Epi-Genetic Modulators of Fear Extinction in Alcohol Dependence
| Status: | Recruiting |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 21 - 65 |
| Updated: | 8/10/2018 |
| Start Date: | May 5, 2015 |
| End Date: | December 30, 2020 |
| Contact: | Falk W Lohoff, M.D. |
| Email: | falk.lohoff@nih.gov |
| Phone: | (301) 827-1542 |
(Epi)Genetic Modulators of Fear Extinction in Alcohol Dependence
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.
- 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.
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.
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.
- INCLUSION AND EXCLUSION CRITERIA:
Inclusion and exclusion criteria will be evaluated following screening conducted under the
NIAAA screening protocols (98-AA-009 and/or 14-AA-0181).
INCLUSION CRITERIA:
INCLUSION CRITERIA FOR AUD GROUP:
- Between 21 and 65 years of age
- Ability to provide written informed consent as determined by successful completion of
consent quiz prior to signing consent
- Females: Negative urine pregnancy test, not currently breastfeeding, agree to abstain
or use accepted form of contraception
- Diagnosed with current alcohol dependence according to Diagnostic and Statistical
Manual for Mental Disorders-Fourth Edition (DSM IV)
- Alcohol consumption within the past month provided by self-report
- Specify alcohol as their preferred drug in a clinical interview
- 98-AA-0009 and/or 14-AA-0181 screening consents signed
- Cleared venous access assessment
- Additional inclusion criteria for non-treatment seeking AUD: Able and willing to
abstain from consuming alcohol 1 day prior to each study visit
INCLUSION CRITERIA FOR NON-AUD (HEALTHY VOLUNTEER) GROUP:
- Between 21 and 65 years of age
- Ability to provide written informed consent as determined by successful completion of
consent quiz prior to signing consent
- Females: Negative urine pregnancy test, not currently breastfeeding, agree to abstain
or use accepted form of contraception
- 98-AA-0009 and/or 14-AA-0181 screening consents signed
- Cleared venous access assessment
EXCLUSION CRITERIA:
EXCLUSION CRITERIA FOR AUD GROUP:
- Neurological symptoms of the wrist or arm, e.g., carpal tunnel syndrome, as determined
by history and physical exam
- Chronic use of psychotropic medications within four weeks of the study, with the
exception of fluoxetine, for which the exclusionary time period is six weeks.
Incidental use of psychotropic medications is allowed, but any use must be
discontinued prior to the study for a time period exceeding 5 half-lives of the
medication in question.
- Presence of any current or past DSM IV diagnosis of bipolar disorder, or psychotic
disorder (e.g, schizophrenia, schizoaffective disorder), or current substance
dependence other than alcohol, nicotine, or caffeine.
- Major medical problems (e.g., central nervous system (CNS), cardiovascular,
respiratory, gastrointestinal (GI), hepatic, renal, endocrine, HIV, reproductive) that
in the judgment of the PI, in consultation with relevant Clinical Center consult
services, cannot be adequately managed at the Clinical Center.
- Presence of ferromagnetic objects in the body, fear of enclosed spaces, or other
standard contraindication to MRI, as determined by self-report
- Left-handedness
- Use of intrauterine device (IUD)
- Excluded from the optional DEX-CRH test if:
- Allergy to dexamethasone or CRH
- Use of medications that can affect the results of the test, including certain
antibiotics, anti-seizure drugs, corticosteroids, and hormonal contraception
- Additional exclusionary criteria for non-treatment seeking AUD:
- Presence of significant alcohol withdrawal symptoms, defined as a CIWA-Ar > 8.
- History of epilepsy or alcohol-related seizures.
- Are currently seeking treatment for alcohol problems
EXCLUSION CRITERIA FOR NON-AUD (HEALTHY VOLUNTEER) GROUP:
- Neurological symptoms of the wrist or arm, e.g., carpal tunnel syndrome, as determined
by history and physical exam.
- Chronic use of psychotropic medications within four weeks of the study, with the
exception of fluoxetine, for which the exclusionary time period is six weeks.
Incidental use of psychotropic medications is allowed, but any use must be
discontinued prior to the study for a time period exceeding 5 half-lives of the
medication in question.
- Presence of any current or past DSM IV diagnosis of bipolar disorder, or psychotic
disorder (e.g, schizophrenia, schizoaffective disorder), or substance dependence other
than nicotine, or caffeine.
- Major medical problems (e.g., CNS, cardiovascular, respiratory, GI, hepatic, renal,
endocrine, HIV, reproductive) that in the judgment of the PI, in consultation with
relevant Clinical Center consult services, cannot be adequately managed at the
Clinical Center
- Presence of ferromagnetic objects in the body, fear of enclosed spaces, or other
standard contraindication to MRI, as determined by self-report
- Current or past DSM IV diagnosis of alcohol dependence or abuse
- Currently seeking treatment for alcohol problems as assessed by self-report
- Positive urine drug test at screening (for opiates, cannabinoids, amphetamines,
cocaine, benzodiazepines)
- Positive breathalyzer test at screening
- Alcohol abstainer (never consumed alcohol in entire life)
- Left-handedness
- Use of intrauterine device (IUD)
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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