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Abstract Introduction Neuroimaging has revealed that migraine is linked to alterations in both the structure and function of the brain. However, the relationship of these changes with aging has not been studied in detail. Here we employ the Brain Age framework to analyze migraine, by building a machine-learning model that predicts age from neuroimaging data. We hypothesize that migraine patients will exhibit an increased Brain Age Gap (the difference between the predicted age and the chronological age) compared to healthy participants. Methods We trained a machine learning model to predict Brain Age from 2,771 T1-weighted magnetic resonance imaging scans of healthy subjects. The processing pipeline included the automatic segmentation of the images, the extraction of 1,479 imaging features (both morphological and intensity-based), harmonization, feature selection and training inside a 10-fold cross-validation scheme. Separate models based only on morphological and intensity features were also trained, and all the Brain Age models were later applied to a discovery cohort composed of 247 subjects, divided into healthy controls (HC, n=82), episodic migraine (EM, n=91), and chronic migraine patients (CM, n=74). Results CM patients showed an increased Brain Age Gap compared to HC (4.16 vs -0.56 years, P=0.01). A smaller Brain Age Gap was found for EM patients, not reaching statistical significance (1.21 vs -0.56 years, P=0.19). No associations were found between the Brain Age Gap and headache or migraine frequency, or duration of the disease. Brain imaging features that have previously been associated with migraine were among the main drivers of the differences in the predicted age. Also, the separate analysis using only morphological or intensity-based features revealed different patterns in the Brain Age biomarker in patients with migraine. Conclusion The brain-predicted age has shown to be a sensitive biomarker of CM patients and can help reveal distinct aging patterns in migraine.

The term free-water volume fraction (FWVF) refers to the signal fraction that could be found as the cerebrospinal fluid of the brain, which has been demonstrated as a sensitive measure that correlates with cognitive performance and various neuropathological processes. It can be quantified by properly fitting the isotropic component of the magnetic resonance (MR) signal in diffusion-sensitized sequences. Using N=287 healthy subjects (178F/109M) aged 25-94, this study examines in detail the evolution of the FWVF obtained with the spherical means technique from multi-shell acquisitions in the human brain white matter across the adult lifespan, which has been previously reported to exhibit a positive trend when estimated from single-shell data using the bi-tensor signal representation. We found evidence of a noticeably non-linear gain after the sixth decade of life, with a region-specific variate and varying change rate of the spherical means-based multi-shell FWVF parameter with age, at the same time, a heteroskedastic pattern across the adult lifespan is suggested. On the other hand, the FW corrected diffusion tensor imaging (DTI) leads to a region-dependent flattened age-related evolution of the mean diffusivity (MD) and fractional anisotropy (FA), along with a considerable reduction in their variability, as compared to the studies conducted over the standard (single-component) DTI. This way, our study provides a new perspective on the trajectory-based assessment of the brain and explains the conceivable reason for the variations observed in FA and MD parameters across the lifespan with previous studies under the standard diffusion tensor imaging.

Diffusion Tensor Imaging (DTI) is the most employed method to assess white matter properties using quantitative parameters derived from diffusion MRI, but it presents known limitations that restrict the evaluation of complex structures. The objective of this study was to validate the reliability and robustness of complementary diffusion measures extracted with a novel approach, Apparent Measures Using Reduced Acquisitions (AMURA), with a typical diffusion MRI acquisition from a clinical context in comparison with DTI with application to clinical studies. Fifty healthy controls, 51 episodic migraine and 56 chronic migraine patients underwent single-shell diffusion MRI. Four DTI-based and eight AMURA-based parameters were compared between groups with tract-based spatial statistics to establish reference results. On the other hand, following a region-based analysis, the measures were assessed for multiple subsamples with diverse reduced sample sizes and their stability was evaluated with the coefficient of quartile variation. To assess the discrimination power of the diffusion measures, we repeated the statistical comparisons with a region-based analysis employing reduced sample sizes with diverse subsets, decreasing 10 subjects per group for consecutive reductions, and using 5,001 different random subsamples. For each sample size, the stability of the diffusion descriptors was evaluated with the coefficient of quartile variation. AMURA measures showed a greater number of statistically significant differences in the reference comparisons between episodic migraine patients and controls compared to DTI. In contrast, a higher number of differences was found with DTI parameters compared to AMURA in the comparisons between both migraine groups. Regarding the assessments reducing the sample size, the AMURA parameters showed a more stable behavior than DTI, showing a lower decrease for each reduced sample size or a higher number of regions with significant differences. However, most AMURA parameters showed lower stability in relation to higher coefficient of quartile variation values than the DTI descriptors, although two AMURA measures showed similar values to DTI. For the synthetic signals, there were AMURA measures with similar quantification to DTI, while other showed similar behavior. These findings suggest that AMURA presents favorable characteristics to identify differences of specific microstructural properties between clinical groups in regions with complex fiber architecture and lower dependency on the sample size or assessing technique than DTI.

The objective of this study is to evaluate the efficacy of deep learning (DL) techniques in improving the quality of diffusion MRI (dMRI) data in clinical applications. The study aims to determine whether the use of artificial intelligence (AI) methods in medical images may result in the loss of critical clinical information and/or the appearance of false information. To assess this, the focus was on the angular resolution of dMRI and a clinical trial was conducted on migraine, specifically between episodic and chronic migraine patients. The number of gradient directions had an impact on white matter analysis results, with statistically significant differences between groups being drastically reduced when using 21 gradient directions instead of the original 61. Fourteen teams from different institutions were tasked to use DL to enhance three diffusion metrics (FA, AD and MD) calculated from data acquired with 21 gradient directions and a b-value of 1000 s/mm2. The goal was to produce results that were comparable to those calculated from 61 gradient directions. The results were evaluated using both standard image quality metrics and Tract-Based Spatial Statistics (TBSS) to compare episodic and chronic migraine patients. The study results suggest that while most DL techniques improved the ability to detect statistical differences between groups, they also led to an increase in false positive. The results showed that there was a constant growth rate of false positives linearly proportional to the new true positives, which highlights the risk of generalization of AI-based tasks when assessing diverse clinical cohorts and training using data from a single group. The methods also showed divergent performance when replicating the original distribution of the data and some exhibited significant bias. In conclusion, extreme caution should be exercised when using AI methods for harmonization or synthesis in clinical studies when processing heterogeneous data in clinical studies, as important information may be altered, even when global metrics such as structural similarity or peak signal-to-noise ratio appear to suggest otherwise.

Abstract Magnetic Resonance Imaging (MRI) of hard biological tissues is challenging due to the fleeting lifetime and low strength of their response to resonant stimuli, especially at low magnetic fields. Consequently, the impact of MRI on some medical applications, such as dentistry, continues to be limited. Here, we present three-dimensional reconstructions of ex-vivo human teeth, as well as a rabbit head and part of a cow femur, all obtained at a field strength of 260 mT. These images are the first featuring soft and hard tissues simultaneously at sub-Tesla fields, and they have been acquired in a home-made, special-purpose, pre-medical MRI scanner designed with the goal of demonstrating dental imaging at low field settings. We encode spatial information with two pulse sequences: Pointwise-Encoding Time reduction with Radial Acquisition and a new sequence we have called Double Radial Non-Stop Spin Echo, which we find to perform better than the former. For image reconstruction we employ Algebraic Reconstruction Techniques (ART) as well as standard Fourier methods. An analysis of the resulting images shows that ART reconstructions exhibit a higher signal-to-noise ratio with a more homogeneous noise distribution.

Abstract Background White matter alterations have been observed in patients with migraine. However, no microstructural white matter alterations have been found particularly in episodic or chronic migraine patients, and there is limited research focused on the comparison between these two groups of migraine patients. Methods Fifty-one healthy controls, 55 episodic migraine patients and 57 chronic migraine patients were recruited and underwent brain T1-weighted and diffusion-weighted MRI acquisition. Using Tract-Based Spatial Statistics (TBSS), fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were compared between the different groups. On the one hand, all migraine patients were compared against healthy controls. On the other hand, patients from each migraine group were compared between them and also against healthy controls. Correlation analysis between clinical features (duration of migraine in years, time from onset of chronic migraine in months, where applicable, and headache and migraine frequency, where applicable) and Diffusion Tensor Imaging measures was performed. Results Fifty healthy controls, 54 episodic migraine and 56 chronic migraine patients were finally included in the analysis. Significant decreased axial diffusivity (p

Diffusion MRI (dMRI) has become an invaluable tool to assess the microstructural organization of brain tissue. Depending on the specific acquisition settings, the dMRI signal encodes specific properties of the underlying diffusion process. In the last two decades, several signal representations have been proposed to fit the dMRI signal and decode such properties. Most methods, however, are tested and developed on a limited amount of data, and their applicability to other acquisition schemes remains unknown. With this work, we aimed to shed light on the generalizability of existing dMRI signal representations to different diffusion encoding parameters and brain tissue types. To this end, we organized a community challenge - named MEMENTO, making available the same datasets for fair comparisons across algorithms and techniques. We considered two state-of-the-art diffusion datasets, including single-diffusion-encoding (SDE) spin-echo data from a human brain with over 3820 unique diffusion weightings (the MASSIVE dataset), and double (oscillating) diffusion encoding data (DDE/DODE) of a mouse brain including over 2520 unique data points. A subset of the data sampled in 5 different voxels was openly distributed, and the challenge participants were asked to predict the remaining part of the data. After one year, eight participant teams submitted a total of 80 signal fits. For each submission, we evaluated the mean squared error, the variance of the prediction error and the Bayesian information criteria. The received submissions predicted either multi-shell SDE data (37%) or DODE data (22%), followed by cartesian SDE data (19%) and DDE (18%). Most submissions predicted the signals measured with SDE remarkably well, with the exception of low and very strong diffusion weightings. The prediction of DDE and DODE data seemed more challenging, likely because none of the submissions explicitly accounted for diffusion time and frequency. Next to the choice of the model, decisions on fit procedure and hyperparameters play a major role in the prediction performance, highlighting the importance of optimizing and reporting such choices. This work is a community effort to highlight strength and limitations of the field at representing dMRI acquired with trending encoding schemes, gaining insights into how different models generalize to different tissue types and fiber configurations over a large range of diffusion encodings.

A number of computational techniques have been lately devised to image the Ensemble Average Propagator (EAP) within the white matter of the brain, propelled by the deployment of multi-shell acquisition protocols and databases: approaches like Mean Apparent Propagator Imaging (MAP-MRI) and its Laplacian-regularized version (MAPL) aim at describing the low frequency spectrum of the EAP (limited by the maximum b-value acquired) and afterwards computing scalar indices that embed useful descriptions of the white matter, e. g. the Return-to-Origin, Plane, or Axis Probabilities (RTOP, RTPP, RTAP). These methods resort to a non-parametric, bandwidth limited representation of the EAP that implies fitting a set of 3-D basis functions in a large-scale optimization problem. We propose a semi-parametric approach inspired by signal theory: the EAP is approximated as the spherical convolution of a Micro-Structure adaptive Gaussian kernel with a non-parametric orientation histogram, which aims at representing the low-frequency response of an ensemble of coherent sets of fiber bundles at the white matter. This way, the optimization involves just the 2 to 3 parameters that describe the kernel, making our approach far more efficient than the related state of the art. We devise dual Fourier domains Integral Transforms to analytically compute RTxP-like scalar indices as moments of arbitrary orders over either the whole 3-D space, particular directions, or particular planes. The so-called MiSFIT is both time efficient (a typical multi-shell data set can be processed in roughly one minute) and accurate: it provides estimates of widely validated indices like RTOP, RTPP, and RTAP comparable to MAPL for a wide variety of white matter configurations.

In diffusion MRI, the Ensemble Average diffusion Propagator (EAP) provides relevant micro-structural information and meaningful descriptive maps of the white matter previously obscured by traditional techniques like Diffusion Tensor Imaging (DTI). The direct estimation of the EAP, however, requires a dense sampling of the Cartesian q-space involving a huge amount of samples (diffusion gradients) for proper reconstruction. A collection of more efficient techniques have been proposed in the last decade based on parametric representations of the EAP, but they still imply acquiring a large number of diffusion gradients with different b-values (shells). Paradoxically, this has come together with an effort to find scalar measures gathering all the q-space micro-structural information probed in one single index or set of indices. Among them, the return-to-origin (RTOP), return-to-plane (RTPP), and return-to-axis (RTAP) probabilities have rapidly gained popularity. In this work, we propose the so-called "Apparent Measures Using Reduced Acquisitions" (AMURA) aimed at computing scalar indices that can mimic the sensitivity of state of the art EAP-based measures to micro-structural changes. AMURA drastically reduces both the number of samples needed and the computational complexity of the estimation of diffusion properties by assuming the diffusion anisotropy is roughly independent from the radial direction. This simplification allows us to compute closed-form expressions from single-shell information, so that AMURA remains compatible with standard acquisition protocols commonly used even in clinical practice. Additionally, the analytical form of AMURA-based measures, as opposed to the iterative, non-linear reconstruction ubiquitous to full EAP techniques, turns the newly introduced apparent RTOP, RTPP, and RTAP both robust and efficient to compute.

The white matter state in migraine has been investigated using diffusion tensor imaging (DTI) measures, but results using this technique are conflicting. To overcome DTI measures, we employed ensemble average diffusion propagator measures obtained with apparent measures using reduced acquisitions (AMURA). The AMURA measures were return-to-axis (RTAP), return-to-origin (RTOP) and return-to-plane probabilities (RTPP). Tract-based spatial statistics was used to compare fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity from DTI, and RTAP, RTOP and RTPP, between healthy controls, episodic migraine and chronic migraine patients. Fifty healthy controls, 54 patients with episodic migraine and 56 with chronic migraine were assessed. Significant differences were found between both types of migraine, with lower axial diffusivity values in 38 white matter regions and higher RTOP values in the middle cerebellar peduncle in patients with a chronic migraine (p < 0.05 family-wise error corrected). Significantly lower RTPP values were found in episodic migraine patients compared to healthy controls in 24 white matter regions (p < 0.05 family-wise error corrected), finding no significant differences using DTI measures. The white matter microstructure is altered in a migraine, and in chronic compared to episodic migraine. AMURA can provide additional results with respect to DTI to uncover white matter alterations in migraine.

Spherical deconvolution (SD) methods are widely used to estimate the intra-voxel white-matter fiber orientations from diffusion MRI data. However, while some of these methods assume a zero-mean Gaussian distribution for the underlying noise, its real distribution is known to be non-Gaussian and to depend on many factors such as the number of coils and the methodology used to combine multichannel MRI signals. Indeed, the two prevailing methods for multichannel signal combination lead to noise patterns better described by Rician and noncentral Chi distributions. Here we develop a Robust and Unbiased Model-BAsed Spherical Deconvolution (RUMBA-SD) technique, intended to deal with realistic MRI noise, based on a Richardson-Lucy (RL) algorithm adapted to Rician and noncentral Chi likelihood models. To quantify the benefits of using proper noise models, RUMBA-SD was compared with dRL-SD, a well-established method based on the RL algorithm for Gaussian noise. Another aim of the study was to quantify the impact of including a total variation (TV) spatial regularization term in the estimation framework. To do this, we developed TV spatially-regularized versions of both RUMBA-SD and dRL-SD algorithms. The evaluation was performed by comparing various quality metrics on 132 three-dimensional synthetic phantoms involving different inter-fiber angles and volume fractions, which were contaminated with noise mimicking patterns generated by data processing in multichannel scanners. The results demonstrate that the inclusion of proper likelihood models leads to an increased ability to resolve fiber crossings with smaller inter-fiber angles and to better detect non-dominant fibers. The inclusion of TV regularization dramatically improved the resolution power of both techniques. The above findings were also verified in human brain data.

Acquisition parameters play a crucial role in Diffusion Tensor Imaging (DTI), as they have a major impact on the values of scalar measures such as Fractional Anisotropy (FA) or Mean Diffusivity (MD) that are usually the focus of clinical studies based on white matter analysis. This paper presents an analysis on the impact of the variation of several acquisition parameters on these scalar measures with a novel double focus. First, a tractography-based approach is employed, motivated by the significant number of clinical studies that are carried out using this technique. Second, the consequences of simultaneous changes in multiple parameters are analyzed: number of gradient directions, b-value and voxel resolution. Results indicate that the FA is most affected by changes in the number of gradients and voxel resolution, while MD is specially influenced by variations in the b-value. Even if the choice of a tractography algorithm has an effect on the numerical values of the final scalar measures, the evolution of these measures when acquisition parameters are modified is parallel.