Epi-Genetic Modulators of Fear Extinction in Alcohol Dependence

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:

• 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.

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)