Functional and structural adaptations to lifelong lack of cone input and its implications for gene therapy outcomes

Abstract

Achromatopsia is a congenital genetic condition of retinal cone dysfunction. While the rod signalling system in individuals with achromatopsia (ACHM) remains intact, the lack of cone signal leaves them with poor visual acuity, a foveal scotoma and complete colour blindness. We recently showed that gene therapies can restore cone function between eye and cortex in some patients, with individual differences in treatment effect. What may explain these differences? Previous studies have reported thickening of foveal visual cortex in ACHM and reduced overall visual cortex area, similar to changes observed in fully blind individuals. This may reflect deprivation related structural processes that can limit treatment amenability. Additionally, one study suggested that, in 3 individuals with ACHM, cortex taking input from the impaired fovea responds to rod-mediated inputs from the more peripheral retina, so treatment may be further limited by hijacked resources. The aim of the present study was to test how such structural and functional reorganisation of the deprived visual cortex combine in ACHM and contribute to individual differences in treatment outcome. To test this, we compared data from 17 children and 10 adults with ACHM, to 101 controls. Of these 21 patients underwent cone restorative gene therapy. Preliminary analyses replicate previous results of structural change in this larger cohort. Specifically, we see a thicker foveal visual cortex and a non-eccentricity specific reduction in surface area in achromats compared to controls. In contrast, unlike previous studies we do not find strong evidence for increased rod-mediated functional activation in cone innervated foveal cortex at the group level in patients, although we note some individual differences. We will discuss how these pre-existing adaptations of the brain to lifelong lack of cone input can explain individual differences in treatment amenability and broader functional outcome.