The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study – Review

This study compared the white matter in the brains of males, females, and male to female transsexuals (MtF).*

White matter is the stuff in your brain that transmits signals from one area to another. It is mostly made up of glial cells and axons. Glial cells are cells in the brain that aren’t nerve cells; they’re like a support system for the nerve cells. Axons are the long skinny part of your nerve cells that transmit information.

MtF transsexuals were similar to males, not females, in the volume of gray matter, white matter, and cerebrospinal fluid in their brains.

In five fasciculi (bundles of nerve fibers), MtF transsexuals had white matter that was different from both males and females. MtF transsexuals’ white matter microstructure pattern fell halfway between the pattern of male and female controls.

The study does not say if there were any other ways in which MtF transsexuals’ white matter was different from both males and females without gender dysphoria. I think they did not look at the question; they seem to have analyzed the data first to find sex differences and then to compare MtF transsexuals to the other groups in those areas.

It would be beyond interesting and relevant to find any areas of the brain in which people with gender dysphoria were different from people without gender dysphoria.

It is worth noting that the MtF transsexuals were all sexually attracted to males while the males were all attracted to females and the females were all attracted to males.

Thus the study was also comparing the brains of two groups of people attracted to males and one group of people attracted to females. The differences they found could be related to sexual orientation.

It is not clear what these differences mean, what caused them, or what their significance would be in brain function.

You can stop here if you just want the gist of the results. Otherwise, back to the study:

The study found sex differences in the volumes of gray matter and white matter in the brain as well as the volume of cerebrospinal fluid (CSF); males have larger volumes than females. They found that the MtF transsexuals had volumes similar to the males and significantly different from the females. In this respect, MtF transsexuals have brains more like male’s than female’s.

The study also find sex differences in the fractional anisotropy (FA) values of white matter in six bundles of nerves with males having a higher FA value. The white matter structures with a higher FA value were the left and the right superior longitudinal fasciculus, the right inferior front-occipital fasciculus, the left cingulum, the forceps minor, and the corticospinal tract.

An earlier, related study of white matter in FtM transsexuals found a sex difference in the white matter in three of the same bundles of nerves: the right superior longitudinal fasciculus, the forceps minor, and the corticospinal tract. They did not report a sex difference in the left superior longitudinal fasciculus, the right inferior front-occipital fasciculus, or the left cingulum. (The earlier study was done by the same people using the same methodology but different control groups.)

In five of these six nerve bundles, the MtF transsexuals had white matter that was significantly different from both males and females. Their FA values fell in-between the values for males and females. In the inferior frontooccipital fasciculus their FA values were also different, but the difference was not statistically significant.

What does this mean?

First of all, it is important to note that for three of the six nerve bundles, the sex difference was not found in another closely related study. It may be that only the sex differences in the right superior longitudinal fasciculus, the forceps minor, and the corticospinal tract are real. The authors do not address this question (they should have).

In any case, the authors conclude that “the white matter microstructure pattern in untreated MtF transsexuals falls halfway between the pattern of male and female controls. The nature of these differences suggests that some fasciculi do not complete the masculinization process in MtF transsexuals during brain development.”

There are other possible explanations, however:

1. MtF transsexuals who are attracted to males might have had different experiences from both males and females. For example, they might have played soccer more than most girls but less than most boys. Similarly, the observed sex differences might have been caused by differences in experiences for girls and boys. This article argues that the superior longitudinal fasciiculus is changed by musical expertise.

2. MtF transsexuals might have had fasciculi that developed like the control males, but then something caused their FA values to decrease. Changes in FA values can be due to age or illnesses, including depression or excessive alcohol consumption. In this model, a lower FA value for females could be due to sex differences, while the lower value for MtF transsexuals might be due to later problems damaging the white matter.

3. There might be two completely separate pathways that cause males and MtF transsexuals to have higher FA values than females – or that cause females and MtF transsexuals to have lower FA values than males.

4. There might be some other confounding variable like left-handedness that affects white matter. The authors do not say if their subjects were right- or left-handed, but transsexuals are more likely to be non-right-handed than the general population.

5, The differences in the white matter in different nerve bundles might have different causes. For example, males might have a higher FA value for white matter connecting the brain to the spinal column due to playing sports, while their white matter in another region was affected by hormones.

We can’t conclude anything about what it means that the MtF transsexuals had FA values between males and females. We don’t know what caused the differences. What we do know is that MtF transsexuals were different from both males and females.

We also don’t know what the sex differences they found mean at a practical level.

This study found a sex difference in the FA values for the following fasciculi (bundles of nerves):

Superior longitudinal fasciculus (right and left) – a pair of long bundles of neurons connecting the front and back of the cerebrum (cerebrum=most of your brain). It is connected to many parts of the brain. One of its functions is to integrate auditory and speech nuclei. An earlier study only found a sex difference in the right superior longitudinal fasciculus.

Forceps minor (right) – a fiber bundle that connects that lateral and medial surfaces of the frontal lobes of the brain. It is part of the corpus collosum. The corpus collosum is responsible for interhemispheric sensory and auditory connectivity.

Inferior fronto-occipital fasciculus (right) – a nerve bundle that goes from the frontal lobe along the caudate nucleus and corona radiata, it also goes into the occipital and temporal lobes. One of its functions is to integrate auditory and visual association cortices with the prefontal cortex.  An earlier study by the same authors did not find a sex difference in this fasciculus. This is also the nerve bundle that was not significantly different for MtF transsexuals.

Corticalspinal tract (right) – connects the brain to the spinal cord. It is responsible for voluntary movement.

Cingulum (right) – a collection of white matter fibers that go from the cingulate gyrus to the entorhinal cortex. One of its functions is to integrate executive function nuclei. It allows the parts of the limbic system to communicate with each other. The limbic system is involved in emotion, behavior, motivation, long-term memory, and the sense of smell. An earlier very similar study did not find a sex difference in the cingulum.

Looking at these descriptions, this study found sex differences in the nerves that connect the front and back of the brain, the nerves that connect the two hemispheres, nerves that go from the front lobe into the occipital and temporal lobes, nerves that connect the brain to the spinal column, and nerves that connect the parts of the limbic system.

The difference does not seem to be related to any particular part of the brain.

The difference was found mostly on the right side of the brain. Does this mean anything?

If we only include the sex differences that were found in both this and the earlier study of FtM transsexuals, all of the sex differences were on the right side of the brain. We would still be looking at nerves that connect the front and back of the brain, nerves that connect the two hemispheres, and nerves that connect the brain and spinal cord.

It’s hard to predict how a difference in so many parts of the brain would affect men’s and women’s cognitive abilities and personalities.

What specifically is the difference they observed in these bundles of nerves? What are FA values?

They authors say that FA values are “related to the ordered arrangement of myelinated fibers” and “an indication of white matter coherence and axonal integration.” Wikipedia says that FA is thought to reflect fiber density, axonal diameter, and myelination in white matter.

So finding higher FA values for males in certain bundles of nerves could mean that they have more dense nerve connections there or that those nerve connections are fatter or that they have more or fatter myelin sheaths. It might mean that the nerve connections in those bundles are more orderly, coherent, and integrated.

The next question, of course, is what does it mean if you have more or fatter or more coherent nerve connections between the front and back of your brain? between the two hemispheres? going to your spine?

Or, to look at it in terms of function, if the white matter responsible for voluntary movement is more coherent in males, it might give them faster reflexes. On the other hand, what does it mean if the white matter that connects auditory and speech nuclei is more coherent in males? It sounds like it ought to make it easier for males to process language.

My basic conclusion from all this is that we have found a sex difference in the brain, but we don’t really know what it means.

The authors of the study don’t see it that way. They try to connect what they’ve found to sex differences in spatial abilities and verbal fluency, because the superior longitudinal fasciculus “connects complex cortical regions that subserve higher cognitive functions.” The problem with that logic is that there are a lot of cognitive functions being processed in the cortex.

I think they are overreaching a great deal there.

Anyhow, here is part of their discussion of their results and how they relate to the brain:

“MtF transsexuals differed from male and female controls in the right and the left superior longitudinal fasciculus. The SLF connects complex cortical regions that subserve higher cognitive functions and that are sexually dimorphic. Sex differences in cognition are consistently found in spatial abilities and verbal fluency ( Kimura, 1999); males outshine females in the former but the females outshine males in the latter. It has been reported that the performance of untreated MtF transsexuals in mental rotation tasks is consistent with that of their biological sex ( Haraldsen et al., 2003 Slabbekoorn et al., 1999 ). Schöning et al. (2010) studied spatial cognition using fMRI and found that untreated and treated MtF transsexuals had increased activation in the temporo-occipital regions and decreased activation in the left parietal lobe compared to control men. We have investigated brain activation during mental rotation in chronically hormone treated MtF transsexuals. These MtF transsexuals present less activation than male controls in the superior parietal lobe (Brodman’s area 7) and higher activation than females in the superior part of the gyrus frontalis (Brodman’s area 9) ( Carrillo et al., 2010). Interestingly, these two cerebral regions are connected by the SLF ( Makris et al., 2005Hua et al., 2009 ).

We found significant differences between MtF transsexuals and male and female controls in the forceps minor and the anterior region of the cingulum, both in the right hemisphere. The forceps minor connects orbitofrontal regions ( Park et al., 2008) and the cingulum is an associative bundle that runs from the anterior temporal gyrus to the orbitofrontal cortex ( Catani and Thiebaut de Schotten, 2008) and both form part of the emotional networks ( Kober et al., 2008 ). There is evidence that the orbitofrontal cortex and anterior cingulate cortices are involved in reinforcement processing and the reward value of reinforcers and punishers ( Cohen, 2008 Kringelbach and Rolls, 2004 ). Moreover, it has been suggested that the anterior cingulated cortex relates current information with an extended history of reward ( Walton et al., 2007).

The FA values of the corticospinal tract in MtF transsexuals also differed from male and female controls. Studies performed in non-human primates ( Lemon, 2008) have shown that this tract is a descending motor pathway originated from several cortical regions (primary motor cortex, premotor cortices, supplementary motor area and cingulate motor area, primary somatosensory cortex, posterior parietal cortex and the parietal operculum). Limb movements that require a high degree of skill and flexibility are controlled by these motor fibers. Lesions of this tract affect fine sensoriomotor function of the hand ( Lemon and Griffith, 2005). The maturation of the corticospinal tract depends on motor experience and genetic factors ( Cheeran et al., 2009 Martin et al., 2007).”

 

Original Article:

The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study by Rametti G, Carrillo B, Gómez-Gil E, Junque C, Zubiarre-Elorza L, Segovia S, Gomez Á, Guillamon A. in J Psychiatr Res. 2011 Jul;45(7):949-54. 

* I am following the language used in the study to refer to trans women and control subjects.

P.S. A fun link on the map of the connections of white matter in young men’s brains.

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