arXiv subjects

Hong-Hsi Lee

Publications and source records attributed to Hong-Hsi Lee.

16 recordsLinked to original sources

arXiv2026

Dependence of the extra-cellular diffusion coefficient on the fractions of neurites and cell bodies in gray matter

Purpose: The dependence of the long-time (tortuosity) limit of the extra-cellular diffusivity on the intra-cellular volume fraction is of fundamental importance for microstructure modeling. While such dependencies have been explored for the white matter, the tortuosity limit in gray matter is unknown due to complex cell composition and geometry. Here we rationalize and validate numerically the analytical relation between the extra-cellular diffusivity and intra-cellular fractions of cell bodies (somas) and neurites. Methods: The tortuosity relation for extra-cellular diffusivity qualitatively follows from effective medium theory, coarse-grained by diffusion outside somas (spheres) and neurites (cylinders), respectively. This problem is equivalent to finding the overall conductivity in a medium of grains in a matrix, with methodology dating back to the 19th century. We extend the effective medium methodology to populations of impermeable spheres and randomly oriented cylinders with various volume fractions, yielding closed-form expressions corroborated by Monte Carlo simulations. Results: We establish the power-law scaling of the extra-cellular diffusivity with the volume fractions of the extra-soma and extra-neurite spaces. We further evaluate the proposed framework using simulations in realistic tissue geometries. Conclusion: Theory and simulations relate extra-cellular tortuosity to soma and neurite fractions, potentially offering a diffusion MRI protocol design optimized for in vivo assessment of soma size and soma/neurite fractions within clinical scan times. Such in vivo measurements can be used to study development, aging and neurodegenerative disorders.

physics.bio-ph↗

arXiv2026

TRACED: In vivo imaging of extracellular intrinsic diffusivity, tortuosity, cell size distribution and cell density in human glioma patients

The lack of analytical models describing diffusion time dependence at intermediate time scales in complex tissue microstructure limits the accurate quantification of extracellular diffusivity and tissue microstructure. We introduce TRACED, a biophysical model that incorporates diffusion time dependence in cell distributions to quantify pathologically-relevant properties in solid tumors. Neural networks were trained on Monte Carlo diffusion simulations using sphere distribution-based geometries to enable the rapid computation of time-dependent diffusion MRI signals in cell populations of variable cell size. Model sensitivity and fit performance were assessed via simulation. Diffusion data from eight mixed-grade glioma patients was fitted using the TRACED model. Data fitting was performed using a novel physics-informed transfer learning pipeline, Sim2PINN. In two patients, cell size measurements were compared directly with image-localized histology. Simulation results indicate improved parameter estimation compared to the simple two-compartment model. TRACED enabled the simultaneous in vivo quantification of intracellular volume fraction, cell size distribution, extracellular intrinsic diffusivity, and tortuosity in glioma patients. Neural network implementations of diffusion time-dependence and tortuosity showed behavior consistent with coarse-graining and effective medium theory, respectively. Future work will explore the clinical utility of TRACED parameters in additional patients.

physics.med-ph↗

arXiv2025

GACELLE: GPU-accelerated tools for model parameter estimation and image reconstruction

Quantitative MRI (qMRI) offers tissue-specific biomarkers that can be tracked over time or compared across populations; however, its adoption in clinical research is hindered by significant computational demands of parameter estimation. Images acquired at high spatial resolution or requiring fitting multiple parameters often require lengthy processing time, constraining their use in routine pipelines and slowing methodological innovation and clinical translation. We present GACELLE, an open source, GPU-accelerated framework for high-throughput qMRI analysis. GACELLE provides a stochastic gradient descent optimiser and a stochastic sampler in MATLAB, enabling fast parameter mapping, improved estimation robustness via spatial regularisation, and uncertainty quantification. GACELLE prioritises accessibility: users only need to provide a forward signal model, while GACELLE's backend manages computational parallelisation, automatic parameter updates, and memory-batching. The stochastic solver performs fully vectorised Markov chain Monte Carlo with identical likelihood on CPU and GPU, ensuring reproducibility across hardware. Benchmarking demonstrates up to 451-fold acceleration for the stochastic gradient descent solver and 14,380-fold acceleration for stochastic sampling compared to CPU-based estimation, without compromising accuracy. We demonstrated GACELLE's versatility on three representative qMRI models and on an image reconstruction task. Across these applications, GACELLE improves parameter precision, enhances test-retest reproducibility, and reduces noise in quantitative maps. By combining speed, usability and flexibility, GACELLE provides a generalisable optimisation framework for medical image analysis. It lowers the computational barrier for qMRI, paving the way for reproducible biomarker development, large-scale imaging studies, and clinical translation.

eess.IV↗

arXiv2025

What if each voxel were measured with a different diffusion protocol?

Expansion of diffusion MRI (dMRI) both into the realm of strong gradients, and into accessible imaging with portable low-field devices, brings about the challenge of gradient nonlinearities. Spatial variations of the diffusion gradients make diffusion weightings and directions non-uniform across the field of view, and deform perfect shells in the q-space designed for isotropic directional coverage. Such imperfections hinder parameter estimation: Anisotropic shells hamper the deconvolution of fiber orientation distribution function (fODF), while brute-force retraining of a nonlinear regressor for each unique set of directions and diffusion weightings is computationally inefficient. Here we propose a protocol-independent parameter estimation (PIPE) method that enables fast parameter estimation for the most general case where the scan in each voxel is acquired with a different protocol in q-space. PIPE applies for any spherical convolution-based dMRI model, irrespective of its complexity, which makes it suitable both for white and gray matter in the brain or spinal cord, and for other tissues where fiber bundles have the same properties within a voxel (fiber response), but are distributed with an arbitrary fODF. Applied to in vivo human MRI with linear tensor encoding on a high-performance system, PIPE maps fiber response and fODF parameters for the whole brain in the presence of significant gradient nonlinearities in under 3 minutes. PIPE enables fast parameter estimation in the presence of arbitrary gradient nonlinearities, eliminating the need to arrange dMRI in shells or to retrain the estimator for different protocols in each voxel. PIPE applies for any model based on a convolution of a voxel-wise fiber response and fODF, and data from varying b-values, diffusion/echo times, and other scan parameters.

physics.med-ph↗

arXiv2025

Scattering approach to diffusion quantifies axonal damage in brain injury

Early diagnosis and noninvasive monitoring of neurological disorders require sensitivity to elusive cellular-level alterations that occur much earlier than volumetric changes observable with the millimeter-resolution of medical imaging modalities. Morphological changes in axons, such as axonal varicosities or beadings, are observed in neurological disorders, as well as in development and aging. Here, we reveal the sensitivity of time-dependent diffusion MRI (dMRI) to the structurally disordered axonal morphology at the micrometer scale. Scattering theory uncovers the two parameters that determine the diffusive dynamics of water along axons: the average reciprocal cross-section and the variance of long-range cross-sectional fluctuations. This theoretical development allows us to predict dMRI metrics sensitive to axonal alterations over tens of thousands of axons in seconds rather than months of simulations in a rat model of traumatic brain injury, and is corroborated with ex vivo dMRI. Our approach bridges the gap between micrometers and millimeters in resolution, offering quantitative and objective biomarkers applicable to a broad spectrum of neurological disorders.

physics.med-ph↗

arXiv2025

Reduced NEXI protocol for the quantification of human gray matter microstructure on the Connectome 2.0 scanner

Biophysical diffusion MRI models like Neurite Exchange Imaging (NEXI) are essential for probing gray matter microstructure, estimating compartment diffusivities, neurite fraction, and exchange time. However, NEXI's multi-shell, multi-diffusion-time requirements cause prohibitively long acquisitions. Leveraging the Connectome 2.0 ultra-high gradient scanner, we developed a time-efficient protocol using an Explainable AI (XAI) framework. Combining XGBoost, SHAP, and Recursive Feature Elimination trained on synthetic signals, XAI identified an optimal 8-feature subset, cutting scan time from 27 to 14 minutes. Validated in vivo in seven healthy participants, the XAI protocol was benchmarked against the full 15-feature acquisition, a Cram'er-Rao Lower Bound (CRLB) theoretical optimum, and two heuristics ("Mid-Range" and "Corner"). It robustly reproduced parameter estimates and maintained test-retest reproducibility. Remarkably, the XAI selection converged to the CRLB optimum. This validates XAI's optimality while highlighting its main advantage: achieving gold-standard optimization without complex analytical Jacobians, making it easily adaptable to numerical models or complex noise where CRLB is intractable. Furthermore, XAI showed superior in vivo robustness over heuristics: "Mid-Range" sampling yielded biased exchange time estimates from insufficient temporal diversity, while "Corner" sampling gave unstable intra-neurite diffusivity estimates (5-fold higher CV) due to noise sensitivity. Ultimately, this robust 14-minute protocol accelerates exchange-sensitive microstructural mapping, establishing a model-agnostic optimization framework adaptable to future ultra-high gradient systems and existing clinical scanners.

physics.med-ph↗

arXiv2025

Interplay between MRI-based axon diameter and myelination estimates in macaque and human brain

Axon diameter and myelin thickness affect the conduction velocity of action potentials in the nervous system. Imaging them non-invasively with MRI-based methods is thus valuable for studying brain microstructure and function. Electron microscopy studies suggest that axon diameter and myelin thickness are closely related to each other. However, the relationship between MRI-based estimates of these microstructural measures, known to be relative indices, have not been investigated across the brain mainly due to methodological limitations. In recent years, studies using ultra-high gradient strength diffusion MRI (dMRI) have demonstrated improved estimation of axon diameter index across white-matter (WM) tracts in the human brain, making such investigations feasible. In this study, we aim to investigate relationships between tissue microstructure properties across white-matter tracts, as estimated with MRI-based methods. We collected dMRI with ultra-high gradient strength and multi-echo spin-echo MRI on ex vivo macaque and human brain samples on a preclinical scanner. From these data, we found that the correlations between axon diameter index and other microstructural imaging parameters were weak but consistent across WM tracts in samples estimated with sufficient signal to noise ratio. In well-myelinated regions, tissue voxels with larger axon diameter indices were associated with lower packing density, lower MWF and a tendency of higher g-ratio. We also found that intra-axonal signal fractions and MWF were not consistently correlated when assessed in different samples. Overall, the findings suggest that MRI-based axon geometry and myelination measures can provide complementary information about fiber morphology, and the relationships between these measures agree with prior electron microscopy studies in smaller field of views.

physics.med-ph↗

arXiv2024

Optimization and Validation of the DESIGNER dMRI preprocessing pipeline in white matter aging

Various diffusion MRI (dMRI) preprocessing pipelines are currently available to yield more accurate diffusion parameters. Here, we evaluated accuracy and robustness of the optimized Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline in a large clinical dMRI dataset and using ground truth phantoms. DESIGNER has been modified to improve denoising and target Gibbs ringing for partial Fourier acquisitions. We compared the revisited DESIGNER (Dv2) (including denoising, Gibbs removal, correction for motion, EPI distortion, and eddy currents) against the original DESIGNER (Dv1) pipeline, minimal preprocessing (including correction for motion, EPI distortion, and eddy currents only), and no preprocessing on a large clinical dMRI dataset of 524 control subjects with ages between 25 and 75 years old. We evaluated the effect of specific processing steps on age correlations in white matter with DTI and DKI metrics. We also evaluated the added effect of minimal Gaussian smoothing to deal with noise and to reduce outliers in parameter maps compared to DESIGNER (Dv2)'s noise removal method. Moreover, DESIGNER (Dv2)'s updated noise and Gibbs removal methods were assessed using ground truth dMRI phantom to evaluate accuracy. Results show age correlation in white matter with DTI and DKI metrics were affected by the preprocessing pipeline, causing systematic differences in absolute parameter values and loss or gain of statistical significance. Both in clinical dMRI and ground truth phantoms, DESIGNER (Dv2) pipeline resulted in the smallest number of outlier voxels and improved accuracy in DTI and DKI metrics as noise was reduced and Gibbs removal was improved. Thus, DESIGNER (Dv2) provides more accurate and robust DTI and DKI parameter maps as compared to no preprocessing or minimal preprocessing.

physics.med-ph↗

arXiv2024

Volume electron microscopy in injured rat brain validates white matter microstructure metrics from diffusion MRI

Biophysical modeling of diffusion MRI (dMRI) offers the exciting potential of bridging the gap between the macroscopic MRI resolution and microscopic cellular features, effectively turning the MRI scanner into a noninvasive in vivo microscope. In brain white matter, the Standard Model (SM) interprets the dMRI signal in terms of axon dispersion, intra- and extra-axonal water fractions and diffusivities. However, for SM to be fully applicable and correctly interpreted, it needs to be carefully evaluated using histology. Here, we perform a comprehensive histological validation of the SM parameters, by characterizing WM microstructure in sham and injured rat brains using volume (3d) electron microscopy (EM) and ex vivo dMRI. Sensitivity is evaluated by how close each SM metric is to its histological counterpart, and specificity by how independent it is from other, non-corresponding histological features. This comparison reveals that SM is sensitive and specific to microscopic properties, clearing the way for the clinical adoption of in vivo dMRI derived SM parameters as biomarkers for neurological disorders.

physics.bio-ph↗

arXiv2023

Universal Sampling Denoising (USD) for noise mapping and noise removal of non-Cartesian MRI

Random matrix theory (RMT) combined with principal component analysis has resulted in a widely used MPPCA noise mapping and denoising algorithm, that utilizes the redundancy in multiple acquisitions and in local image patches. RMT-based denoising relies on the uncorrelated identically distributed noise. This assumption breaks down after regridding of non-Cartesian sampling. Here we propose a Universal Sampling Denoising (USD) pipeline to homogenize the noise level and decorrelate the noise in non-Cartesian sampled k-space data after resampling to a Cartesian grid. In this way, the RMT approaches become applicable to MRI of any non-Cartesian k-space sampling. We demonstrate the denoising pipeline on MRI data acquired using radial trajectories, including diffusion MRI of a numerical phantom and ex vivo mouse brains, as well as in vivo $T_2$ MRI of a healthy subject. The proposed pipeline robustly estimates noise level, performs noise removal, and corrects bias in parametric maps, such as diffusivity and kurtosis metrics, and $T_2$ relaxation time. USD stabilizes the variance, decorrelates the noise, and thereby enables the application of RMT-based denoising approaches to MR images reconstructed from any non-Cartesian data. In addition to MRI, USD may also apply to other medical imaging techniques involving non-Cartesian acquisition, such as PET, CT, and SPECT.

physics.med-ph↗

arXiv2021

Realistic Microstructure Simulator (RMS): Monte Carlo simulations of diffusion in three-dimensional cell segmentations of microscopy images

Background: Monte Carlo simulations of diffusion are commonly used as a model validation tool as they are especially suitable for generating the diffusion MRI signal in complicated tissue microgeometries. New method: Here we describe the details of implementing Monte Carlo simulations in three-dimensional (3d) voxelized segmentations of cells in microscopy images. Using the concept of the corner reflector, we largely reduce the computational load of simulating diffusion within and exchange between multiple cells. Precision is further achieved by GPU-based parallel computations. Results: Our simulation of diffusion in white matter axons segmented from a mouse brain demonstrates its value in validating biophysical models. Furthermore, we provide the theoretical background for implementing a discretized diffusion process, and consider the finite-step effects of the particle-membrane reflection and permeation events, needed for efficient simulation of interactions with irregular boundaries, spatially variable diffusion coefficient, and exchange. Comparison with existing methods: To our knowledge, this is the first Monte Carlo pipeline for MR signal simulations in a substrate composed of numerous realistic cells, accounting for their permeable and irregularly-shaped membranes. Conclusions: The proposed RMS pipeline makes it possible to achieve fast and accurate simulations of diffusion in realistic tissue microgeometry, as well as the interplay with other MR contrasts. Presently, RMS focuses on simulations of diffusion, exchange, and T1 and T2 NMR relaxation in static tissues, with a possibility to straightforwardly account for susceptibility-induced T2* effects and flow.

physics.med-ph↗

arXiv2020

The impact of realistic axonal shape on axon diameter estimation using diffusion MRI

To study axonal microstructure with diffusion MRI, axons are typically modeled as straight impermeable cylinders, whereby the transverse diffusion MRI signal can be made sensitive to the cylinder's inner diameter. However, the shape of a real axon varies along the axon direction, which couples the longitudinal and transverse diffusion of the overall axon direction. Here we develop a theory of the intra-axonal diffusion MRI signal based on coarse-graining of the axonal shape by 3d diffusion. We demonstrate how the estimate of the inner diameter is confounded by the diameter variations (beading), and by the local variations in direction (undulations) along the axon. We analytically relate diffusion MRI metrics, such as time-dependent radial diffusivity D(t) and kurtosis K(t), to the axonal shape, and validate our theory using Monte Carlo simulations in synthetic undulating axons with randomly positioned beads, and in realistic axons reconstructed from electron microscopy images of mouse brain white matter. We show that (i) In the narrow pulse limit, the inner diameter from D(t) is overestimated by about twofold due to a combination of axon caliber variations and undulations (each contributing a comparable effect size); (ii) The narrow-pulse kurtosis K$_{t\to\infty}$ deviates from that in an ideal cylinder due to caliber variations; we also numerically calculate the fourth-order cumulant for an ideal cylinder in the wide pulse limit, which is relevant for inner diameter overestimation; (iii) In the wide pulse limit, the axon diameter overestimation is mainly due to undulations at low diffusion weightings b; and (iv) The effect of undulations can be considerably reduced by directional averaging of high-b signals, with the apparent inner diameter given by a combination of the axon caliber (dominated by the thickest axons), caliber variations, and the residual contribution of undulations.

physics.med-ph↗

arXiv2020

In vivo observation and biophysical interpretation of time-dependent diffusion in human cortical gray matter

The dependence of the diffusion MRI signal on the diffusion time $t$ is a hallmark of tissue microstructure at the scale of the diffusion length. Here we measure the time-dependence of the mean diffusivity $D(t)$ and mean kurtosis $K(t)$ in cortical gray matter and in 25 gray matter sub-regions, in 10 healthy subjects. Significant diffusivity and kurtosis time-dependence is observed for $t=21.2$-100 ms, and is characterized by a power-law tail $\sim t^{-\vartheta}$ with dynamical exponent $\vartheta$. To interpret our measurements, we systematize the relevant scenarios and mechanisms for diffusion time-dependence in the brain. Using effective medium theory formalisms, we derive an exact relation between the power-law tails in $D(t)$ and $K(t)$. The estimated power-law dynamical exponent $\vartheta\simeq1/2$ in both $D(t)$ and $K(t)$ is consistent with one-dimensional diffusion in the presence of randomly positioned restrictions along neurites. We analyze the short-range disordered statistics of synapses on axon collaterals in the cortex, and perform one-dimensional Monte Carlo simulations of diffusion restricted by permeable barriers with a similar randomness in their placement, to confirm the $\vartheta=1/2$ exponent. In contrast, the Kärger model of exchange is less consistent with the data since it does not capture the diffusivity time-dependence, and the estimated exchange time from $K(t)$ falls below our measured $t$-range. Although we cannot exclude exchange as a contributing factor, we argue that structural disorder along neurites is mainly responsible for the observed time-dependence of diffusivity and kurtosis. Our observation and theoretical interpretation of the $t^{-1/2}$ tail in $D(t)$ and $K(t)$ alltogether establish the sensitivity of a macroscopic MRI signal to micrometer-scale structural heterogeneities along neurites in human gray matter in vivo.

physics.med-ph↗

arXiv2020

A time-dependent diffusion MRI signature of axon caliber variations and beading

MRI provides a unique non-invasive window into the brain, yet is limited to millimeter resolution, orders of magnitude coarser than cell dimensions. Here we show that diffusion MRI is sensitive to the micrometer-scale variations in axon caliber or pathological beading, by identifying a signature power-law diffusion time-dependence of the along-fiber diffusion coefficient. We observe this signature in human brain white matter, and uncover its origins by Monte Carlo simulations in realistic substrates from 3d electron microscopy of mouse corpus callosum. Simulations reveal that the time-dependence originates from axon caliber variation, rather than from mitochondria or axonal undulations. We report a decreased amplitude of time-dependence in multiple sclerosis lesions, illustrating the sensitivity of our method to axonal beading in a plethora of neurodegenerative disorders. This specificity to microstructure offers an exciting possibility of bridging across scales to image cellular-level pathology with a clinically feasible MRI technique.

physics.med-ph↗

arXiv2018

Solving the paradox of the folded falling chain by considering horizontal kinetic energy and link geometry

A folded chain, with one end fixed at the ceiling and the other end released from the same elevation, is commonly modeled as an energy-conserving system in one-dimension. However, the analytical paradigms in previous literature is unsatisfying: The theoretical prediction of the tension at the fixed end becomes infinitely large when the free end reaches the bottom, contradicting to the experimental observations. Furthermore, the dependence of the total falling time on the link number demonstrated in numerical simulations is still unexplained. Here, considering the horizontal kinetic energy and the geometry of each link, we derived analytical solutions of the maximal tension as well as the total falling time, in agreement with simulation results and experimental data reported in previous studies. This theoretical perspective shows a simple representation of the complicated two-dimensional falling chain system and, in particular, specifies the signature of the chain properties.

physics.class-ph↗

arXiv2017

What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

Brownian motion of water molecules provides an essential length scale, the diffusion length, commensurate with cell dimensions in biological tissues. Measuring the diffusion coefficient as a function of diffusion time makes in vivo diffusion MRI uniquely sensitive to the cellular features about three orders of magnitude below imaging resolution. However, there is a longstanding debate, regarding which contribution --- intra- or extra-cellular --- is more relevant in the overall time-dependence of the diffusion metrics. Here we resolve this debate in the human brain white matter. By varying not just the diffusion time, but also the gradient pulse duration of a standard diffusion pulse sequence, we identify a functional form of the measured time-dependent diffusion coefficient transverse to white matter tracts in 5 healthy volunteers. This specific functional form is shown to originate from the extra-axonal space, and provides estimates of the fiber packing correlation length for axons in a bundle. Our results offer a metric for the outer axonal diameter, a promising candidate marker for demyelination in neurodegenerative diseases. From the methodological perspective, our analysis demonstrates how competing models, which describe different physics yet interpolate standard measurements equally well, can be distinguished based on their prediction for an independent "orthogonal" measurement.

physics.bio-ph↗