White matter microstructural integrity continues to develop from adolescence to young adulthood in mice and humans: Same phenotype, different mechanism.

As direct evaluation of a mouse model of human neurodevelopment, adolescent and young adult mice and humans underwent MR diffusion tensor imaging to quantify age-related differences in microstructural integrity of brain white matter fibers. Fractional anisotropy (FA) was greater in older than younger mice and humans. Despite the cross-species commonality, the underlying developmental mechanism differed: whereas evidence for greater axonal extension contributed to higher FA in older mice, evidence for continuing myelination contributed to higher FA in human adolescent development. These differences occurred in the context of species distinctions in overall brain growth: whereas the continued growth of the brain and skull in the murine model can accommodate volume expansion into adulthood, human white matter volume and myelination continue growth into adulthood within a fixed intracranial volume. Appreciation of the similarities and differences in developmental mechanism can enhance the utility of animal models of brain white matter structure, function, and response to exogenous manipulation.

The distortions of the free water model for diffusion MRI data when assuming single compartment relaxometry and proton density.

Objective.To document the bias of thesimplifiedfree water model of diffusion MRI (dMRI) signal vis-à-vis aspecificmodel which, in addition to diffusion, incorporates compartment-specific proton density (PD), T1 recovery during repetition time (TR), and T2 decay during echo time (TE).Approach.Both models assume that volume fractionfof the total signal in any voxel arises from the free water compartment (fw) such as cerebrospinal fluid or edema, and the remainder (1-f) from hindered water (hw) which is constrained by cellular structures such as white matter (WM). Thespecificandsimplifiedmodels are compared on a synthetic dataset, using a range of PD, T1 and T2 values. We then fit the models to anin vivohealthy brain dMRI dataset. For bothsyntheticandin vivodata we use experimentally feasible TR, TE, signal-to-noise ratio (SNR) and physiologically plausible diffusion profiles.Main results.From the simulations we see that the difference between the estimatedsimplified fandspecific fis largest for mid-range ground-truthf, and it increases as SNR increases. The estimation of volume fractionfis sensitive to the choice of model,simplifiedorspecific, but the estimated diffusion parameters are robust to small perturbations in the simulation.Specific fis more accurate and precise thansimplified f. In the white matter (WM) regions of thein vivoimages,specific fis lower thansimplified f.Significance.In dMRI models for free water, accounting for compartment specific PD, T1 and T2, in addition to diffusion, improves the estimation of model parameters. This extra model specification attenuates the estimation bias of compartmental volume fraction without affecting the estimation of other diffusion parameters.

Artificial intelligence, osteoporosis and fragility fractures.

PURPOSE OF REVIEW: Artificial intelligence tools have found new applications in medical diagnosis. These tools have the potential to capture underlying trends and patterns, otherwise impossible with previous modeling capabilities. Machine learning and deep learning models have found a role in osteoporosis, both to model the risk of fragility fracture, and to help with the identification and segmentation of images. RECENT FINDINGS: Here we survey the latest research in the artificial intelligence application to the prediction of osteoporosis that has been published between January 2017 and March 2019. Around half of the articles that are covered here predict (by classification or regression) an indicator of osteoporosis, such as bone mass or fragility fractures; the other half of studies use tools for automatic segmentation of the images of patients with or at risk of osteoporosis. The data for these studies include diverse signal sources: acoustics, MRI, CT, and of course, X-rays. SUMMARY: New methods for automatic image segmentation, and prediction of fracture risk show promising clinical value. Though these recent developments have had a successful initial application to osteoporosis research, their development is still under improvement, such as accounting for positive/negative class bias. We urge care when reporting accuracy metrics, and when comparing such metrics between different studies.

VERDICT MRI for Prostate Cancer: Intracellular Volume Fraction versus Apparent Diffusion Coefficient.

Background Biologic specificity of diffusion MRI in relation to prostate cancer aggressiveness may improve by examining separate components of the diffusion MRI signal. The Vascular, Extracellular, and Restricted Diffusion for Cytometry in Tumors (VERDICT) model estimates three distinct signal components and associates them to (a) intracellular water, (b) water in the extracellular extravascular space, and (c) water in the microvasculature. Purpose To evaluate the repeatability, image quality, and diagnostic utility of intracellular volume fraction (FIC) maps obtained with VERDICT prostate MRI and to compare those maps with apparent diffusion coefficient (ADC) maps for Gleason grade differentiation. Materials and Methods Seventy men (median age, 62.2 years; range, 49.5-82.0 years) suspected of having prostate cancer or undergoing active surveillance were recruited to a prospective study between April 2016 and October 2017. All men underwent multiparametric prostate and VERDICT MRI. Forty-two of the 70 men (median age, 67.7 years; range, 50.0-82.0 years) underwent two VERDICT MRI acquisitions to assess repeatability of FIC measurements obtained with VERDICT MRI. Repeatability was measured with use of intraclass correlation coefficients (ICCs). The image quality of FIC and ADC maps was independently evaluated by two board-certified radiologists. Forty-two men (median age, 64.8 years; range, 49.5-79.6 years) underwent targeted biopsy, which enabled comparison of FIC and ADC metrics in the differentiation between Gleason grades. Results VERDICT MRI FIC demonstrated ICCs of 0.87-0.95. There was no significant difference between image quality of ADC and FIC maps (score, 3.1 vs 3.3, respectively; P = .90). FIC was higher in lesions with a Gleason grade of at least 3+4 compared with benign and/or Gleason grade 3+3 lesions (mean, 0.49 ± 0.17 vs 0.31 ± 0.12, respectively; P = .002). The difference in ADC between these groups did not reach statistical significance (mean, 1.42 vs 1.16 × 10-3 mm2/sec; P = .26). Conclusion Fractional intracellular volume demonstrates high repeatability and image quality and enables better differentiation of a Gleason 4 component cancer from benign and/or Gleason 3+3 histology than apparent diffusion coefficient. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Sigmund and Rosenkrantz in this issue.

Artificial Intelligence Applied to Osteoporosis: A Performance Comparison of Machine Learning Algorithms in Predicting Fragility Fractures From MRI Data.

BACKGROUND: A current challenge in osteoporosis is identifying patients at risk of bone fracture. PURPOSE: To identify the machine learning classifiers that predict best osteoporotic bone fractures and, from the data, to highlight the imaging features and the anatomical regions that contribute most to prediction performance. STUDY TYPE: Prospective (cross-sectional) case-control study. POPULATION: Thirty-two women with prior fragility bone fractures, of mean age = 61.6 and body mass index (BMI) = 22.7 kg/m2 , and 60 women without fractures, of mean age = 62.3 and BMI = 21.4 kg/m2 . Field Strength/ Sequence: 3D FLASH at 3T. ASSESSMENT: Quantitative MRI outcomes by software algorithms. Mechanical and topological microstructural parameters of the trabecular bone were calculated for five femoral regions, and added to the vector of features together with bone mineral density measurement, fracture risk assessment tool (FRAX) score, and personal characteristics such as age, weight, and height. We fitted 15 classifiers using 200 randomized cross-validation datasets. Statistical Tests: Data: Kolmogorov-Smirnov test for normality. Model Performance: sensitivity, specificity, precision, accuracy, F1-test, receiver operating characteristic curve (ROC). Two-sided t-test, with P < 0.05 for statistical significance. RESULTS: The top three performing classifiers are RUS-boosted trees (in particular, performing best with head data, F1 = 0.64 ± 0.03), the logistic regression and the linear discriminant (both best with trochanteric datasets, F1 = 0.65 ± 0.03 and F1 = 0.67 ± 0.03, respectively). A permutation of these classifiers comprised the best three performers for four out of five anatomical datasets. After averaging across all the anatomical datasets, the score for the best performer, the boosted trees, was F1 = 0.63 ± 0.03 for All-features dataset, F1 = 0.52 ± 0.05 for the no-MRI dataset, and F1 = 0.48 ± 0.06 for the no-FRAX dataset. Data Conclusion: Of many classifiers, the RUS-boosted trees, the logistic regression, and the linear discriminant are best for predicting osteoporotic fracture. Both MRI and FRAX independently add value in identifying osteoporotic fractures. The femoral head, greater trochanter, and inter-trochanter anatomical regions within the proximal femur yielded better F1-scores for the best three classifiers. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1029-1038.

Diffusion tensor imaging of articular cartilage using a navigated radial imaging spin-echo diffusion (RAISED) sequence.

OBJECTIVE: To validate a radial imaging spin-echo diffusion tensor (RAISED) sequence for high-resolution diffusion tensor imaging (DTI) of articular cartilage at 3 T. METHODS: The RAISED sequence implementation is described, including the used non-linear motion correction algorithm. The robustness to eddy currents was tested on phantoms, and accuracy of measurement was assessed with measurements of temperature-dependent diffusion of free water. Motion correction was validated by comparing RAISED with single-shot diffusion-weighted echo-planar imaging (EPI) measures. DTI was acquired in asymptomatic subjects (n = 6) and subjects with doubtful (Kellgren-Lawrence [KL] grade 1, n = 9) and mild (KL = 2, n = 9) symptomatic knee osteoarthritis (OA). MD and FA values without correction, and after all corrections, were calculated. A test-retest evaluation of the DTI acquisition on three asymptomatic and three OA subjects was also performed. RESULTS: The root mean squared coefficient of variation of the global test-restest reproducibility was 3.54% for MD and 5.34% for FA. MD was significantly increased in both femoral condyles (7-9%) of KL 1 and in the medial (11-17%) and lateral (10-12%) compartments of KL 2 subjects. Averaged FA presented a trend of lower values with increasing KL grade, which was significant for the medial femoral condyle (-11%) of KL 1 and all three compartments in KL 2 subjects (-18 to -11%). Group differences in MD and FA were only significant after motion correction. CONCLUSION: The RAISED sequence with the proposed reconstruction framework provides reproducible assessment of DTI parameters in vivo at 3 T and potentially the early stages of the disease in large regions of interest. KEY POINTS: • DTI of articular cartilage is feasible at 3T with a multi-shot RAISED sequence with non-linear motion correction. • RAISED sequence allows estimation of the diffusion indices MD and FA with test-retest errors below 4% (MD) and 6% (FA). • RAISED-based measurement of DTI of articular cartilage with non-linear motion correction holds potential to differentiate healthy from OA subjects.

A robust diffusion tensor model for clinical applications of MRI to cartilage.

PURPOSE: Diffusion tensor imaging (DTI) of articular cartilage is a promising technique for the early diagnosis of osteoarthritis (OA). However, in vivo diffusion tensor (DT) measurements suffer from low signal-to-noise ratio (SNR) that can result in bias when estimating the six parameters of the full DT, thus reducing sensitivity. This study seeks to validate a simplified four-parameter DT model (zeppelin) for obtaining more robust and sensitive in vivo DTI biomarkers of cartilage. METHODS: We use simulations in a substrate to mimic changes during OA; and analytic simulations of the DT drawn from a range of fractional anisotropies (FA) measured with high-quality DT data from ex vivo human cartilage. We also use in vivo data from the knees of a healthy subject and two OA patients with Kellgren-Lawrence (KL) grades 1 and 2. RESULTS: For simulated in vivo cartilage SNR (∼25) and anisotropy levels, the estimated mean values of MD from the DT and zeppelin models were identical to the ground truth values. However, zeppelin's FA is more accurate in measuring water restriction. More specifically, the FA estimations of the DT model were additionally biased by between +2% and +48% with respect to zeppelin values. Additionally, both mean diffusivity (MD) and FA of the zeppelin had lower parameter variance compared to the full DT (F-test, P < 0.05). We observe the same trends from in vivo values of patient data. CONCLUSION: The zeppelin is more robust than the full DT for cartilage diffusion anisotropy and SNR at levels typically encountered in clinical applications of articular cartilage. Magn Reson Med 79:1157-1164, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Diffusion MRI microstructure models with in vivo human brain Connectome data: results from a multi-group comparison.

A large number of mathematical models have been proposed to describe the measured signal in diffusion-weighted (DW) magnetic resonance imaging (MRI). However, model comparison to date focuses only on specific subclasses, e.g. compartment models or signal models, and little or no information is available in the literature on how performance varies among the different types of models. To address this deficiency, we organized the 'White Matter Modeling Challenge' during the International Symposium on Biomedical Imaging (ISBI) 2015 conference. This competition aimed to compare a range of different kinds of models in their ability to explain a large range of measurable in vivo DW human brain data. Specifically, we assessed the ability of models to predict the DW signal accurately for new diffusion gradients and b values. We did not evaluate the accuracy of estimated model parameters, as a ground truth is hard to obtain. We used the Connectome scanner at the Massachusetts General Hospital, using gradient strengths of up to 300 mT/m and a broad set of diffusion times. We focused on assessing the DW signal prediction in two regions: the genu in the corpus callosum, where the fibres are relatively straight and parallel, and the fornix, where the configuration of fibres is more complex. The challenge participants had access to three-quarters of the dataset and their models were ranked on their ability to predict the remaining unseen quarter of the data. The challenge provided a unique opportunity for a quantitative comparison of diverse methods from multiple groups worldwide. The comparison of the challenge entries reveals interesting trends that could potentially influence the next generation of diffusion-based quantitative MRI techniques. The first is that signal models do not necessarily outperform tissue models; in fact, of those tested, tissue models rank highest on average. The second is that assuming a non-Gaussian (rather than purely Gaussian) noise model provides little improvement in prediction of unseen data, although it is possible that this may still have a beneficial effect on estimated parameter values. The third is that preprocessing the training data, here by omitting signal outliers, and using signal-predicting strategies, such as bootstrapping or cross-validation, could benefit the model fitting. The analysis in this study provides a benchmark for other models and the data remain available to build up a more complete comparison in the future.

Diffusion tensor imaging of articular cartilage at 3T correlates with histology and biomechanics in a mechanical injury model.

PURPOSE: We establish a mechanical injury model for articular cartilage to assess the sensitivity of diffusion tensor imaging (DTI) in detecting cartilage damage early in time. Mechanical injury provides a more realistic model of cartilage degradation compared with commonly used enzymatic degradation. METHODS: Nine cartilage-on-bone samples were obtained from patients undergoing knee replacement. The 3 Tesla DTI (0.18 × 0.18 × 1 mm3 ) was performed before, 1 week, and 2 weeks after (zero, mild, and severe) injury, with a clinical radial spin-echo DTI (RAISED) sequence used in our hospital. We performed stress-relaxation tests and used a quasilinear-viscoelastic (QLV) model to characterize cartilage mechanical properties. Serial histology sections were dyed with Safranin-O and given an OARSI grade. We then correlated the changes in DTI parameters with the changes in QLV-parameters and OARSI grades. RESULTS: After severe injury the mean diffusivity increased after 1 and 2 weeks, whereas the fractional anisotropy decreased after 2 weeks (P < 0.05). The QLV-parameters and OARSI grades of the severe injury group differed from the baseline with statistical significance. The changes in mean diffusivity across all the samples correlated with the changes in the OARSI grade (r = 0.72) and QLV-parameters (r = -0.75). CONCLUSION: DTI is sensitive in tracking early changes after mechanical injury, and its changes correlate with changes in biomechanics and histology. Magn Reson Med 78:69-78, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

White matter compartment models for in vivo diffusion MRI at 300mT/m.

This paper compares a range of compartment models for diffusion MRI data on in vivo human acquisitions from a standard 60mT/m system (Philips 3T Achieva) and a unique 300mT/m system (Siemens Connectom). The key aim is to determine whether both systems support broadly the same models or whether the Connectom higher gradient system supports significantly more complex models. A single volunteer underwent 8h of acquisition on each system to provide uniquely wide and dense sampling of the available space of pulsed-gradient spin-echo (PGSE) measurements. We select a set of promising models from the wide set of possible three-compartment models for in vivo white matter (WM) that previous work and preliminary experiments suggest as strong candidates, but extend them to fit for compartmental T2 and diffusivity. We focus on the corpus callosum where the WM fibre architecture is simplest and compare their ability to explain the measured data, using Akaike's information criterion (AIC), and to predict unseen data, using cross-validation. We also compare the stability of parameter estimates in the presence of i) noise, using bootstrapping, and ii) spatial variation, using visual assessment and comparison with anatomical knowledge. Broadly similar models emerge from the AIC and cross-validation experiments in both data sets. Specifically, a three-compartment model consisting of either a Bingham distribution of sticks or a Cylinder for the intracellular compartment, an anisotropic diffusion tensor (DT) model for the extracellular compartment, as well as an isotropic CSF compartment, performs consistently well. However, various other models also perform well and no single model emerges as clear winner. The WM data (with virtually no CSF contamination) do not support compartmental T2 but partially support compartmental diffusivity. Evaluation of parameter stability favours simpler models than those identified by AIC or cross-validation. They suggest that the level of complexity in models underpinning currently popular microstructure imaging techniques such as NODDI, CHARMED, or ActiveAx, where the number of free parameters is about 4 or 5 rather than 10 or 11, may reflect the level of complexity achievable for a useful technique on current systems, although the 300mT/m data may support more complex models.

A ranking of diffusion MRI compartment models with in vivo human brain data.

PURPOSE: Diffusion magnetic resonance imaging (MRI) microstructure imaging provides a unique noninvasive probe into tissue microstructure. The technique relies on biophysically motivated mathematical models, relating microscopic tissue features to the magnetic resonance (MR) signal. This work aims to determine which compartment models of diffusion MRI are best at describing measurements from in vivo human brain white matter. METHODS: Recent work shows that three compartment models, designed to capture intra-axonal, extracellular, and isotropically restricted diffusion, best explain multi-b-value data sets from fixed rat corpus callosum. We extend this investigation to in vivo by using a live human subject on a clinical scanner. The analysis compares models of one, two, and three compartments and ranks their ability to explain the measured data. We enhance the original methodology to further evaluate the stability of the ranking. RESULTS: As with fixed tissue, three compartment models explain the data best. However, a clearer hierarchical structure and simpler models emerge. We also find that splitting the scanning into shorter sessions has little effect on the ranking of models, and that the results are broadly reproducible across sessions. CONCLUSION: Three compartments are required to explain diffusion MR measurements from in vivo corpus callosum, which informs the choice of model for microstructure imaging applications in the brain.

The importance of being dispersed: A ranking of diffusion MRI models for fibre dispersion using in vivo human brain data.

In this work we compare parametric diffusion MRI models which explicitly seek to explain fibre dispersion in nervous tissue. These models aim at providing more specific biomarkers of disease by disentangling these structural contributions to the signal. Some models are drawn from recent work in the field; others have been constructed from combinations of existing compartments that aim to capture both intracellular and extracellular diffusion. To test these models we use a rich dataset acquired in vivo on the corpus callosum of a human brain, and then compare the models via the Bayesian Information Criteria. We test this ranking via bootstrapping on the data sets, and cross-validate across unseen parts of the protocol. We find that models that capture fibre dispersion are preferred. The results show the importance of modelling dispersion, even in apparently coherent fibres.