Achromatopsia: Exploring nature and plasticity of vision in the absence of functional cones

• Applicant: Professor Dr. Michael Hoffmann
• Subject Area: Ophthalmology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262033421

• Final Report Year: 2022

Final Report Abstract

Current gene therapeutic initiatives to restore retinal cone function in individuals born without functioning cone photoreceptors, i.e., autosomal recessive achromatopsia, might be severely confounded by visual cortex remapping. Consequently, a detailed characterization of visual cortex plasticity and visual function in achromatopsia is important in order to optimize therapy. In a multi-center fMRI study, we assessed visual cortex function and plasticity in a genetically confirmed achromatopsia cohort of unprecedented sample size (n=17). We found that remapping of the cortical representation of the central visual field was not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. Specifically, we obtained the following main results and conclusions: • Visual acuity– scotopic/photopic & conventional/hyperacuity: In none of the conditions tested did we find visual acuities in the achromatopsia cohort that exceeded those of the healthy control group. For photopic conditions we report reduced visual acuities in achromatopsia. „ We conclude from the absence of improved scotopic acuities in achromatopsia that previously reported potential neural plasticity of the visual cortex in achromatopsia might not be functionally relevant. • fMRI-based mapping of the primary visual cortex: We report an absence of activation of the deafferented cortical representation of the central visual field in achromatopsia. Previous case reports on activations by paracentral representations were not confirmed.„ We conclude that the deafferented proportion of the visual cortex in achromatopsia is not reorganised to take up processing of the parafoveal visual field. • MRI-based morphometry of the primary visual cortex: We report a thickening of the gray matter of the deafferented cortical representation of the central visual field in achromatopsia, which is reminiscent of the cortical thickening of the entire visual cortex previously observed in early blind.„ We conclude that the deafferented cortical representation of the central visual field in achromatopsia fails to undergo the typical maturation of the visual cortex. • MRI-based morphometry of the early visual cortex: We report an overall reduction of gray matter volume and surface area that affects the early visual areas including V1, V2, V3, and V4. „ We conclude that the lack of input from the retinal cones induces developmental changes to large expanses of the visual cortex. These are not restricted to the representation of the central visual field. In summary, these findings indicate that visual function and structure and function of the visual cortex in ACHM do not support the notion of remapping as a group feature of ACHM. We did not find evidence for functional mapping of the parafoveal visual field into the foveal representation of the primary visual cortex and did not find an improvement of visual function as tested with a comprehensive set of visual acuity tests. In contrast, the visual cortex receiving projections from the fovea is thickened and reduced in surface area, a reminiscence of developmental changes to the visually deprived cortex of early blind. Morevoer, the early visual cortex in achromatopsia is generally reduced in surface area and cortical thickness. In conclusion, to avoid confounding effects of these cortical changes, treatment with gene-therapy is recommended to be performed early in life, i.e. before experience dependent changes to the cortical morphology are manifest.

Publications

• (2017) Potential von fMRT für die Funktionsüberprüfung des pathologischen Sehsystems. Klinische Monatsblätter für Augenheilkunde 234:303-310
  Hoffmann MB, Thieme H, Ahmadi K
  
• (2019) Scotopic multifocal visual evoked potentials. Clinical Neurophysiology 130:379-387
  Muranyi DS, Kramer FH, Herbik A, Hoffmann MB
  
• (2020) Determination of scotopic and photopic conventional visual acuity and hyperacuity. Graefe's Archive of Clinical & Experimental Ophthalmology 258(1), 129-135
  Freundlieb PH, Herbik A, Kramer FH, Bach M, Hoffmann MB
  
• (2021) Neuro-computational approaches for objective visual function assessment. Ophthalmologe 118:900-906
  Hoffmann MB, Choritz L, Thieme H, Prabhakaran G, Puzniak RJ
  
• Structural differences across multiple visual cortical regions in the absence of cone function in congenital achromatopsia. Frontiers in Neuroscience 15:718958
  Lowndes R, Molz B, Warriner L, Herbik A, De Best PB, Raz N, Gouws AD, Ahmadi K, Mclean RJ, Gottlob I, Kohl S, Choritz L, Maguire J, Kanowski M, Käsmann-Kellner B, Wieland I, Banin E, Levin N, Hoffmann MB, Morland AB, Baseler HA
  
• (2022) Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia. Neuroimage Clinical 33:102925
  Molz B; Herbik A; Baseler HA; de Best PB; Vernon R; Raz N; Gouws AD; IF Ahmadi K; Lowndes RH; McLean RJ; Gottlob I; Kohl S; Choritz L; Maguire J; Kanowski M; Käsmann-Kellner B; Wieland I; Banin E; Levin N; Hoffmann MB; Morland AB