User interaction has the potential to greatly facilitate the exploration and understanding of 3D medical images for diagnosis and treatment. However, in certain specialized environments such as in an operating room (OR), technical and physical constraints such as the need to enforce strict sterility rules, make interaction challenging. In this paper, we propose to facilitate the intraoperative exploration of angiographic volumes by leveraging the motion of a tracked surgical pointer, a tool that is already manipulated by the surgeon when using a navigation system in the OR. We designed and implemented three interactive rendering techniques based on this principle. The benefit of each of these techniques is compared to its non-interactive counterpart in a psychophysics experiment where 20 medical imaging experts were asked to perform a reaching/targeting task while visualizing a 3D volume of angiographic data. The study showed a significant improvement of the appreciation of local vascular structure when using dynamic techniques, while not having a negative impact on the appreciation of the global structure and only a marginal impact on the execution speed. A qualitative evaluation of the different techniques showed a preference for dynamic chroma-depth in accordance with the objective metrics but a discrepancy between objective and subjective measures for dynamic aerial perspective and shading.

Quantification of cerebral white matter hyperintensities (WMH) of presumed vascular origin is of key importance in many neurological research studies. Currently, measurements are often still obtained from manual segmentations on brain MR images, which is a laborious procedure. The automatic WMH segmentation methods exist, but a standardized comparison of the performance of such methods is lacking. We organized a scientific challenge, in which developers could evaluate their methods on a standardized multi-center/-scanner image dataset, giving an objective comparison: the WMH Segmentation Challenge. Sixty T1 + FLAIR images from three MR scanners were released with the manual WMH segmentations for training. A test set of 110 images from five MR scanners was used for evaluation. The segmentation methods had to be containerized and submitted to the challenge organizers. Five evaluation metrics were used to rank the methods: 1) Dice similarity coefficient; 2) modified Hausdorff distance (95th percentile); 3) absolute log-transformed volume difference; 4) sensitivity for detecting individual lesions; and 5) F1-score for individual lesions. In addition, the methods were ranked on their inter-scanner robustness; 20 participants submitted their methods for evaluation. This paper provides a detailed analysis of the results. In brief, there is a cluster of four methods that rank significantly better than the other methods, with one clear winner. The inter-scanner robustness ranking shows that not all the methods generalize to unseen scanners. The challenge remains open for future submissions and provides a public platform for method evaluation.

Segmentation and volumetric quantification of white matter hyperintensities (WMHs) is essential in assessment and monitoring of the vascular burden in aging and Alzheimer's disease (AD), especially when considering their effect on cognition. Manually segmenting WMHs in large cohorts is technically unfeasible due to time and accuracy concerns. Automated tools that can detect WMHs robustly and with high accuracy are needed. Here, we present and validate a fully automatic technique for segmentation and volumetric quantification of WMHs in aging and AD. The proposed technique combines intensity and location features frommultiplemagnetic resonance imaging contrasts and manually labeled training data with a linear classifier to perform fast and robust segmentations. It provides both a continuous subject specific WMH map reflecting different levels of tissue damage and binary segmentations. Themethodwas used to detectWMHs in 80 elderly/AD brains (ADC data set) as well as 40 healthy subjects at risk of AD (PREVENT-AD data set). Robustness across different scanners was validated using ten subjects from ADNI2/GO study. Voxel-wise and volumetric agreements were evaluated using Dice similarity index (SI) and intra-class correlation (ICC), yielding ICC=0.96 , SI = 0.62±0.16 for ADC data set and ICC=0.78 , SI=0.51±0.15 for PREVENT-AD data set. The proposed method was robust in the independent sample yielding SI=0.64±0.17 with ICC=0.93 for ADNI2/GO subjects. The proposed method provides fast, accurate, and robust segmentations on previously unseen data from different models of scanners, making it ideal to study WMHs in large scale multi-site studies.

Susceptibility-weighted imaging (SWI) venography can produce detailed venous contrast and complement arterial dominated MR angiography (MRA) techniques. However, these dense reversed-contrast SWI venograms pose new segmentation challenges. We present an automatic method for whole-brain venous blood segmentation in SWI using Conditional Random Fields (CRF). The CRF model combines different first and second order potentials. First-order association potentials are modeled as the composite of an appearance potential, a Hessian-based shape potential and a non-linear location potential. Second-order interaction potentials are modeled using an auto-logistic (smoothing) potential and a data-dependent (edge) potential. Minimal post-processing is used for excluding voxels outside the brain parenchyma and visualizing the surface vessels. The CRF model is trained and validated using 30 SWI venograms acquired within a population of deep brain stimulation (DBS) patients (age range [Formula: see text] years). Results demonstrate robust and consistent segmentation in deep and sub-cortical regions (median kappa = 0.84 and 0.82), as well as in challenging mid-sagittal and surface regions (median kappa = 0.81 and 0.83) regions. Overall, this CRF model produces high-quality segmentation of SWI venous vasculature that finds applications in DBS for minimizing hemorrhagic risks and other surgical and non-surgical applications.

We propose a conditional random field (CRF) based classifier for segmentation of small enhanced pathologies. Specifically, we develop a temporal hierarchical adaptive texture CRF (THAT-CRF) and apply it to the challenging problem of gad enhancing lesion segmentation in brain MRI of patients with multiple sclerosis. In this context, the presence of many nonlesion enhancements (such as blood vessels) renders the problem more difficult. In addition to voxel-wise features, the framework exploits multiple higher order textures to discriminate the true lesional enhancements from the pool of other enhancements. Since lesional enhancements show more variation over time as compared to the nonlesional ones, we incorporate temporal texture analysis in order to study the textures of enhanced candidates over time. The parameters of the THAT-CRF model are learned based on 2380 scans from a multi-center clinical trial. The effect of different components of the model is extensively evaluated on 120 scans from a separate multi-center clinical trial. The incorporation of the temporal textures results in a general decrease of the false discovery rate. Specifically, THAT-CRF achieves overall sensitivity of 95% along with false discovery rate of 20% and average false positive count of 0.5 lesions per scan. The sensitivity of the temporal method to the trained time interval is further investigated on five different intervals of 69 patients. Moreover, superior performance is achieved by the reviewed labelings of our model compared to the fully manual labeling when applied to the context of separating different treatment arms in a real clinical trial.

In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.

In this work, we present a novel algorithm for registration of 3-D volumetric ultrasound (US) and MR using Robust PaTch-based cOrrelation Ratio (RaPTOR). RaPTOR computes local correlation ratio (CR) values on small patches and adds the CR values to form a global cost function. It is therefore invariant to large amounts of spatial intensity inhomogeneity. We also propose a novel outlier suppression technique based on the orientations of the RaPTOR gradients. Our deformation is modeled with free-form cubic B-splines. We analytically derive the derivatives of RaPTOR with respect to the transformation, i.e., the displacement of the B-spline nodes, and optimize RaPTOR using a stochastic gradient descent approach. RaPTOR is validated on MR and tracked US images of neurosurgery. Deformable registration of the US and MR images acquired, respectively, preoperation and postresection is of significant clinical significance, but challenging due to, among others, the large amount of missing correspondences between the two images. This work is also novel in that it performs automatic registration of this challenging dataset. To validate the results, we manually locate corresponding anatomical landmarks in the US and MR images of tumor resection in brain surgery. Compared to rigid registration based on the tracking system alone, RaPTOR reduces the mean initial mTRE over 13 patients from 5.9 to 2.9 mm, and the maximum initial TRE from 17.0 to 5.9 mm. Each volumetric registration using RaPTOR takes about 30 sec on a single CPU core. An important challenge in the field of medical image analysis is the shortage of publicly available dataset, which can both facilitate the advancement of new algorithms to clinical settings and provide a benchmark for comparison. To address this problem, we will make our manually located landmarks available online.

Mutual information (MI) quantifies the information that is shared between two random variables and has been widely used as a similarity metric for multi-modal and uni-modal image registration. A drawback of MI is that it only takes into account the intensity values of corresponding pixels and not of neighborhoods. Therefore, it treats images as "bag of words" and the contextual information is lost. In this work, we present Contextual Conditioned Mutual Information (CoCoMI), which conditions MI estimation on similar structures. Our rationale is that it is more likely for similar structures to undergo similar intensity transformations. The contextual analysis is performed on one of the images offline. Therefore, CoCoMI does not significantly change the registration time. We use CoCoMI as the similarity measure in a regularized cost function with a B-spline deformation field and efficiently optimize the cost function using a stochastic gradient descent method. We show that compared to the state of the art local MI based similarity metrics, CoCoMI does not distort images to enforce erroneous identical intensity transformations for different image structures. We further present the results on nonrigid registration of ultrasound (US) and magnetic resonance (MR) patient data from image-guided neurosurgery trials performed in our institute and publicly available in the BITE dataset. We show that CoCoMI performs significantly better than the state of the art similarity metrics in US to MR registration. It reduces the average mTRE over 13 patients from 4.12 mm to 2.35 mm, and the maximum mTRE from 9.38 mm to 3.22 mm.

Cerebral vascular images obtained through angiography are used by neurosurgeons for diagnosis, surgical planning, and intraoperative guidance. The intricate branching of the vessels and furcations, however, make the task of understanding the spatial three-dimensional layout of these images challenging. In this paper, we present empirical studies on the effect of different perceptual cues (fog, pseudo-chromadepth, kinetic depth, and depicting edges) both individually and in combination on the depth perception of cerebral vascular volumes and compare these to the cue of stereopsis. Two experiments with novices and one experiment with experts were performed. The results with novices showed that the pseudo-chromadepth and fog cues were stronger cues than that of stereopsis. Furthermore, the addition of the stereopsis cue to the other cues did not improve relative depth perception in cerebral vascular volumes. In contrast to novices, the experts also performed well with the edge cue. In terms of both novice and expert subjects, pseudo-chromadepth and fog allow for the best relative depth perception. By using such cues to improve depth perception of cerebral vasculature, we may improve diagnosis, surgical planning, and intraoperative guidance.

Detection of new Multiple Sclerosis (MS) lesions on magnetic resonance imaging (MRI) is important as a marker of disease activity and as a potential surrogate for relapses. We propose an approach where sequential scans are jointly segmented, to provide a temporally consistent tissue segmentation while remaining sensitive to newly appearing lesions. The method uses a two-stage classification process: 1) a Bayesian classifier provides a probabilistic brain tissue classification at each voxel of reference and follow-up scans, and 2) a random-forest based lesion-level classification provides a final identification of new lesions. Generative models are learned based on 364 scans from 95 subjects from a multi-center clinical trial. The method is evaluated on sequential brain MRI of 160 subjects from a separate multi-center clinical trial, and is compared to 1) semi-automatically generated ground truth segmentations and 2) fully manual identification of new lesions generated independently by nine expert raters on a subset of 60 subjects. For new lesions greater than 0.15 cc in size, the classifier has near perfect performance (99% sensitivity, 2% false detection rate), as compared to ground truth. The proposed method was also shown to exceed the performance of any one of the nine expert manual identifications.

Gadolinium-enhancing lesions in brain magnetic resonance imaging of multiple sclerosis (MS) patients are of great interest since they are markers of disease activity. Identification of gadolinium-enhancing lesions is particularly challenging because the vast majority of enhancing voxels are associated with normal structures, particularly blood vessels. Furthermore, these lesions are typically small and in close proximity to vessels. In this paper, we present an automatic, probabilistic framework for segmentation of gadolinium-enhancing lesions in MS using conditional random fields. Our approach, through the integration of different components, encodes different information such as correspondence between the intensities and tissue labels, patterns in the labels, or patterns in the intensities. The proposed algorithm is evaluated on 80 multimodal clinical datasets acquired from relapsing-remitting MS patients in the context of multicenter clinical trials. The experimental results exhibit a sensitivity of 98% with a low false positive lesion count. The performance of the proposed algorithm is also compared to a logistic regression classifier, a support vector machine and a Markov random field approach. The results demonstrate superior performance of the proposed algorithm at successfully detecting all of the gadolinium-enhancing lesions while maintaining a low false positive lesion count.

In this paper, we propose a new multi-scale technique for multi-modal image registration based on the alignment of selected gradient orientations of reduced uncertainty. We show how the registration robustness and accuracy can be improved by restricting the evaluation of gradient orientation alignment to locations where the uncertainty of fixed image gradient orientations is minimal, which we formally demonstrate correspond to locations of high gradient magnitude. We also embed a computationally efficient technique for estimating the gradient orientations of the transformed moving image (rather than resampling pixel intensities and recomputing image gradients). We have applied our method to different rigid multi-modal registration contexts. Our approach outperforms mutual information and other competing metrics in the context of rigid multi-modal brain registration, where we show sub-millimeter accuracy with cases obtained from the retrospective image registration evaluation project. Furthermore, our approach shows significant improvements over standard methods in the highly challenging clinical context of image guided neurosurgery, where we demonstrate misregistration of less than 2 mm with relation to expert selected landmarks for the registration of pre-operative brain magnetic resonance images to intra-operative ultrasound images.

Mixed reality visualizations are increasingly studied for use in image guided surgery (IGS) systems, yet few mixed reality systems have been introduced for daily use into the operating room (OR). This may be the result of several factors: the systems are developed from a technical perspective, are rarely evaluated in the field, and/or lack consideration of the end user and the constraints of the OR. We introduce the Data, Visualization processing, View (DVV) taxonomy which defines each of the major components required to implement a mixed reality IGS system. We propose that these components be considered and used as validation criteria for introducing a mixed reality IGS system into the OR. A taxonomy of IGS visualization systems is a step toward developing a common language that will help developers and end users discuss and understand the constituents of a mixed reality visualization system, facilitating a greater presence of future systems in the OR. We evaluate the DVV taxonomy based on its goodness of fit and completeness. We demonstrate the utility of the DVV taxonomy by classifying 17 state-of-the-art research papers in the domain of mixed reality visualization IGS systems. Our classification shows that few IGS visualization systems' components have been validated and even fewer are evaluated.

We present a new automatic method for segmentation of multiple sclerosis (MS) lesions in magnetic resonance images. The method performs tissue classification using a model of intensities of the normal appearing brain tissues. In order to estimate the model, a trimmed likelihood estimator is initialized with a hierarchical random approach in order to be robust to MS lesions and other outliers present in real images. The algorithm is first evaluated with simulated images to assess the importance of the robust estimator in presence of outliers. The method is then validated using clinical data in which MS lesions were delineated manually by several experts. Our method obtains an average Dice similarity coefficient (DSC) of 0.65, which is close to the average DSC obtained by raters (0.66).

EMPIRE10 (Evaluation of Methods for Pulmonary Image REgistration 2010) is a public platform for fair and meaningful comparison of registration algorithms which are applied to a database of intrapatient thoracic CT image pairs. Evaluation of nonrigid registration techniques is a nontrivial task. This is compounded by the fact that researchers typically test only on their own data, which varies widely. For this reason, reliable assessment and comparison of different registration algorithms has been virtually impossible in the past. In this work we present the results of the launch phase of EMPIRE10, which comprised the comprehensive evaluation and comparison of 20 individual algorithms from leading academic and industrial research groups. All algorithms are applied to the same set of 30 thoracic CT pairs. Algorithm settings and parameters are chosen by researchers expert in the configuration of their own method and the evaluation is independent, using the same criteria for all participants. All results are published on the EMPIRE10 website (http://empire10.isi.uu.nl). The challenge remains ongoing and open to new participants. Full results from 24 algorithms have been published at the time of writing. This paper details the organization of the challenge, the data and evaluation methods and the outcome of the initial launch with 20 algorithms. The gain in knowledge and future work are discussed.

This paper presents feature-based morphometry (FBM), a new, fully data-driven technique for identifying group-related differences in volumetric imagery. In contrast to most morphometry methods which assume one-to-one correspondence between all subjects, FBM models images as a collage of distinct, localized image features which may not be present in all subjects. FBM thus explicitly accounts for the case where the same anatomical tissue cannot be reliably identified in all subjects due to disease or anatomical variability. A probabilistic model describes features in terms of their appearance, geometry, and relationship to subgroups of a population, and is automatically learned from a set of subject images and group labels. Features identified indicate group-related anatomical structure that can potentially be used as disease biomarkers or as a basis for computer-aided diagnosis. Scale-invariant image features are used, which reflect generic, salient patterns in the image. Experiments validate FBM clinically in the analysis of normal (NC) and Alzheimer's (AD) brain images using the freely available OASIS database. FBM automatically identifies known structural differences between NC and AD subjects in a fully data-driven fashion, and obtains an equal error classification rate of 0.78 on new subjects.

Automated computer classification (ACC) techniques are needed to facilitate physician's diagnosis of complex diseases in individual patients. We provide an example of ACC using computational techniques within the context of cross-sectional analysis of magnetic resonance images (MRI) in neurodegenerative diseases, namely Alzheimer's dementia (AD). In this paper, the accuracy of our ACC methodology is assessed when presented with real life, imperfect data, i.e., cohorts of MRI with varying acquisition parameters and imaging quality. The comparative methodology uses the Jacobian determinants derived from dense deformation fields and scaled grey-level intensity from a selected volume of interest centered on the medial temporal lobe. The ACC performance is assessed in a series of leave-one-out experiments aimed at separating 75 probable AD and 75 age-matched normal controls. The resulting accuracy is 92% using a support vector machine classifier based on least squares optimization. Finally, it is shown in the Appendix that determinants and scaled grey-level intensity are appreciably more robust to varying parameters in validation studies using simulated data, when compared to raw intensities or grey/white matter volumes. The ability of cross-sectional MRI at detecting probable AD with high accuracy could have profound implications in the management of suspected AD candidates.

This paper describes the construction of simulated SPECT and MRI databases that account for realistic anatomical and functional variability. The data is used as a gold-standard to evaluate four SPECT/MRI similarity-based registration methods. Simulation realism was accounted for using accurate physical models of data generation and acquisition. MRI and SPECT simulations were generated from three subjects to take into account inter-subject anatomical variability. Functional SPECT data were computed from six functional models of brain perfusion. Previous models of normal perfusion and ictal perfusion observed in Mesial Temporal Lobe Epilepsy (MTLE) were considered to generate functional variability. We studied the impact noise and intensity non-uniformity in MRI simulations and SPECT scatter correction may have on registration accuracy. We quantified the amount of registration error caused by anatomical and functional variability. Registration involving ictal data was less accurate than registration involving normal data. MR intensity nonuniformity was the main factor decreasing registration accuracy. The proposed simulated database is promising to evaluate many functional neuroimaging methods, involving MRI and SPECT data.

Simulations provide a way of generating data where ground truth is known, enabling quantitative testing of image processing methods. In this paper, we present the construction of 20 realistic digital brain phantoms that can be used to simulate medical imaging data. The phantoms are made from 20 normal adults to take into account intersubject anatomical variabilities. Each digital brain phantom was created by registering and averaging four T1, T2, and proton density (PD)-weighted magnetic resonance imaging (MRI) scans from each subject. A fuzzy minimum distance classification was used to classify voxel intensities from T1, T2, and PD average volumes into grey-matter, white matter, cerebro-spinal fluid, and fat. Automatically generated mask volumes were required to separate brain from nonbrain structures and ten fuzzy tissue volumes were created: grey matter, white matter, cerebro-spinal fluid, skull, marrow within the bone, dura, fat, tissue around the fat, muscles, and skin/muscles. A fuzzy vessel class was also obtained from the segmentation of the magnetic resonance angiography scan of the subject. These eleven fuzzy volumes that describe the spatial distribution of anatomical tissues define the digital phantom, where voxel intensity is proportional to the fraction of tissue within the voxel. These fuzzy volumes can be used to drive simulators for different modalities including MRI, PET, or SPECT. These phantoms were used to construct 20 simulated T1-weighted MR scans. To evaluate the realism of these simulations, we propose two approaches to compare them to real data acquired with the same acquisition parameters. The first approach consists of comparing the intensities within the segmented classes in both real and simulated data. In the second approach, a whole brain voxel-wise comparison between simulations and real T1-weighted data is performed. The first comparison underlines that segmented classes appear to properly represent the anatomy on average, and that inside these classes, the simulated and real intensity values are quite similar. The second comparison enables the study of the regional variations with no a priori class. The experiments demonstrate that these variations are small when real data are corrected for intensity nonuniformity.

Most of the approaches dedicated to automatic morphometry rely on a point-by-point strategy based on warping each brain toward a reference coordinate system. In this paper, we describe an alternative object-based strategy dedicated to the cortex. This strategy relies on an artificial neuroanatomist performing automatic recognition of the main cortical sulci and parcellation of the cortical surface into gyral patches. A set of shape descriptors, which can be compared across subjects, is then attached to the sulcus and gyrus related objects segmented by this process. The framework is used to perform a study of 142 brains of the International Consortium for Brain Mapping (ICBM) database. This study reveals some correlates of handedness on the size of the sulci located in motor areas, which was not detected previously using standard voxel based morphometry.

Although numerous methods to register brains of different individuals have been proposed, no work has been done, as far as we know, to evaluate and objectively compare the performances of different nonrigid (or elastic) registration methods on the same database of subjects. In this paper, we propose an evaluation framework, based on global and local measures of the relevance of the registration. We have chosen to focus more particularly on the matching of cortical areas, since intersubject registration methods are dedicated to anatomical and functional normalization, and also because other groups have shown the relevance of such registration methods for deep brain structures. Experiments were conducted using 6 methods on a database of 18 subjects. The global measures used show that the quality of the registration is directly related to the transformation's degrees of freedom. More surprisingly, local measures based on the matching of cortical sulci did not show significant differences between rigid and non rigid methods.

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype- phenotype-behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders.

Systematic mapping of the variability in cortical sulcal anatomy is an area of increasing interest which presents numerous methodological challenges. To address these issues, we have implemented sulcal extraction and assisted labeling (SEAL) to automatically extract the two-dimensional (2-D) surface ribbons that represent the median axis of cerebral sulci and to neuroanatomically label these entities. To encode the extracted three-dimensional (3-D) cortical sulcal schematic topography (CSST) we define a relational graph structure composed of two main features: vertices (representing sulci) and arcs (representing the relationships between sulci). Vertices contain a parametric representation of the surface ribbon buried within the sulcus. Points on this surface are expressed in stereotaxic coordinates (i.e., with respect to a standardized brain coordinate system). For each of these vertices, we store length, depth, and orientation as well as anatomical attributes (e.g., hemisphere, lobe, sulcus type, etc.). Each arc stores the 3-D location of the junction between sulci as well as a list of its connecting sulci. Sulcal labeling is performed semiautomatically by selecting a sulcal entity in the CSST and selecting from a menu of candidate sulcus names. In order to help the user in the labeling task, the menu is restricted to the most likely candidates by using priors for the expected sulcal spatial distribution. These priors, i.e., sulcal probabilistic maps, were created from the spatial distribution of 34 sulci traced manually on 36 different subjects. Given these spatial probability maps, the user is provided with the likelihood that the selected entity belongs to a particular sulcus. The cortical structure representation obtained by SEAL is suitable to extract statistical information about both the spatial and the structural composition of the cerebral cortical topography. This methodology allows for the iterative construction of a successively more complete statistical models of the cerebral topography containing spatial distributions of the most important structures, their morphometrics, and their structural components.

After conception and implementation of any new medical image processing algorithm, validation is an important step to ensure that the procedure fulfills all requirements set forth at the initial design stage. Although the algorithm must be evaluated on real data, a comprehensive validation requires the additional use of simulated data since it is impossible to establish ground truth with in vivo data. Experiments with simulated data permit controlled evaluation over a wide range of conditions (e.g., different levels of noise, contrast, intensity artefacts, or geometric distortion). Such considerations have become increasingly important with the rapid growth of neuroimaging, i.e., computational analysis of brain structure and function using brain scanning methods such as positron emission tomography and magnetic resonance imaging. Since simple objects such as ellipsoids or parallelepipedes do not reflect the complexity of natural brain anatomy, we present the design and creation of a realistic, high-resolution, digital, volumetric phantom of the human brain. This three-dimensional digital brain phantom is made up of ten volumetric data sets that define the spatial distribution for different tissues (e.g., grey matter, white matter, muscle, skin, etc.), where voxel intensity is proportional to the fraction of tissue within the voxel. The digital brain phantom can be used to simulate tomographic images of the head. Since the contribution of each tissue type to each voxel in the brain phantom is known, it can be used as the gold standard to test analysis algorithms such as classification procedures which seek to identify the tissue "type" of each image voxel. Furthermore, since the same anatomical phantom may be used to drive simulators for different modalities, it is the ideal tool to test intermodality registration algorithms. The brain phantom and simulated MR images have been made publicly available on the Internet (http://www.bic.mni.mcgill.ca/brainweb).

Many critical functionally distinct subcortical structures are not distinguishable on anatomical magnetic resonance imaging (MRI) scans. In order to provide the neurosurgeon with this missing information, a deformable volumetric atlas of the basal ganglia and thalamus has been created from the Schaltenbrand and Wahren atlas of cryogenic slices. The volumetric atlas can be automatically deformed to an individual patient's MRI. To facilitate the clinical use of the atlas, a visualization platform has been developed for preoperative and intraoperative use which permits manipulation of the merged atlas and MRI data sets in two- and three-dimensional views. The platform includes graphical tools which allow the visualization of projections of a leukotome and other surgical tools with respect to the atlas data, as well as preregistered images from any other imaging modality. In addition, a graphical interface has been designed to create custom virtual lesions using computer models of neurosurgical tools for intraoperative planning. To date this system has been employed as an adjunct to over 30 functional neurosurgical cases including surgery for movement disorders.

Magnetic resonance imaging (MRI) has become the modality of choice for neuro-anatomical imaging. Quantitative analysis requires the accurate and reproducible labeling of all voxels in any given structure within the brain. Since manual labeling is prohibitively time-consuming and error-prone we have designed an automated procedure called ANIMAL (Automatic Nonlinear Image Matching and Anatomical Labeling) to objectively segment gross anatomical structures from 3D MRIs of normal brains. The procedure is based on nonlinear registration with a previously labeled target brain, followed by numerical inverse transformation of the labels to the native MRI space. Besides segmentation, ANIMAL has been applied to non-rigid registration and to the analysis of morphometric variability. In this paper, the nonlinear registration approach is validated on five test volumes, produced with simulated deformations. Experiments show that the ANIMAL recovers 64% of the nonlinear residual variability remaining after linear registration. Segmentations of the same test data are presented as well. The paper concludes with two applications of ANIMAL using real data. In the first, one MRI volume is nonlinearly matched to a second and is automatically segmented using labels, predefined on the second MRI volume. The automatic segmentation compares well with manual labeling of the same structures. In the second application, ANIMAL is applied to seventeen MRI data sets, and a 3D map of anatomical variability estimates is produced. The automatic variability estimates correlate well (r =0.867, p = 0.01) with manual estimates of inter-subject variability.

Human investigators instinctively segment medical images into their anatomical components, drawing upon prior knowledge of anatomy to overcome image artifacts, noise, and lack of tissue contrast. The authors describe: 1) the development and use of a brain tissue probability model for the segmentation of multiple sclerosis (MS) lesions in magnetic resonance (MR) brain images, and 2) an empirical comparison of the performance of statistical and decision tree classifiers, applied to MS lesion segmentation. Based on MR image data obtained from healthy volunteers, the model provides prior probabilities of brain tissue distribution per unit voxel in a standardized 3-D "brain space". In comparison to purely data-driven segmentation, the use of the model to guide the segmentation of MS lesions reduced the volume of false positive lesions by 50-80%