Cone Signal Contributions to Electrograms in
Dichromats and Trichromats
Jan Kremers,1 Tomoaki Usui,12 Hendrik P. N. Scholl,1 and Lindsay T. Sharpe1
PURPOSE. TO find out how the different cone types contribute to the electroretinogram (ERG) by
quantifying the contribution of the signal pathways originating in the long (L-) and the middle (M-)
wavelength-sensitive cones to the total ERG response amplitude and phase.
ERG response amplitudes and phases were measured to cone-isolating stimuli and to
different combinations of L- and M-cone modulation. Conditions were chosen to exclude any
contribution of the short wavelength-sensitive (S-) cones. The sensitivity of the ERG to the L and
the M cones was denned as the cone contrast gain.
METHODS.
RESULTS. In
the present paper, a model is provided that describes the ERG contrast gains and ERG
thresholds in dichromats and color normal trichromats. For the X-chromosome-linked dichromats,
the contrast gains of only one cone type (either the L or the M cones) sufficed to describe the ERG
thresholds for all stimulus conditions. Data suggest that the M-cone contrast gains of protanopes are
larger than the L-cone contrast gains of deuteranopes. The response thresholds of the trichromats
are modeled by assuming a vector summation of signals originating in the L and the M cones. Their
L- and M-cone contrast gains are close to a linear interpolation of the data obtained from the
dichromats. Nearly all trichromats had larger L- than M-cone contrast gains. Data from a large
population of trichromats were examined to study the individual variations in cone weightings and
in the phases of the cone pathway responses.
CONCLUSIONS. The
data strongly suggest that the missing cone type in dichromats is replaced by the
remaining cone type. The mean L-cone to M-cone weighting ratio in trichromats was found to be
approximately 4:1. But there is a substantial interindividual variability between trichromats. The
response phases of the L- and the M-cone pathways can be reliably quantified using the response
phases to the cone-isolating stimuli or using a vector addition of L- and M-cone signals. (Invest
Ophthalmol Vis Set. 1999;40:920-930)
T
he classical electroretinogram (ERG) is measured with
stimuli that usually excite more than one photoreceptor
type simultaneously. Thus, it is generally not possible to
quantify the stimulus strength for each photoreceptor type or
to know whether the long (L-) and the middle (M-) wavelength-sensitive cones and their respective postreceptoral pathways
contribute in a similar manner to the ERG signal or how their
signals interact when stimulated simultaneously. To investigate
such questions, chromatic adaptation procedures have been
used in ERG recordings.' '2 However, although the response of
the adapted or desensitized cone type in such procedures may
often be very small, it may not be negligible. Furthermore,
these techniques have the disadvantage that the system may be
From the ' Department of Experimental Ophthalmology, University Eye Hospital, Tubingen, Germany; and the 2 Department of Ophthalmology, Niigata University School of Medicine, Niigata, Japan.
Supported by Deutsche Forschungsgemeinschait (DFG; German
Research Council) Grant Zr 1/9-3, DFG SFB 43O/C3, and a DFG Heisenberg fellowship (KR 1317/5-1) to JK; DFG SFB 430, a DAAD Fellowship
and fortune program F.1222147.2 (Tubingen) to TU; DFG SFB 307 to
HPNS; and DFG SFB 430/A6, DFG Sh23/5-2, and a Hermann- und
Lilly-Schilling-Stiftung Professorship to LTS.
Submitted for publication June 11, 1998; revised October 23,
1998; accepted December 10, 1998.
Proprietary interest category: N.
Reprint requests: Jan Kremers, Department of Experimental Ophthalmology, Rontgenweg 11, 72076 Tubingen, Germany.
920
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pushed into a nonlinear range. Finally, it is difficult to come to
a quantitative description of the interaction between photoreceptor signals when only cone-isolating conditions are used.
The present paper provides new data on ERG responses to
cone-isolating stimuli and to stimuli in which the L and M
cones are stimulated simultaneously with known contrasts
without changing the overall state of adaptation.3'4 Our technique is reminiscent of the silent substitution paradigm (see
review in Ref. 5) and of the heterochromatic flicker photometry ERG.6'7 We extend these stimulus paradigms to conditions
in which the L- and M-cone types are modulated simultaneously and quantify the modulation of the individual cone
excitations in terms of cone contrast. A similar method has
been used by Brainard et al.8 and by Shapley and Brodie.9 Our
chosen stimuli did not modulate the short-wavelength-sensitive (S) cones. Moreover, the mean luminance (66 candela
[cd]/m2) and the temporal frequency of the stimulus (30 Hz)
were both high enough to desensitize the rods substantially.3
We introduce a model that describes the response amplitude data of both trichromats and X-chromosome-linked dichromats. This allows us to address several important issues.
Because all stimuli were quantified in terms of cone contrast, the response data of deuteranopes, missing functional M
cones, and protanopes, missing functional L cones, could be
directly compared. We find that L-cone pathway signals in
deuteranopes are significantly larger than M-cone pathway signals in protanopes.
Investigative Ophthalmology & Visual Science, April 1999, Vol. 40, No. 5
Copyright © Association for Research in Vision and Ophthalmology
IOVS, April 1999, Vol. 40, No. 5
Model fits to the trichromatic data allow the ratios of
L-cone to M-cone weightings to be estimated and reveals phase
differences between the responses of the L- and the M-cone
pathways. Considerable interindividual variations of the cone
weighting ratios and of the phase differences are implied. The
response phase differences of L- and M-cone pathways obtained from the fits could be compared for each subject separately with directly measured response phase differences using
the cone-isolating stimuli.
It is controversial whether the missing cone types in
X-linked dichromats are completely1011 or incompletely12 replaced by the remaining cone type. Our ERG measurements
argue for a complete replacement.
A subset of the data was reported previously.3'4
Cone Signal Contributions to ERGs
921
trasts. The emission spectra of the three phosphors were measured with an Instruments Systems spectroradiometer. The red
phosphor had multiple narrow peaks at approximately 594,
6l6, 626 (the largest peak), and 704 nm. The blue and green
phosphors had relatively broad emission spectra with peak
emissions at 448 nm (bandwidth at half-maximum 62 nm) and
530 nm (bandwidth at half-maximum 76 nm), respectively. The
time-averaged luminance of the monitor was 66 cd/m2 (40
cd/m2 for the green phosphor, 20 cd/m2 for the red phosphor,
and 6 cd/m2 for the blue phosphor). The excitations in each
cone type by the monitor phosphors were calculated by multiplying the phosphor emission spectra with psychophysically
based cone fundamentals14 and integrated over the wavelength
range. For example, the excitation of the L cones by the red
phosphor (£LiR) was calculated as follows:
METHODS
Subjects
Thirty-six trichromats (9 to 57 years of age), 6 protanopes (20
to 46 years of age), and 9 deuteranopes (18 to 41 years of age)
participated in this study. The classification of dichromacy was
based on Rayleigh matches made on a Nagel type I anomaloscope (Schmidt & Haensch, Berlin, Germany). The genotypes
of the dichromats were obtained by molecular genetic (DNA)
analysis of venous blood samples, using Southern blot hybridization. The molecular genetic methods and the genotypes of
the X-linked dichromats are documented in Sharpe et al.13 Of
the six protanopes, two had a single M-cone opsin gene, and
four had multiples genes, presumably expressing the same
M-cone pigment. All protanopes had the alanine amino acid
residue at position 180. Of the nine deuteranopes, five had a
single L-cone opsin gene, and four had multiple genes, presumably expressing the same L-cone pigment (with the serine
amino acid residue at position 180). There was no evidence of
a functional M-cone opsin gene in the deuteranopes or of a
functional L-cone opsin gene in the protanopes. The trichromats were color normal, as established with the Ishihara plates,
the Nagel type I anomaloscope, or the panel D15, and had
normal ophthalmologic findings with corrected visual acuity of
20/20. A genetical analysis was performed on blood samples of
some of the male trichromats, and the presence of functional
genes expressing for the L- and the M-cone photopigment was
established.
In all subjects, one eye was dilated with a mydriatic (0.5%
tropicamide) and kept light-adapted at least 10 minutes before
ERG recording to reduce rod responses. Corneal ERG responses were measured with a DTL fiber electrode. The reference and ground skin electrodes were attached to the ipsilateral temple and the forehead, respectively. Informed consent
was obtained from all subjects after explanation of the purpose
and possible conseqviences of the study. This study was conducted in accordance with the tenets of the Declaration of
Helsinki and with the approval of our institutional ethics committee in human experimentation.
Visual Stimuli and ERG Recording
The method of ERG recording has been described previously.3
The stimuli were presented on a computer controlled monitor.
The monitor subtended 124 by 108° at the 10-cm viewing
distance. We used a 30-Hz square wave modulation of the red,
green, and blue phosphors, with predefined Michelson con-
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LR(i)
in which ZR is the luminance of the red phosphor. LR and thus
£LR changes as a function of time t. /R(A) is the emission
spectrum of the red phosphor at 1 cd/m2 luminance. We have
checked that the emission spectrum did not change with the
luminance output of the phosphors. AX(K) is the L-cone fundamental. FR is a conversion factor for the red phosphor relating
the photometric measurements to the cone fundamentals,
which are expressed in radiometric terms. The total excitation
of the L cones is the sum of the excitations caused by each
phosphor. Similarly, the excitation in the S and M cones could
be calculated.
Recalculations of the cone excitations using another set of
cone fundamentals15 resulted in only minor differences in
stimulus conditions. The modulation of cone excitation was
quantified by the cone contrast [100% X (Emax - £mill)/(£m.,x
+ i?min)], where Emax and i?min are the maximal and minimal
cone excitations, respectively. The stimulus strength for each
cone type was defined separately. The S cones were not modulated (S-cone contrast was 0%) in this study.
The ERGs were measured with two different but similar
setups. With the first setup, we measured all the dichromats
and 12 trichromats. The monitor was a BARCO CCID 7751
MKII (100-Hz frame rate) driven by a VSG 2/2 graphics card
(Cambridge Research Systems). The time-averaged chromaticity in CIE (1964) large field coordinates were as follows: x =
0.3329, y = 0.3181. We calculated that the average foveal
quantal catches were approximately 4.42 log quanta • s~' •
cone"' in the L cones and approximately 4.31 log quanta • s~'
• cone" 1 in the M cones. ERG responses to 32 different stimuli
were measured: eight conditions with different L-cone to Mcone contrast ratios (1:0, 2:1, 1:1, 1:2, 0:1, -1:2, - 1 : 1 , - 2 : 1 ;
negative ratios and negative cone contrasts indicate counterphase modulation) with four contrasts within each condition
(100%, 40%, 20%, and 10% of the maximally possible cone
contrast). A threshold contrast increase for a 1 /JLV ERG response increase was determined at each condition. The spaces
of possible L- and M-cone contrasts that can be generated by
the monitor are displayed in Figure 1, in our previous publication.3 The largest possible cone contrast was 28.6% in the
M-cone-isolating condition and 22.7% in the L-cone-isolating
condition. Signals were amplified and band-pass filtered be-
922
Kremers et al.
tween 10- and 100-Hz corner frequencies (half amplitude at —6
dB; Grass Instruments). The signal was sampled at 1000 Hz
with a CED 1401 on-line computer. ERG responses to 12 runs,
each lasting 4 seconds, were averaged in each measurement.
The stimulus and the data acquisition were synchronized by a
trigger pulse generated by the VSG graphics card.
With the second setup, 25 trichromats were measured. It
was designed to be implemented in the clinical routine, requiring only minor hardware and software differences. The monitor was a BARCO CCID 121 driven at 100 Hz by a VSG 2/3
graphics card. The same mean values of luminance of the three
phosphors were used as in the first setup, resulting in nearly
identical mean quantal catches in the L and M cones, and in a
very similar space of feasible cone contrasts. The largest possible cone contrast was 31.2% in the M-cone-isolating condition and 24.7% in the L-cone-isolating condition. The responses were measured at 100%, 75%, 50%, and 25% of the
maximally possible cone contrasts at each L-cone to M-cone
contrast ratio. The signals, recorded with the second setup,
were amplified and filtered between 1 Hz and 300 Hz (half
amplitude at —6 dB; Grass Instruments) and sampled at 1000
Hz with a National Instruments AT-MIO-16DE-10 data acquisition card. The gain set by the analysis software was different.
As a result, the response data were qualitatively very similar to
those obtained with the first series, but the absolute amplitudes differed. Therefore, these data cannot be compared directly with the dichromatic data. One subject (LTS) was measured with the two setups. The results for the ratio of cone
weightings (cf. Tables 2 and 3) for this subject were very
similar.
An estimation of the magnitude of stimulus artifacts,
caused by electromagnetic radiation of the monitor, was obtained using a signal recording when the monitor displayed a
stimulus but was covered by black cardboard. In all cases, the
stimulus artifacts were negligibly small.
There are inherent limitations when a monitor is used as a
stimulator, which in principle, can interfere with our measurements,16 including the different excitation and decay times of
the different phosphors and the sequential excitation of the
pixels, which could influence the response phase. As described previously,4 the first potentially confounding factor
could be excluded, because we found that in dichromats the
ERG response amplitudes and phases were very similar in
stimulus conditions that were physically different but that
resulted in equal cone contrasts. Furthermore, measurement of
the phosphor excitations with a photodiode revealed that the
differences in peak excitation times between the three phosphors are much less than 1 msec, which is smaller than the
phase effects measured here (see the Results section). The
sequential pixel excitation might influence the phase data
when there is an asymmetry in L- and M-cone distributions
between the upper and the lower parts of the retina. However,
we found that the response phases were not influenced by
rotating the stimulus monitor by 180°, excluding a possible
artifact of the sequential pixel excitation.
Data Analysis
The thresholds for a 1-piV ERG response increase were determined at each ratio of L-cone to M-cone contrast (see the
Results section). These ERG thresholds were fitted with a
model that is based on the assumption that the ERG responses
are the result of a vector summation of the ERG signals origi-
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IOVS, April 1999, Vol. 40, No. 5
nating in the two cone types. The response to pure L-cone
modulation has an amplitude ALX CL (which depends linearly
on L-cone contrast CL with a gain of Ax; as described in the
Results section and as is displayed in Fig. 3 of a report published by our group previously,3 this linearity was found in all
conditions) and phase aL. Similarly, pure M-cone modulation
results in a response amplitude AM X CM and phase aM. For
each condition at which a threshold is measured, the ratio of
the L-cone to M-cone contrast is constant and predefined
(CJCM = K, when CM =£ 0). The response vectors can be
described asi?L = 4 t X C L x ( ^ "L) responses originating in
the L-cones and/? M = AM x C
for the responses
originating in the M cones. We assume that the threshold will
be reached when the sum of these vectors has a certain length
(i.e., the sum of the signals has a threshold amplitude):
y]Al • C\ + Al -Cl + 2 ' A L - AM • C . • C M • c o s ( a L - a M )
=
-^Thresh
(2)
This model is identical to the model used by Lee et al.17 to
explain the contribution of chromatic and luminance signals to
the responses of retinal ganglion cells.
With ^4LA4ThreSh = ^* (which is the L-cone weighting or
L-cone contrast gain) and AM/AThrcsh = AM* (the M-cone
weighting or M-cone contrast gain) Equation 2 becomes
(K • CM)2 + A ?
C2, • cos («,. - aM)
= 1 (3)
and thus the contrasts CM and C, at threshold are
l2 • K2 + 2 • At • AM • K • cos (o L - aM) + 4 M 2
and
When CM = 0, the contrast C, at threshold, defined by Equation 2 is
(5)
The model predicts elliptical threshold curves. For the fits,
there were three free parameters: A* and .4^, which quantify
the L- and M-cone contrast gains or weightings, respectively
(which by definition are the inverse of the threshold contrasts
for the cone-isolating stimuli) and (aL — aM), which is the
phase difference between the L- and M-cone responses.
The cellular origins of the flicker ERG are not unequivocally established yet, but postreceptoral processes are almost
certainly involved.18 However, this is not crucial for the model.
The model only assumes that the responses originate in the
photoreceptors. In the rest of the present article, the term
"cone response" is used to refer to the ERG response that
originates in a particular cone class including the subsequent
postreceptoral stages. Therefore, the cone weightings we find
should not be confused with cone numbers, because postreceptoral mechanisms can modify the cone weightings. However, the cone density will almost certainly influence the cone
weightings as well.
IOVS, April 1999, Vol. 40, No. 5
RESULTS
Amplitude Data
Figure 1 shows the ERG responses to pure M-cone modulation
(L:M cone contrast ratio 0:1; M-cone contrast: —28.6% M-cone
contrast, the negative contrast indicates a counter-phase modulation relative to the trigger pulse), to pure L-cone modulation
(L:M cone contrast ratio 1:0; 22.7% L-cone contrast), and to in
phase modulation of the L and the M cones (L:M cone contrast
ratio 1:1; 76.8% L-cone contrast and 76.8% M-cone contrast) for
a protanope (A), a deuteranope (B), and a trichromat (C). As
expected, the responses to pure L-cone modulation were very
small or absent in the protanope, whereas the deuteranope
showed small responses to the M-cone-isolating stimulus. Substantial responses were measured in the trichromat in both
conditions. For this trichromat, the response to the L-cone isolating stimulus is larger than the response to the M-coneisolating stimulus, despite the slightly larger M-cone contrast.
Furthermore, the two dichromats display larger ERG responses
to the stimuli isolating their remaining cone type than does the
trichromat to the same stimuli. The responses to the condition
in which the L and M cones are modulated in phase are very
similar in the three subjects.
The ERG responses were Fourier analyzed, and the ERG
response amplitude was denned as the amplitude of the fundamental component. As reported previously,3 we found a
linear relationship between ERG response amplitude and cone
contrast in all conditions. The slope of this line was denned as
the cone contrast gain and quantifies the increase of the ERG
amplitude caused by a 1% increase of cone contrast. A linear
relationship between response amplitude and stimulus contrast has also been reported by Wu et al.20 at a very similar
temporal frequency (28 Hz) but not at lower and higher temporal frequencies. This is potentially troublesome because a
linear relationship between contrast and response amplitude is
assumed for our model. However, for the model it is only
necessary that linearity approximately holds near threshold.
The inverse of the contrast gain is the ERG threshold
contrast needed for a 1-JU.V increase in response. These thresholds were obtained for all ratios of L-cone to M-cone contrasts.
Figure 2 shows the measured thresholds for a protanope and a
deuteranope. For the dichromats, the response thresholds are
determined by a single cone type. When plotted as in Figure 2,
the threshold data should lie on a straight line either parallel to
the L-cone threshold axis (for the protanopes) or to the M-cone
threshold axis (for the deuteranopes). This indeed seems to be
the case, confirming the notion that the cone space of dichromats in the L-/M-cone contrast coordinate system is one-dimensional. The ERG responses in protanopes to L-cone-isolating
stimuli were extremely small. In the deuteranopes, we measured a small but substantial response in the M-cone-isolating
condition. This is possibly caused by small imperfections in the
calculations of the phosphor contrasts or by intrusion of small
responses originating in the rods (we calculated that the maximal rod contrast is approximately 28% in this condition). In
psychophysical control experiments,3 deuteranopes were able
to detect this stimulus, although their sensitivity was about a
factor of eight smaller than that for the L-cone-isolating stimuli.
Figure 3 shows the measured ERG thresholds for three
different trichromats. The data of most trichromats can easily
be distinguished from those of dichromats (A and B), although
the thresholds of some subjects (an example is shown in Fig.
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Cone Signal Contributions to ERGs
923
3C) are similar to those of deuteranopes. This has been observed previously.3'9'21 Furthermore, the displayed data indicate a substantial variability between trichromats.
We estimated the cone contrast gains from the model fits
to the data when all conditions were measured or from the
direct measurements for the dichromats, for whom only the
cone-isolating stimuli were used. In Tables 1 and 2, the M- and
L-cone contrast gains are shown for the dichromatic and
trichromatic subjects measured with the first setup. The contrast gains differed between die groups: the M-cone contrast
gains for the protanopes were 2.01 ± 0.45 (mean ± SD) and
1.90 ± 1.06 for the trichromats. The L-cone contrast gains was
2.66 ± 0.57 for the deuteranopes and 0.57 ± 0.45 for the
trichromats.
Nearly all trichromats had larger L- than M-cone contrast
gains, although a considerable interindividual variability is
present. One female subject (JB; data are displayed in Fig. 3A)
exhibited a ratio of L-cone to M-cone contrast gains that was
considerably smaller than unity. This subject is possibly a
carrier for protanopia (which is presently being investigated)
because her mother's father was a protanope. The mean L-cone
to M-cone contrast gain ratio was 4.24 ± 2.31.
Table 3 shows the results from measurement of 25 trichromats with the second setup in which different filter and gain
settings were used. The mean ratio of the L-cone to M-cone
contrast gains is 4.51 ± 5.57. This value is very similar to the
one obtained with the first setup. The large SD again reflects a
large interindividual variability of the ratio.
Phase Data
So far we have shown only the amplitude data of the ERG
responses. We now consider the response phases. Extensive
data on dichromats have been published previously.'' Here, we
show extended data from trichromats. In Figure 4, the relationship between response phase and cone contrast is shown for
the M- and L-cone-isolating stimuli. Only data obtained with
cone-isolating stimuli at which all four cone contrasts were
larger than 6% are shown. For these conditions, the response
amplitudes at all contrasts were large enough to get reliable
response phases. The response phase increases with increasing
cone contrast. A similar relationship between response phase
and cone contrast was found for the conditions in which the
two cone types were modulated simultaneously. In 10 subjects
included in this analysis, the M-cone response led the L-cone
response, whereas in 7 subjects the L-cone response led the
M-cone response.
To compare the response phases of L and M cones shown
in Figure 4, we assumed that for the displayed cone-contrast
range the relationship between response phase and cone contrast was linear. Previous data4 have shown that an exponential
function might describe these data more adequately when
smaller cone contrasts are included. Using the linear regression
through all data points we normalized the response phases to
equal cone contrasts. With a paired t-test we found that the
M-cone responses were significantly advanced relative to the
L-cone responses (JP = 0.035). The mean phase difference
between M- and L-cone responses was approximately 15°. This
would correspond to a 1.4-msec time difference, assuming that
a delay difference is the cause of the phase difference.
In Tables 2 and 3 (fifth data column), the measured phase
differences are given. Only phases at cone contrasts between
20% and 30% are shown, to avoid complications owing to the
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Kremers et al.
IOVS, April 1999, Vol. 40, No. 5
Flicker ERGs in different subjects
M-cone modulation
L-cone modulation
In phase L+M-cone
(M-cone contrast: -28.6%) (L-cone contrast: 22.7%) modulation
(L-cone contrast: 76.8%;
A: Subject MH (protanope)
M-cone contrast: 76.8%)
10 -i
0 -
B: Subject MM (deuteranope)
C: Subject JK (trichromat)
40 -i
200-20-40 -60-80
10 -i
o-10 -20 -30 -40
D: Stimulus
Red phosphor
Green phosphor
Blue phosphor
80 - i
^
60 H
8 40
I 20 50
100
50
100
50
100
Time (msec)
FIGURE 1. Averaged ERG responses to pure M-cone modulation (leftpanels: M-cone contrast: —28.6%), pure
L-cone modulation (middlepanels: L-cone contrast: 22.7%), and in-phase modulation of the L and the M cones
with equal cone contrasts (rightpanels: L-cone contrast: 76.8%; M-cone contrast: 76.8%) for a protanope (A;
subject MH), a deuteranope (B; subject MM), and a trichromat (C; subject JK). The ERG signal is an average of
12 runs, and 150 msec of the responses are displayed. Note the different response scale for die in-phase
modulation of the L and M cones. The small response in the deuteranope to the M-cone-isolating stimulus (B,
left) might be caused by small errors in the calculation of the stimulus conditions or by rod response intrusion.
The mean DC level is nonzero, owing to a small DC offset in die output of the amplifier. This DC offset had
no influence on the data analysis, because only the first harmonic component of the Fourier transform was
used. The ERG response in the M-cone-isolating condition is approximately 180° phase-shifted relative to the
two other ERG measurements (also indicated by the negative cone contrast). This is because the M-cone
excitation modulated in counter-phase with the trigger pulse generated by the graphics card; whereas in the
two other conditions (L cone and L+M cone) the cone excitations and the trigger pulse modulated in phase.
This phase shift has no influence on the amplitude data and was corrected for when analyzing the phase data.
(D) Stimulus waveforms for the three conditions, separately displayed for the three phosphors. The values for
mean luminance were 6 cd/m 2 for the blue phosphor, 40 cd/m 2 for the green phosphor, and 20 cd/m 2 for the
red phosphor. The phosphor contrasts (red, green, blue) were 100%, -69.4%, and 4.3%, respectively, for the
-28.6% pure M-cone modulation; 100%, -25.2%, and -2.8% for the 22.7% pure L-cone modulation; and 64%,
100%, and —20.3% for the 76.8% L- and 76.8% in phase M-cone condition. (Negative contrasts indicate
counter-phase modulation.)
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IOVS, April 1999, Vol. 40, No. 5
Cone Signal Contributions to ERGs
925
ERG-thresholds and model fits in dichromats
RB: deuteranope
B
2 1-
-e-3
-2
-1 J)
1
2
3
-3-2
M-cone threshold
-1
-2 -3 c
o
o
FIGURE 2. Threshold contrasts (inverse of the contrast gains) in dichromats for the eight different ratios
of L-cone to M-cone modulation. Data are shown for a deuteranope (A) and a protanope (B). A straight line
is fitted to the data for each subject. The fits are based on the assumption that thresholds are determined
by only one cone type in all conditions. The threshold data for the stimulus that isolated the nonpresent
cone type were excluded from the fits. There was a very small response to the L-cone-isolating stimulus
in protanopes even at the highest contrast. In the deuteranopes, a small but substantial response to the
M-cone-isolating stimulus was measurable, possibly caused by small imperfections of our calculations or
by rod response intrusion.
interrelation between the phase and cone contrast. Sometimes,
it was not possible to determine the phase differences because
the response amplitude in the M-cone-isolating condition was
too small to obtain a reliable measure for the response phase of
the M-cone pathway. In seven subjects, the responses to L-cone
modulation were found to lead the responses to M-coneisolating stimuli. This is indicated by the negative values of the
differences. In all other subjects the M cones were found to be
ERG thresholds and model fits in trichromats
JK
JB
B
6H
3 -
1 2
3
-6
M-cone contrast
-3
•
-6
ERG thresholds
Model fits
FIGURE 3. Threshold contrasts in three different trichromats for the different ratios of L-cone to M-cone
contrast. The ellipses are best fits of a vector addition model to the data points. The orientations of the
ellipses span a large range of orientations found in our population of subjects. The ratio of L-cone to
M-cone weighting was 0.28 for JB (A), 5.44 for subject HK (C), and 1.84 for JK (B).
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Kremers et al.
IOVS, April 1999, Vol. 40, No. 5
TABLE 1. M- and L-Cone Contrast Gains Measured in Protanopes and in
Deuteranopes
Protanopes
M-Cone Contrast Gain
AA
AO
MP
MH*
PH*
ML
L-Cone Contrast Gain
2.992
2.768
2.466
2.387
1.477
2.743
2.602
3.630
2.846
2.66 ± 0.57
DS
GE
1.823
1.925
1.870
2.729
2.295
1.409
Mean ± SD
Deuteranopes
JH
SJ
JS
AZ
MM*
MB
RB*
2.01 ± 0.45
In most subjects, the contrast gains were exclusively measured with cone-isolating stimuli. In four
subjects, responses were obtained for all combinations of cone modulation. The given contrast gain for
these subjects is the mean contrast gain of the remaining cone type in all these measurements, excluding
only the condition in which the missing cone type was isolated.
* For these subjects, the responses were measured at all L-cone to M-cone contrast ratios.
leading (indicated by positive phase differences). The phase
difference varies considerably between subjects.
Apart from the direct measurements, an independent
value for the phase difference was obtained from the model fit
to the threshold data (the vector angle [aL - a M] of the L- and
M-cone responses). In Tables 2 and 3 (fourth column), the
values of a L — a M are given for the trichromats. Fit data are
only given when the cone weighting ratio was between 0.20
and 5, because for ratios beyond this range one of the cones
dominated the response, and the response of the other cone
type was too small to obtain reliable response-phase differences. The fits provided only absolute values of phase differences, and therefore are not conclusive about which cone
response is leading. We decided to give the phase differences
calculated from the fits the same sign as those obtained from
the direct measurements. In Figure 5, the two values of the
phase differences are plotted against each other. There is a
clearly positive correlation between the two (the description
of linear regression through the data points is as follows: y =
1.82 + 0.92*; r2 = 0.77), indicating that two ERG measurements are sensitive enough to determine the phase difference
in each subject.
DISCUSSION
Contrast Gain of L- and M-Cone Signals in
Dichromats
A comparison between the cone contrast gains in dichromats
(Table 1) reveals that the L-cone contrast gains of deuteranopes
are significantly (unpaired taest; P — 0.036) larger than the
M-cone contrast gains in protanopes by a factor of approximately 1.32. This difference is possibly caused by differences
between the states of adaptation in the M and the L cones,
TABLE 2. L- and M-Cone Contrast Gains in Trichromats
Trichromats
HK
LTS
JK
HKS
AT
JB
TU
SM
MU
CF
SW
HM
Mean ± SD
L-Cone
Contrast
Gain (=Af)
M-Cone
Contrast
Gain (=/4M)
L-/M-Cone
Contrast
Gain Ratio
2.99
3.28
0.89
0.55
0.38
0.48
0.35
0.43
1.95
0.40
0.45
0.36
0.30
0.79
0.37
0.57 ± 0.45
5.44
8.66
1.84
3.15
4.14
0.28
3.46
6.27
4.51
6.45
4.68
1.97
4.24 ± 2.31
1.11
1.78
0.55
1.37
2.82
1.62
1.95
3.68
0.73
1.90 ± 1.06
Vector Angle
- « M , deg)
OL
Measured M-/L-Cone
Phase Difference (deg)*
94.83
—
1996
33-08
0.08
32.64
58.35
—
76.01
—
0.11
10.08
—
16.14
—
13-30
49.10
64.58
95.36
75.83
114.22
2.08
21.70
The cone contrast gains (first two data columns), the ratio of the L-cone to M-cone contrast gains (third data column), and the phase difference
between the L- and M-cone responses obtained from the model fits to the threshold data (fourth data column) were obtained with the first setup
(see the Methods section). The directly measured phase differences (fifth data column) for each subject were obtained from the measurements with
the cone isolating stimuli.
* M-cone contrast: 28.6%; L-cone contrast: 22.7%
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Cone Signal Contributions to ERGs
IOVS, April 1999, Vol. 40, No. 5
927
TABLE 3- Data as for Table 2 for a Different Population of Trichromats
Trichromats
EUB
HI
SK
MW
EB
HL
HS
JR
US
swt
AWt
RKt
BKt
LS
BS
Q
MC
WF
FH
DBt
FGt
RBt
Jit
PM
LTSt
Mean ± SD
L-Cone
Contrast
Gain (=Af)
M-Cone
Contrast
Gain (=>!£,)
L-/M-Cone
Contrast
Gain Ratio
0.14
0.34
0.23
0.24
0.22
0.23
0.40
0.23
0.15
0.27
0.31
0.46
0.36
0.31
0.24
0.28
0.20
0.40
0.47
0.22
0.41
0.29
0.30
0.42
0.28
0.30 ± 0.09
0.20
0.06
0.17
0.20
0.05
0.12
0.09
0.17
0.24
0.06
0.13
0.03
0.09
0.16
0.09
0.12
0.15
0.16
0.02
0.04
0.10
0.24
0.06
0.12
0.03
0.12 ± 0.06
0.69
6.08
1.37
1.23
4.48
1.86
4.28
1.40
0.65
4.13
2.36
13.32
4.29
1.95
2.55
2.34
1.38
2.48
28.16
5.29
4.12
1.22
5.27
3.56
9.13
4.51 ± 5.57
Vector Angle
(a L - aM, deg)
Measured M-/L-Cone
Phase Difference (deg)*
1.43
—
19-77
26.25
-27.10
43.10
20.30
9.59
31.98
-4.25
36.08
—
44.28
-8.69
54.60
34.38
-8.60
-25.13
—
—
69-56
11.07
—
83.88
—
14.212
—
17.115
62.822
-3.232
—
4.908
—
26.041
-21.139
24.534
—
17.282
-10.894
—
18.488
-8.337
-31.796
—
-42.879
—
1.917
-35.954
83.438
—
These measurements were obtained with the second setup (see the Methods section).
* M-cone contrast: 23.4%; L-cone contrast: 24.7%.
t For these subjects, the responses were measured at only four conditions, with L- to M-cone contrast ratios: 0:1, 1:0, 1:1, and —1:1.
±:
80-
o>
T3 a>
CD
3
L-cone response phase
M-cone response phase
ice
-360
E
o
0)
ati
E
-340
60
sti
eas
-320
s
._
"5
40-
o
CO
20-
hase
-cone
•5
0_ -380
o
Q.
•o
Q. -400
0)
DC
CO
3
-420-
b[0]=1.82
b[1]=0.92
rz=0.77
0-
•o
c
CO
CO i
CO ^ j
0)
-20 -
S
-440
10
15
20
25
30
35
Cone contrast (%)
FIGURE 4. Response phase as a function of cone contrast in trichromats for the cone-isolating stimuli. A phase increase indicates a decrease of response lag. Clearly, the phase lags decrease with increasing
cone contrast. A similar decrease in phase lag as a function of contrast
is observed when more than one cone type is involved (not shown).
There is a considerable interindividual variability in the phase data. But
for the majority of subjects, the M-cone response leads the L-cone
response.
Downloaded From: http://iovs.arvojournals.org/ on 06/16/2017
-20
0
20
40
60
80
Phase difference calculated from
fits to threshold data (deg)
FIGURE 5- Phase differences between responses originating in the L
and the M cones in trichromats obtained from the model fits to
threshold data plotted against the directly measured phase differences.
There is a clearly positive correlation between the two values. The
linear regression through the data (drawn line) lies close to the
expected diagonal.
928
Kremers et al.
because the mean quantal catches in the L cones (4.42 log
quanta • s~' • cone 1 ; see the Methods section) are larger than
in the M cones (4.31 log quanta • s" 1 • cone" 1 ). But, a similar
difference was also found with other methods. Based on colormatching data on normal subjects, the ratio of peak optical
density of the L-cone to M-cone photopigments has been estimated to be approximately 1.33.22'24 Fundus reflectrometric
measurement has revealed that the double density of L-cone
photopigments in deuteranopes is approximately 1.13 times
larger than the M-cone photopigment double density in protanopes.l2 Thus, the difference between the L- and M-cone
contrast gains might at least partially be caused by differences
between the optical densities of the L- and M-cone photopigments. Assuming that deuteranopes and protanopes have the
same number of cones, there might be several possible causes
for this difference. According to Berendschot et al.,12 absorption by photopigment products in the short wavelength range
or more reflection of long wavelength light from deeper layers
might increase the relative absorption in the L cones. Alternatively, the L cones might possess more photopigment than the
M cones. This would result in a stronger cone signal at the
same cone contrast. Possibly, the gain of the L-cone signal
transmission in the pathway leading to an ERG response is
larger than that of the M-cone signal. However, this would not
explain the ratios found with fundus reflectometry.
Variability of L-/M-Cone Contrast Gains in
Trichromats
The ratios of L- and M-cone contrast gains obtained from the fits
with the vector addition model differ substantially between
different color normal subjects. One possible explanation
might be that the relative amount of L and M cones differs
between subjects. Alternatively, there might be gain differences in the postreceptoral pathways leading to the ERG response. Individual differences in cone weightings have been
inferred from previous studies, in which different techniques
have been used. 101125 " 31 Recently, we found that the cone
weightings in the ERGs can be correlated with cone weightings
obtained psychophysically, provided that the luminance channel (and not the chromatic channel) is isolated in the psychophysical experiments.32 This suggests that the individual differences originate in those parts of the receptoral and
postreceptoral pathways that are shared by the ERG signal and
the signal leading to a visual percept in the luminance channel.
Most trichromatic subjects display a larger L-cone weighting than M-cone weighting. The average weighting was approximately 4:1, measured with the two setups. However,
cone weighting ratios exceeding a value of approximately 10:1
cannot be resolved by the fitting procedure so that excessively
large values occasionally might occur (e.g., subjects RK and FH
in Table 3). This might lead to a small overestimation of the
mean values.
In one female subject (JB, Table 2) with normal color
vision as established by the Nagel anomaloscope, we found
that the L-cone to M-cone weighting ratio was substantially
smaller than unity, implying that her retina has more M than L
cones or larger M-cone than L-cone signal gains. She is possibly
a carrier of protanopia, because her grandfather on her mother's side was a protanope. Similar cone weightings have been
found psychophysically in other female carriers of protanopia.33 It therefore seems that a defective gene for a cone
photopigment on the X-chromosome in a female carrier may
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IOVS, April 1999, Vol. 40, No. 5
lead to a change in the cone signal weighting. The simplest
mechanism to explain such a change would be an alteration in
the relative numbers of L and M cones, rather than a change in
the gains in the postreceptoral signal pathways.
L- and M-Cone Phase Differences
The results presented here confirm previous results420 that in
normal subjects the response phase of the ERG increases with
increasing cone contrast. But Wu et al.20 found that the relationship may differ at other temporal frequencies.
The data further confirm our previous observation that
ERG responses to pure M-cone modulation are slightly phase
advanced relative to the response phase to pure L-cone modulation (Fig. 4). In the previous paper,4 we noted that the
phase differences between the responses to M- and L-cone isolating stimuli vary between subjects but were relatively
stable within subjects when repeatedly measured. Here, in a
larger population of color normal subjects, we indeed find that
the phase differences can vary between approximately —30°
and 80°. Independently from the direct measurements, we
obtained absolute values of phase differences from the model
fits to the threshold data. The strong correlation between both
values favors the conclusion that there is a consistent interindividual variability that has a physiological basis.
The smaller phase lags of the responses to M-cone-selective stimuli in the majority of subjects suggests that the M-cone
signals are most often faster than the L-cone signals. Similar
conclusions have been drawn in other studies in which several
different techniques were used, including ERG recordings,34
psychophysics,35 and extracellular recording from retinal ganglion cells.36 Recordings of currents in single cones using the
suction electrode method also indicate a tendency for M cones
to be slightly faster than L cones, although this difference is not
significant.37 Our data also show that there is a substantial
interindividual variability in the phase of the cone ERGs that
originates in response dynamics differences of the two cone
types or their postreceptoral pathways.
Cone Substitution in Dichromats
Another aspect that can be addressed with our results is the
question of whether missing cones are replaced in dichromats.
A comparison between the ERGs of trichromats and dichromats is only valid when the postreceptoral processing in the
ERG signals is identical in trichromats and protanopes (for
signals originating in the M cones) and in trichromats and
deuteranopes (for signals originating in the L cones), so that
the postreceptoral processes have identical influence on the
ERG signals in dichromats and trichromats. The fact that the
mean M-cone contrast gain of protanopes is larger than that of
trichromats, and that the mean L-cone contrast gain in deuteranopes is larger than in trichromats (cf. Tables 1 and 2),
strongly suggests at least a partial replacement of the photopigment in dichromats.
The mean contrast gains for the dichromats and the
trichromats are displayed in Figure 6. The drawn line connects
the mean dichromatic mean data (2.66 and 2.01; open symbols) when only the contrast gains of the remaining cone types
are considered. The connecting line can be described as follows: Al = 2.66 - (2.66/2.01) X A^, in which A* and A^ are the
mean L- and M-cone contrast gains, respectively. Despite the
large standard deviations in the trichromats, caused by the
Cone Signal Contributions to ERGs 929
IOVS, April 1999, Vol. 40, No. 5
the remaining cone type in dichromats. This interpretation is
confirmed by the equal response amplitudes to the in-phase
modulation of the L and M cones with equal cone contrasts
(Fig. 1, right). A complete replacement of the missing cones
might also explain why dichromats and trichromats in psychophysical experiments are about equally sensitive to luminance
temporal modulation.38 The responses in the dichromats are
driven solely by the L cones (in deuteranopes) or by the M
cones (in protanopes). These responses are very similar to the
responses found in the trichromats, which are driven by both
the L and M cones. In contrast, the data of Meigen et al. suggest
a much larger difference between the trichromatic data and the
connecting line, probably caused by a large variability in the
responses of dichromats. However, we found only a limited
variation in the dichromatic contrast gains.
From fundus reflectometric measurements, Berendschot
et al.12 concluded that there is a replacement of cones in
dichromats but that the pigment density is lower in dichromats
than in trichromats. This is only partially in agreement with our
data, unless there are compensator)' mechanisms in the ERG
pathways of dichromats.
Mean contrast gains
3.5-1
•
3.0-
T
O
v
D
Protanopes
Deuteranopes
Trichromats
2.5 ctt
™ 2.0
I
8 1.5CD
O
5 i.o H
0.5-
0.00.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
M-cone contrast gain
FIGURE 6. Mean L- and M-cone contrast gains obtained in dichromats
and trichromats. The data of the dichromats are displayed in two
different ways. The open symbols, connected by the continuous line,
represent the contrast gains when only the L cone (deuteranopes;
open triangles) or the M cones (protanopes; open circles) are considered. The contrast gain values of the trichromats (open square) lie
close to this line, indicating a complete photopigment replacement in
the dichromats. The closed symbols connected by the dashed line
represent the contrast gains of the dichromats when the responses to
the stimuli that isolate the nonpresent cone types are also considered.
Error bars, SD.
individual differences, the mean L- and M-cone contrast gains
for the trichromats are close to this connecting line (filling in
the trichromatic mean M-cone contrast gain, 0.57, results in a
predicted L-cone contrast gain of 1.91, which is close to the
measured mean value of 1.89). This implies a complete replacement of the missing photopigment in dichromats.
However, Meigen et al.21 measured ERG responses in
dichromats and trichromats using cone-isolating stimuli and
found that trichromatic responses were much smaller than the
linear interpolation between the dichromatic data. This would
suggest that dichromats would have even more photopigment
than expected from a complete pigment and cone replacement. However, Meigen et al. also used the responses of the
dichromats to stimuli that isolated the missing cone type. This
may cause a bias toward excessively large responses for the
dichromats, especially for the deuteranopes in whom the ERG
responses to the M-cone stimuli might be influenced by rod
intrusion. To test this hypothesis, we analyzed our data in a
way similar to the method used by Meigen et al. by also
including the contrast gains of dichromats for the stimuli isolating the missing cone type. The results are shown in Figure 6
(closed symbols). The data of the trichromats are still close to
the connecting (dashed) line, indicating that even in this worstcase situation a complete replacement cannot be rejected and
that there is no need to postulate a supranormal response of
Downloaded From: http://iovs.arvojournals.org/ on 06/16/2017
Acknowledgments
The authors thank Sabine Meierkord and Eva Burkhardt for technical
assistance, Jeremy Nathans for providing the genotypes, and Eberhart
Zrenner for general support.
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