Friday, January 28, 2011

White Matter Differences in Pre-Op Transsexuals Should NOT be the Basis for Childhood Interventions

Diagram showing principal systems of association fibers in the human brain. The superior longitudinal fasciculus (SLF) is labeled at the center top (marked by purple arrows).

New Scientist covered two journal articles by Rametti and colleagues (2010, 2011), a group of Spanish researchers and clinicians affiliated with Unidad Trastorno Identidad de Género [Gender Identity Disorder Unit]. Using the diffusion tensor imaging (DTI) method, they initially wanted to identify any sex differences in the white mater of the brains of non-transgendered male and female heterosexuals. Then the next step was a prediction that FTM (Female-to-Male) transsexuals would be more like males, while MTF (Male-to-Female) transsexuals would be more like females.
Transsexual differences caught on brain scan

12:16 26 January 2011 by Jessica Hamzelou

Differences in the brain's white matter that clash with a person's genetic sex may hold the key to identifying transsexual people before puberty. Doctors could use this information to make a case for delaying puberty to improve the success of a sex change later.
In 5 years of writing this blog, I have come across a multitude of news stories and press releases that make outrageous claims. Here's another one to add to the list. On the basis of two highly variable DTI studies in 36 pre-operative, pre-hormone treatment transgender individuals, now we're supposed to screen children for gender variant behavior and scan them at a young age, so their hormones can be altered before puberty?

Returning to the structural imaging experiments, were there any hypotheses at the outset, or were these completely exploratory studies? The authors cite the work of Zhou et al. (1995) on postmortem staining of the bed nucleus of the stria terminalis (BST). This subcortical nucleus connects the amygdala to the septal nuclei, hypothalamus, and thalamus. BST has been shown to play a role in the sexual behavior of male rats. The size of this nucleus in MTF brains was similar to that in female controls, both being smaller than male controls.

However, it's not possible to visualize the BST in living humans, so the authors went with DTI to look for cortical white matter changes. The participants in the first study were 18 FTM transgendered persons (before undergoing hormonal treatment), along with 24 male and 19 female heterosexual controls. The major findings in terms of sex differences between groups were located mainly in 3 fiber tracts:
  • anterior and posterior parts of the right superior longitudinal fasciculus - contains connections between the frontal, parietal, occipital, and temporal lobes including language-related areas (Mori et al., 2008).
  • forceps minor (anterior forceps) - fiber bundle connecting the lateral and medial surfaces of the frontal lobes, crossing the midline via the genu of the corpus callosum.
  • corticospinal tract - connects the cerebral cortex and the spinal cord, contains mostly motor axons.
In all 3 tracts, males showed higher fractional anisotropy (FA) than females. FA is a measure of local tissue properties including density, coherence, diameter, and myelination.

Fig. 1 (Rametti et al., 2010). Sex differences in fractional anisotropy (FA). FA is lower in female than in male controls in the superior longitudinal fasciculus with a posterior (A) and anterior (B) predominance. Control females also show lower than control male FA values in the forceps minor (C) and the corticospinal tract (D). The group skeleton used for the between group contrast study is green. The red color shows the clusters of significantly decreased FA in female compared to male controls. The threshold for significance was set at p < 0.05 corrected for multiple comparisons.

FTM individuals showed greater FA values in all 3 tracts than did the control females. They were similar to control males for anterior and posterior SLF and forceps minor, and in between control male and female FA values for the corticospinal tract.

What does this mean? Basically, at this point, it's like reading tea leaves. We have no indication of other potential differences between the groups in cognitive, emotional, personality, or motor measures, in alcohol use, or in other psychiatric diagnoses. We do know that testosterone levels of the FTM participants were like those of control females, because they had yet to undergo hormone treatment.

Moving right along to the second experiment, which compared MTF individuals to controls (Rametti et al., 2011)... The participants were 18 untreated MTF transsexuals (mean age = 25 yrs), 19 female (mean = 33 yrs) and 19 male controls (mean age = 32 yrs). Yes, the MTF individuals were significantly younger than controls [the human frontal lobe in particular is known to continue maturation processes into the 20's]. Procedures were similar to those used previously. Results in this study showed a greater number of differences in the white matter of male vs. female controls (again, with larger FA values for males):
  • left and the right SLF
  • forceps minor
  • right inferior front-occipital fasciculus (IFOF)
  • corticospinal tract
  • left cingulum
So what's new in this list? Left SLF, Right IFOF, Left cingulum. This finding indicates that individual differences were observed between two groups of male and female control subjects [or else there were unreported methodological differences]. If normal sex differences in DTI studies include IFOF and cingulum here but not there, that presents a problem for comparison to the transgendered populations.

Nonetheless, what did that comparison show? The MTF individuals showed FA values between those of male and female controls for all tracts (except for IFOF, where they did not differ from males).

Fig. 2 (Rametti et al., 2011). Histograms showing the FA means between control females (black), male to female transsexuals (MtF) (red) and control males (green). MtF transsexuals significantly differed from female and male controls in almost of all the fascicles in which control males differed from control females. (*At least p < 0.01).

So the MTF participants showed an intermediate pattern, but FTM individuals were more like biological males. The authors state:
Considering the present work and the data available in the literature, what can we say of the brain of MtF transsexuals? Most importantly, we would suggest that MtF transsexuals do not show a simple feminization of their brain –rather, they present a complex picture in which feminization and incomplete masculinization are present depending on the brain region studied and the kind of measurements taken.
So don't scan your little football-playing tomboy or haute couture-loving son just yet...

In the end, I don't doubt that there are differences between the brains of transgendered and non-transgendered people. But these two DTI studies1 do not provide a rationale for initiating treatments in young children.

For an interesting perspective on these studies in relation to gender identity and sexual orientation, I highly recommend Seeing the world in Grey and White…


1 I haven't even mentioned criticisms of the DTI technique in general...


Mori S, Oishi K, Jiang H, Jiang L, Li X, Akhter K, Hua K, Faria AV, Mahmood A, Woods R, Toga AW, Pike GB, Neto PR, Evans A, Zhang J, Huang H, Miller MI, van Zijl P, Mazziotta J. (2008). Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template. Neuroimage 40:570-82.

Rametti, G., Carrillo, B., Gómez-Gil, E., Junque, C., Segovia, S., Gomez, Á., & Guillamon, A. (2011). White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study Journal of Psychiatric Research, 45 (2), 199-204 DOI: 10.1016/j.jpsychires.2010.05.006

Rametti, G., Carrillo, B., Gómez-Gil, E., Junque, C., Zubiarre-Elorza, L., Segovia, S., Gomez, Á., & Guillamon, A. (2010). The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2010.11.007

Zhou JN, Hofman MA, Gooren LJ, Swaab DF. (1995). A sex difference in the human brain and its relation to transsexuality. Nature 378:68-70.


To celebrate the 5 year anniversary of this blog, here are the other entries from Jan 27/28:

2006: Men are Torturers, Women are Nurturers...

2007: Gambling On Obscurity

2008: Cost of the War in Iraq

2009: Voodoo Gurus

2010: Mirror Neurons and Magical EFT Therapy Bears

Thanks for reading!

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