Image Features for Brain Phenotypes Core Publications

Poynton CB, Jenkinson M, Adalsteinsson E, Sullivan EV, Pfefferbaum A, Wells III WM. Quantitative Susceptibility Mapping by Inversion of a Perturbation Field Model: Correlation with Brain Iron in Normal Aging. IEEE Trans Med Imaging. 2015;34 (1) :339-53.Abstract

There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or "QSIP." The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B0 inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase, and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in vivo FDRI: statistically significant Spearman correlations ranging from Rho=0.905 to Rho=1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions.

Pujol S, Wells III WM, Pierpaoli C, Brun C, Gee J, Cheng G, Vemuri B, Commowick O, Prima S, Stamm A, et al. The DTI Challenge: Toward Standardized Evaluation of Diffusion Tensor Imaging Tractography for Neurosurgery. J Neuroimaging. 2015;25 (6) :875-82.Abstract
BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) tractography reconstruction of white matter pathways can help guide brain tumor resection. However, DTI tracts are complex mathematical objects and the validity of tractography-derived information in clinical settings has yet to be fully established. To address this issue, we initiated the DTI Challenge, an international working group of clinicians and scientists whose goal was to provide standardized evaluation of tractography methods for neurosurgery. The purpose of this empirical study was to evaluate different tractography techniques in the first DTI Challenge workshop. METHODS: Eight international teams from leading institutions reconstructed the pyramidal tract in four neurosurgical cases presenting with a glioma near the motor cortex. Tractography methods included deterministic, probabilistic, filtered, and global approaches. Standardized evaluation of the tracts consisted in the qualitative review of the pyramidal pathways by a panel of neurosurgeons and DTI experts and the quantitative evaluation of the degree of agreement among methods. RESULTS: The evaluation of tractography reconstructions showed a great interalgorithm variability. Although most methods found projections of the pyramidal tract from the medial portion of the motor strip, only a few algorithms could trace the lateral projections from the hand, face, and tongue area. In addition, the structure of disagreement among methods was similar across hemispheres despite the anatomical distortions caused by pathological tissues. CONCLUSIONS: The DTI Challenge provides a benchmark for the standardized evaluation of tractography methods on neurosurgical data. This study suggests that there are still limitations to the clinical use of tractography for neurosurgical decision making.
Toews M, Wachinger C, Estepar RSJ, Wells III WM. A Feature-Based Approach to Big Data Analysis of Medical Images. Inf Process Med Imaging. 2015;24 :339-50.Abstract

This paper proposes an inference method well-suited to large sets of medical images. The method is based upon a framework where distinctive 3D scale-invariant features are indexed efficiently to identify approximate nearest-neighbor (NN) feature matches-in O (log N) computational complexity in the number of images N. It thus scales well to large data sets, in contrast to methods based on pair-wise image registration or feature matching requiring O(N) complexity. Our theoretical contribution is a density estimator based on a generative model that generalizes kernel density estimation and K-nearest neighbor (KNN) methods.. The estimator can be used for on-the-fly queries, without requiring explicit parametric models or an off-line training phase. The method is validated on a large multi-site data set of 95,000,000 features extracted from 19,000 lung CT scans. Subject-level classification identifies all images of the same subjects across the entire data set despite deformation due to breathing state, including unintentional duplicate scans. State-of-the-art performance is achieved in predicting chronic pulmonary obstructive disorder (COPD) severity across the 5-category GOLD clinical rating, with an accuracy of 89% if both exact and one-off predictions are considered correct.

Parisot S, Arslan S, Passerat-Palmbach J, Wells III WM, Rueckert D. Tractography-Driven Groupwise Multi-scale Parcellation of the Cortex. Inf Process Med Imaging. 2015;24 :600-12.Abstract

The analysis of the connectome of the human brain provides key insight into the brain's organisation and function, and its evolution in disease or ageing. Parcellation of the cortical surface into distinct regions in terms of structural connectivity is an essential step that can enable such analysis. The estimation of a stable connectome across a population of healthy subjects requires the estimation of a groupwise parcellation that can capture the variability of the connectome across the population. This problem has solely been addressed in the literature via averaging of connectivity profiles or finding correspondences between individual parcellations a posteriori. In this paper, we propose a groupwise parcellation method of the cortex based on diffusion MR images (dMRI). We borrow ideas from the area of cosegmentation in computer vision and directly estimate a consistent parcellation across different subjects and scales through a spectral clustering approach. The parcellation is driven by the tractography connectivity profiles, and information between subjects and across scales. Promising qualitative and quantitative results on a sizeable data-set demonstrate the strong potential of the method.

Wachinger C, Toews M, Langs G, Wells III WM, Golland P. Keypoint Transfer Segmentation. Inf Process Med Imaging. 2015;24 :233-45.Abstract

We present an image segmentation method that transfers label maps of entire organs from the training images to the novel image to be segmented. The transfer is based on sparse correspondences between keypoints that represent automatically identified distinctive image locations. Our segmentation algorithm consists of three steps: (i) keypoint matching, (ii) voting-based keypoint labeling, and (iii) keypoint-based probabilistic transfer of organ label maps. We introduce generative models for the inference of keypoint labels and for image segmentation, where keypoint matches are treated as a latent random variable and are marginalized out as part of the algorithm. We report segmentation results for abdominal organs in whole-body CT and in contrast-enhanced CT images. The accuracy of our method compares favorably to common multi-atlas segmentation while offering a speed-up of about three orders of magnitude. Furthermore, keypoint transfer requires no training phase or registration to an atlas. The algorithm's robustness enables the segmentation of scans with highly variable field-of-view.

Lee JW, Norden AD, Ligon KL, Golby AJ, Beroukhim R, Quackenbush J, Wells III WM, Oelschlager K, Maetzold D, Wen PY. Tumor Associated Seizures in Glioblastomas are Influenced by Survival Gene Expression in a Region-specific Manner: A Gene Expression Imaging Study. Epilepsy Res. 2014;108 (5) :843-52.Abstract

Tumor associated seizures (TAS) are common and cause significant morbidity. Both imaging and gene expression features play significant roles in determining TAS, with strong interactions between them. We describe gene expression imaging tools which allow mapping of brain regions where gene expression has significant influence on TAS, and apply these methods to study 77 patients who underwent surgical evaluation for supratentorial glioblastomas. Tumor size and location were measured from MRI scans. A 9-set gene expression profile predicting long-term survivors was obtained from RNA derived from formalin-fixed paraffin embedded tissue. A total of 32 patients (42%) experienced preoperative TAS. Tumor volume was smaller (31.1 vs. 58.8 cubic cm, p<0.001) and there was a trend toward median survival being higher (48.4 vs. 32.7 months, p=0.055) in patients with TAS. Although the expression of only OLIG2 was significantly lower in patients with TAS in a groupwise analysis, gene expression imaging analysis revealed regions with significantly lower expression of OLIG2 and RTN1 in patients with TAS. Gene expression imaging is a powerful technique that demonstrates that the influence of gene expression on TAS is highly region specific. Regional variability should be evaluated with any genomic or molecular markers of solid brain lesions.

Fedorov A, Wells III WM, Kikinis R, Tempany CM, Vangel MG. Application of Tolerance Limits to the Characterization of Image Registration Performance. IEEE Trans Med Imaging. 2014;33 (7) :1541-50.Abstract

Deformable image registration is used increasingly in image-guided interventions and other applications. However, validation and characterization of registration performance remain areas that require further study. We propose an analysis methodology for deriving tolerance limits on the initial conditions for deformable registration that reliably lead to a successful registration. This approach results in a concise summary of the probability of registration failure, while accounting for the variability in the test data. The (β, γ) tolerance limit can be interpreted as a value of the input parameter that leads to successful registration outcome in at least 100β% of cases with the 100γ% confidence. The utility of the methodology is illustrated by summarizing the performance of a deformable registration algorithm evaluated in three different experimental setups of increasing complexity. Our examples are based on clinical data collected during MRI-guided prostate biopsy registered using publicly available deformable registration tool. The results indicate that the proposed methodology can be used to generate concise graphical summaries of the experiments, as well as a probabilistic estimate of the registration outcome for a future sample. Its use may facilitate improved objective assessment, comparison and retrospective stress-testing of deformable.

Wachinger C, Golland P, Reuter M, Wells III WM. Gaussian Process Interpolation for Uncertainty Estimation in Image Registration. Med Image Comput Comput Assist Interv. 2014;17 (Pt 1) :267-74.Abstract

Intensity-based image registration requires resampling images on a common grid to evaluate the similarity function. The uncertainty of interpolation varies across the image, depending on the location of resampled points relative to the base grid. We propose to perform Bayesian inference with Gaussian processes, where the covariance matrix of the Gaussian process posterior distribution estimates the uncertainty in interpolation. The Gaussian process replaces a single image with a distribution over images that we integrate into a generative model for registration. Marginalization over resampled images leads to a new similarity measure that includes the uncertainty of the interpolation. We demonstrate that our approach increases the registration accuracy and propose an efficient approximation scheme that enables seamless integration with existing registration methods.

Toews M, Golby AJ, Wells III WM. Inter-slice Correspondence for 2D Ultrasound-guided Procedures. Int Conf Med Image Comput Comput Assist Interv. Workshop on Clinical Image-based Procedures: Transitional Research in Medical Imaging. 2013;16 (WS).Abstract
This paper reports on a new computational methodology, inter-slice correspondence (ISC), for robustly aligning sets of 2D ultrasound (US) slices during image-guided medical procedures. Correspondences are derived from distinctive, local scale-invariant features, which are used in one-to-many matching of US slices in near real-time despite out-of-plane rotation, in addition to global in-plane similarity transforms, occlusion, missing tissue, US plane mirroring, changes in US probe depth settings. Experiments demonstrate that ISC can align manually-acquired US slices without probe tracking information in the context of image-guided neurosurgery, with an accuracy of 1.3mm. A novel reconstruction-without-calibration application based on ISC is proposed, where 3D US reconstruction results are very similar to those obtained via traditional phantom-based calibration.
Toews MICCAI WS 2013
Toews M, Zöllei L, Wells III WM. Feature-based Alignment of Volumetric Multi-modal Images. Inf Process Med Imaging. 2013;23 :25-36.Abstract

This paper proposes a method for aligning image volumes acquired from different imaging modalities (e.g. MR, CT) based on 3D scale-invariant image features. A novel method for encoding invariant feature geometry and appearance is developed, based on the assumption of locally linear intensity relationships, providing a solution to poor repeatability of feature detection in different image modalities. The encoding method is incorporated into a probabilistic feature-based model for multi-modal image alignment. The model parameters are estimated via a group-wise alignment algorithm, that iteratively alternates between estimating a feature-based model from feature data, then realigning feature data to the model, converging to a stable alignment solution with few pre-processing or pre-alignment requirements. The resulting model can be used to align multi-modal image data with the benefits of invariant feature correspondence: globally optimal solutions, high efficiency and low memory usage. The method is tested on the difficult RIRE data set of CT, T1, T2, PD and MP-RAGE brain images of subjects exhibiting significant inter-subject variability due to pathology.

Tunç B, Smith AR, Wasserman D, Pennec X, Wells III WM, Verma R, Pohl KM. Multinomial Probabilistic Fiber Representation for Connectivity Driven Clustering. Inf Process Med Imaging. 2013;23 :730-41.Abstract

The clustering of fibers into bundles is an important task in studying the structure and function of white matter. Existing technology mostly relies on geometrical features, such as the shape of fibers, and thus only provides very limited information about the neuroanatomical function of the brain. We advance this issue by proposing a multinomial representation of fibers decoding their connectivity to gray matter regions. We then simplify the clustering task by first deriving a compact encoding of our representation via the logit transformation. Furthermore, we define a distance between fibers that is in theory invariant to parcellation biases and is equivalent to a family of Riemannian metrics on the simplex of multinomial probabilities. We apply our method to longitudinal scans of two healthy subjects showing high reproducibility of the resulting fiber bundles without needing to register the corresponding scans to a common coordinate system. We confirm these qualitative findings via a simple statistical analyse of the fiber bundles.

Risholm P, Janoos F, Norton I, Golby AJ, Wells III WM. Bayesian Characterization of Uncertainty in Intra-subject Non-rigid Registration. Med Image Anal. 2013;17 (5) :538-55.Abstract

In settings where high-level inferences are made based on registered image data, the registration uncertainty can contain important information. In this article, we propose a Bayesian non-rigid registration framework where conventional dissimilarity and regularization energies can be included in the likelihood and the prior distribution on deformations respectively through the use of Boltzmann's distribution. The posterior distribution is characterized using Markov Chain Monte Carlo (MCMC) methods with the effect of the Boltzmann temperature hyper-parameters marginalized under broad uninformative hyper-prior distributions. The MCMC chain permits estimation of the most likely deformation as well as the associated uncertainty. On synthetic examples, we demonstrate the ability of the method to identify the maximum a posteriori estimate and the associated posterior uncertainty, and demonstrate that the posterior distribution can be non-Gaussian. Additionally, results from registering clinical data acquired during neurosurgery for resection of brain tumor are provided; we compare the method to single transformation results from a deterministic optimizer and introduce methods that summarize the high-dimensional uncertainty. At the site of resection, the registration uncertainty increases and the marginal distribution on deformations is shown to be multi-modal.

Zhou B, Konstorum A, Duong T, Tieu KH, Wells III WM, Brown GG, Stern HS, Shahbaba B. A Hierarchical Modeling Approach to Data Analysis and Study Design in a Multi-site Experimental fMRI Study. Psychometrika. 2013;78 (2) :260-78.Abstract

We propose a hierarchical Bayesian model for analyzing multi-site experimental fMRI studies. Our method takes the hierarchical structure of the data (subjects are nested within sites, and there are multiple observations per subject) into account and allows for modeling between-site variation. Using posterior predictive model checking and model selection based on the deviance information criterion (DIC), we show that our model provides a good fit to the observed data by sharing information across the sites. We also propose a simple approach for evaluating the efficacy of the multi-site experiment by comparing the results to those that would be expected in hypothetical single-site experiments with the same sample size.

Toews M, Wells III WM. Efficient and Robust Model-to-image Alignment using 3D Scale-invariant Features. Med Image Anal. 2013;17 (3) :271-82.Abstract

This paper presents feature-based alignment (FBA), a general method for efficient and robust model-to-image alignment. Volumetric images, e.g. CT scans of the human body, are modeled probabilistically as a collage of 3D scale-invariant image features within a normalized reference space. Features are incorporated as a latent random variable and marginalized out in computing a maximum a posteriori alignment solution. The model is learned from features extracted in pre-aligned training images, then fit to features extracted from a new image to identify a globally optimal locally linear alignment solution. Novel techniques are presented for determining local feature orientation and efficiently encoding feature intensity in 3D. Experiments involving difficult magnetic resonance (MR) images of the human brain demonstrate FBA achieves alignment accuracy similar to widely-used registration methods, while requiring a fraction of the memory and computation resources and offering a more robust, globally optimal solution. Experiments on CT human body scans demonstrate FBA as an effective system for automatic human body alignment where other alignment methods break down.

Lemaire J-J, Golby A, Wells III WM, Pujol S, Tie Y, Rigolo L, Yarmarkovich A, Pieper S, Westin C-F, Jolesz FA, et al. Extended Broca's Area in the Functional Connectome of Language in Adults: Combined Cortical and Subcortical Single-subject Analysis using fMRI and DTI Tractography. Brain Topogr. 2013;26 (3) :428-41.Abstract

Traditional models of the human language circuitry encompass three cortical areas, Broca's, Geschwind's and Wernicke's, and their connectivity through white matter fascicles. The neural connectivity deep to these cortical areas remains poorly understood, as does the macroscopic functional organization of the cortico-subcortical language circuitry. In an effort to expand current knowledge, we combined functional MRI (fMRI) and diffusion tensor imaging to explore subject-specific structural and functional macroscopic connectivity, focusing on Broca's area. Fascicles were studied using diffusion tensor imaging fiber tracking seeded from volumes placed manually within the white matter. White matter fascicles and fMRI-derived clusters (antonym-generation task) of positive and negative blood-oxygen-level-dependent (BOLD) signal were co-registered with 3-D renderings of the brain in 12 healthy subjects. Fascicles connecting BOLD-derived clusters were analyzed within specific cortical areas: Broca's, with the pars triangularis, the pars opercularis, and the pars orbitaris; Geschwind's and Wernicke's; the premotor cortex, the dorsal supplementary motor area, the middle temporal gyrus, the dorsal prefrontal cortex and the frontopolar region. We found a functional connectome divisible into three systems-anterior, superior and inferior-around the insula, more complex than previously thought, particularly with respect to a new extended Broca's area. The extended Broca's area involves two new fascicles: the operculo-premotor fascicle comprised of well-organized U-shaped fibers that connect the pars opercularis with the premotor region; and (2) the triangulo-orbitaris system comprised of intermingled U-shaped fibers that connect the pars triangularis with the pars orbitaris. The findings enhance our understanding of language function.

Janoos F, Brown G, Mórocz IA, Wells III WM. State-space Analysis of Working Memory in Schizophrenia: An fBIRN Study. Psychometrika. 2013;78 (2) :279-307.Abstract

The neural correlates of working memory (WM) in schizophrenia (SZ) have been extensively studied using the multisite fMRI data acquired by the Functional Biomedical Informatics Research Network (fBIRN) consortium. Although univariate and multivariate analysis methods have been variously employed to localize brain responses under differing task conditions, important hypotheses regarding the representation of mental processes in the spatio-temporal patterns of neural recruitment and the differential organization of these mental processes in patients versus controls have not been addressed in this context. This paper uses a multivariate state-space model (SSM) to analyze the differential representation and organization of mental processes of controls and patients performing the Sternberg Item Recognition Paradigm (SIRP) WM task. The SSM is able to not only predict the mental state of the subject from the data, but also yield estimates of the spatial distribution and temporal ordering of neural activity, along with estimates of the hemodynamic response. The dynamical Bayesian modeling approach used in this study was able to find significant differences between the predictability and organization of the working memory processes of SZ patients versus healthy subjects. Prediction of some stimulus types from imaging data in the SZ group was significantly lower than controls, reflecting a greater level of disorganization/heterogeneity of their mental processes. Moreover, the changes in accuracy of predicting the mental state of the subject with respect to parametric modulations, such as memory load and task duration, may have important implications on the neurocognitive models for WM processes in both SZ and healthy adults. Additionally, the SSM was used to compare the spatio-temporal patterns of mental activity across subjects, in a holistic fashion and to derive a low-dimensional representation space for the SIRP task, in which subjects were found to cluster according to their diagnosis.

Toews M, Wells III WM. Source Code for the Paper Titled: Efficient and Robust Model-to-Image Alignment using 3D Scale-Invariant Features. 2012.Abstract
This paper presents feature-based alignment (FBA), a general method for efficient and robust model-to-image alignment. Volumetric images, e.g. CT scans of the human body, are modeled probabilistically as a collage of 3D scale-invariant image features within a normalized reference space. Features are incorporated as a latent random variable and marginalized out in computing a maximum a-posteriori alignment solution. The model is learned from features extracted in pre-aligned training images, then fit to features extracted from a new image to identify a globally optimal locally linear alignment solution. Novel techniques are presented for determining local feature orientation and efficiently encoding feature intensity in 3D. Experiments involving difficult magnetic resonance (MR) images of the human brain demonstrate FBA achieves alignment accuracy similar to widely-used registration methods, while requiring a fraction of the memory and computation resources and offering a more robust, globally optimal solution. Experiments on CT human body scans demonstrate FBA as an effective system for automatic human body alignment where other alignment methods break down.
Toews featExtract1.4
Janoos F, Lee W, Subrahmanya N, Mórocz IA, Wells III WM. Identification of Recurrent Patterns in the Activation of Brain Networks. Adv. In Neural Info. Proc. Sys (NIPS). 2012 :1-9.Abstract
Identifying patterns from the neuroimaging recordings of brain activity related to the unobservable psychological or mental state of an individual can be treated as a unsupervised pattern recognition problem. The main challenges, however, for such an analysis of fMRI data are: a) defining a physiologically meaningful feature-space for representing the spatial patterns across time; b) dealing with the high-dimensionality of the data; and c) robustness to the various artifacts and confounds in the fMRI time-series. In this paper, we present a network-aware feature-space to represent the states of a general network, that enables comparing and clustering such states in a manner that is a) meaningful in terms of the network connectivity structure; b)computationally efficient; c) low-dimensional; and d) relatively robust to structured and random noise artifacts. This feature-space is obtained from a spherical relaxation of the transportation distance metric which measures the cost of trans- porting “mass” over the network to transform one function into another. Through theoretical and empirical assessments, we demonstrate the accuracy and efficiency of the approximation, especially for large problems.
Janoos NIPS 2012