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The multifocal visual evoked potential: An objective measure of visual fields?
Vision Research 45 (2005) 1155–1163 www.elsevier.com/locate/visres
The multifocal visual evoked potential: An objective measure of visual fields? William Seiple a,*, Karen Holopigian a, Colleen Clemens a, Vivienne C. Greenstein b, Donald C. Hood b a
Department of Ophthalmology, New York University School of Medicine, BEL 5N15, 550 First Avenue, New York, NY 10016, USA b Department of Psychology, Columbia University, New York, NY 10027, USA Received 10 June 2004; received in revised form 21 October 2004
Abstract We examined the effects of inter-modal attention and mental arithmetic on Humphrey visual field sensitivity and multifocal visual evoked potential (mfVEP) amplitude. Four normally sighted subjects (ages ranging from 24 to 58 years) participated in this study. Monocular visual field sensitiv ity was measured under two conditions: (1) standard testing condition and (2) while the subject performed a Paced Auditory Serial Addition Task (PASAT). Monocular mfVEPs were recorded in response to a 60-sector stimulus. The checkerboard pattern in each sector was contrast reversed according to a binary m-sequence. mfVEPs were recorded under two conditions: (1) standard testing conditions and (2) while the subject performed a PASAT. We found that, when compared to the notask condition, all subjects had locations of significantly reduced Humphrey visual field sensitivities when performing the PASAT. In contrast, there were no significant decreases in mfVEP amplitude in any sector for any of the subjects while performing the PASAT. Our findings indicate that divided attention and ongoing mental processes did not affect the mfVEP. Therefore, the mfVEP provides an objective measure of visual field function that may be useful for some patients with unreliable automated static perimetry results. 2004 Elsevier Ltd. All rights reserved. Keywords: Multifocal visual evoked potential; Visual field; Divided attention
1. Introduction Automated perimeters, such as the Humphrey Field Analyzer (HFA), have made it possible to rapidly screen patients for visual field losses associated with eye diseases. Although the reliability of these visual field measures can be high in some patients, it can be quite low in others (Bengtsson & Heijl, 2000; Birt et al., 1997; Choplin & Russell, 1995; Heijl, 1977; Heijl, Lindgren, & Olsson, 1987; Holmin & Krakau, 1979; Katz & Sommer, 1990; Katz, Sommer, & Witt, 1991; Keltner et al., 2000; Wall et al., 1998; Werner, Petrig, Krupin, & *
Corresponding author. Tel.: +1 212 263 6076; fax: +1 212 263 8749. E-mail address: [email protected] (W. Seiple). 0042-6989/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2004.11.010
Bishop, 1989). Some of the variability in patientsÕ responses may be due to the disease process (Hart & Becker, 1982; Werner, Saheb, & Thomas, 1982). Other factors that contribute to variability include practice, fatigue, the response bias of the patient, and vigilance (Fujimoto & Adachi Usami, 1992; Kutzko, Brito, & Wall, 2000; Wall, Woodward, & Brito, 2004; Werner, Adelson, & Krupin, 1988; Werner, Krupin, Adelson, & Feitl, 1990; Wild, Dengler_Harles, Searle, O_Neill, & Crews, 1989). The impact of these factors is demonstrated by increased testing times and error rates (Bengtsson & Heijl, 2000; Birt et al., 1997; Heijl et al., 1987; Katz & Sommer, 1990; Wall et al., 1998). Divided attention and competing ongoing mental activity also may contribute to the inaccuracies and variability in performance on clinical tests of vision, such as
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the HFA (Choplin & Russell, 1995). Aspects of the attention mechanism have been shown to be capacitylimited under conditions where the subjects were required to perform two or more tasks concurrently (Bonnel & Hafter, 1998; Fernandes & Moscovitch, 2000; Lavie, 2001; Liebowitz & Appelle, 1969; Mangun & Buck, 1998; Rantanen & Goldberg, 1999; Webster & Haslerud, 1964). The increased processing load for dual-task performance has been demonstrated using functional magnetic resonance imaging (fMRI). During dual-task performance, fMRI studies have shown recruitment of cortical areas that were not activated by either single task alone (DÕEsposito et al., 1995; Dove, Pollmann, Schubert, Wiggins, & von Cramon, 2000; Herath, Klingberg, Young, Amunts, & Roland, 2001; Koechlin, Basso, Pietrini, Panzer, & Grafman, 1999). In vision, attention is usually directed at the item that falls on the fovea. If visual attention is spatially divided between a central task and a peripheral task, performance on the peripheral task decreases (Ball, Beard, Roenker, Miller, & Griggs, 1988; Rantanen & Goldberg, 1999; Seiple, Szlyk, Yang, & Holopigian, 1996; Williams, 1982). Adding more visual information in the form of distractors (Sekuler & Ball, 1986) or increasing the number of test points (Fujimoto & Adachi Usami, 1992) can further decrease peripheral sensitivity. Intramodal splitting of attention also can decrease performance. When subjects were required to attend to auditory information, performance on psychophysical visual detection tasks decreased (Schmitter-Edgecombe, 1996; Webster & Haslerud, 1964). Similarly, Humphrey visual field sensitivity decreases when subjects are required to simultaneously perform mental arithmetic (Wall et al., 2004). Recently, the multifocal visual evoked potential (mfVEP), an electrophysiologic technique, has been used to measure visual field function (Hood, 2003; Hood & Greenstein, 2003; Hood & Zhang, 2000; Klistorner & Graham, 1999). Based on the findings of reliable amplitudes in some patients who had unreliable Humphrey results, the mfVEP has been proposed as an objective measure of visual fields (Hood, 2003; Hood & Greenstein, 2003; Hood & Zhang, 2000). In the present study, we examined whether the dichotomy between performances on HFA and mfVEP fields could be due to a differential effect of divided attention and ongoing mental activity on these two measures.
The research followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. The research was approved by the New York University School of Medicine Institutional Review Board. 2.2. Automated visual field Monocular (the contralateral eye was patched) visual field sensitivity was measured with a HFA (Model 750; Humphrey Systems, Dublin, CA) using the 24-2 program and the SITA standard method (Bengtsson & Heijl, 1998, 1999). Visual fields were first measured under standard testing conditions (labeled A: no-task condition). In the second run (labeled B: task condition), the subject performed a Paced Auditory Serial Addition Task (PASAT) while undergoing visual field testing (Gronwall, 1977). An audiotape of a male speaker reading from lists of randomly generated numbers was played while the subject performed the visual field test. The separation between the spoken numbers was two seconds. To make the mental task condition as close as possible to those of the mfVEP (described below), a series of 14 numbers was presented. The subjectÕs task was to mentally add the numbers and report the sum at the end of the series. The subject was then instructed to hold the HFA response key down to pause the field test and report the sum. The subject also was instructed to pause the test if he/she lost count. If this occurred, a new series of numbers was begun and the test continued. The subjectÕs pupil position was viewed throughout the test and if large eye movements were seen the test was paused. The order of the runs was counterbalanced (A1B1B2A2). 2.3. Multifocal VEP 2.3.1. Stimulus The stimulus was displayed on a 21-inch black-andwhite monitor (frame rate 75 Hz). The mfVEP stimulus array consisted of 60 sectors (Fig. 1A). At the viewing distance of 32 cm, the stimulus diameter was 47.2. The black checks had a luminance of 2 cd/m2, and the white checks had a luminance of 280 cd/m2. The checkerboard pattern in each sector was contrast reversed according to a binary m-sequence (Baseler, Sutter, Klein, & Carney, 1994; Sutter & Tran, 1992).
2. Methods 2.1. Subjects Four normally sighted subjects (ages ranging from 24 to 58 years) participated in this study. All were experienced psychophysical and electrophysiologic observers.
2.3.2. Recording The active electrode was placed on the midline 4 cm above the inion and referenced to an electrode placed at the inion. An electrode placed on the forehead served as ground. The raw EEG was band-pass filtered (1–100 Hz) and amplified 100,000 times. The amplified
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Fig. 1. (A) The display used for the mfVEP recordings and grouping of sectors for the eccentricity analysis. Each of the 60 sectors contains a contrast-reversed checkerboard pattern. (B) Locations of the visual field test locations for the Humphrey 24-2 program.
signal was digitized (1200 Hz), and second-order local responses were calculated using the VERIS software (EDI, San Mateo, CA). Artifact removal and averaging with neighbors were turned off. The total recording time was divided into short segments in order to maintain subject compliance with the demands of the task. Testing was done monocularly; the contralateral eye was patched. Eye position was monitored using a CCD camera, and small saccades or fixation movements (on the order of 1) were easily detected. Segments containing these artifacts were discarded and re-recorded. 2.3.3. Procedure In the first run (no-task condition A1), the subject was instructed to monocularly fixate the center of the screen and concentrate on the fixation target. In the next run (task condition B1), the subject again was instructed to fixate the center of the screen and to listen to a series of 14 numbers played on an audiotape. The separation between the spoken numbers was two seconds. The subjectÕs task was to add the numbers. The sum of this addition was reported after each recording segment ended. If the subjectÕs addition was incorrect by more than ±2, that segment was discarded and recorded again. The order of the runs was counterbalanced (A1B1B2A2). 2.3.4. Analysis Second-order mfVEP responses for each sector were exported from the VERIS system, and root-meansquare (RMS) voltages were calculated using a custom MATLAB program (Hood, 2003; Hood & Zhang, 2000; Hood, Zhang, Hong, & Chen, 2002). RMS voltages were calculated for two time intervals: signal was measured as the RMS voltage between 45 and 150 ms, and noise was measured as the RMS voltage between 325 and 430 ms (Zhang, Hood, Chen, & Hong, 2002).
The ratio of signal-to-noise RMS voltages (s2n) was calculated for each sector for each run.
3. Results 3.1. Testing the effects of mental addition In Fig. 2A, Humphrey sensitivities for all subjects are plotted for the repeat no task conditions: A2 versus A1. In this figure, data for three concentric rings (Fig. 1B) are shown as circles, triangles, and square symbols for the inner, middle, and outer rings, respectively. The repeat data clustered around the diagonal line that represents no change in sensitivity between runs. The comparison between the average Humphrey sensitivities for the task condition (B) versus the averages for the no task conditions (A) are shown in Fig. 2B. Most of the points fall below the equality line, representing a decrease in sensitivity during the task condition. The mfVEP s2n data are plotted in the same manner in Fig. 2C and D. Once again, the data for the no task repeat runs clustered around the diagonal. The plot of the average task versus the average no task s2n ratios also showed no consistent deviation as a function of task. The data were also summarized by comparing the proportion of data points that increased (difference P 0) or decreased (difference < 0). For the Humphrey repeat no task data, 62% of the A2 data had higher sensitivity and 38% had lower sensitivity than on the A1 trial. For the task condition, 22% of the Humphrey sensitivity values increased and 78% of the values decreased relative to their values during the no task condition. These proportions were significantly different (v2 = 70.3, P < 0.001). For the VEP no task data, s2n ratios increased in 48% and decreased in 52% of the repeat values. For the task condition, s2n ratios increased in 59% and decreased in 41% of the points relative to their no task ratios. These proportions were not significantly different (v2 = 0.004, P = 0.95).
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Fig. 2. (A) Scatterplot of the Humphrey threshold values for all subjects for the first and second no task runs. The diagonal line is drawn through the points of no change in sensitivity. Data for the inner, middle, and outer rings are shown as circles, triangles, and squares, respectively. (B) Scatterplot of the Humphrey threshold values for all subjects averaged for the task and no task conditions. (C) Scatterplot of the mfVEP signal to noise ratios for all subjects for the first and second no task runs. (D) Scatterplot of the mfVEP signal to noise ratios for all subjects averaged for the task and no task conditions.
3.2. Testing the local effects of mental addition For the HFA, the differences between the average of the two task runs (Aavg) minus the average of the two no-task runs (Bavg) were calculated in decibels (dB) for each test point for each subject. Comparisons were only made between conditions within a test (HFA or mfVEP). For the mfVEP, the differences were calculated as the ratios of task to no-task amplitude averages for each sector for each subject: log(Bavg/Aavg) · 10 (i.e., in dB). We used the standard deviation (SD) of the differences between the two no-task runs (A2 A1) to calculate statistical probability. The logic was that, if the variability in the no-task condition was due to random noise, then the differences would be normally distributed around a mean of zero, and the SD of the distribution could be used as a measure of inherent variability. Frequency distributions of the dB difference scores between the two no-task runs are plotted for the HFA and the mfVEP in Fig. 3. These data pass the KolmogorovSmirnov Normality Test (KS = 0.037 and 0.35, respectively). The SDs for the HFA data were 1.6, 1.5, 2.7, and 2.1 dB for the four subjects. The repeat reliability of Humphrey sensitivities significantly decreased with increasing eccentricity. Calculated across three concen-
Fig. 3. Frequency distributions of the differences (in dB) between the first (A1) and second (A2) no-task runs: filled circles—Humphrey visual fields; open circles—mfVEP.
tric rings (Fig. 1B), the average SDs were 1.1, 2.1, and 2.2 dB (F(2,9) = 6.8, P = 0.015), with a post-hoc analysis showing a significant difference between the inner ring and outer ring (q = 5.2, P = 0.013) (Fig. 4). Other investigators have also reported poorer reliability for peripheral test points than for central points for Humphrey visual fields (Heijl et al., 1987; Parks et al., 1997). For the mfVEP data, the SD values averaged 1.6, 2.0, 1.7, and 1.9 dB for the four subjects. For the three concentric rings (Fig. 1A), SDs averaged 2.1, 1.8, and
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Fig. 4. Standard deviations of the differences (in dB) between the first (A1) and second (A2) no-task runs as a function of eccentricity (inner, middle, and outer rings) for Humphrey visual field thresholds (filled bars) and for mfVEP amplitudes (open bars).
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t = 3.15, df = 7, P = 0.02). Although 25% of the task runs had fixation losses above the normal criterion, 25% of the task runs had 0% fixation losses. There was a statistically significant difference between the average false positive responses for the no-task runs (average 2.0 ± 2.8%) and the task runs (average 9.0 ± 6.4%) (Paired t = 3.22, df = 7, P = 0.015). There were no false negative responses during the no-task runs and an average of 9.3 ± 6.4% during the task runs (paired t = 4.65, df = 7, P = 0.002). There were no statistically significant relationships (Spearman correlations) between any of the reliability indexes and either the number of locations with significantly reduced sensitivity or the average dB difference between the task and no-task conditions.
1.9 dB (F(2,9) = 0.1, P = 0.89) for the inner, middle, and outer rings, respectively (Fig. 4). Chen et al. (2003) found that mfVEP amplitude reliability was poorer for the central sectors (mean SD = 2.0) than for more peripheral sectors (mean SDs = 1.61 and 1.55 for the middle and outer rings, respectively). Because of this eccentricity effect, each subjectÕs average SD for each ring was used to calculate z-scores for the differences between task and no-task conditions for the points within the corresponding ring: (Btask avg Ano-task avg)/SDno-task repeats. Points (HFA) or sectors (mfVEP) that had z-scores less than 2.57 (P = 0.005, two-tailed test) were coded as significantly reduced by the mental arithmetic task.
3.2.2. Multifocal VEP The mfVEP waveforms for one subject (#2) are shown in Fig. 6 for no task (dotted lines) and task (solid lines) conditions. If the VEP were affected by performing the PASAT task, then the tracings for the task conditions should be smaller in amplitude than those of the no task condition. There were no significant decreases in amplitude in any sector for any of the subjects while performing the PASAT compared to the no-task condition. The mean differences in dB between the task and no-task conditions were 0.3, 0.5, and 0.7 for the inner, middle, and outer rings, respectively. There was no significant main effect of eccentricity (F = 0.11, P = 0.89).
3.2.1. Automated visual fields Compared to the no-task condition, all subjects had locations of significantly reduced HFA sensitivities when performing the PASAT (shaded circles in Fig. 5A–D). These findings are a replication of the findings of Wall et al. (2004) for the HFA. On average, there was a greater loss for the more eccentric test points. The average decrease in sensitivity for the inner ring was 2.8 ± 4.5 dB; for the middle ring, 2.9 ± 4.1 dB; and for the outer ring, 4.4 ± 5.8 dB. These differences among the rings, however, were not statistically significant (F = 1.91, P = 0.15). There are three indexes calculated by the HFA that provide information about a patientÕs response reliability: fixation losses, false positive errors, and false negative errors (Humphrey, 1998). Fixation losses are quantified by presenting stimuli at the estimated location of the patientÕs blind spot and counting the number of these presentations that are detected. False positive errors are responses that occurred when no stimuli are presented, and false negative errors are when no responses are given to supra-threshold stimuli. In our current experiment, there was a significant difference in mean fixation losses between the no-task runs (average 4.5 ± 5.3%) and task runs (16.8 ± 12.6%) (Paired
4. Discussion We found that performing mental arithmetic significantly decreased sensitivity on the HFA. There are numerous reports of decreased visual field sensitivity under conditions of divided visual attention or when performing concurrent mental tasks (Ball et al., 1988; Liebowitz & Appelle, 1969; Plainis, Murray, & Chauhan, 2001; Rantanen & Goldberg, 1999; Seiple et al., 1996; Sekuler & Ball, 1986; Wall et al., 2004; Webster & Haslerud, 1964). Some of these reports have described constriction of the visual field (Ball et al., 1988; Liebowitz & Appelle, 1969; Plainis et al., 2001; Seiple et al., 1996; Sekuler & Ball, 1986), whereas others have found no single pattern of field loss (Rantanen & Goldberg, 1999; Wall et al., 2004). In our present experiment, we did not find a consistent pattern of sensitivity loss across the four subjects, but there was a tendency for losses to occur in the periphery. In contrast to the Humphrey visual field findings, there was no effect of mental arithmetic on mfVEP amplitude. Previous work has demonstrated that visual spatial attention increases the amplitude and/or decreases the latency of the standard VEP in response to stimuli presented in the attended area (Belmonte, 1998;
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Fig. 5. Plots of the locations of the Humphrey visual field test points (24-2) for the right eye of each subject (A–D). The locations with significantly reduced sensitivity (P 6 0.005) for the PASAT conditions versus the no task conditions are indicated by shaded points.
Fig. 6. Averaged mfVEP waveforms for the two no task runs (dotted lines) and for the two task runs (solid lines) for subject #2. There were no consistent increase or decreases in amplitude as a function of performing the mental arithmetic task.
Di Russo & Spinelli, 1999; Eason, Harter, & White, 1969; Harter, Seiple, & Salmon, 1972; Hoshiyama & Kakigi, 2001; Kutas & Hillyard, 1980; Luck & Girelli,
1998; Luck & Hillyard, 1990; Mangun, 1995; Mangun & Buck, 1998; Muller et al., 1998; Seiple, Clemens, Greenstein, Holopigian, & Zhang, 2002; Van Voorhis
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& Hillyard, 1997). We have previously demonstrated that covert spatial attention significantly increases the amplitude of the local mfVEP in an attended sector (Seiple et al., 2002). However, we found no evidence for inhibition of amplitude in the non-attended sectors . The effects of spatial attention can be seen on early VEP components (100–170 ms) (Hillyard, Vogel, & Luck, 1998; Mangun & Hillyard, 1987), and the magnitude of the attention effect increases with increasing component latency (Kutas & Hillyard, 1980; Mehta, Ulbert, & Schroeder, 2000; Seiple et al., 2002). These spatial visual attention findings are consistent with a modulating mechanism that acts as a sensory gain process (Di Russo, Spinelli, & Morrone, 2001; Eason et al., 1969; Hillyard et al., 1998; Mangun & Buck, 1998). The PASAT imposes a large demand on working memory, information processing, and attention, but not on primary visual processing. fMRI data have shown that performing a PASAT increases the activation of cortical areas associated with executive control, sustained attention, and visual information processing, including the superior and inferior parietal lobes, the superior frontal gyrus, the left medial frontal gyrus, the left inferior frontal gyrus, the cingulate gyrus, and several cerebellar regions (Herath et al., 2001). This pattern of activation suggests a possible locus for the selective losses observed in the Humphrey task. The HFA requires the subject to visually detect a luminance increment and then to plan and execute a manual response. Consistent with interference at the output stage, we found increased test duration and increased false positive and false negative error rates when our subjects concurrently performed a PASAT. Stager and Laabs (1977) also reported that somatosensory reaction times were approximately 100 ms longer when a mental addition task was added to their paradigm.
5. Conclusions Over the last 40 years, the pattern VEP has been used as an ‘‘objective’’ assay of many psychophysically elicited responses, including visual acuity (Balachandran, Klistorner, & Graham, 2003; Harter & White, 1970; Nelson, Seiple, Kupersmith, & Carr, 1984; Norcia & Tyler, 1985; Regan, 1983; Sokol, Moskowitz, McCormack, & Augliere, 1988; Towle & Harter, 1977; White, 1969; Yu, Wu, Liang, & Wu, 1997), contrast sensitivity (Allen, Tyler, & Norcia, 1996; Chen, Wu, & Wu, 1990; Kupersmith, Seiple, Nelson, & Carr, 1984; Norcia, Tyler, & Hamer, 1990; Seiple, Kupersmith, Nelson, & Carr, 1984; Strasburger, Remky, Murray, Hadjizenonos, & Rentschler, 1996), and color vision (Aine & Harter, 1984; Gerling, Meigen, & Bach, 1997; Gerth, Delahunt, Crognale, & Werner, 2003; Regan, 1970). In this literature ‘‘objective’’ is defined as (1) requiring no motor or
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verbal response from the subject, and (2) relatively uninfluenced by ‘‘higher’’ cognitive activity. Recently, the mfVEP has been proposed as an objective measure of visual fields. In the current work, we have demonstrated that the mfVEP meets both of the definitions of an objective test. Our findings suggest that the mfVEP may be clinically useful in some patients who are unable to perform, or who have unreliable, automated static perimetry. Acknowledgements Supported in part by grants from the Rehabilitation Research and Development Service of the Department of Veterans Affairs, Washington, DC. The Foundation Fighting Blindness, Hunt Valley, MD; Research to Prevent Blindness, Inc., New York, NY; the Allene Reuss Foundation, New York, NY. The Starr Foundation, New York, NY; and NEI EY02115.
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The multifocal visual evoked potential: An objective measure of visual fields? William Seiple a,*, Karen Holopigian a, Colleen Clemens a, Vivienne C. Greenstein b, Donald C. Hood b a
Department of Ophthalmology, New York University School of Medicine, BEL 5N15, 550 First Avenue, New York, NY 10016, USA b Department of Psychology, Columbia University, New York, NY 10027, USA Received 10 June 2004; received in revised form 21 October 2004
Abstract We examined the effects of inter-modal attention and mental arithmetic on Humphrey visual field sensitivity and multifocal visual evoked potential (mfVEP) amplitude. Four normally sighted subjects (ages ranging from 24 to 58 years) participated in this study. Monocular visual field sensitiv ity was measured under two conditions: (1) standard testing condition and (2) while the subject performed a Paced Auditory Serial Addition Task (PASAT). Monocular mfVEPs were recorded in response to a 60-sector stimulus. The checkerboard pattern in each sector was contrast reversed according to a binary m-sequence. mfVEPs were recorded under two conditions: (1) standard testing conditions and (2) while the subject performed a PASAT. We found that, when compared to the notask condition, all subjects had locations of significantly reduced Humphrey visual field sensitivities when performing the PASAT. In contrast, there were no significant decreases in mfVEP amplitude in any sector for any of the subjects while performing the PASAT. Our findings indicate that divided attention and ongoing mental processes did not affect the mfVEP. Therefore, the mfVEP provides an objective measure of visual field function that may be useful for some patients with unreliable automated static perimetry results. 2004 Elsevier Ltd. All rights reserved. Keywords: Multifocal visual evoked potential; Visual field; Divided attention
1. Introduction Automated perimeters, such as the Humphrey Field Analyzer (HFA), have made it possible to rapidly screen patients for visual field losses associated with eye diseases. Although the reliability of these visual field measures can be high in some patients, it can be quite low in others (Bengtsson & Heijl, 2000; Birt et al., 1997; Choplin & Russell, 1995; Heijl, 1977; Heijl, Lindgren, & Olsson, 1987; Holmin & Krakau, 1979; Katz & Sommer, 1990; Katz, Sommer, & Witt, 1991; Keltner et al., 2000; Wall et al., 1998; Werner, Petrig, Krupin, & *
Corresponding author. Tel.: +1 212 263 6076; fax: +1 212 263 8749. E-mail address: [email protected] (W. Seiple). 0042-6989/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2004.11.010
Bishop, 1989). Some of the variability in patientsÕ responses may be due to the disease process (Hart & Becker, 1982; Werner, Saheb, & Thomas, 1982). Other factors that contribute to variability include practice, fatigue, the response bias of the patient, and vigilance (Fujimoto & Adachi Usami, 1992; Kutzko, Brito, & Wall, 2000; Wall, Woodward, & Brito, 2004; Werner, Adelson, & Krupin, 1988; Werner, Krupin, Adelson, & Feitl, 1990; Wild, Dengler_Harles, Searle, O_Neill, & Crews, 1989). The impact of these factors is demonstrated by increased testing times and error rates (Bengtsson & Heijl, 2000; Birt et al., 1997; Heijl et al., 1987; Katz & Sommer, 1990; Wall et al., 1998). Divided attention and competing ongoing mental activity also may contribute to the inaccuracies and variability in performance on clinical tests of vision, such as
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the HFA (Choplin & Russell, 1995). Aspects of the attention mechanism have been shown to be capacitylimited under conditions where the subjects were required to perform two or more tasks concurrently (Bonnel & Hafter, 1998; Fernandes & Moscovitch, 2000; Lavie, 2001; Liebowitz & Appelle, 1969; Mangun & Buck, 1998; Rantanen & Goldberg, 1999; Webster & Haslerud, 1964). The increased processing load for dual-task performance has been demonstrated using functional magnetic resonance imaging (fMRI). During dual-task performance, fMRI studies have shown recruitment of cortical areas that were not activated by either single task alone (DÕEsposito et al., 1995; Dove, Pollmann, Schubert, Wiggins, & von Cramon, 2000; Herath, Klingberg, Young, Amunts, & Roland, 2001; Koechlin, Basso, Pietrini, Panzer, & Grafman, 1999). In vision, attention is usually directed at the item that falls on the fovea. If visual attention is spatially divided between a central task and a peripheral task, performance on the peripheral task decreases (Ball, Beard, Roenker, Miller, & Griggs, 1988; Rantanen & Goldberg, 1999; Seiple, Szlyk, Yang, & Holopigian, 1996; Williams, 1982). Adding more visual information in the form of distractors (Sekuler & Ball, 1986) or increasing the number of test points (Fujimoto & Adachi Usami, 1992) can further decrease peripheral sensitivity. Intramodal splitting of attention also can decrease performance. When subjects were required to attend to auditory information, performance on psychophysical visual detection tasks decreased (Schmitter-Edgecombe, 1996; Webster & Haslerud, 1964). Similarly, Humphrey visual field sensitivity decreases when subjects are required to simultaneously perform mental arithmetic (Wall et al., 2004). Recently, the multifocal visual evoked potential (mfVEP), an electrophysiologic technique, has been used to measure visual field function (Hood, 2003; Hood & Greenstein, 2003; Hood & Zhang, 2000; Klistorner & Graham, 1999). Based on the findings of reliable amplitudes in some patients who had unreliable Humphrey results, the mfVEP has been proposed as an objective measure of visual fields (Hood, 2003; Hood & Greenstein, 2003; Hood & Zhang, 2000). In the present study, we examined whether the dichotomy between performances on HFA and mfVEP fields could be due to a differential effect of divided attention and ongoing mental activity on these two measures.
The research followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. The research was approved by the New York University School of Medicine Institutional Review Board. 2.2. Automated visual field Monocular (the contralateral eye was patched) visual field sensitivity was measured with a HFA (Model 750; Humphrey Systems, Dublin, CA) using the 24-2 program and the SITA standard method (Bengtsson & Heijl, 1998, 1999). Visual fields were first measured under standard testing conditions (labeled A: no-task condition). In the second run (labeled B: task condition), the subject performed a Paced Auditory Serial Addition Task (PASAT) while undergoing visual field testing (Gronwall, 1977). An audiotape of a male speaker reading from lists of randomly generated numbers was played while the subject performed the visual field test. The separation between the spoken numbers was two seconds. To make the mental task condition as close as possible to those of the mfVEP (described below), a series of 14 numbers was presented. The subjectÕs task was to mentally add the numbers and report the sum at the end of the series. The subject was then instructed to hold the HFA response key down to pause the field test and report the sum. The subject also was instructed to pause the test if he/she lost count. If this occurred, a new series of numbers was begun and the test continued. The subjectÕs pupil position was viewed throughout the test and if large eye movements were seen the test was paused. The order of the runs was counterbalanced (A1B1B2A2). 2.3. Multifocal VEP 2.3.1. Stimulus The stimulus was displayed on a 21-inch black-andwhite monitor (frame rate 75 Hz). The mfVEP stimulus array consisted of 60 sectors (Fig. 1A). At the viewing distance of 32 cm, the stimulus diameter was 47.2. The black checks had a luminance of 2 cd/m2, and the white checks had a luminance of 280 cd/m2. The checkerboard pattern in each sector was contrast reversed according to a binary m-sequence (Baseler, Sutter, Klein, & Carney, 1994; Sutter & Tran, 1992).
2. Methods 2.1. Subjects Four normally sighted subjects (ages ranging from 24 to 58 years) participated in this study. All were experienced psychophysical and electrophysiologic observers.
2.3.2. Recording The active electrode was placed on the midline 4 cm above the inion and referenced to an electrode placed at the inion. An electrode placed on the forehead served as ground. The raw EEG was band-pass filtered (1–100 Hz) and amplified 100,000 times. The amplified
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Fig. 1. (A) The display used for the mfVEP recordings and grouping of sectors for the eccentricity analysis. Each of the 60 sectors contains a contrast-reversed checkerboard pattern. (B) Locations of the visual field test locations for the Humphrey 24-2 program.
signal was digitized (1200 Hz), and second-order local responses were calculated using the VERIS software (EDI, San Mateo, CA). Artifact removal and averaging with neighbors were turned off. The total recording time was divided into short segments in order to maintain subject compliance with the demands of the task. Testing was done monocularly; the contralateral eye was patched. Eye position was monitored using a CCD camera, and small saccades or fixation movements (on the order of 1) were easily detected. Segments containing these artifacts were discarded and re-recorded. 2.3.3. Procedure In the first run (no-task condition A1), the subject was instructed to monocularly fixate the center of the screen and concentrate on the fixation target. In the next run (task condition B1), the subject again was instructed to fixate the center of the screen and to listen to a series of 14 numbers played on an audiotape. The separation between the spoken numbers was two seconds. The subjectÕs task was to add the numbers. The sum of this addition was reported after each recording segment ended. If the subjectÕs addition was incorrect by more than ±2, that segment was discarded and recorded again. The order of the runs was counterbalanced (A1B1B2A2). 2.3.4. Analysis Second-order mfVEP responses for each sector were exported from the VERIS system, and root-meansquare (RMS) voltages were calculated using a custom MATLAB program (Hood, 2003; Hood & Zhang, 2000; Hood, Zhang, Hong, & Chen, 2002). RMS voltages were calculated for two time intervals: signal was measured as the RMS voltage between 45 and 150 ms, and noise was measured as the RMS voltage between 325 and 430 ms (Zhang, Hood, Chen, & Hong, 2002).
The ratio of signal-to-noise RMS voltages (s2n) was calculated for each sector for each run.
3. Results 3.1. Testing the effects of mental addition In Fig. 2A, Humphrey sensitivities for all subjects are plotted for the repeat no task conditions: A2 versus A1. In this figure, data for three concentric rings (Fig. 1B) are shown as circles, triangles, and square symbols for the inner, middle, and outer rings, respectively. The repeat data clustered around the diagonal line that represents no change in sensitivity between runs. The comparison between the average Humphrey sensitivities for the task condition (B) versus the averages for the no task conditions (A) are shown in Fig. 2B. Most of the points fall below the equality line, representing a decrease in sensitivity during the task condition. The mfVEP s2n data are plotted in the same manner in Fig. 2C and D. Once again, the data for the no task repeat runs clustered around the diagonal. The plot of the average task versus the average no task s2n ratios also showed no consistent deviation as a function of task. The data were also summarized by comparing the proportion of data points that increased (difference P 0) or decreased (difference < 0). For the Humphrey repeat no task data, 62% of the A2 data had higher sensitivity and 38% had lower sensitivity than on the A1 trial. For the task condition, 22% of the Humphrey sensitivity values increased and 78% of the values decreased relative to their values during the no task condition. These proportions were significantly different (v2 = 70.3, P < 0.001). For the VEP no task data, s2n ratios increased in 48% and decreased in 52% of the repeat values. For the task condition, s2n ratios increased in 59% and decreased in 41% of the points relative to their no task ratios. These proportions were not significantly different (v2 = 0.004, P = 0.95).
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Fig. 2. (A) Scatterplot of the Humphrey threshold values for all subjects for the first and second no task runs. The diagonal line is drawn through the points of no change in sensitivity. Data for the inner, middle, and outer rings are shown as circles, triangles, and squares, respectively. (B) Scatterplot of the Humphrey threshold values for all subjects averaged for the task and no task conditions. (C) Scatterplot of the mfVEP signal to noise ratios for all subjects for the first and second no task runs. (D) Scatterplot of the mfVEP signal to noise ratios for all subjects averaged for the task and no task conditions.
3.2. Testing the local effects of mental addition For the HFA, the differences between the average of the two task runs (Aavg) minus the average of the two no-task runs (Bavg) were calculated in decibels (dB) for each test point for each subject. Comparisons were only made between conditions within a test (HFA or mfVEP). For the mfVEP, the differences were calculated as the ratios of task to no-task amplitude averages for each sector for each subject: log(Bavg/Aavg) · 10 (i.e., in dB). We used the standard deviation (SD) of the differences between the two no-task runs (A2 A1) to calculate statistical probability. The logic was that, if the variability in the no-task condition was due to random noise, then the differences would be normally distributed around a mean of zero, and the SD of the distribution could be used as a measure of inherent variability. Frequency distributions of the dB difference scores between the two no-task runs are plotted for the HFA and the mfVEP in Fig. 3. These data pass the KolmogorovSmirnov Normality Test (KS = 0.037 and 0.35, respectively). The SDs for the HFA data were 1.6, 1.5, 2.7, and 2.1 dB for the four subjects. The repeat reliability of Humphrey sensitivities significantly decreased with increasing eccentricity. Calculated across three concen-
Fig. 3. Frequency distributions of the differences (in dB) between the first (A1) and second (A2) no-task runs: filled circles—Humphrey visual fields; open circles—mfVEP.
tric rings (Fig. 1B), the average SDs were 1.1, 2.1, and 2.2 dB (F(2,9) = 6.8, P = 0.015), with a post-hoc analysis showing a significant difference between the inner ring and outer ring (q = 5.2, P = 0.013) (Fig. 4). Other investigators have also reported poorer reliability for peripheral test points than for central points for Humphrey visual fields (Heijl et al., 1987; Parks et al., 1997). For the mfVEP data, the SD values averaged 1.6, 2.0, 1.7, and 1.9 dB for the four subjects. For the three concentric rings (Fig. 1A), SDs averaged 2.1, 1.8, and
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Fig. 4. Standard deviations of the differences (in dB) between the first (A1) and second (A2) no-task runs as a function of eccentricity (inner, middle, and outer rings) for Humphrey visual field thresholds (filled bars) and for mfVEP amplitudes (open bars).
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t = 3.15, df = 7, P = 0.02). Although 25% of the task runs had fixation losses above the normal criterion, 25% of the task runs had 0% fixation losses. There was a statistically significant difference between the average false positive responses for the no-task runs (average 2.0 ± 2.8%) and the task runs (average 9.0 ± 6.4%) (Paired t = 3.22, df = 7, P = 0.015). There were no false negative responses during the no-task runs and an average of 9.3 ± 6.4% during the task runs (paired t = 4.65, df = 7, P = 0.002). There were no statistically significant relationships (Spearman correlations) between any of the reliability indexes and either the number of locations with significantly reduced sensitivity or the average dB difference between the task and no-task conditions.
1.9 dB (F(2,9) = 0.1, P = 0.89) for the inner, middle, and outer rings, respectively (Fig. 4). Chen et al. (2003) found that mfVEP amplitude reliability was poorer for the central sectors (mean SD = 2.0) than for more peripheral sectors (mean SDs = 1.61 and 1.55 for the middle and outer rings, respectively). Because of this eccentricity effect, each subjectÕs average SD for each ring was used to calculate z-scores for the differences between task and no-task conditions for the points within the corresponding ring: (Btask avg Ano-task avg)/SDno-task repeats. Points (HFA) or sectors (mfVEP) that had z-scores less than 2.57 (P = 0.005, two-tailed test) were coded as significantly reduced by the mental arithmetic task.
3.2.2. Multifocal VEP The mfVEP waveforms for one subject (#2) are shown in Fig. 6 for no task (dotted lines) and task (solid lines) conditions. If the VEP were affected by performing the PASAT task, then the tracings for the task conditions should be smaller in amplitude than those of the no task condition. There were no significant decreases in amplitude in any sector for any of the subjects while performing the PASAT compared to the no-task condition. The mean differences in dB between the task and no-task conditions were 0.3, 0.5, and 0.7 for the inner, middle, and outer rings, respectively. There was no significant main effect of eccentricity (F = 0.11, P = 0.89).
3.2.1. Automated visual fields Compared to the no-task condition, all subjects had locations of significantly reduced HFA sensitivities when performing the PASAT (shaded circles in Fig. 5A–D). These findings are a replication of the findings of Wall et al. (2004) for the HFA. On average, there was a greater loss for the more eccentric test points. The average decrease in sensitivity for the inner ring was 2.8 ± 4.5 dB; for the middle ring, 2.9 ± 4.1 dB; and for the outer ring, 4.4 ± 5.8 dB. These differences among the rings, however, were not statistically significant (F = 1.91, P = 0.15). There are three indexes calculated by the HFA that provide information about a patientÕs response reliability: fixation losses, false positive errors, and false negative errors (Humphrey, 1998). Fixation losses are quantified by presenting stimuli at the estimated location of the patientÕs blind spot and counting the number of these presentations that are detected. False positive errors are responses that occurred when no stimuli are presented, and false negative errors are when no responses are given to supra-threshold stimuli. In our current experiment, there was a significant difference in mean fixation losses between the no-task runs (average 4.5 ± 5.3%) and task runs (16.8 ± 12.6%) (Paired
4. Discussion We found that performing mental arithmetic significantly decreased sensitivity on the HFA. There are numerous reports of decreased visual field sensitivity under conditions of divided visual attention or when performing concurrent mental tasks (Ball et al., 1988; Liebowitz & Appelle, 1969; Plainis, Murray, & Chauhan, 2001; Rantanen & Goldberg, 1999; Seiple et al., 1996; Sekuler & Ball, 1986; Wall et al., 2004; Webster & Haslerud, 1964). Some of these reports have described constriction of the visual field (Ball et al., 1988; Liebowitz & Appelle, 1969; Plainis et al., 2001; Seiple et al., 1996; Sekuler & Ball, 1986), whereas others have found no single pattern of field loss (Rantanen & Goldberg, 1999; Wall et al., 2004). In our present experiment, we did not find a consistent pattern of sensitivity loss across the four subjects, but there was a tendency for losses to occur in the periphery. In contrast to the Humphrey visual field findings, there was no effect of mental arithmetic on mfVEP amplitude. Previous work has demonstrated that visual spatial attention increases the amplitude and/or decreases the latency of the standard VEP in response to stimuli presented in the attended area (Belmonte, 1998;
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Fig. 5. Plots of the locations of the Humphrey visual field test points (24-2) for the right eye of each subject (A–D). The locations with significantly reduced sensitivity (P 6 0.005) for the PASAT conditions versus the no task conditions are indicated by shaded points.
Fig. 6. Averaged mfVEP waveforms for the two no task runs (dotted lines) and for the two task runs (solid lines) for subject #2. There were no consistent increase or decreases in amplitude as a function of performing the mental arithmetic task.
Di Russo & Spinelli, 1999; Eason, Harter, & White, 1969; Harter, Seiple, & Salmon, 1972; Hoshiyama & Kakigi, 2001; Kutas & Hillyard, 1980; Luck & Girelli,
1998; Luck & Hillyard, 1990; Mangun, 1995; Mangun & Buck, 1998; Muller et al., 1998; Seiple, Clemens, Greenstein, Holopigian, & Zhang, 2002; Van Voorhis
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& Hillyard, 1997). We have previously demonstrated that covert spatial attention significantly increases the amplitude of the local mfVEP in an attended sector (Seiple et al., 2002). However, we found no evidence for inhibition of amplitude in the non-attended sectors . The effects of spatial attention can be seen on early VEP components (100–170 ms) (Hillyard, Vogel, & Luck, 1998; Mangun & Hillyard, 1987), and the magnitude of the attention effect increases with increasing component latency (Kutas & Hillyard, 1980; Mehta, Ulbert, & Schroeder, 2000; Seiple et al., 2002). These spatial visual attention findings are consistent with a modulating mechanism that acts as a sensory gain process (Di Russo, Spinelli, & Morrone, 2001; Eason et al., 1969; Hillyard et al., 1998; Mangun & Buck, 1998). The PASAT imposes a large demand on working memory, information processing, and attention, but not on primary visual processing. fMRI data have shown that performing a PASAT increases the activation of cortical areas associated with executive control, sustained attention, and visual information processing, including the superior and inferior parietal lobes, the superior frontal gyrus, the left medial frontal gyrus, the left inferior frontal gyrus, the cingulate gyrus, and several cerebellar regions (Herath et al., 2001). This pattern of activation suggests a possible locus for the selective losses observed in the Humphrey task. The HFA requires the subject to visually detect a luminance increment and then to plan and execute a manual response. Consistent with interference at the output stage, we found increased test duration and increased false positive and false negative error rates when our subjects concurrently performed a PASAT. Stager and Laabs (1977) also reported that somatosensory reaction times were approximately 100 ms longer when a mental addition task was added to their paradigm.
5. Conclusions Over the last 40 years, the pattern VEP has been used as an ‘‘objective’’ assay of many psychophysically elicited responses, including visual acuity (Balachandran, Klistorner, & Graham, 2003; Harter & White, 1970; Nelson, Seiple, Kupersmith, & Carr, 1984; Norcia & Tyler, 1985; Regan, 1983; Sokol, Moskowitz, McCormack, & Augliere, 1988; Towle & Harter, 1977; White, 1969; Yu, Wu, Liang, & Wu, 1997), contrast sensitivity (Allen, Tyler, & Norcia, 1996; Chen, Wu, & Wu, 1990; Kupersmith, Seiple, Nelson, & Carr, 1984; Norcia, Tyler, & Hamer, 1990; Seiple, Kupersmith, Nelson, & Carr, 1984; Strasburger, Remky, Murray, Hadjizenonos, & Rentschler, 1996), and color vision (Aine & Harter, 1984; Gerling, Meigen, & Bach, 1997; Gerth, Delahunt, Crognale, & Werner, 2003; Regan, 1970). In this literature ‘‘objective’’ is defined as (1) requiring no motor or
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verbal response from the subject, and (2) relatively uninfluenced by ‘‘higher’’ cognitive activity. Recently, the mfVEP has been proposed as an objective measure of visual fields. In the current work, we have demonstrated that the mfVEP meets both of the definitions of an objective test. Our findings suggest that the mfVEP may be clinically useful in some patients who are unable to perform, or who have unreliable, automated static perimetry. Acknowledgements Supported in part by grants from the Rehabilitation Research and Development Service of the Department of Veterans Affairs, Washington, DC. The Foundation Fighting Blindness, Hunt Valley, MD; Research to Prevent Blindness, Inc., New York, NY; the Allene Reuss Foundation, New York, NY. The Starr Foundation, New York, NY; and NEI EY02115.
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