arXiv subjects

Marco Palombo

Publications and source records attributed to Marco Palombo.

At least 19 recordsLinked to original sources

arXiv2026

Contextual Cellular Growth (ConCeG) of neural cells for realistic grey matter tissue generation for diffusion MRI simulations

Accurate interpretation of diffusion magnetic resonance imaging (dMRI) signals in grey matter (GM) remains challenging due to the complex, heterogeneous, and densely packed cellular environment. Numerical phantoms provide a controlled framework for investigating the relationship between microstructure and diffusion signals, yet existing approaches often lack the morphological realism and multi-cellular organisation required to faithfully represent GM tissue. In this work, we introduce Contextual Cellular Growth (ConCeG), a generative framework for creating individual cells or constructing dense, three-dimensional, multi-cellular GM substrates informed by real neuronal and glial morphologies. The method combines topological neuron synthesis with a spatially constrained growth network, allowing for the controlled generation of heterogeneous cellular environments with realistic intra- and extracellular compartments. Synthetic cells are generated using morphological and topological characteristics derived from biological reconstructions. We validate the framework through comparisons of structural features with real cellular data, demonstrating strong agreement in branch order, length, angle, and tortuosity distributions. Power spectrum analysis further shows that both intracellular compartments reproduce the spatial correlations observed in biological tissue. Together, these results show ConCeG provides a biologically grounded framework for generating grey matter substrates suitable for large scale diffusion MRI simulation.

physics.med-ph↗

arXiv2026

Realistic noise synthesis reduces bias and improves tissue microstructure estimation with supervised machine learning

Diffusion MRI enables non-invasive probing of tissue microstructure, but accurate parameter estimation is challenged by noise-related effects. In supervised machine learning frameworks trained on simulated data, discrepancies between the noise characteristics of simulated and acquired signals introduce a form of covariate shift, whereby the input signal distribution differs between training and inference. We investigated the impact of this mismatch on microstructure parameter estimation and propose a realistic noise synthesis (RNS) framework to mitigate it. RNS incorporates both the Rician expectation and the effective post-processing noise variance into simulated training signals. The Rician expectation was modelled using a noise standard deviation estimated with MPPCA, while the effective standard deviation was derived from spherical harmonic residuals of preprocessed data. The method was evaluated using the cylinder-zeppelin and the SANDI models on simulated datasets across multiple SNR levels and on in vivo diffusion data with repeated acquisitions. Sensitivity to noise misestimation was also assessed. Ignoring magnitude-induced noise effects during training produced systematic, SNR-dependent parameter bias, particularly at low SNR. Incorporating the Rician expectation substantially reduced bias to the level of noise-aware nonlinear least-squares fitting. Modelling the effective standard deviation further improved precision. Performance was largely independent of regression architecture but sensitive to accurate noise estimation. These findings demonstrate that realistic noise modelling in simulated training data mitigates signal-domain covariate shift and is essential for unbiased supervised microstructure estimation, particularly in low-SNR regimes associated with high b-values or high spatial resolution.

cs.LG↗

arXiv2026

Synthetic Data in MR Spectroscopy: Current Practices, Applications, and Considerations

The use of synthetic data has emerged as an essential tool in Magnetic Resonance Spectroscopy (MRS) research and applications, providing advantages for optimization of acquisition, software validation, deep learning applications, and enhanced reproducibility. Importantly, synthetic data addresses challenges of limited training data availability, particularly for clinical populations, and offers controlled solutions for investigating uncertainties and unexplained variance with in vivo data. This work provides a review and evaluation of current practices in the use and generation of synthetic data within the MRS field. Conducted by the MRS Synthetic Data Working Group under the Code & Data Sharing Committee of the MRS Study Group of the International Society for Magnetic Resonance in Medicine (ISMRM), this manuscript encompasses existing literature, supplemented by collective experience and in-house methodologies.

physics.med-ph↗

arXiv2025

Ultra-Strong Gradient Diffusion MRI with Self-Supervised Learning for Prostate Cancer Characterization

Diffusion MRI (dMRI) enables non-invasive assessment of prostate microstructure but conventional dMRI metrics such as the Apparent Diffusion Coefficient in multiparametric MRI and reflect a mixture of underlying tissues features rather than distinct histologic characteristics. Integrating dMRI with the compartment-based biophysical VERDICT (Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumours) framework offers richer microstructural insights, though clinical gradient systems (40-80 mT/m) often suffer from poor signal-to-noise ratio at stronger diffusion weightings due to prolonged echo times. Ultra-strong gradients (e.g., 300 mT/m) can mitigate these limitations by improving SNR and contrast-to-noise ratios. This study investigates whether physics-informed self-supervised VERDICT (ssVERDICT) fitting when combined with ultra-strong gradient data, enhances prostate microstructural characterization relative to current fitting approaches and clinical gradient systems. We developed enhanced ssVERDICT fitting approaches using dense multilayer perceptron and convolutional U-Net architectures, comparing them against non-linear least-squares (NLLS) VERDICT fitting, original ssVERDICT implementation, and Diffusion Kurtosis Imaging across clinical- to ultra-strong gradient systems. For the same ultra-strong gradient data, Dense ssVERDICT outperformed NLLS VERDICT, boosting median CNR by 47%, cutting inter-patient Coefficient of Variation by 52%, and reducing pooled $f_{ic}$ variation by 50%. Overall, Dense ssVERDICT delivered the highest CNR, the most stable parameter estimates, and the clearest tumour-normal contrast compared with conventional fitting methods and clinical gradient systems. These findings underscore that meaningful gains in non-invasive prostate cancer characterization arise from the combination of advanced gradient systems and deep learning-based modelling.

eess.IV↗

arXiv2025

Bayesian Insights into Exchange and Restriction in Gray Matter Diffusion MRI

Biophysical models in diffusion MRI (dMRI) hold promise for characterizing gray matter tissue microstructure. Yet, the reliability of their parameter estimates remains largely under-studied, especially in models that incorporate water exchange. In this study, we investigate the accuracy, precision, and presence of degeneracy of two recently proposed gray matter models, NEXI and SANDIX, using established acquisition protocols, on both simulated and \textit{in vivo} data. We employ $\mu$GUIDE, a Bayesian inference framework based on deep learning, to quantify parameter uncertainty and detect degeneracies, enabling a more interpretable assessment of model fits. Our results show that while some microstructural parameters, such as extra-cellular diffusivity and neurite signal fraction, are robustly estimated, others, including exchange time and soma radius, are often associated with high uncertainty and estimation bias, particularly under realistic noise conditions and reduced acquisition protocols. Comparison with non-linear least squares fitting highlights the critical advantage of uncertainty-aware methods: the ability to flag and filter out unreliable estimates. Together, these findings emphasize the need to report uncertainty and account for model degeneracies when interpreting model-based estimates. Our study advocates for the integration of probabilistic fitting approaches into imaging pipelines to improve reproducibility and biological interpretability.

physics.med-ph↗

arXiv2025

The role of dendritic spines in water exchange measurements with diffusion MRI: Time-Dependent Single Diffusion Encoding MRI

Time-dependent diffusion MRI (dMRI) with single diffusion encoding (SDE) probes water dynamics in biological tissues, but signal interpretation depends on microstructure. While prior work focused on restricted/hindered diffusion and membrane permeation, diffusion-mediated exchange between dendritic shafts and spines in gray matter (GM) remains understudied. We hypothesize that impermeable spiny dendrites produce time-dependent SDE signals mimicking permeative exchange and investigate how spine density biases exchange time estimates. Using Monte Carlo simulations and narrow escape theory, we quantify spine-shaft exchange times (3-26 ms), matching cortical permeative exchange estimates. A modified two-compartment Karger model characterizes time-dependent SDE signals but yields biased exchange estimates, reflecting spine volume fraction rather than morphology. Unaccounted diffusion-mediated exchange introduces up to 80% bias in NEXI/SMEX model estimates. We propose an extended three-compartment Karger model incorporating both diffusion-mediated (spine-shaft) and permeative (intra-extracellular) exchange. However, this model cannot uniquely separate membrane permeability from spine volume effects. Our findings emphasize that dendritic spines should be considered in SDE-based exchange studies and caution against attributing exchange solely to permeability. Advanced methods are needed to disentangle these mechanisms in GM.

physics.med-ph↗

arXiv2025

The role of dendritic spines in water exchange measurements with diffusion MRI: Double Diffusion Encoding and free-waveform MRI

Time-dependent diffusion MRI enables the estimation of water exchange rates in vivo, yet reported values in grey matter remain inconsistent. While most studies attribute these estimates to membrane permeability, non-permeative geometric exchange has also been proposed. The present study investigates the contribution of geometric exchange between dendritic spines and shafts to diffusion MRI-derived exchange estimates. Monte Carlo simulations were performed in synthetic dendrites with varying spine morphology, density, and membrane permeability. Diffusion-weighted signals were generated using multiple protocols - including single diffusion encoding, double diffusion encoding, and free waveforms - and were analysed using four frameworks: the K\"arger model (via kurtosis time-dependence), correlation tensor imaging, Restriction-Exchange, and Multi-Gaussian Exchange with transient kurtosis (tMGE). Dendritic spines were found to impart similar time-dependence signatures on the diffusion-weighted signal as permeative exchange (signal decrease with diffusion time). The effect was modulated by both spine morphology and density. Both the exchange rate and microscopic kurtosis increased with spine density. The tMGE method demonstrated the ability to disentangle geometric from permeative exchange. Non-permeative exchange in dendritic spines has a non-negligible impact on exchange estimates obtained with diffusion MRI and should be considered in future studies. Diffusion MRI exchange estimates may provide a non-invasive proxy for dendritic spine density, with potential applications in studies of neurological disorders.

physics.med-ph↗

arXiv2025

Decoding Gray Matter: large-scale analysis of brain cell morphometry to inform microstructural modeling of diffusion MR signals

The structure of grey matter has long been a key focus in neuroscience, as cell morphology varies by type and can be affected by neurological conditions. Understanding these variations is essential for studying brain function and disease. Diffusion-weighted MRI (dMRI) is a powerful non-invasive tool for examining cellular microstructure in vivo. However, for dMRI to accurately reflect cellular features, it is crucial to determine which aspects of morphology influence its measurements. Proper interpretation of dMRI data depends on understanding its sensitivity to different cellular characteristics. Despite growing interest in cellular morphology, there has been no systematic report on the key features defining different neural cell types. To address this, we analyzed over 11,500 three-dimensional cellular reconstructions across three species and nine cell types, establishing reference values for critical morphological traits. These traits fall into three categories: structural features that define the cell's skeletal framework, shape features that describe spatial organization, and topological features that break down cellular structure to distinguish cell types. Beyond reporting these reference values, we examine their relevance for dMRI, identifying which neural features dMRI can detect and which cell types may be distinguishable. To complement the statistical analysis, we also provide high resolution 3D surface meshes representative of each cell type and species. This work provides essential benchmarks for grey matter research, offering new guidelines on linking neuroimaging measurements to neurobiology. These reference values will be a valuable resource for neuroscientists and neuroimaging researchers, aiding in the interpretation of imaging data and the refinement of brain tissue models.

physics.bio-ph↗

arXiv2024

Probing lactate exchange and compartmentation in Gray Matter via time-dependent diffusion-weighted MRS

Lactate is crucial in the brain, as it is involved in neuronal activity and memory formation. This is thought to be related to the astrocyte-neuron lactate shuttle hypothesis (ANLS), which has been debated for 30 years, not least because it is difficult to measure lactate compartmentation and exchange in vivo. In particular, while ANLS requires transfer of lactate via the extracellular space, intracellular/extracellular exchange rate remains unknown. In this work, we propose to use time-dependent diffusion MRS to assess lactate exchange and lactate compartmentation in mouse brain gray matter in vivo. First, by comparing lactate time-dependent diffusivity and kurtosis with those of water and purely intracellular metabolites (which exhibit "fast" and "no" exchange signatures, respectively), we estimate that lactate exchange is slow (i.e. on the order of hundreds of milliseconds). Then, using biophysical models neglecting exchange, we estimate extracellular, neuronal and astrocytic lactate fractions compatible with the ANLS hypothesis.

physics.med-ph↗

arXiv2024

$μ$GUIDE: a framework for quantitative imaging via generalized uncertainty-driven inference using deep learning

This work proposes $μ$GUIDE: a general Bayesian framework to estimate posterior distributions of tissue microstructure parameters from any given biophysical model or MRI signal representation, with exemplar demonstration in diffusion-weighted MRI. Harnessing a new deep learning architecture for automatic signal feature selection combined with simulation-based inference and efficient sampling of the posterior distributions, $μ$GUIDE bypasses the high computational and time cost of conventional Bayesian approaches and does not rely on acquisition constraints to define model-specific summary statistics. The obtained posterior distributions allow to highlight degeneracies present in the model definition and quantify the uncertainty and ambiguity of the estimated parameters.

eess.IV↗

arXiv2024

Image Quality Transfer of Diffusion MRI Guided By High-Resolution Structural MRI

Prior work on the Image Quality Transfer on Diffusion MRI (dMRI) has shown significant improvement over traditional interpolation methods. However, the difficulty in obtaining ultra-high resolution Diffusion MRI scans poses a problem in training neural networks to obtain high-resolution dMRI scans. Here we hypothesise that the inclusion of structural MRI images, which can be acquired at much higher resolutions, can be used as a guide to obtaining a more accurate high-resolution dMRI output. To test our hypothesis, we have constructed a novel framework that incorporates structural MRI scans together with dMRI to obtain high-resolution dMRI scans. We set up tests which evaluate the validity of our claim through various configurations and compare the performance of our approach against a unimodal approach. Our results show that the inclusion of structural MRI scans do lead to an improvement in high-resolution image prediction when T1w data is incorporated into the model input.

eess.IV↗

arXiv2024

Investigating exchange, structural disorder and restriction in Gray Matter via water and metabolites diffusivity and kurtosis time-dependence

Water diffusion MRI is a very powerful tool for probing tissue microstructure, but disentangling the contribution of compartment-specific structural disorder from cellular restriction and inter-compartment exchange remains an open challenge. Here, we use diffusion MR spectroscopy (dMRS) of water and metabolites as a function of diffusion time in vivo in mouse Gray Matter (GM) to shed light on: which of these concomitant mechanisms dominates the MR measurements and with which specific signature. We report the diffusion time-dependence of water with excellent SNR conditions up to 500 ms. Water kurtosis decreases with increasing diffusion time, showing the concomitant influence of both structural disorder and exchange. Despite the excellent SNR, we were not able to identify clearly the nature of the structural disorder (i.e. 1D versus 2D/3D short-range disorder). Measurements of intracellular metabolites diffusion time-dependence (up to 500 ms) show opposite behavior to water, with metabolites kurtosis increasing as a function of diffusion time. We show that this is a signature of diffusion restricted in the intracellular space from which cellular microstructural features can be estimated. Finally, by comparing water and metabolites diffusion time-dependencies, we attempt to disentangle the effect of intra/extracellular exchange and structural disorder of the extracellular space (both impacting water diffusion only). Our results suggest a relatively short intra/extracellular exchange time (1-50 ms) and short-range disorder (still unclear if 1D or 2D/3D) most likely coming from the extracellular compartment. This work provides novel insights to interpret water diffusion time-dependent measurements in terms of the underlying GM microstructure and suggests that diffusion time-dependent measurements of intracellular metabolites may offer a new way to quantify microstructural restrictions in GM.

physics.med-ph↗

arXiv2023

Quantifying human gray matter microstructure using NEXI and 300 mT/m gradients

Biophysical models of diffusion tailored to quantify gray matter microstructure are gathering increasing interest. The two-compartment Neurite EXchange Imaging ($NEXI$) model has been proposed recently to account for neurites, extra-cellular space and exchange across the cell membrane. $NEXI$ parameter estimation requires multi-shell multi-diffusion time data and has so far only been implemented experimentally on animal data collected on a preclinical MRI set-up. In this work, the first ever translation of $NEXI$ to the human cortex in vivo was achieved using a 3T Connectom MRI system with 300 mT/m gradients, that enables the acquisition of a broad range of b-values (0 - 7.5 ms/$μm^{2}$) with a window of diffusion times (20 - 49 ms) suitable for the expected characteristic exchange times (10 - 50 ms). Microstructure estimates of four model variants: $NEXI$, $NEXI_{dot}$ (its extension with the addition of a dot compartment) and their respective versions that correct for the Rician noise floor ($NEXI_{RM}$ and $NEXI_{dot,RM}$) that particularly impacts high b-value signal, were compared. The reliability of estimates in each model variant was evaluated in synthetic and human in vivo data. In the latter, the intra-subject (scan-rescan) vs between-subjects variability of microstructure estimates were compared in the cortex. The better performance of $NEXI_{RM}$ highlights the importance of correcting for Rician bias in the $NEXI$ model to obtain accurate estimates of microstructure parameters in the human cortex, and the sensitivity of the $NEXI$ framework to individual differences in cortical microstructure. This groundbreaking application of $NEXI$ in humans marks a pivotal moment, unlocking new avenues for studying neurodevelopment, ageing, and various neurodegenerative disorders.

physics.med-ph↗

arXiv2023

Diffusion-weighted MR spectroscopy: consensus, recommendations and resources from acquisition to modelling

Brain cell structure and function reflect neurodevelopment, plasticity and ageing, and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to non-invasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MR spectroscopy (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modelling and interpretation of results. These challenges were the motivation behind the organisation of the Lorentz Workshop on 'Best Practices and Tools for Diffusion MR Spectroscopy' held in Leiden in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting and modelling dMRS data and provides links to useful resources.

physics.med-ph↗

arXiv2022

Fitting a Directional Microstructure Model to Diffusion-Relaxation MRI Data with Self-Supervised Machine Learning

Machine learning is a powerful approach for fitting microstructural models to diffusion MRI data. Early machine learning microstructure imaging implementations trained regressors to estimate model parameters in a supervised way, using synthetic training data with known ground truth. However, a drawback of this approach is that the choice of training data impacts fitted parameter values. Self-supervised learning is emerging as an attractive alternative to supervised learning in this context. Thus far, both supervised and self-supervised learning have typically been applied to isotropic models, such as intravoxel incoherent motion (IVIM), as opposed to models where the directionality of anisotropic structures is also estimated. In this paper, we demonstrate self-supervised machine learning model fitting for a directional microstructural model. In particular, we fit a combined T1-ball-stick model to the multidimensional diffusion (MUDI) challenge diffusion-relaxation dataset. Our self-supervised approach shows clear improvements in parameter estimation and computational time, for both simulated and in-vivo brain data, compared to standard non-linear least squares fitting. Code for the artificial neural net constructed for this study is available for public use from the following GitHub repository: https://github.com/jplte/deep-T1-ball-stick

eess.IV↗

arXiv2022

Lossy compression of multidimensional medical images using sinusoidal activation networks: an evaluation study

In this work, we evaluate how neural networks with periodic activation functions can be leveraged to reliably compress large multidimensional medical image datasets, with proof-of-concept application to 4D diffusion-weighted MRI (dMRI). In the medical imaging landscape, multidimensional MRI is a key area of research for developing biomarkers that are both sensitive and specific to the underlying tissue microstructure. However, the high-dimensional nature of these data poses a challenge in terms of both storage and sharing capabilities and associated costs, requiring appropriate algorithms able to represent the information in a low-dimensional space. Recent theoretical developments in deep learning have shown how periodic activation functions are a powerful tool for implicit neural representation of images and can be used for compression of 2D images. Here we extend this approach to 4D images and show how any given 4D dMRI dataset can be accurately represented through the parameters of a sinusoidal activation network, achieving a data compression rate about 10 times higher than the standard DEFLATE algorithm. Our results show that the proposed approach outperforms benchmark ReLU and Tanh activation perceptron architectures in terms of mean squared error, peak signal-to-noise ratio and structural similarity index. Subsequent analyses using the tensor and spherical harmonics representations demonstrate that the proposed lossy compression reproduces accurately the characteristics of the original data, leading to relative errors about 5 to 10 times lower than the benchmark JPEG2000 lossy compression and similar to standard pre-processing steps such as MP-PCA denosing, suggesting a loss of information within the currently accepted levels for clinical application.

eess.IV↗

arXiv2022

Impact of within-voxel heterogeneity in fibre geometry on spherical deconvolution

Axons in white matter have been shown to have varying geometries within a bundle using ex vivo imaging techniques, but what does this mean for diffusion MRI (dMRI) based spherical deconvolution (SD)? SD attempts to estimate the fibre orientation distribution function (fODF) by assuming a single dMRI fibre response function (FRF) for all white matter populations and deconvolving this FRF from the dMRI signal at each voxel to estimate the fODF. Variable fibre geometry within a bundle however suggests the FRF might not be constant even within a single voxel. We test what impact realistic fibre geometry has on SD by simulating the dMRI signal in a range of realistic white matter numerical phantoms, including synthetic phantoms and real axons segmented from electron microscopy. We demonstrate that variable fibre geometry leads to a variable FRF across axons and that in general no single FRF is effective to recover the underlying fibre orientation distribution function (fODF). This finding suggests that assuming a single FRF can lead to misestimation of the fODF, causing further downstream errors in techniques such as tractography.

physics.med-ph↗

arXiv2022

Neurite Exchange Imaging (NEXI): A minimal model of diffusion in gray matter with inter-compartment water exchange

Biophysical models of diffusion in white matter are based on what is now commonly referred to as the "Standard Model" (SM) of non-exchanging anisotropic Gaussian compartments. In this work, we focus on diffusion MRI in gray matter, which requires rethinking basic microstructure modeling blocks. In particular, at least three contributions beyond the SM need to be considered: water exchange across the cell membrane - between neurites and the extracellular space; non-Gaussian diffusion along neuronal and glial processes - resulting from structural disorder; and signal contribution from soma. For the first contribution, we propose Neurite Exchange Imaging (NEXI) as an extension of the SM of diffusion, which builds on the anisotropic Kärger model of two exchanging compartments. Using datasets acquired at multiple diffusion weightings (b) and diffusion times (t) in the rat brain in vivo, we show that for the investigated diffusion time window (~10-45 ms) there is minimal diffusivity time-dependence and more pronounced kurtosis decay with time in gray matter, which is well fit by the exchange model. Moreover, we observe lower signal for longer diffusion times at high b. In light of these observations, we identify exchange as the mechanism that best explains these signal signatures in both low-b and high-b regime, and thereby propose NEXI as the minimal model for gray matter microstructure mapping. We finally highlight multi-b multi-t acquisitions protocols as being best suited to estimate NEXI model parameters reliably. Using this approach, we estimate the inter-compartment water exchange time to be 15 - 60 ms in the rat cortex and hippocampus in vivo, which is of the same order or shorter than the diffusion time in typical diffusion MRI acquisitions. This suggests water exchange as an essential component for interpreting diffusion MRI measurements in gray matter.

physics.med-ph↗