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2.  Weismann-Netter-Stuhl Syndrome:A family report 
Weismann-Netter-Stuhl (WNS) syndrome is a rare skeletal anomaly that affects the diaphyseal part of both the tibiae and fibulae with posterior cortical thickening and anteroposterior bowing. This anomaly is usually bilateral and symmetrical. The patients are generally of short stature. In some cases, a family history suggesting genetic transmission of a mutation with an unknown locus has been reported. In this paper we present an infant with WNS syndrome with bilateral involvement of the femur. Similar clinical findings were defined in three other family members.
Conflict of interest:None declared.
PMCID: PMC3005653  PMID: 21274295
Weismann-Netter-Stuhl syndrome; femur involvement; radiography
3.  Netter's Sports Medicine 
Mayo Clinic Proceedings  2010;85(9):752-e69.
PMCID: PMC2931631
5.  Professor Arnold Netter 
British Medical Journal  1936;1(3925):671.
PMCID: PMC2458331
6.  Recurrent Dislocation of the Shoulder Joint 
Dr. Anthony F. DePalma is shown. Photograph provided with kind permission of the Art Committee of Thomas Jefferson University, Philadelphia, PA.
Dr. DePalma was the first editor of Clinical Orthopaedics and Related Research, established by the recently formed Association of Bone and Joint Surgeons. The idea of forming the Association of Bone and Joint surgeons had been conceived by Dr. Earl McBride of Oklahoma City in 1947, and organized by a group of twelve individuals (Drs. Earl McBride, Garrett Pipkin, Duncan McKeever, Judson Wilson, Fritz Teal, Louis Breck, Henry Louis Green, Howard Shorbe, Theodore Vinke, Paul Williams, Eugene Secord, and Frank Hand) [9]. The first organizational meeting was held in conjunction with the 1949 Annual Meeting of the AAOS [9] and the first annual meeting held April 1–2, 1949 in Oklahoma City. Drs. McBride and McKeever invited Dr. DePalma to attend that meeting and join the society. According to DePalma, “Even at this small gathering, there were whisperings of the need of another journal to provide an outlet for the many worthy papers written on clinical and basic science subjects” [7]. The decision to form a new journal was finalized in 1951, and Drs. DePalma and McBride signed a contract with J.B. Lippincott Company. Dr. DePalma was designated Editor-in-Chief, and the journal became a reality in 1953 with the publication of the first volume. From the outset he established the “symposium” as a unique feature, in which part of the articles were devoted to a particular topic. Dr. DePalma served as Editor for 13 years until 1966, when he resigned the position and recommended the appointment of Dr. Marshall R. Urist. At his retirement, Clinical Orthopaedics and Related Research was well established as a major journal.
Dr. Anthony F. DePalma was born in Philadelphia in 1904, the son of immigrants from Alberona in central Foggia, Italy [1]. He attended the University of Maryland for his premedical education, then Jefferson Medical College, from which he graduated in 1929. He then served a two-year internship (common at the time) at Philadelphia General Hospital. Jobs were scarce owing to the Depression, and he felt fortunate to obtain in 1931 a position as assistant surgeon at the Coaldale State Hospital, in Coaldale, Pennsylvania, a mining town. However, he became attracted to orthopaedics and looked for a preceptorship (postgraduate training in specialties was not well developed at this time before the establishments of Boards). In the fall of 1932, he was appointed as a preceptor at the New Jersey Orthopaedic Hospital, an extension of the New York Orthopaedic Hospital. In 1939 he acquired Board certification (the first board examination was offered in 1935 for a fee of $25.00 [2]) and was appointed to the NJOH staff [1].
Dr. DePalma volunteered for military service in 1942, and served first at the Parris Island Naval Hospital in South Carolina, then on the Rixey, a hospital ship. In addition to serving to evacuate casualties to New Zealand, his ship was involved in several of the Pacific island assaults (Guam, Leyte, Okinawa). In 1945, he was assigned to the Naval Hospital in Philadelphia [1].
On his return to Philadelphia, he contacted staff members at Jefferson Medical College, including the Chair, Dr. James Martin, and became good friends with Dr. Bruce Gill (a professor of Orthopaedics at the University of Pennsylvania, and one of the earliest Presidents of the AAOS). After he was discharged from the service, he joined the staff of the Department of Orthopaedic Surgery at Jefferson, where he remained the rest of his career. He succeeded Dr. Martin as Chair in 1950, a position he held until 1970 when he reached the mandatory retirement age of 65. He closed his practice and moved briefly to Pompano Beach, Florida, but the lure of academia proved too powerful, and in January, 1971, he accepted the offer to develop a Division of Orthopaedics at the New Jersey College of Medicine and became their Chair. He committed to a five-year period, and then again moved to Pompano Beach, only to take the Florida State Boards and open a private practice in 1977. His practice grew, and he continued that practice until 1983 at the age of nearly 79. Even then he continued to travel and lecture [1].
We reproduce here four of his many contributions on the shoulder. The first comes from his classic monograph, “Surgery of the Shoulder,” published by J. B. Lippincott in 1950 [2]. In this article he describes the evolutionary development of the shoulder, focusing on the distinction between various primates, and relates the anatomic changes to upright posture and prehensile requirements. The remaining three are journal articles related to frozen shoulder [1], recurrent dislocation [3], and surgical anatomy of the rotator cuff [6], three of the most common shoulder problems then and now. He documented the histologic inflammation and degeneration in various tissues including the coracohumeral ligaments, supraspinatus tendon, bursal wall, subscapularis musculotendinous junction, and biceps tendon. Thus, the problem was rather more global than localized. He emphasized, “Manipulation of frozen shoulders is a dangerous and futile procedure.” For recurrent dislocation he advocated the Magnuson procedure (transfer of the subscapularis tendon to the greater tuberosity) to create a musculotendinous sling. All but two of 23 patients he treated with this approach were satisfied with this relatively simple procedure. (Readers will note the absence of contemporary approaches to ascertain outcomes and satisfaction. The earliest outcome musculoskeletal measures were introduced in the 60s by Larson [11] and then by Harris [10], but these instruments were physician-generated and do not reflect the rather more rigorously validated patient-generated outcome measures we use today. Nonetheless, the approach used by Dr. DePalma reflected the best existing standards of reporting results.) Dr. DePalma’s classic article, “Surgical Anatomy of the Rotator Cuff and the Natural History of Degenerative Periarthritis,” [6] reflected his literature review and dissections of 96 shoulders from 50 individuals “unaware of any (shoulder) disability” and mostly over the age of 40. By the fifth decade, most specimens began to show signs of rotator cuff tearing and he found complete tears in nine specimens from “the late decades.” He concluded,
“Based on the…observations, one can reasonably construct the natural history of periarthritis of the shoulder. It is apparent that aging is an important etiological factor, and with aging certain changes take place in the connective tissue elements of the musculotendinous cuff…it is also apparent that in slowly developing lesions of this nature compensating adjustments in the mechanics of the joint take place so that severe alterations in the mechanics of the joint do not appear. However, one must admit that such a joint is very vulnerable and, if subjected to minor trauma, the existing degenerative lesion would be extended and aggravated.”
Thus, he clearly defined the benign effects of rotator cuff tear in many aging individuals, but also the potential to create substantial pain and disability.
Dr. DePalma was a prolific researcher and writer. In addition to his “Surgery of the Shoulder,” he wrote three other books, “Diseases of the Knee: Management in Medicine and Surgery” (published by J.B. Lippincott in 1954) [4], “The Management of Fractures and Dislocations” (a large and comprehensive two volume work published by W.B. Saunders in 1959, and going through 5 reprintings) [5], and “The Intervertebral Disc” (published by W.B. Saunders in 1970, and written with his colleague, Dr. Richard Rothman) [8]. PubMed lists 62 articles he published from 1948 until 1992.
We wish to pay tribute to Dr. DePalma for his vision in establishing Clinical Orthopaedics and Related Research as a unique journal and for his many contributions to orthopaedic surgery.
DePalma A. Loss of scapulohumeral motion (frozen shoulder). Ann Surg. 1952;135:193–204.DePalma AF. Origin and comparative anatomy of the pectoral limb. In: DePalma AF, ed. Surgery of the Shoulder. Philadelphia: JB Lippincott; 1950:1–14.DePalma AF. Recurrent dislocation of the shoulder joint. Ann Surg. 1950;132:1052–1065.DePalma AF. Diseases of the Knee: Management in Medicine and Surgery. Philadelphia, PA: JB Lippincott Company; 1954.DePalma AF. The Management of Fractures and Dislocations—An Atlas. Philadelphia: WB Saunders Company; 1959.DePalma AF. Surgical anatomy of the rotator cuff and the natural history of degenerative periarthritis. Surg Clin North Am. 1963;43:1507–1520.DePalma AF. A lifetime of devotion to the Janus of orthopedics. Bridging the gap between the clinic and laboratory. Clin Orthop Relat Res. 1991;265:146–169.DePalma AF, Rothman RH. The Intervertebral Disc. Philadelphia: WB Saunders Company; 1970.Derkash RS. History of the Association of Bone and Joint Surgeons. Clin Orthop Relat Res. 1997;337:306–309.Harris WH. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am. 1969;51:737–755.Larson CB. Rating scale for hip disabilities. Clin Orthop Relat Res. 1963;31:85–93.
PMCID: PMC2505210  PMID: 18264840
7.  Segmentation of Brain Images Using Adaptive Atlases with Application to Ventriculomegaly 
Segmentation of brain images often requires a statistical atlas for providing prior information about the spatial position of different structures. A major limitation of atlas-based segmentation algorithms is their deficiency in analyzing brains that have a large deviation from the population used in the construction of the atlas. We present an expectation-maximization framework based on a Dirichlet distribution to adapt a statistical atlas to the underlying subject. Our model combines anatomical priors with the subject’s own anatomy, resulting in a subject specific atlas which we call an “adaptive atlas”. The generation of this adaptive atlas does not require the subject to have an anatomy similar to that of the atlas population, nor does it rely on the availability of an ensemble of similar images. The proposed method shows a significant improvement over current segmentation approaches when applied to subjects with severe ventriculomegaly, where the anatomy deviates significantly from the atlas population. Furthermore, high levels of accuracy are maintained when the method is applied to subjects with healthy anatomy.
PMCID: PMC3478153  PMID: 21761641
8.  Creation of Computerized 3D MRI-Integrated Atlases of the Human Basal Ganglia and Thalamus 
Functional brain imaging and neurosurgery in subcortical areas often requires visualization of brain nuclei beyond the resolution of current magnetic resonance imaging (MRI) methods. We present techniques used to create: (1) a lower resolution 3D atlas, based on the Schaltenbrand and Wahren print atlas, which was integrated into a stereotactic neurosurgery planning and visualization platform (VIPER); and (2) a higher resolution 3D atlas derived from a single set of manually segmented histological slices containing nuclei of the basal ganglia, thalamus, basal forebrain, and medial temporal lobe. Both atlases were integrated to a canonical MRI (Colin27) from a young male participant by manually identifying homologous landmarks. The lower resolution atlas was then warped to fit the MRI based on the identified landmarks. A pseudo-MRI representation of the high-resolution atlas was created, and a non-linear transformation was calculated in order to match the atlas to the template MRI. The atlas can then be warped to match the anatomy of Parkinson's disease surgical candidates by using 3D automated non-linear deformation methods. By way of functional validation of the atlas, the location of the sensory thalamus was correlated with stereotactic intraoperative physiological data. The position of subthalamic electrode positions in patients with Parkinson's disease was also evaluated in the atlas-integrated MRI space. Finally, probabilistic maps of subthalamic stimulation electrodes were developed, in order to allow group analysis of the location of contacts associated with the best motor outcomes. We have therefore developed, and are continuing to validate, a high-resolution computerized MRI-integrated 3D histological atlas, which is useful in functional neurosurgery, and for functional and anatomical studies of the human basal ganglia, thalamus, and basal forebrain.
PMCID: PMC3167101  PMID: 21922002
brain atlas; Parkinson's disease; stereotactic neurosurgery; image guidance
9.  Hypertext atlas of fetal and neonatal pathology 
Diagnostic Pathology  2008;3(Suppl 1):S9.
Hypertext atlas of fetal and neonatal pathology is a free resource for pregraduate students of medicine, pathologists and other health professionals dealing with prenatal medicine. The atlas can be found at . The access is restricted to registered users. Concise texts summarize the gross and microscopic pathology, etiology, and clinical signs of both common and rare fetal and neonatal conditions. The texts are illustrated with over 300 images that are accompanied by short comments. The atlas offers histological pictures of high quality. Virtual microscope interface is used to access the high-resolution histological images. Fetal ultrasound video clips are included. Case studies integrate clinical history, prenatal ultrasonographic examination, gross pathology and histological features. The atlas is available in English (and Czech) and equipped with an active index. The atlas is suitable both for medical students and pathologists as a teaching and reference tool. The atlas is going to be further expanded while keeping the high quality of the images.
PMCID: PMC2500115  PMID: 18673523
10.  A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo 
PLoS Biology  2011;9(1):e1000582.
The manuscript describes the “digital transcriptome atlas” of the developing mouse embryo, a powerful resource to determine co-expression of genes, to identify cell populations and lineages and to identify functional associations between genes relevant to development and disease.
Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (, consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.
Author Summary
In situ hybridization (ISH) can be used to visualize gene expression in cells and tissues in their native context. High-throughput ISH using nonradioactive RNA probes allowed the Eurexpress consortium to generate a comprehensive, interactive, and freely accessible digital gene expression atlas, the Eurexpress transcriptome atlas (, of the E14.5 mouse embryo. Expression data for over 15,000 genes were annotated for hundreds of anatomical structures, thus allowing us to systematically identify tissue-specific and tissue-overlapping gene networks. We illustrate the value of the Eurexpress atlas by finding novel regional subdivisions in the developing brain. We also use the transcriptome atlas to allocate specific components of the complex Wnt signaling pathway to kidney development, and we identify regionally expressed genes in liver that may be markers of hematopoietic stem cell differentiation.
PMCID: PMC3022534  PMID: 21267068
11.  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.
PMCID: PMC2915788  PMID: 20017133
brain atlas; multi-spectral magnetic resonance imaging; diffusion tensor imaging; unbiased population registration; spatial normalization; label propagation
12.  A method of 2D/3D registration of a statistical mouse atlas with a planar X-ray projection and an optical photo 
Medical image analysis  2013;17(4):401-416.
The development of sophisticated and high throughput whole body small animal imaging technologies has created a need for improved image analysis and increased automation. The registration of a digital mouse atlas to individual images is a prerequisite for automated organ segmentation and uptake quantification. This paper presents a fully-automatic method for registering a statistical mouse atlas with individual subjects based on an anterior-posterior X-ray projection and a lateral optical photo of the mouse silhouette. The mouse atlas was trained as a statistical shape model based on 83 organ-segmented micro-CT images. For registration, a hierarchical approach is applied which first registers high contrast organs, and then estimates low contrast organs based on the registered high contrast organs. To register the high contrast organs, a 2D-registration-back-projection strategy is used that deforms the 3D atlas based on the 2D registrations of the atlas projections. For validation, this method was evaluated using 55 subjects of preclinical mouse studies. The results showed that this method can compensate for moderate variations of animal postures and organ anatomy. Two different metrics, the Dice coefficient and the average surface distance, were used to assess the registration accuracy of major organs. The Dice coefficients vary from 0.31±0.16 for the spleen to 0.88±0.03 for the whole body, and the average surface distance varies from 0.54±0.06 mm for the lungs to 0.85±0.10 mm for the skin. The method was compared with a direct 3D deformation optimization (without 2D-registration-back-projection) and a single-subject atlas registration (instead of using the statistical atlas). The comparison revealed that the 2D-registration-back-projection strategy significantly improved the registration accuracy, and the use of the statistical mouse atlas led to more plausible organ shapes than the single-subject atlas. This method was also tested with shoulder xenograft tumor-bearing mice, and the results showed that the registration accuracy of most organs was not significantly affected by the presence of shoulder tumors, except for the lungs and the spleen.
PMCID: PMC3667217  PMID: 23542374
13.  DigiWarp: a method for deformable mouse atlas warping to surface topographic data 
Physics in medicine and biology  2010;55(20):6197-6214.
For pre-clinical bioluminescence or fluorescence optical tomography, the animal's surface topography and internal anatomy need to be estimated for improving the quantitative accuracy of reconstructed images. The animal's surface profile can be measured by all-optical systems, but estimation of the internal anatomy using optical techniques is non-trivial. A 3D anatomical mouse atlas may be warped to the estimated surface. However, fitting an atlas to surface topography data is challenging because of variations in the posture and morphology of imaged mice. In addition, acquisition of partial data (for example, from limited views or with limited sampling) can make the warping problem ill-conditioned. Here, we present a method for fitting a deformable mouse atlas to surface topographic range data acquired by an optical system. As an initialization procedure, we match the posture of the atlas to the posture of the mouse being imaged using landmark constraints. The asymmetric L2 pseudo-distance between the atlas surface and the mouse surface is then minimized in order to register two data sets. A Laplacian prior is used to ensure smoothness of the surface warping field. Once the atlas surface is normalized to match the range data, the internal anatomy is transformed using elastic energy minimization. We present results from performance evaluation studies of our method where we have measured the volumetric overlap between the internal organs delineated directly from MRI or CT and those estimated by our proposed warping scheme. Computed Dice coefficients indicate excellent overlap in the brain and the heart, with fair agreement in the kidneys and the bladder.
PMCID: PMC3051844  PMID: 20885019
14.  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.
PMCID: PMC3408558  PMID: 22634215
Diffuse optical tomography; NIRS; MRI; Anatomical atlas; Registration
15.  A Delphi consensus study to identify current clinically most valuable orthopaedic anatomy components for teaching medical students 
BMC Medical Education  2014;14(1):230.
Over recent years, wide ranging changes have occurred in undergraduate medical curricula with reduction of hours allocated for teaching anatomy. Anatomy forms the foundation of clinical practice. However, the challenge of acquiring sufficient anatomical knowledge in undergraduate medical education for safe and competent clinical practice remains. The purpose of this study is to identify clinically most valuable orthopaedic anatomy components that are relevant to current clinical practice in order to reinforce anatomy teaching.
Modified Delphi technique with three rounds involving twenty currently practicing orthopaedic consultants and senior speciality orthopaedic registrars (StR, year six and above) was conducted. Anatomical components applied in corresponding clinical situations were generated from the opinions of this expert panel in the first round and the clinical importance of each of these components were rated with a four point Likert scale in the subsequent two rounds to generate consensus. Percentage agreement was utilised as outcome measure for components rated as considerably/very important with consensus of more than 94%.
Response rates were 90% for the first round and 100% for the next two rounds. After three Delphi rounds, thirty four anatomy components applied in general/ specific clinical conditions and clinical tests were identified as clinically most valuable following iteration.
The findings of this study provide clinicians opinions regarding the current required essential anatomical knowledge for a graduating medical student to apply during their orthopaedic clinical encounters. The information obtained can be utilised to encourage further development of clinical anatomy curriculum reflecting the evolving nature of health care.
PMCID: PMC4287337  PMID: 25342498
Delphi; Orthopaedics; Clinical anatomy
16.  Evaluation of Node-Inhomogeneity Effects on the Functional Brain Network Properties Using an Anatomy-Constrained Hierarchical Brain Parcellation 
PLoS ONE  2013;8(9):e74935.
To investigate functional brain networks, many graph-theoretical studies have defined nodes in a graph using an anatomical atlas with about a hundred partitions. Although use of anatomical node definition is popular due to its convenience, functional inhomogeneity within each node may lead to bias or systematic errors in the graph analysis. The current study was aimed to show functional inhomogeneity of a node defined by an anatomical atlas and to show its effects on the graph topology. For this purpose, we compared functional connectivity defined using 138 resting state fMRI data among 90 cerebral nodes from the automated anatomical labeling (AAL), which is an anatomical atlas, and among 372 cerebral nodes defined using a functional connectivity-based atlas as a ground truth, which was obtained using anatomy-constrained hierarchical modularity optimization algorithm (AHMO) that we proposed to evaluate the graph properties for anatomically defined nodes. We found that functional inhomogeneity in the anatomical parcellation induced significant biases in estimating both functional connectivity and graph-theoretical network properties. We also found very high linearity in major global network properties and nodal strength at all brain regions between anatomical atlas and functional atlas with reasonable network-forming thresholds for graph construction. However, some nodal properties such as betweenness centrality did not show significant linearity in some regions. The current study suggests that the use of anatomical atlas may be biased due to its inhomogeneity, but may generally be used in most neuroimaging studies when a single atlas is used for analysis.
PMCID: PMC3776746  PMID: 24058640
17.  Computer-based Learning of Neuroanatomy: A Longitudinal Study of Learning, Transfer, and Retention 
A longitudinal experiment was conducted to evaluate the effectiveness of new methods for learning neuroanatomy with computer-based instruction. Using a 3D graphical model of the human brain, and sections derived from the model, tools for exploring neuroanatomy were developed to encourage adaptive exploration. This is an instructional method which incorporates graphical exploration in the context of repeated testing and feedback. With this approach, 72 participants learned either sectional anatomy alone or whole anatomy followed by sectional anatomy. Sectional anatomy was explored either with perceptually continuous navigation through the sections or with discrete navigation (as in the use of an anatomical atlas). Learning was measured longitudinally to a high performance criterion. Subsequent tests examined transfer of learning to the interpretation of biomedical images and long-term retention. There were several clear results of this study. On initial exposure to neuroanatomy, whole anatomy was learned more efficiently than sectional anatomy. After whole anatomy was mastered, learners demonstrated high levels of transfer of learning to sectional anatomy and from sectional anatomy to the interpretation of complex biomedical images. Learning whole anatomy prior to learning sectional anatomy led to substantially fewer errors overall than learning sectional anatomy alone. Use of continuous or discrete navigation through sectional anatomy made little difference to measured outcomes. Efficient learning, good long-term retention, and successful transfer to the interpretation of biomedical images indicated that computer-based learning using adaptive exploration can be a valuable tool in instruction of neuroanatomy and similar disciplines.
PMCID: PMC3551584  PMID: 23349552
learning; instruction; neuroanatomy; graphics; interactive
18.  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
19.  eMouseAtlas, EMAGE, and the spatial dimension of the transcriptome 
Mammalian Genome  2012;23(9-10):514-524.
eMouseAtlas ( is a comprehensive online resource to visualise mouse development and investigate gene expression in the mouse embryo. We have recently deployed a completely redesigned Mouse Anatomy Atlas website ( that allows users to view 3D embryo reconstructions, delineated anatomy, and high-resolution histological sections. A new feature of the website is the IIP3D web tool that allows a user to view arbitrary sections of 3D embryo reconstructions using a web browser. This feature provides interactive access to very high-volume 3D images via a tiled pan-and-zoom style interface and circumvents the need to download large image files for visualisation. eMouseAtlas additionally includes EMAGE (Edinburgh Mouse Atlas of Gene Expression) (, a freely available, curated online database of in situ gene expression patterns, where gene expression domains extracted from raw data images are spatially mapped into atlas embryo models. In this way, EMAGE introduces a spatial dimension to transcriptome data and allows exploration of the spatial similarity between gene expression patterns. New features of the EMAGE interface allow complex queries to be built, and users can view and compare multiple gene expression patterns. EMAGE now includes mapping of 3D gene expression domains captured using the imaging technique optical projection tomography. 3D mapping uses WlzWarp, an open-source software tool developed by eMouseAtlas.
PMCID: PMC3463796  PMID: 22847374
Estimation of internal mouse anatomy is required for quantitative bioluminescence or fluorescence tomography. However, only surface range data can be recovered from all-optical systems. These data are at times sparse or incomplete. We present a method for fitting an elastically deformable mouse atlas to surface topographic range data acquired by an optical system. In this method, we first match the postures of a deformable atlas and the range data of the mouse being imaged. This is achieved by aligning manually identified landmarks. We then minimize the asymmetric L2 pseudo-distance between the surface of the deformable atlas and the surface topography range data. Once this registration is accomplished, the internal anatomy of the atlas is transformed to the coordinate system of the range data using elastic energy minimization. We evaluated our method by using it to register a digital mouse atlas to a surface model produced from a manually labeled CT mouse data set. Dice coefficents indicated excellent agreement in the brain and heart, with fair agreement in the kidneys and bladder. We also present example results produced using our method to align the digital mouse atlas to surface range data.
PMCID: PMC2975998  PMID: 21072317
Deformable atlas; mouse registration; optical tomography
21.  Atlas Generation for Subcortical and Ventricular Structures with its Applications in Shape Analysis 
Atlas-driven morphometric analysis has received great attention for studying anatomical shape variation across clinical populations in neuroimaging research as it provides a local coordinate representation for understanding the family of anatomic observations. We present a procedure for generating atlas of subcortical and ventricular structures, including amygdala, hippocampus, caudate, putamen, globus pallidus, thalamus, and lateral ventricles, using the large deformation diffeomorphic metric atlas generation algorithm. The atlas was built based on manually labeled volumes of 41 subjects randomly selected from the database of Open Access Series of Imaging Studies (OASIS, 10 young adults, 10 middle age adults, 10 healthy elders, and 11 patients with dementia). We show that the estimated atlas is representative of the population in terms of its metric distance to each individual subject in the population. In the application of detecting shape variations, using the estimated atlas may potentially increase statistical power in identifying group shape difference when comparing with using a single subject atlas. In shape-based classification, the metric distances between subjects and each of within-class estimated atlases construct a shape feature space, which allows for performing a variety of classification algorithms to distinguish anatomies.
PMCID: PMC2909363  PMID: 20129863
subcortical structures; brain atlas; shape classification; shape comparison; diffeomorphic mapping
22.  A histology-based atlas of the C57BL/6J mouse brain deformably registered to in vivo MRI for localized radiation and surgical targeting 
Physics in Medicine and Biology  2009;54(24):7315-7327.
The C57BL/6J laboratory mouse is commonly used in neurobiological research. Digital atlases of the C57BL/6J brain have been used for visualization, genetic phenotyping and morphometry, but currently lack the ability to accurately calculate deviations between individual mice. We developed a fully three-dimensional digital atlas of the C57BL/6J brain based on the histology atlas of Paxinos and Franklin (2001 The Mouse Brain in Stereotaxic Coordinates 2nd edn (San Diego, CA: Academic)). The atlas uses triangular meshes to represent the various structures. The atlas structures can be overlaid and deformed to individual mouse MR images. For this study, we selected 18 structures from the histological atlas. Average atlases can be created for any group of mice of interest by calculating the mean three-dimensional positions of corresponding individual mesh vertices. As a validation of the atlas’ accuracy, we performed deformable registration of the lateral ventricles to 13 MR brain scans of mice in three age groups: 5, 8 and 9 weeks old. Lateral ventricle structures from individual mice were compared to the corresponding average structures and the original histology structures. We found that the average structures created using our method more accurately represent individual anatomy than histology-based atlases alone, with mean vertex deviations of 0.044 mm versus 0.082 mm for the left lateral ventricle and 0.045 mm versus 0.068 mm for the right lateral ventricle. Our atlas representation gives direct spatial deviations for structures of interest. Our results indicate that MR-deformable histology-based atlases represent an accurate method to obtain accurate morphometric measurements of a population of mice, and that this method may be applied to phenotyping experiments in the future as well as precision targeting of surgical procedures or radiation treatment.
PMCID: PMC3365531  PMID: 19926915
23.  White Matter Atlas Generation using HARDI based Automated Parcellation 
Neuroimage  2011;59(4):4055-4063.
Most diffusion imaging studies have used subject registration to an atlas space for enhanced quantification of anatomy. However, standard diffusion tensor atlases lack information in regions of fiber crossing and are based on adult anatomy. The degree of error associated with applying these atlases to studies of children for example has not yet been estimated but may lead to suboptimal results. This paper describes a novel technique for generating population-specific high angular resolution diffusion imaging (HARDI)-based atlases consisting of labeled regions of homogenous white matter. Our approach uses a fiber orientation distribution (FOD) diffusion model and a data driven clustering algorithm. White matter regional labeling is achieved by our automated data driven clustering algorithm that has the potential to delineate white matter regions based on fiber complexity and orientation. The advantage of such an atlas is that it is study specific and more comprehensive in describing regions of white matter homogeneity as compared to standard anatomical atlases. We have applied this state of the art technique to a dataset consisting of adolescent and preadolescent children, creating one of the first examples of a HARDI-based atlas, thereby establishing the feasibility of the atlas creation framework. The white matter regions generated by our automated clustering algorithm have lower FOD variance than when compared to the regions created from a standard anatomical atlas.
PMCID: PMC3272315  PMID: 21893205
Diffusion; Atlas Generation; HARDI Template; White Matter Parcellation
24.  Using Frankenstein’s Creature Paradigm to Build a Patient Specific Atlas 
Conformal radiotherapy planning needs accurate delineations of the critical structures. Atlas-based segmentation has been shown to be very efficient to delineate brain structures. It would therefore be very interesting to develop an atlas for the head and neck region where 7 % of the cancers arise. However, the construction of an atlas in this region is very difficult due to the high variability of the anatomies. This can generate segmentation errors and over-segmented structures in the atlas. To overcome this drawback, we present an alternative method to build a template locally adapted to the patient’s anatomy. This is done first by selecting in a database the images that are the most similar to the patient on predefined regions of interest, using on a distance between transformations. The first major contribution is that we do not compute every patient-to-image registration to find the most similar image, but only the registration of the patient towards an average image. This method is therefore computationally very efficient. The second major contribution is a novel method to use the selected images and the predefined regions to build a Frankenstein’s creature” for segmentation. We present a qualitative and quantitative comparison between the proposed method and a classical atlas-based segmentation method. This evaluation is performed on a subset of 58 patients among a database of 105 head and neck CT images and shows a great improvement of the specificity of the results.
PMCID: PMC3687084  PMID: 20426208
25.  Atlas-Based Analysis of Neurodevelopment from Infancy to Adulthood Using Diffusion Tensor Imaging and Applications for Automated Abnormality Detection 
NeuroImage  2010;52(2):415-428.
Quantification of normal brain maturation is a crucial step in understanding developmental abnormalities in brain anatomy and function. The aim of this study was to develop atlas-based tools for time-dependent quantitative image analysis, and to characterize the anatomical changes that occur from 2 years of age to adulthood. We used large deformation diffeomorphic metric mapping to register diffusion tensor images of normal participants into the common coordinates and used a pre-segmented atlas to segment the entire brain into 176 structures. Both voxel- and atlas-based analyses reported structure that showed distinctive changes in terms of its volume and diffusivity measures. In the white matter, fractional anisotropy (FA) linearly increased with age in logarithmic scale, while diffusivity indices, such as apparent diffusion coefficient (ADC), and axial and radial diffusivity, decreased at a different rate in several regions. The average, variability, and the time course of each measured parameter are incorporated into the atlas, which can be used for automated detection of developmental abnormalities. As a demonstration of future application studies, the brainstem anatomy of cerebral palsy patients was evaluated and the altered anatomy was delineated.
PMCID: PMC2886186  PMID: 20420929

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