An exploration of pre-attentive visual discrimination using event-related potentials

The Mismatch Negativity (MMN) has been characterised as a ‘pre-attentive’ component of an Event-Related Potential (ERP) that is related to discriminatory processes. Although well established in the auditory domain, characteristics of the MMN are less well characterised in the visual domain. The five main studies presented in this thesis examine visual cortical processing using event-related potentials. Novel methodologies have been used to elicit visual detection and discrimination components in the absence of a behavioural task. Developing paradigms in which a behavioural task is not required may have important clinical applications for populations, such as young children, who cannot comply with the demands of an active task. The ‘pre-attentive’ nature of visual MMN has been investigated by modulating attention. Generators and hemispheric lateralisation of visual MMN have been investigated by using pertinent clinical groups. A three stimulus visual oddball paradigm was used to explore the elicitation of visual discrimination components to a change in the orientation of stimuli in the absence of a behavioural task. Monochrome stimuli based on pacman figures were employed that differed from each other only in terms of the orientation of their elements. One such stimulus formed an illusory figure in order to capture the participant’s attention, either in place of, or alongside, a behavioural task. The elicitation of a P3a to the illusory figure but not to the standard or deviant stimuli provided evidence that the illusory figure captured attention. A visual MMN response was recorded in a paradigm with no task demands. When a behavioural task was incorporated into the paradigm, a P3b component was elicited consistent with the allocation of attentional resources to the task. However, visual discrimination components were attenuated revealing that the illusory figure was unable to command all attentional resources from the standard deviant transition. The results are the first to suggest that the visual MMN is modulated by attention. Using the same three stimulus oddball paradigm, generators of visual MMN were investigated by recording potentials directly from the cortex of an adolescent undergoing pre-surgical evaluation for resection of a right anterior parietal lesion. To date no other study has explicitly recorded activity related to the visual MMN intracranially using an oddball paradigm in the absence of a behavioural task. Results indicated that visual N1 and visual MMN could be temporally and spatially separated, with visual MMN being recorded more anteriorly than N1. The characteristic abnormality in retinal projections in albinism afforded the opportunity to investigate each hemisphere in relative isolation and was used, for the first time, as a model to investigate lateralisation of visual MMN and illusory contour processing. Using the three stimulus oddball paradigm, no visual MMN was elicited in this group, and so no conclusions regarding the lateralisation of visual MMN could be made. Results suggested that both hemispheres were equally capable of processing an illusory figure. As a method of presenting visual test stimuli without conscious perception, a continuous visual stream paradigm was developed that used a briefly presented checkerboard stimulus combined with masking for exploring stimulus detection below and above subjective levels of perception. A correlate of very early cortical processing at a latency of 60-80 ms (CI) was elicited whether stimuli were reported as seen or unseen. Differences in visual processing were only evident at a latency of 90 ms (CII) implying that this component may represent a correlate of visual consciousness/awareness. Finally, an oddball sequence was introduced into the visual stream masking paradigm to investigate whether visual MMN responses could be recorded without conscious perception. The stimuli comprised of black and white checkerboard elements differing only in terms of their orientation to form an x or a +. Visual MMN was not recorded when participants were unable to report seeing the stimulus. Results therefore suggest that behavioural identification of the stimuli was required for the elicitation of visual MMN and that visual MMN may require some attentional resources. On the basis of these studies it is concluded that visual MMN is not entirely independent of attention. Further, the combination of clinical and non-clinical investigations provides a unique opportunity to study the characterisation and localisation of putative mechanisms related to conscious and non-conscious visual processing

Molecular and clinical characterization of albinism in a large cohort of Italian patients.

PURPOSE: The purpose of this study was to identify the molecular basis of albinism in a large cohort of Italian patients showing typical ocular landmarks of the disease and to provide a full characterization of the clinical ophthalmic manifestations. METHODS: DNA samples from 45 patients with ocular manifestations of albinism were analyzed by direct sequencing analysis of five genes responsible for albinism: TYR, P, TYRP1, SLC45A2 (MATP), and OA1. All patients studied showed a variable degree of skin and hair hypopigmentation. Eighteen patients with distinct mutations in each gene associated with OCA were evaluated by detailed ophthalmic analysis, optical coherence tomography (OCT), and fundus autofluorescence. RESULTS: Disease-causing mutations were identified in more than 95% of analyzed patients with OCA (28/45 [62.2%] cases with two or more mutations; 15/45 [33.3%] cases with one mutation). Thirty-five different mutant alleles were identified of which 15 were novel. Mutations in TYR were the most frequent (73.3%), whereas mutations in P occurred more rarely (13.3%) than previously reported. Novel mutations were also identified in rare loci such as TYRP1 and MATP. Mutations in the OA1 gene were not detected. Clinical assessment revealed that patients with iris and macular pigmentation had significantly higher visual acuity than did severe hypopigmented phenotypes. CONCLUSIONS: TYR gene mutations represent a relevant cause of oculocutaneous albinism in Italy, whereas mutations in P present a lower frequency than that found in other populations. Clinical analysis revealed that the severity of the ocular manifestations depends on the degree of retinal pigmentation

Neurodevelopmental Disorders Associated with Chromosome 15

Chromosome 15 is a focus of increasing interest to both psychiatry and neurology. Several neurodevelopmental disorders are genetically associated with this autosome, including Prader-Willi syndrome, Angelman syndrome, Dyslexia, Autism, Hyperlexia, Ring 15 Chromosome syndrome, and Trisomy 15 syndrome. This report provides a review of the molecular biology of chromosome 15 and these associated disorders

Using magnetic resonance imaging to assess visual deficits : a review

PURPOSE: Over the last two decades, magnetic resonance imaging (MRI) has been widely used in neuroscience research to assess both structure and function in the brain in health and disease. With regard to vision research, prior to the advent of MRI, researchers relied on animal physiology and human post-mortem work to assess the impact of eye disease on visual cortex and connecting structures. Using MRI, researchers can non-invasively examine the effects of eye disease on the whole visual pathway, including the lateral geniculate nucleus, striate and extrastriate cortex. This review aims to summarise research using MRI to investigate structural, chemical and functional effects of eye diseases, including: macular degeneration, retinitis pigmentosa, glaucoma, albinism, and amblyopia. RECENT FINDINGS: Structural MRI has demonstrated significant abnormalities within both grey and white matter densities across both visual and non-visual areas. Functional MRI studies have also provided extensive evidence of functional changes throughout the whole of the visual pathway following visual loss, particularly in amblyopia. MR spectroscopy techniques have also revealed several abnormalities in metabolite concentrations in both glaucoma and age-related macular degeneration. GABA-edited MR spectroscopy on the other hand has identified possible evidence of plasticity within visual cortex. SUMMARY: Collectively, using MRI to investigate the effects on the visual pathway following disease and dysfunction has revealed a rich pattern of results allowing for better characterisation of disease. In the future MRI will likely play an important role in assessing the impact of eye disease on the visual pathway and how it progresses over time

Ophthalmological Manifestations of Oculocutaneous and Ocular Albinism: Current Perspectives

Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism

Aberrant visual pathway development in albinism: from retina to cortex

Albinism refers to a group of genetic abnormalities in melanogenesis that are associated neuronal misrouting through the optic chiasm. Previous imaging studies have shown structural alterations at different points along the visual pathway of people with albinism (PWA) including foveal hypoplasia, optic nerve and chiasm size alterations and visual cortex reorganisation, but fail to provide a holistic in-vivo characterisation of the visual neurodevelopmental alterations from retina to visual cortex. We perform quantitative assessment of visual pathway structure and function in 23 PWA and 20 matched controls using optical coherence tomography (OCT), volumetric magnetic resonance imaging (MRI), diffusion tensor imaging and visual evoked potentials (VEP). PWA had a higher streamline decussation index (percentage of total tractography streamlines decussating at the chiasm) compared to controls (Z=-2.24, p=0.025), and streamline decussation index correlated weakly significantly with inter-hemispheric asymmetry measured using VEP (r=0.484, p=0.042). For PWA, a significant correlation was found between foveal development index and total number of streamlines (r=0.662, p less than 0.001). Optic nerve (p=0.001) and tract (p=0.010) width, and chiasm width (P less than 0.001), area (p=0.006) and volume (p=0.005), were significantly smaller in PWA compared to controls. Significant positive correlations were found between peri-papillary retinal nerve fibre layer thickness and optic nerve (r=0.642, p less than 0.001) and tract (r=0.663, p less than 0.001) width. Occipital pole cortical thickness was 6.88% higher (Z=-4.10, p less than 0.001) in PWA and was related to anterior visual pathway structures including foveal retinal pigment epithelium complex thickness (r=-0.579, p=0.005), optic disc (r=0.478, p=0.021) and rim areas (r=0.597, p=0.003). We were unable to demonstrate a significant relationship between OCT-derived foveal or optic nerve measures and MRI-derived chiasm size or streamline decussation index. Non-invasive imaging techniques demonstrate aberrant development throughout the visual pathways of PWA compared to controls. Our novel tractographic demonstration of altered chiasmatic decussation in PWA corresponds to VEP measured cortical asymmetry and is consistent with chiasmatic misrouting in albinism. We also demonstrate a significant relationship between retinal pigment epithelium and visual cortex thickness indicating that retinal pigmentation defects in albinism lead to downstream structural reorganisation of the visual cortex

Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia

Background: Septo-optic dysplasia (SOD) is a condition that affects the early development of the brain and eyes. It presents with a combination of optic nerve hypoplasia, brain midline structure abnormalities, and pituitary gland hypoplasia. Methods: This is a case report of a 4-year-old male who presented with low amplitude horizontal nystagmus and decreased visual acuity 20/60 OU. Further imaging and electrophysiology were conducted to classify the ocular presentation. Results: No iris transillumination was noted, but foveal hypoplasia and disc edema were evident on fundus examination. This prompted neurology consultation and MRI imaging. The MRI was consistent with the diagnosis of SOD showing hypoplasia of the optic nerves, chiasm, and tracts and an absent septum pellucidum, but with normal pituitary development and function. Lumbar puncture and intracranial pressure were normal. Genetic testing identified one pathogenic variant in the SLC45A2, indicating carrier status for oculocutaneous albinism type 4 (OCA4). Flash Visual Evoked Potentials (VEPs) were consistent with chiasm dysfunction or hypoplasia rather than the chiasmal misrouting of OCA. Conclusion: This case report further elaborates the phenotypic variation of SOD, with the finding of blurred disc margins, in the absence of the typical optic nerve double ring sign and with normal intracranial pressure. The findings of fovea hypoplasia and blond fundi lead to the suspicion of OCA either as a separate diagnosis with a second pathogenic variant in SCL45A2 not yet identified or in association with SOD. This case highlights the importance of electrophysiology to help distinguish chiasmal hypoplasia or dysfunction from OCA misrouting