Identification of genetically mediated cortical networks: a multivariate study of pediatric twins and siblings.

Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.

High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice.

Detailed anatomical atlases can provide considerable interpretive power in studies of both human and rodent neuroanatomy. Here we describe a three-dimensional atlas of the mouse brain, manually segmented into 62 structures, based on an average of 32 mum isotropic resolution T(2)-weighted, within skull images of forty 12 week old C57Bl/6J mice, scanned on a 7 T scanner. Individual scans were normalized, registered, and averaged into one volume. Structures within the cerebrum, cerebellum, and brainstem were painted on each slice of the average MR image while using simultaneous viewing of the coronal, sagittal and horizontal orientations. The final product, which will be freely available to the research community, provides the most detailed MR-based, three-dimensional neuroanatomical atlas of the whole brain yet created. The atlas is furthermore accompanied by ancillary detailed descriptions of boundaries for each structure and provides high quality neuroanatomical details pertinent to MR studies using mouse models in research.

Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype.

The epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for the development of AD. The authors compared longitudinal rates of change in hippocampal volume as a function of APOE genotype in nondemented elderly individuals. Rate of volumetric loss was significantly greater among epsilon4+ compared with epsilon4- individuals. These results indicate that individuals positive for the APOE epsilon4 allele may show a greater rate of hippocampal atrophy than their epsilon4- counterparts, even in the absence of a diagnosis of AD.

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.

Thrombolytic therapy for pulmonary embolism: reversal of shock in the early postoperative period.

Life-threatening acute pulmonary embolism (PE) associated with circulatory shock requires effective therapy directed at removing the obstruction to flow in the pulmonary vasculature and improving hemodynamics. Options for treatment are pulmonary embolectomy and thrombolytic therapy. Although safe and effective, thrombolytic therapy is relatively contraindicated within 10 days of major surgery due to the risk of bleeding. Intravenous streptokinase was administered to a man on the third postoperative day for treatment of a massive PE associated with circulatory shock. Within 2 hours of initiating therapy, the patient experienced marked improvement in hemodynamics and tissue perfusion. No bleeding complications were noted. This case demonstrates that intravenous thrombolytics may be administered safely to patients who have recently undergone surgery. It also underscores that the decision to apply the therapy when relatively contraindicated must be made on an individual patient basis and thus ensure that potentially life-saving therapy is not withheld from those who require it most.

Design and construction of a realistic digital brain phantom.

After conception and implementation of any new medical image processing algorithm, validation is an important step to ensure that the procedure fulfills all requirements set forth at the initial design stage. Although the algorithm must be evaluated on real data, a comprehensive validation requires the additional use of simulated data since it is impossible to establish ground truth with in vivo data. Experiments with simulated data permit controlled evaluation over a wide range of conditions (e.g., different levels of noise, contrast, intensity artefacts, or geometric distortion). Such considerations have become increasingly important with the rapid growth of neuroimaging, i.e., computational analysis of brain structure and function using brain scanning methods such as positron emission tomography and magnetic resonance imaging. Since simple objects such as ellipsoids or parallelepipedes do not reflect the complexity of natural brain anatomy, we present the design and creation of a realistic, high-resolution, digital, volumetric phantom of the human brain. This three-dimensional digital brain phantom is made up of ten volumetric data sets that define the spatial distribution for different tissues (e.g., grey matter, white matter, muscle, skin, etc.), where voxel intensity is proportional to the fraction of tissue within the voxel. The digital brain phantom can be used to simulate tomographic images of the head. Since the contribution of each tissue type to each voxel in the brain phantom is known, it can be used as the gold standard to test analysis algorithms such as classification procedures which seek to identify the tissue "type" of each image voxel. Furthermore, since the same anatomical phantom may be used to drive simulators for different modalities, it is the ideal tool to test intermodality registration algorithms. The brain phantom and simulated MR images have been made publicly available on the Internet (http://www.bic.mni.mcgill.ca/brainweb).

Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study.

Studies of mouse cerebral vasculature to date have focused on the circle of Willis without examining the morphological distribution of blood vessels through the rest of the brain. Since mouse models are frequently used in brain-related studies, there is a need for a comprehensive cerebral vasculature atlas for the mouse with an emphasis on the location of vessels with respect to neuroanatomical structures, the watershed regions associated with specific arteries, as well as a consistent nomenclature of the cerebral vessels. This article describes such an atlas, based on a combination of magnetic resonance and computed tomography technology to yield high-resolution volumetric and vasculature data on CBA mouse. This three-dimensional vasculature dataset provides an anatomical resource for future mouse studies.

Automated 3-D extraction of inner and outer surfaces of cerebral cortex from MRI.

Automatic computer processing of large multidimensional images such as those produced by magnetic resonance imaging (MRI) is greatly aided by deformable models, which are used to extract, identify, and quantify specific neuroanatomic structures. A general method of deforming polyhedra is presented here, with two novel features. First, explicit prevention of self-intersecting surface geometries is provided, unlike conventional deformable models, which use regularization constraints to discourage but not necessarily prevent such behavior. Second, deformation of multiple surfaces with intersurface proximity constraints allows each surface to help guide other surfaces into place using model-based constraints such as expected thickness of an anatomic surface. These two features are used advantageously to identify automatically the total surface of the outer and inner boundaries of cerebral cortical gray matter from normal human MR images, accurately locating the depths of the sulci, even where noise and partial volume artifacts in the image obscure the visibility of sulci. The extracted surfaces are enforced to be simple two-dimensional manifolds (having the topology of a sphere), even though the data may have topological holes. This automatic 3-D cortex segmentation technique has been applied to 150 normal subjects, simultaneously extracting both the gray/white and gray/cerebrospinal fluid interface from each individual. The collection of surfaces has been used to create a spatial map of the mean and standard deviation for the location and the thickness of cortical gray matter. Three alternative criteria for defining cortical thickness at each cortical location were developed and compared. These results are shown to corroborate published postmortem and in vivo measurements of cortical thickness.

Monoamines and their metabolites in somatosensory, visual, and cingulate cortices of adult rat: differences in content and lack of sidedness.

Small areas of somatosensory, visual and cingulate cortex were microdissected and assayed for their monoamine content by high-performance liquid chromatography with electrochemical detection. No differences were found between the right and the left hemisphere for any area nor for any of the monoamines. The values averaged from left and right hemispheres for the sensory areas were significantly different from the cingulate in the content of norepinephrine, 4-hydroxy-3-methoxyphenylglycol, dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 5-hydroxy-1-tryptophan, serotonin and 5-hydroxyindole-3-acetic acid. The two sensory cortices differed in their levels of norepinephrine, dopamine, 3-4-dihydroxyphenylacetic acid and homovanillic acid. In the latter comparison, the measured amounts were higher in somatosensory than in visual cortex. This biochemical heterogeneity in monoamine distribution may reflect specific innervation patterns for these compounds in these discrete cortical areas and allows differences in content to be related to functional specializations of the cerebral cortex.

Measurement of cortical thickness using an automated 3-D algorithm: a validation study.

A validation study was conducted to assess the accuracy of the algorithm developed by MacDonald et al. (1999) for measuring cortical thickness. This algorithm automatically determines the cortical thickness by 3-D extraction of the inner and outer surfaces of the cerebral cortex from an MRI scan. A manual method of tagging the grey-csf and grey-white interface was used on 20 regions (10 cortical areas found in each hemisphere) in 40 MRIs of the brain to validate the algorithm. The regions were chosen throughout the cortex to get broad assessment of the algorithm's performance. Accuracy was determined by an anatomist tagging the csf-grey and grey-white borders of selected gyri and by allowing the algorithm to determine the csf-grey and grey-white borders and the corresponding cortical thickness of the same region. Results from the manual and automatic methods were statistically compared using overall ANOVA and paired t tests for each region. The manual and automatic methods were in agreement for all but 4 of the 20 regions tested. The four regions where there were significant differences between the two methods were the insula left and right, the right cuneus, and the right parahippocampus. We conclude that the automatic algorithm is valid for most of the cortex and provides a viable alternative to manual methods of determining cortical thickness in vivo. However, caution should be taken when measuring the regions mentioned previously where the results of the algorithm can be biased by surrounding grey structures.

A new anatomical landmark for reliable identification of human area V5/MT: a quantitative analysis of sulcal patterning.

The location of human area V5 (or MT) has been correlated with the intersection of the ascending limb of the inferior temporal sulcus (ALITS) and the lateral occipital sulcus (LO). This study was undertaken to attempt a replication and quantification of these observations using functional magnetic resonance imaging. V5 was significantly activated in 19 hemispheres with alternating, low contrast, random checkerboard patterns. We confirmed the stereotaxic location of V5 and were able to describe a fairly consistent sulcal pattern in the parieto-temporo-occipital cortex. V5 was usually (95%) buried within a sulcus, most commonly within the inferior temporal sulcus (ITS) (11%), the ascending limb of the ITS (ALITS) (53%) and the posterior continuation of the ITS (26%). The average distance from V5 of two identified anatomical landmarks of V5, the junctions of the LO and the ALITS, and the ITS and ALITS, were both 1 cm. However, the LO-ALITS junction often had to be determined by interpolation (47%), and was not always present even with interpolation (21%). In contrast, the ITS-ALITS junction was always present and V5 was usually (90%) located in a sulcus intersecting with this junction, making it a more reliable landmark for localizing V5 with respect to gross morphological features on individual cortical surfaces.

Volumetry of hippocampus and amygdala with high-resolution MRI and three-dimensional analysis software: minimizing the discrepancies between laboratories.

Within the medial temporal lobe, both the hippocampus and amygdala are frequently targeted by researchers and clinicians for volumetric analysis based on magnetic resonance imaging (MRI). However, different data acquisition techniques, analysis software and anatomical boundaries have in the past made it difficult to compare results of MRI studies from different laboratories. In order to reduce these differences, a segmentation protocol was established with 40 healthy normal control subjects recently scanned in our laboratory. Data acquisition was performed with a three-dimensional gradient echo technique, and scans were corrected for non-uniformity and registered into standard stereotaxic space prior to segmentation. Volumetric analysis was performed manually using three-dimensional software that allows simultaneous analysis of sagittal, coronal and horizontal images. Intra- and inter-rater coefficients yielded correlation coefficients comparable with other protocols. The hippocampal volume was larger in the right hemisphere (3324 versus 3208 mm(3)), while no interhemispheric differences for the amygdala (1154 versus 1160 mm(3)) could be observed. Most importantly, results from recent segmentation protocols for hippocampus and amygdala seem to approach each other with regard to mean volumes and interhemispheric differences. This indicates that the advances in scanning technique, volume preparation and segmentation protocols allow a more precise definition of medial temporal lobe structures with MRI, and that results for mean volumes for hippocampus and amygdala from different laboratories will eventually become comparable.

Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space.

We have prepared an atlas of the human cerebellum using high-resolution magnetic resonance-derived images warped into the proportional stereotaxic space of Talairach and Tournoux. Software that permits simultaneous visualization of the three cardinal planes facilitated the identification of the cerebellar fissures and lobules. A revised version of the Larsell nomenclature facilitated a simple description of the cerebellum. This atlas derived from a single individual was instrumental in addressing longstanding debates about the gross morphologic organization of the cerebellum. It may serve as the template for more precise identification of cerebellar topography in functional imaging studies in normals, for investigating clinical-pathologic correlations in patients, and for the development of future probabilistic maps of the human cerebellum.

A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).

Motivated by the vast amount of information that is rapidly accumulating about the human brain in digital form, we embarked upon a program in 1992 to develop a four-dimensional probabilistic atlas and reference system for the human brain. Through an International Consortium for Brain Mapping (ICBM) a dataset is being collected that includes 7000 subjects between the ages of eighteen and ninety years and including 342 mono- and dizygotic twins. Data on each subject includes detailed demographic, clinical, behavioural and imaging information. DNA has been collected for genotyping from 5800 subjects. A component of the programme uses post-mortem tissue to determine the probabilistic distribution of microscopic cyto- and chemoarchitectural regions in the human brain. This, combined with macroscopic information about structure and function derived from subjects in vivo, provides the first large scale opportunity to gain meaningful insights into the concordance or discordance in micro- and macroscopic structure and function. The philosophy, strategy, algorithm development, data acquisition techniques and validation methods are described in this report along with database structures. Examples of results are described for the normal adult human brain as well as examples in patients with Alzheimer's disease and multiple sclerosis. The ability to quantify the variance of the human brain as a function of age in a large population of subjects for whom data is also available about their genetic composition and behaviour will allow for the first assessment of cerebral genotype-phenotype-behavioural correlations in humans to take place in a population this large. This approach and its application should provide new insights and opportunities for investigators interested in basic neuroscience, clinical diagnostics and the evaluation of neuropsychiatric disorders in patients.