SPATIAL FREQUENCY (CPD) Contrast evoked potentials in strabismic and anisometropic amblyopia. DENNIS M. LEVI 10; 6 :

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1 Number 6 Reports 571 Contrast evoked potentials in strabismic and anisometropic amblyopia. DENNIS. VI AND RONALD S. HARWERTH. Steady-state visual evoked potentials were elicited by the appearance I disappearance of sinusoidal gratings of varying spatial frequency for both eyes of amblyopic subjects. The amblyopic eyes showed reduced responses and a phase shift relative to the nonamblyopic eyes across a wide range of spatial frequencies. Both the nonamblyopic and amblyopic eyes showed a linear relationship between the evoked potential amplitude and the logarithm of the stimulus contrast; however, the slope of the line was flatter for the amblyopic eyes. 10; SUBJECT:. O O.D. O.S. 0 SUBJECT: L.N. O O.D. Q O.S 0 Amblyopia, due to strabismus or anisometropia in humans, is a unilateral condition in which the corrected visual acuity is reduced although there are no organic signs. In addition to the reduced acuity as measured by the high-contrast letters of a Snellen acuity test, we have recently shown that the contrast sensitivity of amblyopes is depressed over a wide range of spatial frequencies.' Analogous data for kittens have been presented by Ikeda and Wright, 2 who have shown that spatial resolution of high-contrast gratings is reduced for neurons in the lateral geniculate nucleus (LGN) of kittens raised with unilateral esotropia. ore recently, Blakemore and Eggers 3 have also demonstrated reduced contrast sensitivity of cortical units in kittens raised with anisometropia. These electrophysiological studies suggest that the anomaly in the responses of amblyopic eyes for threshold spatial contrast 1 ' 3 is probably present over a wide range of contrast values above threshold. 2 Thus an investigation of the response properties of the amblyopic eye for a variety of spatial frequencies at contrast values well above threshold should provide extremely valuable information in the characterization and description of the mechanism of amblyopia. The psychophysical methods necessary for such an investigation (e.g., magnitude estimation) are difficult to employ efficiently; however, the visual evoked response (VER) amplitude is proportional to the logarithm of the stimulus contrast 4 and has also been shown to correlate well with the magnitude of perceived contrast. 5 Therefore we have employed the VER in order to assess the response of the amblyopic eye to spatial contrast at suprathreshold levels and in an attempt to bridge the gap between the psychophysics and electrophysiology. In order to provide a direct comparison with the psychophysical and electrophysiological studies de- 2 3H 10: 3- SUBJECT: S.H O O.S. 20/15 O.D. 20/60 SUBJECT: T.T. O 0.0. O.S. 20/ SUBJECT: H.T. O O.D. 20/15 0 O.S. 20/60.5 I SPATIAL FQUENCY (CPD) Fig. 1. VER spatial tuning functions for the nonamblyopic (circles) and amblyopic (squares) eyes of the five subjects. Stimulus contrast was scribed above, the stimuli used in this study were sinusoidal gratings. This type of stimulus provides several advantages. The gratings consist of only a single spatial frequency component, whereas checks or square wave gratings have multiple spa /78/ $00.50/ Assoc. for Res. in Vis. and Ophthal., Inc.

2 572 Reports Invest. Ophthalmol. Visual Sci. June 1978 Table I. Visual characteristics of subjects Subject Sex Age Visual acuity Ametropia Fixation Binocular status Previous treatment.. L. N. T. T. S. H. H. T. F F /80 20/60 20/15 20/15 20/ /-2.50 x /-0.25 x /-0.50 x Piano +0.50/-0.50 x 70 Piano +3.00/-1.00 x nasal and superior steady eccentric fixation 6A E. T., L. E. No strabismus No strabismus 6A E. T., R. E. icro E. T., L. E. Strabismus surgery and occlusion at age 7 Direct occlusion at age 4 tial frequency components which may be differentially detected by amblyopic and nonamblyopic eyes. The size, contrast, and temporal frequency of appearance of the gratings can be varied with no change in the mean luminance. In addition, detection of these stimuli is relatively unaffected by eye movements. Although the physiological genesis of the VER is not well understood, if the VER reflects the amblyopic process, then the neural origin can be assumed to be at or prior to the neurons which generate the VER. ethods. The visual stimuli were similar to those used in our phychophysical studies.' Gratings with a sinusoidal luminance profile were electronically generated on an oscilloscope (odel 5103N with a P31 phosphor; Tektronix, Inc., Beaverton, Ore.) with the method of Campbell and Green. 6 This system allowed the spatial frequency and contrast to be varied while maintaining a constant mean luminance of 15.0 cd/m 2. The screen size was approximately 7 degrees at a viewing distance of 72 cm. An analogue switch gated the z-axis, so that the gratings appeared and disappeared at 8 or 16 Hz. A maximum contrast of 0.44 was used in these studies. Procedures. VER's were recorded with monopolar "referential" electrodes, with the active electrode on the midline 2 cm above the inion and referenced to one ear, and with the other ear serving as ground. Responses were amplified via a Grass amplifier (Grass Instrument Co., Quincy, ass.) with a gain of 10 4 and a high and low 3 db. roll off of 300 and 0.01 Hz, respectively. One hundred stimulus presentations were averaged in a 24 to 48 sec test period, in a Nicolet 1080 signal processor (Nicolet Instrument Corp., adison, Wise), which was programmed to compute a discrete Fourier transform of the averaged VER. The external address advance of the signal processor was electronically stepped 256 times for each pattern appearance, thus ensuring an exact integer number of stimulus repetitions (four) within the recording window and eliminating windowing considerations in the data transform. Subjects. The subjects were five unilateral amblyopes between 15 and 30 years of age with acuity of 20/60 to 0 in the amblyopic eye. The visual characteristics of the subjects are summarized in Table I. All subjects had clear media and normal fundi and were appropriately corrected for refractive error during the experiments. Two of the subjects (H. T. and S. H.) had undergone direct occlusion treatment in early childhood. Results. The "steady-state" VER's produced by our techniques are a repetitive sinewave with most of the power at the frequency of pattern appearance. Blank field trials were used to establish a "noise" level, and the data are plotted in terms of the signal/noise ratio (i.e., the ratio of the amplitude of the fundamental Fourier component elicited by the stimulus relative to the amplitude of the same frequency component during a blank field trial). Fig. 1 shows the VER data for the amblyopic (squares) and nonamblyopic (circles) eyes of the subjects. In these data the contrast of the gratings for all spatial frequencies was The data are plotted in terms of the signal/noise ratio of the VER as a function of spatial frequency. The log-log

3 Number 6 Reports ,0- z3.0- CO 7* o y 0 N \ SUBJECT. O D \ O.D. OS C PD.025 O.I S.H. 21- leoh LJ CO < ^ O O 10-1 ^ SPATIAL FQUENCY(CPD) Fig. 2. A, VER spatial tuning functions for the nonamblyopic (circles) and amblyopic (squares) eyes of subject.. Stimulus contrast was B, Psychophysical threshold contrast sensitivity functions for the nonamblyopic (circles) and amblyopic (squares) eyes of subject.. coordinates are used to facilitate comparison with the psychophysical threshold data, which are usually plotted in this manner. For all subjects, the VER for the nonamblyopic eyes shows a high degree of spatial specificity, with a peak at 3 to 4 cpd, and considerable high and low spatial frequency attenuation. The data for the amblyopic eyes are markedly different, with lower signal/noise ratios across most of the spatial frequency spectrum. Although the absolute VER amplitudes varied somewhat from trial to trial, the shapes of the spatial tuning functions remained consistent. The noise levels (as operationally defined above) for the amblyopic and nonamblyopic eyes did not differ systematically, although for several of the subjects more alpha was evident in the ongoing electroencephalogram while the amblyopic eye viewed the stimulus than with the cr 9 ; CONTRAST O.I 0.25 PLANO I.OOD. DEFOCUS A2.00D.DEF0CUS.25 Fig. 3. VER signal/noise ratio vs. stimulus contrast for gratings of 4 cpd. A, Subject.. Nonamblyopic eyes (circles) and amblyopic eyes (squares). B, Subject S. H. Nonamblyopic eyes (circles) and amblyopic eyes (squares). C, Optical defocus of 0.00 D (filled circles), 1.00 D (filled squares) and 2.00 D (filled triangles). nonamblyopic eyes. The data for the three strabismic subjects showed little difference between the two eyes at 0.50 cpd, whereas the data of the two nonstrabismic subjects (L. N. andt. T.) were similar in showing reduced signal/noise ratios for all spatial frequencies. The reason for this intersubject variability at the lowest spatial frequency is not clear; however, it is probably not greater than the intersubject variation for VER's to low spatial frequencies in normal subjects. 7 For all the subjects, the difference in the amplitude of the

4 574 Reports Invest. Ophthalmol. Visual Sci. June 1978 fundamental component of the VER between the two eyes is greater for high spatial frequencies than at low spatial frequencies. For both amblyopic and nonamblyopic eyes, the phase lag of the fundamental Fourier component of the VER increased with increasing spatial frequency. This finding is consistent with the longer response time for high spatial frequencies observed psychophysically. 8 In addition, for a given spatial frequency, the phase lag of the amblyopic eye was generally longer than that of the nonamblyopic eye, particularly at higher spatial frequencies, although variability in the phase data was considerable. Fig. 2 shows a comparison of the suprathreshold spatial tuning curves (Fig. 2, A) and the psychophysical threshold contrast sensitivity curves (Fig. 2, B) determined under precisely the same stimulus conditions for subject.. The qualitative similarity between the VER and psychophysical data is apparent, with both functions reflecting the amblyopic process. In order to further assess the responses of the amblyopic eye to suprathreshold contrast stimuli, we varied the contrast in 4 db steps over a contrast range of 0.02 to 0.40 for several spatial frequencies. Fig. 3, A and B, shows examples of data for subject.. and S. H. for a spatial frequency of 4 cpd. The abscissa is the contrast of the stimulus grating (plotted on a logarithmic scale), and the ordinate represents the signal/noise ratio of the VER. For both the nonamblyopic and amblyopic eyes, the relationship between the logarithm of the stimulus contrast and the evoked potential amplitude is linear over some range of contrast values. 4 We have fitted the ascending points via linear regression, and the correlation coefficients of the points to the line for all the data varied from 0.95 to 0.99 for the nonamblyopic eyes, and from 0.87 to 0.97 for the amblyopic eyes. Characteristically, the data for the amblyopic eyes show a lower slope than those of the nonamblyopic eyes, particularly at spatial frequencies of 4 cpd and higher. The contrast responses of the amblyopic and nonamblyopic eyes appear to saturate within a similar range of contrast values, although we have not evaluated the responses to higher contrast levels; however, the contrast levels at which saturation appears to occur are similar to the levels reported by Spekreijse et al. 9 We have noted a fair degree of individual variation in the range of contrast values over which the VER amplitudes show a linear change; for example, the data for both eyes of subject S. H. (Fig. 3, B) appear to saturate at higher contrast values than those of subject..; however, the lower slope of the amblyopic eye data compared to the nonamblyopic eye was quite characteristic. The lower slope of the contrast function of the amblyopic eye is not explained on the basis of optical blur, since die effect of blur is to simply reduce the effective contrast. An optical blur should result in a shift of the line to the right, but no change in the slope. Fig. 3, C, shows the results of control experiments widi varying amounts of defocus. The effect of optical blurring is simply to shift the line to die right without significantly altering the slope. Discussion. The VER data suggest abnormal contrast responses of the amblyopic eyes across a wide range of spatial frequencies, with the differences between the amblyopic and nonamblyopic eye being most marked for high spatial frequencies. The abnormality was manifest as a lower amplitude and a phase lag of the fundamental component of the VER and for some subjects a change in the shape of the VER spatial tuning function. These findings are consistent with psychophysical contrast sensitivity functions in strabismic and anisometropic amblyopia 1 and also with the findings of reduced spatial resolution of LGN cells of esotropic cats 2 and the reduced contrast sensitivity of cortical cells in kittens raised with induced anisometropia. 3 Although the finding of reduced VER amplitudes of the amblyopic eye to patterned stimuli is not new, previous VER studies of amblyopia have used square wave gratings or checkerboard patterns. These stimuli consist of multiple spatial-frequency components which may differentially affect the VER of die amblyopic and nonamblyopic eyes. In the present study, these difficulties were eliminated by the use of sinusoidal gratings, each grating consisting of only a single spatial frequency. Thus these data provide direct information relative to the spatial frequency characteristics of the VER of the amblyopic visual system. In addition, die data allow a direct comparison with psychophysical contrast sensitivity functions. It is interesting that the contrast functions of the amblyopic eye as well as those of the nonamblyopic eye are described by a linear relationship between the logarithm of the stimulus contrast and the VER amplitude; however, the reduced slope of the contrast function of the amblyopic eye also suggests that, at least at the level of the structures which generate the VER, there is no compensation for the reduced contrast sensitivity as has been shown psychophysically in some meridional amblyopes. 10

5 Number 6 Reports 575 Since a deficit in the contrast sensitivity of the amblyopic eye shown to be present in psychophysical threshold data 1 is also evident in the suprathreshold VER data, this provides a valuable technique for the assessment of subjects in which psychophysical data are not readily obtainable, e.g., infants or young children. In addition, the lower slope of the VER contrast functions in amblyopic eyes serves to differentiate between reduced responses due to optical blur and the neural consequences of amblyopia. From the University of Houston College of Optometry, Houston, Texas. Supported by Research grants R01 EY 01728, R01 EY 01139, and K07 EY from the National Eye Institute, Bethesda, d. Submitted for publication Sept. 23, Reprint requests: Dr. Dennis. Levi, College of Optometry, University of Houston, Houston, Texas Key words: amblyopia, contrast sensitivity, visual evoked responses FENCES 1. Levi, D.., and Harwerth, R. S.: Spatio-temporal interactions in anisometropic and strabismic amblyopia, INVEST. OPHTHALOL. VISUAL SCI. 16:90, Ikeda, H., and Wright,. J.: Properties of LGN cells in kittens reared with convergent squint: a neurophysiological demonstration of amblyopia, Exp. Brain Res. 25:63, Blakemore, C, and Eggers, H.. Animal models for human visual development. In Cool, S. J., and Smith, E. L., editors: Frontiers in Visual Science, Berlin, Springer-Verlag (in press, 1978). 4. Campbell, F. W., and affei, L.: Electrophysiological evidence for the existence of orientation and size detectors in the human visual system, J. Physiol. 207:635, Fiorentini, A., and affei, L.: Suprathreshold contrast perception and its electrophysiological correlate, Optica Acta 190:363, Campbell, F. W., and Green, D. G.: Optical and retinal factors affecting visual resolution, J. Physiol. 81:576, Padmos, P., Haagman, J., and Spekreijse, H.: Visual evoked potentials to patterned stimuli in monkey and man, Electroencephalogr. Clin. Neurophysiol. 35:153, Breitmeyer, B. G.: Simple reaction time as a measure of the temporal response properties of transient and sustained channels, Vision Res. 15:1411, Spekreijse, H., vandertweel, L. H., andzuidema, T.: Contrast evoked responses in man, Vision Res. 13:1577, Georgeson,. A., and Sullivan, G. D.: Contrast constancy: deblurring in human vision by spatial frequency channels, J. Physiol. 252:627, Cup electrode for human ERG. ARTHUR KOBLASZ. This report describes a cup electrode for measuring, the human electroretinogram which improves the comfort of a subject while providing sufficiently large signal-tonoise ratios for most applications. The cup electrode is demonstrated by measuring the electroretinogram for small-amplitude flash stimuli. We have developed an electrode for measuring the human electroretinogram (ERG) with some features similar to a design proposed by Hartline. 1 The cup electrode shown in Fig. 1 improves the comfort of a subject and reduces the subject's urge to blink, which is a major problem for continuous stimuli such as sinewave or white-noise modulations. The eyecup depicted in Fig. 1 is normally oriented in an upright position and is filled with a solution which approximates tear fluid. The subject merely submerges his eye downward into this electrolytic solution, and a Ag/AgCl electrode suspended in the solution measures the ERG response to light projected through the front clear surface of the eyecup. Hence, only the fluid touches the subject's eye. A similar cup electrode measures the ERG of the unstimulated eye and is used as a reference. This reduces the effects of noise signals which are common to both eyes, e.g., electro-oculogram signals resulting from conjugate eye movements. It also tends to further reduce the frequency of eye blinks, since both eyes are bathed in the artificial tear fluid solution. In fact, if the ph and temperature of the solution are matched to those of natural tears, the urge to blink can be nearly suppressed. The eyecup is mounted to an optical assembly also shown in Fig. 1 which creates either a 45 axwellian view or a 45 diffuse view of the light stimulus. For diffuse viewing, a small hole can be drilled into the diffuser plate, presenting the end surface of the fiber optic as afixationtarget. Alternatively, a target stimulus can be presented to the other eye. For axwellian viewing, an aspheric lens is substituted for the diffuser plate, and a cross-hair target is positioned to appear virtually at infinity. The optical assembly with attached cup electrode is mounted to a supporting structure which permits easy movement to any orientation that is comfortable for the subject. Furthermore, the assembly can be optically coupled via the fiber optic to any existing light source /78/ $00.30/ Assoc. for Res. in Vis. and Ophthal., Inc.