Effects of Oxytocin on Cognitive and Reactive Fear

Study Overview
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Brief Summary
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The study examines the (sub)regional specificity of anxiolytic oxytocin (OXT) effects on emotional face processing and reactive and cognitive fear. Preliminary data indicate that the Receptor for Advanced Glycation End Products (RAGE) may regulate oxytocin transport into the brain. Thus, the study aims to replicate previous observations of oxytocin effects on the processing of fearful faces in the centro-medial amygdala and to assess whether a RAGE polymorphism (-374 T/A: rs1800624; TT vs. TA/AA), that has been shown to alter transcriptional activity, modulates anxiolytic OXT effects.

Detailed Description
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So far, no study examined selective oxytocin (OXT) effects on reactive (midbrain periaqueductal gray (PAG), central amygdala (CeA), hypothalamus, and the midcingulate cortex (MCC)) and cognitive fear (ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), hippocampus, and basolateral amygdala) and the reward system (striatum) with high spatial resolution. Previous studies showed that 7T functional magnetic resonance imaging (fMRI) results in a higher spatial resolution and specificity than 3T MRI in these brain regions and would thus allow for a more detailed characterization of the neural effects. To disentangle (sub)region-specific effects of OXT on task-related activations of the cingulate structures, the amygdala, the striatum, PAG and VMPFC, the investigators plan to acquire ultra-high field 7T fMRI data from healthy male participants while they perform (i) an emotional face matching task and (ii) a flight initiation distance (FID) task involving fast- or slow-attacking virtual predators that elicit distinct activations in the reactive and cognitive fear circuits. Furthermore, participants will be pre-stratified depending on RAGE polymorphisms to elucidate possible RAGE-related differential OXT effects.

Official Title
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Disentangling Effects of Oxytocin on Cognitive and Reactive Fear and the Moderating Role of the Receptor for Advanced Glycation End-products

Conditions
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Oxytocin

Intervention / Treatment
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* Drug: Oxytocin nasal spray
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RAGE polymorphism (-374 T/A: rs1800624; TT vs. TA/AA) healthy male volunteers right handed Exclusion Criteria: current psychiatric illness current psychiatric medication or psychotherapy MRI contraindication (e.g. metal in body, claustrophobia)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study is designed as a double-blind, within-subject, placebo-controlled, non-clinical trial and will involve healthy male participants (n = 60), who will be scanned twice in a randomized order after a single dose of intranasal OXT (24 IU) or placebo. Furthermore participants will be pre-stratified based on a RAGE polymorphism (-374 T/A: rs1800624; n = 30 with TT alleles and n = 30 with TA/AA alleles).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAGE polymorphism (TT)<br>30 participants with the RAGE polymorphism (-374 T/A: rs1800624; TT) will be selected and scanned twice. | Drug: Oxytocin nasal spray<br>* Intranasal administration of 24 International Units oxytocin 30 minutes before the start of the tasks.<br>Drug: Placebo<br>* The placebo nasal sprays contain identical ingredients except for the peptide itself (30 minutes before the start of the tasks).<br>|
| Experimental: RAGE polymorphism (TA/AA)<br>30 participants with the RAGE polymorphism (-374 T/A: rs1800624; TA/AA) will be selected and scanned twice. | Drug: Oxytocin nasal spray<br>* Intranasal administration of 24 International Units oxytocin 30 minutes before the start of the tasks.<br>Drug: Placebo<br>* The placebo nasal sprays contain identical ingredients except for the peptide itself (30 minutes before the start of the tasks).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neural substrates of emotion processing, measured via blood-oxygen-level dependent (BOLD) signal in the amygdala and striatum | Functional magnetic resonance imaging will be performed to measure the BOLD signal in response to emotional face stimuli. The investigators specifically plan to investigate neural responses to emotional faces in amygdala and striatal subregions. The BOLD signal in response to fearful faces relative to neutral faces and happy faces relative to neutral will be compared between the oxytocin and placebo sessions. To examine effects of the Receptor for Advanced Glycation End Products (RAGE), analyses of variance (ANOVAs) with the between subjects factor RAGE polymorphism (-374 T/A: rs1800624; TT vs. TA/AA) will be conducted on the second level. For analyses of fMRI data, default procedures of the software SPM12 will be adapted for ultra-high-field imaging. The family-wise error rate will be used to correct p-values for multiple comparisons and p < .05 will be considered significant. | 30 minutes after nasal spray administration | 
| Neural responses in the flight initiation distance (FID) task | Functional magnetic resonance imaging will be performed to measure the blood-oxygen-level dependent (BOLD) signal in a flight initiation distance (FID) task, involving fast-, medium- and slow-attacking virtual predators that elicit distinct activations in the reactive and cognitive fear circuits. BOLD signals to different predator velocities will be analyzed. Analyses will focus on regions-of-interest associated with the processing of cognitive fear (vmPFC, PCC, hippocampus, and basolateral amygdala) and reactive fear (midbrain PAG, central amygdala, hypothalamus, and the MCC) and the reward system (striatum). To examine effects of the Receptor for Advanced Glycation End Products (RAGE), ANOVAs with the between-subject factor RAGE polymorphism (-374 T/A: rs1800624; TT vs. TA/AA) will be conducted on the 2nd level. For the fMRI data, default procedures of the software SPM12 will be adapted for ultra-high-field imaging. | 45 minutes after nasal spray administration | 
| Flight distance and difficulty ratings in the flight initiation distance (FID) task | Behavioral data of the FID task (flight distance and difficulty ratings ) will be analyzed using mixed ANOVAs in the software SPSS with treatment (oxytocin vs. placebo) as within-subject factor and RAGE polymorphism (TT vs. TA/AA) as between-subject factor. Post-hoc t-tests will be Bonferroni-corrected. Behavioral data will be correlated with fMRI data of the FID task. | 45 minutes after nasal spray administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxytocin concentration in blood plasma | Blood samples will be collected before and after the nasal spray administration to assess changes in oxytocin concentrations. Oxytocin concentrations will be analyzed using mixed ANOVAs in SPSS with time (pre vs. post) and treatment (oxytocin vs. placebo) as within-subject factors and RAGE polymorphism (TT vs. TA/AA) as between-subject factor. | 10 minutes before nasal spray administration and 75 minutes after nasal spray administration | 
| Concentration of receptor for advanced glycation endproducts (extracellular domain) in blood plasma | Blood samples will be collected before the nasal spray administration to assess the RAGE (extracellular domain) concentration in blood plasma. RAGE concentrations will be compared between RAGE polymorphisms (TT vs. TA/AA) with independent t-tests. Furthermore, the investigators plan to examine if the RAGE concentration moderates the effects of oxytocin on primary and secondary outcomes. | 10 minutes before nasal spray administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fMRI, receptor for advanced glycation end-products (RAGE), fear, 7T MRI