounting is associated with adolescents' risky sexual behavior. Purpose: To determine whether a relationship exists between adolescents' risky sexual behavior and neural activation during delay discounting. Methods: Adolescent participants completed a delay discounting paradigm during functional magnetic resonance imaging (fMRI) scanning, and they reported risky sexual behavior at baseline, 3-, 6-, 9-, and 12-month follow-up time points. Latent growth curve models were employed to determine relationships between brain activation during delay discounting and change in risky sexual behavior over time. Results: Greater activation in brain regions associated with reward and cognitive control (caudate, putamen, nucleus accumbens, anterior cingulate, insula, orbitofrontal cortex, inferior frontal gyrus, dorsolateral prefrontal cortex) during delay discounting was associated with lower mean levels of risky sexual behavior but greater growth over the period from baseline to 6 months. Conclusions: Neural activation during delay discounting is cross-sectionally and prospectively associated with risky sexual behavior in adolescence, highlighting a neural basis of risky decision-making as well as opportunities for early identification and intervention.

Neural Correlates of Risky Sex and Response Inhibition in High-Risk Adolescents.

Adolescence is a neurodevelopmental period of heightened sexual risk taking. Neuroimaging can help elucidate crucial neurocognitive mechanisms underlying adolescent sexual risk behavior, yet few empirical studies have investigated this neural link. To address this gap in the literature, we examined the association between neurocognitive function during response inhibition-a known correlate of risk behaviors-and frequency of intercourse without a condom among adolescents. We examined the correlation between condom use and fMRI-based Stroop response in a large ethnically diverse sample of high-risk adolescents (n = 171). Partially replicating previous literature, sexual risk was positively correlated with blood-oxygen-level-dependent (BOLD) activation in the middle frontal gyrus during response inhibition, highlighting the relevance of this region during risky sexual decision making within this age group.

Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults.

BACKGROUND AND AIMS: Chronic alcohol use is associated with lower gray matter volume, and we reported recently that alcohol use showed negative associations with widespread gray matter (GM) volume even among young adults. The current study aimed to test the strength of association between (1) alcohol use and GM volume; (2) alcohol use and white matter (WM) integrity; (3) cannabis use and GM volume; and (4) cannabis use and WM integrity among adults and adolescents. DESIGN AND SETTING: General linear models within large pooled cross-sectional samples of adolescents and adults who had participated in studies collecting substance use and neuroimaging data in the southwestern United States. PARTICIPANTS: The current analysis included adults aged 18-55 years (n = 853) and adolescents aged 14-18 years (n = 439) with a range of alcohol and cannabis use. MEASUREMENTS: The dependent variable was GM volume or WM integrity, with key predictors of alcohol use [Alcohol Use Disorders Identification Test (AUDIT) score] and cannabis use (past 30-day use). FINDINGS: Alcohol use showed large clusters of negative associations (ηp2  = 0.028-0.145, P < 0.001) with GM volume among adults and to a lesser extent (one cluster; ηp2  = 0.070, P < 0.05) among adolescents. Large clusters showed significant associations (ηp2  = 0.050-0.124, P < 0.001) of higher alcohol use with poorer WM integrity, whereas adolescents showed no significant associations between alcohol use and WM. No associations were observed between structural measures and past 30-day cannabis use in adults or adolescents. CONCLUSIONS: Alcohol use severity is associated with widespread lower gray matter volume and white matter integrity in adults, and with lower gray matter volume in adolescents.

Negative and interactive effects of sex, aging, and alcohol abuse on gray matter morphometry.

Chronic alcohol use is associated with declines in gray matter (GM) volume, as is the normal aging process. Less apparent, however, is how the interaction between aging and heavy alcohol use affects changes in GM across the lifespan. There is some evidence that women are more vulnerable to the negative effects of alcohol use on GM than men. In the current study, we examined whether localized GM was related to measures of alcohol use disorder (e.g., AUDIT score) in a large sample (N = 436) of participants, ages 18-55 years, with a range of disease severity, using both voxel-based morphometry (VBM) and surface-based morphometry (SBM). We also explored whether GM associations with alcohol use disorder (AUD) severity are moderated by sex and age. Results showed significant negative associations between AUD severity and GM volume throughout temporal, parietal, frontal, and occipital lobes. Women showed more negative effects of alcohol use than men for cortical thickness in left orbitofrontal cortex, but evidence for increased vulnerability based on sex was limited overall. Similarly, a specific age by alcohol use interaction was observed for volume of right insula, but other regional or global interactions were not statistically supported. However, significant negative associations between heavy alcohol use and GM volumes were observed as early as 18-25 years. These findings support that alcohol has deleterious effects on global and regional GM above and beyond age, and, of particular importance, that regional associations emerge in early adulthood. Hum Brain Mapp 37:2276-2292, 2016. © 2016 Wiley Periodicals, Inc.

Associations of White Matter Microstructure with Clinical and Demographic Characteristics in Heavy Drinkers.

Damage to the brain's white matter is a signature injury of alcohol use disorders (AUDs), yet understanding of risks associated with clinical and demographic characteristics is incomplete. This study investigated alcohol problem severity, recent drinking behavior, and demographic factors in relation to white matter microstructure in heavy drinkers. Magnetic resonance imaging (MRI) scans, including diffusion tensor imaging (DTI), were collected from 324 participants (mean age = 30.9 ± 9.1 years; 30% female) who reported five or more heavy drinking episodes in the past 30 days. Drinking history and alcohol problem severity were assessed. A common white matter factor was created from fractional anisotropy (FA) values of five white matter tracts: body of corpus callosum, fornix, external capsule, superior longitudinal fasciculus, and cingulate gyrus. Previous research has implicated these tracts in heavy drinking. Structural equation modeling (SEM) analyses tested the hypothesis that, after controlling for duration of alcohol exposure, clinical and behavioral measures of alcohol use severity would be associated with lower white matter factor scores. Potential interactions with smoking status, gender, age, treatment-seeking status, and depression or anxiety symptoms also were tested. Controlling for number of years drinking, greater alcohol problem severity and recent drinking frequency were significantly associated with lower white matter factor scores. The effect of drinking frequency differed significantly for men and women, such that higher drinking frequency was linked to lower white matter factor scores in women but not in men. In conclusion, alcohol problem severity was a significant predictor of lower white matter FA in heavy drinkers, after controlling for duration of alcohol exposure. In addition, more frequent drinking contributed to lower FA in women but not men, suggesting gender-specific vulnerability to alcohol neurotoxicity.

Daily marijuana use is not associated with brain morphometric measures in adolescents or adults.

Recent research has suggested that marijuana use is associated with volumetric and shape differences in subcortical structures, including the nucleus accumbens and amygdala, in a dose-dependent fashion. Replication of such results in well controlled studies is essential to clarify the effects of marijuana. To that end, this retrospective study examined brain morphology in a sample of adult daily marijuana users (n = 29) versus nonusers (n = 29) and a sample of adolescent daily users (n = 50) versus nonusers (n = 50). Groups were matched on a critical confounding variable, alcohol use, to a far greater degree than in previously published studies. We acquired high-resolution MRI scans, and investigated group differences in gray matter using voxel-based morphometry, surface-based morphometry, and shape analysis in structures suggested to be associated with marijuana use, as follows: the nucleus accumbens, amygdala, hippocampus, and cerebellum. No statistically significant differences were found between daily users and nonusers on volume or shape in the regions of interest. Effect sizes suggest that the failure to find differences was not due to a lack of statistical power, but rather was due to the lack of even a modest effect. In sum, the results indicate that, when carefully controlling for alcohol use, gender, age, and other variables, there is no association between marijuana use and standard volumetric or shape measurements of subcortical structures.

Reduced executive and default network functional connectivity in cigarette smokers.

Altered functional connectivity has been associated with acute and chronic nicotine use. Connectivity alterations, specifically in the right and left executive control networks (RECN/LECN) and the default mode network (DMN), may contribute to the addiction cycle. The objective of this study was to determine if executive control network (ECN) and DMN connectivity is different between non-smokers and smokers and whether reductions in connectivity are related to chronic cigarette use. The RECN, LECN, and DMN were identified in resting state functional magnetic resonance imaging data in 650 subjects. Analyses tested for group differences in network connectivity strength, controlling for age and alcohol use. There was a significant group effect on LECN and DMN connectivity strength with smokers (n = 452) having lower network strengths than non-smokers (n = 198). Smokers had lower connectivity than non-smokers associated with key network hubs: the dorsolateral prefrontal cortex, and parietal nodes within ECNs. Further, ECN connectivity strength was negatively associated with pack years of cigarette use. Our data suggest that chronic nicotine use negatively impacts functional connectivity within control networks that may contribute to the difficulty smokers have in quitting.

Reduced left executive control network functional connectivity is associated with alcohol use disorders.

BACKGROUND: Altered functional connectivity in critical networks has been associated with chronic alcohol abuse. In turn, changes in connectivity in executive control networks (ECNs) may undermine the ability to control alcohol consumption. It was hypothesized that network connectivity would be reduced in individuals with problematic alcohol use (ALC) compared with controls and that diminished network connectivity would be associated with greater failure to control drinking. METHODS: Resting-state functional magnetic resonance imaging was analyzed to identify 14 previously identified intrinsic connectivity networks (ICNs) using a priori regions of interest in cases ranging from binge drinkers to those with severe alcohol use disorder, as well as control subjects. Analyses tested for differences in network connectivity strength between 255 ALC cases and 87 age- and gender-matched controls. Further, structural equation analysis, using 383 ALC cases, tested whether functional connectivity strength mediated the relationship between years of regular drinking and alcohol problems. RESULTS: The age- and gender-matched analysis showed that ALC had significantly lower network connectivity strength than controls in the left executive control (LECN), basal ganglia, and primary visual networks. For all ALC, LECN connectivity strength is negatively correlated with failed control and alcohol disorder severity. Edges connecting parietal regions with dorsolateral prefrontal, middle frontal, and temporal regions within the LECN drove these relationships. A positive association between years of drinking and severity of alcohol problems was mediated by reduced ECN connectivity. CONCLUSIONS: This study reports relationships between network strength and problematic alcohol use, suggesting that chronic drinking negatively impacts brain connectivity, specifically in the LECN. Altered functional connectivity, related to chronic alcohol abuse, may contribute to the etiology of alcohol dependence and relapse.

Preliminary functional MRI results from a combined stop-signal alcohol-cue task.

OBJECTIVE: Individuals suffering from alcohol use disorders tend to show impairments in inhibitory control, and these deficits may be exacerbated in the presence of craving-inducing alcohol cues. Imbalances between neural reward and control networks can influence the trajectory of alcohol use disorders such that individuals for whom the reward (craving) network strongly overpowers the control (inhibition) network tend to have worse outcomes. Brain activation related to inhibitory control can be examined using the stop-signal task (SST), which requires balancing speed and accuracy in the context of frequent go and infrequent stop stimuli. Further, brain areas related to cue-induced craving can be studied using visual cue tasks comparing neural responses to alcohol and control images. This study aims to explore the interaction of inhibitory control and cue-elicited craving using a single functional neuroimaging task. METHOD: We developed a novel task involving presentation of alcohol and control cues concurrently with a standard SST paradigm and administered it to 53 heavy drinkers (29 women). RESULTS: Successful response inhibition during alcohol compared to control picture trials was associated with significant activation in anterior cingulate, supplementary motor, and frontal inferior regions, and this activation was differentially related to alcohol use symptom severity across several self-report measures. CONCLUSIONS: RESULTS suggest that recruitment of compensatory error detection and inhibitory control resources may be required for successful inhibition in the presence of alcohol cues among more severe drinkers. These preliminary findings support the construct validity of the task and indicate several methodological alterations to the task's design that should be implemented in future studies.

Association of genetic copy number variations at 11 q14.2 with brain regional volume differences in an alcohol use disorder population.

This study investigates the relationship between genetic copy number variations and brain volume differences in an alcohol use disorder (AUD) population. We hypothesized that copy number variations may influence subject's risk for alcohol use disorders through variations in regional gray and white matter brain volumes. Since genetic influences upon behavior are the result of many complicated interactions we focus on differences in brain volume as a putative intermediate phenotype between genetic variation and behavior. Copy number variation, alcohol use assessments and brain structural magnetic resonance images from 283 subjects, 199 male and 84 females who were enrolled in two AUD studies were obtained and analyzed using a combination of the Freesurfer image analysis suite and independent component analysis. Because brain volume varies by age we compared participant's volume variation with that derived from a control cohort of 75 subjects. In addition we also regressed out the possible brain volume changes induced by long term alcohol consumption. Small cerebral cortex, cerebellar and caudate along with large cerebral white matter and 5th ventricle volumes are shown to be significantly associated with increased AUD severity. When these volume variations are compared with control subject volumes; the variations seen in subjects with AUD are markedly different from normal aging effects. CNVs at 11 q14.2 are marginally (p < 0.05 uncorrected) correlated with such brain volume variations and the correlation holds true after controlling for long-term alcohol consumption; deletion carriers have smaller cerebral cortex, cerebellar, caudate and larger cerebral white matter and 5th ventricle volumes than insertion carriers or subjects with no variation in this region. Similarly, deletion carriers also demonstrate higher AUD severity scores than insertion carriers or subjects with no variation. The results presented here suggest that copy number variation and in particular the variation at chromosome 11 q14.2 may have an impact in brain volume variation, potentially influencing AUD behavior.

Identifying neurobiological phenotypes associated with alcohol use disorder severity.

Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies.

How psychosocial alcohol interventions work: a preliminary look at what FMRI can tell us.

BACKGROUND: Current work in motivational interviewing (MI) has supported the role of in-session client and therapist language in predicting postintervention substance use outcomes. In particular, a relationship has been found between specific therapist language (e.g., MI-consistent behaviors), specific types of client speech (e.g., change talk; CT and counterchange talk; CCT), and subsequent drinking outcomes. One hypothesis to explain this phenomenon is that CT is an indication of a neurocognitive shift that happens during the course of a psychosocial intervention. And, it is possible that this shift is responsible for catalyzing and maintaining changes in drinking behaviors following MI interventions. To investigate this question, the effect of CT on blood oxygen level-dependent (BOLD) response during the presentation of alcohol cues was evaluated using functional magnetic resonance imaging. METHODS: To examine changes in neural response to alcohol cues following client language, 10 adults with alcohol dependence (50% men; 40% Caucasian; 40% Hispanic; M age = 42.6; M years of education = 13.3) were presented with CT and CCT derived from their prescan MI session during the presentation of alcohol cues. RESULTS: Following CCT, there was significant neural response to alcohol cues in several key reward areas (cluster-corrected p < 0.05, z > 2.3; orbitofrontal cortex, nucleus accumbens, anterior insula, posterior insula, caudate, and putamen). On the contrary, there were no areas of significant reward activation following CT. CONCLUSIONS: These results indicate that CT may be effectively inhibiting activation in brain regions that respond to the salience of alcohol cues. These findings provide preliminary biological support of the psychosocial literature findings, highlighting the critical importance of change talk during psychosocial interventions.