Dissecting the Role of Estradiol in Mediating Gender-specific Anxiolytic and Prosocial Effects of Oxytocin (ESMory)

The study aims to examine a behavioral and neural framework for understanding the sex-specific effects of the neuropeptide oxytocin (OXT). Using hormonal, behavioral and neuroimaging readouts, it is planned to explore the interplay of OXT and estradiol as a potential mechanism mediating sexual dimorphic effects.

Study Overview

• Status: Completed
• Conditions: Oxytocin; Memory; Estrogen; Fear Extinction; Emotion Processing
• Intervention / Treatment: Drug: Oxytocin nasal spray; Drug: Estrogen Gel; Drug: Placebo Gel; Drug: Placebo nasal spray

Detailed Description

The study comprises two subprojects (Study 1 and Study 2). In Study 1, the investigators will compare the effects of OXT on fear extinction and fear recall as well as on emotion recognition between women and men. Additionally, the investigators plan to test whether a pretreatment with exogenous estradiol can be used to augment these OXT effects. In Study 2, the investigators will use functional magnetic resonance imaging (fMRI) to elucidate the effects of OXT-estradiol interactions on neural responses in an emotional face matching task and an emotional memory task. Half of the participants will be included in Study 1 and the other half in Study 2.

Study 1 contains three test sessions (after the screening). In the first session participants will complete a fear conditioning paradigm. The second session will take place on the following day and will start with the administration of estradiol gel (Divigel; 2 mg) or placebo (PLC). Three hours after the gel administration the participants will intranasally self-administer 24 IU of OXT or PLC under supervision and 30 min later a fear extinction task will commence, followed by an emotion recognition paradigm. A fear extinction recall task (identical with the fear conditioning task except for the electric shocks) will be conducted in the third session (with a 24-hours break between the second and the third session).

In Study 2, participants will be randomly assigned to four different treatment conditions (1. OXT + PLC gel; 2. OXT + estradiol gel; 3. PLC + PLC gel; 4. PLC + estradiol gel) after the screening session. The timing of the drug administration and blood sample collection will be identical to that of the second session of Study 1. The fMRI paradigms (resting state, emotional face matching and emotional memory) will start 30 minutes after nasal spray administration. Three days after the scanning, participants will be tested with a surprise recognition task, which includes pictures shown in the scanner and distractors.

• Study Type: Interventional
• Enrollment (Actual): 487
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Bonn, Germany, 53105
    • Deparment of Psychiatry and Medical Psychology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• right handed
• healthy male & female volunteers
• women will be tested in their follicular phase (Day 0-5)

Exclusion Criteria:

• smoking
• pregnancy
• hormonal contraception
• current psychiatric illness
• current psychiatric medication or psychotherapy
• Study 2: MRI contraindication (e.g. metal in body, claustrophobia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1. Oxytocin spray, 2. Estrogen gel	Drug: Oxytocin nasal spray; Intranasal administration of 24 International Units, Oxytocin will be given 30 minutes before the fear extinction task (Study 1) or fMRI measurement (Study 2).; Drug: Estrogen Gel; Participants received a single dose of estradiol gel (Estramon 2 mg estradiol, Hexal AG, Holzkirchen, Germany), applied to their shoulder, 3 hours prior to the fear extinction task (Study 1) or fMRI measurement (Study 2).
EXPERIMENTAL: 1. Oxytocin spray, 2. Placebo gel	Drug: Oxytocin nasal spray; Intranasal administration of 24 International Units, Oxytocin will be given 30 minutes before the fear extinction task (Study 1) or fMRI measurement (Study 2).; Drug: Placebo Gel; Participants received a single dose of the placebo gel (ultrasonic gel, 2 mg), applied to their shoulder, 3 hours prior to the fear extinction task (Study 1) or fMRI measurement (Study 2).
EXPERIMENTAL: 1. Placebo spray, 2. Estrogen gel	Drug: Estrogen Gel; Participants received a single dose of estradiol gel (Estramon 2 mg estradiol, Hexal AG, Holzkirchen, Germany), applied to their shoulder, 3 hours prior to the fear extinction task (Study 1) or fMRI measurement (Study 2).; Drug: Placebo nasal spray; The placebo spray contains the identical ingredients, except for the peptide itself. It will be given 30 minutes before the fear extinction task (Study 1) or fMRI measurement (Study 2).
PLACEBO_COMPARATOR: 1. Placebo spray, 2. Placebo gel	Drug: Placebo Gel; Participants received a single dose of the placebo gel (ultrasonic gel, 2 mg), applied to their shoulder, 3 hours prior to the fear extinction task (Study 1) or fMRI measurement (Study 2).; Drug: Placebo nasal spray; The placebo spray contains the identical ingredients, except for the peptide itself. It will be given 30 minutes before the fear extinction task (Study 1) or fMRI measurement (Study 2).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Electrodermal responses to fear-conditioned stimuli	In Study 1, electrodermal responses will be measured during the fear conditioning and fear extinction tasks. The paradigm is an adapted version of a validated fear-conditioning procedure. Before the start of the paradigm a baseline of electrodermal activity is recorded for 60 seconds. During the conditioning session four neutral conditioned stimuli (two CS+ A and two CS+ B) are paired with an aversive US (electric shock) in 75 % contingency, whereas two other neutral stimuli are never paired with the US (non-fear-associated stimulus [CS-]). In CS+ trials electric shocks are administered during the last 500 milliseconds of the trial. In the fear extinction session all CS+ and CS- are presented in the absence of electric shocks. Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	3 hours after gel administration and 30 minutes after nasal spray administration
Emotion recognition thresholds	In Study 1, emotion recognition will be measured. During the emotion recognition task, emotional faces are presented and participants are required to indicate the perceived emotion ("neutral", "fearful", "happy", "disgusted", "angry", "not sure") in a following self-paced phase. A Bayesian adaptive procedure ("QUEST") will be used to determine the stimulus presentation and to estimate individual emotion thresholds. Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	200 minutes after gel administration and 50 minutes after nasal spray administration
Resting state functional connectivity	In Study 2, resting state functional connectivity will be measured. The resting state fMRI analysis will focus on functional connectivity between regions-of-interest (ROIs) associated with emotional processing (i.e. amygdala, cingulate and prefrontal cortex, insula, striatal areas). Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	3 hours after gel administration and 30 minutes after nasal spray administration
Neural responses to emotional faces	In Study 2, neural responses to emotional faces will be measured. Functional magnetic resonance imaging will be performed to measure the blood-oxygen-level dependent signal in response to emotional faces. Analyses will focus on regions-of-interest associated with emotional processing (i.e. amygdala, cingulate and prefrontal cortex, insula, striatal areas). Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	190 minutes gel administration and 40 minutes after nasal spray administration
Neural responses to an emotional subsequent memory task	In Study 2, neural responses to an emotional subsequent memory task will be measured. Functional magnetic resonance imaging will be performed to measure the blood-oxygen-level dependent signal in response to emotional scenes. The investigators plan to analyze scenes depending on valence (positive, negative, neural) and sociality (social, non-social). Furthermore, remembered and non-remembered emotional pictures will be compared. To classify pictures as remembered and non-remembered, participants will perform a memory recognition task three days after the MRI scan. The recognition task will include pictures shown in the scanner and distractors. Analyses will focus on regions-of-interest associated with emotional processing and memory (i.e. amygdala, hippocampus, cingulate and prefrontal cortex, insula, striatal areas). Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	200 minutes after gel administration and 50 minutes after nasal spray administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in oxytocin plasma concentration	In both studies, blood samples will be collected 5 minutes before gel administration and 5 minutes after the last task.	5 minutes before gel administration and 5 minutes after the last task
Changes in estrogen plasma concentration	In both studies, blood samples will be collected 5 minutes before gel administration and 5 minutes after the last task.	5 minutes before gel administration and 5 minutes after the last task
Contingency ratings of fear-conditioned stimuli	In Study 1, during the first 3500 ms of a trial in the fear conditioning and fear extinction tasks participants will be required to indicate via button press whether they expect to receive an electric shock (yes, no, not sure). Oxytocin and estradiol baseline concentrations will be tested as moderator variables.	3 hours after gel administration and 30 minutes after nasal spray administration
Ultimatum game tasks	In Study 1, bargaining behavior will be measured in three different versions of the Ultimatum Game (restricted, unrestricted and computer ultimatum game). All participants will play as responders in the three versions. As a cover story, participants will be told that they play against real partners, who took part in previous experiments. In the restricted version of the Ultimatum Game, the proposer can only decide between two given options. As such, chosen offers are either framed as fair or unfair depending on the alternative option. In the unrestricted Ultimatum Game, the proposer can freely decide how to split 10 Euro. In addition, participants will complete 24 trials of a computer version of the unrestricted Ultimatum Game, in which the word "computer" will be shown instead of a picture of the proposer. Estradiol baseline concentrations will be tested as moderator variables.	150 minutes after gel administration
Delayed discounting task	In Study 1, subjects will perform a delayed discounting task in order to assess their control of impulsive preferences. Participants will be asked to choose between small immediate rewards and larger later rewards. Estradiol baseline concentrations will be tested as moderator variables.	170 minutes after gel administration
Changes in the Multifaceted Empathy Test (MET)	In Study 2, participants' empathy will be assessed with the Multifaceted Empathy Test (MET) which includes photographs showing people in emotionally charged situations. Participants will be asked to infer the mental states of the individuals shown (cognitive empathy) and to rate their emotional response to the picture (emotional empathy). Participants will perform the MET twice: 1. before the fMRI in the second session and and 2. three days following the fMRI. Estradiol baseline concentrations will be tested as moderator variables.	135 minutes after the gel administration on the fMRI acquisition day and three days after the fMRI acquisition day
Changes in the Prisoner's Dilemma	In Study 2, the investigators will use an iterated version of the prisoner's dilemma to evaluate the participant's cooperative behavior. The participants will have to decide multiple times whether they want to betray their opponent or whether they choose to cooperate. Participants will perform the Prisoner's Dilemma twice: 1. before the fMRI in the second session and and 2. three days following the fMRI.Estradiol baseline concentrations will be tested as moderator variables.	155 minutes after the gel administration on the fMRI acquisition day and three days after the fMRI acquisition day

Collaborators and Investigators

• Sponsor: University Hospital, Bonn

Publications and helpful links

General Publications

• Hariri AR, Tessitore A, Mattay VS, Fera F, Weinberger DR. The amygdala response to emotional stimuli: a comparison of faces and scenes. Neuroimage. 2002 Sep;17(1):317-23. doi: 10.1006/nimg.2002.1179.

Helpful Links

• Neuromodulation of Emotion (NEMO) research group

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 18, 2016
• Primary Completion (ACTUAL): January 25, 2020
• Study Completion (ACTUAL): January 25, 2020

Study Registration Dates

• First Submitted: March 30, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (ACTUAL): April 1, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 7, 2020
• Last Update Submitted That Met QC Criteria: April 3, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Oxytocin; fMRI; Memory; Estrogen; Emotion Processing
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Oxytocics; Oxytocin; Estrogens
• Other Study ID Numbers: ESMory

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No