Publications

2017
Shaffer JJ, Ghayoor A, Long JD, Kim RE-Y, Lourens S, O'Donnell LJ, Westin C-F, Rathi Y, Magnotta V, Paulsen JS, et al. Longitudinal Diffusion Changes in Prodromal and Early HD: Evidence of White-matter Tract Deterioration. Hum Brain Mapp. 2017;38 (3) :1460-77.Abstract

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. 

Ning L, Setsompop K, Westin C-F, Rathi Y. New Insights about Time-varying Diffusivity and its Estimation from Diffusion MRI. Magn Reson Med. 2017;78 (2) :763-74.Abstract

PURPOSE: Characterizing the relation between the applied gradient sequences and the measured diffusion MRI signal is important for estimating the time-dependent diffusivity, which provides important information about the microscopic tissue structure. THEORY AND METHODS: In this article, we extend the classical theory of Stepišnik for measuring time-dependent diffusivity under the Gaussian phase approximation. In particular, we derive three novel expressions which represent the diffusion MRI signal in terms of the mean-squared displacement, the instantaneous diffusivity, and the velocity autocorrelation function. We present the explicit signal expressions for the case of single diffusion encoding and oscillating gradient spin-echo sequences. Additionally, we also propose three different models to represent time-varying diffusivity and test them using Monte-Carlo simulations and in vivo human brain data. RESULTS: The time-varying diffusivities are able to distinguish the synthetic structures in the Monte-Carlo simulations. There is also strong statistical evidence about time-varying diffusivity from the in vivo human data set. CONCLUSION: The proposed theory provides new insights into our understanding of the time-varying diffusivity using different gradient sequences. The proposed models for representing time-varying diffusivity can be utilized to study time-varying diffusivity using in vivo human brain diffusion MRI data. 

Ning L, Özarslan E, Westin C-F, Rathi Y. Precise Inference and Characterization of Structural Organization (PICASO) of Tissue from Molecular Diffusion. Neuroimage. 2017;146 :452-73.Abstract

Inferring the microstructure of complex media from the diffusive motion of molecules is a challenging problem in diffusion physics. In this paper, we introduce a novel representation of diffusion MRI (dMRI) signal from tissue with spatially-varying diffusivity using a diffusion disturbance function. This disturbance function contains information about the (intra-voxel) spatial fluctuations in diffusivity due to restrictions, hindrances and tissue heterogeneity of the underlying tissue substrate. We derive the short- and long-range disturbance coefficients from this disturbance function to characterize the tissue structure and organization. Moreover, we provide an exact relation between the disturbance coefficients and the time-varying moments of the diffusion propagator, as well as their relation to specific tissue microstructural information such as the intra-axonal volume fraction and the apparent axon radius. The proposed approach is quite general and can model dMRI signal for any type of gradient sequence (rectangular, oscillating, etc.) without using the Gaussian phase approximation. The relevance of the proposed PICASO model is explored using Monte-Carlo simulations and in-vivo dMRI data. The results show that the estimated disturbance coefficients can distinguish different types of microstructural organization of axons.

Pujol S, Cabeen R, Sébille SB, Yelnik J, François C, Fernandez Vidal S, Karachi C, Zhao Y, Cosgrove RG, Jannin P, et al. In vivo Exploration of the Connectivity between the Subthalamic Nucleus and the Globus Pallidus in the Human Brain using Multi-Fiber Tractography. Front Neuroanat. 2017;10 :119.Abstract

The basal ganglia is part of a complex system of neuronal circuits that play a key role in the integration and execution of motor, cognitive and emotional function in the human brain. Parkinson's disease is a progressive neurological disorder of the motor circuit characterized by tremor, rigidity, and slowness of movement. Deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus pars interna provides an efficient treatment to reduce symptoms and levodopa-induced side effects in Parkinson's disease patients. While the underlying mechanism of action of DBS is still unknown, the potential modulation of white matter tracts connecting the surgical targets has become an active area of research. With the introduction of advanced diffusion MRI acquisition sequences and sophisticated post-processing techniques, the architecture of the human brain white matter can be explored in vivo. The goal of this study is to investigate the white matter connectivity between the subthalamic nucleus and the globus pallidus. Two multi-fiber tractography methods were used to reconstruct pallido-subthalamic, subthalamo-pallidal and pyramidal fibers in five healthy subjects datasets of the Human Connectome Project. The anatomical accuracy of the tracts was assessed by four judges with expertise in neuroanatomy, functional neurosurgery, and diffusion MRI. The variability among subjects was evaluated based on the fractional anisotropy and mean diffusivity of the tracts. Both multi-fiber approaches enabled the detection of complex fiber architecture in the basal ganglia. The qualitative evaluation by experts showed that the identified tracts were in agreement with the expected anatomy. Tract-derived measurements demonstrated relatively low variability among subjects. False-negative tracts demonstrated the current limitations of both methods for clinical decision-making. Multi-fiber tractography methods combined with state-of-the-art diffusion MRI data have the potential to help identify white matter tracts connecting DBS targets in functional neurosurgery intervention.

Sastry R, Bi WL, Pieper S, Frisken S, Kapur T, Wells III WM, Golby AJ. Applications of Ultrasound in the Resection of Brain Tumors. J Neuroimaging. 2017;27 (1) :5-15.Abstract

Neurosurgery makes use of preoperative imaging to visualize pathology, inform surgical planning, and evaluate the safety of selected approaches. The utility of preoperative imaging for neuronavigation, however, is diminished by the well-characterized phenomenon of brain shift, in which the brain deforms intraoperatively as a result of craniotomy, swelling, gravity, tumor resection, cerebrospinal fluid (CSF) drainage, and many other factors. As such, there is a need for updated intraoperative information that accurately reflects intraoperative conditions. Since 1982, intraoperative ultrasound has allowed neurosurgeons to craft and update operative plans without ionizing radiation exposure or major workflow interruption. Continued evolution of ultrasound technology since its introduction has resulted in superior imaging quality, smaller probes, and more seamless integration with neuronavigation systems. Furthermore, the introduction of related imaging modalities, such as 3-dimensional ultrasound, contrast-enhanced ultrasound, high-frequency ultrasound, and ultrasound elastography, has dramatically expanded the options available to the neurosurgeon intraoperatively. In the context of these advances, we review the current state, potential, and challenges of intraoperative ultrasound for brain tumor resection. We begin by evaluating these ultrasound technologies and their relative advantages and disadvantages. We then review three specific applications of these ultrasound technologies to brain tumor resection: (1) intraoperative navigation, (2) assessment of extent of resection, and (3) brain shift monitoring and compensation. We conclude by identifying opportunities for future directions in the development of ultrasound technologies.

2016
Peters TM, Linte CA. Image-guided Interventions and Computer-integrated Therapy: Quo Vadis?. Med Image Anal. 2016;33 :56-63.Abstract
Significant efforts have been dedicated to minimizing invasiveness associated with surgical interventions, most of which have been possible thanks to the developments in medical imaging, surgical navigation, visualization and display technologies. Image-guided interventions have promised to dramatically change the way therapies are delivered to many organs. However, in spite of the development of many sophisticated technologies over the past two decades, other than some isolated examples of successful implementations, minimally invasive therapy is far from enjoying the wide acceptance once envisioned. This paper provides a large-scale overview of the state-of-the-art developments, identifies several barriers thought to have hampered the wider adoption of image-guided navigation, and suggests areas of research that may potentially advance the field.
Binder P, Batmanghelich KN, Estepar RSJ, Golland P. Unsupervised Discovery of Emphysema Subtypes in a Large Clinical Cohort. Int Conf Med Image Comput Comput Assist Interv. Workshop on Machine Learning in Medical Imaging. 2016;19 (WS) :180-7.
Fan Z, Peter S, Cai W, Song Y, Verma R, Carl-Fredrik W, O'Donnell LJ. Fiber Clustering Based White Matter Connectivity Analysis for Prediction of Autism Spectrum Disorder using Diffusion Tensor Imaging. IEEE Int Symp Biomed Imaging. 2016.Abstract
Autism Spectrum Disorder (ASD) has been suggested to associate with alterations in brain connectivity. In this study, we focus on a fiber clustering tractography segmentation strategy to observe white matter connectivity alterations in ASD. Compared to another popular parcellation-based approach for tractography segmentation based on cortical regions, we hypothesized that the clustering-based method could provide a more anatomically correspondent division of white matter. We applied this strategy to conduct a population-based group statistical analysis for the automated prediction of ASD. We obtained a maximum classification accuracy of 81.33% be- tween ASDs and controls, compared to the results of 78.00% from the parcellation-based method.
 
Zhang ISBI 2016
Bartling S, Jakab M, Kikinis R. CT-based Atlas of the Ear. Surgical Planning Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; 2016. Publisher's VersionAbstract
The Surgical Planning Laboratory at Brigham and Women's Hospital, Harvard Medical School, developed the SPL Ear Atlas. The atlas was derived from a high-resolution flat-panel computed tomography (CT) scan (aprox 140 µm high contrast resultion), using semi-automated image segmentation and three-dimensional reconstruction techniques [Gupta, Bartling, et al. AJNR Am J Neuroradiol. 2004.]. The current version consists of: 1. the original CT scan; 2. a set of detailed label maps; 3. a set of three-dimensional models of the labeled anatomical structures; 4. mrb (Medical Reality Bundle) file archive that contains the mrml scene file and all data for loading into Slicer 4 for displaying the volumes in 3D Slicer version 4.0 or greater; 5. several pre-defined 3D-views (“anatomy teaching files”). The SPL Ear Atlas provides important reference information for surgical planning, anatomy teaching, and template driven segmentation. Visualization of the data requires 3D Slicer. This software package can be downloaded from here. We are pleased to make this atlas available to our colleagues for free download. Please note that the data is being distributed under the Slicer license. By downloading these data, you agree to acknowledge our contribution in any of your publications that result form the use of this atlas. This work is funded as part of the Neuroimaging Analysis Center, grant number P41 RR013218, by the NIH's National Center for Research Resources (NCRR) and grant number P41 EB015902, by the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Google Faculty Research Award.
Kapur T, Tempany CM. Proceedings of the 8th Image Guided Therapy Workshop. 2016;8 :1-68. 2016 IGT Workshop Proceedings
Langs G, Wang D, Golland P, Mueller S, Pan R, Sabuncu MR, Sun W, Li K, Liu H. Identifying Shared Brain Networks in Individuals by Decoupling Functional and Anatomical Variability. Cereb Cortex. 2016;26 (10) :4004-14.Abstract
The connectivity architecture of the human brain varies across individuals. Mapping functional anatomy at the individual level is challenging, but critical for basic neuroscience research and clinical intervention. Using resting-state functional connectivity, we parcellated functional systems in an "embedding space" based on functional characteristics common across the population, while simultaneously accounting for individual variability in the cortical distribution of functional units. The functional connectivity patterns observed in resting-state data were mapped in the embedding space and the maps were aligned across individuals. A clustering algorithm was performed on the aligned embedding maps and the resulting clusters were transformed back to the unique anatomical space of each individual. This novel approach identified functional systems that were reproducible within subjects, but were distributed across different anatomical locations in different subjects. Using this approach for intersubject alignment improved the predictability of individual differences in language laterality when compared with anatomical alignment alone. Our results further revealed that the strength of association between function and macroanatomy varied across the cortex, which was strong in unimodal sensorimotor networks, but weak in association networks.
Zhang M, Wells WM, Golland P. Low-Dimensional Statistics of Anatomical Variability via Compact Representation of Image Deformations. Med Image Comput Comput Assist Interv. 2016;9902 :166-73.Abstract
Using image-based descriptors to investigate clinical hypotheses and therapeutic implications is challenging due to the notorious "curse of dimensionality" coupled with a small sample size. In this paper, we present a low-dimensional analysis of anatomical shape variability in the space of diffeomorphisms and demonstrate its benefits for clinical studies. To combat the high dimensionality of the deformation descriptors, we develop a probabilistic model of principal geodesic analysis in a bandlimited low-dimensional space that still captures the underlying variability of image data. We demonstrate the performance of our model on a set of 3D brain MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our model yields a more compact representation of group variation at substantially lower computational cost than models based on the high-dimensional state-of-the-art approaches such as tangent space PCA (TPCA) and probabilistic principal geodesic analysis (PPGA).
Dalca AV, Bobu A, Rost NS, Golland P. Patch-Based Discrete Registration of Clinical Brain Images. Patch Based Tech Med Imaging. 2016;9993 :60-67.Abstract
We introduce a method for registration of brain images acquired in clinical settings. The algorithm relies on three-dimensional patches in a discrete registration framework to estimate correspondences. Clinical images present significant challenges for computational analysis. Fast acquisition often results in images with sparse slices, severe artifacts, and variable fields of view. Yet, large clinical datasets hold a wealth of clinically relevant information. Despite significant progress in image registration, most algorithms make strong assumptions about the continuity of image data, failing when presented with clinical images that violate these assumptions. In this paper, we demonstrate a non-rigid registration method for aligning such images. The method explicitly models the sparsely available image information to achieve robust registration. We demonstrate the algorithm on clinical images of stroke patients. The proposed method outperforms state of the art registration algorithms and avoids catastrophic failures often caused by these images. We provide a freely available open source implementation of the algorithm.
Wang C, Ji F, Hong Z, Poh JS, Krishnan R, Lee J, Rekhi G, Keefe RSE, Adcock RA, Wood SJ, et al. Disrupted Salience Network Functional Connectivity and White-Matter Microstructure in Persons at Risk For Psychosis: Findings from the LYRIKS Study. Psychol Med. 2016;46 (13) :2771-83.Abstract

BACKGROUND: Salience network (SN) dysconnectivity has been hypothesized to contribute to schizophrenia. Nevertheless, little is known about the functional and structural dysconnectivity of SN in subjects at risk for psychosis. We hypothesized that SN functional and structural connectivity would be disrupted in subjects with At-Risk Mental State (ARMS) and would be associated with symptom severity and disease progression. METHOD: We examined 87 ARMS and 37 healthy participants using both resting-state functional magnetic resonance imaging and diffusion tensor imaging. Group differences in SN functional and structural connectivity were examined using a seed-based approach and tract-based spatial statistics. Subject-level functional connectivity measures and diffusion indices of disrupted regions were correlated with CAARMS scores and compared between ARMS with and without transition to psychosis. RESULTS: ARMS subjects exhibited reduced functional connectivity between the left ventral anterior insula and other SN regions. Reduced fractional anisotropy (FA) and axial diffusivity were also found along white-matter tracts in close proximity to regions of disrupted functional connectivity, including frontal-striatal-thalamic circuits and the cingulum. FA measures extracted from these disrupted white-matter regions correlated with individual symptom severity in the ARMS group. Furthermore, functional connectivity between the bilateral insula and FA at the forceps minor were further reduced in subjects who transitioned to psychosis after 2 years. CONCLUSIONS: Our findings support the insular dysconnectivity of the proximal SN hypothesis in the early stages of psychosis. Further developed, the combined structural and functional SN assays may inform the prognosis of persons at-risk for psychosis.

Gao Y, Ratner V, Zhu L, Diprima T, Kurc T, Tannenbaum A, Saltz J. Hierarchical Nucleus Segmentation in Digital Pathology Images. Proc SPIE Int Soc Opt Eng. 2016;9791.Abstract

Extracting nuclei is one of the most actively studied topic in the digital pathology researches. Most of the studies directly search the nuclei (or seeds for the nuclei) from the finest resolution available. While the richest information has been utilized by such approaches, it is sometimes difficult to address the heterogeneity of nuclei in different tissues. In this work, we propose a hierarchical approach which starts from the lower resolution level and adaptively adjusts the parameters while progressing into finer and finer resolution. The algorithm is tested on brain and lung cancers images from The Cancer Genome Atlas data set.

Gao Y, Liu W, Arjun S, Zhu L, Ratner V, Kurc T, Saltz J, Tannenbaum A. Multi-scale Learning Based Segmentation of Glands in Digital Colonrectal Pathology Images. Proc SPIE Int Soc Opt Eng. 2016;9791.Abstract

Digital histopathological images provide detailed spatial information of the tissue at micrometer resolution. Among the available contents in the pathology images, meso-scale information, such as the gland morphology, texture, and distribution, are useful diagnostic features. In this work, focusing on the colon-rectal cancer tissue samples, we propose a multi-scale learning based segmentation scheme for the glands in the colon-rectal digital pathology slides. The algorithm learns the gland and non-gland textures from a set of training images in various scales through a sparse dictionary representation. After the learning step, the dictionaries are used collectively to perform the classification and segmentation for the new image.

Sandhu RS, Georgiou TT, Tannenbaum AR. Ricci Curvature: An Economic Indicator for Market Fragility and Systemic Risk. Sci Adv. 2016;2 (5) :e1501495.Abstract

Quantifying the systemic risk and fragility of financial systems is of vital importance in analyzing market efficiency, deciding on portfolio allocation, and containing financial contagions. At a high level, financial systems may be represented as weighted graphs that characterize the complex web of interacting agents and information flow (for example, debt, stock returns, and shareholder ownership). Such a representation often turns out to provide keen insights. We show that fragility is a system-level characteristic of "business-as-usual" market behavior and that financial crashes are invariably preceded by system-level changes in robustness. This was done by leveraging previous work, which suggests that Ricci curvature, a key geometric feature of a given network, is negatively correlated to increases in network fragility. To illustrate this insight, we examine daily returns from a set of stocks comprising the Standard and Poor's 500 (S&P 500) over a 15-year span to highlight the fact that corresponding changes in Ricci curvature constitute a financial "crash hallmark." This work lays the foundation of understanding how to design (banking) systems and policy regulations in a manner that can combat financial instabilities exposed during the 2007-2008 crisis.

Mirzaalian H, Ning L, Savadjiev P, Pasternak O, Bouix S, Michailovich O, Grant G, Marx CE, Morey RA, Flashman LA, et al. Inter-site and Inter-scanner Diffusion MRI Data Harmonization. Neuroimage. 2016;135 :311-23.Abstract

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.

Chen Y, Oh JH, Sandhu R, Lee S, Deasy JO, Tannenbaum A. Transcriptional Responses to Ultraviolet and Ionizing Radiation: An Approach Based on Graph Curvature. Proceedings (IEEE Int Conf Bioinformatics Biomed). 2016;2016 :1302-6.Abstract

More than half of all cancer patients receive radiotherapy in their treatment process. However, our understanding of abnormal transcriptional responses to radiation remains poor. In this study, we employ an extended definition of Ollivier-Ricci curvature based on LI-Wasserstein distance to investigate genes and biological processes associated with ionizing radiation (IR) and ultraviolet radiation (UV) exposure using a microarray dataset. Gene expression levels were modeled on a gene interaction topology downloaded from the Human Protein Reference Database (HPRD). This was performed for IR, UV, and mock datasets, separately. The difference curvature value between IR and mock graphs (also between UV and mock) for each gene was used as a metric to estimate the extent to which the gene responds to radiation. We found that in comparison of the top 200 genes identified from IR and UV graphs, about 20~30% genes were overlapping. Through gene ontology enrichment analysis, we found that the metabolic-related biological process was highly associated with both IR and UV radiation exposure.

Binder P, Batmanghelich NK, Estepar RSJ, Golland P. Unsupervised Discovery of Emphysema Subtypes in a Large Clinical Cohort. Mach Learn Med Imaging. 2016;10019 :180-7.Abstract

Emphysema is one of the hallmarks of Chronic Obstructive Pulmonary Disorder (COPD), a devastating lung disease often caused by smoking. Emphysema appears on Computed Tomography (CT) scans as a variety of textures that correlate with disease subtypes. It has been shown that the disease subtypes and textures are linked to physiological indicators and prognosis, although neither is well characterized clinically. Most previous computational approaches to modeling emphysema imaging data have focused on supervised classification of lung textures in patches of CT scans. In this work, we describe a generative model that jointly captures heterogeneity of disease subtypes and of the patient population. We also describe a corresponding inference algorithm that simultaneously discovers disease subtypes and population structure in an unsupervised manner. This approach enables us to create image-based descriptors of emphysema beyond those that can be identified through manual labeling of currently defined phenotypes. By applying the resulting algorithm to a large data set, we identify groups of patients and disease subtypes that correlate with distinct physiological indicators.

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