1. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria
2. Department of Obstetrics and Gynecology, Medical University of Vienna, Austria
3. MR Centre of Excellence, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria

Background: Diffusion tensor imaging (DTI) provides an excellent method for the assessment of white matter microstructural organization in the human brain by measuring the diffusion of water molecules in the three-dimensional space [1]. A frequently used parameter is fractional anisotropy (FA) which indicates the degree of diffusion anisotropy. Large studies investigating sex differences in WM microstructure demonstrated FA differences between sexes with lower FA values in multiple regions in women compared to men [2]. Although specific biological underpinnings of these differences remain to be determined, sex-steroid hormones, such as estradiol, may play a crucial role. To test this hypothesis, changes in hormone levels over time were investigated in a healthy female population with normal menstrual cycle and correlated with FA value changes.

Methods: Thirteen healthy female controls (FC) (mean age ± SD: 25.0 ± 6.2) were included and measured at two time points with an interval of 4 months. Participants underwent MRI scans on a 3T TIM Trio Scanner (Siemens Medical, Germany). DTI acquisition was performed with an isotropic resolution of 1.6 mm³ acquiring diffusion-weighted images in 30 directions with a b value of 800 s/mm². Calculation of fractional anisotropy (FA) maps was done in FSL (www.fmrib.ox.ac.uk/fsl/) after eddy current correction. Correlational analysis between changes of FA values and estradiol levels between the two time points was performed with tract-based spatial statistics to evaluate specific influences on DTI metrics.

Results: We observed a negative correlation between changes in estradiol levels and FA values in several white matter tracts. Increases in estradiol were associated with decreases in FA values and vice versa. Significant clusters were found in splenium of corpus callosum, left anterior, posterior and retrolenticular part of internal capsule, left superior and posterior corona radiata, left external capsule, left fornix / stria terminalis, left superior longitudinal fasciculus, left precentral and superior parietal blades. All reported correlations were p < 0.05 FWE-corrected.

Discussion: Our results indicate that fluctuating hormonal levels in a population of healthy female controls affect white matter micro-structure metrics. More specifically, a negative correlation between estradiol and FA values has been observed in several white matter tracts. As FA values are thought to reflect the constitution of axon caliber, myelination and fiber organization in white matter pathways [3, 4] our results suggest that even fluctuating levels of estradiol in the adult human brain affect those biological domains. Our results are in line with recent animal research showing that hormones contribute essentially to the regulation of axon biology [5].

Acknowledgements: This research was supported by a grant of the Austrian Science Fund FWF (P23021) to R. L.

References:

1. Le Bihan D, Mangin JF, Poupon C, Clark CA, Pappata S, Molko N, Chabriat H: Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging, 2001; 13(4):​534–546.
2. Inano S, Takao H, Hayashi N, Abe O, Ohtomo K: Effects of age and gender on white matter integrity. AJNR Am J Neuroradiol, 2011; 32(11):​2103–2109.
3. Beaulieu C: The basis of anisotropic water diffusion in the nervous system – a technical review. NMR Biomed, 2002; 15(7-8):​435–455.
4. Alexander AL, Lee JE, Lazar M, Field AS: Diffusion tensor imaging of the brain. Neurotherapeutics, 2007; 4(3):​316–329.
5. Pesaresi M, Soon-Shiong R, French L, Kaplan DR, Miller FD, Paus T: Axon diameter and axonal transport: in vivo and in vitro effects of androgens. Neuroimage, 2015; 115:​191–202.