Anatomically Guided Latent Diffusion for Brain MRI Progression Modeling

Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving state-of-the-art image quality and 15-20\% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (up to 31.5x higher sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.

Anatomical Similarity as a New Metric to Evaluate Brain Generative Models

Generative models enhance neuroimaging through data augmentation, quality improvement, and rare condition studies. Despite advances in realistic synthetic MRIs, evaluations focus on texture and perception, lacking sensitivity to crucial anatomical fidelity. This study proposes a new metric, called WASABI (Wasserstein-Based Anatomical Brain Index), to assess the anatomical realism of synthetic brain MRIs. WASABI leverages \textit{SynthSeg}, a deep learning-based brain parcellation tool, to derive volumetric measures of brain regions in each MRI and uses the multivariate Wasserstein distance to compare distributions between real and synthetic anatomies. Based on controlled experiments on two real datasets and synthetic MRIs from five generative models, WASABI demonstrates higher sensitivity in quantifying anatomical discrepancies compared to traditional image-level metrics, even when synthetic images achieve near-perfect visual quality. Our findings advocate for shifting the evaluation paradigm beyond visual inspection and conventional metrics, emphasizing anatomical fidelity as a crucial benchmark for clinically meaningful brain MRI synthesis. Our code is available at https://github.com/BahramJafrasteh/wasabi-mri.

Spectral Graph Sample Weighting for Interpretable Sub-cohort Analysis in Predictive Models for Neuroimaging

Recent advancements in medicine have confirmed that brain disorders often comprise multiple subtypes of mechanisms, developmental trajectories, or severity levels. Such heterogeneity is often associated with demographic aspects (e.g., sex) or disease-related contributors (e.g., genetics). Thus, the predictive power of machine learning models used for symptom prediction varies across subjects based on such factors. To model this heterogeneity, one can assign each training sample a factor-dependent weight, which modulates the subject's contribution to the overall objective loss function. To this end, we propose to model the subject weights as a linear combination of the eigenbases of a spectral population graph that captures the similarity of factors across subjects. In doing so, the learned weights smoothly vary across the graph, highlighting sub-cohorts with high and low predictability. Our proposed sample weighting scheme is evaluated on two tasks. First, we predict initiation of heavy alcohol drinking in young adulthood from imaging and neuropsychological measures from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). Next, we detect Dementia vs. Mild Cognitive Impairment (MCI) using imaging and demographic measurements in subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Compared to existing sample weighting schemes, our sample weights improve interpretability and highlight sub-cohorts with distinct characteristics and varying model accuracy.

Brain-Cognition Fingerprinting via Graph-GCCA with Contrastive Learning

Many longitudinal neuroimaging studies aim to improve the understanding of brain aging and diseases by studying the dynamic interactions between brain function and cognition. Doing so requires accurate encoding of their multidimensional relationship while accounting for individual variability over time. For this purpose, we propose an unsupervised learning model (called \underline{\textbf{Co}}ntrastive Learning-based \underline{\textbf{Gra}}ph Generalized \underline{\textbf{Ca}}nonical Correlation Analysis (CoGraCa)) that encodes their relationship via Graph Attention Networks and generalized Canonical Correlational Analysis. To create brain-cognition fingerprints reflecting unique neural and cognitive phenotype of each person, the model also relies on individualized and multimodal contrastive learning. We apply CoGraCa to longitudinal dataset of healthy individuals consisting of resting-state functional MRI and cognitive measures acquired at multiple visits for each participant. The generated fingerprints effectively capture significant individual differences and outperform current single-modal and CCA-based multimodal models in identifying sex and age. More importantly, our encoding provides interpretable interactions between those two modalities.

Latent 3D Brain MRI Counterfactual

The number of samples in structural brain MRI studies is often too small to properly train deep learning models. Generative models show promise in addressing this issue by effectively learning the data distribution and generating high-fidelity MRI. However, they struggle to produce diverse, high-quality data outside the distribution defined by the training data. One way to address the issue is using causal models developed for 3D volume counterfactuals. However, accurately modeling causality in high-dimensional spaces is a challenge so that these models generally generate 3D brain MRIS of lower quality. To address these challenges, we propose a two-stage method that constructs a Structural Causal Model (SCM) within the latent space. In the first stage, we employ a VQ-VAE to learn a compact embedding of the MRI volume. Subsequently, we integrate our causal model into this latent space and execute a three-step counterfactual procedure using a closed-form Generalized Linear Model (GLM). Our experiments conducted on real-world high-resolution MRI data (1mm) demonstrate that our method can generate high-quality 3D MRI counterfactuals.

Enforcing Conditional Independence for Fair Representation Learning and Causal Image Generation

Conditional independence (CI) constraints are critical for defining and evaluating fairness in machine learning, as well as for learning unconfounded or causal representations. Traditional methods for ensuring fairness either blindly learn invariant features with respect to a protected variable (e.g., race when classifying sex from face images) or enforce CI relative to the protected attribute only on the model output (e.g., the sex label). Neither of these methods are effective in enforcing CI in high-dimensional feature spaces. In this paper, we focus on a nascent approach characterizing the CI constraint in terms of two Jensen-Shannon divergence terms, and we extend it to high-dimensional feature spaces using a novel dynamic sampling strategy. In doing so, we introduce a new training paradigm that can be applied to any encoder architecture. We are able to enforce conditional independence of the diffusion autoencoder latent representation with respect to any protected attribute under the equalized odds constraint and show that this approach enables causal image generation with controllable latent spaces. Our experimental results demonstrate that our approach can achieve high accuracy on downstream tasks while upholding equality of odds.

Metadata-Conditioned Generative Models to Synthesize Anatomically-Plausible 3D Brain MRIs

Generative AI models hold great potential in creating synthetic brain MRIs that advance neuroimaging studies by, for example, enriching data diversity. However, the mainstay of AI research only focuses on optimizing the visual quality (such as signal-to-noise ratio) of the synthetic MRIs while lacking insights into their relevance to neuroscience. To gain these insights with respect to T1-weighted MRIs, we first propose a new generative model, BrainSynth, to synthesize metadata-conditioned (e.g., age- and sex-specific) MRIs that achieve state-of-the-art visual quality. We then extend our evaluation with a novel procedure to quantify anatomical plausibility, i.e., how well the synthetic MRIs capture macrostructural properties of brain regions, and how accurately they encode the effects of age and sex. Results indicate that more than half of the brain regions in our synthetic MRIs are anatomically accurate, i.e., with a small effect size between real and synthetic MRIs. Moreover, the anatomical plausibility varies across cortical regions according to their geometric complexity. As is, our synthetic MRIs can significantly improve the training of a Convolutional Neural Network to identify accelerated aging effects in an independent study. These results highlight the opportunities of using generative AI to aid neuroimaging research and point to areas for further improvement.

LSOR: Longitudinally-Consistent Self-Organized Representation Learning

Interpretability is a key issue when applying deep learning models to longitudinal brain MRIs. One way to address this issue is by visualizing the high-dimensional latent spaces generated by deep learning via self-organizing maps (SOM). SOM separates the latent space into clusters and then maps the cluster centers to a discrete (typically 2D) grid preserving the high-dimensional relationship between clusters. However, learning SOM in a high-dimensional latent space tends to be unstable, especially in a self-supervision setting. Furthermore, the learned SOM grid does not necessarily capture clinically interesting information, such as brain age. To resolve these issues, we propose the first self-supervised SOM approach that derives a high-dimensional, interpretable representation stratified by brain age solely based on longitudinal brain MRIs (i.e., without demographic or cognitive information). Called Longitudinally-consistent Self-Organized Representation learning (LSOR), the method is stable during training as it relies on soft clustering (vs. the hard cluster assignments used by existing SOM). Furthermore, our approach generates a latent space stratified according to brain age by aligning trajectories inferred from longitudinal MRIs to the reference vector associated with the corresponding SOM cluster. When applied to longitudinal MRIs of the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=632), LSOR generates an interpretable latent space and achieves comparable or higher accuracy than the state-of-the-art representations with respect to the downstream tasks of classification (static vs. progressive mild cognitive impairment) and regression (determining ADAS-Cog score of all subjects). The code is available at https://github.com/ouyangjiahong/longitudinal-som-single-modality.

Imputing Brain Measurements Across Data Sets via Graph Neural Networks

Publicly available data sets of structural MRIs might not contain specific measurements of brain Regions of Interests (ROIs) that are important for training machine learning models. For example, the curvature scores computed by Freesurfer are not released by the Adolescent Brain Cognitive Development (ABCD) Study. One can address this issue by simply reapplying Freesurfer to the data set. However, this approach is generally computationally and labor intensive (e.g., requiring quality control). An alternative is to impute the missing measurements via a deep learning approach. However, the state-of-the-art is designed to estimate randomly missing values rather than entire measurements. We therefore propose to re-frame the imputation problem as a prediction task on another (public) data set that contains the missing measurements and shares some ROI measurements with the data sets of interest. A deep learning model is then trained to predict the missing measurements from the shared ones and afterwards is applied to the other data sets. Our proposed algorithm models the dependencies between ROI measurements via a graph neural network (GNN) and accounts for demographic differences in brain measurements (e.g. sex) by feeding the graph encoding into a parallel architecture. The architecture simultaneously optimizes a graph decoder to impute values and a classifier in predicting demographic factors. We test the approach, called Demographic Aware Graph-based Imputation (DAGI), on imputing those missing Freesurfer measurements of ABCD (N=3760) by training the predictor on those publicly released by the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N=540)...

An Explainable Geometric-Weighted Graph Attention Network for Identifying Functional Networks Associated with Gait Impairment

One of the hallmark symptoms of Parkinson's Disease (PD) is the progressive loss of postural reflexes, which eventually leads to gait difficulties and balance problems. Identifying disruptions in brain function associated with gait impairment could be crucial in better understanding PD motor progression, thus advancing the development of more effective and personalized therapeutics. In this work, we present an explainable, geometric, weighted-graph attention neural network (xGW-GAT) to identify functional networks predictive of the progression of gait difficulties in individuals with PD. xGW-GAT predicts the multi-class gait impairment on the MDS Unified PD Rating Scale (MDS-UPDRS). Our computational- and data-efficient model represents functional connectomes as symmetric positive definite (SPD) matrices on a Riemannian manifold to explicitly encode pairwise interactions of entire connectomes, based on which we learn an attention mask yielding individual- and group-level explainability. Applied to our resting-state functional MRI (rs-fMRI) dataset of individuals with PD, xGW-GAT identifies functional connectivity patterns associated with gait impairment in PD and offers interpretable explanations of functional subnetworks associated with motor impairment. Our model successfully outperforms several existing methods while simultaneously revealing clinically-relevant connectivity patterns. The source code is available at https://github.com/favour-nerrise/xGW-GAT .