Censoring Distances Based on Labeled Cortical Distance Maps in Cortical Morphometry

Shape differences are manifested in cortical structures due to neuropsychiatric disorders. Such differences can be measured by labeled cortical distance mapping (LCDM) which characterizes the morphometry of the laminar cortical mantle of cortical structures. LCDM data consist of signed distances of gray matter (GM) voxels with respect to GM/white matter (WM) surface. Volumes and descriptive measures (such as means and variances) for each subject and the pooled distances provide the morphometric differences between diagnostic groups, but they do not reveal all the morphometric information contained in LCDM distances. To extract more information from LCDM data, censoring of the distances is introduced. For censoring of LCDM distances, the range of LCDM distances is partitioned at a fixed increment size; and at each censoring step, and distances not exceeding the censoring distance are kept. Censored LCDM distances inherit the advantages of the pooled distances. Furthermore, the analysis of censored distances provides information about the location of morphometric differences which cannot be obtained from the pooled distances. However, at each step, the censored distances aggregate, which might confound the results. The influence of data aggregation is investigated with an extensive Monte Carlo simulation analysis and it is demonstrated that this influence is negligible. As an illustrative example, GM of ventral medial prefrontal cortices (VMPFCs) of subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy control (Ctrl) subjects are used. A significant reduction in laminar thickness of the VMPFC and perhaps shrinkage in MDD and HR subjects is observed when compared to Ctrl subjects. The methodology is also applicable to LCDM-based morphometric measures of other cortical structures affected by disease.Comment: 25 pages, 10 figure

3D Normal Coordinate Systems for Cortical Areas

A surface-based diffeomorphic algorithm to generate 3D coordinate grids in the cortical ribbon is described. In the grid, normal coordinate lines are generated by the diffeomorphic evolution from the grey/white (inner) surface to the grey/csf (outer) surface. Specifically, the cortical ribbon is described by two triangulated surfaces with open boundaries. Conceptually, the inner surface sits on top of the white matter structure and the outer on top of the gray matter. It is assumed that the cortical ribbon consists of cortical columns which are orthogonal to the white matter surface. This might be viewed as a consequence of the development of the columns in the embryo. It is also assumed that the columns are orthogonal to the outer surface so that the resultant vector field is orthogonal to the evolving surface. Then the distance of the normal lines from the vector field such that the inner surface evolves diffeomorphically towards the outer one can be construed as a measure of thickness. Applications are described for the auditory cortices in human adults and cats with normal hearing or hearing loss. The approach offers great potential for cortical morphometry

Doctor of Philosophy in Computing

dissertationStatistical shape analysis has emerged as an important tool for the quantitative analysis of anatomy in many medical imaging applications. The correspondence based approach to evaluate shape variability is a popular method, based on comparing configurations of carefully placed landmarks on each shape. In recent years, methods for automatic placement of landmarks have enhanced the ability of this approach to capture statistical properties of shape populations. However, biomedical shapes continue to present considerable difficulties in automatic correspondence optimization due to inherent geometric complexity and the need to correlate shape change with underlying biological parameters. This dissertation addresses these technical difficulties and presents improved shape correspondence models. In particular, this dissertation builds on the particle-based modeling (PBM) framework described by Joshua Cates' 2010 Ph.D. dissertation. In the PBM framework, correspondences are modeled as a set of dynamic points or a particle system, positioned automatically on shape surfaces by optimizing entropy contained in the model, with the idea of balancing model simplicity against accuracy of the particle system representation of shapes. This dissertation is a collection of four papers that extend the PBM framework to include shape regression and longitudinal analysis and also adds new methods to improve modeling of complex shapes. It also includes a summary of two applications from the field of orthopaedics. Technical details of the PBM framework are provided in Chapter 2, after which the first topic related to the study of shape change over time is addressed (Chapters 3 and 4). In analyses of normative growth or disease progression, shape regression models allow characterization of the underlying biological process while also facilitating comparison of a sample against a normative model. The first paper introduces a shape regression model into the PBM framework to characterize shape variability due to an underlying biological parameter. It further confirms the statistical significance of this relationship via systematic permutation testing. Simple regression models are, however, not sufficient to leverage information provided by longitudinal studies. Longitudinal studies collect data at multiple time points for each participant and have the potential to provide a rich picture of the anatomical changes occurring during development, disease progression, or recovery. The second paper presents a linear-mixed-effects (LME) shape model in order to fully leverage the high-dimensional, complex features provided by longitudinal data. The parameters of the LME shape model are estimated in a hierarchical manner within the PBM framework. The topic of geometric complexity present in certain biological shapes is addressed next (Chapters 5 and 6). Certain biological shapes are inherently complex and highly variable, inhibiting correspondence based methods from producing a faithful representation of the average shape. In the PBM framework, use of Euclidean distances leads to incorrect particle system interactions while a position-only representation leads to incorrect correspondences around sharp features across shapes. The third paper extends the PBM framework to use efficiently computed geodesic distances and also adds an entropy term based on the surface normal. The fourth paper further replaces the position-only representation with a more robust distance-from-landmark feature in the PBM framework to obtain isometry invariant correspondences. Finally, the above methods are applied to two applications from the field of orthopaedics. The first application uses correspondences across an ensemble of human femurs to characterize morphological shape differences due to femoroacetabular impingement. The second application involves an investigation of the short bone phenotype apparent in mouse models of multiple osteochondromas. Metaphyseal volume deviations are correlated with deviations in length to quantify the effect of cancer toward the apparent shortening of long bones (femur, tibia-fibula) in mouse models

Variation and covariation of external shape and cross‐sectional geometry in the human metacarpus

Objectives Analyses of external bone shape using geometric morphometrics (GM) and cross‐sectional geometry (CSG) are frequently employed to investigate bone structural variation and reconstruct activity in the past. However, the association between these methods has not been thoroughly investigated. Here, we analyze whole bone shape and CSG variation of metacarpals 1–5 and test covariation between them. Materials and Methods We analyzed external metacarpal shape using GM and CSG of the diaphysis at three locations in metacarpals 1–5. The study sample includes three modern human groups: crew from the shipwrecked Mary Rose (n = 35 metacarpals), a Pre‐industrial group (n = 50), and a Post‐industrial group (n = 31). We tested group differences in metacarpal shape and CSG, as well as correlations between these two aspects of metacarpal bone structure. Results GM analysis demonstrated metacarpus external shape variation is predominately related to changes in diaphyseal width and articular surface size. Differences in external shape were found between the non‐pollical metacarpals of the Mary Rose and Pre‐industrial groups and between the third metacarpals of the Pre‐ and Post‐industrial groups. CSG results suggest the Mary Rose and Post‐industrial groups have stronger metacarpals than the Pre‐industrial group. Correlating CSG and external shape showed significant relationships between increasing external robusticity and biomechanical strength across non‐pollical metacarpals (r: 0.815–0.535; p ≤ 0.05). Discussion Differences in metacarpal cortical structure and external shape between human groups suggest differences in the type and frequency of manual activities. Combining these results with studies of entheses and kinematics of the hand will improve reconstructions of manual behavior in the past

A four-dimensional probabilistic atlas of the human brain

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

A four-dimensional probabilistic atlas of the human brain

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

Physiology of rodent olfactory bulb interneurons

The sense of olfaction is a central gateway of perceiving and evaluating an animal’s environment filled with volatile chemicals. It affects individual and social behavior in an evaluative way, i.e. by helping to find food sources, warning from dangers like toxins or predators or influencing mating choice. Already the first central station for vertebrate olfactory processing, the olfactory bulb (OB), is astonishingly complex. Its structure features several horizontal layers of signal transformation that includes a large variety of local interneurons (INs). Most of these cells are subject to adult neurogenesis, which rejuvenates and remodels the circuitry throughout life. One of those interneuron subtypes, the granule cell (GC), poses the most numerous cell type of the olfactory bulb. As the major synaptic connection of the bulb, linking different glomerular units, it participates in numerous reported tasks like odor discrimination or memory formation. Many of those capacities are attributable to the function of peculiar spines with long necks and enormous bulbar heads called gemmules. They accommodate pre- and postsynaptic specializations of the reciprocal synapse with mitral cells (MCs) that are topographically and functionally linked and feature many modes of signal integration and transmission. As of yet, the mechanistic underpinnings of activation and neurotransmitter release are not yet resolved in great detail. This gave rise to the first project of this thesis, which focusses on the detailed granule cell gemmule physiology during local glutamatergic activation. With the help of two-photon glutamate uncaging and concomitant calcium imaging, the spine could be selectively stimulated and its physiological dynamics tested. By the use of different pharmacological agents, we could verify the importance of voltage gated sodium channels (Nav) for local signal amplification and the involvement of NMDA and high voltage activated calcium channels (HVACCs) in the calcium elevation during local stimulation, which is important for γ-aminobutyric acid (GABA) release from the spine. The superthreshold depolarizing signal and strong calcium elevation during local input are exclusively restricted to the spine, which affirms the chemical and electrical isolation of gemmules from the rest of the cell. In this study we thereby confirmed the theoretical prediction of active computation within single spines in our system, emphasizing the functional importance of morphological compartmentalization for the cell’s physiology. The second largest population of interneurons in the olfactory bulb is located in the glomerular layer (GL) of the olfactory bulb and subsumes a plethora of different cell types, categorized in terms of molecular characteristics (mostly neurotransmitter), morphology and function. Among those, dopaminergic (DAergic) juxtaglomerular cells (JGCs) form a subpopulation, which the second part of this thesis is focused on. Innervated by the first or second synapse in the olfactory pathway, these cells exert strong influence in very early stages of olfactory signaling. The gating and transformation of inputs locally and very importantly also laterally over large distances originate from several factors. This cell grouping usually expresses two neurotransmitters at the same time, GABA and dopamine (DA), and encompass many different morphologies and synaptic arrangements with other cell types. Utilizing dopamine transporter (DAT) based staining methods in three animal populations differing in age and species, this study revealed a larger diversity of dopaminergic cell types in the glomerular layer. New ‘uniglomerular’ and a ‘clasping’ cell types were discriminated, showing distinct dendritic formations and glomerulus innervations, which was assessed with a new morphometric tool kit. The clasping cell type features dendritic specializations, densely clasping around single cell bodies. These morphological traits occur in higher abundance and complexity specifically among adult animals and could be structures of neurotransmitter output since they show strong calcium influx upon soma depolarization. Comparisons of the three animal populations showed age- and/or species-dependent changes in the subtype composition of dopaminergic JGCs. Concordant with recent research, the inclusion of age-dependent comparisons in bulbar studies turned out to be of great significance

Secular Change of the Modern Human Bony Pelvis: Examining Morphology in the United States using Metrics and Geometric Morphometry

The human bony pelvis has evolved into its current form through competing selective forces. Bipedalism and parturition of large headed babies resulted in a form that is a complex compromise. While the morphology of the human pelvis has been extensively studied, the changes that have occurred since the adoption of the modern form, the secular changes that continue to alter the size and shape of the pelvis, have not received nearly as much attention. This research aims to examine the changes that have altered the morphology of the human bony pelvic girdle of individuals in the United States born between 1840 and1981. Secular changes in the human skeleton have been documented. Improvements in nutrition, decreased disease load, exogamy, activity, climate, and other factors have led to unprecedented growth in stature and weight. The size and shape of the pelvic canal, os coxa, and bi-iliac breadth were all examined in this study. Coordinate data from males and females, blacks and whites were digitized. Calculated inter-landmark data was analyzed using traditional metric methods and the coordinate data was analyzed using 3D geometric morphometrics. After separating the samples into cohorts by sex and ancestry, results indicate that there is secular change occurring in the modern human bony pelvis. Changes in shape are significant across the groups while only white males exhibit increases in size. The dimensions of the pelvic canal have changed over time. The birth canal is becoming more rounded with the inlet anteroposterior diameter and the outlet transverse diameter becoming longer. These diameters, once limiters, are believed to have led to an adoption of the rotational birth method practiced by modern humans. In addition, the bowl of the pelvis is becoming less flared. Childhood improvements in nutrition and decreases in strenuous activity may be the cause of the dimension changes in the bony pelvis. The similar changes across both sexes and ancestries indicate a similar environmental cause. However, it is likely a combination of factors that are difficult to tease apart. Whether the increases continue remains to be determined