GENDER IDENTITY DISORDER (GID) is a condition characterized by a disagreement between sex at birth and subjective gender identification.1 Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). In recent years a possible biological basis of GID has become a topic of examination. Various studies regarding endocrine disorders such as congenital adrenal hyperplasia (CAH), in which there is an exposure to high levels of androgens in the prenatal and early postnatal period, have supported the importance of sex hormone environment in gender identity. In these studies, female CAH patients were examined and were found to be more likely to prefer cross-gender behavior and be less comfortable with their sense of ‘femininity’.2–4 Another study considered sex steroid-related genes focusing on MTF subjects.5 MTF subjects had a long allele of the estrogen receptor gene compared to the male controls, and the possibility of an increase in the risk of GID by certain combinations of sex-related genes was suggested. Sex hormone environment and genetic factors may affect nervous system development and may be related to the onset of GID. It is important to note, however, that despite a range of research on GID, to a great extent, a biological basis for the disease has yet to be determined. It is desirable that the basis of GID be evaluated from a multilateral perspective. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders.6,7 GID also should be evaluated from this perspective.
Aims: Despite a range of research on gender identity disorder (GID), at present there is no scientific consensus on whether the etiology of GID is mental or physical. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders. GID also should be evaluated from this perspective. The aim of the present study was therefore to do the first trial to examine the regional cerebral blood flow (rCBF) in GID.
Methods: Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). We compared 11 FTM subjects and nine age- and handedness-matched female control subjects. None of the subjects was regularly taking medication and none had any kind of physical or psychiatric comorbidity. To evaluate rCBF in GID subjects and control subjects, statistical parametric mapping analysis of 99mTc-ethyl-cysteinate dimer single-photon emission computed tomography was used.
Results: GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects.
Conclusions: The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.
For the GID group, 11 FTM subjects were recruited from the GID clinic of Fukuoka University Hospital and for the control group, nine age- and handedness-matched female volunteers were recruited from hospital staff (Table 1).The mean age of the GID group (±SD) was 23.4 ± 4.2 years and the mean age of the control group was 23.6 ± 1.8 years. GID subjects met the DSM-IV criteria for GID,1 and sexual dysphoria in all GID subjects was discovered in the pre-elementary school years. The direction of sexual attraction of all of the present GID subjects was towards the biological female. Control subjects did not meet the DSM-IV criteria for GID and expressed no experience of gender dysphoria at any time in their lives. The direction of sexual attraction of control subjects was towards the biological male. None of the GID or control subjects was regularly taking medication, including psychotropic drugs, and none had any kind of physical or psychiatric comorbidity. Zung Self-Rating Depression Scale (SDS) and State-Trait Anxiety Inventory (STAI) were used to compare the mental stability of the two groups. The mean total score (±SD) of SDS for the GID group was 39.2 ± 7.7 and that of STAI was 90.2 ± 18.2. For the control group, the mean total SDS score was 37.8 ± 6.9 and that of STAI was 89.2 ± 22.8. There was no significant difference between the GID group and the control group in the total score of SDS or STAI. These evaluations were all performed by a psychiatrist with special knowledge and experience in the diagnosis and treatment of GID. Furthermore, magnetic resonance imaging (MRI) of the brain on all subjects was examined by a radiologist, and no mass lesions, cerebrovascular problems or any structural abnormalities were found. All subjects were required to provide written informed consent for all study-related procedures. The study protocol was approved by the Independent Ethics Committee/Institution Review Board of Fukuoka University Hospital and was carried out from September 2006 to December 2007.
|Sex at birth||Female||Female|
|Onset of gender dysphoria||All in pre-elementary school||None|
|Handedness||All right-handed||All right-handed|
|Age (years) (mean ± SD)||23.4 ± 4.2||23.6 ± 1.8|
|SDS Total score (mean ± SD)||39.2 ± 7.7||37.8 ± 6.9|
|STAI Total score (mean ± SD)||90.2 ± 18.2||89.2 ± 22.8|
Single-photon emission computed tomography (SPECT) was performed for GID subjects and control subjects between 14.00 and 16.00 hours. Subjects rested horizontally on the imaging bed with eyes masked and environmental noise kept to a minimum. An i.v. line was established in the right arm of all subjects, and each subject received 600 MBq of 99mTc-ethyl-cysteinate dimer (99mTc-ECD). Five minutes later, brain images were obtained using a triple-detector gamma camera (Prism Irix; Shimadzu, Tokyo, Japan) equipped with low-energy and high-resolution parallel collimators. Transaxial images were obtained using the filtered back-projection method with a Butterworth filter (order 8, cut-off frequency 0.22 cycle/pixel), and attenuation correction was performed with Chang's method. An attenuation correction coefficient of 0.15 was used. Images were obtained on a 128 × 128 matrix. Total acquisition time for each subject was 16 min.
Spatial reprocessing and statistical analysis of images was performed on a voxel-by-voxel basis using statistical parametric mapping 2 (SPM2, Welcome Department of Imaging Neuroscience, London, UK) running on MATLAB (Mathworks, Natick, MA, USA). All of the SPECT images for each subject were normalized to a standard brain of the Montreal Neurological Institute and the spatial normalization was performed with 12-parameter affine and non-linear transformations.8,9 The voxel sizes of the re-slice option were 2 mm, 2 mm, 2 mm. The non-linear parameter was set at a 25-mm cut-off basis functions and 16-iterations. All of the normalized SPECT images were then smoothed with an isotropic Gaussian kernel filter (12-mm full-width at half-maximum). To examine the images for specific regions showing differences in perfusion, two sample t-tests were performed. Global normalization was performed by proportional scaling with the mean voxel value. Masking was applied with the threshold method (0.8-fold the global value). The statistical threshold was set at P < 0.005, extent 300, uncorrected for multiple comparisons.
The GID group had a significant decrease in regional cerebral blood flow (rCBF) in the left anterior cingulate cortex (ACC) and a significant increase in rCBF in the right insula compared to the control group (Fig. 1; Table 2).
|Direction of difference||No. voxels||Peak Z scores||Coordinates (MNI)||Brain regions|
|Decreased uptake in GID||1462||4.25||−28||16||56||Left anterior cingulate gyrus extending to left superior frontal gyrus and left medial frontal gyrus.|
|Increased uptake in GID||334||3.37||46||14||−14||Right insula extending to right superior lateral gyrus.|
In the present study we detected a differential rCBF in the left ACC and right insula in GID subjects compared to control subjects. It is these regions that have been noted as being related to human sexual behavior and consciousness, and we will consider them in this discussion of GID.
There are several regions of the brain that are related to human sexual behavior and they are the prefrontal cortex, limbic cortex, amygdala, hypothalamus and also the ACC and insula.10,11 For example, recent neuroimaging studies have shown that the ACC and insula are activated during sexual arousal.12,13 It is known that dysfunction in these neuron networks related to sexual behavior causes various sexual behavior abnormalities.14,15 Ablations of the pre-optic area of the anterior hypothalamus in ferrets cause ferrets to display opposite sexual typical behavior such as responding to same-sex ferret odors and not to conspecific odors.16–18 Some human case reports of limbic system injury also showed altered sexual attraction from heterosexual to homosexual.14,15,19 In other studies, ablations of the cingulate cortex in female rats resulted in marked deficits in the female gender role, including nest building, nursing, and retrieval of the young.20,21 These findings suggest that dysfunction of neuron networks related to sexual behavior can cause change of sexual attraction and change of gender role. This in turn suggests that alterations in rCBF in the ACC and insula could affect neuron networks related to sexual behavior, and correlate with changes of sexual attraction and inappropriateness in gender roles in GID.
In other areas of study, there is a suggestion that the ACC and right (non-dominant) insula are the neural basis of consciousness.22,23 It is well known that the ACC and right insula are associated with various neural functions such as those related to autonomic nervous systems, somatic perceptions and subjective emotions.23,24 For example, the ACC and insula are activated when subjects themselves receive pain, and also when they perceive a loved one to be in pain.25 Because of these specific functions dealing with various somatic perceptions connected with subjective emotions, the ACC and right insula are regarded as integral for the generation of the mental image of one's physical state, which underlies the basis of our perceptions of ourselves, and therefore of consciousness and identity.22,23 Moreover, a unique cytological feature has been described in the ACC and insula of humans and higher sub-human primates that is not present in lower animals.26 This may be evidence that the ACC and insula contribute to highly-developed mind work, producing a basis of consciousness and identity that is not present in lower animals. Consciousness and identity in GID may be affected by rCBF changes in the ACC and insula.
The present study had several limitations. First, we do not know whether alterations in rCBF in GID are primary to the onset of GID or whether they are secondary to GID, but there is interesting neuropathological research about GID. Zhou et al. conducted research about the central subdivision of the bed nucleus of the stria terminalis (BST) in GID, which is regarded as an essential component in human sexual behavior and is known to be different in volume and neuron number between the sexes.27,28 They found that the volume and neuron number of BST in MTF subjects were within the female range and not the male range, and also that BST in FTM were within the male range. Because of the very small size of BST, we cannot evaluate rCBF in BST due to a limitation in SPM imaging analysis capability but the ACC and insula are cortical regions that have a direct or indirect neural connection to BST.29,30 Alterations in rCBF in GID may have a neuropathological background represented in BST.
Second, the present subjects were exclusively FTM subjects. It is impossible to conclude that the results of the present study represent the entirely of GID. If the neuropathological background in GID is common to FTM and MTF, rCBF changes in the left ACC and the right insula may be also expected in MTF subjects. Thus further study of MTF subjects is needed.
Third, we could not discuss a decrease of rCBF in the left ACC and an increase of rCBF in the right insula separately. The ACC and insula have a strong connection and work together in various ways due to various stimuli,23,24 but we could not separate the role of these two regions related to GID. In future studies, the correlations of rCBF alteration and symptoms in GID (e.g. strength of sexual dysphoria and the direction of sexual attraction) should be examined. It will therefore be important to discuss the role of the two regions in more detail and separately.
In summary, with regard to rCBF, we can suggest a potential biological basis of GID. There is a possibility that rCBF changes in the ACC and insula, as detected in the present study, affect neuron networks related to human sexual behavior together with consciousness, and finally contribute to a biological basis of GID. The present study involved only early onset typical GID subjects and we think that such subjects are suitable for a discussion of a biological basis of GID. The well-matched background (age, handedness, medication, comorbidity, mental stability) of the comparison groups increased the reliability of the present study but these preliminary findings should be replicated in larger number studies. Further neuroimaging studies in GID are needed.
We thank T. Soma, Department of Medical Physics and Engineering, Division of Medical Technology and Science, Osaka University, Japan for assistance with conducting SPM analysis.