Elsevier

Psychoneuroendocrinology

Volume 68, June 2016, Pages 194-201
Psychoneuroendocrinology

Testosterone reduces functional connectivity during the ‘Reading the Mind in the Eyes’ Test

https://doi.org/10.1016/j.psyneuen.2016.03.006Get rights and content

Highlights

  • Testosterone impairs cognitive empathy on the Reading the Mind in Eyes-test.

  • Using fMRI, we investigated how testosterone reduces cognitive empathy.

  • Testosterone reduced connectivity of the left IFG with the ACC and the SMA.

  • This network underlies integration of sensory information and action preparation.

Abstract

Women on average outperform men in cognitive-empathic abilities, such as the capacity to infer motives from the bodily cues of others, which is vital for effective social interaction. The steroid hormone testosterone is thought to play a role in this sexual dimorphism. Strikingly, a previous study shows that a single administration of testosterone in women impairs performance on the ‘Reading the Mind in Eyes’ Test (RMET), a task in which emotions have to be inferred from the eye-region of a face. This effect was mediated by the 2D:4D ratio, the ratio between the length of the index and ring finger, a proxy for fetal testosterone. Research in typical individuals, in individuals with autism spectrum conditions (ASC), and in individuals with brain lesions has established that performance on the RMET depends on the left inferior frontal gyrus (IFG). Using functional magnetic resonance imaging (fMRI), we found that a single administration of testosterone in 16 young women significantly altered connectivity of the left IFG with the anterior cingulate cortex (ACC) and the supplementary motor area (SMA) during RMET performance, independent of 2D:4D ratio. This IFG-ACC-SMA network underlies the integration and selection of sensory information, and for action preparation during cognitive empathic behavior. Our findings thus reveal a neural mechanism by which testosterone can impair emotion-recognition ability, and may link to the symptomatology of ASC, in which the same neural network is implicated.

Introduction

Human social interaction is characterized by the employment of cognitive empathy: our capacity to infer motives, intentions, thoughts and feelings from the bodily cues of others (Baron-Cohen, 1995, Frith and Frith, 1999). The ability to identify emotional expressions of others shows sexual dimorphism: on average, women outperform men, a difference for which accumulating evidence suggests an underlying role for the steroid hormone testosterone (Baron-Cohen, 2003, Baron-Cohen et al., 2005). Indeed, a single administration of testosterone has been demonstrated to reduce emotion recognition abilities in typical young women (van Honk et al., 2011a). After testosterone administration (compared to placebo) women show impaired performance on the ‘Reading the Mind in the Eyes’ Test (RMET: Baron-Cohen et al., 2001). On the RMET, both basic and complex mental states (emotions, motives, intentions, and thoughts) need to be inferred from pictures of the eye-region of the face alone. This effect of testosterone on the RMET varied with a proxy of fetal testosterone (fT), the 2D:4D ratio (Breedlove, 2010). A lower 2D:4D ratio, a proxy for higher levels of fT, predicted greater impairment on the RMET after testosterone administration (van Honk et al., 2011a).

Exposure to fT is also an important underlying factor in the etiology of autism spectrum conditions (ASC) (Baron-Cohen, 2003, Baron-Cohen et al., 2015a, Baron-Cohen et al., 2005), a condition characterized by impaired ability in emotion recognition (Baron-Cohen, 1995), for which the RMET was developed as a sensitive measure (Baron-Cohen et al., 2001). In the current pharmacological functional Magnetic Resonance Imaging (fMRI) study, typical young women performed the RMET during neuroimaging after a single testosterone and placebo administration, in a double-blind design, to investigate the neural mechanisms by which testosterone brings about its down-regulating effect on cognitive empathic abilities.

Studies into the mechanisms supporting cognitive empathic abilities have identified several brain regions involved in the inference of mental states using the RMET. A study that included more than a hundred patients with brain lesion shows that lesions in the left inferior frontal gyrus (IFG) impair performance on the RMET (Dal Monte et al., 2014), suggesting that left IFG is crucial for the identification of subtle emotional expressions. Consistent with this, studies comparing neural responses during the RMET between cultures and throughout development have also revealed consistent activation of the IFG, together with the posterior part of the superior temporal sulcus (pSTS) (Adams et al., 2010, Baron-Cohen et al., 2006, Baron-Cohen et al., 1999, Moor et al., 2012). Interestingly, in relation to the role of testosterone, sex differences have been observed in the function of the left IFG (Baron-Cohen et al., 2006), and in connectivity of the left IFG with the superior temporal cortices (Schmithorst and Holland, 2007). Also, the amount of exposure to fT and baseline testosterone levels predicts brain structure (Koolschijn et al., 2014, Lombardo et al., 2012, Witte et al., 2010), and structural connectivity of the IFG and pSTS (Peper et al., 2013, Rametti et al., 2012). Altered activation and connectivity of the same regions have also been implicated in the social deficits of ASC (Hadjikhani et al., 2007, Vissers et al., 2012).

Although based on these studies a relation between testosterone and activation or connectivity of the left IFG can be predicted, direct effects of testosterone administration on the IFG have not yet been reported. Studies have reported acute down-regulation of prefrontal-amygdala functional connectivity after testosterone administration (Bos et al., 2012a, van Wingen et al., 2010), both in the context of emotion processing paradigms. In these studies, altered connectivity was observed in the absence of changed activation in the prefrontal cortex, indicating that endocrine manipulations can affect neural activity and connectivity independently. Thus, testosterone can be regarded a modulator of the network involved in emotion recognition, provisionally by altering connectivity of the prefrontal cortex with other brain regions (van Honk et al., 2011b). Given these findings, we predict that testosterone will selectively affect connectivity of the prefrontal regions involved in cognitive empathic abilities (i.e. left IFG), underlying the down-regulation effect of testosterone during RMET performance (van Honk et al., 2011a).

Section snippets

Participants

16 right-handed typical young women (mean age 20.8 years, SD 2.0) participated in the study, and were recruited at the university campus of Utrecht University. Only women using single-phase oral contraceptives were included, since contraceptive use suppresses cyclic fluctuations in levels of estrogens and progesterone (Fleischman et al., 2010). Also, no scans were performed during menstruation. Also, participants were scanned at the same time of day on two separate days with an interval of at

Behavioral data

First, the data was checked for outliers based on a criterion of 3 times the SD above or below the mean. No outliers were detected. The distribution of the data was further checked using the Shapiro-Wilk normality test. With the exception of the unmatched control condition after testosterone (W = 0.834, p = 0.008), and the matched control condition after placebo (W = 0.825, p = 0.006), none of the number of errors made by the participants deviated from normality (all W > 0.896, p > 0.05). The reaction

Discussion

We investigated the neural mechanism by which testosterone impairs the cognitive-empathic abilities during performance on the RMET (van Honk et al., 2011a). The data show that the left IFG is activated specifically during the emotion-recognition condition, that is, when participants had to infer the emotional state in the stimulus. Critically, compared to the placebo-condition, testosterone reduced connectivity of the left IFG with the bilateral ACC and SMA during emotion-recognition compared

Conflict of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Contributors

Peter A. Bos, Dennis Hofman, Erno J. Hermans, Estrella R. Montoya, Simon Baron-Cohen & Jack van Honk.

Authors PAB and EJH and JvH designed the study and wrote the protocol. Authors PAB, DH, EJH and ERM managed the literature searches and facilitated data analyses. Authors PAB, EJH, and ERM undertook the statistical analysis, and authors PAB, DH, SBC, and JvH contributed to the writing of the manuscript. All authors contributed to and have approved the final manuscript.

Role of the funding source

The work in this paper was supported by a grant from the Netherlands Society of Scientific Research to PAB (451-14-015) and to JvH (056-24-010). SBC was supported by grants from the Medical Research Council (MRC), Wellcome Trust, and the Autism Research Trust. The funding sources had no further role in study design; in the collection, analysis and interpretation of the data; in the writing of the report; or the decision to submit the paper for publication.

REFERENCES (63)

  • Y. Fan et al.

    Is there a core neural network in empathy? An fMRI based quantitative meta-analysis

    Neurosci. Biobehav. Rev.

    (2011)
  • D.A. Granger et al.

    The trouble with salivary testosterone

    Psychoneuroendocrinology

    (2004)
  • A.J. Guastella et al.

    Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders

    Biol. Psychiatry

    (2010)
  • P. Hagoort

    On Broca, brain, and binding: a new framework

    Trends Cogn. Sci.

    (2005)
  • R.K. Kana et al.

    Inhibitory control in high-functioning autism: decreased activation and underconnectivity in inhibition networks

    Biol. Psychiatry

    (2007)
  • N. Kemmotsu et al.

    Activity and functional connectivity of inferior frontal cortex associated with response conflict

    Brain Res. Cogn. Brain Res.

    (2005)
  • N. Kohn et al.

    Neural network of cognitive emotion regulation—an ALE meta-analysis and MACM analysis

    NeuroImage

    (2014)
  • G. Liakakis et al.

    Diversity of the inferior frontal gyrus—a meta-analysis of neuroimaging studies

    Behav. Brain Res.

    (2011)
  • J.C. Lynch et al.

    Cortico-cortical networks and cortico-subcortical loops for the higher control of eye movements

    Prog. Brain Res.

    (2006)
  • G. Rametti et al.

    Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study

    Psychoneuroendocrinology

    (2012)
  • V.J. Schmithorst et al.

    Sex differences in the development of neuroanatomical functional connectivity underlying intelligence found using Bayesian connectivity analysis

    NeuroImage

    (2007)
  • A. Shenhav et al.

    The expected value of control: an integrative theory of anterior cingulate cortex function

    Neuron

    (2013)
  • N. Tzourio-Mazoyer et al.

    Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain

    NeuroImage

    (2002)
  • M.E. Vissers et al.

    Brain connectivity and high functioning autism: a promising path of research that needs refined models methodological convergence, and stronger behavioral links

    Neurosci. Biobehav. Rev.

    (2012)
  • S. Wheelwright et al.

    Predicting autism spectrum quotient (AQ) from the systemizing quotient-Revised (SQ-R) and empathy quotient (EQ)

    Brain Res.

    (2006)
  • R.M. Willems et al.

    Differential roles for left inferior frontal and superior temporal cortex in multimodal integration of action and language

    NeuroImage

    (2009)
  • A.V. Witte et al.

    Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain

    NeuroImage

    (2010)
  • J. van Honk et al.

    Further notes on testosterone as a social hormone

    Trends Cogn. Sci.

    (2011)
  • G.A. van Wingen et al.

    Testosterone reduces amygdala-orbitofrontal cortex coupling

    Psychoneuroendocrinology

    (2010)
  • J.X. Zhang et al.

    Is left inferior frontal gyrus a general mechanism for selection?

    NeuroImage

    (2004)
  • D.A. Abrams et al.

    Underconnectivity between voice-selective cortex and reward circuitry in children with autism

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • Cited by (43)

    • Sex and age interact in reading the mind in the eyes

      2022, Comprehensive Psychoneuroendocrinology
    • Reading language of the eyes

      2022, Neuroscience and Biobehavioral Reviews
    • Single-dose testosterone administration modulates instant empathic responses to others’ pain: An EEG study

      2022, Psychoneuroendocrinology
      Citation Excerpt :

      Enhanced neural responses to pain empathy after testosterone administration might largely reflect how testosterone facilitates the affective aspect of empathy (e.g., emotional contagion and personal distress in response to the perception of others’ pain). In contrast, empathy in other studies was quantified by the skill at inferring other’s mental abilities (Bos et al., 2016; Carré et al., 2015; Grainger et al., 2021; Olsson et al., 2016; Van Honk et al., 2011), e.g., using the ‘Reading the Mind in the Eyes’ Test. The findings that testosterone impaired empathic accuracy (Nitschke and Bartz, 2020) and the theory of mind (Khorashad et al., 2018) could largely reflect how testosterone suppresses the cognitive aspect of empathy (e.g., our capacity to infer from the observed emotions, beliefs, and goals of other people).

    • Testosterone administration does not alter the brain activity supporting cognitive and affective empathy

      2022, Comprehensive Psychoneuroendocrinology
      Citation Excerpt :

      For cognitive empathy, we found brain activation in the bilateral ventral TPJ, temporal pole, precuneus, STS, and the medial prefrontal cortex. Our results closely match the networks highlighted in previous validation studies [31,33]. Since participants were not asked to reflect upon the actors' mental states, our results may reflect spontaneous mentalizing.

    View all citing articles on Scopus
    View full text