Elsevier

Psychoneuroendocrinology

Volume 62, December 2015, Pages 180-188
Psychoneuroendocrinology

Sex differences in effective fronto-limbic connectivity during negative emotion processing

https://doi.org/10.1016/j.psyneuen.2015.08.012Get rights and content

Highlights

  • We report sex differences in effective connectivity during negative emotion processing.

  • Hormonal factors do not explain fully sex differences in fronto-limbic connectivity.

  • Gender roles and identity contribute to sex differences in effective connectivity.

ABSTRACT

Background

In view of the greater prevalence of depression and anxiety disorders in women than in men, functional magnetic resonance imaging (fMRI) studies have examined sex-differences in brain activations during emotion processing. Comparatively, sex-differences in brain connectivity received little attention, despite evidence for important fronto-limbic connections during emotion processing across sexes. Here, we investigated sex-differences in fronto-limbic connectivity during negative emotion processing.

Methods

Forty-six healthy individuals (25 women, 21 men) viewed negative, positive and neutral images during an fMRI session. Effective connectivity between significantly activated regions was examined using Granger causality and psychophysical interaction analyses. Sex steroid hormones and feminine-masculine traits were also measured.

Results

Subjective ratings of negative emotional images were higher in women than in men. Across sexes, significant activations were observed in the dorso-medial prefrontal cortex (dmPFC) and the right amygdala. Granger connectivity from right amygdala was significantly greater than that from dmPFC during the ‘high negative’ condition, an effect driven by men. Magnitude of this effect correlated negatively with highly negative image ratings and feminine traits and positively with testosterone levels.

Discussion

These results highlight critical sex differences in brain connectivity during negative emotion processing and point to the fact that both biological (sex steroid hormones) and psychosocial (gender role and identity) variables contribute to them. As the dmPFC is involved in social cognition and action planning, and the amygdala—in threat detection, the connectivity results suggest that compared to women, men have a more evaluative, rather than purely affective, brain response during negative emotion processing.

Introduction

Investigation of neural correlates of sex and gender differences (where ‘sex’ refers to a biological and ‘gender’ to a psychosocial construct) in emotion processing is of great interest, not only from purely cognitive and endocrinological perspectives, but because it is critical for a better understanding of some psychopathologies with different prevalence and/or clinical expression between men and women. For instance, depression and anxiety disorders are about twice as common in women than in men (Steel et al., 2014). Some researchers and clinicians believe that these sex/gender differences may be due to the overall greater emotional reactivity (behavioral and physiological) in women than men (Kelly et al., 2008), but the evidence has been equivocal.

In one of the earliest functional magnetic resonance imaging (fMRI) investigations of neural correlates of happiness and sadness, Wrase et al. (2003) observed that women exhibited stronger activation for affectively negative pictures in the anterior and medial cingulate gyrus. In a different study from that early period, men exhibited bilateral frontal, right temporal, and right lentiform activations, whereas women showed left parietal, left lentiform, and right occipital activations when processing emotional faces (Lee et al., 2005, Lee et al., 2002). Since then, numerous other studies have reported different pattern of brain activations in men and women during various emotional tasks, but there were many inconsistencies across them (Canli et al., 2002, Fischer et al., 2004, Lee et al., 2005, Lee et al., 2002).

A recent meta-analysis (Stevens and Hamann, 2012) combined functional neuroimaging studies of emotion processing explicitly examining sex differences with studies that investigated only women or only men. Results revealed that the majority of sex differences with greater neural activations in women were observed for negative emotions. During negative emotions, both sexes activated the right amygdala, the dorso-medial prefrontal cortex and the left insula. However, women exhibited greater activation than men in the left amygdala and the medial prefrontal cortex, consistently with the notion that women display greater neural reactivity during negative emotions. These findings could be attributed to differences between men and women in sex steroid hormones and/or gender role socialization, as many studies report a link between emotional processing and testosterone (Bos et al., 2013, Stevens and Hamann, 2012), estrogen, progesterone (Sundstrom Poromaa and Gingnell, 2014, Toffoletto et al., 2014), and masculine/feminine traits (Sundstrom Poromaa and Gingnell, 2014).

Several functional or effective connectivity studies have examined the neural pathways involved in emotion processing. Across sexes, important connections have been reported between the limbic system (e.g., amygdala, insula) and various sub-regions of the frontal lobe (medial and dorsolateral prefrontal, anterior cingulate) during the processing of negative emotions, such as fear, anger or sadness (Coutlee and Huettel, 2012, Moriguchi et al., 2014). Comparatively, only a few functional connectivity studies have examined the neural bases of sex-differences in emotion processing. Although the specific pathways differentiating women and men are yet to be identified, sex-differences have been observed in various fronto-limbic pathways (Labus et al., 2013, Moriguchi et al., 2014). These neuro-functional differences may reflect differences in emotion regulation or action preparation. Indeed, a recent neuroanatomical study found a positive correlation between emotion regulation and gray matter volume in the right dorsolateral prefrontal cortex in men, whereas in women there was a stronger positive relationship between emotion regulation and a gray matter volume in a cluster including the left hippocampus, the amygdala and the insula (Kong et al., 2014).

The extent to which the sex-differences in emotion-related brain activations and connectivity are explained by hormonal or psychosocial variables (e.g., femininity, masculinity) remains yet to be determined. Some studies have shown that the premenstrual dysphoric disorder (PMDD) is associated with impaired activations of the left amygdala and the dorsal anterior cingulate gyrus during emotional processing (Toffoletto et al., 2014). Given that progesterone plays a role in the pathophysiology of PMDD (Rapkin and Akopians, 2012), such results provide indirect evidence of the involvement of progesterone in the distinct neural responses of women and men to emotional material [Note: The role of estrogen in that regard remains unclear (Pruis et al., 2009, Toffoletto et al., 2014)]. Behavioral and fMRI studies have been performed on the modulating effects of testosterone on emotion processing. In women, significant associations (mostly positive, but negative in some cases) have been shown between testosterone and amygdala reactivity in response to angry faces or threatening stimuli (Bos et al., 2013, Manuck et al., 2010). On the other hand, it has been shown that testosterone administration to women impairs cognitive and emotional abilities (e.g., emotion recognition, empathy, etc.) underlying altruistic social behavior (Bos et al., 2012, Hermans et al., 2006, van Honk et al., 2011). In men, increased testosterone levels have been associated with reduced amygdala-orbitofrontal connectivity (Peters et al., 2015). While there is growing evidence showing that hormones underlie sex-differences in the neural correlates of emotion processing, the influence of gender-related variables on the brain responses of women and men to emotional stimuli is unknown.

The common wisdom is that women exhibit greater emotional reactivity than men when processing negative emotional stimuli (Kelly et al., 2008). An alternative view could be that men have different emotional coping mechanisms (e.g., emotion regulation, action planning, etc.) than women (Nolen-Hoeksema, 2012, Wager et al., 2003). Another unresolved issue is the extent to which sex-differences in brain responses to emotional material are influenced by endocrine and/or psychosocial factors (e.g., femininity, masculinity). Thus, the current study sought to investigate sex-differences in fronto-limbic connectivity during processing of negative emotions, and to examine the potential influence of sex steroid hormones and gender-related variables on connectivity analyses.

Section snippets

Participants

Forty-six healthy individuals (25 women) participated in the study. Men and women did not differ in age, handedness (Edinburgh Inventory) (Oldfield, 1971), education level, marital status, ethnicity, and parental socio-economic status (National Occupational Classification; NOC) (Human Resources and Skills Development Canada, 2001) (Table 1). Participants were screened with the non-patient edition of the Clinical Interview for DSM-IV (SCID) (Michael et al., November 2002). General exclusion

Demographic, clinical and behavioral data

Table 1 shows the demographic information pertaining to participants in this study and presented separately by sex, as well as sex differences regarding participants' subjective ratings for all types of stimuli, hormone levels and the results at the gender-related questionnaires.

Correlations between sex hormones and sex role questionnaires

Testosterone and progesterone levels correlated in opposite directions with individuals’ subjective evaluation of high arousal negative stimuli (r = −0.417, N = 38, p = 0.009 for testosterone and r = +0.343, N = 38, p = 0.04 for

Discussion

In view of the greater prevalence of depression and anxiety disorders in women than in men, we investigated sex-differences in fronto-limbic connectivity during negative emotion processing, while verifying the influence of sex steroid hormones and gender-related variables on connectivity analyses. At the behavioral level, subjective ratings of negative emotional images were higher in women than men, a result consistent with some studies on emotion (Gardener et al., 2013, Kong et al., 2014),

Conflict of interest

This study was funded by the Canadian Institutes of Health Research (AM). Drs. Lungu, Potvin, and Mendrek, as well as M. Tikàsz, reported no biomedical financial interests or potential conflicts of interest.

Contributions

O.L. wrote the manuscript and did the brain imaging analyses; S.P. was involved in the brain imaging analyses, as well as the writing of the manuscript; A.T. was involved in the brain imaging analyses, as well as provided critical comments about the manuscript; A.M. was involved in study design, as well as provided critical comments about the manuscript; All authors contributed to and have approved the final manuscript.

Role of the funding source

The funding sources had no input in the design of the study, data collection, data analysis and interpretation, and in writing the final report.

Acknowledgments

S.P. is holder of the Eli Lilly Chair on Schizophrenia Research; A.T. was supported by a fellowship from Eli Lilly; A.M. is holder of a Junior 1 grant for young investigators from the Fonds de recherche du Québec - Santé.

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