A fundamental challenge in neuroscience is to estimate the structure of white matter connectivity inthehuman brainorconnectomes [14,29]. Connectomes aremadeupofneuronal axonbundles wrapped with myelin sheaths, called fascicles, and connect different areas ofthe brain.

Structural connectomes are detailed graphs that map how different brain regions are physically connected, offering critical insight into aging, cognition, and neurodegenerative diseases. However, these connectomes are high-dimensional and densely interconnected, which makes them difficult to interpret and analyze at scale. While low-dimensional spaces like PCA and autoencoders are often used to capture major sources of variation, their latent spaces are generally continuous and cannot fully reflect the mixed nature of variability in connectomes, which include both continuous (e.g., connectivity strength) and discrete factors (e.g., imaging site). Motivated by this, we propose a variational autoencoder (VAE) with a hybrid latent space that jointly models the discrete and continuous components. We analyze a large dataset of 5,761 connectomes from six Alzheimer's disease studies with ten acquisition protocols. Each connectome represents a single scan from a unique subject (3579 females, 2182 males), aged 22 to 102, with 4338 cognitively normal, 809 with mild cognitive impairment (MCI), and 614 with Alzheimer's disease (AD). Each connectome contains 121 brain regions defined by the BrainCOLOR atlas. We train our hybrid VAE in an unsupervised way and characterize what each latent component captures. We find that the discrete space is particularly effective at capturing subtle site-related differences, achieving an Adjusted Rand Index (ARI) of 0.65 with site labels, significantly outperforming PCA and a standard VAE followed by clustering (p < 0.05). These results demonstrate that the hybrid latent space can disentangle distinct sources of variability in connectomes in an unsupervised manner, offering potential for large-scale connectome analysis.

Diffusion-weighted MRI allows us to estimate structural brain connections in-vivo by measuring the diffusion of water molecules at different spatial directions.

Shape measures have emerged as promising descriptors of white matter tractography, offering complementary insights into anatomical variability and associations with cognitive and clinical phenotypes. However, conventional methods for computing shape measures are computationally expensive and time-consuming for large-scale datasets due to reliance on voxel-based representations. We propose Tract2Shape, a novel multimodal deep learning framework that leverages geometric (point cloud) and scalar (tabular) features to predict ten white matter tractography shape measures. To enhance model efficiency, we utilize a dimensionality reduction algorithm for the model to predict five primary shape components. The model is trained and evaluated on two independently acquired datasets, the HCP-YA dataset, and the PPMI dataset. We evaluate the performance of Tract2Shape by training and testing it on the HCP-YA dataset and comparing the results with state-of-the-art models. To further assess its robustness and generalization ability, we also test Tract2Shape on the unseen PPMI dataset. Tract2Shape outperforms SOTA deep learning models across all ten shape measures, achieving the highest average Pearson's r and the lowest nMSE on the HCP-YA dataset. The ablation study shows that both multimodal input and PCA contribute to performance gains. On the unseen testing PPMI dataset, Tract2Shape maintains a high Pearson's r and low nMSE, demonstrating strong generalizability in cross-dataset evaluation. Tract2Shape enables fast, accurate, and generalizable prediction of white matter shape measures from tractography data, supporting scalable analysis across datasets. This framework lays a promising foundation for future large-scale white matter shape analysis.

--Early and accurate assessment of brain microstruc-ture using diffusion Magnetic Resonance Imaging (dMRI) is crucial for identifying neurodevelopmental disorders in neonates, but remains challenging due to low signal-to-noise ratio (SNR), motion artifacts, and ongoing myelination. In this study, we propose a rotationally equivariant Spherical Convolutional Neural Network (sCNN) framework tailored for neonatal dMRI. We predict the Fiber Orientation Distribution (FOD) from multi-shell dMRI signals acquired with a reduced set of gradient directions (30% of the full protocol), enabling faster and more cost-effective acquisitions. We train and evaluate the performance of our sCNN using real data from 43 neonatal dMRI datasets provided by the Developing Human Connectome Project (dHCP). Our results demonstrate that the sCNN achieves significantly lower mean squared error (MSE) and higher angular correlation coefficient (ACC) compared to a Multi-Layer Perceptron (MLP) baseline, indicating improved accuracy in FOD estimation. Furthermore, tractography results based on the sCNN-predicted FODs show improved anatomical plausibility, coverage, and coherence compared to those from the MLP . These findings highlight that sCNNs, with their inherent rotational equivariance, offer a promising approach for accurate and clinically efficient dMRI analysis, paving the way for improved diagnostic capabilities and characterization of early brain development. Medical diagnostics is undergoing a transformative shift, fueled by the rapid advancements in artificial intelligence (AI) and deep learning.

A data-driven approach, however, could overcome limitations in such rule-based approaches and improve precision mappings for individuals.

Anatomic tracer studies are critical for validating and improving diffusion MRI (dMRI) tractography. However, large-scale analysis of data from such studies is hampered by the labor-intensive process of annotating fiber bundles manually on histological slides. Existing automated methods often miss sparse bundles or require complex post-processing across consecutive sections, limiting their flexibility and generalizability. We present a streamlined, fully automated framework for fiber bundle segmentation in macaque tracer data, based on a U-Net architecture with large patch sizes, foreground aware sampling, and semi-supervised pre-training. Our approach eliminates common errors such as mislabeling terminals as bundles, improves detection of sparse bundles by over 20% and reduces the False Discovery Rate (FDR) by 40% compared to the state-of-the-art, all while enabling analysis of standalone slices. This new framework will facilitate the automated analysis of anatomic tracing data at a large scale, generating more ground-truth data that can be used to validate and optimize dMRI tractography methods.

Tractography algorithms leverage diffusion MRI to reconstruct the fibrous architecture of the brain's white matter. Among machine learning approaches, reinforcement learning (RL) has emerged as a promising framework for tractography, outperforming traditional methods in several key aspects. TractOracle-RL, a recent RL-based approach, reduces false positives by incorporating anatomical priors into the training process via a reward-based mechanism. In this paper, we investigate four extensions of the original TractOracle-RL framework by integrating recent advances in RL, and we evaluate their performance across five diverse diffusion MRI datasets. Results demonstrate that combining an oracle with the RL framework consistently leads to robust and reliable tractography, regardless of the specific method or dataset used. We also introduce a novel RL training scheme called Iterative Reward Training (IRT), inspired by the Reinforcement Learning from Human Feedback (RLHF) paradigm. Instead of relying on human input, IRT leverages bundle filtering methods to iteratively refine the oracle's guidance throughout training. Experimental results show that RL methods trained with oracle feedback significantly outperform widely used tractography techniques in terms of accuracy and anatomical validity.

Diffusion MRI (dMRI) tractography enables in vivo mapping of brain structural connections, but traditional connectome generation is time-consuming and requires gray matter parcellation, posing challenges for large-scale studies. We introduce DeepMultiConnectome, a deep-learning model that predicts structural connectomes directly from tractography, bypassing the need for gray matter parcellation while supporting multiple parcellation schemes. Using a point-cloud-based neural network with multi-task learning, the model classifies streamlines according to their connected regions across two parcellation schemes, sharing a learned representation. We train and validate DeepMultiConnectome on tractography from the Human Connectome Project Young Adult dataset ($n = 1000$), labeled with an 84 and 164 region gray matter parcellation scheme. DeepMultiConnectome predicts multiple structural connectomes from a whole-brain tractogram containing 3 million streamlines in approximately 40 seconds. DeepMultiConnectome is evaluated by comparing predicted connectomes with traditional connectomes generated using the conventional method of labeling streamlines using a gray matter parcellation. The predicted connectomes are highly correlated with traditionally generated connectomes ($r = 0.992$ for an 84-region scheme; $r = 0.986$ for a 164-region scheme) and largely preserve network properties. A test-retest analysis of DeepMultiConnectome demonstrates reproducibility comparable to traditionally generated connectomes. The predicted connectomes perform similarly to traditionally generated connectomes in predicting age and cognitive function. Overall, DeepMultiConnectome provides a scalable, fast model for generating subject-specific connectomes across multiple parcellation schemes.

Diffusion Tensor Imaging (DTI) tractography offers detailed insights into the structural connectivity of the brain, but presents challenges in effective representation and interpretation in deep learning models. In this work, we propose a novel 2D representation of DTI tractog-raphy that encodes tract-level fractional anisotropy (F A) values into a 9 9 grayscale image. This representation is processed through a Beta-Total Correlation Variational Autoencoder ( β -TCV AE) with a Spatial Broadcast Decoder to learn a disentangled and interpretable latent embedding. We evaluate the quality of this embedding using supervised and unsupervised representation learning strategies, including auxiliary classification, triplet loss, and SimCLR-based contrastive learning. Compared to the 1D Group deep neural network (DNN) baselines, our approach improves the F1 score in a downstream sex classification task by 12.64% and shows a better disentanglement than the 3D representation.