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