The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of Gender Dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural grey matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in left superior-medial frontal cortex, while boys had more volume in the bilateral superior-posterior hemispheres of the cerebellum and hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.

Author/-s:       Elseline Hoekzema; Sebastian Schagen; Baudewijntje Kreukels; Dick J. Veltman; Peggy Cohen-Kettenis; Henriette Delemarre-van de Waal; Julie Bakker

Publication:     Psychoneuroendocrinology, 2015

Web link:          http://www.psyneuen-journal.com/article/S0306-4530(15)00030-X/abstract

Abstract: 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.

Discussion (excerpt): […] In the TX group, the body representation network showed a more extensive connection with the brain regions associated with sensorimotor processing. These findings suggest a distinct neural circuitry of the body representation in TXs, which is in agreement with their long-term dysphoric experience with their physical bodies. These findings are corroborated by evidence that the MTFs showed structural (GM volume) changes in the pre/postcentral gyrus and the thalamus, which are related to the processing of body perception. Collectively, these convergent findings posit a neurological base for the dysphoric experience of TXs.

Author/-s:       Chia-Shu Lin; Hsiao-Lun Ku; Hsiang-Tai Chao, Pei-Chi Tu; Cheng-Ta Li; Chou-Ming Cheng; Tung-Ping Su; Ying-Chiao Lee;  Jen-Chuen Hsieh

Publication:     PLOS one, 2014

Web link:          http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085914

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.

Author/-s:       Andreas Hahn; Georg S. Kranz;  Martin Küblböck; Ulrike Kaufmann; Sebastian Ganger; Allan Hummer; Rene Seiger; Marie Spies; Dietmar Winkler; Siegfried Kasper; Christian Windischberger; Dick F. Swaab; Rupert Lanzenberger

Publication:     Cerebral Cortex, 2014

Web link:          http://cercor.oxfordjournals.org/content/early/2014/09/12/cercor.bhu194.full

Individuals with gender identity disorder (GID), who are commonly referred to as transsexuals (TXs), are afflicted by negative psychosocial stressors. Central to the psychological complex of TXs is the conviction of belonging to the opposite sex. Neuroanatomical and functional brain imaging studies have demonstrated that the GID is associated with brain alterations. In this study, we found that TXs identify, when viewing male-female couples in erotic or non-erotic (“neutral”) interactions, with the couple member of the desired gender in both situations. By means of functional magnetic resonance imaging, we found that the TXs, as opposed to controls (CONs), displayed an increased functional connectivity between the ventral tegmental area, which is associated with dimorphic genital representation, and anterior cingulate cortex subregions, which play a key role in social exclusion, conflict monitoring and punishment adjustment. The neural connectivity pattern suggests a brain signature of the psychosocial distress for the gender-sex incongruity of TXs.

Author/-s:       Hsiao-Lun Ku; Chia-Shu Lin; Hsiang-Tai Chao; Pei-Chi Tu; Cheng-Ta Li; Chou-Ming Cheng; Tung-Ping Su; Ying-Chiao Lee; Jen-Chuen Hsieh

Publication:     PloS one, 2013

Web link:          http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0070808

Summary: Children may show variability in their gender role behaviors, interests and preferences and/or their experienced gender identity (their experience to be male, female or a different gender). Within the male-female continuum of gender role expressions and gender identity three groups can be distinguished. First, the gender normative children: Their gender role and gender identity are congruent with their natal sex. Second, the gender variant children: These children show (mild) cross-gender behaviors, interests and preferences, and may experience a gender identity which is congruent with their natal sex to a lesser extent than is the case in gender normative children. And third, the gender dysphoric children: These children show extreme and enduring forms of cross-gender role expressions, experience a cross-gender identity and fulfill the criteria of a DSM-IV-TR diagnosis of Gender Identity Disorder (GID) (American Psychiatric Association 2000). In contrast to most of the gender variant children, gender dysphoric children may need clinical attention as a result of significant distress or a significant risk of distress, and/or impairment in important areas of functioning. Knowledge about the future development, the trajectories and possible associated factors of gender non-normative children (both gender variant and genderdysphoric) is however limited.
The studies described in this thesis aimed to enhance our understanding of the development of gender variant and gender dysphoric children and adolescents, and to identify factors associated with the persistence and desistence of gender dysphoria.

In chapter 2, we provided an overview of what is currently known about the trajectories and contributing factors to gender identity development, particularly during adolescence in the general population and in gender variant/gender dysphoric youth. Compared to what is known from gender identity development in gender variant or gender dysphoric children, studies of normative gender identity development during adolescence in the general population are lacking behind.

With regard to the factors contributing to non-normative gender identity development, earlier studies mainly focused on the role of psychosocial factors. Factors such as elevated levels of psychopathology in the parents, increased anxiety of the child, and a lack of parental limit setting have been put forward as possible determinants. However, the evidence from these studies showed to be equivocal and it is unclear whether the factors that were associated with a non-normative gender identity development were the cause of this development or a consequence of the gender variance or gender dysphoria. More recently, research has focused on the role of biological factors on a non-normative gender identity development. Studies of individuals with a Disorder of Sex Development (DSD), congenital condi- tions in which the development of chromosomal, gonadal and/or anatomical sex is atypical (Hughes et al. 2006), point to the role of prenatal exposure to gonadal hormones and their effects on gender role behavior and possibly on gender identity development. From post mortem, neuropsychological, and brain imaging studies of individuals with gender dysphoria, differences between gender dysphoric individuals and members of their natal sex have been found. However, these differences were not found for all measures and the direction of the differences is not always consistent or not yet sufficient to form a basis for a broad theory on gender identity development. The current evidence makes clear that there is no simple relationship between psychological and social factors and gender identity development, and brain development and the development of gender identity. In addition to this, although several researchers have acknowledged that nature and nurture interact, they have not tried to integrate both aspects in their studies thus far.

As for the future development of gender dysphoric children, our overview of the literature indicated that gender identity in childhood seems more malleable than later in adolescence or in adulthood. Furthermore, we described that adolescence is a crucial period for the consolidation of gender identity and persistence of gender dysphoria. We discussed that the onset of physical puberty in this period may steer this process, but that there are also indications that cognitive aspects of gender identity (e.g. confusion and ambivalence with ones gender identity) has its own influence. For those without a history of childhood gender dysphoria, adolescence may initiate gender dysphoria. Regardless of the various developmental trajectories of a non-normative gender identity development, adolescence can be denoted as a crucial developmental period for gender identity.

In chapter 3 we reported on a study where we validated a 12-item dimensional scale that aims to measure gender dysphoria, in a sample of 1119 adolescents and adults (M age 24.6, range 12–75). The male (UGDS-M) and female (UGDS-F) versions of the Utrecht Gender Dysphoria Scale (UGDS) were assessed in a group of participants diagnosed with a GID (N=545), a group who was subthreshold for GID (N=103), participants with a DSD (N=60), and non-transgender heterosexual (N=219), gay/lesbian (N=150), and bisexual (N=42) controls. Both versions of the UGDS appeared to be reliable scales with a strong ability to discriminate between clinically referred gender dysphoric individuals and non-clinically referred controls and DSD participants. Sensitivity was 88.3 % (UGDS-M) and 98.5 % (UGDS-F), specificity was 99.5 % (UGDS-M) and 97.9 % (UGDS-F). Comparison of the mean total scores showed that there was significantly more gender dysphoria in participants diagnosed with a GID, compared to participants who were subthreshold for GID, for both versions. The two transgender groups showed significantly more gender dysphoria than the DSD and control participants. We concluded from our findings that these qualities make the instrument useful for clinical and research purposes.

Chapter 4 reported on a 24 years longitudinal study where we examined whether childhood gender variance was associated with the report of a bi- or homosexual sexual orientation and gender discomfort in adulthood in the general population. In a sample of 406 boys and 473 girls we measured gender variance in childhood (M age 7.5, range 4–11) and sexual orientation and gender dysphoria in adulthood (M age 30.9, range  27–36). Our findings showed that the intensity and presence of childhood gender variance was higher in girls than in boys, and that gender variance was reported more frequently in younger children than in older children. Furthermore, we found that the presence of childhood gender variance was associated with the presence of a homosexual orientation in adulthood, but not with bisexuality. The chance of a homosexual orientation in sexual attraction, sexual fantasy, sexual behavior, and sexual identity were 8 to 15 times higher for both male and female participants with a history of gender variance as reported by the parents (10.2 % to12.2 %), compared to participants without a history of gender variance (1.2 % to 1.7 %). The presence of childhood gender variance was not significantly associated with gender discomfort/gender dysphoria in adulthood. We concluded in this study that childhood gender variance, at least as measured by the Child Behavior Checklist (CBCL), is not predictive for a gender dysphoric outcome in adulthood in the general population. Furthermore, the presence of childhood gender variance and a homosexual sexual orientation in adulthood are associated in the general population, but this association is much weaker than in clinically referred gender dysphoric children.

Chapter 5 described the findings from a qualitative study where we tried to obtain a better understanding of the developmental trajectories of persistence and desistence of childhood gender dysphoria and the psychosexual outcome of gender dysphoric children. We interviewed 25 adolescents (M age 15.9, range 14–18), who were diagnosed with a Gender Identity Disorder (DSM-IV or DSM-IV-TR) in childhood (M age 9.4, range 6–12). Our findings on possible predictors in childhood for the different trajectories showed that the 14 persisters and 11 desisters reported quite similar childhood experiences, but subtle differences in their experience of gender and the labelling of their feelings were observed.

As for underlying mechanisms and experiences that may have steered the persistence and desistence of gender dysphoria, we identified the period between the ages of 10 and 13 to be crucial. In the perceptions of the adolescents, three factors were related in this period to the intensification of gender dysphoria in persisters or remittance of gender dysphoric feelings in the desisters; (1) the changing social environment, where the social distance between boys and girls gradually increases, (2) the anticipation of, and actual body changes during puberty, and (3) the experience of falling in love, sexual attraction and sexual experiences. Interestingly, even in this relatively small sample of adolescents, we observed that the feelings of gender dysphoria did not completely remit in all desisters. Furthermore, our observation of high reports of sexual orientations and sexual attractions directed towards individuals of the same natal sex seemed to be in concordance with the earlier findings from the prospective quantitative literature on gender dysphoric children. Finally, the stories of the persisters and desisters on the effect of social role transitioning (in appearance and/or a name change or pronoun change) revealed that transitioning was experienced as a relief in persisters, but could result in a troublesome process of changing back to their original gender for desisters.

Chapter 6 reported on a quantitative follow-up study that examined the factors associated with the persistence and desistence of childhood gender dysphoria, and adolescent feelings of gender dysphoria and sexual orientation. In a sample of 127 adolescents (79 boys, 48 girls), who were referred for gender dysphoria in childhood (age range 6–12) and followed up in adolescence (age range 15–19), we observed a persistence rate of 37 % (47 persisters out of the 127 adolescents). We examined childhood differences among persisters (N=47) and desisters (N=80) in demographics, developmental background, childhood psychological functioning, the quality of peer relations and childhood gender dysphoria, and adolescent reports of gender dysphoria, body image and sexual orientation. Our findings showed that persisters reported higher intensities of gender dysphoria, more body dissatisfaction and higher reports of a same natal-sex sexual orientation, compared to the desisters, and were in line with earlier findings from prospective follow-up studies in clinical populations.

As for the factors associated with the persistence of gender dysphoria, we found that a higher intensity of childhood gender dysphoria (through self- and parental report, and through cognitive and/or affective gender identity responses), an older age at referral, and transitioning (at least partially) to the preferred gender role were predictive of childhood gender dysphoria persistence. In addition to this, we found that the chance of persisting was higher in natal gender dysphoric girls than in boys, but that factors such as psychological functioning, the quality of peer relations, demographic (e.g. family structure, parents’ social economic class), and developmental background (e.g. birth weight, pregnancy duration) were not associated with the persistence of childhood gender dysphoria. Finally, our findings showed that the factors associated with the persistence of gender dysphoria were different for the two natal sexes. For natal boys, the age at referral, the gender role presentation, the self report of a cross-gender identification (“I am a boy” or “I am a girl”), and the parental report of the intensity of gender role behavior showed to be the major predictive factors for the persistence of gender dysphoria, whereas for girls, the self reported cross-gender identification and the intensity of gender dysphoria turned out to have a higher predictive value than the other evaluated factors.

Chapter 7 presented a communication where we addressed the topic of social transitioning in gender dysphoric children in early childhood. We reported on our observation of increasing numbers in our clinical population of children who completely (change in clothing and hair style, first name, and use of pronouns) or partially (change in clothing and hair style, but did not have a name and pronoun change) transitioned between the period of the year 2000 and 2009.

Before the year 2000, 2 prepubertal boys, out of 112 referred children to our clinic, were living completely in the female gender role. Between 2000 and 2004, 3.3 % (4 out of 121 children) had completely transitioned, and 19 % (23 out of 121 children) were partially transitioned when they were referred. In the period between 2005 and 2009 we observed that 8.9 % (16 out of 180 children) completely transitioned and 33.3 % (60 out of 180 children) partially transitioned at the time of referral.

In discussing the increasing rates of socially transitioned gender dysphoric children we noted that follow-up studies show that the persistence rate of childhood gender dysphoria is about 15.8 %, and wondered what would happen to children who transitioned in childhood, but turned out to be desisters. We referred to two cases of natal girls, who transitioned early in childhood and for whom the gender dysphoria desisted. Their process of changing back to their original gender was reported to be a troublesome process (Chapter 5 and Steensma et al. 2011). We concluded that it is advisable to be very careful when taking steps regarding social transitioning during the early childhood years, as they might be difficult to reverse.

In chapter 8 we described a cross-national investigation that examined the psychological functioning and the quality of peer relations between gender dysphoric youth from Toronto, Canada and Amsterdam, the Netherlands. In a sample of 544 children and 174 adolescents, referred to the specialized gender identity clinics in both countries, we assessed the Teacher’s Report Form to measure emotional and behavioral problems, the quality of peer relations and gender dysphoria. Our findings in both countries showed that the children were, on average, better functioning than the adolescents, and that the gender dysphoric boys showed to have poorer peer relations and more internalizing than externalizing problems compared to the gender dysphoric girls. As for the degree of behavioral problems in both countries, the quality of peer relations showed to be the strongest predictor. In discussing our findings we concluded that gender dysphoric children and adolescents showed the same pattern of emotional and behavioral problems in both countries, although there were significant differences in the prevalence of problems.

Between the two countries, we found clear differences: Both the children and the adolescents from Canada had more emotional and behavioral problems and a poorer quality of peer relations than the children and adolescents from the Netherlands. In line with previous comparisons of gender dysphoric children from the two countries, we found that children and adolescents from the Netherlands presented with significantly more cross-gender behavior than those from Canada. The differences between the two countries seemed to be an effect of a poorer quality of peer relations in Canada, compared to the Netherlands. We hypothesized that this may be the result of a difference in social tolerance towards gender variant expressions, as cross-cultural studies indicate that the Netherlands is much more tolerant towards homosexuality, and most likely also towards gender variance, than most countries in the world (Veenhoven 2005).

Author/-s:       Thomas Dirk Steensma

Publication:     Dissertation, Vrije Universiteit Amsterdam, 2013

Web link:          http://hdl.handle.net/1871/40250

Introduction: Inconsistent data have been reported on neuropsychological abnormalities in transsexual patients and on the effects of a cross-sex hormone therapy on cognitive functions. Some studies point to neuropsychological alterations/abnormalities in untreated transsexual patients, suggesting differences in underlying neurobiological processes. The aim of the present study was to investigate visual spatial competence in male-to-female transsexual (MFTS) patients before and during hormone therapy.

Methods: This study included 11 MFTS patients before hormone therapy, 11 MFTS patients during cross-sex hormone therapy of at least six months (HT) and 11 male controls without gender identity disorder (GID), age 36.3 ± 9.8 years (mean ± stdev). Functional imaging was performed applying a blocked mental rotation paradigm with proven sexual dimorphism, projecting the classical threedimensional objects from the standard mental rotation test (3) onto a screen at the rear of the scanner tunnel. fMRI data were acquired at 3 T (Gyroscan Intera 3.0T. Philips, Best, NL) with a whole head EPI sequence (single shot EPI, 36 slices parallel to the AC-PC line, isotropic voxels of 3.6 mm edge length, TR/TE 3000/50 ms). In addition, immediately before fMRT examination sex steroid hormone levels in the serum were determined in all participants. After the fMRI scan, the performance of mental rotation was assessed outside the scanner. Analysis of fMRI data was done with SPM5 (Wellcome Department of Cognitive Neurology, London).

Results: All three investigated groups showed typical activation patterns for the mental rotation task in fronto parietal areas. However, there were significant differences between groups within this network. Men without GID had significantly stronger activations in the left parietal cortex (BA 40), a key region for mental rotation processes, while both groups of transsexual patients showed stronger activations in fronto-temporal areas.

Discussion: The present study gives clues that there are differences in the activation pattern for mental rotation between MFTS patients and male controls already before a hormone therapy, and that these differences remain stable during hormonal treatment. An increase of the differences during hormone therapy could not be found. Possible causes for the functional differences between MFTS patients and controls may be different strategies to cope with the mental rotation task as well as altered neurobiological processes.

Author/-s:       Harald Kugel; Sonja Schoening; Almut Engelien; Anette Kersting; Cornelia Roestel; Pienie Zwitserlood; Wolfgang Lehmann; Walter Heindel; Volker Arolt; Carsten Konrad

Publication:     Journal of Psychiatric Research, 2013

Web link:          http://cds.ismrm.org/protected/10MProceedings/files/2291_3977.pdf

Early-onset gender identity disorder (EO-GID) describes a strong and persistent development of cross-gender identification. Using structural magnetic resonance imaging (sMRI) and blood samples, we studied 13 female to male patients with EO-GID and compared them to 11 biological female controls. We found that the EO-GID group in comparison to its control group showed several significant differences in regional brain volumes. These include an increase in cerebral gray matter and a decrease in volume of cerebellar white matter in the mid anterior and posterior part of the corpus callosum. Furthermore, we showed statistically significant relationships between hormone levels and regional brain volume. These include relationships between the free thyroid hormone thyroxine (T4) and volumes of the frontal lobe, the temporal lobe and cerebral white matter; between sex-hormone binding globulin (SHGB) and the frontal lobe; as well as between thyroid-stimulating hormone (TSH) and cerebral gray matter. The results of regression analyses indicate that brain volume (outcome variables) decreases with the lower thyroid hormone levels (predictor variables). We propose that abnormal hormonal development of thyroid hormones influences white matter volume in our EO-GID group. Such an abnormal development further might affect both structural and functional properties of the brain.

Author/-s:       Muriel Marisa Katharina Bruchhage

Publication:     Master Thesis, Department of Psychology, Universitetet i Oslo, 2013

Web link:          https://www.duo.uio.no/handle/10852/36754

Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disorder sand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life.

Author/-s:       Anna-Martha V. Fontanari; Tahiana Andreazza; Ângelo B. Costa; Jaqueline Salvador; Walter J. Koff; Bianca Aguiar; Pamela Ferrari; Raffael Massuda; Mariana Pedrini; Esalba Silveira; Paulo S. Belmonte-de-Abreu; Clarissa S. Gama; Marcia Kauer-Sant’Anna; Flavio Kapczinski; Maria Ines R. Lobato

Publication:     Journal of Psychiatric Research, 2013

Web link:          http://www.journalofpsychiatricresearch.com/article/S0022-3956(13)00138-6/abstract

The intermediate nucleus (InM) in the preoptic area of the human brain, also known as the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the interstitial nucleus of the anterior hypothalamus-1 (INAH-1) is explored here. We investigated its population of galanin-immunoreactive (Gal-Ir) neurons in relation to sex, age, and gender identity in the postmortem brain of 77 subjects. First we compared the InM volume and number of Gal-Ir neurons of 22 males and 22 females in the course of aging. In a second experiment, we compared for the first time the InM volume and the total and Gal-Ir neuron number in 43 subjects with different gender identities: 14 control males (M), 11 control females (F), 10 male-to-female (MtF) transsexual people, and 5 men who were castrated because of prostate cancer (CAS). In the first experiment we found a sex difference in the younger age group (<45 years of age), i.e., a larger volume and Gal-Ir neuron number in males and an age difference, with a decrease in volume and Gal-Ir neuron number in males > 45 years. In the second experiment the MtF transsexual group presented an intermediate value for the total InM neuron number and volume that did not seem different in males and females. Because the CAS group did not have total neuron numbers that were different from the intact males, the change in adult circulating testosterone levels does not seem to explain the intermediate values in the MtF group. Organizational and activational hormone effects on the InM are discussed.

Author/-s:       Alicia Garcia-Falgueras; Lisette Ligtenberg; Frank P. M. Kruijver; Dick F. Swaab

Publication:     The Journal of Comparative Neurology, 2011

Web link:          http://europepmc.org/abstract/MED/21618223

Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus. The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.

Author/-s:       Ivanka Savic; Stefan Arver

Publication:     Cerebral cortex, 2011

Web link:          http://cercor.oxfordjournals.org/content/21/11/2525.abstract

There is strong evidence of sex differences in mental rotation tasks. Transsexualism is an extreme gender identity disorder in which individuals seek cross-gender treatment to change their sex. The aim of our study was to investigate if male-to-female (MF) and female-to-male (FM) transsexuals receiving cross-sex hormonal treatment have different patterns of cortical activation during a three-dimensional (3D) mental rotation task. An fMRI study was performed using a 3-T scan in a sample of 18 MF and 19 FM under chronic cross-sex hormonal treatment. Twenty-three males and 19 females served as controls. The general pattern of cerebral activation seen while visualizing the rotated and non-rotated figures was similar for all four groups showing strong occipito-parieto-frontal brain activation. However, compared to control males, the activation of MF transsexuals during the task was lower in the superior parietal lobe. Compared to control females, MF transsexuals showed higher activation in orbital and right dorsolateral prefrontal regions and lower activation in the left prefrontal gyrus. FM transsexuals did not differ from either the MF transsexual or control groups. Regression analyses between cerebral activation and the number of months of hormonal treatment showed a significant negative correlation in parietal, occipital and temporal regions in the MF transsexuals. No significant correlations with time were seen in the FM transsexuals. In conclusion, although we did not find a specific pattern of cerebral activation in the FM transsexuals, we have identified a specific pattern of cerebral activation during a mental 3D rotation task in MF transsexuals under cross-sex hormonal treatment that differed from control males in the parietal region and from control females in the orbital prefrontal region. The hypoactivation in MF transsexuals in the parietal region could be due to the hormonal treatment or could reflect a priori cerebral differences between MF transsexual and control subjects.

Author/-s:       Beatriz Carrillo; Esther Gómez-Gil; Giuseppina Rametti; Carme Junque; Ángel Gomez; Kazmer Karad; Santiago Segovia; Antonio Guillamon

Publication:     Psychoneuroendocrinology, 2010

Web link:          http://www.ncbi.nlm.nih.gov/pubmed/20219285

Introduction: Neuropsychological abnormalities in transsexual patients have been reported in comparison with subjects without gender identity disorder (GID), suggesting differences in underlying neurobiological processes. However, these results have not consistently been confirmed. Furthermore, studies on cognitive effects of cross-sex hormone therapy also yield heterogeneous results.

Aim: We hypothesized that untreated transsexual patients differ from men without GID in activation pattern associated with a mental rotation task and that these differences may further increase after commencing of hormonal treatment.

Method: The present study investigated 11 male-to-female transsexual (MFTS) patients prior to cross-sex hormone therapy and 11 MFTS patients during hormone therapy in comparison with healthy men without GID. Using functional magnetic resonance imaging at 3-Tesla, a mental rotation paradigm with proven sexual dimorphism was applied to all subjects. Data were analyzed with SPM5.

Main Outcome Measures: Patterns of brain activation associated with a mental rotation task.

Results: The classical mental rotation network was activated in all three groups, but significant differences within this network were observed. Men without GID exhibited significantly greater activation of the left parietal cortex (BA 40), a key region for mental rotation processes. Both transsexual groups revealed stronger activation of temporo-occipital regions in comparison with men without GID.

Conclusions: Our results confirmed previously reported deviances of brain activation patterns in transsexual men from men without GID and also corroborated these findings in a group of transsexual patients receiving cross-sex hormone therapy. The present study indicates that there are a priori differences between men and transsexual patients caused by different neurobiological processes or task-solving strategies and that these differences remain stable over the course of hormonal treatment.

Author/-s:       Sonja Schöning; Almut Engelien; Christine Bauer; Harald Kugel; Anette Kersting; Cornelia Roestel; Pienie Zwitserlood; Martin Pyka; Udo Dannlowski; Wolfgang Lehmann; Walter Heindel; Volker Arolt; Carsten Konrad

Publication:     The Journal of Sexual Medicine, 2010

Web link:          http://europepmc.org/abstract/MED/19751389

Aims: Despite a range of research on gender identity disorder (GID), at present there is no scientific consensus on whether the etiology of GID is mental or physical. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders. GID also should be evaluated from this perspective. The aim of the present study was therefore to do the first trial to examine the regional cerebral blood flow (rCBF) in GID.

Methods: Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). We compared 11 FTM subjects and nine age- and handedness-matched female control subjects. None of the subjects was regularly taking medication and none had any kind of physical or psychiatric comorbidity. To evaluate rCBF in GID subjects and control subjects, statistical parametric mapping analysis of (99m)Tc-ethyl-cysteinate dimer single-photon emission computed tomography was used.

Results: GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects.

Conclusions: The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.

Author/-s:       H. Nawata; K. Ogomori; M. Tanaka; R. Nishimura; H. Urashima; R. Yano; K. Takano; Y. Kuwabara

Publication:     Psychiatry and clinical neurosciences, 2010

Web link:          http://www.ncbi.nlm.nih.gov/pubmed/20132527

Translation: Brain activation in during mental rotation and synonym formation was examined using fMRI.

Mental rotation (8 men, 7 women, 8 male-to-female transsexuals): Men activated parietally and frontally more than women. Further superior frontally, women activated more than men. Men also activated frontally and parietally more strongly than MF-TS. Women and MF-TS activated in the precuneus and right frontal gyrus medius more than men.

Synonym formation (each 6 men, women, MF-TS): Men activated frontally left and pre-centrally stronger than the women. The MF-TS activated, like the women, frontally left less than men. Temporally left both women and MF-TS activated less than men. Men and MF TS activated parietooccipital stronger than the women.

In summary, the MF-TS showed in many areas deviations compared to the men and similarities with the women. MF-TS probably have a different brain organization than men.

Original: Die Aktivierung im fMRT bei mentaler Rotation und Synonymbildung wurde untersucht.

Mentale Rotation (8 Männer, 7 Frauen, 8 Mann-zu-Frau-Transsexuelle): Die Männer aktivierten parietal und frontal stärker als die Frauen. Weiter superior frontal aktivierten die Frauen stärker als die Männer. Frontal und parietal aktivierten die Männer auch stärker als die MF-TS. Frauen und MF-TS aktivierten im Precuneus und Gyrus frontalis medius rechts stärker als die Männer.

Synonymbildung (je 6 Männer, Frauen, MF-TS): Die Männer aktivierten links frontal und präzentral stärker als die Frauen. Die MF-TS aktivierten wie die Frauen links frontal schwächer als die Männer. Temporal links aktivierten Frauen und MF-TS schwächer als die Männer. Männer und MF-TS aktivierten parietookzipital stärker als die Frauen.

Zusammenfassend zeigten die MF-TS in vielen Arealen Abweichungen zu den Männern und Gemeinsamkeiten mit den Frauen. Wahrscheinlich haben MF-TS eine von Männern abweichende Hirnorganisation.

Author/-s:       Eva Pletziger

Publication:     Dissertation, Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, 2009

Web link:          http://miami.uni-muenster.de/Record/4a695f8e-3e3f-4d46-a8cf-44f7b737bd43

Gender identity – one’s sense of being a man or a woman – is a fundamental perception experienced by all individuals that extends beyond biological sex. Yet, what contributes to our sense of gender remains uncertain. Since individuals who identify as transsexual report strong feelings of being the opposite sex and a belief that their sexual characteristics do not reflect their true gender, they constitute an invaluable model to understand the biological underpinnings of gender identity. We analyzed MRI data of 24 male-to-female (MTF) transsexuals not yet treated with cross-sex hormones in order to determine whether gray matter volumes in MTF transsexuals more closely resemble people who share their biological sex (30 control men), or people who share their gender identity (30 control women). Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men. These findings provide new evidence that transsexualism is associated with distinct cerebral pattern, which supports the assumption that brain anatomy plays a role in gender identity.

Author/-s:       Eileen Luders; Francisco J. Sánchez; Christian Gaser; Arthur W. Toga; Katherine L. Narr; Liberty S. Hamilton; Eric Vilain

Publication:     NeuroImage, 2009

Web link:          http://www.ncbi.nlm.nih.gov/pubmed/19341803

Background: Transsexualism is thought to be related to cortical processes reflecting a complex mosaic of biological, psychological and social/cultural information. Since the P300 component of event-related potentials is considered as an index of attentional processes, the present study focuses on auditory P300 elicited during a short memory test in male to female (MF) transsexuals, compared with that in healthy controls.

Method: The P300 component was evaluated during the anticipatory period of a short memory test in 13 MF transsexuals who had a gender reassignment operation, at least 3 years previously (mean time 17.6 years, range 3–31 years) and 26 healthy subjects (11 males and 15 females) matched for age and educational level.

Results: MF transsexuals exhibited significant reduction of P300 amplitude in the left frontal and temporoparietal areas in comparison to the control group. Furthermore, the group of transsexuals showed a significant delay of P300 latency in comparison to the controls, at the central frontal region.

Conclusions: These findings point to significant psychophysiological alterations of distributed cortical circuits in MF transsexuals. These alterations may be critically related to the biological substrate of MF transsexualism.

Author/-s:       C. Papageorgiou; P. Papageorgaki; G. Tolis; A. D. Rabavilas; G. N. Christodoulou

Publication:     Psychological Medicine, 2003

Web link:          http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=147217

Atypical handedness patterns, i.e., persons being less exclusively right-handed, have been found previously in large samples of male and female homosexuals and in small samples of male and female transsexuals compared to controls. The posited role of prenatal androgen influencing both cerebral hemispheric dominance and psychosexual development warrants further study with large samples of transsexuals. 443 male-to-female transsexuals and 93 female-to-male transsexuals were studied for their use of the right or left hand in six common one-handed tasks. Both male and female transsexuals were more often nonright-handed than male and female controls were. Results suggest an altered pattern of cerebral hemispheric organisation in male and female transsexuals.

Author/-s:       Richard Green; Robert Young

Publication:     Archives of sexual behaviour, 2001

Web link:          http://www.ncbi.nlm.nih.gov/pubmed/11725455