Brain Dynamics of Oxytocin

Study Overview
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Brief Summary
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Oxytocin is a neuropeptide that is well known for its role in social and affiliative behavior in humans. Oxytocin receptors are significantly lowered in autistic individuals and administration of oxytocin has shown benefits in enhancing social recognition and behavior in autistic children. However, more recent research has refined the behavioral effects of oxytocin, moving away from the notion that the neuropeptide blindly induces love and trust, towards the view that it actually increases social perception in assessing friend vs. foe: supporting cohesion with 'insiders' and distrust and aggression for 'outsiders.' Oxytocin is responsible for the selective aggression shown by lactating female mammals protecting their young, an effect demonstrated also in humans, and has been shown to strengthen feelings of ethnocentrism. However, no neuroimaging study to date has investigated this effect, with the consequence that its neurobiological basis is still unknown. The general aim of our study is to determine meso-circuit brain dynamics that underlie oxytocin's amplification of both trust and aggression; and specifically, using neuroimaging (fMRI, magnetoencephalography, and behavioral testing) whether oxytocin amplifies kinship bias by attenuating social reward learning.

Detailed Description
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The purpose of the study is to understand how oxytocin affects brain and behavior. The study will compare Syntocinon Nasal Spray to placebo. The specific aims are to: Determine the default circuitry of oxytocin (OT). Determine time-course and gender differences for default neural response to OT. Using an iterative version of the classical neuroeconomic game (Trust Study), behaviorally test whether OT down-regulates reward learning, thereby enhancing the effects of kinship bias, to account for the polarizing effects (in which OT increases trust for 'in-groups' and increases aggression for 'out-groups'). Identify the down-regulation of reward learning neurobiologically, via data-driven control systems modeling of the reward circuit using MRI (fMRI: time-series analysis of the orbitofrontal cortex, amygdala, anterior and posterior cingulate, and nucleus accumbens, and magnetic resonance spectroscopy: focusing on gamma-Aminobutyric acid neurotransmitters within the nucleus accumbens) and magnetoencephalography (focusing on the dynamics within the prefrontal cortex). FMRI and MRS will be conducted during the same MRI scan, while MEG will be conducted separately. STUDY PROCEDURES: Nasal Obstruction/Anosmia Screening: All potential subjects will be screened for total or partial anosmia and nasal congestion using the University of Pennsylvania Smell Identification Test (Psychological Assessment Resources, Lutz FL). Pregnancy and Lactation Screening: Oxytocin is often used clinically to trigger labor in late-stage pregnancy. Although none of our subjects will be in late-stage pregnancy and subjects will be receiving dosages far smaller that those used to trigger labor, to be safe all potential female subjects will be urine screened for pregnancy immediately during the history and physical. Lactation screening will be performed via self-report, and is conducted to avoid confounds due to endogenously produced OT during the milk-ejection reflex. Oxytocin/Placebo Procedures: Oxytocin intranasal spray is manufactured as the Syntocinon Nasal Spray. The typical dose oxytocin of for short-term intranasal use is 40IU, and has an expected half-life of 20 minutes. Placebos, identical in preparation except for the oxytocin component, will be administered in the same manner in a double blind procedure. To avoid bleed-through between conditions while controlling for order effects, sessions will not be mixed between drug and placebo conditions: each session, conducted on separate days, will be either 'drug' or 'placebo.' Scanning Procedures: Scanning procedure for MRI will include: structural scan (6 minutes), fMRI or MRS resting state (10 minutes), and a neuroeconomic task scan (10 minutes). Scanning procedure for MEG will include: resting state (10 minutes), and a neuroeconomic task scan (20 minutes). Behavioral Task: During scans, subjects will participate in an interactive neuroeconomic game, an iterative version of the classical Trust Study. During this game, the subject ('investor') is first provided a sum of money. He then has the choice in terms of how much to invest in a fictional computer-generated trustee or, in forced-choice versions, to choose between different trustees. The trustee then sends some percentage back to the subject ('investor'), and the game iterates over many trials. Previous research has shown that OT disrupts participant's use of the optimal solution, eliciting greater trust in the trustee than would be expected by Nash Equilibrium. To modulate reward learning, algorithms for trustee behavior will be modulated towards greater and lesser generosity. To modulate kinship bias, trustees will be represented on the screen using faces of greater and lesser similarity to that of the subject, created using MorphMan video-editing software (STOIK Imaging, Moscow Russia).

Official Title
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Computational Modeling of Oxytocin in the Regulation of Trust

Conditions
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Brain Dynamics in Healthy Adults

Intervention / Treatment
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* Drug: Syntocinon Nasal Spray, 40IU
* Drug: Syntocinon Placebo Formulation, 40IU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-45 years of age Exclusion Criteria: any significant known medical condition, including mental disorders (confounds interpretation of brain activity) metal in the body or claustrophobia (contraindicated for fMRI) current use of any type of psychotropic medication (confounds interpretation of brain activity) body mass index of greater than 30 (to permit matched dosing across subjects) pregnancy (contraindicated for OT) breastfeeding (lactation endogenously triggers OT, which would not permit a placebo condition) smoking (affects use of nasal spray) use of drugs of abuse (confounds interpretation of brain activity) blood pressure above the normal range (140/90 mm Hg) or controlled with medication (may theoretically increase risk for OT side-effects) anosmia (affects use of nasal spray)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oxytocin<br>Healthy adult subjects will receive several puffs of Syntocinon Nasal Spray, 40IU, once, prior to MRI and/or MEG scanning. | Drug: Syntocinon Nasal Spray, 40IU<br>* Subjects will be scanned twice. Prior to first brain scanning session, they will be randomly assigned to receive either Syntocinon or Placebo. Prior to second scanning session, they will receive what they have not received in the first session; i.e., same subjects will be receiving both Syntocinon and placebo on two different days.<br>Drug: Syntocinon Placebo Formulation, 40IU<br>* Subjects will be scanned twice. Prior to first brain scanning session, they will be randomly assigned to receive either Syntocinon or Placebo. Prior to second scanning session, they will receive what they have not received in the first session; i.e., same subjects will be receiving both Syntocinon and placebo on two different days.<br>|
| Placebo Comparator: Placebo<br>Healthy adult subjects will receive several puffs of Syntocinon Placebo Formulation, 40IU, once, prior to MRI and/or MEG scanning. | Drug: Syntocinon Nasal Spray, 40IU<br>* Subjects will be scanned twice. Prior to first brain scanning session, they will be randomly assigned to receive either Syntocinon or Placebo. Prior to second scanning session, they will receive what they have not received in the first session; i.e., same subjects will be receiving both Syntocinon and placebo on two different days.<br>Drug: Syntocinon Placebo Formulation, 40IU<br>* Subjects will be scanned twice. Prior to first brain scanning session, they will be randomly assigned to receive either Syntocinon or Placebo. Prior to second scanning session, they will receive what they have not received in the first session; i.e., same subjects will be receiving both Syntocinon and placebo on two different days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Benevolent Rounds | This study recruited healthy adults. Subjects participated in an interactive neuroeconomic game, an iterative version of the classical Trust Study. During this game, the subject ('investor') is first provided a sum of money (20 units). He then has the choice in terms of how much to invest in a fictional computer-generated trustee. The trustee then sends some percentage back to the subject ('investor'), and the game iterates over 20 trials (rounds). We computed the investment ratio as the ratio of the actual investment and the maximum allowed amount of 20 units, and analogously for the repayment ratio. Benevolent rounds were defined as those with increased investment ratios even after a decreased repayment ratio. | Immediately after completion of the study, for each subject. | 
| Number of Malevolent Rounds | This study recruited healthy adults. Subjects participated in an interactive neuroeconomic game, an iterative version of the classical Trust Study. During this game, the subject ('investor') is first provided a sum of money (20 units). He then has the choice in terms of how much to invest in a fictional computer-generated trustee. The trustee then sends some percentage back to the subject ('investor'), and the game iterates over 20 trials (rounds). We computed the investment ratio as the ratio of the actual investment and the maximum allowed amount of 20 units, and analogously for the repayment ratio. Malevolent rounds were defined as those with decreased investment ratios even after an increased repayment ratio. | Immediately after completion of the study, for each subject. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Connectivity Between OFC and AMY | During functional scans, subjects participated in an interactive neuroeconomic game, an iterative version of the classical Trust Study. Subjects participated in an interactive neuroeconomic game, an iterative version of the classical Trust Study. During this game, the subject ('investor') is first provided a sum of money (20 units). He then has the choice in terms of how much to invest in a fictional computer-generated trustee. The trustee then sends some percentage back to the subject ('investor'), and the game iterates over 20 trials (rounds). Using Dynamical Causal Modeling (DCM) we modeled the dynamic interaction between amygdala (AMY), nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC). We observed altered connectivity strength between AMY and OFC under OT as compared to PL conditions. | Within two weeks of enrollment completion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxytocin, trust, kinship, kin selection