Authors: Atlee A. Witt, Anna J. E. Combes, Grace Sweeney, Logan E. Prock, Delaney Houston, Seth Stubblefield, Colin D. McKnight, Kristin P. O’Grady, Seth A. Smith, Kurt G. Schilling

Journal: Frontiers in Neuroimaging (2025)

Link: https://www.frontiersin.org/journals/neuroimaging/articles/10.3389/fnimg.2025.1599966/full

Summary

Leveraging diffusion tensor imaging and an along-level analysis, this study assesses structural integrity across multiple spatial scales, offering a comprehensive framework to understand both the magnitude and localization of multiple sclerosis (MS)-related spinal cord alterations. By utilizing the anatomic localization inherently defined by cervical levels, this study provides an alternative, complementary approach to tractography for modeling white matter (WM) integrity and mapping microstructural (i.e. fractional anisotropy) and macrostructural (i.e. cross-sectional area) variations along specific pathways. 

Key findings include no noted group differences in whole cord WM or gray matter (GM) macrostructure between healthy controls and persons with MS, with demonstrated differences in WM/GM microstructure. Additionally, along-level analyses provided enhanced sensitivity to group differences at specific spatial locations, with detailed segmentation of WM tracts and GM subregions revealing spatially discrete alterations along the cord. Notably, while GM atrophy was associated with clinical disability, microstructural changes did not exhibit significant correlations with disability measures. These findings underscore the utility of level-specific analysis in detecting localized pathology and suggest a refined framework for characterizing spinal cord alterations in MS.

Authors: Kurt G. Schilling, Marco Palombo, Atlee A. Witt, Kristin P. O’Grady, Marco Pizzolato, Bennett A. Landmana, Seth A. Smith

Journal: Imaging Neuroscience (2025)

Link: https://direct.mit.edu/imag/article/doi/10.1162/IMAG.a.111/132048/Characterization-of-neurite-and-soma-organization

Abstract

The central nervous system (CNS), comprising both the brain and spinal cord, is a complex network of white and gray matter responsible for sensory, motor, and cognitive functions. Advanced diffusion MRI (dMRI) techniques offer a promising mechanism to non-invasively characterize CNS architecture, however, most studies focus on the brain or spinal cord in isolation. Here, we implemented a clinically feasible dMRI protocol on a 3T scanner to simultaneously characterize neurite and soma microstructure of both the brain and spinal cord. The protocol enabled the use of Diffusion Tensor Imaging (DTI), Standard Model Imaging (SMI), and Soma and Neurite Density Imaging (SANDI), representing the first time SMI and SANDI have been evaluated in the cord, and in the cord and brain simultaneously. Our results demonstrate high image quality even at high diffusion weightings, reproducibility of SMI-and SANDI-derived metrics similar to those of DTI with few exceptions, and biologically feasible contrasts between and within white and gray matter regions. Reproducibility and contrasts were decreased in the cord compared with that of the brain, revealing challenges due to partial volume effects and image preprocessing. This study establishes a harmonized approach for brain and cord microstructural imaging, and the opportunity to study CNS pathologies and biomarkers of structural integrity across the neuroaxis.

Authors: Kurt G. Schilling, Allen Newton, Chantal Tax, Markus Nilsson, Maxime Chamberland, Adam Anderson, Bennett Landman, Maxime Descoteaux

Journal: Human Brain Mapping (2025)

Link: http://dx.doi.org/10.1002/hbm.70282

Summary

Background: The perivascular space (PVS) is integral to glymphatic function, facilitating fluid exchange and waste clearance in the brain. Here, we take a critical look at a recently proposed noninvasive marker of perivascular diffusion: the Diffusion tensor imaging along the perivascular space (DTI-ALPS) index. The ALPS measure inherently assumes that diffusion perpendicular to white matter pathways is the same in all directions (i.e., radial symmetry, characterized by equal transverse diffusion eigenvalues, λ2 = λ3), and interprets deviations (i.e., radial asymmetry, where λ2 > λ3) as reflecting PVS contributions. However, we test whether anatomical or microstructural features may incluence these measures. 

Results: We show that radial asymmetry is widespread across white matter and persists even at high b-values, suggesting a dominant contribution from axonal geometry rather than faster PVS-specific diffusion. Crossing fibers significantly inflate ALPS indices, with greater radial asymmetry observed in regions with a greater prevalence of crossing fibers. Furthermore, anisotropic axonal dispersion and undulations introduce systematic asymmetry independent of perivascular diffusion. Finally, high-resolution vascular imaging reveals substantial heterogeneity in medullary vein orientation, challenging the assumption that PVS consistently aligns with the left–right axis in ALPS regions. 

Why this matters: ALPS indices are significantly influenced by white matter microstructure, including fiber crossings, undulations, and dispersion. These findings suggest that ALPS-derived metrics may not provide a direct measure of glymphatic function but rather reflect underlying axonal geometry. Interpretations of ALPS-derived metrics as biomarkers of glymphatic function must consider these anatomical complexities

Authors: Kurt Schilling, Fan Zhang, Claudio Román, Lauren O’Donnell, Pamela Guevara

Journal: Brain Structure and Function (2025)

Summary: This correspondence outlines key insights into the tractography of short association fibers (SAFs), using a “Did You Know” format to highlight current challenges, progress, and future directions. (1) Did you know SAFs form a dense mesh of superficial white matter and differ from long-range tracts in structure, development, and vulnerability? (2) Did you know reconstructing SAFs is difficult due to their short length, high curvature, and proximity to cortex? (3) Did you know recent advances in acquisition, modeling, and segmentation - like deep learning and high-resolution MRI - have made SAF tractography feasible? (4) Did you know there is no standard classification for SAFs, with atlases and clustering strategies still evolving? (5) Did you know SAFs are sensitive to developmental and pathological changes and are implicated in Alzheimer’s, schizophrenia, autism, and MS?

Authors: Chloe Cho, Maxime Chamberland, Francois Rheault, Daniel Moyer, Bennett Landman, Kurt Schilling

Journal: Human Brain Mapping (2025)

Summary: This study investigates the microstructural development of short association fibers (SAFs) in relation to long-range white matter tracts during normative development. Using DTI and NODDI models in a large cohort of youth aged 5–22 years, we identify shared and distinct developmental trajectories across superficial and deep white matter. Key differences emerged in features like FA, AD, and ODI, suggesting unique maturation profiles between these types of fibers. Significant sex and age-sex interaction effects were also observed. This study provides insights into typical microstructural changes of SAFs and long-range white matter tracts during development, laying a foundation for future research to investigate atypical development and dysfunction in disease pathology.

Authors: Ileana O. Jelescu, Francesco Grussu, Andrada Ianus, Brian Hansen, Rachel L. C. Barrett, Manisha Aggarwal, Stijn Michielse, Fatima Nasrallah, Warda Syeda, Nian Wang, Jelle Veraart, Alard Roebroeck, Andrew F. Bagdasarian, Cornelius Eichner, Farshid Sepehrband, Jan Zimmermann, Lucas Soustelle, Christien Bowman, Benjamin C. Tendler, Andreea Hertanu, Ben Jeurissen, Marleen Verhoye, Lucio Frydman, Yohan van de Looij, David Hike, Jeff F. Dunn, Karla Miller, Bennett A. Landman, Noam Shemesh, Adam Anderson, Emilie McKinnon, Shawna Farquharson, Flavio Dell’Acqua, Carlo Pierpaoli, Ivana Drobnjak, Alexander Leemans, Kevin D. Harkins, Maxime Descoteaux, Duan Xu, Hao Huang, Mathieu D. Santin, Samuel C. Grant, Andre Obenaus, Gene S. Kim, Dan Wu, Denis Le Bihan, Stephen J. Blackband, Luisa Ciobanu, Els Fieremans, Ruiliang Bai, Trygve B. Leergaard, Jiangyang Zhang, Tim B. Dyrby, G. Allan Johnson, Julien Cohen-Adad, Matthew D. Budde, Kurt G. Schilling

Journal: Magnetic Resonance in Medicine (2025)

Summary: These three papers from the ISMRM Diffusion Study Group provide best practices and recommendations for preclinical diffusion MRI (dMRI). Part 1 focuses on in vivo small-animal imaging, detailing considerations for species selection, imaging protocols, and analysis to enhance rigor and reproducibility​. Part 2 explores ex vivo imaging, highlighting its advantages—such as higher resolution, improved signal-to-noise ratio (SNR), and direct histological comparisons—while addressing challenges in tissue preparation and acquisition​. Part 3 covers ex vivo data processing, discussing preprocessing steps, diffusion model fitting, and comparisons with microscopy and tractography, aiming to improve methodological validation and open science efforts​. Together, these works provide a comprehensive guide to optimizing preclinical dMRI research.