43 research outputs found

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function

    A novel optogenetics-based therapy for obstructive sleep apnoea

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    Obstructive sleep apnoea (OSA) is characterised by repeat upper airway narrowing and/or collapse during sleep. Many patients are sub-optimally treated due to poor tolerance or incomplete response to established therapies. We propose a novel, optogenetics-based therapy, that enables light-stimulation induced upper airway dilator muscle contractions to maintain airway patency. The primary aims of this thesis were to determine feasibility in a rodent model of OSA, and identify effective optogenetic constructs for activating upper airway muscles. Chapters 2 and 3 outline the development of a novel construct for the expression of light-sensitive proteins (opsins) in upper airway muscles, comparing two promotors and two recombinant adeno-associated virus capsids (rAAV) for optogenetic gene transfer. Results show that a muscle-specific promotor (tMCK) was superior to a non-specific promotor (CAG). With tMCK, opsin expression in the tongue was 470% greater (p=0.013, RM-ANOVA), brainstem expression was abolished, and light stimulation facilitated a 66% increase in muscle activity from that recorded during unstimulated breaths in an acute model of OSA (p<0.001, linear mixed model) (Chapter 2). Moreover, a novel, highly myotropic rAAV serotype, AAVMYO, was superior to a wild-type serotype, AAV9. The AAVMYO serotype driven by tMCK facilitated a further increase in muscle activity with light stimulation to 194% of that recorded during unstimulated breaths (p<0.001, linear mixed model) (Chapter 3). Finally, ultrasound imaging confirmed that the optimised construct was able to generate effective light-induced muscle contractions and airway dilation (Chapter 4). A secondary aim was to advance preclinical trials for the proposed therapy. To this end, a surgical protocol for chronic implantation of light delivery hardware and recording electrodes in rodents was developed (Chapter 5). The final protocol will allow us to determine the effects of acute and chronic light stimulation on opsin-expressing upper airway muscles during natural sleep. In summary, Chapters 2 to 4 provide proof-of-concept for a non-invasive optogenetics-based OSA therapy. The combination of a muscle-specific promotor and a muscle-specific viral vector presents a novel and highly effective method of inducing light sensitivity into skeletal muscle and facilitating light-evoked airway dilation. Finally, Chapter 5 commences the development of a surgical protocol that will aid ongoing preclinical trials

    Translation of quantitative MRI analysis tools for clinical neuroradiology application

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    Quantification of imaging features can assist radiologists by reducing subjectivity, aiding detection of subtle pathology, and increasing reporting consistency. Translation of quantitative image analysis techniques to clinical use is currently uncommon and challenging. This thesis explores translation of quantitative imaging support tools for clinical neuroradiology use. I have proposed a translational framework for development of quantitative imaging tools, using dementia as an exemplar application. This framework emphasises the importance of clinical validation, which is not currently prioritised. Aspects of the framework were then applied to four disease areas: hippocampal sclerosis (HS) as a cause of epilepsy; dementia; multiple sclerosis (MS) and gliomas. A clinical validation study for an HS quantitative report showed that when image interpreters used the report, they were more accurate and confident in their assessments, particularly for challenging bilateral cases. A similar clinical validation study for a dementia reporting tool found improved sensitivity for all image interpreters and increased assessment accuracy for consultant radiologists. These studies indicated benefits from quantitative reports that contextualise a patient’s results with appropriate normative reference data. For MS, I addressed a technical translational challenge by applying lesion and brain quantification tools to standard clinical image acquisitions which do not include a conventional T1-weighted sequence. Results were consistent with those from conventional sequence inputs and therefore I pursued this concept to establish a clinically applicable normative reference dataset for development of a quantitative reporting tool for clinical use. I focused on current radiology reporting of gliomas to establish which features are commonly missed and may be important for clinical management decisions. This informs both the potential utility of a quantitative report for gliomas and its design and content. I have identified numerous translational challenges for quantitative reporting and explored aspects of how to address these for several applications across clinical neuroradiology

    Identifying the Neurocognitive bases of creativity to increase human and computational creativity

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    En esta Tesis Doctoral se ha identificado la estructura neurocognitiva que sustenta la creatividad humana a partir del análisis conjunto de más de 800 referencias bibliográficas que muestran las investigaciones más importantes realizadas hasta la fecha. Sobre la base de esta estructura, se ha identificado un paradigma neurocognitivo de la creatividad humana y se ha propuesto un modelo neurocognitivo del proceso creativo. Finalmente, también se ha propuesto un paradigma creativo neurocognitivo computacional y se ha diseñado la estructura de un sistema computacional creativo, basado en una estructura multiagente. La investigación que se ha realizado sobre el tema hasta la fecha es muy especializada y se centra en aspectos muy concretos de la creatividad, y en muchos casos tienen poca relación entre sí. Por ello, y para tener una idea conjunta y holística de los procesos neurocognitivos de la creatividad humana, es necesario estudiar todas estas investigaciones de forma interconectada. Esta idea conjunta permitiría dirigir investigaciones más específicas para ser más efectivos. Por ello, lo primero que se ha hecho ha sido clasificar, agrupar, analizar, entrelazar y estructurar, de forma ordenada, las investigaciones más importantes que se han realizado hasta la fecha. Sin embargo, el trabajo realizado va mucho más allá, ya que estructurando y entrelazando las investigaciones existentes ha sido posible identificar ciertos patrones, correlaciones y paralelismos, y realizar ciertas deducciones, que en su conjunto, han permitido identificar los procesos neurocognitivos fundamentales. bases de la creatividad humana. La Tesis se estructura en los siguientes capítulos: Capitulo 2 Análisis de los principales métodos para estimular la creatividad Se analizan las principales definiciones de creatividad, y se ha decidido que el mejor enfoque para su análisis es estructurarla taxonómicamente, bajo el modelo 4P. Se ha realizado una recopilación y análisis de los métodos más efectivos que estimulan la creatividad humana, mostrando las ventajas y desventajas de cada uno. Capítulo 3 Estructura funcional del cerebro humano y su relación con el proceso creativo Se identifica la estructura neurocognitiva general del cerebro humano que permite generar los procesos fundamentales y básicos de su actividad creativa. Capítulo 4 El papel fundamental de la DMN en el proceso creativo Se ha observado que la red de modo predeterminado (DMN) tiene un papel principal en la creatividad. Por ello, se ha dedicado un capítulo a su estudio, y se han identificado varios factores que la involucran directamente en la actividad creativa del cerebro humano. Capítulo 5 Identificación y análisis de las bases neurocognitivas de la creatividad humana Se ha identificado el conjunto general de factores neurocognitivos que sustentan los procesos creativos en el cerebro humano. Capítulo 6 Paradigma neurocognitivo de la creatividad humana Se ha propuesto un modelo neurocognitivo del proceso creativo que reestructura, completa y detalla todos los modelos conceptuales propuestos hasta el momento. Capítulo 7 Paradigma computacional de la creatividad basado en la estructura neurocognitiva humana Analizando las diferentes bases neurocognitivas que sustentan la creatividad humana, se han establecido paralelismos computacionales y se han realizado diferentes sugerencias para el diseño de un sistema computacional creativo.In this Doctoral Thesis, the neurocognitive structure that supports human creativity has been identified based on the joint analysis of more than 800 bibliographical references that show the most important investigations carried out to date. Based on this structure, a neurocognitive paradigm of human creativity has been described, and a neurocognitive model of creative process has been proposed. Finally, a computational neurocognitive creative paradigm has been also proposed, and the structure of a creative computational multi-agent system has been designed. The research that has been carried out on the subject is very specialized and focuses on very specific aspects of creativity, and in many cases they have little relationship with each other. For this reason, and in order to have a joint and holistic idea of the neurocognitive processes of human creativity, it is necessary to study all these investigations in an interconnected way. This joint idea would allow directing more specific investigations in order to be more effective. For this reason, the first thing that has been done has been to classify, group, analyze, intertwine and structure, in an orderly manner, the most important investigations that have been carried out to date. However, the work carried out goes much further, since by structuring and intertwining the existing research it has been possible to identify certain patterns, correlations and parallelisms, and make certain deductions, which as a whole, have made it possible to identify the fundamental neurocognitive bases of human creativity. Chapter 2 Analysis of the main methods to stimulate creativity The main definitions of creativity are analyzed, and it has been decided that the best approach for its analysis is to structure it taxonomically, under the 4P model. A compilation and analysis of the most effective methods that stimulate human creativity has been carried out, showing the advantages and disadvantages of each one. Chapter 3 Functional structure of the human brain and its relationship with the creative process The general neurocognitive structure of the human brain that allows the generation of the fundamental and basic processes of its creative activity are identified. Chapter 4 The fundamental role of the DMN in the creative process It has been observed that the Default mode network (DMN) has a main role in creativity. For this reason, a chapter has been dedicated to its study, and several factors have been identified that directly involve it in the creative activity of the human brain. Chapter 5 Identification and analysis of the neurocognitive bases of human creativity The general set of neurocognitive factors that underpin creative processes in the human brain has been identified. Chapter 6 Neurocognitive paradigm of human creativity A neurocognitive model of the creative process has been proposed, which restructures, completes and details all the conceptual models proposed so far. Chapter 7 Computational paradigm of creativity based on the human neurocognitive structure Analyzing the different neurocognitive bases that support human creativity, computational parallels have been established and different suggestions have been made for the design of a creative computational system

    The Shared Genetic Architecture of Modifiable Risk for Dementia and its Influence on Brain Health

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    Targeting modifiable risk factors for dementia may prevent or delay dementia. However, the mechanisms by which risk factors influence dementia remain unclear and current research often ignores commonality between risk factors. Therefore, my thesis aimed to model the shared genetic architecture of modifiable risk for dementia and explored how these shared pathways may influence dementia and brain health. I used linkage disequilibrium score regression and genomic structural equation modelling (SEM) to create a multivariate model of the shared genetics between Alzheimer’s disease (AD) and its modifiable risk factors. Although AD was genetically distinct, there was widespread genetic overlap between most of its risk factors. This genetic overlap formed an overarching Common Factor of general modifiable dementia risk, in addition to 3 subclusters of distinct sets of risk factors. Next, I performed two multivariate genome-wide association studies (GWASs) to identify the risk variants that underpinned the Common Factor and the 3 subclusters of risk factors. Together, these uncovered 590 genome-wide significant loci for the four latent factors, 34 of which were novel findings. Using post-GWAS analyses I found evidence that the shared genetics between risk factors influence a range of neuronal functions, which were highly expressed in brain regions that degenerate in dementia. Pathway analysis indicated that shared genetics between risk factors may impact dementia pathogenesis directly at specific loci. Finally, I used Mendelian randomisation to test whether the shared genetic pathways between modifiable dementia risk factors were causal for AD. I found evidence of a causal effect of the Common Factor on AD risk. Taken together, my thesis provides new insights into how modifiable risk factors for dementia interrelate on a genetic level. Although the shared genetics between modifiable risk factors for dementia seem to be distinct from dementia pathways on a genome-wide level, I provide evidence that they influence general brain health, and so they may increase dementia risk indirectly by altering cognitive reserve. However, I also found that shared genetics risk between risk factors in certain genomic regions may directly influence dementia pathogenesis, which should be explored in future work to determine whether these regions represent targets to prevent dementia

    Glaucoma

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    This book addresses the basic and clinical science of glaucomas, a group of diseases that affect the optic nerve and visual fields and is usually accompanied by increased intraocular pressure. The book incorporates the latest development as well as future perspectives in glaucoma, since it has expedited publication. It is aimed for specialists in glaucoma, researchers, general ophthalmologists and trainees to increase knowledge and encourage further progress in understanding and managing these complicated diseases

    Advanced MRI techniques in the study of cerebellar cortex

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    The cerebellum (from the Latin "little brain") is the dorsal portion of the metencephalon and is located in the posterior cranial fossa. Although representing only 10% of the total brain volume, it contains more than 50% of the total number of neurons of the central nervous system (CNS). Its organization resembles the one found in the telencephalon, with the presence of a superficial mantle of gray matter (GM) known as the cerebellar cortex, covering the cerebellar white matter (WM) in which three pairs of deep cerebellar GM nuclei are embedded. The number of studies dedicated to the study of the cerebellum and its function has significantly increased during the last years. Nevertheless, although many theories on the cerebellar function have been proposed, to date we still are not able to answer the question about the exact function of this structure. Indeed, the classical theories focused on the role of the cerebellum in fine-tuning for muscle control has been widely reconsidered during the last years, with new hypotheses that have been advanced. These include its role as sensory acquisition device, extending beyond a pure role in motor control and learning, as well as a pivotal role in cognition, with a recognized cerebellar participation in a variety of cognitive functions, ranging from mood control to language, memory, attention and spatial data management. A huge contribution to our understanding of how the cerebellum participates in all these different aspects of motor and non-motor behavior comes from the application of advanced imaging techniques. In particular, Magnetic Resonance Imaging (MRI) can provide a non-invasive evaluation of anatomical integrity, as well as information about functional connections with other brain regions. This thesis is organized as follows: - In Chapter 1 is presented a general introduction to the cerebellar anatomy and functions, with particular reference to the anatomical organization of cerebellar cortex and its connections with the telencephalon - Chapter 2 will contain a general overview about some of the major advanced MRI methods that can be applied to investigate the anatomical integrity and functional status of the cerebellar cortex - In Chapter 3 will be presented a new method to evaluate the anatomy and integrity of cerebellar cortex using ultra-high field MRI scanners - Chapters 4, 5 and 6 will contain data obtained from the application of some of the previously described advanced imaging techniques to the study of cerebellar cortex in neurodegenerative and neuroinflammatory disorders affecting the CNS

    Protective microglial activation in Alzheimer’s disease pathogenesis

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    Here it was of interest to determine the spatiotemporal relationships between Aβ, tau, and microglial pathological changes in post-mortem human AD brains by comparing differentially affected brain regions. Immunohistochemistry and fluorescence immunohistochemistry targeting Aβ, tau, and the pan-microglia marker ionised calcium binding adaptor molecule 1 (Iba1) was performed in four regions of decreasing pathological severity: inferior temporal cortex, superior frontal cortex, primary visual cortex, and primary motor cortex of ten controls, five controls with Alzheimer changes (CAc), and eight AD cases. Following a validated modified disector sampling approach, using manual and corroborative automated methods, the results showed that activated microglia predominated in the inferior temporal cortex of CAc. AD brains were characterised by increased clustering of activated microglia in the primary visual cortex and a substantial loss of clustering and ramified healthy microglia in the inferior temporal cortex. Activated microglia were found to internalise Aβ pathology but not tau pathology. Further, microglia were found to phagocytose greater quantities of pre-synapses in AD compared to both CAc and controls in a study using super-resolution microscopy. Gene amplification studies of a number of candidate genes were performed in coronal neonatal mouse brain slice cultures treated with synthetic preparations of Aβ. Findings demonstrated the upregulation of select phagocytic and anti-inflammatory markers in response to low-dose Aβ monomers. Additionally, a validation amplification study confirmed findings from an RNA-Seq study which demonstrated the upregulation of gene transcripts related to immune pathways and phagocytosis in mildly affected regions of the AD brain. Taken together, these findings are indicative of neuroprotective activation of microglia early in the pathogenesis of AD

    Immunohistochemical and electrophysiological investigation of E/I balance alterations in animal models of frontotemporal dementia

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    Behavioural variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterised by changes in behaviour. Apathy, behavioural disinhibition and stereotyped behaviours are the first symptoms to appear and all have a basis in reward and pleasure deficits. The ventral striatum and ventral regions of the globus pallidus are involved in reward and pleasure. It is therefore reasonable to suggest alterations in these regions may underpin bvFTD. One postulated contributory factor is alteration in E/I balance in striatal regions. GABAergic interneurons play a role in E/I balance, acting as local inhibitory brakes, they are therefore a rational target for research investigating early biological predictors of bvFTD. To investigate this, we will carry out immunohistochemical staining for GABAergic interneurons (parvalbumin and neuronal nitric oxide synthase) in striatal regions of brains taken from CHMP2B mice, a validated animal model of bvFTD. We hypothesise that there will be fewer GABAergic interneurons in the striatum which may lead to ‘reward-seeking’ behaviour in bvFTD. This will also enable us to investigate any preclinical alterations in interneuron expression within this region. Results will be analysed using a mixed ANOVA and if significant, post hoc t-tests will be used. The second part of our study will involve extracellular recordings from CHMP2B mouse brains using a multi-electrode array (MEA). This will enable us to determine if there are alterations in local field potentials (LFP) in preclinical and symptomatic animals. We will also be able to see if neuromodulators such as serotonin and dopamine effect LFPs after bath application. We will develop slice preparations to preserve pathways between the ventral tegmental area and the ventral pallidum, an output structure of the striatum, and the dorsal raphe nucleus and the VP. Using the MEA we will stimulate an endogenous release of dopamine and serotonin using the slice preparations as described above. This will enable us to see if there are any changes in LFPs after endogenous release of neuromodulators. We hypothesise there will be an increase in LFPs due to loss of GABAergic interneurons
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