Estradiol modulates functional brain organization during the menstrual cycle: an analysis of interhemispheric inhibition

Abstract

According to the hypothesis of progesterone-mediated interhemispheric decoupling (Hausmann and Güntürkün, 2000), functional cerebral asymmetries (FCAs), which are stable in men and change during the menstrual cycle in women, are generated by interhemispheric inhibition of the dominant on the nondominant hemisphere. The change of lateralization during the menstrual cycle in women might indicate that sex hormones play an important role in modulating FCAs. We used functional magnetic resonance imaging to examine the role of estradiol in determining cyclic changes of interhemispheric inhibition. Women performed a word-matching task, while they were scanned twice during the cycle, once during the menstrual and once during the follicular phase. By use of a connectivity analysis we found that the inhibitory influence of left-hemispheric language areas on homotopic areas of the right hemisphere is strongest during the menses, resulting in a pronounced lateralization. During the follicular phase, due to rising estradiol levels, inhibition and thus functional cerebral asymmetries are reduced. These results reveal a powerful neuromodulatory action of estradiol on the dynamics of functional brain organization in the female brain. They may further contribute to the ongoing discussion of sex differences in brain function in that they help explain the dynamic part of functional brain organization in which the female differs from the male brain.

Figure 1.

Functional activations of the normally cycling women and the male group. A, Female subjects: regions activated for word-matching compared with baseline during the menstrual phase (p < 0.01, corrected for multiple comparisons). B, Female subjects: regions activated for word-matching compared with baseline during the follicular phase (p < 0.01, corrected for multiple comparisons). C, Male subjects: regions activated for word-matching compared with baseline during experimental session 1 (p < 0.01, corrected for multiple comparisons). D, Male subjects: regions activated for word-matching compared with baseline during experimental session 2 (p < 0.01, corrected for multiple comparisons).

Figure 2.

Functional imaging and connectivity analysis. The most significant activation during word-matching compared with rest across cycle phases in the female group was located in left IFG (A). A seed region was defined in each female subject as a sphere around the individual local maximum located closest to the maximum of the group activation. Then a PPI analysis was used to identify those brain regions on which the seed region exerts a significantly stronger inhibitory influence for word-matching during the menstrual compared with the follicular phase. The only such region was located in right IFG (B). The activation maps (conjunction analysis at p < 0.01, corrected for multiple comparisons in A, PPI analysis at p < 0.01, corrected for multiple comparisons in B) are shown overlaid onto a canonical brain rendered in three dimensions. The anatomical location of the most significant activation in left IFG (shown in red) and the area in right IFG which is inhibited more significantly during the follicular phase (shown in yellow) is shown overlaid onto the mean high-resolution T1 scan of the female group at the maximum of the left IFG activation (C) and the maximum of the inhibited area (D).

Figure 3.

Sex interaction analysis. The interaction effect of the PPI analysis between repeated tests and sexes at p < 0.01, uncorrected, at a minimal cluster size of 10 voxels is shown overlaid onto the mean high-resolution T1 scan of the male and female group at the maximum of the right IFG activation. Parameter estimates of in the maximum of the cluster are depicted. Parameter estimates are given in arbitrary units (a.u.).

Figure 4.

Correlation of estradiol and strength of interhemispheric inhibition. The correlation of estradiol level and strength of interhemispheric inhibition in right IFG is significant both during the menstrual (r = −0.546, p < 0.05, shown in A) and the follicular (r = −0.614, p < 0.02, shown in B) phase. As a measure for the strength of interhemispheric inhibition we used the size of the parameter estimates, which were extracted from the right inferior frontal cluster identified in the PPI analysis. Parameter estimates are given in arbitrary units (a.u.).