Whole-brain dynamics differentiate among cisgender and transgender individuals

Whole-brain dynamics differentiate among cisgender and transgender individuals. Carme Uribe et al. Human Brain Mapping, Apr 28 2022. https://onlinelibrary.wiley.com/doi/10.1002/hbm.25905

Abstract: How the brain represents gender identity is largely unknown, but some neural differences have recently been discovered. We used an intrinsic ignition framework to investigate whether there are gender differences in the propagation of neural activity across the whole-brain and within resting-state networks. Studying 29 trans men and 17 trans women with gender incongruence, 22 cis women, and 19 cis men, we computed the capability of a given brain area in space to propagate activity to other areas (mean-ignition), and the variability across time for each brain area (node-metastability). We found that both measurements differentiated all groups across the whole brain. At the network level, we found that compared to the other groups, cis men showed higher mean-ignition of the dorsal attention network and node-metastability of the dorsal and ventral attention, executive control, and temporal parietal networks. We also found higher mean-ignition values in cis men than in cis women within the executive control network, but higher mean-ignition in cis women than cis men and trans men for the default mode. Node-metastability was higher in cis men than cis women in the somatomotor network, while both mean-ignition and node-metastability were higher for cis men than trans men in the limbic network. Finally, we computed correlations between these measurements and a body image satisfaction score. Trans men's dissatisfaction as well as cis men's and cis women's satisfaction toward their own body image were distinctively associated with specific networks in each group. Overall, the study of the whole-brain network dynamical complexity discriminates gender identity groups, functional dynamic approaches could help disentangle the complex nature of the gender dimension in the brain.

4 DISCUSSION

For the first time, we characterize the spatiotemporal whole-brain dynamics of cisgender and transgender binary groups. Our findings corroborate the existence of four brain phenotypes (Guillamon et al., 2016; Uribe et al., 2020b) beyond the classic, lately questioned, conception that the human brain can be split into two configurations, the male and the female (Legato, 2018). To characterize the propagation of information and measure the degree of integration of spontaneously occurring events while at rest, we applied the intrinsic ignition framework (Deco & Kringelbach, 2017; Deco, Tagliazucchi, et al., 2017). This framework was very sensitive in detecting functional dynamics differences between young adults grouped by gender. Some of these group differences had been elusive when using stationary functional connectivity measurements (Uribe et al., 2020b), or sliding windows approach to study brain connectivity states (Uribe et al., 2021). In addition, spatial and temporal brain dynamics measurements were specifically related with the satisfaction toward body parts for cis men, cis women, and trans men.

The main novelty here is that we provide the first description of the spatiotemporal dynamics underlying the gender dimension in the brain, and more importantly, characterize the regional contribution to the whole-brain dynamics. Mean-ignition is an informative measurement of the spatial diversity and broadness of communication across the brain. On the other hand, node-metastability captures the variability over time across the whole brain. Both the spatial and temporal variability that defined each gender group were widespread across the whole brain, with nodes from all functional networks. Likewise, when using a support vector machine algorithm inputting stationary group independent component maps and clinical data as features, four gender groups were obtained based on the different patterns of brain connectivity (Clemens et al., 2020). In addition, our results stress the importance of using fine-grained dynamic measurements to study spatiotemporal oscillations over grand averaged functional connectivity measurements; these latter enabling a more narrowed investigation of differences that would be accountable for gender, and the incongruence felt in the transgender community.

Group differences in the two subdivisions of the attentional networks and in executive control were in line with previous findings of functional connectivity differences, both stationary (Uribe et al., 2020a) and dynamic (Uribe et al., 2021). The particular group differences in the dorsal and the ventral subdivisions of the attentional network underline the need to study them separately. More relevantly, the spatial broadness of communication of nodes in the default mode network was higher in cis women with respect to cis men and trans men. Higher functional connectivity in default mode regions has been reported in cis women in contrast to cis men (Biswal et al., 2010; de Lacy et al., 2019; Ritchie et al., 2018). Also, in the transgender literature, weaker connectivity strength has been reported in these network regions in the trans men group in contrast to cis men (Feusner et al., 2017; Uribe et al., 2020a) and cis women (Feusner et al., 2017), but this finding is not generalized as other studies had negative reports (Clemens et al., 2017; Nota et al., 2017).

On the other hand, the reported pattern of activation in cis men relies on sensory–motor regions (Ritchie et al., 2018). The somatomotor network in the Schaefer parcellation included areas of motor action and sensory inputs from the external world, making it the network with the most direct interaction with our environment. Despite the previous relevance given to this functional network in understanding the own body perception and subsequently explaining the incongruence in transgender people (Burke et al., 2019; Manzouri et al., 2017), the intrinsic ignition framework only differentiated between cisgender groups in terms of temporal variability. Indeed, our previous work on functional connectivity dynamics identified a sensorimotor state, although no differences between trans- and cisgender groups were noted (Uribe et al., 2021). The spatial and temporal dynamism of the limbic network was greater in the cis man group than in trans men. On the other hand, increased limbic connectivity in transgender individuals has been reported when viewing “ambiguous, androgynous images of themselves morphed toward their gender identity” (Majid et al., 2020). Such findings should be further explored. Different functional MRI measurements do not permit further discussion, and greater integration, broadness of communication, and temporal variability do not necessarily translate to increased averaged connectivity.

The superior parietal cortex has been previously linked to gender differences when comparing cis men with cis women and transgender groups, structurally (Zubiaurre-Elorza et al., 2013) and functionally (Uribe et al., 2020b). The choice of the Schaefer parcellation (Schaefer et al., 2018) allowed a high representation of the temporal parietal network in terms of brain dynamics in agreement with temporoparietal junction findings in trans men with respect to cisgender groups (Manzouri et al., 2017). The spatial diversity and broadness of communication of temporal parietal regions were greater in cis men than in the other three gender groups, namely cis women, trans men, and trans women.

The fact that cis men present higher brain dynamism than other gender groups, especially cis women and trans men, would be in line with previous brain states occupancy where cis men occupied more combinations of connectivity patterns over time than cis women (Yaesoubi et al., 2015). Nonetheless, these results have not been consistently replicated, as has occurred with other brain flexibility measurements through brain states using sliding windows that reported differential regional brain dynamism for both cis men and cis women (Mao et al., 2017). In addition, the increased spatial and temporal variability of brain oscillations in cis men was not homogeneous across all networks, for instance, in the default mode network.

Trans women presented a lateralized predominance in the regions with the highest node-metastability in the left hemisphere. The discussion of these findings is hampered by the scarcity of the literature investigating gender differences in brain dynamism. To the best of our knowledge, previous reports of the gender effects in the lateralization of brain connectivity patterns found these were mostly comparable between a large sample of cis men and women, with two marginal findings that did not survive false discovery rate correction and were considered a trend-level effect (Agcaoglu et al., 2015; Eliot et al., 2021), although there was a marginal leftwards lateralization in cis women only in the inferior frontal cortex (Tomasi & Volkow, 2012). Given these and the small sample of individuals investigated, especially in the trans woman group, our results should be taken carefully.

Finally, the (dis)satisfaction toward one's own body parts is not simply associated with a specific network, but differently according to the group, which suggests a different way of understanding and accepting the body depending on gender. The trans men group image (dissatisfaction) relied on the ventral attentional, that is, salience network. If one key element in the construction of gender is the perception of our own body (Burke et al., 2019; Peelen & Downing, 2007), the salience network has been highly related to trans- and cisgender differences that may explain the gender incongruence (Uribe et al., 2020b; Uribe et al., 2021). However, such a landmark is not helpful for the functional correlates of cisgender groups. These differences in the network correlates could be driven by the fact that the trans men group scores were within the range of the unconformity toward the body parts—4–5 points in the Likert scale of Lindgren and Pauly (1975)—, while cisgender groups would range mainly within the neutral satisfaction scores (1– points). Another potential explanation is that trans- and cisgender individuals' ratings may not be comparable between groups as the reported dissatisfaction may underlie different reasons for transgender people in contrast to what it would mean for cisgender groups. The cis man group's satisfaction and/or neutrality was positively associated with the limbic network and negatively with executive control. On the other hand, the network with higher spatial dynamical complexity, that is, the default mode, was also associated with body parts satisfaction in cis women. These networks have been largely associated with gender groups' differences described in previous works (Clemens et al., 2017; Manzouri et al., 2017; Uribe et al., 2020b; Uribe et al., 2021). However, our work provide evidence that gender group differences depict interplay by a whole-brain network in terms of spatial and temporal variability that exceeds the rather specific correlates of the degree of satisfaction toward the own body.

Some shortcomings should be addressed in future works. First, the need to increase the sample size that would add more power to the findings. Currently ongoing collaborative initiatives like the ENIGMA initiative on transgender health are trying to overcome this persistent limitation in the neuroimaging field (Mueller et al., 2021). However, this initiative lacks standard acquisition protocols to reduce the variability among sites that may hamper group discrimination. Second, the menstrual cycle of cis women and trans men was not accounted as a variable of interest, while there is growing evidence of functional dynamic differences between the phases of the menstrual cycle (De Filippi et al., 2021). Likewise, the sexual orientation of all participants was not systematically assessed as a variable of interest (Frigerio et al., 2021; Guillamon et al., 2016; Skorska et al., 2021). Including minority gender groups when investigating the gender phenomenon in the brain is imperative to understand the complexity of the gender experience. Nonetheless, future studies should include other gender groups, such as nonbinary or other genderqueer identities. Our exploratory work could potentially impact awareness, the development of healthcare guidelines, societal and political evidence-based changes accounting for this heterogeneity, and improve the quality of life while raising visibility that can help fight stigma (Janssen & Voss, 2021). Finally, it is important to note that the sample characteristics and analytical approach employed here prevent us from discriminating actual gender identity differences from other phenomena such as experiences of stigma that transgender people may have undergone. Future experimental designs should address such issues.