Faculty Bibliography

Axon caliber plays a crucial role in determining conduction velocity and, consequently, in the timing and synchronization of neural activation. Noninvasive measurement of axon radii could have significant impact on the understanding of healthy and diseased neural processes. Until now, accurate axon radius mapping has eluded in vivo neuroimaging, mainly due to a lack of sensitivity of the MRI signal to micron-sized axons. Here, we show how - when confounding factors such as extra-axonal water and axonal orientation dispersion are eliminated - heavily diffusion-weighted MRI signals become sensitive to axon radii. However, diffusion MRI is only capable of estimating a single metric, the effective radius, representing the entire axon radius distribution within a voxel that emphasizes the larger axons. Our findings, both in rodents and humans, enable noninvasive mapping of critical information on axon radii, as well as resolve the long-standing debate on whether axon radii can be quantified.

22q11.2 deletion syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia and autism spectrum disorders, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterization of white matter microstructure in participants with 22q11.2DS (12-15 years) and those undergoing typical development (8-18 years) using a customized magnetic resonance imaging scanner which is sensitive to axonal morphology. A rich array of diffusion MRI metrics are extracted to present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences in individuals with 22q11.2DS. A recent, large-scale consortium study of 22q11.2DS identified higher diffusion anisotropy and reduced overall diffusion mobility of water as hallmark microstructural alterations of white matter in individuals across a wide age range (6-52 years). We observed similar findings across the white matter tracts included in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that abnormal microstructural connectivity in 22q11.2DS may be mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo white matter phenotype of 22q11.2DS, and promote the continued investigation of shared features in neurodevelopmental and psychiatric disorders.

PURPOSE/OBJECTIVE:The general utility of diffusion kurtosis imaging (DKI) is challenged by its poor robustness to imaging artifacts and thermal noise that often lead to implausible kurtosis values. THEORY AND METHODS/UNASSIGNED:A robust scalar kurtosis index can be estimated from powder-averaged diffusion-weighted data. We introduce a novel DKI estimator that uses this scalar kurtosis index as a proxy for the mean kurtosis to regularize the fit. RESULTS:The regularized DKI estimator improves the robustness and reproducibility of the kurtosis metrics and results in parameter maps with enhanced quality and contrast. CONCLUSION/CONCLUSIONS:Our novel DKI estimator promotes the wider use of DKI in clinical research and potentially diagnostics by improving the reproducibility and precision of DKI fitting and, as such, enabling enhanced visual, quantitative, and statistical analyses of DKI parameters.

Development of therapies for neurological disorders depends on our ability to non-invasively diagnose and monitor the progression of underlying pathologies at the cellular level. Physics and physiology limit the resolution of human MRI to be orders of magnitude coarser than cell dimensions. Here we identify and quantify the MRI signal coming from within micrometer-thin axons in human white matter tracts in vivo, by utilizing the sensitivity of diffusion MRI to Brownian motion of water molecules restricted by cell walls. We study a specific power-law scaling of the diffusion MRI signal with the diffusion weighting, predicted for water confined to narrow axons, and quantify axonal water fraction and orientation dispersion.

PURPOSE/OBJECTIVE:Ultra-low-field (ULF) MRI offers a promising path to accessible neuroimaging, with potential to address global healthcare disparities and advance population-level brain health research. However, the inherently low signal-to-noise ratio (SNR), reduced spatial resolution, and altered tissue contrasts relative to conventional high-field (HF) scans are significant barriers to ULF analysis and interpretation. While deep learning (DL) approaches have been proposed to enhance ULF image quality, many rely on synthetic training data due to the lack of available subject-matched ULF and HF scans, introducing potential "domain shift" errors when applied to real acquisitions. Here, we present a DL framework trained on real ULF and HF-MRIs to address these limitations and improve ULF-derived brain volume analysis. METHODS:A CycleGAN framework was developed for image-to-image translation across field strengths, while mitigating the need for large subject-matched ULF- and HF-MRIs. This approach enabled pretraining on large open-access MRI datasets followed by fine-tuning on real ULF scans. Model performance was evaluated through downstream brain volumetric analysis, assessing volumetric agreement with HF-derived measurements and test-retest reproducibility. We additionally explored a framework to reduce input acquisition requirements, improving scan protocol efficiency while preserving enhanced performance. RESULTS:The proposed methods significantly improved hippocampal volumetric agreement and brain segmentation accuracy between ULF- and HF-MRI compared with existing strategies. Test-retest reproducibility for DL-enhanced images was superior to that of direct segmentation on ULF scans. CONCLUSION/CONCLUSIONS:The proposed framework substantially improved the accuracy and reliability of ULF-derived brain volume measurements, particularly for subcortical structures such as the hippocampus.

Diffusion MRI fiber tractography is sensitive to noise and artifacts in diffusion-weighted images, and these challenges can propagate into fiber-orientation estimation and the tractography process. In this “Did You Know” communication, we synthesize evidence that state-of-the-art preprocessing improves tractography anatomical fidelity and test-retest reproducibility compared to minimally processed data. We summarize best-practice preprocessing – including denoising, motion and eddy current correction, EPI distortion correction, and Gibbs ringing removal – along with additional and emerging steps, and highlight integrated, publicly available pipelines that implement these methods in standardized, containerized workflows. We also outline practical acquisition and data-handling considerations that maximize the benefits of modern processing, providing a foundation for reliable tractography-based studies of the brain.

Tractography is a key component of efforts to map brain connectivity. As a rapidly evolving field of neuroscience, current tractography methods are diverse, often varying across research laboratories and different software pipelines. Therefore, it suffers from a lack of standardization, leading to inconsistencies in results, which can limit reproducibility and affect the robustness needed for research and clinical applications of these methods. Variability in data acquisition procedures, inconsistencies in spatial referencing schemes and implementations, and anatomical heterogeneity-at the individual level, across the lifespan, and across species-hinder comparative analyses. Additionally, the lack of consensus on best practices complicates the development of robust automated quality control pipelines and limits the clinical translation of tractography-based procedures. Establishing standardized protocols for acquisition, preprocessing, and tractography reconstruction is critical toward enabling reliable tract-specific analyses, facilitating cross-study harmonization, and supporting replicable large-scale population studies. The present article provides an overview of the current challenges in tractography standardization and identifies the key aspects that require standardization for reliable, reproducible, and robust tractography.

PURPOSE/OBJECTIVE:Rotational invariants (RIs) are at the root of many dMRI applications. Among others, they are presented as a sensible way of reducing the dimensionality of biophysical models. While thermal noise impact on diffusion metrics has been well studied, little is known on its effect on spherical harmonics-based RI (RISH) features and derived markers. In this work, we evaluate the effect of noise on RISH features and downstream Standard Model Imaging (SMI) estimates. THEORY AND METHODS/METHODS:Using simulated and test/retest multishell MRI data, we assess the accuracy and precision of RISH features and SMI parameters in the presence of thermal noise, as well as its robustness to variations in protocol design. We further propose and evaluate correction strategies that bypass the need of rotational invariant features as an intermediate step. RESULTS:Both RISH features and SMI estimates are impacted by SNR-dependent Rician biases. However, higher-order RISH features are susceptible to a secondary noise-related source of bias, which not only depends on SNR, but also protocol and underlying microstructure. Rician bias-correcting techniques are insufficient to maximize the accuracy of RISH and SMI features, or to ensure consistency across protocols. SMI estimators that avoid RISH features by fitting the model to the directional diffusion MRI data outperform RISH-based approaches in accuracy, repeatability, and reproducibility across acquisition protocols. CONCLUSIONS:RISH features are increasingly used in dMRI analysis, yet they are prone to various sources of noise that lower their accuracy and reproducibility. Understanding the impact of noise and mitigating such biases is critical to maximize the validity, repeatability, and reproducibility of dMRI studies.

Diffusion-weighted Magnetic Resonance Imaging (dMRI) has emerged as an imaging modality of interest to measure axon diameters noninvasively. The previously observed b ^-½ power law scaling suggests that high b-value dMRI signals originate from water confined within "stick" geometries, representing impermeable cellular processes. A key assumption is that any deviation from this power law at high b-values-modeled as a non-zero perpendicular intracellular diffusivity-must be specifically axonal in origin. Recent developments in axon diameter mapping build upon such assumptions, thereby neglecting the possibility that other cellular structures, such as glial processes, may also exhibit similar "stick"-like characteristics. This explorative study investigates the validity of axon diameter mapping by evaluating its robustness to experimental variation. In particular, it compares the mapping of the axon diameter using the zeroth- (spherical mean) and second-order (spherical variance) rotationally invariant spherical harmonic (RISH) features. As a condition for validity, axon diameter should be robust to such variations in RISH order. A novel log-linear estimator with a closed-form solution for computationally efficient axon diameter mapping is introduced, which can be applied with a minimum of two high b-value measurements. Using this estimator, it was observed that axon diameter measurements vary with RISH order, suggesting that high b-value signals from non-axonal cellular sources may confound axon diameter mapping. Monte Carlo simulations show that such dependence on RISH order could be explained by the presence of glial processes. Overall, these results highlight the need for caution in the interpretation of dMRI-derived "axon" diameter.

Optimal treatment of glioma has been a subject of debate over the last few decades, since maximal resection can improve survival, whereas preservation of functional peritumoral brain tissue minimizes the risk of postoperative neurological deficits. Our preliminary study uses tractography and neural tissue microstructure modeling based on diffusion MRI to quantify progressive axonal degeneration in proximity to frontotemporal glioma. For this, we sample major white matter pathways that traverse peritumoral penumbra at two time points. The results show a pattern of decreased intra-axonal water fraction beyond anatomical MRI abnormalities, which may indicate a tumor invasion of normal-appearing white matter that potentially advocates supratotal resection.