Enhanced cortical thickness measurements for rodent brains via Lagrangian-based RK4 streamline computation

The cortical thickness of the mammalian brain is an important morphological characteristic that can be used to investigate and observe the brain's developmental changes that might be caused by biologically toxic substances such as ethanol or cocaine. Although various cortical thickness analysis methods have been proposed that are applicable for human brain and have developed into well-validated open-source software packages, cortical thickness analysis methods for rodent brains have not yet become as robust and accurate as those designed for human brains. Based on a previously proposed cortical thickness measurement pipeline for rodent brain analysis,1 we present an enhanced cortical thickness pipeline in terms of accuracy and anatomical consistency. First, we propose a Lagrangian-based computational approach in the thickness measurement step in order to minimize local truncation error using the fourth-order Runge-Kutta method. Second, by constructing a line object for each streamline of the thickness measurement, we can visualize the way the thickness is measured and achieve sub-voxel accuracy by performing geometric post-processing. Last, with emphasis on the importance of an anatomically consistent partial differential equation (PDE) boundary map, we propose an automatic PDE boundary map generation algorithm that is specific to rodent brain anatomy, which does not require manual labeling. The results show that the proposed cortical thickness pipeline can produce statistically significant regions that are not observed in the previous cortical thickness analysis pipeline

Noxious effect of Moringa oleifera leave extract on the developing brain, morphology and behaviour of Wistar rat

The effects of Moringa oleifera leave extracts on the morphology and behaviour of the postnatal developing rat brain was studied. Twenty pregnant rats of Wistar strain weighing between 160 g and 180 g were used in the study. The pregnant rats were divided into two groups of ten animals per group. Group I animals received distilled water and served as control animals, while group II animals received 200 mg/kg body weight of Moringa oleifera leave extract orally. All the animals were provided with rat cubes and water ad libitum during pregnancy and lactation. After birth, five pups of day 21 were weighed and subjected to behavioural study. Animals of days 1, 7, 14, 21 and 28 of age were sacrificed by cervical dislocation, the brain dissected out, weighed and fixed in 10% formol-saline for microscopic studies. Some congenital malformations such as meromelia, phocomelia and amelia were observed in the Moringa oleifera group only. There was a significant increase in body weight of the Moringa oleifera animals on days 7, 14 and 21, in brain weight on days 1 and 7, and in cerebral weight on days 1, 7 and 21 (p<0.05). The behaviour of the rats was significantly worse in the Moringa oleifera group, especially in the area of motor function. Microscopically, there was significant reduction in the cerebral cortical thickness of Moringa oleifera group on days 21 and 28. Immunohistochemical studies revealed poor myelination in the Moringa oleifera group. The results indicate that maternal consumption of Moringa oleifera significantly affected the general morphology as well as behaviour of their pups, therefore it should be consumed with caution in pregnancy until better knowledge on humans is available

Synergy of Image Analysis for Animal and Human Neuroimaging Supports Translational Research on Drug Abuse

The use of structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) in animal models of neuropathology is of increasing interest to the neuroscience community. In this work, we present our approach to create optimal translational studies that include both animal and human neuroimaging data within the frameworks of a study of post-natal neuro-development in intra-uterine cocaine-exposure. We propose the use of non-invasive neuroimaging to study developmental brain structural and white matter pathway abnormalities via sMRI and DTI, as advanced MR imaging technology is readily available and automated image analysis methodology have recently been transferred from the human to animal imaging setting. For this purpose, we developed a synergistic, parallel approach to imaging and image analysis for the human and the rodent branch of our study. We propose an equivalent design in both the selection of the developmental assessment stage and the neuroimaging setup. This approach brings significant advantages to study neurobiological features of early brain development that are common to animals and humans but also preserve analysis capabilities only possible in animal research. This paper presents the main framework and individual methods for the proposed cross-species study design, as well as preliminary DTI cross-species comparative results in the intra-uterine cocaine-exposure study

Synergy of image analysis for animal and human neuroimaging supports translational research on drug abuse

pre-printThe use of structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) in animal models of neurophysiology is of increasing interest to the neuroscience community. In this work, we present our approach to create optimal translational studies that include both animal and human neuroimaging data within the frameworks of a study of post-natal neuro-development in intra-uterine cocaine-exposure. We propose the use of non-invasive neuroimaging to study developmental brain structural and white matter pathway abnormalities via sMRI and DTI, as advanced MR imaging technology is readily available and automated image analysis methodology have recently been transferred from the human to animal imaging setting. For this purpose, we developed a synergistic, parallel approach to imaging and image analysis for the human and the rodent branch of our study. We propose an equivalent design in both the selection of the developmental assessment stage and the neuroimaging setup. This approach brings significant advantages to study neurobiological features of early brain development that are common to animals and humans but also preserve analysis capabilities only possible in animal research. This paper presents the main framework and individual methods for the proposed cross-species study design, as well as preliminary DTI cross-species comparative results in the intra-uterine cocaine-exposure study

A midas plugin to enable construction of reproducible web-based image processing pipelines

Image processing is an important quantitative technique for neuroscience researchers, but difficult for those who lack experience in the field. In this paper we present a web-based platform that allows an expert to create a brain image processing pipeline, enabling execution of that pipeline even by those biomedical researchers with limited image processing knowledge. These tools are implemented as a plugin for Midas, an open-source toolkit for creating web based scientific data storage and processing platforms. Using this plugin, an image processing expert can construct a pipeline, create a web-based User Interface, manage jobs, and visualize intermediate results. Pipelines are executed on a grid computing platform using BatchMake and HTCondor. This represents a new capability for biomedical researchers and offers an innovative platform for scientific collaboration. Current tools work well, but can be inaccessible for those lacking image processing expertise. Using this plugin, researchers in collaboration with image processing experts can create workflows with reasonable default settings and streamlined user interfaces, and data can be processed easily from a lab environment without the need for a powerful desktop computer. This platform allows simplified troubleshooting, centralized maintenance, and easy data sharing with collaborators. These capabilities enable reproducible science by sharing datasets and processing pipelines between collaborators. In this paper, we present a description of this innovative Midas plugin, along with results obtained from building and executing several ITK based image processing workflows for diffusion weighted MRI (DW MRI) of rodent brain images, as well as recommendations for building automated image processing pipelines. Although the particular image processing pipelines developed were focused on rodent brain MRI, the presented plugin can be used to support any executable or script-based pipeline

The Translational Role of Diffusion Tensor Image Analysis in Animal Models of Developmental Pathologies

Diffusion Tensor Magnetic Resonance Imaging (DTI) has proven itself a powerful technique for clinical investigation of the neurobiological targets and mechanisms underlying developmental pathologies. The success of DTI in clinical studies has demonstrated its great potential for understanding translational animal models of clinical disorders, and preclinical animal researchers are beginning to embrace this new technology to study developmental pathologies. In animal models, genetics can be effectively controlled, drugs consistently administered, subject compliance ensured, and image acquisition times dramatically increased to reduce between-subject variability and improve image quality. When pairing these strengths with the many positive attributes of DTI, such as the ability to investigate microstructural brain organization and connectivity, it becomes possible to delve deeper into the study of both normal and abnormal development. The purpose of this review is to provide new preclinical investigators with an introductory source of information about the analysis of data resulting from small animal DTI studies to facilitate the translation of these studies to clinical data. In addition to an in depth review of translational analysis techniques, we present a number of relevant clinical and animal studies using DTI to investigate developmental insults in order to further illustrate techniques and to highlight where small animal DTI could potentially provide a wealth of translational data to inform clinical researchers

Dissecting pathology in mouse models in Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth disease

Neuromuscular junctions (NMJs) are the synapses connecting motor neurons to muscle fibres. Dysfunction of the NMJ has been implicated in the pathology of amyotrophic lateral sclerosis (ALS) and Charcot-Marie- Tooth (CMT) disease, partly due to the progressive loss of skeletal muscle control in these disorders, and due to the common final NMJ phenotype, regardless of the genetic mutation. These motor system diseases are associated with skeletal muscle fibre and protein pathologies in the central or peripheral nervous system. Modelling NMJ dysfunction using mouse models is important for us to investigate pathological mechanisms and to identify how gene mutations involved in diverse biological functions lead to a common NMJ phenotype. However, NMJ structural studies are based mostly on manual analysis with potential intra- and inter-rater variability, limiting reproducibility. Methods: Mouse models of ALS and CMT were investigated, each containing a single mutation caused by transgenic or knock-in technology or chemical mutagenesis. We carried out an extensive pathological analysis in the nervous tissues and hindlimb muscles in the ALS mice and NMJ studies in both ALS and CMT mice. The NMJ studies were further developed by creating a python- script coupled to a machine learning algorithm. Results and discussion: To address the subjective nature of manual NMJ analysis, we developed a novel high-throughput screening method for NMJ structural analysis and a machine learning system for automatic identification of NMJ innervation status. Using this system, ‘NMJ analyser’ we have identified changes in multiple morphological parameters across ALS and CMT mouse strains supporting the idea that the NMJ denervation process seems to be different in these models. Furthermore, within FUS-ALS mice, we did not find upper motor neuron loss and gliosis in the motor cortex nor fibretype pathology at multiple timepoints analysed. Our results lead to a 1) more comprehensive and precise study of NMJ pathology, 2) systematic study of NMJs in mice and 3) precise identification of NMJ morphological changes across different mouse models with NMJ pathology. Further understanding of NMJ denervation process could lead to novel and earlier therapeutic interventions in patients where NMJ pathology is observed

Analysis of telomere length dynamics and telomerase activity in neurosenescence and neurodegenerative diseases of the central nervous system

Telomeres get shortened with each replicative cycle and are thus crucial for genome integrity. Telomere lengths are species-specific; however, there is a week correlation between telomere length and lifespan. Moreover ultra-long telomeres in laboratory mice appear to arise from excessive cross-mating with in small colonies. Most of the knowledge about telomeres arise from replication competent tissues however the importance of telomere attrition in low level replicative CNS is unknown. Here we determined the impact of ageing and genetic refreshment on the relative telomere length (RTL) in the brain of two C57BL/6 strains as a function of cell cycle activity. We show that telomere shortening eventuates in the ageing murine brain in both replication-dependent and -independent manner but in the absence of genetic refreshment. Hermetically inbred mice exhibited a substantially faster rate of age-associated telomere erosion in neural cells compared to genetically refreshed mice. Additionally, telomerase enzyme activity responsible for de novo addition of telomere repeats, remained unchanged with ageing in genetically non-refreshed strain relative to conventionally inbred strain which coincided with upregulated levels of RelA, a subunit of the classical NF-B cascade for which a feed-forward interaction with TERT has recently been demonstrated in a malignant environment. Additionally, we analyzed the telomere length and telomerase activity in a murine model mimicking amyotrophic lateral sclerosis (ALS) pathology. ALS is a neurodegenerative disorder with complex pathomechanism. Our data revealed unexpected telomere lengthening in the cortex and spinal cord with disease progression. Furthermore, we showed specific disease-associated patterns of telomerase activity for different CNS regions Thus, differential regulation of telomere length and telomerase activity occurs in the ageing and diseased CNS and it will be interesting to investigate the role of specific neural cell types in the telomere erosion process and its link to the ageing and neurodegenerative brain