Registration is a core component of many imaging pipelines. In case of clinical scans, with lower resolution and sometimes substantial motion artifacts, registration can produce poor results. Visual assessment of registration quality in large clinical datasets is inefficient. In this work, we propose to automatically assess the quality of registration to an atlas in clinical FLAIR MRI scans of the brain. The method consists of automatically segmenting the ventricles of a given scan using a neural network, and comparing the segmentation to the atlas ventricles propagated to image space. We used the proposed method to improve clinical image registration to a general atlas by computing multiple registrations - one directly to the general atlas and others via different age-specific atlases - and then selecting the registration that yielded the highest ventricle overlap. Finally, as an example application of the complete pipeline, a voxelwise map of white matter hyperintensity burden was computed using only the scans with registration quality above a predefined threshold. Methods were evaluated in a single-site dataset of more than 1000 scans, as well as a multi-center dataset comprising 142 clinical scans from 12 sites. The automated ventricle segmentation reached a Dice coefficient with manual annotations of 0.89 in the single-site dataset, and 0.83 in the multi-center dataset. Registration via age-specific atlases could improve ventricle overlap compared to a direct registration to the general atlas (Dice similarity coefficient increase up to 0.15). Experiments also showed that selecting scans with the registration quality assessment method could improve the quality of average maps of white matter hyperintensity burden, instead of using all scans for the computation of the white matter hyperintensity map. In this work, we demonstrated the utility of an automated tool for assessing image registration quality in clinical scans. This image quality assessment step could ultimately assist in the translation of automated neuroimaging pipelines to the clinic.

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Finding automatically multiple lesions in large images is a common problem in medical image analysis. Solving this problem can be challenging if, during optimization, the automated method cannot access information about the location of the lesions nor is given single examples of the lesions. We propose a new weakly supervised detection method using neural networks, that computes attention maps revealing the locations of brain lesions. These attention maps are computed using the last feature maps of a segmentation network optimized only with global image-level labels. The proposed method can generate attention maps at full input resolution without need for interpolation during preprocessing, which allows small lesions to appear in attention maps. For comparison, we modify state-of-the-art methods to compute attention maps for weakly supervised object detection, by using a global regression objective instead of the more conventional classification objective. This regression objective optimizes the number of occurrences of the target object in an image, e.g. the number of brain lesions in a scan, or the number of digits in an image. We study the behavior of the proposed method in MNIST-based detection datasets, and evaluate it for the challenging detection of enlarged perivascular spaces – a type of brain lesion – in a dataset of 2202 3D scans with point-wise annotations in the center of all lesions in four brain regions. In MNIST-based datasets, the proposed method outperforms the other methods. In the brain dataset, the weakly supervised detection methods come close to the human intrarater agreement in each region. The proposed method reaches the best area under the curve in two out of four regions, and has the lowest number of false positive detections in all regions, while its average sensitivity over all regions is similar to that of the other best methods. The proposed method can facilitate epidemiological and clinical studies of enlarged perivascular spaces and help advance research in the etiology of enlarged perivascular spaces and in their relationship with cerebrovascular diseases.

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Scoliosis is a condition defined by an abnormal spinal curvature. For diagnosis and treatment planning of scoliosis, spinal curvature can be estimated using Cobb angles. We propose an automated method for the estimation of Cobb angles from X-ray scans. First, the centerline of the spine was segmented using a cascade of two convolutional neural networks. After smoothing the centerline, Cobb angles were automatically estimated using the derivative of the centerline. We evaluated the results using the mean absolute error and the average symmetric mean absolute percentage error between the manual assessment by experts and the automated predictions. For optimization, we used 609 X-ray scans from the London Health Sciences Center, and for evaluation, we participated in the international challenge “Accurate Automated Spinal Curvature Estimation, MICCAI 2019” (100 scans). On the challenge’s test set, we obtained an average symmetric mean absolute percentage error of 22.96.

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The gap between predicted brain age using magnetic resonance imaging (MRI) and chronological age may serve as a biomarker for early-stage neurodegeneration. However, owing to the lack of large longitudinal studies, it has been challenging to validate this link. We aimed to investigate the utility of such a gap as a risk biomarker for incident dementia using a deep learning approach for predicting brain age based on MRI-derived gray matter (GM). We built a convolutional neural network (CNN) model to predict brain age trained on 3,688 dementia-free participants of the Rotterdam Study (mean age 66 ± 11 y, 55% women). Logistic regressions and Cox proportional hazards were used to assess the association of the age gap with incident dementia, adjusted for age, sex, intracranial volume, GM volume, hippocampal volume, white matter hyperintensities, years of education, and APOE ε4 allele carriership. Additionally, we computed the attention maps, which shows which regions are important for age prediction. Logistic regression and Cox proportional hazard models showed that the age gap was significantly related to incident dementia (odds ratio [OR] = 1.11 and 95% confidence intervals [CI] = 1.05-1.16; hazard ratio [HR] = 1.11, and 95% CI = 1.06-1.15, respectively). Attention maps indicated that GM density around the amygdala and hippocampi primarily drove the age estimation. We showed that the gap between predicted and chronological brain age is a biomarker, complimentary to those that are known, associated with risk of dementia, and could possibly be used for early-stage dementia risk screening.

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Localization of focal vascular lesions on brain MRI is an important component of research on the etiology of neurological disorders. However, manual annotation of lesions can be challenging, time-consuming and subject to observer bias. Automated detection methods often need voxel-wise annotations for training. We propose a novel approach for automated lesion detection that can be trained on scans only annotated with a dot per lesion instead of a full segmentation. From the dot annotations and their corresponding intensity images we compute various distance maps (DMs), indicating the distance to a lesion based on spatial distance, intensity distance, or both. We train a fully convolutional neural network (FCN) to predict these DMs for unseen intensity images. The local optima in the predicted DMs are expected to correspond to lesion locations. We show the potential of this approach to detect enlarged perivascular spaces in white matter on a large brain MRI dataset with an independent test set of 1000 scans. Our method matches the intra-rater performance of the expert rater that was computed on an independent set. We compare the different types of distance maps, showing that incorporating intensity information in the distance maps used to train an FCN greatly improves performance. @en

Hippocampal volume and shape are known magnetic resonance imaging biomarkers of neurodegeneration. Recently, hippocampal texture has been shown to improve prediction of dementia in patients with mild cognitive impairment, but it is unknown whether texture adds prognostic information beyond volume and shape and whether the predictive value extends to cognitively healthy individuals. Using 510 subjects from the Rotterdam Study, a prospective, population-based cohort study, we investigated if hippocampal volume, shape, texture, and their combination were predictive of dementia and determined how predictive performance varied with time to diagnosis and presence of early clinical symptoms of dementia. All features showed significant predictive performance with the area under the receiver operating characteristic curve ranging from 0.700 for texture alone to 0.788 for the combination of volume and texture. Although predictive performance extended to those without objective cognitive complaints or mild cognitive impairment, performance decreased with increasing follow-up time. We conclude that a combination of multiple hippocampal features on magnetic resonance imaging performs better in predicting dementia in the general population than any feature by itself.

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Deep learning techniques are often criticized to heavily depend on a large quantity of labeled data. This problem is even more challenging in medical image analysis where the annotator expertise is often scarce. We propose a novel data-augmentation method to regularize neural network regressors that learn from a single global label per image. The principle of the method is to create new samples by recombining existing ones. We demonstrate the performance of our algorithm on two tasks: estimation of the number of enlarged perivascular spaces in the basal ganglia, and estimation of white matter hyperintensities volume. We show that the proposed method improves the performance over more basic data augmentation. The proposed method reached an intraclass correlation coefficient between ground truth and network predictions of 0.73 on the first task and 0.84 on the second task, only using between 25 and 30 scans with a single global label per scan for training. With the same number of training scans, more conventional data augmentation methods could only reach intraclass correlation coefficients of 0.68 on the first task, and 0.79 on the second task.

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Enlarged perivascular spaces (PVS) are structural brain changes visible in MRI, are common in aging, and are considered a reflection of cerebral small vessel disease. As such, assessing the burden of PVS has promise as a brain imaging marker. Visual and manual scoring of PVS is a tedious and observer-dependent task. Automated methods would advance research into the etiology of PVS, could aid to assess what a “normal” burden is in aging, and could evaluate the potential of PVS as a biomarker of cerebral small vessel disease. In this work, we propose and evaluate an automated method to quantify PVS in the midbrain, hippocampi, basal ganglia and centrum semiovale. We also compare associations between (earlier established) determinants of PVS and visual PVS scores versus the automated PVS scores, to verify whether automated PVS scores could replace visual scoring of PVS in epidemiological and clinical studies. Our approach is a deep learning algorithm based on convolutional neural network regression, and is contingent on successful brain structure segmentation. In our work we used FreeSurfer segmentations. We trained and validated our method on T2-contrast MR images acquired from 2115 subjects participating in a population-based study. These scans were visually scored by an expert rater, who counted the number of PVS in each brain region. Agreement between visual and automated scores was found to be excellent for all four regions, with intraclass correlation coefficients (ICCs) between 0.75 and 0.88. These values were higher than the inter-observer agreement of visual scoring (ICCs between 0.62 and 0.80). Scan-rescan reproducibility was high (ICCs between 0.82 and 0.93). The association between 20 determinants of PVS, including aging, and the automated scores were similar to those between the same 20 determinants of PVS and visual scores. We conclude that this method may replace visual scoring and facilitate large epidemiological and clinical studies of PVS.

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© 2018 Enlarged perivascular spaces (EPVS) in the brain are an emerging imaging marker for cerebral small vessel disease, and have been shown to be related to increased risk of various neurological diseases, including stroke and dementia. Automated quantification of EPVS would greatly help to advance research into its etiology and its potential as a risk indicator of disease. We propose a convolutional network regression method to quantify the extent of EPVS in the basal ganglia from 3D brain MRI. We first segment the basal ganglia and subsequently apply a 3D convolutional regression network designed for small object detection within this region of interest. The network takes an image as input, and outputs a quantification score of EPVS. The network has significantly more convolution operations than pooling ones and no final activation, allowing it to span the space of real numbers. We validated our approach using a dataset of 2000 brain MRI scans scored visually. Experiments with varying sizes of training and test sets showed that a good performance can be achieved with a training set of only 200 scans. With a training set of 1000 scans, the intraclass correlation coefficient (ICC) between our scoring method and the expert's visual score was 0.74. Our method outperforms by a large margin - more than 0.10 - four more conventional automated approaches based on intensities, scale-invariant feature transform, and random forest. We show that the network learns the structures of interest and investigate the influence of hyper-parameters on the performance. We also evaluate the reproducibility of our network using a set of 60 subjects scanned twice (scan-rescan reproducibility). On this set our network achieves an ICC of 0.93, while the intrarater agreement reaches 0.80. Furthermore, the automated EPVS scoring correlates similarly to age as visual scoring.@en

© 2018 Enlarged perivascular spaces (EPVS) in the brain are an emerging imaging marker for cerebral small vessel disease, and have been shown to be related to increased risk of various neurological diseases, including stroke and dementia. Automated quantification of EPVS would greatly help to advance research into its etiology and its potential as a risk indicator of disease. We propose a convolutional network regression method to quantify the extent of EPVS in the basal ganglia from 3D brain MRI. We first segment the basal ganglia and subsequently apply a 3D convolutional regression network designed for small object detection within this region of interest. The network takes an image as input, and outputs a quantification score of EPVS. The network has significantly more convolution operations than pooling ones and no final activation, allowing it to span the space of real numbers. We validated our approach using a dataset of 2000 brain MRI scans scored visually. Experiments with varying sizes of training and test sets showed that a good performance can be achieved with a training set of only 200 scans. With a training set of 1000 scans, the intraclass correlation coefficient (ICC) between our scoring method and the expert's visual score was 0.74. Our method outperforms by a large margin - more than 0.10 - four more conventional automated approaches based on intensities, scale-invariant feature transform, and random forest. We show that the network learns the structures of interest and investigate the influence of hyper-parameters on the performance. We also evaluate the reproducibility of our network using a set of 60 subjects scanned twice (scan-rescan reproducibility). On this set our network achieves an ICC of 0.93, while the intrarater agreement reaches 0.80. Furthermore, the automated EPVS scoring correlates similarly to age as visual scoring.@en

Event-based models (EBM) are a class of disease progression models that can be used to estimate temporal ordering of neuropathological changes from cross-sectional data. Current EBMs only handle scalar biomarkers, such as regional volumes, as inputs. However, regional aggregates are a crude summary of the underlying high-resolution images, potentially limiting the accuracy of EBM. Therefore, we propose a novel method that exploits high-dimensional voxel-wise imaging biomarkers: n-dimensional discriminative EBM (nDEBM). nDEBM is based on an insight that mixture modeling, which is a key element of conventional EBMs, can be replaced by a more scalable semi-supervised support vector machine (SVM) approach. This SVM is used to estimate the degree of abnormality of each region which is then used to obtain subject-specific disease progression patterns. These patterns are in turn used for estimating the mean ordering by fitting a generalized Mallows model. In order to validate the biomarker ordering obtained using nDEBM, we also present a framework for Simulation of Imaging Biomarkers’ Temporal Evolution (SImBioTE) that mimics neurodegeneration in brain regions. SImBioTE trains variational auto-encoders (VAE) in different brain regions independently to simulate images at varying stages of disease progression. We also validate nDEBM clinically using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In both experiments, nDEBM using high-dimensional features gave better performance than state-of-the-art EBM methods using regional volume biomarkers. This suggests that nDEBM is a promising approach for disease progression modeling.

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Shape analysis is increasingly becoming important to study changes in brain structures in relation to clinical neurological outcomes. This is a challenging task due to the high dimensionality of shape representations and the often limited number of available shapes. Current techniques counter the poor ratio between dimensions and sample size by using regularization in shape space, but do not take into account the spatial relations within the shapes. This can lead to models that are biologically implausible and difficult to interpret. We propose to use P-spline based regression, which combines a generalized linear model (GLM) with the coefficients described as B-splines and a penalty term that constrains the regression coefficients to be spatially smooth. Owing to the GLM, this method can naturally predict both continuous and discrete outcomes and can include non-spatial covariates without penalization. We evaluated our method on hippocampus shapes extracted from magnetic resonance (MR) images of 510 non-demented, elderly people. We related the hippocampal shape to age, memory score, and sex. The proposed method retained the good performance of current techniques, such as ridge regression, but produced smoother coefficient fields that are easier to interpret.

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An automated method for registering B-mode ultrasound (US) and magnetic resonance imaging (MRI) of the carotid arteries is proposed. The registration uses geometric features, namely, lumen centerlines and lumen segmentations, which are extracted fully automatically from the images after manual annotation of three seed points in US and MRI. The registration procedure starts with alignment of the lumen centerlines using a point-based registration algorithm. The resulting rigid transformation is used to initialize a rigid and subsequent non-rigid registration procedure that jointly aligns centerlines and segmentations by minimizing a weighted sum of the Euclidean distance between centerlines and the dissimilarity between segmentations. The method was evaluated in 28 carotid arteries from eight patients and six healthy volunteers. First, the automated US lumen segmentation method was validated and optimized in a cross-validation experiment. Next, the effect of the weighting parameter of the proposed registration dissimilarity metric and the control point spacing in the non-rigid registration was evaluated. Finally, the proposed registration method was evaluated in comparison to an existing intensity-and-point-based method, a registration using only the centerlines and a registration using manual US lumen segmentations. Registration accuracy was measured in terms of the mean surface distance between manual US segmentations and the registered MRI segmentations. The average mean surface distance was 0.78 ± 0.34 mm for all subjects, 0.65 ± 0.09 mm for healthy volunteers and 0.87 ± 0.42 mm for patients. The results for the complete set were significantly better (Wilcoxon test, p <0.01) than the results for the intensity-and-point-based method and the centerline-based registration method. We conclude that the proposed method can robustly and accurately register US and MR images of the carotid artery, allowing multimodal analysis of the carotid plaque to improve plaque assessment.

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We propose a novel convolutional neural network for lesion detection from weak labels. Only a single, global label per image - the lesion count - is needed for training. We train a regression network with a fully convolutional architecture combined with a global pooling layer to aggregate the 3D output into a scalar indicating the lesion count. When testing on unseen images, we first run the network to estimate the number of lesions. Then we remove the global pooling layer to compute localization maps of the size of the input image. We evaluate the proposed network on the detection of enlarged perivascular spaces in the basal ganglia in MRI. Our method achieves a sensitivity of 62% with on average 1.5 false positives per image. Compared with four other approaches based on intensity thresholding, saliency and class maps, our method has a 20% higher sensitivity.

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