Effect of Experimental Glaucoma in Primates on Oscillatory Potentials of the Slow-Sequence mfERG

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide.1 The death of retinal ganglion cells in POAG is reflected by increased cupping of the optic disc, loss of nerve fiber layer and functional visual field defects.2 Perimetry has been considered to be the gold standard in the diagnosis of glaucoma. However, a disadvantage of standard perimetry is that the first visual field defects appear only after a significant proportion (~25%–40%) of ganglion cells and nerve fibers have died.3-5 Therefore, more sensitive tests that can detect early retinal ganglion cell changes in glaucoma would be useful. One technique that objectively measures retinal function is the electroretinogram (ERG). The ERG is a useful tool for noninvasive assessment of function in normal and diseased retinas. In recent years, several studies in patients with glaucoma and in primate models of glaucoma have shown that the photopic ERG has components that are sensitive to glaucomatous optic neuropathy. These components include the negative potential at 95 ms of the transient pattern (p)ERG, known as the N956-8; the photopic negative response (PhNR) of the photopic full-field flash ERG9-12; and the oscillatory potentials (OPs) recorded in response to high-intensity flashes13,14 (Rangaswamy NV et al. IOVS 2002;43:E-Abstract 2170; Rangaswamy NV et al. IOVS 2003;44:E-Abstract 2702). Although these components of the ERG are sensitive to glaucomatous damage, they reflect activity of the whole or large regions of the retina, and do not provide information about regional ganglion cell defects. In contrast, the results of perimetry indicate the regional nature of damage to the ganglion cells and their axons. A test that measures responses from different retinal locations might be more sensitive to early changes in the retinal ganglion cell responses that occur locally and would be lost in averaging of ERG responses over the entire retina. The multifocal ERG (mfERG) technique developed by Sutter has made it possible to obtain a topographic representation of the retinal function15,16 in analogy to the topographical representation of the light sensitivity by perimetry. Commonly, the mfERG is recorded at a frame rate of 75 Hz where every frame of the m-sequence changes every 13.3 ms. The mfERG obtained using this paradigm is called the fast-sequence mfERG. The fast-sequence mfERG response is mainly composed of an on- and off-bipolar cell contribution with a small contribution from the inner retina.17 The inner retinal contributions are oscillatory in nature and are in the form of nasotemporal asymmetries in the waveform. The response was determined by recording the fast-sequence mfERG in monkeys, before and after pharmacologic inner retinal blockade and/or experimental glaucoma.18-20 OPs are better described and more prominent in the full-field flash ERG, than in the fast-sequence mfERG. The mfERG waveforms can be made similar to those of the full-field flash ERG by slowing the presentation. This can be done by interleaving blank frames between m-sequence presentations,21 to produce what has been named the slow-sequence mfERG. In a recent study involving the slow-sequence mfERG in monkeys,22 we described OPs that had nasotemporal asymmetries (i.e., larger amplitudes in temporal macula than nasal macula), similar to those described when using discrete focal stimuli,23,24 and when using slow-sequence mfERGs (three frames interleaved) in humans.25,26 These OPs were reduced or eliminated by pharmacologic blockade of inner retinal neuronal activity (i.e., amacrine and ganglion cells), consistent with previous studies in monkeys that showed the dependence of the OPs on the integrity of the inner retina.27 However, the exact cellular origin (amacrine versus ganglion cell) of the OPs is still not known. OPs in human ERGs have long been reported to have an inner retinal origin, and several studies have reported a reduction in the OPs recorded in the full-field ERG in diseases that affect the inner retina, such as diabetes and glaucoma.13,14,28-30 Recent studies using the slow-sequence mfERG to study patients with diabetic retinopathy, glaucoma, and laser-induced retinal nerve fiber layer defects have also confirmed that the oscillatory components of the slow-sequence mfERG are reduced by these inner retinal diseases.31-34 Because OPs are reduced in inner retinal diseases or by pharmacologic blockade of the inner retina, and they are easy to see and to quantify in the slow-sequence mfERG, we decided to study, in a primate model, the effect of experimental glaucoma on these OPs. This enabled us to separate the contribution likely to be generated by the ganglion versus amacrine cells, and to look for local changes in ganglion cell contributions. The results of the present study show that experimental glaucoma reduced both the amplitude of high frequency Ops, which had a peak frequency of approximately 145 Hz, and the nasotemporal asymmetries in the response. In contrast, a slower set of OPs, with peak frequency approximately half that of the high-frequency OPs was less affected by experimental glaucoma.