Computer-Electronystagmography: A Useful Tool in Evaluating Influence of Psychopharmacological Drugs on Traffic SafetyJurgen C. A schoff,1 Wolfgang Becker and Dieter Weinert

Reliable tests for measures of alertness, the state of arousal or vigilance, all of which can be used synonymously, have long been of interest in experimental psychology. In modern aviation and space medicine as well as for problems associated with the in­creasing traffic density, changes in vigilance are of major importance because they represent an uncontrolled safety factor. Special psychological tests have been used as an index of moment-to-moment and day-to-day changes in vigilance such as skin resistance, heart rate, fluctuations in respiration, EEG-changes, tapping rates or other simple motor performances, reaction times, tremor and hand-steadiness measures. The EEG is viewed as the most reliable test procedure but computer analysis of electro­encephalograms are still in a developmental state and need extensive and expensive equipment.

We have found that the analysis of saccadic eye movements is useful in assessing the state o f vigilance (1,2). Saccadic eye movements — the flick-like movements of the eyes which occur as gaze is shifted from one point of interest in the visual surround­ings to another — have generally been accepted as invariant for a given subject. The velocity of these saccades is too high for continuous feedback regulation while the eye is actually in motion. The eyes therefore jump with a ballistic type of movement, and most often do not reach exactly the preselected target point. Following this first saccade, a corrective saccade is needed after the error is perceived. From this it is obvious that velocity and duration as well as the error of saccadic eye movements cannot be changed at will. Velocity and duration, and to some extent the error of movement, are entirely dependent upon the magnitude of the eye movement.

Velocity, duration and accuracy of saccadic eye movements can therefore be viewed as relevant criteria for psychomotor performance in man. While these para­meters cannot be changed voluntarily, it has been found by various workers that fatique, extended periods of wakefulness (7), alcohol (4), or tranquilizers (5,6) show striking and reproducible effects on the oculomotor system: the velocity of eye movements decreases (8), duration and saccadic reaction time increase, and eye move­ments are executed less accurately than under normal circumstances.

The influence of psychopharmacological drugs on vigilance and psychomotor performance is of considerable interest, seeing that these drugs are used on a vast scale throughout the population without proper controls. We have chosen two drugs, (1) the1 University of Uim, Department of Neurology, 9 Steinhovelstraj3e, 79 Ulm, West Germany.

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well known tranquilizer diazepam and (2) a new psycho-active drug with a chemical structure and therapeutic properties different from any other psychotropic drug currently in use. The generic name is sulpiride, a chemical derivative of meto- clopramide, with therapeutic effects somewhere between the neuroleptics and thymo- leptics, sulpiride can also be used as a powerful suppressant of vestibular vertigo. It has been claimed that sulpiride, in spite of its neuroleptic and thymoleptic action, does not interact with the patient’s alertness (3). Short and long term experiments were performed with these two drugs, whereby velocity, duration, accuracy and reaction times of saccadic eye movements were recorded, analysing and computed with out PDP-12 laboratory computer.

METHODSTen persons participated in short term tests, and five persons in a long term test. In the short term test saccadic eye movements were always recorded in the late afternoon. Tests were carried out in all ten subjects following a medication of 4 x 100 mg sulpiride started the previous evening. One week later the test was repeated with five persons receiving 5 mg diazepam and with the other five persons receiving 10 mg diazepam. In a previous experiment six persons had received 5 mg diazepam intra­venously. In the long term experiment five subjects were investigated each participat­ing in four experiments. Two experiments were conducted with no drug given. One experiment was undertaken after 3 x 5 mg diazepam a day for one week, the last experiment after a daily administration of 3 x 100 mg sulpiride during one week. The sequence of experimental conditions was randomly varied between the five subjects.

Procedure Used to R ecord E ye M ovem entsEye movements are recorded by means of the bitemporal electrooculogram (EOG). After amplification (dc-amplifier) the signal is fed into a PDP-12 laboratory computer and monitored on an ink-writer. The PDP-12 computer simultaneously controls the experimental sequence and measures the subject’s eye movements retaining all relevant data.

Subjects are seated facing a TV screen with the head fixed. A single light-spot is displayed on the screen as fixation target. The target can appear only in the horizontal plane to the left or to the right of the subject’s primary direction at 0°, 10 , 20 or 30°. On pressing a button the operator causes a jump of the target from one to the next position. The sequence of succeeding positions is determined by a random list stored in the computer memory. By pressing the button the operator calls the next entry from that list which is then converted into an analog voltage which controls the target position. The subjects were instructed to fixate upon the target and to track target jumps as fast and as accurately as possible. Eye movements in this situation are exclusively saccadic in nature as opposed to smooth pursuit movements. In each experiment 512 eye movements are recorded and analysed.

Data AcquisitionFrom each saccadic reaction the following parameters were measured by the PDP-12 computer: 1) latency between target jump and onset of the saccade (reaction time) 2) amplitude of the saccade and 3) maximum velocity of the eye movement.

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The automatic data acquisition of these parameters involved the following steps. The output of the dc-amplifier (amplified EOG) was adjusted approximately to a value of 0.5 volts per 100°, and was subsequently differentiated by an analog com­puter. If the differentiated signal (eye movement velocity) exceeded a critical thres­hold the analog computer would generate an impulse indicating the occurrence of a saccadic movement. The three outputs of the analog device (adjusted EOG signal, velocity signal, and saccade pulse) were sampled by the PDP-12 computer at a rate of 400 Hz. At the occurrence of a saccade pulse the PDP-12 would check the EOG pattern against a set of given time and amplitude criteria which are characteristic for saccadic eye movements. If these saccadic criteria were met, the computer would store the amplitude of the target jump and the 3 parameters described above. Exact calibra­tion was performed by recording eight target jumps of 40° amplitude.Statistical Treatm ent o f Com puter DataStatistical treatment was carried out for the following parameters retrieved from the PDP-12 computer: 1) amplitudes (average and standard deviation (SD)) of the eye movements as a function of the target amplitude, 2) saccadic reaction times (average and SD) pooled for all saccades, and 3) maximum velocity (average and SD) of the saccadic eye movements as a function of their amplitude. Amplitudes were sorted into ten degree bins. Mean values obtained in different experimental conditions were then tested for the null-hypothesis by means of the Wilcoxon-test for ranged matched pairs. The level of statistical significance was fixed at 10%. Ratios of variances were com­pared by means of the F-distribution, the level of significance being 5%. The statistical procedures did not take full advantage of the capabilities of our PDP-12 computer. However, in these pilot experiments we refrained from carrying out a complete program of multiple factor variance analysis; instead we stressed the qualitative aspects. Further experiments will have to be based on a rigorous variance analysis.RESULTSSaccadic Velocity and DurationAn example of a computer plot of maximum angular velocity is shown in Figure 1, and of saccadic duration in Figure 2. Each dot represents a single eye movement. No significant difference was found between the short term and long term experiments. Diazepam always produced a significant reduction of saccadic velocity as well as an increased saccadic duration and standard deviation. On the other hand, only a slight change could be produced with sulpiride.

Mean values for maximum velocities are shown in Figures 3 and 4. In Figure 3 an example is given for a single subject (one of the authors), in which diazepam produced marked reduction in saccadic velocity while sulpiride matched even the faster velocities of the two tests under normal conditions. Slowing of angular velocity of eye movements under the influence of psychopharmacological drugs is a dose-dependent effect, as seen in Figure 4. Mean reduction of angular velocity amounts to 2.5% under sulpiride medication, and, depending upon the dose, to between 11 and 21% following a diazepam medication. All eye movements can be plotted and analysed, therefore, either for a single person or for a group, for short term effects or for long term effects. No difference has been found between measurements of saccadic velocity (Figure 1) or of saccadic duration (Figure 2). Either one of the two parameters can be used for retrieving the information described above.

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Figure 1 Computer p lo t o f saccadic eye movements: maximum angular velocity against magnitude o f eye movements. Each d o t represents a single saccade. On the right: slowing and deterioration o f eye movements following diazepam medication.

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Figure 3 Maximum angular velocity o f saccadic eye movements in subject A. Each line repre­sents 500 eye movements. No change occurs after sulpiride medication while diazepam reduces significantly angular velocity.

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Figure 4 Maximum angular velocity o f saccadic eye movements following therapeutic doses o f sulpiride and o f diazepam.

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Accuracy o f Eye M ovem entsNormally a voluntary saccadic eye movement is executed some degrees short of the preselected target point, a phenomenon called hypometria. Around 100 msec after this first saccade a corrective saccade must therefore follow. The amount of hypometria can be taken as an objective measurement of psychomotor performance. In Figure 5 and 6 “normal I” and “normal II” correspond to the two tests carried out under normal conditions while “ Sulpiride” and “Diazepam” represent mean values of the five subjects who participated in the long term experiment. In Figure 5 the error has been plotted against the target angle. As can be seen, psychomotor performance under the influence of sulpiride either matches the performance during the better of the two normal tests (Figure 5), or is even enhanced with regard to the variance in this error (Figure 6). Diazepam, in contrast, causes a marked hypometria; the standard deviation is three times higher than under normal conditions. The two plots give useful informa­tion about differences between normal tests as well as about changes in oculomotor performance under the influence of either sulpiride or diazepam.

Figure 5 Analysis o f accuracy o f human eye movements indicating psychom otor performance.Following medication o f sulpiride the oculom otor behavior matches the performance o f the better o f tw o normal tests. Diazepam causes marked hypometria.

Saccadic Reaction TimeAll subjects were asked to follow and fixate the computer-switched target point as rapidly as possible. The time difference between the computer-triggered jump of the light-spot and the start of saccadic eye movement is termed the saccadic reaction time. This reaction time is independent of saccadic amplitude, with only an insignificant increase towards larger angles.

Mean values in the long term experiment are shown in Figure 7. There is clear indication that diazepam impairs oculomotor function while sulpiride does not. An example of excessive changes in reaction times in a single person (subject F) is given in Figure 8: a weekly medication of diazepam increases reaction times significantly, the longest reaction times being twice the normal values.

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Standard deviation in the error o f the first large saccade as an i in oculom otor performance.

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Reaction times o f saccadic eye movements. Pooled data from 5 subjects. From the tw o tests under normal conditions the faster reaction times from each person have been pooled and marked as "normal fa s t”, the slower test is called “normal slow ”. Each bar represents 2500 reaction times.

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NORMAL TEST SULPIRIDE D IAZEPAM300 mg /d for 1 Week 15 mg / d for 1 Week

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Figure 8 Saccadic reaction times o f subject F.

DISCUSSIONFor all data, statistical analysis was performed according to the procedure described above. It is not the purpose of this paper to show statistical differences between the effects for different psychopharmacological drugs, nor between these substances and the normal state. It is, however, of interest that the statistical analysis has proven that the maximum velocity and the accuracy of human saccadic eye movements showed consistent and significant differences between the two substances tested, while reaction times were less useful. In summary, sulpiride, both in the short as well as in the long term experiments, produced slight but not statistically significant reduction of maximal angular velocity of saccadic eye movements. Diazepam, as compared to sulpiride and non-drug conditions, significantly reduced eye movement velocity in the short as well as in the long term experiments. Marked differences were detected between different subjects.

The most useful analysis turned out to be the measurement of accuracy of eye movements. In all subjects, accuracy decreased under the influence of diazepam, whereas sulpiride led to an equal or better performance than that seen under normal conditions. The results, therefore, support the findings of (3) who reported increased attention and better psychomotor performance following sulpiride.

We strongly suggest that angular velocity, accuracy and saccadic reation times of eye movements, measured and analysed as described, should be used as test procedures in evaluating psychopharmacological or other drugs with respect to traffic safety. These tests are reproducible, objective, and the results cannot be voluntarily in­fluenced. Data sampling is easy, and the duration of one test (500 eye movements) amounts to less than two hours. If normal tests have been performed previously, at the end of each experiment, changes in psychomotor performance and vigilance produced by any given drug, can be taken from the computer in absolute or percentage values.

Maximum angular velocity indicates mainly changes in vigilance, while the error of the first large saccade with respect to the preselected target point is especially representative for changes in psychomotor performance. These two parameters

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exhibited consistent changes in all subjects tested under various conditions and may therefore be used in evaluating group reactions. Measurements of saccadic reaction times are less useful for group reactions but may be used as a sensitive indicator for individual changes in vigilance.

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