Testosterone affects language areas of the adult human brain

Andreas Hahn, Georg S Kranz, Ronald Sladky, Ulrike Kaufmann, Sebastian Ganger, Allan Hummer, Rene Seiger, Marie Spies, Thomas Vanicek, Dietmar Winkler, Siegfried Kasper, Christian Windischberger, Dick F Swaab, Rupert Lanzenberger, Andreas Hahn, Georg S Kranz, Ronald Sladky, Ulrike Kaufmann, Sebastian Ganger, Allan Hummer, Rene Seiger, Marie Spies, Thomas Vanicek, Dietmar Winkler, Siegfried Kasper, Christian Windischberger, Dick F Swaab, Rupert Lanzenberger

Abstract

Although the sex steroid hormone testosterone is integrally involved in the development of language processing, ethical considerations mostly limit investigations to single hormone administrations. To circumvent this issue we assessed the influence of continuous high-dose hormone application in adult female-to-male transsexuals. Subjects underwent magnetic resonance imaging before and after 4 weeks of testosterone treatment, with each scan including structural, diffusion weighted and functional imaging. Voxel-based morphometry analysis showed decreased gray matter volume with increasing levels of bioavailable testosterone exclusively in Broca's and Wernicke's areas. Particularly, this may link known sex differences in language performance to the influence of testosterone on relevant brain regions. Using probabilistic tractography, we further observed that longitudinal changes in testosterone negatively predicted changes in mean diffusivity of the corresponding structural connection passing through the extreme capsule. Considering a related increase in myelin staining in rodents, this potentially reflects a strengthening of the fiber tract particularly involved in language comprehension. Finally, functional images at resting-state were evaluated, showing increased functional connectivity between the two brain regions with increasing testosterone levels. These findings suggest testosterone-dependent neuroplastic adaptations in adulthood within language-specific brain regions and connections. Importantly, deteriorations in gray matter volume seem to be compensated by enhancement of corresponding structural and functional connectivity. Hum Brain Mapp 37:1738-1748, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: functional connectivity; language; neuroplasticity; probabilistic tractography; testosterone; voxel-based morphometry.

© 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Figures

Figure 1
Figure 1
Associations between bioavailable testosterone and GMV. Voxel‐wise linear regression analysis was conducted between changes in bioavailable testosterone and changes in GMV between MRI scan 1 and scan 2. Results are superimposed on a 3D surface of the brain (a) and on axial slices at z = 20 mm (b) and z = 4 mm (c), P < 0.05 FWE‐corrected for multiple comparisons at cluster level. Significant negative associations were observed in the left inferior frontal gyrus (b, peak voxel t = −7.55, x/y/z = −54/23/15 mm, mean cluster t = −4.63, cluster size = 1985 mm3) and the left middle superior temporal gyrus (c, peak t = −7.08, x/y/z = −60/‐21/1 mm, mean cluster t = −4.60, cluster size = 2396 mm3). The scatterplot exemplarily represents the association at the peak voxel in the left middle superior temporal gyrus (d). r: Pearson's correlation coefficient. ***P < 0.001 uncorrected. Axial slices are in radiological convention (left is right). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
Figure 2
Figure 2
Associations between bioavailable testosterone and white matter diffusivity. Individual tract reconstruction was carried out using probabilistic tractography for the white matter fiber pathway of the extreme capsule. Average tract probabilities across all subjects are superimposed on a 3D surface of the brain (a) and on axial slices at z=‐7/‐2/3 mm (b). The scatterplot represents the association of changes in bioavailable testosterone and changes in mean diffusivity between MRI scan 1 and scan 2 (c). Since one individual was a clear outlier, Spearman's rho was calculated for all subjects, whereas Pearson's r and the regression line were computed without the outlier (denoted in brackets). **P < 0.01, ***P < 0.001. Axial slices are in radiological convention (left is right). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
Figure 3
Figure 3
Association between bioavailable testosterone and functional connectivity. Resting‐state functional MRI was used to compute functional connectivity between left inferior frontal gyrus and left superior temporal gyrus (i.e., clusters identified in the VBM analysis, figure 1). Cluster centers are schematically superimposed on a 3D surface of the brain (a). The scatterplot represents the association of changes in bioavailable testosterone and changes in functional connectivity between MRI scan 1 and scan 2 (b). Since one individual was an outlier Spearman's rho was computed and the regression line plotted without this subject. *P < 0.05. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

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