Brain (1996), 119, 723-740
Retinal and cortical evoked responses to chromatic
contrast stimuli
Specific losses in both eyes of patients with multiple sclerosis
and unilateral optic neuritis
Vittorio Porciatti1 and Ferdinando Sartucci2
1
Institute of Neurophysiology, CNR and the 2Institute of
Neurology, University of Pisa, Italy
Correspondence to: Dr V. Porciatti, Istituto di
Neurofisiologia del C.N.R., 51, via S. Zeno, 1-56127 Pisa,
Italia
Summary
// is known that colour vision may be altered in optic neuritis.
Our aim was to establish whether chromatic and achromatic
vision are differentially impaired using stimuli designed
to favour the activity of either the magnocellular or the
parvocellular stream of the visual pathway. Fourteen patients
with a past history of unilateral optic neuritis in the course
of multiple sclerosis and 10 age-matched control subjects
were included in the study. Patients had relatively good
visual acuity in the affected eyes and no gross colour deficits
(Ishihara). Stimuli were alternating gratings of low spatial
frequency and of different chromaticity along the red-green
axis. The psychophysical contrast sensitivity (CS) was
measured at 5 Hz as a function of colour ratio [red/
(red+green)] to evaluate both the equiluminant point (the
colour ratio corresponding to the lowest CS) and the CS for
isochromatic, luminance gratings (red-black and greenblack). Steady-state (2-24 Hz) and transient pattern
electroretinograms (PERGs) and visually evoked potentials
(VEPs) were recorded in response to high contrast (90%)
stimuli of low spatial frequency (0.3 cycles deg~') modulated
in either pure chromatic contrast (equiluminant red-green)
or pure luminance contrast (yellow-black). On average, CSs
were reduced (10 dB) in optic neuritis eyes compared with
controls for both luminance and chromatic gratings. In the
VEPs (both transient and steady-state) amplitude losses and
latency delays were far larger for the chromatic VEPs than
for the luminance VEPs. Chromatic VEP latency delays
were remarkable also in the fellow, clinically normal, eyes.
Significant losses were apparent in both the luminance
and chromatic PERG. However, the chromatic PERG was
comparatively more altered. In agreement with previous
reports, selective losses were not apparent at threshold.
By contrast, suprathreshold electrophysiological responses
displayed a clear dissociation between luminance and colour,
suggesting that the parvocellular stream, compared with the
magnocellular stream is more impaired in optic neuritis.
Keywords: chromatic contrast; pattern electroretinogram; visually evoked potential; optic neuritis; multiple sclerosis
Abbreviations: CS = contrast sensitivity; G = green; L = long; M = medium; PERG = pattern electroretinogram; R = red;
RCAL = retino-cortical apparent latency; VEP = visually evoked potential
Introduction
It has been known for many years that colour vision may be
altered in optic neuritis (Nettleship, 1884; Gunn and Buzzard,
1897; Kollner, 1912; Sloan, 1942; Griffin and Wray, 1978;
Hart, 1987), in addition to many other spatiotemporal
achromatic visual functions (Medjbeur and Tulunay-Keesey,
1985; for review, see Hess and Plant, 1986).
An interesting question is whether chromatic and
achromatic vision are differentially impaired. Indeed, the
post-receptoral visual pathway of primates contains two major
© Oxford University Press 1996
parallel streams specific for colour contrast and luminance
contrast, respectively (De Monasterio and Gouras, 1975;
Dreher et al., 1976; Shapley and Perry, 1986; Livingstone
and Hubel, 1988; Tootell et al., 1988a, b; for reviews, see
Lee and Martin, 1989; Merigan, 1989; Lennie et al., 1990;
Shapley, 1990; Zrenner et al., 1990; Van Essen and Gallant,
1994). The colour opponent system originates from small,
tonic ganglion cells (-80% of the whole population) relaying
to parvocellular laminae of the lateral geniculate nucleus and
724
V. Porciatti et al.
then projecting to layer 4C-fi of the striate cortex. Within
the chromatic parvocellular stream, red-green opponent cells
largely outnumber blue-yellow ones (~80% of the parvocellular-cell population). The achromatic stream originates
from large, phasic ganglion cells (-10% of the whole
population) projecting to magnocellular layers of the lateral
geniculate nucleus and then to lamina 4C-a of the striate
visual cortex. It is worth noting that parvocellular cells may
also respond well to achromatic contrast stimuli of relatively
high spatial frequency. However, within the range of spatial
frequencies to which both streams respond, magnocellular
cells are relatively more sensitive to achromatic contrast, and
this characteristic is more prominent at higher temporal
frequencies.
Colour vision testing in neuro-ophthalmology is
traditionally carried out with Ishihara pseudoisochromatic
plates or Farnsworth-Munsell 100 Hue test. These tests are
very sensitive in detecting congenital colour vision deficiences
and are also reported to be useful in monitoring optic nerve
dysfunction (Verriest, 1963; Foster et al., 1985; for review,
see Zrenner, 1983). However, these tests do not appear
well designed for isolating post-receptoral, colour opponent
processes. In addition, the output scores of these tests
cannot be easily converted to losses of visual sensitivity.
Consequently, the question remains as to whether chromatic
vision is selectively altered in optic neuritis.
Patterned stimuli of pure chromatic contrast have been
designed to allow colour modulation (red-green or blueyellow) at constant mean luminance (equiluminant stimuli).
The spatial and temporal CS functions for luminance gratings
are band-pass while those for equiluminant gratings are
low-pass and cut-off at a lower frequency compared with
luminance (van der Horst et al., 1967; Kelly, 1983; Mullen,
1985; Fiorentini et al., 1991). These differences are consistent
with the hypothesis that colour information is processed
mainly by the parvocellular stream, and luminance
information by both parvocellular and magnocellular streams.
Mullen and Plant (1986) used equiluminant gratings, in
addition to luminance gratings, to compare psychophysical
chromatic and achromatic sensitivity losses in human optic
neuritis. They reported greater colour deficit than luminance
deficit in patients. However, other psychophysical studies
addressing the same matter with uniform stimuli designed to
separate luminance and chromatic mechanisms did not
provide consistent evidence for selective damage of either
chromatic or achromatic vision at threshold (Alvarez et al.,
1982; Alvarez and King-Smith, 1984; Fallowfield and
Krauskopf, 1984; Foster et al., 1985; Travis and Thompson,
1989; Russell et al., 1991).
More recently, PERGs (Arden and Vaegan, 1983; Korth
and Rix, 1988; Berninger et al., 1989; Kulikowski and
Russell, 1989; Bach and Gerling, 1992; Korth and Horn,
1992; Korth et al., 1993; Morrone et al., 1994a, b; Porciatti
et al., 1994) and VEPs (Regan, 1973; Regan and Spekreijse,
1974; Murray et al., 1987; Berninger et al., 1989; Fiorentini
et al., 1991; Thompson and Drasdo, 1992; Crognale et al..
1993; Korth et al., 1993; Morrone et al., 1993; Rabin
et al., 1994; Girard and Morrone, 1995) in response to
suprathreshold, equiluminant stimuli have been reliably
recorded for a wide range of spatiotemporal frequencies and
contrasts. Overall, the spatiotemporal properties of the PERG
and VEP for chromatic contrast differ from corresponding
properties for luminance contrast stimuli, suggesting that
these responses reflect the largely distinct contribution of
parvocellular and magnocellular generators at retinal and
cortical level.
In this study, we report results obtained recording chromatic
and luminance PERGs and VEPs in a group of patients with
unilateral optic neuritis during the course of multiple sclerosis.
Both transient and steady-state responses to a number of
temporal frequencies have been evaluated. Evidence is
provided that the electrophysiological responses show far
larger losses for chromatic than luminance patterns in both
the affected and fellow eyes. Preliminary results have been
previously published in abstract (Porciatti and Sartucci, 1995).
Methods
Subjects
Fourteen patients attending the Department of Clinical
Neurology at the University of Pisa during the last year were
included in the study. Nine were females and five males;
their ages ranged from 23 to 50 years (mean 35.4 years,
SD = 9). All cases exhibited symptoms or had a past history
of unilateral optic neuritis at different stages, with or without
visual field abnormalities, and most of them were diagnosed
having multiple sclerosis on the basis of standard clinical
criteria and a battery of tests, including multimodality evoked
potentials (e.g. Sartucci et al., 1993), MRI and CSF analysis.
In addition, patients had a standard ophthalmological
examination which included Goldmann kinetic perimetry,
Humphrey static perimetry (program 30-2) and the Ishihara
colour vision test.
Clinically, all cases showed signs of multiple, disseminated
white matter dysfunction, and had multiple evoked potential
abnormalities. MRI scan, performed using spin-echo
sequencies, displayed abnormal areas of hyperintensity,
disseminated either at periventricular or subtentorial levels
in 10 patients. CSF analysis showed an intrathecal synthesis
of IgG in three and a lymphocitic pleiocytosis in four.
According to the criteria of Poser et al. (1983), patients were
divided into three categories: definite multiple sclerosis (« =
8); probable multiple sclerosis (n = 2) and isolated optic
neuritis (n = 4). A summary of clinical details of patients'
group is reported in Table 1. Ten normal control subjects,
age- and sex-matched with the patients' group (four males,
six females, age range 23-43 years, mean 28.7 years, SD =
6.2: / test for difference with patients not significant) were
also included in the study. All subiects had no or small
refractive errors, and were fully corrected according to the
different viewing distances of psychophysical and
Chromatic PERG and VEPs in optic neuritis
725
Table 1 Summary of clinical features of patients
Case
Sex
Age
Diagnosis
Duration
Eye
Visual
acuity
Optic disc
Humphrey
mean defect
Ishihara
score
1
TC
F
29
6 months
2
PS
F
23
3
PG
M
29
BC
F
40
5
CD
F
30
6
PF
F
23
7
MM
M
27
8
SP
F
50
9
TE
M
29
10
BL
F
45
11
BP
M
43
12
GM
F
39
13
GD
F
14
GM
M
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
1.25
1.25
1.25
1.25
1.25
1.25
0.6
1
0.8
0.35
0.4
1.0
1.0
1.25
0.25
0.8
1.0
1.2
1.25
0.5
1.0
0.7
0.9
0.45
1.2
0.1
1.1
0.6
tp
n
n
n
P
n
4
Right ON
definite MS
Left ON
definite MS
Right ON
definite MS
Right ON
definite MS
Left ON
definite MS
Right ON
probable MS
Right ON
definite MS
Right ON
n
n
n
n
n
n
a
n
n
n
n
n
n
n
a
n
n
n
n
a
n
n
n
n
n
a
n
a
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
Patient
no.
3.5 months
5.5 months
7 years
10 months
15 months
2.5 months
5 years
Right ON
definite MS
Left ON
1 year
4 years
41
Left ON
probable MS
Left ON
definite MS
Left ON
47
Left ON
1 month
1 month
1 month
1 year
P
n
n
n
P
n
n
n
P
n
n
n
n
n
n
n
n
n
n
tp
n
0
ON = optic neuritis; n = normal; a = abnormal; p = pallor: tp = temporal pallor; o = oedema.
electrophysiological experiments. No artificial pupils or
dilatory agents were used. All experiments followed the
tenets of the declaration of Helsinki. Informed consent was
obtained after the aims and the experimental techniques were
fully explained. The experiments had the approval of the
local ethical committee.
Visual stimuli
The stimuli were horizontal sinusoidal gratings, modulated
in either luminance or chromaticity, generated by framestore
(Cambridge Research VSG, UK), and displayed on the face
of a colour monitor at a frame rate of 120 Hz, 512 lines per
frame, 14 bits per colour per pixel (Barco Calibrator, Kortrizk,
Belgium) suitably linearized by gamma correction (Minolta
Chromameter CS100, Japan). The peak spectral response for
the red phosphor was at 628 nm (Comission Internationale
d'Eclairage coordinates: x = 0.618, y = 0.351) and that of
the phosphor 531 nm (Comission Internationale d'Eclairage
coordinates: .v = 0.286, y = 0.601). Stimuli were obtained
by combining red and green gratings of identical contrast
and luminance. Luminance (yellow-black) stimuli were made
by summing the red and green gratings in phase, and
the chromatic stimuli (red-green) by summing them in
counterphase. Following the procedure introduced by Mullen
(1985), the relative contribution of the red and green was
varied by modulating the red (R) and green (G) guns. The
ratio [r = R/(R+G)%] of the red-to-total luminance could
be varied from 0 to 100, where r = 0% defined a greenblack pattern, r = 100% a red-black pattern, and intermediate
values a red-green chromatic pattern. To minimize the
response from short-wavelength cones, the patterns were
viewed through yellow filters (Kodak Wratten 16) that heavily
attenuated wavelengths below 500 nm. Viewed through the
filter, the Comission Internationale d'Eclairage coordinates
for the red were x = 0.647, y = 0.351, and for the green x =
0.392, v = 0.606. The response of the long (L) and medium
(M) wavelength cones was calculated from the Comission
Internationale d'Eclairage values of the display phosphors
and human cone fundamentals (Smith and Pokorny, 1975).
Data showed that under the above experimental conditions
L and M cones do not modulate at r = 43% and r =
68%, respectively (points of silent substitution; Estevez and
Spekreijse, 1982). For r = 50% the response of L and M
cones is equal and opposite. The equiluminant point for
normal adult observers is near this ratio (Fiorentini et al.,
726
V. Porciatti et al.
1996). Further details on the evaluation of the silent
substitution points for the red and green, and evaluation
of the cone contrast can be found elsewhere (Morrone
et al., 1993, 1994a). The visible screen was 26 cm wide
and 24 cm high, subtending an area of 53X49 deg when
viewed from 28 cm (electrophysiological experiments) and
15X14 deg from 100 cm (psychophysical experiments). Mean
luminance was 17 cd ITT2, producing a retinal illuminance of
330 Troland when viewed through natural pupils, measured
to be ~5 mm in all subjects.
Psychophysical technique
In all subjects the colour ratio corresponding to the
equiluminant point was established monocularly by
evaluating the lowest CS for red-green gratings (1 cycles
deg"1) of different chromaticities reversed at 5 Hz (see Fig. 1).
Higher frequencies (i.e. 15 Hz most used for heterochromatic
flicker photometry) precluded the evaluation of the
equiluminant point in optic neuritis patients with low CS.
Previous controls in normal subjects (not shown in figures)
demonstrated that the equiluminat point measured at 5 Hz
did not significantly differ from that measured at 15 Hz. The
CS for luminance contrast stimuli was obtained from the
average CS for red-black and green-black gratings (r = 90%
and r = 10%, respectively). This CS for luminance gratings
did not differ from that for yellow-black gratings, obtained
by superimposing the red and green guns in phase (Mullen,
1985). Sensitivity estimates were obtained by the method of
ascending limits. The experimenter decreased the contrast of
the stimulus until the observer reported that the stimulus was
no longer visible. The contrast was further lowered by 0.20.4 log units, and then increased by small steps (0.05 log
units) until the subject reported seeing it, to yield threshold.
Threshold was measured for several values of colour ratios
(r = 10-90%) in 10% intervals over most of the range,
decreasing the interval width to 2.5% near 50%. At least two
measures were made for colour ratios near equiluminance.
Electrophysiological techniques
After the equiluminant point had been established,
electrophysiological recordings were made with stimuli (0.3
cycles deg""1 spatial frequency) modulated in either pure
luminance (yellow-black) or pure chromaticity (equiluminant
red-green), reversed sinusoidally in contrast at frequencies
ranging from 2 to 24 Hz (for steady-state response) and
at 1 Hz (square wave) for transient responses. Pattern
electroretinograms were recorded monocularly by means of
Ag/AgCl superfical cup electrodes, 9 mm diameter, positioned
over the lower eyelid. An equal electrode, positioned over
the eyelid of the contralateral, patched eye, served as
reference. As the recording protocol was extensive, this
electrode placement represented a good compromise between
signal-to-noise ratio and signal stability. Discussion on the
inter-ocular PERG by skin electrodes and its relationship to
the PERG by corneal electrodes can be found elsewhere
(e.g. Porciatti, 1987; Hawlina and Konec, 1992; Porciatti and
Falsini, 1993). Visually evoked potentials were recorded
simultaneously using the same type of electrodes, placed
2 cm above the inion (active) and at the right mastoid
(reference). The common ground for all recordings was
located on the forehead. Pattern electroretinogram and
VEP signals were amplified (PERG 100 000 fold; VEP
50 000 fold), band-pass filtered between 1 and 100 Hz (6 dB
octave"1), digitized at 1024 Hz with 12 bit resolution and
averaged on-line by a personal computer. The computer
rejected single sweeps over a threshold voltage (4 V) to
minimize gross potential changes induced by eye blinks,
ocular movements, or other biological activities. The
computer averaged the PERG and VEP in synchrony with
the stimulus periodicity, and performed a discrete Fourier
tranform to evaluate the amplitude and phase of the dominant
response component (second harmonic). As averaging was
performed over one integer stimulus period, discrete Fourier
transform spectra contained only the harmonics of stimulus
frequency without leakage to neighbouring frequency bands,
and windowing was not necessary. Second harmonic
amplitude and phase were also calculated separately for
partial sums (40-sum packets) of the total average (at least
280 sums), from which the standard error of the amplitude
and phase estimates were derived to test response reliability
(Porciatti et al., 1992). The program also averaged the signals
asynchronously at 1.1 times the temporal frequency of the
stimulus to give an estimate of background noise. Transient
PERGs were smoothed off-line by running average over 10
points to remove most of high frequency noise coming from
eyelid muscle activity, thereby allowing a more precise
evaluation of amplitude and latency measurements.
Results
Psychophysics
Figure 1 shows how the detection thresholds for red-green
gratings modulated in counterphase at 5 Hz change as
function of the colour ratio. For control, fellow and optic
neuritis eyes there is a clear minimum at around the 50%
colour ratio and the function is symmetrical around that. The
colour ratio corresponding to the lowest sensitivity has been
taken as the equiluminant point (see Methods). In some cases
in which the function was rather shallow, detection thresholds
were also measured at higher frequencies (10 or 15 Hz) in
order to define equiluminance better. In one patient, the
equiluminant point was significantly different (65%) from
the normal average but equal in the two eyes. In the same
patient the Ishihara test was normal. We interpreted this
departure from the normal colour ratio (Fiorentini et al.,
1996) as reflecting a mild, congenital protanomaly. In Fig. 1
four major aspects are readily apparent: (i) the isoluminant
point is similar in control, fellow and optic neuritis eyes; (ii)
there is a drop of sensitivity in patients; (iii) the threshold
Chromatic PERG and VEPs in optic neuritis
50
100
0
50
100
0
50
727
100
Colour ratio %R/(R+G)
Fig. 1 Thresholds for detection of red-green gratings of various chromaticities modulated in
counterphase at 5 Hz, measured in the right eyes of control observers and in either eye of patients with
unilateral optic neuritis (ON). Eyes with optic neuritis display an overall, marked loss of sensitivity.
Some sensitivity loss is also present in the fellow eyes. Note that the colour ratio at which the sensitvity
is lowest (equiluminat point) is of the order of 50% and is comparable in the different eye groups.
elevation is larger in optic neuritis eyes than in the fellow
eyes; (iv) the threshold elevation is rather uniform across
chromaticity
In individual eyes of patients, sensitivity differences from
the normal average were established for colour (at the
equiluminant point) and luminance (average of sensitivities
at colour ratio 10% and 90%). The results are reported in
Fig. 2. In optic neuritis eyes, the average sensitivity loss is
of the order of 10 dB [t test for difference from zero:
luminance, r(26) = 3.8, P< 0.001; colour, t(26) = 4.59,
P < 0.0001] and it is comparable for colour and luminance
[/ test for difference: t(26) = 0.95, P = 0.9]. In the fellow
eyes losses are smaller (~4 dB for colour and 6 dB for
luminance) but still significant [/ test for difference from
zero: luminance, f(26) = 4.9, P< 0.0001; colour, t(26) =
4.1, P < 0.001]. As for optic neuritis eyes, in the fellow eyes
the loss is comparable for colour and luminance [t test for
difference: /(26) =1.62, P = 0.11]. That colour losses are
virtually identical to luminance losses is also seen in Fig. 2C
and D, where data of individual eyes are compared.
Electrophysiology: steady-state responses
Examples of steady-state PERGs and VEPs, simultaneously
recorded from a representative control subject, in response to
equiluminant red-green gratings modulated in counterphase at
6 Hz are reported in Fig. 3 (C and D, respectively). Figure 3A
and B displays, for the same subject, PERG and VEP
waveforms to yellow-black stimuli of the same contrast
(90%) and colour ratio (50%). For all responses the sweep
period is equal to the stimulus period (166.6 ms: two
reversals). As all responses show strong modulation at twice
the stimulus frequency, amplitude and latency values can
well be summarized by second harmonic amplitude and
phase, whose values are reported in Fig. 3E (PERG) and
Fig. 3F (VEP). Pattern electroretinograms and VEPs were
dominated by the second harmonic component at all temporal
frequencies tested, in agreement with previous results
(Fiorentini et al., 1991; Morrone et al., 1993, 1994a). In
Fellow eyes
CO
ON eyes
12
12 -,
A
f
I
Lum
Col
B
to
o
T
6 -
6 -
T
<D
CO
0 -
Lum
Col
30 -_
D
o ..-••'
20 10 -
r
oQ.-o6
.0
0 -10 -
I " '' I
-10
0
10
20
30
Colour loss (dB)
40
-10
0
10
20
30
40
Colour loss (dB)
Fig. 2 (A-B) Average (±SEM) sensitivity losses (difference from
the mean of normal controls) for equiluminant- and luminance
gratings evaluated in the affected (B) and fellow (A) eyes of
patients. (C-D) Scatterplots of colour versus luminance losses for
fellow (C) and optic neuritis (ON) (D) eyes. Note in A, B, C and
D that colour- and luminance-sensitivity losses occur to a
comparable extent.
Fig. 3E and F, vertical and horizontal errors bars give an
estimate of the variability of amplitude and phase of partial
averages (40 sums) of responses (average of at least 280
sums) to colour (filled symbols) or luminance (open symbols).
With the particular stimuli used in this study, PERGs and
VEPs have a very small amplitude. However, the responses
are sufficiently reliable, (the coefficient of variation in
amplitude is typically -25% for both PERGs and VEPs) [for
discussions, see Porciatti (1987) and Morrone et al. (1993)]
and well above the noise level (dotted lines at the figure
bottom). In addition, the phase variability is small. It can be
728
V. Porciatti et al.
-.
PERG
VEP
Lum
A
B
T3
0)
•D
-
"5.
<
AA
>
<D
T3
Q.
<
Time (83.3 msdiv" 1 )
Time (83.3 msdiv~1)
11.0
3-
o
•
ra
.y
o
0.5
}
-
I
Lum
Col
*
1-
#
0-1
0
1
Phase (it rad)
-1
0
1
Phase (n rad)
Fig. 3 Samples of steady-state PERGs (A and C) and VEPs
(B and D), averaged over one full stimulus period, in response to
either yellow-black luminance gratings (A and B) or red-green
equiluminant gratings (C and D) of 0.3 cycles deg"1 and 90%
contrast, modulated in counterphase at 6 Hz. All responses show
strong modulation at twice the stimulus frequency, and are well
summarized by the second harmonic components, whose
amplitude and phase are shown in E and F. Vertical and
horizontal error bars indicate the variability of amplitude and
phase, respectively, of partial averages (40 sums) of responses (at
least 280 sums). In E and F, the dotted lines represent the second
harmonic amplitude of 'noise' responses, obtained by
asynchronous averaging at a frequency 10% higher than that of
the stimulus.
noted that the phases of both PERG and VEPs to colour
stimuli differ from those to luminance stimuli. The response
phase bears a relationship to latency. For a frequency of 12
Hz (second harmonic of the stimulus frequency) a phase lag
of 27t rad (radians) corresponds to 83.3 ms delay in latency.
However, it is not possible to have an absolute estimate of
latency from a single steady-state response, since there is an
infinite set of phases separated by 2JI rad. Response latency
(apparent latency) can be evaluated by measuring phase as
a function of temporal frequency, and estimating the slope
of the curve according the formula [apparent latency (ms) =
phase slope (n rad Hz"')X 1000/4 (2X2TC rad: period of the
second harmonic)] (Regan, 1966; Spekreijse et al., 1977;
Porciatti et al., 1992; Morrone et al., 1994a).
The effect of temporal frequency on the PERG to yellow-
black stimuli is summarized in Fig. 4. The left-hand graphs
show the amplitude spectra (averaged over subjects) and the
right-hand graphs show the corresponding phase spectra. As
shown in Fig. 4A, the luminance PERG of control subjects
is temporally tuned in amplitude, with a broad maximum
between 6 and 12 Hz, a secondary maximum at -20 Hz and
a high temporal frequency cut-off between 25 and 30 Hz.
On average, the PERG amplitude of optic neuritis eyes is
reduced by ~23% (inset in Fig. 4A) compared with control
eyes [two-way ANOVA: F{ 1,263) = 26.9), /><0.01]. In
addition, amplitude reduction in optic neuritis eyes appears
more marked for the low (6-12 Hz) than for the high
(20-22 Hz) temporal frequency range [two-way ANOVA:
interaction effect eye by temporal frequency: F(10,263) =
7.8, P < 0.01]. In the fellow eyes, the changes are smaller
and not significant compared with control eyes. Inspection
of Fig. 4A {see also Figs 5A, 6A and 7A) indicates that the
average noise level (dashed lines at the figure bottom) is
similar for all groups of eyes. This suggests that amplitude
reduction of the optic neuritis eyes does not result from
inherent difficulties in registration (which should lead to
increased noise level), but reflects real change in average
amplitude levels. As shown in Fig. 4B, the response phases lag
linearly with temporal frequency in all eyes with comparable
slopes, corresponding to apparent latencies of 56 ms for
control eyes, 55 ms for fellow eyes and 58 ms for optic
neuritis eyes. The difference in slope among different groups
of eyes is small and not significant when tested by two-way
ANOVA.
Figure 5 shows how the chromatic PERG ampliltude and
phase change as a function of temporal frequency. In control
subjects (Fig. 5A), the chromatic PERG has broad maximum
between 4 and 8 Hz and a steep attenuation for higher
frequencies. No reliable responses can be recorded at 15 Hz
or higher, indicating a lower cut-off compared with the
luminance PERG (in agreement with Morrone et al., 1994a,
b; but see Bach and Gerling, 1992). In optic neuritis eyes,
but not fellow eyes, the colour PERG is reduced in amplitude
(inset in Fig. 5A) by ~21% on average [two-way ANOVA:
F( 1,239) = 1.2, / ) < 0 . 0 1 ] . Interaction between eye and
temporal frequency was not significant. The PERG phases
(Fig. 5B) lag linearly with temporal frequency with comparable apparent latencies in all eye groups (control eyes:
80 ms, fellow eyes: 81 ms, optic neuritis eyes: 80 ms). It is
worth noting that these slopes are steeper than those of the
luminance PERG (Fig. 4B) by -20 ms.
Results obtained by recording steady-state VEPs to yellowblack stimuli of different temporal frequencies are
summarized in Fig. 6. As previously reported for luminance
contrast gratings (Plant et al., 1986; Porciatti et al., 1992;
Simon, 1992), the frequency function of the VEP second
harmonic (Fig. 6A) has in control subjects a complex form,
with a maximum at 6-8 Hz, a local minimum at -15 Hz, a
secondary maximum between 15 and 20 Hz and a cut-off
between 25 and 30 Hz. This complex form suggests at least
two different underlying generators that contribute to the
Chromatic PERG and VEPs in optic neuritis
729
Luminance PERG
0 6
A
l
0.4 -
i ;
(1)
Ampli
"g 0 . 4 -
0.2 -
1&
B
Oil
4r* \ 4
0.0 -
-12 -
Controls: 56 ms
Fellow eyes: 55 ms
ON eyes: 58 ms
-14 0.0 -
-16
5
10
15
20
25
30
0
Temporal frequency (Hz)
5
10
15
20
25
30
Temporal frequency (Hz)
Fig. 4 Group averages of the second harmonic amplitude (A) and phase (B) of the steady-state PERG
to yellow-black luminance gratings for control, fellow and optic neuritis (ON) eyes of subjects, as a
function of temporal frequency. In optic neuritis eyes, but not fellow eyes, the luminance PERG
amplitude is reduced compared with control eyes mainly at low temporal frequencies (6-10 Hz). The
PERGs phase lags with temporal frequency with comparable slopes in all groups of eyes. Error bars
represent the SEM.
Colour PERG
0.6
0
0.6 -,
A
0.4 -
-a
r
•Q.
E 0.2
<
-2
0.4 -
iy
H
\
N 1
sXh
-4
0.2 -
0.0 -
(D
-6
K
"8
^
w
_g -10
0-12 -
•7
-14 -
0.0
Controls: 80 ms
Fellow eyes: 81 ms
ON eyes: 80 ms
-16
0
5
10
15
Temporal frequency (Hz)
0
5
10
15
Temporal frequency (Hz)
Fig. 5 Variation with temporal frequency of the average second harmonic amplitude (A) and phase (B)
of the steady-state PERG to equiluminant red-green gratings for control, fellow and optic neuritis (ON)
eyes of subjects. In optic neuritis eyes, but not fellow eyes, the colour PERG amplitude is reduced
rather uniformly as a function of temporal frequency. The PERG phase lags with temporal frequency
with comparable slopes in all groups of eyes. Error bars represent the SEM.
response with different weight, depending on the temporal
frequency. In optic neuritis eyes, there is a tendency to a
selective reduction in amplitude in the peak region, but
overall the changes are small and not significantly different
from controls [two-way ANOVA: F( 1,241) = 1.6, P = 0.24].
As shown in Fig. 6B, the VEP phases lag linearly with
temporal frequency with comparable slopes in all eyes,
corresponding to apparent latencies of 109 ms (control eyes),
110 ms (fellow eyes) and 109 ms (optic neuritis eyes).
The temporal function of VEPs to red-green equiluminant
gratings differs from that of the luminance VEPs in control
subjects. As shown in Fig. 7A, the form of the function is
simpler, with a single broad maximum at ~5 Hz. For higher
frequencies there is a steep fall off in amplitude and no
reliable responses can be recorded at 15 Hz or higher (in
agreement with previous results; Fiorentini et al., 1991). In
control subjects, the slope of the VEP phase lag with temporal
frequency (Fig. 7B) also differs from that of luminance VEPs,
being steeper (129 ms versus 109 ms apparent latency).
Overall, significant amplitude reduction (inset in Fig. 7A)
occurs both in the fellow eyes [-21%: two-way ANOVA:
F( 1,217) = 5.4, /><0.05] and optic neuritis eyes [-34%:
730
V. Porciatti et al.
Luminance VEP
B
Controls: 109 ms
Fellow eyes: 110 ms
ON eyes: 109 ms
0
5
10
15
20
25
0
30
Temporal frequency (Hz)
5
10
15
20
25
30
Temporal frequency (Hz)
Fig. 6 Average second harmonic amplitude (A) and phase (B) of the steady-state VEPs to yellow-black
luminance gratings for control, fellow and optic neuritis (ON) eyes of subjects. In both fellow and optic
neuritis eyes, the VEP amplitude and phase slopes as a function of temporal frequency are not
significantly different from those of control eyes. Error bars represent the SEM.
Colour VEP
B
>
2 +2
Controls: 129 ms
Fellow eyes: 170 ms
ON eyes: 173 ms
-16
5
10
Temporal frequency (Hz)
5
10
15
Temporal frequency (Hz)
Fig. 7 Variation with temporal frequency of the average second harmonic amplitude (A) and phase (B)
of the steady-state VEPs to equiluminant red-green gratings for control, fellow and optic neuritis (ON)
eyes of subjects. In both optic neuritis and fellow eyes the amplitude is reduced and the phase slope is
steeper compared with control eyes. Error bars represent the SEM.
two-way ANOVA: F(l,217) = 14.4, P< 0.001]. However,
the interaction between eye group and temporal frequency
was not significant for either eye group. Figure 7B shows
that in optic neuritis eyes there is a marked increase in the
steepness of the phase plot compared with controls [twoway ANOVA, interaction effect eye by temporal frequency:
F(9,239) = 3.14, P < 0.001], corresponding to a delay of 44
ms. A delay of -40 ms can also be observed in the fellow
eyes [two-way ANOVA, interaction effect eye by temporal
frequency: F( 1,239) = 2.65, P < 0.001]. Comparable delays
in apparent latency were also found by evaluating phase
slopes of individual patients (see Fig. 10).
Electrophysiology: transient responses
Transient PERGs of all subjects are summarized in Fig. 8.
The left-hand panels show the waveforms of the luminance
PERG and the right-hand panels those of the colour PERG.
The bold line waveforms represent the grand mean of
individual subjects (dotted waveforms). It is readily apparent
that, in control subjects, the colour PERG has a waveform
comparable to that of the luminance PERG. However, it
is slightly smaller in amplitude (-16% on average) and
significantly delayed in the latency of the positive peak (P80
versus Pgg). A similar delay is also found in the steadystate responses (see above) and corresponds to previously
Chromatic PERG and VEPs in optic neuritis
PERG
VEP
Luminance
Luminance
Colour
3> Controls
0
0
50 100 150 200 250 300
731
6 -
A
4 -
B
2 0 -2 •
--^
••••: f ^ " V V - - - ! Controls
-4 -6 -8 -
0
50 100 150 200 250 300
Colour
10
8
6
4
2
0
-2
-4
-6
0
50 100 150 200 250 300
50 100 150 200 250 300
10
Fellow
eyes
Fellow
eyes
0
0
50 100 150 200 250 300
0
50 100 150 200 250 300
50 100 150 200 250 300
0
50 100 150 200 250 300
0
50 100 150 200 250 300
10
F
2 1 0 -
ON
eyes
-1 -2 -3 -4 -
0
50 100 150 200 250 300
0
,,
50 100 150 200 250 300
Time (ms)
Fig. 8 Transient PERGs in response to either yellow-black
luminance gratings (A, C and E) or red-green equiluminant
gratings (B, D and F) recorded in control eyes (A and B), fellow
eyes (C and D) or optic neuritis (ON) eyes (E and F). Individual
waveforms are presented by dotted lines. For each panel, the bold
line represent the grand mean. Note that the chromatic, but not
luminance PERG is reduced in optic neuritis. Amplitude reduction
is more evident for the slow, negative component.
published data for human (Arden and Vaegan, 1983; Korth
and Rix, 1988; Berninger et al., 1989; Morrone et al., 1994a)
and non-human primates (Morrone et al., 1994b; Porciatti
et al., 1994). On average, the peak-to-trough amplitude of
the transient colour PERG is markedly reduced in patients
(-61% in optic neuritis eyes, Fig. 8F; -36% in the fellow
eyes, Fig. 8D). If the positive and negative components are
evaluated independently, then it appears that the latter is
much more reduced than the former (-90% versus -20% in
optic neuritis eyes and -46% versus -20% in the fellow
eyes). By contrast, the peak-to-trough amplitude of the
luminance PERG is slightly reduced or not reduced at all in
patients (-12% in optic neuritis eyes: Fig. 8E and - 9 % in
the fellow eyes: Fig. 8C). Differences between luminance
and colour PERGs were also evaluated from amplitude and
latencies values of individual waveforms (see Fig. 10).
Figure 9 displays VEPs recorded simultaneously with
PERGs presented in Fig. 8. In control subjects, the waveform
of VEPs to yellow-black gratings (Fig. 9A) consists mainly
0
50 100 150 200 250 300
Time (ms)
Fig. 9 Transient VEPs in response to either yellow-black
luminance gratings (A, C and E) or red-green equiluminant
gratings (B, D and F) recorded in control eyes (A and B), fellow
eyes (C and D) or optic neuritis (ON) eyes (E and F). Individual
waveforms are represented by dotted lines. For each panel, the
bold line represent the grand mean.
of a broad positive peak with an average latency of -120 ms.
The time to peak of this positive wave and the amplitude
from the preceding negativity were taken as representative
of latency and amplitude values of individual responses. The
average colour VEP (Fig. 9B) displays a positive-negative
complex. However, the positive peak is less consistent among
subjects and the most reliable wave is a negative one peaking
at 170 ms on average. This agrees with previous reports
showing that the VEPs to red-green chromatic contrast
consists mainly of a late negative wave (Murray et al., 1987;
Berninger et al., 1989; Fiorentini et al., 1991, 1996). The
time to peak of this negative wave and the amplitude from
the preceding positivity were taken as representative of
latency and amplitude values of individual responses. In
patients, luminance (Fig. 9C and E) and colour (Fig. 9D and
F) transient VEPs are altered, showing both delay in latency
and reduction in amplitude. Alterations are marked in optic
neuritis eyes but are also meaningful in the fellow eyes. In
addition, alterations appear of different extent in the
luminance and chromatic VEPs. Due to the strong latency
jitter in patients, the grand mean waveform is not
732
V. Porciatti et al.
PERG
VEP
12 -
gO
8 -
4 -
B
o _
*°%M
«
o
A
Transient
•<^A
% \
'
' iA
- - --0 A
0 40
60
80
100
50
Peak latency (ms)
O •
OAA A ;
o
0.2 -
2
o
I
^
300
D
*
J.
2 -
i[
°~/ - ^ «*-
Steady
state
V
1 _~]^^n
A
0.0 -
40
250
3 -
c
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200
a)
^t :
|
150
Peak latency (ms)
c
A
0.6 -
100
••
A
A
jA
^
a*
-
0 60
80
100
Apparent latency (ms)
50
100
150
200
250
300
Apparent latency (ms)
Fig. 10 Amplitude versus latency scatterplots of transient and steady-state PERGs and VEPs measured
in individual eyes of patients (circles, fellow eyes; triangles, optic neuritis eyes) for either yellow-black
luminance gratings (open symbols) or red-green equiluminant gratings (filled symbols). For transient
responses (A and B), the peak latency and the peak-to-through amplitude refer to data evaluated from
the representative response component (see Results for details). For steady-state responses (C and D),
the average second harmonic amplitudes and apparent latencies refer to data evaluated from the whole
range of temporal frequencies tested (see Results for details). Dotted and long-dashed lines represent the
limits of the normal range.
representative of the group mean and it is difficult to judge
overall losses from that. More precise evaluation of VEP
changes in disease can be obtained from the measurement
of individual responses shown below.
In Fig. 10 are summarized individual PERG and VEP data
obtained from both transient (upper panels) and steadystate responses (lower panels) as amplitude versus latency
scatterplots. For transient responses, data represent the
amplitude and peak latency of the main component (see
above). For steady-state responses the amplitude data
represent the second harmonic averaged across temporal
frequency, whereas apparent latency represent data which
have been evaluated from the slope of the phase lag with
temporal frequency. Dotted and dashed lines indicate the
confidence limits of the normal range for responses to
luminance and colour, respectively. Luminance and colour
VEPs are altered differently in patients, the highest number
of abnormal responses being found in the responses to colour.
In particular, in optic neuritis eyes, nine out of 14 steadystate and nine out of 14 transient colour VEPs display values
beyond the normal range, whereas luminance VEPs do in
six out of 14 steady-state and four out of 14 transient
responses. Luminance and colour VEPs of fellow eyes also
are altered differently (steady-state: colour eight out of 14,
luminance two out of 14; transient: colour five out of 14,
luminance two out of 14). Steady-state colour VEPs,
compared with transient ones, display larger latency delays
and, remarkably, a comparable number of alterations in optic
neuritis eyes and fellow eyes.
In the PERG, luminance and colour responses also display
a different number of abnormal values. In optic neuritis eyes,
six out of 14 steady-state and nine out of 14 transient colour
PERGs fall beyond the normal range, whereas luminance
PERGs do in four out of 14 steady-state and four out of 14
transient responses. PERGs of some fellow eyes also are
altered (steady-state: colour five out of 14, luminance three
out of 14; transient: colour four out of 14, luminance three
out of 14). It is worth noting that latency abnormalities are
more frequent in the colour PERG than in the luminance
PERG.
Retinal versus post-retinal defects
It is interesting to establish the retinal contribution to the
visual impairment. Evaluating differences between PERG
and VEPs, however, may yield ambiguous estimates under
Chromatic PERG and VEPs in optic neuritis
150 -
A
100 -
°§ /
Controls
o'
o
50 -
.••co
CO
0 -
-1—1—1—1—I—1—1—1—1—1—1—1—[—
50
0
o
I
150 -
58?
100 -
o
-
o
oo
o
o
V
o
c
.•••
Fellow eyes
o
-
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150
8
B
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o
100
o ?•
50 -
co'
;
•••'
o
o150 -
100 -
ON eyes
733
responses and therefore provides a means to normalize
amplitude and latency evaluation. In particular, the different
slope of the phase lag with temporal frequency between the
PERG and VEPs yields a meaningful estimate of the retinocortical apparent latency (RCAL). This measure includes a
pure transmission delay and the cortical temporal integration
(see Discussion).
Figure 11 summarizes RCALs obtained from individual
control subjects and patients. Data for luminance contrast
are plotted against corresponding data for colour contrast
stimuli. Overall, there is little correlation between RCAL for
luminance and that for colour. In control subjects (Fig. 11 A),
the average RCALs for luminance and colour do not differ
significantly (47.6 versus 56.0 ms, respectively: / test, P =
n.s.). In the fellow eyes (Fig. 11B), compared with control
eyes, there is an marked increase in the average RCAL for
colour (90.4 ms: t test, P < 0.05) but not for luminance
(52.4 ms). In optic neuritis eyes (Fig. 11C), data show a
considerable scatter. Interestingly, the average RCALs for
either luminance or colour (54.6 and 55.2 ms, respectively)
do not significantly differ (t test) from control values. In
particular, the RCAL for colour in optic neuritis eyes is
smaller than that for the fellow eyes. This may be in part
due to the fact that PERG, in addition to VEPs, is delayed in
optic neuritis eyes (see Fig. 10), resulting in a smaller RCAL.
50 -
Discussion
100
150
Luminance
retino-cortical apparent latency (ms)
Fig. 11 Summary of retino-cortical (VEP minus PERG) apparent
latencies (RCALs) for control eyes (A), fellow eyes (B) and optic
neuritis (ON) eyes (C). Retino-cortical apparent latencies for
yellow-black luminance gratings are plotted against corresponding
values for red-green equiluminant gratings. Note the specific
increase of the RCAL for colour stimuli in most of fellow eyes
and some of optic neuritis eyes.
many circumstances. It is known that VEP amplitude saturates
at low contrast, whereas that of the PERG does not. This is
true for both luminance contrast and colour contrast
(Fiorentini et al., 1991; Morrone et al., 1993; Morrone et al.,
1994a, b). As to latency, there are reports on the so called
retino-cortical time for luminance contrast stimuli (e.g.
Celesia and Kaufman, 1985), obtained by subtracting the
peak latency of the major transient PERG component (P50)
from that of the major VEP component (Pioo)- The implicit
assumption for this measure is that the PERG P50 and the
VEP Pioo bear comparable physiological significance. This
may be difficult to demonstrate, especially when the
waveform of transient responses differs not only between
PERG and VEPs, but also between luminance and colour.
A less ambiguous comparison may be offered by the
analysis of steady-state responses. Indeed, the steady-state
second harmonic is the principal component of all kind of
The PERG and VEPs in response to chromatic, equiluminant
gratings have only recently been reliably recorded in human
and non-human primates. The spatial and temporal properties
of these responses differ from corresponding properties of
the PERG and VEPs to luminance contrast, in such a way
as to suggest that these responses reflect distinct contribution
of parvocellular and magnocellular generators at retinal and
cortical level. Pattern electroretinograms and VEPs to either
pure chromatic contrast or pure luminance contrast have been
recorded in subjects with unilateral optic neuritis, in order to
establish possible evidence of selective impairment of the
parvocellular pathway, known to subserve colour vision.
Indeed, it is a classical notion that colour vision may be
altered in optic neuritis.
Contrast sensitivity for red-green gratings
An essential step to obtain stimuli of pure chromatic contrast
is to evaluate the equiluminant point. This procedure is
necessary for each eye of every subject since it is known
that there are individual differences (Mullen, 1985; Fiorentini
et al., 1996) and, in addition, optic neuritis may cause an
acquired dyschromatopsia (Zrenner, 1983), resulting in a
pathological shift in the equiluminant point. In this study
the equiluminant point has been established by evaluating
psychophysically the minimum sensitivity as a function of
red/(red+green) colour ratio for gratings alternating at 5 Hz.
A measure of this kind also yields estimates of the CS to
734
V. Porciatti et al.
luminance contrast (average of red-black and green-black),
allowing a comparison between sensitivity to chromatic and
luminance contrast. As shown by our results, optic neuritis
eyes display a marked loss of CS (~10 dB on average) for
both colour and luminance. A smaller loss is also evident in
the fellow eyes (~5 dB on average). The equiluminant point
is comparable between optic neuritis and fellow eyes and
does not differ substantially from that of control subjects, in
keeping with Travis and Thompson (1989). Overall, results
obtained by measuring CS indicate unspecific losses, in
agreement with some previous reports (Alvarez and KingSmith, 1984; Fosters al., 1985, 1986; Travis and Thompson,
1989; Dain et al., 1990; Russell et al., 1991) but see Alvarez
et al. (1982) for greater luminance loss, and Fallowfield and
Kraupskopf (1984) and Mullen and Plant (1986) for greater
colour loss. On the other hand, comparable loss of sensitivity
for colour and luminance does not necessarily mean unspecific
damage of the parvocellular and magnocellular pathway.
The parvocellular pathway may mediate both luminance
and chromatic sensitivity. Indeed, selective lesions of the
parvocellular layers of the lateral geniculate body in the
monkey have been reported to induce severe losses of both
luminance and chromatic CS (Schiller et al., 1990; Merigan
et al., 1991). By contrast, selective lesion of the magnocellular
layer did cause loss of luminance CS and no change in
chromatic sensitivity.
Electrophysiology: steady-state PERG and VEPs
In this study we used a low spatial frequency (0.3 cycles
deg"1) for both colour and luminance stimuli in order to
favour responses of generators with parvocellular-like or
magnocellular-like characteristics, respectively. They had a
very large area (53X49°) to include several stimulus cycles.
It is known that red-green opponent parvocellular cells
respond well to chromatic patterns of low spatial frequency,
whereas magnocellular cells respond only weakly at
equiluminance. On the other hand, parvocellular cells respond
less well than magnocellular cells to a low spatial frequency
stimulus modulated in luminance contrast (Derrington et al.,
1984; Kaplan and Shapley, 1986; Tootell et al., 1988a, b).
Indeed, the spatial-temporal properties of the PERG and
VEP for red-green equiluminant stimuli are reported to
differ markedly from corresponding properties for luminance
contrast stimuli. Evidence suggested that the chromatic
responses are driven predominantly by parvocellular cells,
whereas both parvocellular and magnocellular cells may
contribute with different weight to the luminance responses
(Murray et al., 1987; Korth and Rix, 1988; Berninger et al.,
1989; Fiorentini et al., 1991; Bach and Ceding, 1992; Korth
and Horn, 1992; Thompson and Drasdo, 1992; Crognale
et al., 1993; Korth et al., 1993; Morrone et al., 1993, 1994a,
b; Porciatti et al., 1994; Rabin et al., 1994: Girard and
Morrone, 1995). However, it is difficult to predict the relative
weight with which parvocellular and magnocellular cells
contribute to the responses to luminance contrast. Certainly
a major factor is the size of the population of parvocellular
and magnocellular generators. This is reported to be -80%
and -10%, respectively, at the retina (Leventhal et al., 1981;
Perry et al., 1984; Schein and De Monasterio, 1987) but it
is probably different at cortical level due to divergence
(Connolly and Van Essen, 1984; Livingstone and Hubel,
1988; Malpeli et al., 1993). A second factor is the ability to
respond to the spatial-temporal characteristics of the stimulus
(Creutzfeld et al., 1979; Benardete and Kaplan, 1993).
Another important weighting variable is represented by the
non-linear characteristics of the response generators. Indeed,
the PERG and VEPs to contrast reversal are non-linear
responses (containing even harmonics only because of the
spatial-temporal symmetry of the stimulus which results in
cancellation of odd harmonics). Most of the magnocellular
cells respond at twice the frequency of stimulus modulation,
and could therefore contribute to the second harmonic of the
PERG and VEP (Kaplan and Shapley, 1982; Kaplan et al.,
1990). Parvocellular cells respond mainly to the first harmonic
of the stimulus and are linear in many respects. However,
the response to counterphase modulation also contains a
significant second-harmonic component [resulting from
rectification and temporal asymmetries (Kremers etai, 1993)]
and this may also contribute to the second harmonic of the
PERG and VEP.
Results obtained by recording the steady-state PERG to
luminance and colour stimuli in control subjects basically
confirm previous results (Porciatti et al., 1992, 1994; Morrone
et al., 1994a, b). In particular, the luminance PERG, compared
with the chromatic PERG, is recordable over a longer range
of temporal frequencies (2-24 Hz versus 2-12 Hz) and has
a shorter apparent latency (56 ms versus 80 ms on average).
In addition, the form of the temporal function of the luminance
PERG has two clear peaks, suggesting that the stimulus
drives more than one temporal channel (Porciatti et al., 1992;
Padovano et al., 1995).
Overall, both luminance and chromatic steady-state PERGs
are diminished in amplitude in optic neuritis. Losses of
smaller entity are also evident in the fellow eyes. Data
on luminance contrast PERG confirm previous findings of
amplitude reduction of the steady-state PERG in optic neuritis
(Bobak et al., 1983; Porciatti and Von Berger, 1984; Plant
et al., 1986; Falsini et al., 1992a, b; for review, see Van
Houvelingen, 1993) and extend them to the whole range of
temporal frequencies at which the PERG is recordable.
Amplitude decrease of the chromatic, steady-state PERG in
optic neuritis is a novel finding and indicates damage of
generators driven by stimuli of pure chromatic contrast. This
implies an impairment of the red-green parvocellular ganglion
cells, which have been hypothesized to represent the major
source of the chromatic PERG (e.g. Korth and Rix, 1988;
Morrone et al., 1994a, b).
In control subjects, the form of the temporal function of
VEPs to luminance contrast is qualitatively similar to that of
the simultaneously recorded PERG, in agreement with
previous reports (Porciatti etal., 1992; Morrone etal., 1994a,
Chromatic PERG and VEPs in optic neuritis
b). The VEP apparent latency evaluated from the slope of
the phase spectrum is ~ 109 ms, which is ~50 ms longer than
the PERG apparent latency. Visual evoked potentials to
luminance contrast stimuli recorded in optic neuritis eyes are
little reduced in amplitude and unaltered in apparent latency.
No significant change in either amplitude or phase is apparent
in the VEPs of fellow eyes. These data indicate that a
stimulus designed to favour activity of the magnocellular
stream in the visual pathway is little affected in multiple
sclerosis. We cannot exclude, however, some understimation
of amplitude loss in patients, since the high contrast stimuli
we used probably saturated the VEP responses.
The temporal frequency function of VEPs in response to
red-green gratings of pure chromatic contrast tends to be
low-pass, rather than band-pass (Fiorentini et al., 1991,
1996). In control subjects, the apparent latency of chromatic
VEPs is 129 ms, which is ~50 ms longer than that of the
simultaneously recorded PERG. Contrary to luminance VEPs,
colour VEPs are markedly altered in multiple sclerosis. On
average, the VEP amplitude is about halved and the
apparent latency is much prolonged both in optic neuritis
eyes (~44 ms) and fellow eyes (~41 ms). These data indicate
that the chromatic stimulus, designed to favour activity of
the parvocellular stream in the visual pathway, is primarily
affected in multiple sclerosis. In addition, alteration of VEPs
of fellow eyes suggests remarkable subclinical damage of
the contralateral visual pathway.
Electrophysiology: transient PERG and VEPs
Transient PERG and VEPs to abrupt reversal of the stimulus
contrast are more conventional electrophysiological measures
than steady-state responses. In this study, transient PERGs
and VEPs to luminance and chromatic contrast have also
been recorded in order to (i) have independent estimates of
amplitude and latency, (ii) compare transient to steady-state
responses, and (iii) compare present data with those available
in the literature.
In agreement with previous reports (Arden and Vaegan,
1983; Korth and Rix, 1988; Morrone et al., 1994a, b), the
waveform of the transient, chromatic PERG is basically
similar to that of the luminance PERG, the obvious difference
being an overall delay of the order of 20 ms. Morrone et al.
(1994a, b), showed that the longer latency of the chromatic
PERG does not depend on the lower effective contrast of the
isoluminant stimulus compared with the luminance stimulus
(the effective contrast for red-green equiluminant stimuli is
about one-quarter that for luminance stimuli, because of the
largely overlapping spectra of red and green cones; Merigan,
1989). The peak latencies of the positive waves of the
equiluminant and luminance PERG (P80 and P^, respectively)
are in a very good agreement with apparent latencies obtained
from the slopes of the phase versus temporal frequency plots.
In optic neuritis, on average, the chromatic PERG is markedly
reduced in amplitude, whereas the luminance PERG is
virtually unchanged. Significant reduction of the chromatic
735
PERG also occurs in the fellow eyes. It is interesting that
amplitude reduction occurs almost exclusively in the negative
component peaking between 120 and 150 ms. This finding
supports the belief of selective vulnerability of the PERG
negative afterpotential in inner retina dysfunction. Indeed,
selective reduction of the negative component (N95) of the
transient PERG in optic neuritis has been previously reported
for luminance stimuli (gratings, checkerboards) whose spatial
frequency spectrum included spatial frequencies higher than
that used in this study (Porciatti and Von Berger, 1984; Ryan
and Arden, 1988; Berningerand Heider, 1990; Holder, 1991;
Froehlich and Kaufman, 1993). Taken together, these results
suggest that (i) the positive component of the transient PERG
to either luminance or colour contrast arises from generators,
at least in part, different from those of the negative component,
(ii) the high vulnerability in optic nerve disease of the
negative afterpotential of the transient PERG in response to
stimuli of either colour contrast, or luminance contrast
containing high spatial frequencies, suggests proximal retinal
generators for this component, and (iii) the relative
contribution of parvocellular-like and magnocellular-like
generators to the luminance PERG may depend on the spatial
frequency content of the stimulus. Indeed, the luminance
PERG to high spatial frequency, compared with that to low
spatial frequency, is reported to be slower and more sustained,
indicating relatively larger contribution of parvocellular-like
generators (Padovano et al., 1995)
The properties of transient VEPs to luminance stimuli are
well known both in control subjects and in patients with
multiple sclerosis (e.g. Regan, 1989). In control subjects, the
major component of VEPs to horizontal yellow-black gratings
of 0.3 cycles deg"1 is a broad positivity peaking at -120 ms.
This value is in the range of the apparent latency (109 ms)
evaluated from the slope of the phase versus temporal
frequency plot of steady-state VEPs. A fairly good agreement
between the peak latency of the major positive peak of
transient VEPs and apparent latency of steady-state VEPs is
a consistent finding for luminance contrast stimuli (Duwaer
and Spekreijse, 1978; Riemslag et al., 1982; Porciatti, 1984;
Simon, 1992). The waveform of the chromatic, transient
VEPs consists of a positive-negative complex. However, the
most reliable component is a negative wave peaking at ~ 170
ms on average. Previous data have been reported, which
show that the colour specific component of the chromatic
VEPs to either contrast reversal or contrast onset is a late
negative wave (Murray et al., 1987; Berninger et al., 1989;
Fiorentini et al., 1991, 1996; Rabin et al., 1994). A positive
component is reported to be consistently present in transient
reversal VEPs to red-green equiluminant stimuli of low
spatial frequency (Murray et al., 1987; Berninger et al.,
1989) and possibly it may be related, in part, to luminance
contribution to the response. Indeed, we cannot exclude that
the use of a large stimulus area might have emphasized
inhomogeneities in local ratios among different cone populations and macular pigmentation (Marc and Sperling, 1977;
Stabell and Stabell, 1980; De Monasterio et al., 1985) as
736
V. Porciatti et al.
well as naso-temporal asymmetries (Silveira and Perry, 1991;
Lima et al., 1993), resulting in some departure from equiluminance. A small contribution of luminance contrast in
the stimulus may be sufficient to drive magnocellular-like
generators, able to respond to stimuli of low contrast and high
temporal frequencies (the square-wave temporal modulation
used for transient responses has a large temporal frequency
spectrum, including high frequencies). This is not the case
for the sinusoidal reversal used for steady-state responses. It
is possible therefore that transient and steady-state chromatic
VEPs reflect different contribution of parvocellular-like and
magnocellular-like generators, making the comparison
between the two responses difficult. Consequently, some
difference between the peak latency of the negative
component (170 ms) of transient response and the apparent
latency (129 ms) of steady-state response may be expected.
When the chromatic stimulus is designed to limit the
contribution of magnocellular-like generators (e.g. by using
a higher spatial frequency and a smaller stimulus area),
then the VEP waveform consists mainly of a late negative
component (Murray et al., 1987; Berninger et al., 1989;
Fiorentini et al., 1991). In addition, the peak latency of
transient VEPs and the apparent latency of steady-state
responses are in closer agreement (Fiorentini et al., 1991,
1996).
In optic neuritis, both luminance and chromatic transient
VEPs are altered, although to a different extent. Luminance
responses are abnormal in latency, whereas chromatic
responses may be abnormal both in amplitude and latency.
Transient colour VEPs display values beyond the normal
range of amplitude and/or latency in nine out of 14 eyes,
whereas luminance VEPs do so in four out of 14 transient
responses. Alterations are marked in optic neuritis eyes but
are also meaningful in the fellow eyes (colour five out of
14, luminance two out of 14 eyes). Alteration of transient
VEPs to luminance contrast is s a well-established notion
(Halliday et al., 1972; for reviews, see Hess and Plant, 1986;
Van Houwelingen, 1993) and discussion on this aspect is
plethoric. It may be of some interest to note that the proportion
of abnormal responses is somehow smaller than that reported
for VEPs in response to the more conventional checkerboard
stimuli in multiple sclerosis (Sanders et al., 1986, 1987). As
discussed above, this may be due to the larger spatial
frequency spectrum of the checkerboard stimulus, compared
with that of a 0.3 cycles deg~' grating. Parvocellular-like
generators are expected to be better driven by a luminance
stimulus containing high spatial frequencies. In keeping with
this rationale, VEP abnormalities are more frequent and
profound for equiluminant stimuli, more specific for the
parvocellular pathway.
In optic neuritis, the proportion of chromatic VEP
abnormalities is similar for transient and steady-state
responses. However, steady-state colour VEPs, compared
with transient ones, display larger latency differences from
control values. This difference between transient and steadystate colour VEPs is more marked in the fellow eyes, the
latter showing both a higher number of alterations and larger
latency differences from control values. For the reasons
expressed above, it is possible that steady-state VEPs,
obtained in response to a spectrum of temporal frequencies
narrower than that contained in the stimulus for transient
VEPs, reflect less contribution of the magnocellular-like
generators. This would again suggest selective vulnerability
of the parvocellular stream of the visual pathway in multiple
sclerosis.
Retinal versus post-retinal defect
Steady-state responses provide a means to compare the RCAL
(difference in apparent latency between PERG and VEPs)
between luminance contrast and chromatic contrast responses.
Previous measures of the so-called retino-cortical time were
obtained by subtracting the peak latency of the PERG P50
component from that of the VEP P, oo component (Celesia
and Kaufman, 1985). This approach could not be used in the
present study since there are differences in response waveform
between luminance and colour. The comparison between
RCALs for luminance stimuli and RCALs for chromatic
stimuli yields three main findings: (i) in control subjects, the
average RCAL for colour is comparable with, albeit not
correlated to, that for luminance; (ii) in the fellow eyes of
patients, there is a marked increase in the RCAL, which is
virtually selective for colour; (iii) in optic neuritis eyes, data
are greatly scattered. In some eyes, the RCAL increases for
both luminance and colour, although increases for colour are
larger. Interestingly, the average increase in RCAL for colour
is somewhat smaller in optic neuritis eyes, compared with
fellow eyes. This is probably due to the fact that in optic
neuritis eyes the PERG apparent latency is often increased,
thereby reducing the RCAL.
The fact that the RCAL for colour and, to a much smaller
extent, the RCAL for luminance, is much prolonged in both
eyes of patients with unilateral optic neuritis, indicates
specific dysfunction of the post-retinal pathway subserving
chromatic vision in multiple sclerosis. Post-retinal delay may
be of remarkable amount and is present in both the pathway
ipsilateral and contrateral to the clinically affected eye. This
suggests that mechanisms responsible for VEP delay cannot
be explained entirely on the basis of optic nerve lesions.
Mechanisms underlying VEP delay
Delayed VEPs in patients affected by optic neuritis have
been traditionally considered evidence of impaired focal
conduction through demyelinating areas (Halliday et al.,
1972; Halliday and McDonald, 1977), by association with
the experimental model of demyelination in the peripheral
nerve (McDonald, 1977). Severe demyelinating processes
usually lead to a total failure of conduction (known as
conduction block), while less severe stages of the disease
usually allow transmission of impulses, even if conduction
velocity is decreased. In these latter cases an increase of
Chromatic PERG and VEPs in optic neuritis
refractoriness on nerve fibre after every single impulse is
also responsible for inability to transmit faster train of
impulses. The clinical consequence of such a prolonged
refractory state is well known for some focal demyelinating
lesions (e.g. those involving the pyramidal tracts), where it
may result in evident paresis. Despite these generally accepted
hypothesis, the pathophysiology of delayed VEPs in multiple
sclerosis is not yet fully understood. Rather, a considerable
body of evidence indicates that demyelination, even if it may
represent a major mechanisms of sensory delay, cannot
adequately account for all VEP changes in optic neuritis and
multiple sclerosis (e.g. Youl et ai, 1991; for review, see Hess
and Plant, 1986). On the basis of original calculations by
McDonald (1977) that a 25 ms delay in CNS fibres must be
related to 1 cm wide demyelinated area, it is difficult to
account for delays as long as to 100 ms often seen in optic
neuritis in the course of multiple sclerosis. Moreover, VEP
delays which depend on stimulus parameters (e.g. mean
luminance, spatial and temporal frequency; Regan et al.,
1980) are not readily explainable by reduced conduction
velocity alone. In addition, orientation dependent
abnormalities (Regan et al., 1980; Camisa et al., 1981)
suggest specific cortical mechanisms of visual impairment.
Additional mechanisms of VEP delay may be related to
possible changes in the synaptic connections secondary
to demyelinating processes and axon loss, or to specific
neurotransmitter deficiency, as pointed out for other diseases
(Bodis-Wollner and Onofrj, 1982),
Further points are raised by the finding of remarkable VEP
delay to stimulation of fellow eyes in clinically monolateral
optic neuritis. Bilaterally delayed responses in monolateral
optic neuritis could be explained by assuming chiasmatic
and/or post-chiasmatic lesions (e.g. Sartucci et al., 1989).
This is a rare event, however, and the only unequivocal
lesion (as determined by MRI) of the visual pathway in our
patient group appeared to be at the level of the optic nerve,
in agreement with Miller (1986) and Ormerod et al. (1987).
Whatever the mechanisms of VEP delay, retinal and cortical
responses to chromatic stimuli appear far more altered, than
the corresponding responses to luminance stimuli.
737
reasonable hypothesis is that parvocellular axons, due to their
smaller diameter and less myelinated sheath, are paticularly
susceptible to demyelination. Small axons of the optic nerve
may indeed be more affected than large axons in experimental
demyelination in mice (Ikeda and Tansey, 1986).
Histopathological evaluation of the visual pathway in multiple
sclerosis has revealed rarefaction of ganglion cells in the
macular region, suggesting involvement of smaller axons
(Toussaint et al., 1983). In the optic tract of primates,
small and large axons, corresponding to parvocellular and
magnocellular ganglion cells, respectively, are largely
segregated (Reese and Cowey, 1988). Selective, subclinical
lesions at this level may well be possible in multiple sclerosis,
resulting in impairment of responses of both eyes. If the
hypothesis of high vulnerability of small axons in multiple
sclerosis is proved to be correct, then a stimulus specific for
the parvocellular stream of the visual pathway should
represent a useful tool for the diagnosis and follow-up in
multiple sclerosis.
Acknowledgements
We wish to thank Professor David C. Burr for generously
providing the stimulus software and Mr Carlo Orsini for
continuous assistance.
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Received August 2, 1995. Revised January 5, 1996.
Accepted February 6, 1996