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1.  Anatomical Atlas-Guided Diffuse Optical Tomography of Brain Activation 
NeuroImage  2009;49(1):561-567.
We describe a neuro imaging protocol that utilizes an anatomical atlas of the human head to guide Diffuse optical tomography of human brain activation. The protocol is demonstrated by imaging the hemodynamic response to median nerve stimulation in three healthy subjects, and comparing the images obtained using a head atlas with the images obtained using the subject-specific head anatomy. The results indicate that using the head atlas anatomy it is possible to reconstruct the location of the brain activation to the expected gyrus of the brain, in agreement with the results obtained with the subject-specific head anatomy. The benefits of this novel method derive from eliminating the need for subject-specific head anatomy and thus obviating the need for a subject-specific MRI to improve the anatomical interpretation of Diffuse optical tomography images of brain activation.
doi:10.1016/j.neuroimage.2009.07.033
PMCID: PMC2858333  PMID: 19643185
Diffuse Optical Tomography; NIRS; anatomical atlas; MRI; segmentation; registration; inverse problem; human study; somatosensory; PACS: 87.19.lf; PACS: 87.19.lh
2.  A 3-Dimensional Atlas of Human Tongue Muscles 
The human tongue is one of the most important yet least understood structures of the body. One reason for the relative lack of research on the human tongue is its complex anatomy. This is a real barrier to investigators as there are few anatomical resources in the literature that show this complex anatomy clearly. As a result, the diagnosis and treatment of tongue disorders lags behind that for other structures of the head and neck. This report intended to fill this gap by displaying the tongue’s anatomy in multiple ways. The primary material used in this study was serial axial images of the male and female human tongue from the Visible Human (VH) Project of the National Library of Medicine. In addition, thick serial coronal sections of three human tongues were rendered translucent. The VH axial images were computer reconstructed into serial coronal sections and each tongue muscle was outlined. These outlines were used to construct a 3-dimensional computer model of the tongue that allows each muscle to be seen in its in vivo anatomical position. The thick coronal sections supplement the 3-D model by showing details of the complex interweaving of tongue muscles throughout the tongue. The graphics are perhaps the clearest guide to date to aid clinical or basic science investigators in identifying each tongue muscle in any part of the human tongue.
doi:10.1002/ar.22711
PMCID: PMC3687025  PMID: 23650264
tongue; intrinsic and extrinsic tongue muscles; neuromuscular compartments; tongue movement; speech; swallowing; respiration; 3-D reconstruction
3.  Web-based access to an online atlas of anatomy: the Digital Anatomist Common Gateway Interface. 
A World Wide Web Common Gateway Interface package is described for accessing existing online interactive atlases of anatomy. The Web interface accesses the same 2-D and 3-D images of human neuroanatomy, knee anatomy and thoracic viscera that are currently accessed by a custom interactive atlas in distance learning courses. Although the Web interface is too slow to replace the existing atlas, it provides a parallel access path that has much broader potential for development of a distributed distance learning network in anatomy. By maintaining both access methods to the same information sources we continue to satisfy the fast interactivity needs for our local courses, while at the same time providing a migration path to the Web as the capabilities of Web browsers evolve.
Images
PMCID: PMC2579146  PMID: 8563336
4.  Robust Non-Local Multi-Atlas Segmentation of the Optic Nerve 
Proceedings of SPIE  2013;8669:86691L-.
Labeling or segmentation of structures of interest on medical images plays an essential role in both clinical and scientific understanding of the biological etiology, progression, and recurrence of pathological disorders. Here, we focus on the optic nerve, a structure that plays a critical role in many devastating pathological conditions – including glaucoma, ischemic neuropathy, optic neuritis and multiple-sclerosis. Ideally, existing fully automated procedures would result in accurate and robust segmentation of the optic nerve anatomy. However, current segmentation procedures often require manual intervention due to anatomical and imaging variability. Herein, we propose a framework for robust and fully-automated segmentation of the optic nerve anatomy. First, we provide a robust registration procedure that results in consistent registrations, despite highly varying data in terms of voxel resolution and image field-of-view. Additionally, we demonstrate the efficacy of a recently proposed non-local label fusion algorithm that accounts for small scale errors in registration correspondence. On a dataset consisting of 31 highly varying computed tomography (CT) images of the human brain, we demonstrate that the proposed framework consistently results in accurate segmentations. In particular, we show (1) that the proposed registration procedure results in robust registrations of the optic nerve anatomy, and (2) that the non-local statistical fusion algorithm significantly outperforms several of the state-of-the-art label fusion algorithms.
doi:10.1117/12.2007015
PMCID: PMC3903299  PMID: 24478826
Multi-Atlas Segmentation; Computed Tomography; Optic Nerve; Non-Local STAPLE
5.  Human Brain White Matter Atlas: Identification and Assignment of Common Anatomical Structures in Superficial White Matter 
NeuroImage  2008;43(3):447-457.
Structural delineation and assignment are the fundamental steps in understanding the anatomy of the human brain. The white matter has been structurally defined in the past only at its core regions (deep white matter). However, the most peripheral white matter areas, which are interleaved between the cortex and the deep white matter, have lacked clear anatomical definitions and parcellations. We used axonal fiber alignment information from diffusion tensor imaging (DTI) to delineate the peripheral white matter, and investigated its relationship with the cortex and the deep white matter. Using DTI data from 81 healthy subjects, we identified nine common, blade-like anatomical regions, which were further parcellated into 21 subregions based on the cortical anatomy. Four short association fiber tracts connecting adjacent gyri (U-fibers) were also identified reproducibly among the healthy population. We anticipate that this atlas will be useful resource for atlas-based white matter anatomical studies.
doi:10.1016/j.neuroimage.2008.07.009
PMCID: PMC2586008  PMID: 18692144
human; white matter; atlas; association fiber; magnetic resonance imaging; diffusion tensor
6.  Ethics and access to teaching materials in the medical library: the case of the Pernkopf atlas* 
Conflicts can occur between the principle of freedom of information treasured by librarians and ethical standards of scientific research involving the propriety of using data derived from immoral or dishonorable experimentation. A prime example of this conflict was brought to the attention of the medical and library communities in 1995 when articles claiming that the subjects of the illustrations in the classic anatomy atlas, Eduard Pernkopf's Topographische Anatomie des Menschen, were victims of the Nazi holocaust. While few have disputed the accuracy, artistic, or educational value of the Pernkopf atlas, some have argued that the use of such subjects violates standards of medical ethics involving inhuman and degrading treatment of subjects or disrespect of a human corpse. Efforts were made to remove the book from medical libraries. In this article, the history of the Pernkopf atlas and the controversy surrounding it are reviewed. The results of a survey of academic medical libraries concerning their treatment of the Pernkopf atlas are reported, and the ethical implications of these issues as they affect the responsibilities of librarians is discussed.
PMCID: PMC31704  PMID: 11209801
7.  Developmental Atlas of the Early First Trimester Human Embryo 
Developmental Dynamics  2010;239(6):1585-1595.
Rapid advances in medical imaging are facilitating the clinical assessment of first trimester human embryos at increasingly earlier stages. To obtain data on early human development, we used magnetic resonance (MR) imaging and episcopic fluorescence capture (EFIC) to acquire digital images of human embryos spanning the time of dynamic tissue remodeling and organogenesis (Carnegie stages 13 to 23). These imaging data sets are readily resectioned digitally in arbitrary planes, suitable for rapid high-resolution three-dimensional (3D) observation. Using these imaging datasets, a web accessible digital Human Embryo Atlas (http://apps.nhlbi.nih.gov/humanaltas) was created containing serial 2D images of human embryos in three standard histological planes – sagittal, frontal, and transverse. In addition, annotations and 3D reconstructions were generated for visualizing different anatomical structures. Overall, this Human Embryo Atlas is a unique resource that provides morphologic data of human developmental anatomy that can accelerate basic research investigations into developmental mechanisms that underlie human congenital anomalies.
doi:10.1002/dvdy.22316
PMCID: PMC3401072  PMID: 20503356
Magnetic resonance imaging; episcopic fluorescence image capture; human embryo; web atlas; development; birth defect
8.  The HUDSEN Atlas: a three-dimensional (3D) spatial framework for studying gene expression in the developing human brain 
Journal of anatomy  2010;217(4):289-299.
Summary
We are developing a three-dimensional (3D) atlas of the human embryonic brain using anatomical landmarks and gene expression data to define major subdivisions through 12 stages of development (Carnegie Stages [CS] 12-23; approx 26-56 days post conception [dpc]). Virtual 3D anatomical models are generated from intact specimens using optical projection tomography (OPT). Using MAPaint software, selected gene expression data, gathered using standard methods of in situ hybridisation and immunohistochemistry, are mapped to a representative 3D model for each chosen Carnegie stage. In these models, anatomical domains, defined on the basis of morphological landmarks and comparative knowledge of expression patterns in vertebrates, are linked to a developmental neuroanatomic ontology. Human gene expression patterns for genes with characteristic expression in different vertebrates (e.g. PAX6, GAD65 and OLIG2) are being used to confirm and/or refine the human anatomical domain boundaries. We have also developed interpolation software that digitally generates a full domain from partial data. Currently, the 3D models and a preliminary set of anatomical domains and ontology are available on the atlas pages along with gene expression data from approximately 100 genes in the HUDSEN Human Spatial Gene Expression Database (www.hudsen.org). The aim is that full 3D data will be generated from expression data used to define a more detailed set of anatomical domains linked to a more advanced anatomy ontology and all of these will be available online, contributing to the long-term goal of the atlas which is to help maximise the effective use and dissemination of data wherever it is generated.
doi:10.1111/j.1469-7580.2010.01290.x
PMCID: PMC2967454  PMID: 20979583
Human embryo; 3D atlas; Gene Expression; OPT; database
9.  Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system 
Nucleic Acids Research  2012;41(Database issue):D996-D1008.
The Allen Brain Atlas (http://www.brain-map.org) provides a unique online public resource integrating extensive gene expression data, connectivity data and neuroanatomical information with powerful search and viewing tools for the adult and developing brain in mouse, human and non-human primate. Here, we review the resources available at the Allen Brain Atlas, describing each product and data type [such as in situ hybridization (ISH) and supporting histology, microarray, RNA sequencing, reference atlases, projection mapping and magnetic resonance imaging]. In addition, standardized and unique features in the web applications are described that enable users to search and mine the various data sets. Features include both simple and sophisticated methods for gene searches, colorimetric and fluorescent ISH image viewers, graphical displays of ISH, microarray and RNA sequencing data, Brain Explorer software for 3D navigation of anatomy and gene expression, and an interactive reference atlas viewer. In addition, cross data set searches enable users to query multiple Allen Brain Atlas data sets simultaneously. All of the Allen Brain Atlas resources can be accessed through the Allen Brain Atlas data portal.
doi:10.1093/nar/gks1042
PMCID: PMC3531093  PMID: 23193282
10.  Histology Atlas of the Developing Mouse Heart with Emphasis on E11.5 to E18.5 
Toxicologic pathology  2009;37(4):395-414.
In humans, congenital heart diseases are common. Since the rapid progression of transgenic technologies, the mouse has become the major animal model of defective cardiovascular development. Moreover, genetically modified mice frequently die in utero, commonly due to abnormal cardiovascular development. A variety of publications address specific developmental stages or structures of the mouse heart, but a single reference reviewing and describing the anatomy and histology of cardiac developmental events, stage by stage, has not been available. The aim of this color atlas, which demonstrates embryonic/fetal heart development, is to provide a tool for pathologists and biomedical scientists to use for detailed histological evaluation of hematoxylin and eosin (H&E)-stained sections of the developing mouse heart with emphasis on embryonic days (E) 11.5–18.5. The selected images illustrate the main structures and developmental events at each stage and serve as reference material for the confirmation of the chronological age of the embryo/early fetus and assist in the identification of any abnormalities. An extensive review of the literature covering cardiac development pre-E11.5 is summarized in the introduction. Although the focus of this atlas is on the descriptive anatomic and histological development of the normal mouse heart from E11.5 to E18.5, potential embryonic cardiac lesions are discussed with a list of the most common transgenic pre- and perinatal heart defects. Representative images of hearts at E11.5-15.5 and E18.5 are provided in Figures 2-4, 6, 8, and 9. A complete set of labeled images (Figures E11.5-18.5) is available on the CD enclosed in this issue of Toxicologic Pathology. All digital images can be viewed online at https://niehsimages.epl-inc.com with the username “ToxPath” and the password “embryohearts.”
doi:10.1177/0192623309335060
PMCID: PMC2773446  PMID: 19359541
heart; embryo; mouse; in utero lethality
11.  Building a Human Brain Atlas Optimized for Normal Adult Anatomy 
Currently no high resolution three-dimensional (3-D) digital atlas exists that is optimized for normal human adult anatomy. We have developed the methods for defining, constructing and evaluating a “minimal deformation target” MDT brain for multi-subject studies, which produces a single reproducible target based on the common features of a group of brain images. We are building a digital brain atlas, based on a high-resolution, high contrast MR study — CH brain. In a preliminary study (N=27) MDT optimization of the CH brain resulted in a significant reduction of its individual features, including changes in the central sulcus, Sylvian fissure, ventricular system and temporal lobe regions. The atlas will be created by optimizing the CH brain to a large population (N>100) of normal subjects
PMCID: PMC2244379
12.  Adding Java and CGI Functionality to an On-Line Atlas of Anatomy for Medical Education 
The use of Java applications through applets, HTML facilities and CGI scripts provides useful interactivity to an on-line atlas of topographic anatomy via Internet, based on the Visible Human Project.
PMCID: PMC2232157
13.  The SRI24 Multi-Channel Atlas of Normal Adult Human Brain Structure 
Human brain mapping  2010;31(5):798-819.
This paper describes the SRI24 atlas, a new standard reference system of normal human brain anatomy, that was created using template-free population registration of high-resolution magnetic resonance images acquired at 3T in a group of 24 normal control subjects. The atlas comprises anatomical channels (T1, T2, and proton density weighted), diffusion-related channels (fractional anisotropy, mean diffusivity, longitudinal diffusivity, mean diffusion-weighted image), tissue channels (CSF probability, gray matter probability, white matter probability, tissue labels), and two cortical parcellation maps. The SRI24 atlas enables multi-channel atlas-to-subject image registration. It is uniquely versatile in that it is equally suited for the two fundamentally different atlas applications: label propagation and spatial normalization. Label propagation, herein demonstrated using DTI fiber tracking, is enabled by the increased sharpness of the SRI24 atlas compared with other available atlases. Spatial normalization, herein demonstrated using data from a young-old group comparison study, is enabled by its unbiased average population shape property. For both propagation and normalization, we also report the results of quantitative comparisons with seven other published atlases: Colin27, MNI152, ICBM452 (warp5 and air12), and LPBA40 (SPM5, FLIRT, AIR). Our results suggest that the SRI24 atlas, although based on 3T MR data, allows equally accurate spatial normalization of data acquired at 1.5T as the comparison atlases, all of which are based on 1.5T data. Furthermore, the SRI24 atlas is as suitable for label propagation as the comparison atlases and detailed enough to allow delineation of anatomical structures for this purpose directly in the atlas.
doi:10.1002/hbm.20906
PMCID: PMC2915788  PMID: 20017133
brain atlas; multi-spectral magnetic resonance imaging; diffusion tensor imaging; unbiased population registration; spatial normalization; label propagation
14.  A spatiotemporal atlas of MR intensity, tissue probability and shape of the fetal brain with application to segmentation 
NeuroImage  2010;53(2):460-470.
Modeling and analysis of MR images of the developing human brain is a challenge due to rapid changes in brain morphology and morphometry. We present an approach to the construction of a spatiotemporal atlas of the fetal brain with temporal models of MR intensity, tissue probability and shape changes. This spatiotemporal model is created from a set of reconstructed MR images of fetal subjects with different gestational ages. Groupwise registration of manual segmentations and voxelwise nonlinear modeling allow us to capture the appearance, disappearance and spatial variation of brain structures over time. Applying this model to atlas-based segmentation, we generate age-specific MR templates and tissue probability maps and use them to initialize automatic tissue delineation in new MR images. The choice of model parameters and the final performance are evaluated using clinical MR scans of young fetuses with gestational ages ranging from 20.57 to 24.71 weeks. Experimental results indicate that quadratic temporal models can correctly capture growth-related changes in the fetal brain anatomy and provide improvement in accuracy of atlas-based tissue segmentation.
doi:10.1016/j.neuroimage.2010.06.054
PMCID: PMC2930902  PMID: 20600970
Structural MRI; Fetal imaging; Atlas building; Tissue segmentation
15.  Atlas-based Segmentation of Developing Tissues in the Human Brain with Quantitative Validation in Young Fetuses 
Human Brain Mapping  2010;31(9):1348-1358.
Imaging of the human fetus using magnetic resonance (MR) is an essential tool for quantitative studies of normal as well as abnormal brain development in utero. However, because of fundamental differences in tissue types, tissue properties and tissue distribution between the fetal and adult brain, automated tissue segmentation techniques developed for adult brain anatomy are unsuitable for this data. In this paper, we describe methodology for automatic atlas-based segmentation of individual tissue types in motion-corrected 3D volumes reconstructed from clinical MR scans of the fetal brain. To generate anatomically correct automatic segmentations, we create a set of accurate manual delineations and build an in utero 3D statistical atlas of tissue distribution incorporating developing grey and white matter as well as transient tissue types such as the germinal matrix. The probabilistic atlas is associated with an unbiased average shape and intensity template for registration of new subject images to the space of the atlas. Quantitative whole brain 3D validation of tissue labeling performed on a set of 14 fetal MR scans (20.57–22.86 weeks gestational age) demonstrates that this atlas-based EM segmentation approach achieves consistently high DSC performance for the main tissue types in the fetal brain. This work indicates that reliable measures of brain development can be automatically derived from clinical MR imaging and opens up possibility of further 3D volumetric and morphometric studies with multiple fetal subjects.
doi:10.1002/hbm.20935
PMCID: PMC3306251  PMID: 20108226
16.  Towards an Elastographic Atlas of Brain Anatomy 
PLoS ONE  2013;8(8):e71807.
Cerebral viscoelastic constants can be measured in a noninvasive, image-based way by magnetic resonance elastography (MRE) for the detection of neurological disorders. However, MRE brain maps of viscoelastic constants are still limited by low spatial resolution. Here we introduce three-dimensional multifrequency MRE of the brain combined with a novel reconstruction algorithm based on a model-free multifrequency inversion for calculating spatially resolved viscoelastic parameter maps of the human brain corresponding to the dynamic range of shear oscillations between 30 and 60 Hz. Maps of two viscoelastic parameters, the magnitude and the phase angle of the complex shear modulus, |G*| and φ, were obtained and normalized to group templates of 23 healthy volunteers in the age range of 22 to 72 years. This atlas of the anatomy of brain mechanics reveals a significant contrast in the stiffness parameter |G*| between different anatomical regions such as white matter (WM; 1.252±0.260 kPa), the corpus callosum genu (CCG; 1.104±0.280 kPa), the thalamus (TH; 1.058±0.208 kPa) and the head of the caudate nucleus (HCN; 0.649±0.101 kPa). φ, which is sensitive to the lossy behavior of the tissue, was in the order of CCG (1.011±0.172), TH (1.037±0.173), CN (0.906±0.257) and WM (0.854±0.169). The proposed method provides the first normalized maps of brain viscoelasticity with anatomical details in subcortical regions and provides useful background data for clinical applications of cerebral MRE.
doi:10.1371/journal.pone.0071807
PMCID: PMC3743755  PMID: 23977148
17.  CONSIDERATION OF DOSE LIMITS FOR ORGANS AT RISK OF THORACIC RADIOTHERAPY: ATLAS FOR LUNG, PROXIMAL BRONCHIAL TREE, ESOPHAGUS, SPINAL CORD, RIBS, AND BRACHIAL PLEXUS 
Purpose
To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
Methods and Materials
The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy and 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists.
Results
Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed.
Conclusions
We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.
doi:10.1016/j.ijrobp.2010.07.1977
PMCID: PMC3933280  PMID: 20934273
Atlas; Lung; Esophagus; Spinal cord; Brachial plexus
18.  A Three-Dimensional Atlas of Human Dermal Leukocytes, Lymphatics, and Blood Vessels 
Dendritic cells (DCs), macrophages (Mφ), and T cells are major components of the skin immune system, but their interstitial spatial organization is poorly characterized. Using four-channel whole-mount immunofluorescence staining of the human dermis, we demonstrated the three-dimensional distribution of CD31+ blood capillaries, LYVE-1+ lymphatics, discrete populations of CD11c+ myeloid DCs, FXIIIa+ Mφ, and lymphocytes. We showed phenotypic and morphological differences in situ between DCs and Mφ. DCs formed the first dermal cellular layer (0–20 μm beneath the dermoepidermal junction), Mφ were located deeper (40–60 μm), and CD3+ lymphocytes were observed throughout (0–60 μm). Below this level, DCs, T cells, and the majority of Mφ formed stable perivascular sheaths. Whole-mount imaging revealed the true extent of dermal leukocytes previously underestimated from cross-section views. The total area of apical dermis (0–30 μm) contained approximately 10-fold more myeloid DCs than the entire blood volume of an average individual. Surprisingly, <1% of dermal DCs occupied lymphatics in freshly isolated skin. Dermal DCs rapidly accumulated within lymphatics, but Mφ remained fixed in skin explants cultured ex vivo. The leukocyte architecture observed in normal skin was distorted in inflammation and disease. These studies illustrate the micro-anatomy of dermal leukocytes and provide further insights into their functional organization.
doi:10.1038/jid.2013.481
PMCID: PMC3961477  PMID: 24352044
19.  A three dimensional atlas of human dermal leukocytes, lymphatics and blood vessels 
Dendritic cells (DCs), macrophages and T cells are major components of the skin immune system but their interstitial spatial organization is poorly characterized. Using four-channel whole mount immunofluorescence staining of the human dermis we demonstrated the three-dimensional distribution of CD31+ blood capillaries, LYVE-1+ lymphatics, discrete populations of CD11c+ myeloid DCs, FXIIIa+ macrophages and lymphocytes. We showed phenotypic and morphological differences in situ between DCs and macrophages. DCs formed the first dermal cellular layer (0-20μm beneath the dermo-epidermal junction), macrophages were located deeper (40-60μm) and CD3+ lymphocytes were observed throughout (0-60μm). Below this level, DCs, T cells and the majority of macrophages formed stable perivascular sheaths. Whole mount imaging revealed the true extent of dermal leukocytes previously under-estimated from cross-section views. The total area of apical dermis (0-30μm) contained approximately tenfold more myeloid DCs than the entire blood volume of an average individual. Surprisingly, <1% of dermal DCs occupied lymphatics in freshly isolated skin. Dermal DCs rapidly accumulated within lymphatics but macrophages remained fixed in skin explants cultured ex vivo. The leukocyte architecture observed in normal skin was distorted in inflammation and disease. These studies illustrate the micro-anatomy of dermal leukocytes and provide further insights into their functional organization.
doi:10.1038/jid.2013.481
PMCID: PMC3961477  PMID: 24352044
20.  Evaluation of group-specific, whole-brain atlas generation using Volume-based Template Estimation (VTE): application to normal and Alzheimer's populations 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.09.011.
MRI-based human brain atlases, which serve as a common coordinate system for image analysis, play an increasingly important role in our understanding of brain anatomy, image registration, and segmentation. Study-specific brain atlases are often obtained from one of the subjects in a study or by averaging the images of all participants after linear or non-linear registration. The latter approach has the advantage of providing an unbiased anatomical representation of the study population. But, the image contrast is influenced by both inherent MR contrasts and residual anatomical variability after the registration; in addition, the topology of the brain structures cannot reliably be preserved. In this study, we demonstrated a population-based template-creation approach, which is based on Bayesian template estimation on a diffeomorphic random orbit model. This approach attempts to define a population-representative template without the cross-subject intensity averaging; thus, the topology of the brain structures is preserved. It has been tested for segmented brain structures, such as the hippocampus, but its validity on whole-brain MR images has not been examined. This paper validates and evaluates this atlas generation approach, i.e., Volume-based Template Estimation (VTE). Using datasets from normal subjects and Alzheimer's patients, quantitative measurements of sub-cortical structural volumes, metric distance, displacement vector, and Jacobian were examined to validate the group-averaged shape features of the VTE. In addition to the volume-based quantitative analysis, the preserved brain topology of the VTE allows surface-based analysis within the same atlas framework. This property was demonstrated by analyzing the registration accuracy of the pre- and post-central gyri. The proposed method achieved registration accuracy within 1 mm for these population-preserved cortical structures in an elderly population.
doi:10.1016/j.neuroimage.2013.09.011
PMCID: PMC3860098  PMID: 24051356
Volume-based Template Estimation (VTE); study-specific atlas; MRI; volume-surface analysis
21.  A Digital Framework to Build, Visualize and Analyze a Gene Expression Atlas with Cellular Resolution in Zebrafish Early Embryogenesis 
PLoS Computational Biology  2014;10(6):e1003670.
A gene expression atlas is an essential resource to quantify and understand the multiscale processes of embryogenesis in time and space. The automated reconstruction of a prototypic 4D atlas for vertebrate early embryos, using multicolor fluorescence in situ hybridization with nuclear counterstain, requires dedicated computational strategies. To this goal, we designed an original methodological framework implemented in a software tool called Match-IT. With only minimal human supervision, our system is able to gather gene expression patterns observed in different analyzed embryos with phenotypic variability and map them onto a series of common 3D templates over time, creating a 4D atlas. This framework was used to construct an atlas composed of 6 gene expression templates from a cohort of zebrafish early embryos spanning 6 developmental stages from 4 to 6.3 hpf (hours post fertilization). They included 53 specimens, 181,415 detected cell nuclei and the segmentation of 98 gene expression patterns observed in 3D for 9 different genes. In addition, an interactive visualization software, Atlas-IT, was developed to inspect, supervise and analyze the atlas. Match-IT and Atlas-IT, including user manuals, representative datasets and video tutorials, are publicly and freely available online. We also propose computational methods and tools for the quantitative assessment of the gene expression templates at the cellular scale, with the identification, visualization and analysis of coexpression patterns, synexpression groups and their dynamics through developmental stages.
Author Summary
We propose a workflow to map the expression domains of multiple genes onto a series of 3D templates, or “atlas”, during early embryogenesis. It was applied to the zebrafish at different stages between 4 and 6.3 hpf, generating 6 templates. Our system overcomes the lack of significant morphological landmarks in early development by relying on the expression of a reference gene (goosecoid, gsc) and nuclear staining to guide the registration of the analyzed genes. The proposed method also successfully maps gene domains from partially imaged embryos, thus allowing greater microscope magnification and cellular resolution. By using the workflow to construct a spatiotemporal database of zebrafish, we opened the way to a systematic analysis of vertebrate embryogenesis. The atlas database, together with the mapping software (Match-IT), a custom-made visualization platform (Atlas-IT), and step-by-step user guides are available from the Supplementary Material. We expect that this will encourage other laboratories to generate, map, visualize and analyze new gene expression datasets.
doi:10.1371/journal.pcbi.1003670
PMCID: PMC4063669  PMID: 24945246
22.  Validating atlas-guided DOT: a comparison of diffuse optical tomography informed by atlas and subject-specific anatomies 
NeuroImage  2012;62(3):1999-2006.
We describe the validation of an anatomical brain atlas approach to the analysis of diffuse optical tomography (DOT). Using MRI data from 32 subjects, we compare the diffuse optical images of simulated cortical activation reconstructed using a registered atlas with those obtained using a subject’s true anatomy. The error in localization of the simulated cortical activations when using a registered atlas is due to a combination of imperfect registration, anatomical differences between atlas and subject anatomies and the localization error associated with diffuse optical image reconstruction. When using a subject-specific MRI, any localization error is due to diffuse optical image reconstruction only. In this study we determine that using a registered anatomical brain atlas results in an average localization error of approximately 18 mm in Euclidean space. The corresponding error when the subject’s own MRI is employed is 9.1 mm. In general, the cost of using atlas-guided DOT in place of subject-specific MRI-guided DOT is a doubling of the localization error. Our results show that despite this increase in error, reasonable anatomical localization is achievable even in cases where the subject-specific anatomy is unavailable.
doi:10.1016/j.neuroimage.2012.05.031
PMCID: PMC3408558  PMID: 22634215
Diffuse optical tomography; NIRS; MRI; Anatomical atlas; Registration
23.  OUT-OF-ATLAS LABELING: A MULTI-ATLAS APPROACH TO CANCER SEGMENTATION 
Conventional automated segmentation techniques for magnetic resonance imaging (MRI) fail to perform in a robust and consistent manner when brain anatomy differs wildly from expectations – as is often the case in brain cancers. We propose a novel out-of-atlas technique to estimate the spatial extent of abnormal brain regions by combining multi-atlas based segmentation with semi-local non-parametric intensity analysis. In a study with 30 clinically-acquired MRI scans of patients with malignant gliomas and 29 atlases of normal anatomy from research acquisitions, we demonstrate that this technique robustly identifies cancerous regions. The resulting segmentations could be used to study cancer morphometrics or guide selection/application/refinement of tumor analysis models or regional image quantification approaches.
doi:10.1109/ISBI.2012.6235785
PMCID: PMC3892947  PMID: 24443679
Cancer Segmentation; Tumors; Multi-Atlas Segmentation; Out-of-Atlas Labeling
24.  Transduction-Specific ATLAS (TS-ATLAS) reveals a cohort of highly active L1 retrotransposons in human populations 
Human mutation  2013;34(7):10.1002/humu.22327.
Long INterspersed Element-1 (LINE-1 or L1) retrotransposons are the only autonomously active transposable elements in the human genome. The average human genome contains ∼80-100 active L1s, but only a subset of these L1s are highly active or ‘hot’. Human L1s are closely related in sequence, making it difficult to decipher progenitor/offspring relationships using traditional phylogenetic methods. However, L1 mRNAs can sometimes bypass their own polyadenylation signal and instead utilize fortuitous polyadenylation signals in 3′ flanking genomic DNA. Retrotransposition of the resultant mRNAs then results in lineage specific sequence ‘tags’ (i.e., 3′ transductions) that mark the descendants of active L1 progenitors. Here, we developed a method (Transduction-Specific Amplification Typing of L1 Active Subfamilies or TS-ATLAS) that exploits L1 3′ transductions to identify active L1 lineages in a genome-wide context. TS-ATLAS enabled the characterisation of a putative active progenitor of one L1 lineage that includes the disease causing L1 insertion L1RP, and the identification of new retrotransposition events within two other ‘hot’ L1 lineages. Intriguingly, the analysis of the newly discovered transduction lineage members suggests that L1 polyadenylation, even within a lineage, is highly stochastic. Thus, TS-ATLAS provides a new tool to explore the dynamics of L1 lineage evolution and retrotransposon biology.
doi:10.1002/humu.22327
PMCID: PMC3880804  PMID: 23553801
human; retrotransposon; transduction; polyadenylation; genome
25.  ATLAS-plus: Multimedia Instruction in Embryology, Gross Anatomy, and Histology 
ATLAS-plus [Advanced Tools for Learning Anatomical Structure] is a multimedia program used to assist in the teaching of anatomy at the University of Michigan Medical School. ATLAS-plus contains three courses: Histology, Embryology, and Gross Anatomy. In addition to the three courses, a glossary containing terms from the three courses is available. All three courses and the glossary are accessible in the ATLAS-plus environment. The ATLAS-plus environment provides a consistent set of tools and options so that the user can navigate easily and intelligently in and between the various courses and modules in the ATLAS-plus world. The program is a collaboration between anatomy and cell biology faculty, medical students, graphic artists, systems analysts, and instructional designers.
PMCID: PMC2248137  PMID: 1482964

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