1,721,099 research outputs found
Functional magnetic resonance imaging of the mouse brain
Full text linkFunctional magnetic resonance imaging (fMRI) measuring a blood-oxygen-level dependent (BOLD) signal is the most commonly used neuroimaging tool to understand brain function in humans. As mouse models are one of the most commonly used neuroscience experimental models, and with the advent of transgenic mouse models of neurodegenerative pathologies, there has been an increasing push in recent years to apply fMRI techniques to the mouse brain. This thesis focuses on the development and implementation of mouse brain fMRI techniques, in particular to describe the mouse visual system. Multiple studies in the literature have noted several technical challenges in mouse fMRI. In this work I have developed methods which go some way to reducing the impact of these issues, and I record robust and reliable haemodynamic-driven signal responses to visual stimuli in mouse brain regions specific to visual processing. I then developed increasingly complex visual stimuli, approaching the level of complexity used in electrophysiology studies of the mouse visual system, despite the geometric and magnetic field constraints of using a 9.4T pre-clinical MRI scanner. I have also applied a novel technique for measuring high-temporal resolution BOLD responses in the mouse superior colliculus, and I used this data to improve statistical parametric mapping of mouse brain BOLD responses. I also describe the first application of dynamic causal modelling to mouse fMRI data, characterising effective connectivity in the mouse brain visual system. This thesis makes significant contributions to the reverse translation of fMRI to the mouse brain, closing the gap between invasive electrophysiological measurements in the mouse brain and non-invasive fMRI measurements in the human brain
Development of imaging methods for the lithium-pilocarpine model of epilepsy
Full text linkAnti-inflammatory therapies are promising candidates for the prevention of brain injury following prolonged seizures (status epilepticus). Biomarkers for therapy monitoring are needed to translate these recent findings to the clinic. The aim of this thesis was to develop imaging methods that can be used to monitor anti-inflammatory therapies and monitor disease progression following prolonged seizures. In order to achieve these goals, the lithium-pilocarpine model was used as a model of status epilepticus and novel MRI imaging methods were employed. Various imaging approaches including: quantitative, structural, molecular and functional imaging were tested for their possible investigative utility as imaging biomarkers for neuroprotective therapies. Alongside this, two different anti-inflammatory therapies were tested for their effectiveness to alter brain injury following status epilepticus. This thesis demonstrates that molecular imaging has potential to monitor neuroprotective therapies. Surprisingly, there was little evidence that the anti-inflammatory therapies tested here had beneficial effects. However, this thesis shows that employing novel imaging approaches and automated analysis methods can enable accurate in vivo assessment of disease altering therapies
Mouse embryo phenotyping using high-resolution 3D imaging
No full textThe immense challenge of annotating the entire mouse genome has stimulated development of cutting-edge imaging technologies in a drive for novel information. These techniques promise to improve our understanding of the genes involved in embryo development, at least one third of which have been shown to be essential. Aligning advanced imaging technologies with biological needs will be fundamental to maximising the number of phenotypes discovered in the coming years. International efforts are underway to meet this challenge through an integrated and sophisticated approach to embryo phenotyping, which will include advanced imaging tools. This thesis investigates advanced imaging methodologies and computational image analysis techniques for mouse embryo phenotyping using magnetic resonance imaging (MRI). Additionally, the novel application of an emerging method called photoacoustic imaging is demonstrated for imaging mouse embryos in utero. First, the lack of tissue staining capabilities that currently limits embryo MR imaging was addressed by investigating the MRI staining properties of two readily available contrast agents and their underlying contrast enhancement mechanisms. A methodological framework was developed for high-throughput screening of embryos using diffusion MRI and implemented to study the splotch mouse model of human neural tube defects. A validation study was carried out to comprehensively assess the accuracy of volumetric measurements generated using a computational image analysis method called segmentation propagation. Finally, an all-optical photoacoustic scanner and novel time-reversal image reconstruction algorithm were developed, enabling photoacoustic imaging of whole embryos in utero. Overall, this thesis presents advanced imaging methodologies and computational image analysis techniques that may form an essential part of the toolkit available for annotating the mouse genome and facilitate identification of novel phenotypes in the coming years
Cardiac Imaging for Regenerative Therapy and Tissue Engineering
Full text linkCardiovascular disease remains the number 1 cause of death worldwide. Over the past 20 years, therapies for treating cardiac disease have come of age and coronary heart disease in particular has seen a revolution in new treatments such as statins, stents and beta blockers. These therapies have slowed death rates and have shown potential to minimise ischemia induced atrophy following myocardial infarction. Crucially however, they are unable to recover lost heart function due to cardiomyocyte death, resulting in poor prognosis for patients. Myocardial regeneration therapy is a new strategy towards treating cardiac disease that engrafts regenerative cells and biomaterials to the myocardium to stimulate repair of tissue and restore contractile function. Cardiac regeneration therapy has made a rapid translation from preclinical research to clinical trials with the first trial in humans published in 2001. Clinical trials in the years since however have produced underwhelming results and there is a general consensus that further preclinical optimisation with powerful non-invasive imaging data will be key to the future success of regenerative medicine in humans. Magnetic resonance imaging is unparalleled in providing non-invasive multiparametric imaging of both global and regional cardiac structure and function. MRI provides high spatiotemporal resolution and multiple contrast mechanisms revealing information about molecular changes in the myocardium. These imaging abilities make MRI a versatile and powerful tool in the preclinical optimisation of cardiac regeneration therapies. Over the chapters presented in this thesis I have established a set of MR imaging techniques that enable valuable in vivo characterisation of cardiac function and structure in for use in studies of regenerative therapy. It is hoped that the methods developed over the course of this thesis aid in the uptake of imaging applications in studies of regenerative medicine and that the wide range of imaging tools demonstrated help to bring regenerative medicine closer to practical clinical therapy
Imaging mouse models of neurodegeneration using multi-parametric MRI
Full text linkAlzheimer’s disease (AD) is a devastating condition characterised by significant cognitive impairment and memory loss. Transgenic mouse models are increasingly being used to further our knowledge of the cause and progression of AD, and identify new targets for therapeutic intervention. These mice permit the study of specific pathological hallmarks of the disease, including intracellular deposits of hyperphosphorylated tau protein and extracellular amyloid plaques. In order to characterise these transgenic mice, robust biomarkers are required to evaluate neurodegenerative changes and facilitate preclinical evaluation of emerging therapeutics. In this work, a platform for in vivo structural imaging of the rTg4510 mouse model of tauopathy was developed and optimised. This was combined with a range of other clinically relevant magnetic resonance imaging (MRI) biomarkers including: arterial spin labelling, diffusion tensor imaging and chemical exchange saturation transfer. These techniques were applied in a single time-point study of aged rTg4510 mice, as well as a longitudinal study to serially assess neurodegeneration in the same cohort of animals. Doxycycline was administered to a subset of rTg4510 mice to suppress the tau transgene; this novel intervention strategy permitted the evaluation of the sensitivity of MRI biomarkers to the accumulation and suppression of tau. Follow-up ex vivo scans were acquired in order to assess the sensitivity of in vivo structural MRI to the current preclinical gold standard. High resolution structural MRI, when used in conjunction with advanced computational analysis, yielded high sensitivity to pathological changes occurring in the rTg4510 mouse. Atrophy was reduced in animals treated with doxycycline. All other MRI biomarkers were able to discriminate between doxycycline-treated and untreated rTg4510 mice as well as wildtype controls, and provided insight into complimentary pathological mechanisms occurring within the disease process. In addition, this imaging protocol was applied to the J20 mouse model of familial AD. This mouse exhibits widespread plaque formation, enabling the study of amyloid-specific pathological changes. Atrophy and deficits in cerebral blood flow were observed; however, the changes occurring in this model were markedly less than those observed in the rTg4510 mouse. This study was expanded to investigate the early-onset AD observed in individuals with Down’s syndrome (DS) by breeding the J20 mouse with the Tc1 mouse model of DS, permitting the relationship between genetics and neurodegeneration to be dissected. This thesis demonstrates the application of in vivo multi-parametric MRI to mouse models of neurodegeneration. All techniques were sensitive to pathological changes occurring in the models, and may serve as important biomarkers in clinical studies of AD. In addition, in vivo multi-parametric MRI permits longitudinal studies of the same animal cohort. This experimental design produces more powerful results, whilst contributing to worldwide efforts to reduce animal usage with respect to the 3Rs principles
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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