Alcoholism is a chronic relapsing illness in which heavy alcohol use results in significant neuroadaptations in brain stress, reward and emotion circuits associated with high stress, alcohol craving and increased risk of relapse. In the previous funding cycle, we identified significant biobehavioral and neural predictors of future alcohol relapse. Hyperactivity of ventromedial prefrontal cortex (VmPFC) during neutral-relaxed states emerged as a primary predictor, meeting sensitivity and specificity criteria for biomarker development, while secondary predictors including alterations of basal morning cortisol and cortisol/ACTH ratio (a measure of adrenal sensitivity), stress-induced blunted Cort/ACTH ratio, stress- and cue-induced craving, smaller gray matter volume (GMV) in medial frontal and parietal-occipital regions, and blunted brain VmPFC and ventral striatal (VS) response during stress and cue-induced craving also predicted future relapse. Thus, extending previous findings, and applying a novel multi-method translational approach, we hypothesize that these alcohol-related neuroendocrine and neural changes are observable in acute and protracted abstinence and can accurately classify future relapse and treatment outcome in separate patient samples, thereby validating them as biomarkers of relapse with potential clinical utility as prognostic markers for identifying and treating those most susceptible to relapse in recovery. In the next 5-year funding period, we propose to assess these primary and secondary predictors in a prospective cohort of 100 treatment engaged abstinent alcohol dependent (AD) individuals and 50 demographic and handedness matched control drinkers (HC), and in an additional 60 AD patients enrolled in a currently ongoing RCT of Prazosin/Placebo (PZ/PL) to determine their predictive power in accurate classification of alcohol relapse and treatment outcomes. The following specific aims are proposed: (1) To examine chronic alcohol-related changes in primary and secondary predictors in AD patients during acute and protracted alcohol abstinence, and in AD patients relative to social drinkers. (2) To examine whether neuroadaptations in primary and secondary predictors during acute and protracted abstinence are each predictive of future relapse, and determine receiver operating characteristics (ROC) for relapse classification accuracy and determine cut-off values for biomarker development and testing. (3) To evaluate whether the primary and secondary predictors improve with PZ/PL treatment and predict alcohol treatment outcomes in the RCT. (4). To assess the effects of demographic (sex, age, race) and clinical (executive function, stress/trauma) variables on primary and secondary predictors and on relapse risk. Exploratory Aim: To assess additional neurophysiological assessments such as heart rate variability, plasma immune responses, diffusion tensor imaging (DTI) of white matter integrity and resting state functional connectivity (rsFC) for changes during abstinence and for prediction of relapse. Successful completion of the proposed aims has the potential to identify the first set of clinical biomarkers of alcohol relapse that may be further developed for clinical use and be targeted for treatment development to significantly improve recovery outcomes in alcoholism.

Public Health Relevance

Alcoholism is a chronic relapsing illness with significant neuroendocrine, brain and behavioral adaptations that are associated with increased stress, alcohol craving and high alcohol relapse risk. This project will validate recently identified novel predictive measures of future relapse using novel multi-method approaches and develop prognostic biomarkers of alcohol relapse and treatment failure. Findings have high clinical relevance as they will identify the first set of clinical biomarkers of alcohol relapse that may thn be further developed for clinical use and be targeted for treatment development to improve alcoholism recovery rates in treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013892-15
Application #
9691083
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Roach, Deidra
Project Start
2003-03-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kong, Xiang-Zhen; Mathias, Samuel R; Guadalupe, Tulio et al. (2018) Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proc Natl Acad Sci U S A 115:E5154-E5163
Goldfarb, Elizabeth V; Sinha, Rajita (2018) Drug-Induced Glucocorticoids and Memory for Substance Use. Trends Neurosci 41:853-868
Milivojevic, Verica; Ansell, Emily; Simpson, Christine et al. (2017) Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers. Alcohol Clin Exp Res 41:585-595
Blaine, Sara K; Sinha, Rajita (2017) Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders. Neuropharmacology 122:136-147
Seo, Dongju; Ahluwalia, Aneesha; Potenza, Marc N et al. (2017) Gender differences in neural correlates of stress-induced anxiety. J Neurosci Res 95:115-125
Fox, Helen C; Milivojevic, Verica; Angarita, Gustavo A et al. (2017) Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving. J Psychopharmacol 31:883-892
Milivojevic, Verica; Sinha, Rajita (2017) Targeting Stress Pathophysiology to Improve Alcoholism Relapse Outcomes. Neuropsychopharmacology 42:987-988
Zakiniaeiz, Yasmin; Scheinost, Dustin; Seo, Dongju et al. (2017) Cingulate cortex functional connectivity predicts future relapse in alcohol dependent individuals. Neuroimage Clin 13:181-187
Milivojevic, Verica; Fox, Helen C; Jayaram-Lindstrom, Nitya et al. (2017) Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence. Drug Alcohol Depend 179:275-279
Blaine, Sara K; Seo, Dongju; Sinha, Rajita (2017) Peripheral and prefrontal stress system markers and risk of relapse in alcoholism. Addict Biol 22:468-478

Showing the most recent 10 out of 54 publications