Tag Archives: gray matter

Sex Dimorphism of the Brain in Male-to-Female Transsexuals – Review

This study found that trans women (born male) had brains like men’s, at least in terms of gray and white matter volumes and hemispheric asymmetry.

In a few areas, trans women’s brains were different from both men’s and women’s brains.

The authors suggest that the differences they found between trans women and cis people’s brains are related to body perception.

They conclude:

“The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.”

The study only looked at trans women who were attracted to women. This is both a strength and a limitation of the study.

It is a strength because it avoids confusion between gender identity and sexual orientation. Many recent studies have compared trans women attracted to men to men attracted to women; if you find a difference between the two groups, you can’t be sure if it is due to sexual orientation or gender identity.

This study, however, compared trans women attracted to women with men attracted to women and women attracted to men.

This is also a limitation because it is extremely unrepresentative of trans women. About half of trans women are attracted to men, much more than in the general population. If we want to understand how gender dysphoria works, we need to look at both groups of trans women.

A study looking at just trans women attracted to women was necessary, but clearly we need some follow-up research. Is this result true for trans women who are attracted to men? How do these results compare to cis gay men’s brains?

You can stop here if you want. You now know the main result of the study.

On to the specifics of the study. What exactly did they find?

Ways trans women’s brains were like men’s brains

1. Total brain tissue volume was smaller in heterosexual women (HeW) than in heterosexual men (HeM)  and gyenephillic male to female transsexuals (MtF-TR).*

(Gyenephillic=attracted to women.)

2. Total intracranial volume was smaller in HeW than in HeM or MtF-TR. There was no difference between the groups in total white matter volume or total gray matter volume when you took into account the total intracranial volume.

3. HeM had a larger gray matter volume than HeW in the lingual gyrus, the cerebellum, right putamen, and left amygdala and perirhinal cortex. HeW had larger gray matter and white matter volumes in the precentral gyrus.

None of these differences were reproduced when comparing HeM to MtF-TR.

4. HeW had larger hippocampi compared to both HeM and MtF-TR, mostly due to the left hippocampus. There was no difference between HeM and MtF-TR.

5. HeM and MtF-TR had rightward assymetries in the brain; HeW did not. Specifically:

a. the volume of the right hemisphere was larger than the left for HeM and MtF-TR, but not for HeW;

b. the volume of the thalamus was significantly larger in the right hemisphere for HeM and MtF-TR, but not for HeW – however, there was no significant differences in the groups’ assymetry indices (volume of right side/volume of left side).

c. the volume of the hippocampus was significantly larger in the right hemisphere for HeM, but not for HeW. The volume was also larger for MtF-TR, but this was not statistically significant – although the p-value was 0.065, so it was close. However, the differences in assymetry indices between MtF-TR and HeW and between HeM and HeW were significant.

Ways trans women’s brains were different from cis people’s brains

1. MtF-TR had larger gray matter volumes than either HeM or HeW in the “right temporo-parietal junction (around the angular gyrus and in the posterior portion of the superior temporal gyrus)**, and right inferior frontal and insular cortex.”

2. MtF-TR had a smaller gray matter volume than either HeM or HeW in the thalamus.

3. MtF-TR had smaller thalamuses and putamens than either HeM or HeW; this was a measurement of the regional structural volume. There was no difference between HeM or HeW.

Areas where they found no differences between the groups

1. There were no group differences in the caudate volume.

2. There was no assymtery in the caudate or putamen.

What does all this mean?

First, it does look like the authors are right; the trans women’s brains were more like men’s than women’s. It is possible that trans women’s brains are like women’s brains in some other way than the ones the authors looked at. Nevertheless, the similarities to men’s brains found in this study are fairly large.

What is perhaps, more interesting, is the ways that the trans women’s brains were different from cis people’s brains, whether they were male or female.

The authors of the study point out that these are new findings and they need to be confirmed with larger studies. “Any interpretation must, therefore, proceed cautiously and can at this point only be highly speculative.”

The authors go on to suggest that their findings might be related to own body perception. As they point out, one of the main symptoms of gender dysphoria is discomfort with your own body. Some studies suggest that the areas of the brain where trans women were different from cis men and women could be part of a network involved in own body perception.

Of course, as in other studies, the parts of the brain involved in this study have multiple functions. For example, the angular gyrus is also involved in language, math, and memory retrieval. So we can’t be sure exactly what it means that trans women have a larger volume of gray matter in those areas.

On the other hand, people with gender dysphoria don’t have problems with language and math, they have problems with dysphoria about their bodies.

More surprisingly, the authors of this study suggest that people with gender dysphoria may have changed their brains by constantly thinking about their bodies. This is possible, but it seems more likely to me that the problem starts with something in the brain causing people to feel uncomfortable with their bodies.

Here is the author’s argument from their conclusion:

“There is no evidence that this feeling [gender dysphoria] is caused by a general sensory deficit in transsexual persons…Several studies propose that own body perception involves networks in the temporo-parietal, inferior parietal cortex, the inferior frontal, and insular cortex, and their connections with the putamen and thalamus. Thus, theoretically, the experience of dissociation of the self from the body may be a result of failure to integrate complex somatosensory and memory processes executed by these networks.

Such disintegration accords with the present findings and could, perhaps, explain recent observation of poorer parietal cortex activation during a spatial orientation task in MtF-TR compared with male controls.

However, it is difficult to explain how such disintergration can be linked to a dysphoria restricted to the own body’s sex characteristics.

Moreover, even if a link exists, it is uncertain whether the here observed morphometric features in transsexual patients underpin their gender identity or are a consequence of being transsexual.

One highly speculative thought is that the enlargement of the GM volume in the insular and inferior frontal cortex and the superior temporal-angular gyrus could derive from a constant rumination about the own body. Brain tissue enlargement has been detected in response to training, and GM enlargement of the insular cortex has been reported in response to meditation, which involves mental focusing on the own body.”

The authors also point out that it might be that something else is causing both gender dysphoria and changes in neuroanatomy.

They stress that we can’t directly connect changes in gray matter volume to effects on the person.

They point out that they did not look at the hypothalamus, so their findings do not contradict earlier studies of it.

Finally, they call for more research, including research which compares trans women attracted to men to trans women attracted to women, and trans women attracted to men to cis gay men. (Yay!)

“Furthermore, they [the results] were generated exclusively from investigations of nonhomosexual, gynephillic MtF-TR. The issue of possible cerebral difference between gynephillic and androphillic (homosexual) MtF-TR and also between androphillic MtF-TR and homosexual healthy men is of special interest and needs to be addressed separately in future studies. Additional studies of the relationship between brain structure and function in transsexual persons and also extending the material to female to male transsexuals are necessary to more precisely interpret the present observations.”

The bottom line: we need more studies confirming these results. Is there a link between gender dysphoria and the network involved in own body perception? If so, which is the cause and which is the effect? Do these results hold true for trans women who are attracted to men? What about trans men?

There were two results the study did not discuss. It may not mean anything, but I think it is worth mentioning.

1. The volume of the amygdala was larger in HeM than HeF; this fits with other studies of sex differences in the brain. For MtF-TR, their amygdalas seems to have been neither bigger nor smaller than males or females. (Table 3)

2. The subcallosum (BA 24, 32) was larger in HeF than HeM. This fits with a study the authors cite showing that women have larger anterior cingulate gyri – the anterior cingulate cortex includes Brodmann Areas 24 and 32. This area seems to have been neither larger nor smaller in MtF-TR.

According to the authors: “Although sex differences have been described also in the amygdala and cingulate gyrus, these structures were not included in the analysis because the identification of anatomical landmarks in these regions is less reliable, especially when using a 1.5-T scanner.”

In other words, they think there could have been an error in the results. Either there was no sex difference in those areas, or they failed to detect differences between trans and cis women in those areas.

Another possibility is that trans women and cis women were not different in those areas because trans women’s volumes were intermediate between cis men’s and cis women’s.

If this is so, there are many possible explanations. It might have something to do with sex hormones, although it is hard to see why trans women’s brains would have developed like cis men’s in most parts of the brain if they weren’t exposed to sex hormones. You would have to assume that there was something different about how their amygdala and cingulate gyrus responded to sex hormones.

Another possibility is that trans women’s amygdalas were as large as men’s amygdalas, but something made them shrink.

Studies have linked a smaller amygdala to obsessive-compulsive disorder (OCD), anxiety, PTSD, sociopathy, and early life stress (abuse, neglect, or poverty). [Click through to see the studies.]

Trans people have higher rates of anxiety than other groups, but this study excluded people with any psychiatric disorders.

Trans people also suffer higher rates of abuse and trauma than most people which might have affected their amygdalas.

A final, hypothetical possibility might be that gender dysphoria is in some way related to OCD.

In the case of the cingulate gyrus, we would have to assume that something happened to trans women’s brains to make the volume of their cingulate gyrus increase to be intermediate between cis women and cis men. This is harder to understand, since OCD, anorexia, and body dysmorphic disorder are all correlated with decreases in the size of the anterior cingulate cortex.

However, there is one study suggesting that a large right anterior cingulate “is related to a temperamental disposition to fear and anticipatory worry.” No doubt the experience of being transgender in our society causes people to worry and feel fear; perhaps this changes the brain. Alternatively, it might be that a tendency to worry is somehow linked to developing gender dysphoria.

Original Study:

Sex Dimorphism of the Brain in Male-to-Female Transsexuals by Savic I, Arver S. in Cereb Cortex. 2011 Nov;21(11):2525-33.

A few fun facts:

You can induce out-of-body experiences by stimulating either the temporo-parietal junction or the angular gyrus. (Read more here and here).

The right temporo-parietal junction is also involved in thinking about thoughts. It, or an area close to it, is involved in directing your attention. (Read more here and here.)

The superior temporal gyrus is involved in recognizing your own face, identifying emotions in other people’s faces, and social cognition.

Information about the self may be processed in the right hemisphere; however, not everyone agrees on this theory. (Read more here.)

Increased volume in the left inferior frontal gyrus and right amygdala are associated with worse symptoms in body dysmorphic disorder. The trans women in this study had increased volumes in the right inferior frontal gyrus only. This does, however, suggest that these areas of the brain are important to perceptions of the body. (Read more here.)

*I am using the language of the study now.

** The original text refers to the superior temporal gurus. A cool idea, but probably a typo.

Increased Cortical Thickness in Male-to-Female Transsexualism – A Review and a Hypothesis

This study found that male-to-female transsexuals* (MTF) had thicker cortexes than control males did in certain areas of the brain. It is not clear what the differences mean.

We don’t know what caused the difference, we don’t know how the difference affects people, and we don’t know if the difference is related to gender identity, sexual orientation, or some other factor.

That’s the essence of the study; we don’t know.

Back to the study. The cerebral cortex is the outer layer of your brain. It is made up of gray matter which contains mostly neuronal cell bodies,

As with many studies, the difference they found might be related to gender identity or to sexual orientation. The MtF group included 6 people who were male-oriented and 18 who were female-oriented, so 25% of them were attracted to men. It is likely that 95% of the control males were attracted to women.

The authors suggest that:

“future studies need to explore the possibilities that brain anatomy in MTF transsexuals varies depending on whether they are attracted to men, attracted to women, or attracted to both. Ideally, those studies will also include heterosexual / homosexual control men, matched to MTF transsexuals with respect to their sexual orientation.

As with other studies, we don’t know what the practical effects of these differences might be. What does it do to you to have a thicker cortex? What does it mean if your cortex is thicker in the front versus the back of your brain? Does it matter if it is only thicker on the right side?

or as the authors put it:

“further research characterizing the relationships between cerebral micro-structure and macro-structure as well as brain function is clearly necessary before these regional structural differences (and any inherent hemispheric effects) can be precisely interpreted.”

The authors suggest that the thicker cortexes in the trans women (MtFs, i.e. born male) “resemble the direction of previously reported gender-typical pattern among non-transsexuals, such as thicker cortices in women than in men.”

In other words, they are similar to females, at least in terms of having thicker cortexes than males.

Maybe, maybe not.

This study did not look at any female brains, so we can’t know how the brains of the males or trans women would have compared to female controls.

Furthermore, studies have also linked thicker cortexes to obsessive-compulsive disorder (OCD), autism, social anxiety disorder (here and here), and, in children, to generalized anxiety disorder.**

There is even a study that found a small area*** of increased cortical thickness in people with xenomelia (the feeling that one of your limbs is foreign, also known as Body Identity Integretive Disorder).

Cortical thickness has also been linked to a positive trait; valuing religion or spirituality.

Finally, a couple of studies have found that meditation and sports training are associated with increased cortical thickness.

If we just go be the direction of the difference, the thicker cortex found in trans women could be linked to OCD, social anxiety disorder, autism, gender identity, xenomelia, spirituality, or life experiences.

These are not crazy possibilities; this Spanish study found that trans people had more social phobias than the general population. This Dutch study found that children and teens with gender dysphoria had a higher rate of autism spectrum disorder than the general population.

The important question is not is the cortex thicker, it’s where is the cortex thicker?

So where is the cortex thicker and what does it mean?

First of all, although some studies have found that females have thicker cortexes than males, the differences are not always in the same place in the brain.

This study found that females had thicker cortexes in the right inferior parietal and posterior temporal regions even without correcting for total brain volume (i.e. the males had bigger brains, but the females cortexes were thicker in these areas anyway). When they corrected for age and brain volume, females had thicker cortexes in the temporal and parietal lobes.

This study, on the other hand, found that females had thicker cortexes in the frontal, parietal, and occipital lobes.

And this study, found that females had thicker cortexes in the frontal, parietal, and occipital lobes on the left, and mostly the parietal lobe on the right. In the temporal lobe “small regions of the left and right caudal superior temporal gyrus (STG) and the left temporal pole showed significantly greater cortical thickness in women.”

Finally, this study found that females had thicker cortexes in all four lobes of the brain and on both sides, unlike the studies listed above.

This is like doing four studies comparing all the bones in men’s and women’s bodies.

One study finds that women have thicker arm and leg bones.

The next finds that they have thicker spines, ribs, and leg bones.

A third study finds thicker ribs, skulls, and elbows.

A fourth finds that women have thicker bones everywhere.

You wouldn’t be sure what this means about women’s bones. You wouldn’t even be sure if women’s arm bones were thicker than men’s without more studies.

The effects of having thicker bones would be very different if women had thicker ribs as opposed to thicker elbows. Knowing exactly where the bones were thicker would also be important if you were trying to figure out what exactly caused women to have thicker bones.

Going back to our brains, the frontal lobe is in the front, the occipital lobe is in the back.

The frontal lobe is involved in evaluating consequences and choosing the best action to take.

The occipital lobe is the visual processing center of the brain.

The parietal lobe integrates sensory information; it is also where we have our internal map of our own body.

The temporal lobe is involved in the retention of visual memories, processing sensory input, comprehending language, storing new memories, emotion, and deriving meaning.

So it matters a great deal where exactly women have thicker cortexes than men. In fact, it matters where exactly the difference in cortical thickness is within the lobes of the brain.

In short, we are still figuring out the differences between men and women when it comes to cortical thickness. What exactly are they and what do they mean? This makes it hard to draw any conclusions about whether or not trans women’s brains are like cis women’s.

To further complicate matters, this study found that age affected the sex differences in cortical thickness.

Going back to the original study, where were the trans women’s cortexes thicker than the control males?

In the left hemisphere, their cortexes were thicker in “the orbito-frontal cortex, the middle frontal gyrus, in the vicinity of the central sulcus (near midline), in perisylvian regions (close to the post central gyrus), as well as within the paracentral gyrus and orbito-frontal gyrus (medial surface).”

These are areas within the frontal lobe and the parietal lobe.

In the right hemisphere, their cortexes were thicker “along the post and pre central gyrus (expanding into middle frontal regions), the parietal cortex (near midline), the superior temporal sulcus, the inferior temporal gyrus, as well as within the orbito-frontal, fusiform, and lingual gyrus, and the precuneus (medial surface).”

These areas are within the frontal lobe, the parietal lobe, the temporal lobe, and the orbital lobe.

Although the areas where trans women have thicker cortexes are in all four lobes of the brain, it looks like the total area where they have thicker cortexes is not large (see Figure 1).

It is very hard to compare, but it does not look like the areas where trans women have thicker cortexes than men in this study are the same as the areas where females have thicker cortexes than males in other studies (Figure from the first study of males and females, above).

It doesn’t look like the areas where the trans women’s cortexes were thicker are the same as in the studies that linked increased cortical thickness to OCD, although there might be some overlap with the patients who had social anxiety disorder.**** Perhaps one of the trans women had social anxiety disorder and it affected part of the results.

On the other hand what if the areas of increased cortical thickness in trans women have to do with something specifically about trans women?

I want to stress that we do not know what the areas of increased cortical thickness mean functionally for trans women or cis women or people with OCD or people who meditate. Many areas of the brain are involved in more than one process. In addition, it may be that what we are looking for is a network of areas, not just one area.

We really can’t tell what it means that trans women have thicker cortexes where they do.

Nevertheless, I want to offer up a hypothesis that I hope someone will test.

Looking at the right side of the brain, the areas where trans women’s cortexes are thicker seem to have something to do with the body and perception.

According to my trusty Wikipedia,

“The postcentral gyrus is the location of the primary somatosensory cortex, the main sensory receptive area for the sense of touch. Like other sensory areas, there is a map of sensory space in this location, called the sensory homunculus.”

The precentral gyrus includes the primary motor cortex which works with other areas of the brain to plan and execute movements. It also includes a map of motor areas corresponding to body parts.

The parietal lobe integrates sensory information.

The superior temporal sulcus is involved in the perception of where others are gazing and the perception of biological motion. It may have multisensory processing capabilities.

The inferior temporal gyrus is associated with visual processing and possibly face perception.

The orbitofrontal gyrus is part of the orbitofrontal cortex which is involved in the cognitive processing of decision-making; it doesn’t seem to fit the pattern here.

The fusiform gyrus  is involved in face and body recognition. Furthermore, “Increased neurophysiological activity in the fusiform face area may produce hallucinations of faces.”

The lingual gyrus is linked to processing vision.

The precuneus is part of the parietal lobe. It includes three subdivisions: a sensorimotor region,  a cognitive/associative region, and a visual posterior region. It is involved in sense of self, memory, and motor imagery and coordination.

On the left side of the brain, most of the areas of relative cortical thickness do not seem to be related to the body. However, the paracentral lobule includes the supplementary motor area in the frontal lobe and part of the parietal lobe.

Could it be that the increased cortical thickness on the right side is somehow related to trans women’s negative feelings about their bodies?

Could something in their body maps or perception be causing their dysphoria?

Could their gender dysphoria have changed their brains?

This might be an area for future research.

Future research into gender identity and the brain should definitely include some gay men and lesbian controls so that we can separate out the effects of gender identity and sexual orientation.

It would also be a good idea for future studies to include more information on other conditions that might affect their results such as depression, anxiety, Aspergers syndrome, etc. Although this study says that the subjects were free of psychosis, they do not discuss issues like OCD, etc.

I don’t think the best approach would be to exclude trans people with other conditions because part of the reality of gender dysphoria is that some people have more than one condition. If we really want to understand what is happening, we need to include that data. However, it might make sense to include some controls who had social anxiety disorder, etc., if only to find where the differences are.

Back, one last time to the study.

The authors’ discussion of their results includes one odd statement:  “In addition, our current findings of significantly thicker cortices in MTF transsexuals than in control men correspond with previous in vivo outcomes revealing that MTF transsexuals show significantly larger gray matter volumes than control men.”

This is an exaggeration of the results of an earlier study that they did on gray matter volume in trans women’s brains.

This earlier study found that trans women’s brains were more like men’s brains in 18 out of 20 areas of the brain. In two areas, the left and right putamen, trans women had more gray matter than both males and females, although within the average range of the females.

Their previous findings could be better summarized as trans women have gray matter volumes that match men’s except in the putamen.

This study did not look at the putamen as it is not in the cortex. The increased gray matter volume in the putamen found in the earlier study is irrelevant to this study.

Actually, at first glance the findings of this study don’t fit well with the findings of the previous study. The cortex is made up of gray matter, so you might expect its thickness to be related to the volume of gray matter. Why do trans women have gray matter volumes that are equal to or less than cis men’s but cortexes that are thicker?

The authors go on to address this question:

Nevertheless, it appears rather surprising that the previous whole-brain approach analysing gray matter did not detect any group differences in cortical regions (e.g., the ones revealed in the current study directed at cortical thickness). It is possible, however, that these two anatomical measurements reflect slightly different aspects on a micro-anatomical level as also suggested by studies investigating direct correlations between cortical thickness and gray matter concentration. Importantly, the current approach also provides an additional dimension of cortical morphology such as its thickness in millimeters, which is not directly captured by voxel-wise analyses of signal intensity changes throughout the brain.

In other words measurements of cortical thickness and gray matter volume may not be the same thing. It is possible that trans women’s gray matter volume is like men’s but their cerebral cortex is thicker in certain areas.

It is still not clear what it means that trans women’s cerebral cortexes are thicker than control males in certain areas.

We don’t know what the difference means functionally.

We don’t know if the difference is related to gender identity, sexual orientation, or some other factor.

We don’t know how the trans women’s cortical thickness would have compared to females since there were no female controls in the study.

We can’t say that trans women’s brains are like females’ brains since both have thicker cortexes than males because a) other factors like social anxiety disorder can make people have thicker cortexes; b) we aren’t sure exactly where females’ cortexes are thicker than males; and c) it looks like trans women and females’ cortexes thicker than males in different places.

And we don’t know if the difference in cortical thickness is related to body perception and sensory integration.

Original Study:

Increased Cortical Thickness in Male-to-Female Transsexualism by Eileen Luders, Francisco J. Sánchez, Duygu Tosun, David W. Shattuck, Christian Gaser, Eric Vilain, and Arthur W. Toga in J Behav Brain Sci. Aug 2012: 2(3): 357-362.

* I am using the language of the study.

** In general, a thicker cortex is probably a good thing; it is associated with meditation and learning. In addition, your cortex thins with age. The volume of the gray matter in your brain also goes down with age or due to illnesses such as depression.

*** the right central sulcus. I thought you’d never ask. And yes, trans women had a thicker central sulcus than control males, but it was on the left side and the overall pattern is different; patients with xenomelia mostly had areas where their cortex was thinner, not thicker. Then again, it might be worth looking further at the central sulcus in trans people’s brains.

**** The study of patients with OCD found that their cortexes were thicker in the right inferior frontal cortex and the right middle temporal gyrus.

This study suggests that the areas of cortical thickness in autism change with age. I don’t see how to compare the data on autism to the data on trans women.

One study of patients with social anxiety disorder found that they had increased cortical thickness in the left inferior temporal cortex. Trans women had increased cortical thickness in the right inferior temporal gyrus – as well as many other areas not found with social anxiety disorder.

Another study of people with social anxiety disorder found that they had increased cortical thickness in two clusters: “One was located in the right middle frontal gyrus extending into superior frontal sulcus, belonging to the dorsolateral prefrontal cortex (DLPFC, Brodmann areas 6/8/9/46). The other covered right superior parietal lobule and angular gyrus and extended in part into right precuneus and inferior parietal lobule (Brodmann areas 7/39/19).”

Trans women also had increased cortical thickness in the right middle frontal region, the right parietal cortex (near the midline), and the precuneus – but they had other areas of increased thickness as well.

Perhaps one of the trans women in the study had social anxiety disorder and it explained some of the areas of increased cortical thickness, but not all.

Or perhaps both conditions involve similar areas of the brain.

Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls—A Voxel Based Morphometry Study – Review

This is a study with intriguing results. The study also has some frustrating flaws.

One of the most interesting things about the study is this:

“The regions found affected in our study are mainly involved in neural networks playing role in body perception, including memory retrieval, self-awareness, visual processing, body and face recognition and sensorimotor functions.”

In other words, gender dysphoria may be linked in some way to body perception.

The study found three types of differences in the brain:

In some areas of the brain trans people had less gray matter than cis people. This suggests that gender dysphoria might be caused in part by differences in body perception – or that gender dysphoria changes areas of the brain related to body perception.

In some areas biological males had more gray matter, in some areas biological females had more gray matter. Males generally have a larger volume of gray matter than females. Other studies have found regions where females have a larger volume of gray matter and regions where males have a larger volume, but there doesn’t seem to be an accepted map of which regions are which yet.

In some areas of the brain the trans people had gray matter volumes that were more like controls of the same sexual orientation and gender identity.

So the biggest flaw of the study is that they don’t control for sexual orientation.

Instead they specifically selected trans people who were attracted to members of their biological sex and then chose controls who shared their age and gender identity.

The authors do not discuss the sexual orientation of the control group, but 95% of the population is attracted to the opposite sex.

Thus, as in a number of other studies,* when the authors compare trans men (born female) to control females, they are comparing a group of people attracted to females to a group of people attracted to males. And when they compare the trans men to control males, they are comparing two groups of people attracted to women.

We know that sexual orientation can affect brain anatomy, so we can’t be sure if we are seeing differences due to gender identity or to sexual orientation.

Studies of gender identity need to start including some gay and lesbian cis people in their control groups.

In addition, if we keep leaving out trans people based on their sexual orientation, we are not properly studying gender dysphoria. About half of all trans women are attracted to females; we can’t just ignore them. We need to understand their brains, too.

A couple of other flaws:

1. The authors never discuss the sex differences they found. What do they mean? Do biological males and females process information about their body differently? How are these differences related to the differences between people with a female or male gender identity?

2. The authors don’t say whether or not they controlled for depression. Depression generally seems to decrease the volume of gray matter in the brain. The control subjects were screened to make sure they had no psychiatric disorders. Psychiatric data was collected on the people with gender dysphoria, but they don’t say if they excluded any trans people with psychiatric disorders like depression.**

People with gender dysphoria are more likely to be depressed than the general population. Since the results of the study involve the volume of gray matter in the brain, it would be important to control for depression – and possibly anxiety, etc.

In short – this study found an intriguing link between gender dysphoria and gray matter volume in areas of the brain that are related to body perception. They found some areas of the brain where trans people and cis people differ. They found some areas of the brain where people with gender dysphoria may be more like people who share their gender identity rather than their biological sex, BUT since they also shared the same sexual orientation, we can’t be sure. In addition, the study found a number of areas where biological sex was more important than gender identity. Finally, it is not clear if they controlled for depression and anxiety which could also have affected their results.

This is part I of my review. I will address specifics of the study in a future article or articles.

Original Article:

Regional Grey Matter Structure Differences between Transsexuals and Healthy Controls – A Voxel Based Morphometry Study by Lajos Simon, Lajos R. Kozák, Viktória Simon mail, Pál Czobor, Zsolt Unoka, Ádám Szabó, Gábor Csukly in PLOS one, December 31, 2013. 

 

*This is not the first study of gender identity and the brain to look only at trans people who were sexually attracted to their birth sex. See also, here and here. I think there are more studies that do this that I haven’t reviewed yet.

This study found that trans women’s brains were more like male controls than females; I think that the people doing these studies are trying to avoid a similar result by only looking at trans people who are attracted to their birth sex.

Except that doing this means they may be studying sexual orientation, not gender identity.

It also means that they don’t know if the brains of trans people attracted to their birth sex actually are different from the brains of trans people who aren’t attracted to their birth sex because, damn it, they aren’t looking!

** The authors say they excluded people with gender dysphoria from the study if they a) were “nonhomosexual,” b) had previously taken hormones, c) had a known chromosomal or hormonal disorder, or d) had a neurological disorder. In addition, when patients were diagnosed with gender dysphoria, they were assessed for psychiatric problems in order to “exclude the presence of other mental disorder behind the symptoms of GID.” (GID=gender identity disorder=the older name for gender dysphoria.) Depression would not rule out gender dysphoria, however. It looks like patients with both gender dysphoria and depression could have been included in this study.

Depression and Gray Matter in the Brain

Depression causes gray matter in the brain to decrease. This is important to keep in mind when looking at studies of trans people’s brains as many trans people have experienced depression.

These are just a few links to studies looking at depression’s effects on the brain. A smaller hippocampus seems to be particularly related to depression, although studies have also found a link to an overall decrease in gray matter.

The bottom line is that studies of gray matter and gender identity need to take into account past and present depression in both trans people and controls.

For anyone with depression, the bad news is that it’s not good for your brain. The good news is that you can do things for your brain – exercise, meditate, and learn.

You may be able increase the volume of your hippocampus with regular exercise. Eight weeks of mindfulness meditation increases the volume of your hippocampus and may increase the gray matter volume in other areas of your brain as well. You can increase your gray matter by learning a new skill like juggling or by reading text written backwards. Going to medical school affects your gray matter.

Back to the studies and the link between gray matter volume and depression.

State-dependent changes in hippocampal grey matter in depression. 

This study found that patients who were currently depressed had lower volumes of gray matter in the hippocampus compared to both healthy controls and people who had had depression before but were not currently depressed. After taking citalopram, the patients with current depression had more gray matter in the hippocampus.

Insular and Hippocampal Gray Matter Volume Reductions in Patients with Major Depressive Disorder.

This study found that patients with major depressive disorder had “a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation.”

The effects were stronger for people who had had more episodes of depression than people who had only had one episode.

The more episodes of depression a patient had, the less gray-matter volume they had in the right hippocampus and right amygdala.

They conclude:

“The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.”

In other words, having depression might affect the hippocampus or having a small hippocampus might make you get depressed more often.

Association of Depression Duration With Reduction of Global Cerebral Gray Matter Volume in Female Patients With Recurrent Major Depressive Disorder

This study found that the more months the patients had spent being depressed, the less total cerebral gray matter they had. More months of depression was also linked to less frontal gray matter, less temporal gray matter, and less parietal gray matter. The study only included female patients who had recurrent depression. They did not control for the anti-depressants the patients used, so it is possible that the medicines affected their gray matter.

Gray matter volume abnormalities in individuals with cognitive vulnerability to depression: A voxel-based morphometry study.

This study looked at people who don’t have depression but who might be vulnerable to it. The “cognitively vulnerable” group was chosen by their answers to two questionnaires. The first questionnaire looked at thinking styles that may contribute to depression – people may be vulnerable to depression based on how they think about causal attributions, consequences, and self-worth characteristics. The second questionnaire asked about symptoms of depression.

Cognitively vulnerable people had less gray matter volume in the left precentral gyrus and right fusiform gyrus compared to controls. In addition their right fusiform gyrus and right thalamus were smaller compared to people who had major depressive disorder. Patients with major depressive disorder had reduced gray matter volume in the left precentral gyrus and increased gray matter volume in the right thalamus.

They conclude:

“Reductions in brain gray matter volume exist widely in individuals with CVD. In addition, there exist similar abnormalities in gray matter volume in both CVD subjects and MDD patients. Reductions of gray matter volume in the left precentral gyrus might be correlated to the negative cognitive styles, as well as an increased risk for depression.”

Of course, we don’t know which way the causality goes – is the cognitive style causing a lower gray matter volume in the left precentral gyrus or is the lower volume of gray matter causing the cognitive style?

Widespread reductions in gray matter volume in depression.

This study found that people with major depressive disorder had 4.4% less global gray matter volume than controls. This would be the decrease expected in 14 years of normal aging.

The differences were greatest in the front and temporal lobes, but there were also significant differences in the parietal and occipital lobes.

There was not a significant difference in the cerebellar volumes.

The cortex was thinner in the left medial orbitofrontal cortex for the patients with depression.

The authors conclude:

“Our data demonstrate conclusively that widespread GM volume abnormalities are present in patients with depression. These alterations are substantial, corresponding to the amount of GM volume loss that, when averaged over the whole brain, would be expected from nearly 14 years of normal aging. The GM loss is also highly regionally specific, with focal regions showing decreases in GM volumes of nearly twice the magnitude of the global measure. The distributed and regionally specific nature of these alterations provides compelling support for considering MDD as a condition that involves the impairment of networks across the brain.”

Small frontal gray matter volume in first-episode depression patients.

This study found that patients who had had their first episode of depression had less gray matter volume in the frontal lobe than healthy controls. The lower volume was not correlated with length or severity of the illness. The patients had not yet taken any medication for their depression. The authors suggest that the changes in gray matter could have occurred before the symptoms of depression. (Although they also could have been caused by the depression, we really can’t tell.)

Anomalous Gray Matter Structural Networks in Major Depressive Disorder

This study found that the gray matter in people with depression is connected differently from in controls.

They say:

“Depressed participants had significantly decreased clustering in their brain networks across a range of network densities. Compared with control subjects, depressed participants had fewer hubs primarily in medial frontal and medial temporal areas, had higher degree in the left supramarginal gyrus and right gyrus rectus, and had higher betweenness in the right amygdala and left medial orbitofrontal gyrus.”

and they conclude:

“Networks of depressed individuals are characterized by a less efficient organization involving decreased regional connectivity compared with control subjects. Regional connections in the amygdala and medial prefrontal cortex may play a role in maintaining or adapting to depressive pathology.”

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.

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.