Clinical trial NCT04292444: Effects of Oxytocin on Cognitive and Reactive Fear
Official title: Disentangling Effects of Oxytocin on Cognitive and Reactive Fear and the Moderating Role of the Receptor for Advanced Glycation End-products
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Oxytocin
Keywords: fMRI
receptor for advanced glycation end-products (RAGE)
fear
7T MRI
Lead sponsor: University Hospital, Bonn
Sponsor class: OTHER
First posted: 2020-03-03
Enrollment: 60
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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).
Primary purpose: BASIC_SCIENCE

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Neural substrates of emotion processing, measured via blood-oxygen-level dependent (BOLD) signal in the amygdala and striatum
timeFrame: 30 minutes after nasal spray administration
measure: Neural responses in the flight initiation distance (FID) task
timeFrame: 45 minutes after nasal spray administration
measure: Flight distance and difficulty ratings in the flight initiation distance (FID) task
timeFrame: 45 minutes after nasal spray administration
Secondary outcomes:
measure: Oxytocin concentration in blood plasma
timeFrame: 10 minutes before nasal spray administration and 75 minutes after nasal spray administration
measure: Concentration of receptor for advanced glycation endproducts (extracellular domain) in blood plasma
timeFrame: 10 minutes before nasal spray administration
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: Department of Psychiatry and Medical Psychology
Study officials:
affiliation: University of Oldenburg
name: Rene Hurlemann, MSc, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Hudson BI, Stickland MH, Futers TS, Grant PJ. Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes. 2001 Jun;50(6):1505-11. doi: 10.2337/diabetes.50.6.1505.
citation: Qi S, Hassabis D, Sun J, Guo F, Daw N, Mobbs D. How cognitive and reactive fear circuits optimize escape decisions in humans. Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):3186-3191. doi: 10.1073/pnas.1712314115. Epub 2018 Mar 5.
citation: Yamamoto Y, Liang M, Munesue S, Deguchi K, Harashima A, Furuhara K, Yuhi T, Zhong J, Akther S, Goto H, Eguchi Y, Kitao Y, Hori O, Shiraishi Y, Ozaki N, Shimizu Y, Kamide T, Yoshikawa A, Hayashi Y, Nakada M, Lopatina O, Gerasimenko M, Komleva Y, Malinovskaya N, Salmina AB, Asano M, Nishimori K, Shoelson SE, Yamamoto H, Higashida H. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun Biol. 2019 Feb 25;2:76. doi: 10.1038/s42003-019-0325-6. eCollection 2019.
citation: 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.