A number of studies have investigated alternations in spatial abilities, emotions and resting-state brain activities¹ during the female menstrual cycle, and the menstrual cycle was found to influence the lateralization in many tasks ^2,3. In this study, we used a voxel-mirrored homotopic connectivity (VMHC) ⁴ method to investigate the correlation of every pair of symmetrical interhemispheric voxels in the whole brain, and we hypothesized that the VMHC would be modulated by menstrual cycle phases in the healthy females.

Sixteen healthy, right-handed women (age 24.1±3.3 yrs) were enrolled in the study with written informed consent. All participants had natural menstrual cycle (cycle 29 -32 days) without using hormonal contraceptives. The participants were asked to record the date of their menstrual onset the month prior to the experiment, and reported regular menstrual cycles. On a Siemens 3T Trio Tim MRI system, the participants were scanned twice, once: during the early follicular phase (low level of estrogen and progesterone in the 0th - 3rd day of the menstrual cycle), and also during their mid-luteal phase (high level of estrogen and progesterone in the 20th - 24th day of the menstrual cycle). Participants were counterbalanced with controls to remove effects caused by unfamiliarity with the scanning environment. Two Both scans were resting state fMRI scans were performed on allin which participants (with kept eyes closed, while and remaining remained awake during a total acquisition time of 12 min. A gradient-echo EPI sequence covering the whole brain was used with the following parameters: including: TR/TE/FA = 2900ms/30 ms/90°, matrix = 64×64, FOV = 192 mm×192 mm2, bandwidth = 2232 Hz/Px, 48 axial slices, thickness/gap = 2.5/0.5 mm. To correct for geometric distortion, a field map was obtained using a gradient echo sequence after the resting-state fMRI scans. Finally, a 3D MP-RAGE sequence was used to acquire T1-weighted images to be used as anfor anatomic reference (voxel size = 1 mm³ isotropically). The images were processed using SPM12 with conventional steps including discarding the first 8 volumes, slice timing correction, geometric distortion correction using field maps, and image realignment, segmentation, smoothing with an 8 mm kernel, and bandwidth filter of 0.01-0.08 Hz. Except that we normalized the functional images to an ICBM symmetric template in the MNI space. The VMHC maps (Fisher z-transformed Pearson correlations) of the bilateral homotopic voxels were calculated using REST toolbox (http://restfmri.net/forum/), which were used for the group analysis of paired-t test between the early follicular and mid-luteal phases. The unilateral hemispheric gray-matter mask was used in the AlphasSim correction (http://rfmri.org/dpabi). And then we investigated whether the resulting significant clusters had altered functional connectivity in different menstrual phases. The significant clusters in the left and right hemispheres were extracted separately as ROIs to get the functional connectivity, and we compared the differences of functional connectivity between the different menstrural cycle phases. The paired-t test results were thresholded at p<0.05, AlphaSim corrected.

We observed that the early follicular phase showed significantly higher (p<0.05, AlphaSim corrected with a signal voxel p <0.05 and cluster size = 3872 mm³) VMHC than the mid-luteal phase in the cerebellum, brainstem, limbic system and parahippocampa gyrus. And then the significant clusters were selected as the left and right ROIs separately. The left and right ROIs showed significantly higher functional connectivity in the early follicular phase than in the mid-luteal phase (AlphaSim corrected p<0.05, with a signal voxel p <0.05, cluster size = 15232 mm³ for the left ROI and 19280 mm3 for the right ROI). The functional connectivity of the left ROI was significantly higher in the precuneus and medial parietal cortex, while those of the right ROI included not only the precuneus, but also the medial prefronal cortex, and bilateral middle temporal cortex.Many previous studies have reported the menstrual cycle of women would influence the lateralizations of language and spatial cognitions, presumably due to the fluctuations of steroid hormones during the menstrual cycle³. And only a few works have been investigating the role of crebellum or brainstem in the premenstrual dysphoric disorder⁵. Our results provided evidence that the modulation of the lateralization of the menstrual cycle may lie in the very ‘basic’ regions of the brain such as the brainstem and cerebellum, as well as the regions of precuneus and medial prefrontal cortex, which were similar to the ‘hubs’ of the default mode network.Our results showed that the interhemispheric functional connectivity was modulated by the menstrual cycle, which may shed light on investigating the mechanism of the varied functional cerebral lateralizations across menstrual cycle.