Evoked potential assessment of cortical adaptation
William Seiple, Mark Kupersmith, Jeremiah Nelson, and Ronald Carr
Visual evoked potential contrast adaptation was measured in normal subjects using a real-time-retrievalswept contrast analysis. Results demonstrated orientation specific adaptation suggesting a cortical locus.Conditions which disturb cortical inhibition (i.e., epilepsy and dopaminergic agents) altered this adaptationeffect.
1. Introduction
Visual adaptation can be exhibited using a variety ofparadigms and measurement techniques. Psycho-physically, visual adaptation is operationally definedas a contrast threshold elevation resulting from preex-posure to a high contrast grating.1-3 Neurophysiologi-cally, adaptation has been defined as an elevation inthreshold and/or a reduction in the slope of the stimu-lus response curve of a single cortical neuron as a resultof prolonged stimulation with a high contrast target.4 -6
This aftereffect shows orientation and spatial frequen-cy specificity using either technique.7-11 The corrobo-rative relationships between psychophysics and neu-rophysiology would be strengthened by an objectiveindex of cortical adaptation in man.
The evoked potential recorded from the scalp inresponse to visual stimulation is one such objectivemeasure. However, the use of evoked potential ampli-tude as an index of adaptation is not ideal due to thelarge amount of variability. It would be preferable toexpress adaptation as an evoked potential threshold,which would be directly comparable to psychophysicalmeasures and which would be independent of responseamplitude slope. A major problem of the standardevoked potential techniques, which are based on com-puter averaging, is that they do not yield direct thresh-old measures. To do that one must make repeatedpostadaptation measurements at a series of fixed con-trasts and extrapolate visual evoked potential (VEP)
When this work was done all authors were with New York Univer-sity Medical Center, Ophthalmology Department, 550 First Avenue,New York, New York 10016; J. Nelson is now with Philipps Universi-ty Physics Department, Marburg, Federal Republic of Germany.
amplitude against log contrast to an estimated thresh-old.12 This procedure has both methodological andpractical problems. Unless attention is paid to inter-trial rests and the order of stimulus presentations, theprolonged testing period may itself contaminate thethreshold measures with an unknown amount of adap-tation. In addition, repeated averaging of a largenumber of stimulus presentations presents difficultiesfor parametric studies or clinical use.
To overcome these problems, we have developed atechnique which makes it possible to measure VEPthreshold in real time over a 20-s testing period. Usingthis technique, we have examined changes in the VEPthreshold as a function of adaptation.
II. Methods
A. Swept VEP Technique
Using two lock-in amplifiers (PAR 9505-SC) set inquadrature (one at 0 and 900 and the other at 45 and1350 relative to the stimulus reversal rate), we moni-tored the output of the four phase sensitive channels.When inverted, these four phase outputs constitute atotal of eight phase channels, providing simultaneousresponse amplitude retrieval at reference phasesaround the clock in 450 increments. The detectorclosest to the phase of the response is used to estimateevoked potential amplitude. As long as the phaseshifts of the response are not large, phase sensitivedetection (PSD) is the method of choice. PSD repre-sents signal-to-noise enhancement over vector compu-tation by eliminating in-band noise (at the frequencyof stimulation) because of its difference in phase.This is a significant improvement when working withstimulation rates which are near peaks in the EEGpower spectrum; see Nelson et al.
13 for a detailed de-scription of this methodology.
To examine the response phase changes over thecontrast range used in our contrast sweeps, we record-ed a series of averaged transient VEPs to stimuli ofincreasing contrasts (between 1.0 and 20%). The la-
tency of the P100 wave was measured at each contrast.At 1.0% contrast, P100 latency was 129 ms, and at 20%contrast, latency was 110 ms. At intermediate con-trasts, the data points fell on a straight line connectingthese two extremes. Thus the total range of latencychanges over this contrast range was 19 ms. Katsumiet al.14 have shown similar VEP latency changes overthis contrast range (Katsumi et al.,14 Fig. 3). At the3.5-Hz stimulus rate (i.e., 7 reversals/s) used in thefollowing series of experiments, these latency shiftsrepresent a phase change of only 470. Actual phasechanges measurement of steady-state response at 7 Hzover this contrast range showed a phase change of,60-800. However, in practice, response slopes aretypically extrapolated over a small range of contrast(i.e., the linear threshold determining portion of theamplitude vs contrast function occurs over a 1-2%contrast range; see Nelson et al. 1 3 and Seiple et al.)15
Phase changes within this small contrast range arenegligible. The accuracy of phase calculations, how-ever, is inversely related to the amplitude of the signal.With a very low amplitude signal, large phase shiftsmight be indicated which are artifactual and not ofbiological origin.
B. Subjects
Five normal subjects consented to participate in theinitial portions of this study. All were acquainted withthe purpose of the study and had good corrected visualacuity (20/20 or better ). Seven seizure patients werealso tested.
C. VEP Recordings
Gold cup electrodes were placed 2.5 cm above theinion and referenced to the right earlobe. The leftearlobe served as earth. The signal was amplified(gain = 10,000) using a Grass P511J preamplifier withbandpass filters set at 0.3 and 30 Hz. The amplifiedsignal was shared by a pair of lock-in amplifiers (PAR9505-SC). The output of the four phase sensitivedetectors of these lock-in amplifiers was stored on thefour channels of a Nicolet 1170 signal averager. Thephase output of the lock-in amplifier (tan-' cosine/sin)was used to determine the phase of the evoked re-sponse, which was then plotted and threshold estimat-ed by extrapolation.
D. Stimulus
Sine wave gratings of 4 cpd were generated (Instituteof London grating generator-T221) on a video monitor(Conrac QQA 14/N). The display subtended 8.25 X11.50 of visual angle and had a mean luminance of 50cd/M2 . Background room luminance was -35 cd/M2 .Contrast, measured in the standard manner, was loga-rithmically swept on a given trial over a range of 0.1-20%. Reversal rate was always 7 reversals/s, and thetotal sweep time was 20 s. Image orientation on theTV monitor was varied by smooth rotation of the mag-netic deflection yoke at a rate of 180°/3 s.
III. Experiments and Results
A. Experiment 1: Basic Adaptation Effect
One would expect the same contrast threshold whenthe contrast is swept downward from initially highcontrasts (20-0.1%) as when contrast is begun belowthreshold and swept upward (0.1-20%). However,downward and upward sweeps produce differentthreshold indications. These differences might becaused by the different opportunities for adaptation.By the time threshold is reached in a downward sweep,the subject has spent much of the 20-s run viewing aninitially potent stimulus. In an upward sweep no su-prathreshold stimulation is present, by definition, be-fore threshold is reached. We wondered if the differ-ences in contrast thresholds obtained using the twotypes of sweep could be attributed to cortical adapta-tion.
To test this, contrast threshold changes were exam-ined using four exposure conditions which have previ-ously been shown to provide variable opportunities foradaptation.'6 The four conditions were: (1) Upwardsweeps. The contrast was increased from belowthreshold (0.1-20%) over 20 s. The subject should beunadapted at threshold determination. (2) Down-ward sweeps. The contrast was decreased from aninitial 20% to below threshold (0.1%). Adaptation isexpected. (3) Downward sweeps with rotation. Thecontrast was decreased from an initial 20%, while theorientation was continuously rotated. Since adapta-tion has been shown to be orientation specific,7'8 itshould be minimized by the procedure. (4) Upwardsweeps with preexposure. Thresholds were measuredusing an upward sweep following 60-s preexposure to a75% contrast grating of the same spatial frequency andorientation as the test stimulus. Strong adaptation inthe VEP measured threshold would be expected fromthis classic adaptation paradigm.
1. Results: Adaptation was measured as the ratioof thresholds obtained from upward and downwardsweeps. A ratio of one indicates that downward andupward sweeps yielded the same contrast threshold.Ratio values greater than one indicate that downwardthresholds are higher than upward thresholds. Wehave found VEP contrast thresholds are elevated ondownward relative to upward sweeps (leftmost set ofbars in Fig. 1). Averaged across observers, downwardthresholds were 5.24 times higher than the upwardthresholds. This effect is similar to the 4.25X incre-ment previously reported in four subjects.16 Likewise,exposure to a high contrast adapting stimulus immedi-ately prior to testing (preadapted condition) elevatedthe upward thresholds in all subjects (middle set ofbars in Fig. 1).
This effect (mean = 3.18) was smaller than the adap-tation effect observed with the downward sweeps. Ifthe higher (downward sweep) threshold is elevated byadaptation of cortical origin, the effect should be ori-entation selective. Elevated thresholds were indeedgreatly lowered (mean ratio = 1.65) by stimulus rota-tion (right set of bars in Fig. 1). The current results
Fig. 1. Thresholds measured in three experimental conditions arecompared with the upward unadapted thresholds. A ratio of 1indicates that thresholds for the two sweep directions were identical.A ratio greater than 1 indicates that downward thresholds werehigher than the upward. Down sweeps were from 20 to 0.1% con-trast; Preadapted were upward sweeps following 1 min of exposureto a 75% contrast grating of the same spatial frequency and orienta-tion; and Rotated were downward sweeps with the orientation of thegrating continuously rotated during the sweep. Each subject's data
can be identified by the unique hatching.
are consistent with those previously obtained in thislaboratory.16
B. Experiment 2: Dopaminergic Agents
Our VEP index of cortical adaptation was used tomeasure the effects of chlorpromazine (50 mg), a dopa-minergic inhibitor, and levodopa (Sinemet, 100 mg), adopaminergic agonist, in two normal subjects (two ofthe authors). Once again, the adaptation index wasthe ratio of upward thresholds to downward thresh-olds. The stimulus and recording conditions remainthe same as in Experiment 1.
1. Results: Chlorpromazine decreased the VEPadaptation effect in the two normal subjects (middlebars of Fig. 2) relative to their untreated ratios (leftbars of Fig. 2). Levadopa increased adaptation com-pared to the untreated effect in the same subject (rightbars of Fig. 2).
C. Experiment 3: Seizure Patients
Seven seizure patients were also tested under thisVEP adaptation paradigm. It has been suggested thatthese patients have reduced cortical inhibition,7"18
and we would expect this to reduce adaptation. Allpatients were medicated with dilantin and/or pheno-barbital.
1. Results: The adaptation effect (threshold ratioof upward vs downward sweeps) was significantly re-duced in all seizure patients tested relative to thegroup of normal subjects (Fig. 3). The average adap-tation effect for the seizure patients was 1.2, which wassignificantly different from the adaptation effect of 5.2for the normals (Student's t = 2.98, df = 11, p < 0.05).
r
Condition
Fig. 2. Threshold elevations for downward relative to upwardsweeps are compared for two subjects in different drug conditions.Leftmost pair of bars is the average of ratios for each subject ob-tained immediately before ingestion of the drug. Crosshatched barsrepresent subject JN and diagonal hatching, subject MK. JN's
threshold ratio in the CPZ condition was 1.08.
2.0
Tn
h0
d
Rat
0
Down Sweeps
Fig. 3. Threshold elevations for downward relative to upwardsweeps are shown for seven seizure patients. The average thresholdratios for the patient group is significantly lower than the average for
the normal group.
This difference in adaptation was not due to elevatedupward thresholds in the seizure patients, since thepatient's upward thresholds (0.86 ± 0.38% contrast)were equivalent to the normal's (0.78 i 0.21% contrast;Student's t = 0.419, df = 11, p > 0.05).
IV. Discussion
Contrast thresholds were measured in man by ob-serving the VEP in real time while changing stimuluscontrast. When the stimulus contrast was sweptdownward from a suprathreshold value, the VEPthreshold was elevated relative to when the stimuluswas swept upward from below threshold. Previousanalysis of the instrumentation and methodology hasshown that these shifts do not have a technical origin.13In fact, any delays caused by the time constant (T = 3 s)
of the lock-in amplifier would cause the threshold on adownward contrast sweep to be decreased, not elevat-ed as was observed in these experiments. Therefore,upward vs downward sweep threshold differences ob-tained with the swept VEP are biological in origin.Since the VEP threshold elevations are spatial fre-quency and orientation selective and can be trans-ferred interocularly,16 they are probably of corticalorigin. Additionally, the magnitude of these VEP ef-fects is comparable in magnitude to adaptation effectsobserved at the cellular level in cats.56
These findings pose practical problems for visualassessment with the evoked potential. Thresholdsinferred from computer averaged VEPs will be elevat-ed due to adaptation caused by the repeated suprath-reshold stimulation. Indeed, when special methodsare employed to resolve individual sweeps of an aver-aged potential, a decreased in amplitude is observedover the course of the averaging session.' 9 The sweptstimulus method of estimating VEP thresholds over-comes the problem of amplitude variation by extrapo-lating stimulus response slopes to a 0-V criterion.Amplitude changes may affect the slope of the func-tion but not the inferred threshold. In addition, veryshort recording epochs are used, and the opportunityfor amplitude changes is minimized. Brief testingsessions are also advantageous in view of recent psy-chophysical research, which has reported long buildupand recovery times for contrast adaptation. 2 0 Ourdata also suggest that when using swept VEP tech-niques, assessment should always be performed withthe stimulus beginning below threshold and increasingin strength.
The amount of VEP contrast threshold elevationreported for downward sweeps in the current study issomewhat greater than that generated by psychophys-ical adaptation paradigms (ranging from 0.35 to 0.6 logunits).8,21-23 The primary procedural difference be-tween these studies and ours is that there is no delaybetween adaptation and threshold measurement in theswept VEP. On downward sweeps, a suprathresholdstimulus is present and producing adaptation until theinstant of threshold determination. Perhaps, even ashort delay between adaptation and measurement pro-duces changes in the strength of the adaptation effect(see Fig. 1, preadapted thresholds, and Martin 2 4 ).Nelson et al.'3 have also shown that the amount ofthreshold elevation on downward sweeps is related tothe total range over which the contrast is swept.Therefore, a combination of both exposure time andcontrast range may be responsible for the observeddifferences.
The VEP adaptation technique can objectively mea-sure changes in the dopaminergic system. Adaptationincreased when a dopaminergic agonist was ingested,and conversely adaptation decreased with a dopamin-ergic antagonist. Recently, DeBruyn and Bonds25
have reported that contrast adaptation in the cat visu-al cortex is not mediated by GABA, and they suggestthat dopaminergic influences may play a role. This issupported by the experiments of Harris et al.
2 6 These
authors have shown that chlorpromazine decreasesmotion aftereffect by 30% and the tilt aftereffect by44%. However, unlike a previous report of loweredpsychophysically measured contrast thresholds withL-dopa administration,27 our findings do not show achange in contrast thresholds for unadapted upwardsweeps as a function of this drug. One possible expla-nation for this discrepancy, aside from the obviousdifferences in threshold measurement techniques, isthat Domenici et al.
2 7 used stationary gratings.The marked loss of adaptation in seizure patients
suggests a defect in cortical inhibitory interaction inepilepsy. Similar explanations for seizure activityhave been presented by a number of authors. 7"18 An-other possible explanation is that the loss of the VEPmeasured adaptation index might be caused by themedications on which these seizure patients weremaintained. Although the patient's unadapted (up-ward) thresholds were not significantly different fromthe normals, these drugs might have some selectiveeffects on adaptation per se. We are currently explor-ing the changes which these drugs might have on adap-tation in normal subjects. Likewise, our sample ofseizure patient is restricted and nonhomogeneous hav-ing a variety of etiologies. Although all the seizurepatients in the present study had similar findings onthe VEP adaptation measure, a large number of pa-tients should be examined to determine if the variousclassifications of this disorder show similar results.
This work was supported by a grant to the RetinaClinic of New York University Medical Center by RPFoundation Fighting Blindness. The authors wish tothank Karen Holopigian and Vivienne Greenstein fortheir helpful comments on earlier versions of thismanuscript.
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Chris Giranda and Martin Squicciarini of the Naval Air Development Center at the 1987 OSA Annual Meeting in Rochester.Photo: F. S. Harris, Jr.
