DESCRIPTION (provided by applicant): Even after decades of careful research, neuroscientists still do not fully understand the neurobiological mechanisms that lead to alcoholism and relapse drinking. Recent advances in neuroimaging technologies have revealed the existence of resting state brain networks that mediate various aspects of cognitive and behavioral functions. However, very little is known about the function of these networks in alcoholism. Of particular interest is the cortical salience network (CSN), which detects internal states such as alcohol intoxication. The CSN, which is anchored by the insula and the anterior cingulate gyrus (ACC), plays a key role in assigning emotional attributes and salience to internal stimuli, and integrates this information to influence behavioral output. Additionally, the insula and ACC are innervated by dopamine (DA), a neurotransmitter heavily implicated in alcoholism and other addictions. We propose that aberrant functioning of the CSN during alcohol intoxication may underlie the development of alcohol use disorders, tolerance, and loss-of-control drinking. The functional and neurochemical signatures of the CSN may prove to be useful tools for development of therapeutic strategies and prediction of treatment response. The long-term goal of this work is to understand the relationships among the CSN, cortical DA, alcohol intoxication, and hazardous drinking behavior. The primary objective of this R21 pilot proposal is to begin a systematic characterization of the CSN with respect to functional connectivity and dopamine D2/D3 receptors. The central hypothesis is that the cortical salience network functions differently in social drinkers (SD) and nontreatment-seeking alcoholics (NTS). The primary endpoints of this study are: (i) functional connectivity of the cortical salience network (fcCSN), as assessed by fMRI and the blood-oxygenation-level-dependent signal, and (ii) relative DA tone, as indexed by DA D2/D3 receptor availability via PET and [18F]fallypride (FAL). We will test the following specific hypotheses: (1) fcCSN will be increased in NTS compared to SD; (2) alcohol intoxication affects fcCSN differently in NTS and SD; (3) insular and ACC D2/D3 receptor availability are related to fcCSN, and these relationships are altered in NTS; (4) alcohol intoxication increases DA levels in the insula and ACC. Ten SD and ten NTS subjects will receive two sets of resting-state MRI and FAL PET scans. One set of scans will be acquired during a baseline state; the other set will be acquired during alcohol intoxication maintained by an IV alcohol infusion at a target breath alcohol concentration of 80mg%. Independent components analysis will be used to quantify fcCSN. Reference region graphical analysis methods will be used to estimate FAL binding potential (BP). Changes in DA levels between alcohol and baseline will be inferred from changes in FAL BP between conditions. The knowledge to be gained from the extension of this work will significantly advance the field of alcohol research by providing novel and important information about how the cortical salience network is related to hazardous alcohol consumption.
|Effective start/end date||5/1/14 → 4/30/16|
- National Institutes of Health: $176,595.00
- National Institutes of Health: $221,030.00