Men and women are different: Diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum☆
Research Highlights
► DTI reveals widespread sex differences in thalamic microstructure. ► DTI confirms microstructural sex differences of the corpus callosum and cingulum. ► All changes can be attributed to differences in myelination. ► Future DTI group studies need to carefully control for gender to avoid confounding.
Introduction
Neuropathological and MRI studies have shown that brains of men and women significantly differ in absolute brain size (Allen et al., 2003, Ankney, 1992, Cosgrove et al., 2007, Shin et al., 2005), in total gray and white matter volumes (Allen et al., 2003, Gur et al., 1999, Paus et al., 1996) and in the gray/white matter ratio, with women having a higher percentage of gray matter and men of white matter (Allen et al., 2003, Goldstein et al., 2001, Gur et al., 1999).
Diffusion tensor imaging (DTI) is a MRI technique that is used to characterize the microstructure of large white matter tracts in physiological and pathological conditions which has successfully been used to evaluate brain alterations in a range of neurological disorders (Abe et al., 2002, Knake et al., 2010, Unger et al., 2010). The method is based on the measurement of molecular diffusion and its directionality which is influenced by the structure of the surrounding brain tissue. Fractional anisotropy (FA) is an unspecific indicator of alterations in white matter microstructure. It reflects the anisotropy or directionality of the diffusion (Peled et al., 1998), which can be further characterized using the measures axial diffusivity (AD) and radial diffusivity (RD). Axial diffusivity measures the diffusivity along the primary diffusion direction and is assumed to contribute information regarding the integrity of axons (Glenn et al., 2003) or changes in extra-axonal/extracellular space (Beaulieu and Allen, 1994). In contrast, RD represents the diffusivities along directions that are orthogonal to the primary diffusion direction and is assumed to characterize changes associated with myelination or glial cell morphology (Song et al., 2002, Song et al., 2003, Song et al., 2005).
The influence of age on DTI measures is well described: A reduction of FA with increasing age was observed (Salat et al., 2005) and studies investigating DTI changes across groups need to carefully account for the influence of age. However, little is known about the effect of sex on DTI measures. Existing studies describe sex differences in predefined, selected Regions of Interest (ROI) like the corpus callosum (Oh et al., 2007, Shin et al., 2005, Westerhausen et al., 2003, Westerhausen et al., 2004), the frontal white matter (Szeszko et al., 2003) or the midcingulum bundle (Huster et al., 2009).
The aim of the present study was to investigate microstructural white matter differences in the brain of male and female subjects using an unbiased hypothesis free automated whole-head analysis approach without a priori selection of regions of interest in order to evaluate the need to account for sex as a stratification factor in future DTI studies.
Section snippets
Subject selection
Fifty right-handed healthy subjects, 25 males (mean age 31.8 ± 8.6 years) and 25 females (mean age 31.1 ± 10.6 years) were included in the study. Two additional subjects, one female and one male, were excluded due to artefacts. Exclusion criteria comprised the diagnosis or history of any neurological disease, abnormalities on neurological examination or structural abnormalities on brain MRI as well as a history of any birth complications including preterm birth or hypoxia. None of the subjects showed
Fractional anisotropy
Using whole-head DTI and an analysis without a-priori hypothesis we discovered regional microstructural white matter sex differences in the thalamus: men showing significantly higher FA values in this region (p < 0.0001). Additionally, FA was increased in male as compared to female subjects in parts of the corpus callosum and cingulum as well as in the capsula extrema and midbrain (p < 0.0001). Results are presented in Table 1, Table 2 and Fig. 1A–C.
Radial and axial diffusivity
Radial diffusivity, the potential marker of
Discussion
Using a hypothesis-free whole-brain analysis (TBSS) to evaluate differences in white matter microstructure, we found increases in FA and decreases in RD in several white matter regions in men as compared to women including the thalamus bilaterally that have not been described or investigated previously. We further found differences in FA and RD in the corpus callosum and cingulum, confirming results of earlier studies (Westerhausen et al., 2003, Westerhausen et al., 2004). These results suggest
Conclusion
Using DTI and TBSS we found extensive microstructural sex differences in the thalamus bilaterally as well as in the cingulum and in the corpus callosum. The changes are mainly due to changes in radial diffusivity, suggesting differences in the myelination or in glial cell morphology. These results fortify the need to account for sex while selecting control groups for DTI studies. The sex differences in microstructure of the described areas provide a sound basis for further studies on behavioral
Acknowledgment
We thank Dr. Thomas Benner, AA Martinos Center, Massachusetts General Hospital, Boston for technical support and for providing the DTI sequence.
References (54)
- et al.
Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis
Neurobiol. Aging
(2002) - et al.
Sexual dimorphism and asymmetries in the gray–white composition of the human cerebrum
Neuroimage
(2003) - et al.
Evolving knowledge of sex differences in brain structure, function, and chemistry
Biol. Psychiatry
(2007) - et al.
Changes in glucose metabolism due to aging and gender-related differences in the healthy human brain
Psychiatry Res.
(2008) - et al.
Sex influences on material-sensitive functional lateralization in working and episodic memory: men and women are not all that different
Neuroimage
(2006) Roles of steroid hormones and their receptors in structural organization in the nervous system
Neurosci. Res.
(1995)- et al.
Anatomical distribution of estrogen target neurons in turtle brain
Brain Res.
(1981) - et al.
Epidemiology and classification of epilepsy: gender comparisons
Int. Rev. Neurobiol.
(2008) - et al.
Tractography-guided statistics (TGIS) in diffusion tensor imaging for the detection of gender difference of fiber integrity in the midsagittal and parasagittal corpora callosa
Neuroimage
(2007) - et al.
Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans
Pain
(1998)
Magnetic resonance imaging shows orientation and asymmetry of white matter fiber tracts
Brain Res.
Unsolved problems in comparing brain sizes in Homo sapiens
Brain Cogn.
Parallel interhemispheric processing in aging and alcoholism: relation to corpus callosum size
Neuropsychologia
Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water
Neuroimage
Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia
Neuroimage
Demyelination increases radial diffusivity in corpus callosum of mouse brain
Neuroimage
The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness
Brain Res. Brain Res. Rev.
Cortical language lateralization in right handed normal subjects using functional magnetic resonance imaging
J. Neurol. Sci.
The influence of handedness and gender on the microstructure of the human corpus callosum: a diffusion-tensor magnetic resonance imaging study
Neurosci. Lett.
Effects of handedness and gender on macro- and microstructure of the corpus callosum and its subregions: a combined high-resolution and diffusion-tensor MRI study
Brain Res. Cogn. Brain Res.
Regional sex differences in grey matter volume are associated with sex hormones in the young adult human brain
Neuroimage
Sex differences in relative brain size: the mismeasure of woman, too?
Intelligence
Diffusion-tensor MRI: theory, experimental design and data analysis—a technical review
NMR Biomed.
Determinants of anisotropic water diffusion in nerves
Magn. Reson. Med.
Sexual dimorphism in the vertebrate nervous system
J. Neurosci.
Toward accurate diagnosis of white matter pathology using diffusion tensor imaging
Magn. Reson. Med.
Forebrain mechanisms of nociception and pain: analysis through imaging
Proc. Natl Acad. Sci. USA
Cited by (151)
Sex/gender differences in cognitive abilities
2023, Neuroscience and Biobehavioral ReviewsDiffusion tensor imaging of superficial prefrontal white matter in healthy aging
2023, Brain ResearchBlood pressure changes impact corticospinal integrity and downstream gait and balance control
2022, Neurobiology of Aging
- ☆
Disclosure: The authors report no financial interest or conflicts of interest related to the manuscript.
- 1
Equal contribution.