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From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago.
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Abstract |
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METHODS. Light-adapted ERGs were recorded from three patients with XLRS and from three control subjects, by using rapid-on and rapid-off sawtooth flicker to emphasize ON and OFF responses, respectively, and by using low-pass sawtooth flicker, from which the high temporal frequencies had been removed to mimic the high-frequency attenuation in XLRS.
RESULTS. For the control subjects, removing the high stimulus frequencies reduced the amplitude of the b-wave component of the ON response but had little effect on the amplitude of the d-wave component of the OFF response. In the patients with XLRS, the b-wave component of the ON response was already diminished using the full sawtooth stimulus, and removing the higher stimulus frequencies had no further effect. Patients’ ERG responses to the 16-Hz stimulus fundamental alone were also abnormal, in that an initial response component normally present in the ERG was absent.
CONCLUSIONS. The overall pattern of findings indicates that two factors contribute to the preferential ON-response deficit in XLRS: first, a high-frequency attenuation of the cone photoreceptor response that effectively produces a low-pass stimulus for the postreceptoral pathway and that affects the ON response more than the OFF response and, second, a relatively greater attenuation of the ON- than of the OFF-bipolar cell response that is evident in the aberrant response to the sawtooth fundamental.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, recent studies have prompted a re-evaluation of this view of the underlying pathophysiology of XLRS. First, the RS1 gene that is mutated in XLRS is expressed in photoreceptor and bipolar cells but not in Müller cells,11 12 so that the exact relationship between the gene defect and the Müller cell abnormalities that have been observed in XLRS is uncertain. Second, patients with XLRS have a relatively greater attenuation of the ERG ON response than OFF response of the cone system, resulting in a reduced b-wave-to-d-wave ratio.13 14 Therefore, the relatively reduced b-wave amplitude of the brief-flash ERG of the cone system just described probably represents an ON-response defect rather than a Müller cell abnormality, per se. This is consistent with recent studies that have shown that Müller cells make little direct contribution to the ERG b-wave.15 16
The exact explanation for the preferential ON-response defect in XLRS is not entirely clear. One possibility is that it represents dysfunction of the depolarizing (ON) bipolar cells (DBCs). In the primate cone system, the initial portion of the b-wave component of the ON response represents primarily the activity of DBCs, with the latter portion of the b-wave modulated by the response of hyperpolarizing bipolar cells (HBCs).17 The initial portion of the d-wave component of the OFF response represents the activity of HBCs in combination with the offset of the cone photoreceptor response.17 Therefore, it is likely that at least part of the significantly reduced b-wave-to-d-wave ratio of the cone system in patients with XLRS is due to a preferential response attenuation within the DBCs.
It is possible, however, that an abnormal temporal response of the cone photoreceptors also contributes to the ON-response deficit in XLRS. It has been reported recently that patients with XLRS have a marked attenuation of the ERG response of the cone system at high temporal frequencies.18 This high-frequency attenuation has been attributed to a cone photoreceptor defect,19 based on an examination of nonlinear beat frequencies in the ERG, using an approach introduced by Burns et al.20 In this approach, ERGs are recorded in response to a stimulus that consists of the sum of two sinusoidal waveforms. The ERG response to this stimulus contains a "difference frequency" that is generated by a retinal nonlinearity and that has a temporal frequency equal to the difference between the two input frequencies. Pairs of sinusoidal stimuli that differ by a small constant value are presented, and the amplitude and phase of the difference frequency is measured as a function of the input frequencies.
This difference-frequency approach was used in a previous study19 to evaluate the likely source of the high-frequency attenuation of the flicker ERG in XLRS, using a logic described by Burns et al.20 If the high-frequency attenuation of the ERG in XLRS occurs before the site of the retinal nonlinearity that generates this difference frequency, then the difference frequency would be reduced in amplitude when either or both of the input frequencies are in the high-frequency range. However, if the amplitude attenuation at high frequencies occurs at or after the site of the nonlinearity, then the difference frequency would have a normal amplitude across pairs of input frequencies, because the input to the nonlinearity would have a normal amplitude. In agreement with the first alternative, the difference-frequency function in patients with XLRS was found to show a selective high-frequency attenuation that was identical with the high-frequency attenuation of the response fundamental.19 Therefore, a major determinant of the loss of ERG amplitude at high temporal frequencies in XLRS is a response attenuation that occurs before the site of the nonlinearity that generates the difference frequency. Current evidence indicates that this nonlinearity is located in the outer retina, at or before the site of the convergence of signals from the different spectral classes of cones.21 This convergence site is thought to occur at the synapse between cone photoreceptors and postreceptor neurons.22 Therefore, the abnormal difference frequency in XLRS is presumed to represent an abnormal cone photoreceptor response.
This high-frequency response attenuation at the presumed photoreceptor
level in XLRS could affect the properties of their ERG ON and OFF
responses, as follows. The sawtooth stimuli that were used by us
previously13
to elicit ERG ON and OFF responses included
high as well as low harmonic temporal frequencies, with the amplitude
decreasing in proportion to harmonic frequency, according to the
following relationship:
 | (1) |
o = 2
/T, where
T is the period. The rapid-on and rapid-off sawtooth
waveforms used to elicit the ON and OFF responses, respectively,
differed only in a 180° phase shift of the temporal frequency
components. It might be expected that the higher harmonics of a sawtooth stimulus would make little contribution to the ERG response because of their relatively low amplitude and that an attenuation of the ERG response to these harmonic components by retinal disease would have little effect on ON and OFF responses. However, the temporal response function for the flicker ERG of visually normal subjects is strongly band-pass, so that response amplitude increases with increasing temporal frequency up to approximately 40 Hz.19 20 Therefore, even though the higher stimulus harmonics of a sawtooth waveform have a smaller amplitude than the low stimulus harmonics, the greater responsiveness of the retina to these higher frequencies could have a significant role in shaping the ERG response to sawtooth stimuli.
Further, it is possible that a relative attenuation of the higher stimulus harmonics due to retinal disease would have a greater effect on the ERG ON response than the OFF response. In a recent study of the temporal response properties of the generators of the ERG of the primate retina,23 it was reported that the peak of the response function for the DBCs occurred at a higher temporal frequency than the peak of the response function for the HBCs, so that the DBCs had a greater response amplitude at high temporal frequencies. Thus, based on these data, the higher harmonics of a sawtooth stimulus would be expected to make a greater contribution to the response of the DBCs than of the HBCs. Given that DBC activity is a primary determinant of the b-wave component of the ON response and HBC activity is a primary determinant of the d-wave of the OFF response,17 it is possible that an effective attenuation of high stimulus temporal frequencies before the level of the bipolar cells would affect the b-wave component of the ON response more than the d-wave component of the OFF response.
The purpose of the present study was to determine whether the response attenuation at a presumed cone photoreceptor level in XLRS contributes to the preferential reduction of the ERG ON response. This possibility was evaluated by comparing ERG responses to standard sawtooth stimuli with ERG responses to low-pass filtered sawtooth stimuli, from which all but the fundamental and second harmonic components had been removed, to mimic the high-frequency attenuation of the ERG in XLRS. ERG responses to the stimulus fundamental frequency were also measured. The results demonstrate that two factors contribute to the ON-response deficits of patients with XLRS: first, a relative attenuation of the high temporal frequency components of the stimulus, presumed to occur at the photoreceptor level,19 and, second, a postreceptoral impairment that appears to affect the DBC system more than the HBC system.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stimuli and Instrumentation
The stimulus consisted of full-field flicker that was presented
against a rod-desensitizing adapting field. Three stimulus waveforms
were used: sawtooth flicker, low-pass sawtooth flicker, and sinusoidal
flicker. The stimulus waveforms for sawtooth and low-pass sawtooth
flicker are illustrated in Figure 1
for a temporal frequency of 16 Hz, which was the primary focus of this
study. Each cycle of rapid-on sawtooth flicker (Fig. 1
, top left)
consisted of an abrupt increment in luminance, to emphasize an ON
response, followed by a linear decrease in luminance. Each cycle of
rapid-off flicker (Fig. 1
, top right) consisted of an abrupt decrement
in luminance, to emphasize an OFF response, followed by a linear
increase in luminance. The two waveforms have the same time-average
luminance, which is indicated by the horizontal lines in the figure.
The low-pass sawtooth waveforms are illustrated at the bottom of Figure 1
. These waveforms consisted of the sum of the fundamental and second
harmonic of the sawtooth, with relative amplitudes given by equation 1
.
They were presented in both rapid-on (left) and rapid-off (right)
phases.
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The stimuli were provided by two optical channels, each with a light source consisting of a 300-W tungsten halogen bulb, each housed within a projector (Eastman Kodak, Rochester, NY) and each with infrared blocking filters. One channel provided the temporally modulated light. The other channel provided a steady, rod-desensitizing adapting field. The light source for the temporally modulated channel was powered by a custom-built, regulated DC power supply. The achromatic stimuli were presented within an integrating sphere (Oriel, Stratford, CT) and the light from the two optical channels was combined with a "y" fiber-optic light guide (Oriel).
Temporal modulation of the test field was controlled by a ferroelectric liquid crystal (FLC) shutter (Displaytech, Longmont, CO) and driver (DR-95; Displaytech). The driver was controlled by a signal-processing board (DAS-801; Keithley, Cleveland, OH) housed within a microcomputer. The FLC shutter was driven at a constant frequency of 1 kHz and was pulse-width modulated under computer control, with the duty cycle governed by a linearized look-up table. A shutter and driver (Vincent Associates, Rochester, NY) within the second optical channel controlled the adapting field presentation.
Luminances were calibrated with a photometer (LS-110; Minolta, Osaka, Japan). The luminance of the adapting field was 17.4 candelas (cd)/m2 (2.9 log troland [td], assuming an 8-mm pupil). The maximum stimulus luminance was 393.0 cd/m2 (4.3 log td) and the minimum luminance was 1.4 cd/m2 (1.8 log td). In the absence of the adapting field, these luminances produced a modulation of 99%. Against the adapting field, the modulation was 91.2%.
Procedure
The pupil of the tested eye was dilated with 2.5% phenylephrine
hydrochloride and 1% tropicamide drops, and the cornea was
anesthetized with proparacaine drops. The subject’s head was held in
position with a chin rest and forehead bar. Subjects were light-adapted
to room illumination before testing and were then adapted for 2 minutes
to the rod-desensitizing adapting field. ERGs were recorded with a
Burian-Allen bipolar contact lens electrode, grounded at the earlobe.
Responses were acquired with a signal-averaging system (Viking IV;
Nicolet, Madison, WI) that was triggered by a transistor–transistor
logic (TTL) signal generated by the signal processing board and
synchronized with the onset of each stimulus cycle. Amplifier band-pass
settings were 0.5 to 500 Hz.
Recordings were begun after the subjects had adapted to each waveform for approximately 30 seconds. For each condition, two 500-msec recordings were obtained to determine reproducibility. Each recording was the average of four sweeps. The two recordings were averaged off-line, so that each waveform included in the analysis consisted of the average of eight 500-msec sweeps. Although the recording epoch was 500 msec, only the first 250 msec of the waveforms are presented in the following figures, so that waveform features can be identified more easily.
Analysis
Response amplitudes at the stimulus harmonic frequencies were
derived from power spectral densities, and response phases were
obtained from fast Fourier transforms, by computer (Matlab Signal
Processing Toolbox; The MathWorks, Natick, MA). The amplitudes of the
harmonic components that are plotted in the figures represent the full
peak-to-trough amplitudes of the derived sinewave components. The
phases are given in cosine phase. In addition, the amplitudes of the ON
and OFF responses were obtained as follows. The amplitude of the b-wave
of the ON response was measured from the a-wave trough to the b-wave
peak, and the amplitude of the d-wave of the OFF response was measured
from the onset of the response to the peak (see Fig. 3
for
illustrations of these waveform features). The values for the eight
response cycles in each 500-msec waveform were averaged. The results
from the patients with XLRS and the control subjects were compared
using repeated-measures analyses of variance, and post-hoc comparisons
were performed with two-tailed t-tests, with a Bonferroni
correction for multiple comparisons (SigmaStat; SPSS, Chicago, IL).
P < 0.05 was considered to be statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ERG Temporal Response Function in XLRS
The high-frequency response attenuation shown by the patients with
XLRS is illustrated in Figure 2
. This figure plots the log amplitude of the fundamental response to
sinusoidal flicker of maximum amplitude across a range of temporal
frequencies. The symbols represent the fundamental responses of the
three patients with XLRS, and the hatched region represents the range
of the values for eight control subjects. For the control subjects, the
response function was band-pass, with a peak at 32 Hz and
systematically declining amplitudes at higher frequencies, although
robust responses were obtained even at a temporal frequency of 96 Hz,
as has been reported previously.18
20
In comparison,
the response functions of the patients with XLRS were less band-pass,
and showed a marked response attenuation at frequencies above 32 Hz.
For two (patients 1 and 3), the response amplitude did not exceed the
noise level at 96 Hz, and the response amplitude of the other (patient
2) was attenuated substantially at that frequency. Statistical analysis
confirmed that there was a significant difference between the
fundamental responses of the patients with XLRS and the control
subjects at temporal frequencies of 32 and 64 Hz (t =
2.88 and 8.58, respectively; P < 0.01), but not at 8
and 16 Hz (t = 0.43 and 0.74, respectively;
P > 0.05 [96 Hz was not included in the analysis
because of the negligible response amplitudes for two of the
patients]). As noted in the introduction, previous evidence indicates
that this amplitude reduction at high temporal frequencies results from
an attenuated cone photoreceptor response.19
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Effect of Low-Pass–Filtered Sawtooth Stimuli
The primary question examined in this study is the extent to which
the high-frequency response attenuation of patients with XLRS,
illustrated in Figure 2
, contributes to their ON-response deficits,
illustrated in Figure 3
. To address this question, we first compared
the patients’ ERG responses to full sawtooth stimuli with their ERG
responses to low-pass sawtooth stimuli that consisted only of the
fundamental and second harmonic. In this analysis, we focused on ERG
responses at a stimulus temporal frequency of 16 Hz. At this frequency,
the patients’ responses were of normal amplitude to the stimulus
fundamental (Fig. 2)
, but the higher stimulus harmonics were within the
region of the high-frequency response attenuation. Therefore, the
potential effect of the response attenuation on ON and OFF responses
could be assessed more readily than at lower stimulus temporal
frequencies. For 16-Hz sawtooth stimuli, statistical analysis confirmed
that there was a significant difference between the b-wave amplitudes
of the three patients with XLRS and the three control subjects
(t = 4.31, P < 0.01) but no
significant difference between their d-wave amplitudes
(t = 0.21, P > 0.05).
Figure 4 presents a comparison between the mean ERG responses of the patients with XLRS (bottom waveform in each panel) and the mean ERG responses of the control subjects (top waveform in each panel) to the full sawtooth stimuli (Figs. 4A 4B) and to the low-pass sawtooth waveforms (Figs. 4C 4D) . Mean responses were plotted to facilitate a comparison between the waveform shapes. The individual subjects showed the same pattern of results that is seen in the averaged data of Figure 4 . The responses to the rapid-on sawtooth stimuli are on the left (Figs. 4A 4C) , and the responses to rapid-off sawtooth stimuli are on the right (Figs. 4B 4D) . The respective stimulus waveforms are indicated below the mean ERG responses.
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To confirm these relationships quantitatively, we measured the b-wave and d-wave amplitudes of each subject in response to both the full and low-pass–filtered sawtooth stimuli. The mean differences in amplitude between the ERG responses to the full- and low-pass filtered sawtooth stimuli are shown in Figure 5 . For the control subjects, low-pass stimulus filtering resulted in a significantly greater reduction in the amplitude of the b-wave than of the d-wave (t = 3.06, P < 0.05). Further, low-pass stimulus filtering resulted in a significantly greater reduction in b-wave amplitude for the control subjects than for the patients with XLRS (t = 5.22, P < 0.001). However, there was no differential effect of low-pass stimulus filtering on d-wave amplitude for the control subjects versus patients with XLRS (t = 0.40, P > 0.05).
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ERG Response to the Sawtooth Fundamental in XLRS
If effective low-pass filtering at an early retinal site is the
sole explanation for the attenuated b-wave component of the response to
rapid-on flicker in XLRS, then the patients’ responses to the stimulus
fundamental alone should be normal in shape, because there would be no
high-frequency components of the stimulus to be attenuated. However, in
a previous report,18
we observed that the ERG waveforms of
patients with XLRS in response to sinusoidal stimuli were abnormal at a
range of temporal frequencies that included 16 Hz. This is illustrated
for the present stimulus conditions in Figure 6
. This figure compares the mean ERG waveform of the three control
subjects with the mean ERG waveform of the three patients with XLRS, in
response to the fundamental component of the 16 Hz sawtooth. The mean
response of the patients (thick trace) did not have the initial
component in each cycle that was present in the normal response (thin
trace), so that the patients’ mean waveform was more sinusoidal in
shape than that of the control subjects, similar to results reported
previously.18
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results indicate that at least part of the preferential b-wave reduction of the ON response in XLRS results from an effective low-pass filtering of the stimulus. Based on previous evidence,19 21 this low-pass filtering occurs at the level of the cone photoreceptors and provides an effectively low-pass signal to the postreceptor pathways. The exact explanation of why this effective low-pass filtering affects the ON response more than the OFF response remains to be determined. However, it may be related to the observation of Kondo and Sieving23 that the high-frequency cutoff of DBCs (which shape the b-wave of the ON response17 ) is higher than that of HBCs (which shape the d-wave of the OFF response17 ), so that a reduction in high-frequency input to bipolar cells in XLRS is more detrimental to the ERG ON response.
Although the high-frequency response attenuation contributes to the ON-response deficit in these patients with XLRS, it cannot be the sole explanation, because their responses to the fundamental component of the 16-Hz sawtooth stimulus were also abnormal. Specifically, the patients’ responses were more sinusoidal than those of the control subjects and were missing an initial waveform component that was present in each cycle of the control response (Fig. 6) . In addition, the amplitude spectra of their ERG responses had a relatively reduced second harmonic compared with the control subjects, and the harmonic components showed a phase lag relative to normal (Fig. 7) . These results confirm those obtained previously in patients with XLRS, in which sinusoidal stimuli of higher contrast were used.18 It is unlikely that this aberrant ERG response to the stimulus fundamental was due to an abnormal cone photoreceptor response, because it has been shown that the nonlinear difference frequency (thought to represent the cone photoreceptor response20 ) is normal in amplitude and phase at temporal frequencies near 16 Hz in patients with XLRS.19
Instead, it is more likely that the abnormal ERG waveform in response to the sawtooth fundamental is related to an impairment within the DBC pathway. According to a recent study of the generators of the primate ERG,23 a similar alteration in waveform shape can be observed after the pharmacologic elimination of the DBC component of the ERG response. That is, intravitreal injection of 2-amino-4-phosphonobutyric acid (AP4), which blocks the DBC light response, resulted in a waveform that had a more sinusoidal shape and a relative phase lag compared with the ERG of the untreated eye. The similarity between this finding and the properties of the flicker ERG in patients with XLRS (Figs. 6 7) suggests that there is a relative impairment in the contribution of the DBCs to the ERG of the cone system that is unrelated to the high-frequency response attenuation. A relative impairment within the DBC pathway could result from a change in synaptic gain between photoreceptors and DBCs, or from a response deficit within the DBCs themselves.
The emphasis of this study was on a temporal frequency of 16 Hz, but it is likely that the high-frequency response attenuation also contributes to the preferential ON-response deficit of patients with XLRS at lower sawtooth frequencies (Fig. 3) , as follows. For stimuli of a lower fundamental frequency, the higher harmonics (i.e., >32 Hz) constitute a smaller portion of the stimulus. Yet, these higher harmonics are still likely to make a significant contribution to the ERG response to sawtooth stimuli because of the band-pass nature of the ERG temporal response function, which shows an approximately sixfold increase in amplitude as the temporal frequency is increased from 8 to 40 Hz.19 Further, the contrast gain of the ERG can be compressive within this range of frequencies,27 so that the response to a low-contrast stimulus can be proportionally larger than the response at high contrast. Therefore, even though the higher harmonics of a low-frequency sawtooth stimulus have a relatively low amplitude, the increased responsiveness of the retina to these higher temporal frequencies probably enhances their contribution to the normal ERG response. A high-frequency response attenuation in XLRS could thus have an effect on ERG ON responses even at low sawtooth frequencies. Pilot data from a control subject and a patient with XLRS confirmed this possibility. For sawtooth stimuli at a fundamental frequency of 8 Hz, adding harmonic components beyond the fourth (i.e., >32 Hz) increased the amplitude of the b-wave component of the ON response substantially in a control subject, but had no effect on the b-wave amplitude of XLRS patient 3.
Our results demonstrate that, in contrast to previous suggestions,6 8 the abnormal ERG responses of the cone system in XLRS are not the result of Müller cell dysfunction per se, but instead represent abnormalities in the responses of the photoreceptors and DBCs. Nevertheless, Müller cell dysfunction may indirectly play a role. As noted in the introduction, there is considerable histologic evidence for Müller cell abnormalities in XLRS.2 3 4 Müller cells have an important role in regulating the extracellular levels of glutamate and potassium.28 High levels of glutamate are potentially toxic to neural elements, and changes in extracellular potassium can affect neuronal responses.28 Further, it has been suggested that the golden-white fundus sheen that has been observed in some patients with XLRS25 26 and that was apparent in one of ours (patient 3) results from an abnormal accumulation of extracellular potassium.25 Therefore, the abnormal neuronal responses that appear to be the source of the ERG response deficits of the cone system in XLRS may result from abnormalities in the extracellular environment, in which Müller cell dysfunction may play a key role.
Our evidence for multiple sources for the ERG deficits in XLRS is consistent with recent information regarding the molecular genetic basis for the disorder. As noted in the introduction, mutations in the RS1 gene are responsible for XLRS.1 The protein product of the RS1 gene, retinoschisin, is secreted by photoreceptors11 12 and bipolar cells.12 Retinoschisin is thought to be involved in cell–cell interactions, particularly within the inner retina and probably involving Müller cells.11 Therefore, it is not unexpected that the gene mutation responsible for XLRS could have functional consequences at several levels within the retina.
In conclusion, our results indicate that two major factors contribute to the preferential ON-response deficits of patients with XLRS: a high-frequency response attenuation at the level of the cone photoreceptors that effectively produces a low-pass input to the postreceptoral pathway, and a relative response deficit within the DBC system that is unrelated to the photoreceptoral abnormality. Because the integrity of the ON response depends not only on an adequate DBC response but also on the viability of the input from cone photoreceptors to the DBCs, an abnormal cone photoreceptor response should be considered as a possible contributor to the preferential ON-response deficits that have been observed in patients with other forms of retinal disease.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health Research Grant EY08301 (KRA) and Core Grant EY01792, a grant from the Campus Research Board of the University of Illinois at Chicago (KRA), a center grant from The Foundation Fighting Blindness (GAF), and an unrestricted departmental grant from Research to Prevent Blindness.
Submitted for publication January 4, 2001; revised April 9, 2001; accepted May 15, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Kenneth R. Alexander, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W. Taylor Street, Chicago, IL 60612. kennalex{at}uic.edu
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