Person:

Wells, William

To address the statistical challenges associated with genome-wide association studies, we present an independent component analysis (ICA) with reference approach to target a specific genetic variation and associated brain networks. First, a small set of single nucleotide polymorphisms (SNPs) are empirically chosen to reflect a feature of interest and these SNPs are used as a reference when applying ICA to a full genomic SNP array. After extracting the genetic component maximally representing the characteristics of the reference, we test its association with brain networks in functional magnetic resonance imaging (fMRI) data. The method was evaluated on both real and simulated datasets. Simulation demonstrates that ICA with reference can extract a specific genetic factor, even when the variance accounted for by such a factor is so small that a regular ICA fails. Our real data application from 48 schizophrenia patients (SZs) and 40 healthy controls (HCs) include 300K SNPs and fMRI images in an auditory oddball task. Using SNPs with allelic frequency difference in two groups as a reference, we extracted a genetic component that maximally differentiates patients from controls ((p < 4 × 10^{−17})), and discovered a brain functional network that was significantly associated with this genetic component ((p < 1 × 10^{−4})). The regions in the functional network mainly locate in the thalamus, anterior and posterior cingulate gyri. The contributing SNPs in the genetic factor mainly fall into two clusters centered at chromosome 7q21 and chromosome 5q35. The findings from the schizophrenia application are in concordance with previous knowledge about brain regions and gene function. All together, the results suggest that the ICA with reference can be particularly useful to explore the whole genome to find a specific factor of interest and further study its effect on brain.

The vervet monkey is an important nonhuman primate model that allows the study of isolated environmental factors in a controlled environment. Analysis of monkey MRI often suffers from lower quality images compared with human MRI because clinical equipment is typically used to image the smaller monkey brain and higher spatial resolution is required. This, together with the anatomical differences of the monkey brains, complicates the use of neuroimage analysis pipelines tuned for human MRI analysis. In this paper we developed an open source image analysis framework based on the tools available within the 3D Slicer software to support a biological study that investigates the effect of chronic ethanol exposure on brain morphometry in a longitudinally followed population of male vervets. We first developed a computerized atlas of vervet monkey brain MRI, which was used to encode the typical appearance of the individual brain structures in MRI and their spatial distribution. The atlas was then used as a spatial prior during automatic segmentation to process two longitudinal scans per subject. Our evaluation confirms the consistency and reliability of the automatic segmentation. The comparison of atlas construction strategies reveals that the use of a population-specific atlas leads to improved accuracy of the segmentation for subcortical brain structures. The contribution of this work is twofold. First, we describe an image processing workflow specifically tuned towards the analysis of vervet MRI that consists solely of the open source software tools. Second, we develop a digital atlas of vervet monkey brain MRIs to enable similar studies that rely on the vervet model.

We introduce an algorithm for segmenting brain magnetic resonance (MR) images into anatomical compartments such as the major tissue classes and neuro-anatomical structures of the gray matter. The algorithm is guided by prior information represented within a tree structure. The tree mirrors the hierarchy of anatomical structures and the sub-trees correspond to limited segmentation problems. The solution to each problem is estimated via a conventional classifier. Our algorithm can be adapted to a wide range of segmentation problems by modifying the tree structure or replacing the classifier. We evaluate the performance of our new segmentation approach by revisiting a previously published statistical group comparison between first-episode schizophrenia patients, first-episode affective psychosis patients, and comparison subjects. The original study is based on 50 MR volumes in which an expert identified the brain tissue classes as well as the superior temporal gyrus, amygdala, and hippocampus. We generate analogous segmentations using our new method and repeat the statistical group comparison. The results of our analysis are similar to the original findings, except for one structure (the left superior temporal gyrus) in which a trend-level statistical significance (p=0.07) was observed instead of statistical significance.

We present a statistical framework that combines the registration of an atlas with the segmentation of magnetic resonance images. We use an Expectation Maximization-based algorithm to find a solution within the model, which simultaneously estimates image inhomogeneities, anatomical labelmap, and a mapping from the atlas to the image space. An example of the approach is given for a brain structure-dependent affine mapping approach. The algorithm produces high quality segmentations for brain tissues as well as their substructures. We demonstrate the approach on a set of 22 magnetic resonance images. In addition, we show that the approach performs better than similar methods which separate the registration and segmentation problems.

BACKGROUND: Change detection is a critical component in the diagnosis and monitoring of many slowly evolving pathologies. OBJECTIVE: This article describes a semiautomatic monitoring approach using longitudinal medical images. We test the method on brain scans of patients with meningioma, which experts have found difficult to monitor because the tumor evolution is very slow and may be obscured by artifacts related to image acquisition. METHODS: We describe a semiautomatic procedure targeted toward identifying difficult-to-detect changes in brain tumor imaging. The tool combines input from a medical expert with state-of-the-art technology. The software is easy to calibrate and, in less than 5 minutes, returns the total volume of tumor change in mm. We test the method on postgadolinium, T1-weighted magnetic resonance images of 10 patients with meningioma and compare our results with experts' findings. We also perform benchmark testing with synthetic data. RESULTS: Our experiments indicated that experts' visual inspections are not sensitive enough to detect subtle growth. Measurements based on experts' manual segmentations were highly accurate but also labor intensive. The accuracy of our approach was comparable to the experts' results. However, our approach required far less user input and generated more consistent measurements. CONCLUSION: The sensitivity of experts' visual inspection is often too low to detect subtle growth of meningiomas from longitudinal scans. Measurements based on experts' segmentation are highly accurate but generally too labor intensive for standard clinical settings. We described an alternative metric that provides accurate and robust measurements of subtle tumor changes while requiring a minimal amount of user input.

Image registration is the process of transforming images acquired at different time points, or with different imaging modalities, into the same coordinate system. It is an essential part of any neurosurgical planning and navigation system because it facilitates combining images with important complementary, structural, and functional information to improve the information based on which a surgeon makes critical decisions. Brigham and Women's Hospital (BWH) has been one of the pioneers in developing intraoperative registration methods for aligning preoperative and intraoperative images of the brain. This article presents an overview of intraoperative registration and highlights some recent developments at BWH.

The overall goal of this research is the design of statistical atlas models that can be created from normal subjects, but may generalize to be applicable to abnormal brains. We present a new style of joint modeling of fMRI, DTI, and structural MRI. Motivated by the fact that a white matter tract and related cortical areas are likely to displace together in the presence of a mass lesion (brain tumor), in this work we propose a rotation and translation invariant model that represents the spatial relationship between fiber tracts and anatomic and functional landmarks. This landmark distance model provides a new basis for representation of fiber tracts and can be used for detection and prediction of fiber tracts based on landmarks. Our results indicate that the measured model is consistent across normal subjects, and thus suitable for atlas building. Our experiments demonstrate that the model is robust to displacement and missing data, and can be successfully applied to a small group of patients with mass lesions.

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.

We present what we believe to be the first investigation into unbiased multi-subject registration of whole brain diffusion tractography of the white matter. To our knowledge, this is also the first entropy-based objective function applied to fiber tract registration. To define the probability of fiber trajectories for the computation of entropy, we take advantage of a pairwise fiber distance used as the basis for a Gaussian-like kernel. By employing several values of the kernel’s scale parameter, the method is inherently multi-scale. Results of experiments using synthetic and real datasets demonstrate the potential of the method for simultaneous joint registration of tractography.

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.