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This study investigated retinal ganglion cell (RGC) changes in the Royal College of Surgeons (RCS) rat. The RCS rat represents a model of retinal dystrophies such as human retinitis pigmentosa. Retinal dystrophies have been attributed to defects in the retinal pigment epithelium and dysfunction and loss of photoreceptors. The process of photoreceptor degeneration has been well documented, however the natural history of changes in RGCs in this model is less well established. Apoptosis is one of the main pathways of cell death and has been investigated genetically and pharmacologically in many neuronal disorders. Apoptosis is an orchestrated form of cell "death by suicide" which is essential both in the development and normal maintenance of tissue function, but also involved in the pathogenesis of a number of severe neurodegenerative disorders such as Alzheimer’s, Parkinson's, and Huntington's disease. The detection of an early apoptotic, before DNA fragmentation occurs, has been proved difficult and is therefore not very well established. The Annexin V labelling technique used in this study allowed the demonstration of cells that are undergoing early apoptosis. The main aims of this study were to investigate RGC changes with age in the RCS rat using different techniques such as in vivo imaging, immunohistochemistry, histological Annexin V positive cell counts, ultrastructural assessment (TEM) of the retina and optic nerve and the functional assessment of the whole retina by electroretinographic recordings (ERGs). There was an-age-related increased intraocular pressure (IOP) with peak apoptosis at 6 months of age within the dystrophic RCS rats compared to the non-dystrophic control rats which had maintained IOPs throughout all age groups. Lowering the elevated IOPs did not affect RGC apoptosis counts, hence the IOP as a causative factor had to be excluded. In vivo images showed some nerve fiber thinning with age in the dystrophic animals and functional assessment revealed dysfuction of the ganglion cells within the dystrophic retinas beginning at 3 months of age. Retrograde Dil labeling, as well as immuhistochemistry confirmed apoptosing RGCs histologically and transmission electron microscopy ultrastructurally. Optic nerve axonal counts showed substantial RGC axon loss at 12 months of age within the dystrophic animals and a mild natural axonal loss with age within the non-dystrophic controls. The findings of this study suggest a much earlier time course of functional and morphological changes of the degenerating RGCs within the dystrophic RCS rat model than previously thought. The mechanism of death has still not been completely understood but this study contributes greatly towards the understanding as it identified apoptosis as the main pathway by which RGCs dye in the dystrophic RCS rat. This will be not only helpful in finding appropriate time points for therapeutical strategies such as electrical stimulation of cells or cell transplantations in RP and other retinal diseases but also help to develop appropriate monitoring methods for ocular diseases with apoptosing cells. An early diagnosis and appropriate follow up monitoring methods are essential for correct treatment therapies and might contribute to an increased success rate in rescuing vision loss.

This thesis recognizes that: in many systems the initial small molecule - receptor recognition processes, and thus signal transduction, is not fully understood to the highest level of scientifc explanation and prediction. One such example of this is olfaction. Molecules cannot necessarily be predicted from a smell, and similarly a smell from molecules. Better understanding of these initial steps, would have important repercussions, especially in the field of rational drug design. So in general the thesis proves the physical feasibility and potential of a novel and generic signaling model, and in particular looks at those processes in olfaction. The conjecture 'Could humans recognize odours through phonon assisted tunneling?' is tested. This is based on the idea (Turin, 1996) that the nose recognizes an odorant's vibrations (phonons) via inelastic electron tunneling (IETS). The nose thus acts as a 'meat spectroscope'. First the background biology of the olfactory system is evaluated, then the conjecture is posed as a soluble problem. Traditional physics ideas are reconciled with the biological environment. It is proven that no physics based objections hold against the working of this new mechanism, thus a predictive and explanatory theory is now introduced to the field. The parameters of odorant discrimination are explored. In particular the 'Huang-Rhys factor' is modeled as a measure of the electron-phonon coupling integral to signal transduction. Several approaches are considered, 'odorant spectra' is created. Objections to the conjecture are considered, in particular the apparent paradox of enantiomer discrimination. The apparent paradox is shown to be obsolete. A correlation between a certain type of flexibility and whether enantiomer pairs smell the same is found. A rule is established: The members of an enantiomer pair will smell alike (type 1) when the molecules are rigid, and will smell different (type 2) when they are flexible. This flexibility refers to a particular property of six-membered rings. A consequence of this finding leads to the investigation of certain steroids in correlation to their bio-effects, and it is found that similar features are apparent, thus the mechanism of biological IETS is applied to other systems.

Objects can be identified from a number of perceptual attributes, including visual, auditory and tactile sensory input. The integration of these perceptual attributes constitutes our semantic knowledge of an object representation. This research uses functional neuroimaging to investigate the brain areas that integrate perceptual features into an object representation, and how these regions are modulated by stimulus- and task-specific features. A series of experiments are reported that utilise different types of perceptual integration, both within and across sensory modalities. These include 1) the integration of visual form with colour, 2) the integration of visual and auditory object features, and 3) the integration of visual and tactile abstract shapes. Across these experiments I have also manipulated additional factors, including the meaning of the perceptual information (meaningful objects versus meaningless shapes), the verbal or non-verbal nature of the perceptual inputs (e.g. spoken words versus environmental sounds) and the congruency of crossmodal inputs. These experiments have identified a network of brain regions both common to, and selective for, different types of object feature integration. For instance, I have identified a common bilateral network involved in the integration and association of crossmodal audiovisual objects and intra-modal auditory or visual object pairs. However, I have also determined that activation in response to the same concepts can be modulated by the type of stimulus input (verbal versus nonverbal), the timing of those inputs (simultaneous versus sequential presentation), and the congruency of stimulus pairs (congruent versus incongruent). Taken together, the results from these experiments demonstrate modulations of neuronal activation by different object attributes at multiple different levels of the object processing hierarchy, from early sensory processing through to stored object representations. Critically, these differential effects have even been observed with the same conceptual stimuli. Together these findings highlight the need for a model of object feature processing that can account for the functional demands that elicit these anatomical differences.

The neuronal underpinnings of visual awareness has recently become the primary question of interest for many researchers, with many theories suggesting distinct mechanisms. The aim of this thesis was to test predictions of the low-level modular theory of visual awareness. This modular view is encapsulated in the 'microconsciousness' framework (Zeki & Bartels, 1999) in which each visual processing system, such as that for colour, is capable of generating a conscious correlate autonomously in parallel across space, within each of the different functionally specialised areas of the visual brain, and across time, with different attributes perceived at different times. Given the scope of this topic, we approached it from three diverse angles: (1) Two psychophysical experiments investigated temporal aspects of visual perception - in particular these addressed the issue of whether the timing of awareness is an 'online* phenomenon rather than integrated into a temporal buffer zone prior to awareness. We measured the relative perceptual times of different magnitudes of direction changes and investigated the 'flash-lag' effect (Nijhawan, 1994) and related illusions of positional localisation. (2) The first two fMRI experiments examined the necessity of frontal and parietal areas for visual awareness in the context of bistable figures, combined with dynamic causal modelling (Friston et al., 2003), and perception outside the focus of attention. (3) We looked to extend the concept of modularity of awareness to that of 'access consciousness', that is the ability to give a report of a conscious experience (Block, 1996), in addition to the previous studies on phenomenal consciousness. To this end, we combined psychophysics with fMRI to investigate the interaction between report modality and visual perception. We conclude that the low-level modular theory of stands up to direct tests of its predictions and remains a viable theory of visual awareness.

This thesis presents an investigation of two general factors affecting speech perception in normal-hearing adults. Two sets of experiments are described, in which speakers of English are presented with degraded (noise-vocoded) speech. The first set of studies investigates the importance of linguistic rhythm as a cue for perceptual adaptation to noise-vocoded sentences. Results indicate that the presence of native English rhythmic patterns benefits speech recognition and adaptation, but not when higher-level linguistic information is absent (i.e. when the sentences are in a foreign language). It is proposed that rhythm may help in the perceptual encoding of degraded speech in phonological working memory. Experiments in this strand also present evidence against a critical role for indexical characteristics of the speaker in the adaptation process. The second set of studies concerns the issue of individual differences in speech perception. A psychometric curve-fitting approach is selected as the preferred method of quantifying variability in noise-vocoded sentence recognition. Measures of working memory and verbal IQ are identified as candidate correlates of performance with noise-vocoded sentences. When the listener is exposed to noise-vocoded stimuli from different linguistic categories (consonants and vowels, isolated words, sentences), there is evidence for the interplay of two initial listening 'modes' in response to the degraded speech signal, representing 'top-down' cognitive-linguistic processing and 'bottom-up' acoustic-phonetic analysis. Detailed analysis of segment recognition presents a perceptual role for temporal information across all the linguistic categories, and suggests that performance could be improved through training regimes that direct attention to the most informative acoustic properties of the stimulus. Across several experiments, the results also demonstrate long-term aspects of perceptual learning. In sum, this thesis demonstrates that consideration of both stimulus-based and listener-based factors forms a promising approach to the characterization of speech perception processes in the healthy adult listener.

This thesis has established the effects of perceptual load and working memory load on the conscious awareness of an expected task-unrelated stimulus. Participants performed a visual search task, in which perceptual load was manipulated, while attempting to detect the presence of a meaningless task-unrelated figure, referred to as the critical stimulus (CS). The results showed a consistent reduction in CS detection rate and detection sensitivity (with no accompanying change in response criterion), when the search task was of high perceptual load, compared to a low perceptual load condition. Alternative accounts of the results in terms of memory failure rather than the absence of conscious awareness, the differential search task reaction times in the low and high conditions of perceptual load, goal-neglect, and strategy were ruled out. The effects of perceptual load were generalised to a CS presented directly at fixation, while demonstrating that detection performance was superior for fixated stimuli than for stimuli in peripheral vision, despite size-scaling to account for cortical magnification. Furthermore, the experiments established a dissociation between the effect of perceptual load and the effect of working memory load on conscious awareness, and a second dissociation between the effect of working memory load on awareness and its effect on distractor interference: whereas detection sensitivity and distractor interference were both reduced alike under high perceptual load, working memory load led to increased distractor interference but had no effect on detection sensitivity. Overall, the results generalised perceptual load theory (e.g., Lavie, 1995) to measures of conscious perception, and established a contrast between the effect of working memory load on awareness and on distractibility.

Background: Almost 2 million people in the UK are blind or partially sighted and this number is expected to double by 2030. Of this number, approximately 85% have residual vision (low vision) that can be used effectively for daily activities with appropriate visual aids. Bilateral macular disease is one of the leading causes of visual impairment especially in the elderly. In advanced age related macular degeneration (AMD) patients develop a scotoma at the fovea, the most sensitive central area of the field of view. In order to read or recognise faces most patients with AMD adopt an eccentric fixation locus (the preferred retinal locus or PRL) that acts as a pseudo-fovea and is used as a reference point for the patient’s oculomotor system. The PRL is placed upon parafoveal or extrafoveal retina depending on the scotoma size and location. Patients use one or more PRLs, depending on the task they are performing. PURPOSE. To investigate how visual function varies with retinal eccentricity, to determine how visual function at the PRL compares to other retinal locations of comparable eccentricity, and to determine whether a more suitable eccentric retinal location could be found for the patient to be trained to use as their PRL. Methods: 24 patients with AMD and 19 normal vision subjects (8 young and 11 similar in age to the patients) were recruited. All AMD patients were tested on a Rodenstock scanning laser ophthalmoscope to identify the PRL location in their better eye. A SMI EyeLink eyetracker was used to assess peripheral visual acuity contrast sensitivity in both groups. 15 AMD patients and 11 normal vision subjects (6 young and 5 similar in age to the patients) were further tested on the SMI Eyelink eyetracker to assess peripheral sustained attention and reading speed with Rapid Serial Visual Presentation (RSVP). Results: In normal vision subjects, visual acuity, contrast sensitivity, attention and reading speed declined with increasing retinal eccentricity, and varied with polar angle. For visual acuity, attention and reading speed performance was best along the horizontal meridian. Young normal vision subjects performed better in the retinal periphery for all tasks compared to the age-similar normal vision subjects. All AMD patients performed best at their PRL in the visual acuity, attention and reading speed tasks, but not in the contrast sensitivity task. Even at the PRL, AMD patients performed worse on all tasks than the age-similar normal vision control subjects at a similar eccentricity. Reading speed was poorly predicted by visual acuity and contrast sensitivity but well predicted by sustained attention. Conclusions: For the visual functions measured in these experiments, it appears that most AMD patients found the area best suited for their PRL. It is the area with best acuity and reading performance, and most easily attended to. This implies that visual rehabilitation training should utilize the patient's selected PRL rather than training a new PRL. However, visual function at the PRL is generally worse than would be expected for healthy retina at that eccentricity. It is not clear whether this is because the peripheral retinal is not functioning normally or that patients are not making full use of this area. The ability to deploy attention at the PRL appears to be important in reading, however more clinical research is needed in this area. These data provide important information about the optimal eccentric retinal area for text presentation to achieve maximal reading rate and may be useful for developing new training programmes to help patients make best use of eccentric fixation.