Abstract

Oxytocin has a fundamental role in social behavior. In humans, supporting evidence shows that oxytocin enhances people's ability to trust or affiliate with others. A key question is whether differences in plasma oxytocin concentration in humans are related to people's differences in their social traits of personality and if such differences are reflected in the structural organization of brain areas responsive to the action of this hormone. We examined the correlation between oxytocin plasma levels and personality traits in 30 healthy subjects, tested with the Inventory revised neuroticism-extroversion-openness personality inventory (NEO-PI-R). By using the voxel-based morphometry technique, we also investigated changes in gray matter volume as a function of the plasma oxytocin level and NEO-PI-R scores. A positive correlation was found between plasma oxytocin and extraversion scores, a dimension that captures social affiliative tendencies. Moreover, we found an inverse correlation between plasma oxytocin and the volume of the right amygdala and the right hippocampus, 2 brain areas implicated in fear and anxiety. Finally, we showed that the amygdala-hippocampal complex correlate negatively with extraversion scores. Our findings provide evidence for a neural mechanism linking physiological oxytocin's variability and structural variation of brain regions relevant for emotion regulation to individual differences in affiliative personality traits.

Introduction

Social interactions are a source of both positive and negative experiences that shape people's personalities. Much evidence has accumulated implicating the neuropeptide oxytocin in a variety of behaviors important for social adaptation such as maternal care, affiliation, pair bonding, and social learning (Pedersen et al. 1982; Insel and Hulihan 1995). Oxytocin is also known for its role in reducing the feelings of stress and anxiety (McCarthy et al. 1996; Yoshida et al. 2009). The oxytocinergic system targets brain regions important for emotion regulation such as the amygdala, hippocampus, and brainstem (Lee et al. 2009). In humans, higher oxytocin plasma levels have been associated with trust (Zak et al. 2005), positive parenting styles (Gordon et al. 2010), and perception of a better quality of life (Light et al. 2005). We may speculate that these prosocial behaviors associated with the higher levels of oxytocin reflect individual's' social tendencies and personalities. An important question is whether the level of endogenous oxytocin can be a biomarker of the degree of engagement of individuals in their social life. Indirect support for this idea comes from animal research. For instance, contrary to solitary montane voles, prairie voles show the high levels of affiliation associated with highest density of oxytocin receptors (OXTRs) in areas crucial for reward processing (Insel and Shapiro 1992; Olazabal and Young 2006). Although social relationships are arguably far more complex in humans than in other species, oxytocin levels may nevertheless be related to our social responses and our personality traits. This may in turn be reflected in the structure of brain areas targeted by oxytocin.

It has been proposed that oxytocin favors attachment and social cooperation by reducing fear and stress generated by social proximity (McCarthy et al. 1996; Andari et al. 2010). Functional magnetic resonance imaging studies show that oxytocin administration attenuates amygdala activity, a brain region involved in the detection of negative cues (Adolphs et al. 2005), during prosocial behaviors or perception of emotional faces (Kirsch et al. 2005; Domes, Heinrichs, Glascher, et al. 2007; Domes, Heinrichs, Michel et al. 2007; Baumgartner et al. 2008; Petrovic et al. 2008). However, oxytocin also increases the activity of another subregion of the amygdala during the classification of happy faces or when subjects shift their gaze toward the eye region regardless of the emotional valence of the face (Gamer et al. 2010). Hence, it seems that oxytocin differentially modulates the activity of the amygdala in accordance with the stimulus valence or its social saliency. Another area targeted by oxytocin's action is the hippocampus, a region well known for memory processes in its dorsal parts, but also involved in the regulation of anxiety and emotion in its ventral part (Fanselow and Dong 2010). Of particular interest, OXTRs are highly expressed in the ventral part of the hippocampus and their binding is modulated by stress and by glucocorticoids (Liberzon and Young 1997). Several experiments have shown that oxytocin infusion in the hippocampus significantly decreases anxiety behavior (Cohen et al. 2010) and freezing in stressed rats (Barkus et al. 2010).

The link between functional and structural amygdala variability and social personalities has been recently addressed. Correlations were found between amygdala volume and extraversion in several studies (Cremers et al. 2011). Different functions of the amygdala were differentially allocated to distinct subnuclei of the amygdala such as the modulation of negative feelings for the lateral ventral part and vigilance and saliency for the dorsal part (Davis et al. 2010). Moreover, different functions of the hippocampus such as memory and anxiety are also differentially related to the dorsal and the ventral regions, respectively (Fanselow and Dong 2010). Thus, oxytocin may have a different action depending on the targeted region within the amygdala/hippocampus complex.

In this study, we asked whether basal plasma oxytocin concentration is linked with people's social personality traits such as social engagement expressed through their capacities to approach others or to affiliate. Personality is a subset of representations of people's behavior, profiles, and emotions. These factors can be assessed using an optimal model of personality: The revised neuroticism-extroversion-openness personality inventory (NEO-PI-R) (Costa et al. 1992), a questionnaire controlled for its temporal stability (6–9 years) and cultural influence. We also reasoned that individual variability in oxytocin plasma levels and social personalities can be associated with structural changes of key brain areas known to be modulated by oxytocin's action.

By using the robust standardized personality test (NEO PI-R) and voxel-based morphometry (VBM) analysis, we examined the correlation between plasma oxytocin levels, personality traits, and brain volume. First, we hypothesized that 2 dimensions of the NEO PI-R inventory, extraversion and Agreeableness would positively correlate with plasma oxytocin given their implications in social affiliative tendencies and prosocial feelings. Whereas affiliative traits stand on one's capacity to approach others and to be gregarious, prosocial traits are more related to our tendencies to trust and to feel empathy toward others. Secondly, we hypothesized that individual's variability in plasma oxytocin and in sociality will be associated with structural differences in subregions of the amygdala and hippocampus complex, subregions which are relevant for oxytocin's action in fear and anxiety reduction.

Materials and Methods

Participants

Thirty French native speaker healthy subjects randomly selected at the University of Lyon 1 (17 men and 13 women, mean age 23.57 ± 3.70, range 18–37; mean years of education 16.47 ± 2.42, range: 9–20), without history of brain injury or psychiatry disorder (as assessed by a psychiatrist through clinical interview), participated in this study. Exclusion criteria were pregnancy, medication, drug or alcohol abuse, and smoking (at present and during the past 6 months). Participants gave a written consent to participate in the study, which was approved by the local ethical committee (Centre Léon Bérard, Lyon IV).

Behavioral Measure

The NEO PI-R (Costa et al. 1992) assesses 5 core personality dimensions: “extraversion” (tendency to enjoy human interactions, enjoy time spent with people, and find less reward in time spent alone), “Neuroticism” (tendency to experience negative emotions, emotional instability), “Openness” (active imagination, aesthetic sensitivity, and intellectual curiosity), “Agreeableness” (tendency to be compassionate and cooperative), and “Conscientiousness” (tendency to show self-discipline, act dutifully, and aim for achievement).

Physiological Measure

Blood samples were collected at the Neurological Hospital in Lyon and frozen within 15 min. Plasma was separated by centrifugation at 2000 × g (for 10 min at 4°C), then stored in a freezer at −70°C until assay. The centrifugation and the storage of ethylenediaminetetraacetic acid tubes were conducted at Neurobiotec Center in Lyon Neurological Hospital. The analysis of immunoreactive oxytocin in the plasma was performed by the University Center of Immunology and Neuroendocrinology in Liège (Belgium). Prior to assay procedure, plasma samples were filtered on Centricon YM-3 (cut-off 3000 Da, Millipore, United States of America) to get the rid of interfering plasma proteins. After filtration, plasma oxytocin assay was performed using specific enzyme immunoassay (Andari et al. 2010). For all participants, blood tests were performed at the same time (10 AM) of the day and under same experimental conditions. Plasma oxytocin levels have been found to be stable in individuals across specific time periods such as the first months of parenthood (Gordon et al. 2010). Longitudinal studies have also established that changes in plasma oxytocin concentration are relatively small in magnitude during pregnancy and postpartum periods (Chatterton et al. 2000; Levine et al. 2007). Hence, we controlled the time of blood withdraw, the age, and the level of education to reduce interindividual variability.

MRI Acquisition and Analysis

Participants were scanned using a 1.5-T magnetic resonance imaging scanner (Siemens Magnetom Sonata) located at the nearby Imagery Center (CERMEP Lyon). Images were acquired using a sagittal 3-dimensional T1-weighted MPRAGE sequence (field of view 256 mm, matrix 256 × 256, repetition time/echo time/flip angle 1970 ms/3.93 ms/20°, slice thickness 1 mm). Participants structural images were preprocessed with SPM2 (http://www.fil.ion.ucl.ac.uk/spm/software/spm2/) according to the optimized voxel-based morphometry protocol (Good et al. 2001). First, a customized anatomical template was created based on the brain of each participant by averaging the images with an optimized VBM script. A spatial normalization of the anatomical images was performed using the international consortium for brain mapping stereotactic space and 12-parameter affine transformations. The normalized images were then segmented into gray and white matter. None of the brain tissues were removed using a priori template. Mean images of the normalized T1-weighted and tissues volumes were then created and smoothed with a Gaussian kernel of 8-mm full-width half maximum. In the second normalization step, a 12-parameter affine transformation was used to match the native anatomical T1-weighted images to the customized template and to refine by using 16 nonlinear iterations (medium regularization and a 25-mm cutoff). Finally, tissue images were smoothed with a Gaussian kernel of 8-mm full-width half maximum. The “anatomy toolbox” (Eickhoff et al. 2005) was used to generate a region of interest analysis (ROI) for the amygdala and hippocampus bilaterally using cytoarchitectonic probability maps. These maps correspond to the most likely anatomical area at each voxel of the Montreal Neurological Institute (MNI) single-subject template based on probabilistic cytoarchitecture maps derived from a sample of 10 human postmortem brains. The amygdala ROIs comprise the centromedial ( including the central and medium nuclei), superficial (SF, including the anterior amygdala area, ventral, and posterior cortical nuclei), and laterobasal groups (LB, including the lateral, basolateral, basomedial, and paralaminar nuclei) of nuclei (Amunts et al. 2005). In addition to the anatomy toolbox methodology, we used the Marsbar toolbox to perform a further anatomical parcellation of the LB and dorsal amygdala (Davis et al. 2010).

Statistics

The plasma oxytocin levels we obtained had a nonGaussian bimodal distribution. Specifically, half of the subjects had high levels of plasma oxytocin (>4.5 pg/mL) and one-third had low levels (<2 pg/mL), while few subjects had intermediate values between 2 and 4.5 pg/mL (Fig. 1). Following this, we performed nonparametric correlations between oxytocin and personality dimensions, using the Spearman's rank correlation coefficient. We further estimated the confidence of the Spearman's rank correlation coefficient using the Jackknife's method (permutation test). For the VBM analysis, we used multiple regression analysis with oxytocin, age, sex, and total gray matter volume as regressors. Another multiple regression was performed with extraversion, age, sex, and total gray matter volume as regressors. We performed both ROI and whole-brain analysis to study the correlation between oxytocin, personality, and gray matter. Based on our hypothesis, we performed ROI analysis on the different subnuclei of the amygdala and the hippocampus (using the SPM anatomy toolbox). We further computed oxytocin-dependent effects on gray matter of the amygdala–hippocampus complex by applying a mask of both regions simultaneously (using the anatomy toolbox) with the 5 domains of personality. Results are reported at a significance level of P < 0.05, family-wise error (FWE) corrected. For the whole-brain analysis, correlations were then considered significant if clusters corrected with a nonstationary correction (ns) exceeded a significance level of P < 0.05 (Poline et al. 1997). All results are presented in MNI coordinates.

Figure 1.

Plasma oxytocin and extraversion. Positive correlation between plasma oxytocin level and extraversion scores (with Bonferroni correction).

Figure 1.

Plasma oxytocin and extraversion. Positive correlation between plasma oxytocin level and extraversion scores (with Bonferroni correction).

Results

Oxytocin and Personality Traits

Oxytocin plasma levels correlated positively with extraversion scores of personality (Spearman's rank correlation coefficient, r = 0.445, P < 0.007 < 0.01, threshold corrected for multiple comparisons; Fig. 1). We further estimated the confidence of the Spearman's rank correlation coefficient using the Jackknife's method (permutation test). When randomly removing 1 subject, the rho coefficient varied from 0.389 (P < 0.02) to 0.512. When removing 2 subjects, the coefficient varied from 0.331 (P < 0.05) to 0.583. We concluded that the significance of the Spearman's test did not depend on the data from 1 or 2 specific subjects. No significant correlation was observed between oxytocin and the other domains of personality (Neuroticism r = −0.151, P > 0.4; Openness r = 0.123, P > 0.5; Agreeableness r = −0.106, P > 0.5; Conscientiousness r = 0.049, P > 0.7). There is no gender effect on these correlations.

A finding recently reported in the literature of autism suggests that social withdrawal (characteristic of autistic behavior) and low level of plasma oxytocin co-occur in this syndrome (Andari et al. 2010). To further investigate whether reduced sociability is associated with plasma oxytocin decrease in the healthy population, we tested an additional independent group of 20 subjects (mean age 22.40 ± 2.70). These subjects, recruited in the context of another study, were selected on the basis of their score in the extraversion dimension scale of the NEO-PI-R. For each dimension, NEO-PI-R scores are divided into “very low,” “low,” “medial,” “high,” and “very high,” Subjects from this new group (Group 2) obtained extraversion scores situated in the lower bound of the scale (between 0 and 55). The lower bound of the scale refers to the low and very low scores of extraversion, which are significantly below the average scores. For the purpose of this analysis only, Group 2 was compared with our experimental group of 30 subjects (Group 1) on 2 measures: NEO-PI-R personality scores for the 5 dimensions and oxytocin plasma levels. As expected, we found a significant difference between the 2 groups for extraversion (Manny–Whitney U-test, z = 2.74; P < 0.0062) with Group 2 obtaining lower scores compared with Group 1 (Supplementary Fig. S1A). In other terms, subjects from the former group perceived themselves as more introverted than subjects from the latter. Remarkably, no differences were found between the 2 groups for the other personality dimensions (Neuroticism: z = −0.9, P > 0.36; Openness: z = 1.94, P > 0.05; Agreeableness: z = −0.139, P > 0.89; Conscientiousness: z = 0.45, P > 0.65). More important, we found the plasma oxytocin level to be significantly different between the 2 groups (z = 2.99; P < 0.002; Supplementary Fig. S1B) with Group 2 showing significant lower concentrations of oxytocin in the plasma comparing with Group 1.

Oxytocin and Regional Gray Matter Volume

We performed ROI analysis in our experimental group of 30 subjects to correlate the plasma oxytocin levels and regional brain volume in the amygdala and the hippocampus. The structural analysis provided evidence for a significant increase in gray matter volume in the right amygdala of individuals having lower levels of plasma oxytocin (t = 4.45, PFWE = 0.012; Fig. 2A, all P-values survive FWE correction, for multiple comparisons). This cluster was entirely located in the right basolateral amygdala (x = 37, y = −6, z = −21). In particular, while performing ROI analysis on amygdala subnuclei (dorsal, ventral lateral, and ventral basal), only the volume of the ventral lateral sector of the right amygdala was found to be negatively correlated with the plasma oxytocin levels (t = 4.45, PFWE = 0.003). In addition, we observed a negative correlation between plasma oxytocin and the volume of the right hippocampus (t = 4.28, PFWE = 0.05; Fig. 2C), with a percentage of 44.8% in the Cornu Ammonis (CA; x = 38, y = −18, z = −26), 33.9% in the enthorinal cortex (EC; x = 36, y = −7, z = −21), and 21.3% in the subiculum (SUB; x = 33, y = −16, z = −34).

Figure 2.

ROI gray matter correlations with oxytocin and extraversion. (A) ROI results showing a larger right LB amygdala (top, coronal view) and a larger right hippocampus (bottom, sagittal view) in individuals having lower levels of plasma oxytocin. (B) ROI results showing a larger right LB and SF amygdala (top, coronal view) and a larger hippocampus (bottom, sagittal view) in individuals having lower scores of extraversion. (C) Graphs show the negative correlations between plasma oxytocin and amygdala gray matter volume (top; r = −0.57, P < 0.002) and hippocampus gray matter volume (bottom; r = −0.56, P < 0.002). (D) Graphs showing the negative correlations between extraversion scores and amygdala gray matter volume (top; r = −0.6, P < 0.0009) and hippocampus gray matter volume (bottom; r = −0.62; P < 0.0005). All P-values survived FWE corrections. Arbitrary unit is the measure for amygdala and hippocampus volume.

Figure 2.

ROI gray matter correlations with oxytocin and extraversion. (A) ROI results showing a larger right LB amygdala (top, coronal view) and a larger right hippocampus (bottom, sagittal view) in individuals having lower levels of plasma oxytocin. (B) ROI results showing a larger right LB and SF amygdala (top, coronal view) and a larger hippocampus (bottom, sagittal view) in individuals having lower scores of extraversion. (C) Graphs show the negative correlations between plasma oxytocin and amygdala gray matter volume (top; r = −0.57, P < 0.002) and hippocampus gray matter volume (bottom; r = −0.56, P < 0.002). (D) Graphs showing the negative correlations between extraversion scores and amygdala gray matter volume (top; r = −0.6, P < 0.0009) and hippocampus gray matter volume (bottom; r = −0.62; P < 0.0005). All P-values survived FWE corrections. Arbitrary unit is the measure for amygdala and hippocampus volume.

Also, based on the known correlation between extraversion, amygdala activation (Canli et al. 2002) and the volume of temporal brain regions (Johnson et al. 1999), we examined whether extraversion scores of subjects correlated with the volume of the amygdala and the hippocampus. The regression analysis demonstrated a significant enlargement of gray matter volume in the right amygdala in individuals presenting the lower scores of extraversion (Fig. 2B). Three clusters have been found for the correlation between extraversion and amygdala volume. The first cluster revealed 100% probability in the basolateral amygdala (t = 3.93, PFWE = 0.034; x = 33, y = −5, z = −22), whereas the 2 other clusters showed 100% probability in the SF amygdala (t = 3.77, PFWE = 0.047; x = 27, y = 2, z = −17; t = 3.76, PFWE = 0.048; x = 25, y = 3, z = −18). In addition, our structural analysis revealed a significant negative correlation between extraversion scores and hippocampus volume (t = 4.54, PFWE = 0.032; Fig. 2D), with a percentage of 97% in the fascia dentate sector and 3% in the CA region of the hippocampus (x = −23, y = −37, z = 0). All P-values survive FWE correction, for multiple comparisons. There was no significant effect of sex, oxytocin, and gray matter as well as between extraversion and gray matter.

Interestingly, whole-brain analysis also provided evidence for a negative correlation between oxytocin plasma levels and the volume of temporal brain regions. One cluster was found in the right amygdala (x = 37, y = −6, z = −21) and the right hippocampus (x = 38, y = −19, z = −27; P < 0.05, corrected for multiple comparisons at the cluster level; Fig. 3A,B; Table 1). A second cluster was found in the right inferior temporal gyrus (x = 63, y = −32, z = −23; Table 1). In accordance with the ROI analysis, whole-brain analysis also revealed an inverse correlation between extraversion scores and temporal brain regions such as inferior temporal gyrus, amygdala, and hippocampus (Table 2).

Table 1

Regional brain volume and endogenous oxytocin levels

Correlation area BA L/R Cluster MNI
 
T-value 
x y z 
Amygdala (LB) 20 1566 37 −6 −21 4.81 
Hippocampus (CA) 20  38 −19 −27 4.32 
Hippocampus 20  34 −16 −35 4.02 
Hippocampus (SUB) 35  37 −18 −26 4.31 
Hippocampus 35  31 −15 −37 3.85 
Inferior temporal gyrus 20 2282 63 −32 −23 4.73 
Inferior temporal gyrus 20  58 −13 −26 4.25 
Inferior temporal gyrus 20  57 −10 −26 4.18 
Middle temporal gyrus 21  53 −7 −26 4.18 
Inferior temporal gyrus 20  55 −20 −29 4.03 
Inferior temporal gyrus 20  54 −20 −31 4.02 
Correlation area BA L/R Cluster MNI
 
T-value 
x y z 
Amygdala (LB) 20 1566 37 −6 −21 4.81 
Hippocampus (CA) 20  38 −19 −27 4.32 
Hippocampus 20  34 −16 −35 4.02 
Hippocampus (SUB) 35  37 −18 −26 4.31 
Hippocampus 35  31 −15 −37 3.85 
Inferior temporal gyrus 20 2282 63 −32 −23 4.73 
Inferior temporal gyrus 20  58 −13 −26 4.25 
Inferior temporal gyrus 20  57 −10 −26 4.18 
Middle temporal gyrus 21  53 −7 −26 4.18 
Inferior temporal gyrus 20  55 −20 −29 4.03 
Inferior temporal gyrus 20  54 −20 −31 4.02 

Note: Whole-brain analysis showing significant correlation between oxytocin and brain volume. Enlargement of temporal regions, including the amygdala and hippocampus, in individuals having lower levels of oxytocin. BA, Brodmann area.

The 2 clusters above and all the coordinates are corrected at the cluster level (P < 0.05). Amygdala LB (laterobasal), hippocampus CA (Cornu Ammonis), hippocampus SUB (subiculum). R for the right side and L for the left side.

Table 2

Regional brain volume and extraversion scores

Correlation area BA L/R Cluster MNI
 
T-value 
x y z 
Inferior temporal gyrus 20 1412 46 −11 −26 4.73 
Inferior temporal gyrus 20  47 −7 −25 4.43 
Inferior temporal gyrus 20  47 −27 −25 4.39 
Inferior temporal gyrus 20  48 −26 −26 4.36 
Middle temporal gyrus 21  60 −8 −26 4.11 
Middle temporal gyrus 21  56 −8 −25 3.95 
Middle temporal gyrus 39 2453 −49 −62 6.17 
Precuneus 30 1620 24 −46 4.98 
Lingual gyrus 30 1620 17 −69 −2 4.70 
Parahippocampal gyrus 19 1620 23 −57 −6 4.42 
Hippocampus (CA) 20 2610 33 −5 −2 3.36 
R amygdala (LB)        
Correlation area BA L/R Cluster MNI
 
T-value 
x y z 
Inferior temporal gyrus 20 1412 46 −11 −26 4.73 
Inferior temporal gyrus 20  47 −7 −25 4.43 
Inferior temporal gyrus 20  47 −27 −25 4.39 
Inferior temporal gyrus 20  48 −26 −26 4.36 
Middle temporal gyrus 21  60 −8 −26 4.11 
Middle temporal gyrus 21  56 −8 −25 3.95 
Middle temporal gyrus 39 2453 −49 −62 6.17 
Precuneus 30 1620 24 −46 4.98 
Lingual gyrus 30 1620 17 −69 −2 4.70 
Parahippocampal gyrus 19 1620 23 −57 −6 4.42 
Hippocampus (CA) 20 2610 33 −5 −2 3.36 
R amygdala (LB)        

Note: Whole-brain analysis showing significant correlations between extraversion and brain volume. Enlargement of temporal regions, including the amygdala and hippocampus, in individuals with lower scores of extraversion. BA, Brodmann area.

Hippocampus CA (Cornu Ammonis), R amygdala LB (laterobasal). R for the right side and L for the left side.

Figure 3.

Whole-brain correlations with oxytocin and extraversion. (A) Whole brain results for sagittal, coronal, and axial view of the right amygdala-hippocampal complex (A–HC) volume, which correlates inversely with oxytocin plasma concentration. (B) Graph showing the negative correlation between oxytocin and the gray matter of A–HC (r = −0.592, P < 0.002). (C) Graph showing the negative correlation between the gray matter of combined amygdala/hippocampus region and extraversion scores (r = −0.46, P < 0.02). Arbitrary unit is the measure for amygdala and hippocampus volume.

Figure 3.

Whole-brain correlations with oxytocin and extraversion. (A) Whole brain results for sagittal, coronal, and axial view of the right amygdala-hippocampal complex (A–HC) volume, which correlates inversely with oxytocin plasma concentration. (B) Graph showing the negative correlation between oxytocin and the gray matter of A–HC (r = −0.592, P < 0.002). (C) Graph showing the negative correlation between the gray matter of combined amygdala/hippocampus region and extraversion scores (r = −0.46, P < 0.02). Arbitrary unit is the measure for amygdala and hippocampus volume.

In addition, given the nonGaussian distribution of plasma oxytocin levels, we have performed additional nonparametric analysis between plasma oxytocin and brain volume by transforming oxytocin plasma values in rank scores. Whole-brain analysis provided further evidence showing a negative correlation between oxytocin plasma levels and the volume of temporal regions [1) t = 5.11; x = 63, y = −32, z = −21; P < 0.05, 2) t = 4.20; x = 62, y = −47, z = −14; P < 0.05; 3) t = 4.04; x = 54, y = −21, z = −29; P < 0.05, corrected for multiple comparisons at the cluster level]. In particular, ROI analysis showed again that the lateral ventral amygdala and hippocampus are negatively correlated with plasma oxytocin levels (t = 3.25, PFWE = 0.005; t = 4.25, PFWE = 0.02, respectively). We did not find any differences between men and women regarding the correlations between oxytocin, extraversion, and brain volume.

When computing personality scores with oxytocin-dependent cluster, we found that only extraversion scores are negatively correlated with the amygdala/hippocampus complex (t = 3.93, P < 0.019, x = 33, y = −5, z = −22; t = 3.88, P < 0.019, x = 24, y = −40, z = −1). This negative correlation between total gray matter volume of the combined amygdala and the hippocampus region and extraversion scores (P < 0.02; r = −0.46) is represented in Figure 3C. Hence, our volumetric analysis demonstrated that introverted individuals presented the lower levels of oxytocin associated with larger volume in the amygdala and hippocampus regions.

Discussion

A large body of evidence in animals and humans supports the role of oxytocin in social behavior and attachment (Meyer-Lindenberg et al. 2011). Our findings corroborate this view and go one step further by suggesting that the basal plasma level of oxytocin in our body is associated with a basic trait of sociability, Extraversion. We found that individuals who perceive themselves as extraverted and seek social contacts present the higher levels of plasma oxytocin compared with introvert ones. This result was confirmed in a second group of 20 subjects chosen a priori for their low level of sociality. Our results are consistent with animal studies showing that in highly affiliative species, oxytocin levels are higher compared with less gregarious ones (Rosenblum et al. 2002). In humans, higher plasma levels of oxytocin have been associated with personalities showing greater social support, spousal support, and a higher frequency of partner hugs (Grewen et al. 2005; Light et al. 2005). Moreover, levels of oxytocin were found to correlate with affectionate parenting behaviors such as the expression of positive affect, affectionate touch, and proprioceptive contact (Gordon et al. 2010). Plasma oxytocin levels are also linked to maternal gaze, human maternal attachment, and mother–infant bonding and can also predict an infant's social growth (Feldman et al. 2007; Levine et al. 2007). Hence, we assume that the plasma level of oxytocin may hold behavioral significance. However, plasma oxytocin levels did not correlate with the Agreeableness dimension. Agreeableness encompasses different prosocial attitudes such as “trust”, “empathy,” and “altruism.” Although oxytocin promotes prosocial behaviors such as mind reading (Domes, Heinrichs, Glascher, et al. 2007; Domes, Heinrichs, Michel, et al. 2007), generosity (Zak et al. 2007), and trust (Kosfeld et al. 2005), its role in empathy and altruism remains ambiguous in the literature. Indeed, oxytocin administration enhances parochial altruism (De Dreu et al. 2010), does not affect the feelings of empathy, and does not modulate the activity of brain regions relevant for empathy (Singer et al. 2008). Therefore, while the role of this molecule in increasing affiliation and bonding is irrefutable, the routes of its implication in prosocial feelings need further investigation.

A crucial issue is whether the level of plasma oxytocin reflects brain oxytocin function. Although the relation between central and plasma oxytocin is not completely understood, there is a large emerging body of evidence in animals (Wotjak et al. 1998; Cushing and Carter 2000) and humans (Burri et al. 2008), demonstrating that central and plasma oxytocin levels are likely to be coordinated. The OXTR risk alleles linked with social dysfunctions are also associated with lower plasma oxytocin and reduced parental touch (Feldman et al. 2012). Thus, plasma oxytocin levels may be related to oxytocin function in the brain.

Regarding the anatomical correlates of plasma oxytocin levels, here, we found 2 brain regions, the right amygdala and the right anterior hippocampus, correlating with oxytocin and extraversion. Individuals with low plasma oxytocin levels and with low scores in extraversion displayed larger volume in these areas. It is tempting to speculate that, for introverted individuals, approaching others is emotionally costly, as they have to regulate their negative reactions, an emotional state controlled by the amygdala. It has been shown that oxytocin modulates autonomic fear responses through an inhibitory action on neurons in the central amygdala (Huber et al. 2005). Our results further suggest that oxytocin is related to the ventral part of the hippocampus, a region selectively mediating anxiety responses (Oler et al. 2010). This ventral part of the hippocampus is strongly connected with the amygdala, the nucleus accumbens, and the bed nucleus of stria terminalis (Sahay and Hen 2007), which make it a good candidate for emotion regulation. Interestingly, chronic oxytocin injections increase neurogenesis and the proliferation of new cells in the ventral portion of the dentate gyrus of hippocampus in rats (Leuner et al. 2012).

One interpretation of our results would be that during social interactions, oxytocin may decrease saliency to negative cues by adjusting the response in the amygdala and therefore by reducing stress and fear in order to promote social proximity. The activation of such an adaptive mechanism may, at the same time, prevent aversive learning and reactivation of the anxiety state through the inhibitory action of oxytocin on the anterior hippocampus. By contrast, a low level of oxytocin and low scores in sociality would be associated with higher neural activity in these structures, thus leading in the long run to their experience-dependent expansion (Maguire et al. 2006). Nevertheless, the triadic interaction between oxytocin, amygdala/hippocampus complex, and social behavior is trickier than previously thought.

One study has, for instance, reported smaller volumes of both the left and the right amygdala in healthy females, carrying a genetic variants of the oxytocin system [OXTR rs2254298 (G allele)] found to confer a risk for autism (Furman et al. 2011). Another study has found extraversion to correlate positively with gray matter concentration in the left amygdala (Omura et al. 2005). In contrast, in another study, extraversion did not correlate with the volume of the amygdala (Wright et al. 2006). A recent report has found an enlargement of the amygdala volume in individuals with a bigger size of a social network (Bickart et al. 2011). Nevertheless, being part of a large social network size does not automatically mean high sociability in the real world. In fact, whereas an enlargement of the amygdala was induced by an increase of the social network size in monkeys, amygdala volume did not correlate with a key sign of qualitative social interaction, namely social dominance (Sallet et al. 2011). Hence, an expansion of the social network size is not equal to a better quality of social interaction.

Our findings are in agreement with previous evidence showing an enlargement of the amygdala in individuals having the OXTR rs2254298A allele, a candidate phenotype to confer the risk for autism spectrums disorders in a Chinese sample (Inoue et al. 2010). Our results are also in agreement with a recent report showing negative correlations between extraversion and regional brain volume, namely in the prefrontal and temporal cortex (Forsman et al. 2012). Notably, the enlargement of the amygdala/hippocampus we found here correlated with the plasma oxytocin levels is lateralized and circumscribed to the right hemisphere. This is in keeping with the growing evidence showing the preferential contribution of the right hemisphere for the regulation of social and emotional behavior (Mychack et al. 2001). In addition, the association that we found between the right amygdala and the low levels of oxytocin in introverted individuals is in congruence with the previous demonstration of the role of the right amygdala in the detection of negative cues as opposing to the left amygdala (Canli et al. 2002).

In the literature, several different mechanisms have been proposed for oxytocin's action on behavior, including anxiety and fear reduction, motivation enhancement, and increased salience to social cues. Moreover, there is a discrepancy in the literature about the brain correlates of oxytocin and extraversion, in particular with regards to key emotional brain regions such as the amygdala. We reasoned that these contradictions are partly due to a lack of consideration of the different contributions of the subparts of the amygdala and hippocampus to social behavior. While the “basolateral amygdala” is linked to threatening feelings and emotional discrimination (Hoffman et al. 2007), the “dorsal amygdala” is implicated in attention and vigilance (Davis et al. 2010). Of particular interest, the lateral nucleus of the basolateral complex receives highly processed sensory information and is highly sensitive to negative valence detection (Davis et al. 2010). As we found that plasma oxytocin selectively correlated with the “lateral amygdale” and the “anterior hippocampus”, our results are more in line with the hypothesis that oxytocin may alter the processing of social information by reducing the saliency of negative affects in order to enhance social affiliation.

Why some people develop with a lesser propensity to be sociable than others is likely to be the effect of a bidirectional interaction between genetic and environmental factors. Oxytocin's action begins from birth (Pedersen et al. 1982). It is likely that during development, oxytocin influences our behavior toward others by favoring the social approach. Reciprocally, social contact may act as a positive reinforcer by increasing the plasma oxytocin levels and modulating oxytocin's action in the brain. While causality cannot be inferred from our findings, recent reports on the effects of exogenous oxytocin administration weights more in favor of a direct influence of the oxytocin system on social attitudes (Cardoso et al. 2012). Moreover, the interplay between the development of the oxytocin system and social experiences is likely to induce structural variations at the brain level. This assumption is in line with recent evidence showing the impact of the social network size on brain volume (Sallet et al. 2011).

Our findings provide evidence for a neural mechanism linking structural brain variation and physiological oxytocin variability to individual differences in affiliative and emotional personality traits. Expanding our results to a larger sample with more variability and taking into account additional adaptive social measures in adults and children will be important in future studies to illustrate the potential role of basal plasma oxytocin as a marker of early features of social functioning. To increase human fitness, oxytocin appears to play an evolutionary role in endowing our brain with the capacity to develop social skills, probably by overthrowing the cost of negative affects triggered by social proximity.

Supplementary Material

Supplementary material can be found at: http://www.cercor.oxfordjournals.org/

Notes

This research is sponsored by CNRS and supported by Fondation pour la Recherche Médicale (FRM) and by Fondation de France to A.S. E.A. is supported by French Ministry of Research and FRM. Conflict of Interest: None declared.

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