Inherited retinal diseases affect the L-, M-, Scones and rods in distinct ways, which calls for new methods that enable quantification of photoreceptor-specific functions. We tested the feasibility of using the silent substitution paradigm to estimate photoreceptor-driven temporal contrast sensitivity (tCS) functions in patients with retinitis pigmentosa. Methods: The silent substitution paradigm is based on substitution of lights of different spectral composition; this offers considerable advantage over other stimulation techniques. We used a four-primary LED stimulator to create perifoveal annular stimuli (2°inner, 12°outer diameters) and used a triple silent substitution to probe photoreceptor-selective tCS. Measurements were performed in a heterogeneous cohort of 15 patients with retinitis pigmentosa and related to those in a control group of nine color-normal healthy observers. Age differences between groups were addressed with a model of age-related normal contrast sensitivity derived from measurements in 20 healthy observers aged between 23 and 83 years. Results: The age-related loss of tCS amounted to 0.1 dB/year in healthy subjects across all photoreceptor subtypes. In patients, tCS was decreased for every photoreceptor subtype; however, Scone and rod-driven sensitivities were most strongly affected. Postreceptoral mechanisms were not affected. Conclusions: This feasibility study provides evidence that the silent substitution technique enables the estimation of photoreceptor-selective tCS functions and can serve as an accurate biomarker of photoreceptor-specific contrast sensitivity loss in patients with retinitis pigmentosa. Translational Relevance: We aim to develop tests of visual function for clinical trials of novel therapies for inherited retinal diseases from methods that can currently be used only in vision research labs. The method of silent substitution (or spectral compensation) is a powerful technique using photoreceptor-isolating stimuli for investigation of retinal processing in normal subjects. 4,5 The method implicates light substitution: light of a specified spectral composition is replaced by another light of a different spectral composition. The spectral composition and intensity of these lights are chosen in such a way that excitation, that is, the rate of photoisomerization, varies only in the target photoreceptor class, but remains constant in other classes. This property distinguishes silent substitution from selective chromatic adaptation, the method where a colored stimulus is superimposed on an adapting background resulting in

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Zusammenfassung Hintergrund Erbliche Netzhauterkrankungen mit Zapfendysfunktion können trotz relativ unauffälligem Fundusbefund ausgeprägte Visusminderung und deutliche Farbsinnstörungen aufweisen. Beispiele hierfür sind die autosomal-dominante okkulte Makuladystrophie (RP1L1-Gen) und die X‑chromosomale Retinitis pigmentosa (RPGR-Gen) – Letztere auch bei heterozygoten, weiblichen Merkmalsträgerinnen (Konduktorinnen). Neue Untersuchungsmethoden erlauben es, das Ausmaß der Farbsinnstörung zu quantifizieren. Methoden Nach einer umfangreichen klinischen Untersuchung führten wir Messungen zur Quantifizierung der Farbdiskriminierung und der Zapfenfunktion durch. Beim Cambridge-Color-Test werden pseudoisochromatische Tafeln mit Landolt-C-Figuren computergesteuert generiert, um die Farbunterscheidungsschwelle entlang mehrerer Achsen im Farbraum zu bestimmen. Bei der Untersuchung der photorezeptorspezifischen zeitlichen Kontrastempfindlichkeit kann durch geschickte zyklische Veränderung der spektralen Zusammensetzung eines Lichtreizes die Kontrastwahrnehmungsschwelle isolierter Photorezeptortypen bestimmt werden. Die molekulargenetische Diagnostik erfolgte mithilfe von Next Generation Sequencing(NGS)-basierter gezielter Genpanelanalyse sowie Sanger-Sequenzierung. Ergebnisse Bei 2 Patienten mit okkulter Makuladystrophie und 2 heterozygoten Trägerinnen von RPGR-Mutationen zeigten sich eine deutlich verminderte Fähigkeit zur Farbdiskriminierung und eine verminderte photorezeptorspezifische zeitliche Kontrastempfindlichkeit. Diskussion Bei erblichen Netzhauterkrankungen sind neben den modernen bildgebenden Verfahren (okuläre Kohärenztomographie [OCT] und Fundusautofluoreszenz) auch die sinnesphysiologischen Untersuchungen diagnostisch wegweisend – der Nachweis von Farbsinnstörungen spielt hierbei eine wichtige Rolle. Neuere Methoden erlauben eine Quantifizierung der Farbsinnstörungen und könnten in klinischen Studien zu gen- und stammzellbasierter Therapie zur Messung des Therapieerfolges dienen.

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Our past anecdotal evidence prompted that a longer response window (RW) in the Trivector test (Cambridge Colour Test) improved mature observers’ estimates of chromatic discrimination. Here, we systematically explored whether RW variation affects chromatic discrimination thresholds measured by the length of Protan, Deutan and Tritan vectors. We employed the Trivector test with three RWs: 3 s, 5 s, and 8 s. Data of 30 healthy normal trichromats were stratified as age groups: ‘young’ (20–29 years), ‘middle-aged’ (31–48 years), and ‘mature’ (57–64 years). We found that for the ‘young’ and ‘middle-aged’, the thresholds were comparable at all tested RWs. However, the RW effect was apparent for the ‘mature’ observers: their Protan and Tritan thresholds decreased at 8-s RW compared to 3-s RW; moreover, their Tritan threshold decreased at 5-s RW compared to 3-s RW. Elevated discrimination thresholds at shorter RWs imply that for accurate performance, older observers require longer stimulus exposure and are indicative of ageing effects manifested by an increase in critical processing duration. Acknowledging low numbers in our ‘middle-aged’ and ‘mature’ samples, we consider our study as pilot. Nonetheless, our findings encourage us to advocate a RW extension in the Trivector protocol for testing mature observers, to ensure veridical measures of their chromatic discrimination by disentangling these from other ageing effects—slowing down of both motor responses and visual processing.