This Mentored Research Scientist Development Award application proposes support for Ansel Hillmer, Ph.D., in his transition to independent research using neuroimaging to study alcohol use disorders in humans. Glutamate's role in both alcohol dependence and neuroplasticity make it a critical system to examine the neurochemical underpinnings of dynamic changes in brain structure and function in alcohol dependence and withdrawal. The goal of this proposed research is to study the role of the metabotropic glutamate 5 receptor (mGluR5), a promising target for alcohol dependence therapeutics, in neural reorganization during alcohol withdrawal. Specific focus is given to examining relationships between neurochemical changes and clinical correlates of alcohol dependence throughout the course of withdrawal. We propose to perform longitudinal neuroimaging in 40 alcohol dependent patients during withdrawal at 7-10 days abstinence and 4 weeks abstinence, and single sessions in 30 matched healthy controls. The recruitment and evaluation of alcohol dependent patients will be mentored by Kelly Cosgrove, Ph.D. and Stephanie O'Malley, Ph.D. Neuroimaging sessions will feature 18F-FPEB PET scans to measure mGluR5 availability, and resting state fMRI connectivity to examine neural organization. First, we will assess differences in both mGluR5 availability and resting state connectivity in patients longitudinally and relative to controls. Next, we will determine relationships of neuroimaging measures with clinical and cognitive correlates of alcohol dependence. The acquisition and analysis of mGluR5-specific PET data will be mentored by Dr. Cosgrove and Richard Carson, Ph.D.; while acquisition and analysis of connectivity measures will be mentored by Todd Constable, Ph.D. Finally, we will develop analysis methods, using techniques such as parallel Independent Component Analysis, to analyze multimodal mGluR5 PET and whole-brain connectivity data in synergy. This work will be co-mentored by Drs. Carson, Constable, and Godfrey Pearlson, Ph.D. These proposed experiments will provide insight into possible uses of mGluR5 therapeutics for alcohol dependence, examine how clinical correlates of dependence change during withdrawal in relation to mGluR5 function and neural organization, and develop analysis methods evaluating neurotransmitter-specific function in neuronal connectivity. The research experience will be supported by a complementary training plan providing scientific development in four key areas: clinical alcohol research, functional Magnetic Resonance neuroimaging (fMRI), Positron Emission Tomography (PET) neuroimaging, and responsible conduct of research. Thus this K01 award will advance the field's understanding of evolving brain function during alcohol withdrawal, and supply a uniquely qualified scientist blending innovative techniques from clinical alcohol research and neuroimaging to advance future understanding of brain dysfunction in alcohol use disorders.

Public Health Relevance

This study will extend our understanding of dynamic changes in brain structure and function during alcohol withdrawal. The findings will guide investigation of future pharmacotherapeutic strategies to improve treatment outcome following alcohol withdrawal, which is a critical need for individuals with this chronically relapsing condition to advance patient outlook and reduce its impact on society.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Matochik, John A
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Yale University
Schools of Medicine
New Haven
United States
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Bhatt, Shivani; Hillmer, Ansel T; Nabulsi, Nabeel et al. (2018) Evaluation of (-)-[18 F]Flubatine-specific binding: Implications for reference region approaches. Synapse 72: