references.bib

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@article{Mueller2017,
    abstract = {gender women and natal men. Differences between trans-gender men and natal men were found in several brain structures, including the medial temporal lobe structures and cerebellum. Differences between transgender men and natal women were found in the medial temporal lobe, nucleus accumbens, and 3rd ventricle. Sexual dimorphism between nontransgender men and women included larger cer-ebellar volumes and a smaller anterior corpus callosum in natal men than in natal women. The results remained stable after correcting for additional factors including age, total in-tracranial volume, anxiety, and depressive symptoms. Conclusions: Neuroanatomical differences were region specific between transgender persons and their natal sex as well as their gender identity, raising the possibility of a localized influence of sex hormones on neuroanatomy.},
    author = {Mueller, Sven C. and Landr{\'e}, Lionel and Wierckx, Katrien and T'Sjoen, Guy},
    doi = {10.1159/000448787},
    issn = {14230194},
    journal = {Neuroendocrinology},
    number = {2},
    pages = {123--130},
    title = {{A Structural Magnetic Resonance Imaging Study in Transgender Persons on Cross-Sex Hormone Therapy}},
    volume = {105},
    year = {2017}
}
@article{VanGoozenS.H.Slabbekoorn2002,
    author = {{van Goozen, S. H., Slabbekoorn} , D. and Gooren, L. J. and Sanders, G. and Cohen-Kettenis, P. T.},
    journal = {Behavioral Neuroscience},
    number = {6},
    pages = {982--988},
    title = {{Organizing and activating effects of sex hormones in homosexual transsexuals. Behavioral neurosci}},
    volume = {116},
    year = {2002}
}
@article{Kranz2015,
    abstract = {BACKGROUND Women are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals. METHODS Thirty-three transsexuals underwent [11C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential. RESULTS One and 4 months of androgen treatment in female-to-male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss. CONCLUSIONS Given the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties.},
    author = {Kranz, Georg S. and Wadsak, Wolfgang and Kaufmann, Ulrike and Savli, Markus and Baldinger, Pia and Gryglewski, Gregor and Haeusler, Daniela and Spies, Marie and Mitterhauser, Markus and Kasper, Siegfried and Lanzenberger, Rupert},
    doi = {10.1016/J.BIOPSYCH.2014.09.010},
    issn = {0006-3223},
    journal = {Biological Psychiatry},
    month = {oct},
    number = {8},
    pages = {525--533},
    publisher = {Elsevier},
    title = {{High-dose testosterone treatment increases serotonin transporer binding in transgender people}},
    volume = {78},
    year = {2015}
}
@article{Manzouri2019,
    abstract = {Although frequently discussed in terms of sex dimorphism, the neurobiology of sexual orientation and identity is unknown. We report multimodal magnetic resonance imaging data, including cortical thickness (Cth), subcortical volumes, and resting state functional magnetic resonance imaging, from 27 transgender women (TrW), 40 transgender men (TrM), and 80 heterosexual (40 men) and 60 homosexual cisgender controls (30 men). These data show that whereas homosexuality is linked to cerebral sex dimorphism, gender dysphoria primarily involves cerebral networks mediating self-body perception. Among the homosexual cisgender controls, weaker sex dimorphism was found in white matter connections and a partly reversed sex dimorphism in Cth. Similar patterns were detected in transgender persons compared with heterosexual cisgender controls, but the significant clusters disappeared when adding homosexual controls, and correcting for sexual orientation. Instead, both TrW and TrM displayed singular features, showing greater Cth as well as weaker structural and functional connections in the anterior cingulate-precuneus and right occipito-parietal cortex, regions known to process own body perception in the context of self.},
    author = {Manzouri, A and Savic, I},
    doi = {10.1093/cercor/bhy090},
    issn = {1047-3211},
    journal = {Cerebral Cortex},
    number = {5},
    pages = {2084--2101},
    title = {{Possible Neurobiological Underpinnings of Homosexuality and Gender Dysphoria}},
    volume = {29},
    year = {2019}
}
@article{Schoning2010,
    abstract = {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.$\backslash$n$\backslash$nAIM: 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.$\backslash$n$\backslash$nMETHOD: 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.$\backslash$n$\backslash$nMAIN OUTCOME MEASURES: Patterns of brain activation associated with a mental rotation task.$\backslash$n$\backslash$nRESULTS: 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.$\backslash$n$\backslash$nCONCLUSIONS: 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 = {Sch{\"o}ning, Sonja and Engelien, Almut and Bauer, Christine and Kugel, Harald and Kersting, Anette and Roestel, Cornelia and Zwitserlood, Pienie and Pyka, Martin and Dannlowski, Udo and Lehmann, Wolfgang and Heindel, Walter and Arolt, Volker and Konrad, Carsten},
    doi = {10.1111/j.1743-6109.2009.01484.x},
    isbn = {1743-6109(Electronic);1743-6095(Print)},
    issn = {17436109},
    journal = {Journal of Sexual Medicine},
    number = {5},
    pages = {1858--1867},
    pmid = {19751389},
    title = {{Neuroimaging differences in spatial cognition between men and male-to-female transsexuals before and during hormone therapy}},
    volume = {7},
    year = {2010}
}
@article{VanGoozen1995,
    abstract = {The relative contribution of organizing and activating effects of sex hormones to the establishment of gender differences in behaviour is still unclear. In a group of 35 female-to-male transsexuals and a group of 15 male-to-female transsexuals a large battery of tests on aggression, sexual motivation and cognitive functioning was administered twice: shortly before and three months after the start of cross-sex hormone treatment. The administration of androgens to females was clearly associated with an increase in aggression proneness, sexual arousability and spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. The effects of cross-sex hormones were just as pronounced in the male-to-female group upon androgen deprivation: anger and aggression proneness, sexual arousability and spatial ability decreased, whereas verbal fluency improved. This study offers evidence that cross-sex hormones directly and quickly affect gender specific behaviours. If sex-specific organising effects of sex hormones do exist in the human, they do not prevent these effects of androgen administration to females and androgen deprivation of males to become manifest.},
    author = {{Van Goozen} , S H and Cohen-Kettenis, P T and Gooren, L J and Frijda, N H and {Van de Poll} , N E},
    doi = {10.1016/0306-4530(94)00076-X},
    issn = {0306-4530},
    journal = {Psychoneuroendocrinology},
    month = {jan},
    number = {4},
    pages = {343--63},
    pmid = {8532819},
    publisher = {Elsevier},
    title = {{Gender differences in behaviour: activating effects of cross-sex hormones.}},
    volume = {20},
    year = {1995}
}
@article{Dannlowski2015,
    author = {Dannlowski, U and Grabe, H J and Wittfeld, K and Klaus, J and Konrad, C and Grotegerd, D and Redlich, R and Suslow, T and Opel, N and Ohrmann, P and Bauer, J and Zwanzger, P and Laeger, I and Hohoff, C and Arolt, V and Heindel, W and Deppe, M and Domschke, K and Hegenscheid, K and V{\"o}lzke, H and Stacey, D and {Meyer zu Schwabedissen} , H and Kugel, H and Baune, B T},
    doi = {10.1038/mp.2014.39},
    issn = {1359-4184},
    journal = {Molecular Psychiatry},
    month = {mar},
    number = {3},
    pages = {398--404},
    title = {{Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure}},
    volume = {20},
    year = {2015}
}
@article{Zhou1995,
    abstract = {Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psychogenic or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminals (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.},
    author = {Zhou, Jiang Ning and Hofman, Michel A. and Gooren, Louis J.G. and Swaab, Dick F.},
    doi = {10.1038/378068a0},
    isbn = {0-262-05087-0 (Hardcover); 978-0-262-05087-6 (Hardcover)},
    issn = {00280836},
    journal = {Nature},
    number = {6552},
    pages = {68--70},
    pmid = {7477289},
    title = {{A sex difference in the human brain and its relation to transsexuality}},
    volume = {378},
    year = {1995}
}
@article{Redlich2018,
    abstract = {Adolescent-onset major depressive disorder (MDD) is associated with an increased risk of recurrent depressive episodes, suicidal behaviors, and psychiatric morbidity throughout the lifespan. The objective of the present study was to investigate brain structural and functional changes in adolescent patients with MDD. Furthermore, we aimed to clarify the influence of early-life stress on brain function and structure. The study investigated adolescent patients with severe MDD (n=20, mean age=16.0, range=15-18 years) and a control sample of matched healthy adolescents (n=21, mean age=16.6, range=15-18 years). Functional MRI data were obtained using a face-matching paradigm to investigate emotion processing. Structural MRI data were analyzed using voxel-based morphometry (VBM). In line with previous studies on adult MDD, adolescent patients showed elevated amygdala activity to negative and reduced amygdala activity to positive emotional stimuli. Furthermore, MDD patients showed smaller hippocampal volumes compared to healthy adolescents. Higher levels of childhood maltreatment were associated with smaller hippocampal volumes in both depressed patients and healthy controls, whereby no associations between amygdala reactivity and childhood maltreatment were found. Our results suggest that hippocampal alterations in youth MDD patients may at least partly be traced back to higher occurrence of early-life adverse experiences. Regarding the strong morphometric impact of childhood maltreatment and its distinctly elevated prevalence in MDD populations, this study provides an alternative explanation for frequently observed limbic structural abnormalities in depressed patients.},
    author = {Redlich, Ronny and Opel, Nils and B{\"u}rger, Christian and Dohm, Katharina and Grotegerd, Dominik and F{\"o}rster, Katharina and Zaremba, Dario and Meinert, Susanne and Repple, Jonathan and Enneking, Verena and Leehr, Elisabeth and B{\"o}hnlein, Joshua Joscha and Winters, Lena and Frob{\"o}se, Neele and Thrun, Sophia and Emtmann, Julia and Heindel, Walter and Kugel, Harald and Arolt, Volker and Romer, Georg and Postert, Christian and Dannlowski, Udo},
    doi = {10.1038/npp.2017.246},
    journal = {Neuropsychopharmacology},
    month = {feb},
    number = {3},
    pages = {546--554},
    pmid = {29039414},
    title = {{The limbic system in youth depression: Brain structural and functional alterations in adolescent in-patients with severe depression}},
    volume = {43},
    year = {2018}
}
@misc{Gaser,
    author = {Gaser, Christian},
    booktitle = {Version 184},
    title = {{Manual Computational Anatomy Toolbox- cat12}}
}
@article{Altinay2019,
    abstract = {Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology ofGD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis ofGD; which leads to the concept ofbrain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals' interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development ofGD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.},
    author = {Altinay, Murat and Anand, Amit},
    doi = {10.1007/s11682-019-00121-8},
    issn = {1931-7557},
    journal = {Brain Imaging and Behavior},
    publisher = {Brain Imaging and Behavior},
    title = {{Neuroimaging gender dysphoria: a novel psychobiological model}},
    year = {2019}
}
@article{McCarthy2011,
    abstract = {In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.},
    author = {McCarthy, Margaret M and Arnold, Arthur P},
    doi = {10.1038/nn.2834},
    issn = {1546-1726},
    journal = {Nature neuroscience},
    month = {jun},
    number = {6},
    pages = {677--83},
    pmid = {21613996},
    publisher = {NIH Public Access},
    title = {{Reframing sexual differentiation of the brain.}},
    volume = {14},
    year = {2011}
}
@article{Bao2011,
    abstract = {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.},
    author = {Bao, Ai-Min and Swaab, Dick F.},
    doi = {10.1016/J.YFRNE.2011.02.007},
    issn = {0091-3022},
    journal = {Frontiers in Neuroendocrinology},
    month = {apr},
    number = {2},
    pages = {214--226},
    publisher = {Academic Press},
    title = {{Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders}},
    volume = {32},
    year = {2011}
}
@article{Savic2011,
    author = {Savic, I. and Arver, S.},
    doi = {10.1093/cercor/bhr032},
    issn = {1047-3211},
    journal = {Cerebral Cortex},
    month = {nov},
    number = {11},
    pages = {2525--2533},
    publisher = {Oxford University Press},
    title = {{Sex dimorphism of the brain in male-to-female transsexuals}},
    volume = {21},
    year = {2011}
}
@article{Zaremba2018,
    author = {Zaremba, Dario and Dohm, Katharina and Redlich, Ronny and Grotegerd, Dominik and Strojny, Robert and Meinert, Susanne and B{\"u}rger, Christian and Enneking, Verena and F{\"o}rster, Katharina and Repple, Jonathan and Opel, Nils and Baune, Bernhard T. and Zwitserlood, Pienie and Heindel, Walter and Arolt, Volker and Kugel, Harald and Dannlowski, Udo},
    doi = {10.1001/jamapsychiatry.2018.0123},
    issn = {2168-622X},
    journal = {JAMA Psychiatry},
    number = {5},
    pages = {484--492},
    publisher = {American Medical Association},
    title = {{Association of brain cortical changes with relapse in patients with major depressive disorder}},
    volume = {75},
    year = {2018}
}
@article{Joel2015,
    abstract = {Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.},
    author = {Joel, Daphna and Berman, Zohar and Tavor, Ido and Wexler, Nadav and Gaber, Olga and Stein, Yaniv and Shefi, Nisan and Pool, Jared and Urchs, Sebastian and Margulies, Daniel S and Liem, Franziskus and H{\"a}nggi, J{\"u}rgen and J{\"a}ncke, Lutz and Assaf, Yaniv},
    doi = {10.1073/pnas.1509654112},
    issn = {1091-6490},
    journal = {Proceedings of the National Academy of Sciences of the United States of America},
    month = {dec},
    number = {50},
    pages = {15468--73},
    pmid = {26621705},
    publisher = {National Academy of Sciences},
    title = {{Sex beyond the genitalia: The human brain mosaic.}},
    volume = {112},
    year = {2015}
}
@article{Spizzirri2018,
    abstract = {Many previous magnetic resonance imaging (MRI) studies have documented sex differences in brain morphology, but the patterns of sexual brain differences in transgender women – male sex assigned at birth – with a diagnosis of gender dysphoria (TW) have been rarely investigated to date. We acquired T1-weighted MRI data for the following four (n = 80) groups: treatment-na{\"i}ve TW (TNTW), TW treated with cross-sex hormones for at least one year (TTW), cisgender men, and cisgender women (cisgender individuals as controls). Differences in whole-brain and regional white matter volume and grey matter volume (GMV) were assessed using voxel-based morphometry. We found lower global brain volumes and regional GMVs in a large portion of the posterior-superior frontal cortex in the cisgender women group than in the TTW and cisgender men groups. Additionally, both transgender groups exhibited lower bilateral insular GMVs than the cisgender women group. Our results highlight differences in the insula in both transgender groups; such differences may be characteristic of TW. Furthermore, these alterations in the insula could be related to the neural network of body perception and reflect the distress that accompanies gender dysphoria.},
    author = {Spizzirri, Giancarlo and Duran, F{\'a}bio Luis Souza and Chaim-Avancini, Tiffany Moukbel and Serpa, Mauricio Henriques and Cavallet, Mikael and Pereira, Carla Maria Abreu and Santos, Pedro Paim and Squarzoni, Paula and da Costa, Naomi Antunes and Busatto, Geraldo F. and Abdo, Carmita Helena Najjar},
    doi = {10.1038/s41598-017-17563-z},
    issn = {2045-2322},
    journal = {Scientific Reports},
    month = {dec},
    number = {1},
    pages = {736},
    publisher = {Nature Publishing Group},
    title = {{Grey and white matter volumes either in treatment-na{\"i}ve or hormone-treated transgender women: a voxel-based morphometry study}},
    volume = {8},
    year = {2018}
}
@article{WhiteHughto2016,
    abstract = {Objectives: To review evidence from prospective cohort studies of the relationship between hormone therapy and changes in psychological functioning and quality of life in transgender individuals accessing hormone therapy over time. Data Sources: MEDLINE, PsycINFO, and PubMed were searched for relevant studies from inception to Novem-ber 2014. Reference lists of included studies were hand searched. Results: Three uncontrolled prospective cohort studies, enrolling 247 transgender adults (180 male-to-female [MTF], 67 female-to-male [FTM]) initiating hormone therapy for the treatment of gender identity disorder (prior diagnostic term for gender dysphoria), were identified. The studies measured exposure to hormone therapy and subsequent changes in mental health (e.g., depression, anxiety) and quality of life outcomes at follow-up. Two studies showed a significant improvement in psychological functioning at 3-6 months and 12 months compared with baseline after initiating hormone therapy. The third study showed improvements in quality of life outcomes 12 months after initiating hormone therapy for FTM and MTF participants; however, only MTF participants showed a statistically significant increase in general quality of life after initiating hormone therapy. Conclusions: Hormone therapy interventions to improve the mental health and quality of life in transgender people with gender dysphoria have not been evaluated in controlled trials. Low quality evidence suggests that hormone therapy may lead to improvements in psychological functioning. Prospective controlled trials are needed to investigate the effects of hormone therapy on the mental health of transgender people.},
    author = {{White Hughto} , Jaclyn M and Reisner, Sari L},
    doi = {10.1089/trgh.2015.0008},
    journal = {Transgender Health},
    number = {1},
    pages = {21--31},
    title = {{A systematic review of the effects of hormone therapy on psychological functioning and quality of life in transgender individuals}},
    volume = {1},
    year = {2016}
}
@article{Vogelbacher2018,
    abstract = {Large, longitudinal, multi-center MR neuroimaging studies require comprehensive quality assurance (QA) protocols for assessing the general quality of the compiled data, indicating potential malfunctions in the scanning equipment, and evaluating inter-site differences that need to be accounted for in subsequent analyses. We describe the implementation of a QA protocol for functional magnet resonance imaging (fMRI) data based on the regular measurement of an MRI phantom and an extensive variety of currently published QA statistics. The protocol is implemented in the MACS (Marburg-M{\"u}nster Affective Disorders Cohort Study, http://for2107.de/), a two-center research consortium studying the neurobiological foundations of affective disorders. Between February 2015 and October 2016, 1214 phantom measurements have been acquired using a standard fMRI protocol. Using 444 healthy control subjects which have been measured between 2014 and 2016 in the cohort, we investigate the extent of between-site differences in contrast to the dependence on subject-specific covariates (age and sex) for structural MRI, fMRI, and diffusion tensor imaging (DTI) data. We show that most of the presented QA statistics differ severely not only between the two scanners used for the cohort but also between experimental settings (e.g. hardware and software changes), demonstrate that some of these statistics depend on external variables (e.g. time of day, temperature), highlight their strong dependence on proper handling of the MRI phantom, and show how the use of a phantom holder may balance this dependence. Site effects, however, do not only exist for the phantom data, but also for human MRI data. Using T1-weighted structural images, we show that total intracranial (TIV), grey matter (GMV), and white matter (WMV) volumes significantly differ between the MR scanners, showing large effect sizes. Voxel-based morphometry (VBM) analyses show that these structural differences observed between scanners are most pronounced in the bilateral basal ganglia, thalamus, and posterior regions. Using DTI data, we also show that fractional anisotropy (FA) differs between sites in almost all regions assessed. When pooling data from multiple centers, our data show that it is a necessity to account not only for inter-site differences but also for hardware and software changes of the scanning equipment. Also, the strong dependence of the QA statistics on the reliable placement of the MRI phantom shows that th {\ldots}},
    author = {Vogelbacher, Christoph and M{\"o}bius, Thomas W.D. and Sommer, Jens and Schuster, Verena and Dannlowski, Udo and Kircher, Tilo and Dempfle, Astrid and Jansen, Andreas and Bopp, Miriam H.A.},
    doi = {10.1016/j.neuroimage.2018.01.079},
    issn = {10538119},
    journal = {NeuroImage},
    month = {may},
    pages = {450--460},
    pmid = {29410079},
    title = {{The Marburg-M{\"u}nster Affective Disorders Cohort Study (MACS): A quality assurance protocol for MR neuroimaging data}},
    volume = {172},
    year = {2018}
}
@article{Hoekzema2015,
    abstract = {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 gray 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 the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the 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 = {Hoekzema, Elseline and Schagen, Sebastian E.E. and Kreukels, Baudewijntje P.C. and Veltman, Dick J. and Cohen-Kettenis, Peggy T. and {Delemarre-van de Waal} , Henriette and Bakker, Julie},
    doi = {10.1016/J.PSYNEUEN.2015.01.016},
    issn = {0306-4530},
    journal = {Psychoneuroendocrinology},
    month = {may},
    pages = {59--71},
    publisher = {Pergamon},
    title = {{Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain}},
    volume = {55},
    year = {2015}
}
@article{Burke2018,
    abstract = {Transgender individuals experience incongruence between their gender identity and birth-assigned sex. The resulting gender dysphoria (GD), which some gender-incongruent individuals experience, is theorized to be a consequence of atypical cerebral sexual differentiation, but support for this assertion is inconsistent. We recently found that GD is associated with disconnected networks involved in self-referential thinking and own body perception. Here, we investigate how these networks in trans men (assigned female at birth with male gender identity) are affected by testosterone. In 22 trans men, we obtained T1-weighted, diffusion-weighted, and resting-state functional magnetic resonance imaging scans before and after testosterone treatment, measuring cortical thickness (Cth), subcortical volumes, fractional anisotropy (FA), and functional connectivity. Nineteen cisgender controls (male and female) were also scanned twice. The medial prefrontal cortex (mPFC) was thicker in trans men than controls pretreatment, and remained unchanged posttreatment. Testosterone treatment resulted in increased Cth in the insular cortex, changes in cortico-cortical thickness covariation between mPFC and occipital cortex, increased FA in the fronto-occipital tract connecting these regions, and increased functional connectivity between mPFC and temporo-parietal junction, compared with controls. Concluding, in trans men testosterone treatment resulted in functional and structural changes in self-referential and own body perception areas.},
    author = {Burke, Sarah M and Manzouri, Amir H and Dhejne, Cecilia and Bergstr{\"o}m, Karin and Arver, Stefan and Feusner, Jamie D and Savic-Berglund, Ivanka},
    doi = {10.1093/cercor/bhx054},
    issn = {1047-3211},
    journal = {Cerebral Cortex},
    month = {may},
    number = {5},
    pages = {1582--1596},
    pmid = {28334217},
    title = {{Testosterone effects on the brain in transgender men}},
    volume = {28},
    year = {2018}
}
@article{Shamim2000,
    abstract = {Animal studies show significant differences in steroid metabolism between male and female subjects. Similar studies in human subjects are still needed. The aim of this study was to evaluate differences in 24-h urinary excretion of cortisol and androgen metabolites between healthy male and female volunteers to estimate if such differences were significant. Urinary metabolite measurements were performed by gas chromatography. The median urinary excretion of total cortisol metabolites was 6965 $\mu$g/day for men and 4595 $\mu$g/day for women (P=0 {\textperiodcentered} 0005). Urinary excretion of 11 $\beta$-hydroxyandrosterone, tetrahydrocortisone, tetrahydrocortisol (5$\beta$), allotetrahydrocortisol (5$\alpha$), $\alpha$-cortolone, $\beta$-cortolone + $\beta$-cortol and $\alpha$-cortol were also significantly different in men compared with women. Total androgen metabolites in men (2660 $\mu$g/day) were also higher than in women (1850 $\mu$g/day) (P {\textless} 0 {\textperiodcentered} 0003). Similarly, urinary excretion of androsterone (5$\alpha$), aetiocholanolone (5$\beta$) and dehydroepiandrosterone were also significantly greater (all P=0 {\textperiodcentered} 01). This confirms significant differences in the steroid metabolite excretion profiles between men and women. Laboratories should consider adopting gender-related reference ranges for cortisol and androgen metabolite excretion in 24-h urine samples.},
    author = {Shamim, Waqar and Yousufuddin, Mohammed and Bakhai, Ameet and Coats, Andrew J.S. and Honour, John W.},
    doi = {10.1258/0004563001900084},
    isbn = {0004563001900},
    issn = {00045632},
    journal = {Annals of Clinical Biochemistry},
    number = {6},
    pages = {770--774},
    pmid = {11085621},
    title = {{Gender differences in the urinary excretion rates of cortisol and androgen metabolites}},
    volume = {37},
    year = {2000}
}
@article{Mueller2017a,
    abstract = {Gender dysphoria describes the psychological distress caused by identifying with the sex opposite to the one assigned at birth. In recent years, much progress has been made in characterizing the needs of transgender persons wishing to transition to their preferred gender, thus helping to optimize care. This critical review of the literature examines their common mental health issues, several individual risk factors for psychiatric comorbidity, and current research on the underlying neurobiology. Prevalence rates of persons identifying as transgender and seeking help with transition have been rising steeply since 2000 across Western countries; the current U.S. estimate is 0.6 {\%} . Anxiety and depression are frequently observed both before and after transition, although there is some decrease afterward. Recent research has identified autistic traits in some transgender persons. Forty percent of transgender persons endorse suicidality, and the rate of self-injurious behavior and suicide are markedly higher than in the general population. Individual factors contributing to mental health in transgender persons include community attitudes, societal acceptance, and posttransition physical attractiveness. Neurobiologically, whereas structural MRI data are thus far inconsistent, functional MRI evidence in trans persons suggests changes in some brain areas concerned with olfaction and voice perception consistent with sexual identification, but here too, a definitive picture has yet to emerge. Mental health clinicians, together with other health specialists, have an increasing role in the assessment and treatment of gender dysphoria in transgender individuals.},
    author = {Mueller, Sven C and {De Cuypere} , Griet},
    doi = {10.1176/appi.ajp.2017.17060626},
    journal = {Am J Psychiatry},
    pages = {1155--1162},
    title = {{Mechanisms of Psychiatric Illness Transgender Research in the 21st Century: A Selective Critical Review From a Neurocognitive Perspective}},
    volume = {174},
    year = {2017}
}
@article{Baldinger-Melich2019,
    author = {Baldinger-Melich, Pia and Castro, Maria F Urquijo and Seiger, Ren{\'e}and Dwyer, Dominic B and Kranz, Georg S and Kl{\"o}bl, Manfred and Kaufmann, Ulrike and Windischberger, Christian and Falkai, Peter and Lanzenberger, Rupert and Koutsouleris, Nikolaos},
    doi = {10.1093/cercor/bhz170},
    journal = {Cerebral Cortex},
    volume = 30,
    pages = {345--1356},
    title = {{Sex Matters : A Multivariate Pattern Analysis of Sex- and Gender-Related Neuroanatomical Differences in Cis- and Transgender Individuals Using Structural Magnetic Resonance Imaging}},
    year = {2020}
}
@article{Pedregosa2012,
    abstract = {Scikit-learn is a Python module integrating a wide range of state-of-the-art machine learning algorithms for medium-scale supervised and unsupervised problems. This package focuses on bringing machine learning to non-specialists using a general-purpose high-level language. Emphasis is put on ease of use, performance, documentation, and API consistency. It has minimal dependencies and is distributed under the simplified BSD license, encouraging its use in both academic and commercial settings. Source code, binaries, and documentation can be downloaded from http://scikit-learn.sourceforge.net.},
    author = {Pedregosa, Fabian and Varoquaux, Ga{\"e}l and Gramfort, Alexandre and Michel, Vincent and Thirion, Bertrand and Grisel, Olivier and Blondel, Mathieu and Prettenhofer, Peter and Weiss, Ron and Dubourg, Vincent and Vanderplas, Jake and Passos, Alexandre and Cournapeau, David and Brucher, Matthieu and Perrot, Matthieu and Duchesnay,{\'E}douard},
    doi = {10.1007/s13398-014-0173-7.2},
    isbn = {1532-4435},
    issn = {15324435},
    journal = {Journal of Machine Learning Research},
    pages = {2825--2830},
    pmid = {1000044560},
    title = {{Scikit-learn: Machine Learning in Python}},
    volume = {12},
    year = {2012}
}
@article{Seiger2016,
    abstract = {Sex-steroid hormones are primarily involved in sexual differentiation and development and are thought to underlie processes related to cognition and emotion. However, divergent results have been reported concerning the effects of hormone administration on brain structure including side effects like brain atrophy and dementia. Cross-sex hormone therapy in transgender subjects offers a unique model for studying the effects of sex hormones on the living human brain. In this study, 25 Female-to-Male (FtM) and 14 Male-to-Female (MtF) subjects underwent MRI examinations at baseline and after a period of at least 4-months of continuous cross-sex hormone administration. While MtFs received estradiol and anti-androgens, FtM subjects underwent high-dose testosterone treatment. The longitudinal processing stream of the FreeSurfer software suite was used for the automated assessment and delineation of brain volumes to assess the structural changes over the treatment period of cross-sex hormone administration. Most prominent results were found for MtFs receiving estradiol and anti-androgens in the form of significant decreases in the hippocampal region. Further analysis revealed that these decreases were reflected by increases in the ventricles. Additionally, changes in progesterone levels correlated with changes in gray matter structures in MtF subjects. In line with prior studies, our results indicate hormonal influences on subcortical structures related to memory and emotional processing. Additionally, this study adds valuable knowledge that progesterone may play an important role in this process.},
    author = {Seiger, Rene and Hahn, Andreas and Hummer, Allan and Kranz, Georg S. and Ganger, Sebastian and Woletz, Michael and Kraus, Christoph and Sladky, Ronald and Kautzky, Alexander and Kasper, Siegfried and Windischberger, Christian and Lanzenberger, Rupert},
    doi = {10.1016/j.psyneuen.2016.09.028},
    issn = {18733360},
    journal = {Psychoneuroendocrinology},
    pages = {371--379},
    publisher = {Elsevier Ltd},
    title = {{Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration}},
    volume = {74},
    year = {2016}
}
@article{Mathews2009,
    abstract = {Influences of early androgen exposure on personality were investigated. Participants were either exposed to abnormal levels of androgens prenatally due to congenital adrenal hyperplasia (CAH, 40 females, 29 males), or were unaffected relative controls (29 females, 30 males). Compared to female controls, females with CAH were less tender-minded (p {\textless} .001; 16 Personality Factor Inventory (16PF)), and reported greater physical aggression (p=.03; Reinisch Aggression Inventory) and less interest in infants (p {\textless} .001; Melson's Questionnaire), but did not differ in dominance (16PF). Males with CAH did not differ from male controls in interest in infants but were less dominant (p=.008), and more tender-minded (p=.033) and reported reduced physical aggression (p=.025). Thus, both males and females with CAH showed alteration in three of the four constructs assessed. Prenatal androgen exposure may shift some, but not all, personality characteristics in the male-typical direction in females. It may also be associated with a decrease in some aspects of male-typical personality development in males, although personality differences in males with CAH could relate to illness.},
    author = {Mathews, Greta A. and Fane, Briony A. and Conway, Gerard S. and Brook, Charles G.D. and Hines, Melissa},
    doi = {10.1016/J.YHBEH.2008.11.007},
    issn = {0018-506X},
    journal = {Hormones and Behavior},
    month = {feb},
    number = {2},
    pages = {285--291},
    publisher = {Academic Press},
    title = {{Personality and congenital adrenal hyperplasia: Possible effects of prenatal androgen exposure}},
    volume = {55},
    year = {2009}
}
@article{Luders2012,
    abstract = {BACKGROUND 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. METHOD 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 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). CONCLUSION 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.},
    author = {Luders, Eileen and S{\'a}nchez, Francisco J and Tosun, Duygu and Shattuck, David W and Gaser, Christian and Vilain, Eric and Toga, Arthur W},
    doi = {10.4236/jbbs.2012.23040},
    issn = {2160-5866},
    journal = {Journal of behavioral and brain science},
    month = {aug},
    number = {3},
    pages = {357--362},
    pmid = {23724358},
    publisher = {NIH Public Access},
    title = {{Increased cortical thickness in male-to-female transsexualism}},
    volume = {2},
    year = {2012}
}
@misc{Head2018,
    author = {Head, Tim and Mik, MechCoder and Louppe, Gilles and Shcherbatyi, Iaroslav and Fcharras and Vin{\'i}cius, Z{\'e}and Hvass-Labs and Cmmalone and Schr{\"o}der, Christopher and Nel215 and Campos, Nuno and Todd, Young and Carlosdanielcsantos and Cereda, Stefano and Schwabedal and Fan, Thomas and Rene-rex and Shi, Kejia (KJ) and Justus},
    title = {scikit-optimize},
    url = https://scikit-optimize.github.io/stable/,
    year = {2018}
}
@article{Cahill2006,
    abstract = {Male–female differences can be seen in brain anatomy, chemistry and function. Cahill reviews the latest findings on sex-related influences on the brain and discusses the importance of recognizing these differences, particularly in the context of disease states.},
    author = {Cahill, Larry},
    doi = {10.1038/nrn1909},
    issn = {1471-003X},
    journal = {Nature Reviews Neuroscience},
    month = {jun},
    number = {6},
    pages = {477--484},
    publisher = {Nature Publishing Group},
    title = {{Why sex matters for neuroscience}},
    volume = {7},
    year = {2006}
}
@book{Wittchen1997,
    address = {G{\"o}ttingen},
    author = {Wittchen, H.-U. and Wunderlich, U. and Gruschwitz, S. and Zaudig, M.},
    publisher = {Hogrefe},
    title = {{SKID-I. Strukturiertes Klinisches Interview f{\"u}r DSM-IV.}},
    year = {1997}
}
@article{Kranz2017,
    abstract = {Sex steroid hormones such as estradiol and testosterone are known to have organizing, as well as activating effects on neural tissue in animals and humans. This study investigated the effects of transgender hormone replacement therapy on white matter microstructure using diffusion tensor imaging. Female-to-male and male-to-female transgender participants were measured at baseline, four weeks and four months past treatment start and compared to female and male controls. We observed androgenization-related reductions in mean diffusivity and increases in fractional anisotropy. We also observed feminization-related increases in mean diffusivity and reductions in fractional anisotropy. In both transgender participants and controls, hormonal fluctuations were correlated with changes in white matter microstructure. Although the present study does not preclude regression to the mean as a potential contributing factor, the results indicate that sex hormones are – at least in part – responsible for white matter variability in the human brain. Studies investigating the effects of sex hormones on adult human brain structure may be an important route for greater understanding of the psychological differences between females and males.},
    author = {Kranz, Georg S. and Seiger, Rene and Kaufmann, Ulrike and Hummer, Allan and Hahn, Andreas and Ganger, Sebastian and Tik, Martin and Windischberger, Christian and Kasper, Siegfried and Lanzenberger, Rupert},
    doi = {10.1016/J.NEUROIMAGE.2017.02.027},
    issn = {1053-8119},
    journal = {NeuroImage},
    month = {apr},
    pages = {60--67},
    publisher = {Academic Press},
    title = {{Effects of sex hormone treatment on white matter microstructure in individuals with gender dysphoria}},
    volume = {150},
    year = {2017}
}
@article{Kircher2018,
    author = {Kircher, Tilo and W{\"o}hr, Markus and Nenadic, Igor and Schwarting, Rainer and Schratt, Gerhard and Alferink, Judith and Culmsee, Carsten and Garn, Holger and Hahn, Tim and M{\"u}ller-Myhsok, Bertram and Dempfle, Astrid and Hahmann, Maik and Jansen, Andreas and Pfefferle, Petra and Renz, Harald and Rietschel, Marcella and Witt, Stephanie H. and N{\"o}then, Markus and Krug, Axel and Dannlowski, Udo},
    doi = {10.1007/s00406-018-0943-x},
    issn = {0940-1334},
    journal = {European Archives of Psychiatry and Clinical Neuroscience},
    month = {sep},
    volume = 269,
    pages = {949--962},
    publisher = {Springer Berlin Heidelberg},
    title = {{Neurobiology of the major psychoses: a translational perspective on brain structure and function—the FOR2107 consortium}},
    year = {2019}
}
@article{Simon2013,
    abstract = {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.},
    author = {Simon, Lajos and Koz{\'a}k, Lajos R. and Simon, Vikt{\'o}ria and Czobor, P{\'a}l and Unoka, Zsolt and Szab{\'o},{\'A}d{\'a}m and Csukly, G{\'a}bor},
    doi = {10.1371/journal.pone.0083947},
    editor = {Gong, Gaolang},
    issn = {1932-6203},
    journal = {PLoS ONE},
    month = {dec},
    number = {12},
    pages = {1--10},
    publisher = {Public Library of Science},
    title = {{Regional grey matter structure differences between transsexuals and healthy controls—a voxel based morphometry study}},
    volume = {8},
    year = {2013}
}
@article{Case2017,
    author = {Case, Laura K. and Brang, David and Landazuri, Rosalynn and Viswanathan, Pavitra and Ramachandran, Vilayanur S.},
    doi = {10.1007/s10508-016-0850-z},
    issn = {0004-0002},
    journal = {Archives of Sexual Behavior},
    month = {jul},
    number = {5},
    pages = {1223--1237},
    publisher = {Springer US},
    title = {{Altered white matter and sensory response to bodily sensation in female-to-male transgender individuals}},
    volume = {46},
    year = {2017}
}
@article{Bao2005,
    author = {Bao, Ai-Min and Hestiantoro, Andon and Someren, Eus J. W. Van and Swaab, Dick F. and Zhou, Jiang-Ning},
    doi = {10.1093/brain/awh448},
    issn = {0006-8950},
    journal = {Brain},
    number = {6},
    pages = {1301--1313},
    title = {{Colocalization of corticotropin-releasing hormone and oestrogen receptor- in the paraventricular nucleus of the hypothalamus in mood disorders}},
    volume = {128},
    year = {2005}
}
@article{Ruigrok2014,
    abstract = {The prevalence, age of onset, and symptomatology of many neuropsychiatric conditions differ between males and females. To understand the causes and consequences of sex differences it is important to establish where they occur in the human brain. We report the first meta-analysis of typical sex differences on global brain volume, a descriptive account of the breakdown of studies of each compartmental volume by six age categories, and whole-brain voxel-wise meta-analyses on brain volume and density. Gaussian-process regression coordinate-based meta-analysis was used to examine sex differences in voxel-based regional volume and density. On average, males have larger total brain volumes than females. Examination of the breakdown of studies providing total volumes by age categories indicated a bias towards the 18–59 year-old category. Regional sex differences in volume and tissue density include the amygdala, hippocampus and insula, areas known to be implicated in sex-biased neuropsychiatric conditions. Together, these results suggest candidate regions for investigating the asymmetric effect that sex has on the developing brain, and for understanding sex-biased neurological and psychiatric conditions.},
    author = {Ruigrok, Amber N.V. and Salimi-Khorshidi, Gholamreza and Lai, Meng-Chuan and Baron-Cohen, Simon and Lombardo, Michael V. and Tait, Roger J. and Suckling, John},
    doi = {10.1016/J.NEUBIOREV.2013.12.004},
    issn = {0149-7634},
    journal = {Neuroscience {\&} Biobehavioral Reviews},
    month = {feb},
    pages = {34--50},
    publisher = {Pergamon},
    title = {{A meta-analysis of sex differences in human brain structure}},
    volume = {39},
    year = {2014}
}
@article{Tzourio-Mazoyer2002,
    author = {Tzourio-Mazoyer, N and Landeau, B and Papathanassiou, D and Crivello, F and Etard, O and Delcroix, N and Mazoyer, B and Joliot, M and Mazoyer, B},
    doi = {10.1006/nimg.2001.0978},
    issn = {1053-8119},
    journal = {NeuroImage},
    month = {jan},
    number = {1},
    pages = {273--289},
    pmid = {11771995},
    title = {{Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain}},
    volume = {15},
    year = {2002}
}
@article{Zubiaurre-Elorza2014,
    abstract = {INTRODUCTION Untreated transsexuals have a brain cortical phenotype. Cross-sex hormone treatments are used to masculinize or feminize the bodies of female-to-male (FtMs) or male-to-female (MtFs) transsexuals, respectively. AIM A longitudinal design was conducted to investigate the effects of treatments on brain cortical thickness (CTh) of FtMs and MtFs. METHODS This study investigated 15 female-to-male (FtMs) and 14 male-to-female (MtFs) transsexuals prior and during at least six months of cross-sex hormone therapy treatment. Brain MRI imaging was performed in a 3-Tesla TIM-TRIO Siemens scanner. T1-weighted images were analyzed with FreeSurfer software to obtain CTh as well as subcortical volumetric values. MAIN OUTCOME MEASURES Changes in brain CTh thickness and volumetry associated to changes in hormonal levels due to cross-sex hormone therapy. RESULTS After testosterone treatment, FtMs showed increases of CTh bilaterally in the postcentral gyrus and unilaterally in the inferior parietal, lingual, pericalcarine, and supramarginal areas of the left hemisphere and the rostral middle frontal and the cuneus region of the right hemisphere. There was a significant positive correlation between the serum testosterone and free testosterone index changes and CTh changes in parieto-temporo-occipital regions. In contrast, MtFs, after estrogens and antiandrogens treatment, showed a general decrease in CTh and subcortical volumetric measures and an increase in the volume of the ventricles. CONCLUSIONS Testosterone therapy increases CTh in FtMs. Thickening in cortical regions is associated to changes in testosterone levels. Estrogens and antiandrogens therapy in MtFs is associated to a decrease in the CTh that consequently induces an enlargement of the ventricular system.},
    author = {Zubiaurre-Elorza, Leire and Junque, Carme and G{\'o}mez-Gil, Esther and Guillamon, Antonio},
    doi = {10.1111/jsm.12491},
    issn = {17436095},
    journal = {The Journal of Sexual Medicine},
    month = {may},
    number = {5},
    pages = {1248--1261},
    pmid = {24617977},
    title = {{Effects of Cross-Sex Hormone Treatment on Cortical Thickness in Transsexual Individuals}},
    volume = {11},
    year = {2014}
}
@article{Teuber2017,
    author = {Teuber, Anja and Sundermann, Benedikt and Kugel, Harald and Schwindt, Wolfram and Heindel, Walter and Minnerup, Jens and Dannlowski, Udo and Berger, Klaus and Wersching, Heike},
    doi = {10.1007/s00330-016-4303-9},
    issn = {0938-7994},
    journal = {European Radiology},
    month = {jan},
    number = {1},
    pages = {231--238},
    title = {{MR imaging of the brain in large cohort studies: feasibility report of the population- and patient-based BiDirect study}},
    volume = {27},
    year = {2017}
}
@article{Varoquaux2018,
    abstract = {Predictive models ground many state-of-the-art developments in statistical brain image analysis: decoding, MVPA, searchlight, or extraction of biomarkers. The principled approach to establish their validity and usefulness is cross-validation, testing prediction on unseen data. Here, I would like to raise awareness on error bars of cross-validation, which are often underestimated. Simple experiments show that sample sizes of many neuroimaging studies inherently lead to large error bars, eg±10 {\%} for 100 samples. The standard error across folds strongly underestimates them. These large error bars compromise the reliability of conclusions drawn with predictive models, such as biomarkers or methods developments where, unlike with cognitive neuroimaging MVPA approaches, more samples cannot be acquired by repeating the experiment across many subjects. Solutions to increase sample size must be investigated, tackling possible increases in heterogeneity of the data.},
    author = {Varoquaux, Ga{\"e}l},
    doi = {10.1016/j.neuroimage.2017.06.061},
    issn = {10538119},
    journal = {NeuroImage},
    month = {oct},
    number = {Pt A},
    pages = {68--77},
    pmid = {28655633},
    title = {{Cross-validation failure: Small sample sizes lead to large error bars}},
    volume = {180},
    year = {2018}
}
@book{AmericanPsychiatricAssociation2013,
    address = {Washington},
    author = {{American Psychiatric Association}},
    edition = {5},
    publisher = {American Psychiatric Association},
    title = {{Diagnostic and Statistical Manual of Mental Disorders 5th Editon: DSM-5}},
    year = {2013}
}
@article{Nguyen2018,
    abstract = {Purpose of Review: With increasing numbers of transgender and gender non-binary individuals presenting for care, knowing how to elucidate the mental health and cognitive outcomes of gender-affirming hormone therapy (GAHT) is necessary. This article reviews the present literature covering GAHT effects on mood, behavioral health, and cognition in these individuals and offers research priorities to address knowledge gaps. Recent Findings: Although there are some conflicting data, GAHT overwhelmingly seems to have positive psychological effects in both adolescents and adults. Research tends to support that GAHT reduces symptoms of anxiety and depression, lowers perceived and social distress, and improves quality of life and self-esteem in both male-to-female and female-to-male transgender individuals. Summary: Clinically, prescribing GAHT can help with gender dysphoria-related mental distress. Thus, timely hormonal intervention represents a crucial tool for improving behavioral wellness in transgender individuals, though effects on cognitive processes fundamental for daily living are unknown. Future research should prioritize better understanding of how GAHT may affect executive functioning.},
    author = {Nguyen, Hillary B. and Chavez, A. M. and Lipner, E. and Hantsoo, Liisa and Kornfield, Sara L. and Davies, R. D. and Epperson, C. N.},
    doi = {10.1007/s11920-018-0973-0},
    issn = {1535-1645},
    journal = {Current Psychiatry Reports},
    number = {12},
    publisher = {Current Psychiatry Reports},
    title = {{Gender-affirming hormone use in transgender individuals: Impact on behavioral health and cognition}},
    volume = {20},
    year = {2018}
}
@article{Luders2009,
    abstract = {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 = {Luders, Eileen and S{\'a}nchez, Francisco J and Gaser, Christian and Toga, Arthur W and Narr, Katherine L and Hamilton, Liberty S and Vilain, Eric},
    doi = {10.1016/j.neuroimage.2009.03.048},
    issn = {1095-9572},
    journal = {NeuroImage},
    month = {jul},
    number = {4},
    pages = {904--7},
    pmid = {19341803},
    publisher = {NIH Public Access},
    title = {{Regional gray matter variation in male-to-female transsexualism.}},
    volume = {46},
    year = {2009}
}
@article{Swaab2009,
    author = {Swaab, Dick F and Garcia-Falgueras, Alicia},
    doi = {10.1016/B978-0-444-53630-3.00004-X},
    isbn = {9780444536303},
    issn = {0079-6123},
    journal = {Functional neurology},
    number = {1},
    pages = {17--28},
    title = {{Sexual differentiation of the human brain in relation to gender identity and sexual orientation}},
    volume = {24},
    year = {2009}
}
@article{Ecker2017,
    abstract = {Importance Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive. Objectives To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD. Design, Setting, and Participants This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used to develop a predictive model of biological sex based on cortical thickness measures assessed via magnetic resonance imaging in neurotypical controls. This normative model was subsequently applied to individuals with ASD. The study dates were June 2005 to October 2009, and this analysis was conducted between June 2015 and July 2016. Main Outcomes and Measures Sample and population ASD probability estimates as a function of normative sex-related diversity in brain structure, as well as neuroanatomical patterns associated with low or high ASD probability in male individuals and female individuals. Results Among the 98 individuals with ASD, 49 were male and 49 female, with a mean (SD) age of 26.88 (7.18) years. Among the 98 controls, 51 were male and 47 female, with a mean (SD) age of 27.39 (6.44) years. The sample probability of ASD increased significantly with predictive probabilities for the male neuroanatomical brain phenotype. For example, biological female individuals with a more male-typic pattern of brain anatomy were significantly (ie, 3 times) more likely to have ASD than biological female individuals with a characteristically female brain phenotype (P = .72 vs .24, respectively; $\chi$21 = 20.26;P {\textless} .001; difference inP values, 0.48; 95 {\%} CI, 0.29-0.68). This finding translates to an estimated variability in population prevalence from 0.2 {\%} to 1.3 {\%} , respectively. Moreover, the patterns of neuroanatomical variability car {\ldots}},
    author = {Ecker, Christine and Andrews, Derek S. and Gudbrandsen, Christina M. and Marquand, Andre F. and Ginestet, Cedric E. and Daly, Eileen M. and Murphy, Clodagh M. and Lai, Meng Chuan and Lombardo, Michael V. and Ruigrok, Amber N.V. and Bullmore, Edward T. and Suckling, John and Williams, Steven C.R. and Baron-Cohen, Simon and Craig, Michael C. and Murphy, Declan G.M.},
    doi = {10.1001/jamapsychiatry.2016.3990},
    isbn = {2168-6238 (Electronic) 2168-622X (Linking)},
    issn = {2168622X},
    journal = {JAMA Psychiatry},
    number = {4},
    pages = {329--338},
    pmid = {28196230},
    title = {{Association between the probability of autism spectrum disorder and normative sex-related phenotypic diversity in brain structure}},
    volume = {74},
    year = {2017}
}
@article{Dannlowski2015a,
    abstract = {BACKGROUND Oxytocin has received much attention as a pro-social and anxiolytic neuropeptide. In human studies, the G-allele of a common variant (rs53576) in the oxytocin receptor gene (OXTR) has been associated with protective properties such as reduced stress response and higher receptiveness for social support. In contrast, recent studies suggest a detrimental role of the rs53576 G-allele in the context of childhood maltreatment. To further elucidate the role of OXTR, gene by maltreatment (GxE) interactions on brain structure and function were investigated. METHODS N=309 healthy participants genotyped for OXTR rs53576 underwent structural as well as functional MRI during a common emotional face-matching task. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire (CTQ). Gray matter volumes were investigated by means of voxel-based morphometry (VBM) across the entire brain. RESULTS Structural MRI data revealed a strong interaction of rs53576 genotype and CTQ-scores, mapping specifically to the bilateral ventral striatum. GG homozygotes but not A-allele carriers showed strong gray matter reduction with increasing CTQ-scores. In turn, lower ventral striatum gray matter volumes were associated with lower reward dependence, a pro-social trait. Furthermore, the G-allele was associated with increased amygdala responsiveness to emotional facial expressions. CONCLUSIONS The findings suggest that the G-allele constitutes a vulnerability factor for specific alterations of limbic brain structure in individuals with adverse childhood experiences, complemented by increased limbic responsiveness to emotional interpersonal stimuli. While oxytocinergic signalling facilitates attachment and bonding in supportive social environments, this attunement for social cues may turn disadvantageous under early adverse conditions.},
    author = {Dannlowski, Udo and Kugel, Harald and Grotegerd, Dominik and Redlich, Ronny and Opel, Nils and Dohm, Katharina and Zaremba, Dario and Gr{\"o}gler, Anne and Schwieren, Juliane and Suslow, Thomas and Ohrmann, Patricia and Bauer, Jochen and Krug, Axel and Kircher, Tilo and Jansen, Andreas and Domschke, Katharina and Hohoff, Christa and Zwitserlood, Pienie and Heinrichs, Markus and Arolt, Volker and Heindel, Walter and Baune, Bernhard T.},
    doi = {10.1016/j.biopsych.2015.12.010},
    issn = {00063223},
    journal = {Biological Psychiatry},
    pages = {1--8},
    pmid = {26858213},
    publisher = {Elsevier},
    title = {{Disadvantage of social sensitivity: Interaction of oxytocin receptor genotype and child maltreatment on brain structure}},
    year = {2015}
}
@article{Nguyen2018a,
    abstract = {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.},
    author = {Nguyen, Hillary B. and Loughead, James and Lipner, Emily and Hantsoo, Liisa and Kornfield, Sara L. and Epperson, C. Neill},
    doi = {10.1038/s41386-018-0140-7},
    issn = {1740634X},
    journal = {Neuropsychopharmacology},
    pages = {22--37},
    title = {{What has sex got to do with it? the role of hormones in the transgender brain}},
    volume = {44},
    year = {2018}
}
@article{Teismann2014,
    abstract = {Depression and cardiovascular diseases due to arteriosclerosis are both frequent and impairing conditions. Depression and (subclinical) arteriosclerosis appear to be related in a bidirectional way, and it is plausible to assume a partly joint causal relationship. However, the biological mechanisms and the behavioral pathways that lead from depression to arteriosclerosis and vice versa remain to be exactly determined. This study protocol describes the rationale and design of the prospective BiDirect Study that aims at investigating the mutual relationship between depression and (subclinical) arteriosclerosis. BiDirect is scheduled to follow-up three distinct cohorts of individuals ((i) patients with acute depression (N = 999), (ii) patients after an acute cardiac event (N = 347), and (iii) reference subjects from the general population (N = 912)). Over the course of 12 years, four personal examinations are planned to be conducted. The core examination program, which will remain identical across follow-ups, comprises a personal interview (e.g. medical diagnoses, health care utilization, lifestyle and risk behavior), a battery of self-administered questionnaires (e.g. depressive symptoms, readiness to change health behavior, perceived health-related quality of life), sensory (e.g. olfaction, pain) and neuropsychological (e.g. memory, executive functions, emotional processing, manual dexterity) assessments, anthropometry, body impedance measurement, a clinical work-up regarding the vascular status (e.g. electrocardiogram, blood pressure, intima media thickness), the taking of blood samples (serum and plasma, DNA), and structural and functional resonance imaging of the brain (e.g. diffusion tensor imaging, resting-state, emotional faces processing). The present report includes BiDirect-Baseline, the first data collection wave. Due to its prospective character, the integration of three distinct cohorts, the long follow-up time window, the diligent diagnosis of depression taking depression subtypes into account, the consideration of relevant comorbidities and risk factors, the assessment of indicators of (subclinical) arteriosclerosis in different vascular territories, and the structural and functional brain imaging that is performed for a large number of participants, the BiDirect Study represents an innovative approach that combines population-based cohorts with sophisticated clinical work-up methods and that holds the potential to overcome many of the drawb {\ldots}},
    author = {Teismann, Henning and Wersching, Heike and Nagel, Maren and Arolt, Volker and Heindel, Walter and Baune, Bernhard T and Wellmann, J{\"u}rgen and Hense, Hans-Werner and Berger, Klaus},
    doi = {10.1186/1471-244X-14-174},
    issn = {1471-244X},
    journal = {BMC Psychiatry},
    month = {dec},
    number = {1},
    pages = {174},
    publisher = {BioMed Central},
    title = {{Establishing the bidirectional relationship between depression and subclinical arteriosclerosis – rationale, design, and characteristics of the BiDirect Study}},
    volume = {14},
    year = {2014}
}
@article{Dannlowski2015b,
    abstract = {Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.},
    author = {Dannlowski, Udo and Kugel, Harald and Grotegerd, Dominik and Redlich, Ronny and Suchy, Janina and Opel, Nils and Suslow, Thomas and Konrad, Carsten and Ohrmann, Patricia and Bauer, Jochen and Kircher, Tilo and Krug, Axel and Jansen, Andreas and Baune, Bernhard T and Heindel, Walter and Domschke, Katharina and Forstner, Andreas J and N{\"o}then, Markus M and Treutlein, Jens and Arolt, Volker and Hohoff, Christa and Rietschel, Marcella and Witt, Stephanie H},
    doi = {10.1038/npp.2015.86},
    issn = {0893-133X},
    journal = {Neuropsychopharmacology},
    month = {oct},
    number = {11},
    pages = {2510--2516},
    pmid = {25801500},
    title = {{NCAN cross-disorder risk variant is associated with limbic gray matter deficits in healthy subjects and major depression}},
    volume = {40},
    year = {2015}
}
@article{Meyer-Bahlburg1996,
    abstract = {The psychoendocrinology of the development of normal gender identity and its variations is poorly understood. Studies of gender development in individuals born with endocrinologically well-characterized intersex conditions are heuristically valuable for the disaggregation of factors that are acting in concert during normal development. Four 46,XX individuals with classical congenital adrenal hyperplasia (CAH) and atypical gender identity entered a comprehensive research protocol including systematic interviews and self-report inventories on gender role behavior and identity, sexual history, and psychiatric history. Some of the data on gender variables were compared to data from 12 CAH women with the salt-wasting variant (CAH-SW) with female gender identity. The four patients (ages 28, 35, 38, and 30 years) represented three different subtypes of classical early-onset CAH: 21-OH deficiency, simple virilizing (CAH-SV); 21-OH deficiency, salt-wasting (CAH-SW); and 11-$\beta$-OH deficiency. Their medical histories were characterized by delay beyond infancy or lack of surgical feminization of the external genitalia and progressive virilization with inconsistent or absent glucocorticoid replacement therapy. Although three patients had undergone one or more genital surgeries, all had retained at least some orgasmic capacity. In regard to childhood gender-role behavior, the four gender-change patients tended to be more masculine or less feminine than (behaviorally masculinized) CAH-SW controls. All patients were sexually attracted to females only. The process of gender change was gradual and extended well into adulthood. The most plausible factors contributing to cross-gender identity development in these patients to be neither a particular genotype or endocrinotype nor a sex-typing bias on the part of the parents but a combination of a genderatypical behavioral self-image, a gender-atypical body image, and the development of erotic attraction to women. Implications for psychosocial management are also discussed.},
    author = {Meyer-Bahlburg, Heino F.L. and Gruen, Rhoda S. and New, Maria I. and Bell, Jennifer J. and Morishima, Akira and Shimshi, Mona and Bueno, Yvette and Vargas, Ileana and Baker, Susan W.},
    doi = {10.1006/HBEH.1996.0039},
    issn = {0018-506X},
    journal = {Hormones and Behavior},
    month = {dec},
    number = {4},
    pages = {319--332},
    publisher = {Academic Press},
    title = {{Gender change from female to male in classical congenital adrenal hyperplasia}},
    volume = {30},
    year = {1996}
}
@software{cat12,
    author = {Christian Gaser and Robert Dahnke},
    title = {Computational Anatomy Toolbox - CAT},
    url = {http://dbm.neuro.uni-jena.de/cat},
    year = 2019,
    version = {Version 184.cat12},
}
@Comment{jabref-meta: databaseType:bibtex;}