Development of the Human Visual System: Monocular and Binocular Pattern VEP Latency

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1 Investigative Ophthalmology & Visual Science, Vol., o., July Copyright Association for Research in Vision and Ophthalmology Development of the Human Visual System: Monocular and Binocular Pattern VEP Latency Daphne L. McCulloch* and Barry Skarf* Pattern visual evoked potentials (P-VEPs) were recorded in human infants who were between weeks and yr of age. The latency of the first reproducible positive peak in the P-VEP was measured monocularly and binocularly for five sizes of phase alterations checkerboard stimuli (range: 0' to.' check widths). Rapid visual maturation in the first months of life was shown by the development of reproducible P-VEPs to smaller check sizes and by a rapid decrease in the latency of the first reproducible positive peak. Monocular P-VEPs have slightly longer latencies than the binocular P-VEPs. This latency difference is invariant with age, but is significantly greater with larger check stimuli. ormal ranges for this large population are provided as a reference for clinical studies. Invest Ophthalmol Vis Sci :-, Visual evoked potentials to pattern stimuli (P- VEPs) have been used to study the development of the human visual system and to test visual function in infants and nonverbal children. " Excellent success rates have been achieved using P-VEPs to test visual function in clinical settings even in populations considered difficult, such as those who are neurologically impaired. High success rates have also been reported using the sweep VEP technique for acuity estimation in normal subjects. Diverse aspects of visual development and maturation can be measured using P-VEPs. With the sweep VEP technique, spatial frequency thresholds can be determined from patterns that alternate at temporal frequencies high enough to generate steady state VEPs. The conventional, transient P-VEP can provide information that is complementary to data obtained with the sweep VEP method. VEP latency, measured with the transient P-VEP, provides an index of visual maturation that can be obtained from suprathreshold visual stimuli. either latency nor sweep VEP threshold depends directly on VEP amplitude, provided a detectable signal is present above the noise level. Recording transient P-VEPs to binocular and monocular stimulation in the same patients permits us to contrast the development of binocular and From the Department of Ophthalmology, The Hospital for Sick Children, Toronto, Canada. Supported by grants MA0 and MA from the Medical Research Council of Canada, Ottawa. Submitted for publication: September 0, 0; accepted March,.' Reprint requests: Daphne McCulloch, OD, PhD, Ophthalmology, Children's Hospital of Los Angeles, 0 Sunset Blvd., Los Angeles, CA 00. monocular spatial vision and to compare the maturation of monocular vision between the two eyes. A second, important reason for studying transient P-VEPs is to provide an extensive base of normal data with which to compare results of clinical studies. It is impractical for every clinical laboratory to establish its own norms for young patients because maturation of VEP latency varies with both age and pattern size. " 0 However, reliance on published data is unsupported unless replication in independent laboratories has been shown. Although there are many reports of P-VEPs from small groups of infants and infants in specific age groups " only one laboratory published normative data derived from populations that span the age range of rapid visual development. - Maturation of the binocular P-VEP latency was reported by Sokol and Jones for sizes of checkerboard stimuli in a longitudinal study of infants born at term. Similar data from a large cross sectional study was reported for check sizes. Recently, Fulton has recommended that clinical P-VEP testing include: ) Responses to at least three pattern sizes, and ) Separate testing of each eye with interocular latency comparisons, since clinical disorders frequently involve only one eye. Monocular P-VEPs have been reported infrequently and results from a large normative population have not been presented. In the present study, we have therefore examined the maturation of P-VEP latencies to sizes of checkerboard stimuli viewed both binocularly and monocularly, by children between weeks and months of age. Materials and Methods Subjects A total of infants and toddlers between the ages of weeks and years participated as subjects. Ten

2 o. PATTER VEPs I HUMA IFATS / McCulloch and Skarf adult subjects, to years of age were also studied. The subjects were recruited from the local area through radio and newspaper announcements and by word of mouth. Parents or guardians signed informed consent documents approved by the institutional human subjects committee. All subjects had a vision screening examination and showed normal pupillary reflexes, normal fixation and following reflexes and clear ocular media. The eyes of all subjects were aligned by cover test. If the parent agreed, a cycloplegic refraction was performed after VEP testing. Subjects were divided into groups by age as shown in Table. Twelve of the infants were tested serially, or times, when they were in different age groups. Thus, a total of testing sessions (visits) were obtained. Results from of these sessions could not be analyzed due to computer disc failure. VEP Recording During each testing session, VEPs to pattern reversing checkerboard stimuli were recorded binocularly and monocularly. A icolet CA-000 clinical evoked potential system was used. The active electrode was placed cm above the inion with the reference and ground electrodes placed on the earlobes. Electrode impedance was below mega ohms. The infant was seated cm in front of a video screen that displayed reversing checkerboard patterns. The mean luminance was ft lamberts ( cd/m ) and the contrast between the black and white checks was %. Phase reversal was at. alterations/sec. Scalp potentials were led to preamplifiers and then filtered through a bandpass of 0.-0 Hz. The VEPs were averaged more for a 00 msec epoch triggered by each phase Table. Author Provide Title Group 0 Adult Age (range weeks) Age (nearest month) 0 Adult o reversal. For each trial, 0-0 epochs epochs were averaged. Several modifications facilitated the testing of infants and young children. The subject was seated in a small, darkened room without distractions. An observer, located behind the stimulus, monitored fixation and operated a gating switch so that VEPs were acquired only while the subject was watching the stimulus. The observer also made sounds and jingled keys in front of the stimulus to attract the infants' attention and to maintain interest. An artifact reject circuit eliminated epochs that were contaminated by head and body movement. Subjects werefirsttested binocularly and then monocularly. An adhesive patch was used to occlude either eye for monocular testing. The sequence in which right and left eyes were tested was randomized among subjects. Checks subtending 0', 0', 0', ', and.' were shown in random order with at least two trials for each size. VEP Measurement: The morphologic features of the transient VEP change rapidly in the first months of life, so that the latency of specific VEP peaks and troughs varies with age. VEPs were defined as present or absent to a specific stimulus based on reproducibility. The VEP is reproducible and hence present, if one or more major peaks or troughs occurs within a 0 msec range when separate trials are compared. A major peak or trough was defined as the largest amplitude peak or trough within a 0 ms segment of that trial, ie, no larger excursions appeared from baseline within ± ms. Two aspects of the VEPs data were analyzed: the minimum check size that produced a reproducible VEP and the latency of the first reproducible positive peak (nominally PI00). The latency was measured from the cumulative response obtained when the separate trials obtained under identical stimulus conditions were summed. Interocular latencies and latencies for monocular and binocular VEPs were compared. Results Success Rates Eighty-five percent of infants and young children completed binocular and both monocular P-VEP recording sequences with at least four pattern sizes (with replications) in a single visit (testing session). Testing binocularly and with at least one eye, was completed in % of visits, and binocular testing was successful in % of visits. Binocular P-VEPs in the eight unsuccessful sessions could not be analyzed because VEPs

3 IVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIECE / July Vol. Fig.. P-VEPs wave forms obtained from three subjects are illustrated for three sizes of checks. 0' (upper), 0' middle, and ' (lower). The latency of the first reproducible positive peaks are given. showed poor reproducibility due to poor cooperation, ie, crying, sessions; high refractive error ( session), and high levels of alpha activity ( visits). Similar success rates (~0%) have been reported by Hamer et al and by Orel-Bixler et al who used the sweep VEP technique. Binocular VEPS The latency of the first major positive peak (nominally the PI00) to all check sizes decreases rapidly in the initial weeks of life. Typical binocular VEPs for infants at,, and 0 weeks of age are shown in Figure. Reproducible VEPs are present to large pattern stimuli (0' and 0') in the youngest babies. Fifty percent of infants show reproducible VEPs to smaller stimuli at - weeks of age for 0' checks, - weeks of age for ' checks, and - weeks of age for the.' checks. Adult values for PI00 are approached earlier for larger stimuli than for smaller stimuli. Table summarizes the PI00 latencies and standard deviations for each check size and each age group. P-VEP latency data are appropriately described by an exponential function in the form: latency = A + B Age c [where A, B, and C are constants]. Our data is shown in Figure, with exponential functions fit by the least squares method and the % upper and lower confidence intervals around the data. Constants A, B, and C for each stimulus condition are given in Table. Constant A, the asymptote or adult latency value, is lowest for the largest checks and increases significantly for each successive smaller check stimulus (P < 0.0, Student-ewman-Keuls method for a posteriori comparison among means ]. Constant B, Table. Latency of PI00: binocular VEPs Age (mo) 0 Adult 0 0.0TT ' '

4 o. PATTER VEPs I HUMA IFATS / McCulloch and Skarf I * \\ A- 0 ' SIZE % ^ titty 0' SIZE»- v A < SIZE '00.' SIZE ; Fig.. Binocular P-VEPs latencies to the first reproducible positive peaks (PI00) are shown for all five check sizes for all subjects. The solid curves are exponential functions fit to the data. The dashed curves are the upper and lower % confidence intervals for the data (see text). 0 - AGE (Months) the slope of the functions is not significantly different among check sizes from 0' through '. Constant C, the deceleration or slope of the log-log plots, is significantly lower for each smaller stimulus size from 0' to '. Thus, the VEP latency approaches adult values more rapidly for larger stimuli than for smaller stim-

5 IVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIECE / July Vol. Table. Values for constants A, B, and C where: latency = A + B (age) c Check size 0' 0' 0' '.' 0' 0' 0' '.' A Binocular P-VEPi B Monocular P-VEPs C uli. The function fit through the data for the.' check stimulus was the only exception, with a steeper slope and more rapid deceleration than all functions for larger check sizes. We expect that this is an artifact that results from the limited data at the youngest ages for this smallest check stimulus. Only the most advanced infants show any reproducible VEP to the.' check before weeks of age. This finding introduces a bias towards those infants who see better in the region of the function that determines constants B andc. Monocular VEPS Although VEPs were recorded from each eye in the majority of subjects, group data for monocular VEPs is presented using the better eye of each infant. Better eye was defined as the eye with the most data in infants with limited co-operation, or the eye with the shortest latency for the first major positive peak. In this manner, we reduce the number of children with poor co-operation included in the data, and eliminate the possibility of including children with unilateral vision problems that may have gone undetected. Table shows the mean and standard deviation values of the PI00 latency for each age group and each pattern size. As with binocular VEPs, the latency of the first reproducible positive peak decreases rapidly in the first few months of life. Data for each pattern size with the best fit exponential function and % confidence intervals are shown in Figure. The exponential functions fit to the data are again in the form: latency = A + B age c (where A, B and C are constants). These three constants vary systematically with the size of the stimulus checks in the same general ways as they varied with the binocular data. Constant A, the asymptote, is greater for smaller check sizes. Constant B, slope, and constant C, slope of the log-log plot, are steeper for larger check sizes. Comparisons among check sizes for the sets of monocular constants were made using a Student-ewman-Keuls test for a posteriori comparisons among means. Differences among means were significant at the 0.0 level for all constants at each check size with the following exceptions. The values of constant A for the 0' and 0' stimuli did not significantly differ and the value for the.' stimulus was smaller than the values for the next two larger sizes. For constant B, values for the.' and ' check sizes were not significantly different. Monocular-Binocular Comparisons We could record monocular VEPs to large checks (0') in 0% of the subjects at -0 weeks of age. VEPs to smaller checks were recordable in 0% of Table. Latency of PI00: monocular VEPs Age (mo) '.' 0 Adult

6 o. PATTER VEPs I HUMA IFATS / McCulloch and Skarf \ SIZE Fig.. Monocular P-VEP latencies to thefirstreproducible positive peak (P00) in the "better eye" are shown for allfivecheck sizes for all subjects. The solid curves are exponential functions fit to the data. The dashed curves are the upper and lower confidence intervals (see text) subjects at - weeks for 0' and 0' sizes, at - weeks for the ' size, and at - weeks for the smallest check stimulus (.'). These age ranges are consistently - weeks older than the comparable ages for binocular VEPs to the same stimuli. We cannot determine whether monocular VEPs were not recordable because of slower development of monocular acuity, or because of other factors such as poor

7 0 IVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIECE / July Vol. 0 attention or poor accommodation in the monocular viewing conditions. A peculiar difference between VEPs recorded to monocular stimulation and to those recorded to binocular stimulation is that there is substantially less variance in the monocular latency data. Power functions fit to the monocular data and the % confidence intervals for this data are entirely within the confidence intervals for the binocular data. The most likely explanation for the lower variance in the monocular data is that the less co-operative children, who generated greater amounts of noise, were often eliminated from monocular testing as they would not tolerate the eye patch. Although monocular data falls within the binocular ranges, the values of constant A, the asymptotes are significantly longer in latency than those values for binocular viewing of the same stimulus, except for the smallest,.-min stimulus (Student-ewman-Keuls test for a posteriori comparison among means). Thus, as found in most studies of adult VEPs, VEPs recorded monocularly have, on average, slightly longer latencies than those recorded binocularly. Differences between binocular latencies and better eye latencies to the first major positive peak of the P-VEP were compared using a two-way analysis of variance (AOVA) to test for the effects of age and check size. Check size showed a highly significant effect (P < 0.00). Binocular latencies are shorter than the better eye latencies for larger check sizes. Differences are. ms,. ms,. ms, 0. ms, and -0. ms for check sizes 0' through.', respectively. The values for 0', ', and.' are not significantly different from zero. Age had no significant effect on the monocular-binocular latency difference. Interocular Comparisons o significant differences exist in latencies to the first major positive peak for the right and left eyes, for all check sizes and age groups (AOVA). The average difference between the right and left eyes for all 0 comparisons is 0.0 ms. Interocular latency differences are significantly more variable for smaller check sizes (P < 0.00 AOVA for right minus left). However, even in the youngest age groups, interocular latency differences were not significantly more variable than interocular latency differences for older children or adults. The upper limits of normal for the latency differences to the first major positive peak are 0.,., 0.,., and. for check sizes 0', 0', 0', ', and.', respectively. Discussion For a range of check sizes in octave steps from very large (0') to very small (.'), P-VEP latencies show rapid maturation early in life, with earlier maturation for larger check sizes. Average latency values lie within one standard deviation of adult values by and months of age for 0' and 0' checks, respectively. VEP latencies to smaller checks (0', ', and.') remain significantly longer than adult values up to yr of age. Generally, our data agree with published PI00 latency values for normal infants ' and with values for infants born prematurely but corrected for gestational age. Mean latency values and ranges fall within our confidence intervals for the appropriate age and check size with a few exceptions. These exceptions are limited to latencies values obtained from young infants (- weeks of age) using ', 0', or 0' checks. Figure shows a comparison of our calculated confidence intervals with data from other laboratories. Data for infants more than months of agefitwithin our exponential % confidence limits. However, the data of Porciatti, who tested younger infants, fit poorly to the exponential function. Both Poraiatti and Harding et al suggested that P-VEP maturation is better fit by a linear model before months of age. Moskowitz and Sokol published exponential functions for VEP latencies to two check sizes, large checks (0' or ') and small checks (' or '). As shown in Figure, functions fit through their data are very similar in shape and position to our curves for corresponding check sizes. However, there are statistically significant differences between our functions and those of Moskowitz and Sokol in all of the three constants: A, B, and C (large sample Z score tests for differences, P >.00). Several reasons could account Fig.. Binocular P-VEP latencies to the first positive peak using a 0' pattern reversing check stimulus are shown for three studies: Sokol and Jones, (O); Moskowitz and Sokol, (+); and Porciatti (A) along with the upper and lower % confidence intervals for our data (). Mean latency values are plotted at the median age of a given age range. Some values were derived from published figures.

8 o. PATTER VEPs I HUMA IFATS / McCulloch and Skarf 00- \ 00- L=.0 Age.I0S " ^ 00- \ \ I " 00- \ ] j ' L= 0 0.S Age m t Age mo III. f 00. ARC ma ' Fig.. Exponential functionsfitto the P-VEP latency data in the current study (- -) are shown with thosefitby Moskowitz and Sokol ( ), for large checks (left) and small checks (right). The insets show the log-log plots. for the differences between the constants calculated in these two very similar studies. Testing and recording methods were similar except that Moskowitz and Sokol combined data from 0' and ' (large) checks and from ' and ' (small) checks. The two check sizes that make up each combined group differ by only one-third of an octave and those investigators found no significant difference in P-VEP latency between the pairs of check sizes that were combined in each group. It is reasonable that the effect of combining sizes would be minimal, although perhaps not insignificant, as both parameters A and C change systematically with check size. Differences in data management may account for a more substantial difference between our functions and the functions fit in their study. Moskowitz and Sokol used age to the nearest month whereas we used actual age (to the nearest day) to calculate the functions. The position of data points in the first two months has a strong effect on constant C (slope of the log vs log plot). Recalculation of our functions with age rounded to the nearest month yielded values for C that are closer to the values calculated by Moskowitz and Sokol. Only parameter C for the large check size was significantly different from that obtained by Sokol and Moskowitz after recalculation (P < 0.00). The age range of our samples differed between our study and theirs. They collected data from children through early childhood up to yr of age. We collected data only in infants up to yr of age but also included adult data when fitting our functions. As the exponential function is only a first-order approximation of the actual maturation function of VEP latency, differences in age range could effect the value of any of the constants A, B, or C. We believe that these differences in methods and analysis are sufficient to account for the small but statistically significant differences between the results of this study and those of Moskowitz and Sokol. The similarity of our results with those found in other laboratories ' has showed that independent laboratories can establish very similar normative values for binocular P- VEP latencies over a large range of age groups. Further studies of young infants may provide some insight into the transition from early postnatal development to the period of rapid visual development between and months of age. Using behavioral methods, binocular acuity estimates are superior to monocular acuity estimates by 0. to octave in infants more than months of age. 0 Binocular superiority is less pronounced or absent in younger infants. In contrast, monocular and binocular sweep VEP thresholds are almost identical in older infants and show a slight (0. octave) superiority of binocular acuity in infants under 0 weeks of age. Our data generally support thefindingsobtained with sweep VEPs. We record binocular P-VEPs - weeks earlier than we can record monocular P-VEPs with comparable check size stimuli. However, binocular P-VEPs are recorded more easily than monocular P-VEPs in young infants and in our protocol, we first tested binocularly. Thus, we cannot determine whether the difference between binocular and monocular VEPs is due to the earlier development of the binocular visual response or simply due to increased attention under binocular viewing conditions. We found slightly shorter binocular PI00 latencies than monocular PI00 latencies. However, no significant trend toward an increase or decrease in the difference between binocular and monocular latencies with age occurred. In behavioral studies, interocular acuity differences are greater for younger infants. " A model of independent monocular acuity development before the

9 0 IVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIECE / July Vol. onset of binocular vision and stereopsis has been proposed. We find that PI00 latencies in the right and left eyes are equal from the earliest age that they can be recorded and that interocular differences are invariant with age. Interocular differences greater than. ms are significant (P <.0) and should arouse suspicion of abnormal vision in one eye (. ms for the very small,.' checks). Thus, our data support the sweep VEPfindings that, up to the level of VEP generators, no evidence for a model of independent monocular visual development before the onset of binocular function exists. In development of VEP latency and spatial frequency threshold, VEPs have more rapid monocular visual development and much closer agreement between the left and right eye, than are obtained with behavioral measures of visual function. Our success rates for binocular and monocular P- VEP recording are % and %, respectively for normal subjects from weeks to yr of age. The youngest babies, however, did not complete the monocular test sequences as frequently. In babies under weeks of age, reliable VEP data was collected binocularly and from one eye in of visits (%). Reliable VEPs were recorded binocularly and monocularly from both eyes in only eight of these young babies (%). In contrast, 0% of the toddlers and infants more than weeks of age completed the entire monocular and binocular sequences, with reproducible VEPs. Although our success rate for monocular VEP testing in normal infants and children was high, success in those less than weeks of age, cannot be expected. More than one visit is often required to obtain reliable monocular P-VEPs from each eye of individual young infants. Only slightly lower success rates are reported for patients with a variety of visual and neurologic disorders. - Odom and Green completed binocular P- VEP testing to multiple pattern sizes in % of patients under yr of age and % of older, neurologically impaired patients. Sokol et al completed binocular P-VEP testing to at least three check sizes and monocular P-VEP testing to a small check size in % of pediatric patients between and months of age. In contrast, the forced choice preferential looking method was successfully completed in only % of these young patients at a single visit. High success rates in nonverbal patients have lead to greater use of P-VEPs for clinical testing and clinical research. The normative values found in this study expand the normative P-VEP data base that is available to include pattern sizes with binocular and monocular values and interocular comparisons. Several types of repetitive pattern stimuli are in use for recording P-VEPs; checkerboards, stripes (squarewave gratings) and sinusoidally modulated gratings. Sinusoidally modulated gratings are very useful to study the development of spatial vision because they present a single-spatial frequency. However, checkerboards have several practical advantages for clinical testing. They elicit larger amplitude VEPs, are easily produced without luminance artifact on video display terminals, and they are available on commercially produced evoked potential systems. Finally, the latency of VEPs to checks is similar to the latency of VEPs to stripes with the same fundamental spatial frequency. In this study, no attempt has been made to estimate visual acuity from transient P-VEP data. Latency of the transient P-VEP is a robust measure of visual maturation, whereas amplitude is quite variable and subject to the effects of co-operation and background noise. Transient P-VEP waveforms are complex and develop from a single, late- positive peak at birth to a double-peak, double-trough complex by months of ag e,,, jhu^ acmty that is estimated by amplitude extrapolation will vary with the peak amplitude that is chosen for analysis. In addition, amplitude as a function of check size does not often decrease linearly in the near-threshold region. ' In a group of - month-old infants, Sokol and Moskowitz estimated acuity by linear amplitude extrapolation in of subjects. The others (%) showed zero slope or unreliable data for extrapolation. Some problems of VEP amplitude extrapolation may be overcome by using steady-state P-VEPs, or steady-state P-VEPs as analyzed with the sweep technique. " Analysis of VEP amplitudes from our normal population is planned. However, reliable assessment of visual development can be made on the basis of P-VEP latencies alone. Key words: visual development, monocular visual acuity, binocular visual acuity, visual evoked potentials, human infant Acknowledgements The authors thank Carole Panton for coordinating the recruitment and testing of subjects, Rena Arshinoff, Hector Rombola, and Indira Geer for data management, and Dr. Don Gilbert for statistical consultation. References. Atkinson J: Human visual development over thefirst months of life. A review and hypothesis. Human eurobiology :,'.. Fulton AB, Hartmann EE, and Hansen RM: Electrophysiologic testing techniques for children. Doc Ophthalmol :,.. Regan D, Beverly KI, and Macpherson H: Pattern visual evoked potentials in amblyopic children. In Evoked Potentials II, odarr and Barber C, editors. Boston, Butterworth Press,, pp. -0.

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