Sex is an important biological variable often used in analyzing and describing the functional organization of the brain during cognitive and behavioral tasks. Several prior studies have shown that blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) functional connectivity (FC) can be used to differentiate sex among individuals. Herein, we demonstrate that sex can be further classified with high accuracy using the intrinsic BOLD signal fluctuations from resting-state fMRI (rs-fMRI). We adopted the amplitude of low-frequency fluctuation (ALFF), and the fraction of ALFF (fALFF) features from the automated anatomical atlas (AAL) and Power’s functional atlas as an input to different machine learning (ML) methods. Using datasets from five independently acquired subject cohorts and with eight fMRI scanning sessions, we comprehensively assessed unbiased performance using nested-cross validation for within-sample and across sample accuracies. The results demonstrated high prediction accuracies for the Human Connectome Project (HCP) dataset (area under cure (AUC) > 0.89). The yielded accuracies suggest that sex difference is embodied and well-pronounced in the low-frequency BOLD signal fluctuation. The performance degrades with the heterogeneity of the cohort and suggests that other factors.e.g. psychiatric disorders and demographics influences the BOLD signal and may interact with the classification of sex. In addition, the results revealed high learning generalizability with the HCP scan, but not across different datasets. The intraclass correlation coefficient (ICC) across HCP scans showed moderate-to-good reliability based on atlas selection (ICC = 0.65 [0.63-0.67] and ICC= 0.78 [0.76-0.80].). We also assessed the effect of scan duration on the predictability of sex and showed that sex differences could be detected even with a short rs-fMRI scan (e.g., 2 minutes). Moreover, we provided statistical maps of the brain regions differentially recruited by or predicting sex using Shapely values and determined an overlap with previous reports of brain response due to sex differences. Altogether, our analysis suggests that sex differences are well-pronounced in rs-fMRI and should be considered seriously in any study design, analysis, or interpretation.
bioRxiv Subject Collection: Neuroscience