Glaucoma: the retina and beyond

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain

Multifocal visual evoked potentials in demyelinating diseases of the visual pathway

Multifocal visual evoked potentials (mfVEP) provide an objective functional measure of the integrity of the visual pathway. This thesis constitutes a comprehensive assessment of mfVEP changes in demyelinating diseases of the visual pathway. The efficacy of the mfVEP technique was compared to full-field pattern-reversal visual evoked potential and the results illustrate a superiority of the mfVEP in detecting focal visual field defects in patients with different visual pathway disorders. The evolution of mfVEP parameters’ changes following acute optic neuritis (ON) was assessed in a longitudinal study of affected and fellow eyes in a large cohort of patients during the first 12 months after attack. The results indicated that mfVEP amplitude can be used as an early predictor of post-ON axonal loss. Additionally, the apparently more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. The analysis of latency delay in fellow eyes in ON patients indicated that the observed changes are most likely due to subclinical demyelination in the visual pathway and a reflection of the burden of disease in MS patients rather than a result of adaptive cortical plasticity to compensate for delayed transmission of visual information. The last study evaluated the relationship between mfVEP latency and posterior visual pathway lesions in MS patients which demonstrated a significant evidence linking the mfVEP changes with retro-geniculate inflammatory demyelinating lesions

Exploring clinical phenotypes of open-angle glaucoma and their significance in practice

There are several enduring questions regarding the differentiation of clinical phenotypes of glaucoma which clinicians may derive clinical meaning directed towards patient’s management and prognostication. This thesis seeks to address the following issues relating to distinguishing clinical phenotypes of glaucoma: “Evaluating the impact of changing visual field test density on macular structure-function relationships to identify central-involving glaucoma phenotypes”; and “Identifying quantitative structural and functional clinical parameters that may distinguish between intraocular pressure (IOP) defined glaucoma phenotypes”; Two studies were undertaken to examine clinical phenotypes of glaucoma. The first study utilised systematic approach to assessing the impact of test point density in macular visual field (VF) testing on structure-function concordance for identifying centrally-involving glaucoma phenotypes. The second study used multivariate regression analysis and principal component analysis (PCA) to examine quantitative structural (using optical coherence tomography) and functional (VF) clinical data of newly-diagnosed glucoma patients to determine if there are clinically meaningful distinctions between IOP-defined phenotypes (i.e. low-tension vs high-tension glaucoma). Study 1) Using a systematic approach of test point addition and subtraction, we identified a critical number of test locations (8-14) in macular VF testing where binarised structure-function concordance is maximised, and discordance minimised. This methodology provides a framework for optimising macular VF test patterns for detection of centrally-involving glaucoma phenotypes. Study 2) Despite statistical significance in differences between low- and high-tension glaucoma, PCA applied to quantitative clinical structural and functional parameters returned no groups of clinical parameters that reliably distinguished between patients in IOP-defined glaucoma phenotypes. The present work provides a framework to identify phenotypic groups of glaucoma, the clinical significance of which may vary. We identified the minimum number of test points required to detect central-involving glaucoma in visual field testing. We also demonstrate that IOP-defined phenotypes are not clinically distinguishable at the point of diagnosis, suggesting that these phenotypes form part of a continuum of open-angle glaucoma. These findings have implications for disease staging and preferred treatment modality

Advanced functional MRI

Abstract Functional Magnetic Resonance Imaging (fMRI) has been widely used to study the responses of the somatosensory cortex, motor cortex and associated neuronal activity in the human cerebral cortex. fMRI is a non-invasive and indirect method for mapping brain activity through measurement of the hemodynamic responses associated with electrical neuronal activity and the neural activity leads directly to changes in blood flow, blood volume and the cerebral metabolic rate of oxygen consumption. Non-invasive neuroimaging technologies such as functional MRI have both advantages, such as good spatial resolution, and disadvantages, such as poor temporal resolution. Some of the disadvantages have been alleviated by incorporating other techniques such as optical spectroscopy or electroencephalography (EEG) which are also non-invasive. All these techniques are sensitive to the vascular response of neuronal activity but in addition we are now investigating the existence of a weak direct electromagnetic effect with advanced fMRI. This neuronal current effect which gives rise to main magnetic field modulation should provide additional information for studying nerve characteristics. In this thesis, methods for fMRI mapping of responses from phantoms, the median nerve, the visual system, the motor sensory cortex and the thalamus are optimised and subsequently quantified. The experimental results strongly support the main hypothesis of the thesis and suggest that the generated magnetic field due to ionic current can be detected by present generation MRI using specific experimental designs and stimulation paradigms. Overall our results show that ionic currents in subjects can generate percentage signal changes in MRI up to 0.1± 0.01% corresponding to mean magnetic axonal fields of 0.7± 0.1nT with a Signal to Noise Ratio (SNR) of 3:1. The responses of the median nerve, motor sensory cortex and thalamus were detected using transcutaneous electrical nerve stimulation (TENS) and the visual cortex using strobe light stimulation in the range of frequencies 2.1 Hz to 4.1 Hz. All these measurements were acquired at 1.5T. Fast fMRI experiments using TENS and finger tapping were also acquired simultaneously. In addition, real and imaginary finger tapping experiments were performed in the motor sensory cortex at 3T. Our results imply that axonal fields that are generated due to action potentials can generate effects on MRI sensitive enough to directly detect neuronal activity using advanced fMRI, although sensitivity is still not fully adequate for clinical use

Double diffusion encoding and applications for biomedical imaging

Diffusion Magnetic Resonance Imaging (dMRI) is one of the most important contemporary non-invasive modalities for probing tissue structure at the microscopic scale. The majority of dMRI techniques employ standard single diffusion encoding (SDE) measurements, covering different sequence parameter ranges depending on the complexity of the method. Although many signal representations and biophysical models have been proposed for SDE data, they are intrinsically limited by a lack of specificity. Advanced dMRI methods have been proposed to provide additional microstructural information beyond what can be inferred from SDE. These enhanced contrasts can play important roles in characterizing biological tissues, for instance upon diseases (e.g. neurodegenerative, cancer, stroke), aging, learning, and development. In this review we focus on double diffusion encoding (DDE), which stands out among other advanced acquisitions for its versatility, ability to probe more specific diffusion correlations, and feasibility for preclinical and clinical applications. Various DDE methodologies have been employed to probe compartment sizes (Section 3), decouple the effects of microscopic diffusion anisotropy from orientation dispersion (Section 4), probe displacement correlations, study exchange, or suppress fast diffusing compartments (Section 6). DDE measurements can also be used to improve the robustness of biophysical models (Section 5) and study intra-cellular diffusion via magnetic resonance spectroscopy of metabolites (Section 7). This review discusses all these topics as well as important practical aspects related to the implementation and contrast in preclinical and clinical settings (Section 9) and aims to provide the readers a guide for deciding on the right DDE acquisition for their specific application

Neurofly 2008 abstracts : the 12th European Drosophila neurobiology conference 6-10 September 2008 Wuerzburg, Germany

This volume consists of a collection of conference abstracts

Innovations and revolutions in reducing retinal ganglion cell loss in glaucoma

Introduction: Glaucoma remains the leading cause of irreversible blindness. Although the loss of retinal ganglion cells (RGCs) is an established hallmark of glaucoma, reduction of intraocular pressure (IOP) is a widely used evidence-based management approach, even in normotensive patients. However, despite optimal pressure control, some patients progress to lose vision. / Areas covered: This review provides a summary of the latest methods aimed at reducing RGC loss with the objective of preserving vision, categorized by the mechanism of action. We discuss both the newest ways in which IOP can be reduced, alongside ‘pressure-independent’ pharmacological therapies and developments in bioengineering. The conducted PubMed search included the terms: ‘glaucoma pathophysiology,’ ‘IOP-lowering agents,’ ‘retinal ganglion cell apoptosis,’ ‘neuroprotection,’ ‘stem cells,’ ‘imaging.’ / Expert opinion: With many agents failing to successfully translate into clinical use, further understanding of the underlying disease process is required, along with novel biomarkers that will enable timely and reliable quantification of treatment effect

Towards in vivo g-ratio mapping using MRI: unifying myelin and diffusion imaging

The g-ratio, quantifying the comparative thickness of the myelin sheath encasing an axon, is a geometrical invariant that has high functional relevance because of its importance in determining neuronal conduction velocity. Advances in MRI data acquisition and signal modelling have put in vivo mapping of the g-ratio, across the entire white matter, within our reach. This capacity would greatly increase our knowledge of the nervous system: how it functions, and how it is impacted by disease. This is the second review on the topic of g-ratio mapping using MRI. As such, it summarizes the most recent developments in the field, while also providing methodological background pertinent to aggregate g-ratio weighted mapping, and discussing pitfalls associated with these approaches. Using simulations based on recently published data, this review demonstrates the relevance of the calibration step for three myelin-markers (macromolecular tissue volume, myelin water fraction, and bound pool fraction). It highlights the need to estimate both the slope and offset of the relationship between these MRI-based markers and the true myelin volume fraction if we are really to achieve the goal of precise, high sensitivity g-ratio mapping in vivo. Other challenges discussed in this review further evidence the need for gold standard measurements of human brain tissue from ex vivo histology. We conclude that the quest to find the most appropriate MRI biomarkers to enable in vivo g-ratio mapping is ongoing, with the potential of many novel techniques yet to be investigated.Comment: Will be published as a review article in Journal of Neuroscience Methods as parf of the Special Issue with Hu Cheng and Vince Calhoun as Guest Editor