- Email: [email protected]
Mechanisms of rod-cone interaction: Evidence from congenital stationary nightblindness
Vision Res. Vol. 28, No. 5, pp. 57%5R3, 1988 Printed in Great Bntain. All rights reserved
004X989/88
$3.00 + 0.00
CopyrightQ 1988PergamonPressplc
MECHANISMS OF ROD-CONE INTERACTION: EVIDENCE FROM CONGENITAL STATIONARY NIGHTBLINDNESS KENNETHR. ALEXANDER,GERALDA. FISHMANand DEBORAHJ. DERLACKI Department of Ophthalmology, University of Illinois College of Medicine at Chicago, 1855 W. Taylor St, Chicago, IL 60612, U.S.A. (Received 23 July 1987; in revisedform 27 October 1987)
‘Abstract-The dark-adapted rod system can elevate cone-mediated thresholds for flicker detection as well as thresholds for the detection of hue. We examined these two types of rod-cone interactions in two individuals with congenital stationary nightblindness (CSNB), a retinal disorder in which rod outer segment function is intact, but in which a defect occurs in the transmission of rod signals within the retina. The two types of rod-cone interaction were differentially affected by the retinal pathology; the rod-cone flicker interaction was normal, but the rodcone hue interaction was absent. These results provide evidence that, despite similarities in the adaptational properties of these two types of rod-cone interaction, they are mediated by different visual mechanisms, Cones
Rods
Flicker
Color
Nightblindness
INTRODUCTION Recent experiments have shown that the darkadapted rod system can elevate the threshold for the detection of flicker by the cone system {e.g. Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). When the rod system is light-adapted or bleached, the cone flicker threshold in the parafoveal retina is reduced by as much as one log unit from its dark-adapted value. Similarly, under darkadapted conditions, the rod system can elevate the threshold for the detection of the hue of a chromatic stimulus (e.g. Lie, 1963; Spillmann and Conlon, 1972; Stabell and Stabell, 1976; Prestrude et al., 1978; Peachey et al., 1987). As with flicker detection, light adaptation or bleaching of the rod system lowers the hue threshold in the parafoveal retina by approximately one log unit from the dark-adapted value. Despite the apparent similarity in the adaptational properties of these two types of rodcone interactions, it has been proposed that different visual mechanisms underlie them. The rod-cone flicker interaction is thought to result from a sustained lateral inhibition between dark-adapted unstimulated rods and stimulated cones (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). In contrast, the rodxone hue interaction appar-
ently occurs between rod and cone signals that are generated directly in response to a flashed test stimulus (Lie, 1963; Spillmann and Conlon, 1972; Stabell and Stabeli, 1976). One way to determine whether different mechanisms underlie the two types of rod-cone interactions is to compare the two phenomena in individuals with circumscribed disorders of the visual system (cf. Enoch et al., 1981). If the two types of interactions are affected differently by the pathology, then different visual mechanisms must underlie them. To investigate this question, we examined the rod-cone flicker and hue interactions in two individuals with congenital stationary nightblindness (CSNB). Evidence indicates that there is a defect in the transmission of rod signals from photoreceptors to secondorder neurons in this condition (Ripps, 1982). For example, the rod photopigment has a normal concentration and normal bleaching kinetics (Carr et al., 1966), and the rod a-wave amplitude of the el~troretinogram (ERG) is normal (Young et af., f986), but the rod b-wave amplitude is considerably reduced, and darkadapted rod thresholds are elevated substantially (e.g. Miyake et al., 1986). In a previous study of the rod-cone flicker interaction in individuals with retinal disorders (Alexander and Fishman, 1985), we observed that the interaction was normal in a person with CSNB, despite a substantial loss of rod system 575
576
KENNETH
R.
ALEXANDER rt ~1.
sensitivity, We now report a similar finding in a second person with this condition. We have also examined the rod-cone hue interaction in these same two individuals. We have found that, whereas the rod-one flicker interaction was normal in both observers, the rod-cone hue interaction was absent. These results support the hypothesis that the two types of rod-cone interactions are mediated by different visual processes. METHOD
Subjects
CSNB subject I was a 15-year-old male with a Snelien visual acuity of 20/40 and a refractive error of - 13.00 + 3.00 x 180 in the tested (left) eye. His fundus was light-colored with a prominent choroidal pattern, consistent with high myopia. CSNB subject 2 was a 38-year-old male with a Snellen visual acuity of 20130 and a refractive error of - 14.75 + 3.00 x 135 in the tested (right) eye. His fundus showed peripapillary atrophy and other changes consistent with high myopia. CSNB subject I was the only known affected family member. CSNB subject 2 had a maternal male cousin who was similarly affected, suggesting an X-linked recessive inheritance. A total of 20 visually normal individuals (age range, 2042 years) provided control data for the psychophysical expe~ments. Three were experienced subjects; the others were experimentally naive. Twenty-one normal subjects provided normative data for the ERG measurements. Apparatus and ~rQce~ure
Testing was carried out with a Tiibinger perimeter. Three types of thresholds were measured: dark-adapted flash thresholds, flicker thresholds, and hue thresholds. In all cases, the test stimulus diameter was 1.7”. Dark-adapted gash thresholds were obtained for both a middle-waveiength test stimulus (Schott interference filter type IL, 3+,,, = 500 nm) and a long-wavelength test stimulus (Oculus bandpass filter, cut-on 11= 620 nm for subject 1; Schott interference filter type IL, &a = 655 nm for subject 2) to determine whether rods or cones mediated the dark-adapted threshold at each eccentricity (cf. Massof and Finkelstein, 1981). The test stimulus duration was 500 msec. For flicker detection, the test stimulus was a white (tungsten) disk with a temporal frequency of 25 Hz and a duration of 3 see; for hue detection
it was a 525 nm disk, 500 msec in duration. Flicker and hue thresholds were measured under three conditions: (1) in the d~rk”adapt~d state, (2) following a 2 min ganzfeld bleach with a luminance of 3.6 log cd/m*, and (3) against a rod-desensitizing ganzfeld background whose luminance was either OS (flicker thresholds} or - 0.8 log cd/m” {hue thresholds}. ln preliminary studies on normal subjects, these background luminances resulted in the greatest change in threshold from the dark-adapted condition. The test stimulus was presented_againsr the perimeter’s diffusing surface ;li selected locations throughout the horiz~~ntal meridian 01 the visual field. The fixation target was either d dim red dot, 30’ in diameter or. for fovea1 testing, a diamond-shaped pattern of four red dots, 10’ in diameter, separated by 2’ _ On-off square-wave flicker was provided by an episcotister rotating in a collimated portion of the optical path. The luminance of the test stimutus was controlled by neutral density filters. A ganzfeld bleaching light was furnished by ;t Feldman Adaptometer. Stimulus iuminances were calibrated by a Spectra Spotmeter; flicker frequencies were checked by a ~h~toccll and oscilloscope. The photopic and scotopic values of the chromatic stimuli were determined from the nominal color temperature of the tungsten source, the spectral transmissions of the filters as determined by an EG&G model 55Oi555 spectroradiometer, and the photopic or scotopic luminosity function (Wyszecki and StiIes, 1982). Prior to an experimental session, the pupil ot the tested eye was dilated by ?..S% phenylephrine hydrochloride and I “x tropicamide drops, and the eye was dark-adapted for 45 min. All thresholds were measured usmg an ascending method of limits. At the beginning ol each trial, the luminance of the test stimulus was set below the threshold and then was increased in 3.1 log unit steps until the subject pressed a buzzer indicating that (I) the test stimulus was detected (flash threshold), (2) it appeared to be flickering (flicker threshold). or (3) it appeared to be green (hue threshold), which is the hut: most commonly associated with the test wavclength of 525 nm (e.g. Boynton rr crf., 19641. Thresholds were defined as the medians (flash and flicker) or the means {hue) of three successive trials, except during bleaching recovery. when each data point represented one trial. In addition, dark-adapted ERGS were recorded using a procedure that has been de scribed previously (Fishman VI al.. 1977)
Rodxone
577
interaction and nightblindness
Briefly, the pupil of the tested eye was dilated 2.5% phenylephrine hydrochloride and 1% tropicamide drops and the eye was darkadapted for at least 30min. The cornea was anesthetized with 0.5% proparacaine hydrochloride drops, and a monopolar Burian-Allen contact lens electrode, wetted with methylcellulose, was inserted under dim longwavelength illumination. The electrode was referenced to the forehead; the left earlobe was grounded. Responses were elicited by a Grass PS-22 photostimulator that illuminated a diffusing sphere to provide ganzfeld stimulation. Signals were amplified by a Grass preamplifier (half-amplitude bandpass, l-300 Hz) and by a Tektronix dual trace amplifier. Waveforms were displayed on an oscilloscope and photographed with an oscilloscope camera. Darkadapted ERGS were recorded in response to single ganzfeld flashes with a luminance of - 0.4 log cd-set/m’ (I- 16 setting). Flash and background luminances were calibrated with an EG&G model 550 photometer equipped with a luminance probe. with
Or
CSNB
+l
-6-A
40
Na8a.I
Eccentricity
C&g)
Temporal
(A)
OrCSNB
r2
RESULTS
Flash thresholds
0 Middle Wavslenpth
and ERGS
The dark-adapted flash thresholds for middleand long-wavelength test stimuli are shown in Fig. l(A) (CSNB subject 1) and l(B) (CSNB subject 2). The hatched regions in these figures represent the normal mean thresholds + 1 SD, while the symbols indicate the thresholds for the CSNB subject. The thresholds, which have been plotted in photopic units, have been corrected for the lack of macular pigment (Wyszecki and Stiles, 1982) at eccentricities of 5” or greater. The difference between the thresholds for the two wavelengths indicates whether the rod or cone system mediates detection, based on the spectral sensitivities of the two receptor systems (Massof and Finkelstein, 1981). A difference of 0.1 log units (middle wavelength higher) indicates that both wavelengths were cone-detected. The difference is not zero because dark-adapted, cone-mediated thresholds deviate slightly from the photopic luminosity function (cf. Guth et al., 1980). A vertical separation of 2.5 log units (middle wavelength lower) indicates that thresholds for both wavelengths were rodmediated. Intermediate vertical separations indicate that the middle-wavelength test flash was rod-detected and the long-wavelength test flash was cone-detected.
Nasal
Eccentricity
(Deg)
Te”woral
@I
Fig. 1. Dark-adapted flash thresholds measured across the horizontal meridian of the visual field of CSNB subjects l(A) and 2(B), using middle-wavelength (open circles) and long-wavelength (solid circles) test stimuli that were 1.7” in diameter and 500msec in duration. Shaded regions represent mean thresholds & 1 SD for seven (A) or eight(B) normal observers.
By this analysis, flash thresholds for the normal subjects were rod-mediated for both wavelengths throughout most of the visual field, confirming previous studies (e.g. Massof and Finkelstein, 1981). Only in the fovea were thresholds for the long-wavelength test stimulus mediated by the cone system in the normals. For the CSNB subjects, flash thresholds for the middle-wavelength test flash (open circles) were rod-mediated in the periphery of the visual field. However, these rod thresholds were elevated by approximately 3 log units above normal. Within 20” of the fovea, the flash thresholds of the CSNB subjects were cone-mediated, as indicated by the nearly coincident data points for the two test stimulus wavelengths.
578
KENNETH
NORMAL
R. ALEXANDER et al.
csNsrt
CBNB +2
Fig. 2. ERG responses of a typical normal subject (left) and of CSNB subjects 1 (middle) and 2 (right) under dark-adapted conditions, with a- and b-waves indicated. The error bar represents the 90% tolerance limits for the mean b-wave amplitude of 21 normal subjects.
The dark-adapted ERG responses of the two CSNB subjects are presented in Fig. 2 (middle and right) together with the results of a typical normal individual (left). The a- and b-waves are indicated. The dark-adapted ERGS of both CSNB subjects showed a CharacEeristic Schubert-Bornschein pattern (Schubert and Bomschein, 1952) that consisted of a marked reduction in the b-wave amplitude compared to that of the a-wave. As discussed previously (Ripps, 1982), the selective reduction in the dark-a~pted b-wave ampliEude and the elevated dark-adapted rod thresholds are indicative of a defect in the transmission of rod signals within the retinas of these individuals.
Figure 3(A) and (B) present flicker thresholds for CSNB subjects 1 and 2 respectively. measured across the horizontal meridi-an of the
Rod-cone flicker interaction The influence of the rod system an cone flicker thresholds was examined in two ways. First, we measured the fficker thresholds of the CSNB subjects at selected locations across the horizontal meridian of the visual field in both the dark-adapEed state and against a roddesensitizing ganzfeld background. Such backgrounds have been shown to reduce flicker thresholds from the dark-adapted values by removing the influence of the rod system (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). The difference between dark- and light-adapted flicker thresholds provides a measure of the magnitude of the rod-cone interacEion (Alexander and Fishman, the flicker 1986). Second, we measured thresholds of the CSNB subjects during bleaching recovery, Previous studies have shown that the rod-cone flicker interaction can be observed as a systematic rise in cone flicker thresholds that occurs during dark adaptation of the rod system (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984).
-20 NWd
-60
-40 Eccentricity G&g)
Tsmporal
(W
Fig. 3. Flicker thresholds measured across the horizontal meridian of the visual field for CSNB subjects l(A) and 2(B) under dark-adapted (solid circles) and l&h&adapt+ (open &&es) conditions, using a I.?, 25 Hz; 3 SW white test stimuius. Background luminance was 0.5 log cd/m_2,shaded regions represnt mean flicker threshal& -& 1SD for six normals.
579
Rod-cone interaction and nightblindness
visual field under dark-adapted conditions and in the presence of a rod-desensitizing ganzfeld background. The symbols represent the results for the two CSNB subjects under dark-adapted (sohd circles) and light-adapted (open circles) conditions, while the hatched regions indicate the mean flicker thresholds + 1 SD for six normal subjects. For the normals, flicker thresholds were highest under dark-adapted conditions and lower against the background, in accordance with previous studies (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). A similar finding was obtained from the CSNB subjects. Their flicker thresholds were substantially lower in the presence of a rod-desensitizing background than in the dark-adapted condition. The difference between light- and darkadapted flicker thresholds is shown in Fig. 4. The hatched region indicates the normal mean difference + I SD. As described previously (Alexander and Fishman, 1986), the magnitude of the threshold reduction for the normal subjects was smallest in the fovea and increased to approximately I log unit at eccentricities beyond 20”. The threshold differences for the two CSNB subjects were similar to those of the normal observers. To confirm that the rod-cone flicker interaction was normal in these individuals with CSNB. we measured their flicker thresholds during bleaching recovery at an eccentricity of 20” in the nasal field. The results are shown in Fig. 5. The hatched region in this figure indicates the mean normal thresholds + 1 SD for
,
t 5
I
I
I
10
I
15
I
I
20
Time (min)
Fig. 5. Flicker thresholds measured following a 2min ganzfefd bleach of 3.610gcd/mZ for CSNB subjects 1 (triangles) and 2 (squares) using a 1.7”, 25 Hz, 3 set white test stimulus presented at 20” in the nasal visual field. The hatched region represents mean thresholds & I SD for the same six normais as in Fig. 3 {thresholds were averaged within 2min time bins).
the same six normal subjects as in Fig. 3. To obtain the mean values for this curve, we averaged six threshold measurements (one per subject) that were obtained during successive 2 min time bins. For the normal subjects, flicker thresholds were initially low once the cone system had recovered from the bleach. Then flicker thresholds rose as the rod system recovered, reaching a plateau at about 15 min following the bleach offset, in agreement with previous studies (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). The results for the two CSNB subjects also followed this pattern. Therefore, despite the substantially elevated rod thresholds of these subjects, the rod system had its normal influence on cone flicker thresholds. Rod-cone hue interaction
Thresholds for hue detection were studied in the same manner as flicker thresholds. First, we measured the hue thresholds of the CSNB subjects in the dark-adapted state and against a rod-desensitizing ganzfeld background. Such backgrounds have been shown previously to reduce hue thresholds from their dark-adapted LJ “‘I ‘I ’ ! ‘I 1 value by removing a rod influence (Spil~mann -20 0 20 40 -40 -f 30 Tsmporst N88ktl Eccentricity (Deg) and Co&on, 1972). Since the accuracy of hue naming by normal observers deteriorates at Fig. 4. Differences between dark- and light-adapted flicker thresholds [from Fig. 3(A) and (B)] for CSNB subjects 1 peripheral field loci (e.g. Boynton et al., 1964), measurements in the present experiment were (triangles) and 2 (squares). The hatched region represents mean differences i f SD for the six normals from Fig. 3. confined to eccentricities of 20” or less. Second,
KENNETH R.
580
ALEXANDER et al.
since the rod-cone hue interaction can also be observed as an increase in hue thresholds during rod-system dark adaptation (Lie, $963; Spilimann and Conlon, 1972; StabelI and Stabell, 1976), we measured the hue thresholds of the CSNB subjects during bleaching recovery. The effect of light adaptation on hue thresholds is shown in Fig. 6(A) (CSNB subject 1) and (3) {CSNB subject 2). The hatched regions indicate the mean hue thresholds F 1 SD for five normal subjects measured both in the dark and against a rod-desensitizing ganzfetd background. The symbols represent the hue thresholds for the two CSNB subjects under the same dark-adapted (solid circles) and light-adapted (open circles) conditions. For the normals, the background field lowered the
r
CSNB * 1
O DwkAdapted
0 Lighthdmted
r csN8+2 a
hue thresholds at non-fovea1 eccentricities. as expected from previous studies, and bad little apparent effect in the fovea. For the CSNB subjects, however, the background field elevated the hue threshold at all visual field loci. The effect of rod-system desensitization can be seen more clearly in Fig. ?, which plots the difference between light- and dark-adapted threshold measurements. The hatched region indicates the mean difference I 1 SD for the same normals as in Fig. 6. In the fovea, the background elevated the hue threshold of the normals slightly, due to light adaptation of the cone system. At non-foveal e~~e~triGities, light adaptation of the rod system lowered the hue thresholds of the normals by approximately 1 log unit from the dark-adapted vatuw For the CSNB subjects, light adaptation elevated the hue threshold at all eccentricities, and the amount of threshold elevation was equivalent to that of the normal fovea. These results indicate, therefore, that the rod system did not have its usual effect on hue thresholds in these individuals with CSNB. To confirm this finding, we measured hue thresholds during bleaching recovery at an eccentricity of 10” in the nasal field, with the results shown in Fig. 8. The hatched region shows the mean hue thresholds f i SD for the same five normals whose data are plotted in Fig, 6. As for flicker detection, six threshold measurements (one per subject] were averaged within successive 2 min time bins during bleaching recovery. Consistent with previous studies (Lie, 1963; Spillmann and Conlon, 1972; Stabell
Dark AdWi?d
0 Light AdllPIQd
Fig. 6. Hue thresholds measured across the horizontal meridian of the visual field for CSNB subjects l(A) and 2(B) under dark-adapted (solid circles) and light-adapted (open circles) conditions, using a 1.7”, 525 nm, 500 msec test stimulus. Background luminance was -0.8 log cd/m’. Shaded regions indicate mean hue threshold & 1 SD for five normals.
-21
’
-20 Nasal
,
I.1
t
i
!
10 0 Eccentricity (De@ -10
11
1
20 T~iTWW~l
Fig. 7. Differences between dark- and light-adapted hue thresholds [from Fii. 6(A) and (B)] for CSNB subjects I (triadic) and-2 @quares). The hafched region represents mean differences i I SD for the five normals from Fig. 6.
Rod-cone interaction and nightblindness
581
be mediated by different mechanisms within the visual system. It should be noted that not all individuals with CSNB exhibit a normal rod-cone flicker interaction. Arden and Hogg (1985) and Greenstein et al. (1986) have reported an absence of the rod-cone flicker interaction in their CSNB subjects, The reason for the discrepancy between their results and those of the present study is unclear. A distinct possibility is that the subjects represent different subtypes of CSNB with perhaps different pathogenetic mechanisms (cf. Miyake et al., 1986). 10 15 20 25 5 0 The precise nature of the processes mediating Time (mid these rod-cone interactions is presently unknown. However, recent experiments provide Fig. 8. Hue thresholds measured a 2 min ganzfeld bleach of suggestive info~ation. Based on its psycho3.610gcd/m2 for CSNB subjects 1 (t~angles) and 2 physical characteristics, the rod-cone flicker in(squares), using a 1.7”, 525 nm, 500 msec test stimulus presented at lo” in the nasal field. The hatched region teraction appears to result from a lateral interrepresents mean thresholds k 1 SD for the same five nor- action between the dark-adapted unstimulated mals as in Fig. 6 (thresholds were averaged within 2min rod system surrounding a test stimulus and the time bins). stimulated cone system. For example, the maximum reduction in cone flicker thresholds occurs and Stabell, 1976), the hue threshold for the only when a substantial region of retina surnormals initially declined as the cone system rounding the test stimulus is light-adapted recovered from the bleach. Then the hue (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984), and the threshold rose as the rod system dark-adapted, reaching an asymptote at approximately 20 min threshold-lowe~ng background has an action following the bleach offset. For the two CSNB spectrum of the rod system (Goldberg et af., subjects, there was also an initial period of 1983). It has been suggested that the rod-cone declining hue thresholds - as the cones dark- flicker interaction may be mediated by a pathadapted. However, there was no subsequent way involving horizontal cells, since intrathreshold rise. Instead, the hue threshold for cellular recordings from horizontal cells of these individuals remained relatively constant Xe~#~~s, mudpuppy, and cat show an enhanceduring bleaching recovery. These results con- ment of cone responses when the rod system is firm that the rod-cone hue interaction was desensitized (Frumkes and Eysteinsson, 1987; absent in these two CSNB subjects. Pflug and Nelson, 1987; Witkovsky and Stone, 1987), a result that appears to be analogous to the human psychophysical finding. DISCUSSION The results from our CSNB subjects are The two individuals with CSNB who were consistent with the possibility that horizontal examined in this study had substantially el- cells mediate the rod-cone flicker interaction. evated dark-adapted rod thresholds and selec- The abnormal ERG responses of the CSNB tively reduced amplitudes of the dark-adapted subjects indicate that the defect in the transERG b-wave. As discussed previously (Ripps, mission of rod signals occurs at, or distal to, the 1982) these results suggest a defect in the generator of the &wave (in the present context, transmission of rod signals within their retinas. the terms distal and proximal refer to levels Consistent with the impairment of rod system within the visual information pathway from function in these individuals, we observed that photoreceptors to visual cortex). Since the 6the rod-cone hue interaction was absent. How- wave is thought to be generated by Miiller cells ever, the rod-cone flicker interaction was nor- (Kline et al., 1978; Newman, 1986) in response mal. Since the two types of rod-cone interaction to on-bipolar cell activity (Knapp and Schiller, were differentially affected in the same individu1984), the defect in CSNB appears to occur at, als with this nightblinding retinal disorder, our or distal to, the bipolar cell level. If this hypothresults demonstrate that the interactions must esis is correct, then the fact that the rod-cone jr
CSNS+l
A
KENNETHR.
582
ALEXANDERel al.
flicker interaction was normal in these CSNB subjects indicates that the interaction is mediated at a retinal locus that is also at, or distal to, the bipolar cell level. Moreover, if the rod-cone flicker interaction is mediated by a horizontal cell pathway, then the normal adaptational properties of the rod-cone flicker interaction in the CSNB subjects (as shown in Figs 3 and 5) indicate that their rod photoreceptors have a normal modulation of neurotransmitter release. The mechanism underlying the rod-cone hue interaction is less certain. Unlike the rod-cone flicker interaction, the rod-cone interaction in the detection of hue apparently occurs between rod and cone signals that are generated directly in response to a test stimulus. One possibility is that an achromatic signal from the stimulated rod system may desaturate a chromatic cone signal (Lie, 1963; Spillmann and Conlon, 1972). A second possibility is that signals from the rod system may modify the response of coloropponent neurons (Stabell and Stabell, 1976). Electrophysiological studies indicate that there are many levels within the visual system at which such an interaction between rod and cone signals could occur (e.g. Wiesel and Hubel, 1966; Raynauld, 1972; Enroth-Cugell et al., 1977; Nelson, 1977; Witkovsky and Stone, 1983; Smith et al., 1986). Nevertheless, the absence of the rod-cone hue interaction in our subjects with CSNB demonstrates that this interaction is mediated at, or proximally to, the site of the visual defect in this disorder. Acknowledgements-The authors thank Neal Peachey for helpful comments on the manuscript and Kathleen Louden for editorial assistance. The research was supported by NE1 Grant EYO4848, NE1 Core Grant EY01792, a Center Grant from the National Retinitis Pigmentosa Foundation Figbting Blindness, Baltimore, Maryland, and an Unrestricted Grant from Research to Prevent Blindness fnc., New York.
REFERENCES Alexander K. R. and Fishman G. A. (1984) Rod-cone interaction in flicker perimetry. Br. J. Oph&zZ. 68, 303-309. Alexander K. R. and Fishman G. A. (1985) Rod-cone interaction in flicker perimetry: evidence for a distal retinal locus. Documenta Ophth. 60, 3-36. Alexander K. R. and Fishman G. A. (1986) Rod influence on cone flicker detection: variation with retinal eccentricity. Vision Res. 26, 827-834. Arden G. B. and Hogg C. R. (1985) Rod-cone interactions and analysis of retinal disease. Br. 1. Ophtkal. 69, 404-415.
Boynton R. M., Schafer W. and Neun M. A. (1964) Hue-wavelength relation measured by color-naming
method for three retinal locations. Science, N.Y. t46, 666-668. Carr R. E., Ripps H., Siegel 1. M. and Weale R. A. (1966) Rhodopsin and the electrical activity of the retina in congenital night blindness. Invest. Ophrhaf. 5, 497-507. Coletta N. J. and Adams A. J. (1984) Rod-uine interaction in flicker detection. Fi.s&r Res. 24, 1333-1340. Enoch J. M., Fitzgerald C. R. and Campos E. C. (1981) @antitative Layer-by-Iayer Analysis. Grune & Stratton,
Perimeter
An
Extended
New York. Enroth-Cugell C., Hertz B. G. and Lennie P. (19’77) Convergence of rod and cone signais in the cat’s retina. J. Physiol., Lond. 269, 297-318. Fishman G. A., Buckman G. and Van Every T. (1977) Fundus flavimaculatus: A clinical classification. Documenta Ophrh. Proc. Ser. 13, 213-220. Frumkes T. E. and Eysteinsson T. (1987) Suppressive rod
Guth S. L., Massof R. W. and Benzschawel T. (1980). Vector model for normal and dichromatic color vision. J. opt. .POC.Am. 70, 197-212. Kline R. P., Ripps H. and Dowling J, E. (1978) Generation of b-wave currents in the skate retina. Proc. nurn. Acad. Sci. U.S.A. 75, 5727-5731. Knapp A. G. and Schiiler P. H. (1984) The contribution of on-bipolar cells to the electroretinogram of rabbits and monkeys: A study u&g 2-amino-%pbosphonobutyrate (APB). Vision Res. 24, 1841.-1846. Lie I. (1963) Dark adaptation and the photochromatic interval. Documenta Uphth. 17, 41 l-510. Massof R. W. and Finkelstein D. (1981) Two forms of autosomal dominant primary retinitis pigmentosa. Documenta Ophth. 52, 289-346.
Miyake Y., Yagasaki K., Horiguchi M., Kawase Y. and Kanada T. (1986) Congenital stationary night blindness with negative electroretinogram: A new classification. Archs ~ph~hai. 104, 1013-1020. Nelson R. (1977) Cat cones have rod input: A comparison of response properties of cones and horizontal cell bodies in the retina of the cat. J. camp. Xewof. 172, 109-136. Newman E. A. (1986) Physiological properties aud possibie functions of Mtiller cells. Neurosri Res., Suppl. 4, s209s220. Peachey N. S., Seiple W. H., Auerbach E. and Armington J. C. (1987) Rod influence on thresboids using different detection criteria during dark adaptation. Acta psyckai. 64, 261-270. PtTug R. and Nelson R. (1987) Background enhancement of cone signals in cat horizontal cegs.. Invesr. Opfirhal. visual Sci., Supll. 28, 240. Prestrude A. M.. Watkins L. and Watkins J. (t9?8) Interocular light adaptation effect on the Lie “specific threshold.” Vision Res. lg. 855-857. Raynauld J.-P. (1972) Gddfish -retina: Sign of the rod input in opponent color ganglion cells. Science, N.Y. 177, 84-85.
Rod-cone interaction and nightblindness Ripps H. (1982) Night blindness revisited: From man IO molecules. Invest. Ophthal visual Sci. 23, 588-609. Schubert G. and Bornschein H. (1952) Beitrage zur Analyse des menschlichen Elektroretinogramms. Ophrhalmologica 123, 396411. Smith R. G., Freed M. A. and Sterhng P. (1986) Microcircuitry of the dark-adapted cat retina: Functional architecture of the rod-cone network. J. Neurusci. 6, 3505-3537.
Spillmann L. and Conlon J. E. (1972) Photochromatic interval during dark adaptation and as a function of background luminance. J. opt. Sac. Am. 62, 182485. Stabell B. and Stabell I-J. (1976) Effects of rod activity on color threshold. Vision Res. 16, 1105-l 110. Wiesel T. N. and Hubel D. H. (1966) Spatial and
583
chromatic interactions in the lateral genicuiate body of the Rhesus monkey. J. Neurophysioi. 29, 1115-1156. Witkovsky P. and Stone S. (1983) Rod and cone inputs to bipolar cells and horizontal cells of the Xenopus retina. Vision Res. 23, 1251-1258.
Witkovsky P. and Stone S. (1987) GABA and glycine modify the balance of rod and cone inputs to horizontal cells in the Xenopus retina. Expl Biol. 47, 13-22. Wyszecki G. and Stiles W. S. (1982) Color Science: Concepts and Methods, 2nd edn. Wiley, New York. Young R. S. L., Price J. and Harrison J. (1986) Psychophysicai study of rod adaptation in patients with congenital stationary night blindness. C&z. Vision Sci. 1, 137-143.
004X989/88
$3.00 + 0.00
CopyrightQ 1988PergamonPressplc
MECHANISMS OF ROD-CONE INTERACTION: EVIDENCE FROM CONGENITAL STATIONARY NIGHTBLINDNESS KENNETHR. ALEXANDER,GERALDA. FISHMANand DEBORAHJ. DERLACKI Department of Ophthalmology, University of Illinois College of Medicine at Chicago, 1855 W. Taylor St, Chicago, IL 60612, U.S.A. (Received 23 July 1987; in revisedform 27 October 1987)
‘Abstract-The dark-adapted rod system can elevate cone-mediated thresholds for flicker detection as well as thresholds for the detection of hue. We examined these two types of rod-cone interactions in two individuals with congenital stationary nightblindness (CSNB), a retinal disorder in which rod outer segment function is intact, but in which a defect occurs in the transmission of rod signals within the retina. The two types of rod-cone interaction were differentially affected by the retinal pathology; the rod-cone flicker interaction was normal, but the rodcone hue interaction was absent. These results provide evidence that, despite similarities in the adaptational properties of these two types of rod-cone interaction, they are mediated by different visual mechanisms, Cones
Rods
Flicker
Color
Nightblindness
INTRODUCTION Recent experiments have shown that the darkadapted rod system can elevate the threshold for the detection of flicker by the cone system {e.g. Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). When the rod system is light-adapted or bleached, the cone flicker threshold in the parafoveal retina is reduced by as much as one log unit from its dark-adapted value. Similarly, under darkadapted conditions, the rod system can elevate the threshold for the detection of the hue of a chromatic stimulus (e.g. Lie, 1963; Spillmann and Conlon, 1972; Stabell and Stabell, 1976; Prestrude et al., 1978; Peachey et al., 1987). As with flicker detection, light adaptation or bleaching of the rod system lowers the hue threshold in the parafoveal retina by approximately one log unit from the dark-adapted value. Despite the apparent similarity in the adaptational properties of these two types of rodcone interactions, it has been proposed that different visual mechanisms underlie them. The rod-cone flicker interaction is thought to result from a sustained lateral inhibition between dark-adapted unstimulated rods and stimulated cones (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). In contrast, the rodxone hue interaction appar-
ently occurs between rod and cone signals that are generated directly in response to a flashed test stimulus (Lie, 1963; Spillmann and Conlon, 1972; Stabell and Stabeli, 1976). One way to determine whether different mechanisms underlie the two types of rod-cone interactions is to compare the two phenomena in individuals with circumscribed disorders of the visual system (cf. Enoch et al., 1981). If the two types of interactions are affected differently by the pathology, then different visual mechanisms must underlie them. To investigate this question, we examined the rod-cone flicker and hue interactions in two individuals with congenital stationary nightblindness (CSNB). Evidence indicates that there is a defect in the transmission of rod signals from photoreceptors to secondorder neurons in this condition (Ripps, 1982). For example, the rod photopigment has a normal concentration and normal bleaching kinetics (Carr et al., 1966), and the rod a-wave amplitude of the el~troretinogram (ERG) is normal (Young et af., f986), but the rod b-wave amplitude is considerably reduced, and darkadapted rod thresholds are elevated substantially (e.g. Miyake et al., 1986). In a previous study of the rod-cone flicker interaction in individuals with retinal disorders (Alexander and Fishman, 1985), we observed that the interaction was normal in a person with CSNB, despite a substantial loss of rod system 575
576
KENNETH
R.
ALEXANDER rt ~1.
sensitivity, We now report a similar finding in a second person with this condition. We have also examined the rod-cone hue interaction in these same two individuals. We have found that, whereas the rod-one flicker interaction was normal in both observers, the rod-cone hue interaction was absent. These results support the hypothesis that the two types of rod-cone interactions are mediated by different visual processes. METHOD
Subjects
CSNB subject I was a 15-year-old male with a Snelien visual acuity of 20/40 and a refractive error of - 13.00 + 3.00 x 180 in the tested (left) eye. His fundus was light-colored with a prominent choroidal pattern, consistent with high myopia. CSNB subject 2 was a 38-year-old male with a Snellen visual acuity of 20130 and a refractive error of - 14.75 + 3.00 x 135 in the tested (right) eye. His fundus showed peripapillary atrophy and other changes consistent with high myopia. CSNB subject I was the only known affected family member. CSNB subject 2 had a maternal male cousin who was similarly affected, suggesting an X-linked recessive inheritance. A total of 20 visually normal individuals (age range, 2042 years) provided control data for the psychophysical expe~ments. Three were experienced subjects; the others were experimentally naive. Twenty-one normal subjects provided normative data for the ERG measurements. Apparatus and ~rQce~ure
Testing was carried out with a Tiibinger perimeter. Three types of thresholds were measured: dark-adapted flash thresholds, flicker thresholds, and hue thresholds. In all cases, the test stimulus diameter was 1.7”. Dark-adapted gash thresholds were obtained for both a middle-waveiength test stimulus (Schott interference filter type IL, 3+,,, = 500 nm) and a long-wavelength test stimulus (Oculus bandpass filter, cut-on 11= 620 nm for subject 1; Schott interference filter type IL, &a = 655 nm for subject 2) to determine whether rods or cones mediated the dark-adapted threshold at each eccentricity (cf. Massof and Finkelstein, 1981). The test stimulus duration was 500 msec. For flicker detection, the test stimulus was a white (tungsten) disk with a temporal frequency of 25 Hz and a duration of 3 see; for hue detection
it was a 525 nm disk, 500 msec in duration. Flicker and hue thresholds were measured under three conditions: (1) in the d~rk”adapt~d state, (2) following a 2 min ganzfeld bleach with a luminance of 3.6 log cd/m*, and (3) against a rod-desensitizing ganzfeld background whose luminance was either OS (flicker thresholds} or - 0.8 log cd/m” {hue thresholds}. ln preliminary studies on normal subjects, these background luminances resulted in the greatest change in threshold from the dark-adapted condition. The test stimulus was presented_againsr the perimeter’s diffusing surface ;li selected locations throughout the horiz~~ntal meridian 01 the visual field. The fixation target was either d dim red dot, 30’ in diameter or. for fovea1 testing, a diamond-shaped pattern of four red dots, 10’ in diameter, separated by 2’ _ On-off square-wave flicker was provided by an episcotister rotating in a collimated portion of the optical path. The luminance of the test stimutus was controlled by neutral density filters. A ganzfeld bleaching light was furnished by ;t Feldman Adaptometer. Stimulus iuminances were calibrated by a Spectra Spotmeter; flicker frequencies were checked by a ~h~toccll and oscilloscope. The photopic and scotopic values of the chromatic stimuli were determined from the nominal color temperature of the tungsten source, the spectral transmissions of the filters as determined by an EG&G model 55Oi555 spectroradiometer, and the photopic or scotopic luminosity function (Wyszecki and StiIes, 1982). Prior to an experimental session, the pupil ot the tested eye was dilated by ?..S% phenylephrine hydrochloride and I “x tropicamide drops, and the eye was dark-adapted for 45 min. All thresholds were measured usmg an ascending method of limits. At the beginning ol each trial, the luminance of the test stimulus was set below the threshold and then was increased in 3.1 log unit steps until the subject pressed a buzzer indicating that (I) the test stimulus was detected (flash threshold), (2) it appeared to be flickering (flicker threshold). or (3) it appeared to be green (hue threshold), which is the hut: most commonly associated with the test wavclength of 525 nm (e.g. Boynton rr crf., 19641. Thresholds were defined as the medians (flash and flicker) or the means {hue) of three successive trials, except during bleaching recovery. when each data point represented one trial. In addition, dark-adapted ERGS were recorded using a procedure that has been de scribed previously (Fishman VI al.. 1977)
Rodxone
577
interaction and nightblindness
Briefly, the pupil of the tested eye was dilated 2.5% phenylephrine hydrochloride and 1% tropicamide drops and the eye was darkadapted for at least 30min. The cornea was anesthetized with 0.5% proparacaine hydrochloride drops, and a monopolar Burian-Allen contact lens electrode, wetted with methylcellulose, was inserted under dim longwavelength illumination. The electrode was referenced to the forehead; the left earlobe was grounded. Responses were elicited by a Grass PS-22 photostimulator that illuminated a diffusing sphere to provide ganzfeld stimulation. Signals were amplified by a Grass preamplifier (half-amplitude bandpass, l-300 Hz) and by a Tektronix dual trace amplifier. Waveforms were displayed on an oscilloscope and photographed with an oscilloscope camera. Darkadapted ERGS were recorded in response to single ganzfeld flashes with a luminance of - 0.4 log cd-set/m’ (I- 16 setting). Flash and background luminances were calibrated with an EG&G model 550 photometer equipped with a luminance probe. with
Or
CSNB
+l
-6-A
40
Na8a.I
Eccentricity
C&g)
Temporal
(A)
OrCSNB
r2
RESULTS
Flash thresholds
0 Middle Wavslenpth
and ERGS
The dark-adapted flash thresholds for middleand long-wavelength test stimuli are shown in Fig. l(A) (CSNB subject 1) and l(B) (CSNB subject 2). The hatched regions in these figures represent the normal mean thresholds + 1 SD, while the symbols indicate the thresholds for the CSNB subject. The thresholds, which have been plotted in photopic units, have been corrected for the lack of macular pigment (Wyszecki and Stiles, 1982) at eccentricities of 5” or greater. The difference between the thresholds for the two wavelengths indicates whether the rod or cone system mediates detection, based on the spectral sensitivities of the two receptor systems (Massof and Finkelstein, 1981). A difference of 0.1 log units (middle wavelength higher) indicates that both wavelengths were cone-detected. The difference is not zero because dark-adapted, cone-mediated thresholds deviate slightly from the photopic luminosity function (cf. Guth et al., 1980). A vertical separation of 2.5 log units (middle wavelength lower) indicates that thresholds for both wavelengths were rodmediated. Intermediate vertical separations indicate that the middle-wavelength test flash was rod-detected and the long-wavelength test flash was cone-detected.
Nasal
Eccentricity
(Deg)
Te”woral
@I
Fig. 1. Dark-adapted flash thresholds measured across the horizontal meridian of the visual field of CSNB subjects l(A) and 2(B), using middle-wavelength (open circles) and long-wavelength (solid circles) test stimuli that were 1.7” in diameter and 500msec in duration. Shaded regions represent mean thresholds & 1 SD for seven (A) or eight(B) normal observers.
By this analysis, flash thresholds for the normal subjects were rod-mediated for both wavelengths throughout most of the visual field, confirming previous studies (e.g. Massof and Finkelstein, 1981). Only in the fovea were thresholds for the long-wavelength test stimulus mediated by the cone system in the normals. For the CSNB subjects, flash thresholds for the middle-wavelength test flash (open circles) were rod-mediated in the periphery of the visual field. However, these rod thresholds were elevated by approximately 3 log units above normal. Within 20” of the fovea, the flash thresholds of the CSNB subjects were cone-mediated, as indicated by the nearly coincident data points for the two test stimulus wavelengths.
578
KENNETH
NORMAL
R. ALEXANDER et al.
csNsrt
CBNB +2
Fig. 2. ERG responses of a typical normal subject (left) and of CSNB subjects 1 (middle) and 2 (right) under dark-adapted conditions, with a- and b-waves indicated. The error bar represents the 90% tolerance limits for the mean b-wave amplitude of 21 normal subjects.
The dark-adapted ERG responses of the two CSNB subjects are presented in Fig. 2 (middle and right) together with the results of a typical normal individual (left). The a- and b-waves are indicated. The dark-adapted ERGS of both CSNB subjects showed a CharacEeristic Schubert-Bornschein pattern (Schubert and Bomschein, 1952) that consisted of a marked reduction in the b-wave amplitude compared to that of the a-wave. As discussed previously (Ripps, 1982), the selective reduction in the dark-a~pted b-wave ampliEude and the elevated dark-adapted rod thresholds are indicative of a defect in the transmission of rod signals within the retinas of these individuals.
Figure 3(A) and (B) present flicker thresholds for CSNB subjects 1 and 2 respectively. measured across the horizontal meridi-an of the
Rod-cone flicker interaction The influence of the rod system an cone flicker thresholds was examined in two ways. First, we measured the fficker thresholds of the CSNB subjects at selected locations across the horizontal meridian of the visual field in both the dark-adapEed state and against a roddesensitizing ganzfeld background. Such backgrounds have been shown to reduce flicker thresholds from the dark-adapted values by removing the influence of the rod system (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). The difference between dark- and light-adapted flicker thresholds provides a measure of the magnitude of the rod-cone interacEion (Alexander and Fishman, the flicker 1986). Second, we measured thresholds of the CSNB subjects during bleaching recovery, Previous studies have shown that the rod-cone flicker interaction can be observed as a systematic rise in cone flicker thresholds that occurs during dark adaptation of the rod system (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984).
-20 NWd
-60
-40 Eccentricity G&g)
Tsmporal
(W
Fig. 3. Flicker thresholds measured across the horizontal meridian of the visual field for CSNB subjects l(A) and 2(B) under dark-adapted (solid circles) and l&h&adapt+ (open &&es) conditions, using a I.?, 25 Hz; 3 SW white test stimuius. Background luminance was 0.5 log cd/m_2,shaded regions represnt mean flicker threshal& -& 1SD for six normals.
579
Rod-cone interaction and nightblindness
visual field under dark-adapted conditions and in the presence of a rod-desensitizing ganzfeld background. The symbols represent the results for the two CSNB subjects under dark-adapted (sohd circles) and light-adapted (open circles) conditions, while the hatched regions indicate the mean flicker thresholds + 1 SD for six normal subjects. For the normals, flicker thresholds were highest under dark-adapted conditions and lower against the background, in accordance with previous studies (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). A similar finding was obtained from the CSNB subjects. Their flicker thresholds were substantially lower in the presence of a rod-desensitizing background than in the dark-adapted condition. The difference between light- and darkadapted flicker thresholds is shown in Fig. 4. The hatched region indicates the normal mean difference + I SD. As described previously (Alexander and Fishman, 1986), the magnitude of the threshold reduction for the normal subjects was smallest in the fovea and increased to approximately I log unit at eccentricities beyond 20”. The threshold differences for the two CSNB subjects were similar to those of the normal observers. To confirm that the rod-cone flicker interaction was normal in these individuals with CSNB. we measured their flicker thresholds during bleaching recovery at an eccentricity of 20” in the nasal field. The results are shown in Fig. 5. The hatched region in this figure indicates the mean normal thresholds + 1 SD for
,
t 5
I
I
I
10
I
15
I
I
20
Time (min)
Fig. 5. Flicker thresholds measured following a 2min ganzfefd bleach of 3.610gcd/mZ for CSNB subjects 1 (triangles) and 2 (squares) using a 1.7”, 25 Hz, 3 set white test stimulus presented at 20” in the nasal visual field. The hatched region represents mean thresholds & I SD for the same six normais as in Fig. 3 {thresholds were averaged within 2min time bins).
the same six normal subjects as in Fig. 3. To obtain the mean values for this curve, we averaged six threshold measurements (one per subject) that were obtained during successive 2 min time bins. For the normal subjects, flicker thresholds were initially low once the cone system had recovered from the bleach. Then flicker thresholds rose as the rod system recovered, reaching a plateau at about 15 min following the bleach offset, in agreement with previous studies (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984). The results for the two CSNB subjects also followed this pattern. Therefore, despite the substantially elevated rod thresholds of these subjects, the rod system had its normal influence on cone flicker thresholds. Rod-cone hue interaction
Thresholds for hue detection were studied in the same manner as flicker thresholds. First, we measured the hue thresholds of the CSNB subjects in the dark-adapted state and against a rod-desensitizing ganzfeld background. Such backgrounds have been shown previously to reduce hue thresholds from their dark-adapted LJ “‘I ‘I ’ ! ‘I 1 value by removing a rod influence (Spil~mann -20 0 20 40 -40 -f 30 Tsmporst N88ktl Eccentricity (Deg) and Co&on, 1972). Since the accuracy of hue naming by normal observers deteriorates at Fig. 4. Differences between dark- and light-adapted flicker thresholds [from Fig. 3(A) and (B)] for CSNB subjects 1 peripheral field loci (e.g. Boynton et al., 1964), measurements in the present experiment were (triangles) and 2 (squares). The hatched region represents mean differences i f SD for the six normals from Fig. 3. confined to eccentricities of 20” or less. Second,
KENNETH R.
580
ALEXANDER et al.
since the rod-cone hue interaction can also be observed as an increase in hue thresholds during rod-system dark adaptation (Lie, $963; Spilimann and Conlon, 1972; StabelI and Stabell, 1976), we measured the hue thresholds of the CSNB subjects during bleaching recovery. The effect of light adaptation on hue thresholds is shown in Fig. 6(A) (CSNB subject 1) and (3) {CSNB subject 2). The hatched regions indicate the mean hue thresholds F 1 SD for five normal subjects measured both in the dark and against a rod-desensitizing ganzfetd background. The symbols represent the hue thresholds for the two CSNB subjects under the same dark-adapted (solid circles) and light-adapted (open circles) conditions. For the normals, the background field lowered the
r
CSNB * 1
O DwkAdapted
0 Lighthdmted
r csN8+2 a
hue thresholds at non-fovea1 eccentricities. as expected from previous studies, and bad little apparent effect in the fovea. For the CSNB subjects, however, the background field elevated the hue threshold at all visual field loci. The effect of rod-system desensitization can be seen more clearly in Fig. ?, which plots the difference between light- and dark-adapted threshold measurements. The hatched region indicates the mean difference I 1 SD for the same normals as in Fig. 6. In the fovea, the background elevated the hue threshold of the normals slightly, due to light adaptation of the cone system. At non-foveal e~~e~triGities, light adaptation of the rod system lowered the hue thresholds of the normals by approximately 1 log unit from the dark-adapted vatuw For the CSNB subjects, light adaptation elevated the hue threshold at all eccentricities, and the amount of threshold elevation was equivalent to that of the normal fovea. These results indicate, therefore, that the rod system did not have its usual effect on hue thresholds in these individuals with CSNB. To confirm this finding, we measured hue thresholds during bleaching recovery at an eccentricity of 10” in the nasal field, with the results shown in Fig. 8. The hatched region shows the mean hue thresholds f i SD for the same five normals whose data are plotted in Fig, 6. As for flicker detection, six threshold measurements (one per subject] were averaged within successive 2 min time bins during bleaching recovery. Consistent with previous studies (Lie, 1963; Spillmann and Conlon, 1972; Stabell
Dark AdWi?d
0 Light AdllPIQd
Fig. 6. Hue thresholds measured across the horizontal meridian of the visual field for CSNB subjects l(A) and 2(B) under dark-adapted (solid circles) and light-adapted (open circles) conditions, using a 1.7”, 525 nm, 500 msec test stimulus. Background luminance was -0.8 log cd/m’. Shaded regions indicate mean hue threshold & 1 SD for five normals.
-21
’
-20 Nasal
,
I.1
t
i
!
10 0 Eccentricity (De@ -10
11
1
20 T~iTWW~l
Fig. 7. Differences between dark- and light-adapted hue thresholds [from Fii. 6(A) and (B)] for CSNB subjects I (triadic) and-2 @quares). The hafched region represents mean differences i I SD for the five normals from Fig. 6.
Rod-cone interaction and nightblindness
581
be mediated by different mechanisms within the visual system. It should be noted that not all individuals with CSNB exhibit a normal rod-cone flicker interaction. Arden and Hogg (1985) and Greenstein et al. (1986) have reported an absence of the rod-cone flicker interaction in their CSNB subjects, The reason for the discrepancy between their results and those of the present study is unclear. A distinct possibility is that the subjects represent different subtypes of CSNB with perhaps different pathogenetic mechanisms (cf. Miyake et al., 1986). 10 15 20 25 5 0 The precise nature of the processes mediating Time (mid these rod-cone interactions is presently unknown. However, recent experiments provide Fig. 8. Hue thresholds measured a 2 min ganzfeld bleach of suggestive info~ation. Based on its psycho3.610gcd/m2 for CSNB subjects 1 (t~angles) and 2 physical characteristics, the rod-cone flicker in(squares), using a 1.7”, 525 nm, 500 msec test stimulus presented at lo” in the nasal field. The hatched region teraction appears to result from a lateral interrepresents mean thresholds k 1 SD for the same five nor- action between the dark-adapted unstimulated mals as in Fig. 6 (thresholds were averaged within 2min rod system surrounding a test stimulus and the time bins). stimulated cone system. For example, the maximum reduction in cone flicker thresholds occurs and Stabell, 1976), the hue threshold for the only when a substantial region of retina surnormals initially declined as the cone system rounding the test stimulus is light-adapted recovered from the bleach. Then the hue (Goldberg et al., 1983; Alexander and Fishman, 1984; Coletta and Adams, 1984), and the threshold rose as the rod system dark-adapted, reaching an asymptote at approximately 20 min threshold-lowe~ng background has an action following the bleach offset. For the two CSNB spectrum of the rod system (Goldberg et af., subjects, there was also an initial period of 1983). It has been suggested that the rod-cone declining hue thresholds - as the cones dark- flicker interaction may be mediated by a pathadapted. However, there was no subsequent way involving horizontal cells, since intrathreshold rise. Instead, the hue threshold for cellular recordings from horizontal cells of these individuals remained relatively constant Xe~#~~s, mudpuppy, and cat show an enhanceduring bleaching recovery. These results con- ment of cone responses when the rod system is firm that the rod-cone hue interaction was desensitized (Frumkes and Eysteinsson, 1987; absent in these two CSNB subjects. Pflug and Nelson, 1987; Witkovsky and Stone, 1987), a result that appears to be analogous to the human psychophysical finding. DISCUSSION The results from our CSNB subjects are The two individuals with CSNB who were consistent with the possibility that horizontal examined in this study had substantially el- cells mediate the rod-cone flicker interaction. evated dark-adapted rod thresholds and selec- The abnormal ERG responses of the CSNB tively reduced amplitudes of the dark-adapted subjects indicate that the defect in the transERG b-wave. As discussed previously (Ripps, mission of rod signals occurs at, or distal to, the 1982) these results suggest a defect in the generator of the &wave (in the present context, transmission of rod signals within their retinas. the terms distal and proximal refer to levels Consistent with the impairment of rod system within the visual information pathway from function in these individuals, we observed that photoreceptors to visual cortex). Since the 6the rod-cone hue interaction was absent. How- wave is thought to be generated by Miiller cells ever, the rod-cone flicker interaction was nor- (Kline et al., 1978; Newman, 1986) in response mal. Since the two types of rod-cone interaction to on-bipolar cell activity (Knapp and Schiller, were differentially affected in the same individu1984), the defect in CSNB appears to occur at, als with this nightblinding retinal disorder, our or distal to, the bipolar cell level. If this hypothresults demonstrate that the interactions must esis is correct, then the fact that the rod-cone jr
CSNS+l
A
KENNETHR.
582
ALEXANDERel al.
flicker interaction was normal in these CSNB subjects indicates that the interaction is mediated at a retinal locus that is also at, or distal to, the bipolar cell level. Moreover, if the rod-cone flicker interaction is mediated by a horizontal cell pathway, then the normal adaptational properties of the rod-cone flicker interaction in the CSNB subjects (as shown in Figs 3 and 5) indicate that their rod photoreceptors have a normal modulation of neurotransmitter release. The mechanism underlying the rod-cone hue interaction is less certain. Unlike the rod-cone flicker interaction, the rod-cone interaction in the detection of hue apparently occurs between rod and cone signals that are generated directly in response to a test stimulus. One possibility is that an achromatic signal from the stimulated rod system may desaturate a chromatic cone signal (Lie, 1963; Spillmann and Conlon, 1972). A second possibility is that signals from the rod system may modify the response of coloropponent neurons (Stabell and Stabell, 1976). Electrophysiological studies indicate that there are many levels within the visual system at which such an interaction between rod and cone signals could occur (e.g. Wiesel and Hubel, 1966; Raynauld, 1972; Enroth-Cugell et al., 1977; Nelson, 1977; Witkovsky and Stone, 1983; Smith et al., 1986). Nevertheless, the absence of the rod-cone hue interaction in our subjects with CSNB demonstrates that this interaction is mediated at, or proximally to, the site of the visual defect in this disorder. Acknowledgements-The authors thank Neal Peachey for helpful comments on the manuscript and Kathleen Louden for editorial assistance. The research was supported by NE1 Grant EYO4848, NE1 Core Grant EY01792, a Center Grant from the National Retinitis Pigmentosa Foundation Figbting Blindness, Baltimore, Maryland, and an Unrestricted Grant from Research to Prevent Blindness fnc., New York.
REFERENCES Alexander K. R. and Fishman G. A. (1984) Rod-cone interaction in flicker perimetry. Br. J. Oph&zZ. 68, 303-309. Alexander K. R. and Fishman G. A. (1985) Rod-cone interaction in flicker perimetry: evidence for a distal retinal locus. Documenta Ophth. 60, 3-36. Alexander K. R. and Fishman G. A. (1986) Rod influence on cone flicker detection: variation with retinal eccentricity. Vision Res. 26, 827-834. Arden G. B. and Hogg C. R. (1985) Rod-cone interactions and analysis of retinal disease. Br. 1. Ophtkal. 69, 404-415.
Boynton R. M., Schafer W. and Neun M. A. (1964) Hue-wavelength relation measured by color-naming
method for three retinal locations. Science, N.Y. t46, 666-668. Carr R. E., Ripps H., Siegel 1. M. and Weale R. A. (1966) Rhodopsin and the electrical activity of the retina in congenital night blindness. Invest. Ophrhaf. 5, 497-507. Coletta N. J. and Adams A. J. (1984) Rod-uine interaction in flicker detection. Fi.s&r Res. 24, 1333-1340. Enoch J. M., Fitzgerald C. R. and Campos E. C. (1981) @antitative Layer-by-Iayer Analysis. Grune & Stratton,
Perimeter
An
Extended
New York. Enroth-Cugell C., Hertz B. G. and Lennie P. (19’77) Convergence of rod and cone signais in the cat’s retina. J. Physiol., Lond. 269, 297-318. Fishman G. A., Buckman G. and Van Every T. (1977) Fundus flavimaculatus: A clinical classification. Documenta Ophrh. Proc. Ser. 13, 213-220. Frumkes T. E. and Eysteinsson T. (1987) Suppressive rod
Guth S. L., Massof R. W. and Benzschawel T. (1980). Vector model for normal and dichromatic color vision. J. opt. .POC.Am. 70, 197-212. Kline R. P., Ripps H. and Dowling J, E. (1978) Generation of b-wave currents in the skate retina. Proc. nurn. Acad. Sci. U.S.A. 75, 5727-5731. Knapp A. G. and Schiiler P. H. (1984) The contribution of on-bipolar cells to the electroretinogram of rabbits and monkeys: A study u&g 2-amino-%pbosphonobutyrate (APB). Vision Res. 24, 1841.-1846. Lie I. (1963) Dark adaptation and the photochromatic interval. Documenta Uphth. 17, 41 l-510. Massof R. W. and Finkelstein D. (1981) Two forms of autosomal dominant primary retinitis pigmentosa. Documenta Ophth. 52, 289-346.
Miyake Y., Yagasaki K., Horiguchi M., Kawase Y. and Kanada T. (1986) Congenital stationary night blindness with negative electroretinogram: A new classification. Archs ~ph~hai. 104, 1013-1020. Nelson R. (1977) Cat cones have rod input: A comparison of response properties of cones and horizontal cell bodies in the retina of the cat. J. camp. Xewof. 172, 109-136. Newman E. A. (1986) Physiological properties aud possibie functions of Mtiller cells. Neurosri Res., Suppl. 4, s209s220. Peachey N. S., Seiple W. H., Auerbach E. and Armington J. C. (1987) Rod influence on thresboids using different detection criteria during dark adaptation. Acta psyckai. 64, 261-270. PtTug R. and Nelson R. (1987) Background enhancement of cone signals in cat horizontal cegs.. Invesr. Opfirhal. visual Sci., Supll. 28, 240. Prestrude A. M.. Watkins L. and Watkins J. (t9?8) Interocular light adaptation effect on the Lie “specific threshold.” Vision Res. lg. 855-857. Raynauld J.-P. (1972) Gddfish -retina: Sign of the rod input in opponent color ganglion cells. Science, N.Y. 177, 84-85.
Rod-cone interaction and nightblindness Ripps H. (1982) Night blindness revisited: From man IO molecules. Invest. Ophthal visual Sci. 23, 588-609. Schubert G. and Bornschein H. (1952) Beitrage zur Analyse des menschlichen Elektroretinogramms. Ophrhalmologica 123, 396411. Smith R. G., Freed M. A. and Sterhng P. (1986) Microcircuitry of the dark-adapted cat retina: Functional architecture of the rod-cone network. J. Neurusci. 6, 3505-3537.
Spillmann L. and Conlon J. E. (1972) Photochromatic interval during dark adaptation and as a function of background luminance. J. opt. Sac. Am. 62, 182485. Stabell B. and Stabell I-J. (1976) Effects of rod activity on color threshold. Vision Res. 16, 1105-l 110. Wiesel T. N. and Hubel D. H. (1966) Spatial and
583
chromatic interactions in the lateral genicuiate body of the Rhesus monkey. J. Neurophysioi. 29, 1115-1156. Witkovsky P. and Stone S. (1983) Rod and cone inputs to bipolar cells and horizontal cells of the Xenopus retina. Vision Res. 23, 1251-1258.
Witkovsky P. and Stone S. (1987) GABA and glycine modify the balance of rod and cone inputs to horizontal cells in the Xenopus retina. Expl Biol. 47, 13-22. Wyszecki G. and Stiles W. S. (1982) Color Science: Concepts and Methods, 2nd edn. Wiley, New York. Young R. S. L., Price J. and Harrison J. (1986) Psychophysicai study of rod adaptation in patients with congenital stationary night blindness. C&z. Vision Sci. 1, 137-143.