Biological Basis of Individual Variation in Social Cooperation

Condition(s) targeted: Healthy

Intervention: Intranasal Oxytocin (Drug); Intranasal Vasopressin 40 or 20 units (Drug); Intranasal Vasopressin (Drug); Intranasal Placebo OT Vehicle (Drug); Intranasal Placebo Saline (Drug); Intranasal Placebo AVP Vehicle (Drug); Lorazepam (Drug)

Phase: N/A

Status: Enrolling by invitation

Sponsored by: James K. Rilling, PhD

Official(s) and/or principal investigator(s):
James K Rilling, Ph.D., Principal Investigator, Affiliation: Emory University

The overall objective of this project is to explore the biological bases of individual variation in cooperative social behavior among normal subjects, with the goal of developing hypotheses to explain more extreme variation that manifests as mental illness. Cooperative behavior will be measured in an interactive social task known as the Prisoner's Dilemma (PD) Game. There are eight specific aims. Aim 1 is to examine the relationship between individual variation in cooperative behavior and individual variation in brain function during the PD game. This will be accomplished by imaging subjects' brains with functional Magnetic Resonance Imaging (fMRI) as they play many rounds of the PD Game with two assumed human partners. Aim 2 is to examine the relationship between individual variation in cooperative behavior and individual variation in prefrontal cortex anatomy. This aim will involve acquiring a structural Magnetic Resonance Imaging (MRI) scan from each subject to measure morphometric variation, as well as a diffusion tensor imaging (DTI) brain scan to measure white matter integrity. Aim 3 is to investigate the impact of intranasal oxytocin (OT) and vasopressin (AVP), neuropeptides associated with social bonding, on cooperative behavior and associated brain activity. In this placebo-controlled, double-blind experiment, subjects will be randomized to one of three conditions: intranasal oxytocin (OT) administration, intranasal vasopressin (AVP) administration, or intranasal placebo administration. Functional brain activity and behavior will be compared across treatment groups. Aim 4 is to examine the effect of oxytocin (OT) and vasopressin (AVP) on cortisol levels. Aim 5 is to examine the relationship between individual variation in cooperative behavior and individual genetic variation. Saliva samples will be collected from each subject for analysis of genes hypothesized to have an influence on cooperative social behavior. Aim 6 is to examine the relationship between individual variation in cooperative behavior and individual variation in personality, as assessed by personality tests. Aim 7 is to examine the relationship between individual variation in social intelligence and individual variation in brain anatomy. Aim 8 is to use functional Magnetic Resonance Imaging (fMRI) to test the effect of vasopressin (AVP) on neural responses to faces, which are powerful social signals important for emotional communication. Aim 9 is to use fMRI to investigate the brain regions active during an empathy and perspective-taking task. Aim 10 involves testing the effect of OT on both empathy-related behavior and functional brain activation, using a within-subjects placebo-controlled design. Aim 11 investigates the role of early life experience, spirituality, self-reported prosocial activities, and general cognition on empathic and cooperative behavior. Aim 12 is to examine the neural and behavioral effect of Lorazepam used as a challenge agent in the context of iterated PD game in healthy controls. Aim 13 is to examine the effect of OT on behavior and brain activity of unmedicated depressed or anxious men in the context of the iterated PD game. Aim 14 is to determine if DNA methylation of the oxytocin receptor gene (OXTR) modulates the effect of intranasal OT on cooperative behavior and associated brain activity in humans subjects immersed in genuine social interactions.

Official title: The Biological Basis of Individual Variation in Social Cooperation

Study design: Allocation: Randomized, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Primary outcome: Functional Magnetic Resonance Imaging (fMRI) Data

Secondary outcome:

Plasma levels of Vasopressin (AVP)

Behavioral data

Plasma levels of Oxytocin (OT)

Plasma levels of Testosterone

Detailed description: Hypothesis 1a: Compared with less cooperative subjects, more cooperative subjects will show either 1) stronger activation in ventral striatum or OFC in response to reciprocated cooperation, 2) stronger activation in OFC during decision-making, 3) weaker activation in right anterior insula in response to unreciprocated cooperation, or 4) weaker activation within DLPFC during decision-making. Hypothesis 2a: Measures of cooperative behavior will be negatively correlated with relative gray matter volume and white matter integrity (FA) in DLPFC and positively correlated with relative gray matter volume and white matter integrity (FA) in OFC. Hypothesis 3a: In men, intranasal vasopressin administration will: 1) decrease rates of cooperation, 2) decrease activation in OFC during decision-making 3) decrease activation in ventral striatum or OFC in response to reciprocated cooperation, 4) increase activation in anterior insula in response to unreciprocated cooperation and 5) decrease activation in DLPFC during decision-making. Hypothesis 3b: In women, intranasal vasopressin administration will: 1) increase rates of cooperation, 2) increase activation in OFC during decision-making 3) increase activation in ventral striatum and OFC in response to reciprocated cooperation and 4) decrease activation in anterior insula in response to unreciprocated cooperation, 5) decrease activation in DLPFC during decision-making. Hypothesis 3c. In both men and women, intranasal oxytocin administration will 1) increase cooperative behavior in the Prisoner's Dilemma Game, 2) increase activation within OFC during decision-making 3) increase activation within the ventral striatum and OFC in response to reciprocated cooperation 4) decrease activation within right anterior insula in response to unreciprocated cooperation, and 5) decrease activation within DLPFC during decision-making. Hypothesis 4a. Salivary cortisol levels will increase in AVP treated subjects and will decrease in OT treated subjects relative to a pre-drug baseline measurement. This change from baseline will be more pronounced after the social interaction in the PD game. Hypothesis 4b. Baseline plasma CRP levels will be inversely correlated with cooperation and positively correlated with neural responses to unreciprocated cooperation. Hypothesis 5a. Longer promoter region repeat lengths of AVPR1a, particularly RS3, will be associated with 1) higher rates of cooperative behavior, 2) stronger activation in regions activated by intranasal AVP and 3) a stronger effect of intranasal AVP administration on behavior and brain activity, presumably due to increased receptor expression and binding. Hypothesis 5b. OT SNP's that have been associated with autism will be associated with 1) decreased rates of cooperative behavior, 2) weaker activation in regions activated by intranasal OT and 3) a weaker effect of intranasal OT administration on behavior and brain activity. Hypothesis 5c. The dopamine D4 receptor (DRD4) exon III 4 repeat allele will be associated with 1) increased rates of cooperation and, 2) stronger activation within the ventral striatum and VMPFC in response to reciprocated cooperation. Hypothesis 5d. The long allele of the serotonin transporter promoter will be associated with 1) increased cooperative behavior in the PD Game, 2) increased activation within VMPFC during decision-making 3) increased activation within the ventral striatum and VMPFC in response to reciprocated cooperation and 4) decreases activation within right anterior insula, amygdala and brainstem in response to unreciprocated cooperation, 5) decreased activation within DLPFC during decision-making. Hypothesis 5e. The number of CAG repeats in AR will be positively correlated with cooperative behavior and negatively correlated with the BOLD fMRI response to unreciprocated cooperation (CD) within the amygdala and anterior insula. Hypothesis 6a. Cooperative behavior will be positively correlated with Warmth (E1), Altruism (A3), Openness to Ideas (O5), and Activity (E4) on the NEO-PIR, and with Reward Dependence (RD4, Dependence) and Persistence (PS4, Perfectionism vs. Pragmatism) on the TCI. Cooperative behavior will be negatively correlated with angry/hostility (N2) and depression (N3) on the NEO-PIR, with both Levenson and PPI psychopathy scores and with Novelty Seeking (NS3, Extravagance vs Reward) on the TCI. Hypothesis 7a. Social intelligence will be positively correlated with neocortical gray matter volume and white matter integrity, particularly within prefrontal cortex. Hypothesis 8a. In males viewing faces of other males, AVP treatment will 1) be associated with increased amygdala, septum, and lateral hypothalamus activation 2) be associated with increased functional connectivity between the amygdala and brainstem 3) be associated with an increased antisocial response, amplifying activation of brain circuits involved in recognizing a "foe" in the follow-up scan for male faces seen after AVP administration when compared to the male faces viewed after placebo administration. Hypothesis 8b. In males viewing female faces, AVP treatment will 1) increase ventral striatum and nucleus accumbens activation, and particularly the ventral pallidum if AVP stimulates affiliative responses associated with the formation of emotional attachments 2) increase activation within the neural circuit affected by opposite sex individuals with whom a pair bond has been established, including the anterior cingulate and insular cortices and, most notably, the ventral pallidum if AVP's long term affiliative effects are specifically related to an emotional attachment mechanism associated with pair bonding. Hypothesis 8c. In females viewing female faces, AVP treatment will 1) increase amygdala activation 2) will increase activation in the ventral striatum and ventral prefrontal, as both areas are activated by simulations of affiliative approach responses towards same sex friends (Guroglu et al., 2008) 3) increase patterns of functional connectivity between ventral striatum and ventral prefrontal cortex. Hypothesis 8d. In females viewing male faces, AVP treatment will 1) increase activation in prosocial circuits, including ventral striatum and ventral prefrontal cortex (Guroglu et al., 2008) if AVP stimulates affiliative responses towards men 2) increase activations towards male faces previously seen after AVP relative to those previously seen after placebo in the follow-up scan for neural circuits associated with "friends" and/or allies, including posterior cingulate, lateral orbitofrontal cortex, fusiform cortex, left insula, left putamen, and nucleus accumbens (Vrticka et al. 2009 and Singer et al., 2004) 3) increase areas activated by emotionally attached partners, including anterior cingulate, insular cortices, and ventral pallidum (Fisher et al., 2006) , if AVP affects affiliative responses towards men. Hypothesis 9a. The empathy task is expected to yield activation of cortical areas involved in cognitive evaluation of social interactions, including dorsomedial prefrontal cortex (DMPFC), superior temporal gyrus (STG), fusiform gyrus (FG), and temporal pole (TP), and the mirror-neuron system (inferior frontal and inferior parietal), as well as cortical regions that mediate affective components of empathy, such as the anterior cingulate cortex (ACC) and insula. Hypothesis 10a. We predict that OT administration will increase activation of social-cognition related structures in the empathy task. Further, in the empathy task we predict that OT will increase the strength of functional connectivity between cortical areas involved in perceptual analysis of the stimuli (specifically the areas in the superior temporal sulcus (STS) that process biological motion), with mirror-neuron areas involved in understanding action and areas involved in generating attributions of mental states (DMPFC, TPJ). Hypothesis 12a. We predict that, like OT, Lorazepam will attenuate the BOLD response to CD outcomes in regions involved in stress and anxiety. However, unlike OT, Lorazepam will not augment the BOLD response to CC outcomes in regions involved in reward and salience. Hypothesis 13a. We predict that, as in the healthy population, intranasal OT will both attenuate the BOLD fMRI response to unreciprocated cooperation and augment the BOLD fMRI response to reciprocated cooperation. Hypothesis 14: Methylation levels of OXTR will be related to the effect of intranasal OT (relative to placebo) on measures of cooperative behavior and associated brain activity as measured by fMRI

Minimum age: 18 Years. Maximum age: 30 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 18-30 years of age

- 21-30 for Faces component

- Normal or corrected-to-normal vision of 20/40

- Unmedicated depressed or anxious men between 18-22 years of age for Anxious and

Depressed component Exclusion Criteria:

- Pregnancy, recent birth, or breastfeeding

- History of seizures

- Neurological Disorder

- Current psychiatric disorder

- Previous psychiatric disorder (can be included as discretion of PI)

- Date last episode (if > 1 year, include; if <1 year, at discretion of PI)

- Current use of psychoactive drugs

- Previous use of psychoactive drugs (can be included as discretion of PI)

- Date last medicated _____Type of medication___________________________________

- Previous head trauma (can be included at discretion of PI)

- Alcoholism or substance abuse

- Hypertension

- Cardiovascular Disease

- Nephritis

- Diabetes

- Endocrine disease or malignancy

- Asthma (can be included as discretion of PI, if episodes are infrequent,

nonmedicated, and no active problems at time of study)

- Medication

- Frequency of episodes

- Date of last episode

- Migraines (can be included as discretion of PI, if episodes are infrequent,

nonmedicated, and no active problems at time of study)

- Medication

- Frequency of migraines

- Date of last migraine

- Claustrophobia (at discretion of PI)

Additional exclusion criteria for Lorazepam arm

- Acute narrow-angle glaucoma

- Compromised respiratory function (e. g. sleep apnea and chronic obstructive pulmonary

disease)

- Impaired renal and hepatic function

Emory University 1462 Clifton Rd, Atlanta, Georgia 30322, United States

Emory University Hospital, Atlanta, Georgia 30307, United States

Related publications:

Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005 Jun 2;435(7042):673-6.

Fisher H, Aron A, Brown LL. Romantic love: an fMRI study of a neural mechanism for mate choice. J Comp Neurol. 2005 Dec 5;493(1):58-62. Review.

Thompson RR, George K, Walton JC, Orr SP, Benson J. Sex-specific influences of vasopressin on human social communication. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7889-94. Epub 2006 May 8.

Vrticka P, Andersson F, Sander D, Vuilleumier P. Memory for friends or foes: the social context of past encounters with faces modulates their subsequent neural traces in the brain. Soc Neurosci. 2009;4(5):384-401. doi: 10.1080/17470910902941793. Epub 2009 Jul 27.

Singer T, Kiebel SJ, Winston JS, Dolan RJ, Frith CD. Brain responses to the acquired moral status of faces. Neuron. 2004 Feb 19;41(4):653-62.

Güroğlu B, Haselager GJ, van Lieshout CF, Takashima A, Rijpkema M, Fernández G. Why are friends special? Implementing a social interaction simulation task to probe the neural correlates of friendship. Neuroimage. 2008 Jan 15;39(2):903-10. Epub 2007 Sep 15.

Starting date: April 2008
Last updated: August 7, 2015