Analysis of cortical morphometric variability using labeled cortical distance maps.

Morphometric (i.e., shape and size) differences in the anatomy of cortical structures are associated with neurodevelopmental and neuropsychiatric disorders. Such differences can be quantized and detected by a powerful tool called Labeled Cortical Distance Map (LCDM). The LCDM method provides distances of labeled gray matter (GM) voxels from the GM/white matter (WM) surface for specific cortical structures (or tissues). Here we describe a method to analyze morphometric variability in the particular tissue using LCDM distances. To extract more of the information provided by LCDM distances, we perform pooling and censoring of LCDM distances. In particular, we employ Brown-Forsythe (BF) test of homogeneity of variance (HOV) on the LCDM distances. HOV analysis of pooled distances provides an overall analysis of morphometric variability of the LCDMs due to the disease in question, while the HOV analysis of censored distances suggests the location(s) of significant variation in these differences (i.e., at which distance from the GM/WM surface the morphometric variability starts to be significant). We also check for the influence of assumption violations on the HOV analysis of LCDM distances. In particular, we demonstrate that BF HOV test is robust to assumption violations such as the non-normality and within sample dependence of the residuals from the median for pooled and censored distances and are robust to data aggregation which occurs in analysis of censored distances. We recommend HOV analysis as a complementary tool to the analysis of distribution/location differences. We also apply the methodology on simulated normal and exponential data sets and assess the performance of the methods when more of the underlying assumptions are satisfied. We illustrate the methodology on a real data example, namely, LCDM distances of GM voxels in ventral medial prefrontal cortices (VMPFCs) to see the effects of depression or being of high risk to depression on the morphometry of VMPFCs. The methodology used here is also valid for morphometric analysis of other cortical structures.

The development of a population of 4D pediatric XCAT phantoms for imaging research and optimization.

PURPOSE: We previously developed a set of highly detailed 4D reference pediatric extended cardiac-torso (XCAT) phantoms at ages of newborn, 1, 5, 10, and 15 yr with organ and tissue masses matched to ICRP Publication 89 values. In this work, we extended this reference set to a series of 64 pediatric phantoms of varying age and height and body mass percentiles representative of the public at large. The models will provide a library of pediatric phantoms for optimizing pediatric imaging protocols. METHODS: High resolution positron emission tomography-computed tomography data obtained from the Duke University database were reviewed by a practicing experienced radiologist for anatomic regularity. The CT portion of the data was then segmented with manual and semiautomatic methods to form a target model defined using nonuniform rational B-spline surfaces. A multichannel large deformation diffeomorphic metric mapping algorithm was used to calculate the transform from the best age matching pediatric XCAT reference phantom to the patient target. The transform was used to complete the target, filling in the nonsegmented structures and defining models for the cardiac and respiratory motions. The complete phantoms, consisting of thousands of structures, were then manually inspected for anatomical accuracy. The mass for each major tissue was calculated and compared to linearly interpolated ICRP values for different ages. RESULTS: Sixty four new pediatric phantoms were created in this manner. Each model contains the same level of detail as the original XCAT reference phantoms and also includes parameterized models for the cardiac and respiratory motions. For the phantoms that were 10 yr old and younger, we included both sets of reproductive organs. This gave them the capability to simulate both male and female anatomy. With this, the population can be expanded to 92. Wide anatomical variation was clearly seen amongst the phantom models, both in organ shape and size, even for models of the same age and sex. The phantoms can be combined with existing simulation packages to generate realistic pediatric imaging data from different modalities. CONCLUSIONS: This work provides a large cohort of highly detailed pediatric phantoms with 4D capabilities of varying age, height, and body mass. The population of phantoms will provide a vital tool with which to optimize 3D and 4D pediatric imaging devices and techniques in terms of image quality and radiation-absorbed dose.

Ventromedial prefrontal cortex thinning in preschool-onset depression.

BACKGROUND: The ventromedial prefrontal cortex (VMPFC) is a key center of affect regulation and processing, fundamental aspects of emotional competence which are disrupted in mood disorders. Structural alterations of VMPFC have consistently been observed in adult major depression and are associated with depression severity, yet it is unknown whether young children with depression demonstrate similar abnormalities. We investigated cortical thickness differences in the VMPFC of children with a history of preschool-onset depression (PO-MDD). METHODS: Participants in a longitudinal study of PO-MDD underwent structural brain imaging between the ages of 7 and 12 years. Using local cortical distance metrics, cortical thickness of the VMPFC was compared in children with and without a history of PO-MDD. RESULTS: Children previously diagnosed with PO-MDD (n=34) had significantly thinner right VMPFC vs. children without a history of PO-MDD [(n=95); F(1,126)=5.97, (p=.016)]. This effect was specific to children with a history of PO-MDD vs. other psychiatric conditions and was independent of comorbid anxiety or externalizing disorders. Decreases in right VMPFC thickness were predicted by preschool depressive symptoms independent of depressive symptoms in school age. LIMITATIONS: Results are cross-sectional and cannot distinguish whether thinner right VMPFC represents a vulnerability marker of MDD, consequence of MDD, or marker of remitted MDD. Longitudinal imaging is needed to contextualize how this difference relates to normative VMPFC structural development. CONCLUSIONS: Onset of depression at preschool age was associated with decreased cortical thickness of right VMPFC. This finding implicates the VMPFC in depression from very early stages of brain development.

A set of 4D pediatric XCAT reference phantoms for multimodality research.

PURPOSE: The authors previously developed an adult population of 4D extended cardiac-torso (XCAT) phantoms for multimodality imaging research. In this work, the authors develop a reference set of 4D pediatric XCAT phantoms consisting of male and female anatomies at ages of newborn, 1, 5, 10, and 15 years. These models will serve as the foundation from which the authors will create a vast population of pediatric phantoms for optimizing pediatric CT imaging protocols. METHODS: Each phantom was based on a unique set of CT data from a normal patient obtained from the Duke University database. The datasets were selected to best match the reference values for height and weight for the different ages and genders according to ICRP Publication 89. The major organs and structures were segmented from the CT data and used to create an initial pediatric model defined using nonuniform rational B-spline surfaces. The CT data covered the entire torso and part of the head. To complete the body, the authors manually added on the top of the head and the arms and legs using scaled versions of the XCAT adult models or additional models created from cadaver data. A multichannel large deformation diffeomorphic metric mapping algorithm was then used to calculate the transform from a template XCAT phantom (male or female 50th percentile adult) to the target pediatric model. The transform was applied to the template XCAT to fill in any unsegmented structures within the target phantom and to implement the 4D cardiac and respiratory models in the new anatomy. The masses of the organs in each phantom were matched to the reference values given in ICRP Publication 89. The new reference models were checked for anatomical accuracy via visual inspection. RESULTS: The authors created a set of ten pediatric reference phantoms that have the same level of detail and functionality as the original XCAT phantom adults. Each consists of thousands of anatomical structures and includes parameterized models for the cardiac and respiratory motions. Based on patient data, the phantoms capture the anatomic variations of childhood, such as the development of bone in the skull, pelvis, and long bones, and the growth of the vertebrae and organs. The phantoms can be combined with existing simulation packages to generate realistic pediatric imaging data from different modalities. CONCLUSIONS: The development of patient-derived pediatric computational phantoms is useful in providing variable anatomies for simulation. Future work will expand this ten-phantom base to a host of pediatric phantoms representative of the public at large. This can provide a means to evaluate and improve pediatric imaging devices and to optimize CT protocols in terms of image quality and radiation dose.

Population of anatomically variable 4D XCAT adult phantoms for imaging research and optimization.

PURPOSE: The authors previously developed the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. The XCAT consisted of highly detailed whole-body models for the standard male and female adult, including the cardiac and respiratory motions. In this work, the authors extend the XCAT beyond these reference anatomies by developing a series of anatomically variable 4D XCAT adult phantoms for imaging research, the first library of 4D computational phantoms. METHODS: The initial anatomy of each phantom was based on chest-abdomen-pelvis computed tomography data from normal patients obtained from the Duke University database. The major organs and structures for each phantom were segmented from the corresponding data and defined using nonuniform rational B-spline surfaces. To complete the body, the authors manually added on the head, arms, and legs using the original XCAT adult male and female anatomies. The structures were scaled to best match the age and anatomy of the patient. A multichannel large deformation diffeomorphic metric mapping algorithm was then used to calculate the transform from the template XCAT phantom (male or female) to the target patient model. The transform was applied to the template XCAT to fill in any unsegmented structures within the target phantom and to implement the 4D cardiac and respiratory models in the new anatomy. Each new phantom was refined by checking for anatomical accuracy via inspection of the models. RESULTS: Using these methods, the authors created a series of computerized phantoms with thousands of anatomical structures and modeling cardiac and respiratory motions. The database consists of 58 (35 male and 23 female) anatomically variable phantoms in total. Like the original XCAT, these phantoms can be combined with existing simulation packages to simulate realistic imaging data. Each new phantom contains parameterized models for the anatomy and the cardiac and respiratory motions and can, therefore, serve as a jumping point from which to create an unlimited number of 3D and 4D variations for imaging research. CONCLUSIONS: A population of phantoms that includes a range of anatomical variations representative of the public at large is needed to more closely mimic a clinical study or trial. The series of anatomically variable phantoms developed in this work provide a valuable resource for investigating 3D and 4D imaging devices and the effects of anatomy and motion in imaging. Combined with Monte Carlo simulation programs, the phantoms also provide a valuable tool to investigate patient-specific dose and image quality, and optimization for adults undergoing imaging procedures.

STATISTICAL ANALYSIS OF CORTICAL MORPHOMETRICS USING POOLED DISTANCES BASED ON LABELED CORTICAL DISTANCE MAPS.

Neuropsychiatric disorders have been demonstrated to manifest shape differences in cortical structures. Labeled Cortical Distance Mapping (LCDM) is a powerful tool in quantifying such morphometric differences and characterizes the morphometry of the laminar cortical mantle of cortical structures. Specifically, LCDM data are distances of labeled gray matter (GM) voxels with respect to the gray/white matter cortical surface. Volumes and descriptive measures (such as means and variances for each subject) based on LCDM distances provide descriptive summary information on some of the shape characteristics. However, additional morphometrics are contained in the data and their analysis may provide additional clues to underlying differences in cortical characteristics. To use more of this information, we pool (merge) LCDM distances from subjects in the same group. These pooled distances can help detect morphometric differences between groups, but do not provide information about the locations of such differences in the tissue in question. In this article, we check for the influence of the assumption violations on the analysis of pooled LCDM distances. We demonstrate that the classical parametric tests are robust to the non-normality and within sample dependence of LCDM distances and nonparametric tests are robust to within sample dependence of LCDM distances. We specify the types of alternatives for which the tests are more sensitive. We also show that the pooled LCDM distances provide powerful results for group differences in distribution of LCDM distances. As an illustrative example, we use GM in the ventral medial prefrontal cortex (VMPFC) in subjects with major depressive disorder (MDD), subjects at high risk (HR) of MDD, and healthy subjects. Significant morphometric differences were found in VMPFC due to MDD or being at HR. In particular, the analysis indicated that distances in left and right VMPFCs tend to decrease due to MDD or being at HR, possibly as a result of thinning. The methodology can also be applied to other cortical structures.

Segmentation of arteries in MPRAGE images of the ventral medial prefrontal cortex.

A method for removing arteries that appear bright with intensities similar to white matter in Magnetized Prepared Rapid Gradient Echo images of the ventral medial prefrontal cortex is described. The Fast Marching method is used to generate a curve within the artery. Then, the largest connected component is selected to segment the artery which is used to mask the image. The surface reconstructed from the masked image yielded cortical thickness maps similar to those generated by manually pruning the arteries from surfaces reconstructed from the original image. The method may be useful in masking vasculature in other cortical regions.

Electromechanical models of the outer hair cell composite membrane.

The outer hair cell (OHC) is an extremely specialized cell and its proper functioning is essential for normal mammalian hearing. This article reviews recent developments in theoretical modeling that have increased our knowledge of the operation of this fascinating cell. The earliest models aimed at capturing experimental observations on voltage-induced cellular length changes and capacitance were based on isotropic elasticity and a two-state Boltzmann function. Recent advances in modeling based on the thermodynamics of orthotropic electroelastic materials better capture the cell's voltage-dependent stiffness, capacitance, interaction with its environment and ability to generate force at high frequencies. While complete models are crucial, simpler continuum models can be derived that retain fidelity over small changes in transmembrane voltage and strains occurring in vivo. By its function in the cochlea, the OHC behaves like a piezoelectric-like actuator, and the main cellular features can be described by piezoelectric models. However, a finer characterization of the cell's composite wall requires understanding the local mechanical and electrical fields. One of the key questions is the relative contribution of the in-plane and bending modes of electromechanical strains and forces (moments). The latter mode is associated with the flexoelectric effect in curved membranes. New data, including a novel experiment with tethers pulled from the cell membrane, can help in estimating the role of different modes of electromechanical coupling. Despite considerable progress, many problems still confound modelers. Thus, this article will conclude with a discussion of unanswered questions and highlight directions for future research.

Labeled cortical mantle distance maps of the cingulate quantify differences between dementia of the Alzheimer type and healthy aging.

The cingulate gyri in 37 subjects with and without early dementia of the Alzheimer type (DAT) were studied by using MRI at 1.0 mm3 isotropic resolution. Groups were segregated into young controls (n = 10), age-matched normal controls (n = 10), very mild DAT (n = 8), and mild DAT (n = 9). By using automated Bayesian segmentation of the cortex and gray matter/white matter (GM/WM) isosurface generation, tissue compartments were labeled into gray, white, and cerebrospinal fluid as a function of distance from the GM/WM isosurface. Cortical mantle distance maps are generated profiling the GM volume and cortical mantle distribution as a function of distance from the cortical surface. Probabilistic tests based on generalizations of Wilcoxon-Mann-Whitney tests were applied to quantify cortical mantle distribution changes with normal and abnormal aging. We find no significant change between young controls and healthy aging as measured by the GM volume and cortical mantle distribution as a function of distance in both anterior and posterior regions of the cingulate. Significant progression of GM loss is seen in the very mild DAT and mild DAT groups in all areas of the cingulate. Posterior regions show both GM volume loss as well as significant cortical mantle distribution decrease with the onset of mild DAT. The "shape of the cortical mantle" as measured by the cortical mantle distance profiles manifests a pronounced increase in variability with mild DAT.

Dynamic programming generation of boundaries of local coordinatized submanifolds in the neocortex: application to the planum temporale.

Dynamic programming is used to define boundaries of cortical submanifolds with focus on the planum temporale (PT) of the superior temporal gyrus (STG), which has been implicated in a variety of neuropsychiatric disorders. To this end, automated methods are used to generate the PT manifold from 10 high-resolution MRI subvolumes ROI masks encompassing the STG. A procedure to define the subvolume ROI masks from original MRI brain scans is developed. Bayesian segmentation is then used to segment the subvolumes into cerebrospinal fluid, gray matter (GM), and white matter (WM). 3D isocontouring using the intensity value at which there is equal probability of GM and WM is used to reconstruct the triangulated graph representing the STG cortical surface, enabling principal curvature at each point on the graph to be computed. Dynamic programming is used to delineate the PT manifold by tracking principal curves from the retro-insular end of the Heschl's gyrus (HG) to the STG, along the posterior STG up to the start of the ramus and back to the retro-insular end of the HG. A coordinate system is then defined on the PT manifold. The origin is defined by the retro-insular end of the HG and the y-axis passes through the point on the posterior STG where the ramus begins. Automated labeling of GM in the STG is robust with L(1) distances between Bayesian and manual segmentation in the range 0.001-0.12 (n = 20). PT reconstruction is also robust with 90% of the vertices of the reconstructed PT within about 1 voxel (n = 20) from semiautomated contours. Finally, the reliability index (based on interrater intraclass correlation) for the surface area derived from repeated reconstructions is 0.96 for the left PT and 0.94 for the right PT, thus demonstrating the robustness of dynamic programming in defining a coordinate system on the PT. It provides a method with potential significance in the study of neuropsychiatric disorders.

Validating cortical surface analysis of medial prefrontal cortex.

This paper describes cortical analysis of 19 high resolution MRI subvolumes of medial prefrontal cortex (MPFC), a region that has been implicated in major depressive disorder. An automated Bayesian segmentation is used to delineate the MRI subvolumes into cerebrospinal fluid (CSF), gray matter (GM), white matter (WM), and partial volumes of either CSF/GM or GM/WM. The intensity value at which there is equal probability of GM and GM/WM partial volume is used to reconstruct MPFC cortical surfaces based on a 3-D isocontouring algorithm. The segmented data and the generated surfaces are validated by comparison with hand segmented data and semiautomated contours, respectively. The L(1) distances between Bayesian and hand segmented data are 0.05-0.10 (n = 5). Fifty percent of the voxels of the reconstructed surface lie within 0.12-0.28 mm (n = 14) from the semiautomated contours. Cortical thickness metrics are generated in the form of frequency of occurrence histograms for GM and WM labelled voxels as a function of their position from the cortical surface. An algorithm to compute the surface area of the GM/WM interface of the MPFC subvolume is described. These methods represent a novel approach to morphometric chacterization of regional cortex features which may be important in the study of psychiatric disorders such as major depression.

Bayesian construction of geometrically based cortical thickness metrics.

This paper describes the construction of cortical metrics quantifying the probabilistic occurrence of gray matter, white matter, and cerebrospinal fluid compartments in their correlation to the geometry of the neocortex as measured in 0.5-1.0 mm magnetic resonance imagery. These cortical profiles represent the density of the tissue types as a function of distance to the cortical surface. These metrics are consistent when generated across multiple brains indicating a fundamental property of the neocortex. Methods are proposed for incorporating such metrics into automated Bayes segmentation.

An analysis of the hydraulic conductivity of the extracisternal space of the cochlear outer hair cell.

The cylindrically shaped cochlear outer hair cell (OHC) plays an important role in the transduction of acoustic energy into electrical energy in the cochlea. The extracisternal space (ECiS) of the lateral wall of the OHC is the fluid-filled space between the plasma membrane (PM) and the intracellular subsurface cisterna (SSC). In the ECiS, an array of cylindrical micropillars extends from the SSC to the PM. We obtain equations for the pressure, osmotic concentration and fluid velocity in the ECiS from the Brinkman-Stokes equations for steady incompressible flow in a plane channel that encloses an array of cylinders and whose upper wall, i.e. the plasma membrane, has a hydraulic conductivity of P(PM). From these equations we obtain an estimate for the hydraulic conductivity of the ECiS, P(ECiS). We show that the ECiS geometry accounts for P(ECiS) being several orders of magnitude larger than P(PM) and that P(ECiS) increases with the width of the ECiS and decreases with the length of the ECiS.

Measurements and a model of the outer hair cell hydraulic conductivity.

The hydraulic conductivity of the cochlear outer hair cell (OHC) is central to the maintenance of the positive intracellular pressure necessary for its function as the cochlear amplifier. A mathematical model of osmotic water transport across the OHC membrane is formulated. The model relates the OHC hydraulic conductivity, Lp, to the rate of volume change in response to osmotic stimuli. Lp is evaluated from osmotic experiments in which isolated OHCs are exposed to an hypotonic solution. The rate of volume increase in response to the hypotonic challenge was determined by a morphometric analysis of video images of cells. Lp was found to be about 10(-14) m s-1 Pa-1 or equivalently, Pf approximately 10(-4) cm s-1. This is on the low side of values reported for different lipid bilayers and is 2 orders of magnitude lower than the hydraulic conductivity of red blood cells. The relation of the low OHC hydraulic conductivity to the composition and morphology of its membranes is discussed.

The ratio of elastic moduli of cochlear outer hair cells derived from osmotic experiments.

Outer hair cells (OHCs) were subjected to three different hypo-osmotic challenges which induced shape changes in OHCs. The longitudinal and circumferential strains, epsilon z and epsilon c, respectively, were extracted from a morphometric analysis of video images of the cells. A value of epsilon z/epsilon c = -0.72 was obtained and was found to be independent of the applied osmotic gradient. Using an elastic isotropic membrane model for the OHC lateral wall, the ratio of the elastic shear modulus mu to the elastic area expansion modulus K was calculated yielding a value of 0.054. The contribution of this ratio to OHC mechanics is discussed.