Monthly Archives: August 2014

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study – Review

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

This is one of a set of studies; another one looked at the white matter in the brains of 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.

In three fasciculi (bundles of nerve fibers), FtM transsexuals had white matter that was like males and different from females.

In the corticospinal tract, FtM transsexuals’ white matter microstructure pattern was between the pattern of the male and female controls.

The study does not say if there were any other ways in which FtM 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 FtM 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 FtM transsexuals were all sexually attracted to females while the females were all attracted to males and the males were all attracted to females.

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 fractional anisotropy (FA) values of white matter in four bundles of nerves with males having a higher FA value. The white matter structures with a higher FA value for males were the anterior** and posterior parts of the right superior longitudinal fasciculus, the forceps minor (right), and the corticospinal tract.***

In three of these four nerve areas, FtM transsexuals had FA values that were significantly larger than females and not significantly different from males.

In the inferior corticospinal tract, FtM transsexuals had FA values that were significantly larger than females and significantly smaller than males.

The authors conclude:

“…the main result of our study is that untreated FtM transsexuals differed from control females in two associative fasciculi (superior longitudinal fasciculus and forceps minor) and in the corticospinal tract. In contrast they only differed from control males in the corticospinal tract. These findings indicates that prior to hormonal cross-sex treatment the white matter microstructure of associative fascicles in untreated FtM transsexuals is more like that of individuals with the same gender identity than of individuals with the same biological sex.”

Their fascicles are also more like that of individuals with the same sexual orientation. We can not conclude that the cause is their gender identity, at least not from this data. We need more research in this area.

It is worth noting that we do not know what exactly made the white matter microstructures develop the way they did. It could be due to hormones or experience or an interaction of the two.

In addition, the microstructure in FtMs might have been affected by a different factor than the microstructure in males.

Finally, in the case of the corticospinal tract, it is possible that FtM transssexuals had white matter 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.

What do the differences they found mean practically?

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

Superior longitudinal fasciculus (right, anterior and posterior) – 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.

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.

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

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, and nerves that connect the brain to the spinal column.

It’s hard to predict how differences in these parts of the brain would affect men’s and women’s cognitive abilities and personalities.

The difference was found only on the right side of the brain. Does this mean anything? Maybe. According to the authors:

“Regarding brain laterality, we found that all the FA value decreases in women compared to men are seen in the right hemisphere. Similar asymmetries are also reported by Schmithorst et al. (2008), they described lower FA values in girls than in boys, and although there were decreases on both sides, the largest lost FA value clusters were on the right, indicating a right hemispheric predominance in sex differences. More recently Huster et al. (2009), focusing on the midcingulum bundle, found lower FA values in the right hemisphere than in the left and in women than in men.”

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

In another study, the 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 try to connect their findings to differences in spatial abilities and verbal fluency, because the superior longitudinal fasciculus is “involved in the integration of inputs from multiple modalities and is a component of the network for spatial awareness that plays a major role in the visual and oculomotor aspects of spatial function such as spatial attention and spatial working memory.”

It might be, but there are a lot of other cognitive functions that use the integrations of inputs from multiple modalities. We have no way of knowing if the connections they observed were for spatial ability or giving a speech or cooking dinner without burning yourself.

I think they are overreaching in their conclusion here.

The authors also discuss the difference they found in the forceps minor. Again, I think it’s hard to know what exactly a sex difference here would mean; the forceps minor connects the two halves of the prefrontal cortex which controls our behavior. Does having more connectivity on the right make men better at controlling themselves or integrating their emotions?

The forceps is part of the corpus collosum. Another study found differences related to sexual orientation in this area of the brain. It is important to make sure that any differences found in this study are not due to sexual orientation.

The authors refer to a study which found that the shape of the corpus collousm in transsexual individuals matched their gender identity not their biological sex. I can only see the abstract of that study, so I don’t know if they looked at the sexual orientation of the people in that study.

Anyhow, here is the discussion of the forceps minor by the authors:

“The forceps minor connects, via the genu of the CC, orbitofrontal regions ( Park et al., 2008) involved in emotional functions and behavioral control. Kringelbach and Roll (2004), suggested that orbital cortex activity is related to the reward value of reinforcers and punishers.

The forceps minor is a part of the anterior region of the corpus callosum. The CC is the major interhemispheric pathway in the human brain and integrates sensory, motor, cognitive and emotional functions from both hemispheres; the isthmal area of the CC is larger in homosexual than in heterosexual males ( Witelson et al., 2008). FA values in the anterior part of the CC change during development ( Lebel et al., 2008). In a sample of children and adolescents, it was reported that girls have lower FA values than boys in the anterior CC region ( Schmithorst et al., 2008). In addition, the boys had lower FA values than girls in a small region of the splenium. We did not observe differences in the splenium between adult male and female controls.

There are only a couple of studies on the transsexual CC. Studying the CC shape, it was concluded that the shape in transsexuals is more similar to their gender identity than to their biological sex ( Yokota et al., 2005). However, when the whole CC surface was studied no differences in CC -regardless of genetic sex or gender- were reported (Emory et al., 1991). Our results cannot be compared to these works, which used surface measurements, while we have used FA analysis, which seems to be a more suitable technique for detecting microstructural white matter differences.”

The authors say less about the corticospinal tract, but they mention that genes and motor experience interact in its development. This is an area where FtM transsexuals were in-between male and female controls, so perhaps they are suggesting that the males had more practice at motor skills.

Of course all of the sex differences found in this study could be related to experience or an interaction of genes and experiences.

The authors of this study imply that the sex differences they found were caused by hormones early in development, but we can’t actually know that.

This study had a couple of serious weaknesses.

1. They did not look for any general differences between the brains of trans and cis people, they only looked at how trans men compared to males and females in areas where they found a sex difference. This assumes that gender dysphoria is caused by something related to hormones – which is what the authors want to prove.

It would be helpful if future studies look at both issues – sex differences and general differences between cis and trans people. Perhaps the authors could of this study would be able to use the data they collected to do this.

2. They did not include any cis lesbians as control groups, although all of the FtM transsexuals were attracted to women. Without doing this, we can not be sure if the similarities between the FtM transsexuals and cis men attracted to women are caused by gender identity or sexual orientation.

The study also has some strengths.

1. They used only trans men who had not yet taken hormones. We know that taking cross-sex hormones changes your brain. (Early studies of gender identity and the brain used people who had already been on hormones.)

2. They tested the actual hormone levels of the FtMs before the brain scans. A Japanese study found that many of the trans men who came to their clinic had poly-cystic ovarian syndrome (PCOS). PCOS can lead to elevated levels of androgens which would confuse the results.

3. Everyone in the study was right-handed.

Original Article:

White matter microstructure in female to male transsexuals before cross-sex hormone treatment. A diffusion tensor imaging study by Rametti G, Carrillo B, Gómez-Gil E, Junque C, Segovia S, Gomez Á, Guillamon A in J Psychiatr Res. 2011 Feb;45(2):199-204.

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

** The abstract says that the white matter was different in the medial and posterior parts of the superior longitudinal fasciculus, but  in the text of the study, the results discuss the anterior and posterior parts. Anterior and posterior refer to front and back while medial means in the middle, so it makes more sense to talk about the anterior and posterior parts of the nerve bundle. I think they made an error in the abstract.

***A later study of white matter in MtF transsexuals found a sex difference in the same three bundles of nerves. They found a sex difference in three additional areas as well: the left superior longitudinal fasciculus, the right inferior front-occipital fasciculus, and the left cingulum. It’s not clear why one study found more sex differences in white matter than the other did. (The earlier study was done by the same people using the same methodology but different control groups.)

 

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

Sexual Orientation and the Brain – Links to studies

A number of studies have found differences in the brain that may be related to sexual orientation.

Because of this, studies of gender identity and the brain need to carefully control for sexual orientation.

It is important to remember that the majority of trans men (born female) are primarily attracted to women while only about 5% of cis women are primarily attracted to women. Thus if you find differences between trans men and a randomly selected group of females, the differences could be due to gender identity or sexual orientation.

Similarly, about half of trans women (born male) are attracted to men while only about 5% of cis men are primarily attracted to men. Again, differences found in studies of the brain could be due to gender identity or sexual orientation.

So far, I have found no studies of the brain and gender identity that included gay and lesbian controls.

Many studies discuss the sexual orientation of the trans people; some studies look only at trans women who are attracted to men or trans women who are attracted to women, but that is only half of what needs to be done.

A group of trans women who are all attracted to men is still different from your average group of cis men in two ways – gender identity and sexual orientation.

The studies listed below are proof this issue matters. We know that sexual orientation can affect the brain.

I have not read these studies, this is just a list of links for you to enjoy.

Sexual orientation and the size of the anterior commissure in the human brain by L.S. Allen, R.A. Gorski in Proc. Natl. Acad. Sci. U. S. A., 89 (1992), pp. 7199–7202.

A fiber tract that is larger in women than in men was even larger in gay men. (But the gay men had died of AIDs).

The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex, sexual orientation, and HIV status by W. Byne, S. Tobet, L.A. Mattiace, M.S. Lasco, E. Kemether, M.A. Edgar, S. Morgello, M.S. Buchsbaum, L.B. Jones in Horm. Behav., 40 (2001), pp. 86–92.

HIV status affected the size of the INAH1 cell group. The INAH3 cell group was bigger in presumed straight males than females and contained more neurons. There was a trend for INAH3 to have a larger volume in straight males than gay males, but they had the same number of neurons in the INAH3.

A difference in hypothalamic structure between heterosexual and homosexual men by S. LeVay in Science, 253 (1991), pp. 1034–1037.

The INAH3 cell group in the hypothalmus was bigger in men than women. It was also bigger in the brains of presumed straight men than in the brains of gay men.

Homosexual women have less grey matter in perirhinal cortex than heterosexual women by J. Ponseti, H.R. Siebner, S. Kloppel, S. Wolff, O. Granert, O. Jansen, H.M. Mehdorn, H.A. Bosinski in PLoS. ONE, 2 (2007), p. e762.

Women had more gray matter than men in a number of areas. In three areas straight women had more gray matter than lesbians; in one of these areas men also had less gray matter than women.

“The perirhinal cortex is located close to entorhinal cortex, hippocampus, parahippocampal gyrus and amygdala, and is known to be involved in a variety of functions like olfactory processing, memory encoding and spatial processing. These functions are related to the processing of sexual stimuli as well.”

PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects by I. Savic, P. Lindstrom in Proc. Natl. Acad Sci. U. S. A., 105 (2008), pp. 9403–9408.

Straight men and lesbians had a rightward cerebral asymmetry, gay men and straight women did not.

“Homosexual subjects also showed sex-atypical amygdala connections. In HoM, as in HeW, the connections were more widespread from the left amygdala; in HoW and HeM, on the other hand, from the right amygdala. Furthermore, in HoM and HeW the connections were primarily displayed with the contralateral amygdala and the anterior cingulate, in HeM and HoW with the caudate, putamen, and the prefrontal cortex. The present study shows sex-atypical cerebral asymmetry and functional connections in homosexual subjects.”

An enlarged suprachiasmatic nucleus in homosexual men by D.F. Swaab, M.A. Hofman in Brain Res., 537 (1990), pp. 141–148.

A nucleus in the hypothalmus is larger in gay men than straight men. A different nucleus that is sexually dimorphic was the same size in gay and straight men.

Corpus callosum anatomy in right-handed homosexual and heterosexual men by S.F. Witelson, D.L. Kigar, A. Scamvougeras, D.M. Kideckel, B. Buck, P.L. Stanchev, M. Bronskill, S. Black in Arch. Sex Behav., 37 (2008), pp. 857–863.

The isthmal area in the corpus callosum was larger for a group of gay men compared to straight men.

The citations for these studies are from the study Regional gray matter variation in male-to-female transsexualism by Luders E, Sánchez FJ, Gaser C, Toga AW, Narr KL, Hamilton LS, Vilain E. in Neuroimage. 2009 Jul 15;46(4):904-7. I reviewed the study here.

Brains of Children with Autism Fail to Trim Synapses – NY Times article and a Question

A fascinating article in the NYTimes about a new study of children with autism.

A few interesting points:

Babies grow many synapses connecting the neurons in their brain. As they grow up, they prune these synapses.

It looks like autistic children may not prune these synapses as well as other children and teenagers do. Their problems with social learning may be due to having too many connections in the brain.

They may also have a problem clearing out old and degraded cells.

From the NYT article:

“‘Impairments that we see in autism seem to be partly due to different parts of the brain talking too much to each other,” he said. “You need to lose connections in order to develop a fine-tuned system of brain networks, because if all parts of the brain talk to all parts of the brain, all you get is noise.'”

This overconnectivity in the brain could explain “symptoms like oversensitivity to noise or social experiences, as well as why many people with autism also have epileptic seizures.”

More than a third of people with autism have epilepsy!!!!

Is there any connection between this and gender dysphoria?

Probably not, but it is interesting to speculate. What if gender dysphoria is also caused by overconnectivity in the brain, just less of it? Perhaps gender dysphoria is caused by too many connections in just one part of the brain. That might explain why there are more people than you would expect with both ASDs and gender dysphoria. Something for someone to research, perhaps.

It might also be interesting to find out if people with gender dysphoria have a higher rate of epilepsy than expected.

Ability of an orally administered lactobacilli preparation to improve the quality of the neovaginal microflora in male to female transsexual women – Review and a possible health benefit

This is a very cool study that found that trans women could improve the microflora in their neovaginas by taking lactobacilli orally.

Trans women might need to keep taking the lactobacilli pills to maintain the good microflora in their neovaginas.

Why would you want to do this?

Well in addition to other benefits, mostly for digestion, lactobacilli can help to treat bacterial infections in the vagina and it may help prevent urinary tract infections.

According to the authors of the study, many trans women don’t have enough lactobacilli in their neovagina.

“The microflora of male to female transsexual women is a complex symbiosis of aerobic and anaerobic species with a very limited number of lactobacilli. It has substantial similarity to the abnormal vaginal microflora characteristic of bacterial vaginosis (BV) [1,2]. Weyers et al. reported that, although transsexual women show serum oestradiol levels comparable to those of postmenopausal women taking oestrogen replacement therapy, their neovaginal environment does not support the growth of lactobacilli [1]. In one study [1], only one of thirty transsexual women had neovaginal colonisation with lactobacilli. Another study of transsexual women, the same authors [2] found a neovaginal lactobacilli colonisation rate of 4%.”

In this study, the authors found a higher rate of neovaginal lactobacilli colonisation, however, everyone who took the lactobacilli improved their scores.

The study was a good, randomized test of whether or not the lactobacilli worked, using 60 trans women split into two groups (one taking the lactobacilli, one not).

The bottom line – Post-op trans women should talk to their doctors about whether they should take lactobacilli.

Their discussion of their results:

“The results of this prospective randomised controlled study show that oral administration of L. crispatus, L. rhamnosus, L. jensenii and L. gasseri significantly improved the neovaginal microflora and reduced the Nugent score in a group of transsexual women. Also, the microflora was significantly enriched with lactobacilli after oral supplementation compared to placebo. The combination of Lactobacillus spp. used in this study is the only one published as the physiologic mixture of female vaginal lactobacilli microflora [15]. We used an innovative probiotic lactobacilli composition containing four of the most common lactobacilli isolated from the microflora of healthy women’s vaginas [15] for treatment of 7 days’ duration. Weyers et al. reported that colonisation of the neovagina of transsexual women with lactobacilli is minimal [1,2]. According to Nugent, an intermediate vaginal microflora is defined by a reduction and BV by an absence of lactobacilli with the presence of Gram negative bacteria in both cases [14]. The small number of publications on the standard neovaginal microflora and the near lack of evidence of lactic acid bacteria in the transsexual genital tract area are a challenge for investigations in this population. While transsexual women have normal female anatomy, there is no uterus and no connection of the neovagina to the pelvic cavity, which is why the risk of pelvic inflammatory disease is low. We were therefore able to include all transsexual women without clinical signs of infection, including those with asymptomatic BV. To our knowledge, this is the first study to allow a direct assessment of the comparative effect of oral probiotic lactobacilli and placebo on BV.

The gastrointestinal tract plays an important role as a reservoir for the vaginal colonisation by Lactobacillusspp. [4], [5] and [6]. Both vaginal and oral applications of lactobacilli have been shown to improve the vaginal microflora of both pre- and post-menopausal women [3], [9], [10] and [11]. The results of this study indicate that oral lactobacilli have a similar effect on the neovaginal flora of transsexual women. Descriptive analyses of the difference in Nugent score showed a reduction of −0.18 in the intervention group and an increase of +0.92 in the control group.

We found a significant improvement in the Nugent score in 48.5% of women in the intervention group, compared with only 14.8% in the control group. Lactobacilli concentrations assessed by culture and real-time PCR were 5–6 times higher in the intervention than in the control group, with these differences being statistically significant.

The sample size calculation in this study was based on neovaginal lactobacilli colonization rates of up to 4% reported in the literature [1] and [2]. In the present study, however, 30% of the women in both the intervention and control groups had a normal lactobacillus microflora (Nugent score ≤3). This was an unexpected finding contrasting with the current literature [1] and [2]. Because oral lactobacillus supplementation cannot be expected to change a neovaginal microflora dominated by lactobacilli, this unexpectedly high proportion of women with a normal lactobacillus flora may have led to an underestimation of the treatment effect. We therefore carried out a subgroup analysis including only women with a baseline Nugent score above 4, corresponding to either an intermediate microflora or BV. Even then, after 7 days of treatment with oral lactobacilli, we found an improvement in the Nugent score in the intervention group and no change in the control group. The results of this subgroup analysis are comparable with the results of one of our earlier studies on the effect of lactobacilli on postmenopausal women, which showed an improvement in Nugent scores [11]. In contrast to the previous study with a lactobacilli treatment duration of 14 days, however, the improvement in the current was already seen after 7 days of oral lactobacilli. The renewed increase of the Nugent score two weeks after the end of oral therapy indicates that extended oral probiotic therapy may be necessary to maintain a lactobacilli-dominated microbiota.

This study had several limitations. With a specific study group of male to female transsexual women and very limited number of patients visiting our clinic we could observe only a small sample size in our study. The therapy duration was limited to 7 days: we assume that longer treatment with probiotics could obtain a better outcome. Microbiology analyses of CFU’s and c/ml were presented only for presumptive lactobacilli. In the next step we will include other bacteria with similar colony characteristics, such as Gardnerella vaginalis and Atopobium vaginae to present more detailed data. This study is first to observe male to female transsexual women using probiotics and we are aware of our initial oversights.

In summary, this first study on the effect of oral probiotics on the neovaginal microflora of transsexual women found that oral administration of lactobacilli resulted in a significant improvement in the Nugent score and a change of the neovaginal microflora. These observations are consistent with previous results obtained in pre- and post-menopausal women. The increase of the Nugent score two weeks after the end of oral therapy provides a possible need for extended oral probiotic therapy for maintenance of a lactobacilli-dominated microbiota. In addition, this study shows that even asymptomatic BV may be improved to a normal microflora by 7 days of oral supplementation of lactobacilli.”

Original Aritcle:

Ability of an orally administered lactobacilli preparation to improve the quality of the neovaginal microflora in male to female transsexual women by Ulrike KaufmannKonrad J. DomigChristina I. LippitschManuel Kraler, Julian Marschalek, Wolfgang Kneifel, Herbert Kiss, Ljubomir Petricevic in European Journal of Obstetrics & Gynecology and Reproductive Biology, Volume 172, January 2014, Pages 102–105.

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.

PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects – Brief Review and a cautionary note

This is the abstract of a study which shows that the brains of gay men are similar to the brains of straight women in certain ways while the brains of lesbians are similar to the brains of straight men.

The study looked at hemispheric asymmetry and functional connectivity, two areas where scientists have found differences between men and women.

They scanned the brains of 25 straight men (HeM), 25 straight women (HeW), 20 gay men (HoM), and 20 lesbians (HoW). Fifty of the subjects also participated in a test of blood flow that is used to analyze connections between the right and left amygdalae.

Results (from the abstract):

“HeM and HoW showed a rightward cerebral asymmetry, whereas volumes of the cerebral hemispheres were symmetrical in HoM and HeW. No cerebellar asymmetries were found. Homosexual subjects also showed sex-atypical amygdala connections. In HoM, as in HeW, the connections were more widespread from the left amygdala; in HoW and HeM, on the other hand, from the right amygdala. Furthermore, in HoM and HeW the connections were primarily displayed with the contralateral amygdala and the anterior cingulate, in HeM and HoW with the caudate, putamen, and the prefrontal cortex.”

They conclude:

“The present study shows sex-atypical cerebral asymmetry and functional connections in homosexual subjects.”

This study shows the critical importance of controlling for sexual orientation when studying the question of gender identity and the brain.

An extremely high proportion of people with gender dysphoria are primarily attracted to people of their birth sex. In the general population, only about 5% of people are primarily gay or lesbian.

Studies of gender identity and the brain should include both gay and straight control groups.

There is also a need for studies comparing the brains of transgender people who are attracted to people of their birth sex to gay men and lesbian women who are cis. This might be the most fruitful avenue of research into what causes gender dysphoria.

Original Abstract:

PET and MRI show differences in cerebral asymmetry and functional connectivity between homo- and heterosexual subjects by Ivanka Savic and Per Lindström in Proceedings of the National Academy of Sciences of the United States of America, July 8, 2008, vol. 105 no. 27.

Regional gray matter variation in male-to-female transsexualism – Review

This article found that trans women’s brains are more similar to men’s brains than cis women’s brains, at least in terms of the pattern of gray matter variation.

They also found that trans women’s brains had more gray matter in the putamen than both cis men and cis women, although the difference was only significant for cis men.*

The authors found 20 areas of the brain where women had more gray matter than men. The male-to-female transsexuals (trans women) had the smallest volume of gray matter in these areas, but their data spectrum mostly overlapped with the men’s.

In two areas of the brain, the left and right putamen, male-to-female transsexuals had the largest volume of gray matter.**

“…the gray matter volume of this particular structure in the MTF transsexual group was both larger than in males and within the average range of females.”

Gray matter, in case you’re wondering, contains more neuronal cell bodies. White matter is mostly made up of axons that transmit signals within the brain. Previous studies have found that there are sex differences in the distribution of gray matter in the brain.

The authors describe the putamen as being “feminized” in MTF transsexuals. That might be, but it might also be that their putamens are simply different from cis people’s for some other reason.

In addition, the putamen has more gray matter in women than in men, but the trans women’s putamens had more gray matter than either, although the difference between trans women and cis women was probably not significant.**

The authors conclude:

“Overall, our study provides evidence that MTF transsexuals possess regional gray matter volumes mostly consistent with control males. However, the putamen was found to be “feminized” in MTF transsexuals….”

“Taken together, these findings lend support to the hypothesis that specific neuroanatomical features are associated with transsexual identity, where the particular role of the putamen requires investigation in future studies.”

The study results also support the idea that trans women’s brains are more similar to men’s brains than to cis women’s brains. Most of the time when men’s and women’s brains differ, the trans women’s brains were like men’s.

In addition, the authors briefly mention a few areas where women’s and men’s brains were similar, but trans women’s brains were different from cis women’s (see details of study below).

On the other hand, we definitely need more studies of the putamen and gender dysphoria.

As the authors point out, we do not know if the differences in the putamen are the cause or result of gender dysphoria – or if the differences are caused by another factor that also causes gender dysphoria.

It is also possible that the observed differences are caused by sexual orientation, not gender identity. The authors explain that their sample included 6 male-oriented people (25%) and 18 female-oriented people (75%). They did not know the sexual orientation of their control groups, but it is likely that 95% of the males were attracted to females and 95% of the females were attracted to males.

Their sample also included more left-handed people than the control groups. It is possible that handedness affects the size of the putamen in some way.

Another huge issue is that we have no flipping idea what the results mean. The putamen is an area of the brain that is believed to be involved in many different functions including motor skills, memory, and processing sensory information. If it is involved in gender dysphoria, we need studies to figure out how.

Hopefully we will see some studies confirming this result, this time with a control group that includes gay men and lesbians. The study should also control for handedness.

Then we will need more studies looking at exactly what is going on.

Original Article:

Regional gray matter variation in male-to-female transsexualism by Luders E, Sánchez FJ, Gaser C, Toga AW, Narr KL, Hamilton LS, Vilain E. in Neuroimage. 2009 Jul 15;46(4):904-7.

Some details of the study:

The authors looked at 24 trans women recruited through the community organizations and professionals who serve trans people. Their average age was 43 (range 23-72). They were genetic males (they had the SRY gene),*** they were free of psychoses, and they passed a physical and neurological exam. 76% of them were right-handed, compared to 90% or more of the controls.

None of them were on hormones, although they all intended to take them.

More about the results:

“females had more gray matter than males in large portions of the brain… Similarly, females had more gray matter than MTF transsexuals… Although the differences between females and MTF transsexuals did partly overlap with the difference between females and males…, they were spatially more extended, and also evident in a few regions where females and males did not differ… There was no region where females had significantly less gray matter than males… or MTF transsexuals… Similarly, there was no region where MTF transsexuals had significantly less gray matter than males… MTF transsexuals, however, showed significantly more gray matter than males in the right putamen… MTF transsexuals also showed significantly more gray matter than males in the left putamen when findings were not corrected for multiple comparisons (p<0.001, maps not shown).”

I am intrigued by the mention of a few regions where females and males did not differ but females had more gray matter than MTF transsexuals. I wish the authors had discussed these areas. Perhaps they would shed some additional light on gender dysphoria.

*The box plot data on the trans women’s putamen looks pretty different from the cis women’s data. Their median value is higher and their range seems to be much bigger and go up higher. However, the difference is probably not significant since the authors say elsewhere that there was no area where females had significantly less gray matter than trans women.

** It may be that the difference was only statistically significant in the right putamen. Elsewhere in the study the authors say that trans women had significantly more gray matter than males in the left putamen only when the findings were not corrected for multiple comparisons. Because brain scans involve collecting so many data points, the chances of finding correlations by chance are much greater. Thus you have to make corrections. On the other hand, in this case, the other half of the putamen was different at a stastically significant level.

*** Zoe Brain has pointed out that someone could have the SRY gene, but still have unusual chromosomes, if they had Kleinfelter’s syndrome (47xxy) or mosaicism (46xx/46xy). Her interpretation of this study is quite different from mine, but well worth reading.