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Gender dysphoria (also known as “transsexualism”) is characterized as a discrepancy between anatomical sex and gender identity. Research points towards neurobiological influences. Due to the sexually dimorphic characteristics of the human voice, voice gender perception provides a biologically relevant function, e.g. in the context of mating selection. There is evidence for a better recognition of voices of the opposite sex and a differentiation of the sexes in its underlying functional cerebral correlates, namely the prefrontal and middle temporal areas. This fMRI study investigated the neural correlates of voice gender perception in 32 male-to-female gender dysphoric individuals (MtFs) compared to 20 non-gender dysphoric men and 19 non-gender dysphoric women. Participants indicated the sex of 240 voice stimuli modified in semitone steps in the direction to the other gender. Compared to men and women, MtFs showed differences in a neural network including the medial prefrontal gyrus, the insula, and the precuneus when responding to male vs. female voices. With increased voice morphing men recruited more prefrontal areas compared to women and MtFs, while MtFs revealed a pattern more similar to women. On a behavioral and neuronal level, our results support the feeling of MtFs reporting they cannot identify with their assigned sex.

The exact neurobiological underpinnings of gender identity (i.e., the subjective perception of oneself belonging to a certain gender) still remain unknown. Combining both resting-state functional connectivity and behavioral data, we examined gender identity in cisgender and transgender persons using a data-driven machine learning strategy. Intrinsic functional connectivity and questionnaire data were obtained from cisgender (men/women) and transgender (trans men/trans women) individuals. Machine learning algorithms reliably detected gender identity with high prediction accuracy in each of the four groups based on connectivity signatures alone. The four normative gender groups were classified with accuracies ranging from 48% to 62% (exceeding chance level at 25%). These connectivity-based classification accuracies exceeded those obtained from a widely established behavioral instrument for gender identity. Using canonical correlation analyses, functional brain measurements and questionnaire data were then integrated to delineate nine canonical vectors (i.e., brain-gender axes), providing a multilevel window into the conventional sex dichotomy. Our dimensional gender perspective captures four distinguishable brain phenotypes for gender identity, advocating a biologically grounded reconceptualization of gender dimorphism. We hope to pave the way towards objective, data-driven diagnostic markers for gender identity and transgender, taking into account neurobiological and behavioral differences in an integrative modeling approach.

IntroductionRecent research found gender‐related differences in resting‐state functional connectivity (rs‐FC) measured by functional magnetic resonance imaging (fMRI). To the best of our knowledge, there are no studies examining the differences in rs‐FC between men, women, and individuals who report a discrepancy between their anatomical sex and their gender identity, i.e. gender dysphoria (GD).MethodsTo address this important issue, we present the first fMRI study systematically investigating the differences in typical resting‐state networks (RSNs) and hormonal treatment effects in 26 male‐to‐female GD individuals (MtFs) compared with 19 men and 20 women.ResultsDifferences between male and female control groups were found only in the auditory RSN, whereas differences between both control groups and MtFs were found in the auditory and fronto‐parietal RSNs, including both primary sensory areas (e.g. calcarine gyrus) and higher order cognitive areas such as the middle and posterior cingulate and dorsomedial prefrontal cortex. Overall, differences in MtFs compared with men and women were more pronounced before cross‐sex hormonal treatment. Interestingly, rs‐FC between MtFs and women did not differ significantly after treatment. When comparing hormonally untreated and treated MtFs, we found differences in connectivity of the calcarine gyrus and thalamus in the context of the auditory network, as well as the inferior frontal gyrus in context of the fronto‐parietal network.ConclusionOur results provide first evidence that MtFs exhibit patterns of rs‐FC which are different from both their assigned and their aspired gender, indicating an intermediate position between the two sexes. We suggest that the present study constitutes a starting point for future research designed to clarify whether the brains of individuals with GD are more similar to their assigned or their aspired gender.

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While general self-referential processes and their neural underpinnings have been extensively investigated with neuroimaging tools, limited data is available on sex differences regarding self- and other-referential processing. To fill this gap, we measured 17 healthy women and men who performed a self- vs. other-appraisal task during functional magnetic resonance imaging (fMRI) using gender-stereotypical adjectives. During the self-appraisal task, typical male (e.g., “dominant,” “competitive”) and female adjectives (e.g., “communicative,” “sensitive”) were presented and participants were asked whether these adjectives applied to themselves. During the other-appraisal task, a prototypical male (Brad Pitt) and female actor (Julia Roberts) was presented and participants were asked again to judge whether typical male and female adjectives applied to these actors. Regarding self-referential processes, women ascribed significantly more female compared to male traits to themselves. At the same time both women and men indicated a stronger desire to exhibit male over female traits. While fMRI did not detect general sex differences in the self- and other-conditions, some subtle differences were revealed between the sexes: both in right putamen and bilateral amygdala stronger gender-congruent activation was found which was however not associated with behavioral measures like the number of self-ascribed female or male attributes. Furthermore, sex hormone levels showed some associations with brain activation pointing to a different pattern in women and men. Finally, the self- vs. other-condition in general led to stronger activation of the anterior cingulate cortex while the other- vs. self-condition activated the right precuneus more strongly which is in line with previous findings. To conclude, our data lend support for subtle sex differences during processing of stereotypical gender attributes. However, it remains unclear whether such differences have a behavioral relevance. We also point to several limitations of this study including the small sample size and the lack of control for potentially different hormonal states in women.

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