Elsevier

Brain Research

Volume 1343, 9 July 2010, Pages 37-45
Brain Research

Research Report
Sex differences in the human corpus callosum microstructure: A combined T2 myelin-water and diffusion tensor magnetic resonance imaging study

https://doi.org/10.1016/j.brainres.2010.04.064Get rights and content

Abstract

Sex differences in structure and organization of the corpus callosum (CC) have been identified in healthy adults and may be linked to distinct functional lateralization and processing in men and women. Magnetic resonance imaging (MRI) has facilitated noninvasive assessment of CC sex differences in morphology by volumetric imaging and microstructural organization by diffusion tensor imaging (DTI). Incorporation of recently developed myelin-water fraction (MWF) imaging may improve our understanding of CC sex differences. The aim of the current study was to combine DTI and diffusion tractography with MWF imaging to investigate CC sex differences in 22 healthy adults (11 male, 11 female). We performed MWF imaging using a 5-echo linear combination of spin echo images, and quantified mean diffusivity, axial diffusivity, radial diffusivity and fractional anisotropy (FA) by DTI. Fiber density index (FDi) was quantified using diffusion tractography. The MWF in males was significantly greater than females for the rostral body (p < 0.05) and posterior midbody (p < 0.005); whereas, the splenium MWF in males was significantly less than females (p < 0.05). The DTI analysis revealed significantly increased FA in males compared with females within the genu of the CC (p < 0.05). No significant sex-differences existed for mean diffusivity, axial diffusivity, radial diffusivity or FDi. Correlations between DTI parameters and MWF were significant but weak. Results of this study demonstrate regionally dependent sex differences in microstructural composition and organization of the CC and the lack of correlation between DTI and MWF suggest both measures provide unique information within the CC.

Introduction

The corpus callosum (CC) is the largest fiber tract in the human brain and plays an integral role in relaying sensory, motor and cognitive information between homologous regions in the two cerebral hemispheres (Clarke and Zaidel, 1994, Sperry, 1968). As such, the CC continues to be a major focus of basic neuroscience research. One particular area of interest is sex differences within the CC and their association with distinct processes of cognition, emotion and functional lateralization between males and females (Muetzel et al., 2008). Key aspects of sexual dimorphism in the CC were initially identified in studies of the post-mortem human brain, which observed that the maximum splenial width and surface area was greater in females than males (DeLacoste-Utamsing and Holloway, 1982). Further post-mortem studies also revealed greater fiber density in female controls compared with male controls in all CC sub-regions, except the posterior midbody and splenium (Highley et al., 1999).

With the advent of magnetic resonance imaging (MRI), it is now possible to non-invasively investigate differences in morphology and microstructural organization of the human brain. Morphological studies using high-resolution structural MRI suggest that females, compared with males, tend to have a larger relative CC (e.g., normalized by total brain volume or skull size) or larger relative posterior portion of the CC (e.g., splenium or isthmas relative to total CC) (Allen et al., 1991, Leonard et al., 2008, Luders et al., 2003, Mitchell et al., 2003). More recently, attention has turned to the noninvasive characterization of tissue microstructure and connectivity with diffusion tensor imaging (DTI), an MR technique that provides a measure of the magnitude and orientation of water self-diffusion. Typical scalar quantities obtained from DTI include the mean diffusivity (MD), a measure of the directionally invariant magnitude of diffusion, and relative or fractional anisotropy (FA), which represents the degree of anisotropy within a voxel of tissue. Previous DTI studies investigating the CC observed greater relative anisotropy in males than females (Oh et al., 2007, Westerhausen et al., 2004), and significant sex-by-age interactions for MD and FA (Schmithorst et al., 2008); whereas, in contrast, other studies have failed to observe FA sex differences in several age groups (Hasan et al., 2005, Hasan et al., 2009, Sullivan et al., 2001). More recently, researchers have investigated additional DTI metrics including axial (λ||) and radial diffusivity (λ), which quantify the magnitude of diffusion parallel and orthogonal to the principal direction of water diffusion. The limited studies that have investigated between-sex λ have failed to observe differences (Hasan et al., 2009). Delineation of fiber tracts and visualization of white matter connectivity may be also achieved using an extension of DTI, diffusion tractography, which utilizes directional information encoded with the diffusion tensor of adjacent voxels to identify white matter fiber tracts. Currently, diffusion tractography primarily yields qualitative results; however, there is great interest in generating quantitative parameters from the analysis. First proposed by Roberts et al. (2005) for evaluating glioblastoma patients, the fiber density index (FDi) provides an indirect measure of the number of fiber paths traversing a region-of-interest (ROI). Linking the DTI parameters and quantitative diffusion tractography with measures of the microstructural composition of neural fibers, such as myelin content, may improve our understanding of microstructural differences between males and females.

Until recently, knowledge of myelin content in the human brain was limited to data obtained from post-mortem studies. The introduction of novel MRI approaches now offer the ability to indirectly assess myelin content in vivo (Laule et al., 2007). One such method makes use of the characteristic T2 relaxation times for the different water compartments in tissue. Empirical evidence suggests healthy brain T2 relaxation can be separated into three components: (1) a short T2 component from water within the myelin sheath (MacKay et al., 1994), (2) an intermediate T2 component from intra- and extracellular water, and (3) a long T2 component from cerebral spinal fluid (CSF). The complete spectrum of T2 relaxation times can be obtained using a single acquisition of 32 different echo times (TEs) processed with a nonnegative least squares (NNLS) algorithm (MacKay et al., 1994). This method allows the quantification of the relative magnitude of each T2 component, but is limited by the long scan time and limited spatial coverage (usually a single slice). An alternative approach is to isolate myelin-water using linear combination filtering of several (3–32) conventional spin echo images and express it as a fraction of the total water content (Brosnan et al., 1988, Jones et al., 2004, Vidarsson et al., 2005) to generate myelin-water fraction (MWF) images. We selected the linear combination approach for this study because it offers reduced scan time and increased spatial coverage relative to the multi-echo technique.

The goal for the current study was to combine DTI and diffusion tractography with MWF imaging to investigate sex differences in the structure and composition of the CC. This enabled concurrent assessment of composition as well as microstructural organization of the CC in both male and female subjects in vivo. We compared MWF, DTI parameters and FDi within different regions of the CC of healthy male (n = 11) and female (n = 11) subjects. Callosal subdivisions investigated (Fig. 1) include, genu (CC2), rostral body (CC3), anterior midbody (CC4), posterior midbody (CC5), isthmus (CC6) and splenium (CC7). Improving our understanding of sex difference in the normal population may provide insights into pathologies that exhibit sex dependencies, such as autism (Baron-Cohen et al., 2005) and schizophrenia (Highley et al., 1999).

Section snippets

Results

A total of 20 (10 male and 10 female) subjects were included in the analysis. The median age was 24 [20–30] years for the male subjects and 23 [21–26] years for the female subjects. Data for two subjects were excluded due to excessive subject motion. Intraclass correlation coefficient (ICC) analysis of the three-independent-reader comparison demonstrated good inter-rater reliability for MWF (ICC = 0.70) and excellent inter-rater reliability for the FDi (ICC = 0.98), FA (ICC = 0.97), MD (ICC = 0.88), λ||

Discussion

With the development of MRI measures of tissue microstructure and water distribution, it is now possible to noninvasively assess neuronal organization and structure beyond simple morphology. In this study, we combined quantitative diffusion tractography and myelin-water content measurements in the CC of healthy adult subjects to investigate differences between males and females. The salient result was the regionally-dependent MWF sex differences we observed in the CC, which points to underlying

Experimental procedures

Twenty-two healthy right-handed, age-matched volunteers (11 males, 11 females, age 19–31 years) underwent both T2 myelin-water and diffusion tensor MR imaging. All imaging studies were performed on a 1.5T clinical MRI system (GE TwinSpeed Excite, Release 11.0, GE HealthCare, Milwaukee, WI) equipped with an 8-channel receive-only head coil. This study was approved by the human ethics review board of the University Health Network and written informed consent was obtained for all subjects.

Acknowledgments

We acknowledge Eugen Hlasny for additional assistance with MRI data collection. We would also like to acknowledge Dr. Greg Stanisz and Dr. Nancy J. Lobaugh for their helpful discussions.

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