PIME: Prototype-based Interpretable MCTS-Enhanced Brain Network Analysis for Disorder Diagnosis

Foundation models provide powerful representations for brain MRI analysis, but their predictions remain difficult to interpret in anatomically meaningful terms. Clinical assessment of brain MRI is commonly organized around anatomically defined structures and regional abnormalities, whereas conventional explanation methods typically produce voxel- or patch-level importance maps that do not explicitly quantify the contributions of individual brain regions. To address this mismatch, we propose RegionFM, an interpretable framework that integrates anatomical segmentation with brain MRI foundation-model embeddings. RegionFM first divides each MRI scan into anatomical regions and constructs a separate MRI volume for each region. A frozen foundation model then encodes each region into an embedding, and a region-additive logistic model combines these embeddings such that every anatomical region contributes an explicit scalar term to the final prediction. This formulation supports both subject-level and cohort-level analyses of regional contributions. We evaluate RegionFM on cognitive-impairment classification using embeddings from multiple pretrained brain MRI foundation models. The results show that RegionFM maintains performance comparable to less interpretable fine-tuning approaches while providing anatomically grounded explanations. Randomized embedding ablations yield near-chance performance, indicating that the predictions rely on meaningful structure captured by the foundation-model embeddings rather than simple feature statistics. Overall, RegionFM better aligns model explanations with anatomy-based clinical reasoning while maintaining competitive predictive performance.

Multi-site functional MRI (fMRI) studies are essential for robust neuropsychiatric diagnosis yet suffer severe domain shifts from scanner heterogeneity, demographics, and site-specific acquisition protocols. Traditional domain adaptation requires concurrent source and target data access, violating clinical privacy regulations. Moreover, functional connectivity matrices lie on the Symmetric Positive Definite (SPD) manifold, where Euclidean operations cause geometric distortions corrupting diagnostic patterns. We propose BrainRiem, a source-free domain adaptation framework learning compact Riemannian brain prototypes via manifold-aware bi-level optimization. It employs the Log-Euclidean Metric to ensure prototypes remain valid SPD matrices, while Dirichlet Energy spectral calibration aligns their frequency characteristics with real brain networks. Only anonymized prototypes are transmitted to target sites, serving as stable anchors for training local models without source data access and reducing leakage under the evaluated attacks. Comprehensive experiments on ABIDE and REST-meta-MDD show BrainRiem consistently outperforms state-of-the-art source-free, traditional, and graph domain adaptation methods across diverse scanners and demographics. Notably, learned prototypes exhibit biologically interpretable connectivity patterns aligning with established neuroscience findings, validating the necessity of Riemannian geometry for brain network analysis.

Brain network analysis based on functional Magnetic Resonance Imaging (fMRI) is pivotal for diagnosing brain disorders. Existing approaches typically rely on predefined functional sub-networks to construct sub-network associations. However, we identified many cross-network interaction patterns with high Pearson correlations that this strict, prior-based organization fails to capture. To overcome this limitation, we propose the Brain Hierarchical Organization Learning (BrainHO) to learn inherently hierarchical brain network dependencies based on their intrinsic features rather than predefined sub-network labels. Specifically, we design a hierarchical attention mechanism that allows the model to aggregate nodes into a hierarchical organization, effectively capturing intricate connectivity patterns at the subgraph level. To ensure diverse, complementary, and stable organizations, we incorporate an orthogonality constraint loss, alongside a hierarchical consistency constraint strategy, to refine node-level features using high-level graph semantics. Extensive experiments on the publicly available ABIDE and REST-meta-MDD datasets demonstrate that BrainHO not only achieves state-of-the-art classification performance but also uncovers interpretable, clinically significant biomarkers by precisely localizing disease-related sub-networks.