My long-term aim is to become an independent investigator studying the neurobiological mechanisms of alcohol use disorder treatment by using functional magnetic resonance imaging (fMRI) to examine effects of treatment on neural circuitry. Such research has the potential to improve upon existing treatments (e.g. by providing rationales for combining medications with different mechanisms of action), to identify the most important neurobiological targets for novel treatments, and to identify predictors of response to treatment using fMRI. I need further training in order to achieve these career goals. My career development plan will prepare me to successfully address the gaps in my knowledge through: (1) Training in the role of inhibitory control and stress reactivity in alcohol use disorders (2) Training in functional neuroimaging analysis with a focus on evoked BOLD analyses, seed-based functional connectivity analyses, and independent components analysis (3) Training in advanced statistical methodology like mediation analyses, moderation analyses, hierarchical linear modeling, structural equation modeling, and multivariate analyses for examining mechanisms of change. The career plan provides for an integrated set of activities that includes ten graduate level courses, attendance at a variety of relevant conferences, attendance at workshops in Hierarchical Linear Modeling and meta- analyses, and use of specific software designed to carry out fMRI analyses. The location of my research will be at the University of New Mexico Department of Psychiatry Center for Psychiatric Research, the Mind Research Network, and The Center on Alcoholism, Substance Abuse, and Addictions (CASAA). In addition to performing secondary analyses of existing datasets during the initial three years, I will also conduct research that will help consolidate knowledge gains and which will provide preliminary data for an R01 application. This research plan will utilize fMRI and other measures to investigate the mechanisms of effect (and explore predictors of effect) of prazosin, an alpha 1 antagonist, on drinking. Prazosin decreases alcohol drinking in individuals with alcohol use disorders, but the mechanism of its effect on drinking has not yet been directly studied. Moreover the effect of prazosin on measures of stress reactivity and inhibitory control, measured by evoked BOLD response, functional connectivity, neuropsychological testing, and self-report, has not yet been identified. We propose a double-blind placebo-controlled trial in which 36 alcohol dependent participants will be randomized to treatment with placebo or prazosin, and will be followed for up to three months. Participants will undergo two fMRI scans: one before starting prazosin or placebo, and one after uptitration of prazosin or placebo. The study aims to replicate prior work showing that there is a main effect of prazosin on drinking outcomes and to identify mediators of this effect using markers of stress reactivity and inhibitory control. In addition, this study will explore predictors of response to prazosin. Findings will provide firm estimates of the magnitude of meditational relationships which will be necessary predecessors for conducting a larger scale R01 clinical trial.
The study uses neurobiological measures through brain imaging, neuropsychological measures, and self- report measures to try to understand how an effective treatment for alcoholism works. On the whole, less than 50% of people with alcoholism get better with treatment. This study will help researchers develop better treatments for alcoholism because if we know why the treatments we use are working, and in whom the treatments work best, then we may be able to make treatment more effective by targeting treatments to individuals who would be most likely to benefit and by guiding development of more effective treatments in the future.
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