Doc Ophthalmol DOI 10.1007/s10633-012-9319-0
ORIGINAL RESEARCH ARTICLE
Effect of different stimulus configurations on the visual evoked potential (VEP) Naveen K. Yadav • Diana P. Ludlam Kenneth J. Ciuffreda
•
Received: 15 August 2011 / Accepted: 2 March 2012 Ó Springer-Verlag 2012
Abstract The purpose of this study was to assess changes in the response profile of the pattern visual evoked potential (VEP) using three stimulus configurations simulating visual-field scotomas: central circular and central blank fields increasing incrementally in diameter from 1° to 15°, hemi-field, and quadrant patterns. Five visually normal adult subjects (ages 22–68 years) were tested binocularly at 1 m for each stimulus configuration on 5 separate days. A checkerboard test pattern (64 9 64 black-and-white checks, 85 % contrast, 64 cd/m2 luminance, 20 s of stimulus duration, 2-Hz temporal frequency) was used. The group mean VEP amplitude increased in a linear manner with increase in the central circular diameter (y = 0.805x ? 2.00; r = 0.986) and decrease in central blank field diameter (y = -0.769x ? 16.22; r = 0.987). There was no significant change in latency in nearly all cases. The group mean coefficient of variability results indicated that the VEP amplitude was repeatable for the different stimulus configurations. The finding of VEP response linearity for the circular stimulus fields, and repeatability for all stimulus configurations, suggests that the clinician may be able to use the VEP technique with the suggested test patterns as a rapid and simple tool for
N. K. Yadav (&) D. P. Ludlam K. J. Ciuffreda Department of Biological and Vision Sciences, SUNY State College of Optometry, 33 West 42nd Street, New York, NY 10036, USA e-mail:
[email protected]
objective assessment for several types of visual-field defects for a range of abnormal visual conditions and special populations. Keywords Visual evoked potential (VEP) VEP amplitude VEP latency Visual fields Linearity Repeatability
Introduction Visual-field testing is used to assess the integrity and functionality of the retinal and early afferent visual pathways. For example, it is used to detect and monitor the progression of visual-field loss in a range of ocular and/or neurological diseases, such as glaucoma, macular degeneration, retinitis pigmentosa (RP), acquired brain injury (ABI), Parkinson’s disease, and Alzheimer’s disease [1, 2]. However, in many cases, assessment of the visual field is considered to be unreliable with poor repeatability [3, 4]. In addition, it is a subjective, time-consuming method. Due to these potential problems, conventional visual-field testing has often been called into question. Furthermore, special populations with cognitive impairment (e.g., ABI) frequently have difficulty performing well with conventional subjective approaches to visual-field testing [5]. These individuals may not understand the task and/or remember the instructions. In addition, they may have limitations due to attentional deficits
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(e.g., in Alzheimer’s disease, ADHD, and ABI). Moreover, those having fixational eye movement deficits cannot maintain accurate central fixation for a sufficient period of time during visual-field testing (e.g., 5–10 min), thus biasing the findings and/or increasing response variability. Studies have been conducted to investigate the important issues of repeatability and reliability of clinical visual-field testing. Newkirk et al. [3] and Katz and Sommer [4] assessed visual-field repeatability in normal individuals and in those with glaucoma using automated perimetry. They assessed three factors: false-positive rate, false-negative rate, and the number of fixational losses. The higher the number, the poorer was the test repeatability and reliability. These latter two aspects are essential in the proper diagnosis and monitoring of the progression of ocular and neurological diseases producing visual-field defects. All three values were higher than normal limits in both groups, thus suggesting poor repeatability and lack of good reliability of the correlated visual-field testing. Katz and Sommer [4] found unreliable visual fields in 41 % of the normal and 67 % of glaucomatous patients, all of which were attributed to fixational problems. Lastly, in a related study by Asman et al. [6], they too found that abnormal fixation resulted in increased difficulty in detecting the visual-field loss, as well as increased threshold variability. The visual evoked potential (VEP) method circumvents to a considerable extent all of the above potential problems involved in conventional visual-field testing. The conventional VEP test paradigm is an objective, rapid, repeatable, and non-invasive method to quantify the integrity and functionality of the retinal and the early afferent visual-cortical pathways [7, 8]. Furthermore, it provides global real-time information as to the patient’s performance (i.e., assessing VEP amplitude and latency as the averaged responses dynamically summate over time) for the specific stimulus pattern. Moreover, the objective VEP information can be used to correlate with, and corroborate, the conventional subjective psychophysical results of a clinical visualfield assessment [9]. Several studies have used a high-contrast central stimulus of progressively increasing size to assess changes in the VEP response in visually normal individuals to simulated visual-field defects in the central field and near retinal periphery. Circular stimulus field sizes ranged from 1.25° to 15°, whereas
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square stimulus field sizes ranged from 2° to 24°, with a full complement of check sizes (6–80 min arc). Some of the studies found a ‘‘nearly’’ linear response profile [10–13], whereas others found a clear nonlinear VEP response profile [14, 15]. Thus, the findings of these earlier studies were equivocal. Second, and of critical importance, none of these studies assessed repeatability in their test populations. Lastly, effect on response latency was not considered in any of the investigations. Several studies have used a central blank field of progressively increasing size surrounded by a highcontrast checkerboard stimulus to assess changes in the VEP response in visually normal individuals to simulated central visual-field defects. Circular blank field sizes ranged from 1.25° to 15°, whereas square blank field sizes ranged from 2° to 24°, with a full complement of check sizes (6–80 min arc). Some of the studies found a ‘‘nearly’’ linear response profile [11–13, 16], whereas others found a clear non-linear VEP response profile [14]. Thus, the findings of these earlier studies were equivocal. Furthermore, only one study assessed the effect on response latency [16]; it remained constant for the range of field sizes tested. Again, and of critical importance, none of these studies assessed repeatability in their test populations. Two studies have investigated the effect of simulated hemi-field and quadrant visual-field stimulus configurations on the VEP response in visually normal subjects using high-contrast, checkerboard patterns. Orban and Muller [17] assessed the effect of simulated hemi-field defects (temporal, nasal) on the VEP amplitude. For each stimulus configuration, the VEP amplitudes were lower than the full-field response, which is expected as these former patterns stimulated fewer cones and overall retinal area as compared to the latter condition. They also found that summation of the individual nasal and temporal hemi-fields amplitude was larger than that found for the full field. However, they attributed this to an artifact due to variable fixation on the stimulus border. Lan et al. [18] compared the VEP amplitude between full-field and simulated quadrant visual-field defects (lower temporal, lower nasal, upper temporal, and upper nasal). The full-field response was larger when compared with the responsivity of the quadrant fields, again as expected. They found a difference in the VEP amplitude between the lower and upper quadrant fields: the lower temporal and nasal field amplitudes were larger
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than the upper temporal and nasal ones. Lan et al. [18] attributed this response inequality to asymmetry in the retinal ganglion cell distribution and/or the retinocortical pathway. However, neither of these studies assessed latency or tested repeatability. Thus, given the aforementioned critical gaps in these earlier pioneering experiments, the purpose of the present study was to assess quantitatively and more comprehensively the response characteristics, and repeatability, for a range of electronically generated stimulus configurations on both the amplitude and latency of the pattern VEP in visually normal adults. Stimulus configurations included circular, hemi-field, and quadrant patterns that simulated visual-field defects. The goal was to determine the feasibility of using the VEP technique with these specific stimulus patterns as a form of objective visual-field testing in patients having visual-field deficits.
Methods Subjects Nine visually normal adults participated in the study comprising students and faculty at the college. Five subjects participated in each of the three experiments. The nine subjects were distributed between the three experiments as follows: one subject participated in all three experiments, four subjects participated in experiment # 1 and 3, and the remaining four subjects participated only in experiment # 2. Subjects had a mean age of 31.1 years (SD = ± 14.2), with a range from 22 to 68 years. They had best corrected visual acuity of 20/20 at distance and at near in each eye. Exclusion criteria were the presence of binocular vision anomalies, such as constant strabismus and amblyopia, or any ocular, systemic, and/or neurological disease. The study was approved by the institutional review board at the SUNY, State College of Optometry. Written informed consent was obtained from all subjects.
presentation and a display monitor for online viewing by the experimenter, as well as a computer for stimulus generation and graphical display. This system is available commercially and has been approved by the FDA. It is used in several pediatric clinics, as well as adult medical and optometric practices [8, 19]. The stimulus was presented on the 1700 LCD display monitor with a refresh rate of 75 Hz. Three Grass (Grass Technologies, Astro-Med, Inc., West Warwick, RI, USA) gold cup electrodes of 1 cm in diameter (one active, one reference, and one ground) were used for the recordings. Stimulus A standard full-field 64 9 64 (17 H° 9 15 V°) checkerboard pattern (20.6 min arc check size at 1 meter) comprising black-and-white checks was used as the comparison stimulus for experiment 3, as well as baseline testing to assess normalcy of response in all of the experimental conditions (Fig. 1). The patterned stimuli for all experiments had a Michelson contrast of 85 % and mean luminance of 64 cd/m2. During the recordings, the checkerboard pattern was modulated at a temporal frequency of 2 Hz (four reversals per second) for a 20-s duration. A small (0.25 deg radius), red, rotating central fixation target was present to control central fixation and maintain visual attention. The VEP amplitude and latency were assessed for each of the three experiments involving different stimulus configurations: Experiment 1 The VEP amplitude and latency were assessed for a central circular stimulus increasing
17o
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Apparatus The DiopsysÒ NOVA-TR system (Diopsys, Inc., Pine Brook, New Jersey, USA) was used to generate a checkerboard pattern stimulus and analyze the VEP data. It consisted of a test monitor for stimulus
Fig. 1 Standard full-field checkerboard pattern stimulus. Not drawn to scale
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incrementally in diameter from 1° to 15°, i.e., 1°, 2°, 4°, 6°, 8°, 12°, 15° (Fig. 2). Experiment 2 The VEP amplitude and latency were assessed for a central circular blank field increasing incrementally in diameter from 1° to 15°, i.e., 1°, 2°, 4°, 6°, 8°, 12°, 15° (Fig. 3). Experiment 3 The VEP amplitude and latency were assessed for simulated hemi-field (right, left) and quadrant (upper right, upper left, lower right, lower left) visual-field defects (Fig. 4), which were compared with the standard full-field (17 H° 9 15 V°) stimulus (Fig. 1). Procedures Electrode placement The VEP amplitude and latency were recorded from over the primary visual cortex (V1). The electrode placement was slightly modified from the International 10/20 system [20], as suggested by the manufacturer. This electrode placement was used to reduce test preparation time in clinical populations. After thorough cleaning of the scalp, the central active
channel electrode was placed at the Oz position, which was 2.5 cm above the inion, the reference electrode was placed at the Fz position, which was approximately 10 % of the distance from the nasion to inion, and the ground electrode was placed at the Fp2 position, which was on the right side of the forehead. A head band was used to keep the electrodes firmly positioned on the scalp. Recordings Each electrode had an impedance of B5 K ohm, per the standards of the International Society for Clinical Electrophysiology of Vision (ISCEV) [7]. An amplification factor of 10 K was used to increase the analog signals. A bandpass filter (0.5–100 Hz) was used to filter any noise. An artifact detector was used to eliminate artifacts in the EEG signals produced by such factors as blinks and gaze shifts. Furthermore, based on our experience with this system, up to five artifacts were allowed to be present before rejecting any record; more than five artifacts typically produced noise and increased variability in the response profile. In addition, an artificat rejection algorithm was used in the DIOPSYS system to assess the digitized response
Fig. 2 Central circular stimulus increasing incrementally in diameter from 1° to 15°, i.e., 1°, 2°, 4°, 6°, 8°, 12°, 15°. Not drawn to scale
Fig. 3 Central blank field diameter increasing incrementally from 1° to 15°, i.e., 1°, 2°, 4°, 6°, 8°, 12°, 15°. Not drawn to scale
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Right visual-field defect
Upper right visual-field defect
Upper left visual-field defect
Left visual-field defect
Lower right visual-field defect
Lower left visual-field defect
Fig. 4 Simulated hemianopic and quadrant visual-field defects. Not drawn to scale
to the stimulus. This algorithm checks the sampled data to ascertain if the maximum amplitude has been maintained over consecutive samples during the trial. Following electrode placement, the subjects were requested to gaze carefully at the central fixation target on the monitor positioned at eye level along the midline. A test distance of 1 m was used. The VEP measurements were obtained binocularly with refractive correction in place. Testing was performed in a darkened room (38 lux) with natural pupils. Subjects were provided 5 min of rest periods between the different test conditions, as needed. Two trials per test condition were obtained. Subjects were tested five times for each stimulus
configuration on each of 5 different days in a counterbalanced manner within each experiment. The repeatability was performed to assess the VEP response variability for each stimulus configuration across subjects and days. The difference between the VEP amplitude at N75 and at P100 latency (delta) was used to define the VEP amplitude (Fig. 5). For most conditions, an automated algorithm developed by DIOPSYS system was used for response identification. However, for the two smallest stimuli in experiment 1 (i.e., 1° and 2°) and 2 (i.e., 12° and 15°), where the peak response amplitude was very small, the cursor was placed at the N75 and P100 peaks to assess the amplitude response difference. This method helped to
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Fig. 5 Typical VEP waveform showing amplitude (lV) and latency at N75-P100 (ms) for the standard full-field stimulus. Crosses are placed at the response peak (P100) and trough (N75). Time scale is 400 ms. Amplitude is autoscaled by the computer software
reduce observer bias regarding peak-to-trough specification, as these standard temporal reference points were always used. The individual and group mean VEP amplitudes and latencies for each stimulus configuration were used for the analysis. Data were analyzed using GraphPad Prism 5 software.
Results Experiment 1 The VEP amplitude and latency were assessed for the central circular stimulus. VEP amplitude The results revealed a linear increase in the mean VEP amplitude with increase in the central circular stimulus diameter in each of the five subjects (Fig. 6a–e). A similar trend was evident in the group data (Fig. 6f). Linear regression analysis was used to assess the slope, which ranged from ?0.56 to ?1.07 across the five subjects. The mean group slope was ?0.80 ± 0.06 SEM. The correlation coefficient values across the five subjects ranged from ?0.97 to ?0.99. The group mean (n = 5) correlation coefficient value was ?0.98. The correlation was significantly different for each individual subject and also for the group mean
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(p \ 0.05). Slopes estimated for each subject, as well as for the group mean, were significantly different from zero (t test, p \ 0.05). A one-way analysis of variance (ANOVA) was performed on the group mean for the factor of stimulus diameter. It revealed a significant effect of stimulus diameter on the VEP amplitude [F(6, 28) = 16.29, p = 0.0001]; response amplitude progressively increased as the central field stimulus diameter increased. The post hoc Tukey test results are summarized in Table 1 for the significant comparisons. Several significant differences were found. In addition, more detailed analyses were performed in each subject, for each stimulus configuration and test session, with respect to VEP amplitude. As performed on the group and individual data above, linear regression was used, and the slope values were assessed. If the slope was statistically equal to zero, then the values obtained over the five sessions would of necessity be deemed similar, and hence repeatable. In contrast, if the slope was not statistically equal to zero, then the values obtained over the five test sessions would of necessity be deemed dissimilar, and hence not repeatable. In all cases for experiment 1, the slopes were not significantly different from zero (p [ 0.05). In addition, a repeated-measures, two-way ANOVA was performed in each subject for the factors of stimulus size and test session, in conjunction with the Bonferroni post hoc test. With regard to the factor
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Subject - 1(S1)
y = 1.076 x + 1.34 r = 0.987
(B) Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
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r = 0.962 20
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Subject - 3 (S3) y = 1.02 x + 3.57 r = 0.992
(D) Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
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y = 0.794 x + 1.01 r = 0.978
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y = 0.561 x + 1.70 r = 0.977
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Stimulus Diameter (degrees)
(F) 25
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(E) Mean Amplitude (microvolts)
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0 1 2
25
4
Stimulus Diameter (degrees)
Stimulus Diameter (degrees)
(C)
y = 0.571 x + 2.41
Mean Group (n=5)
y = 0.805 x + 2.00 r = 0.986
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0
0 1 2
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15 FF
Stimulus Diameter (degrees) Fig. 6 Experiment 1: Plots a–e present increasing stimulus diameter (°) versus mean ± 1 SD VEP amplitude (microvolts) for subjects S1, S2, S3, S4 and S5, respectively, as well as
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Stimulus Diameter (degrees) related linear regressions. Plot f presents the group data (n = 5) ± 1 SEM VEP amplitude (microvolts) and related linear regression. FF represents full field
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Doc Ophthalmol Table 1 Experiment 1: post hoc Tukey test significant findings (p \ 0.05 = *) with increase in central stimulus diameter
Experiment 2
Stimulus diameter (°)
The VEP amplitude and latency were assessed for the central blank stimulus.
Stimulus diameter (°) 6
1
8
*
2
12
15
*
*
*
*
*
*
4
*
VEP amplitude The results revealed a linear decrease in the mean VEP amplitude with increase in central blank field diameter in each of the five subjects (Fig. 8a–e). A similar trend was evident in the group data (Fig. 8f). Linear regression analysis was used to assess the slope, which ranged from -0.92 to -0.59 across the five subjects. The mean group slope was -0.76 ± 0.05 SEM. The correlation coefficient values across the five subjects ranged from ?0.92 to ?0.99. The mean group correlation coefficient value was ?0.98. The correlation was significantly different for each individual subject and also for the group mean (p \ 0.05). Slopes estimated for each subject, as well as for the mean group, were significantly different from zero (t test, p \ 0.05). A one-way ANOVA was performed on the mean group for the factor of stimulus diameter. It revealed a significant effect of stimulus diameter on the VEP amplitude [F(6, 28) = 40.89, p = 0.0001]; response amplitude progressively decreased as the blank field stimulus diameter increased. The post hoc Tukey test results are summarized in Table 3 for the significant comparisons. In addition, more detailed analyses were performed in each subject, for each stimulus configuration and test session, with respect to VEP amplitude. As performed on the group and individual data above, linear regression was used, and the slope values were assessed. If the slope was statistically equal to zero, then the values obtained over the five sessions would
*
6
*
of test session, none of the multiple comparisons were significant (p [ 0.05). In contrast, with regard to the factor of stimulus size, all of the multiple comparisons were significant (p \ 0.05). There was no interaction (p [ 0.05). The coefficient of variability (COV = standard deviation/response mean amplitude) of the VEP amplitude was calculated for each subject for each stimulus diameter (Table 2). The results revealed that the COV decreased as stimulus diameter increased; the smaller the value, the lesser was the variability. The group mean range of the COV was from ?16 to 31 %. Latency (N75-P100) Figure 7a–e presents the latency values at N75 and P100 (ms) with increase in stimulus diameter in each of the five subjects. The mean group latency values are presented in Fig. 7f. A one-way ANOVA was performed for the factor of stimulus diameter. The results revealed that the group mean latency at N75 [F(6, 28) = 0.99, p = 0.44] and at P100 [F(6, 28) = 1.17, p = 0.35] was not significantly different for any of the stimulus diameters.
Table 2 Experiment 1: coefficient of variability (COV, %) for the five subjects with increase in central stimulus diameter
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Stimulus diameter (°)
Subject 1 COV
Subject 2 COV
Subject 3 COV
Subject 4 COV
Subject 5 COV
Group Mean COV
1
26
23
28
37
40
31
2
41
29
30
27
17
29
4
7
30
20
28
23
22
6
13
19
19
21
9
16
8
12
11
12
23
14
14
12
11
15
16
16
14
14
15
13
15
17
19
16
16
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150
Mean Latency P 100
Subject - 1(S1)
Mean Latency N 75
130
110
90
70
(B) 150
Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
(A)
Subject - 2(S2)
Mean Latency N 75
130
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70
50
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1 2
Stimulus Diameter (degrees)
Mean Latency N 75
130
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12
(D) Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
Mean Latency P100
Subject - 3 (S3)
150
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Mean Latency P 100 Mean Latency N 75
Subject - 4(S4)
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Stimulus Diameter (degrees)
Stimulus Diameter (degrees)
(E)
(F)
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Subject - 5(S5)
Mean Latency N 75
130
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Stimulus Diameter (degrees) Fig. 7 Experiment 1: Plots a–e present increasing stimulus diameter (°) versus mean ± 1 SD VEP latency at N 75 and P 100 (ms) for subjects S1, S2, S3, S4 and S5, respectively. Plot
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Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
4
Stimulus Diameter (degrees)
(C) 150
Mean Latency P 100
Mean Group (n=5)
Mean Latency P 100 Mean Latency N 75
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Stimulus Diameter (degrees) f presents the group data (n = 5) ± 1 SEM VEP latency at N 75–P 100 (ms). FF represents full field
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25
y = - 0.835 x + 18.78 r = 0.983
Subject - 1(S1)
(B)
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(D) 25
y = - 0.746 x + 14.84 r = 0.969
Subject - 3(S3)
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y = - 0.599 x + 13.76 r = 0.991
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FF 1
Subject - 5(S5)
(F)
y = - 0.926 x + 17.78 r = 0.986
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15
Central Blank Field Diameter (deg.)
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
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Subject - 4 (S4)
Central Blank Field Diameter (deg.) 25
Group Mean (n=5) y = - 0.769 x + 16.22 r = 0.987
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Central Blank Field Diameter (deg.) Fig. 8 Experiment 2: Plots a–e presents increasing central blank field diameter (°) versus mean ± 1 SD VEP amplitude (microvolts) for subjects S1, S2, S3, S4 and S5, respectively, as
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4
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25
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1
Central Blank Field Diameter (deg.)
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
(C)
y = - 0.737 x + 15.95 r = 0.927
Subject - 2(S2)
25
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
(A)
FF
1
2
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15
Central Blank Field Diameter (deg.) well as related linear regressions. Plot f presents the group data (n = 5) ± 1 SEM VEP amplitude (microvolts) and related linear regression. FF represents full field
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of necessity be deemed similar and hence repeatable. In contrast, if the slope was not statistically equal to zero, then the values obtained over the five test sessions would of necessity be deemed dissimilar, and hence not repeatable. In all cases for experiment 2, the slopes were not significantly different from zero (p [ 0.05). In addition, a repeated-measures, two-way ANOVA was performed in each subject for the factors of stimulus size and test session, in conjunction with the Bonferroni post hoc test. With regard to the factor of test session, none of the multiple comparisons were significant (p [ 0.05). In contrast, with regard to the factor of stimulus size, all of the multiple comparisons were significant (p \ 0.05). There was no interaction (p [ 0.05). The COV of the VEP amplitude was calculated in each subject for each stimulus diameter (Table 4). The results revealed that the COV increased as central blank field diameter increased. The group mean range of the COV was from ?7 % to ?32 %.
Table 3 Experiment 2: post hoc Tukey test significant findings (p \ 0.05 = *) with increase in central blank field diameter Central blank field diameter (°) 1
*
2
6
8
12
*
*
*
*
*
*
*
*
*
*
*
*
6 8
Table 4 Experiment 2: coefficient of variability (COV, %) for the five subjects with increase in central blank field diameter
15
*
4
Figure 9a–e presents the VEP latency values at N75 and P100 (ms) for increasing central blank field diameter in the individual subjects. The mean group latency values are shown in Fig. 9f. A one-way ANOVA was performed for the factor of stimulus diameter. The results revealed that the group mean latency at N75 [F(6, 28) = 4.45, p = 0.0028] and at P100 [F(6, 28) = 5.64, p = 0.0006] was significantly different for the factor of stimulus diameter. The post hoc Tukey test results at N75 and P100 (ms) latency are summarized in Tables 5 and 6 showing the significant comparisons. Tukey test results revealed that at N75, the 15° central blank field diameter was significantly different from the 1°, 2°, 4°, 6°, 8° patterns. Similar trends were found for the P100 component, except that the 1° central blank field diameter was also significantly different from 12°. Experiment 3 The VEP amplitude and latency were assessed for the simulated hemi-field (right, left) and quadrant (upper right, upper left, lower right, lower left) visual-field defects. VEP amplitude
Central blank field diameter (°) 4
Latency (N75-P100)
*
For the simulated hemi- and quadrant visual-field defects, the VEP amplitude was greater for the simulated quadrant than for the hemi-field defect in each of the five subjects (Fig. 10a–e). A similar trend was evident in the group data (Fig. 10f). A one-way ANOVA performed on the mean group for the factor of type of simulated visual-field defect revealed no
Central blank field diameter (°)
Subject 1 COV
Subject 2 COV
Subject 3 COV
Subject 4 COV
Subject 5 COV
Group Mean COV
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20
24
36
55
27
32
12
41
27
42
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32
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Mean Latency (N 75 - P 100 ms)
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Mean Latency P 100 Mean Latency N 75
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(F) Mean Latency P 100 Mean Latency N 75
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Mean Latency P 100 Mean Latency N 75
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Central Blank Field Diameter (deg.) Fig. 9 Experiment 2: Plots a–e present increasing central blank field diameter (°) versus mean ± 1 SD VEP latency at N 75 and P 100 (ms) for subjects S1, S2, S3, S4 and S5, respectively. Plot
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Mean Latency (N 75 - P 100 ms)
(E)
2
Central Blank Field Diameter (deg.)
Central Blank Field Diameter (deg.)
Mean Latency (N 75 - P 100 ms)
2
Central Blank Field Diameter (deg.)
Central Blank Field Diameter (deg.)
(C)
Mean Latency P 100 Mean Latency N 75
Subject - 2(S2)
FF
1
2
4
6
8
12
15
Central Blank Field Diameter (deg.) f presents the group data (n = 5) ± 1 SEM VEP latency at N 75–P 100 (ms). FF represents full field
Doc Ophthalmol Table 5 Experiment 2: post hoc Tukey test significant findings (p \ 0.05 = *) for latency at N75 (ms) for increase in central blank field diameter Central blank field diameter (°)
Central blank field diameter (°) 15
1
*
2 4
* *
6
*
8
*
Table 6 Experiment 2: post hoc Tukey test significant findings (p \ 0.05 = *) for latency at P100 (ms) for increase in central blank field diameter Central blank field diameter (°)
1
Central blank field diameter (°)
slopes were not significantly different from zero (p [ 0.05). The mean COV was 15 % for the full field, which was lower than either the hemi-field (right and left = 24 and 22 %, respectively) or quadrant (upper right, upper left, lower right, and lower left = 19, 17, 17, and 19 %, respectively) visual-field defects. The average effect of these simulated visual-field defects on the VEP amplitude was assessed, i.e., hemi-field (right ? left/2) and quadrant field (upper right ? upper left ? lower right ? lower left/4) (Fig. 11). T test results revealed that average hemi-field response was significantly different and smaller than the average of the quadrant fields responses [t(4) = 3.18, p = 0.01], and furthermore that the average simulated hemi-field defect was significantly different from the full-field findings [t(5) = 2.05, p = 0.04].
12
15
Latency (N75-P100)
*
*
Figure 12a–e presents the VEP latency at N75 and P100 (ms) for the simulated hemi- and quadrant visual-field defects in the individual subjects. The mean group latency values are presented in Fig. 12f. A one-way ANOVA was performed for the factor of type of simulated visual-field defect. The results revealed that the mean latency at N75 [F(6, 28) = 0.06, p = 0.99] and at P100 [F(6, 28) = 0.27, p = 0.94] was not significantly different for any of the simulated field defects.
2 4
* *
6
*
8
*
significant effect on the VEP amplitude [F(6, 28) = 2.31, p = 0.06], although a trend was suggested. A one-way ANOVA performed on the mean group for the factor of the quadrant only simulated visual-field defect (upper right, upper left, lower right, and lower left) revealed no significant effect on VEP amplitude [F(3, 16) = 0.20, p = 0.89]. The COV of the VEP amplitude was calculated in each subject for each hemi- and quadrant-simulated visual-field defect (Table 7). In addition, more detailed analyses were performed in each subject, for each stimulus configuration and test session, with respect to VEP amplitude. As performed on the group and individual data above, linear regression was used, and the slope values were assessed. If the slope was statistically equal to zero, then the values obtained over the five sessions would of necessity be deemed similar, and hence repeatable. In contrast, if the slope was not statistically equal to zero, then the values obtained over the five test sessions would of necessity be deemed dissimilar, and hence not repeatable. In all cases for experiment 3, the
Discussion The results of the present study have demonstrated a relatively linear VEP response profile to changes in test target diameter for both the central circular and the central blank fields. Some of the earlier studies found either a ‘‘nearly’’ linear or clear non-linear response profile with either of the aforementioned stimulus configurations. However, some of these earlier studies plotted the VEP response amplitude profile in relation to its stimulus area (cm2), rather than its stimulus diameter (cm) [10, 14, 15] as was done in the present investigation. Thus, a non-linear response profile might in fact be expected in these earlier area-based studies. Rover et al. [15] stated that due to the nonlinear VEP response they found with increase in stimulus area, it would not be possible to conceptualize
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25
(B)
Subject - 1(S1)
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
(A)
20
15
10
5
25
Subject - 2(S2)
20
15
10
5
0
0 RH
LH
LUQ
RUQ
LUQ
RUQ
RH
FF
30
(D)
Subject - 3(S3)
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
(C)
25 20 15 10 5 0
25
LH
LUQ RUQ LLQ RLQ
RUQ
FF
15
10
5
RH
LH
LUQ
RUQ
LLQ
RLQ
FF
Simulated Field Defects 25
Mean Group (n=5)
Subject - 5(S5)
Mean Amplitude (microvolts)
Mean Amplitude (microvolts)
LUQ
20
FF
(F)
20
15
10
5
0
20
15
10
5
0 RH
LH
LUQ
RUQ
LLQ
RLQ
FF
Simulated Field Defects Fig. 10 Experiment 3: Plots a–e present simulated visual field defects versus mean ± 1 SD VEP amplitude (microvolts) for subjects S1, S2, S3, S4 and S5, respectively. Plot f presents the group data (n = 5) ± 1 SEM VEP amplitude in microvolts. RH,
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RUQ
Subject - 4(S4)
Simulated Field Defects 25
LUQ
0
RH
(E)
LH
Simulated Field Defects
Simulated Field Defects
RH
LH
LUQ
RUQ
LLQ
RLQ
FF
Simulated Field Defects LH, LUQ, RUQ, LLQ, RLQ, and FF represent right hemi-field, left hemi-field, left upper quadrant, right upper quadrant, left lower quadrant, right lower quadrant, and full field, respectively
Doc Ophthalmol Table 7 Experiment 3: coefficient of variability (COV, %) for the five subjects with simulated hemi and quadrant visual field Field defects
Subject 1 COV
Subject 2 COV
Subject 3 COV
Subject 4 COV
Subject 5 COV
Group Mean COV
Right hemi-field
25
22
26
15
33
24
Left hemi-field
15
21
37
15
23
22
LUQ
19
11
22
18
25
19
RUQ
18
32
5
18
11
17
LLQ
28
7
15
17
16
17
RLQ Full field
5
21
21
35
12
19
10
14
19
11
20
15
Half-field
25
Mean Amplitude (microvolts)
Quadrant-field Full-field 20
15
10
5
0 Half-field
Quadrant-field
Full-field
Visual-Field Test Condition Fig. 11 Visual-field test condition versus mean response amplitude in microvolts. Plotted is the mean ?1 SEM (n = 5)
and develop the VEP as an objective clinical screening test to detect visual-field defects in ocular disease conditions; it would be too complicated for all but the research environment. Linearity of the VEP response found in the present study as assessed and compared statistically using the parameters of stimulus diameter per se, however, provides a way by which the VEP method can be more readily and easily adapted clinically to assess visual-field defects in individual patients. For example, in a patient having only a small central region (e.g., 8° diameter) of healthy retina, the initial linear VEP response profile would begin to exhibit a non-linear, ‘‘saturation-like’’ effect, and hence to flatten, as the VEP stimulus exceeded this diameter (see later, Discussion). Thus, as used in the present study, VEP may provide an important
objective means of assessing the degree and type of visual-field defects in the future in specific ocular disease conditions, such as glaucoma, macular degeneration, and RP, especially when there is conventional visual-field test uncertainty and/or conflicting results. In the present study, the correlation coefficient values were preliminarily assessed using both linear and exponential fits. The linear fit always provided a slightly higher correlation than the exponential fit (e.g., 0.992 vs. 0.953). Therefore, the linear fit provided a better mathematical description of the overall response function, at least up to the retinal eccentricity tested in the present study. If one were to test further in the retinal periphery, it is likely that the exponential fit would be equal or perhaps even better. However, despite the best fit statistically being linear in nature, the data profile suggests some degree of response non-linearity prior to the maximum stimulus diameter tested of 15°. Thus, it is especially important for the clinician to exercise caution in using the proposed protocol to assess the presence and/or degree of peripheral visual field impairment in a patient with respect to its departure from the 1:1 line. There are possible three scenarios as shown in Fig. 13: first, in the patient not having any visual field defect, the predicted response will lie within the gray region, that is, below the 1:1 line. Second, and in contrast, in the case of a patient with an absolute scotoma, the change in response over the affected visual field region will effectively be zero, thus reflecting complete/full (‘‘hard’’) response saturation. Third, in the case of a patient with a relative scotoma, the change in response over the affected visual field region will be present, but reduced as compared to a normal patient, thus reflecting partial (‘‘soft’’) response saturation. It is in this last scenario that the clinician must be especially
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(A)
(B) Mean Latency P 100
Subject - 1(S1)
Mean Latency N 75
140 130 120 110 100 90 80 70 60
150
Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
150
Subject - 2(S2)
130 120 110 100 90 80 70 60 50
50 RH
LH
LUQ
RUQ
LLQ
RLQ
RH
FF
Mean Latency P 100 Mean Latency N 75
140 130 120 110 100 90 80 70 60 50 RH
LH
LUQ
RUQ
LLQ
RLQ
150
Subject - 4(S4)
130 120 110 100 90 80 70 60 50 RH
FF
(F)
Subject - 5(S5)
Mean Latency P 100 Mean Latency N 75
140 130 120 110 100 90 80 70 60
LUQD RUQD LLQD RLQD
FF
150
Mean Latency P 100 Mean Latency N 75
Group mean (n=5)
140 130 120 110 100 90 80 70 60 50
50 RH
LH
LUQ
RUQ
LLQ
RLQ
Simulated Field Defects
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LH
Simulated Field Defects Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
150
Mean Latency P 100 Mean Latency N 75
140
Simulated Field Defects
(E)
FF
(D)
Subject - 3(S3)
Mean Latency (N 75 - P 100 ms)
Mean Latency (N 75 - P 100 ms)
150
LH LUQD RUQD LLQD RLQD
Simulated Field Defects
Simulated Field Defects
(C)
Mean Latency P 100 Mean Latency N 75
140
FF
RH
LH
LUQ
RUQ
LLQ
RLQ
Simulated Field Defects
FF
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defects versus mean ± 1 SD VEP latency at N 75 and P 100 in milliseconds (ms) for subjects S1, S2, S3, S4 and S5, respectively. Plot f presents the group data (n = 5) ± 1 SEM VEP latency at N 75 and P 100 in milliseconds (ms). RH, LH, LUQ, RUQ, LLQ, RLQ, and FF represent right hemi-field, left hemi-field, left upper quadrant, right upper quadrant, left lower quadrant, right lower quadrant and full field, respectively
Total Increase in Cumulative Cone 2 Number (x1000/mm )
b Fig. 12 Experiment 3: Plots a–e present simulated visual field
y = 5.99x + 193
300
r 2 = 0.913 r = 0.955
250
200
150 0
5
10
15
Mean Amplitude (microvolts)
Fig. 14 Relationship between total cumulative increase in cone number (X 1,000/mm2) and mean VEP amplitude (microvolts) with increase in stimulus diameter
Fig. 13 Plot schematically representing the three possible response profiles (normal, partial saturation, and complete saturation) for stimulus diameter (°) and relative amplitude per experiment 1, along with the 1:1 line
astute and observant: a small and normal partial saturation response must be differentiated from cases of slightly greater but abnormal partial saturation. It may require additional test repetitions to segregate these two latter ensemble responses. The relatively linear VEP response profile was likely due to the cumulative change in total cone number (i.e., the integration/summation in total cone number with changes in test stimulus area) with increase in either the central circular or the central blank field diameter stimulation, respectively, at least for the range of retinal eccentricities tested. This is suggested by the significant correlation presented in Fig. 14 between these two parameters. To construct this graph, the mean VEP amplitude for each eccentricity tested in Experiment 1 was plotted against the total increase in cumulative cone number. For example, in Experiment 1, the VEP amplitude progressively and significantly increased with increase in cumulative mean cone number (r = 0.95) per Osterberg’s [21] human retinal topographic findings. It accounted
for over 90 % of the variance. This relationship also confirms that the VEP is a cone-mediated response. Furthermore, the present finding is consistent with the speculation of Meredith and Celesia [22], namely that the VEP amplitude is related to the density of the retinal cone photoreceptors. None of the earlier studies assessed repeatability of the VEP response, which includes both amplitude and latency, for the present array of different stimulus configurations. The results of the present study revealed that the VEP linear response was highly repeatable for the simulated circular, hemi-field, and quadrant visual-field defects in each subject. The COV values for the different stimulus configurations provided additional evidence regarding repeatability of the VEP amplitude responsivity and resultant overall profile, as these values were consistently relatively low [8]. Similarly, the VEP latency (N75-P100 ms) values remained relatively constant for nearly all of the stimulus configurations, with the exception of the 12° and 15° central blank field diameters, which revealed increased latency. This finding may be due to the lower signal-to-noise ratio when the aggregate cone stimulation was minimal with those very peripheral-only stimuli. The notion of high repeatability, in conjunction with the aforementioned finding of relatively good linearity, support the concept of using the VEP as an objective indicator of visual-field dysfunction, as has been suggested and tested to some degree in earlier studies [9, 23–29].
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There was response differentiation for the hemianopic and quadrant stimulus configurations when compared with the standard full-field stimulus. The VEP amplitude was lower for the simulated hemianopic defect as compared to the simulated quadrant defect and the full-field stimulus, as would be expected due to reduced area of overall cone stimulation. Thus, the results of the present study revealed that the conventional VEP may be a feasible objective future tool to assess hemi- and quadrant visual-field defects in different ocular and neurological conditions in individual patients. The question of possible luminance effects on the data is both interesting and important. There were no luminance changes/compensations made to the various stimulus patterns used during testing in the present experiment. The blank areas had very low luminance (1.27 cd/m2). This was purposely done to best simulate that which would be found in a clinic patient, for example, a patient with dense hemianopia (i.e., absolute scotoma as frequently found in stroke). Thus, while the overall retinal luminance would be different when averaged over the entire 15°V 9 17°H region of the retina (as well as the stimulus display), it would not change for the local retinal region under investigation and being tested. For example, in Experiment 3 using the hemianopic configuration, 50 % of the test field would have very low luminance, whereas the other 50 % would have the specified luminance of 64 cd/m2. Thus, the average luminance combined over the two half-field would be approximately 32 cd/m2, with 0.3 log unit difference. In the only study directly relevant to the present investigation [30], VEP amplitude and latency were assessed under two relatively extreme luminance conditions: 55 cd/m2 and 0.76 cd/m2, a 1.86 log unit difference. They found an average reduction in amplitude (but not latency) of approximately 35 % under the lower luminance condition as compared with the higher one. However, both the ‘‘average’’ (32 cd/m2) and ‘‘local’’ (64 cd/m2) luminance levels used in the present investigation were much less extreme and similar to each other, as compared to the two levels used by Brannan et al. [30]. Lastly, we performed five VEP repetitions on one experienced subject used in the present study monocularly, using our standard full-field array with and without a 0.3-ND filter, which reduced the stimulus luminance by 50 %. There was no significant change in the VEP amplitude. Thus, based on the above
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information, we believe that any possible changes in test field luminance did not have an effect on the data. There have been several previous studies which in fact have used the VEP technique to assess visual-field defects objectively for a limited range of stimuli [23, 25–27, 31–33]. However, most used a focal flash stimulus rather than the pattern reversal approach [31–33]. The latter is more effective in detecting visual-field defects [23, 25–27]. Furthermore, results of many of these earlier studies were limited by the techniques used to measure the VEP amplitude, which resulted in lower signal-to-noise ratios and longer test times [31–33]. Therefore, Bradnam et al. [9] performed an investigation which attempted to overcome these two limitations. They used an adaptive noise canceling method to measure the VEP response, and a test duration of only 2 min. Nine patients with hemiand quadrant visual field defects due to different pathological conditions were assessed using the pattern VEP (check size = 90 min of arc, temporal frequency = 3.85 Hz, contrast = 99 %, luminance = 20 cd/m2). Bradnam et al. [9] confirmed the presence of visual-field defects using the objective VEP technique, as well as corroborated the findings with subjective perimetry, which were in reasonable agreement. In addition, the results and concepts put forth in the present study regarding use of the VEP method to detect visual-field defects are consistent with a series of studies performed by the Harding group in clinical populations [34–37]. They found that the VEP technique provided reliable results in both children and adults with epilepsy. Lastly, increased use of the multifocal VEP (mfVEP) technique in the future should further help to improve resolution and specificity of visual-field dysfunction in these populations [38, 39], perhaps in conjunction with conventional visual field testing and/or the objective VEP approach described in the present paper. We are enthusiastic about the potential use of the VEP to assess visual field dysfunctions in a range of diagnostic groups. However, special consideration may need to be exercised at times. First, all testing in the present experiments was performed binocularly, with binocular summation resulting in a 26 % increase in amplitude over that found monocularly [40]. Since most of the clinical testing for which the proposed stimulus configurations will be employed will be performed with monocular testing of each eye, the resultant reduced VEP amplitude will make
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differentiation for the various test fields somewhat more difficult. Thus, more trials may be needed to make a differential diagnosis. Second, in patients with fixational abnormalities (e.g., saccadic intrusions), more trials may be required to obtain reliable responses. Third, in cases where the visual field defect may be relatively mild in the retinal periphery, addition test repetitions may be required to differentiate between ‘‘normal’’ and ‘‘abnormal’’ partial response saturation effects.
7.
8.
9.
10.
Conclusions The results of the present study presented several new and important results. First, response linearity was a consistent finding, which was equivocal in the previous studies. Second, repeatability was found, which has never been so comprehensively tested in the past. Third, such a wide array of stimulus configurations has not been tested in the same visually normal population. These findings pave the way for increased clinical utility of the VEP and the suggested stimulus patterns, especially as a rapid and new tool for objective assessment of visual-field dysfunction for a range of abnormal visual conditions and special populations (e.g., young children, cognitively impaired) in the near future. Acknowledgments We thank DIOPSYS Inc., Pine Brook, New Jersey, USA for providing the test system.
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