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Fullfield and extrafoveal visual evoked potentials in healthy eyes: reference data for a curved OLED display

Fullfield and extrafoveal visual evoked potentials in healthy eyes: reference data for a curved... Doc Ophthalmol (2022) 145:247–262 https://doi.org/10.1007/s10633-022-09897-5 ORIGINAL RESEARCH ARTICLE Fullfield and extrafoveal visual evoked potentials in healthy eyes: reference data for a curved OLED display Sabine Baumgarten  · Tabea Hoberg · Tibor Lohmann · Babac Mazinani · Peter Walter · Antonis Koutsonas Received: 26 March 2022 / Accepted: 24 August 2022 / Published online: 10 September 2022 © The Author(s) 2022 Abstract VEP (FF-P-ON/OFF-VEP) was performed. A 55-inch Purpose Visual evoked potentials (VEP) present curved OLED display (LG55EC930V, LG Electron- an important diagnostic tool in various ophthalmo- ics Inc., Seoul, South Korea) was used as visual logic and neurologic diseases. Quantitative response stimulator. data varied among patients but are also dependent on Results Mean P100 latency of the FF-PR-VEP was the recording and stimulating equipment. We estab- 103.81 ± 7.77  ms (ss 20.4′) and 102.58 ± 7.26  ms lished VEP reference values for our setting which was (ss 1.4°), and mean C2 latency of the EF-P-ON/ recently modified by using a curved OLED display as OFF-VEP was 102.95 ± 11.84  ms (ss 1.4°) and visual stimulator. Distinction is made between full- 113.58 ± 9.87  ms (ss 2.8°). For all stimulation set- field (FF) and extrafoveal (EF) conduction, and the tings (FF-PR-VEP, EF-P-ON/OFF-VEP), a signifi- effect of sex, age and lens status was determined. cant effect of age with longer latencies and smaller Methods This prospective cross-sectional study amplitudes in older subjects and higher amplitudes included 162 healthy eyes of 162 test persons older in women was observed. We saw no significant dif- than 10  years. A fullfield pattern-reversal visual ference in latency or amplitude between phakic and evoked potential (FF-PR-VEP) with two stimulus pseudophakic eyes and between EF-P-ON/OFF-VEP sizes (ss) (20.4′ and 1.4°) as well as an extrafoveal and FF-P-ON/OFF-VEP. pattern onset–offset VEP (EF-P-ON/OFF-VEP) (ss Conclusions A curved OLED visual stimulator is 1.4° and 2.8°) was derived in accordance with the well suited to obtain VEP response curves with a rea- International Society for Clinical Electrophysiology sonable interindividual variability. We found signifi- of Vision guidelines. Amplitudes and latencies were cant effects of age and gender in our responses but no recorded, and the mean values as well as standard effect of the lens status. EF-P-ON/OFF-VEP tends to deviations were calculated. Age- and sex-dependent show smaller amplitudes. influences and the difference between phakic and pseudophakic eyes were examined. A subanalysis of Keywords Electrophysiology · Visual evoked EF-P-ON/OFF-VEP and fullfield pattern onset–offset potentials · Fullfield pattern-reversal VEP · Extrafoveal pattern onset–offset VEP S. Baumgarten (*) · T. Hoberg · T. Lohmann · B. Mazinani · P. Walter · A. Koutsonas  Department of Ophthalmology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany e-mail: sabaumgarten@ukaachen.de Vol.: (0123456789) 1 3 248 Doc Ophthalmol (2022) 145:247–262 Introduction use as visual stimulators to elicit pattern VEPs [16]. The specific material properties of OLED screens Visual evoked potentials (VEP) present an important, make it possible to use curved screens, however, not non-invasive diagnostic tool in various ophthalmo- as good as, e.g., in projection spheres being used for logic and neurologic diseases. They are used to test visual field testing, but in a first step it reduces at least the visual conduction pathway from the optic nerve partly the geometric distortion of the different dis- to the visual cortex [1]. They provide information tances between the pattern elements in the center and concerning sensory function and the integrity of the in the periphery of the stimulator screen which might visual system [2]. be important to obtain VEPs from the periphery. Three stimulus modalities are commonly used: Depending on which area of the retina is stimu- pattern-reversal (PR), pattern onset–offset (P-ON/ lated, different responses are expected. With the OFF) and diffuse flash stimulation [3]. The preferred development of the binary m-sequence and its use stimulus for many cases is PR because of its relatively in multifocal VEPs and ERGs, it became possible to low variability of waveform and peak latency intra- deduce cortical potentials depending on the locali- and interindividually [4]. zation of visual stimulation in the visual field [17]. Main recorded parameters are latency and ampli- Masking the central five degrees as performed in our tude. Latency describes the time from stimulus onset study is expected to evoke different VEP responses. to the largest amplitude of a positive or negative Differing pattern sizes will do so as well as finer pat- deflection [5], and usually, two main peak-to-trough terns (< 15′) are supposed to evoke mainly foveal amplitudes are looked at (N75-P100 and P100-N135). VEPs, whereas coarser patterns (> 30′) evoke VEPs A normal VEP response to a pattern-reversal also via extrafoveal stimulation [18]. stimulus consists of a triple-headed waveform: It The present study was performed in order to begins with a negative deflection (N75), followed by determine the normative values in fullfield pattern- a prominent positive spike (P100) and a later negative reversal VEPs (FF-PR-VEP) and extrafoveal pattern deflection (N135) [4]. Here, the P100 is the most con- onset–offset VEPs (EF-P-ON/OFF-VEP) in healthy sistent and shows least variability compared with the test persons, respecting the influence of sex and age. N75 and N135 waves [6]. As an experimental approach we deduced extrafoveal Three main peaks are also seen in standard P-ON/ VEPs in PR- as well as P-ON/OFF-VEPs. OFF-VEPs: The positive C1 peak is recorded approx- imately after 75  ms, the negative C2 approximately after 125  ms followed by the positive C3 peak, Probands and methods approximately appearing after 150 ms [5]. Given the potential impact of laboratory-specific Included in the analysis of this prospective cross-sec- factors, such as background lighting conditions or dis- tional study were 162 healthy eyes of 162 test persons tance between the subject and the stimulus displays 10 years or older. In total, 69 were males, and 93 were each laboratory has to establish its own reference val- females. Excluded from the analysis were 32 eyes ues using its own stimulus and recording parameters because of inadequate impedance measuring or very [4, 7]. The resulting data collection of a normal sam- poor quality of measuring curves. Evaluation of the ple for reference values should respect age, sex and curve quality was handled very strictly as the imped- interocular asymmetry [5]. Anyhow, in the literature ance of every electrode had to be < 5 kΩ and a differ - there is clear agreement regarding general trends in ence of > 1 kΩ between the electrodes should not be the normative values [1, 2, 8–14]. exceeded. In the past, cathode-ray tube (CRT) monitors have To guarantee balanced age distribution test sub- been used as visual stimulators in most electrophysi- jects were assigned to different age groups: group ological laboratories, but they were replaced by liq- A: 10 to 19 years, group B: 20 to 39 years, group C: uid crystal displays (LCD) and the recently developed 40 to 59  years and group D included all study par- OLED (organic light-emitting diode) screens [15, ticipants that were 60  years or older. In group D, a 16]. The characteristics of the latter have been ana- subdivision was made distinguishing between phakic lyzed, and the results proofed the suitability of their and pseudophakic eyes (see Table  1). There were no Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 249 Table 1 Test persons’ characteristics (number of test persons, mean age, sex, lens status) Group A Group B Group C Group D Phakic Pseudophakic Total Number of test persons 28 44 34 32 24 56 Mean age (years) ± standard deviation 17.5 ± 2.0 26.3 ± 4.5 50.9 ± 5.5 69.7 ± 7.0 74.3 ± 7.8 71.7 ± 7.6 Number of males Percentage (%) 12 18 15 15 9 24 42.9 40.9 44.1 46.9 37.5 42.9 Number of females Percentage (%) 16 26 19 17 15 32 57.1 59.1 55.9 53.1 62.5 57.1 significant differences between the groups concern- The test person was positioned one meter in front ing sex (p = 0.993 from Pearson’s χ test) and age of the 55-inch (height 68.00  cm, width 122.03  cm) (p = 0.940, see Table 2). OLED monitor (LG55EC930V, LG Electronics Inc., All VEP measurements were taken in the electro- Seoul, South Korea), so the monitor was presented physiological laboratory of the Department of Oph- under a visual angle of 37.6°. The radius of the curva- thalmology at RWTH Aachen University between ture of the monitor was 5000 mm. The resolution was January 2019 and August 2020. To minimize inves- 1920 × 1080 px. The bit level of representation was tigator-dependent influences all deductions were per - 8 bit. Signal input was 60  Hz. Input lag was 39  ms formed by one specialist (TH). measured with the Leo Bodnar device. The input lag Inclusion criteria were a visual acuity of better was a preset value and was automatically substracted than 0.2 LogMAR per eye, and the test person had from the latencies. The CPU used in this study was to reach the age of ten. Exclusion criteria implied a Intel ®Core™ i5-2500 CPU. condition after retinal arterial or venous occlusive Pupils were not treated by miotic or mydriatic disease, any history of retinal detachment, strabismus, drugs, and the test person was optimally refracted for any glaucomatous optic nerve damage as well as any the viewing distance of the screen and respective age. kind of optic nerve or retinal damage due to underly- After cleaning the skin with colorless skin anti- ing diseases such as arterial hypertension or diabetes septic (octeniderm® farblos, Schülke & Mayr mellitus. For safety reasons, persons with epilepsy GmbH, Norderstedt, Germany) and with the elec- were excluded. trode paste II produced by the in-house pharmacy Test persons were recruited from the patient pool (containing tragacanth 5.0  g, glycerol 85% 8.0  g, and visitors of the Department of Ophthalmology at distilled water 150.0  g, sodium chlorid 34.0  g, RWTH Aachen University, providing the above-men- potassium tartrat 2.0 g, sorbic acid 0.1 g, potassium tioned inclusion and exclusion criteria were fulfilled. sorbat 0.2 g, pumice stone 25.0 g, sea sand 25.0 g), The Institutional Ethical Review Board of the the EEG scalp gold cup electrodes (GRASS® RWTH Aachen University approved the study Cup electrodes LTM, 75  cm cable length, diam- (EK204/18). The described research adhered to the eter 10 mm, 1,5 mm DIN socket, Grass, Italy) were tenets of the Declaration of Helsinki. positioned. As conductive-adhesive paste we used the Ten-20 Conductive Paste (Weaver and Com- pany, Aurora, USA) to ensure stable electrical con- VEP measurements nection. To fixate the scalp electrodes two elastic bands with associated buttons were utilized. Scalp The procedure of the VEP examination was explained electrodes were positioned according to the Ten- to all subjects, and written informed consent was Twenty-System. The active electrode was placed on taken. VEP was recorded with a one-channel montage the scalp over the visual cortex at Oz, the reference provided by Roland Consult (Brandenburg an der electrode was positioned on the forehead at Fz, and Havel, Germany). Recordings were taken in a dark- the ground electrode was fixated on the vertex, Cz. ened room with a quiet environment. Referring to the International Society for Clinical Vol.: (0123456789) 1 3 250 Doc Ophthalmol (2022) 145:247–262 Electrophysiology of Vision (ISCEV) standard, electrode impedances were below five kΩ and the impedance should not differ > one kΩ between the active electrode and the reference electrode. Occlusion plasters (Piratoplast, Dortmund, Ger- many) covered the fellow eye during monocular testing. Each test person underwent two measuring sessions per eye. Monocular stimulation was given to both eyes separately. Firstly, the FF-PR-VEP pro- tocol was presented. Here, we used two stimulus sizes (ss): For the large stimulus, we used checks with a width of 1.4 angle degree (1.4°). For the smaller ss, checks width was 20.4 min of arc (20.4′). The black and white checks changed abruptly and repeatedly at three reversals per second (1.5 Hertz (Hz)) generating a transient VEP. The anal- ysis time (sweep duration) was 250  ms and more than hundred responses were averaged (number of sweeps). An amplification rate of 20.000 to 50.000 was used. The mean luminance of black checks was 2 2 0.58  cd/m and for the white checks 105.8  cd/m . The parameters of the display were measured by the high-precision luminance meter MAVO-MON- ITOR (Gossen, Nürnberg, Germany). The contrast between black and white squares was high with 99%, as defined by Michelson contrast. A red fixa- tion cross was positioned in the center at the corner of four checks. The stimulus pattern was presented on the full monitor (see Fig. 1). Except for slightly larger check sizes and higher reversal rates given above, the recording and stimu- lus parameters followed the ISCEV Standards for clinical PR-VEPs [19]. In the second measuring program, the EF-P-ON/ OFF-VEP was elicited. Here, the central visual field was blocked with a black disc with a diameter of 9 cm placed onto the screens center. Thus, the cen- tral 5.15° of the retina was not stimulated. Again, two ss were used. As large stimulus, we used checks with a width of 2.8° and checks with a width of 1.4° for the smaller stimuli. Pattern onset duration was 17  ms and the diffuse gray background appeared afterward for 650  ms. This setting corresponded to the ISCEV-standard from 2004 [4]. Essential was the constant mean luminance of the diffuse back - ground and the checkerboard with no change of luminance during the transition from pattern to dif- fuse blank screen. Vol:. (1234567890) 1 3 Table 2 Mean age (years) and standard deviation (SD) of males versus females for the different age groups: A00 = all phakic males of group A (10–19  years), B00 = all pha- kic males of group B (20–39 years), B10 = all phakic females of group B (20–39 years), C00 = all phakic males of group C (40–59 years), C10 = all phakic females of group C (40–59 years), D00 = all phakic males of group D (sixty or older), D10 = all phakic females of group D (sixty or older), D01 = all pseudophakic males of group D (sixty or older), D11 = all pseudophakic females of group D (sixty or older) Group A00 Group A10 Group B00 Group B10 Group C00 Group C10 Group D00 Group D10 Group D01 Group D11 Mean age 17.8 17.3 26.4 26.3 50.5 51.1 71.9 67.7 75.4 73.6 SD 1.2 2.5 4.1 4.9 6.2 5.0 6.3 7.1 6.8 8.5 Doc Ophthalmol (2022) 145:247–262 251 Fig. 1 Left: stimulation setting for the fullfield pattern-rever - disc with a diameter of 9 cm. In each case, two stimulus sizes sal visual evoked potential (FF-PR-VEP); right: stimulation (ss) were used (FF-PR-VEP: 1.4° and 20.4′; EF-P-ON/OFF- setting for the extrafoveal pattern onset–offset VEP (EF-P-ON/ VEP: 2.8° and 1.4°) OFF-VEP) with the central visual field blocked with a black The other recording and stimulus parameters were For group D and the analysis of phakic and pseu- the same as in the pattern-reversal setting according dophakic eyes, an independent samples Student’s t to the ISCEV standards [19]. test was applied. In order to compare the EF-P-ON/OFF-VEP with For the subanalysis of EF-P-ON/OFF-VEP versus the pattern onset/offset where the central retina is also FF-P-ON/OFF-VEP, a paired samples t test was used. stimulated (fullfield = FF-P-ON/OFF-VEP), we meas- ured ten test subjects with both investigation pro- grams (EF-P-ON/OFF-VEP vs. FF-P-ON/OFF-VEP). Results Statistical analysis Fullfield pattern-reversal VEP (FF -PR-VEP) For descriptive statistics, all metric values were expressed as the mean ± standard deviation (range The VEP as a response to fullfield stimulation minimum to maximum). Multivariate linear regres- (37.6  deg of visual angle) with pattern-reversal sion was used for the explorative data analysis (Soft- checkerboards of 1.4° check size was analyzed for the ware IBM® SPSS Statistics, version 25.0). Normal whole group as well as for each age group of phakic distribution was verified using the Shapiro–Wilk patients (n = 138) and is summarized in Table  3, and test on a 5% level of significance and considering averaged waveforms are presented in Figs. 2 and 3 for the graphic distribution by histograms and Q–Q dia- male and female test persons. grams. If the distribution of the target variable in a The P100 latency was significantly larger the older subpopulation was not normal, a transformation was the test person was (F(2,135) = 6.162, p = 0.003). The performed using the natural logarithm (y = ln(x)). amplitude (N75-P100) was significantly smaller in Mainly right eyes were evaluated. If there was a elderly test subjects (F(2,135) = 15.558, p < 0.001). test person with one eye pseudophakic and the other The P100 latency was significantly shorter in women eye phakic, we evaluated only one eye per test person (p = 0.003), and the amplitude (N75-P100) was for the corresponding group so there was never more significantly greater in female study participants than one eye per study subject included. Including (p < 0.001). For the N75 component of the PR- both the right and left eye of a single test person was FF-VEP, age and gender did not cause significant not admitted due to the lower intra-individual vari- changes although the tendency was the same as for ance between right and left eyes of the same subject the P100. N135 values showed no significant effect of compared to the variance between subjects [20, 21]. age and sex (see Table 4). Vol.: (0123456789) 1 3 252 Doc Ophthalmol (2022) 145:247–262 Table 3 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic test persons for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Total (n = 138) 69,55 ± 10,24 102,58 ± 7,26 145,31 ± 15,82 15,66 ± 6,42 (4,40 – 45,30) (47,20 – 96,50) (85,30 – 125,00) (109,00 – 190,00) Group A (n = 28) 67,44 ± 7,00 (50,70 – 80,10) 102,13 ± 8,29 147,68 ± 19,95 18,49 ± 8,26 (6,33 – 45,30) (91,20 – 125,00) (118,00 – 190,00) Group B (n = 44) 69,83 ± 9,43 (51,30 – 88,90) 100,01 ± 6,41 147,05 ± 16,78 15,45 ± 6,25 (6,38 – 35,00) (85,30 – 114,00) (114,00 – 189,00) Group C (n = 34) 69,50 ± 9,52 (54,20 – 91,80) 103,98 ± 6,32 141,97 ± 12,45 15,89 ± 5,46 (7,96 – 31,30) (91,20 – 120,00) (125,00 – 179,00) Group D (n = 32) 71,07 ± 13,93 105,02 ± 7,48 144,41 ± 13,47 13,22 ± 4,86 (4,40 – 23,80) (47,20 – 96,50) (91,80 – 119,00) (109,00 – 181,00) Fig. 2 Averaged waveforms of fullfield pattern-reversal visual B00 = all phakic males of group B (20–39  years), C00 = all evoked potential (FF-PR-VEP) of male phakic test persons phakic males of group C (40–59 years), D00 = all phakic males with 1.4° ss. A00 = all phakic males of group A (10–19 years), of group D (sixty years or older) When stimulating with small checks (ss The subdivision of group D in phakic and pseu- 20.4′), mean P100 latency was 103.81 ± 7.77  ms dophakic eyes showed no significant difference for (84.20–124.00) for the phakic eyes and the mean N75, P100, N135 and N75-P100 when stimulat- amplitude was 16.30 ± 7.53 µV (5.07–44.30 µV) (see ing with large checks (ss 1.4°) (N75: t(54) = 0.724, Table 5). p = 0.472, P100: t(54) = − 0.158, p = 0.875, N75, P100 and N135 were significantly larger the N135: t(54) = − 1.140, p = 0.259, N75-P100: older the test person was (N75: F(2,135) = 13.32, t(54) = − 0.561, p = 0.577) and also when stimulat- p < 0.001, P100: F(2,135) = 11.16, p < 0.001, N135: ing with small checks (ss 20.4′) (N75: t(65) = − 0.654, F(2;135) = 6.849, p = 0.001). There was no significant p = 0.516, P100: t(54) = − 1.027, p = 0.309, N135: difference concerning the amplitude when referring to t(54) = − 0.923, p = 0.363, N75-P100: t(54) = − 1.070, the age of the test person. The amplitude was signifi- p = 0.290) (see Tables 7 and 8). cantly larger in women compared to men (t = 6.247, p < 0.001) (see Table 6). Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 253 Fig. 3 Averaged waveforms of fullfield pattern-reversal vis- 19 years), B10 = all phakic females of group B (20–39 years), ual evoked potential (FF-PR-VEP) of female phakic test per- C10 = all phakic females of group C (40–59  years), D10 = all sons with 1.4° ss. A10 = all phakic females of group A (10– phakic females of group D (sixty years or older) Table 4 Multiple regression analysis for phakic eyes for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss; Target variable ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex N75 [ms] 0,520 0,338 0,487 0,037 − 1,230 P100 [ms] 0,003* 0,016* 0,020* 0,071* − 2,844* N135 [ms] 0,110 0,163 0,096 − 0,091 − 4,521 Ln(N75-P100) [μV] < 0,001* 0,011* < 0,001* − 0,004* (0,996) 0,292* (1,339) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Table 5 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic test persons for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ ss N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Total (n = 138) 78,09 ± 7,30 (55,40–98,30) 103,81 ± 7,77 (84,20– 144,95 ± 12,78 (112,00– 16,30 ± 7,53 (5,07–44,30) 124,00) 185,00) Group A (n = 28) 74,93 ± 6,35 (62,40–84,80) 101,50 ± 8,43 (84,20– 138,21 ± 11,21 (112,00– 17,19 ± 8,82 (6,14–44,30) 122,00) 156,00) Group B (n = 44) 75,99 ± 7,33 (55,40–87,10) 101,54 ± 6,21 (91,80– 145,14 ± 12,13 (122,00– 15,57 ± 8,30 (5,07–41,40) 120,00) 185,00) Group C (n = 34) 79,19 ± 5,73 (64,80–88,90) 103,96 ± 7,78 (90,00– 144,97 ± 14,39 (123,00– 17,12 ± 5,77 (7,08–31,50) 124,00) 181,00) Group D (n = 32) 82,58 ± 7,30 (67,70–98,30) 108,78 ± 7,05 (93,00– 150,56 ± 10,69 (135,00– 15,65 ± 7,00 (5,65–31,40) 121,00) 176,00) Vol.: (0123456789) 1 3 254 Doc Ophthalmol (2022) 145:247–262 Table 6 Multiple regression analysis for phakic eyes for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ ss; Target variable ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex N75 [ms] FF 20.4′ < 0,001* < 0,001* 0,911 0,144* − 0,129 P100 [ms] FF 20.4′ < 0,001* < 0,001* 0,965 0,142* − 0,055 Ln(N135) [ms] FF 20.4′ 0,001* < 0,001* 0,337 0,001* (1,001) 0,014 (1,014) Ln(N75-P100) [μV] FF 20.4′ < 0,001* 0,749 < 0,001* 0,001 (1,001) 0,430* (1,537) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Table 7 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic and pseudophakic test persons of group D for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss Target variable N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Phakic (n = 32) 71,07 ± 13,93 (47,20– 105, 02 ± 7,48 (91,80– 144,41 ± 13,47 (109,00– 13,22 ± 4,86 (4,40–23,80) 96,50) 119,00) 181,00) Pseudophakic (n = 24) 68,38 ± 13,45 (51,30– 105,37 ± 9,33 (83,60– 149,25 ± 18,36 (121,00– 13,98 ± 5,16 (6,89–23,50) 96,50) 119,00) 203,00) Table 8 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic and pseudophakic test persons of group D for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4° stimulus size (ss) Target variable N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Phakic (n = 32) 82,58 ± 7,30 (67,70–98,30) 108,78 ± 7,05 (93,00– 150,56 ± 10,69 (135,00– 15,65 ± 7,00 (5,65–31,40) 121,00) 176,00) Pseudophakic (n = 24) 83,86 ± 7,20 (68,90–99,40) 110,89 ± 8,33 (98,80– 154,96 ± 21,41 (126,00– 17,69 ± 7,18 (7,56–36,20) 128,00) 227,00) Fig. 4 Fullfield pattern- reversal VEP (FF-PR-VEP) with double-peaked con- figuration of a female test subject in group D (ss 20.4′) Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 255 Double-peaked VEP p < 0.001). There were no gender-specific signifi- cant differences. These two latter aspects apply to In group D, in the FF-PR-VEP (ss 20.4′), 11 double- both ss (1.4° and 2.8°). The amplitude (C1-C2) peaked P100 wave configurations (see Fig.  4, Fig.  5 was significantly greater the older the test subject and Table  9) were seen (15.6% (5/32) of phakic eyes was (F(2,135) = 39.423, p < 0.001), and the ampli- and 25.0% (6/24) of pseudophakic eyes). tude was again significantly greater in women (see Tables 12 and 13). Extrafoveal pattern onset–offset VEP (EF -P-ON/ For both ss (1.4° and 2.8°), there were no statis- OFF-VEP) tic significant differences in the EF-P-ON/OFF-VEP between phakic and pseudophakic eyes in C1, C2 and Data for the EF-P-ON/OFF-VEP of phakic eyes C3 and C1-C2. for both check sizes (ss 2.4° and 2.8°) are given in In the subanalysis (n = 10) of EF-P-ON/OFF-VEP Tables 10 and 11: versus FF-P-ON/OFF-VEP, for ss 1.4°, there were In the EF-P-ON/OFF-VEP, C1, C2 and C3 no significant differences found for C1, C2 and C3 were significantly larger the older the test sub- (C1: W = 19.50, p = 0.449, C2: W = 19.00, p = 0.432, ject was (C1: F(2,135) = 12.886, p < 0.001, C2: C3: W = 12.00, p = 0.238). The amplitude C1–C2 was F(2,135) = 39.840, p < 0.001, C3: F(2,135) = 32.730, significantly greater after FF stimulation compared to Fig. 5 Fullfield pattern- reversal VEP (FF-PR-VEP) waveforms (n = 11) with double-peak configuration of phakic and pseudopha- kic test subject in group D (stimulus size (ss) 20.4′) Table 9 Mean value ± standard deviation (range)) for latencies (N75, P100 1. peak and P100 2. peak) of phakic and pseudophakic test persons (n = 11) with double-peak configurations for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ stimulus size (ss) N75 [ms] P100 [ms] 1. peak P100 [ms] 2.peak Total (n = 11) 68.89 ± 16.95 (47.20–94.10) 77.85 ± 5.66 (70.40–88.60) 105.73 ± 8.87 (91.8–118.00) Vol.: (0123456789) 1 3 256 Doc Ophthalmol (2022) 145:247–262 Table 10 Reference values (mean value ± standard deviation (range)) for latencies (C1, C2, C3) and amplitude (C1–C2) of phakic test persons for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 1.4° ss C1 [ms] C2 [ms] C3 [ms] C1–C2 [μV] Total (n = 138) 77,18 ± 8,34 (56,00–115,00) 102,95 ± 11,84 (73,60– 134,72 ± 21,99 (89,40– 13,48 ± 9,29 (0,02–63,60) 131,00) 217,00) Group A (n = 28) 74,91 ± 10,68 (61,30– 94,79 ± 12,00 (73,60– 121,35 ± 20,24 (89,40– 7,58 ± 6,86 (0,02–25,60) 115,00) 126,00) 171,00) Group B (n = 44) 73,65 ± 7,14 (56,00–90,60) 98,02 ± 8,45 (74,80–121,00) 126,00 ± 20,11 (101,00– 9,13 ± 5,42 (0,95–22,70) 176,00) Group C (n = 34) 78,68 ± 6,61 (63,00–94,10) 106,48 ± 8,42 (88,90– 140,88 ± 12,61 (111,00– 19,07 ± 10,69 (5,40–63,60) 122,00) 174,00) Group D (n = 32) 82,43 ± 6,12 (71,80–94,10) 113,10 ± 10,21 (93,00– 151,84 ± 20,87 (107,00– 18,70 ± 7,54 (7,15–38,00) 131,00) 217,00) Table 11 Reference values (mean value ± standard deviation (range)) for latencies (C1, C2, C3) and amplitude (C1–C2) of phakic test persons for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 2.8° ss C1 [ms] C2 [ms] C3 [ms] C1–C2 [μV] Total (n = 138) 77,76 ± 6,71 102,79 ± 12,41 131,67 ± 23,96 12,43 ± 9,15 (0,01 – 63,20) (59,50 – 94,10) (71,80 – 131,00) (88,90 – 213,00) Group A (n = 28) 76,06 ± 6,52 93,73 ± 10,83 114,61 ± 18,23 6,45 ± 5,58 (0,01 – 21,70) (64,80 – 90,60) (71,80 – 120,00) (88,90 – 169,00) Group B (n = 44) 76,32 ± 5,66 97,07 ± 7,43 120,30 ± 18,48 8,04 ± 5,06 (0,34 – 19,00) (66,00 – 88,90) (81,80 – 113,00) (98,30 – 181,00) Group C (n = 34) 78,27 ± 6,85 107,51 ± 11,45 140,03 ± 17,38 17,13 ± 10,98 (2,61 – 63,20) (59,50 – 93,00) (75,90 – 131,00) (106,00 – 179,00) Group D (n = 32) 80,68 ± 7,27 (61,30 – 113,58 ± 9,87 153,34 ± 21,06 18,69 ± 7,41 (7,93 – 37,50) 94,10) (93,00 – 129,00) (107,00 – 213,00) Table 12 Multiple regression analysis for phakic eyes for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 1.4° ss; Target value ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex C1 [ms] < 0,001* < 0,001* 0,612 0,162* 0,672 C2 [ms] < 0,001* < 0,001* 0,820 0,349* − 0,370 C3 [ms] < 0,001* < 0,001* 0,837 0,609* − 0,644 C1-C2 [μV] < 0,001* < 0,001* < 0,001* 0,255* 4,892* Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); level of significance is 5% (*); n = 138 EF (W = 7.50, p = 0.041). Effect size according to the Discussion classification by Cohen was strong with r = 0.64. When stimulating with ss 2.8°, all parameters (C1, In this study we established age-related reference C2, C3, C1–C2) showed no significant differences values for the FF-PR- and EF-P-ON/OFF-VEPs (C1: W = 18.00, p = 0.375, C2: W = 19.00, p = 0.434, in healthy eyes for our laboratory and examined C3: W = 18.00 p = 0.375, C1–C2: W = 25.00, age- and gender-specific influences on latencies and p = 0.846). amplitudes. Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 257 Table 13 Multiple regression analysis for phakic eyes for the extrafoveal pattern onset/offset VEP (EF-ON/OFF-VEP) with 2.8° ss; Target value ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex C1 [ms] 0,006* 0,002* 0,520 0,085* − 0,723 C2 [ms] < 0,001* < 0,001* 0,767 0,387* − 0,489 C3 [ms] < 0,001* < 0,001* 0,950 0,779* 0,193 Ln(C1–C2) [μV] < 0,001* < 0,001* < 0,001* 0,030* (1,030) 0,561* (1,752) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Influence of age on latency also in studying aging effects as reported before in the literature. Sokol et  al. showed that the rate of We found age-dependent significant differences latency increases with age twice as fast for checks for the P100 latency in the FF-PR-VEP for both ss of 12′ than for checks of 48′ [9]. (20.4′ and 1.4°). In group A, the P100 latency was greater (mean P100 = 102.13 ± 8.29  ms) than in group B (mean P100 = 100.01 ± 6.41  ms) for 1.4° Influence of age on amplitude ss and in group C and D, P100 latency was increas- ing again (group C P100 = 103.98 ± 6.32  ms, group N75-P100 amplitude was also modulated by age: D P100 = 105.02 ± 7.48  ms). So between twenty and In the FF-PR-VEP, a significant decrease in N75- 39 years, P100 latency was the shortest. P100 amplitude of 0.4% per year was observed Significant slowing of the P100 latency in elderly when stimulating with large checks (ss 1.4°) and persons has been demonstrated in previous reports no statistically significant age-related change was [20–23]. The recent study by Benedek et  al. sup- seen when stimulating with smaller checks (ss ported most of the findings in the literature con- 20.4′). In the EF-P-ON/OFF-VEP, C1-C2 amplitude cerning the aging of VEP components [22]: They increased statistically significant each year for both showed that latencies of P100 and N135 decrease up stimulus sizes (ss 1.4° and 2.8°). In the literature, to the third decade of life and then show an increase there also exist miscellaneous data concerning age- again. In our study, we saw an average increase in related amplitude changes. Shaw et  al. reported in P100 latency of 0.07 ms per year in the FF-PR-VEP. 1981 P100 amplitudes being the greatest in child- In the EF-P-ON/OFF-VEP, a statistically signifi- hood, then declining until the forth decade, increas- cant increase in C1-, C2-, C3-latency was also seen. ing again and after the sixth decade, a decrease of Benedek et  al. hypothesized that the P100 latency P100 amplitude is again observed [12]. Tobimatsu is the most sensitive component to age and many et  al. observed no aging effect on P100 amplitude; studies confirm this hypothesis [8 , 24–27]. There here PR-VEPs were recorded in 109 normal subjects are reports that the N75 latency is also affected by with different stimulus conditions (inter alia high aging processes, however, in a different way com- versus low luminance or different check sizes) [29]. pared to the P100 latency: N75 is being modulated Their results suggested that age-related changes linearly and P100 curvilineary with U-shaped con- in the human visual system are not uniform, but figurations [10, 11, 28]. In our study, there was no rather different in the specific functional subdivi- statistic significant difference in N75 concerning sions [29]. They hypothesized that aging may dif- age when stimulating with large checks (ss 1.4°). ferentially influence the separate channels of human However, when stimulating with smaller checks visual system [29]. This is also true for our study (ss 20.4′), we observed a statistic significant as different retinal stimulus localizations (EF vs FF) increase in N75, P100 and N135 latency (p < 0.001). caused different age-related VEP changes. So our data confirm the importance of check size Vol.: (0123456789) 1 3 258 Doc Ophthalmol (2022) 145:247–262 Influence of sex on latency and amplitude general senile changes in the optic pathway and not due to reduced transparency of the crystalline lens in Considering the influence of sex on FF-PR-VEP elderly [37]. components (ss 1.4°) we observed the following: The P100 latency was on average 2.84  ms shorter Double-peaked VEP in female test persons compared to male subjects of the same age. Furthermore, the N75-P100 amplitude A particular phenomenon that we noticed in patients was on average 33.9% greater in women compared older than sixty for the P100 response in the FF- to men. When stimulating with 20.4°, the N75-P100 PR-VEP was several double-peaked P100 wave amplitude was on average 53.7% greater in females configurations. In the literature we found that this compared to males (p < 0.001) and in the EF-P-ON/ phenomenon is sometimes considered as a sign of OFF-VEP, the C1–C2 amplitude was again signifi- demyelization [39] but can also be found in healthy cantly greater in women compared to men for both ss older adults [40]. (1.4° and 2.8°, p < 0.001). There seems to be general agreement in the literature that sex has a significant Comparison to VEP reference values with other influence on VEP components: With different check display types sizes various authors reported on greater N75-P100 amplitudes and shorter P100 latencies in women We compared our VEP reference values with those compared to men [11, 13, 14, 30–33]. The exact rea- reported by Ekayanti et  al.[41]. They used a 24-in son of these gender differences in VEP parameters is DELL LCD monitor (Dell, Round Rock, USA) for not totally understood, but it may be associated with their pattern-reversal VEP examination in 120 healthy endocrinal, anatomical and behavioral differences. subjects between 18 and 65  years. Their reference Some investigators associated a shorter head cir- values were slightly slower than ours in each age cumference with a shorter VEP latency: Guthkelch group (approx. 1–3 ms). They did not see significant et al. reported on eight male and eight female healthy differences between the P100 latency values of gen- young adults showing the shortest latency to P100 der and age groups [41]. However, as in our study, the when having the lowest occipito-frontal circumfer- P100 amplitude was significantly higher in females ence (OFC) [32]. This variation in P100 latency was compared to males [41]. It is known that LCD dis- even more highly correlated with OFC than with gen- plays cause apparent (artificial) delay in the P100 der: Men with the same OFC as women showed com- latency due to the input lag of the monitor [42]. There parable latencies [32]. A more recent study includ- are some software modifications that can compensate ing 400 eyes showed a positive correlation of P100 for the lag [43]. The study by Husain et al. [42] con- latency with mean head circumference, while a highly firmed the assumption that substituting a cathode-ray significant negative correlation was observed of N75- tube (CRT) monitor with a LCD monitor results in a P100 amplitude with head circumference [34]. They significant prolongation of P100 latency. CRT moni- concluded that a larger head circumferences indicate tors have become less available in the market and a larger brain size and a longer conduction pathway, liquid crystal displays (LCD) [16] have an inherent thus prolonging VEP latencies [34]. problem as visual stimulators that is called “the flash effect” [44]. LCDs take several milliseconds for the Influence of lens status crystal molecules to change their alignment to per- mit the light to pass through the polarizing filter of Regardless of ss there was no statistic significant dif- the LCD [16, 45], and this causes a transient change ference to be seen between phakic and pseudophakic of the mean luminance of the entire LCD screen at eyes in the FF-PR-VEP as well as in the EF-P-ON/ the time of the reversal and this luminance change OFF-VEP for latencies and amplitudes. In the litera- can elicit flash VEPs; that’s where the “flash effect” ture different studies report that the senile opacity of comes from [44]. So the question is how the recently the crystalline lens does not contribute to changes developed OLED monitor influences VEP values and of PR-VEPs [37, 38]. Yamamoto et  al. assumed whether this monitor is suitable for eliciting VEPs. that longer latencies in elder test subjects are due to Here we think that the work published by Matsumoto Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 259 et al. is very important [16] as they examined whether or 13° response [59]. They suggested that cortical OLED screens can be used as visual stimulators. magnification factor in AMD might be higher than in They showed that p-VEPs elicited by OLED screens normal controls [59]. were not significantly different from those elicited by In our study, in the FF-P-ON/OFF-VEP (ss 1.4°), conventional CRT screens [16, 44] as OLED screens amplitudes were significantly greater to amplitudes have a faster response time than standard LCD in the EF-P-ON/OFF-VEP (p = 0.041), but there screens [46, 47]. They showed that OLED displays were no statistically significant differences for the are suitable for a visual stimulator to elicit p-VEPs. C1-, C2, and C3-latencies (p = 0.238). However, in Other authors explored the characteristics of this subanalysis only ten test persons were included OLED displays for its applicability in visual research so the validity of this subanalysis is limited. Compar- [48, 49]. They found the new display to be superior ing our reference values of the EF-P-ON/OFF-VEP to other display types in terms of spatial uniformity, with data on FF-P-ON/OFF-VEPs by Thompson and color gamut and contrast ratio [48]. However, there colleagues on 24 healthy adult test persons, the C1-, are no studies on VEP data when a curved OLED C2- and C3-latencies of our extrafoveal VEP were monitor was used and this is new in our study. shorter [60]. Hagler [61] confirmed significantly shorter latencies after peripheral compared to peri- Extrafoveal stimulation foveal stimulation in PR-VEP, and we did expect this tendency of shorter latencies when occluding the cen- The contribution of the peripheral retina to pattern tral retina due to the differences in axonal conduction VEP is a matter of debate. Some authors stated that speed between the magnocellular and parvocellular the VEP is primarily a reflection of activity origi- pathways. nating in the central two to six degrees of the visual In order to explain the contribution of the periph- field [50] so the central macular response dominates eral retina to VEP components the anatomical com- the VEP response [34, 51–53]. It had been known position of neural macro-networks that process the for nearly a century now that each visual area has a visual information has to be considered. Starting in retinotopic organization in human striate cortex. Mer- non-human primates much about the two major par- edith and Celesia reported in 16 healthy volunteers on allel retinocortical pathways, the magnocellular (M) an amplitude distribution of evoked responses in rela- and the parvocellular (P) pathway, has been described tion to retinal eccentricity [54] and confirmed previ- [62–64]: The M pathway begins with the parasol gan- ous research, namely that the amplitude distribution glion cells of the retina [65]. These cells have large correlates well with (1) the decline in cone density receptive fields and selectively project to the magno- in relation to retinal eccentricity [55], (2) the density cellular layers of the lateral geniculate nucleus (LGN) distribution of human ganglion cell population along [65]. Midget cells of the retina are the origin of the the horizontal axis [56] and (3) the decline of visual P pathway, representing approximately eighty percent acuity in relation to eccentricity [57, 58]. These cor- of ganglion cells [65]. Midget cells have small den- relations further suggest that a visual stimulus outside dritic and receptive fields and project mainly to the the fovea has to reach the threshold of visual percep- parvocellular layers of the LGN [65]. Both pathways tion to be effective and needs to activate sufficient project in different layers of the primary visual cortex numbers of receptors and ganglion cells [54]. (V1) to become dorsal (M) and ventral (P) streams Walter and colleagues compared amplitudes in [66]. PR-VEPs in patients with age-related macular degen- Concerning physiological aspects, M cells of the eration (AMD) and found a few individuals showing retina and the LGN are relatively insensitive to pure larger amplitudes after stimulation of a central 3° chromatic contrast, but highly sensitive to luminance field compared to stimulation of a 13° field although contrast [65, 67]. P cells are sensitive to chromatic in normals and the majority of AMD patients, VEP contrast, but less sensitive to luminance contrast com- amplitudes increased with increasing field size [59]. pared to M cells [64, 65, 68]. The M pathway is sensi- After stimulation of different macular zones they tive to lower spatial frequencies and higher temporal found that the 3° central area and the perifoveal frequencies and has transient responses [69]. The P region contributed differently to the macular response pathway is responsive to higher spatial frequencies Vol.: (0123456789) 1 3 260 Doc Ophthalmol (2022) 145:247–262 or beliefs) in the subject matter or materials discussed in this and lower temporal frequencies and sustained manuscript. responses [69–71]. The relative distributions of neurons within the Statement of the welfare of animals Not applicable. M and P pathway are still discussed [65]. A study in macaque LGN by Malpeli et al. estimated the magno- Ethical approval  / Statement of human rights All proce- cellular/parvocellular ratio to increase from the fove- dures performed in studies involving human participants were in accordance with the ethical standards of the institutional olar to far periphery by a factor of at least 14 [72]. research committee (Medical Ethical Review Board, University More recent studies compared the magno- and parvo- RWTH Aachen) and with the 1964 Helsinki Declaration and its cellular distributions in the human retina and found later amendments or comparable ethical standards. a decrease in parvocellular/magnocellular ratio with Informed consent Informed consent was obtained from all eccentricity which was even more distinctive than individual participants included in the study. that of macques [73, 74]. There exist several studies that report on the differences in the relative speed of Consent publication The data of this publication are content the magnocellular and parvocellular pathways: Dif- of a doctoral thesis. ferences in axonal conduction speeds in the retina, optic nerve and optic radiation are expected to cause Open Access This article is licensed under a Creative Com- parvocellular signals approximately 3 ms longer than mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any magnocellular signals to travel to the LGN and about medium or format, as long as you give appropriate credit to the 5  ms longer to get to the cerebral cortex [75–77]. original author(s) and the source, provide a link to the Crea- In our study, for the EF-P-ON/OFF-VEP, we chose tive Commons licence, and indicate if changes were made. The larger ss as for the FF-PR-VEP (1.4° und 2.8° com- images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated pared to 20.4′ and 1.4°) to favor the lower resolution otherwise in a credit line to the material. If material is not of the M pathway. included in the article’s Creative Commons licence and your The EF approach in our study has an experimental intended use is not permitted by statutory regulation or exceeds character, and with this analysis, we aim to pave the the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit way for new VEP testing modalities that allow us to http:// creat iveco mmons. org/ licen ses/ by/4. 0/. use VEPs effectively for example in the diagnosis and management of glaucoma. 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Fullfield and extrafoveal visual evoked potentials in healthy eyes: reference data for a curved OLED display

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Doc Ophthalmol (2022) 145:247–262 https://doi.org/10.1007/s10633-022-09897-5 ORIGINAL RESEARCH ARTICLE Fullfield and extrafoveal visual evoked potentials in healthy eyes: reference data for a curved OLED display Sabine Baumgarten  · Tabea Hoberg · Tibor Lohmann · Babac Mazinani · Peter Walter · Antonis Koutsonas Received: 26 March 2022 / Accepted: 24 August 2022 / Published online: 10 September 2022 © The Author(s) 2022 Abstract VEP (FF-P-ON/OFF-VEP) was performed. A 55-inch Purpose Visual evoked potentials (VEP) present curved OLED display (LG55EC930V, LG Electron- an important diagnostic tool in various ophthalmo- ics Inc., Seoul, South Korea) was used as visual logic and neurologic diseases. Quantitative response stimulator. data varied among patients but are also dependent on Results Mean P100 latency of the FF-PR-VEP was the recording and stimulating equipment. We estab- 103.81 ± 7.77  ms (ss 20.4′) and 102.58 ± 7.26  ms lished VEP reference values for our setting which was (ss 1.4°), and mean C2 latency of the EF-P-ON/ recently modified by using a curved OLED display as OFF-VEP was 102.95 ± 11.84  ms (ss 1.4°) and visual stimulator. Distinction is made between full- 113.58 ± 9.87  ms (ss 2.8°). For all stimulation set- field (FF) and extrafoveal (EF) conduction, and the tings (FF-PR-VEP, EF-P-ON/OFF-VEP), a signifi- effect of sex, age and lens status was determined. cant effect of age with longer latencies and smaller Methods This prospective cross-sectional study amplitudes in older subjects and higher amplitudes included 162 healthy eyes of 162 test persons older in women was observed. We saw no significant dif- than 10  years. A fullfield pattern-reversal visual ference in latency or amplitude between phakic and evoked potential (FF-PR-VEP) with two stimulus pseudophakic eyes and between EF-P-ON/OFF-VEP sizes (ss) (20.4′ and 1.4°) as well as an extrafoveal and FF-P-ON/OFF-VEP. pattern onset–offset VEP (EF-P-ON/OFF-VEP) (ss Conclusions A curved OLED visual stimulator is 1.4° and 2.8°) was derived in accordance with the well suited to obtain VEP response curves with a rea- International Society for Clinical Electrophysiology sonable interindividual variability. We found signifi- of Vision guidelines. Amplitudes and latencies were cant effects of age and gender in our responses but no recorded, and the mean values as well as standard effect of the lens status. EF-P-ON/OFF-VEP tends to deviations were calculated. Age- and sex-dependent show smaller amplitudes. influences and the difference between phakic and pseudophakic eyes were examined. A subanalysis of Keywords Electrophysiology · Visual evoked EF-P-ON/OFF-VEP and fullfield pattern onset–offset potentials · Fullfield pattern-reversal VEP · Extrafoveal pattern onset–offset VEP S. Baumgarten (*) · T. Hoberg · T. Lohmann · B. Mazinani · P. Walter · A. Koutsonas  Department of Ophthalmology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany e-mail: sabaumgarten@ukaachen.de Vol.: (0123456789) 1 3 248 Doc Ophthalmol (2022) 145:247–262 Introduction use as visual stimulators to elicit pattern VEPs [16]. The specific material properties of OLED screens Visual evoked potentials (VEP) present an important, make it possible to use curved screens, however, not non-invasive diagnostic tool in various ophthalmo- as good as, e.g., in projection spheres being used for logic and neurologic diseases. They are used to test visual field testing, but in a first step it reduces at least the visual conduction pathway from the optic nerve partly the geometric distortion of the different dis- to the visual cortex [1]. They provide information tances between the pattern elements in the center and concerning sensory function and the integrity of the in the periphery of the stimulator screen which might visual system [2]. be important to obtain VEPs from the periphery. Three stimulus modalities are commonly used: Depending on which area of the retina is stimu- pattern-reversal (PR), pattern onset–offset (P-ON/ lated, different responses are expected. With the OFF) and diffuse flash stimulation [3]. The preferred development of the binary m-sequence and its use stimulus for many cases is PR because of its relatively in multifocal VEPs and ERGs, it became possible to low variability of waveform and peak latency intra- deduce cortical potentials depending on the locali- and interindividually [4]. zation of visual stimulation in the visual field [17]. Main recorded parameters are latency and ampli- Masking the central five degrees as performed in our tude. Latency describes the time from stimulus onset study is expected to evoke different VEP responses. to the largest amplitude of a positive or negative Differing pattern sizes will do so as well as finer pat- deflection [5], and usually, two main peak-to-trough terns (< 15′) are supposed to evoke mainly foveal amplitudes are looked at (N75-P100 and P100-N135). VEPs, whereas coarser patterns (> 30′) evoke VEPs A normal VEP response to a pattern-reversal also via extrafoveal stimulation [18]. stimulus consists of a triple-headed waveform: It The present study was performed in order to begins with a negative deflection (N75), followed by determine the normative values in fullfield pattern- a prominent positive spike (P100) and a later negative reversal VEPs (FF-PR-VEP) and extrafoveal pattern deflection (N135) [4]. Here, the P100 is the most con- onset–offset VEPs (EF-P-ON/OFF-VEP) in healthy sistent and shows least variability compared with the test persons, respecting the influence of sex and age. N75 and N135 waves [6]. As an experimental approach we deduced extrafoveal Three main peaks are also seen in standard P-ON/ VEPs in PR- as well as P-ON/OFF-VEPs. OFF-VEPs: The positive C1 peak is recorded approx- imately after 75  ms, the negative C2 approximately after 125  ms followed by the positive C3 peak, Probands and methods approximately appearing after 150 ms [5]. Given the potential impact of laboratory-specific Included in the analysis of this prospective cross-sec- factors, such as background lighting conditions or dis- tional study were 162 healthy eyes of 162 test persons tance between the subject and the stimulus displays 10 years or older. In total, 69 were males, and 93 were each laboratory has to establish its own reference val- females. Excluded from the analysis were 32 eyes ues using its own stimulus and recording parameters because of inadequate impedance measuring or very [4, 7]. The resulting data collection of a normal sam- poor quality of measuring curves. Evaluation of the ple for reference values should respect age, sex and curve quality was handled very strictly as the imped- interocular asymmetry [5]. Anyhow, in the literature ance of every electrode had to be < 5 kΩ and a differ - there is clear agreement regarding general trends in ence of > 1 kΩ between the electrodes should not be the normative values [1, 2, 8–14]. exceeded. In the past, cathode-ray tube (CRT) monitors have To guarantee balanced age distribution test sub- been used as visual stimulators in most electrophysi- jects were assigned to different age groups: group ological laboratories, but they were replaced by liq- A: 10 to 19 years, group B: 20 to 39 years, group C: uid crystal displays (LCD) and the recently developed 40 to 59  years and group D included all study par- OLED (organic light-emitting diode) screens [15, ticipants that were 60  years or older. In group D, a 16]. The characteristics of the latter have been ana- subdivision was made distinguishing between phakic lyzed, and the results proofed the suitability of their and pseudophakic eyes (see Table  1). There were no Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 249 Table 1 Test persons’ characteristics (number of test persons, mean age, sex, lens status) Group A Group B Group C Group D Phakic Pseudophakic Total Number of test persons 28 44 34 32 24 56 Mean age (years) ± standard deviation 17.5 ± 2.0 26.3 ± 4.5 50.9 ± 5.5 69.7 ± 7.0 74.3 ± 7.8 71.7 ± 7.6 Number of males Percentage (%) 12 18 15 15 9 24 42.9 40.9 44.1 46.9 37.5 42.9 Number of females Percentage (%) 16 26 19 17 15 32 57.1 59.1 55.9 53.1 62.5 57.1 significant differences between the groups concern- The test person was positioned one meter in front ing sex (p = 0.993 from Pearson’s χ test) and age of the 55-inch (height 68.00  cm, width 122.03  cm) (p = 0.940, see Table 2). OLED monitor (LG55EC930V, LG Electronics Inc., All VEP measurements were taken in the electro- Seoul, South Korea), so the monitor was presented physiological laboratory of the Department of Oph- under a visual angle of 37.6°. The radius of the curva- thalmology at RWTH Aachen University between ture of the monitor was 5000 mm. The resolution was January 2019 and August 2020. To minimize inves- 1920 × 1080 px. The bit level of representation was tigator-dependent influences all deductions were per - 8 bit. Signal input was 60  Hz. Input lag was 39  ms formed by one specialist (TH). measured with the Leo Bodnar device. The input lag Inclusion criteria were a visual acuity of better was a preset value and was automatically substracted than 0.2 LogMAR per eye, and the test person had from the latencies. The CPU used in this study was to reach the age of ten. Exclusion criteria implied a Intel ®Core™ i5-2500 CPU. condition after retinal arterial or venous occlusive Pupils were not treated by miotic or mydriatic disease, any history of retinal detachment, strabismus, drugs, and the test person was optimally refracted for any glaucomatous optic nerve damage as well as any the viewing distance of the screen and respective age. kind of optic nerve or retinal damage due to underly- After cleaning the skin with colorless skin anti- ing diseases such as arterial hypertension or diabetes septic (octeniderm® farblos, Schülke & Mayr mellitus. For safety reasons, persons with epilepsy GmbH, Norderstedt, Germany) and with the elec- were excluded. trode paste II produced by the in-house pharmacy Test persons were recruited from the patient pool (containing tragacanth 5.0  g, glycerol 85% 8.0  g, and visitors of the Department of Ophthalmology at distilled water 150.0  g, sodium chlorid 34.0  g, RWTH Aachen University, providing the above-men- potassium tartrat 2.0 g, sorbic acid 0.1 g, potassium tioned inclusion and exclusion criteria were fulfilled. sorbat 0.2 g, pumice stone 25.0 g, sea sand 25.0 g), The Institutional Ethical Review Board of the the EEG scalp gold cup electrodes (GRASS® RWTH Aachen University approved the study Cup electrodes LTM, 75  cm cable length, diam- (EK204/18). The described research adhered to the eter 10 mm, 1,5 mm DIN socket, Grass, Italy) were tenets of the Declaration of Helsinki. positioned. As conductive-adhesive paste we used the Ten-20 Conductive Paste (Weaver and Com- pany, Aurora, USA) to ensure stable electrical con- VEP measurements nection. To fixate the scalp electrodes two elastic bands with associated buttons were utilized. Scalp The procedure of the VEP examination was explained electrodes were positioned according to the Ten- to all subjects, and written informed consent was Twenty-System. The active electrode was placed on taken. VEP was recorded with a one-channel montage the scalp over the visual cortex at Oz, the reference provided by Roland Consult (Brandenburg an der electrode was positioned on the forehead at Fz, and Havel, Germany). Recordings were taken in a dark- the ground electrode was fixated on the vertex, Cz. ened room with a quiet environment. Referring to the International Society for Clinical Vol.: (0123456789) 1 3 250 Doc Ophthalmol (2022) 145:247–262 Electrophysiology of Vision (ISCEV) standard, electrode impedances were below five kΩ and the impedance should not differ > one kΩ between the active electrode and the reference electrode. Occlusion plasters (Piratoplast, Dortmund, Ger- many) covered the fellow eye during monocular testing. Each test person underwent two measuring sessions per eye. Monocular stimulation was given to both eyes separately. Firstly, the FF-PR-VEP pro- tocol was presented. Here, we used two stimulus sizes (ss): For the large stimulus, we used checks with a width of 1.4 angle degree (1.4°). For the smaller ss, checks width was 20.4 min of arc (20.4′). The black and white checks changed abruptly and repeatedly at three reversals per second (1.5 Hertz (Hz)) generating a transient VEP. The anal- ysis time (sweep duration) was 250  ms and more than hundred responses were averaged (number of sweeps). An amplification rate of 20.000 to 50.000 was used. The mean luminance of black checks was 2 2 0.58  cd/m and for the white checks 105.8  cd/m . The parameters of the display were measured by the high-precision luminance meter MAVO-MON- ITOR (Gossen, Nürnberg, Germany). The contrast between black and white squares was high with 99%, as defined by Michelson contrast. A red fixa- tion cross was positioned in the center at the corner of four checks. The stimulus pattern was presented on the full monitor (see Fig. 1). Except for slightly larger check sizes and higher reversal rates given above, the recording and stimu- lus parameters followed the ISCEV Standards for clinical PR-VEPs [19]. In the second measuring program, the EF-P-ON/ OFF-VEP was elicited. Here, the central visual field was blocked with a black disc with a diameter of 9 cm placed onto the screens center. Thus, the cen- tral 5.15° of the retina was not stimulated. Again, two ss were used. As large stimulus, we used checks with a width of 2.8° and checks with a width of 1.4° for the smaller stimuli. Pattern onset duration was 17  ms and the diffuse gray background appeared afterward for 650  ms. This setting corresponded to the ISCEV-standard from 2004 [4]. Essential was the constant mean luminance of the diffuse back - ground and the checkerboard with no change of luminance during the transition from pattern to dif- fuse blank screen. Vol:. (1234567890) 1 3 Table 2 Mean age (years) and standard deviation (SD) of males versus females for the different age groups: A00 = all phakic males of group A (10–19  years), B00 = all pha- kic males of group B (20–39 years), B10 = all phakic females of group B (20–39 years), C00 = all phakic males of group C (40–59 years), C10 = all phakic females of group C (40–59 years), D00 = all phakic males of group D (sixty or older), D10 = all phakic females of group D (sixty or older), D01 = all pseudophakic males of group D (sixty or older), D11 = all pseudophakic females of group D (sixty or older) Group A00 Group A10 Group B00 Group B10 Group C00 Group C10 Group D00 Group D10 Group D01 Group D11 Mean age 17.8 17.3 26.4 26.3 50.5 51.1 71.9 67.7 75.4 73.6 SD 1.2 2.5 4.1 4.9 6.2 5.0 6.3 7.1 6.8 8.5 Doc Ophthalmol (2022) 145:247–262 251 Fig. 1 Left: stimulation setting for the fullfield pattern-rever - disc with a diameter of 9 cm. In each case, two stimulus sizes sal visual evoked potential (FF-PR-VEP); right: stimulation (ss) were used (FF-PR-VEP: 1.4° and 20.4′; EF-P-ON/OFF- setting for the extrafoveal pattern onset–offset VEP (EF-P-ON/ VEP: 2.8° and 1.4°) OFF-VEP) with the central visual field blocked with a black The other recording and stimulus parameters were For group D and the analysis of phakic and pseu- the same as in the pattern-reversal setting according dophakic eyes, an independent samples Student’s t to the ISCEV standards [19]. test was applied. In order to compare the EF-P-ON/OFF-VEP with For the subanalysis of EF-P-ON/OFF-VEP versus the pattern onset/offset where the central retina is also FF-P-ON/OFF-VEP, a paired samples t test was used. stimulated (fullfield = FF-P-ON/OFF-VEP), we meas- ured ten test subjects with both investigation pro- grams (EF-P-ON/OFF-VEP vs. FF-P-ON/OFF-VEP). Results Statistical analysis Fullfield pattern-reversal VEP (FF -PR-VEP) For descriptive statistics, all metric values were expressed as the mean ± standard deviation (range The VEP as a response to fullfield stimulation minimum to maximum). Multivariate linear regres- (37.6  deg of visual angle) with pattern-reversal sion was used for the explorative data analysis (Soft- checkerboards of 1.4° check size was analyzed for the ware IBM® SPSS Statistics, version 25.0). Normal whole group as well as for each age group of phakic distribution was verified using the Shapiro–Wilk patients (n = 138) and is summarized in Table  3, and test on a 5% level of significance and considering averaged waveforms are presented in Figs. 2 and 3 for the graphic distribution by histograms and Q–Q dia- male and female test persons. grams. If the distribution of the target variable in a The P100 latency was significantly larger the older subpopulation was not normal, a transformation was the test person was (F(2,135) = 6.162, p = 0.003). The performed using the natural logarithm (y = ln(x)). amplitude (N75-P100) was significantly smaller in Mainly right eyes were evaluated. If there was a elderly test subjects (F(2,135) = 15.558, p < 0.001). test person with one eye pseudophakic and the other The P100 latency was significantly shorter in women eye phakic, we evaluated only one eye per test person (p = 0.003), and the amplitude (N75-P100) was for the corresponding group so there was never more significantly greater in female study participants than one eye per study subject included. Including (p < 0.001). For the N75 component of the PR- both the right and left eye of a single test person was FF-VEP, age and gender did not cause significant not admitted due to the lower intra-individual vari- changes although the tendency was the same as for ance between right and left eyes of the same subject the P100. N135 values showed no significant effect of compared to the variance between subjects [20, 21]. age and sex (see Table 4). Vol.: (0123456789) 1 3 252 Doc Ophthalmol (2022) 145:247–262 Table 3 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic test persons for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Total (n = 138) 69,55 ± 10,24 102,58 ± 7,26 145,31 ± 15,82 15,66 ± 6,42 (4,40 – 45,30) (47,20 – 96,50) (85,30 – 125,00) (109,00 – 190,00) Group A (n = 28) 67,44 ± 7,00 (50,70 – 80,10) 102,13 ± 8,29 147,68 ± 19,95 18,49 ± 8,26 (6,33 – 45,30) (91,20 – 125,00) (118,00 – 190,00) Group B (n = 44) 69,83 ± 9,43 (51,30 – 88,90) 100,01 ± 6,41 147,05 ± 16,78 15,45 ± 6,25 (6,38 – 35,00) (85,30 – 114,00) (114,00 – 189,00) Group C (n = 34) 69,50 ± 9,52 (54,20 – 91,80) 103,98 ± 6,32 141,97 ± 12,45 15,89 ± 5,46 (7,96 – 31,30) (91,20 – 120,00) (125,00 – 179,00) Group D (n = 32) 71,07 ± 13,93 105,02 ± 7,48 144,41 ± 13,47 13,22 ± 4,86 (4,40 – 23,80) (47,20 – 96,50) (91,80 – 119,00) (109,00 – 181,00) Fig. 2 Averaged waveforms of fullfield pattern-reversal visual B00 = all phakic males of group B (20–39  years), C00 = all evoked potential (FF-PR-VEP) of male phakic test persons phakic males of group C (40–59 years), D00 = all phakic males with 1.4° ss. A00 = all phakic males of group A (10–19 years), of group D (sixty years or older) When stimulating with small checks (ss The subdivision of group D in phakic and pseu- 20.4′), mean P100 latency was 103.81 ± 7.77  ms dophakic eyes showed no significant difference for (84.20–124.00) for the phakic eyes and the mean N75, P100, N135 and N75-P100 when stimulat- amplitude was 16.30 ± 7.53 µV (5.07–44.30 µV) (see ing with large checks (ss 1.4°) (N75: t(54) = 0.724, Table 5). p = 0.472, P100: t(54) = − 0.158, p = 0.875, N75, P100 and N135 were significantly larger the N135: t(54) = − 1.140, p = 0.259, N75-P100: older the test person was (N75: F(2,135) = 13.32, t(54) = − 0.561, p = 0.577) and also when stimulat- p < 0.001, P100: F(2,135) = 11.16, p < 0.001, N135: ing with small checks (ss 20.4′) (N75: t(65) = − 0.654, F(2;135) = 6.849, p = 0.001). There was no significant p = 0.516, P100: t(54) = − 1.027, p = 0.309, N135: difference concerning the amplitude when referring to t(54) = − 0.923, p = 0.363, N75-P100: t(54) = − 1.070, the age of the test person. The amplitude was signifi- p = 0.290) (see Tables 7 and 8). cantly larger in women compared to men (t = 6.247, p < 0.001) (see Table 6). Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 253 Fig. 3 Averaged waveforms of fullfield pattern-reversal vis- 19 years), B10 = all phakic females of group B (20–39 years), ual evoked potential (FF-PR-VEP) of female phakic test per- C10 = all phakic females of group C (40–59  years), D10 = all sons with 1.4° ss. A10 = all phakic females of group A (10– phakic females of group D (sixty years or older) Table 4 Multiple regression analysis for phakic eyes for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss; Target variable ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex N75 [ms] 0,520 0,338 0,487 0,037 − 1,230 P100 [ms] 0,003* 0,016* 0,020* 0,071* − 2,844* N135 [ms] 0,110 0,163 0,096 − 0,091 − 4,521 Ln(N75-P100) [μV] < 0,001* 0,011* < 0,001* − 0,004* (0,996) 0,292* (1,339) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Table 5 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic test persons for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ ss N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Total (n = 138) 78,09 ± 7,30 (55,40–98,30) 103,81 ± 7,77 (84,20– 144,95 ± 12,78 (112,00– 16,30 ± 7,53 (5,07–44,30) 124,00) 185,00) Group A (n = 28) 74,93 ± 6,35 (62,40–84,80) 101,50 ± 8,43 (84,20– 138,21 ± 11,21 (112,00– 17,19 ± 8,82 (6,14–44,30) 122,00) 156,00) Group B (n = 44) 75,99 ± 7,33 (55,40–87,10) 101,54 ± 6,21 (91,80– 145,14 ± 12,13 (122,00– 15,57 ± 8,30 (5,07–41,40) 120,00) 185,00) Group C (n = 34) 79,19 ± 5,73 (64,80–88,90) 103,96 ± 7,78 (90,00– 144,97 ± 14,39 (123,00– 17,12 ± 5,77 (7,08–31,50) 124,00) 181,00) Group D (n = 32) 82,58 ± 7,30 (67,70–98,30) 108,78 ± 7,05 (93,00– 150,56 ± 10,69 (135,00– 15,65 ± 7,00 (5,65–31,40) 121,00) 176,00) Vol.: (0123456789) 1 3 254 Doc Ophthalmol (2022) 145:247–262 Table 6 Multiple regression analysis for phakic eyes for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ ss; Target variable ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex N75 [ms] FF 20.4′ < 0,001* < 0,001* 0,911 0,144* − 0,129 P100 [ms] FF 20.4′ < 0,001* < 0,001* 0,965 0,142* − 0,055 Ln(N135) [ms] FF 20.4′ 0,001* < 0,001* 0,337 0,001* (1,001) 0,014 (1,014) Ln(N75-P100) [μV] FF 20.4′ < 0,001* 0,749 < 0,001* 0,001 (1,001) 0,430* (1,537) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Table 7 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic and pseudophakic test persons of group D for the fullfield pattern-reversal VEP (FF-PR-VEP) with 1.4° ss Target variable N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Phakic (n = 32) 71,07 ± 13,93 (47,20– 105, 02 ± 7,48 (91,80– 144,41 ± 13,47 (109,00– 13,22 ± 4,86 (4,40–23,80) 96,50) 119,00) 181,00) Pseudophakic (n = 24) 68,38 ± 13,45 (51,30– 105,37 ± 9,33 (83,60– 149,25 ± 18,36 (121,00– 13,98 ± 5,16 (6,89–23,50) 96,50) 119,00) 203,00) Table 8 Reference values (mean value ± standard deviation (range)) for latencies (N75, P100, N135) and amplitude (N75-P100) of phakic and pseudophakic test persons of group D for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4° stimulus size (ss) Target variable N75 [ms] P100 [ms] N135 [ms] N75-P100 [μV] Phakic (n = 32) 82,58 ± 7,30 (67,70–98,30) 108,78 ± 7,05 (93,00– 150,56 ± 10,69 (135,00– 15,65 ± 7,00 (5,65–31,40) 121,00) 176,00) Pseudophakic (n = 24) 83,86 ± 7,20 (68,90–99,40) 110,89 ± 8,33 (98,80– 154,96 ± 21,41 (126,00– 17,69 ± 7,18 (7,56–36,20) 128,00) 227,00) Fig. 4 Fullfield pattern- reversal VEP (FF-PR-VEP) with double-peaked con- figuration of a female test subject in group D (ss 20.4′) Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 255 Double-peaked VEP p < 0.001). There were no gender-specific signifi- cant differences. These two latter aspects apply to In group D, in the FF-PR-VEP (ss 20.4′), 11 double- both ss (1.4° and 2.8°). The amplitude (C1-C2) peaked P100 wave configurations (see Fig.  4, Fig.  5 was significantly greater the older the test subject and Table  9) were seen (15.6% (5/32) of phakic eyes was (F(2,135) = 39.423, p < 0.001), and the ampli- and 25.0% (6/24) of pseudophakic eyes). tude was again significantly greater in women (see Tables 12 and 13). Extrafoveal pattern onset–offset VEP (EF -P-ON/ For both ss (1.4° and 2.8°), there were no statis- OFF-VEP) tic significant differences in the EF-P-ON/OFF-VEP between phakic and pseudophakic eyes in C1, C2 and Data for the EF-P-ON/OFF-VEP of phakic eyes C3 and C1-C2. for both check sizes (ss 2.4° and 2.8°) are given in In the subanalysis (n = 10) of EF-P-ON/OFF-VEP Tables 10 and 11: versus FF-P-ON/OFF-VEP, for ss 1.4°, there were In the EF-P-ON/OFF-VEP, C1, C2 and C3 no significant differences found for C1, C2 and C3 were significantly larger the older the test sub- (C1: W = 19.50, p = 0.449, C2: W = 19.00, p = 0.432, ject was (C1: F(2,135) = 12.886, p < 0.001, C2: C3: W = 12.00, p = 0.238). The amplitude C1–C2 was F(2,135) = 39.840, p < 0.001, C3: F(2,135) = 32.730, significantly greater after FF stimulation compared to Fig. 5 Fullfield pattern- reversal VEP (FF-PR-VEP) waveforms (n = 11) with double-peak configuration of phakic and pseudopha- kic test subject in group D (stimulus size (ss) 20.4′) Table 9 Mean value ± standard deviation (range)) for latencies (N75, P100 1. peak and P100 2. peak) of phakic and pseudophakic test persons (n = 11) with double-peak configurations for the fullfield pattern-reversal VEP (FF-PR-VEP) with 20.4′ stimulus size (ss) N75 [ms] P100 [ms] 1. peak P100 [ms] 2.peak Total (n = 11) 68.89 ± 16.95 (47.20–94.10) 77.85 ± 5.66 (70.40–88.60) 105.73 ± 8.87 (91.8–118.00) Vol.: (0123456789) 1 3 256 Doc Ophthalmol (2022) 145:247–262 Table 10 Reference values (mean value ± standard deviation (range)) for latencies (C1, C2, C3) and amplitude (C1–C2) of phakic test persons for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 1.4° ss C1 [ms] C2 [ms] C3 [ms] C1–C2 [μV] Total (n = 138) 77,18 ± 8,34 (56,00–115,00) 102,95 ± 11,84 (73,60– 134,72 ± 21,99 (89,40– 13,48 ± 9,29 (0,02–63,60) 131,00) 217,00) Group A (n = 28) 74,91 ± 10,68 (61,30– 94,79 ± 12,00 (73,60– 121,35 ± 20,24 (89,40– 7,58 ± 6,86 (0,02–25,60) 115,00) 126,00) 171,00) Group B (n = 44) 73,65 ± 7,14 (56,00–90,60) 98,02 ± 8,45 (74,80–121,00) 126,00 ± 20,11 (101,00– 9,13 ± 5,42 (0,95–22,70) 176,00) Group C (n = 34) 78,68 ± 6,61 (63,00–94,10) 106,48 ± 8,42 (88,90– 140,88 ± 12,61 (111,00– 19,07 ± 10,69 (5,40–63,60) 122,00) 174,00) Group D (n = 32) 82,43 ± 6,12 (71,80–94,10) 113,10 ± 10,21 (93,00– 151,84 ± 20,87 (107,00– 18,70 ± 7,54 (7,15–38,00) 131,00) 217,00) Table 11 Reference values (mean value ± standard deviation (range)) for latencies (C1, C2, C3) and amplitude (C1–C2) of phakic test persons for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 2.8° ss C1 [ms] C2 [ms] C3 [ms] C1–C2 [μV] Total (n = 138) 77,76 ± 6,71 102,79 ± 12,41 131,67 ± 23,96 12,43 ± 9,15 (0,01 – 63,20) (59,50 – 94,10) (71,80 – 131,00) (88,90 – 213,00) Group A (n = 28) 76,06 ± 6,52 93,73 ± 10,83 114,61 ± 18,23 6,45 ± 5,58 (0,01 – 21,70) (64,80 – 90,60) (71,80 – 120,00) (88,90 – 169,00) Group B (n = 44) 76,32 ± 5,66 97,07 ± 7,43 120,30 ± 18,48 8,04 ± 5,06 (0,34 – 19,00) (66,00 – 88,90) (81,80 – 113,00) (98,30 – 181,00) Group C (n = 34) 78,27 ± 6,85 107,51 ± 11,45 140,03 ± 17,38 17,13 ± 10,98 (2,61 – 63,20) (59,50 – 93,00) (75,90 – 131,00) (106,00 – 179,00) Group D (n = 32) 80,68 ± 7,27 (61,30 – 113,58 ± 9,87 153,34 ± 21,06 18,69 ± 7,41 (7,93 – 37,50) 94,10) (93,00 – 129,00) (107,00 – 213,00) Table 12 Multiple regression analysis for phakic eyes for the extrafoveal pattern onset/offset VEP (EF-P-ON/OFF-VEP) with 1.4° ss; Target value ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex C1 [ms] < 0,001* < 0,001* 0,612 0,162* 0,672 C2 [ms] < 0,001* < 0,001* 0,820 0,349* − 0,370 C3 [ms] < 0,001* < 0,001* 0,837 0,609* − 0,644 C1-C2 [μV] < 0,001* < 0,001* < 0,001* 0,255* 4,892* Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); level of significance is 5% (*); n = 138 EF (W = 7.50, p = 0.041). Effect size according to the Discussion classification by Cohen was strong with r = 0.64. When stimulating with ss 2.8°, all parameters (C1, In this study we established age-related reference C2, C3, C1–C2) showed no significant differences values for the FF-PR- and EF-P-ON/OFF-VEPs (C1: W = 18.00, p = 0.375, C2: W = 19.00, p = 0.434, in healthy eyes for our laboratory and examined C3: W = 18.00 p = 0.375, C1–C2: W = 25.00, age- and gender-specific influences on latencies and p = 0.846). amplitudes. Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 257 Table 13 Multiple regression analysis for phakic eyes for the extrafoveal pattern onset/offset VEP (EF-ON/OFF-VEP) with 2.8° ss; Target value ANOVA (p-value) Significance of coefficient Regression coefficient B Age Sex Age Sex C1 [ms] 0,006* 0,002* 0,520 0,085* − 0,723 C2 [ms] < 0,001* < 0,001* 0,767 0,387* − 0,489 C3 [ms] < 0,001* < 0,001* 0,950 0,779* 0,193 Ln(C1–C2) [μV] < 0,001* < 0,001* < 0,001* 0,030* (1,030) 0,561* (1,752) Results of ANOVA, the significance of coefficient and the regression coefficient B; transformation by natural logarithm (ln); data in brackets refer to back transformed values; level of significance is 5% (*); n = 138 Influence of age on latency also in studying aging effects as reported before in the literature. Sokol et  al. showed that the rate of We found age-dependent significant differences latency increases with age twice as fast for checks for the P100 latency in the FF-PR-VEP for both ss of 12′ than for checks of 48′ [9]. (20.4′ and 1.4°). In group A, the P100 latency was greater (mean P100 = 102.13 ± 8.29  ms) than in group B (mean P100 = 100.01 ± 6.41  ms) for 1.4° Influence of age on amplitude ss and in group C and D, P100 latency was increas- ing again (group C P100 = 103.98 ± 6.32  ms, group N75-P100 amplitude was also modulated by age: D P100 = 105.02 ± 7.48  ms). So between twenty and In the FF-PR-VEP, a significant decrease in N75- 39 years, P100 latency was the shortest. P100 amplitude of 0.4% per year was observed Significant slowing of the P100 latency in elderly when stimulating with large checks (ss 1.4°) and persons has been demonstrated in previous reports no statistically significant age-related change was [20–23]. The recent study by Benedek et  al. sup- seen when stimulating with smaller checks (ss ported most of the findings in the literature con- 20.4′). In the EF-P-ON/OFF-VEP, C1-C2 amplitude cerning the aging of VEP components [22]: They increased statistically significant each year for both showed that latencies of P100 and N135 decrease up stimulus sizes (ss 1.4° and 2.8°). In the literature, to the third decade of life and then show an increase there also exist miscellaneous data concerning age- again. In our study, we saw an average increase in related amplitude changes. Shaw et  al. reported in P100 latency of 0.07 ms per year in the FF-PR-VEP. 1981 P100 amplitudes being the greatest in child- In the EF-P-ON/OFF-VEP, a statistically signifi- hood, then declining until the forth decade, increas- cant increase in C1-, C2-, C3-latency was also seen. ing again and after the sixth decade, a decrease of Benedek et  al. hypothesized that the P100 latency P100 amplitude is again observed [12]. Tobimatsu is the most sensitive component to age and many et  al. observed no aging effect on P100 amplitude; studies confirm this hypothesis [8 , 24–27]. There here PR-VEPs were recorded in 109 normal subjects are reports that the N75 latency is also affected by with different stimulus conditions (inter alia high aging processes, however, in a different way com- versus low luminance or different check sizes) [29]. pared to the P100 latency: N75 is being modulated Their results suggested that age-related changes linearly and P100 curvilineary with U-shaped con- in the human visual system are not uniform, but figurations [10, 11, 28]. In our study, there was no rather different in the specific functional subdivi- statistic significant difference in N75 concerning sions [29]. They hypothesized that aging may dif- age when stimulating with large checks (ss 1.4°). ferentially influence the separate channels of human However, when stimulating with smaller checks visual system [29]. This is also true for our study (ss 20.4′), we observed a statistic significant as different retinal stimulus localizations (EF vs FF) increase in N75, P100 and N135 latency (p < 0.001). caused different age-related VEP changes. So our data confirm the importance of check size Vol.: (0123456789) 1 3 258 Doc Ophthalmol (2022) 145:247–262 Influence of sex on latency and amplitude general senile changes in the optic pathway and not due to reduced transparency of the crystalline lens in Considering the influence of sex on FF-PR-VEP elderly [37]. components (ss 1.4°) we observed the following: The P100 latency was on average 2.84  ms shorter Double-peaked VEP in female test persons compared to male subjects of the same age. Furthermore, the N75-P100 amplitude A particular phenomenon that we noticed in patients was on average 33.9% greater in women compared older than sixty for the P100 response in the FF- to men. When stimulating with 20.4°, the N75-P100 PR-VEP was several double-peaked P100 wave amplitude was on average 53.7% greater in females configurations. In the literature we found that this compared to males (p < 0.001) and in the EF-P-ON/ phenomenon is sometimes considered as a sign of OFF-VEP, the C1–C2 amplitude was again signifi- demyelization [39] but can also be found in healthy cantly greater in women compared to men for both ss older adults [40]. (1.4° and 2.8°, p < 0.001). There seems to be general agreement in the literature that sex has a significant Comparison to VEP reference values with other influence on VEP components: With different check display types sizes various authors reported on greater N75-P100 amplitudes and shorter P100 latencies in women We compared our VEP reference values with those compared to men [11, 13, 14, 30–33]. The exact rea- reported by Ekayanti et  al.[41]. They used a 24-in son of these gender differences in VEP parameters is DELL LCD monitor (Dell, Round Rock, USA) for not totally understood, but it may be associated with their pattern-reversal VEP examination in 120 healthy endocrinal, anatomical and behavioral differences. subjects between 18 and 65  years. Their reference Some investigators associated a shorter head cir- values were slightly slower than ours in each age cumference with a shorter VEP latency: Guthkelch group (approx. 1–3 ms). They did not see significant et al. reported on eight male and eight female healthy differences between the P100 latency values of gen- young adults showing the shortest latency to P100 der and age groups [41]. However, as in our study, the when having the lowest occipito-frontal circumfer- P100 amplitude was significantly higher in females ence (OFC) [32]. This variation in P100 latency was compared to males [41]. It is known that LCD dis- even more highly correlated with OFC than with gen- plays cause apparent (artificial) delay in the P100 der: Men with the same OFC as women showed com- latency due to the input lag of the monitor [42]. There parable latencies [32]. A more recent study includ- are some software modifications that can compensate ing 400 eyes showed a positive correlation of P100 for the lag [43]. The study by Husain et al. [42] con- latency with mean head circumference, while a highly firmed the assumption that substituting a cathode-ray significant negative correlation was observed of N75- tube (CRT) monitor with a LCD monitor results in a P100 amplitude with head circumference [34]. They significant prolongation of P100 latency. CRT moni- concluded that a larger head circumferences indicate tors have become less available in the market and a larger brain size and a longer conduction pathway, liquid crystal displays (LCD) [16] have an inherent thus prolonging VEP latencies [34]. problem as visual stimulators that is called “the flash effect” [44]. LCDs take several milliseconds for the Influence of lens status crystal molecules to change their alignment to per- mit the light to pass through the polarizing filter of Regardless of ss there was no statistic significant dif- the LCD [16, 45], and this causes a transient change ference to be seen between phakic and pseudophakic of the mean luminance of the entire LCD screen at eyes in the FF-PR-VEP as well as in the EF-P-ON/ the time of the reversal and this luminance change OFF-VEP for latencies and amplitudes. In the litera- can elicit flash VEPs; that’s where the “flash effect” ture different studies report that the senile opacity of comes from [44]. So the question is how the recently the crystalline lens does not contribute to changes developed OLED monitor influences VEP values and of PR-VEPs [37, 38]. Yamamoto et  al. assumed whether this monitor is suitable for eliciting VEPs. that longer latencies in elder test subjects are due to Here we think that the work published by Matsumoto Vol:. (1234567890) 1 3 Doc Ophthalmol (2022) 145:247–262 259 et al. is very important [16] as they examined whether or 13° response [59]. They suggested that cortical OLED screens can be used as visual stimulators. magnification factor in AMD might be higher than in They showed that p-VEPs elicited by OLED screens normal controls [59]. were not significantly different from those elicited by In our study, in the FF-P-ON/OFF-VEP (ss 1.4°), conventional CRT screens [16, 44] as OLED screens amplitudes were significantly greater to amplitudes have a faster response time than standard LCD in the EF-P-ON/OFF-VEP (p = 0.041), but there screens [46, 47]. They showed that OLED displays were no statistically significant differences for the are suitable for a visual stimulator to elicit p-VEPs. C1-, C2, and C3-latencies (p = 0.238). However, in Other authors explored the characteristics of this subanalysis only ten test persons were included OLED displays for its applicability in visual research so the validity of this subanalysis is limited. Compar- [48, 49]. They found the new display to be superior ing our reference values of the EF-P-ON/OFF-VEP to other display types in terms of spatial uniformity, with data on FF-P-ON/OFF-VEPs by Thompson and color gamut and contrast ratio [48]. However, there colleagues on 24 healthy adult test persons, the C1-, are no studies on VEP data when a curved OLED C2- and C3-latencies of our extrafoveal VEP were monitor was used and this is new in our study. shorter [60]. Hagler [61] confirmed significantly shorter latencies after peripheral compared to peri- Extrafoveal stimulation foveal stimulation in PR-VEP, and we did expect this tendency of shorter latencies when occluding the cen- The contribution of the peripheral retina to pattern tral retina due to the differences in axonal conduction VEP is a matter of debate. Some authors stated that speed between the magnocellular and parvocellular the VEP is primarily a reflection of activity origi- pathways. nating in the central two to six degrees of the visual In order to explain the contribution of the periph- field [50] so the central macular response dominates eral retina to VEP components the anatomical com- the VEP response [34, 51–53]. It had been known position of neural macro-networks that process the for nearly a century now that each visual area has a visual information has to be considered. Starting in retinotopic organization in human striate cortex. Mer- non-human primates much about the two major par- edith and Celesia reported in 16 healthy volunteers on allel retinocortical pathways, the magnocellular (M) an amplitude distribution of evoked responses in rela- and the parvocellular (P) pathway, has been described tion to retinal eccentricity [54] and confirmed previ- [62–64]: The M pathway begins with the parasol gan- ous research, namely that the amplitude distribution glion cells of the retina [65]. These cells have large correlates well with (1) the decline in cone density receptive fields and selectively project to the magno- in relation to retinal eccentricity [55], (2) the density cellular layers of the lateral geniculate nucleus (LGN) distribution of human ganglion cell population along [65]. Midget cells of the retina are the origin of the the horizontal axis [56] and (3) the decline of visual P pathway, representing approximately eighty percent acuity in relation to eccentricity [57, 58]. These cor- of ganglion cells [65]. Midget cells have small den- relations further suggest that a visual stimulus outside dritic and receptive fields and project mainly to the the fovea has to reach the threshold of visual percep- parvocellular layers of the LGN [65]. Both pathways tion to be effective and needs to activate sufficient project in different layers of the primary visual cortex numbers of receptors and ganglion cells [54]. (V1) to become dorsal (M) and ventral (P) streams Walter and colleagues compared amplitudes in [66]. PR-VEPs in patients with age-related macular degen- Concerning physiological aspects, M cells of the eration (AMD) and found a few individuals showing retina and the LGN are relatively insensitive to pure larger amplitudes after stimulation of a central 3° chromatic contrast, but highly sensitive to luminance field compared to stimulation of a 13° field although contrast [65, 67]. P cells are sensitive to chromatic in normals and the majority of AMD patients, VEP contrast, but less sensitive to luminance contrast com- amplitudes increased with increasing field size [59]. pared to M cells [64, 65, 68]. The M pathway is sensi- After stimulation of different macular zones they tive to lower spatial frequencies and higher temporal found that the 3° central area and the perifoveal frequencies and has transient responses [69]. The P region contributed differently to the macular response pathway is responsive to higher spatial frequencies Vol.: (0123456789) 1 3 260 Doc Ophthalmol (2022) 145:247–262 or beliefs) in the subject matter or materials discussed in this and lower temporal frequencies and sustained manuscript. responses [69–71]. The relative distributions of neurons within the Statement of the welfare of animals Not applicable. M and P pathway are still discussed [65]. A study in macaque LGN by Malpeli et al. estimated the magno- Ethical approval  / Statement of human rights All proce- cellular/parvocellular ratio to increase from the fove- dures performed in studies involving human participants were in accordance with the ethical standards of the institutional olar to far periphery by a factor of at least 14 [72]. research committee (Medical Ethical Review Board, University More recent studies compared the magno- and parvo- RWTH Aachen) and with the 1964 Helsinki Declaration and its cellular distributions in the human retina and found later amendments or comparable ethical standards. a decrease in parvocellular/magnocellular ratio with Informed consent Informed consent was obtained from all eccentricity which was even more distinctive than individual participants included in the study. that of macques [73, 74]. There exist several studies that report on the differences in the relative speed of Consent publication The data of this publication are content the magnocellular and parvocellular pathways: Dif- of a doctoral thesis. ferences in axonal conduction speeds in the retina, optic nerve and optic radiation are expected to cause Open Access This article is licensed under a Creative Com- parvocellular signals approximately 3 ms longer than mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any magnocellular signals to travel to the LGN and about medium or format, as long as you give appropriate credit to the 5  ms longer to get to the cerebral cortex [75–77]. original author(s) and the source, provide a link to the Crea- In our study, for the EF-P-ON/OFF-VEP, we chose tive Commons licence, and indicate if changes were made. The larger ss as for the FF-PR-VEP (1.4° und 2.8° com- images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated pared to 20.4′ and 1.4°) to favor the lower resolution otherwise in a credit line to the material. If material is not of the M pathway. included in the article’s Creative Commons licence and your The EF approach in our study has an experimental intended use is not permitted by statutory regulation or exceeds character, and with this analysis, we aim to pave the the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit way for new VEP testing modalities that allow us to http:// creat iveco mmons. org/ licen ses/ by/4. 0/. use VEPs effectively for example in the diagnosis and management of glaucoma. 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Journal

Documenta OphthalmologicaSpringer Journals

Published: Dec 1, 2022

Keywords: Electrophysiology; Visual evoked potentials; Fullfield pattern-reversal VEP; Extrafoveal pattern onset–offset VEP

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