Epi-Genetic Modulators of Fear Extinction in Alcohol Dependence
Condition: Fear; Stress; Alcohol Dependence
MeSH terms: Alcoholism
Study type: Observational

Summary: 
      Background:

      - Researchers want to learn if people with alcohol dependence have more difficulty learning
      to feel calm, or learn to fear things more easily. They also want to study how early life
      stress (ELS) affects the ability to learn to feel calm.

      Objective:

      - To see if people with alcohol dependence and/or ELS have a harder time learning to feel
      calm than people without these. Also, to see if DNA is changed by ELS and if this change
      affects fear conditioning and extinction.

      Eligibility:

        -  Adults ages 21-65 with and without an alcohol use disorder (AUD) and with and without
           ELS.

        -  Healthy volunteers.

      Design:

        -  Participants will be screened with:

             -  Medical history

             -  Physical exam

             -  Blood and urine tests

             -  Psychological tests

             -  Treatment for symptoms of alcohol withdrawal, if needed

        -  Healthy volunteers will have 1 overnight visit (2 days, 1 night). AUD participants will
           stay at the clinic for about 4 weeks.

        -  Participants will:

             -  Rate alcohol use/craving, depression, anxiety, and childhood trauma.

             -  Have psychophysiological measures: electrodes and mild electric shock.

        -  Have a functional magnetic resonance imaging (MRI) scan. Participants will lie on a
           table in a metal cylinder with a coil over their head. In the first scanning session,
           they will see pictures, do a simple task, and may get shocks. Participants will also do
           a second scanning session in which they will perform the aforementioned fear
           conditioning and extinction task, as well as a facial expression matching task, an
           affective word processing task, and a task measuring valuation of monetary rewards.

             -  Answer questions about their emotions (some participants).

             -  Have blood drawn from an arm vein or intravenous (IV) line.

             -  AUD participants will get a dexamethasone pill. The next day, they will get a
                hormone injected in and have blood drawn from an IV line.

        -  AUD participants will have 3 follow-up visits with questions and blood and lab tests.
    

Detailed description: 
      Objective:

      The primary goal of this study is to evaluate the role and interaction of (epi)genetic
      factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal
      mechanisms of fear conditioning and extinction.

      The central hypothesis is that participants with AUD and ELS will have disrupted fear
      extinction, and in addition, those with ELS will also have disrupted fear extinction. AUD
      with ELS will have the most severe disruption of fear extinction as observed clinically in
      alcoholics with severe trauma - often presenting with the most severe phenotypes and being
      most treatment resistant. A disruption in fear extinction or living in constant fear after
      stress/trauma could thus put the individual at risk for AUD.

      Identification and characterization of the neurobiological correlates underlying this
      mechanism is thus essential and could provide new avenues for treatment of AUD; namely
      developing interventions that normalize abnormal fear extinctions. These interventions could
      be for example, cognitive-behavior based or molecular by targeting genetic/epigenetic
      pathways potentially identified.

      Our proposal, if successful, will first establish a reliable measureable endophenotype of
      fear extinction in AUD/ELS, both behaviorally (skin conductance response) and neuronal (using
      an fMRI paradigm). Furthermore, we will carry out exploratory genetic and epigenetics studies
      that might influence these measures. This model can then be used in follow up studies for
      novel therapeutic interventions that could target treatment of these mechanisms in AUD.

      Study Population:

      The study sample includes two patient groups and two control groups:

        1. treatment-seeking or non-treatment-seeking individuals with AUD and ELS exposure;

        2. treatment-seeking or non-treatment-seeking individuals with AUD without ELS exposure;

        3. healthy volunteers with ELS exposure;

        4. healthy volunteers without ELS exposure.

      Target accrual for each of these groups is 25.

      Design:

      Subjects will be evaluated for fear conditioning and extinction using shock conditioning
      (extinction procedure combined with fMRI imaging that utilizes galvanic skin response). All
      participants will undergo whole-genome methylome analyses to assess genome wide methylation
      patterns. Genotyping of variants in candidate genes implicated in the biology of fear
      conditioning/extinction will be carried out.

      Outcome Parameters:

      The primary outcome of interest is fear extinction, measured by fMRI paradigms. Secondary
      objectives include: (1) explore the role of genetic variants and epigenetic factors and their
      impact on fear extinction in AUD and healthy controls with or without ELS; (2) explore
      differences in reward processing and emotion processing, measured by fMRI as a function of
      AUD, ELS, and (epi)genetic modulators; and (3) examine the relationship between fear
      extinction and clinical outcomes in both AUD and ELS participants sample.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        AUD participants will be recruited from participants in the NIAAA screening platform
        protocols 14-AA-0181. Non-AUD participants will be recruited from participants in the NIAAA
        protocol 14-AA-0181. We will recruit all racial and ethnic groups in the greater Washington
        DC area
      
Keywords: Alcohol; Alcohol Dependence; Stress; Fear Conditioning; Natural History