Mollie A. Monnig, Ph.D. - US grants

DESCRIPTION (provided by applicant): Understanding the neural basis of alcohol use disorders (AUD) requires integration of neurophysiology, behavior, and psychological concepts. Neuroscientific models of AUD posit an imbalance between top-down cortical control networks and subcortical networks of motivation and reward, leading to impaired insight and compulsive drug-seeking behavior (Koob and Volkow, 2010). White matter tracts, which form the connective structure enabling communication among neurons, are a critical element in this conceptualization. White matter damage is a hallmark injury of AUD, with substantial volume loss found in both postmortem and in vivo studies (Kril and Halliday, 1999; Monnig et al., under review-c; Oscar-Berman and Marinkovic, 2007; Sullivan, 2000). Diffusion tensor imaging (DTI), an application of magnetic resonance imaging (MRI), quantifies integrity of white matter, yielding richer information than simple volumetric measures. Several DTI investigations have found abnormality in reward and self-regulation networks in individuals with AUD (Harris et al., 2008; Monnig et al., under review-a; Monnig et al., under review-b; Pfefferbaum et al., 2009; Yeh et al., 2009). These findings may be especially problematic because psychosocial interventions for AUD typically rely on self-reflection, effortful information processing, and reevaluation of reward Although previous investigations provide clear evidence of white matter abnormality in AUD, its causes and correlates remain obscure. The applicant's recent meta-analysis of white matter volume in AUD indicated that atrophy was greater in those who were seeking treatment and who had been abstinent for shorter periods of time, thus relating AUD severity and recent drinking behavior to white matter damage (Monnig et al., under review-c). The goal of the current project is to test and extend these findings in a representative sample of 261 heavy drinkers. These individuals range widely in their alcohol intake, health consequences of drinking, and extent to which they identify with psychological constructs of AUD (e.g., loss of control over drinking). Neuroimaging and behavioral data from this sample reside in an extant dataset to which I have access for this dissertation proposal through collaboration with the primary sponsor, Dr. Kent E. Hutchison. The proposed project will use structural equation modeling to identify key psychological, behavioral, and biological markers of white matter damage in heavy drinkers. Next, mediation, moderation, and moderated mediation of the relationship between chronic drinking and white matter abnormality will be tested with hierarchical linear modeling. Finally, associations between white matter abnormality and cognition will be evaluated to determine the functional consequences of white matter damage. Identifying markers of alcohol- related brain damage from clinical assessments enhances the translation of findings to real-world interventions. This project will add to understanding of how cognitive deficits arising from compromise of white matter networks may undermine the effectiveness of cognitive-behavioral treatment for AUD. PUBLIC HEALTH RELEVANCE: This study will contribute to neuroscientific understanding of AUD by systematically testing how alcohol consumption, psychological constructs of AUD severity, and biomarkers of alcohol-related health consequences impact white matter integrity. Its ultimate aim is to elucidate how alcohol-related damage occurs in white matter networks underlying reward and self-regulation and how this damage may affect functional outcomes.

PROJECT ABSTRACT HIV infection and heavy alcohol use independently cause inflammation in systemic and neural immune systems through multiple mechanisms. Both HIV and alcohol induce microbial translocation from the gut, systemic immune activation, compromise of the blood-brain barrier, and neuroinflammation. Because 15% of people living with HIV (PLWH) report heavy drinking in the past 30 days, the potential for alcohol to exacerbate immunological and neural dysfunction in HIV is a serious public health concern. Observational research links alcohol use in PLWH to brain abnormalities, cognitive impairment, and increased mortality. However, direct experimental evidence on alcohol-HIV interactions in humans is scarce. COBRE CADRE Research Project 1 (RP1) will investigate whether alcohol use in the context of HIV infection exacerbates inflammatory signaling in the peripheral immune system and central nervous system. Specifically, the study will examine acute effects of moderate alcohol consumption on immune biomarkers, neurometabolites, brain white matter, and cognition in PLWH and healthy controls. We will recruit 48 moderate drinkers who differ on HIV serostatus (24 seropositive individuals, 24 seronegative matched controls) to participate in controlled beverage administration and magnetic resonance imaging (MRI). Participants will be randomized to consume placebo (0 g alcohol/kg body weight) or alcoholic beverage (.60 g/kg; target blood alcohol=.07g/dL). Blood samples will be taken at baseline and for 3 hours after beverage consumption and assayed for plasma biomarkers of microbial translocation, monocyte/macrophage activation, and cytokine response. The plasma ratio of kynurenine to tryptophan will be used as a measure of immune activation relevant to HIV and drinking behavior. Cognition and subjective intoxication will be assessed during the experiment using the standardized measures from the COBRE Clinical Laboratory Core. MRI scans will be collected on the descending limb of alcohol and will focus on correlates of neuroinflammation, including: 1) neurometabolites (choline, Glx, glutathione) in thalamus and frontal white matter, using MR spectroscopy; 2) white matter diffusivity and extracellular free water, using diffusion-weighted imaging (DWI). We hypothesize that alcohol will induce greater pro-inflammatory effects in PLWH, relative to controls, 1) in the peripheral immune system, as reflected in plasma biomarker perturbations and tryptophan degradation; 2) in the brain, as reflected in neurometabolic changes, diffusivity alterations, and increased extracellular water. An exploratory aim tests the prediction that PLWH will show greater subjective intoxication and cognitive impairment in the alcohol condition. The interdisciplinary research team and mentors have experience and expertise in biobehavioral alcohol-HIV research to enable successful completion of this project. RP1 aligns with the overarching COBRE CADRE goal: to identify mechanisms through which substance use exacerbates adverse health outcomes in chronic disease. Results will advance understanding of pathogenic mechanisms of alcohol use and inform efforts to prevent and treat alcohol-related harms, particularly in PLWH.