Diffusion MRI

3D FLAIR MRI is widely recommended as one of the standard MRI sequences for brain imaging in multiple sclerosis (MS), but publicly available MS datasets remain relatively small and vary across scanners, acquisition protocols, and lesion patterns. This scarcity and variability hinder the development of robust neuroimaging machine learning models and are particularly challenging for generative models that aim to synthesize images while preserving small, sparse lesions. We propose Lesion-DDPM, a 3D conditional diffusion framework for lesion-aware FLAIR synthesis that incorporates multi-level anatomical mask injection together with a lesion-weighted reconstruction loss to emphasize lesion voxels while maintaining global brain structure. Using a curated subset of the MSLesSeg dataset, we compare Lesion-DDPM with representative state-of-the-art GAN- and diffusion-based models, assessing both image-generation metrics and downstream 3D U-Net segmentation. In our experiments, Lesion-DDPM achieved the lowest lesion-region reconstruction error among all methods. In a downstream 3D U-Net lesion segmentation task, a model trained only on Lesion-DDPM-generated scans and evaluated on real MRIs reached a Dice score of 0.616 compared with 0.569 for the best competing synthetic dataset. When Lesion-DDPM images were added to the real training set, the Dice score further increased to 0.685.

Diffusion MRI (dMRI) tractography is the only noninvasive approach for mapping white-matter pathways in the living human brain. It represents each brain as a tractogram: a large, unordered set of three-dimensional streamlines that includes information about both local streamline geometry and whole-brain anatomical organization. This structure makes tractograms a natural but challenging target for representation learning. Existing methods treat streamline classification and subject-level prediction as separate problems: streamline classifiers focus on geometric patterns, whereas subject-level prediction often depends on hand-crafted features. As a result, current methods do not learn reusable representations that connect streamline anatomy with whole-brain inter-subject variation. Here we introduce TractFM, a tractogram foundation model that learns reusable representations directly from whole-brain streamline sets. TractFM combines a local streamline encoder with a permutation-equivariant tractogram encoder, allowing all streamlines from a subject to be contextualized jointly in a single forward pass. Pretraining on dense anatomical tract parcellation, i.e., assigning anatomical labels to individual streamlines, yields two complementary representations: contextualized streamline-level embeddings for tract parcellation and compact subject-level descriptors for downstream prediction of subject phenotypes. Across three tractography algorithms and five dMRI datasets, TractFM transfers to both streamline-level and subject-level tasks. Its frozen representations achieve accurate tract parcellation and predict age and sex across independent datasets. These results show that whole-brain geometric context, learned once, can generalize across tractography pipelines, datasets, and prediction tasks.

Diffusion-weighted imaging (DWI) is used for whole-body cancer screening, but it typically requires a long acquisition time. When the scan time is reduced, the image quality often suffers, leading to increased noise in the scans. Magnitude reconstruction in DWI introduces signal-dependent Rician noise, which makes denoising more challenging for conventional convolution-based methods. To address this limitation, we propose a noise-aware attention-driven denoising framework that integrates hierarchical Swin Transformer window attention with transformer-based multi-dimensional gated refinement for DWI restoration. The model incorporates explicit noise-level conditioning and residual reconstruction to enable adaptive suppression of heteroscedastic noise across a wide range of corruption levels. Experimental evaluation on corrupted DWI scans demonstrates strong restoration performance. Our model achieves a mean PSNR of 33.69~dB and SSIM of 0.8539 across noise levels from 1% to 15%, while maintaining stable behavior under severe noise conditions. These results indicate that attention-guided contextual modeling combined with channel-adaptive refinement provides a robust and generalizable solution for DWI denoising.

Diffusion MRI enables non-invasive probing of tissue microstructure, but accurate parameter estimation is challenged by noise-related effects. In supervised machine learning frameworks trained on simulated data, discrepancies between the noise characteristics of simulated and acquired signals introduce a form of covariate shift, whereby the input signal distribution differs between training and inference. We investigated the impact of this mismatch on microstructure parameter estimation and propose a realistic noise synthesis (RNS) framework to mitigate it. RNS incorporates both the Rician expectation and the effective post-processing noise variance into simulated training signals. The Rician expectation was modelled using a noise standard deviation estimated with MPPCA, while the effective standard deviation was derived from spherical harmonic residuals of preprocessed data. The method was evaluated using the cylinder-zeppelin and the SANDI models on simulated datasets across multiple SNR levels and on in vivo diffusion data with repeated acquisitions. Sensitivity to noise misestimation was also assessed. Ignoring magnitude-induced noise effects during training produced systematic, SNR-dependent parameter bias, particularly at low SNR. Incorporating the Rician expectation substantially reduced bias to the level of noise-aware nonlinear least-squares fitting. Modelling the effective standard deviation further improved precision. Performance was largely independent of regression architecture but sensitive to accurate noise estimation. These findings demonstrate that realistic noise modelling in simulated training data mitigates signal-domain covariate shift and is essential for unbiased supervised microstructure estimation, particularly in low-SNR regimes associated with high b-values or high spatial resolution.

Multimodal MRI provides complementary information for neuroimaging analysis, where different imaging modalities capture distinct anatomical, tissue, and pathological features that support the development and evaluation of downstream AI applications. Although large-scale structural MRI resources are increasingly available, their modality coverage is often uneven across public and pooled neuroimaging datasets. This uneven modality coverage is further complicated by heterogeneity across sites, scanners, and acquisition protocols, as well as demographic and clinical variables that are often sparse, inconsistently recorded, or unavailable across studies. Synthetic MRI generation can help address this imbalance by synthesizing target-modality volumes for dataset augmentation and controlled synthetic cohort creation. However, many existing MRI synthesis approaches are trained on narrow modality sets or relatively homogeneous cohorts, limiting their applicability to large pooled neuroimaging resources where modality availability, acquisition protocols, and metadata coverage vary substantially across datasets. Diffusion models have become an attractive approach for MRI synthesis because of their strong sample fidelity and diversity, but sampling directly in 3D voxel space is computationally expensive and slow at inference. Latent diffusion improves practicality by synthesizing MRI in a learned, 3D latent space, although generation quality depends on the autoencoder's reconstruction fidelity and the resulting latent distribution. Our approach combines a Wavelet-Fusion variational autoencoder (WF-VAE) latent compressor with a conditional 3D U-Net diffusion model trained in the learned latent space using explicit modality and metadata conditioning. Our proposed Wavelet-Fusion Diffusion Model (WFDM) achieved the strongest distributional alignment among the evaluated synthetic MRI generators.

Geometric distortion in prostate diffusion-weighted imaging (DWI) can impair lesion localization and reduce the reliability of MRI-based clinical assessment. We propose AutoIQ, an ensemble machine learning framework for automatic quantification and classification of DWI geometric distortion severity. A total of 140 retrospective prostate biparametric MRI examinations were analyzed, including 33 scans with severe distortion requiring repeat acquisition and 107 scans with acceptable distortion based on expert radiologist assessment. AutoIQ combines two complementary distortion quantification strategies: a segmentation-based method measuring prostate boundary mismatch between T2-weighted imaging (T2WI) and DWI, and a registration-based method estimating deformation magnitude after DWI-to-T2WI alignment. The resulting distortion scores were used to train individual classifiers and a logistic-regression ensemble model. Both computational methods significantly differentiated severe from acceptable distortion cases (p < 0.001). On an independent test set, the ensemble model achieved an accuracy of 0.95, F1-score of 0.93, and AUC of 0.98, outperforming individual models. These results suggest that AutoIQ can provide automated, quantitative quality assessment for prostate DWI and may help identify scans that require repeat acquisition.

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.

Clinical application of high-resolution diffusion MRI is hindered by hardware limitations and prohibitive scan times, motivating computational super-resolution. This study investigates the efficacy of a feature-based loss function in preserving diffusion signal consistency in deep learning super-resolution. Using 7T data from the human connectome project to generate pairs of low- and high-resolution diffusion weighted images (DWI), we trained UNets for 2D super-resolution. Ablation and isolation studies evaluated different VGG16-layers for feature-based losses against an image-based L1 baseline. Deeper layers and combinations thereof resulted in grid-like artifacts in super-resolution DWIs, which persisted in diffusion parameters like quantitative and fractional anisotropy. No such artifacts were present when using the shallowest layer. Downstream analysis for this layer showed great consistency with the ground truth, even for 9-fold super-resolution. Image SNR and used VGG16-layer depths modulated artifact appearance and severity, mandating careful selection of contributing layers for application in and beyond diffusion MRI.

Recently, diffusion models have attracted considerable attention for magnetic resonance image reconstruction due to their high sample quality. However, most existing methods rely on large networks with opaque time-conditioning mechanisms, and require offline coil sensitivity estimation. This results in limited interpretability of the reconstruction process and reduced flexibility in the acquisition setup. To address these limitations, we jointly reconstruct the image and the coil sensitivities by combining the parameter-efficient product-of-Gaussian-mixture diffusion model as an image prior with a classical smoothness prior on the coil sensitivities. The proposed method is fast and robust to both contrast and anatomical distribution shifts as well as changing k-space trajectories. Finally, we propose a more expressive parameterization of the image prior which improves results in denoising and magnetic resonance image reconstruction.

Rotating-view thick-slice acquisition is highly SNR-efficient for mesoscale diffusion MRI (dMRI) but requires numerous rotating views to satisfy Nyquist sampling, resulting in long scan time. We propose a self-supervised Spatial-Angular Implicit Neural Representation (SA-INR) that reconstructs high-resolution dMRI from a single view per diffusion direction, representing a massive acceleration. Our model, an MLP conditioned on a b=0 structural prior and the b-direction via FiLM, is trained end-to-end on the anisotropic input. The framework not only accurately reconstructs the trained b-directions (spatial SR) but also learns a continuous q-space representation, enabling high-fidelity "zero-shot" synthesis of unseen b-directions (angular SR). On simulated data, our method achieved high fidelity for both trained (34.82 dB) and unseen (33.08 dB) directions. Most importantly, the synthesized angular data also improved the quantitative accuracy of downstream DTI model fitting. Our SA-INR framework breaks the classical sampling limits, paving the way for fast, quantitative high-resolution dMRI.

Diffusion MRI microstructure fitting is nonconvex and often performed voxelwise, which limits fiber peak recovery in narrow crossings. This work introduces PRISM, a differentiable analysis-by-synthesis framework that fits an explicit multi-compartment forward model end-to-end over spatial patches. The model combines cerebrospinal fluid (CSF), gray matter, up to K white-matter fiber compartments (stick-and-zeppelin), and a restricted compartment, with explicit fiber directions and soft model selection via repulsion and sparsity priors. PRISM supports a fast MSE objective and a Rician negative log-likelihood (NLL) that jointly learns sigma without oracle information. A lightweight nuisance calibration module (smooth bias field and per-measurement scale/offset) is included for robustness and regularized to identity in clean-data tests. On synthetic crossing-fiber data (SNR=30; five methods, 16 crossing angles), PRISM achieves 3.5 degrees best-match angular error with 95% recall, which is 1.9x lower than the best baseline (MSMT-CSD, 6.8 degrees, 83% recall); in NLL mode with learned sigma, error drops to 2.3 degrees with 99% recall, resolving crossings down to 20 degrees. On the DiSCo1 phantom (NLL mode), PRISM improves connectivity correlation over CSD baselines at all four tracking angles (best r=.934 at 25 degrees vs. .920 for MSMT-CSD). Whole-brain HCP fitting (~741k voxels, MSE mode) completes in ~12 min on a single GPU with near-identical results across random seeds.

Echo-planar imaging (EPI) remains the cornerstone of diffusion MRI, but it is prone to severe geometric distortions due to its rapid sampling scheme that renders the sequence highly sensitive to $B_{0}$ field inhomogeneities. While deep learning has helped improve MRI reconstruction, integrating robust geometric distortion correction into a self-supervised framework remains an unmet need. To address this, we present FINDER (Field-Integrated Network for Distortion-free EPI Reconstruction), a novel zero-shot, scan-specific framework that reformulates reconstruction as a joint optimization of the underlying image and the $B_{0}$ field map. Specifically, we employ a physics-guided unrolled network that integrates dual-domain denoisers and virtual coil extensions to enforce robust data consistency. This is coupled with an Implicit Neural Representation (INR) conditioned on spatial coordinates and latent image features to model the off-resonance field as a continuous, differentiable function. Employing an alternating minimization strategy, FINDER synergistically updates the reconstruction network and the field map, effectively disentangling susceptibility-induced geometric distortions from anatomical structures. Experimental results demonstrate that FINDER achieves superior geometric fidelity and image quality compared to state-of-the-art baselines, offering a robust solution for high-quality diffusion imaging.

Diffusion Magnetic Resonance Imaging (dMRI) plays a critical role in studying microstructural changes in the brain. It is, therefore, widely used in clinical practice; yet progress in learning general-purpose representations from dMRI has been limited. A key challenge is that existing deep learning approaches are not well-suited to capture the unique properties of diffusion signals. Brain dMRI is normally composed of several brain volumes, each with different attenuation characteristics dependent on the direction and strength of the diffusion-sensitized gradients. Thus, there is a need to jointly model spatial, diffusion-weighting, and directional dependencies in dMRI. Furthermore, varying acquisition protocols (e.g., differing numbers of directions) further limit traditional models. To address these gaps, we introduce a diffusion space rotatory positional embedding (D-RoPE) plugged into our dMRI transformer to capture both the spatial structure and directional characteristics of diffusion data, enabling robust and transferable representations across diverse acquisition settings and an arbitrary number of diffusion directions. After self-supervised masked autoencoding pretraining, tests on several downstream tasks show that the learned representations and the pretrained model can provide competitive or superior performance compared to several baselines in these downstream tasks (even compared to a fully trained baseline); the finetuned features from our pretrained encoder resulted in a 6% higher accuracy in classifying mild cognitive impairment and a 0.05 increase in the correlation coefficient when predicting cognitive scores. Code is available at: github.com/gustavochau/D-RoPE.

Harmonization methods such as ComBat and its variants are widely used to mitigate diffusion MRI (dMRI) site-specific biases. However, ComBat assumes that subject distributions exhibit a Gaussian profile. In practice, patients with neurological disorders often present diffusion metrics that deviate markedly from those of healthy controls, introducing pathological outliers that distort site-effect estimation. This problem is particularly challenging in clinical practice as most patients undergoing brain imaging have an underlying and yet undiagnosed condition, making it difficult to exclude them from harmonization cohorts, as their scans were precisely prescribed to establish a diagnosis. In this paper, we show that harmonizing data to a normative reference population with ComBat while including pathological cases induces significant distortions. Across 7 neurological conditions, we evaluated 10 outlier rejection methods with 4 ComBat variants over a wide range of scenarios, revealing that many filtering strategies fail in the presence of pathology. In contrast, a simple MLP provides robust outlier compensation enabling reliable harmonization while preserving disease-related signal. Experiments on both control and real multi-site cohorts, comprising up to 80% of subjects with neurological disorders, demonstrate that Robust-ComBat consistently outperforms conventional statistical baselines with lower harmonization error across all ComBat variants.

Diffusion MRI tractography enables in vivo reconstruction of white matter (WM) pathways. Two key tasks in tractography analysis include: 1) tractogram registration that aligns streamlines across individuals, and 2) streamline clustering that groups streamlines into compact fiber bundles. Although both tasks share the goal of capturing geometrically similar structures to characterize consistent WM organization, they are typically performed independently. In this work, we propose TractoRC, a unified probabilistic framework that jointly performs tractogram registration and streamline clustering within a single optimization scheme, enabling the two tasks to leverage complementary information. TractoRC learns a latent embedding space for streamline points, which serves as a shared representation for both tasks. Within this space, both tasks are formulated as probabilistic inference over structural representations: registration learns the distribution of anatomical landmarks as probabilistic keypoints to align tractograms across subjects, and clustering learns streamline structural prototypes that capture geometric similarity to form coherent streamline clusters. To support effective learning of this shared space, we introduce a transformation-equivariant self-supervised strategy to learn geometry-aware and transformation-invariant embeddings. Experiments demonstrate that jointly optimizing registration and clustering significantly improves performance in both tasks over state-of-the-art methods that treat them independently. Code will be made publicly available at https://github.com/yishengpoxiao/TractoRC .

Purpose: Combining multi-site diffusion MRI (dMRI) data is hindered by inter-scanner variability, which confounds subsequent analysis. Previous harmonization methods require large, matched or traveling human subjects from multiple sites, which are impractical to acquire in many situations. This study aims to develop a deep learning-based dMRI harmonization framework that eliminates the reliance on multi-site in-vivo traveling human data for training. Methods: HARP employs a voxel-wise 1D neural network trained on an easily transportable diffusion phantom. The model learns relationships between spherical harmonics coefficients of different sites without memorizing spatial structures. Results: HARP reduced inter-scanner variability levels significantly in various measures. Quantitatively, it decreased inter-scanner variability as measured by standard error in FA (12%), MD (10%), and GFA (30%) with scan-rescan standard error as the baseline, while preserving fiber orientations and tractography after harmonization. Conclusion: We believe that HARP represents an important first step toward dMRI harmonization using only phantom data, thereby obviating the need for complex, matched in vivo multi-site cohorts. This phantom-only strategy substantially enhances the feasibility and scalability of quantitative dMRI for large-scale clinical studies.

Diffusion MRI (dMRI) is sensitive to microstructural barriers, yet most existing methods either assume impermeable boundaries or estimate voxel-level parameters without recovering explicit interfaces. We present Spinverse, a permeability-aware reconstruction method that inverts dMRI measurements through a fully differentiable Bloch-Torrey simulator. Spinverse represents tissue on a fixed tetrahedral grid and treats each interior face permeability as a learnable parameter; low-permeability faces act as diffusion barriers, so microstructural boundaries whose topology is not fixed a priori (up to the resolution of the ambient mesh) emerge without changing mesh connectivity or vertex positions. Given a target signal, we optimize face permeabilities by backpropagating a signal-matching loss through the PDE forward model, and recover an interface by thresholding the learned permeability field. To mitigate the ill-posedness of permeability inversion, we use mesh-based geometric priors; to avoid local minima, we use a staged multi-sequence optimization curriculum. Across a collection of synthetic voxel meshes, Spinverse reconstructs diverse geometries and demonstrates that sequence scheduling and regularization are critical to avoid outline-only solutions while improving both boundary accuracy and structural validity.

Diffusion-weighted imaging (DWI) can support lesion detection and characterization in breast magnetic resonance imaging (MRI), however especially high b-value diffusion-weighted acquisitions can be prone to intensity artifacts that can affect diagnostic image assessment. This study aims to detect both hyper- and hypointense artifacts on high b-value diffusion-weighted images (b=1500 s/mm2) using deep learning, employing either a binary classification (artifact presence) or a multiclass classification (artifact intensity) approach on a slice-wise dataset.This IRB-approved retrospective study used the single-center dataset comprising n=11806 slices from routine 3T breast MRI examinations performed between 2022 and mid-2023. Three convolutional neural network (CNN) architectures (DenseNet121, ResNet18, and SEResNet50) were trained for binary classification of hyper- and hypointense artifacts. The best performing model (DenseNet121) was applied to an independent holdout test set and was further trained separately for multiclass classification. Evaluation included area under receiver operating characteristic curve (AUROC), area under precision recall curve (AUPRC), precision, and recall, as well as analysis of predicted bounding box positions, derived from the network Grad-CAM heatmaps. DenseNet121 achieved AUROCs of 0.92 and 0.94 for hyper- and hypointense artifact detection, respectively, and weighted AUROCs of 0.85 and 0.88 for multiclass classification on single-slice high b-value diffusion-weighted images. A radiologist evaluated bounding box precision on a 1-5 Likert-like scale across 200 slices, achieving mean scores of 3.33+-1.04 for hyperintense artifacts and 2.62+-0.81 for hypointense artifacts. Hyper- and hypointense artifact detection in slice-wise breast DWI MRI dataset (b=1500 s/mm2) using CNNs particularly DenseNet121, seems promising and requires further validation.

Plug-and-Play diffusion prior (PnPDP) frameworks have emerged as a powerful paradigm for solving imaging inverse problems by treating pretrained generative models as modular priors. However, we identify a critical flaw in prevailing PnP solvers (e.g., based on HQS or Proximal Gradient): they function as memoryless operators, updating estimates solely based on instantaneous gradients. This lack of historical tracking inevitably leads to non-vanishing steady-state bias, where the reconstruction fails to strictly satisfy physical measurements under heavy corruption. To resolve this, we propose Dual-Coupled PnP Diffusion (DC-PnPDP), which restores the classical dual variable to provide integral feedback, progressively enforce agreement between the data-consistency and prior. However, this rigorous geometric coupling introduces a secondary challenge: the accumulated dual residuals exhibit spectrally colored, structured artifacts that violate the Additive White Gaussian Noise (AWGN) assumption of diffusion priors, causing severe hallucinations. To bridge this gap, we introduce Spectral Homogenization (SH), a frequency-domain adaptation mechanism that modulates these structured residuals into statistically compliant pseudo-AWGN inputs. This effectively aligns the solver's rigorous optimization trajectory with the denoiser's valid statistical manifold. Extensive experiments on CT and MRI reconstruction demonstrate that our approach resolves the bias-hallucination trade-off, achieving state-of-the-art fidelity with significantly accelerated convergence. The code is available at https://github.com/duchenhe/DC-PnPDP

Diffusion magnetic resonance imaging (dMRI) plays a vital role in both clinical diagnostics and neuroscience research. However, its inherently low signal-to-noise ratio (SNR), especially under high diffusion weighting, significantly degrades image quality and impairs downstream analysis. Recent self-supervised and unsupervised denoising methods offer a practical solution by enhancing image quality without requiring clean references. However, most of these methods do not explicitly account for the non-Gaussian noise characteristics commonly present in dMRI magnitude data during the supervised learning process, potentially leading to systematic bias and heteroscedastic variance, particularly under low-SNR conditions. To overcome this limitation, we introduce noise-corrected training objectives that explicitly model Rician statistics. Specifically, we propose two alternative loss functions: one derived from the first-order moment to remove mean bias, and another from the second-order moment to correct squared-signal bias. Both losses include adaptive weighting to account for variance heterogeneity and can be used without changing the network architecture. These objectives are instantiated in an image-specific, unsupervised Deep Image Prior (DIP) framework. Comprehensive experiments on simulated and in-vivo dMRI show that the proposed losses effectively reduce Rician bias and suppress noise fluctuations, yielding higher image quality and more reliable diffusion metrics than state-of-the-art denoising baselines. These results underscore the importance of bias- and variance-aware noise modeling for robust dMRI analysis under low-SNR conditions.

Brain tumors induce complex structural deformations that obscure the patient' s original neuroanatomy, making it difficult to distinguish tumor-induced changes from inherent anatomical variability. Reconstructing a subject-specific pseudo-healthy brain can provide a critical reference for such analysis, but this task is inherently counterfactual, as paired pre-tumor scans and explicit healthy guidance are unavailable. We propose BrainNormalizer, a diffusion-based framework for subject-specific pseudo-healthy brain MRI reconstruction that enables anatomy-informed reconstruction without requiring paired data or explicit healthy references. The framework learns anatomical priors and edge-based structural conditioning through a two-stage training strategy consisting of inpainting-based diffusion fine-tuning and ControlNet-based edge conditioning. At inference, counterfactual pseudo-healthy reconstruction is achieved through a deliberate misalignment strategy, where tumorous inputs are paired with non-tumorous prompts and mirrored contralateral edge maps. This allows subject-specific anatomical guidance to be constructed from the patient's own anatomy, enabling anatomically consistent pseudo-healthy reconstruction that preserves individual structural characteristics. Experiments on the BraTS2020 dataset demonstrate that BrainNormalizer achieves improved distributional realism, symmetry-based structural consistency, and reduced false positive detection compared to existing methods. These results indicate that the proposed framework provides a principled approach for subject-specific counterfactual reconstruction and supports downstream analysis of tumor-induced deformation.