Doc Ophthalmol (2008) 117:215–222 DOI 10.1007/s10633-008-9125-x

ORIGINAL RESEARCH ARTICLE

Human oscillatory potentials: intensity-dependence of timing and amplitude Heather A. Hancock Æ Timothy W. Kraft

Received: 12 November 2007 / Accepted: 25 March 2008 / Published online: 30 April 2008 Ó Springer-Verlag 2008

Abstract Oscillatory potentials (OPs) have been described as reduced in amplitude or delayed in diabetic retinopathy, glaucoma, and vascular occlusions. Although OPs are thought to have useful diagnostic applications, some of their basic physiologic properties remain to be fully described. In the present study, we examined the relationship between the timing and amplitude of OPs and stimulus intensity. Five normal volunteers had one eye anesthetized and dilated. Dark-adapted full-field ERGs were recorded to white stimuli of 0.0125–40 cd s/m2. The timing of the OPs was measured as the sum of the time to the peak (TTP) of four peaks beginning at 15 ms after the stimulus. The amplitude was taken as the sum of the amplitudes of those same peaks. As an alternative value, OP strength was represented by the

area under the OP curve or power around 150 Hz (±30 Hz) in the frequency domain. The OP timing, as measured by TTP, was found to be inversely related to stimulus intensity. OP-amplitudes grew with intensity, but then declined for stimulus intensities above about 4 cd s/m2. At bright light intensities, the TTP continued to shorten, yet amplitudes, power, and area all declined. Individual OPs behaved similarly and reflected the overall response pattern of the group as a whole. Brighter stimuli produced larger, faster OPs for stimulus strengths up to the intensity standard used to produce OPs (3.5 cd s/m2). We have extended the range of stimuli to some 10-fold higher than the ISCEV standard for producing OPs and found that the timing continued to accelerate but that OP-amplitudes, OP-area, and OP-power all decline at higher stimulus intensities. These alternative measures of OP energy are easily measured and may be useful for further studies.

H. A. Hancock (&) Department of Ophthalmology, University of South Carolina School of Medicine, 4 Medical Park Suite 300, Columbia, SC 29203, USA e-mail: [email protected]

Keywords Electroretinogram
Electrophysiology
Oscillatory potentials
Physiology
Retina

Present Address: H. A. Hancock Charles Retina Institute, 6401 Poplar Avenue, Suite 190, Memphis, TN 38119, USA

Introduction

T. W. Kraft Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA e-mail: [email protected]

Human oscillatory potentials (OPs) are of scientific interest because they may be a sensitive indicator of retinal disease. OPs, first described by Cobb and Morton in 1953 [1], are a high-frequency component of

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the electroretinogram (ERG) occurring simultaneously with the rising phase of the b-wave. Pharmacologic studies indicate that they arise from the inner nuclear layer of the retina [2, 3]. Although the neural generator of the OPs has not been precisely defined, it is thought that they originate from amacrine cell feedback [4, 5]. The major features of OPs are similar across species, but lower mammals have been found to have generally lower OP frequency spectra than higher mammals [6, 7]. The source of the OPs in primates is in the inner retina. It is thought to originate in the bipolar cells, amacrine cells, and interplexiform cells [8]. Numerous authors have attempted to trace the precise neural generators of the individual OP peaks [9]. Recently Dong et al. (2004) separated the OPs into early (photoreceptor), middle (action potential independent), and late (action potential dependent) mechanisms [10]. Four to six OPs are typically recorded with peaks 2–3 being considered ‘‘middle’’ and 4–6 considered ‘‘late’’ [9]. Some clinical papers [11, 12], and our earlier work [7], focused on the middle and late OPs generated in the inner retina. Individual OPs are often measured by either the peaktrough method or the caliper-square method. In the peak-trough method, the individual peak is measured from the preceding trough to its peak. In the calipersquare method, a line is formed between the trough before and after the wavelet. The amplitude is measured from this baseline to the peak [13]. Alternatively, the amplitude can be represented by the sum of the amplitude of the four major wavelets [14]. OPs are markedly effected in diabetes [15–18]. Yonemura et al. first described diminished OP-amplitudes in diabetic patients relative to controls [19]. Electrophysiologic changes have been shown to occur before the onset of vascular changes visible on fluorescein angiography [17]. It has been independently reported that OPs are delayed [20] or reduced in amplitude in diabetic patients [16, 21]. Some studies have found no change in diabetic patients [22]. In other studies, OPs have been shown to be a better predictor of progression of retinopathy than age or duration of diabetes [23, 24]. For a comprehensive review of electrophysiology and diabetic retinopathy see Tzekov and Arden [25]. OPs have also been shown to be delayed in some patients with glaucoma [26], hepatic retinopathy [27], congenital stationary night blindness [28], and retinitis pigmentosa [29]; thus they may be sensitive indicators of other types of retinal damage.

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Previously, we observed that a linear relationship exists between OP-amplitude and kinetics in normal and diabetic rats [7]. We found that for matched OPamplitudes, there was a delay in the oscillatory peaks in diabetic animals. In this study, we wished to investigate the intensity–response relationship of the human OPs individually and collectively. In order to fully describe OP changes in disease states, the response parameters of the OPs in normal human subjects must be fully characterized.

Materials and methods Subjects were healthy volunteers between the ages of 26 and 47 (four males, one female) with no reported ocular disease or diabetes. The study was approved by UAB’s Institutional Review Board, and all subjects gave their written informed consent according to the Helsinki declaration. The ERG potential was digitized at 5 kHz by the Diagnosys software and hardware (Espion 1, Diagnosys LLC, Littleton, MA). After 20 min of dark adaptation, one eye was anesthetized with a drop of proparacaine hydrochloride 0.5% and then dilated with 1% tropicamide and 2.5% phenylephrine. A small drop of hydroxypropyl methylcellulose 2.5% (CibaVision) was applied to a DTL electrode (Diagnosys, Littleton, MA) which was then placed on the eye. A reference electrode was placed on the forehead and a ground was placed immediately behind the ear. Stimuli consisted of 4ms flashes of white light delivered via LEDs from a Diagnosys Colorburst mini-Ganzfeld bowl over an intensity range of 0.0125–40 cd s/m2. Series of flashes were presented according to ISCEV recommendations for OPs; these series consisted of five flashes, 4-ms duration with an interstimulus interval of 15 s [22]. The first flash was discarded and the others were averaged. Duration of recording was approximately 10 min. Our recording system used Espion V2 software, included a gain of 109 and signal filtering by a FIR digital 256 tap, time invariance, equi-ripple design. Amplitude and timing of individual OP peaks were measured off-line using Igor Pro software (version 5.03, Wavemetrics, Lake Oswego, OR). The timing of the OP peak was defined as the sum of the time-topeak of each of the four peaks beginning 15 ms after the stimulus, and the amplitude of the OP was defined

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as the sum of the four individual amplitudes measured from baseline [7]. If a fifth peak appeared in the series, it was ignored. The area of the OPs was calculated by summing the absolute values of the positive and negative areas of the isolated OP waves over the time from 15 to 55 ms after the stimulating flash. Another measure of OP strength was derived by taking the fast Fourier transform (FFT) of all wavelets over the time interval from the stimulus onset to 65 ms post-stimulus. We then measured the area under the main peak of the power versus frequency curve, that is from 120 to 180 Hz (see Fig. 3). For the brightest two intensity stimuli the awave begins to have sufficient power above 100 Hz and appears in the OP trace, and a second peak arises in the power analysis, but this was considered a contamination and therefore not included in the area under the power versus frequency function.

Results Bright flash ERG records demonstrate a family of OPs concurrent with the rising phase of the b-wave. Oscillatory potentials were generated by flashes with intensities as low as 0.0125 cd s/m2 (Fig. 1). It is clear that the OP-amplitudes initially increased with increasing stimulus intensity. In addition, at flash intensities above 1 cd s/m2, the a-wave became prominent in both amplitude and duration. The traces have been separated vertically for presentation. In Fig. 1b, the OPs have been isolated by high-pass filtering. Note in the bottom two traces of Fig. 1b that the standard 100 Hz high-pass filtering permits some of the a-wave signal to intrude for stimulus strengths above 1 cd s/m2. A prominent early wavelet is present in the responses to stimuli of 10 and 40 cd s/m2. Oscillatory potential timing is dependent on stimulus intensity. Here OP kinetics are defined by the sum TTP, measured as the sum of the time to peak for the first four peaks. The sum TTP for five subjects is plotted versus logarithm stimulus intensity in cd s/m2 in Fig. 2. OP kinetics speed up progressively with increasing stimulus intensity. The brightest stimuli produced the fastest OPs. There is a linear relationship between OP kinetics and Log stimulus intensity over the entire range tested, and the decline in TTP with increasing stimulus intensity found in all five subjects showed similar slopes (Fig. 2). Linear

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Fig. 1 ERG responses to the eight standard stimulus intensities from one subject; responses are offset vertically for clarity. From top to bottom the stimulus strength increases 320-fold, from 0.0125 to 40 cd s/m2. (a) The raw ERG traces showing the a-wave, b-wave, and superimposed oscillatory potentials. Note the vertical scale bar is 250 lV. (b) ERG responses as in (a) high-pass filtered (cutoff 100 Hz) to isolate the oscillatory potentials. Note the vertical scale bar represents 50 lV

regression of individual data sets suggests a flattening out or decline in the slope above 1.0 cd s/m2. There are various ways to measure the strength of the OP response; a simple measure is OP-amplitude. Another approach to measuring the OPs is to use Fourier analysis to assess the relative strengths of periodic components over a specific frequency range. Figure 3 shows the power spectra of one set of responses over the frequencies from 70 to 250 Hz. In Fig. 3a, the power spectra for OPs generated by the dimmest five intensities are plotted. A peak around 150 Hz is present and grows with increases in stimulus intensity up to 1.0 cd s/m2. In Fig. 3b, the power spectra for the OPs generated by the upper end of our stimulus range are plotted. For stimuli above 1.0 cd s/m2 the peak at 150 Hz declines and a second peak near 100 Hz arises. The dashed vertical lines in Fig. 3 mark the range over which the OP-power was summed (120–180 Hz) for Fig. 4c. Three different means of assessing the strength of the OPs were employed: amplitude measured from

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Doc Ophthalmol (2008) 117:215–222 Subject 1 Subject 2 Subject 3 Subject 4 Subject 5

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baseline, total area under the curve from 15 to 55 ms, and power around 150 Hz (Fig. 3). The OP-amplitude versus intensity relationship is plotted in Fig. 4a; it showed good consistency between subjects, although the relationship was not monotonic and cannot be described by a linear fit. OP-amplitude increased with stimulus intensity up to the ISCEV standard ‘‘bright-flash stimulus’’ of 1.5–4.5 cd s/m2 (indicated by the gray bar in Fig. 4a) [30]. Beyond the ISCEV standard, OP-amplitude declined with further increases in stimulus intensity. OP-amplitude was measured as the amplitude measured from baseline. The sum of the OP-amplitude is defined as the sum of the amplitudes of the four OP peaks. A second measure of the strength of the OPs was taken by calculating the total area under the curve of the positive and negative peaks from 15 to 55 ms after the flash. The shape of the OP-area versus intensity function matched that of the OP-amplitude versus intensity function (Fig. 4b). The OP-area peaks then declines for stimuli above the strength of ISCEV standard flash (gray bar, Fig. 4b). The OP-power calculated as described above is plotted versus stimulus intensity in Fig. 4c. All these measures of OP strength exhibit a function which peaks at or near the ISCEV range of stimulus intensities. Individual OPs were also tested to determine if they have intensity–response functions or timing properties with individually distinct features. The time-to-peak of OP1, shown by the open circles in

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Fig. 2 Human OP kinetics depended on stimulus intensity. OP timing (sum TTP) from five subjects responding to stimuli over a 3.5 log unit range of intensity. Each point was derived from the averaged response of four repeated stimuli. The timing of the peaks was accelerated at higher light intensities. The sum TTP is the sum of t1 + t2 + t3 + t4, where tn was the time after stimulus to the point of maximum amplitude

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Fig. 3 The discrete Fourier transform was used to compute the power of the OP traces over the first 65 ms of the response. (a) The power over the range from 70 to 250 Hz is graphed for responses to five stimulus intensities from 0.013 to 1.0 cd s/m2. (b) The main peak at 150 Hz declines and a second peak at 100 Hz arises for responses above 1.0 cd s/m2. The dashed lines indicate the range over which the area was calculated for Fig. 4c

Fig. 5, declines very steadily across the entire range of stimuli tested. A similar pattern is seen for OP2, OP3, and OP4. Figure 5b shows individual OPamplitude instead of timing and each trace represents one of the OP peaks, averaged for four subjects. The open circles represent the amplitude of OP1 plotted against the log of the stimulus intensity. OP2 and OP3, the OPs with the largest amplitude, peak near the ISCEV standard stimulus intensity and then decline. In fact, the amplitudes of each of the individual OPs peak at the ISCEV standard and then decline with further increases of stimulus strength.

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Fig. 5 Amplitude and kinetic measures for individual OPs. (a) The times to the peak of the individual OPs are plotted versus stimulus intensity. The different symbols represent OP1 (open circle), OP2 (filled circle), OP3 (filled triangles), and (OP4 filled squares) (mean ± s.e.m., n = 4). (b) A similar analysis performed on the individual OP-amplitudes, symbols as in a, above

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Log I (cd.s/m2) Fig. 4 (a) When the sum of the amplitudes for the four OP peaks (top panel) is plotted versus the stimulus intensity, a peaked function is found. (b) If instead we quantify the OP by the area (15–55 ms, middle panel) or (c) use the FFT to determine the power (120–180 Hz; bottom panel), then similar functions are found. The ISCEV standard stimulus is given by the gray bar (1.5–4.5 photopic cd s/m2). Each symbol represents a different subject

Thus, the individual OPs have intensity–response and kinetic properties similar to the ensemble. Figure 6 shows a graph of OP-amplitude versus timing; the amplitude is inversely related to timing for stimuli of 1.0 cd s/m2 or less. Analysis of OP-area versus OP kinetics (TTP) produces a similarly appearing data set for normal subjects.

Discussion A comprehensive understanding of the OPs’ response properties is needed if we are to develop clear and

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Fig. 6 (a) Oscillatory potential amplitude versus timing is roughly linear for stimuli of 1.0 cd s/m2 or less. (b) Analysis of area versus TTP produces a similar set of curves. Different sets of symbols represent results from different subjects

consistent standards for the measurement of OPs in disease states. In previous work, we described how the OP timing and amplitudes are intensity-dependent in rats [7]. Herein we describe that human OPamplitude and timing are similarly intensity dependent, but at the highest stimulus intensities currently available the OP-amplitude versus intensity function declines. Algvere, Wachtmeister, and Westbeck (1972) found a linear increase in OP energy over 3 log units of intensity, but over the range of stimulus intensities used, they did not observe a plateau or decline of OP energy at high intensities [31]. The stimulus intensity range used by Algvere and colleagues overlaps our own, but importantly they also varied the interstimulus interval, settling on 30 s, whereas in our study a 15-s interval was used. Decreases in the implicit time of the OP peaks with

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increasing stimulus intensity was observed 50 years ago by Bornschein et al. [32]. and repeatedly by others [7, 31, 33, 34]. Frequency analysis has proven a reliable and efficient means of extracting the strength of the OP signal [31, 35]. Mathematically the extraction of power, or the relative strengths of periodic components, over a specific frequency range is easier to automate and less effected by drift and line noise than measuring amplitudes from baseline [9, 14] or from the preceding and following negative peaks [24, 36]. Current computer technology permits these mathematical steps to be performed rather easily and automatically. Similarly, the total OP-area can be used as an indicator of OP strength although instrument noise in the recordings could skew the results minimizing the intensity-dependent differences, especially for small signals. Power measurements are less likely to be affected by instrument noise because of the different primary frequencies of the OPs versus instrument noise. This particular OP measurement can be further refined by restricting the bandwidth of interest, as we have done, to 120–180 Hz. The a-wave responses to high intensity stimuli grew dramatically and its rapid onset and offset introduced some complexity in the first 15 ms of the OP waveform. This intrusion and augmentation of the amplitude of OP1 was not subtracted but the OP-area and OP-power calculations were defined in ways to minimize this effect. The OP-amplitude, defined as the sum of the four OP-amplitudes measured from baseline, increases for stimuli up to 1.0 cd s/m2, then plateaus and declines for brighter stimuli. OP-amplitude, OP-area, and OPpower decrease for intensities above the ISCEV standard (1.5–4.5 cd s/m2) as shown in Fig. 5; thus, all measures of the OP strength demonstrated a pattern reminiscent of a ‘‘photopic hill.’’ The term photopic hill was originally used to describe the b-wave intensity–response relationship [37, 38], and recently it has been suggested to be due to reductions of the ON-component and delays in part of the OFFcomponent for responses to stimuli of high intensities [39]. The a-wave is not reported to exhibit a photopic hill [34, 40]. However, those reports did not find a decline in the sum of the OP-amplitudes for stimuli up to 6 cd s/m2 on backgrounds of 18 cd s/m2 or higher, but did note a decline in the amplitude of OP4. Our results, as in Fig. 1b, showed a decline in OP4, as well as OP3 and OP2 at highest intensities

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(above 2.25 cd s/m2). OP1 is involved in a complex way with the a-wave at high intensities. That is, the awave is normally excluded by the band-pass filtering used to isolate the OPs. However, with stimuli at the upper end of our range, the onset and offset of the awave are now so rapid and large that a new peak at 100 Hz appears and then grows in the FFT analysis of the OPs. The width of the a-wave becomes so broad that its timing overlaps with that of OP1. Our alternate measure of OP strength also showed a decline at high stimulus intensities; however all of our responses were measured without background light, and so the conditions of the two experiments are not matched. It is well established that OPs of dark-adapted ERGs include contributions from both rods and cones [12, 33]. Since our measures were all made without adapting backgrounds and with a constant 15-s interstimulus interval, adaptation and lack of recovery within the 15-s interval could account for the declines at the upper end of our stimulus range. Algvere et al. showed OP-amplitude to be independent of ISI above 30 s, suggesting indeed that 15 s is not a sufficient interval for stimulus strengths above 4.0 cd s/m2. Below the ISCEV standard the amplitude and timing are approximately linear functions of the log of the stimulus intensity, and thus they are linearly related to one another. Put simply, the larger amplitude OPs are faster. Therefore, OP speed and size should not be considered independently. Therefore, we suggest that electrophysiologists consider recording responses to four or more intensities at and below the ISCEV standard to document the linear relationship. If a single bright flash is to be used in studies, it at least should be calibrated over time to ensure stability of stimulus energy. Importantly, we should consider the interstimulus interval of stimuli used to collect OPs. Hopefully, increased understanding of the properties will lead to improvements in ERG analysis and ultimately greater clarity in identifying changes in retinal function in disease states. Acknowledgments This work was supported by a resident Grant-in-Aid award from the Palmetto Health Alliance.

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