Chow-Wing-Bom, Hugo Thomas; (2025) Neurodegeneration and Adaptation in Late Onset Sight Loss: Insights from MRI into Leber Hereditary Optic Neuropathy (LHON). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Leber Hereditary Optic Neuropathy (LHON) is a mitochondrial disorder that leads to rapid central vision loss through degeneration of retinal ganglion cells. While structural MRI studies have identified volumetric and white matter changes along the visual pathways, the underlying microstructural mechanisms – whether demyelination, axonal loss, or both – remain unclear. Additionally, large central scotomas and associated fixation difficulties complicate the measurement of visual function, resulting in limited functional measures and understanding of visual processing in LHON. This thesis addresses these gaps using advanced structural and functional MRI approaches to characterise changes beyond the retina in LHON. First, diffusion MRI and multi-parametric mapping (MPM) were combined with biophysical modelling to disentangle axonal and myelin loss along the visual pathways. Results showed concurrent axonal degeneration and demyelination in the optic tracts, and widespread axonal disruption with localised demyelination near V1 in the optic radiations. These changes were accompanied by volume loss in the lateral geniculate nucleus and V1, particularly in regions representing central vision. Second, I developed a large-field fMRI approach to map contrast sensitivity across the visual field at the cortical level. This method, combining a contrast sensitivity task with population receptive field (pRF) mapping, reliably captured known sensitivity gradients across the visual field (up to 20º eccentricity) in normal-sighted individuals. Crucially, these patterns were preserved when using a fixation-free retinotopic atlas, enabling application in patients with impaired fixation. This approach yielded repeatable, eye-specific cortical sensitivity maps and showed partial correspondence with behavioural and retinal measures. Overall, this work provides new insights into the microstructural mechanisms underlying neural changes along the visual pathways and introduces a novel fixation-free, brain-based approach for mapping visual field defects in LHON. These tools offer potential sensitive outcome measures, crucial for tracking disease progression and evaluating therapeutic efficacy, especially given promising sight recovery from gene-therapy.

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