The Effect of Ethanol on Brain Activity
Condition: Healthy
Study type: Observational

Summary: 
      This study is divided into two parts; each designed to answer a separate but related
      question:

      Which brain regions are activated in humans by the rewarding properties of ethanol
      administration?

      Is it possible to demonstrate a conditioned response to a stimulus paired with rising blood
      alcohol concentrations (BAC) in humans and can this response be observed in the brain using
      functional magnetic resonance images (fMRI) techniques?

      Part 1. In order to determine which brain regions are activated by the rewarding properties
      of ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI
      techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic,
      mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show
      significant increases in cerebral blood flow. Healthy, non-alcoholic subjects will be given
      intravenous (IV) ethanol or placebo infusions on separate days. The infusions will have three
      phases. On each day, during the first phase a saline infusion will be used to measure basal
      brain blood flow. The second phase will be an ethanol infusion delivered at rates calculated
      to produce a BAC of 0.08 plus or minus 0.005 g/dl at 10 minutes. The rate of the infusion for
      the next 10 minutes (third phase) will be calculated to maintain BAC at the target level of
      0.08 plus or minus 0.005 g/dl for the duration of the infusion. On the placebo day, subjects
      will receive a saline infusion at the same set of rates for phases two and three as used
      during their ethanol infusion. Continuous multi-slice fMRI data will be collected during each
      infusion.

      Part 2. In order to investigate conditioned response to ethanol, three groups of healthy,
      non-alcoholic subjects will be given a series of IV infusions on separate days. The
      experimental group will receive ethanol infusion paired with a conditioned stimulus (CS)
      which will be presented while the BAC is rising. One control group (I) of healthy,
      non-alcoholic subjects will also be given a series of intravenous ethanol infusions on
      separate days, but these infusions will not be paired with a CS. The other control group (II)
      will be given only saline infusions during the CS presentation. After three training
      sessions, all three groups will undergo an fMRI scan during which the CS will be paired with
      saline infusion. This will allow the response to the CS alone to be observed. After 10
      minutes of CS presentation, the ethanol infusion will begin and continue for another 15
      minutes. Conditioned response (CR) will be demonstrated if the experimental group shows
      greater increase in BOLD signal than the control groups in motivation areas such as
      mesolimbic, mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain in
      response to the CS while they receive the saline infusion. Control group II will also undergo
      an fMRI scan and will be given saline infusion followed by ethanol infusion during their last
      15 minutes in the scanner to control for the non-specific effects of repeated infusions &
      scans on BOLD response to ethanol. If we are able to produce a CR in brain regions associated
      with motivation, it may be possible to use this CR as an experimental model for human alcohol
      craving.
    

Detailed description: 
      This study is designed to answer four questions:

        1. Which brain regions are activated in humans by the rewarding properties of ethanol
           administration?

        2. How does ethanol administration affect the brain response to visual cues known to evoke
           positive or negative emotion?

        3. Do individuals who regularly drink in ethanol in large amounts (heavy drinkers) differ
           from individuals who do not regularly drink large amounts of ethanol (social drinkers)
           in how ethanol affects brain function?

        4. Does ethanol administration affect the brain regions activated in a risk-taking task in
           social drinkers and heavy drinkers?

      In order to determine which brain regions are activated by the rewarding properties of
      ethanol administration, we propose to use Blood Oxygenation Level Dependent (BOLD) fMRI
      techniques to test the hypothesis that during the time of rising and peak BAC, mesolimbic,
      mesocortical, and nigrostriatal dopamine (DA) terminal areas of the brain will show
      significant increases in cerebral blood flow. Healthy, subjects who are not seeking treatment
      for an alcohol use disorder will be given intravenous (IV) ethanol or placebo infusions on
      separate days. An ethanol infusion will delivered at rates calculated to produce a BAC of
      0.08 plus or minus. An ethanol infusion will delivered at rates calculated to produce a BAC
      of 0.08 plus or minus 0.005 g/dl at 15 minutes. Then the rate of the infusion will be
      adjusted so that for the next 30 minutes (second phase) BAC will be maintained at the target
      level of 0.08 0.005 g/dl. On the placebo day, subjects will receive a saline infusion at the
      same set of rates as used during their ethanol infusion. Continuous multi-slice fMRI data
      will be collected during each infusion. During each infusion, BOLD response to visual stimuli
      designed to evoke emotion will also be examined. In addition, we will compare the BOLD
      response of healthy social drinkers to that of healthy heavy drinkers. We will also compare
      the BOLD response elicited by risk-taking during the ethanol infusion to that during the
      placebo infusion in both social and heavy drinkers.
    

Keywords: Ethanol; fMRI; Blood Flow; Conditioning; Reinforcement