Data-Driven Identification Of Sex Differences In Cerebral Blood Flow Using Arterial Spin Labelling And Explainable Artificial Intelligence

Purpose: To investigate sex differences in cerebral blood flow through densely parcellated cortical and subcortical regions using explainable artificial intelligence methods and identify neurobiologically interpretable perfusion biomarkers. Methods: High-resolution pseudo-continuous arterial spin labelling (1.875 mm x 1.875 mm x 3 mm) and structural MRI data were curated from 215 healthy young adults (150 females, 95 males; age 18-30 years) from the publicly available I See your Brains (ISYB) dataset. Cerebral blood flow was quantified using atlas-based regional analysis with the Brainnetome Atlas (246 regions) and optimized registration procedures. Sex classification employed diverse machine learning paradigms including linear classifiers, ensemble methods, and kernel-based approaches for regional CBF features, with deep convolutional neural networks (CNN) applied to whole-brain 3D imaging data. Model interpretability was achieved using SHapley Additive exPlanations (SHAP), computed over an ensemble of 500 logistic regression models (100 iterations x 5-fold cross-validation). Regions appearing among the top 20% of discriminative features more than 289 times were considered statistically significant using binomial testing. GradCAM was used to obtain class-specific attribution maps from the CNN model. Results: Perfusion-based features demonstrated superior sex classification performance compared to structural morphometry. Regional CBF analysis using logistic regression achieved 91 +/- 2% balanced accuracy and 0.95 +/- 0.05 ROC-AUC, substantially outperforming morphometric features (85 +/- 8% balanced accuracy, 0.88 +/- 0.06 ROC-AUC). Deep learning classification of 3D CBF maps achieved a performance of 92 +/- 5% balanced accuracy, 0.92 +/- 0.05 ROC-AUC. SHAP analysis identified 30 statistically significant aggregation-agnostic CBF-based biomarker regions using regional CBF, predominantly involving frontoparietal control networks (27%) and default mode networks (17%). Grad-CAM revealed that the 3D CNN model primarily focused on regions within the frontal lobe. Morphometry-based analysis identified 28 discriminative regions with markedly different anatomical distribution (r = 0.21) emphasizing visual (32%) and default mode (14%) networks. Conclusion: Cerebral blood flow patterns provide highly sensitive and biologically interpretable markers of sex differences in young adult brain. The identification of robust perfusion biomarkers through explainable AI demonstrates the clinical potential of ASL imaging for precision medicine applications in neuroscience. We establish a methodological framework for investigating sex-specific brain physiology using non-invasive neuroimaging.