The advancement of the computational biology field hinges on progress in three fundamental directions--the development of new computational algorithms, the availability of informatics resource management infrastructures and the capability of tools to interoperate and synergize. There is an explosion in algorithms and tools for computational biology, which makes it difficult for biologists to find, compare and integrate such resources. We describe a new infrastructure, iTools, for managing the query, traversal and comparison of diverse computational biology resources. Specifically, iTools stores information about three types of resources--data, software tools and web-services. The iTools design, implementation and resource meta-data content reflect the broad research, computational, applied and scientific expertise available at the seven National Centers for Biomedical Computing. iTools provides a system for classification, categorization and integration of different computational biology resources across space-and-time scales, biomedical problems, computational infrastructures and mathematical foundations. A large number of resources are already iTools-accessible to the community and this infrastructure is rapidly growing. iTools includes human and machine interfaces to its resource meta-data repository. Investigators or computer programs may utilize these interfaces to search, compare, expand, revise and mine meta-data descriptions of existent computational biology resources. We propose two ways to browse and display the iTools dynamic collection of resources. The first one is based on an ontology of computational biology resources, and the second one is derived from hyperbolic projections of manifolds or complex structures onto planar discs. iTools is an open source project both in terms of the source code development as well as its meta-data content. iTools employs a decentralized, portable, scalable and lightweight framework for long-term resource management. We demonstrate several applications of iTools as a framework for integrated bioinformatics. iTools and the complete details about its specifications, usage and interfaces are available at the iTools web page http://iTools.ccb.ucla.edu.
Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.
BACKGROUND: We have acquired dual-echo spin-echo (DE SE) MRI data of the rhesus monkey brain since 1994 as part of an ongoing study of normal aging. To analyze these legacy data for regional volume changes, we have created a reference label atlas for the Template Driven Segmentation (TDS) algorithm.
METHODS: The atlas was manually created from DE SE legacy MRI data of one behaviorally normal, young, male rhesus monkey and consisted of 14 regions of interest (ROI's). We analyzed the reproducibility and validity of the TDS algorithm using the atlas relative to manual segmentation.
RESULTS: ROI volumes were comparable between the two segmentation methodologies, except TDS overestimated the volume of basal ganglia regions. Both methodologies were highly reproducible, but TDS had lower sensitivity and comparable specificity.
CONCLUSIONS: TDS segmentation calculates accurate volumes for most ROI's. Sensitivity will be improved in future studies through the acquisition of higher quality data.
In non-rigid registration, the tradeoff between warp regularization and image fidelity is typically determined empirically. In atlas-based segmentation, this leads to a probabilistic atlas of arbitrary sharpness: weak regularization results in well-aligned training images and a sharp atlas; strong regularization yields a "blurry" atlas. In this paper, we employ a generative model for the joint registration and segmentation of images. The atlas construction process arises naturally as estimation of the model parameters. This framework allows the computation of unbiased atlases from manually labeled data at various degrees of "sharpness", as well as the joint registration and segmentation of a novel brain in a consistent manner. We study the effects of the tradeoff of atlas sharpness and warp smoothness in the context of cortical surface parcellation. This is an important question because of the increasingly availability of atlases in public databases, and the development of registration algorithms separate from the atlas construction process. We find that the optimal segmentation (parcellation) corresponds to a unique balance of atlas sharpness and warp regularization, yielding statistically significant improvements over the FreeSurfer parcellation algorithm. Furthermore, we conclude that one can simply use a single atlas computed at an optimal sharpness for the registration-segmentation of a new subject with a pre-determined, fixed, optimal warp constraint. The optimal atlas sharpness and warp smoothness can be determined by probing the segmentation performance on available training data. Our experiments also suggest that segmentation accuracy is tolerant up to a small mismatch between atlas sharpness and warp smoothness.
BACKGROUND: We developed an image-guided robot system to provide mechanical assistance for skull base drilling, which is performed to gain access for some neurosurgical interventions, such as tumour resection. The motivation for introducing this robot was to improve safety by preventing the surgeon from accidentally damaging critical neurovascular structures during the drilling procedure.
METHODS: We integrated a Stealthstation navigation system, a NeuroMate robotic arm with a six-degree-of-freedom force sensor, and the 3D Slicer visualization software to allow the robotic arm to be used in a navigated, cooperatively-controlled fashion by the surgeon. We employed virtual fixtures to constrain the motion of the robot-held cutting tool, so that it remained in the safe zone that was defined on a preoperative CT scan.
RESULTS: We performed experiments on both foam skull and cadaver heads. The results for foam blocks cut using different registrations yielded an average placement error of 0.6 mm and an average dimensional error of 0.6 mm. We drilled the posterior porus acusticus in three cadaver heads and concluded that the robot-assisted procedure is clinically feasible and provides some ergonomic benefits, such as stabilizing the drill. We obtained postoperative CT scans of the cadaver heads to assess the accuracy and found that some bone outside the virtual fixture boundary was cut. The typical overcut was 1-2 mm, with a maximum overcut of about 3 mm.
CONCLUSIONS: The image-guided cooperatively-controlled robot system can improve the safety and ergonomics of skull base drilling by stabilizing the drill and enforcing virtual fixtures to protect critical neurovascular structures. The next step is to improve the accuracy so that the overcut can be reduced to a more clinically acceptable value of about 1 mm.
In this work, we describe a white matter trajectory clustering algorithm that allows for incorporating and appropriately weighting anatomical information. The influence of the anatomical prior reflects confidence in its accuracy and relevance. It can either be defined by the user or it can be inferred automatically. After a detailed description of our novel clustering framework, we demonstrate its properties through a set of preliminary experiments.
In this work, we explore the use of classification algorithms in predicting mental states from functional neuroimaging data. We train a linear support vector machine classifier to characterize spatial fMRI activation patterns. We employ a general linear model based feature extraction method and use the t-test for feature selection. We evaluate our method on a memory encoding task, using participants' subjective prediction about learning as a benchmark for our classifier. We show that the classifier achieves better than random predictions and the average accuracy is close to subject's own prediction performance. In addition, we validate our tool on a simple motor task where we demonstrate an average prediction accuracy of over 90%. Our experiments demonstrate that the classifier performance depends significantly on the complexity of the experimental design and the mental process of interest.
We explore unsupervised, hypothesis-free methods for fMRI analysis in two different types of experiments. First, we employ clustering to identify large-scale functionally homogeneous systems. We formulate a generative mixture model, derive the EM algorithm and apply it to delineate functional systems. We also investigate spectral clustering in application to this problem and demonstrate that both methods give rise to similar partitions of the brain based on resting state fMRI data. Second, we demonstrate how to extend this approach to include information about the experimental protocol. Specifically, we formulate a mixture model in the space of possible profiles of brain response to stimuli. In both applications, our methods confirm previously known results in brain mapping and point to new research directions for exploratory analysis of fMRI data.
We present iCluster, a fast and efficient algorithm that clusters a set of images while co-registering them using a parameterized, nonlinear transformation model. The output is a small number of template images that represent different modes in a population. This is in contrast with traditional approaches that assume a single template to construct atlases. We validate and explore the algorithm in two experiments. First, we employ iCluster to partition a data set of 416 whole brain MR volumes of subjects aged 18-96 years into three sub-groups, which mainly correspond to age groups. The templates reveal significant structural differences across these age groups that confirm previous findings in aging research. In the second experiment, we run iCluster on a group of 30 patients with dementia and 30 age-matched healthy controls. The algorithm produced three modes that mainly corresponded to a sub-population of healthy controls, a sub-population of patients with dementia and a mixture group that contained both types. These results suggest that the algorithm can be used to discover sub-populations that correspond to interesting structural or functional "modes".
We present a method for discovering patterns of activation observed through fMIRI in experiments with multiple stimuli/tasks. We introduce an explicit parameterization for the profiles of activation and represent fMRI time courses as such profiles using linear regression estimates. Working in the space of activation profiles, we design a mixture model that finds the major activation patterns along with their localization maps and derive an algorithm for fitting the model to the fMRI data. The method enables functional group analysis independent of spatial correspondence among subjects. We validate this model in the context of category selectivity in the visual cortex, demonstrating good agreement with prior findings based on hypothesis-driven methods.
We propose a novel l1l2-norm inverse solver for estimating the sources of EEG/MEG signals. Based on the standard l1-norm inverse solver, the proposed sparse distributed inverse solver integrates the l1-norm spatial model with a temporal model of the source signals in order to avoid unstable activation patterns and "spiky" reconstructed signals often produced by the original solvers. The joint spatio-temporal model leads to a cost function with an l1l2-norm regularizer whose minimization can be reduced to a convex second-order cone programming problem and efficiently solved using the interior-point method. Validation with simulated and real MEG data shows that the proposed solver yields source time course estimates qualitatively similar to those obtained through dipole fitting, but without the need to specify the number of dipole sources in advance. Furthermore, the l1l2-norm solver achieves fewer false positives and a better representation of the source locations than the conventional l2 minimum-norm estimates.
We describe a method for correcting the distortions present in echo planar images (EPI) and registering the EPI to structural MRI. A fieldmap is predicted from an air / tissue segmentation of the MRI using a perturbation method and subsequently used to unwarp the EPI data. Shim and other missing parameters are estimated by registration. We obtain results that are similar to those obtained using fieldmaps, however neither fieldmaps, nor knowledge of shim coefficients is required.
Several recent studies explored the use of unsupervised segmentation methods for segmenting thalamic nuclei from diffusion tensor images. These methods provide a plausible segmentation on individual subjects; however, they do not address the problem of consistently identifying the same functional areas in a population. The lack of correspondence between the segmented nuclei make it more difficult to use the results from the unsupervised segmentation tools for morphometry. In this paper we present a novel segmentation algorithm to automatically segment the gray matter nuclei while ensuring consistency between subjects in a population. This new algorithm, referred to as Consistency Clustering, finds correspondence between the nuclei as the segmentation is achieved through a single model for the whole population, similar to the brain atlases experts use to identify thalamic nuclei.
In this paper, we propose a natural framework that allows any region-based segmentation energy to be re-formulated in a local way. We consider local rather than global image statistics and evolve a contour based on local information. Localized contours are capable of segmenting objects with heterogeneous feature profiles that would be difficult to capture correctly using a standard global method. The presented technique is versatile enough to be used with any global region-based active contour energy and instill in it the benefits of localization. We describe this framework and demonstrate the localization of three well-known energies in order to illustrate how our framework can be applied to any energy. We then compare each localized energy to its global counterpart to show the improvements that can be achieved. Next, an in-depth study of the behaviors of these energies in response to the degree of localization is given. Finally, we show results on challenging images to illustrate the robust and accurate segmentations that are possible with this new class of active contour models.
Recent developments in MR data acquisition technology are starting to yield images that show anatomical features of the hippocampal formation at an unprecedented level of detail, providing the basis for hippocampal subfield measurement. Because of the role of the hippocampus in human memory and its implication in a variety of disorders and conditions, the ability to reliably and efficiently quantify its subfields through in vivo neuroimaging is of great interest to both basic neuroscience and clinical research. In this paper, we propose a fully-automated method for segmenting the hippocampal subfields in ultra-high resolution MRI data. Using a Bayesian approach, we build a computational model of how images around the hippocampal area are generated, and use this model to obtain automated segmentations. We validate the proposed technique by comparing our segmentation results with corresponding manual delineations in ultra-high resolution MRI scans of five individuals.
BACKGROUND: A reduction in interhemispheric connectivity is thought to contribute to the etiology of schizophrenia. Diffusion Tensor Imaging (DTI) measures the diffusion of water and can be used to describe the integrity of the corpus callosum white matter tracts, thereby providing information concerning possible interhemispheric connectivity abnormalities. Previous DTI studies in schizophrenia are inconsistent in reporting decreased Fractional Anisotropy (FA), a measure of anisotropic diffusion, within different portions of the corpus callosum. Moreover, none of these studies has investigated corpus callosum systematically, using anatomical subdivisions. METHODS: DTI and structural MRI scans were obtained from 32 chronic schizophrenic subjects and 42 controls. Corpus callosum cross sectional area and its probabilistic subdivisions were determined automatically from structural MRI scans using a model based deformable contour segmentation. These subdivisions employ a previously generated probabilistic subdivision atlas, based on fiber tractography and anatomical lobe subdivision. The structural scan was then co-registered with the DTI scan and the anatomical corpus callosum subdivisions were propagated to the associated FA map. RESULTS: Results revealed decreased FA within parts of the corpus interconnecting frontal regions in schizophrenia compared with controls, but no significant changes for callosal fibers interconnecting parietal and temporo-occipital brain regions. In addition, integrity of the anterior corpus was statistically significantly correlated with negative as well as positive symptoms, while posterior measures correlated with positive symptoms only. CONCLUSIONS: This study provides quantitative evidence for a reduction of interhemispheric brain connectivity in schizophrenia, involving corpus callosum, and further points to frontal connections as possibly disrupted in schizophrenia.
In this paper, we explore the use of over-complete spherical wavelets in shape analysis of closed 2D surfaces. Previous work has demonstrated, theoretically and practically, the advantages of overcomplete over bi-orthogonal spherical wavelets. Here we present a detailed formulation of over-complete wavelets, as well as shape analysis experiments of cortical folding development using them. Our experiments verify in a quantitative fashion existing qualitative theories of neuroanatomical development. Furthermore, the experiments reveal novel insights into neuro-anatomical development not previously documented.
We present the fast Spherical Demons algorithm for registering two spherical images. By exploiting spherical vector spline interpolation theory, we show that a large class of regularizers for the modified demons objective function can be efficiently implemented on the sphere using convolution. Based on the one parameter subgroups of diffeomorphisms, the resulting registration is diffeomorphic and fast - registration of two cortical mesh models with more than 100k nodes takes less than 5 minutes, comparable to the fastest surface registration algorithms. Moreover, the accuracy of our method compares favorably to the popular FreeSurfer registration algorithm. We validate the technique in two different settings: (1) parcellation in a set of in-vivo cortical surfaces and (2) Brodmann area localization in ex-vivo cortical surfaces.
We introduce a versatile framework for characterizing and extracting salient structures in three-dimensional symmetric second-order tensor fields. The key insight is that degenerate lines in tensor fields, as defined by the standard topological approach, are exactly crease (ridge and valley) lines of a particular tensor invariant called mode. This reformulation allows us to apply well-studied approaches from scientific visualization or computer vision to the extraction of topological lines in tensor fields. More generally, this main result suggests that other tensor invariants, such as anisotropy measures like fractional anisotropy (FA), can be used in the same framework in lieu of mode to identify important structural properties in tensor fields. Our implementation addresses the specific challenge posed by the non-linearity of the considered scalar measures and by the smoothness requirement of the crease manifold computation. We use a combination of smooth reconstruction kernels and adaptive refinement strategy that automatically adjust the resolution of the analysis to the spatial variation of the considered quantities. Together, these improvements allow for the robust application of existing ridge line extraction algorithms in the tensor context of our problem. Results are proposed for a diffusion tensor MRI dataset, and for a benchmark stress tensor field used in engineering research.