Amithrupa Sabbineni

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.

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.

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.

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.

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 subjects 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 participants 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.

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.