Loss of the low-frequency component of the global-flash multifocal electroretinogram in primate eyes with experimental glaucoma.

The multifocal (mf)ERG technique, developed by Sutter and Tran,1 is a noninvasive method for simultaneous functional testing of multiple retinal locations. The stimuli are presented in a pseudorandom m-sequence. A fast-flicker mfERG protocol (typically, 75 Hz) with 214 − 1 m-steps can test more than 100 retinal regions in less than 7 minutes of recording time, providing sufficient spatial resolution and signal-to-noise ratio (SNR) to resolve focal defects with clinically acceptable time efficiency. Although the mfERG technique has been demonstrated to be useful in the diagnosis and monitoring degenerative diseases of the outer retina as well as some diseases that affect inner retina (such as diabetic retinopathy2,3), its value in diagnosis and monitoring of progression of glaucoma, a disease that mainly affects retinal ganglion cells (RGCs) and their axons, remains controversial. It has been noted that the nasotemporal asymmetry in mfERG waveforms in the fast flicker mfERG is reduced or eliminated by both tetrodotoxin (TTX, a blocker of sodium-dependent action potentials) injected intravitreally (in monkeys) and glaucoma (in monkeys and humans), indicating an inner retinal origin, mainly RGCs, of this phenomenon.4–8 Effects of TTX and experimental glaucoma on nasotemporal asymmetry have also been described in monkeys for the slow-sequence mfERG, in which the flicker rate was slowed by interposing 7 to 14 black frames between each m-step.9–11 The nasotemporal asymmetry can be accounted for by the optic nerve head component (ONHC) model proposed by Sutter and Bearse,12 which links the asymmetry mainly to the different regional delays in propagation of action potentials in the unmyelinated RGC axons carrying these signals to the optic nerve head (ONH). Action potentials traveling a longer distance (e.g., from temporal retina) before arriving at the ONH are relatively delayed compared with those traveling a shorter distance (e.g., from the nasal retina). The mfERG component reflecting these delays is identified in the model of Sutter and Bearse as the ONHC, whereas the component devoid of these delays is called the retinal component (RC). The ONHC can be extracted from control mfERG recordings in both humans and monkeys with a time-domain algorithm introduced by Sutter and Bearse.12,13 The ONHC can be enhanced in the first-order kernel signal of the mfERG by appending one or more global flashes after the m-frame.14,15 Waveforms obtained with these global flash paradigms are usually divided into a direct component (DC) and one to several induced component(s) (IC) for analysis. The DC is the direct response to the focal flash, whereas the IC is the response to the corresponding global flash under the influence of the preceding focal flash, a response that is believed to be generated in the inner retina.16,17 Several global-flash paradigms have been used, DC and ICs have been measured, and the ONHC has been extracted with the algorithm to assess inner retinal function.9,10,12,13,16,18–20 The validity of the relation between the ONHC and inner retina function has been based on studies of glaucoma, which is a disease of RGC loss in the inner retina. Consequently, the ONHC should also be correlated with other clinical measures of RGC function, such as visual field sensitivity (VS) and peripapillary retinal nerve fiber layer thickness (RNFLT). The relationship between the ONHC and RNFLT is especially interesting, because it does not involve a psychophysiological link and, in fact, may represent two objective measures of the stage of neuropathy. However, the nature of the relationships between the mfERG ONHC, regional peripapillary RNFLT, and local VS have not been studied quantitatively. The purpose of the present study was to investigate this issue in a frequency-domain approach that has shown promise in several recent studies for identifying focal changes in frequency bands of mfERG responses that include contributions from the ONHC.10,11,21 Some of the findings have been reported previously in abstract form (Luo X, et al. IOVS 2007;48:ARVO E-Abstract 5982).