GenTract: Generative Global Tractography

Tractography is the process of inferring the trajectories of white-matter pathways in the brain from diffusion magnetic resonance imaging (dMRI). Local tractography methods, which construct streamlines by following local fiber orientation estimates stepwise through an image, are prone to error accumulation and high false positive rates, particularly on noisy or low-resolution data. In contrast, global methods, which attempt to optimize a collection of streamlines to maximize compatibility with underlying fiber orientation estimates, are computationally expensive. To address these challenges, we introduce GenTract, the first generative model for global tractography. We frame tractography as a generative task, learning a direct mapping from dMRI to complete, anatomically plausible streamlines. We compare both diffusion-based and flow matching paradigms and evaluate GenTract's performance against state-of-the-art baselines. Notably, GenTract achieves precision 2.1x higher than the next-best method, TractOracle. This advantage becomes even more pronounced in challenging low-resolution and noisy settings, where it outperforms the closest competitor by an order of magnitude. By producing tractograms with high precision on research-grade data while also maintaining reliability on imperfect, lower-resolution data, GenTract represents a promising solution for global tractography.

LLM enhanced graph inference for long-term disease progression modelling

Understanding the interactions between biomarkers among brain regions during neurodegenerative disease is essential for unravelling the mechanisms underlying disease progression. For example, pathophysiological models of Alzheimer's Disease (AD) typically describe how variables, such as regional levels of toxic proteins, interact spatiotemporally within a dynamical system driven by an underlying biological substrate, often based on brain connectivity. However, current methods grossly oversimplify the complex relationship between brain connectivity by assuming a single-modality brain connectome as the disease-spreading substrate. This leads to inaccurate predictions of pathology spread, especially during the long-term progression period. Meanhwile, other methods of learning such a graph in a purely data-driven way face the identifiability issue due to lack of proper constraint. We thus present a novel framework that uses Large Language Models (LLMs) as expert guides on the interaction of regional variables to enhance learning of disease progression from irregularly sampled longitudinal patient data. By leveraging LLMs' ability to synthesize multi-modal relationships and incorporate diverse disease-driving mechanisms, our method simultaneously optimizes 1) the construction of long-term disease trajectories from individual-level observations and 2) the biologically-constrained graph structure that captures interactions among brain regions with better identifiability. We demonstrate the new approach by estimating the pathology propagation using tau-PET imaging data from an Alzheimer's disease cohort. The new framework demonstrates superior prediction accuracy and interpretability compared to traditional approaches while revealing additional disease-driving factors beyond conventional connectivity measures.

A Stage-Aware Mixture of Experts Framework for Neurodegenerative Disease Progression Modelling

The long-term progression of neurodegenerative diseases is commonly conceptualized as a spatiotemporal diffusion process that consists of a graph diffusion process across the structural brain connectome and a localized reaction process within brain regions. However, modeling this progression remains challenging due to 1) the scarcity of longitudinal data obtained through irregular and infrequent subject visits and 2) the complex interplay of pathological mechanisms across brain regions and disease stages, where traditional models assume fixed mechanisms throughout disease progression. To address these limitations, we propose a novel stage-aware Mixture of Experts (MoE) framework that explicitly models how different contributing mechanisms dominate at different disease stages through time-dependent expert weighting.Data-wise, we utilize an iterative dual optimization method to properly estimate the temporal position of individual observations, constructing a co hort-level progression trajectory from irregular snapshots. Model-wise, we enhance the spatial component with an inhomogeneous graph neural diffusion model (IGND) that allows diffusivity to vary based on node states and time, providing more flexible representations of brain networks. We also introduce a localized neural reaction module to capture complex dynamics beyond standard processes.The resulting IGND-MoE model dynamically integrates these components across temporal states, offering a principled way to understand how stage-specific pathological mechanisms contribute to progression. The stage-wise weights yield novel clinical insights that align with literature, suggesting that graph-related processes are more influential at early stages, while other unknown physical processes become dominant later on.