Corneal guttae, which are the abnormal growth of extracellular matrix in the corneal endothelium, are observed in specular images as black droplets that occlude the endothelial cells. To estimate the corneal parameters (endothelial cell density [ECD], coefficient of variation [CV], and hexagonality [HEX]), we propose a new deep learning method that includes a novel attention mechanism (named fNLA), which helps to infer the cell edges in the occluded areas. The approach first derives the cell edges, then infers the well-detected cells, and finally employs a postprocessing method to fix mistakes. This results in a binary segmentation from which the corneal parameters are estimated. We analyzed 1203 images (500 contained guttae) obtained with a Topcon SP-1P microscope. To generate the ground truth, we performed manual segmentation in all images. Several networks were evaluated (UNet, ResUNeXt, DenseUNets, UNet++, etc.) and we found that DenseUNets with fNLA provided the lowest error: a mean absolute error of 23.16 [cells/mm²] in ECD, 1.28 [%] in CV, and 3.13 [%] in HEX. Compared with Topcon’s built-in software, our error was 3–6 times smaller. Overall, our approach handled notably well the cells affected by guttae, detecting cell edges partially occluded by small guttae and discarding large areas covered by extensive guttae.

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Optical properties, such as the attenuation coefficients of multi-layer tissue samples, could be used as a biomarker for diagnosis and disease progression in clinical practice. In this paper, we present a method to estimate the attenuation coefficients in a multi-layer sample by fitting a single scattering model for the OCT signal to the recorded OCT signal. In addition, we employ numerical simulations to obtain the theoretically achievable precision and accuracy of the estimated parameters under various experimental conditions. Finally, the method is applied to two sets of measurements obtained from a multi-layer phantom by two experimental OCT systems: One with a large and one with a small Rayleigh length. Numerical and experimental results show an accurate estimation of the attenuation coefficients when using multiple B-scans.

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The attenuation coefficient (AC) is an optical property of tissue that can be estimated from optical coherence tomography (OCT) data. In this paper, we aim to estimate the AC accurately by compensating for the shape of the focused beam. For this, we propose a method to estimate the axial PSF model parameters and AC by fitting a model for an OCT signal in a homogenous sample to the recorded OCT signal. In addition, we employ numerical analysis to obtain the theoretical optimal precision of the estimated parameters for different experimental setups. Finally, the method is applied to OCT B-scans obtained from homogeneous samples. The numerical and experimental results show accurate estimations of the AC and the focus location when the focus is located inside the sample.

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Purpose: To present a fully automatic method to estimate the corneal endothelium parameters from specular microscopy images and to use it to study a one-year follow-up after ultrathin Descemet stripping automated endothelial keratoplasty. Methods: We analyzed 383 post ultrathin Descemet stripping automated endothelial keratoplasty images from 41 eyes acquired with a Topcon SP-1P specular microscope at 1, 3, 6, and 12 months after surgery. The estimated parameters were endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX). Manual segmentation was performed in all images. Results: Our method provided an estimate for ECD, CV, and HEX in 98.4% of the images, whereas Topcon’s software had a success rate of 71.5% for ECD/CV and 30.5% for HEX. For the images with estimates, the percentage error in our method was 2.5% for ECD, 5.7% for CV, and 5.7% for HEX, whereas Topcon’s software provided an error of 7.5% for ECD, 17.5% for CV, and 18.3% for HEX. Our method was significantly better than Topcon’s (P < 0.0001) and was not statistically significantly different from the manual assessments (P > 0.05). At month 12, the subjects presented an average ECD = 1377 ± 483 [cells/mm² ], CV = 26.1 ± 5.7 [%], and HEX = 58.1 ± 7.1 [%]. Conclusions: The proposed method obtains reliable and accurate estimations even in challenging specular images of pathologic corneas. Translational Relevance: CV and HEX, not currently used in the clinic owing to a lack of reliability in automatic methods, are useful biomarkers to analyze the postoperative healing process. Our accurate estimations allow now for their clinical use.

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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

Corneal endothelium (CE) images provide valuable clinical information regarding the health state of the cornea. Computation of the clinical morphometric parameters requires the segmentation of endothelial cell images. Current techniques to image the endothelium in vivo deliver low quality images, which makes automatic segmentation a complicated task. Here, we present two convolutional neural networks (CNN) to segment CE images: a global fully convolutional approach based on U-net, and a local sliding-window network (SW-net). We propose to use probabilistic labels instead of binary, we evaluate a preprocessing method to enhance the contrast of images, and we introduce a postprocessing method based on Fourier analysis and watershed to convert the CNN output images into the final cell segmentation. Both methods are applied to 50 images acquired with an SP-1P Topcon specular microscope. Estimates are compared against a manual delineation made by a trained observer.

Results

U-net (AUC=0.9938) yields slightly sharper, clearer images than SW-net (AUC=0.9921). After postprocessing, U-net obtains a DICE=0.981 and a MHD=0.22 (modified Hausdorff distance), whereas SW-net yields a DICE=0.978 and a MHD=0.30. U-net generates a wrong cell segmentation in only 0.48% of the cells, versus 0.92% for the SW-net. U-net achieves statistically significant better precision and accuracy than both, Topcon and SW-net, for the estimates of three clinical parameters: cell density (ECD), polymegethism (CV), and pleomorphism (HEX). The mean relative error in U-net for the parameters is 0.4% in ECD, 2.8% in CV, and 1.3% in HEX. The computation time to segment an image and estimate the parameters is barely a few seconds.

Conclusions

Both methods presented here provide a statistically significant improvement over the state of the art. U-net has reached the smallest error rate. We suggest a segmentation refinement based on our previous work to further improve the performance.@en

Purpose Pharmacokinetic models facilitate assessment of properties of the micro-vascularization based on DCE-MRI data. However, accurate pharmacokinetic modeling in the liver is challenging since it has two vascular inputs and it is subject to large deformation and displacement due to respiration. Methods We propose an improved pharmacokinetic model for the liver that (1) analytically models the arrival-time of the contrast agent for both inputs separately; (2) implicitly compensates for signal fluctuations that can be modeled by varying applied flip-angle e.g. due to B1-inhomogeneity. Orton’s AIF model is used to analytically represent the vascular input functions. The inputs are independently embedded into the Sourbron model. B1-inhomogeneity-driven variations of flip-angles are accounted for to justify the voxel’s displacement with respect to a pre-contrast image. Results The new model was shown to yield lower root mean square error (RMSE) after fitting the model to all but a minority of voxels compared to Sourbron’s approach. Furthermore, it outperformed this existing model in the majority of voxels according to three model-selection criteria. Conclusion Our work primarily targeted to improve pharmacokinetic modeling for DCE-MRI of the liver. However, other types of pharmacokinetic models may also benefit from our approaches, since the techniques are generally applicable.

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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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Objectives: To compare Gd-EOB-DTPA dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) with ^99m Tc-mebrofenin hepatobiliary scintigraphy (HBS) as quantitative liver function tests for the preoperative assessment of patients undergoing liver resection. Methods: Patients undergoing liver surgery and preoperative assessment of future remnant liver (FRL) function using ^99m Tc-mebrofenin HBS were included. Patients underwent DHCE-MRI. Total liver uptake function was calculated for both modalities: mebrofenin uptake rate (MUR) and Ki respectively. The FRL was delineated with both SPECT-CT and MRI to calculate the functional share. Blood samples were taken to assess biochemical liver parameters. Results: A total of 20 patients were included. The HBS-derived MUR and the DHCE-MRI-derived mean Ki correlated strongly for both total and FRL function (Pearson r = 0.70, p = 0.001 and r = 0.89, p < 0.001 respectively). There was a strong agreement between the functional share determined with both modalities (ICC = 0.944, 95% CI 0.863–0.978, n = 20). There was a significant negative correlation between liver aminotransferases and bilirubin for both MUR and Ki. Conclusions: Assessment of liver function with DHCE-MRI is comparable with that of ^99m Tc-mebrofenin HBS and has the potential to be combined with diagnostic MRI imaging. This can therefore provide a one-stop-shop modality for the preoperative assessment of patients undergoing liver surgery. Key Points: • Quantitative assessment of liver function using hepatobiliary scintigraphy is performed in the preoperative assessment of patients undergoing liver surgery in order to prevent posthepatectomy liver failure. • Gd-EOB-DTPA dynamic hepatocyte-specific contrast-enhanced MRI (DHCE-MRI) is an emerging method to quantify liver function and can serve as a potential alternative to hepatobiliary scintigraphy. • Assessment of liver function with dynamic gadoxetate-enhanced MRI is comparable with that of hepatobiliary scintigraphy and has the potential to be combined with diagnostic MRI imaging.

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In images of the corneal endothelium (CE) acquired by specular microscopy, endothelial cells are commonly only visible in a part of the image due to varying contrast, mainly caused by challenging imaging conditions as a result of a strongly curved endothelium. In order to estimate the morphometric parameters of the corneal endothelium, the analyses need to be restricted to trustworthy regions - the region of interest (ROI) - where individual cells are discernible. We developed an automatic method to find the ROI by Dense U-nets, a densely connected network of convolutional layers. We tested the method on a heterogeneous dataset of 140 images, which contains a large number of blurred, noisy, and/or out of focus images, where the selection of the ROI for automatic biomarker extraction is vital. By using edge images as input, which can be estimated after retraining the same network, Dense U-net detected the trustworthy areas with an accuracy of 98.94% and an area under the ROC curve (AUC) of 0.998, without being affected by the class imbalance (9:1 in our dataset). After applying the estimated ROI to the edge images, the mean absolute percentage error (MAPE) in the estimated endothelial parameters was 0.80% for ECD, 3.60% for CV, and 2.55% for HEX.

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The morphometric parameters of the corneal endothelium – cell density (ECD), cell size variation (CV), and hexagonality (HEX) – provide clinically relevant information about the cornea. To estimate these parameters, the endothelium is commonly imaged with a non-contact specular microscope and cell segmentation is performed to these images. In previous work, we have developed several methods that, combined, can perform an automated estimation of the parameters: the inference of the cell edges, the detection of the region of interest (ROI), a post-processing method that combines both images (edges and ROI), and a refinement method that removes false edges. In this work, we first explore the possibility of using a CNN-based regressor to directly infer the parameters from the edge images, simplifying the framework. We use a dataset of 738 images coming from a study related to the implantation of a Baerveldt glaucoma device and a standard clinical care regarding DSAEK corneal transplantation, both from the Rotterdam Eye Hospital and both containing images of unhealthy endotheliums. This large dataset allows us to build a large training set that makes this approach feasible. We achieved a mean absolute percentage error (MAPE) of 4.32% for ECD, 7.07% for CV, and 11.74% for HEX. These results, while promising, do not outperform our previous work. In a second experiment, we explore the use of the CNN-based regressor to improve the post-processing method of our previous approach in order to adapt it to the specifics of each image. Our results showed no clear benefit and proved that our previous post-processing is already highly reliable and robust.@en

Clinical parameters related to the corneal endothelium can only be estimated by segmenting endothelial cell images. Specular microscopy is the current standard technique to image the endothelium, but its low SNR make the segmentation a complicated task. Recently, we proposed a method to segment such images by starting with an oversegmented image and merging the superpixels that constitute a cell. Here, we show how our merging method provides better results than optimizing the segmentation itself. Furthermore, our method can provide accurate results despite the degree of the initial oversegmentation, resulting into a precision and recall of 0.91 for the optimal oversegmentation.

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Background: Pharmacokinetic (PK) models can describe microvascular density and integrity. An essential component of PK models is the arterial input function (AIF) representing the time-dependent concentration of contrast agent (CA) in the blood plasma supplied to a tissue. Purpose/Hypothesis: To evaluate a novel method for subject-specific AIF estimation that takes inflow effects into account. Study Type: Retrospective study. Subjects: Thirteen clinical patients referred for spine-related complaints; 21 patients from a study into luminal Crohn's disease with known Crohn's Disease Endoscopic Index of Severity (CDEIS). Field Strength/Sequence: Dynamic fast spoiled gradient echo (FSPGR) at 3T. Assessment: A population-averaged AIF, AIFs derived from distally placed regions of interest (ROIs), and the new AIF method were applied. Tofts' PK model parameters (including v_p and K^trans) obtained with the three AIFs were compared. In the Crohn's patients K^trans was correlated to CDEIS. Statistical Tests: The median values of the PK model parameters from the three methods were compared using a Mann–Whitney U-test. The associated variances were statistically assessed by the Brown-Forsythe test. Spearman's rank correlation coefficient was computed to test the correlation of K^trans to CDEIS. Results: The median v_p was significantly larger when using the distal ROI approach, compared to the two other methods (P < 0.05 for both comparisons, in both applications). Also, the variances in v_p were significantly larger with the ROI approach (P < 0.05 for all comparisons). In the Crohn's disease study, the estimated K^trans parameter correlated better with the CDEIS (r = 0.733, P < 0.001) when the proposed AIF was used, compared to AIFs from the distal ROI method (r = 0.429, P = 0.067) or the population-averaged AIF (r = 0.567, P = 0.011). Data Conclusion: The proposed method yielded realistic PK model parameters and improved the correlation of the K^trans parameter with CDEIS, compared to existing approaches. Level of Evidence: 3. Technical Efficacy Stage 1. J. Magn. Reson. Imaging 2018;47:1197–1204.

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In the field of pathology there is an ongoing transition to the use of Whole Slide Imaging (WSI) systems which scan tissue slides at intermediate resolution (0∼.25 μm) and high throughput (15mm²=min) to digital image files. Most scanners currently on the market are line-sensor based push-broom scanners for three-color (RGB) brightfield imaging. Adding the ability of fluorescence imaging opens up a wide range of possibilities to the field, in particular the use of specific molecular (proteins, genes) imaging techniques. We propose an extension to fluorescence imaging for a highly efficient WSI systems based on a line scanning technique using multi-color led epi-illumination. The use of multi-band dichroics eliminates the need for filter wheels or any other moving parts in the system, the use of color sequential illumination with leds enables imaging of multiple color channels with a single sensor. Our approach offers a solution to fluorescence WSI systems that is technologically robust and cost-effective. We present design details of a four-color led based epi-illumination with a quad-band dichroic filter optimized for leds. We provide a thorough analysis regarding the obtained optical and spectral efficiency. The primary throughput limitation is the minimum Signal-to-Noise-Ratio (SNR) given the available optical power in the illumination etendue, and indicates that a throughput on the order of 1000 lines/sec can be obtained.

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The Couinaud classification of hepatic anatomy partitions the liver into eight functionally independent segments. Detection and segmentation of the hepatic vein (HV), portal vein (PV) and inferior vena cava (IVC) plays an important role in the subsequent delineation of the liver segments. To facilitate pharmacokinetic modeling of the liver based on the same data, a 4D DCE-MR scan protocol was selected. This yields images with high temporal resolution but low spatial resolution. Since the liver's vasculature consists of many tiny branches, segmentation of these images is challenging. The proposed framework starts with registration of the 4D DCE-MRI series followed by region growing from manually annotated seeds in the main branches of key blood vessels in the liver. It calculates the Pearson correlation between the time intensity curves (TICs) of a seed and all voxels. A maximum correlation map for each vessel is obtained by combining the correlation maps for all branches of the same vessel through a maximum selection per voxel. The maximum correlation map is incorporated in a level set scheme to individually delineate the main vessels. Subsequently, the eight liver segments are segmented based on three vertical intersecting planes fit through the three skeleton branches of HV and IVC's center of mass as well as a horizontal plane fit through the skeleton of PV. Our segmentation regarding delineation of the vessels is more accurate than the results of two state-of-the-art techniques on five subjects in terms of the average symmetric surface distance (ASSD) and modified Hausdorff distance (MHD). Furthermore, the proposed liver partitioning achieves large overlap with manual reference segmentations (expressed in Dice Coefficient) in all but a small minority of segments (mean values between 87% and 94% for segments 2-8). The lower mean overlap for segment 1 (72%) is due to the limited spatial resolution of our DCE-MR scan protocol.

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We present a comparison of image reconstruction techniques for optical projection tomography. We compare conventional filtered back projection, sinogram filtering using the frequency–distance relationship (FDR), image deconvolution, and 2D point-spread-function-based iterative reconstruction. The latter three methods aim to remove the spatial blurring in the reconstructed image originating from the limited depth of field caused by the point spread function of the imaging system. The methods are compared based on simulated data, experimental optical projection tomography data of single fluorescent beads, and high-resolution optical projection tomography imaging of an entire zebrafish larva. We demonstrate that the FDR method performs poorly on data acquired with high numerical aperture optical imaging systems. We show that the deconvolution technique performs best on highly sparse data with low signal-to-noise ratio. The point-spread-function-based reconstruction method is superior for nonsparse objects and data of high signal-to-noise ratio.

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The attenuation coefficient (AC) is a property related to the microstructure of tissue on a wavelength scale that can be estimated from optical coherence tomography (OCT) data. Since the OCT signal sensitivity is affected by the finite spectrometer/detector resolution called roll-off and the shape of the focused beam in the sample arm, ignoring these effects leads to severely biased estimates of AC. Previously, the signal intensity dependence on these factors has been modeled. In this paper, we study the dependence of the estimated AC on the beam-shape and focus depth experimentally. A method is presented to estimate the axial point spread function model parameters by fitting the OCT signal model for single scattered light to the averaged A-lines of multiple B-scans obtained from a homogeneous single-layer phantom. The estimated model parameters were used to compensate the signal for the axial point spread function and roll-off in order to obtain an accurate estimate of AC. The result shows a significant improvement in the accuracy of the estimation of AC after correcting for the shape of the OCT beam.@en

Better insight into white matter (WM) alterations after stroke onset could help to understand the underlying recovery mechanisms and improve future interventions. MR diffusion imaging enables to assess such changes. Our goal was to investigate the relation of WM diffusion characteristics derived from diffusion models of increasing complexity with the motor function of the upper limb. Moreover, we aimed to evaluate the variation of such characteristics across different WM structures of chronic stroke patients in comparison to healthy subjects. Subjects were scanned with a two b-value diffusion-weighted MRI protocol to exploit multiple diffusion models: single tensor, single tensor with isotropic compartment, bi-tensor model, bi-tensor with isotropic compartment. From each model we derived the mean tract fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivities outside the lesion site based on a WM tracts atlas. Asymmetry of these measures was correlated with the Fugl-Meyer upper extremity assessment (FMA) score and compared between patient and control groups. Eighteen chronic stroke patients and eight age-matched healthy individuals participated in the study. Significant correlation of the outcome measures with the clinical scores of stroke recovery was found. The lowest correlation of the corticospinal tract FA_asymmetry and FMA was with the single tensor model (r = -0.3, p = 0.2) whereas the other models reported results in the range of r = -0.79 ÷ -0.81 and p = 4E-5 ÷ 8E-5. The corticospinal tract and superior longitudinal fasciculus showed most alterations in our patient group relative to controls. Multiple compartment models yielded superior correlation of the diffusion measures and FMA compared to the single tensor model.

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Rationale and Objectives: The objective of this study was to develop and validate a predictive magnetic resonance imaging (MRI) activity score for ileocolonic Crohn disease activity based on both subjective and semiautomatic MRI features. Materials and Methods: An MRI activity score (the “virtual gastrointestinal tract [VIGOR]” score) was developed from 27 validated magnetic resonance enterography datasets, including subjective radiologist observation of mural T2 signal and semiautomatic measurements of bowel wall thickness, excess volume, and dynamic contrast enhancement (initial slope of increase). A second subjective score was developed based on only radiologist observations. For validation, two observers applied both scores and three existing scores to a prospective dataset of 106 patients (59 women, median age 33) with known Crohn disease, using the endoscopic Crohn's Disease Endoscopic Index of Severity (CDEIS) as a reference standard. Results: The VIGOR score (17.1 × initial slope of increase + 0.2 × excess volume + 2.3 × mural T2) and other activity scores all had comparable correlation to the CDEIS scores (observer 1: r = 0.58 and 0.59, and observer 2: r = 0.34–0.40 and 0.43–0.51, respectively). The VIGOR score, however, improved interobserver agreement compared to the other activity scores (intraclass correlation coefficient = 0.81 vs 0.44–0.59). A diagnostic accuracy of 80%–81% was seen for the VIGOR score, similar to the other scores. Conclusions: The VIGOR score achieves comparable accuracy to conventional MRI activity scores, but with significantly improved reproducibility, favoring its use for disease monitoring and therapy evaluation.

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Purpose: To develop a method for intra-patient registration of pre- and post-contrast abdominal MR images with large local deformations and large intensity variations. Method: A hybrid method is proposed to deal with this problem. It consists of two coupled techniques: (1) descriptor matching (DM) at the original resolution using a discrete optimization strategy to avoid getting trapped in a local minimum; (2) continuous optimization to refine the registration outcome based on autocorrelation of local image structure (ALOST). Our method—called DM-ALOST—has become insensitive to the local uptake of contrast agent by exploiting the mean phase and the phase congruency extracted from the multi-scale monogenic signal. The method was extensively tested on abdominal MR data of 30 patients with Crohn’s disease. Results: DM-ALOST produced significantly larger mean Dice coefficients than two state-of-the-art methods (Formula presented.). Conclusion: Both qualitative and quantitative tests demonstrated improved registration using the proposed method compared to the state-of-the-art. The DM-ALOST method facilitates measurement of corresponding features from different abdominal MR images, which can aid to assess certain diseases, particularly Crohn’s disease.

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