Sex differences of signal complexity at resting-state functional magnetic resonance imaging and their associations with the estrogen-signaling pathway in the brain

Abstract

Sex differences in the brain have been widely reported and may hold the key to elucidating sex differences in many medical conditions and drug response. However, the molecular correlates of these sex differences in structural and functional brain measures in the human brain remain unclear. Herein, we used sample entropy (SampEn) to quantify the signal complexity of resting-state functional magnetic resonance imaging (rsfMRI) in a large neuroimaging cohort (N = 1,642). The frontoparietal control network and the cingulo-opercular network had high signal complexity while the cerebellar and sensory motor networks had low signal complexity in both men and women. Compared with those in male brains, we found greater signal complexity in all functional brain networks in female brains with the default mode network exhibiting the largest sex difference. Using the gene expression data in brain tissues, we identified genes that were significantly associated with sex differences in brain signal complexity. The significant genes were enriched in the gene sets that were differentially expressed between the brain cortex and other tissues, the estrogen-signaling pathway, and the biological function of neural plasticity. In particular, the G-protein-coupled estrogen receptor 1 gene in the estrogen-signaling pathway was expressed more in brain regions with greater sex differences in SampEn. In conclusion, greater complexity in female brains may reflect the interactions between sex hormone fluctuations and neuromodulation of estrogen in women.

Supplementary information: The online version contains supplementary material available at 10.1007/s11571-023-09954-y.

Keywords: Default mode network; Estrogen-signaling pathway; Resting-state functional magnetic resonance imaging; Sample entropy; Sex differences.

Fig. 1

SampEn analysis of rsfMRI signal for each ROI. This example uses the Dosenbach template without the global-signal regression. The ROI 65 is the left ventral frontal cortex, which had the highest SampEn. The ROI 160 is the right inferior cerebellum, which exhibited the lowest SampEn. Abbreviations: SampEn Sample entropy, rsfMRI resting-state functional magnetic resonance imaging, ROI Region of interest

Fig. 2

Sex characteristics and differences of SampEn. A The top row shows the SampEn pattern of the female brain and the difference between different networks. B The middle row represents the SampEn pattern of the male brain and the difference between different networks. C The bottom row shows the sex difference pattern of SampEn. The color bars at the top and middle rows represent the mean SampEn values of women and men, respectively, and redder colors indicate greater SampEn values. The color bar at the bottom row represents the t values of sex variable in the multiple regression model, and greener colors represent higher t values. All results were corrected by FDR or Tukey-HSD (p < 0.05) *: p < 0.05; **: p < 0.01; ***: p < 0.001. Abbreviations: SampEn Sample entropy, DMN Default mode network, FPCN Frontoparietal control network, COPN Cinguloperopercular network, SOM Sensorimotor network, OCCPI Occipital network, CERE Cerebellar network, R Right, L Left

Fig. 3

Meta-analysis of sex difference of the DMN network SampEn. The results of meta-analysis show that the SampEn of female DMN network was significantly higher than that of male whether without (A) or with GSR (B), (p < 0.0001). Abbreviations: SampEn Sample entropy, DMN Default mode network, GSR Global-signal regression, SD Standard derivation, SMD Standardized mean difference

Fig. 4

Enrichment analysis of genes associated with sex differences of SampEn. A The DEG analysis shows that the genes associated with sex difference in SampEn are significantly enriched in brain tissues. The GO (B–D) and KEGG (E) analyses indicate that the genes related to sex differences in SampEn are significantly enriched for synapse, channel and receptor activity, neurotransmitter receptors, and signal transduction activity. F The correlation analysis reveals that the coefficient of sex variable in the multiple regression model is significantly correlated with the expression values of the GPER1 gene on the estrogen-signaling pathway. The size of the circles represents the gene numbers overlapping with each term and the color of each circle represents the significance level of enrichment. The color bars represent the – log₁₀ (p.adjust), (FDR-BH corrected, p < 10^− 2). Abbreviations: SampEn Sample entropy, DEG Differentially expressed genes, KEGG Kyoto Encyclopedia of Genes and Genomes, GO Gene ontology, GPER1 G-protein-coupled estrogen receptor 1