Genetically induced impairment of retinal ganglion cells at the axonal level is linked to extrastriate cortical plasticity.

Abstract

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder, which leads to initially silent visual loss due to retinal ganglion cell (RGC) degeneration. We aimed to establish a link between features of retinal progressive impairment and putative cortical changes in a cohort of 15 asymptomatic patients harboring the 11778G>A mutation with preserved visual acuity and normal ocular examination. To study plasticity evoked by clinically silent degeneration of RGC we only studied mutation carriers. We phenotyped pre-clinical silent degeneration from the psychophysical, neurophysiological and structural points of view to understand whether retinal measures could be related to cortical reorganization, using pattern electrophysiology, chromatic contrast sensitivity and high-resolution optical coherence tomography to measure macular, RGC nerve fiber layer as well as inner/outer retinal layer thickness. We then performed correlation analysis of these measures with cortical thickness estimates in functionally mapped retinotopic visual cortex. We found that compensatory cortical plasticity occurring in V2/V3 is predicted by the swelling (indicating deficits of axonal transport and intracellular edema) of the macular RGC axonal layer. Increased cortical thickness (CT) in V2 and V3 was observed in peripheral regions, like visual field loss, in these mutation carriers. CT was a very discriminative measure between carriers and controls, as revealed by ROC analysis. Importantly, the substantial cortical reorganization that occurs in the carrier state can be used to provide statistical discrimination between carriers and controls to a level that is similar to measures of retinal dysfunction. We conclude that peripheral cortical compensatory plasticity in early visual areas V2/V3 may be triggered by pathology in peripheral RGC axons in combination with potential developmental changes.