quicksilver
Predictive Image Registration
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This paper introduces Quicksilver, a fast deformable image registration method. Quicksilver registration for imagepairs works by patchwise prediction of a deformation model based directly on image appearance. A deep encoderdecoder network is used as the prediction model. While the prediction strategy is general, we focus on predictions for the Large Deformation Diffeomorphic Metric Mapping (LDDMM) model. Specifically, we predict the momentumparameterization of LDDMM, which facilitates a patchwise prediction strategy while maintaining the theoretical properties of LDDMM, such as guaranteed diffeomorphic mappings for sufficiently strong regularization. We also provide a probabilistic version of our prediction network which can be sampled during the testing time to calculate uncertainties in the predicted deformations. Finally, we introduce a new correction network which greatly increases the prediction accuracy of an already existing prediction network. We show experimental results for unimodal atlastoimage as well as uni / multi modal imagetoimage registrations. These experiments demonstrate that our method accurately predicts registrations obtained by numerical optimization, is very fast, achieves stateoftheart registration results on four standard validation datasets, and can jointly learn an image similarity measure. Quicksilver is freely available as an opensource software.
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Image registration is a key component for medical image analysis to provide spatial correspondences. Image registration is typically formulated as an optimization problem modersitzki2004 , optimizing the parameters of a transformation model. The goal is to achieve the best possible agreement between a transformed source and a target image, subject to transformation constraints. Apart from simple,
lowdimensional parametric models (e.g., rigid or affine transformations), more complex, highdimensional parametric or nonparametric registration models are able to capture subtle, localized image deformations. However, these methods, in particular, the nonparametric approaches, have
a very large numbers of parameters. Therefore, numerical optimization to solve the registration problems becomes computationally costly, even with acceleration by graphics processing units (GPUs).While computation time may not be overly critical for imaging studies of moderate size, rapid registration approaches are needed to (i) allow for interactive analysis, to (ii) allow their use as building blocks for more advanced image analysis algorithms; and to (iii) time and costefficiently analyze very large imaging studies. As a case in point, sample sizes of neuroimaging studies are rapidly increasing. While, only two decades ago, neuroimaging studies with few tens of subjects were not unusual, we are now witnessing the emergence of truly largescale imaging studies. For example, the UK Biobank study is, at the moment, the world’s largest health imaging study and will image “the brain, bones, heart, carotid arteries and abdominal fat of 100,000 participants” using magnetic resonance (MR) imaging within the next few years
biobankWebsite . Furthermore, image sizes are increasing drastically. While, a decade ago, structural MR images of human brains with voxel sizes of mm were typical for stateoftheart MR acquisitions, today we have voxel sizes smaller than mm as, for example, acquired by the human connectome project vanessen2013 . This increase in image resolution increases the data size by an order of magnitude. Even more dramatically, the microscopy field now routinely generates gigabytes of highresolution imaging data, for example, by 3D imaging via tissue clearing chung2013clarity . Hence, fast, memoryefficient, and parallelizable image analysis approaches are critically needed. In particular, such approaches are needed for deformable image registration, which is a key component of many medical image analysis systems.Attempts at speedingup deformable image registration have primarily focused on GPU implementations shams2010survey , with impressive speedups over their CPUbased counterparts. However, these approaches are still relatively slow. Runtimes in the tens of minutes are the norm for popular deformable image registration solutions. For example, a GPUbased registration of a image volume using LDDMM will take about 10 minutes on a current GPU (e.g., a Nvidia TitanX). This is much too slow to allow for largescale processing, the processing of large datasets, or close to interactive registration tasks. Hence, improved algorithmic approaches are desirable. Recent work has focused on better numerical methods and approximate approaches. For example, Ashburner and Friston ashburner2011 use a Gauss–Newton method to accelerate convergence for LDDMM and Zhang et al. zhang2015 propose a finitedimensional approximation of LDDMM, achieving a roughly speedup over a standard LDDMM optimizationbased solution.
An alternative approach to improve registration speed is to predict deformation parameters, or deformation parameter update steps in the optimization via a regression model, instead of directly minimizing a registration energy gutierrez2017 ; gutierrez2016learning ; chou20132d . The resulting predicted deformation fields can either be used directly, or as an initialization of a subsequent optimizationbased registration. However, the high dimensionality of the deformation parameters as well as the nonlinear relationship between the images and the parameters pose a significant challenge. Among these methods, Chou et al. chou20132d propose a multiscale linear regressor which only applies to affine deformations and lowrank approximations of nonlinear deformations. Wang et al. Wang201561
predict deformations by keypoint matching using sparse learning followed by dense deformation field generation with radial basis function interpolation. The performance of the method heavily depends on the accuracy of the key point selection. Cao et al.
Tian2015 use a semicoupled dictionary learning method to directly model the relationship between the image appearance and the deformation parameters of the LDDMM model beg2005 . However, only a linear relationship is assumed between image appearance and the deformation parameters. Lastly, Gutierrez et al. gutierrez2016learning use a regression forestand gradient boosted trees
gutierrez2017 based on handcrafted features to learn update steps for a rigid and a Bspline registration model.In this work, we propose a deep regression model to predict deformation parameters using image appearances in a timeefficient manner. Deep learning has been used for optical flow estimation
deepflow ; flownet and deformation parameter prediction for affine transformations Miao2016 . We investigate a nonparametric image registration approach, where we predict voxelwise deformation parameters from image patches. Specifically, we focus on the initial momentum LDDMM shooting model Vialard2012 , as it has many desirable properties:It is based on Riemannian geometry, and hence induces a distance metric on the space of images.
It can capture large deformations.
It results in highly desirable diffeomorphic spatial transformations (if regularized sufficiently). I.e., transformations which are smooth, onetoone and have a smooth inverse.
It uses the initial momentum as the registration parameter, which does not need to be spatially smooth, and hence can be predicted patchbypatch, and from which the whole geodesic path can be computed.
The LDDMM shooting model in
of itself is important for various image analysis tasks such as principal component analysis
Vaillant2004S161 and image regression Niethammer2011 ; Yi2012 .Our contributions are as follows:
Convenient parameterization: Diffeomorphic transformations are desirable in medical image analysis applications to smoothly map between fixed and moving images, or to and from an atlas image. Methods, such as LDDMM, with strong theoretical guarantees exist, but are typically computationally very demanding. On the other hand, direct prediction, e.g., of optical flow deepflow ; flownet , is fast, but the regularity of the obtained solution is unclear as it is not considered within the regression formulation. We demonstrate that the momentumparameterization for LDDMM shooting Vialard2012 is a convenient representation for regression approaches as (i) the momentum is typically compactly supported around image edges and (ii) there are no smoothness requirements on the momentum itself. Instead, smooth velocity fields are obtained in LDDMM from the momentum representation by subsequent smoothing. Hence, by predicting the momentum, we retain all the convenient mathematical properties of LDDMM and, at the same time, are able to predict diffeomorphic transformations fast. As the momentum has compact support around image edges, no ambiguities arise within uniform image areas (in which predicting a velocity or deformation field would be difficult).
Fast computation:
We use a sliding window to locally predict the LDDMM momentum from image patches. We experimentally show that by using patch pruning and a large sliding window stride, our method achieves dramatic speedups compared to the optimization approach, while maintaining good registration accuracy.
Uncertainty quantification: We extend our network to a Bayesian model which is able to determine the uncertainty of the registration parameters and, as a result, the uncertainty of the deformation field. This uncertainty information could be used, e.g., for uncertaintybased smoothing simpson2011longitudinal , or for surgical treatment planning, or could be directly visualized for qualitative analyses.
Correction network: Furthermore, we propose a correction network to increase the accuracy of the prediction network. Given a trained prediction network, the correction network predicts the difference between the ground truth momentum and the predicted result. The difference is used as a correction to the predicted momentum to increase prediction accuracy. Experiments show that the correction network improves registration results to the point where optimizationbased and predicted registrations achieve a similar level of registration accuracy on registration validation experiments.
Multimodal registration: We also explore the use of our framework for multimodal image registration prediction. The goal of multimodal image registration is to establish spatial correspondences between images acquired by different modalities. Multimodal image registration is, in general, significantly more difficult than unimodal image registration since image appearance can change drastically between different modalities. General approaches address multimodal image registration by either performing image synthesis cao2014 ; wein2008 to change the problem to an unimodal image registration task, or by proposing complex, handcrafted viola1997 ; Meyer1998 ; Hermosillo2002 ; Lorenzen2006 or learned Guetter2005 ; Lee2009 ; Michel2011 ; Cheng2015 ; simonovsky2016 multimodal image similarity measures. In contrast, we demonstrate that our framework can simultaneously predict registrations and learn a multimodal image similarity measure. Our experiments show that our approach also predicts accurate deformations for multimodal registration.
Extensive validation: We extensively validate our predictive image registration approach for unimodal image registration on the four validation datasets of Klein et al. Klein2009786 and demonstrate registration accuracies on these datasets on par with the stateoftheart. Of note, these registration results are achieved using a model that was trained on an entirely different dataset (images from the OASIS dataset). Furthermore, we validate our model trained for multimodal image registration using the IBIS 3D dataset hazlett2017early . Overall, our results are based on more than 2,400 image registration pairs.
The registration method described here, which we name Quicksilver, is an extension of the preliminary ideas we presented in a recent workshop paper YangFast2016 and in a conference paper yang2017multimodal . This paper offers more details of our proposed approaches, introduces the idea of improving registration accuracy via a correction network, and includes a comprehensive set of experiments for imagetoimage registration.
Organization. The remainder of the paper is organized as follows. Sec. 2.1 reviews the registration parameterization of the shootingbased LDDMM registration algorithm. Sec. 2.2 introduces our deep network architecture for deformation parameter prediction, the Bayesian formulation of our network, as well as our strategy for speeding up the deformation prediction. Sec. 2.3 discusses the correction network and the reason why it improves the registration prediction accuracy over an existing prediction network. Sec. 3 presents experimental results for atlastoimage and imagetoimage registration. Finally, Sec. 4 discusses potential extensions and applications of our method.
Given a moving (source) image and a target image , the goal of image registration is to find a deformation map , which maps the moving image to the target image in such a way that the deformed moving image is similar to the target image, i.e., . Here, denotes the spatial dimension and is the spatial coordinate of the fixed target image . Due to the importance of image registration, a large number of different approaches have been proposed modersitzki2004 ; hill2001 ; sotiras2013 ; oliveira2014 . Typically, these approaches are formulated as optimization problems, where one seeks to minimize an energy of the form
(1) 
where is a balancing constant, regularizes the spatial transformation, , by penalizing spatially irregular (for example nonsmooth) spatial transformations, and is an image dissimilarity measure, which becomes small if images are similar to each other. Image dissimilarity is commonly measured by computing the sum of squared differences (SSD) between the warped source image () and the target image (), or via (normalized) crosscorrelation, or mutual information Hermosillo2002 ; modersitzki2004 . For simplicity, we use SSD in what follows, but other similarity measures could also be used. The regularizer encodes what should be considered a plausible spatial transformation^{1}^{1}1A regularizer is not necessarily required for simple, lowdimensional transformation models, such as rigid or affine transformations.. The form of the regularizer depends on how a transformation is represented. In general, one distinguishes between parametric and nonparametric transformation models modersitzki2004 . Parametric transformation models make use of a relatively lowdimensional parameterization of the transformation. Examples are rigid, similarity, and affine transformations. But also the highly popular Bspline models rueckert1999
are examples of parametric transformation models. Nonparametric approaches on the other hand parameterize a transformation locally, with a parameter (or parameter vector) for each voxel. The most direct nonparametric approach is to represent voxel displacements,
. Regularization then amounts to penalizing norms involving the spatial derivatives of the displacement vectors. Regularization is necessary for nonparametric approaches to avoid illposedness of the optimization problem. Optical flow approaches, such as the classical Horn and Schunck optical flow horn1981 , the more recent total variation approaches zach2007 , or methods based on linear elasticity theory modersitzki2004 are examples for displacementbased registration formulations. Displacementbased approaches typically penalize large displacements strongly and hence have difficulty capturing large image deformations. Furthermore, they typically also only offer limited control over spatial regularity. Both shortcomings can be circumvented. The first by applying greedy optimization strategies (for example, by repeating registration and image warping steps) and the second, for example, by explicitly enforcing image regularity by constraining the determinant of the Jacobian of the transformation haber2007 . An alternative approach to allow for large deformations, while assuring diffeomorphic transformations, is to parameterize transformations via static or timedependent velocity fields vercauteren2009 ; beg2005 . In these approaches, the transformation is obtained via time integration. For sufficiently regular velocity fields, diffeomorphic transformations can be obtained. As the regularizer operates on the velocity field(s) rather than the displacement field, large deformations are no longer strongly penalized and hence can be captured.LDDMM is a nonparametric registration method which represents the transformation via spatiotemporal velocity fields. In particular, the soughtfor mapping, , is obtained via an integration of a spatiotemporal velocity field for unit time, where indicates time and , such that and the soughtfor mapping is . To singleout desirable velocityfields, nonspatialsmoothness at any given time is penalized by the regularizer , which is applied to the velocity field instead of the transform directly. Specifically, LDDMM aims at minimizing the energy^{2}^{2}2When clear from the context, we suppress spatial dependencies for clarity of notation and only specify the time variable. E.g., we write to mean . beg2005
(2) 
where , , is a selfadjoint differential operator^{3}^{3}3Note that we define here as instead of as for example in Beg et al. beg2005 ., id is the identity map, and the differential equation constraint for can be written in Eulerian coordinates as , where is the derivative of with respect to time , and is the Jacobian matrix. In this LDDMM formulation (termed the relaxation formulation as a geodesic path – the optimal solution – is only obtained at optimality) the registration is parameterized by the full spatiotemporal velocity field . From the perspective of an individual particle, the transformation is simply obtained by following the velocity field over time. To optimize over the spatiotemporal velocity field one solves the associated adjoint system backward in time, where the final conditions of the adjoint system are determined by the current image mismatch as measured by the chosen similarity measure beg2005 . This adjoint system can easily be determined via a constrained optimization approach hart2009 (see borzi2003 for the case of optical flow). From the solution of the adjoint system one can compute the gradient of the LDDMM energy with respect to the velocity field at any point in time^{4}^{4}4
This approach is directly related to what is termed error backpropagation in the neural networks community
lecun88 as well as the reverse mode in automatic differentiation griewank2008. The layers in neural networks are analogous to discretized timesteps for LDDMM. The weights which parameterize a neural network are analogous to the velocity fields for LDDMM. Errorbackpropagation via the chain rule in neural networks corresponds to the adjoint system in LDDMM, which is a partial differential equation when written in the Eulerian form in the continuum.
and use it to numerically solve the optimization problem, for example, by a linesearch nocedal2006 . At convergence, the optimal solution will fulfill the optimality conditions of the constrained LDDMM energy of Eq. (2). These optimality conditions can be interpreted as the continuous equivalent of the KarushKuhnTucker conditions of constrained optimization nocedal2006 . On an intuitive level, if one were to find the shortest path between two points, one would (in Euclidean space) obtain the straight line connecting these two points. This straight line is the geodesic path in Euclidean space. For LDDMM, one instead tries to find the shortest path between two images based on the minimizer of the inexact matching problem of Eq. (2). The optimization via the adjoint equations corresponds to starting with a possible path and then successively improving it, until the optimal path is found. Again, going back to the example of matching points, one would start with any possible path connecting the two points and then successively improve it. The result at convergence is the optimal straight line path.Convergence to the shortest path immediately suggests an alternative optimization formulation. To continue the point matching example: if one knows that the optimal solution needs to be a straight line (i.e., a geodesic) one can consider optimizing only over the space of straight lines instead of all possible paths connecting the two points. This dramatically reduces the parameter space for optimization as one now only needs to optimize over the yintercept and the slope of the straight line. LDDMM can also be formulated in such a way. One obtains the shooting formulation Vialard2012 ; Niethammer2011 , which parameterizes the deformation via the initial momentum vector field and the initial map , from which the map can be computed for any point in time. The initial momentum corresponds to the slope of the line and the initial map corresponds to the yintercept. The geodesic equations correspond to the line equation. The geodesic equations, in turn, correspond to the optimality conditions of Eq. (2). Essentially, the shooting formulation enforces these optimality conditions of Eq. (2) as a constraint. In effect, one then searches only over geodesic paths, as these optimality conditions are geodesic equations. They can be written in terms of the momentum alone. In particular, the momentum is the dual of the velocity , which is an element in the reproducing kernel Hilbert space ; and are connected by a positivedefinite, selfadjoint differential smoothing operator by and , where is the inverse of . Given , the complete spatiotemporal deformation is determined.
Specifically, the energy to be minimized for the shooting formulation of LDDMM is Singh2013
(3) 
(4) 
where id is the identity map, and the operator is the dual of the negative JacobiLie bracket of vector fields, i.e., . The optimization approach is similar to the one for the relaxation formulation. I.e., one determines the adjoint equations for the shooting formulation and uses them to compute the gradient with respect to the unknown initial momentum Singh2013 ; Vialard2012 . Based on this gradient an optimal solution can, for example, be found via a linesearch or by a simple gradient descent scheme.
A natural approach for deformation prediction would be to use the entire 3D moving and target images as input, and to directly predict the 3D displacement field. However, this is not feasible in our formulation (for large images) because of the limited memory in modern GPUs. We circumvent this problem by extracting image patches from the moving image and target image at the same location, and by then predicting deformation parameters for the patch. The entire 3D image prediction is then accomplished patchbypatch via a sliding window approach. Specifically, in our framework, we predict the initial momentum given the moving and target images patchbypatch. Using the initial momentum for patchbased prediction is a convenient parameterization because (i) the initial momentum is generally not smooth, but is compactly supported at image edges and (ii) the initial velocity is generated by applying a smoothing kernel to the initial momentum. Therefore, the smoothness of the deformation does not need to be specifically considered during the parameter prediction step, but is imposed after the prediction. Since governs the theoretical properties or LDDMM, a strong assures diffeomorphic transformations^{5}^{5}5See beg2005 ; dupuis1998 for the required regularity conditions., making predicting the initial momentum an ideal choice. However, predicting alternative parameterizations such as the initial velocity or directly the displacement field would make it difficult to obtain diffeomorphic transformations. Furthermore, it is hard to predict initial velocity or displacement for homogeneous image regions, as these regions locally provide no information from which to predict the spatial transformation. In these regions the deformations are purely driven by regularization. This is not a problem for the initial momentum parameterization, since the initial momentum in these areas, for imagebased LDDMM, is zero. This can be seen as for imagebased LDDMM Vialard2012 ; Niethammer2011 ; hart2009 the momentum can be written as , where is a scalar field and is the spatial gradient of the image. Hence, for homogeneous areas, and consequentially . Fig. 1 illustrates this graphically. In summary, the initial momentum parameterization is ideal for our patchbased prediction method. Note that since the initial momentum can be written as one can alternatively optimize LDDMM over the scalarvalued momentum . This is the approach that has historically been taken for LDDMM beg2005 ; hart2009 ; Vialard2012 . However, optimizing over the vectorvalued momentum, , instead is numerically better behaved Singh2013 , which is why we focus on it for our predictions. While we are not exploring the prediction of the scalarvalued momentum here, it would be interesting to see how scalarvalued and vectorvalued momentum predictions compare. In particular, since the prediction of the scalarvalued momentum would allow for simpler prediction approaches (see details in Sec. 2.2).
The overall training strategy for our prediction models is as follows: We assume that we already have a set of LDDMM parameters which result in good registration results. We obtain these registration results by numerically optimizing the shooting formulation of LDMMM. These numerical optimizations can be based on images alone or could, of course, also make use of additional information available at training time, for example, object labels. For simplicity we only use image information here, but note that using additional information during training may result in increased prediction performance. The resulting initial momenta serve as training data. The goal is then to train a model to locally predict initial momenta from image patches of the moving and the target images. These predicted momenta should be good approximations of the initial momenta obtained via numerical optimization. In short, we train our deep learning framework to predict the initial momenta from image patches based on training data obtained from numerical optimization of the LDDMM shooting formulation. During testing, we predict the initial momenta for the test image pairs, and generate the predicted deformation result simply by performing LDDMM shooting.
Fig. 2 shows the structure of the initial momentum prediction network. We first discuss the deterministic version of the network without dropout layers. We then introduce the Bayesian version of our network where dropout layers are used to convert the architecture into a probabilistic deep network. Finally, we discuss our strategy for patch pruning to reduce the number of patches needed for whole image prediction.
Our goal is to learn a prediction function that takes two input patches, extracted at the same location^{6}^{6}6The locations of these patches are the same locations with respect to image grid coordinates, as the images are still unregistered at this point. from the moving and target image, and predicts a desired initial vectorvalued momentum patch, separated into the , and dimensions, respectively. This prediction function should be learned from a set of training sample patches. These initial vectorvalued momentum patches are obtained by numerical optimization of the LDDMM shooting formulation. More formally, given a 3D patch of size voxels, we want to learn a function . In our formulation, is implemented by a deep neural network. Ideally, for two 3D image patches , with , we want to be as close as possible to the desired LDDMM optimization momentum patch
with respect to an appropriate loss function (e.g., the 1norm). Our proposed architecture (for
) consists of two parts: an encoder and a decoder which we describe next.Encoder. The Encoder consists of two parallel encoders which learn features from the moving/target image patches independently. Each encoder contains two blocks of three 3D convolution layers and PReLU PReLU activation layers, followed by another convolution+PReLU with a stride of two, cf. Fig. 2
. The convolution layers with a stride of two reduce the size of the output patch, and essentially perform pooling operations. PReLU is an extension of the ReLU activation
ReLU , given aswhere is a parameter that is learned when training the network. In contrast to ReLU, PReLU avoids a zero gradient for negative inputs, effectively improving the network performance. The number of features in the first block is and increases to in the second block. The learned features from the two encoders are then concatenated and sent to three parallel decoders (one per dimension ). Decoder. Each decoder’s structure is the inverse of the encoder, except that the number of features is doubled ( in the first block and in the second block) as the decoder’s input is obtained from the two encoder branches. We use 3D transposed convolution layers Long2015 with a stride of 2, which are shown as the cyan layers in Fig. 2 and can be regarded as the backward propagation of 3D convolution operations, to perform “unpooling”. We also omit the nonlinearity after the final convolution layer, cf. Fig. 2.
The idea of using convolution and transpose of convolution to learn the pooling/unpooling operation is motivated by SpringenbergDBR14 , and it is especially suited for our network as the two encoders perform pooling independently which prevents us from using the pooling index for unpooling in the decoder. During training, we use the 1norm between the predicted and the desired momentum to measure the prediction error.
We chose the 1norm instead of the 2norm as our loss function to be able to tolerate outliers
and to generate sharper momentum predictions. Ultimately, we are interested in predicting the deformation map and not the patchwise momentum. However, this would require forming the entire momentum image from a collection of patches followed by shooting as part of the network training. Instead, predicting the momentum itself patchwise significantly simplifies the network training procedure. Also note that, while we predict the momentum patchbypatch, smoothing is performed over the full momentum image (reassembled from the patches) based on the smoothing kernel, , of LDDMM. Specifically, when predicting the deformation parameters for the whole image, we follow a sliding window strategy to predict the initial momentum in a patchbypatch manner and then average the overlapping areas of the patches to obtain the final prediction result.The number of 3D filters used in the network is 975,360. The overall number of parameters is 21,826,344. While this is a large number of parameters, we also have a very large number of training patches. For example, in our imagetoimage registration experiments (see Sec. 3), the total number of 3D training patches to train the prediction network is 1,002,404. This amounts to approximately 3.4 billion voxels and is much larger than the total number of parameters in the network. Moreover, recent research Gao2016
suggests that the degrees of freedom for a deep network can be significantly smaller than the number of its parameters.
One question that naturally arises is why to use independent encoders/decoders in the prediction network. For the decoder part, we observed that an independent decoder structure is much easier to train than a network with one large decoder (3 times the number of features of a single decoder in our network) to predict the initial momentum in all dimensions simultaneously. In our experiments, such a combined network easily got stuck in poor local minima. As to the encoders, experiments do not show an obvious difference in prediction accuracy between using two independent encoders and one single large encoder. However, such a twoencoder strategy is beneficial when extending the approach to multimodal image registration yang2017multimodal . Hence, using a twoencoder strategy here will make the approach easily retrainable for multimodal image registration. In short, our network structure can be viewed as a multiinput multitask network, where each encoder learns features for one patch source, and each decoder uses the shared image features from the encoders to predict one spatial dimension of the initial momenta. We remark that, if one were to predict the scalarvalued momentum, , instead of the vectorvalued momentum, , the network architecture could remain largely unchanged. The main difference would be that only one decoder would be required. Due to the simpler network architecture such an approach could potentially speedup predictions. However, it remains to be investigated how such a network would perform in practice as the vectorvalued momentum has been found to numerically better behave for LDDMM optimizations Singh2013 .
We extend our architecture to a probabilistic network using dropout srivastava14a , which can be viewed as (Bernoulli) approximate inference in Bayesian neural networks Gal2015Bayesian ; Gal16a . In the following, we briefly review the basic concepts, but refer the interested reader to the corresponding references for further technical details.
In our problem setting, we are given training patch tuples with associated desired initial momentum patches . We denote the collection of this training data by and . In the standard, nonprobabilistic setting, we aim for predictions of the form , given a new input patch , where is implemented by the proposed encoderdecoder network. In the probabilistic setting, however, the goal is to make predictions of the form
. As this predictive distribution is intractable for most underlying models (as it would require integrating over all possible models, and neural networks in particular), the idea is to condition the model on a set of random variables
. In case of (convolutional) neural networks with
layers, these random variables are the weight matrices, i.e., . However, evaluation of the predictive distribution then requires the posterior over the weights which can (usually) not be evaluated analytically. Therefore, in variational inference, is replaced by a tractable variational distributionand one minimizes the KullbackLeibler divergence between
and with respect to the variational parameters . This turns out to be equivalent to maximization of the log evidence lower bound (ELBO). When the variational distribution is defined as(5) 
where is the convolutional weight, ,
is the probability that
and is chosen appropriately to match the dimensionality of , Gal et al. Gal2015Bayesian show that ELBO maximization is achieved by training with dropout srivastava14a . In the case of convolutional neural networks, dropout is applied after each convolution layer (with dropout probability )^{7}^{7}7with additional regularization on the weight matrices of each layer.. In Eq. (5), is the variational parameter which is optimized during training. Evaluation of the predictive distribution can then be approximated via MonteCarlo integration, i.e.,(6) 
In detail, this corresponds to averaging the output of forward passes through the network with dropout enabled. Note that and now correspond to random variables, as dropout means that we sample, in each forward pass, which connections are dropped. In our implementation, we add dropout layers after all convolutional layers except for those used as pooling/unpooling layers (which are considered nonlinearities applied to the weight matrices Gal2015Bayesian
), as well as the final convolution layer in the decoder, which generates the predicted momentum. We train the network using stochastic gradient descent (SGD).
Network evaluation. For testing, we keep the dropout layers enabled to maintain the probabilistic property of the network, and sample the network to obtain multiple momentum predictions for one moving/target image pair. We then choose the sample mean as the prediction result, see Eq. (6
), and perform LDDMM shooting using all the samples to generate multiple deformation fields. The local variance of these deformation fields can then be used as an uncertainty estimate of the predicted deformation field. When selecting the dropout probability,
, a probability of would provide the largest variance, but may also enforce too much regularity for a convolutional network, especially in our case where dropout layers are added after every convolution layer. In our experiments, we use a dropout probability of (for all dropout units) as a balanced choice.As discussed in Sec. 2.2.1, we use a slidingwindow approach to predict the deformation parameters (the momenta for Quicksilver) patchbypatch for a whole image. Thus, computation time is proportional to the number of the patches we need to predict. When using a 1voxel sliding window stride, the number of patches to predict for a whole image could be substantial. For a typical 3D image of size using a patch for prediction will require more than 1.4 million patch predictions. Hence, we use two techniques to drastically reduce the number of patches needed for deformation prediction. First, we perform patch pruning by ignoring all patches that belong to the background of both the moving image and the target image. This is justified, because according to LDDMM theory the initial momentum in constant image regions, and hence also in the image background, should be zero. Second, we use a large voxel stride (e.g., 14 for patches) for the sliding window operations. This is reasonable for our initial momentum parameterization because of the compact support (at edges) of the initial momentum and the spatial shift invariance we obtain via the pooling/unpooling operations. By using these two techniques, we can reduce the number of predicted patches for one single image dramatically. For example, by for 3D brain images of dimension .
There are two main shortcomings of the deformation prediction network. (i) The complete iterative numerical approach typically used for LDDMM registration is replaced by a single prediction step. Hence, it is not possible to recover from any prediction errors. (ii) To facilitate training a network with a small number of images, to make predictions easily parallelizable, and to be able to perform predictions for large 3D image volumes, the prediction network predicts the initial momentum patchbypatch. However, since patches are extracted at the same spatial grid locations from the moving and target images, large deformations may result in drastic appearance changes between a source and a target patch. In the extreme case, corresponding image information may no longer be found for a given source and target patch pair. This may happen, for example, when a small patchsize encounters a large deformation. While using larger patches would be an option (in the extreme case the entire image would be represented by one patch), this would require a network with substantially larger capacity (to store the information for larger image patches and all meaningful deformations) and would also likely require much larger training datasets^{8}^{8}8In fact, we have successfully trained prediction models with as little as ten images using all combinations of pairwise registrations to create training data yang2017multimodal . This is possible, because even in such a case of severely limited training data the number of patches that can be used for training is very large..
To address these shortcomings, we propose a twostep prediction approach to improve overall prediction accuracy. The first step is our already described prediction network. We refer to the second step as the correction network. The task of the correction network is to compensate for prediction errors of the first prediction step. The idea is grounded in two observations: The first observation is that patchbased prediction is accurate when the deformation inside the patch is small. This is sensible as the initial momentum is concentrated along the edges, small deformations are commonly seen in training images, and less deformation results in less drastic momentum values. Hence, more accurate predictions are expected for smaller deformations. Our second observation is that, given the initial momentum, we are able to generate the whole geodesic path using the geodesic shooting equations. Hence, we can generate two deformation maps: the forward warp that maps the moving image to the coordinates of the target image, and the backward warp mapping the target image back to the coordinates of the moving image. Hence, after the first prediction step using our prediction network, we can warp the target image back to the moving image via . We can then train the correction network based on the difference between the moving image and the warpedback target image , such that it makes adjustments to the initial momentum predicted in the first step by our prediction network. Because and are in the same coordinate system, the differences between these two images are small as long as the predicted deformation is reasonable, and more accurate predictions can be expected. Furthermore, the correction for the initial momentum is then performed in the original coordinate space (of the moving image) which allows us to obtain an overall corrected initial momentum, . This is for example a useful property when the goal is to do statistics with respect to a fixed coordinate system, for example, an atlas coordinate system.
Fig. 3 shows a graphical illustration of the resulting twostep prediction framework. In the framework, the correction network has the same structure as the prediction network, and the only difference is the input of the networks and the output they produce. Training the overall framework is done sequentially:
Train the prediction network using training images and the ground truth initial momentum obtained by numerical optimization of the LDDMM registration model.
Use the predicted momentum from the prediction network to generate deformation fields to warp the target images in the training dataset back to the space of the moving images.
Use the moving images and the warpedback target images to train the correction network. The correction network learns to predict the difference between the ground truth momentum and the predicted momentum from the prediction network.
Using the framework during testing is similar to the training procedure, except here the outputs from the prediction network (using moving and target images as input) and the correction network (using moving and warpedback target images as input) are summed up to obtain the final predicted initial momentum. This summation is justified from the LDDMM theory as it is performed in a fixed coordinate system (a fixed tangent space), which is the coordinate system of the moving image. Experiments show that our prediction+correction approach results in lower training and testing error compared with only using a prediction network, as shown in Sec. 2.4 and Sec. 3.
training loss per patch. The loss is averaged across all iterations for every epoch for both the AtlastoImage case and the ImagetoImage case.
The combined prediction + correction networks obtain a lower loss per patch than the loss obtained by simply training the prediction networks for more epochs.We evaluate our method using three 3D brain image registration experiments. The first experiment is designed to assess atlastoimage registration. In this experiment, the moving image is always the atlas image. The second experiment addresses general imagetoimage registration. The final experiment explores multimodal image registration; specifically, the registration of T1weighted (T1w) and T2weighted (T2w) magnetic resonance images.
Deformation Error for each voxel [mm]  
Data percentile for all voxels  0.3%  5%  25%  50%  75%  95%  99.7%  
Affine  0.0613  0.2520  0.6896  1.1911  1.8743  3.1413  5.3661  N/A 
D, velocity, stride 5  0.0237  0.0709  0.1601  0.2626  0.4117  0.7336  1.5166  100% 
D, velocity, stride 14  0.0254  0.075  0.1675  0.2703  0.415  0.743  1.5598  100% 
D, deformation, stride 5  0.0223  0.0665  0.1549  0.2614  0.4119  0.7388  1.5845  56% 
D, deformation, stride 14  0.0242  0.0721  0.1671  0.2772  0.4337  0.7932  1.6805  0% 
P, momentum, stride 14, 50 samples  0.0166  0.0479  0.1054  0.1678  0.2546  0.4537  1.1049  100% 
D, momentum, stride 5  0.0129  0.0376  0.0884  0.1534  0.2506  0.4716  1.1095  100% 
D, momentum, stride 14  0.013  0.0372  0.0834  0.1359  0.2112  0.3902  0.9433  100% 
D, momentum, stride 14, 40 epochs  0.0119  0.0351  0.0793  0.1309  0.2070  0.3924  0.9542  100% 
D, momentum, stride 14 + correction  0.0104  0.0309  0.0704  0.1167  0.185  0.3478  0.841  100% 
For the atlastoimage registration experiment, we use 3D image volumes from the OASIS longitudinal dataset OASIS . Specifically, we use the first scan of all subjects, resulting in 150 brain images. We select the first 100 images as our training target images and the remaining 50 as our test target images. We create an unbiased atlas joshi2004 from all training data using PyCA^{9}^{9}9https://bitbucket.org/scicompanat/pyca Singh2013 ; Singh2013HGM , and use the atlas as the moving image. We use the LDDMM shooting algorithm to register the atlas image to all 150 OASIS images. The obtained initial momenta from the training data are used to train our network; the remaining momenta are used for validation.
For the imagetoimage registration experiment, we use all 373 images from the OASIS longitudinal dataset as the training data, and randomly select target images from different subjects for every image, creating 373 registrations for the training of our prediction and correction networks. For testing, we choose the four datasets (LPBA40, IBSR18, MGH10, CUMC12) evaluated in Klein2009786 . We perform LDDMM shooting for all training registrations, and follow the evaluation procedure described in Klein2009786 to perform pairwise registrations within all datasets, resulting in a total of 2168 registration (1560 from LPBA40, 306 from IBSR18, 90 from MGH10, 132 from CUMC12) test cases.
For the multimodal registration experiment, we use the IBIS 3D Autism Brain image dataset hazlett2017early . This dataset contains 375 T1w/T2w brain images from 2 years old subjects. We select 359 of the images for training and use the remaining 16 images for testing. For training, we randomly select T1wT1w image pairs and perform LDDMM shooting to generate the optimization momenta. We then train the prediction and correction networks to predict the momenta obtained from LDDMM T1wT1w optimization using the image patches from the corresponding T1w moving image and T2w target image as network inputs. For testing, we perform pairwise T1wT2w registrations for all 16 test images, resulting in 250 test cases. For comparison, we also train a T1wT1w prediction+correction network that performs prediction on the T1wT1w test cases. This network acts as the “upperbound” of the potential performance of our multimodal networks as it addresses the unimodal registration case and hence operates on image pairs which have very similar appearance. Furthermore, to test prediction performance when using very limited training data, we also train a multimodal prediction network and a multimodal prediction+correction network using only 10 of the 365 training images which are randomly chosen for training. In particular, we perform pairwise T1wT1w registration on the 10 images, resulting in 90 registration pairs. We then use these 90 registration cases to train the multimodal prediction networks.
For skull stripping, we use FreeSurfer FreeSurfer for the OASIS dataset and AutoSeg AutoSeg for the IBIS dataset. The 4 evaluation datasets for imagetoimage experiment are already skull stripped as described in Klein2009786 . All images used in our experiments are first affinely registered to the ICBM MNI152 nonlinear atlas Grabner2006 using NiftyReg^{10}^{10}10https://cmiclab.cs.ucl.ac.uk/mmodat/niftyreg and intensity normalized via histogram equalization prior to atlas building and LDDMM registration. All 3D volumes are of size except for the LPBA dataset (), where we add additional blank image voxels for the atlas to keep the cerebellum structure. LDDMM registration is done using PyCA^{11}^{11}11https://bitbucket.org/scicompanat/pyca Singh2013 with SSD as the image similarity measure. We set the parameters for the regularizer of LDDMM^{12}^{12}12This regularizer is too weak to assure a diffeomorphic transformation based on the sufficient regularity conditions discussed in beg2005 . For these conditions to hold in 3D, would need to be at least a differential operator of order 6. However, as long as the obtained velocity fields are finite over the unit interval, i.e., for an of at least order 6, we will obtain a diffeomorphic transform dupuis1998 . In the discrete setting, this condition will be fulfilled for finite velocity fields. To sidestep this issue, models based on Gaussian or multiGaussian kernels bruveris2012 could also be used instead. to as , and in Eqn. 3 to 0.2. We use a patch size for deformation prediction in all cases, and use a sliding window with stepsize 14 to extract patches for training. The only exception is for the multimodal network which is trained using only 10 images, where we choose a stepsize of 10 to generate more training patches. Note that using a stride of 14 during training means that we are in fact discarding available training patches to allow for reasonable network training times. However, we still retain a very large number of patches for training. To check that our number of patches for training is sufficient, we performed additional experiments for the imagetoimage registration task using smaller strides when selecting training patches. Specifically, we doubled and tripled the training size for the prediction network. These experiments indicated that increasing the training data size further only results in marginal improvements, which are clearly outperformed by a combined prediction + correction strategy. Exploring alternative network structures, which may be able to utilize larger training datasets, is beyond the scope of this paper, but would be an interesting topic for future research.
The network is implemented in PyTorch^{13}^{13}13https://github.com/pytorch/pytorch, and optimized using Adam kingma2014adam . We set the learning rate to 0.0001 and keep the remaining parameters at their default values. We train the prediction network for 10 epochs for the imagetoimage registration experiment and the multimodal image registration experiment, and 20 epochs for the atlastoimage experiment. The correction networks are trained using the same number of epochs as their corresponding prediction networks. Fig. 4 shows the training loss per patch averaged for every epoch for the atlastoimage and the imagetoimage experiments. For both, using a correction network in conjunction with a prediction network results in lower training error compared with training the prediction network for more epochs.
For the atlastoimage registration experiment, we test two different sliding window strides for our patchbased prediction method: stride = 5 and stride = 14. We trained additional prediction networks predicting the initial velocity and the displacement field of LDDMM to show the effect of different deformation parameterizations on deformation prediction accuracy. We generate the predicted deformation map by integrating the shooting equation 4 for the initial momentum and the initial velocity parameterization respectively. For the displacement parameterization we can directly readoff the map from the network output. We quantify the deformation errors per voxel using the voxelwise twonorm of the deformation error with respect to the result obtained via numerical optimization for LDDMM using PyCA. Table 1 shows the error percentiles over all voxels and test cases.
We observe that the initial momentum network has better prediction accuracy compared to the results obtained via the initial velocity and displacement parameterization in both the 5stride and 14stride cases. This validates our hypothesis that momentumbased LDDMM is better suited for patchwise deformation prediction. We also observe that the momentum prediction result using a smaller sliding window stride is slightly worse than the one using a stride of 14. This is likely the case, because in the atlastoimage setting, the number of atlas patches that extract features from the atlas image is very limited, and using a stride of 14 during the training phase further reduces the available data from the atlas image. Thus, during testing, the encoder will perform very well for the 14stride test cases since it has already seen all the input atlas patches during training. For a stride of 5 however, unseen atlas patches will be input to the network, resulting in reduced registration accuracy^{14}^{14}14This behavior could likely be avoided by randomly sampling patch locations during training instead of using a regular grid. However, since we aim at reducing the number of predicted patches we did not explore this option and instead maintained the regular grid sampling.. In contrast, the velocity and the displacement parameterizations result in slightly better predictions for smaller sliding window strides. That this is not the case for the momentum parameterization suggests that it is easier for the network to learn to predict the momentum, as it indeed has become more specialized to the training data which was obtained with a stride of 14. One of the important properties of LDDMM shooting is its ability to generate diffeomorphic deformations. To assess this property, we calculate the local Jacobians of the resulting deformation maps. Assuming no flips of the entire coordinate system, a diffeomorphic deformation map should have positive Jacobian determinants everywhere, otherwise foldings occur in the deformation maps. We calculate the ratio of test cases with positive Jacobian determinants of the deformation maps to all test cases, shown as in Table 1. We observe that the initial momentum and the initial velocity networks indeed generate diffeomorphic deformations in all scenarios. However, the deformation accuracy is significantly worse for the initial velocity network. Predicting the displacement directly cannot guarantee diffeomorphic deformations even for a small stride. This is unsurprising as, similar to existing optical flow approaches deepflow ; flownet , directly predicting displacements does not encode deformation smoothness. Hence, the initial momentum parameterization is the preferred choice among our three tested parameterizations as it achieves the best prediction accuracy and guarantees diffeomorphic deformations. Furthermore, the initial momentum prediction including the correction network with a stride of 14 achieves the best registration accuracy overall among the tested methods, even outperforming the prediction network alone trained with more training iterations (D, stride 14, 40 epochs). This demonstrates that the correction network is capable of improving the initial momentum prediction beyond the capabilities of the original prediction network.
Fig. 5 shows one example atlastoimage registration case. The predicted deformation result is very similar to the deformation from LDDMM optimization. We compute the square root of the sum of the variance of the deformation in the , and directions to quantify deformation uncertainty, and visualize it on the rightmost column of the figure. The uncertainty map shows high uncertainty along the ventricle areas where drastic deformations occur, as shown in the moving and target images.
performance in the lower quartile to upper quartile (bestviewed in color).
The medians of the overlapping scores for [LPBA40, IBSR18, CUMC12, MGH10] for LO, LP and LPC are: LO: [0.702, 0.537, 0.536, 0.563]; LP: [0.696, 0.518, 0.515, 0.549]; LPC: [0.702, 0.533, 0.526, 0.559]. Bestviewed in color.In this experiment, we use a sliding window stride of 14 for both the prediction network and the correction network during evaluation. We mainly compare the following three LDDMMbased methods: (i) the numerical LDDMM optimization approach (LO) as implemented in PyCA, which acts as an upper bound on the performance of our prediction methods; and two flavors of Quicksilver: (ii) only the prediction network (LP) and (iii) the prediction+correction network (LPC). Example registration cases are shown in Fig. 9.
LDDMM energy for imagetoimage test datasets  
LPBA40  
initial  LO  LP  LPC 
IBSR18  
initial  LO  LP  LPC 
CUMC12  
initial  LO  LP  LPC 
MGH10  
initial  LO  LP  LPC 
Mean and standard deviation of the LDDMM energy for four imagetoimage test datasets.
initial: the initial LDDMM energy between the original moving image and the target image after affine registration to the atlas space, i.e. the original image matching energy. LO: LDDMM optimization. LP: prediction network. LPC: prediction+correction network.To test the ability of our prediction networks to replace numerical optimization, we compare the LDDMM energies obtained using optimization from LO with the energies corresponding to the predicted momenta from LP and LPC. Low energies for the predicted momenta, which are comparable to the energies obtained by numerical optimization (LO), would suggest that our prediction models can indeed act as replacements for numerical optimization. However, note that, in general, a low energy will only imply a good registration result if the registration model is fully appropriate for the registration task. Ultimately, registration quality should be assessed based on a particular task: most directly by measuring landmark errors or (slightly more indirectly) by measuring overlaps of corresponding regions as done in Section 3.2.2. Note also that our networks for imagetoimage registration are trained on the OASIS dataset. Hence, improved results may be achievable by training dataset specific models. Table 2 shows the results for the four test datasets. Compared with the initial LDDMM energy based on affine registration to the atlas space in the initial column, both LP and LPC have drastically lower LDDMM energy values; further, these values are only slightly higher than those for LO. Furthermore, compared with LP, LPC generates LDDMM energy values that are closer to LO, which indicates that using the prediction+correction approach results in momenta which are closer to the optimal solution than the ones obtained by using the prediction network only.
For imagetoimage registration we follow the approach in Klein2009786 and calculate the target overlap (TO) of labeled brain regions after registration: , where and indicate the corresponding labels for the moving image (after registration) and the target image. We then evaluate the mean of the target overlap averaged first across all labels for every registration case. The evaluation results for other methods tested in Klein2009786 are available online. We compare our registration approaches to these results. An interesting question is if the prediction network and the correction network are identical, and whether the prediction network can be used in the correction step. Another question is if the correction network can be applied multiple times in the correction step to further improve results. Thus, to test the usefulness of the correction network in greater depth, we also create three additional formulations of our prediction framework: (i) prediction network + using the same prediction network to replace the correction network in the correction step (LPP); (ii) applying the correction network twice (LPC2) and (iii) applying the correction network three times (LPC3).
Fig. 6 shows the evaluation results. Several points should be noted: first, the LDDMM optimization performance is on par with SyN Avants200826 , ART Ardekani200567 and the SPM5 DARTEL Toolbox (SPM5D) Ashburner200795 . This is reasonable as these methods are all nonparametric diffeomorphic or homeomorphic registration methods, allowing the modeling of large deformations between image pairs. Second, using only the prediction network results in a slight performance drop compared to the numerical optimization results (LO), but the result is still competitive with the topperforming registration methods. Furthermore, also using the correction network boosts the deformation accuracy nearly to the same level as the LDDMM optimization approach (LO). The red horizontal lines in Fig. 6 show the lower and upper quartiles of the target overlap score of the prediction+correction method. Compared with other methods, our prediction+correction network achieves toptier performance for label matching accuracy at a small fraction of the computational cost. Lastly, in contrast to many of the other methods Quicksilver produces virtually no outliers. One can speculate that this may be the benefit of learning to predict deformations from a large population of data, which may result in a prediction model which conservatively rejects unusual deformations. Note that such a populationbased approach is very different from most existing registration methods which constrain deformations based on a regularizer chosen for a mathematical registration model. Ultimately, a deformation model for image registration should model what deformations are expected. Our populationbased approach is a step in this direction, but, of course, still depends on a chosen regularizer to generate training data. Ideally, this regularizer itself should be learned from data.
An interesting discovery is that LPP, LPC2 and LPC3 produce label overlapping scores that are onpar with LPC. However, as we will show in Sec. 3.2.3, LPP, LPC2 and LPC3 deviate from our goal of predicting deformations that are similar to the LDDMM optimization result (LO). In fact, they produce more drastic deformations that can lead to worse label overlap and even numerical stability problems. These problems can be observed in the LPBA40 results shown in Fig. 6, which show more outliers with low overlapping scores for LPP and LPC3. In fact, there are 12 cases for LPP where the predicted momentum cannot generate deformation fields via LDDMM shooting using PyCA, due to problems related to numerical integration. These cases are therefore not included in Fig. 6. PyCA uses an explicit RungeKutta method (RK4) for timeintegration. Hence, numerical instability is likely due to the use of a fixed step size for this timeintegration which is small enough for the deformations expected to occur for these brain registration tasks, but which may be too large for the more extreme momenta LPP and LPC3 create for some of these cases. Using a smaller stepsize would regain numerical stability in this case.




The significance level for rejection of the nullhypothesis is
. Bestviewed in color.




To study the differences among registration algorithms statistically, we performed paired tests^{15}^{15}15To safeguard against overly optimistic results due to multiple comparisons, we used Bonferroni correction for all statistical tests in the paper (paired tests and paired TOST) by dividing the significance level by the total number (204) of statistical tests we performed. This resulted in an effective significance level . The Bonferroni correction is likely overly strict for our experiments as the different registration results will be highly correlated, because they are based on the same input data. with respect to the target overlap scores between our LDDMM variants (LO, LP, LPC) and the methods in Klein2009786 . Our nullhypothesis is that the methods show the same target overlap scores. We use a significance level of for rejection of this nullhypothesis. We also computed the mean and the standard deviation of pairwise differences between our LDDMM variants and these other methods. Table 3 shows the results. We observe that direct numerical optimization of the shooting LDDMM formulation via PyCA (LO) is a highly competitive registration method and shows better target overlap scores than most of the other registration algorithms for all four datasets (LPBA40, IBSR18, CUMC12, and MGH10). Notable exceptions are ART (on LPBA40), SyN (on LBPA40), and SPM5D (on IBSR18). However, performance decreases are generally very small: , , and mean decrease in target overlap ratio for the three aforementioned exceptions, respectively. Specifically, a similar performance of LO to SyN, for example, is expected as SyN (as used in Klein2009786 ) is based on a relaxation formulation of LDDMM, whereas LO is based on the shooting formulation of LDDMM. Performance differences may be due to differences in the used regularizer and the image similarity measure. In particular, where SyN was used with Gaussian smoothing and crosscorrelation, we used SSD as the image similarity measure and a regularizer involving up to second order spatial derivatives.
LO is the algorithm that our predictive registration approaches (LP and LPC) are based on. Hence, LP and LPC are not expected to show improved performance with respect to LO. However, similar performance for LP and LPC would indicate high quality predictions. Indeed, Table 3 shows that our prediction+correction approach (LPC) performs similar (with respect to the other registration methods) to LO. A slight performance drop with respect to LO can be observed for LPC and a slightly bigger performance drop for LP, which only uses the prediction model, but no correction model.
To assess statistical equivalence of the top performing registration algorithms we performed paired two onesided tests (paired TOST) wellek2010testing with a relative threshold difference of 2%. In other words, our nullhypothesis is that methods show a relative difference of larger than 2%. Rejection of this nullhypothesis at a significance level of then indicates evidence for statistical equivalence. Table 4 shows the paired TOST results. For a relative threshold difference of 2% LPC can be considered statistically equivalent to LO for all four datasets and to many of the other top methods (e.g., LPC vs. SyN on MGH10 and IBSR18).
Overall, these statistical tests confirm that our prediction models, in particular LPC, are highly competitive registration algorithms. Computational cost, however, is very small. This is discussed in detail in Sec. 3.4.
As shown in Sec. 3.2.2, LPP, LPC2 and LPC3 all result in label overlapping scores which are similar to the label overlapping scores obtained via LPC. This raises the question which method should be preferred for the correction step. Note that among these methods, only LPC is specifically trained to match the LDDMM optimization results and in particular to predict corrections to the initial momentum obtained by the prediction model (LP) in the tangent space of the moving image. In contrast, LPP, LPC2 and LPC3 lack this theoretical motivation. Hence, it is unclear for these methods what the overall optimization goal is. To show what this means in practice, we computed the determinant of the Jacobian of the deformation maps () for all voxels for all four registration cases of Klein2009786 inside the brain mask and calculated the histogram of the computed values. Our goal is to check the similarity (in distribution) between deformations generated by the prediction models (LP, LPC, LPP, LPC2, LPC3) in comparison to the results obtained via numerical LDDMM optimization (LO).
As an example, Fig. 7 shows the result for the LPBA40 dataset. The other three datasets show similar results. Fig. 7(left) shows the histogram of the logarithmically transformed determinant of the Jacobian () for all the methods. A value of 0 on the xaxis indicates no deformation or a volume preserving deformation, indicates volumetric shrinkage and indicates volumetric expansion. We can see that LPC is closest to LO. LP generates smoother deformations compared with LO, which is sensible as onestep predictions will likely not be highly accurate and, in particular, may result in predicted momenta which are slightly smoother than the ones obtained by numerical optimization. Hence, in effect, the predictions may result in a more strongly spatially regularized deformation. LPP, LPC2 and LPC3 generate more drastic deformations (i.e., more spread out histograms indicating areas of stronger expansions and contractions). Fig. 7(right) shows this effect more clearly; it shows the differences between the histogram of the prediction models and the registration result obtained by numerical optimization (LO). Hence, a method which is similar to LO in distribution will show a curve close to .
This assessment also demonstrates that the correction network (of LPC) is different from the prediction network (LP): the correction network is trained specifically to correct minor errors in the predicted momenta of the prediction network with respect to the desired momenta obtained by numerical optimization (LO), while the prediction network is not. Thus, LPC is the only model among the prediction models (apart from LP) that has the explicit goal of predicting the behavior of the LDDMM optimization result (LO). When we use the prediction network in the correction step, the high label overlapping scores are due to more drastic deformations compared with LP, but there is no clear theoretical justification of LPP. In fact, it is more reminiscent of a greedy solution strategy, albeit still results in geodesic paths as the predicted momenta are added in the tangent space of the undeformed moving image. Similar arguments hold for LPC2 and LPC3: using the correction network multiple times (iteratively) in the correction step also results in increasingly drastic deformations, as illustrated by the curves for LPC, LPC2 and LPC3 in Fig. 7. Compared to the label overlapping accuracy boost from LP to LPC, LPC2 and LPC3 do not greatly improve the registration accuracy, and may even generate worse results (e.g., LPC3 on LPBA40). Furthermore, the additional computation cost for more iterations of the correction network + LDDMM shooting makes LPC2 and LPC3 less favorable, in comparison to LPC.
Table 5 shows the range of deformations and associated percentiles for the deformation fields generated by LDDMM optimization for the four imagetoimage test datasets. All computations were restricted to locations inside the brain mask. Table 5 also shows the means and standard deviations of the differences of deformations between the results for the prediction models and the results obtained by numerical optimization (LO). As shown in the table, the largest deformations that LDDMM optimization generates are 23.393 mm for LPBA40, 36.263 mm for IBSR18, 18.753 mm for CUMC12 and 18.727 mm for MGH10.
Among the prediction models, LPC improves the prediction accuracy compared with LP, and generally achieves the highest deformation prediction accuracy for up to 80% of the voxels. It is also onpar with other prediction models for up to 99% of the voxels, where the largest deformations are in the range between 7.317 mm9.026 mm for the four datasets. For very large deformations that occur for 1% of the total voxels, LPC does not drastically reduce the deformation error. This is due to the following three reasons: First, the input patch size of the deep learning framework is , which means that the receptive field for the network input is limited to . This constrains the network’s ability to predict very large deformations, and can potentially be solved by implementing a multiscale input network for prediction. Second, the deformations in the OASIS training images have a median of 2.609 mm, which is similar to the median observed in the four testing datasets. However, only 0.2% of the voxels in the OASIS training dataset have deformations larger than 10 mm. Such a small number of training patches containing very large deformations makes it difficult to train the network to accurately predict these very large deformations in the test data. If capturing these very large deformations is desired, a possible solution could be to provide a larger number of training examples for large deformations or to weight samples based on their importance. Third, outliers in the dataset whose appearances are very different from the other images in the dataset can cause very large deformations. For example, in the IBSR18 dataset, only three distinct images are needed as moving or target images to cover the 49 registration cases that generate deformations larger than 20 mm. These large deformations created by numerical LDDMM optimization are not always desirable; and consequentially registration errors of the prediction models with respect to the numerical optimization result are in fact sometimes preferred. As a case in point, Fig. 8 shows a registration failure case from the IBSR18 dataset for LDDMM optimization and the corresponding prediction result. In this example, the brain extraction did not extract consistent anatomy for the moving image and the target image. Specifically, only inconsistent parts of the cerebellum remain between the moving and the target images. As optimizationbased LDDMM does not know about this inconsistency, it attempts to match the images as well as possible and thereby creates a very extreme deformation. Our prediction result, however, still generates reasonable deformations (where plausibility is based on the deformations that were observed during training) while matching the brain structures as much as possible. This can be regarded as an advantage of our network, where the conservative nature of patchwise momentum prediction is more likely to generate reasonable deformations.




Deformation Error w.r.t LDDMM optimization on T1wT1w data [mm]  
Data percentile for all voxels  0.3%  5%  25%  50%  75%  95%  99.7% 
Affine (Baseline)  0.1664  0.46  0.9376  1.4329  2.0952  3.5037  6.2576 
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