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.
Existing foundation models for neuroimaging are often prohibitively large and data-intensive. We introduce BrainSymphony, a lightweight, parameter-efficient foundation model that achieves state-of-the-art performance while being pre-trained on significantly smaller public datasets. BrainSymphony's strong multimodal architecture processes functional MRI data through parallel spatial and temporal transformer streams, which are then efficiently distilled into a unified representation by a Perceiver module. Concurrently, it models structural connectivity from diffusion MRI using a novel signed graph transformer to encode the brain's anatomical structure. These powerful, modality-specific representations are then integrated via an adaptive fusion gate. Despite its compact design, our model consistently outperforms larger models on a diverse range of downstream benchmarks, including classification, prediction, and unsupervised network identification tasks. Furthermore, our model revealed novel insights into brain dynamics using attention maps on a unique external psilocybin neuroimaging dataset (pre- and post-administration). BrainSymphony establishes that architecturally-aware, multimodal models can surpass their larger counterparts, paving the way for more accessible and powerful research in computational neuroscience.
The organization and connectivity of the arcuate fasciculus (AF) in nonhuman primates remain contentious, especially concerning how its anatomy diverges from that of humans. Here, we combined cross-scale single-neuron tracing - using viral-based genetic labeling and fluorescence micro-optical sectioning tomography in macaques (n = 4; age 3 - 11 years) - with whole-brain tractography from 11.7T diffusion MRI. Complemented by spectral embedding analysis of 7.0T MRI in humans, we performed a comparative connectomic analysis of the AF across species. We demonstrate that the macaque AF originates in the temporal-parietal cortex, traverses the auditory cortex and parietal operculum, and projects into prefrontal regions. In contrast, the human AF exhibits greater expansion into the middle temporal gyrus and stronger prefrontal and parietal operculum connectivity - divergences quantified by Kullback-Leibler analysis that likely underpin the evolutionary specialization of human language networks. These interspecies differences - particularly the human AF's broader temporal integration and strengthened frontoparietal linkages - suggest a connectivity-based substrate for the emergence of advanced language processing unique to humans. Furthermore, our findings offer a neuroanatomical framework for understanding AF-related disorders such as aphasia and dyslexia, where aberrant connectivity disrupts language function.
Diffusion magnetic resonance imaging (dMRI) enables non-invasive investigation of tissue microstructure. The Standard Model (SM) of white matter aims to disentangle dMRI signal contributions from intra- and extra-axonal water compartments. However, due to the model its high-dimensional nature, extensive acquisition protocols with multiple b-values and diffusion tensor shapes are typically required to mitigate parameter degeneracies. Even then, accurate estimation remains challenging due to noise. This work introduces a novel estimation framework based on implicit neural representations (INRs), which incorporate spatial regularization through the sinusoidal encoding of the input coordinates. The INR method is evaluated on both synthetic and in vivo datasets and compared to parameter estimates using cubic polynomials, supervised neural networks, and nonlinear least squares. Results demonstrate superior accuracy of the INR method in estimating SM parameters, particularly in low signal-to-noise conditions. Additionally, spatial upsampling of the INR can represent the underlying dataset anatomically plausibly in a continuous way, which is unattainable with linear or cubic interpolation. The INR is fully unsupervised, eliminating the need for labeled training data. It achieves fast inference ($\sim$6 minutes), is robust to both Gaussian and Rician noise, supports joint estimation of SM kernel parameters and the fiber orientation distribution function with spherical harmonics orders up to at least 8 and non-negativity constraints, and accommodates spatially varying acquisition protocols caused by magnetic gradient non-uniformities. The combination of these properties along with the possibility to easily adapt the framework to other dMRI models, positions INRs as a potentially important tool for analyzing and interpreting diffusion MRI data.
Diffusion MRI (dMRI) tractography enables in vivo mapping of brain structural connections, but traditional connectome generation is time-consuming and requires gray matter parcellation, posing challenges for large-scale studies. We introduce DeepMultiConnectome, a deep-learning model that predicts structural connectomes directly from tractography, bypassing the need for gray matter parcellation while supporting multiple parcellation schemes. Using a point-cloud-based neural network with multi-task learning, the model classifies streamlines according to their connected regions across two parcellation schemes, sharing a learned representation. We train and validate DeepMultiConnectome on tractography from the Human Connectome Project Young Adult dataset ($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.
Accurately delineating the visual pathway (VP) is crucial for understanding the human visual system and diagnosing related disorders. Exploring multi-parametric MR imaging data has been identified as an important way to delineate VP. However, due to the complex cross-sequence relationships, existing methods cannot effectively model the complementary information from different MRI sequences. In addition, these existing methods heavily rely on large training data with labels, which is labor-intensive and time-consuming to obtain. In this work, we propose a novel semi-supervised multi-parametric feature decomposition framework for VP delineation. Specifically, a correlation-constrained feature decomposition (CFD) is designed to handle the complex cross-sequence relationships by capturing the unique characteristics of each MRI sequence and easing the multi-parametric information fusion process. Furthermore, a consistency-based sample enhancement (CSE) module is developed to address the limited labeled data issue, by generating and promoting meaningful edge information from unlabeled data. We validate our framework using two public datasets, and one in-house Multi-Shell Diffusion MRI (MDM) dataset. Experimental results demonstrate the superiority of our approach in terms of delineation performance when compared to seven state-of-the-art approaches.
Over the years, ComBAT has become the standard method for harmonizing MRI-derived measurements, with its ability to compensate for site-related additive and multiplicative biases while preserving biological variability. However, ComBAT relies on a set of assumptions that, when violated, can result in flawed harmonization. In this paper, we thoroughly review ComBAT's mathematical foundation, outlining these assumptions, and exploring their implications for the demographic composition necessary for optimal results. Through a series of experiments involving a slightly modified version of ComBAT called Pairwise-ComBAT tailored for normative modeling applications, we assess the impact of various population characteristics, including population size, age distribution, the absence of certain covariates, and the magnitude of additive and multiplicative factors. Based on these experiments, we present five essential recommendations that should be carefully considered to enhance consistency and supporting reproducibility, two essential factors for open science, collaborative research, and real-life clinical deployment.
Diffusion MRI (dMRI) is essential for studying brain microstructure, but high-resolution imaging remains challenging due to the inherent trade-offs between acquisition time and signal-to-noise ratio (SNR). Conventional methods often optimize only the diffusion-weighted images (DWIs) without considering their relationship with the non-diffusion-weighted (b=0) reference images. However, calculating diffusion metrics, such as the apparent diffusion coefficient (ADC) and diffusion tensor with its derived metrics like fractional anisotropy (FA) and mean diffusivity (MD), relies on the ratio between each DWI and the b=0 image, which is crucial for clinical observation and diagnostics. In this study, we demonstrate that solely enhancing DWIs using a conventional pixel-wise mean squared error (MSE) loss is insufficient, as the error in ratio between generated DWIs and b=0 diverges. We propose a novel ratio loss, defined as the MSE loss between the predicted and ground-truth log of DWI/b=0 ratios. Our results show that incorporating the ratio loss significantly improves the convergence of this ratio error, achieving lower ratio MSE and slightly enhancing the peak signal-to-noise ratio (PSNR) of generated DWIs. This leads to improved dMRI super-resolution and better preservation of b=0 ratio-based features for the derivation of diffusion metrics.
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.
The segmentation of cranial nerves (CNs) tract provides a valuable quantitative tool for the analysis of the morphology and trajectory of individual CNs. Multimodal CNs tract segmentation networks, e.g., CNTSeg, which combine structural Magnetic Resonance Imaging (MRI) and diffusion MRI, have achieved promising segmentation performance. However, it is laborious or even infeasible to collect complete multimodal data in clinical practice due to limitations in equipment, user privacy, and working conditions. In this work, we propose a novel arbitrary-modal fusion network for volumetric CNs tract segmentation, called CNTSeg-v2, which trains one model to handle different combinations of available modalities. Instead of directly combining all the modalities, we select T1-weighted (T1w) images as the primary modality due to its simplicity in data acquisition and contribution most to the results, which supervises the information selection of other auxiliary modalities. Our model encompasses an Arbitrary-Modal Collaboration Module (ACM) designed to effectively extract informative features from other auxiliary modalities, guided by the supervision of T1w images. Meanwhile, we construct a Deep Distance-guided Multi-stage (DDM) decoder to correct small errors and discontinuities through signed distance maps to improve segmentation accuracy. We evaluate our CNTSeg-v2 on the Human Connectome Project (HCP) dataset and the clinical Multi-shell Diffusion MRI (MDM) dataset. Extensive experimental results show that our CNTSeg-v2 achieves state-of-the-art segmentation performance, outperforming all competing methods.
This work aims to characterise renal tumour microstructure using diffusion MRI (dMRI); via the Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumours (VERDICT)-MRI framework with self-supervised learning. Comprehensive datasets were acquired from 14 patients with 15 biopsy-confirmed renal tumours, with nine b-values in the range b=[0,2500]s/mm2. A three-compartment VERDICT model for renal tumours was fitted to the dMRI data using a self-supervised deep neural network, and ROIs were drawn by an experienced uroradiologist. An economical acquisition protocol for future studies with larger patient cohorts was optimised using a recursive feature selection approach. The VERDICT model described the diffusion data in renal tumours more accurately than IVIM or ADC. Combined with self-supervised deep learning, VERDICT identified significant differences in the intracellular volume fraction between cancerous and normal tissue, and in the vascular volume fraction between vascular and non-vascular. The feature selector yields a 4 b-value acquisition of b = [70,150,1000,2000], with a duration of 14 minutes.
Early and accurate assessment of brain microstructure 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.
Whole-brain tractography in diffusion MRI is often followed by a parcellation in which each streamline is classified as belonging to a specific white matter bundle, or discarded as a false positive. Efficient parcellation is important both in large-scale studies, which have to process huge amounts of data, and in the clinic, where computational resources are often limited. TractCloud is a state-of-the-art approach that aims to maximize accuracy with a local-global representation. We demonstrate that the local context does not contribute to the accuracy of that approach, and is even detrimental when dealing with pathological cases. Based on this observation, we propose PETParc, a new method for Parallel Efficient Tractography Parcellation. PETParc is a transformer-based architecture in which the whole-brain tractogram is randomly partitioned into sub-tractograms whose streamlines are classified in parallel, while serving as global context for each other. This leads to a speedup of up to two orders of magnitude relative to TractCloud, and permits inference even on clinical workstations without a GPU. PETParc accounts for the lack of streamline orientation either via a novel flip-invariant embedding, or by simply using flips as part of data augmentation. Despite the speedup, results are often even better than those of prior methods. The code and pretrained model will be made public upon acceptance.
Diffusion MRI (dMRI) plays a crucial role in studying brain white matter connectivity. Cortical surface reconstruction (CSR), including the inner whiter matter (WM) and outer pial surfaces, is one of the key tasks in dMRI analyses such as fiber tractography and multimodal MRI analysis. Existing CSR methods rely on anatomical T1-weighted data and map them into the dMRI space through inter-modality registration. However, due to the low resolution and image distortions of dMRI data, inter-modality registration faces significant challenges. This work proposes a novel end-to-end learning framework, DDCSR, which for the first time enables CSR directly from dMRI data. DDCSR consists of two major components, including: (1) an implicit learning module to predict a voxel-wise intermediate surface representation, and (2) an explicit learning module to predict the 3D mesh surfaces. Compared to several baseline and advanced CSR methods, we show that the proposed DDCSR can largely increase both accuracy and efficiency. Furthermore, we demonstrate a high generalization ability of DDCSR to data from different sources, despite the differences in dMRI acquisitions and populations.
Brain nuclei are clusters of anatomically distinct neurons that serve as important hubs for processing and relaying information in various neural circuits. Fine-scale parcellation of the brain nuclei is vital for a comprehensive understanding of its anatomico-functional correlations. Diffusion MRI tractography is an advanced imaging technique that can estimate the brain's white matter structural connectivity to potentially reveal the topography of the nuclei of interest for studying its subdivisions. In this work, we present a deep clustering pipeline, namely DeepNuParc, to perform automated, fine-scale parcellation of brain nuclei using diffusion MRI tractography. First, we incorporate a newly proposed deep learning approach to enable accurate segmentation of the nuclei of interest directly on the dMRI data. Next, we design a novel streamline clustering-based structural connectivity feature for a robust representation of voxels within the nuclei. Finally, we improve the popular joint dimensionality reduction and k-means clustering approach to enable nuclei parcellation at a finer scale. We demonstrate DeepNuParc on two important brain structures, i.e. the amygdala and the thalamus, that are known to have multiple anatomically and functionally distinct nuclei subdivisions. Experimental results show that DeepNuParc enables consistent parcellation of the nuclei into multiple parcels across multiple subjects and achieves good correspondence with the widely used coarse-scale atlases. Our codes are available at https://github.com/HarlandZZC/deep_nuclei_parcellation.
Registration of diffusion MRI tractography is an essential step for analyzing group similarities and variations in the brain's white matter (WM). Streamline-based registration approaches can leverage the 3D geometric information of fiber pathways to enable spatial alignment after registration. Existing methods usually rely on the optimization of the spatial distances to identify the optimal transformation. However, such methods overlook point connectivity patterns within the streamline itself, limiting their ability to identify anatomical correspondences across tractography datasets. In this work, we propose a novel unsupervised approach using deep learning to perform streamline-based dMRI tractography registration. The overall idea is to identify corresponding keypoint pairs across subjects for spatial alignment of tractography datasets. We model tractography as point clouds to leverage the graph connectivity along streamlines. We propose a novel keypoint detection method for streamlines, framed as a probabilistic classification task to identify anatomically consistent correspondences across unstructured streamline sets. In the experiments, we compare several existing methods and show highly effective and efficient tractography registration performance.
Diffusion MRI tractography technique enables non-invasive visualization of the white matter pathways in the brain. It plays a crucial role in neuroscience and clinical fields by facilitating the study of brain connectivity and neurological disorders. However, the accuracy of reconstructed tractograms has been a longstanding challenge. Recently, deep learning methods have been applied to improve tractograms for better white matter coverage, but often comes at the expense of generating excessive false-positive connections. This is largely due to their reliance on local information to predict long range streamlines. To improve the accuracy of streamline propagation predictions, we introduce a novel deep learning framework that integrates image-domain spatial information and anatomical information along tracts, with the former extracted through convolutional layers and the later modeled via a Transformer-decoder. Additionally, we employ a weighted loss function to address fiber class imbalance encountered during training. We evaluate the proposed method on the simulated ISMRM 2015 Tractography Challenge dataset, achieving a valid streamline rate of 66.2%, white matter coverage of 63.8%, and successfully reconstructing 24 out of 25 bundles. Furthermore, on the multi-site Tractoinferno dataset, the proposed method demonstrates its ability to handle various diffusion MRI acquisition schemes, achieving a 5.7% increase in white matter coverage and a 4.1% decrease in overreach compared to RNN-based methods.
We propose Microscopic Propagator Imaging (MPI) as a novel method to retrieve the indices of the microscopic propagator which is the probability density function of water displacements due to diffusion within the nervous tissue microstructures. Unlike the Ensemble Average Propagator indices or the Diffusion Tensor Imaging metrics, MPI indices are independent from the mesoscopic organization of the tissue such as the presence of multiple axonal bundle directions and orientation dispersion. As a consequence, MPI indices are more specific to the volumes, sizes, and types of microstructures, like axons and cells, that are present in the tissue. Thus, changes in MPI indices can be more directly linked to alterations in the presence and integrity of microstructures themselves. The methodology behind MPI is rooted on zonal modeling of spherical harmonics, signal simulation, and machine learning regression, and is demonstrated on both synthetic and Human Diffusion MRI data.
Diffusion MRI (dMRI) provides unique insights into fetal brain microstructure in utero. Longitudinal and cross-sectional fetal dMRI studies can reveal crucial neurodevelopmental changes but require precise spatial alignment across scans and subjects. This is challenging due to low data quality, rapid brain development, and limited anatomical landmarks. Existing registration methods, designed for high-quality adult data, struggle with these complexities. To address this, we introduce FetDTIAlign, a deep learning approach for fetal brain dMRI registration, enabling accurate affine and deformable alignment. FetDTIAlign features a dual-encoder architecture and iterative feature-based inference, reducing the impact of noise and low resolution. It optimizes network configurations and domain-specific features at each registration stage, enhancing both robustness and accuracy. We validated FetDTIAlign on data from 23 to 36 weeks gestation, covering 60 white matter tracts. It consistently outperformed two classical optimization-based methods and a deep learning pipeline, achieving superior anatomical correspondence. Further validation on external data from the Developing Human Connectome Project confirmed its generalizability across acquisition protocols. Our results demonstrate the feasibility of deep learning for fetal brain dMRI registration, providing a more accurate and reliable alternative to classical techniques. By enabling precise cross-subject and tract-specific analyses, FetDTIAlign supports new discoveries in early brain development.
We propose ReMiDi, a novel method for inferring neuronal microstructure as arbitrary 3D meshes using a differentiable diffusion Magnetic Resonance Imaging (dMRI) simulator. We first implemented in PyTorch a differentiable dMRI simulator that simulates the forward diffusion process using a finite-element method on an input 3D microstructure mesh. To achieve significantly faster simulations, we solve the differential equation semi-analytically using a matrix formalism approach. Given a reference dMRI signal $S_{ref}$, we use the differentiable simulator to iteratively update the input mesh such that it matches $S_{ref}$ using gradient-based learning. Since directly optimizing the 3D coordinates of the vertices is challenging, particularly due to ill-posedness of the inverse problem, we instead optimize a lower-dimensional latent space representation of the mesh. The mesh is first encoded into spectral coefficients, which are further encoded into a latent $\textbf{z}$ using an auto-encoder, and are then decoded back into the true mesh. We present an end-to-end differentiable pipeline that simulates signals that can be tuned to match a reference signal by iteratively updating the latent representation $\textbf{z}$. We demonstrate the ability to reconstruct microstructures of arbitrary shapes represented by finite-element meshes, with a focus on axonal geometries found in the brain white matter, including bending, fanning and beading fibers. Our source code is available online.