Epi-Genetic Modulators of Fear Extinction in Alcohol Dependence
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|ClinicalTrials.gov Identifier: NCT02438969|
Recruitment Status : Recruiting
First Posted : May 8, 2015
Last Update Posted : June 22, 2020
- 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.
- 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.
- Adults ages 21-65 with and without an alcohol use disorder (AUD) and with and without ELS.
- Healthy volunteers.
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.
- 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.
|Condition or disease|
|Fear Stress Alcohol Dependence|
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.
The study sample includes two patient groups and two control groups:
- treatment-seeking or non-treatment-seeking individuals with AUD and ELS exposure;
- treatment-seeking or non-treatment-seeking individuals with AUD without ELS exposure;
- healthy volunteers with ELS exposure;
- healthy volunteers without ELS exposure.
Target accrual for each of these groups is 25.
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.
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.
|Study Type :||Observational|
|Estimated Enrollment :||120 participants|
|Official Title:||(Epi)Genetic Modulators of Fear Extinction in Alcohol Dependence|
|Actual Study Start Date :||August 13, 2015|
|Estimated Primary Completion Date :||December 31, 2021|
|Estimated Study Completion Date :||December 31, 2021|
Treatment-seeking or non-treatment-seeking individuals with AUD and ELS exposure
Treatment-seeking or non-treatment-seeking individuals with AUD without ELS exposure
Healthy volunteers with ELS exposure
Healthy volunteers without ELS exposure
- The primary objective of the study is to evaluate the role and interaction of epigenetic /genetic factors, ELS exposure, and AUD on neuronal mechanisms of fear conditioning and extinction. [ Time Frame: Ongoing ]Fear extinction, measured by fMRI paradigms
- Explore the influence of genetic variants and epigenetic factors on fear extinction in AUD and non-AUD participants w/w-out ELS; examine differences in reward and emotion processing; examine relationship btwn fear extinction and clinical outcome... [ Time Frame: Ongoing ]Examine the differences in reward and emotion processing, and neural response to alcohol
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02438969
|Contact: Falk W Lohoff, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Falk W Lohoff, M.D.||National Institute on Alcohol Abuse and Alcoholism (NIAAA)|