Retinal pathway origins of the pattern electroretinogram (PERG).

The pattern electroretinogram (PERG) is commonly recorded noninvasively from the cornea under light-adapted conditions using a checkerboard or grating pattern with equal numbers of bright and dark elements. The pattern stimulus covers the central retina and commonly reverses in contrast at full-cycle temporal frequencies between 1 and 8 Hz (2 and 16 reversals per second [r/s]). The lower frequencies (e.g., 1 to 2 Hz, 2 to 4 r/s) elicit transient PERGs with discrete positive- and negative-going (P50 and N95) responses to each stimulus contrast reversal, peaking approximately at the time in milliseconds past the reversal noted in the subscripts, whereas the higher frequencies (e.g., 8 Hz, 16 r/s) produce steady state second-harmonic responses. It is assumed that since the overall luminance of the pattern stimulus remains constant, the linear responses for all frequencies of stimulation that contribute to standard waves (e.g., a-, b-, and d-waves) of the full-field flash ERG will cancel, leaving only nonlinear responses in the signal. Previous studies have shown that the PERG can be substantially reduced or eliminated after optic nerve crush/section or severe glaucoma in humans, or experimental glaucoma in rodents and monkeys.1–10 The PERG in macaque, whose retina is very similar to that of humans, can also be substantially reduced, but not completely eliminated, by blocking Na+-dependent spiking with intravitreal tetrodotoxin (TTX).10,11 N95 of the transient PERG was found to be affected to a greater degree by TTX than P50 was, similar to findings in several optic nerve disorders in humans.4,10,11 Together these findings indicate a primary role for retinal ganglion cells (RGCs) and their spiking activity, in generating the PERG. However, nonspiking portions of P50 may, in some pathologic situations, reflect activity of more distal neurons. The PERG has been used clinically for many years to assess RGC function in diseases that affect their integrity (e.g., glaucoma).1,4 The PERG is sensitive to early ganglion cell dysfunction caused by ocular hypertension and early glaucoma when visual field defects are minimal.12–19 PERG amplitude reduction in early glaucoma also exceeds that predicted from ganglion cell axon loss, suggesting the presence of a group of viable but dysfunctional ganglion cells (or glial cells whose currents are likely involved in generation of the PERG) at this stage.19 Although it is established that generation of the PERG is dependent on functional ganglion cells, the exact contributions from spiking versus nonspiking activity of retinal ON and OFF pathways to the primate PERG remain unclear. Indications with respect to these issues from other studies have not been entirely consistent. A recent study of the mouse transient PERG using TTX and pharmacologic blockade of ON or OFF pathways indicates that P1 in the mouse PERG (the counterpart of P50 in primate transient PERG) is dominated by spiking activity from the ON pathway, whereas N2 (the counterpart of N95) depends on spiking activity and nonspiking activity from the OFF pathway.8 The finding that X-linked congenital stationary night blindness (CSNB), which eliminates ON pathway responses, practically eliminates the human transient PERG,4 raising the possibility of ON pathway dominance for the human PERG. The predominance of a particular pathway in formation of PERG waveforms is somewhat surprising. Viswanathan et al.20 demonstrated in macaques that the PERG could be simulated by averaging ON and OFF responses to long-duration uniform-field flashes, both of which contained negative-going photopic negative responses (PhNRs) after the b- and d-waves. It was proposed that N95 of the transient PERG reflects an average of the PhNR in the ON and OFF responses.10 PhNRs, like the PERGs, are believed to have origins from ganglion cells, particularly the TTX-sensitive activity of those neurons.20 In the present study, we used both uniform-field flash ERGs and pharmacologic agents that targeted specific retinal receptors and channels to further investigate ON versus OFF pathway origins (both spiking and nonspiking) of the PERG in macaque monkeys. The results should provide useful information for interpretation of the PERG in human patients, with pathologies that affect pathway elements distal to the ganglion cells, as well as the ganglion cells themselves. Some of the findings were reported previously in abstract form (Luo X, et al. IOVS 2009;50:ARVO E-Abstract 2177).