Explainable Normative Modeling for Brain Disorder Identification in Resting-State fMRI

Accurate identification of brain disorders enables timely intervention and improved patient outcomes. While numerous studies have developed AI models for resting-state functional magnetic resonance imaging (rs-fMRI) analysis, most rely on supervised learning, which can overlook hidden patterns that are less discriminatively associated with labels and require large annotated datasets. To address these limitations, we propose leveraging normative modeling, an unsupervised approach that constructs a model of normality based on healthy controls' data. Deviations from normality indicate potential disorders. However, applying normative modeling to rs-fMRI faces two significant challenges: constructing normality and ensuring explainability. To tackle these challenges, we propose BRAINEXA, a novel framework enhancing normative modeling for rs-fMRI-based brain disorder identification. Specifically, to construct accurate and stable normality, BRAINEXA introduces a training strategy that predicts more informative regions from less informative regions, discouraging trivial self-supervised learning solutions and improving representation learning without additional overhead. Furthermore, we incorporate spatiotemporal mutual information regularization to preserve distinctiveness between more informative regions and less informative regions during latent encoding, preventing potential representational distortions. For interpretability, BRAINEXA extracts normality-defining (ND) subregions, the core regions that characterize normal brain function. By combining ND subregions with anomaly scores, BRAINEXA can offer region- and connection-wise explanations that help identify clinically meaningful disruptions of normality in an unsupervised setting. We demonstrate the effectiveness of BRAINEXA on four public rs-fMRI datasets: REST-meta-MDD, ABIDE I, ADHD-200, and OASIS-3. Our code is available at https://github.com/ku-milab/BRAINEXA.