Fractional anisotropy; gender; gender incongruence; gonadotropin-releasing hormone analogs; inferior fronto-occipital fasciculus; puberty; sex; Applied Psychology; Psychiatry and Mental Health
Abstract :
[en] BACKGROUND: Increasing numbers of adolescents seek help for gender-identity questions. Consequently, requests for medical treatments, such as puberty suppression, are growing. However, studies investigating the neurobiological substrate of gender incongruence (when birth-assigned sex and gender identity do not align) are scarce, and knowledge about the effects of puberty suppression on the developing brain of transgender youth is limited.
METHODS: Here we cross-sectionally investigated sex and gender differences in regional fractional anisotropy (FA) as measured by diffusion MR imaging, and the impact of puberty on alterations in the white-matter organization of 35 treatment-naive prepubertal children and 41 adolescents with gender incongruence, receiving puberty suppression. The transgender groups were compared with 79 age-matched, treatment-naive cisgender (when sex and gender align) peers.
RESULTS: We found that transgender adolescents had lower FA in the bilateral inferior fronto-occipital fasciculus (IFOF), forceps major and corpus callosum than cisgender peers. In addition, average FA values of the right IFOF correlated negatively with adolescents' cumulative dosage of puberty suppressants received. Of note, prepubertal children also showed significant FA group differences in, again, the right IFOF and left cortico-spinal tract, but with the reverse pattern (transgender > cisgender) than was seen in adolescents.
CONCLUSIONS: Importantly, our results of lower FA (indexing less longitudinal organization, fiber coherence, and myelination) in the IFOF of gender-incongruent adolescents replicate prior findings in transgender adults, suggesting a salient neural correlate of gender incongruence. Findings highlight the complexity with which (pubertal) sex hormones impact white-matter development and add important insight into the neurobiological substrate associated with gender incongruence.
Disciplines :
Neurosciences & behavior
Author, co-author :
van Heesewijk, Jason ; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Steenwijk, Martijn D; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Kreukels, Baudewijntje P C; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Veltman, Dick J; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Bakker, Julie ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Neuroendocrinology ; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Burke, Sarah M; Center of Expertise on Gender Dysphoria, Amsterdam University Medical Centers, location VUmc, De Boelelaan 1131, Amsterdam, Noord-Holland, Netherlands
Language :
English
Title :
Alterations in the inferior fronto-occipital fasciculus - a specific neural correlate of gender incongruence?
Aitken, M., VanderLaan, D. P., Wasserman, L., Stojanovski, S., & Zucker, K. J. (2016). Self-harm and suicidality in children referred for gender dysphoria. Journal of the American Academy of Child and Adolescent Psychiatry, 55, 513-520. doi: 10.1016/j.jaac.2016.04.001
Anacker, C., Sydnor, E., Chen, B. K., LaGamma, C. C., McGowan, J. C., Mastrodonato, A., & Denny, C. A. (2020). Behavioral and neurobiological effects of GnRH agonist treatment in mice-potential implications for puberty suppression in transgender individuals. Neuropsychopharmacology, 46, 882-890. doi: 10.1038/s41386-020-00826-1
Bava, S., Boucquey, V., Goldenberg, D., Thayer, R. E., Ward, M., Jacobus, J., & Tapert, S. F. (2011). Sex differences in adolescent white matter architecture. Brain Research, 1375, 41-48. doi: 10.1016/j.brainres.2010.12.051
Braun, H. M., Garcia-Grossman, I. R., Quinones-Rivera, A., & Deutsch, M. B. (2017). Outcome and impact evaluation of a transgender health course for health profession students. LGBT Health, 4 (1), 55-61. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28075699. doi:10.1089/lgbt.2016.0119.
Buchanan, B. G., Rossell, S. L., Maller, J. J., Toh, W. L., Brennan, S., & Castle, D. J. (2013). Brain connectivity in body dysmorphic disorder compared with controls: A diffusion tensor imaging study. Psychological Medicine, 43, 2513-2521. doi: 10.1017/S0033291713000421
Burke, S. M. (2020). Commentary: Gender diversity and adolescent mental health-a reflection on potter et al. 2020. Journal of Child Psychology and Psychiatry, 62, 180-183. doi: 10.1111/JCPP.13309
Burke, S. M., Cohen-Kettenis, P. T., Veltman, D. J., Klink, D. T., & Bakker, J. (2014). Hypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescents. Frontiers in Endocrinology, 5, 1-10. doi: 10.3389/fendo.2014.00060
Burke, S. M., Manzouri, A. H., Dhejne, C., Bergstrom, K., Arver, S., Feusner, J. D., & Savic-Berglund, I. (2018). Testosterone effects on the brain in transgender Men. Cerebral Cortex, 28, 1582-1596. doi: 10.1093/cercor/bhx054
Burke, S. M., Manzouri, A. H., & Savic, I. (2017). Structural connections in the brain in relation to gender identity and sexual orientation. Scientific Reports, 7, 17954. doi: 10.1038/s41598-017-17352-8
Catani, M. (2006). Diffusion tensor magnetic resonance imaging tractography in cognitive disorders. Current Opinion in Neurology, 19, 599-606. doi: 10.1097/01.wco.0000247610.44106.3f
Catani, M. (2007). From hodology to function. Brain, 130, 602-605. doi: 10.1093/brain/awm008
Catani, M., & Thiebaut de Schotten, M. (2008). A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex; A Journal Devoted to The Study of the Nervous System and Behavior, 44, 1105-1132. doi: 10.1016/j.cortex.2008.05.004
Chahal, R., Vilgis, V., Grimm, K. J., Hipwell, A. E., Forbes, E. E., Keenan, K., & Guyer, A. E. (2018). Girls' pubertal development is associated with white matter microstructure in late adolescence. Neuroimage, 181, 659-669. doi: 10.1016/J.NEUROIMAGE.2018.07.050
Chen, D., Strang, J. F., Kolbuck, V. D., Rosenthal, S. M., Waber, D. P., Steinberg, L., & Garofalo, R. (2020). Consensus parameter: Research methodologies to evaluate neurodevelopmental effects of pubertal suppression in transgender youth. Transgender Health, 5, 246-257.
Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P., DeCuypere, G., Feldman, J., & Zucker, K. (2012). Standards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7. International Journal of Transgenderism, 13, 165-232. doi: 10.1080/15532739.2011.700873
Costa, R., Dunsford, M., Skagerberg, E., Holt, V., Carmichael, P., & Colizzi, M. (2015). Psychological support, puberty suppression, and psychosocial functioning in adolescents with gender dysphoria. The Journal of Sexual Medicine, 12, 2206-2214. doi: 10.1111/jsm.13034
Cox, S. R., Ritchie, S. J., Tucker-Drob, E. M., Liewald, D. C., Hagenaars, S. P., Davies, G., & Deary, I. J. (2016). Ageing and brain white matter structure in 3513 UK biobank participants. Nature Communications, 7, 1-13. doi: 10.1038/ncomms13629
Den Braber, A., Van't Ent, D., Stoffers, D., Linkenkaer-Hansen, K., Boomsma, D. I., & De Geus, E. J. C. (2013). Sex differences in gray and white matter structure in age-matched unrelated males and females and opposite-sex siblings. International Journal of Psychological Research, 6, 7-21. doi: 10.21500/20112084.712
de Vries, A. L. C., Doreleijers, T. A. H., Steensma, T. D., & Cohen-Kettenis, P. T. (2011). Psychiatric comorbidity in gender dysphoric adolescents. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 52, 1195-1202. doi: 10.1111/j.1469-7610.2011.02426.x
Doricchi, F., Thiebaut de Schotten, M., Tomaiuolo, F., & Bartolomeo, P. (2008). White matter (dis)connections and gray matter (dys)functions in visual neglect: Gaining insights into the brain networks of spatial awareness. Cortex, 44, 983-995. doi: 10.1016/j.cortex.2008.03.006
Dörner, G. (1988). Neuroendocrine response to estrogen and brain differentiation in heterosexuals, homosexuals, and transsexuals. Archives of Sexual Behavior, 17, 57-75.
Fausto-Sterling, A. (2019). Gender/Sex, sexual orientation, and identity are in the body: How did they Get there? Journal of Sex Research, 56, 529-555. doi: 10.1080/00224499.2019.1581883
Feusner, J. D., Dervisic, J., Kosidou, K., Dhejne, C., Bookheimer, S., & Savic, I. (2016). Female-to-Male transsexual individuals demonstrate different Own body identification. Archives of Sexual Behavior, 45, 525-536. doi: 10.1007/s10508-015-0596-z
Field, A. (2013). Discovering statistics using IBM SPSS statistics (4th ed.). London: Sage.
Garibotto, V., Scifo, P., Gorini, A., Alonso, C. R., Brambati, S., Bellodi, L., & Perani, D. (2010). Disorganization of anatomical connectivity in obsessive-compulsive disorder: A multi-parameter diffusion tensor imaging study in a subpopulation of patients. Neurobiology of Disease, 37, 468-476. doi: 10.1016/j.nbd.2009.11.003
Genc, S., Seal, M. L., Dhollander, T., Malpas, C. B., Hazell, P., & Silk, T. J. (2017). White matter alterations at pubertal onset. Neuroimage, 156, 286-292. doi: 10.1016/j.neuroimage.2017.05.017
Griffin, L., Clyde, K., Byng, R., & Bewley, S. (2020). Sex, gender and gender identity: A re-evaluation of the evidence. BJPsych Bulletin, 45, 1-9. doi: 10.1192/bjb.2020.73
Guillamon, A., Junque, C., & Gómez-Gil, E. (2016). A review of the status of brain structure research in transsexualism. Archives of Sexual Behavior, 45, 1615-1648. doi: 10.1007/s10508-016-0768-5
Halim, M. L., & Ruble, D. (2010). Gender identity and stereotyping in early and middle childhood. New York: Springer, pp. 495-525.
Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., & T'Sjoen, G. G. (2017). Endocrine treatment of gender-dysphoric/ gender-incongruent persons: An endocrine society × clinical practice guideline. Journal of Clinical Endocrinology and Metabolism, 102, 3869-3903. doi: 10.1210/jc.2017-01658
Herting, M. M., Kim, R., Uban, K. A., Kan, E., Binley, A., & Sowell, E. R. (2017). Longitudinal changes in pubertal maturation and white matter microstructure. Psychoneuroendocrinology, 81, 70-79. doi: 10.1016/j.psyneuen.2017.03.017
Herting, M. M., Maxwell, E. C., Irvine, C., & Nagel, B. J. (2012). The impact of sex, puberty, and hormones on white matter microstructure in adolescents. Cerebral Cortex, 22, 1979-1992. doi: 10.1093/cercor/bhr246
Herting, M. M., & Sowell, E. R. (2017). Puberty and structural brain development in humans. Frontiers in Neuroendocrinology, 44, 122-137. doi: 10.1016/j.yfrne.2016.12.003
Ho, T. C., Colich, N. L., Sisk, L. M., Oskirko, K., Jo, B., & Gotlib, I. H. (2020). Sex differences in the effects of gonadal hormones on white matter microstructure development in adolescence. Developmental Cognitive Neuroscience, 42, 100773. doi: 10.1016/j.dcn.2020.100773
Holt, V., Skagerberg, E., & Dunsford, M. (2016). Young people with features of gender dysphoria: Demographics and associated difficulties. Clinical Child Psychology and Psychiatry, 21, 108-118. doi: 10.1177/1359104514558431
Hsu, J.-L. L., Leemans, A., Bai, C.-H. H., Lee, C.-H. H., Tsai, Y.-F. F., Chiu, H.-C. C., & Chen, W.-H. H. (2008). Gender differences and age-related white matter changes of the human brain: A diffusion tensor imaging study. NeuroImage, 39, 566-577. doi: 10.1016/j.neuroimage.2007.09.017
Inano, S., Takao, H., Hayashi, N., Abe, O., & Ohtomo, K. (2011). Effects of Age and gender on white matter integrity. American Journal of Neuroradiology, 32, 2103-2109.
Juraska, J. M., & Willing, J. (2017). Pubertal onset as a critical transition for neural development and cognition. Brain Research, 1654, 87-94. doi: 10.1016/j.brainres.2016.04.012
Kaltiala-Heino, R., Sumia, M., Työläjärvi, M., & Lindberg, N. (2015). Two years of gender identity service for minors: Overrepresentation of natal girls with severe problems in adolescent development. Child and Adolescent Psychiatry and Mental Health, 9, 9. doi: 10.1186/s13034-015-0042-y
Kochunov, P., Jahanshad, N., Marcus, D., Winkler, A., Sprooten, E., Nichols, T. E., & Van Essen, D. C. (2015). Heritability of fractional anisotropy in human white matter: A comparison of human connectome project and ENIGMA-DTI data. Neuroimage, 111, 300-311. doi: 10.1016/j.neuroimage.2015.02.050
Koehler, A., Strauss, B., Briken, P., Szuecs, D., & Nieder, T. O. (2021). Centralized and decentralized delivery of transgender health care services: A systematic review and a global expert survey in 39 countries. Front Endocrinol (Lausanne), 12, 717914. doi: 10.3389/fendo.2021.717914, Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/34630327.
Kranz, G. S., Hahn, A., Kaufmann, U., Küblböck, M., Hummer, A., Ganger, S., & Lanzenberger, R. (2014). White matter microstructure in transsexuals and controls investigated by diffusion tensor imaging. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 34, 15466-15475. doi: 10.1523/JNEUROSCI.2488-14.2014
Kreukels, B. P. C., & Cohen-Kettenis, P. T. (2011). Puberty suppression in gender identity disorder: The Amsterdam experience. Nature Reviews, Endocrinology, 7, 466-472. doi: 10.1038/nrendo.2011.78
Kreukels, B. P. C., & Guillamon, A. (2016). Neuroimaging studies in people with gender incongruence. International Review of Psychiatry, 28, 120-128. doi: 10.3109/09540261.2015.1113163
Liao, M., Yang, F., Zhang, Y., He, Z., Su, L., & Li, L. (2014). White matter abnormalities in adolescents with generalized anxiety disorder: A diffusion tensor imaging study. BMC Psychiatry, 14, 41. doi: 10.1186/1471-244X-14-41
Lo, S., & Horton, R. (2016). Transgender health: An opportunity for global health equity. Lancet, 388 (10042), 316-318. doi: 10.1016/S0140-6736(16)30675-4, Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27323923.
Lu, M., Yang, C., Chu, T., & Wu, S. (2018). Cerebral white matter changes in young healthy individuals with high trait anxiety: A tract-based spatial statistics study. Frontiers in Neurology, 9, 1-8. doi: 10.3389/fneur.2018.00704
Manzouri, A. H., & Savic, I. (2019). Possible neurobiological underpinnings of homosexuality and gender dysphoria. Cerebral Cortex, 29, 2084-2101. doi: 10.1093/cercor/bhy090
Marshall, W. A., & Tanner, J. M. (1969). Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood, 44, 291-303. doi: 10.1136/adc.44.235.291
Marshall, W. A., & Tanner, J. M. (1970). Variations in the pattern of pubertal changes in boys. Archives of Disease in Children, 45, 13-23. doi: 10.1136/adc.45.239.13
Menzler, K., Belke, M., Wehrmann, E., Krakow, K., Lengler, U., Jansen, A., & Knake, S. (2011). Men and women are different: Diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum. Neuroimage, 54, 2557-2562. doi: 10.1016/j.neuroimage.2010.11.029
Mori, S., Wakana, S., Nagae-Poetsche, L. M., & van Zijl, P. C. M. (2005). MRI Atlas of Human White Matter (1st ed.). Amsterdam: Elsevier.
Nguyen, H. B., Loughead, J., Lipner, E., Hantsoo, L., Kornfield, S. L., & Epperson, C. N. (2019). What has sex got to do with it? The role of hormones in the transgender brain. Neuropsychopharmacology, 44, 22-37. doi: 10.1038/s41386-018-0140-7
Nota, N. M., Kreukels, B. P. C., den Heijer, M., Veltman, D. J., Cohen-Kettenis, P. T., Burke, S. M., & Bakker, J. (2017). Brain functional connectivity patterns in children and adolescents with gender dysphoria: Sex-atypical or not? Psychoneuroendocrinology, 86, 187-195. doi: 10.1016/j.psyneuen.2017.09.014
Pang, K. C., de Graaf, N. M., Chew, D., Hoq, M., Keith, D. R., Carmichael, P., & Steensma, T. D. (2020). Association of media coverage of transgender and gender diverse issues with rates of referral of transgender children and adolescents to specialist gender clinics in the UK and Australia. JAMA Network Open, 3, 1-10. doi: 10.1001/jamanetworkopen.2020.11161
Pangelinan, M. M., Leonard, G., Perron, M., Pike, G. B., Richer, L., Veillette, S., & Paus, T. (2016). Puberty and testosterone shape the corticospinal tract during male adolescence. Brain Structure and Function, 221, 1083-1094. doi: 10.1007/s00429-014-0956-9
Peper, J. S., de Reus, M. A., van den Heuvel, M. P., & Schutter, D. J. L. G. (2015). Short fused? Associations between white matter connections, sex steroids, and aggression across adolescence. Human brain mapping, 36, 1043-1052. doi: 10.1002/hbm.22684
Peper, J. S., Mandl, R. C. W., Braams, B. R., de Water, E., Heijboer, A. C., Koolschijn, P. C. M. P., & Crone, E. A. (2013). Delay discounting and frontostriatal fiber tracts: A combined DTI and MTR study on impulsive choices in healthy young adults. Cerebral Cortex, 23, 1695-1702. doi: 10.1093/cercor/bhs163
Philippi, C. L., Mehta, S., Grabowski, T., Adolphs, R., & Rudrauf, D. (2009). Damage to association fiber tracts impairs recognition of the facial expression of emotion. Journal of Neuroscience, 29, 15089-15099. doi: 10.1523/JNEUROSCI.0796-09.2009
Potter, A., Dube, S., Allgaier, N., Loso, H., Ivanova, M., Barrios, L. C., & Johns, M. M. (2020). Early adolescent gender diversity and mental health in the adolescent brain cognitive development study. Journal of Child Psychology and Psychiatry, 62, 171-179. doi: 10.1111/jcpp.13248
Rametti, G., Carrillo, B., Gomez-Gil, E., Junque, C., Segovia, S., Gomez, A., & Guillamon, A. (2011a). White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study. Journal of Psychiatric Research, 45, 199-204. doi: 10.1016/j.jpsychires.2010.05.006
Rametti, G., Carrillo, B., Gomez-Gil, E., Junque, C., Zubiarre-Elorza, L., Segovia, S., & Guillamon, A. (2011b). The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study. Journal of Psychiatric Research, 45, 949-954. doi: 10.1016/j.jpsychires.2010.11.007
Riem, M. M. E., van Hoof, M. J., Garrett, A. S., Rombouts, S. A. R. B., van der Wee, N. J. A., van IJzendoorn, M. H., & Vermeiren, R. R. J. M. (2019). General psychopathology factor and unresolved-disorganized attachment uniquely correlated to white matter integrity using diffusion tensor imaging. Behavioural Brain Research, 359, 1-8. doi: 10.1016/j.bbr.2018.10.014
Ruble, D. N., Martin, C. L., & Berenbaum, S. A. (2006). Gender development. John Wiley & Sons Inc., pp. 858-932.
Schmithorst, V. J., Holland, S. K., & Dardzinski, B. J. (2008). Developmental differences in white matter architecture between boys and girls. Human Brain Mapping, 29, 696-710. doi: 10.1002/hbm.20431
Schneider, M. A., Spritzer, P. M., Soll, B. M. B., Fontanari, A. M. V., Carneiro, M., Tovar-Moll, F., & Lobato, M. I. R. (2017). Brain maturation, cognition and voice pattern in a gender dysphoria case under pubertal suppression. Frontiers in Human Neuroscience, 11, 1-9. doi: 10.3389/fnhum.2017.00528
Staphorsius, A. S., Kreukels, B. P., Cohen-Kettenis, P. T., Veltman, D. J., Burke, S. M., Schagen, S. E., & Bakker, J. (2015). Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria. Psychoneuroendocrinology, 56, 190-199. doi: 10.1016/j.psyneuen.2015.03.007
Swaab, D. F., & Hofman, M. A. (1995). Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trends in Neurosciences, 18, 264-270. doi: 10.1016/0166-2236(95)80007-O
Taddei, M., Tettamanti, M., Zanoni, A., Cappa, S., & Battaglia, M. (2012). Brain white matter organisation in adolescence is related to childhood cerebral responses to facial expressions and harm avoidance. Neuroimage, 61, 1394-1401. doi: 10.1016/j.neuroimage.2012.03.062
Uribe, C., Junque, C., Gómez-Gil, E., Abos, A., Mueller, S. C., & Guillamon, A. (2020). Brain network interactions in transgender individuals with gender incongruence. Neuroimage, 211, 116613. doi: 10.1016/j.neuroimage.2020.116613
van der Miesen, A. I. R., Steensma, T. D., de Vries, A. L. C., Bos, H., & Popma, A. (2020). Psychological functioning in transgender adolescents before and after gender-affirmative care compared with cisgender general population peers. Journal of Adolescent Health, 66, 699-704. doi: 10.1016/j.jadohealth.2019.12.018
van Hemmen, J., Saris, I. M. J., Cohen-Kettenis, P. T., Veltman, D. J., Pouwels, P. J. W., & Bakker, J. (2016). Sex differences in white matter microstructure in the human brain predominantly reflect differences in sex hormone exposure. Cerebral Cortex, 27, 2994-3001. doi: 10.1093/cercor/bhw156
World Health Organization (2018). International classification of diseases. WHO.
Zhou, J.-N., Hofman, M. A., Gooren, L. J. G., & Swaab, D. F. (1995). A sex difference in the human brain and its relation to transsexuality. Nature, 378, 68-70. doi: 10.1038/378068a0
Zucker, K. J. (2019). Adolescents with gender dysphoria: Reflections on some contemporary clinical and research issues. Archives of Sexual Behavior, 48, 1983-1992. doi: 10.1007/s10508-019-01518-8
