Elsevier

NeuroImage

Volume 54, Issue 4, 14 February 2011, Pages 2557-2562
NeuroImage

Men and women are different: Diffusion tensor imaging reveals sexual dimorphism in the microstructure of the thalamus, corpus callosum and cingulum

https://doi.org/10.1016/j.neuroimage.2010.11.029Get rights and content

Abstract

Introduction

Numerous magnetic resonance imaging (MRI) studies have addressed the question of morphological differences of the brain of men and women, reporting conflicting results regarding brain size and the ratio of gray and white matter. In the present study, we used diffusion tensor imaging (DTI) to delineate sex differences of brain white matter.

Methods

We investigated brain microstructure in 25 male and 25 female healthy subjects using a 3 T MRI scanner. Whole-head DTI scans were analyzed without a-priori hypothesis using Tract-Based Spatial Statistics (TBSS) calculating maps of fractional anisotropy (FA), radial diffusivity (RD, a potential marker of glial alteration and changes in myelination) and axial diffusivity (AD, a potential marker of axonal changes).

Results

DTI revealed regional microstructural differences between the brains of male and female subjects. Those were prominent in the thalamus, corpus callosum and cingulum. Men showed significantly (p < 0.0001) higher values of fractional anisotropy and lower radial diffusivity in these areas, suggesting that the observed differences are mainly due to differences in myelination.

Discussion

As a novel finding we showed widespread differences in thalamic microstructure that have not been described previously. Additionally, the present study confirmed earlier DTI studies focusing on sexual dimorphism in the corpus callosum and cingulum. All changes appear to be based on differences in myelination. The sex differences in thalamic microstructure call for further studies on the underlying cause and the behavioral correlates of this sexual dimorphism.

Future DTI group studies may carefully control for gender to avoid confounding.

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.

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