Dichoptic Suppression of mfVEP Amplitude: Effect of Retinal Eccentricity and Simulated Unilateral Visual Impairment

Abstract

Purpose.: To investigate the effect of retinal eccentricity on the phenomenon of dichoptic suppression of the mfVEP amplitude and to examine the relationship between the degree of simulated unilateral visual impairment and the possible release of dichoptic suppression in the contralateral eye.

Method.: Eight subjects with corrected visual acuity (VAc) >6/6 and stereoacuity >60 sec arc underwent monocular and dichoptic pattern-pulse mfVEP. Dichoptic stimulation was repeated with refractively induced blur of one eye with +4-D and +6-D lenses above distance correction.

Results.: Dichoptic recording resulted in significant reduction of averaged mfVEP amplitude (19.8% ± 4.9%, paired t-test, P = 0.00003). The magnitude of suppression, while statistically significant at all eccentricities, was significantly larger in the central part of the visual field and diminished toward the periphery. Refractive blur, used to simulate visual impairment produced variable degrees of amplitude reduction in the blurred eye and resulted in amplitude increases in the contralateral eye. There was a highly significant correlation between the magnitude of amplitude reduction in the blurred eye and increase in amplitude (i.e., release of dichoptic suppression) in the contralateral eye (r = 0.91, P < 0.0001).

Conclusions.: The study demonstrated that dichoptic stimulation results in eccentricity-dependent suppression of mfVEP amplitude. Factors affecting visual performance of one eye (monocular blur) promote the release of dichoptic suppression in the fellow (unaffected) eye. This phenomenon leads to an increase in intereye asymmetry and therefore may improve early detection of ocular diseases, especially monocular pathologic processes.

Multifocal visually evoked potentials (mfVEPs) have multiple applications in various fields of diagnostic ophthalmic medicine, including multiple sclerosis and glaucoma, ^1,2 and provide a reliable and objective method of assessing neural damage to the optic pathways. ^3,4 The method of presentation typically involves a pseudorandom sequence of contrast-reversing checkerboard patterns, scaled for eccentricity, presented monocularly to a subject with bipolar electrodes mounted over the occipital lobe. ⁵ The techniques for presenting and recording mfVEPs have developed over the past 16 years (since Baseler et al. ⁶ first made inroads into presentation of multifocal stimuli), including the use of multiple electrodes, ⁵ EEG scaling and intereye asymmetry analysis, ^7,8 and introduction of pattern–pulse sparse stimulation. ^{9 –12}  

However, the technique, as typically applied, is performed monocularly and requires 20 to 30 minutes of recording time. Monocular recording also results in unequal psychophysical conditions during the recording of each eye. As has been reported, asymmetry analysis of mfVEP amplitude is the most sensitive way to detect early changes. ^8,9 However, toward the end of the test, the patient may fatigue or lose attention, which may negatively affect recording of the second eye, producing artificial asymmetry and therefore false-positive results. Simultaneous recording of both eyes would therefore be beneficial. 

Dichoptic and binocular VEP recording has been described by using full-field VEPs with pattern-reversal viewing, ¹³ followed later by the use of pseudorandom binary sequences to independently stimulate each eye. ¹⁴  

James ¹² demonstrated the feasibility of dichoptic independent mfVEP recording conditions with liquid crystal polarizing shutters. These alternately stimulate the two eyes, but reduce luminance substantially. He also described the benefits of temporal sparseness on recording. ¹¹ We demonstrated the feasibility of dichoptic mfVEP recordings with virtual-reality goggles. ^15,16 The advantage of using identical recording conditions for both eyes is decreased intereye variability and reduced recording time. ¹⁵ Intrinsic to dichoptic recording, however, is a degree of mfVEP amplitude suppression as a result of having two competing images presented simultaneously. ^{17 –19} The degree of suppression was demonstrated to be related to the closeness, in timing, of the presentation of images to each eye, with increasing temporal separation resulting in increased amplitude. ¹⁵  

When applied to a group of patients with early glaucoma, dichoptic stimulation demonstrated more extensive abnormalities (namely, larger intereye asymmetry) than did a monocular technique. ¹⁶ A few possible explanations for the observed trend were suggested, including a closer asymmetry among normal eyes, additional cortical suppression of a relatively less-defined image from a glaucomatous eye or release of suppression in the contralateral eye, which may increase intereye asymmetry (Graham S, et al. IOVS 2007;48:ARVO E-Abstract 219). Therefore, the phenomenon of dichoptic suppression of the mfVEP, despite its negative affect on the magnitude of the mfVEP, may be helpful in detection of early unilateral abnormalities. 

Most frequently, early glaucoma presents as a localized midperipheral visual field defect rather than diffuse reduction of sensitivity. Therefore, in the present study, we sought to investigate the effect of retinal eccentricity on the described phenomenon of dichoptic suppression of the mfVEP amplitude. The second purpose was to examine the relationship between degree of simulated unilateral visual impairment (with visual blur) and possible release of dichoptic suppression of the mfVEP amplitude in the contralateral eye as a probable mechanism for increased intereye asymmetry in early glaucoma. Since dioptric blur eliminates higher spatial frequencies of the mfVEP stimulus (which predominantly stimulate central field), it was expected to produce a wide range of amplitude reduction at different eccentricities in the blurred eye. ²⁰  

Methods

Dichoptic Setup

We used a novel binocular VEP setup for dichoptic mfVEP testing. Previous reports by Arvind et al. ^15,16 described the use of virtual-reality goggles. However, inability to monitor fixation during recording made the technology difficult to implement. The new setup consisted of two mounted LCD screens (response time 2 ms; Flatron L1954TQS monitor; LG, Englewood Cliffs, NJ) on each side of the subject reflected through centrally located semitransparent mirrors to project a stimulus of 0° to 24° of eccentricity simultaneously to each eye. Mounted behind the mirrors were two infrared cameras, which continually monitored pupil position. Four infrared light-emitting diodes were placed around a lens holder to illuminate the eyes (Fig. 1). 

Figure 1.

 

(A) Stimulus with eccentricities, ranging from 0.5° (target) to 24° in the periphery. (B) The binocular (dichoptic) mfVEP setup: Stimuli from right and left monitors are projected through one-way mirrors and viewed by the subject as a single image. Two infrared cameras are positioned behind the mirror to monitor pupil position.

Stimuli were presented simultaneously (dichoptically) to both eyes, as described previously. ¹⁵ Briefly, the display to each eye consisted of a cortically scaled dartboard (Fig. 1A) with 56 segments arranged in five concentric rings (1°–2.5°, 2.5°–5°, 5°–10°, 10°–16°, and 16°–24°) and a central fixation target extending up to 0.5°. The stimulus in any segment consisted of a 4 × 4 blue-on-yellow (BonY) ²¹ check pattern. Segment size was scaled according to the cortical magnification factor. ²² Corresponding to the size of the segments, the size of the individual checks also increased with eccentricity. The luminance of the blue check was 40 cd/m², and the luminance of the yellow background was 125 cd/m². A central fixation target was provided that consisted of rotating and slowly changing letters. These features—the ring arrangement and the fixation target—were identical for both eyes, which helped to fuse the images. The patient, therefore, perceived a single binocular image of the dartboard stimulus. 

Pseudorandom binary sequences (PRBSs) were used to drive the stimuli at each test location, so that the presentation at each location was random and independent of other locations. Each binary sequence had a 50% probability of being 1 or 0 at any point of time. Element 1 was represented by two consecutive states: pattern on, lasting two frames of the screen (33.3 ms), when the stimulus pattern was displayed, and pattern off, lasting 16 frames (266.4 ms), when the whole segment was diffusely illuminated with an intensity of the mean luminance. Element 0 consisted of the pattern-off state for 18 frames. The average rate of presentation at each segment was 1.66 times/s. The presentation of the stimulus to the corresponding segment of the second eye was always shifted by nine frames; therefore, the minimum separation between stimuli to corresponding areas of the visual fields of both eyes was seven frames (116.7 ms). Three runs were recorded, each lasting 139 seconds. The technique is described in detail elsewhere. ^15,16 Monocular recordings were performed with the same setup with one eye covered. 

Recording

Four gold cup electrodes (Grass, West Warwick, RI) mounted in an occipital cross-electrode holder were used for bipolar recording. Two electrodes were positioned 4 cm on either side of the inion: one in the midline 2.5 cm above the inion and one 4.5 cm below the inion. Electrical signals were recorded along four channels as the difference between superior and inferior and between left and right, and obliquely between the left and inferior and right and inferior electrodes. A ground electrode was placed on one ear lobe. Cortical responses were amplified 100,000 times and band-pass filtered (1–20 Hz). Uniquely designed software correlated the responses with the stimulating PRBS and attributed the calculated signals to the respective segments of the visual field. This software also scaled the responses to the background EEG to reduce the interindividual variability, described elsewhere. ²³ For every segment, the largest peak-to-trough amplitude of each wave within the interval of 60 to 200 ms was determined for each channel. The wave of maximum amplitude from each segment in the field from the four channels was automatically selected, and the software created a combined topographic map. ²⁴  

Subjects

Eight subjects (average age, 30.2 ± 7.9 years) were recruited for the study. All had best-corrected visual acuity of 6/6 or better in both eyes, anisometropia (if any) less than 1.5 D, stereoacuity of 40 sec arc on Titmus fly stereogram, and normal ophthalmic examination results. Written, informed consent was obtained, and the experiments were conducted according to the tenets of Declaration of Helsinki. There were five men and three women. A hole-in-the-card test was used to assess ocular dominance, with seven right eyes and one left eye determined to be dominant. 

All subjects underwent monocular and dichoptic mfVEP recordings in random order. Both eyes were optimally corrected for distance with near correction, if needed, for all recordings. 

To simulate reduced visual input in one eye, we placed lenses of +4 and +6 D over distance correction in front of each subject's right eye before additional dichoptic recordings were performed thus effectively inducing +1 and +3 D, respectively, of blur for near. 

Analysis

The coefficient of dichoptic suppression of the VEP amplitude was calculated as the difference between the averaged monocular amplitude (A _m) and the averaged dichoptic amplitude (A _b), divided by the monocular amplitude. To investigate the effect of retinal eccentricity the amplitude of all segments within each ring of the stimulus was also averaged and the coefficient of dichoptic suppression was calculated for each ring.  

 

P < 0.05 was considered significant (SPSS software; SPSS, Chicago, IL). 

Results

The dichoptic recording setup allowed simultaneous acquisition of mfVEPs from both eyes in all subjects. A typical example is presented in Figure 2. 

Figure 2.

 

Typical result of dichoptic recording.

Dichoptic Suppression versus Eccentricity

The average dichoptic suppression of the mfVEP amplitude across the entire field was 19.8% ± 4.9% (paired t-test, P < 0.0001). When analyzed ring-wise, dichoptic amplitude suppression was significant at all eccentricities (Table 1). 

Table 1.

 

Average Dichoptic Suppression at Different Eccentricities

	Eccentricity
	Ring 1	Ring 2	Ring 3	Ring 4	Ring 5
Suppression	34.3 ± 5.9	25.5 ± 5.4	17.0 ± 5.0	14.5 ± 6.0	12.8 ± 8.6
	P < 0.0001	P < 0.0001	P < 0.0001	P = 0.0006	P = 0.004

 Data are the mean percentage of dichoptic suppression ± SD.

The central part of the visual field, however, demonstrated significantly greater suppression compared with the more peripheral areas (P < 0.0001, one-way ANOVA) 

The pattern of dichoptic suppression declined smoothly with eccentricity toward an asymptotic value of ∼10% (Fig. 3). Dichoptic suppression declined from 34% at 2° to 17% at around 10° and changed little beyond that eccentricity. Post hoc analysis (Tukey t-test) demonstrated significant differences for rings 1 and 2, when compared with each other and with the remaining rings (P < 0.01 for all), whereas there was no significant difference between the rings outside 10° of eccentricity. 

Figure 3.

 

Suppression versus eccentricity for dichoptic recording. There is a clearly nonlinear relationship between suppression and distance from the center with a much steeper gradient within the central 10° of eccentricity and flattening of the curve at the periphery.

Effect of Dioptric Blur on Dichoptic Recordings

In dichoptic recording conditions, the visual blur resulted in significant reduction of mfVEP amplitude of the blurred eye. Thus, introduction of a +4-D lens produced 19.6% ± 12.6% reduction of averaged mfVEP amplitude (P = 0.004, paired t-test), whereas a +6-D lens yielded an even larger reduction (38.7 ± 5.1%, P < 0.0001, paired t-test). 

When analyzed ring-wise, amplitude reduction was significant at all eccentricities (Table 2). 

Table 2.

 

Average Reduction Due to Blur versus Eccentricity Showing Significant Suppression through all Eccentricities, with +4-D or +6-D Lens Applied

Lens	Eccentricity
	Ring 1	Ring 2	Ring 3	Ring 4	Ring 5
+4 D	43.5 ± 13.0	37.0 ± 16.6	18.3 ± 14.5	12.2 ± 9.3	8.1 ± 9.6
	P < 0.001	P < 0.001	P < 0.01	P < 0.01	P < 0.05
+6 D	58.8 ± 5.0	56.6 ± 7.0	40.2 ± 9.9	27.7 ± 5.4	20.9 ± 5.7
	P < 0.00001	P < 0.0001	P < 0.0001	P < 0.0001	P = 0.0001

 Data are the mean percentage of reduction due to blur ± SD.

The pattern of amplitude reduction was eccentricity-dependent, with the reduction significantly declining from center to periphery for both levels of visual blur. An individual example is presented in Figure 4. 

Figure 4.

 

An example of mfVEP dichoptic recording with +4-D (top row) and +6-D (bottom row) lenses to induce blur in the right eye.

With blurring, the contralateral eye demonstrated a significant increase in amplitude that was proportional to the degree of blurring. The averaged amplitude of the contralateral eye increased by 9.3% ± 5.0% (P = 0.003) with the +4-D lens and by 16.7% ± 9.3% (P = 0.002) when the +6-D lens was applied. 

Ring-wise analysis demonstrated amplitude increase in the contralateral eye at all eccentricities for both levels of blurring. It was statistically significant in three central rings for both blurring conditions and additionally in ring 4 with the +6-D lens (Table 3). The pattern of amplitude increase again demonstrated strong relations to retinal eccentricity with the central part of the visual field showing a maximum amplitude increase, which gradually diminished toward the periphery. 

Table 3.

 

Release of Suppression in the Left Eye with Right Eye +4-D or +6-D Lens Applied

Lens	Eccentricity
	Ring 1	Ring 2	Ring 3	Ring 4	Ring 5
+4 D	17.6 ± 9.5	14.2 ± 4.5	7.8 ± 4.4	4.6 ± 10	3.1 ± 12.1
	P < 0.01	P < 0.01	P < 0.01	P = 0.25	P = 0.52
+6 D	31.6 ± 17.0	23.8 ± 12.7	12.3 ± 8.1	8.9 ± 10.7	6.2 ± 11.1
	P < 0.001	P < 0.001	P < 0.01	P < 0.05	P = 0.13

 Data are the mean percentage release of suppression in the left eye ± SD.

There was a highly significant correlation (r = 0.95, P < 0.0001) between the degree of amplitude reduction caused by visual blur in one eye and the extent of amplitude increase in the contralateral eye (Fig. 4). 

Latencies were analyzed at different eccentricities and at all four dichoptic settings (monocular/dichoptic/+4D/+6D), and no significant difference was found (P > 0.05, one-way ANOVA). 

Discussion

Dichoptic stimulation has been explored in various forms previously ^11,15,16 and has been shown to be a robust and repeatable method of recording mfVEPs. The technique benefits from shorter testing time and identical psychophysical setting for each eye. It has demonstrated superior capability in detection of abnormalities in early glaucoma compared with monocular recording. ¹⁶ However, the additional defects detected by dichoptic recording tended to be more central, rather than arcuate, as is classically expected of glaucomatous defects. We hypothesized that the release of interocular suppression by early unilateral visual loss contributes to enhanced asymmetry and better detection. Therefore, in the present study, we investigated the degree of interocular suppression induced by dichoptic stimulation at various eccentricities of the visual field and tested the hypothesis that possible release of suppression in the contralateral eye could result in greater intereye amplitude asymmetry in unilateral disease (Graham S, et al. IOVS 2007;48:ARVO E-Abstract 219). 

There were two main findings in this study, both of which have not been reported before. First, there was a strong dependence of the magnitude of suppression of the mfVEP amplitude elicited by dichoptic stimulation on retinal eccentricity. Although average suppression across the whole tested field was under 20%, it reached almost 35% in central region and fell to 12% at around 20° of eccentricity. It was suggested earlier that interocular suppression has cortical origins. Thus, both inhibitory interactions between adjacent ocular dominance columns in the striate cortex ²⁵ and low temporal resolution of binocular neurons ²⁶ have been proposed as mechanisms of interocular suppression. ¹⁵  

The variable degree of suppression across the visual field, however, may also be, at least in part, related to temporal characteristics of neurons in the anterior visual pathway. There are two major pathways, parvocellular and magnocellular, that are anatomically segregated up to the major input layer (4C) of the striate cortex, but converge in higher visual areas. ²⁷ One of the characteristic features of the functional dichotomy between parvocellular and magnocellular neurons is a functional difference in temporal properties of two types of neurons. Parvocellular neurons are slow with sustained response to light (low-pass filter with 5–10-Hz corner frequency), whereas the magnocellular pathway is more transient with band-pass temporal characteristics having maximum sensitivity at approximately 20 Hz. ²⁸ The distribution of parvocellular and magnocellular neurons across the retina is also different. Whereas the central visual field is dominated by P-cells, the relative number of magnocellular neurons increases with retinal eccentricity by a factor of 10. ²⁹ Although most cells in layer 4C are almost completely monocular, neurons in other (higher) layers of the striate cortex tend to be binocular. ³⁰ Therefore, the change in the relative contribution of parvo- and magnocellular neurons into the binocular neurons at higher levels of the striate cortex may result in an increase in their temporal resolution in the more peripheral part of the visual field and lead to a reduction in dichoptic suppression with eccentricity. Further studies (with targeted stimuli) are needed to explore the potential role of each pathway in the mechanism of cortical suppression. 

Second, the study not only confirmed the existence of the phenomenon of the release of amplitude suppression, but more important, demonstrated a strong relationship between the degree of mfVEP amplitude reduction caused by visual impairment in one eye and release of amplitude suppression in the contralateral eye (Fig. 5, 6). 

Figure 5.

 

Relationship between amplitude reduction due to blur and release of suppression in the contralateral (left) eye. The degree of suppression in the blurred eye is directly proportional to the release of suppression in the fellow (nonblurred) eye.

Figure 6.

 

Example of segmental traces from a typical subject, note the decrease in amplitude from monocular, dichoptic and blurring and the subsequent increase in corresponding sector in the nonblurred (contralateral) eye. This is the basis for an increase in asymmetry between scotoma and a healthy corresponding segment. (A) An inferior segment, eccentricity 2.5° to 5°; (B) a superior segment, eccentricity 5° to 10°. The effect is greater for the more central location.

The use of refractive blur was intended to simulate disruption of the normal visual function monocularly. The loss of amplitude due to blur is most likely derived from loss of edge definition of the high-frequency spatial elements, which predominate the central field as stipulated by Winn et al. ²⁰ Because of the variable effect of blur on central and peripheral vision, a wide range of amplitude reductions were produced (varying from 8% to 59% at different eccentricities and different lens strengths). This variation allowed us to study the mechanism of the release of dichoptic suppression of mfVEP amplitude in the contralateral eye quantitatively. The high degree of correlation between reduced visual input to one eye and release of amplitude suppression in the contralateral eye implies that both mechanisms operate at the same level of the visual pathway. It also showed that release of amplitude suppression occurs across the whole visual field, provided suppression itself is large enough. It is noteworthy that as amplitude reduction due to blur in one eye approached 60% (which is comparable to the level of background noise), the release of suppression in the fellow eye reached its maximum value (increase of approximately 30%), coming close to an amplitude of a monocular recording. The central–peripheral differences in the release of interocular suppression may explain the central clustering of the defects that we found earlier among subjects with glaucoma. ¹⁶  

The averaged dichoptic suppression over all eccentricities found in this study was considerably larger than that found by Arvind et al. ¹⁵ with virtual reality goggles. The reason for this difference most likely lies in the difference between the monitors used (liquid crystal on silicon technology, used by Arvind et al., has much faster response time than the LCD monitor used here). In addition the BonY stimulation used in the present study (as opposed to achromatic black-and-white stimulation used previously) may contribute to an increase in suppression, since the temporal sluggishness of the koniocellular pathway is well known. ^31,32  

It should be noted that one limitation of the present study is that the use of a lens to create a monocular visual impairment may not adequately mimic a real scotoma, as a lens-induced blur reduces mostly high-frequency spatial elements. 

Conclusion

The study demonstrated that dichoptic stimulation results in eccentricity-dependent suppression of mfVEP amplitude. It also revealed that factors affecting visual performance in one eye (monocular blur or possibly a monocular pathologic process) not only have a negative effect on dichoptic mfVEP amplitude of the affected eye, but also promote release of dichoptic suppression in the fellow (unaffected) eye. This phenomenon supports our earlier hypothesis that unilateral loss leads to a relative increase in intereye asymmetry and therefore may be used for early detection of unilateral pathologic processes (Graham S, et al. IOVS 2007;48:ARVO E-Abstract 219). 

Footnotes

 Supported in part by an External Collaborative Grant from Macquarie University and Pfizer Australia. AK was supported by the Sydney Foundation for Medical Research.

Footnotes

 Disclosure: J. Leaney, None; A. Klistorner, P; H. Arvind, None; S.L. Graham, P