MR fingerprinting (MRF) is a promising method for quantitative characterization of tissues. Often, voxel-wise measurements are made, assuming a single tissue-type per voxel. Alternatively, the Sparsity Promoting Iterative Joint Non-negative least squares Multi-Component MRF method (SPIJN-MRF) facilitates tissue parameter estimation for identified components as well as partial volume segmentations. The aim of this paper was to evaluate the accuracy and repeatability of the SPIJN-MRF parameter estimations and partial volume segmentations. This was done (1) through numerical simulations based on the BrainWeb phantoms and (2) using in vivo acquired MRF data from 5 subjects that were scanned on the same week-day for 8 consecutive weeks. The partial volume segmentations of the SPIJN-MRF method were compared to those obtained by two conventional methods: SPM12 and FSL. SPIJN-MRF showed higher accuracy in simulations in comparison to FSL- and SPM12-based segmentations: Fuzzy Tanimoto Coefficients (FTC) comparing these segmentations and Brainweb references were higher than 0.95 for SPIJN-MRF in all the tissues and between 0.6 and 0.7 for SPM12 and FSL in white and gray matter and between 0.5 and 0.6 in CSF. For the in vivo MRF data, the estimated relaxation times were in line with literature and minimal variation was observed. Furthermore, the coefficient of variation (CoV) for estimated tissue volumes with SPIJN-MRF were 10.5% for the myelin water, 6.0% for the white matter, 5.6% for the gray matter, 4.6% for the CSF and 1.1% for the total brain volume. CoVs for CSF and total brain volume measured on the scanned data for SPIJN-MRF were in line with those obtained with SPM12 and FSL. The CoVs for white and gray matter volumes were distinctively higher for SPIJN-MRF than those measured with SPM12 and FSL. In conclusion, the use of SPIJN-MRF provides accurate and precise tissue relaxation parameter estimations taking into account intrinsic partial volume effects. It facilitates obtaining tissue fraction maps of prevalent tissues including myelin water which can be relevant for evaluating diseases affecting the white matter.

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In this paper, we propose the use of Recurrent Inference Machines (RIMs) to perform T₁ and T₂ mapping. The RIM is a neural network framework that learns an iterative inference process based on the signal model, similar to conventional statistical methods for quantitative MRI (QMRI), such as the Maximum Likelihood Estimator (MLE). This framework combines the advantages of both data-driven and model-based methods, and, we hypothesize, is a promising tool for QMRI. Previously, RIMs were used to solve linear inverse reconstruction problems. Here, we show that they can also be used to optimize non-linear problems and estimate relaxometry maps with high precision and accuracy. The developed RIM framework is evaluated in terms of accuracy and precision and compared to an MLE method and an implementation of the Residual Neural Network (ResNet). The results show that the RIM improves the quality of estimates compared to the other techniques in Monte Carlo experiments with simulated data, test-retest analysis of a system phantom, and in-vivo scans. Additionally, inference with the RIM is 150 times faster than the MLE, and robustness to (slight) variations of scanning parameters is demonstrated. Hence, the RIM is a promising and flexible method for QMRI. Coupled with an open-source training data generation tool, it presents a compelling alternative to previous methods.

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For the segmentation of magnetic resonance brain images into anatomical regions, numerous fully automated methods have been proposed and compared to reference segmentations obtained manually. However, systematic differences might exist between the resulting segmentations, depending on the segmentation method and underlying brain atlas. This potentially results in sensitivity differences to disease and can further complicate the comparison of individual patients to normative data. In this study, we aim to answer two research questions: 1) to what extent are methods interchangeable, as long as the same method is being used for computing normative volume distributions and patient-specific volumes? and 2) can different methods be used for computing normative volume distributions and assessing patient-specific volumes? To answer these questions, we compared volumes of six brain regions calculated by five state-of-the-art segmentation methods: Erasmus MC (EMC), FreeSurfer (FS), geodesic information flows (GIF), multi-atlas label propagation with expectation–maximization (MALP-EM), and model-based brain segmentation (MBS). We applied the methods on 988 non-demented (ND) subjects and computed the correlation (PCC-v) and absolute agreement (ICC-v) on the volumes. For most regions, the PCC-v was good ((Formula presented.)), indicating that volume differences between methods in ND subjects are mainly due to systematic differences. The ICC-v was generally lower, especially for the smaller regions, indicating that it is essential that the same method is used to generate normative and patient data. To evaluate the impact on single-subject analysis, we also applied the methods to 42 patients with Alzheimer’s disease (AD). In the case where the normative distributions and the patient-specific volumes were calculated by the same method, the patient’s distance to the normative distribution was assessed with the z-score. We determined the diagnostic value of this z-score, which showed to be consistent across methods. The absolute agreement on the AD patients’ z-scores was high for regions of thalamus and putamen. This is encouraging as it indicates that the studied methods are interchangeable for these regions. For regions such as the hippocampus, amygdala, caudate nucleus and accumbens, and globus pallidus, not all method combinations showed a high ICC-z. Whether two methods are indeed interchangeable should be confirmed for the specific application and dataset of interest.

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Quantitative MRI methods that estimate multiple physical parameters simultaneously often require the fitting of a computational complex signal model defined through the Bloch equations. Repeated Bloch simulations can be avoided by matching the measured signal with a precomputed signal dictionary on a discrete parameter grid (i.e. lookup table) as used in MR Fingerprinting. However, accurate estimation requires discretizing each parameter with a high resolution and consequently high computational and memory costs for dictionary generation, storage, and matching. Here, we reduce the required parameter resolution by approximating the signal between grid points through B-spline interpolation. The interpolant and its gradient are evaluated efficiently which enables a least-squares fitting method for parameter mapping. The resolution of each parameter was minimized while obtaining a user-specified interpolation accuracy. The method was evaluated by phantom and in-vivo experiments using fully-sampled and undersampled unbalanced (FISP) MR fingerprinting acquisitions. Bloch simulations incorporated relaxation effects $(\boldsymbol {T}_{\boldsymbol {1}},\boldsymbol {T}_{\boldsymbol {2}})$ , proton density $\left ({\boldsymbol {PD} }\right)$ , receiver phase ( $\boldsymbol {\varphi }_{\boldsymbol {0}}$ ), transmit field inhomogeneity ( $\boldsymbol {B}_{\boldsymbol {1}}^{\boldsymbol {+}}$ ), and slice profile. Parameter maps were compared with those obtained from dictionary matching, where the parameter resolution was chosen to obtain similar signal (interpolation) accuracy. For both the phantom and the in-vivo acquisition, the proposed method approximated the parameter maps obtained through dictionary matching while reducing the parameter resolution in each dimension ( $\boldsymbol {T}_{\boldsymbol {1}},\boldsymbol {T}_{\boldsymbol {2}},\boldsymbol {B}_{\boldsymbol {1}}^{\boldsymbol {+}}$ ) by - on average - an order of magnitude. In effect, the applied dictionary was reduced from .47GB$ to $464KB$. Furthermore, the proposed method was equally robust against undersampling artifacts as dictionary matching. Dictionary fitting with B-spline interpolation reduces the computational and memory costs of dictionary-based methods and is therefore a promising method for multi-parametric mapping.

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Background: Identifying persons at risk for cognitive decline may aid in early detection of persons at risk of dementia and to select those that would benefit most from therapeutic or preventive measures for dementia. Objective: In this study we aimed to validate whether cognitive decline in the general population can be predicted with multivariate data using a previously proposed supervised classification method: Disease State Index (DSI). Methods: We included 2,542 participants, non-demented and without mild cognitive impairment at baseline, from the population-based Rotterdam Study (mean age 60.9 ± 9.1 years). Participants with significant global cognitive decline were defined as the 5% of participants with the largest cognitive decline per year. We trained DSI to predict occurrence of significant global cognitive decline using a large variety of baseline features, including magnetic resonance imaging (MRI) features, cardiovascular risk factors, APOE-ε4 allele carriership, gait features, education, and baseline cognitive function as predictors. The prediction performance was assessed as area under the receiver operating characteristic curve (AUC), using 500 repetitions of 2-fold cross-validation experiments, in which (a randomly selected) half of the data was used for training and the other half for testing. Results: A mean AUC (95% confidence interval) for DSI prediction was 0.78 (0.77–0.79) using only age as input feature. When using all available features, a mean AUC of 0.77 (0.75–0.78) was obtained. Without age, and with age-corrected features and feature selection on MRI features, a mean AUC of 0.70 (0.63–0.76) was obtained, showing the potential of other features besides age. Conclusion: The best performance in the prediction of global cognitive decline in the general population by DSI was obtained using only age as input feature. Other features showed potential, but did not improve prediction. Future studies should evaluate whether the performance could be improved by new features, e.g., longitudinal features, and other prediction methods.

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The goal of this paper is to increase the statistical power of crossing-fiber statistics in voxelwise analyses of diffusion-weighted magnetic resonance imaging (DW-MRI) data. In the proposed framework, a fiber orientation atlas and a model complexity atlas were used to fit the ball-and-sticks model to diffusion-weighted images of subjects in a prospective population-based cohort study. Reproducibility and sensitivity of the partial volume fractions in the ball-and-sticks model were analyzed using TBSS (tract-based spatial statistics) and compared to a reference framework. The reproducibility was investigated on two scans of 30 subjects acquired with an interval of approximately three weeks by studying the intraclass correlation coefficient (ICC). The sensitivity to true biological effects was evaluated by studying the regression with age on 500 subjects from 65 to 90 years old. Compared to the reference framework, the ICC improved significantly when using the proposed framework. Higher t-statistics indicated that regression coefficients with age could be determined more precisely with the proposed framework and more voxels correlated significantly with age. The application of a fiber orientation atlas and a model complexity atlas can significantly improve the reproducibility and sensitivity of crossing-fiber statistics in TBSS.

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Purpose: To identify the optimal combination of pharmacokinetic model and arterial input function (AIF) for quantitative analysis of blood perfusion in the patellar bone using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Materials and Methods: This method design study used a random subset of five control subjects from an Institutional Review Board (IRB)-approved case–control study into patellofemoral pain, scanned on a 3T MR system with a contrast-enhanced time-resolved imaging of contrast kinetics (TRICKS) sequence. We systematically investigated the reproducibility of pharmacokinetic parameters for all combinations of Orton and Parker AIF models with Tofts, Extended Tofts (ETofts), and Brix pharmacokinetic models. Furthermore, we evaluated if the AIF should use literature parameters, be subject-specific, or group-specific. Model selection was based on the goodness-of-fit and the coefficient of variation of the pharmacokinetic parameters inside the patella. This extends previous studies that were not focused on the patella and did not evaluate as many combinations of arterial and pharmacokinetic models. Results: The vascular component in the ETofts model could not reliably be recovered (coefficient of variation [CV] of v_p >50%) and the Brix model parameters showed high variability of up to 20% for k_el across good AIF models. Compared to group-specific AIF, the subject-specific AIF's mostly had higher residual. The best reproducibility and goodness-of-fit were obtained by combining Tofts' pharmacokinetic model with the group-specific Parker AIF. Conclusion: We identified several good combinations of pharmacokinetic models and AIF for quantitative analysis of perfusion in the patellar bone. The recommended combination is Tofts pharmacokinetic model combined with a group-specific Parker AIF model. Level of Evidence: 2. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2018;47:848–858.

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The most widespread technique used to register sets of medical images consists of selecting one image as fixed reference, to which all remaining images are successively registered. This pairwise scheme requires one optimization procedure per pair of images to register. Pairwise mutual information is a common dissimilarity measure applied to a large variety of datasets. Alternative methods, called groupwise registrations, have been presented to register two or more images in a single optimization procedure, without the need of a reference image. Given the success of mutual information in pairwise registration, we adapt one of its multivariate versions, called total correlation, in a groupwise context. We justify the choice of total correlation among other multivariate versions of mutual information, and provide full implementation details. The resulting total correlation measure is remarkably close to measures previously proposed by Huizinga et al. based on principal component analysis. Our experiments, performed on five quantitative imaging datasets and on a dynamic CT imaging dataset, show that total correlation yields registration results that are comparable to Huizinga’s methods. Total correlation has the advantage of being theoretically justified, while the measures of Huizinga et al. were designed empirically. Additionally, total correlation offers an alternative to pairwise mutual information on quantitative imaging datasets.

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Both normal aging and neurodegenerative disorders such as Alzheimer's disease (AD) cause morphological changes of the brain. It is generally difficult to distinguish these two causes of morphological change by visual inspection of magnetic resonance (MR) images. To facilitate making this distinction and thus aid the diagnosis of neurodegenerative disorders, we propose a method for developing a spatio-temporal model of morphological differences in the brain due to normal aging. The method utilizes groupwise image registration to characterize morphological variation across brain scans of people with different ages. To extract the deformations that are due to normal aging we use partial least squares regression, which yields modes of deformations highly correlated with age, and corresponding scores for each input subject. Subsequently, we determine a distribution of morphologies as a function of age by fitting smooth percentile curves to these scores. This distribution is used as a reference to which a person's morphology score can be compared. We validate our method on two different datasets, using images from both cognitively normal subjects and patients with Alzheimer disease (AD). Results show that the proposed framework extracts the expected atrophy patterns. Moreover, the morphology scores of cognitively normal subjects are on average lower than the scores of AD subjects, indicating that morphology differences between AD subjects and healthy subjects can be partly explained by accelerated aging. With our methods we are able to assess accelerated brain aging on both population and individual level. A spatio-temporal aging brain model derived from 988 T1-weighted MR brain scans from a large population imaging study (age range 45.9–91.7y, mean age 68.3y) is made publicly available at www.agingbrain.nl.@en

Background: Altered perfusion might play an important role in the pathophysiology of patellofemoral pain (PFP), a common knee complaint with unclear pathophysiology. Purpose: To investigate differences in dynamic contrast-enhanced (DCE)-MRI perfusion parameters between patients with PFP and healthy control subjects. Population/Subjects/Phantom/Specimen/Animal Model: Thirty-five adult patients with PFP and 44 healthy adult control subjects. Field Strength/Sequence: 3T DCE-MRI consisting of a sagittal, anterior-posterior, frequency-encoded, fat-suppressed 3D spoiled gradient-echo sequence with intravenous contrast administration. Assessment: Patellar bone volumes of interest (VOIs) were delineated by a blinded observer. Quantitative perfusion parameters (k_ep and k_trans) were calculated from motion-compensated DCE-MRI data by fitting Tofts' model. Weighted mean and unweighted median values of k_ep and k_trans were computed within the patellar bone VOIs. Statistical Tests: Differences in patellar bone perfusion parameters were compared between groups by linear regression analyses, adjusted for confounders. Results: Mean differences of weighted mean and unweighted median were 0.0039 (95% confidence interval [CI] –0.0013; 0.0091) and 0.0052 (95% CI –0.0078; 0.018) for k_trans, and 0.046 (95% CI –0.021; 0.11) and 0.069 (95% CI –0.017; 0.15) for k_ep, respectively. All perfusion parameters were not significantly different between groups (P-values: 0.32; 0.47 for k_trans, and 0.24; 0.15) for k_ep. However, a significant difference in variance between populations was observed for k_trans (P-value 0.007). Data Conclusion: Higher patellar bone perfusion parameters were found in patients with PFP when compared to healthy control subjects, but these differences were not statistically significant. This result, and the observed significant difference in k_trans variance, warrant further research. Level of Evidence: 1. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2018;47:1344–1350.

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The goal of this paper is to develop a method for assessment of microstructural properties of the fornix in conventional (low resolution, single non-zero b-value) diffusion-weighted magnetic resonance imaging (DW-MRI) data. For this purpose, a bi-tensor model, comprising of an isotropic and an anisotropic diffusion compartment, was fitted to the diffusion-weighted images. Two subject-specific constraints were studied to solve the ill-posedness of the parameter estimation at a single (non-zero) b-value, namely by fixating the mean diffusivity (MD) or the axial diffusivity (AxD) of the anisotropic compartment. The bi-tensor statistics were compared to conventional diffusion statistics using simulated fiber bundles with different diameters and using fornix segmentations of 577 elderly subjects. Based on simulated fiber bundles, the anisotropy (FA) estimated by the bi-tensor model did not become biased with decreasing fiber bundle diameter, unlike conventional diffusion statistics such as FA and MD estimated by the single tensor model. In the population-based study, the bi-tensor tissue fraction decreased significantly with age, suggesting an increase of free water. The FA estimated by the bi-tensor model decreased with age, but this relation was not significant when the subject-specific values to which MD or AxD were constrained were added as covariates in the regression analysis. The distinction of an isotropic and an anisotropic diffusion compartment may allow a more sophisticated analysis of the fornix based on conventional DW-MRI data.@en

Purpose: To increase the sensitivity in longitudinal analysis of DW-MRI data with the ball-and-sticks model.

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Purpose
Myocardial blood flow (MBF) obtained by dynamic CT perfusion (CTP) has been recently introduced to assess hemodynamic significance of coronary stenosis in coronary artery disease. The diagnostic performance of dynamic CTP MBF is limited due to subjective interpretation of MBF maps and MBF variations caused by physiological, methodological, and technical issues. In this paper, we introduce a novel method to quantify the hypoperfused volume (HPV) in myocardial territories derived from CT angiography (CTA) to overcome the limitations of current dynamic CTP MBF analysis methods.


Methods
The diagnostic performance of HPV in classifying significant stenoses was evaluated on 22 patients (57 vessels) that underwent CTA, CTP and invasive fractional flow reserve (FFR). FFR was used as the standard of reference to determine stenosis significance. The diagnostic performance was compared to that of the mean MBF computed in regions manually annotated by an expert (MA-MBF). HPV was derived by thresholding the MBF in myocardial territories constructed from CTA by locating the closest artery. Diagnostic performance was evaluated using leave-one-case out cross-validation. Inter-observer reproducibility was assessed by performing annotations of coronary seeds (HPV) and manual regions (MA-MBF) with two users. In addition, the influence of different parameter settings on the diagnostic performance of HPV was assessed.


Results
Leave-one-case out cross-validation showed that HPV has an accuracy of 72% (58–83%) with sensitivity of 72% (47–90%) and specificity of 72% (58–83%). The accuracy of MA-MBF was 70% (57–82%) with a sensitivity of 50% (26–74%) and a specificity of 79% (64–91%). The Spearman correlation and the kappa statistic was (ρ = 0.94, κ = 0.86) for HPV and (ρ = 0.72, κ = 0.82) for MA-MBF. The influence of parameter settings on HPV based diagnostic performance was not significant.


Conclusions
The proposed HPV accurately classifies hemodynamically significant stenoses with a level of accuracy comparable to the mean MBF in regions annotated by an expert. HPV improves inter-observer reproducibility as compared to MA-MBF by providing a more objective criterion to associate the stenotic coronary with the supplied myocardial territory.
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Purpose: Quantitative T₁ mapping is a magnetic resonance imaging technique that estimates the spin-lattice relaxation time of tissues. Even though T₁ mapping has a broad range of potential applications, it is not routinely used in clinical practice as accurate and precise high resolution T₁ mapping requires infeasibly long acquisition times. Method: To improve the trade-off between the acquisition time, signal-to-noise ratio and spatial resolution, we acquire a set of low resolution T₁-weighted images and directly estimate a high resolution T₁ map by means of super-resolution reconstruction. Results: Simulation and in vivo experiments show an increased spatial resolution of the T₁ map, while preserving a high signal-to-noise ratio and short scan time. Moreover, the proposed method outperforms conventional estimation in terms of root-mean-square error. Conclusion: Super resolution T₁ estimation enables resolution enhancement in T₁ mapping with the use of standard (inversion recovery) T₁ acquisition sequences. Magn Reson Med, 2016.

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Image registration is typically formulated as an optimization process, which aims to find the optimal transformation parameters of a given transformation model by minimizing a cost function. Local minima may exist in the optimization landscape, which could hamper the optimization process. To eliminate local minima, smoothing the cost function would be desirable. In this paper, we investigate the use of a randomized smoothing (RS) technique for stochastic gradient descent (SGD) optimization, to effectively smooth the cost function. In this approach, Gaussian noise is added to the transformation parameters prior to computing the cost function gradient in each iteration of the SGD optimizer. The approach is suitable for both rigid and nonrigid registrations. Experiments on synthetic images, cell images, public CT lung data, and public MR brain data demonstrate the effectiveness of the novel RS technique in terms of registration accuracy and robustness.

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In quantitative magnetic resonance imaging (qMRI), quantitative tissue properties can be estimated by fitting a signal model to the voxel intensities of a series of images acquired with different settings. To obtain reliable quantitative measures, it is necessary that the qMRI images are spatially aligned so that a given voxel corresponds in all images to the same anatomical location. The objective of the present study is to describe and evaluate a novel automatic groupwise registration technique using a dissimilarity metric based on an approximated form of total correlation. The proposed registration method is applied to five qMRI datasets of various anatomical locations, and the obtained registration performances are compared to these of a conventional pairwise registration based on mutual information. The results show that groupwise total correlation yields better registration performances than pairwise mutual information. This study also establishes that the formulation of approximated total correlation is quite analogous to two other groupwise metrics based on principal component analysis (PCA). Registration performances of total correlation and these two PCA-based techniques are therefore compared. The results show that total correlation yields performances that are analogous to these of the PCAbased techniques. However, compared to these PCA-based metrics, total correlation has two main advantages. Firstly, it is directly derived from a multivariate form of mutual information, while the PCA-based metrics were obtained empirically. Secondly, total correlation has the advantage of requiring no user-defined parameter.

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Both normal aging and neurodegenerative diseases such as Alzheimer's disease cause morphological changes of the brain. To better distinguish between normal and abnormal cases, it is necessary to model changes in brain morphology owing to normal aging. To this end, we developed a method for analyzing and visualizing these changes for the entire brain morphology distribution in the general aging population. The method is applied to 1000 subjects from a large population imaging study in the elderly, from which 900 were used to train the model and 100 were used for testing. The results of the 100 test subjects show that the model generalizes to subjects outside the model population. Smooth percentile curves showing the brain morphology changes as a function of age and spatiotemporal atlases derived from the model population are publicly available via an interactive web application at agingbrain.bigr.nl.

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Purpose
This paper presents and studies a framework for reliable modeling of diffusion MRI using a data-acquisition adaptive prior.

Methods
Automated relevance determination estimates the mean of the posterior distribution of a rank-2 dual tensor model exploiting Jeffreys prior (JARD). This data-acquisition prior is based on the Fisher information matrix and enables the assessment whether two tensors are mandatory to describe the data. The method is compared to Maximum Likelihood Estimation (MLE) of the dual tensor model and to FSL’s ball-and-stick approach.

Results
Monte Carlo experiments demonstrated that JARD’s volume fractions correlated well with the ground truth for single and crossing fiber configurations. In single fiber configurations JARD automatically reduced the volume fraction of one compartment to (almost) zero. The variance in fractional anisotropy (FA) of the main tensor component was thereby reduced compared to MLE. JARD and MLE gave a comparable outcome in data simulating crossing fibers. On brain data, JARD yielded a smaller spread in FA along the corpus callosum compared to MLE. Tract-based spatial statistics demonstrated a higher sensitivity in detecting age-related white matter atrophy using JARD compared to both MLE and the ball-and-stick approach.

Conclusions
The proposed framework offers accurate and precise estimation of diffusion properties in single and dual fiber regions.
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