Apart from phototransmission, adaptation to luminance and contrast are among the retina’s most important functions. A comprehensive study of aging processes in the function of the retina must therefore include consideration of the retina’s highly nonlinear response dynamics. As a nonlinear systems analysis technique, the multifocal ERG permits us to study these processes locally. However, the information on adaptation and recovery from photostress is presented in the form of a series of binary kernels that is not directly amenable to an intuitive interpretation.
Specifically, the first-order kernel is the mean response to all focal flashes that occur during stimulation minus the response sequence in the absence of a focal flash regardless of the context. It includes effects that a focal flash may have on responses to following as well as preceding flash responses. Similarly, the first slice of the second-order kernel represents the difference between the double-flash response and the two corresponding single-flash responses, again regardless of context. It thus follows that both first- and second-order kernels contain effects of a two-flash as well as multiflash interactions. A comparison of responses in the presence and absence of preceding and following flash responses would provide a much more direct and intuitive understanding of adaptive processes and their age-related changes. Although such response comparisons are not directly accessible from a multifocal data set, they can be synthesized from the series of binary kernels.
14 In this study, we compared the synthesized response sequences that we believe to be most revealing and studied their changes with age in a large group of subjects.
The present isolated flash response analysis revealed an age-related decrease in response density P1 − N1 in all analyzed areas and an increase in implicit time N1 in areas 2 and 3 and in implicit time P1 in area 3. Previous aging studies of mfERG responses have reported various results.
1 2 3 4 5 6 In our previous study the first-order kernel analysis revealed an age-related linear decline in log response density and an increase in log implicit time of P1 in all six concentric rings (71 subjects, ages 9 to 80 years). Jackson et al.,
5 in 46 subjects, age-groups 19 to 30 years and 60 to 74 years, detected an age-related reduction in amplitude density in the central 36°. Fortune and Johnson
4 found among 32 subjects ages 16 to 69 years an age-related response density decrease and implicit time increase that they concluded has predominately optical origins. Nabeshima et al.
6 found in their study of 52 subjects aged 12 to 76 years a linear decline in response density from the 50-year-old age group in all rings, whereas implicit time P1 did not show a change with age. Mohidin et al.
2 did not find an age-related response density change within the central 5° (90 subjects, ages 18–52 years). These variations may be due to the small sample sizes and different age ranges used in some studies, or they may be due to insufficient screening for retinal abnormalities and/or testing under different conditions (not in room light, with undilated pupils). The analysis of the first-order kernel of the data set used herein
3 demonstrated significant age-related decreases in response density P1 − N1 and increase in implicit time P1 in all six analyzed concentric rings. In addition, we repeated the first-order kernel analysis for the three areas analyzed in this article (see the Methods section). Again, response density P1 − N1 and implicit times N1 and P1 showed significant age-related changes in all three areas. Thus, the isolated flash response revealed a smaller aging effect for implicit times. This may be attributed to the absence of flash-flash interactions in the isolated flash response.
Studies on aging of photopic full-field ERG responses have shown a linear change in amplitude and/or latency.
17 18 19 Birch and Anderson
19 reported a decline of 7.9%/decade and 8.4%/decade in the single-flash cone response and in the 30-Hz flicker response, respectively. In the present study we found a 1.3%, 2.3%, and 3.4% decline per decade in the isolated flash response density in areas 1, 2, and 3, respectively. Hood et al.
20 demonstrated, that multifocal and the full-field ERG responses can be compared only under certain testing conditions. The higher change with age in the full-field ERG compared with that in the isolated flash response may originate from the different retinal areas stimulated, flash and background intensity, flash or frame frequency, or state of light adaptation.
An important question is whether age-related changes in the isolated flash response are due to neural and/or optical factors, such as age-related decreases in ocular media transmission attributable to an increase in lenticular density and an increase in intraocular scatter. This question has been addressed previously only for the first-order kernel.
3 4 5 We showed in this study that the change in the isolated flash response due to those optical factors did not explain entirely both the age-related decrease in the synthesized isolated flash response density P1 − N1 and the increase in implicit time P1. Thus, both optical and neural factors are needed to account for the age-related changes in the isolated flash response.
The comparison of the isolated flash responses and fast adaptive effects revealed that for the unadapted state (isolated flash response) latency P1 changed more with age than in the adapted state (in the context of preceding and following flashes). Psychophysical data by Schefrin et al.
21 indicate that much of the sensitivity loss in elderly subjects is due to age-related changes that are mathematically equivalent to a reduction in photon capture. Adjustment in cone sensitivity, or gain control may be responsible for this smaller aging effect for the adapted state.
22 Retinal gain controls could partially compensate for the aging effect in the isolated flash response.
Psychophysically measured IRFs using a double-pulse method revealed a significant decline in amplitude and nearly constant latency with age except in a small subset of elderly observers.
23 The psychophysically derived IRF may be compared with the isolated flash response derived from mfERGs if the latter is accepted as a linear approximation of the retinal response. For this reason, the isolated flash extracted from the binary kernels was derived from the same area, 5° to 10° in radius, that was tested in the psychophysical experiment.
23 The results of this analysis are consistent with the aging effects measured in the psychophysically derived IRF. They showed a significant age-related decrease in log response density (
P < 0.0001), a small but significant increase in log implicit time N1 (
P = 0.048), and nearly constant log implicit time of P1 (
P = 0.08).
Are the age-related changes in short-term adaptive effects related to the responses of one retinal cell type? Physiological studies have shown that amacrine cells exhibit a nonlinear response to temporally and spatially modulated inputs (reviewed in Ref.
24 ). Most amacrine cells are inhibitory in their connection to bipolar cells, ganglion cells, and other amacrine cells and form a complex network with several levels of inhibition under different control mechanisms (also reviewed in Ref.
25 ). Hood et al.
26 described retinal responses in rhesus monkeys after suppressing inner retinal activity with different pharmacological agents. The shelf in the waveform of the first-order kernel after the first prominent peak P1 (
Fig. 8 in Ref.
26 ) was removed after applying
N-methyl-
d-aspartate (NMDA), a glutamate agonist that is expected to suppress inner retinal activity. This shelf may be a higher-order kernel contribution, or in other words, a result of adaptive effects.
14 15 However, not all amacrine cells have NMDA receptors. In addition, the amacrine cell output should not be directly affected by NMDA. Most of these cells are GABAergic or glycerinergic or even use other neurotransmitters.
25 Therefore, the contribution removed from the first-order kernel
26 may derive at least partly from amacrine cells.
Does the outer retina (e.g., the receptor-horizontal-bipolar cell network) contribute to the adaptive effect? Horizontal cells behave linearly in their interactions with photoreceptors and bipolar cells.
27 The highly nonlinear amacrine cells are therefore more likely to contribute the adaptive effects seen in the higher-order kernels.
The authors thank Martin Wilson for helpful discussions.