Connectivity Patterns in the Core Resting-State Networks and Their Influence on Cognition.

Introduction: Three prominent resting-state networks (rsNW) (default mode network [DMN], salience network [SN], and central executive network [CEN]) are recognized for their important role in several neuropsychiatric conditions. However, our understanding of their relevance in terms of cognition remains insufficient. Materials and Methods: In response, this study aims at investigating the patterns of different network properties (resting-state activity [RSA] and short- and long-range functional connectivity [FC]) in these three core rsNWs, as well as the dynamics of age-associated changes and their relation to cognitive performance in a sample of healthy controls (N = 74) covering a large age span (20-79 years). Using a whole-network based approach, three measures were calculated from the functional magnetic resonance imaging (fMRI) data: amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and degree of network centrality (DC). The cognitive test battery covered the following domains: memory, executive functioning, processing speed, attention, and visual perception. Results: For all three fMRI measures (ALFF, ReHo, and DC), the highest values of spontaneous brain activity (ALFF), short- and long-range connectivity (ReHo, DC) were observed in the DMN and the lowest in the SN. Significant age-associated decrease was observed in the DMN for ALFF and DC, and in the SN for ALFF and ReHo. Significant negative partial correlations were observed for working memory and ALFF in all three networks, as well as for additional cognitive parameters and ALFF in CEN. Discussion: Our results show that higher RSA in the three core rsNWs may have an unfavorable effect on cognition. Conversely, the pattern of network properties in healthy subjects included low RSA and FC in the SN. This complements previous research related to the three core rsNW and shows that the chosen approach can provide additional insight into their function. Impact statement Using a whole network-based approach, our study characterizes the normal patterns (including resting-state activity [RSA], short- and long-range functional connectivity [FC]) of three prominent resting-state networks (rsNW) within the context of age-dependent changes and explores their relevance for different cognitive domains. Our results revealed a pattern with low RSA and FC in the salience network in healthy volunteers, whereas higher RSA, particularly in the central executive network, seemed to have a negative effect on cognition. These results increase the knowledge about the three core rsNWs and the understanding about their relevance for cognition.

Predictive Pattern Classification Can Distinguish Gender Identity Subtypes from Behavior and Brain Imaging.

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.

Exploring Sex Differences in the Neural Correlates of Self-and Other-Referential Gender Stereotyping.

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.

Cerebral and behavioural response to human voices is mediated by sex and sexual orientation.

Several studies report sex differences in sensitivity to gendered stimuli. We assume many of these to reflect differences as to the sex to which one feels attracted rather than to biological sex per se. Investigating voice perception, a function of high social relevance, we show that the behavioural and neural (BOLD) responses to male and female voices are mediated by sex and sexual orientation. In heterosexual men and women, we found an opposite-sex effect, reflected in higher classification accuracy for and a response bias towards voices of the other sex, while the effect became apparent as same-sex effect in homosexual men and women. Overall, sexual orientation had a greater impact in women than in men and homosexual women were closer to men in their behavioural responses to female voices. The activation patterns were similar for hetero- and homosexual men, both groups showing increased activation in response to male compared to female voices in regions distributed across the temporo-parietal and insular cortex. In contrast, women had increased activation in response to voices of the desired sex. It appears that both sex and sexual orientation impact on a function as basal as voice perception. Our results underline the need to assess sexual orientation in study participants if conclusions on sex differences shall be drawn. Many of the reported sex differences in behaviour and brain function might be mediated by sexual orientation and we encourage further research into the interplay between sex and sexual orientation.

Gender incongruence and the brain - Behavioral and neural correlates of voice gender perception in transgender people.

The phenomenon of gender incongruence is hypothesized to arise from a discrepant sexual development of the brain and the genitals, contingent on genetic and hormonal mechanisms. We aimed at visualizing transgender identity on a neurobiological level, assuming a higher functional similarity to individuals of the aspired rather than assigned sex. Implementing a gender perception paradigm featuring male and female voice stimuli, behavioral and functional imaging data of transmen were compared to men and women, and to transwomen, respectively. Men had decreased activation in response to voices of the other sex in regions across the frontoparietal and insular cortex, while the activation patterns of women and transmen were characterized by little or no differentiation between male and female voices. Further, transmen had a comparatively high discrimination performance for ambiguous male voices, possibly reflecting a high sensitivity for voices of the aspired sex. Comparing transmen and transwomen yielded only few differences in the processing of male compared to female voices. In the insula, we observed a pattern similar to that of men and women, the neural responses of the transgender group being in accordance with their gender identity rather than assigned sex. Notwithstanding the similarities found dependent on biological sex, the findings support the hypothesis of gender incongruence being a condition in which neural processing modes are partly incongruent with one's assigned sex.

Male-to-female gender dysphoria: Gender-specific differences in resting-state networks.

INTRODUCTION: Recent 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). METHODS: To 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. RESULTS: Differences 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. CONCLUSION: Our 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.

The transsexual brain--A review of findings on the neural basis of transsexualism.

Transsexualism describes the condition when a person's psychological gender differs from his or her biological sex and is commonly thought to arise from a discrepant cerebral and genital sexual differentiation. This review intends to give an extensive overview of structural and functional neurobiological correlates of transsexualism and their course under cross-sex hormonal treatment. Research in this field enables insight into the stability or variability of gender differences and their relation to hormonal status. For a number of sexually dimorphic brain structures or processes, signs of feminisation or masculinisation are observable in transsexual individuals, which, during hormonal treatment, partly seem to further adjust to characteristics of the desired sex. Still, it appears the data are quite inhomogeneous, mostly not replicated and in many cases available for male-to-female transsexuals only. As the prevalence of homosexuality is markedly higher among transsexuals than among the general population, disentangling correlates of sexual orientation and gender identity is a major problem. To resolve such deficiencies, the implementation of specific research standards is proposed.

More than just two sexes: the neural correlates of voice gender perception in gender dysphoria.

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.

Sex matters: Neural correlates of voice gender perception.

The basis for different neural activations in response to male and female voices as well as the question, whether men and women perceive male and female voices differently, has not been thoroughly investigated. Therefore, the aim of the present study was to examine the behavioral and neural correlates of gender-related voice perception in healthy male and female volunteers. fMRI data were collected while 39 participants (19 female) were asked to indicate the gender of 240 voice stimuli. These stimuli included recordings of 3-syllable nouns as well as the same recordings pitch-shifted in 2, 4 and 6 semitone steps in the direction of the other gender. Data analysis revealed a) equal voice discrimination sensitivity in men and women but better performance in the categorization of opposite-sex stimuli at least in men, b) increased responses to increasing gender ambiguity in the mid cingulate cortex and bilateral inferior frontal gyri, and c) stronger activation in a fronto-temporal neural network in response to voices of the opposite sex. Our results indicate a gender specific processing for male and female voices on a behavioral and neuronal level. We suggest that our results reflect higher sensitivity probably due to the evolutionary relevance of voice perception in mate selection.