The INCF Digital Atlasing Program: Report on Digital Atlasing Standards in the Rodent Brain

The goal of the INCF Digital Atlasing Program is to provide the vision and direction necessary to make the rapidly growing collection of multidimensional data of the rodent brain (images, gene expression, etc.) widely accessible and usable to the international research community. This Digital Brain Atlasing Standards Task Force was formed in May 2008 to investigate the state of rodent brain digital atlasing, and formulate standards, guidelines, and policy recommendations.

Our first objective has been the preparation of a detailed document that includes the vision and specific description of an infrastructure, systems and methods capable of serving the scientific goals of the community, as well as practical issues for achieving
the goals. This report builds on the 1st INCF Workshop on Mouse and Rat Brain Digital Atlasing Systems (Boline et al., 2007, _Nature Preceedings_, doi:10.1038/npre.2007.1046.1) and includes a more detailed analysis of both the current state and desired state of digital atlasing along with specific recommendations for achieving these goals

Digital Atlas of Anatomical Subdivisions and Boundaries of the Rat Hippocampal Region

The rat hippocampal region is frequently studied in relation to learning and memory processes and brain diseases. The region is complex, consisting of multiple subdivisions that are challenging to delineate anatomically. Published atlases of the rat brain typically lack the underlying histological criteria necessary to identify boundaries, and textbooks descriptions of the region are often inadequately illustrated and thus difficult to relate to experimental data. An overview of both anatomical features and criteria used to delineate boundaries is required to assign location to experimental material from the hippocampal region. To address this issue, we have developed a web-based atlas application in which images of histological sections are integrated with new and up-to-date criteria for subdividing the rat hippocampus formation, fasciola, and associated parahippocampal regions. The atlas application consists of an interactive image viewer with high-resolution images of an extensive series of sections stained for NeuN, calbindin, and parvalbumin, and an index of structures with detailed descriptions of the criteria used to define the boundaries. Images can be inspected with a graphical overlay of selected subregions. Bi-directional links between images and the index of structures are provided. In summary, we provide a novel content-rich digital atlas resource facilitating identification of morphological features relevant for delineating the anatomical subdivisions of the rat hippocampal region. The atlas application is available at http://www.rbwb.org

Computational methods to create and analyze a digital gene expression atlas of embryo development from microscopy images

Abstract The creation of atlases, or digital models where information from different subjects can be combined, is a field of increasing interest in biomedical imaging. When a single image does not contain enough information to appropriately describe the organism under study, it is then necessary to acquire images of several individuals, each of them containing complementary data with respect to the rest of the components in the cohort. This approach allows creating digital prototypes, ranging from anatomical atlases of human patients and organs, obtained for instance from Magnetic Resonance Imaging, to gene expression cartographies of embryo development, typically achieved from Light Microscopy. Within such context, in this PhD Thesis we propose, develop and validate new dedicated image processing methodologies that, based on image registration techniques, bring information from multiple individuals into alignment within a single digital atlas model. We also elaborate a dedicated software visualization platform to explore the resulting wealth of multi-dimensional data and novel analysis algo-rithms to automatically mine the generated resource in search of bio¬logical insights. In particular, this work focuses on gene expression data from developing zebrafish embryos imaged at the cellular resolution level with Two-Photon Laser Scanning Microscopy. Disposing of quantitative measurements relating multiple gene expressions to cell position and their evolution in time is a fundamental prerequisite to understand embryogenesis multi-scale processes. However, the number of gene expressions that can be simultaneously stained in one acquisition is limited due to optical and labeling constraints. These limitations motivate the implementation of atlasing strategies that can recreate a virtual gene expression multiplex. The developed computational tools have been tested in two different scenarios. The first one is the early zebrafish embryogenesis where the resulting atlas constitutes a link between the phenotype and the genotype at the cellular level. The second one is the late zebrafish brain where the resulting atlas allows studies relating gene expression to brain regionalization and neurogenesis. The proposed computational frameworks have been adapted to the requirements of both scenarios, such as the integration of partial views of the embryo into a whole embryo model with cellular resolution or the registration of anatom¬ical traits with deformable transformation models non-dependent on any specific labeling. The software implementation of the atlas generation tool (Match-IT) and the visualization platform (Atlas-IT) together with the gene expression atlas resources developed in this Thesis are to be made freely available to the scientific community. Lastly, a novel proof-of-concept experiment integrates for the first time 3D gene expression atlas resources with cell lineages extracted from live embryos, opening up the door to correlate genetic and cellular spatio-temporal dynamics. La creación de atlas, o modelos digitales, donde la información de distintos sujetos puede ser combinada, es un campo de creciente interés en imagen biomédica. Cuando una sola imagen no contiene suficientes datos como para describir apropiadamente el organismo objeto de estudio, se hace necesario adquirir imágenes de varios individuos, cada una de las cuales contiene información complementaria respecto al resto de componentes del grupo. De este modo, es posible crear prototipos digitales, que pueden ir desde atlas anatómicos de órganos y pacientes humanos, adquiridos por ejemplo mediante Resonancia Magnética, hasta cartografías de la expresión genética del desarrollo de embrionario, típicamente adquiridas mediante Microscopía Optica. Dentro de este contexto, en esta Tesis Doctoral se introducen, desarrollan y validan nuevos métodos de procesado de imagen que, basándose en técnicas de registro de imagen, son capaces de alinear imágenes y datos provenientes de múltiples individuos en un solo atlas digital. Además, se ha elaborado una plataforma de visualization específicamente diseñada para explorar la gran cantidad de datos, caracterizados por su multi-dimensionalidad, que resulta de estos métodos. Asimismo, se han propuesto novedosos algoritmos de análisis y minería de datos que permiten inspeccionar automáticamente los atlas generados en busca de conclusiones biológicas significativas. En particular, este trabajo se centra en datos de expresión genética del desarrollo embrionario del pez cebra, adquiridos mediante Microscopía dos fotones con resolución celular. Disponer de medidas cuantitativas que relacionen estas expresiones genéticas con las posiciones celulares y su evolución en el tiempo es un prerrequisito fundamental para comprender los procesos multi-escala característicos de la morfogénesis. Sin embargo, el número de expresiones genéticos que pueden ser simultáneamente etiquetados en una sola adquisición es reducido debido a limitaciones tanto ópticas como del etiquetado. Estas limitaciones requieren la implementación de estrategias de creación de atlas que puedan recrear un multiplexado virtual de expresiones genéticas. Las herramientas computacionales desarrolladas han sido validadas en dos escenarios distintos. El primer escenario es el desarrollo embrionario temprano del pez cebra, donde el atlas resultante permite constituir un vínculo, a nivel celular, entre el fenotipo y el genotipo de este organismo modelo. El segundo escenario corresponde a estadios tardíos del desarrollo del cerebro del pez cebra, donde el atlas resultante permite relacionar expresiones genéticas con la regionalización del cerebro y la formación de neuronas. La plataforma computacional desarrollada ha sido adaptada a los requisitos y retos planteados en ambos escenarios, como la integración, a resolución celular, de vistas parciales dentro de un modelo consistente en un embrión completo, o el alineamiento entre estructuras de referencia anatómica equivalentes, logrado mediante el uso de modelos de transformación deformables que no requieren ningún marcador específico. Está previsto poner a disposición de la comunidad científica tanto la herramienta de generación de atlas (Match-IT), como su plataforma de visualización (Atlas-IT), así como las bases de datos de expresión genética creadas a partir de estas herramientas. Por último, dentro de la presente Tesis Doctoral, se ha incluido una prueba conceptual innovadora que permite integrar los mencionados atlas de expresión genética tridimensionales dentro del linaje celular extraído de una adquisición in vivo de un embrión. Esta prueba conceptual abre la puerta a la posibilidad de correlar, por primera vez, las dinámicas espacio-temporales de genes y células

1st INCF Workshop on Genetic Animal Models for Brain Diseases

The INCF Secretariat organized a workshop to focus on the “role of neuroinformatics in the processes of building, evaluating, and using genetic animal models for brain diseases” in Stockholm, December 13–14, 2009. Eight scientists specialized in the fields of neuroinformatics, database, ontologies, and brain disease participated together with two representatives of the National Institutes of Health and the European Union, as well as three observers of the national INCF nodes of Norway, Poland, and the United Kingdom

Assembling models of embryo development: Image analysis and the construction of digital atlases

Digital atlases of animal development provide a quantitative description of morphogenesis, opening the path toward processes modeling. Prototypic atlases offer a data integration framework where to gather information from cohorts of individuals with phenotypic variability. Relevant information for further theoretical reconstruction includes measurements in time and space for cell behaviors and gene expression. The latter as well as data integration in a prototypic model, rely on image processing strategies. Developing the tools to integrate and analyze biological multidimensional data are highly relevant for assessing chemical toxicity or performing drugs preclinical testing. This article surveys some of the most prominent efforts to assemble these prototypes, categorizes them according to salient criteria and discusses the key questions in the field and the future challenges toward the reconstruction of multiscale dynamics in model organisms

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

Curated Databases in the Life Sciences: The Edinburgh Mouse Atlas Project

This case study scopes and assesses the data curation aspects of the Edinburgh Mouse Atlas Project (EMAP), a programme funded by the Medical Research Council (MRC). The principal goal for EMAP is to develop an expression summary for each gene in the mouse embryo, which collectively has been named the Edinburgh Mouse Atlas Gene-Expression Database (EMAGE)

Cognitive dysfunction in patients treated with androgen deprivation therapy: a multimodality functional imaging study to evaluate neuroinflammation

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer's disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI. METHODS: Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps. RESULTS: Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex. CONCLUSIONS: We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI

Diffusion Tensor Imaging Biomarkers of Brain Development and Disease

<p>Understanding the structure of the brain has been a major goal of neuroscience research over the past century, driven in part by the understanding that brain structure closely follows function. Normative brain maps, or atlases, can be used to understand normal brain structure, and to identify structural differences resulting from disease. Recently, diffusion tensor magnetic resonance imaging has emerged as a powerful tool for brain atlasing; however, its utility is hindered by image resolution and signal limitations. These limitations can be overcome by imaging fixed ex-vivo specimens stained with MRI contrast agents, a technique known as diffusion tensor magnetic resonance histology (DT-MRH). DT-MRH represents a unique, quantitative tool for mapping the brain with unprecedented structural detail. This technique has engendered a new generation of 3D, digital brain atlases, capable of representing complex dynamic processes such as neurodevelopment. This dissertation explores the use of DT-MRH for quantitative brain atlasing in an animal model and initial work in the human brain. </p><p>Chapter 1 describes the advantages of the DT-MRH technique, and the motivations for generating a quantitative atlas of rat postnatal neurodevelopment. The second chapter covers optimization of the DT-MRH hardware and pulse sequence design for imaging the developing rat brain. Chapter 3 details the acquisition and curation of rat neurodevelopmental atlas data. Chapter 4 describes the creation and implementation of an ontology-based segmentation scheme for tracking changes in the developing brain. Chapters 5 and 6 pertain to analyses of volumetric changes and diffusion tensor parameter changes throughout rat postnatal neurodevelopment, respectively. Together, the first six chapters demonstrate many of the unique and scientifically valuable features of DT-MRH brain atlases in a popular animal model.</p><p>The final two chapters are concerned with translating the DT-MRH technique for use in human and non-human primate brain atlasing. Chapter 7 explores the validity of assumptions imposed by DT-MRH in the primate brain. Specifically, it analyzes computer models and experimental data to determine the extent to which intravoxel diffusion complexity exists in the rhesus macaque brain, a close model for the human brain. Finally, Chapter 8 presents conclusions and future directions for DT-MRH brain atlasing, and includes initial work in creating DT-MRH atlases of the human brain. In conclusion, this work demonstrates the utility of a DT-MRH brain atlasing with an atlas of rat postnatal neurodevelopment, and lays the foundation for creating a DT-MRH atlas of the human brain.</p>Dissertatio