Realistic noise synthesis reduces bias and improves tissue microstructure estimation with supervised machine learning

Brain tissue microstructure estimation with machine learning provides higher computational efficiency than conventional fitting. However, machine learning still presents important limitations that hamper its clinical utility. Specifically, current models typically lack generalisation across diffusion MRI acquisition protocols and require retraining whenever b-vectors or b-values change. Moreover, the recent machine learning methods that were developed to address protocol generalisation lack rotational equivariance. Particularly suitable for dMRI parameter estimation is a geometric deep learning model known as spherical convolutional neural network (SCNN), which guarantees rotational equivariance and b-vector generalisation. However, this architecture currently does not account for b-values. Therefore, obtaining a model that combines protocol generalisation and rotational equivariance remains an open challenge. In this paper, we directly address this issue by incorporating explicit b-value dependence into an SCNN architecture via a hypernetwork. This new approach is illustrated using NODDI as an example forward model for estimating brain tissue microstructure. To evaluate b-value generalisation, the original and newly proposed SCNN architectures are trained on synthetic data and tested on both synthetic and real data across different b-value pairs. Results demonstrate that the proposed method achieves reduced RMSE and bias on synthetic data, as well as higher agreement with conventional NODDI fitting on real data, indicating improved robustness to unseen b-values and a reduced need for retraining. By combining generalisation across b-values with generalisation across b-vectors and rotational equivariance, the proposed framework enhances the applicability of deep learning to clinical diffusion MRI parameter estimation. Code available at https://github.com/aerdnairo/arXiv\_generalisedSCNN.

Understanding the human brain requires access to its microscopic tissue architecture. Diffusion magnetic resonance imaging (MRI) provides the only noninvasive window into whole-brain microstructure in vivo, yet reliable quantitative mapping remains confined to specialized research settings requiring dense sampling and optimized acquisition protocols. To address this gap, we present a physics-informed generative microstructure network (PIGMENT) that learns a universal generative prior of human brain microstructure and adapts it zero-shot to each participant's measured data to recover subject-specific maps. Trained on 11375 scans spanning multiple sites, vendors, and field strengths, PIGMENT enabled reliable quantitative mapping for tensor, kurtosis, and NODDI models across external datasets from five independent centers. It remains effective where conventional fitting becomes unreliable, recovering meaningful maps from extremely sparse acquisitions while supporting downstream tractography and structural connectivity mapping. PIGMENT estimates demonstrated strong biological validity, preserving submillimeter cortical microarchitectural patterns and early-childhood white matter developmental trajectories from 10-fold accelerated scans. Furthermore, PIGMENT enables reliable quantitative tensor mapping on cost-efficient low-field systems and the extraction of tumor-related biomarkers using ultra-fast clinical protocols. Together, these results establish PIGMENT as a physics-informed foundation model that extends quantitative diffusion MRI into regimes traditionally too sparse, heterogeneous, or clinically constrained for reliable analysis.

Diffusion Probabilistic Models have demonstrated remarkable performance across a wide range of generative tasks. However, we have observed that these models often suffer from a Signal-to-Noise Ratio-timestep (SNR-t) bias. This bias refers to the misalignment between the SNR of the denoising sample and its corresponding timestep during the inference phase. Specifically, during training, the SNR of a sample is strictly coupled with its timestep. However, this correspondence is disrupted during inference, leading to error accumulation and impairing the generation quality. We provide comprehensive empirical evidence and theoretical analysis to substantiate this phenomenon and propose a simple yet effective differential correction method to mitigate the SNR-t bias. Recognizing that diffusion models typically reconstruct low-frequency components before focusing on high-frequency details during the reverse denoising process, we decompose samples into various frequency components and apply differential correction to each component individually. Extensive experiments show that our approach significantly improves the generation quality of various diffusion models (IDDPM, ADM, DDIM, A-DPM, EA-DPM, EDM, PFGM++, and FLUX) on datasets of various resolutions with negligible computational overhead. The code is at https://github.com/AMAP-ML/DCW.