Barbara J. Weiland

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. Hum Brain Mapp 36:872–882, 2015.

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.

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.

Does incentive-elicited nucleus accumbens activation differ by substance of abuse? An examination with adolescents

Highlights • We measure brain activation during anticipation of reward and loss in adolescents.• We compare incentive responses in six groups formed based on substance use patterns.• No activation differences emerge between the cannabis-only group and the other groups.• Tobacco-only users have less reward response than polysubstance and alcohol-only users.• Tobacco-only users show decreased reward activation compared to the control group.

Developmental Cognitive Neuroscience of Adolescent Sexual Risk and Alcohol Use

Abstract Human adolescents engage in very high rates of unprotected sex. This behavior has a high potential for unintended, serious, and sustained health consequences including HIV/AIDS. Despite these serious health consequences, we know little about the neural and cognitive factors that influence adolescents’ decision-making around sex, and their potential overlap with behaviorally co-occurring risk behaviors, including alcohol use. Thus, in this review, we evaluate the developmental neuroscience of sexual risk and alcohol use for human adolescents with an eye to relevant prevention and intervention implications.ResumenAdolescentes humanos participan en muy altas tasas de relaciones sexuales sin protección. Este comportamiento tiene un alto potencial de consecuencias para la salud que no están intencionales, y que son severos y sostenidos, incluyendo VIH/SIDA. A pesar de estos consecuencias para la salud, sabemos muy poco de los factores neurales y cognitivos que influyen los decisiones de comportamiento sexual y la coincidencia potencial de estos mechanismos con los que forman la base de comportamientos de riesgo que son fuertemente asociadas con relaciones sexuales sin protección, incluyendo el uso del alcohol. Así, en esto revisión, evaluamos la neurociencia del desarrollo del riesgo sexual y el uso de alcohol en adolescentes humanos poniendo el acento en las implicaciones de prevención y intervención pertinentes.

Associations between fractional anisotropy and problematic alcohol use in juvenile justice-involved adolescents

Abstract Background: Studies have shown associations between heavy alcohol use and white matter alterations in adolescence. Youth involved with the juvenile justice system engage in high levels of risk behavior generally and alcohol use in particular as compared to their non-justice-involved peers. Objectives: This study explored white matter integrity among justice-involved adolescents. Analyses examined fractional anisotropy (FA) and mean diffusivity (MD) between adolescents with low and high levels of problematic alcohol use as assessed by the Alcohol Use Disorders Identification Test (AUDIT). Methods: Participants (N = 125; 80% male; 14–18 years) completed measures assessing psychological status and substance use followed by diffusion tensor imaging (DTI). DTI data for low (n = 51) and high AUDIT (n = 74) adolescents were subjected to cluster-based group comparisons on skeletonized FA and MD data. Results: Whole-brain analyses revealed significantly lower FA in clusters in the right and left posterior corona radiata (PCR) and right superior longitudinal fasciculus (SLF) in the high AUDIT group, as well as one cluster in the right anterior corona radiata that showed higher FA in the high AUDIT group. No differences in MD were identified. Exploratory analyses correlated cluster FA with measures of additional risk factors. FA in the right SLF and left PCR was negatively associated with impulsivity. Conclusion: Justice-involved adolescents with alcohol use problems generally showed poorer FA than their low problematic alcohol use peers. Future research should aim to better understand the nature of the relationship between white matter development and alcohol use specifically as well as risk behavior more generally.

Exploring the Relationship of Functional Network Connectivity to Latent Trajectories of Alcohol Use and Risky Sex

Alcohol use is a major risk factor associated with unprotected sexual behavior, leading to higher risk of sexually transmitted infections (STI) including the human immunodeficiency virus (HIV). Emerging largely cross-sectional data suggest functional network connectivity strength is associated with problematic alcohol use, and as evidence supports a relationship between risky sexual behaviors and alcohol use, we hypothesized that functional connectivity might be associated with both categories of risk behavior. As part of a sexual risk reduction intervention study, juvenile justice-involved adolescents (N = 239) underwent a baseline functional magnetic resonance imaging scan and completed questionnaires about their alcohol use and risky sexual behavior at 3-month intervals over 12 months of follow up. To test both cross-sectional and longitudinal relationships between alcohol use and sexual risk behaviors, we estimated a parallel process latent growth model that simultaneously modeled the trajectories of alcohol use and sexual risk behavior. Functional connectivity strength was included as an exogenous variable to evaluate its relationship with level of risk and change in risk over time in both behaviors. Associations were found between baseline alcohol use and risky sex, and between longitudinal trajectories of alcohol use and risky sex. Network functional connectivity strength of the dorsal default mode network was associated with initial and longitudinal alcohol use, which may suggest that self-awareness of the effects of alcohol could serve as a useful target to decrease subsequent risky sexual behavior in adolescence.

The Impact of Combinations of Alcohol, Nicotine, and Cannabis on Dynamic Brain Connectivity

Alcohol, nicotine, and cannabis are among the most commonly used drugs. A prolonged and combined use of these substances can alter normal brain wiring in different ways depending on the consumed cocktail mixture. Brain connectivity alterations and their change with time can be assessed using functional magnetic resonance imaging (fMRI) because of its spatial and temporal content. Here, we estimated dynamic functional network connectivity (dFNC) as derived from fMRI data to investigate the effects of single or combined use of alcohol, nicotine, and cannabis. Data from 534 samples were grouped according to their substance use combination as controls (CTR), smokers (SMK), drinkers (DRN), smoking-and-drinking subjects (SAD), marijuana users (MAR), smoking-and-marijuana users (SAM), marijuana-and-drinking users (MAD), and users of all three substances (ALL). The DRN group tends to exhibit decreased connectivity mainly in areas of sensorial and motor control, a result supported by the dFNC outcome and the alcohol use disorder identification test. This trend dominated the SAD group and in a weaker manner MAD and ALL. Nicotine consumers were characterized by an increment of connectivity between dorsal striatum and sensorimotor areas. Where possible, common and separate effects were identified and characterized by the analysis of dFNC data. Results also suggest that a combination of cannabis and nicotine have more contrasting effects on the brain than a single use of any of these substances. On the other hand, marijuana and alcohol might follow an additive effect trend. We concluded that all of the substances have an impact on brain connectivity, but the effect differs depending on the dFNC state analyzed.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity: DRD2 methylation and alcohol

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue‐elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.