Preferential Loss of Contrast Decrement Responses in Human Glaucoma

Abstract

Purpose The purpose of this study was to determine whether glaucoma in human patients produces preferential damage to OFF visual pathways, as suggested by animal experimental models, patient electroretinogram (ERG), and retinal imaging data. Methods Steady-state visual evoked potentials (SSVEPs) were recorded monocularly from 50 patients with glaucoma and 28 age-similar controls in response to equal Weber contrast increments and decrements presented using 2.73 hertz (Hz) sawtooth temporal waveforms. Results The eyes of patients with glaucoma were separated into mild (better than −6 decibel [dB] mean deviation; n = 28) and moderate to severe (worse than −6 dB mean deviation, n = 22) groups based on their Humphrey 24-2 visual field measurements. Response amplitudes and phases from the two glaucoma-severity groups were compared to controls at the group level. SSVEP amplitudes were depressed in both glaucoma groups, more so in the moderate to severe glaucoma group. The differences between controls and the moderate-severe glaucoma groups were more statistically reliable for decrements than for increments. Mean responses to decremental sawtooth stimuli were larger than those to increments in controls and in the mild glaucoma but not in the moderate to severe glaucoma group at the first harmonic. OFF/decrement responses at the first harmonic were faster in controls, but not in patients. Conclusions The observed pattern of preferential loss of decremental responses in human glaucoma is consistent with prior reports of selective damage to OFF retinal ganglion cells in murine models and in data from human ERG and retinal imaging. These data motivate pursuit of SSVEP as a biomarker for glaucoma progression.

Utility of Light-Adapted Full-Field Electroretinogram ON and OFF Responses for Detecting Glaucomatous Functional Damage

“…Their results confirmed that cortical responses to decrements are normally larger and faster than responses to increments in healthy persons, but in the subgroup of eyes with moderate-to-advanced glaucoma (worse than −6 dB visual field mean deviation), decrement responses were statistically significantly reduced and delayed and the normally strong ON–OFF asymmetry was diminished. 28 Although these results were interpreted as representing preferential damage of the OFF pathway in glaucoma, there was a trend evident in the subgroup of eyes with mild glaucoma for greater loss of increment (ON pathway) responses than OFF responses. Thus, again, it may be that relative functional loss of ON and OFF pathways depends on the stage of glaucoma severity with relatively worse OFF pathway function occurring only at later stages.…”

“…Another recent study, by Norcia et al, 28 used an elegant approach for analysis of steady-state visual evoked cortical responses to sawtooth increment and decrement stimuli favoring ON and OFF visual pathways, respectively. Their results confirmed that cortical responses to decrements are normally larger and faster than responses to increments in healthy persons, but in the subgroup of eyes with moderate-to-advanced glaucoma (worse than −6 dB visual field mean deviation), decrement responses were statistically significantly reduced and delayed and the normally strong ON–OFF asymmetry was diminished.…”

“… 27 Similarly, studies in human glaucoma have provided conflicting evidence, with some suggesting there may be preferential loss of the OFF pathway and others finding either no differential effect or a greater deficit of the ON pathway. 16 , 22 , 24 – 26 , 28 , 29 …”

Visual field asymmetries in responses to ON and OFF pathway biasing stimuli

“…This means we have a near absent quantitative understanding of the supra-threshold visual experience across the visual field of patients with ocular pathology. We have previously used the SSVEP to demonstrate an OFF-pathway vulnerability in Glaucoma (Norcia et al, 2022), but at a single contrast. Recently, Bham et al (2020) measured behavioural contrast matching thresholds in patients with partial Glaucomatous field loss.…”

“…Describing the degree of ON-and OFFpathway VF asymmetry may then allow us to better simulate human behavior. Additionally, it would provide a more detailed understanding of the perceptual experiences of individuals with pathology that affects one pathway more than the other, like amblyopia (Pons et al, 2019) and glaucoma (Norcia et al, 2022).…”