Probing ON and OFF Retinal Pathways in Glaucoma Using Electroretinography

Abstract

Glaucoma is a progressive neurodegenerative disease involving damage and eventually death of retinal ganglion cells (RGCs) that comprise the optic nerve. This review summarizes current understanding of specific RGC type vulnerability in glaucoma and how electroretinography (ERG) may provide an objective measure of these functional perturbations. There is building evidence to suggest that ON RGCs, which respond to light increments, may be more resilient to elevated intraocular pressure and glaucoma, whereas OFF RGCs, which respond to light decrements, may be more susceptible. ERG experiments in nonhuman primates and mice have also shown that the ON-and OFFpathways can be separated using a variety of techniques such as pattern ERG and the photopic negative response. Another ERG paradigm of interest to separate the ON and OFF responses is a flicker stimulus at varying temporal frequencies. Response to lower temporal frequencies is associated with the ON-pathway, and ERG response to higher frequencies is associated with the OFF-pathway. In mice, experimental glaucoma models have shown greater decreases in ERG response at higher frequencies, suggesting that the OFF-pathway is more susceptible. We also summarize current clinical ERG protocols used for glaucoma and discuss innovations for developing new types of stimuli that can further separate the ON-and OFF-pathways. Applying these novel paradigms that distinguish ON-and OFF-pathways may ultimately improve glaucoma diagnostics and monitoring of glaucoma progression. Translational Relevance: Based on our current understanding of specific RGC type vulnerability in glaucoma, we explore how ERG may provide an objective measure of ON-versus OFF-pathway functional perturbations.

Predicting Visual Field Progression by Optical Coherence Tomography Angiography and Pattern Electroretinography in Glaucoma

“…The N95 amplitude is presumably related to the RGC action potential, with changes clearly evident at the N95 peak. However, changes within the inner retina and nonspiking activity within the RGCs likely contribute to changes in P50, as demonstrated in other glaucoma studies 23,24. Along with the P50-N95 amplitude, the N35-P50 amplitude was correlated with the baseline MD or MD slope and had a significant association with the MD slope in univariate regression analysis in the present study.…”

“…However, changes within the inner retina and nonspiking activity within the RGCs likely contribute to changes in P50, as demonstrated in other glaucoma studies. 23,24 Along with the P50-N95 amplitude, the N35-P50 amplitude was correlated with the baseline MD or MD slope and had a significant association with the MD slope in univariate regression analysis in the present study. Although the N35-P50 amplitude was not a significant risk factor related to VF progression according to the GPA of the Humphrey Field Analyzer, it may indicated RGC dysfunction, because the P50 peak has been associated with the bipolar cells-RGC synapse and the current within RGC somata/dendrites.…”

7,8-Dihydroxiflavone Maintains Retinal Functionality and Protects Various Types of RGCs in Adult Rats with Optic Nerve Transection

“…Thus, our assessment provides indirect evidence for the wellbeing of large number of retinal neurons contributing to each of the main recorded components. Further studies using additional stimulating parameters could help discern the main ON- and OFF-pathway alterations following IONT [ 107 ].…”

Intraocular Sustained Release of EPO-R76E Mitigates Glaucoma Pathogenesis by Activating the NRF2/ARE Pathway

“…Deficits in the amplitudes of the VEP and the b-wave of the ERG (measuring bipolar cell function) have been reported at 4–6 weeks post-IOP elevation [ 33 , 34 , 35 ]. The ERG b-wave amplitude (b max ) was similar between PBS controls and PLGA.EPO-R76E injected mice at 2 weeks post-IOP elevation, however mice injected with empty PLGA particles already showed deficits in bipolar cell function (n = 6, 11 or 17 eyes/group respectively; p = 0.0097; Figure 1 D).…”