Ksenija Marinkovic - US grants

DESCRIPTION (provided by applicant): Although alcohol intoxication affects functioning at multiple levels of the neuraxis, executive abilities in situations of increased complexity or novelty are especially disrupted. Alcohol may interfere with cognitive assessment of novel cues and the capacity to inhibit impulsive responses, contributing to the societally-important hazards, poor impulse control and alcohol dependence. The overall goal of the proposed research is to identify spatial and temporal characteristics of the brain circuits involved in novelty processing and response disinhibition and to determine their dose-related sensitivity to the acute effects of alcohol. A multimodal approach integrates respective advantages of complementary neuroimaging methods. Functional magnetic resonance imaging (fMRI) will be used in order to determine where the alcohol-induced, changes are occurring. Excellent temporal resolution of magneto- (MEG) and electro-encephalography (EEG) will elucidate the timing of these abnormalities. Furthermore, the candidate's preliminary work suggests that concurrent measures of sympathetic arousal are crucial for interpreting the effects of alcohol upon the integrated response to novelty. Functional investigations will focus on the acute disruptive effects of alcohol on the distributed neural systems underlying novelty processing, inhibitory control and arousal. Healthy subjects will serve as their own controls as they participate in alcohol (low and high dose) and placebo conditions at two different levels of task complexity. In order to achieve these goals, the candidate seeks training in 1) fMRI measurement and analytic techniques including event-related FMRI design, cortical reconstruction and multimodal integration and 2) psychopharmacology of alcohol and drug use and dependence. The integrated training and research program will enable the candidate to independently apply these multimodal imaging tools to advance our knowledge of alcohol's effects on the brain.

[unreadable] DESCRIPTION (provided by applicant): This is a revised application for an NIAAA-sponsored Research Project Grant (R01) entitled "Spatiotemporal Brain Imaging of Alcohol Effects on Inhibitory Control" Problem drinkers often exhibit deficits in self-control and sustained goal-oriented behavior. This observation is consistent with the evidence suggesting that acute intoxication interferes with the ability to evaluate conflicting task demands, inhibit impulsive responses and execute cognitive control. These impairments may result in a decreased ability to exert self restraint, contributing to increased drinking and alcohol dependence. The overall goal of the proposed research is to use multimodal brain imaging to identify the temporal ("when") and spatial ("where") characteristics of the neural circuits subserving inhibitory control and to determine their sensitivity to the acute effects of alcohol. Functional magnetic resonance imaging (fMRI) will be used in order to determine where the alcohol-induced induced changes are occurring. Excellent temporal resolution of magneto- (MEG) and electroencephalography (EEG) will elucidate the timing of these abnormalities. Effects of alcohol on both "input" (stimulus evaluation) and "output" (response preparation, inhibition and execution) will be studied concurrently and with the multimodal neuroimaging approach. It is hypothesized that alcohol intoxication primarily disrupts integrated prefrontal circuitry that exerts inhibitory top-down control on behavior. Since the strategic control is exerted via a complex system involving multiple stages of these integrated "input" and "output" streams in addition to error monitoring and regulatory feedback loops, multimodal imaging approach may reveal the real-time stages of the underlying neural areas and their sensitivity to alcohol intoxication. Healthy subjects will serve as their own controls as they participate in alcohol and placebo conditions in three tasks probing inhibitory control and selective attention. In addition, dispositional traits obtained in the same individuals will be considered together with the neurophysiological indices and may reveal the idiosyncratic aspects of alcohol effects on the brain and the multidimensional nature of inhibitory control. This research has ramifications for traffic- or work-related hazards and may elucidate the alcohol-induced impairment of self-regulatory functions contributing to alcohol abuse and dependence [unreadable] [unreadable] [unreadable]

ABSTRACT Binge or heavy episodic drinking has been on the rise and is associated with a range of harmful consequences that scale up with the high intensity drinking prevalent among young adults. Evidence on the nature and extent of neural changes associated with binge drinking (BD) is scant, especially as regards sex differences, so more sensitive, high-precision imaging modalities are needed to examine persistent brain alterations. Magnetic resonance imaging (MRI)-based methods are sensitive to brain function, as well as different neural tissue properties, and are well suited to provide multidimensional insight into the structure and organization of the brain. Despite a paucity of neuroimaging studies in BD, evidence obtained from individuals with alcohol use disorder suggests that degradation of prefrontal functions may contribute to impaired executive functions and an inability to refrain from hazardous drinking. Consistent with findings in alcohol use disorder, our data and other evidence indicate that BD participants show compensatory engagement of additional brain areas to maintain adequate performance on cognitively demanding tasks. Complementary MRI modalities can reveal the nature and regional specificity of structural degradation that underlies and constrains the compensatory reorganization. The overall aim of this project is to use a range of MRI-based methods to examine functional indices and structural correlates of executive deficits and compensatory mechanisms in young adult binge drinking men and women. Because of their spatial precision and sensitivity to different neural tissue properties and functional features, MRI-based methods can provide insights into structural and functional alterations at the level of an interactive system. Specifically, BOLD fMRI will evaluate functional activation during tasks that probe cognitive control; resting state functional connectivity (RSFC) analysis will examine alterations at the level of a functional network, while structural degradation will be reflected in gray and white matter morphometric features. Diffusion tensor imaging (DTI) will characterize white matter microstructure and tract-based changes. These measures will be obtained from young adult men and women (18-30 yrs) who will be assigned to binge drinking (BD) and light drinking (LD) groups based on their drinking patterns and will be equated on age, race/ethnicity, and family history of alcoholism. Interactions between binge drinking and sex will be examined in all analyses. Overall, we hypothesize that neural alterations will correlate with a range of alcohol-related variables, with greater deficits and increased compensatory activity observed in BDs who engage in higher intensity drinking, with BD women being especially susceptible to functional deficits and structural degradation. Data will be integrated across imaging modalities in a machine learning classifier framework that will inform a predictive model of drinking trajectories based on 6-mos and 12-mos longitudinal follow-ups. Combined with a rich set of drinking indices, personality and behavioral variables, a constellation of brain measures will provide a mechanistic insight into the type and extend of the neural degradation underlying executive deficits and compensatory brain reorganization.