Article

Gender transition affects neural correlates of empathy: A resting state functional connectivity study with ultra high-field 7T MR imaging

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Abstract

Sex-steroid hormones have repeatedly been shown to influence empathy, which is in turn reflected in resting state functional connectivity (rsFC). Cross-sex hormone treatment in transgender individuals provides the opportunity to examine changes to rsFC over gender transition. We aimed to investigate whether sex-steroid hormones influence rsFC patterns related to unique aspects of empathy, namely emotion recognition and description as well as emotional contagion. RsFC data was acquired with 7 Tesla magnetic resonance imaging in 24 male-to-female (MtF) and 33 female-to-male (FtM) transgender individuals before treatment, in addition to 33 male- and 44 female controls. Of the transgender participants, 15 MtF and 20 FtM were additionally assessed after four weeks and four months of treatment. Empathy scores were acquired at the same time-points. MtF differed at baseline from all other groups and assimilated over the course of gender transition in a rsFC network around the supramarginal gyrus, a region central to interpersonal emotion processing. While changes to sex-steroid hormones did not correlate with rsFC in this network, a sex hormone independent association between empathy scores and rsFC was found. Our results underline that 1) MtF transgender persons demonstrate unique rsFC patterns in a network related to empathy and 2) changes within this network over gender transition are likely related to changes in emotion recognition, − description, and -contagion, and are sex-steroid hormone independent.

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... A study (18 MtF, 13 FtM, 21 MC, 18 FC) conducted with rs-fMRI investigated functional connectivity patterns and reported that in pre-puberal children functional connectivity was similar in all groups (Nota et al., 2017), although stressed the necessity of increasing the sample to draw meaningful conclusions. Another study (24 MtF, 33 FtM, 33 MC, 44 FC) that also investigated resting state functional connectivity (i.e., also a rs-fMRI study) found significant differences within a network around the supramarginal gyrus (i.e., a subregion within the parietal lobe) (Spies et al., 2016). A study (8 MtF,14 FtM,25 MC,26 FC) conducted with fMRI did not report any differences between transgender subjects and control group population during a verbal fluency test (Soleman et al., 2013). ...
... A study that conducted rs-MRI in young adults aged 19-22 years old, found MtF, FtM and FC having less resting state activations in parietal regions than MC; and MtF having also weaker functional connectivity in some regions in frontal cortex than MC (Uribe et al., 2020). Similar to the study from Spies et al. (2016), also in rs-fMRI, this study suggests that in MtF some parietal and frontal cortex regions exhibit similar activation patterns as FC. Another fMRI study (body self-identification task) on 30 cisgenders and 30 transgenders found greater involvement of the limbic system in transgenders, who activated similar self-and body-processing neural systems aligned with their experienced gender and not with their birth-assigned sex (Majid et al., 2020). ...
... First, some studies did not report statistical parameters and just reported whether or not there were significant differences between cisgenders and transgenders and between heterosexuals and homosexuals. Second, other studies reported statistical parameters only in case of significant differences between groups, and omitted reporting negative results (i.e., when no differences were found) (gender identity investigation: Burke et al., 2014;Kranz et al., 2014bKranz et al., , 2015Ku et al., 2013;Lin et al., 2014;Luders et al., 2009;Nota et al., 2017;Pol et al., 2006;Santarnecchi et al., 2012;Soleman et al., 2013;Spies et al., 2016;Yokota et al., 2005;Zubiaurre-Elorza et al., 2013; sexual orientation investigation: Hu et al., 2008;Ponseti et al., 2007;Savic and Lindström, 2008;Sylva, 2013;Zeki & Romaya, 2010; for more detailed information, please see analysis of bias in Appendix 5 and 6). A complete presentation of scientific data, including negative results, is important to precisely evaluate scientific investigations on a certain topic (Matosin et al., 2014). ...
Article
Full-text available
This review systematically explored structural, functional, and metabolic features of the cisgender brain compared with the transgender brain before hormonal treatment and the heterosexual brain compared to the homosexual brain from the analysis of the neuroimaging literature up to 2018, and identified and discussed subsequent studies published up to March 2021. Our main aim was to help identifying neuroradiological brain features that have been related to human sexuality to contribute to the understanding of the biological elements involved in gender identity and sexual orientation. We analyzed 39 studies on gender identity and 24 on sexual orientation. Our results suggest that some neuroanatomical, neurophysiological, and neurometabolic features in transgender individuals resemble those of their experienced gender despite the majority resembling those from their natal sex. In homosexual individuals the majority resemble those of their same-sex heterosexual population rather than their opposite-sex heterosexual population. However, it is always difficult to interpret findings with noninvasive neuroimaging. Given the gross nature of these measures, it is possible that more differences too subtle to measure with available tools yet contributing to gender identity and sexual orientation could be found. Conflicting results contributed to the difficulty of identifying specific brain features which consistently differ between cisgender and transgender or between heterosexual and homosexual groups. The small number of studies, the small-to-moderate sample size of each study, and the heterogeneity of the investigations made it impossible to meta-analyze all the data extracted. Further studies are necessary to increase the understanding of the neurological substrates of human sexuality.
... Neuronale Korrelate der Empathie wurden bei Mann-zu-Frau-und Frauzu-Mann-Trans*Menschen vor und nach Therapiebeginn und bei männlichen und weiblichen Kontrollen in einer Konnektivitätsstudie mit 7-T-rsfMRT untersucht. Es zeigten sich spezifische Muster um den supramarginalen Gyrus bei den Mann-zu-Frau-Trans*Menschen, allerdings war keine Veränderung unter der Therapie festzustellen, sodass diese spezifischen Aktivitätsmuster bei Empathie steroidhormonunabhängig zu sein scheinen [39]. ...
Article
Full-text available
In der funktionellen Magnetresonanztomographie (fMRT) können Aktivitätsmuster in bestimmten Hirnregionen dargestellt werden. Bei der Ausführung bestimmter Aufgaben oder Handlungen und bei Präsentation verschiedener Reize lassen sich spezifische Muster darstellen, die sich in definierten Kollektiven unterscheiden. Mit neueren Methoden wie der Resting-state-fMRT werden zudem die spontanen Hirnaktivitäten analysiert, die ebenfalls spezifische Veränderungen in unterschiedlichen Gruppen zeigen können. So gibt es auch geschlechtstypische Aktivitätsmuster bei Männern und Frauen. Es wurde zunächst angenommen, dass Trans*Menschen hierbei Ergebnisse zeigen, die zwischen den Geschlechtern liegen. Die Studien müssen jedoch differenzierter interpretiert werden und zeigen widersprüchliche Resultate, gerade in Abhängigkeit von den präsentierten Reizen. Der Einfluss der Hormontherapie auf kognitive Fähigkeiten und Korrelate in den zerebralen Aktivitätsmustern wird ebenso kontrovers diskutiert. Insgesamt spiegeln die Ergebnisse bildgebender Verfahren bei Trans*Menschen ein spannendes Zusammenspiel von gesellschaftlichen, biologischen, kognitiven und beispielsweise sexuellen Komponenten wider, zeigen aber auch die Grenzen der Methodik auf.
... We previously reported decreased connectivity of the supramarginal gyrus in TM with respect to CM 4 ; and thicker cortex in TM and CW with respect to CM using a different cohort 5 . Functional connectivity differences in the supramarginal gyrus between cisgender 44 and transgender groups 11 were also reported in relation to the own body perception 11,44 ; and to interpersonal emotion processing 45 . Multimodal translational approaches 46 are needed for understanding these compelling yet challenging findings contributing to the formation of the gendered-self. ...
Article
Full-text available
Large-scale brain network interactions have been described between trans- and cis -gender binary identities. However, a temporal perspective of the brain's spontaneous fluctuations is missing. We investigated the functional connectivity dynamics in transmen with gender incongruence and its relationship with interoceptive awareness. We describe four states in native and meta-state spaces: (i) one state highly prevalent with sparse overall connections; (ii) a second with strong couplings mainly involving components of the salience, default, and executive control networks. Two states with global sparse connectivity but positive couplings (iii) within the sensorimotor network, and (iv) between salience network regions. Transmen had more dynamical fluidity than cismen, while cismen presented less meta-state fluidity and range dynamism than transmen and ciswomen. A positive association between attention regulation and fluidity and meta-state range dynamism was found in transmen. There exist gender differences in the temporal brain dynamism, characterized by distinct interrelations of the salience network as catalyst interacting with other networks. We offer a functional explanation from the neurodevelopmental cortical hypothesis of a gendered -self.
... A total sample of n = 50, consisting of 25 FtMs and 25 controls (12 FCs and 13 MCs), were included and analyzed. Data from these participants were taken from a larger study and have partly been published previously Kranz et al. 2014;Spies et al. 2016). Subjects' age was comparable between groups (FtM 27.24 ± 6.2, FC 24.42 ± 5.4, MC 28.77 ± 6.5, mean ± SD, p = 0.21, ANOVA). ...
Article
Full-text available
Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.
... Performance on measures of empathy and emotional processing are also known to vary by sex (Hall, 1978;McClure, 2000;Schulte-Rüther, 2008). Empathy scores and resting state functional connectivity (rsFC) measurements were examined in male and female controls as well as both MTFs and FTMs prior to, and after 4 weeks and 4 months of GAHT (Spies et al., 2016). MTFs differed at baseline from all other groups in a rsFC network around the supramarginal gyrus, a region important for interpersonal emotion processing, but became more similar to the other groups over the course of GAHT administration. ...
Article
Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.
... In parallel, sex-and age-matched control subjects were scanned at similar time points. Data of respective subsamples of subjects have been published in five previous cross-sectional (Kranz et al. 2014;Ganger et al. 2015;Hahn et al. 2015aHahn et al. , 2015bSeiger et al. 2015) and five longitudinal investigations Seiger et al. 2016;Spies et al. 2016;Kranz et al. 2017;Kranz et al. 2018). The models created in the current study are based on the structural baseline scans in transgender and control subjects. ...
Article
Full-text available
Univariate analyses of structural neuroimaging data have produced heterogeneous results regarding anatomical sex- and gender-related differences. The current study aimed at delineating and cross-validating brain volumetric surrogates of sex and gender by comparing the structural magnetic resonance imaging data of cis- and transgender subjects using multivariate pattern analysis. Gray matter (GM) tissue maps of 29 transgender men, 23 transgender women, 35 cisgender women, and 34 cisgender men were created using voxel-based morphometry and analyzed using support vector classification. Generalizability of the models was estimated using repeated nested cross-validation. For external validation, significant models were applied to hormone-treated transgender subjects (n = 32) and individuals diagnosed with depression (n = 27). Sex was identified with a balanced accuracy (BAC) of 82.6% (false discovery rate [pFDR] < 0.001) in cisgender, but only with 67.5% (pFDR = 0.04) in transgender participants indicating differences in the neuroanatomical patterns associated with sex in transgender despite the major effect of sex on GM volume irrespective of the self-identification as a woman or man. Gender identity and gender incongruence could not be reliably identified (all pFDR > 0.05). The neuroanatomical signature of sex in cisgender did not interact with depressive features (BAC = 74.7%) but was affected by hormone therapy when applied in transgender women (P < 0.001).
... and thicker cortex in TM and CW with respect to CM using a different cohort 5 . Functional connectivity differences in the supramarginal gyrus between cisgender 33 and transgender groups 11 were also reported in relation to the own body perception 11,33 ; and to interpersonal emotion processing 34 . ...
Preprint
Full-text available
Large-scale brain network interactions have been described between trans- and cis -gender identities. However, a temporal perspective of the brain spontaneous fluctuations is missing. We investigated the functional connectivity dynamics in transmen with gender incongruence and its relationship with interoceptive awareness. We describe four states in native and meta-state spaces: i) one state highly prevalent with sparse overall connections; ii) a second with strong couplings mainly involving components of the salience, default and executive control networks. Two states with global sparse connectivity but positive couplings iii) within the sensorimotor network, and iv) between salience network regions. Transmen had more dynamical fluidity than cismen, while cismen presented less meta-state fluidity and range dynamism than transmen and ciswomen. A positive association between attention regulation and fluidity, and meta-state range dynamism was found in transmen. There exist gender differences in the temporal brain dynamism, characterized by distinct interrelations of the salience network as catalyst interacting with other networks. We provide a functional explanation to the neurodevelopmental hypothesis proposing different brain phenotypes in the construction of the gendered -self.
... Indeed, beyond the classic somatosensory and proprioceptive processing (Gazzaniga, Ivry, & Mangun, 2006), supramarginal activity especially in the right hemisphere is involved in empathic reactivity to vicarious pain both in neurotypical (Benuzzi et al., 2018;Silani et al., 2013;Steinbeis, Bernhardt, & Singer, 2015) and neuropathic populations (Flasbeck et al., 2019;Hoffmann et al., 2016). In addition, neural activity in rSMG is correlated with the ability to emotionally distinguish the self from the other (Steinbeis et al., 2015), the regulation of emotional egocentricity (Silani et al., 2013), and is further modulated by dispositional empathic understanding (Ruff et al., 2019) and intake of hormones affecting empathic reactivity (Spies et al., 2016). Finally, SMG is generally involved in the differentiation between empathy-related processing related to oneself versus somebody else, both in neurotypical (Beckes, Coan, & Hasselmo, 2013;Lawrence et al., 2006) and emotionally impaired clinical populations (Hoffmann et al., 2016). ...
Article
Full-text available
Personal and vicarious experience of pain activate partially overlapping brain networks. This brain activity is further modulated by low- and high-order factors, e.g., the perceived intensity of the model's pain and the model's similarity with the onlooker, respectively. We investigated which specific aspect of similarity modulates such empathic reactivity, focusing on the potential differentiation between visual similarity and psychological closeness between the onlooker and different types of models. To this aim, we recorded fMRI data in neurotypical participants who observed painful and tactile stimuli delivered to an adult human hand, a baby human hand, a puppy dog paw, and an anthropomorphic robotic hand. The interaction between type of vicarious experience (pain, touch) and nature of model (adult, baby, dog, robot) showed that the right supramarginal gyrus (rSMG) was selectively active for visual similarity (more active during vicarious pain for the adult and baby models), while the anterior cingulate cortex (ACC) was more sensitive to psychological closeness (specifically linked to vicarious pain for the baby model). These findings indicate that visual similarity and psychological closeness between onlooker and model differentially affect the activity of brain regions specifically implied in encoding interindividual sharing of sensorimotor and affective aspects of vicarious pain, respectively.
... In addition to the use of nonpreferred terminology when referring to transgender patients, several articles misgendered their transgender patients and discussed their transgender subjects as a "midpoint" between the sexual binary of male and female. A number of neuroradiology articles, the subspecialty that represented the majority of the prospective studies, investigated hypotheses about proposed underlying neurologic differences of transgender people rather than seeking to improve the health of transgender patients [30][31][32][33][34][35]. These articles focused on the physical or physiologic differences of transgender patients without acknowledging the social components of gender and gender expression. ...
Article
Purpose: The ACR has established that diversity and inclusion are central to its mission of excellence in the radiologic professions; therefore, radiologists have a responsibility to serve the imaging needs of the transgender community. To understand radiologists' current knowledge of transgender topics, the authors performed a systematic review of publications from radiology journals. Methods: A lexicon of 14 transgender-related terms was created and expanded through a PubMed keyword search. From the 129 journals from the radiology, nuclear medicine, and medical imaging category of Journal Citation Reports, 106 journals met the inclusion criteria, including English translation and Scopus data for the study period. Using the Scopus advanced search feature, articles with titles, abstracts, Medical Subject Headings terms, or keywords including 1 of 14 transgender terms were identified and analyzed. Results: Of the more than 200,000 articles published by the 106 journals from January 2008 to July 2019, 29 relevant articles were identified. Only 14 of the 106 journals published any transgender-related topics. The volume of articles has increased over time. The largest proportion of articles was published under the "general radiology" subsection, with the majority of these being editorials (6 of 10). Most of the original research was published under "neuroradiology" (7 of 13). Use of nonpreferred language, such as "transsexual" and "natal sex" was present through 2019. Conclusions: Publication on transgender-related topics was uncommon among radiology journals. It is important to encourage further research and publication on transgender topics, as well as use of respectful, accepted language in radiology journals.
... The data analyzed was combined from two larger studies conducted by our group and partly has been published earlier addressing other research questions (Baldinger-Melich et al., 2020;Hahn et al., 2016;Kranz et al., 2014;Kranz et al., 2018;Kranz et al., 2017;Spies et al., 2016). For this analysis, we considered data from 125 right-handed subjects who underwent two magnetic resonance imaging (MRI) measurements in a longitudinal design. ...
Preprint
Full-text available
Sex steroid hormones influence hypothalamic micro- and macrostructure in humans and animal models. Neuroimaging studies have suggested that estrogen and anti-androgen treatment decreases volumes of multiple cortical and subcortical brain areas in transgender individuals, including total hypothalamus volume. Here, we aim to further explore potential effects of gender-affirming hormone treatment (GHT) in transgender individuals on hypothalamic volume by providing additional information on hypothalamic subfields. 38 transgender men (TM) and 15 transgender women (TW), with gender dysphoria (DSM-5), as well as 32 cisgender women (CW) and 21 cisgender men (CM) underwent two magnetic resonance imaging (MRI) measurements with an interval of at least four months (median interval TM= 134.5 days (interquartile range (IQR): 126-152.25); TW= 149 days (IQR: 126-178.5); CW= 147 days (IQR: 139.75-170.5); CM= 146 days (IQR: 132-247)) between both sessions. In transgender individuals GHT, consisting of estrogen and anti-androgen treatment in TW and testosterone treatment in TM, was initiated directly after the first measurement. To assess how GHT interacts with hypothalamic structures, the hypothalamus and its subunits were segmented using FreeSurfer. Subject group x time interaction effects were evaluated using repeated measures ANCOVA models. The Bonferroni method was used to correct for multiple comparisons. Significant decreases of total hypothalamic volume and associated subunits were detected in TW after estrogen and anti-androgen treatment compared to cisgender groups. Effects were found in the total hypothalamus volume (p corr = 0.001), the left and right hypothalamus (p corr = 0.002), the inferior tubular subunit bilaterally (right: p corr = 0.001; left: p corr = 0.001), the left superior tubular subunit (p corr = 0.003) the right anterior inferior subunit (p corr = 0.002), as well as the right anterior superior subunit (p corr = 0.0002) of the hypothalamus. Here, we observed significant volumetric effects on the adult human hypothalamus after an interval of at least four months of estrogen and anti-androgen treatment in TW and added knowledge on associated subfields. Further studies investigating influences of sex steroid hormones on brain structure and functional connections are still needed.
... To minimise the potential confounding effect of different fMRI scanners on resting-state scans obtained, we excluded 10 participants whose resting-state scans were acquired from a different 3.0 Tesla Siemens scanner. Transgender individuals (n = 2) were excluded given the small sample sizes and potential differences in resting-state functional connectivity (Spies et al., 2016). There were 97 participants whose fMRI data were available for preprocessing and GICA analysis. ...
Conference Paper
Background. Recent synthesis of neuroimaging evidence proposed that aberrant intrinsic functional connectivity in three large-scale neurocognitive networks; the default mode network, salience network, and central executive network, contributes to psychopathology. Current findings from rest-state functional magnetic resonance imaging (fMRI) studies on borderline personality disorder (BPD) were inconsistent and limited to BPD-specific differences. Objective. The study aims to identify resting-state intrinsic functional connectivity differences in BPD. The secondary aim was to explore resting-state intrinsic functional connectivity associated with resilience. Method. Resting-state fMRI scans were obtained from 66 participants (29 healthy controls and 37 individuals with BPD). Group independent component analysis was conducted to examine intrinsic functional connectivity within and between the default mode network, salience network and central executive network associated with group and resilient functioning. Resilience was quantified as the residual resulting from the difference between the participant’s predicted and observed psychopathology symptoms, based on the severity of their self-reported childhood trauma. The participant’s predicted psychopathology symptoms were derived from a linear regression model which examined the relationship between psychopathology and childhood trauma (N = 198; 111 individuals with BPD and 87 healthy controls). Results. Healthy individuals showed increased intrinsic functional connectivity within the bilateral precuneus compared to individuals with BPD, p < .05, false discovery rate (FDR) corrected, and these group differences remained after controlling for childhood trauma and psychopathology symptoms. Higher resilient functioning in the healthy individuals was associated with decreased intrinsic functional connectivity within the left ventral central executive network, p < .05, FDR corrected. Furthermore, the association between decreased intrinsic functional connectivity in the anterior cingulate and high resilient functioning were only replicated in the healthy individuals and not in the BPD group. Conclusion. Preliminary findings suggest different patterns of intrinsic functional connectivity within the default mode network and central executive network between healthy individuals and individuals with BPD. Implicated regions were associated with self-referential processing, autobiographical memory and cognitive control. The findings contribute to future investigations on BPD-specific differences and general resilience mechanisms in intrinsic brain architecture.
... Interestingly, progesterone, together with estrogen, is nowadays also part of the cross-sex hormone therapy for male-to-female patients with gender dysphoria (Spack, 2013, Prior, 2019. For the effect of this treatment on the brain, please see the neuroimaging studies performed by Lanzenberger and colleagues (Kranz et al., 2014, Kranz et al., 2015, Spies et al., 2016, Kranz et al., 2017. ...
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Estradiol is the “prototypic” sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
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Evidence suggests that women outperform men in core aspects of odor perception, and sex hormones may play a significant role in moderating this effect. The gender-affirming treatment (GAT) of transgender persons constitutes a powerful natural experiment to study the psychological and behavioral effects of high dosages of cross-sex hormone applications. Therefore, our aim was to investigate the effects of GAT on odor perception in a sample of 131 participants including female and male controls, as well as transmen and transwomen over their first four months of gender transition. The Sniffin' Sticks test battery was used to measure odor detection, discrimination and identification at baseline, as well as one and four months after the start of GAT. Plasma levels of estradiol, testosterone and sex hormone-binding globulin was analyzed for each assessment point. Results revealed no significant change of olfactory performance in the two transgender groups compared to female and male controls. There was no significant difference between groups at baseline or any other time point. Neither biological sex, nor gender identity had an influence on odor perception. Moreover, there was no significant correlation between sex hormones and odor perception and between GAT-induced changes in sex hormones and changes in odor perception. Our results indicate that effects of sex hormones on olfactory performance are subtle, if present at all. However, our results do not preclude hormonal effects on odors not included in the Sniffin' Sticks test battery, such as body odors or odors associated with sex.
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Objective: The purpose of this paper is to provide an overview of helpful clinical practices when working with transgender adult individuals. Method: While the number of openly transgender individuals appears to be growing with society's increased acceptance and awareness, many neuropsychologists have had few opportunities to gain experience with this patient population. In this article, we review the existing literature as it relates to clinical neuropsychological practice. Results: We describe important terminology, ideals for creating an environment of respect, and how existing clinical guidelines for transgender individuals may apply to neuropsychology. In addition, we review the primary steps in the assessment process and provide a set of principles and recommendations for conducting neuropsychological assessments with transgender patients. Conclusions: There is a paucity of guidance in the field for working with transgender individuals. This article represents a step forward in the dialog and we look forward to future research that develops appropriate normative information, increases understanding of psychosocial factors, and better appreciates the range of hormonal influences for transgender individuals.
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Empathy is the capacity to feel and understand others’ mental states. In some individuals, there is an imbalance between the affective and cognitive components of empathy, which can lead to deficits. This study investigated the functional connectivity of the anterior insula (AI) and dorsomedial prefrontal cortex (dmPFC), which play key roles in empathy, in covariation with the affective and cognitive subscales of the Interpersonal Reactivity Index (IRI), as a function of age and sex, as an exploratory analysis. Seed-based functional connectivity analyses were performed on 33 healthy participants that were subdivided according to their age (16 adults and 17 adolescents) and sex (16 women and 17 men). Adolescents reported lower cognitive empathy than adults and men less affective empathy than women. The connectivity of the dmPFC and AI, in covariation with the cognitive and affective subscales of empathy, respectively, differed between adolescents and adults, but was similar in men and women. Adolescents had patterns of negative covariations between the regions of interest and many brain regions associated with the default-mode and salience networks. These findings support that lower self-report levels of empathy in certain individuals could be reflected in the functional connectivity patterns of the dmPFC and AI.
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Investigating the effects of the gender-affirming hormone treatment of transgender people using neuroimaging provides a unique opportunity to study the impact of high dosages of sex hormones on human brain structure and function. This line of research is of relevance from a basic neuroscientific as well as from a psychiatric viewpoint. Prevalence rates, etiopathology, and disease course of many psychiatric disorders exhibit sex differences which are linked to differences in sex hormone levels. Here, we review recent neuroimaging studies from others and our group that investigate the effects of gender-affirming hormone treatment in a longitudinal design utilizing structural and functional magnetic resonance imaging and positron emission tomography. Studies point to a general anabolic and anticatabolic effect of testosterone on grey and white matter structure, whereas estradiol and antiandrogen treatment seems to have partly opposite effects. Moreover, preliminary research indicates that gender-affirming hormone treatment influences serotonergic neurotransmission, a finding that is especially interesting for psychiatry. A clear picture of a hormonal influence on brain activity has yet to emerge. In conclusion, the available evidence reviewed here clearly indicates that sex hormone applications influence brain structure and function in the adult human brain.
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Millions of women worldwide use oral contraceptives (i.e., birth control pill; OCs), often starting during puberty/adolescence; however, it is unknown how OC use during this critical period of development affects the brain, especially with regard to emotional working memory. Here, we examined stress reactivity, and brain structure and function in OC users using the Trier Social Stress Test and structural and functional magnetic resonance imaging (MRI). Our results show that OC use during puberty/adolescence gives rise to a blunted stress response and alters brain activation during working memory processing. OC use, in general, is also linked to increased prefrontal brain activation during working memory processing for negatively arousing stimuli. OC use is also related to significant structural changes in brain regions implicated in memory and emotional processing. Together, these findings highlight that OC use induces changes to brain structure and function and alters stress reactivity. These findings may provide a mechanistic insight for the increased vulnerability to mood-related mental illness in women after OC use.
Preprint
This review systematically explored structural, functional, and metabolic features of the cisgender brain compared with the transgender brain before hormonal treatment and the heterosexual brain compared to the homosexual brain from the analysis of the neuroimaging literature up to 2018, and identified and discussed subsequent studies published up to March 2021. Our main aim was to help identifying neuroradiological brain features that have been related to human sexuality to contribute to the understanding of the biological elements involved in gender identity and sexual orientation. We analyze 39 studies on gender identity and 24 on sexual orientation. Our results suggest that some neuroanatomical, neurophysiological, and neurometabolic features in transgender individuals resemble those of their experienced gender despite the majority resembling those from their natal sex. In homosexual individuals the majority resemble those of their same sex heterosexual population rather than their opposite sex heterosexual population. However, it is always difficult to interpret findings with non-invasive neuroimaging. Given the gross nature of these measures, it is possible that more differences too subtle to measure with available tools yet contributing to gender identity and sexual orientation could be found. Conflicting results contributed to the difficulty of identifying specific brain features which consistently differ between cisgender and transgender or between heterosexual and homosexual groups. The small number of studies, the small-to-moderate sample size of each study, and the heterogeneity of the investigations made it impossible to meta-analyze all the data extracted. Further studies are necessary to increase the understanding of the neurological substrates of human sexuality.
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Research on the interaction between gender and emotions has largely been constrained by the gender binary. This article seeks to advance theory of constructed emotions as relates to marginalized identities by describing the emotional experiences of individuals with a nonbinary gender identity. We conducted a two-phase analysis (grounded theory, content analysis) of nonbinary individuals’ (N = 13) reported emotional experiences to determine their degree of alignment with a prevailing emotion model. The analysis revealed that several new emotion labels are related to gender-based oppression (e.g., internalized shame, invisibility, and exhaustion). We conclude that predominant emotion models are hindered by the constraints of the gender binary. We propose that gender minority stressand broader systemic oppressioninfluence how emotions are experienced among nonbinary individuals. We offer specific recommendations for psychotherapists working with transgender and nonbinary individuals.
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The sex hormones testosterone and estradiol influence brain structure and function and are implicated in the pathogenesis, prevalence and disease course of major depression. Recent research employing gender-affirming hormone treatment (GHT) of gender dysphoric individuals and utilizing positron emission tomography (PET) indicates increased serotonin transporter binding upon high-dosages of testosterone treatment. Here, we investigated the effects of GHT on levels of monoamine oxidase A (MAO-A), another key target of antidepressant treatment. Participants underwent PET with the radioligand [¹¹C]harmine to assess cerebral MAO-A distribution volumes (VT) before and four months after initiation of GHT. By the time this study was terminated for technical reasons, 18 transgender individuals undergoing GHT (11 transmen, TM and 7 transwomen, TW) and 17 cis-gender had been assessed. Preliminary analysis of available data revealed statistically significant MAO-A VT reductions in TM under testosterone treatment in six of twelve a priori defined regions of interest (middle frontal cortex (-10%), anterior cingulate cortex (-9%), medial cingulate cortex (-10.5%), insula (-8%), amygdala (-9%) and hippocampus (-8.5%, all p<0.05)). MAO-A VT did not change in TW receiving estrogen treatment. Despite the limited sample size, pronounced MAO-A VT reduction could be observed, pointing towards a potential effect of testosterone. Considering MAO-A’s central role in regulation of serotonergic neurotransmission, changes to MAO-A VT should be further investigated as a possible mechanism by which testosterone mediates risk for, symptomatology of, and treatment response in affective disorders.
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Millions of women worldwide use oral contraceptives (OCs), often starting during puberty/adolescence. It is, however, unknown how OC use during this critical period of development affects the brain. The objective of the current study was to examine resting state functional connectivity (FC) in the default mode network (DMN), central executive network (CEN), salience network (SN), reward network (RN), and subcortical limbic network of the brain using independent component analysis (ICA) between pubertal- and adult-onset OC users (n = 27) and naturally cycling women (n = 48). It was hypothesized that OC use would result in network-specific increases and decreases in FC and that pubertal-onset OC use would result in differences to the aforementioned networks compared to adult-onset OC use. Pubertal-onset OC use is related to heightened FC in the SN compared to adult-onset OC users. In general, OC use also increases connectivity in the SN, CEN, RN, and subcortical limbic network compared to NC women. No significant differences in connectivity were observed in the DMN between OC users and NC women. These findings provide a mechanistic insight for the altered executive functioning and emotion/reward processing previously seen in OC users, which may then increase their vulnerability to mental health conditions.
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Gender dysphoria (GD) is characterized by incongruence between onés gender assigned at birth and the gender that one identifies with. The biological mechanisms of GD are unclear, especially in female-to-male transsexuals (FtM-TR). Here, we investigate whether distinct structural and functional patterns along cerebral midline networks processing own-body perception may constitute a biological correlate. Method: MRI of functional connectivity, cortical thickness, surface area, and gray matter volume was carried out in 28 female-to-male transsexuals (FtM-TR) and 68 cis-sexual controls (34 male). FtM-TR displayed thicker mid-frontal, precuneal-parietal, and lingual cortex than both male and female controls, whereas, in regions with reported anatomical sex differences among the controls, FtM-TR followed patterns of the gender assigned at their birth. FtM-TR also displayed weaker functional connections from the pregenual anterior cingulate to the insular cortex, and the temporo parietal junction compared with both control groups. Distinct structural and functional pattern in the own-body image network may represent biological markers for the dysphoric own-body perception in transgender individuals.
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The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC) mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal Resting-state functional Magnetic Resonance Imaging (rs-fMRI) design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.
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Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.
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Despite increasing empirical and theoretical work on empathy, particularly on the content of empathic representations, there is a relative lack of consensus regarding the information processing necessary for empathy to occur. Here we attempt to delineate a mechanistic cognitive model of empathy in order to provide a framework within which neuroimaging work on empathy can be located, and which may be used in order to understand various disorders characterised by atypical levels of empathy. To this end data from individuals with psychopathy, autism, and alexithymia inform the model, and the model is used to provide a unifying framework for any empathy impairments seen in these disorders. The model adopts a developmental framework and tries to address the four difficult questions of empathy: How do we know what another is feeling? What is the role of theory of mind in empathy? How does the state of another cause a corresponding state in the self? How do we represent another's emotion once emotional contagion has taken place?
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Although previous investigations of transsexual people have focused on regional brain alterations, evaluations on a network level, especially those structural in nature, are largely missing. Therefore, we investigated the structural connectome of 23 female-to-male (FtM) and 21 male-to-female (MtF) transgender patients before hormone therapy as compared with 25 female and 25 male healthy controls. Graph theoretical analysis of whole-brain probabilistic tractography networks (adjusted for differences in intracranial volume) showed decreased hemispheric connectivity ratios of subcortical/limbic areas for both transgender groups. Subsequent analysis revealed that this finding was driven by increased interhemispheric lobar connectivity weights (LCWs) in MtF transsexuals and decreased intrahemispheric LCWs in FtM patients. This was further reflected on a regional level, where the MtF group showed mostly increased local efficiencies and FtM patients decreased values. Importantly, these parameters separated each patient group from the remaining subjects for the majority of significant findings. This work complements previously established regional alterations with important findings of structural connectivity. Specifically, our data suggest that network parameters may reflect unique characteristics of transgender patients, whereas local physiological aspects have been shown to represent the transition from the biological sex to the actual gender identity.
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To what degree resting state fMRI is stable or susceptible to internal mind states of the individual is currently an issue of debate. To address this issue, the present study focuses on sex differences and investigates whether resting state fMRI is stable in men and women or changes within relative short-term periods (i.e., across the menstrual cycle). Due to the fact that we recently reported menstrual cycle effects on cognitive control based on data collected during the same sessions, the current study is particularly interested in fronto-parietal resting state networks. Resting state fMRI was measured in sixteen women during three different cycle phases (menstrual, follicular, and luteal). Fifteen men underwent three sessions in corresponding time intervals. We used independent component analysis to identify four fronto-parietal networks. The results showed sex differences in two of these networks with women exhibiting higher functional connectivity in general, including the prefrontal cortex. Menstrual cycle effects on resting states were non-existent. It is concluded that sex differences in resting state fMRI might reflect sexual dimorphisms in the brain rather than transitory activating effects of sex hormones on the functional connectivity in the resting brain.
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Sex differences have been reported in autistic traits and systemizing (male advantage), and empathizing (female advantage) among typically developing individuals. In individuals with autism, these cognitive-behavioural profiles correspond to predictions from the "extreme male brain" (EMB) theory of autism (extreme scores on autistic traits and systemizing, below average on empathizing). Sex differences within autism, however, have been under-investigated. Here we show in 811 adults (454 females) with autism and 3,906 age-matched typical control adults (2,562 females) who completed the Empathy Quotient (EQ), the Systemizing Quotient-Revised (SQ-R), and the Autism Spectrum Quotient (AQ), that typical females on average scored higher on the EQ, typical males scored higher on the SQ-R and AQ, and both males and females with autism showed a shift toward the extreme of the "male profile" on these measures and in the distribution of "brain types" (the discrepancy between standardized EQ and SQ-R scores). Further, normative sex differences are attenuated but not abolished in adults with autism. The findings provide strong support for the EMB theory of autism, and highlight differences between males and females with autism.
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Empathizing is the drive to identify the mental status of other individuals and respond to it with an appropriate emotion; systemizing is the drive to analyze a system. Previously, we have shown that structures associated with the default mode network (DMN) and external attention system (EAS) are associated with empathizing and systemizing, respectively. Here we investigated the association between resting-state functional connectivity (RSFC) and empathizing/systemizing in 248 healthy young adults. We considered the medial prefrontal cortex (mPFC) and bilateral dorsolateral prefrontal cortices (DLPFCs), which are key nodes of DMN and EAS, as seed regions, and investigated correlations across subjects between individual empathizing/systemizing and RSFC between each seed region and other brain regions. We found that higher empathizing was associated with larger RSFC between the mPFC and areas in (a) the dorsal anterior cingulate cortex (dACC), (b) precuneus, and (c) left superior temporal sulcus (STS). Furthermore, there was an interaction effect between sex and systemizing on RSFC between the left DLPFC and dACC: males showed positive correlations between this RSFC and systemizing, whereas females showed the opposite tendency. Thus, empathizing was associated with increased positive functional coupling with the key node and other nodes of DMN, as well as the area associated with feeling another's pain. Systemizing was associated with increased positive functional coupling between the key nodes of EAS in males. These findings provide further support for the concept of an association between DMN/EAS and empathizing/systemizing.
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What does it mean to have a "verbal cognitive style?" We adopt the view that a cognitive style represents a cognitive strategy, and we posit the conversion hypothesis - the notion that individuals with a proclivity for the verbal cognitive style tend to code nonverbal information into the verbal domain. Here we used repetitive transcranial magnetic stimulation (rTMS) to disrupt this hypothesized verbal conversion strategy. Following our previous research implicating left supramarginal gyrus (SMG) in the verbal cognitive style, we used an fMRI paradigm to localize left SMG activity for each subject, then these functional peaks became rTMS targets. Left SMG stimulation impaired performance during a task requiring conversion from pictures to verbal labels. The magnitude of this effect was predicted by individuals' level of verbal cognitive style, supporting the hypothesized role of left SMG in the verbal labeling strategy, and more generally supporting the conversion hypothesis for cognitive styles.
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Body image is the internal representation of an individual's own physical appearance. Individuals with gender identity disorder (GID), commonly referred to as transsexuals (TXs), are unable to form a satisfactory body image due to the dissonance between their biological sex and gender identity. We reasoned that changes in the resting-state functional connectivity (rsFC) network would neurologically reflect such experiential incongruence in TXs. Using graph theory-based network analysis, we investigated the regional changes of the degree centrality of the rsFC network. The degree centrality is an index of the functional importance of a node in a neural network. We hypothesized that three key regions of the body representation network, i.e., the primary somatosensory cortex, the superior parietal lobule and the insula, would show a higher degree centrality in TXs. Twenty-three pre-treatment TXs (11 male-to-female and 12 female-to-male TXs) as one psychosocial group and 23 age-matched healthy cissexual control subjects (CISs, 11 males and 12 females) were recruited. Resting-state functional magnetic resonance imaging was performed, and binarized rsFC networks were constructed. The TXs demonstrated a significantly higher degree centrality in the bilateral superior parietal lobule and the primary somatosensory cortex. In addition, the connectivity between the right insula and the bilateral primary somatosensory cortices was negatively correlated with the selfness rating of their desired genders. These data indicate that the key components of body representation manifest in TXs as critical function hubs in the rsFC network. The negative association may imply a coping mechanism that dissociates bodily emotion from body image. The changes in the functional connectome may serve as representational markers for the dysphoric bodily self of TXs.
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Gender identity disorder (GID) refers to transsexual individuals who feel that their assigned biological gender is incongruent with their gender identity and this cannot be explained by any physical intersex condition. There is growing scientific interest in the last decades in studying the neuroanatomy and brain functions of transsexual individuals to better understand both the neuroanatomical features of transsexualism and the background of gender identity. So far, results are inconclusive but in general, transsexualism has been associated with a distinct neuroanatomical pattern. Studies mainly focused on male to female (MTF) transsexuals and there is scarcity of data acquired on female to male (FTM) transsexuals. Thus, our aim was to analyze structural MRI data with voxel based morphometry (VBM) obtained from both FTM and MTF transsexuals (n = 17) and compare them to the data of 18 age matched healthy control subjects (both males and females). We found differences in the regional grey matter (GM) structure of transsexual compared with control subjects, independent from their biological gender, in the cerebellum, the left angular gyrus and in the left inferior parietal lobule. Additionally, our findings showed that in several brain areas, regarding their GM volume, transsexual subjects did not differ significantly from controls sharing their gender identity but were different from those sharing their biological gender (areas in the left and right precentral gyri, the left postcentral gyrus, the left posterior cingulate, precuneus and calcarinus, the right cuneus, the right fusiform, lingual, middle and inferior occipital, and inferior temporal gyri). These results support the notion that structural brain differences exist between transsexual and healthy control subjects and that majority of these structural differences are dependent on the biological gender.
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Abstract Multifaceted and idiosyncratic aberrancies in social cognition characterize autism spectrum disorders (ASDs). To advance understanding of underlying neural mechanisms, we measured brain hemodynamic activity with functional magnetic resonance imaging (fMRI) in individuals with ASD and matched-pair neurotypical (NT) controls while they were viewing a feature film portraying social interactions. Pearson's correlation coefficient was used as a measure of voxelwise similarity of brain activity (InterSubject Correlations—ISCs). Individuals with ASD showed lower ISC than NT controls in brain regions implicated in processing social information including the insula, posterior and anterior cingulate cortex, caudate nucleus, precuneus, lateral occipital cortex, and supramarginal gyrus. Curiously, also within NT group, autism-quotient scores predicted ISC in overlapping areas, including, e.g., supramarginal gyrus and precuneus. In ASD participants, functional connectivity was decreased between the frontal pole and the superior frontal gyrus, angular gyrus, superior parietal lobule, precentral gyrus, precuneus, and anterior/posterior cingulate gyrus. Taken together these results suggest that ISC and functional connectivity measure distinct features of atypical brain function in high-functioning autistic individuals during free viewing of acted social interactions. Our ISC results suggest that the minds of ASD individuals do not ‘tick together’ with others while perceiving identical dynamic social interactions.
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Humans tend to use the self as a reference point to perceive the world and gain information about other people's mental states. However, applying such a self-referential projection mechanism in situations where it is inappropriate can result in egocentrically biased judgments. To assess egocentricity bias in the emotional domain (EEB), we developed a novel visuo-tactile paradigm assessing the degree to which empathic judgments are biased by one's own emotions if they are incongruent to those of the person we empathize with. A first behavioral experiment confirmed the existence of such EEB, and two independent fMRI experiments revealed that overcoming biased empathic judgments is associated with increased activation in the right supramarginal gyrus (rSMG), in a location distinct from activations in right temporoparietal junction reported in previous social cognition studies. Using temporary disruption of rSMG with repetitive transcranial magnetic stimulation resulted in a substantial increase of EEB, and so did reducing visuo-tactile stimulation time as shown in an additional behavioral experiment. Our findings provide converging evidence from multiple methods and experiments that rSMG is crucial for overcoming emotional egocentricity. Effective connectivity analyses suggest that this may be achieved by early perceptual regulation processes disambiguating proprioceptive first-person information (touch) from exteroceptive third-person information (vision) during incongruency between self- and other-related affective states. Our study extends previous models of social cognition. It shows that although shared neural networks may underlie emotional understanding in some situations, an additional mechanism subserved by rSMG is needed to avoid biased social judgments in other situations.
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This article is part of a Special Issue "Puberty and Adolescence". There is increasing evidence that puberty plays an important role in the structural and functional brain development seen in adolescence, but little is known of the pubertal influence on changes in functional connectivity. We explored how pubertal indicators (salivary concentrations of testosterone, oestradiol and DHEA; pubertal stage; menarcheal status) relate to functional connectivity between components of a mentalising network identified to be engaged in social emotion processing by our prior work, using psychophysiological interaction (PPI) analysis. Female adolescents aged 11 to 13years were scanned whilst silently reading scenarios designed to evoke either social emotions (guilt and embarrassment) or basic emotions (disgust and fear), of which only social compared to basic emotions require the representation of another person's mental states. Pubertal stage and menarcheal status were used to assign participants to pre/early or mid/late puberty groups. We found increased functional connectivity between the dorsomedial prefrontal cortex (DMPFC) and the right posterior superior temporal sulcus (pSTS) and right temporo-parietal junction (TPJ) during social relative to basic emotion processing. Moreover, increasing oestradiol concentrations were associated with increased functional connectivity between the DMPFC and the right TPJ during social relative to basic emotion processing, independent of age. Our analysis of the PPI data by phenotypic pubertal status showed that more advanced puberty stage was associated with enhanced functional connectivity between the DMPFC and the left anterior temporal cortex (ATC) during social relative to basic emotion processing, also independent of age. Our results suggest increased functional maturation of the social brain network with the advancement of puberty in girls.
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The aim of this research is to establish the validity and reliability of the Bermond–Vorst Alexithymia Questionnaire (BVAQ). The BVAQ consists of five subscales, each comprising of eight items. The subscales are denoted Emotionalizing, Fantasizing, Identifying, Analyzing, and Verbalizing. The validity of the instruments was investigated by comparing results of psychometric analyses in three language groups. In addition BVAQ scores were correlated, for comparison, with the TAS-20 test scores and with measures of psychological problems. Two studies were carried out.In the first study the BVAQ was administered to a sample of Dutch students (n=375), a sample of French-speaking Belgian students (n=175), and a sample of English students (n=129). Cronbach’s alpha was found to be about the same in the three samples (means of subscales about 0.79; total scales about 0.85). Principal components analyses of the 40 items revealed comparable five-factor solutions in the three samples. The mean total score of UK students differs about 0.29 SD from that of the Dutch and Belgian students. The intercorrelations of subscales were the same in the three samples. However, principal components analyses of the subscale scores of the English subjects revealed a different factor structure compared to that in the other samples.In the second study, the BVAQ and the Dutch version of the TAS-20 were administered to 430 Dutch students. Correlations between (sub)scales of the Dutch BVAQ and (sub)scales of the TAS-20 support the validity of the BVAQ. The validity of the BVAQ is further supported by correlations between BVAQ scores and measurements of psychological problems.
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Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.
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The degree to which one identifies as male or female has a profound impact on one's life. Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity. In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals. To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males. Results revealed thicker cortices in MTF transsexuals, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus). These findings provide further evidence that brain anatomy is associated with gender identity, where measures in MTF transsexuals appear to be shifted away from gender-congruent men.
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People believe that women are more emotionally intense than men, but the scientific evidence is equivocal. In this study, we tested the novel hypothesis that men and women differ in the neural correlates of affective experience, rather than in the intensity of neural activity, with women being more internally (interoceptively) focused and men being more externally (visually) focused. Adult men (n = 17) and women (n = 17) completed a functional magnetic resonance imaging study while viewing affectively potent images and rating their moment-to-moment feelings of subjective arousal. We found that men and women do not differ overall in their intensity of moment-to-moment affective experiences when viewing evocative images, but instead, as predicted, women showed a greater association between the momentary arousal ratings and neural responses in the anterior insula cortex, which represents bodily sensations, whereas men showed stronger correlations between their momentary arousal ratings and neural responses in the visual cortex. Men also showed enhanced functional connectivity between the dorsal anterior insula cortex and the dorsal anterior cingulate cortex, which constitutes the circuitry involved with regulating shifts of attention to the world. These results demonstrate that the same affective experience is realized differently in different people, such that women's feelings are relatively more self-focused, whereas men's feelings are relatively more world-focused.
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Previous studies have demonstrated variable influences of sexual hormonal states on female brain activation and the necessity to control for these in neuroimaging studies. However, systematic investigations of these influences, particularly those of hormonal contraceptives as compared to the physiological menstrual cycle are scarce. In the present study, we investigated the hormonal modulation of neural correlates of erotic processing in a group of females under hormonal contraceptives (C group; N = 12), and a different group of females (nC group; N = 12) not taking contraceptives during their mid-follicular and mid-luteal phases of the cycle. We used functional magnetic resonance imaging to measure hemodynamic responses as an estimate of brain activation during three different experimental conditions of visual erotic stimulation: dynamic videos, static erotic pictures, and expectation of erotic pictures. Plasma estrogen and progesterone levels were assessed in all subjects. No strong hormonally modulating effect was detected upon more direct and explicit stimulation (viewing of videos or pictures) with significant activations in cortical and subcortical brain regions previously linked to erotic stimulation consistent across hormonal levels and stimulation type. Upon less direct and less explicit stimulation (expectation), activation patterns varied between the different hormonal conditions with various, predominantly frontal brain regions showing significant within- or between-group differences. Activation in the precentral gyrus during the follicular phase in the nC group was found elevated compared to the C group and positively correlated with estrogen levels. From the results we conclude that effects of hormonal influences on brain activation during erotic stimulation are weak if stimulation is direct and explicit but that female sexual hormones may modulate more subtle aspects of sexual arousal and behaviour as involved in sexual expectation. Results may provide a basis for future imaging studies on sexual processing in females, especially in the context of less explicit erotic stimulation.
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Recent studies have demonstrated developmental changes of functional brain networks derived from functional connectivity using graph theoretical analysis, which has been rapidly translated to studies of brain network organization. However, little is known about sex- and IQ-related differences in the topological organization of functional brain networks during development. In this study, resting-state fMRI (rs-fMRI) was used to map the functional brain networks in 51 healthy children. We then investigated the effects of age, sex, and IQ on economic small-world properties and regional nodal properties of the functional brain networks. At a global level of whole networks, we found significant age-related increases in the small-worldness and local efficiency, significant higher values of the global efficiency in boys compared with girls, and no significant IQ-related difference. Age-related increases in the regional nodal properties were found predominately in the frontal brain regions, whereas the parietal, temporal, and occipital brain regions showed age-related decreases. Significant sex-related differences in the regional nodal properties were found in various brain regions, primarily related to the default mode, language, and vision systems. Positive correlations between IQ and the regional nodal properties were found in several brain regions related to the attention system, whereas negative correlations were found in various brain regions primarily involved in the default mode, emotion, and language systems. Together, our findings of the network topology of the functional brain networks in healthy children and its relationship with age, sex, and IQ bring new insights into the understanding of brain maturation and cognitive development during childhood and adolescence.
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Evidence has accumulated that emotion recognition performance varies with menstrual cycle phase. However, according to some empathy models, facial affect recognition constitutes only one component of empathic behavior, besides emotional perspective taking and affective responsiveness. It remains unclear whether menstrual cycle phase and thus estradiol and progesterone levels are also associated with the two other empathy constructs. Therefore, we investigated 40 healthy right-handed females, 20 during their follicular phase and 20 during their midluteal phase and compared their performance in three tasks tapping the empathic components as well as self-report data. Salivary hormone levels were obtained and correlated with performance parameters. Subjects were matched for age and education and did not differ in neuropsychological function. Analysis of empathy performance revealed a significant effect of phase in emotion recognition, showing higher accuracy in the follicular group. Regarding affective responsiveness, we observed a significant difference in reaction times, with faster responses for sad and angry stimuli in the midluteal group. No significant group difference emerged for emotional perspective taking. Furthermore, significant correlations between progesterone levels and emotion recognition accuracy and affective responsiveness emerged only in the luteal group. However, groups did not differ in self-reported empathy. Our results indicate that menstrual cycle phase and thus ovarian hormone concentration are differentially related to empathic behavior, particularly emotion recognition and responsiveness to negative situations, with progesterone covarying with both in the luteal phase.
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Neuroendocrine theories of brain development hold testosterone as the predominant factor mediating sex-specific cortical growth and the ensuing lateralization of hemispheric function. However, studies to date have focussed on prenatal testosterone rather than pubertal changes in testosterone. Yet, animal studies have shown a high density of androgen-sensitive receptors in multiple key cortical areas, and puberty is known to coincide with both a significant rise in testosterone and the emergence of behavioral sex differences, suggesting peripubertal influences of testosterone on brain development. Here, we used linear mixed models to examine sex-specific cortical maturation associated with changes in testosterone levels in a longitudinal sample of developmentally healthy children and adolescents. A significant "sex by age by testosterone" interaction on cortical thickness (CTh) involving widespread areas of the developing brain was found. Testosterone levels were associated with CTh changes in regions of the left hemisphere in males and of the right hemisphere in females. In both sexes, the relationship between testosterone and CTh varied across the age span. These findings show the association between testosterone and CTh to be complex, highly dynamic, and to vary, depending on sex and age; they also suggest sex-related hemispheric lateralization effects of testosterone in humans.
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Resting-state functional magnetic resonance imaging (RS-FMRI) holds the promise of revealing brain functional connectivity without requiring specific tasks targeting particular brain systems. RS-FMRI is being used to find differences between populations even when a specific candidate target for traditional inferences is lacking. However, the problem with RS-FMRI is a lacking definition of what constitutes noise and signal. RS-FMRI is easy to acquire but is not easy to analyze or draw inferences from. In this commentary we discuss a problem that is still treated lightly despite its significant impact on RS-FMRI inferences; global signal regression (GSReg), the practice of projecting out signal averaged over the entire brain, can change resting-state correlations in ways that dramatically alter correlation patterns and hence conclusions about brain functional connectedness. Although Murphy et al. in 2009 demonstrated that GSReg negatively biases correlations, the approach remains in wide use. We revisit this issue to argue the problem that GSReg is more than negative bias or the interpretability of negative correlations. Its usage can fundamentally alter interregional correlations within a group, or their differences between groups. We used an illustrative model to clearly convey our objections and derived equations formalizing our conclusions. We hope this creates a clear context in which counterarguments can be made. We conclude that GSReg should not be used when studying RS-FMRI because GSReg biases correlations differently in different regions depending on the underlying true interregional correlation structure. GSReg can alter local and long-range correlations, potentially spreading underlying group differences to regions that may never have had any. Conclusions also apply to substitutions of GSReg for denoising with decompositions of signals aggregated over the network's regions to the extent they cannot separate signals of interest from noise. We touch on the need for careful accounting of nuisance parameters when making group comparisons of correlation maps.
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At rest, brain activity can be characterized not by an absence of organized activity but instead by spatially and temporally correlated patterns of activity. In this experiment, we investigated whether and to what extent resting state functional connectivity is modulated by sex hormones in women, both across the menstrual cycle and when altered by oral contraceptive pills. Sex hormones have been shown to have important effects on task-related activity, but few studies have investigated the extent to which they can influence the behavior of functional networks at rest. These hormones are dramatically altered by the use of hormonal contraception, which is used by approximately 100 million women worldwide. However, potential cognitive side effects of hormonal contraception have been given little attention. Here, we collected resting state data for naturally-cycling women (n=45) and women using combined oral contraceptive pills (n=46) and evaluated the differences in resting state activity between these two groups using Independent Components Analysis. We found that in the default mode network and in a network associated with executive control, resting state dynamics were altered both by the menstrual cycle and by oral contraceptive use. Specifically, the connectivity of the left angular gyrus, the left middle frontal gyrus, and the anterior cingulate cortex were different between groups. Because the anterior cingulate cortex and left middle frontal gyrus are important for higher-order cognitive and emotional processing, including conflict monitoring, changes in the relationship of these structures to the functional networks with which they interact may have important consequences for attention, affect, and/or emotion regulation.
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It was the aim of the present study to investigate menstrual cycle effects on selective attention and its underlying functional cerebral networks. Twenty-one healthy, right-handed, normally cycling women were investigated by means of functional magnetic resonance imaging (fMRI) using a go/no-go paradigm during the menstrual, follicular and luteal phase. On the behavioural level there was a significant interaction between visual half field and cycle phase with reaction times to right-sided compared to left-sided stimuli being faster in the menstrual compared to the follicular phase. These results might argue for a more pronounced functional cerebral asymmetry (FCA) towards the left hemisphere in selective attention during the menstrual phase with low estradiol and progesterone levels. Functional imaging, however, did not reveal clear-cut menstrual phase related changes in activation pattern in parallel to these behavioural findings. A functional connectivity analysis identified differences between the menstrual and the luteal phase: During the menstrual phase, left inferior parietal cortex showed a stronger negative correlation with the right middle frontal gyrus while left medial frontal cortex showed a stronger negative correlation with the left middle frontal gyrus. These results can serve as further evidence of a modulatory effect of steroid hormones on networks of lateralised cognitive functions not only by interhemispheric inhibition but also by affecting intrahemispheric functional connectivity.
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Previous neuroimaging studies on empathy have not clearly identified neural systems that support the three components of empathy: affective congruence, perspective-taking, and prosocial motivation. These limitations stem from a focus on a single emotion per study, minimal variation in amount of social context provided, and lack of prosocial motivation assessment. In the current investigation, 32 participants completed a functional magnetic resonance imaging session assessing empathic responses to individuals experiencing painful, anxious, and happy events that varied in valence and amount of social context provided. They also completed a 14-day experience sampling survey that assessed real-world helping behaviors. The results demonstrate that empathy for positive and negative emotions selectively activates regions associated with positive and negative affect, respectively. In addition, the mirror system was more active during empathy for context-independent events (pain), whereas the mentalizing system was more active during empathy for context-dependent events (anxiety, happiness). Finally, the septal area, previously linked to prosocial motivation, was the only region that was commonly activated across empathy for pain, anxiety, and happiness. Septal activity during each of these empathic experiences was predictive of daily helping. These findings suggest that empathy has multiple input pathways, produces affect-congruent activations, and results in septally mediated prosocial motivation.
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Persons with gender identity disorder (GID) often suffer from psychiatric co-morbidity, and it is an important prognostic factor for long-term psychosocial adjustment in GID. However, previous research has not addressed the risk factors of psychiatric co-morbidity. In this study, we tried to clarify the risk factors among individuals with GID in Japan. A total of 326 consecutive GID persons were evaluated independently by two senior psychiatrists at the GID clinic using personal clinical interviews and results of examinations. The prevalence of current psychiatric co-morbidity was 17.8% of the total sample. School refusal was significantly associated with psychiatric co-morbidity. Sexual attraction to neither males nor females among GID persons and sexual attraction to females among male-to-female (MtF) GID persons were also significantly related to psychiatric co-morbidity. This is the first report to demonstrate a close relationship between patterns of sexual orientation and psychiatric co-morbidity among GID persons. We should pay more attention to psychiatric co-morbidity, especially among GID persons with non-homosexual sexual orientations.
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It has been shown that social deficits contribute to psychopathology in schizophrenia, such as the bleulerian autism. A possible dysfunction in the mirror neuron system may be the reason for these deficits in the disorder. We wanted to better characterize the neural networks involved in the perception of social behavior. Fifteen healthy participants were presented with video clips of 8 seconds' duration depicting either (1) one actor manipulating an object, (2) two actors with only one manipulating an object or (3) two actors cooperating in manipulating an object and 2 other control conditions. Functional magnetic resonance imaging data were acquired during watching these videos. We found the perception of social cooperation is supported by a neural network comprising the precuneus, the temporoparietal junction (supramarginal gyrus, angular gyrus, BA 39/40), the middle temporal gyrus (including superior temporal sulcus) and frontal regions (medial frontal gyrus, inferior frontal gyrus). These areas form a complex network also being activated during theory of mind and cooperative behavior tasks. Its nodes overlap with those of the mirror neuron system. Consequently, both theory of mind abilities and mirror mechanisms are relevant in the perception and understanding of social cooperative behavior. We outline the consequences of these results for a further understanding of schizophrenic psychopathology with respect to social deficits and ego disturbances.
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The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.
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Three studies (N = 1988) describe the development and validation of the Emotional Contagion (EC) Scale, a 15-item unidimensional measure of susceptibility to others'' emotions resulting from afferent feedback generated by mimicry. Study 1 assesses the EC Scale''s reliability (Cronbach''s = .90). Study 2 finds susceptibility (a) positively related to reactivity, emotionality, sensitivity to others, social functioning, self-esteem, and more associated with emotional than cognitive modes of empathy, (b) negatively related to alienation, self-assertiveness, and emotional stability and, (c) unrelated to masculinity and approval motivation. Study 3, an experiment, finds that EC Scale scores reliably predict biases in participants'' evaluations and are correlated with a measure of responsiveness to afferent feedback and self-reports of emotional experience following exposure to emotional expressions.
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Previous studies suggest organizing effects of sex hormones on brain structure during early life and puberty, yet little is known about the adult period. The aim of the present study was to elucidate the role of 17β-estradiol, progesterone, and testosterone on cortical sex differences in grey matter volume (GM) of the adult human brain. To assess sexual dimorphism, voxel-based morphometry (VBM) was applied on structural magnetic resonance images of 34 healthy, young adult humans (17 women, 17 men, 26.6 ± 5 years) using analyses of covariance. Subsequently, circulating levels of sex hormones were associated with regional GM using linear regression analyses. After adjustment for sex and total GM, significant associations of regional GM and 17β-estradiol were observed in the left inferior frontal gyrus (β = 0.39, p = 0.02). Regional GM was inversely associated with testosterone in the left inferior frontal gyrus (β = −0.16, p = 0.04), and with progesterone in the right temporal pole (β = −0.39, p = 0.008). Our findings indicate that even in young adulthood, sex hormones exert organizing effects on regional GM. This might help to shed further light on the underlying mechanisms of both functional diversities and congruence between female and male brains.
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About 150 researchers around the world convened at the Chateau Lake Louise on February 20-23, 2011 to present and discuss the latest research in human and animal imaging and spectroscopy at field strengths of 7 T or above (termed ultrahigh field) at the third ISMRM-sponsored high field workshop. The clear overall message from the workshop presentations and discussion is that ultrahigh field imaging is gaining momentum with regard to new clinically relevant findings, anatomic and functional MRI results, susceptibility contrast advancements, solutions to high field-related image quality challenges, and to generally push the limits of resolution and speed of high field imaging. This meeting report is organized in a manner reflecting the meeting organization itself, covering the seven sessions that were approximately titled: (1) high field overview from head to body to spectroscopy; (2) susceptibility imaging; (3) proffered session on susceptibility, ultrafast imaging, unique contrast at 7 T, and angiography; (4) neuroscience applications; (5) proffered session on coils, shimming, parallel imaging, diffusion tensor imaging, and MRI-PET fusion; (6) high field animal imaging and spectroscopy, as well as a vendor overview, and (7) Cutting edge technology at 7 T.
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During adolescence, numerous factors influence the organization of the brain. It is unclear what influence sex and puberty have on white matter microstructure, as well as the role that rapidly increasing sex steroids play. White matter microstructure was examined in 77 adolescents (ages 10-16) using diffusion tensor imaging. Multiple regression analyses were performed to examine the relationships between fractional anisotropy (FA) and mean diffusivity (MD) and sex, puberty, and their interaction, controlling for age. Follow-up analyses determined if sex steroids predicted microstructural characteristics in sexually dimorphic and pubertal-related white matter regions, as well as in whole brain. Boys had higher FA in white matter carrying corticospinal, long-range association, and cortico-subcortical fibers, and lower MD in frontal and temporal white matter compared with girls. Pubertal development was related to higher FA in the insula, while a significant sex-by-puberty interaction was seen in superior frontal white matter. In boys, testosterone predicted white matter integrity in sexually dimorphic regions as well as whole brain FA, whereas estradiol showed a negative relationship with FA in girls. Sex differences and puberty uniquely relate to white matter microstructure in adolescents, which can partially be explained by sex steroids.
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During the intrauterine period a testosterone surge masculinizes the fetal brain, whereas the absence of such a surge results in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other. Sex differences in cognition, gender identity (an individual's perception of their own sexual identity), sexual orientation (heterosexuality, homosexuality or bisexuality), and the risks of developing neuropsychiatric disorders are programmed into our brain during early development. There is no evidence that one's postnatal social environment plays a crucial role in gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with any changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.