A physics-informed foundation model for quantitative diffusion MRI

Diffusion MRI probes brain microstructure with particular sensitivity to early cerebrovascular and neurodegenerative changes. Neurite Orientation Dispersion and Density Imaging (NODDI) decomposes the diffusion signal into three biophysically interpretable maps: neurite density index (NDI), orientation dispersion index (ODI), and free water fraction (FWF), capturing neurite packing, fiber coherence, and extracellular fluid. These 3D maps offer a rich substrate for transferable microstructural representations, yet integrating them is challenging: standard representation learning struggles to disentangle the unique information in each map from their shared and synergistic interactions. We present BrainFIBRE, the first foundation model for brain microstructure, pretrained on NODDI-derived maps from 55,592 UK Biobank participants. We propose Self-supervised Partial Information Decomposition (SPID), which extends PID-guided multimodal learning to the self-supervised regime for the first time. A novel Counterfactual Candidate Construction (CCC) paradigm perturbs inter-modality alignment through modality dropping and swapping, providing the contrastive signal for a Mixture-of-Experts architecture to disentangle unique, synergistic, and redundant information without any downstream label. On both Caucasian and Asian cohorts, BrainFIBRE achieves state-of-the-art performance across diverse tasks predicting age, sex, cerebrovascular and neurodegenerative markers, and cognition, while yielding neurobiologically interpretable representations that reveal task- and cohort-specific interaction patterns. BrainFIBRE establishes a versatile foundation for neuroimaging analysis at the microstructural level.

Quantitative MRI (qMRI) provides standardised tissue parameter maps, but the reliability of deep learning-based qMRI mapping methods is often not explicitly characterised. In this work we systematically evaluate uncertainty maps for quantitative MRI derived from multiple inferences of a data-consistent diffusion model-based qMRI framework. Evaluation on synthetic test data assessed error-awareness, high-error detection, selective prediction, and Gaussian interval calibration. Diffusion model-derived uncertainty was positively associated with the mapping error, while risk-coverage analysis showed that excluding high-uncertainty voxels reduced the retained error. However, the raw uncertainty was poorly calibrated for quantitative interval interpretation. Calibration was substantially improved using a post-hoc procedure combining prediction-value-dependent bias correction with scalar uncertainty scaling. Qualitative evaluation on a healthy volunteer showed spatially meaningful uncertainty patterns. These results indicate that diffusion model-derived uncertainty is informative for reliability assessment and selective prediction, but requires calibration for quantitative interval interpretation.

Resolving complex fiber geometries in brain white matter requires high-resolution diffusion MRI at the cost of long acquisition times. This leads many clinical protocols to opt for low-resolution scans, making downstream microstructure estimation and tractography challenging. Implicit neural representations (INRs) can model the diffusion signal continuously, enabling native single-subject super-resolution by querying the network at arbitrary spatial coordinates, yet existing methods often suffer from long training times and lack a mechanism to incorporate anatomical priors to regularize super-resolution by constraining the space of plausible reconstructions. To address these limitations, we propose a novel transfer-learning framework that pre-trains an INR on a high-resolution template and then adapts it to subject-specific scans via registration and fine-tuning. For $4\times$ through-plane super-resolution from 5 mm to 1.25 mm on Human Connectome Project (HCP) data, our method reduces NRMSE by 36-49% and increases FSIM by 24-43% over a recent baseline with $6\times$ faster training, outperforming competing INR-based methods across both image quality and domain-specific metrics. Code is available on the project page at https://abdulkaderghandoura.github.io/research/msc-thesis/ .