Retinal origins of the primate multifocal ERG: implications for the human response

To better understand the cellular contributions to the human multifocal ERG (mfERG), rhesus monkey and human mfERGs were recorded using the same stimulus conditions. The monkey mfERGs were recorded before and after injections of pharmacologic agents known to selectively block activity of particular cells and circuits in the retina.

Photopic mfERGs were recorded with Dawson-Trick-Litzkow (DTL) fiber electrodes from 16 eyes of 10 anesthetized adult rhesus monkeys (Macaca mulatta) and from 4 normal humans. The display consisted of 103 equal-sized hexagons within 17 degrees of the fovea. Monkey mfERGs were obtained before and after inner retinal responses were suppressed with intravitreal injections of tetrodotoxin (TTX), TTX+N-methyl-D-aspartic acid (NMDA), TTX+NMDA with the gamma-aminobutyric acid (GABA(A&C)) antagonist picrotoxin (PTX), or the inhibitory amino acid GABA and after L-2 amino-4-phosphonobutyric acid (APB) to block signal transmission to ON-bipolar cells. Finally, a combination of APB and cis-2,3 piperidine dicarboxylic acid (PDA) was used to isolate the contributions from the cone photoreceptors.

TTX, which blocks sodium-based action potentials, removes a large contribution from the monkey's mfERG, but it does not remove all inner retinal influences. After administration of TTX, the mfERG is further modified by the addition of NMDA. TTX+NMDA, TTX+NMDA+PTX, or GABA alone have similar effects, suggesting that, at the concentrations used, they are largely removing the inner retinal contributions. After removing the inner retinal influences, the monkey's mfERG is mainly composed of ON- and OFF-bipolar contributions, as revealed after APB and PDA were injected. The leading edge of the first negative potential (N1) is largely shaped by the initial hyperpolarization of the OFF-bipolar cells. The photoreceptors also contribute to the leading edge of N1, but this contribution is small, except in the central 6 degrees. The depolarization of the ON-bipolars and the recovery of the OFF-bipolars contribute to the leading edge of the major positive component (P1), with the recovery of the ON-bipolars being the dominant influence on the trailing edge. The waveform of the human mfERG most closely resembles the rhesus monkey's mfERG after administration of TTX.

The monkey's mfERG is shaped by large contributions from ON- and OFF-bipolar cells, combined with both spiking and nonspiking inner retinal contributions, and a small contribution from the photoreceptors. In comparison, the human mfERG resembles the monkey's mfERG after reduction of inner retinal contributions. Based on the pharmacologic dissection of the monkey's mfERG, a model of the waveform of the human mfERG is proposed. This model suggests that the waveform can be understood as a combination of overlapping ON- and OFF-bipolar cell contributions combined with smaller contributions from inner retina and photoreceptors.