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Human oculomotor function: Reliability and diurnal variation
Human Oculomotor Function: Reliability and Diurnal Variation Peter Roy-Byrne, Allen Radant, Dane Wingerson, and Deborah S. Cowley
To provide information on test-retest reliabilityJor seven oculomotor paradigms currently used in studies of schi=ophrenia and other neuropsychiatric conditions, we tested eight controls at four weekly inten'als, twice in the morning 18-10 aM) and re,ice in the afternoon (3-5 PM). Intraclass correlation coefficients were signi[icant (p < .05) for both AM and PM pairs of measures as well as for mean aM and PM pairs Jor closed-loop pursuit gain, open-loop pursuit gain (using velocio, as the measure), saccadic frequency during pursuit and fixation, visually and nonvisuallv guided saccadic latency and veloci~', antisaccadic latency, and premature reflexive saccades during the memoo,-guided saccade task. Acceleration as a measure of open-loop gain (for slower targets) and accuracy of saccades to a moving target were only reliable at PM testing time. Nonvisually guided saccadic accuracy and inappropriate reflexive saccades during the antisaccade task were not reliable, possibly due to the narrow range of values for these measures. Except Jor approximately 10% fewer saccades during pursuit and fixation in the morning, there were no consistent diurnal differences. These findings suggest that, in a small sample of subjects, most measures of oculomotorfunction are stable across time and may reflect underlying neurophysiologic traits. Key Words: Reliability, diurnal variation, oculomotor, saccade, pursuit
Introduction Testing ofoculomotor function has three major applications in clinical psychiatric research. The most widespread and promising application is based on the well-replicated finding of abnormal pursuit tracking in a proportion of patients with schizophrenia and schizophrenia spectrum conditions, as well as in their first-degree relatives (Levy et al 1993). Recent reports have emphasized the use of this abnormality as a physiologic marker for genetic linkage studies (Clementz et al 1992; lacono et al 1992). Abnormalities of oculomotor function also provide a way of identifying subFrom the Department of Psychiatry and Behavioral Sciences, University of Washing ton and Harborview Medical Center, Seattle, WA. Address reprint requests to Peter Roy-Byrne. M.D.. Chief ~1 Psi~chiatry, Harbor~ ie~ Medical Center, ZA- 15, Seattle, WA 9811)4 Received December 14, 1993: revised July 22, 1994.
© 1995 Society of Bit~h)gica[ Psychiatry
fie central nervous system (CNS) dysfunction in neuropsychiatric conditions besides schizophrenia (Sweeney et al 1992; Merrill et al 1991). The use of multiple oculomotor tests may help clarify the neurophysiologic underpinnings of different disorders because of the different collection of neuroanatomic substrates mediating various oculomotor tasks (Leigh and Zee 1991). Finally, oculomotor function can be used as a pharmacodynamic measure in studies of the clinical effects of psychotropic medication (Tedeschi et al 1989: Roy-Byrne et al 1993; Glue et a11991). Because of the slow progression from qualitative to quantitative analysis of oculomotor function in clinical psychiatric studies (Clementz and Sweeney 1990), the reliability of newer analytic methods that allow more precise characterization of ocular motility and identification of specific defects contributing to "abnormal" eye movements has not 11006-3223/95/$09.50 SSDI 0006 3223194~00225-R
H u m a n O c u l o m o t o r Function
been investigated extensively. The majority of studies that have examined reliability (Shagass et al 1974; Iacono et al 1979; Iacono and Lykken 1981; Siever et al 1986; Smeraldi et al 1987; Campion et al 1992; Van den Bosch and Rozendaal 1988; Versino et al 1993) have focused on the single paradigm of smooth pursuit tracking. All found acceptable retest reliability from a week to a month later, One study in monozygotic twins (Iacono and Lykken 1979) showed good reliability 2 years later. All but two (Campion et al 1992; Versino et al 1993) of these studies have used qualitative or global quantitative measures, and all but two (Iacono and Lykken 1979; Versino et al 1993) have reported reliability using Pearson' s correlation rather than the more appropriate intraclass correlation coefficient (Bartko 1991). Three studies have reported reliability for saccadic characteristics, such as latency, velocity, and accuracy (Griffiths et al 1984; Versino et al 1993; Wilson et al 1993), although only one employed intraclass correlations (Versino et al 1993). No study has reported reliability for more specialized paradigms, such as saccades made to remembered or moving targets, open-loop smooth pursuit, fixation, or antisaccade tasks. In this study, we sought to provide information on test-retest reliability in normal control subjects for seven oculomotor paradigms being used in our laboratory in studies of schizophrenia and other neuropsychiatric conditions such as human immunovirus (HIV) infection.
Materials and Methods
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Waltham, MA), which has a precision of -+ 0.25 ° and a time constant of 4 milliseconds. Sensors were mounted on a rigid forehead support and bite bar attached to a solid table. Visual targets were displayed in a darkened room on a computer screen placed 38 cm from the sensors. The target was a small, bright square that subtended a visual angle of less than 0.25 ° . Data were acquired on line with an IBMcompatible computer and customized interface. Eye position data was digitized at 500 Hz using a 12 bit analogue to digital converter. Calibration was achieved by asking the subject to fixate targets at 0 ° and 15 ° left and fight of center before each individual task. Recalibration after each task minimized error due to head movement.
Procedure Subjects were tested four times at approximately weekly to bimonthly intervals, twice in the morning (8-10 AM) and twice in the afternoon (3-5 PM), in random order to assess possible diurnal variation in either reliability or performance. All subjects performed a series of 12 eye movement tasks in fixed order. Each task required 60-90 seconds with a 2-3-minute rest period between tasks. Tasks were carefully explained to subjects, but there was no practice prior to data acquisition. This study reports on the first seven eye movement tasks, which represent those tasks that have been utilized more often in clinical psychiatric and neuropsychiatric studies. Specific description of these paradigms follows, with each paradigm listed in the order that it was performed.
Subjects Medically healthy subjects between the ages of 18 and 50 were recruited by advertisement and word of mouth. Elderly subjects were not included, because oculomotor performance declines with age. All subjects were free of current and lifetime psychiatric illness according to the structured clinical interview for DSM-III-R (SCID; APA 1987). There were four males and four females ranging in age from 2243. No subject had any current medical illness, nor had any subject received any medication in the last month. No subject had any prior history of drug or alcohol abuse according to the SCID interview, and no subject was a smoker. Six of eight subjects were regular coffee drinkers (1,2,2,2,5, and 8 cups daily) and continued normal use. Five of eight subjects were social drinkers (1,1,2,4,10 drinks per week). Testing was performed at least 12 hours after last alcohol intake and 1 hour after last caffeine intake. Recency of caffeine intake varied for all seven subjects on at least two of the four testing days.
Eye Movement Recording Apparatus Horizontal eye movements were recorded using an infrared photoelectric limbus device (Eyetrac model 210, ASL,
FIXATION. Subjects' ability to maintain central fixation for a period of 60 seconds was tested. We recorded both the number of saccadic eye movements away from the central fixation point and the total number of saccades (including those refixation saccades that brought the eye back on the target after either slow drift or saccades away from the target). VISUALLY GUIDED SACCADES. Subjects followed a series of flashing targets that moved every 2 seconds to one of I l equally spaced locations, 3 ° apart. A total of 27 saccades were presented with amplitudes randomly varying between 3 ° and 27 ° . Subjects were instructed to watch the lights and not to try to anticipate where the next target would be. Saccadic latency was recorded as the mean time in msec from target movement to onset of initiation of eye movement, for all saccades. Because saccadic velocity increases in a curvilinear fashion as a function of saccadic amplitude (this relationship is known as the "main sequence"), the observed velocities at various amplitudes were fitted to an exponential equation of the form: Peak Velocity = A+B --'/' (Bahili et al 1975) where x = the saccade amplitude and A,B, C are constants that are determined by the solution to
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this nonlinear regression equation that describes the relation between saccadic velocity and amplitude. In order to include the entire range of saccade amplitudes in determining an individual's velocity value, and to avoid the use of multiple velocity comparisons at different saccadic amplitudes, we used the main sequence equation to calculate peak velocity for a 20 ° saccade. This amplitude was selected because the curvilinear plot of velocity and amplitude gets close to the asymptote at 20 ° . CLOSED-LOOP PURSUIT. The target moved in a trapezoidal pattern. Ramps consisted of constant 10°/see target motion for three seconds followed by 1400 msec of fixation at 15 ° to the left or right. After two practice ramps, data were collected from 14 consecutive ramps (total task duration, 71.8 see). Subjects were instructed to follow the target with their eyes as it moved. Eye movements during periods of fixation, and within 250 msec of the end of each ramp, were removed prior to analysis. After identification of saccades and artifacts based on characteristic velocity and acceleration patterns, remaining pursuit segments were used to compute time-weighted average gain (Friedman et ali 992). Gain averaged over time was calculated for each subject by taking the sum of the product of gain and duration for each segment and dividing by the summed durations of all pursuit segments (Friedman et al ! 992). The frequency of all saccades were recorded, and saccades were further identified as forward saccades, catch-up saccades, intrusive saccades, and square wave jerks, by the following method. Square wave jerks (SWJ) were defined as paired saccades, of roughly the same amplitude, with an intersaccadic interval of ongoing pursuit (gain <0.6) lasting 50-500 msec. Forward saccades were defined as any saccade moving in the direction of target motion (excluding the first saccade of a square wave jerk) regardless of its effect on position error. Catch-up saccades were defined as those forward saccades that significantly decreased position error. Intrusive saccades were defined as those forward saccades that significantly increased position error. Forward saccades that straddled the target (e.g., started l° behind and ended up l ° ahead of the target) were not counted as either catch-up or intrusive. Any saccade that moved in the direction opposite target motion that was not part of a SWJ was considered a back-up saccade. OPEN-LOOP PURSUIT. A rashbass (Rashbass 1961) task was used to measure open-loop pursuit. In this task, the subject focused on a central fixation point for 2 seconds. The target then jumped several degrees to either the right or left of center and then began to move rapidly in the opposite direction so that it crossed the midpoint 100 msec after the initial jump. This enabled the subject to pick up pursuit at the point of initial central fixation. Target speed was either 10 or 20 d/s; speed and direction were varied
pseudorandomly. Two different pseudorandom sequences of 24 step ramps were presented to each subject. Indices of open-loop pursuit were acceleration in the 50 msec surrounding initiation of movement (prior to the point where eye position feedback is possible) (Lisberger et al 1987), along with peak velocity immediately following initial acceleration. MEMORY-GUIDED SACCADES. A paradigm similar to that used for visually guided saccadic eye movements was employed. All targets appeared along a single horizontal dimension with maximal excursion 15 ° to the left and right of center. Subjects were instructed to maintain fixation on the most recent target while noting, but not looking at, a cue light which appeared for 100 msec in a different location in the periphery of their vision. When the target light went off (800 msec after the cue light), subjects were instructed to refocus their gaze where the cue light had been. After 600 msec. the new target light appeared where the cue light had been, and subjects were instructed to correct the location of their fixation and wait for the next cue light which came in 1500 msec. Hence, there was a 3-second interval between different targets. A series of 26 cues was presented, and the velocity (main sequence) and latency were determined for these memory-guided saccades. In addition, the accuracy of memory-guided saccades was recorded by noting the difference between the initial eye position and the final corrected eye position occurring after the light went back on to signal the correct location of the target. Since only a single, horizontal location was possible, accuracy was recorded as "gain," that is, the ratio of "remembered" saccadic amplitude to amplitude of target jump or step. The frequency of saccades made to the initial cue (premature, reflexive saccades) was also recorded. ANTISACCADE TASK. Following two seconds of central fixation, a flashing target appeared in either the right or left peripheral field; the subject was instructed to look in a direction opposite of where this target was located, at approximately the same distance from the central fixation point. After 1 second, the target appeared at the correct location to cue the subject, who then refixated gaze at the central point. The latency of this response was recorded, as well as the number and velocity of both accurate antisaccades and inappropriate reflexive saccades (i.e., those made toward the peripheral target rather than away from it). SACCADE TO MOVING TARGET. A step-ramp task was employed. The patient fixated on a central point until the target jumped 3 °, 6 °, or 9 ° pseudorandomly to the right or left of center and then continued to move at a speed of 10°/second. The latency and accuracy of the initial saccade made to "catch" the target was calculated, as well as the initial pursuit velocity in the first 50 msec after
H u m a n O c u i o m o t o r Function
pursuit had begun. This initial pursuit velocity is an approximate measure of "open-loop" pursuit, though it is contaminated by the characteristics of the preceding saccade.
Data Analysis The data were analyzed with a custom-computerized, pattern-recognition software program. The software identifies saccadic and pursuit segments and removes artifactual segments caused by eyeblinks and head movements. This program has been described in more detail previously (Radant and Hommer 1992). Reliability was assessed by computing intraclass correlation coefficients (ICCs) (Bartko 1991) for morning and afternoon pairs or measures. In addition, AM and PM pairs of measures were averaged to yield single values, and intraclass correlation coefficients were computed to assess diurnal variations. Mean AM and mean PM pairs of measures were also compared by paired t tests to determine whether there was any consistent difference according to time of day.
Results Table 1 displays morning and afternoon means and standard deviations, as well as ICCs for all measures. ICCs were significant for both AM and PM pairs of measures as well as for mean AM and PM pairs for closed-loop pursuit gain, saccadic frequency of all types during both pursuit and fixation, visually and nonvisually guided saccadic latency and velocity, antisaccadic latency, reflexive (inappropriate) saccades during the memory-guided saccadic task, and open-loop gain measured as both velocity and acceleration (except for acceleration for slower target speeds, which was not significant for AM pairs of measures). The latency of saccades to a moving target for both AM and PM pairs of measures and the accuracy of these saccades for PM but not AM pairs of measures demonstrated low, and nonsignificant, test-retest reliability. Nonvisually guided saccadic accuracy and reflexive saccades during the antisaccade task also demonstrated low and nonsignificant test-retest reliability. Performance in the morning and afternoon was not significantly different, except for subjects having fewer (p < .05) saccades during pursuit and fixation in the morning.
Discussion These findings suggest that oculomotor function is stable across both morning and afternoon measurement times for a wide range of testing paradigms in medically and psychiatrically healthy subjects. This stability occurred in the face of a limited range of values for many paradigms, the possibility of practice effects, and the absence of control for usual
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caffeine intake which resulted in several subjects being tested on some occasions within 1-2 hours of caffeine intake and on other occasions within 6 hours of such intake. The stability of gain and saccadic frequency found in this study in normals is similar to that found by Campion et al (1992) in schizophrenic patients, although he only reported Pearson correlations. The few unreliable measures can be explained by a variety of factors. The number of reflexive (inappropriate) saccades made by our subjects in the antisaccade task was small (range 0°2) and may have limited our ability to assess reliability. In contrast, the range of premature reflexive saccades made during the memory-guided saccade task was larger (range 0-10), and this measure showed significant reliability. The reliability for accuracy of memory-guided saccades was poor, despite a reasonable range (0.86--1.0) of gain values. This may be due to the rapidity of this task, which presents new stimuli every 3 seconds and randomly varies the location of the new target. A more simplified task is being developed currently and may demonstrate better reliability. Two measures curiously demonstrated poor reliability only in the morning. Although initial pursuit velocity appeared to be a stable measure of open-loop gain, acceleration was not reliable for morning pairs of measures for the slowest (10°/sec) target speed. Similarly, the reliability for accuracy of saccades made to a target was poor for morning but good for afternoon measurements. The reason for the diurnal difference in reliability for these measures is not clear. It is possible that variability in alertness and ability to concentrate may be greater early in the morning compared with later in the afternoon. For most measures, it did not seem to matter whether patients were tested in the morning or late afternoon. We avoided testing in the early afternoon because of evidence that alertness reaches its lowest point during this time. However, saccadic frequency of all types was about 10% higher in the afternoon. The reason for this isolated finding is unclear, although the small variation is unlikely to be of functional significance. These findings, while reassuring, do not necessarily apply to patient groups (i.e., schizophrenia) with abnormal oculomotor function. Reliability needs to be separately determined for those groups. Nonetheless, these findings imply a basic stability to human oculomotor function and suggest that oculomotor function reflects basic underlying neurophysiologic traits or functions.
The authors acknowledgethe expert technical assistanceof Linda Floyd who managedcomputeranalysesof the oculomotordata.
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Table 1. M o r n i n g a n d A f t e r n o o n M e a s u r e m e n t s o f 7 0 c u i o m o t o r P a r a d i g m s i n E i g h t Healthy Subjects Mean + SD
ICC
AM
PM
AM
PM
AM--PM
Fixation Total saccades/sec Intrusive saccades/sec
.11 ± .t3 .04 ± .05
.14 ± .13" .06 ± .05"
.73b .71"
.87h .71"
.92" .83"
Visually guided saccades Mean latency (msec) 20° velocity (°/sec)
191 + 15 511 ± 55
194 ± 19 517 ± 51
.69° .95h
.61 ° .84"
.75" .94"
.93 ± . 10 1.61 ± .83" 1.26 ± ,58" .68 ± .48" .43 ± . 17 .61 ± .50-
.96" .88 ~ .81 b .87" .76" .83"
.94" .77 b .75" .71" .78" .85"
.97" .91 ~ .93 b .76 h .73" .85 h
36 38 2,8 3.9
.31 .56.82" .82 b
.83 b .74 ~' .96" .95"
.76 ~' .83" ,93" .96"
Closed-loop pursuit G a i n (eye speed/target speed) Total saccades/sec F o r w a r d saccades/sec Intrusive saccades/sec C a t c h - u p saccades/sec Square w a v e j e r k s / s e c
.93 1.43 I. 12 .60 .39 .41
+-. 10 ± .87 -+ .54 -+ .47 ± . 10 ± .40
O p e n - l o o p pursuit Initial acceleration ( 10 °/sec) Initial acceleration (20 °/sec) Initial velocity ( l0 °/secl Initial velocity (20 °/sec)
164 169 8.7 9.2
+- 26 + 36 ± 2.4 ± 3.5
157 165 8.1 9.2
= ± ± +
M e m o r y - g u i d e d saccades M e a n latency (msec) 20 ° velocity (°/sec) M e a n gain (eye amplitude/ target amplitude) Reflexive saccades (per 26 trials)
206 -+ 32 455 -+ 61
224 ± 34 469 - 54
.7Y' .7 I"
.69" .76 ~'
.67" .86"
.94 ± .05 2.94 ± 1.86
.97 ± .08 4.31 ± 3.20
.40 .86"
.06 .87"
.53 .7 I"
Antisaccade task Mean latency (msec) Reflexive saccades (per 20 trials)
149 + 146 .44 -+ .50
254 ± 96 .81 -+ .53
.78 ~' ,22
.80" -.30
.62" .15
193 ± 23 1.15 ± . 13 7.83 ± 3.3
202 ± 36 1.12 ± . 11 8.74 ± 2.6
.67" .38 .83"
.74 ~' ,69" .70"
.82 p' .82" .78"
Saccade to m o v i n g target Mean latency Mean accuracy (gain) Initial pursuit velocity
ICC = Intraclass correlation coefficient. Paired t tests used to compare AM and PM measures for each subject. "p < .05. ~'p < .01.
References American Psychiatric Association ( 1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington DC: American Psychiatric Association. Bahill AT, Clark MR, Stork L ( 1975): The main sequence: a tool for studying human eye movements. Math Biosci 24:191-204. Bartko JJ ( 1991 ): Measurement and reliability: statistical thinking considerations. Schizophr Bull 17:483-489. Campion D, Thibaut F, Denise P, Courtin P, Pottier M, Levillain D (1992): SPEM impairment in drug-naive schizophrenic patients: evidence for a trait marker. Biol Psychiatry 32:891-902. Clementz BA, Grove WM, Iacono WG, Sweeney JA (1992): Smooth-pursuit eye movement dysfunction and liability for schizophrenia: implications for genetic modeling. J Abnorm Psychol 101:117-129. Clementz BA, Sweeney JA (1990): Is eye movement dysfunction a biological marker for schizophrenia? A methodological review. Psychological Bull 108:77-92.
Friedman L, Jasberger JA, Meltzer HV ( 1992): Effect of typical antipsychotic medications and clozapine on smooth pursuit performance in patients with schizophrenia. Psychiato" Res 41:25-36. Glue P, White E, Wilson S, Ball DM, Nutt DJ (1991): Pharmacology of saccadic eye movements in man. Psychopharmacology 105:368-373. Griffiths AN, Marshall RW, Richens A (1984): Saccadic eye m o v e m e n t analysis as a measure of drug effects on h u m a n psychomotor performance. Br J Clin Pharmacol 18:735825. Iacono WG, Lykken DT ( 1979): Eye tracking and psychopathology: New procedures applied to a sample of normal monozygotic twins. Arch Gen Psychiato' 36:1361-1369. lacono WG, Moreau M, Beiser M, Fleming JAE, Lin TY (1992): Smooth-pursuit eye tracking in first-episode psychotic patients and their relatives. JAbnorm Psychol 101:104-116.
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Iacono WG, Lykken DT ( 1981 ): Two-year retest stability of eye tracking performance and a comparison of electro-oculographic and infrared recording techniques: evidence of EEG in the electro-oculogram. Psychophysiology 18:49-55.
Siever LJ, van Kammen DP, Linnoila M, Alterman I, Hare T, Murphy DL (1986): Smooth pursuit eye movement disorder and its psychobiologic correlates in unmedicated schizophrenics. Biol Psychiatry" 21 : 1167-1174.
Leigh RJ, Zee DS ( 1991 ): The Neurology of Eye Movements, 2nd ed. Philadelphia: F.A. Davis Company.
Smeraldi E, Gambini O, Beilodi L, et al (1987): Combined measure of smooth pursuit eye movements and ventricle-brain ratio in schizophrenic disorders. Psychiat~' Res 21:293-301.
Levy DL, Holzman PS, Matthysse S, Mendell NR (1993): Eye tracking dysfunction and schizophrenia: a critical perspective. Schizophr Bull 19:461-505. Lisberger SG, Morris EJ, Tychsen L: Visual motion processing and sensory motor integration for smooth pursuit eye movements. Annu Rev Neurosci 10:97-129. Merrill PT, Paige GD, Abrams RA, Jacoby RG, Clifford DB (1991): Ocular motor abnormalities in human immunodeficiency virus infection. Ann Neuro130:130-138. Radant A, Hommer DW (1992): A quantitative analysis of saccades and smooth pursuit during visual pursuit tracking: A comparison of schizophrenics with normals and substance abusing controls. Schizophr Res 6: 225-235. Rashbass C ( 1961 ): The relationship between saccadic and smooth tracking eye movements. J Phvsiol 159:326-338. Roy-Byrne PP, Cowley DS, Radant A, Hommer D, Greenblatt DJ (1993): Benzodiazepine pharmacodynamics: utility of eye movement measures. Psychopharmacology 110:85-91. Shagass C, Amadeo M, Overton DA ( 1974): Eye-tracking performance in psychiatric patients. Biolog Psychiato' 9:245-260.
Sweeney JA, Palumbo DR, Halper JP, Shear MK (1992): Pursuit eye movement dysfunction in obsessive-compulsive disorder. Psychiato' Res 42:1-11.19. Tedeschi G, Casucci G, Allocca S, et al ( 1989): Computer analysis of saccadic eye movements: assessment of two different carbamazepine formulations. Eur J Clin Pharmaco137 :513-516. Tien AY, Pearlson GD, Machlin SR, Bylsma FW, Hoehn-Saric R ( 1992): Oculomotor performance in obsessive-compulsive disorder. Am J Psychiato' 149:641-646. Van den Bosch RJ, Rozendaal N (1988): Subjective cognitive dysfunction, eye tracking, and slow brain potentials in schizophrenic and schizoaffective patients. Biol Psychiatry 24:741746. Versino M, Castelnovo C, Bergameshi R, et al (1993): Quantitative evaluation of saccadic and smooth pursuit eye movements: ls it reliable? Invest Ophthalmol Vis Sci 34:1702-1709. Wilson SJ, Gene P, Ball D, Nuh DJ (1993): Saccadic eye movement parameters in normal subjects. Electroencephalogr Clin Neurophysio186:69-74.
To provide information on test-retest reliabilityJor seven oculomotor paradigms currently used in studies of schi=ophrenia and other neuropsychiatric conditions, we tested eight controls at four weekly inten'als, twice in the morning 18-10 aM) and re,ice in the afternoon (3-5 PM). Intraclass correlation coefficients were signi[icant (p < .05) for both AM and PM pairs of measures as well as for mean aM and PM pairs Jor closed-loop pursuit gain, open-loop pursuit gain (using velocio, as the measure), saccadic frequency during pursuit and fixation, visually and nonvisuallv guided saccadic latency and veloci~', antisaccadic latency, and premature reflexive saccades during the memoo,-guided saccade task. Acceleration as a measure of open-loop gain (for slower targets) and accuracy of saccades to a moving target were only reliable at PM testing time. Nonvisually guided saccadic accuracy and inappropriate reflexive saccades during the antisaccade task were not reliable, possibly due to the narrow range of values for these measures. Except Jor approximately 10% fewer saccades during pursuit and fixation in the morning, there were no consistent diurnal differences. These findings suggest that, in a small sample of subjects, most measures of oculomotorfunction are stable across time and may reflect underlying neurophysiologic traits. Key Words: Reliability, diurnal variation, oculomotor, saccade, pursuit
Introduction Testing ofoculomotor function has three major applications in clinical psychiatric research. The most widespread and promising application is based on the well-replicated finding of abnormal pursuit tracking in a proportion of patients with schizophrenia and schizophrenia spectrum conditions, as well as in their first-degree relatives (Levy et al 1993). Recent reports have emphasized the use of this abnormality as a physiologic marker for genetic linkage studies (Clementz et al 1992; lacono et al 1992). Abnormalities of oculomotor function also provide a way of identifying subFrom the Department of Psychiatry and Behavioral Sciences, University of Washing ton and Harborview Medical Center, Seattle, WA. Address reprint requests to Peter Roy-Byrne. M.D.. Chief ~1 Psi~chiatry, Harbor~ ie~ Medical Center, ZA- 15, Seattle, WA 9811)4 Received December 14, 1993: revised July 22, 1994.
© 1995 Society of Bit~h)gica[ Psychiatry
fie central nervous system (CNS) dysfunction in neuropsychiatric conditions besides schizophrenia (Sweeney et al 1992; Merrill et al 1991). The use of multiple oculomotor tests may help clarify the neurophysiologic underpinnings of different disorders because of the different collection of neuroanatomic substrates mediating various oculomotor tasks (Leigh and Zee 1991). Finally, oculomotor function can be used as a pharmacodynamic measure in studies of the clinical effects of psychotropic medication (Tedeschi et al 1989: Roy-Byrne et al 1993; Glue et a11991). Because of the slow progression from qualitative to quantitative analysis of oculomotor function in clinical psychiatric studies (Clementz and Sweeney 1990), the reliability of newer analytic methods that allow more precise characterization of ocular motility and identification of specific defects contributing to "abnormal" eye movements has not 11006-3223/95/$09.50 SSDI 0006 3223194~00225-R
H u m a n O c u l o m o t o r Function
been investigated extensively. The majority of studies that have examined reliability (Shagass et al 1974; Iacono et al 1979; Iacono and Lykken 1981; Siever et al 1986; Smeraldi et al 1987; Campion et al 1992; Van den Bosch and Rozendaal 1988; Versino et al 1993) have focused on the single paradigm of smooth pursuit tracking. All found acceptable retest reliability from a week to a month later, One study in monozygotic twins (Iacono and Lykken 1979) showed good reliability 2 years later. All but two (Campion et al 1992; Versino et al 1993) of these studies have used qualitative or global quantitative measures, and all but two (Iacono and Lykken 1979; Versino et al 1993) have reported reliability using Pearson' s correlation rather than the more appropriate intraclass correlation coefficient (Bartko 1991). Three studies have reported reliability for saccadic characteristics, such as latency, velocity, and accuracy (Griffiths et al 1984; Versino et al 1993; Wilson et al 1993), although only one employed intraclass correlations (Versino et al 1993). No study has reported reliability for more specialized paradigms, such as saccades made to remembered or moving targets, open-loop smooth pursuit, fixation, or antisaccade tasks. In this study, we sought to provide information on test-retest reliability in normal control subjects for seven oculomotor paradigms being used in our laboratory in studies of schizophrenia and other neuropsychiatric conditions such as human immunovirus (HIV) infection.
Materials and Methods
BIOL PSYCHIATRY 1995:38:92-97
93
Waltham, MA), which has a precision of -+ 0.25 ° and a time constant of 4 milliseconds. Sensors were mounted on a rigid forehead support and bite bar attached to a solid table. Visual targets were displayed in a darkened room on a computer screen placed 38 cm from the sensors. The target was a small, bright square that subtended a visual angle of less than 0.25 ° . Data were acquired on line with an IBMcompatible computer and customized interface. Eye position data was digitized at 500 Hz using a 12 bit analogue to digital converter. Calibration was achieved by asking the subject to fixate targets at 0 ° and 15 ° left and fight of center before each individual task. Recalibration after each task minimized error due to head movement.
Procedure Subjects were tested four times at approximately weekly to bimonthly intervals, twice in the morning (8-10 AM) and twice in the afternoon (3-5 PM), in random order to assess possible diurnal variation in either reliability or performance. All subjects performed a series of 12 eye movement tasks in fixed order. Each task required 60-90 seconds with a 2-3-minute rest period between tasks. Tasks were carefully explained to subjects, but there was no practice prior to data acquisition. This study reports on the first seven eye movement tasks, which represent those tasks that have been utilized more often in clinical psychiatric and neuropsychiatric studies. Specific description of these paradigms follows, with each paradigm listed in the order that it was performed.
Subjects Medically healthy subjects between the ages of 18 and 50 were recruited by advertisement and word of mouth. Elderly subjects were not included, because oculomotor performance declines with age. All subjects were free of current and lifetime psychiatric illness according to the structured clinical interview for DSM-III-R (SCID; APA 1987). There were four males and four females ranging in age from 2243. No subject had any current medical illness, nor had any subject received any medication in the last month. No subject had any prior history of drug or alcohol abuse according to the SCID interview, and no subject was a smoker. Six of eight subjects were regular coffee drinkers (1,2,2,2,5, and 8 cups daily) and continued normal use. Five of eight subjects were social drinkers (1,1,2,4,10 drinks per week). Testing was performed at least 12 hours after last alcohol intake and 1 hour after last caffeine intake. Recency of caffeine intake varied for all seven subjects on at least two of the four testing days.
Eye Movement Recording Apparatus Horizontal eye movements were recorded using an infrared photoelectric limbus device (Eyetrac model 210, ASL,
FIXATION. Subjects' ability to maintain central fixation for a period of 60 seconds was tested. We recorded both the number of saccadic eye movements away from the central fixation point and the total number of saccades (including those refixation saccades that brought the eye back on the target after either slow drift or saccades away from the target). VISUALLY GUIDED SACCADES. Subjects followed a series of flashing targets that moved every 2 seconds to one of I l equally spaced locations, 3 ° apart. A total of 27 saccades were presented with amplitudes randomly varying between 3 ° and 27 ° . Subjects were instructed to watch the lights and not to try to anticipate where the next target would be. Saccadic latency was recorded as the mean time in msec from target movement to onset of initiation of eye movement, for all saccades. Because saccadic velocity increases in a curvilinear fashion as a function of saccadic amplitude (this relationship is known as the "main sequence"), the observed velocities at various amplitudes were fitted to an exponential equation of the form: Peak Velocity = A+B --'/' (Bahili et al 1975) where x = the saccade amplitude and A,B, C are constants that are determined by the solution to
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this nonlinear regression equation that describes the relation between saccadic velocity and amplitude. In order to include the entire range of saccade amplitudes in determining an individual's velocity value, and to avoid the use of multiple velocity comparisons at different saccadic amplitudes, we used the main sequence equation to calculate peak velocity for a 20 ° saccade. This amplitude was selected because the curvilinear plot of velocity and amplitude gets close to the asymptote at 20 ° . CLOSED-LOOP PURSUIT. The target moved in a trapezoidal pattern. Ramps consisted of constant 10°/see target motion for three seconds followed by 1400 msec of fixation at 15 ° to the left or right. After two practice ramps, data were collected from 14 consecutive ramps (total task duration, 71.8 see). Subjects were instructed to follow the target with their eyes as it moved. Eye movements during periods of fixation, and within 250 msec of the end of each ramp, were removed prior to analysis. After identification of saccades and artifacts based on characteristic velocity and acceleration patterns, remaining pursuit segments were used to compute time-weighted average gain (Friedman et ali 992). Gain averaged over time was calculated for each subject by taking the sum of the product of gain and duration for each segment and dividing by the summed durations of all pursuit segments (Friedman et al ! 992). The frequency of all saccades were recorded, and saccades were further identified as forward saccades, catch-up saccades, intrusive saccades, and square wave jerks, by the following method. Square wave jerks (SWJ) were defined as paired saccades, of roughly the same amplitude, with an intersaccadic interval of ongoing pursuit (gain <0.6) lasting 50-500 msec. Forward saccades were defined as any saccade moving in the direction of target motion (excluding the first saccade of a square wave jerk) regardless of its effect on position error. Catch-up saccades were defined as those forward saccades that significantly decreased position error. Intrusive saccades were defined as those forward saccades that significantly increased position error. Forward saccades that straddled the target (e.g., started l° behind and ended up l ° ahead of the target) were not counted as either catch-up or intrusive. Any saccade that moved in the direction opposite target motion that was not part of a SWJ was considered a back-up saccade. OPEN-LOOP PURSUIT. A rashbass (Rashbass 1961) task was used to measure open-loop pursuit. In this task, the subject focused on a central fixation point for 2 seconds. The target then jumped several degrees to either the right or left of center and then began to move rapidly in the opposite direction so that it crossed the midpoint 100 msec after the initial jump. This enabled the subject to pick up pursuit at the point of initial central fixation. Target speed was either 10 or 20 d/s; speed and direction were varied
pseudorandomly. Two different pseudorandom sequences of 24 step ramps were presented to each subject. Indices of open-loop pursuit were acceleration in the 50 msec surrounding initiation of movement (prior to the point where eye position feedback is possible) (Lisberger et al 1987), along with peak velocity immediately following initial acceleration. MEMORY-GUIDED SACCADES. A paradigm similar to that used for visually guided saccadic eye movements was employed. All targets appeared along a single horizontal dimension with maximal excursion 15 ° to the left and right of center. Subjects were instructed to maintain fixation on the most recent target while noting, but not looking at, a cue light which appeared for 100 msec in a different location in the periphery of their vision. When the target light went off (800 msec after the cue light), subjects were instructed to refocus their gaze where the cue light had been. After 600 msec. the new target light appeared where the cue light had been, and subjects were instructed to correct the location of their fixation and wait for the next cue light which came in 1500 msec. Hence, there was a 3-second interval between different targets. A series of 26 cues was presented, and the velocity (main sequence) and latency were determined for these memory-guided saccades. In addition, the accuracy of memory-guided saccades was recorded by noting the difference between the initial eye position and the final corrected eye position occurring after the light went back on to signal the correct location of the target. Since only a single, horizontal location was possible, accuracy was recorded as "gain," that is, the ratio of "remembered" saccadic amplitude to amplitude of target jump or step. The frequency of saccades made to the initial cue (premature, reflexive saccades) was also recorded. ANTISACCADE TASK. Following two seconds of central fixation, a flashing target appeared in either the right or left peripheral field; the subject was instructed to look in a direction opposite of where this target was located, at approximately the same distance from the central fixation point. After 1 second, the target appeared at the correct location to cue the subject, who then refixated gaze at the central point. The latency of this response was recorded, as well as the number and velocity of both accurate antisaccades and inappropriate reflexive saccades (i.e., those made toward the peripheral target rather than away from it). SACCADE TO MOVING TARGET. A step-ramp task was employed. The patient fixated on a central point until the target jumped 3 °, 6 °, or 9 ° pseudorandomly to the right or left of center and then continued to move at a speed of 10°/second. The latency and accuracy of the initial saccade made to "catch" the target was calculated, as well as the initial pursuit velocity in the first 50 msec after
H u m a n O c u i o m o t o r Function
pursuit had begun. This initial pursuit velocity is an approximate measure of "open-loop" pursuit, though it is contaminated by the characteristics of the preceding saccade.
Data Analysis The data were analyzed with a custom-computerized, pattern-recognition software program. The software identifies saccadic and pursuit segments and removes artifactual segments caused by eyeblinks and head movements. This program has been described in more detail previously (Radant and Hommer 1992). Reliability was assessed by computing intraclass correlation coefficients (ICCs) (Bartko 1991) for morning and afternoon pairs or measures. In addition, AM and PM pairs of measures were averaged to yield single values, and intraclass correlation coefficients were computed to assess diurnal variations. Mean AM and mean PM pairs of measures were also compared by paired t tests to determine whether there was any consistent difference according to time of day.
Results Table 1 displays morning and afternoon means and standard deviations, as well as ICCs for all measures. ICCs were significant for both AM and PM pairs of measures as well as for mean AM and PM pairs for closed-loop pursuit gain, saccadic frequency of all types during both pursuit and fixation, visually and nonvisually guided saccadic latency and velocity, antisaccadic latency, reflexive (inappropriate) saccades during the memory-guided saccadic task, and open-loop gain measured as both velocity and acceleration (except for acceleration for slower target speeds, which was not significant for AM pairs of measures). The latency of saccades to a moving target for both AM and PM pairs of measures and the accuracy of these saccades for PM but not AM pairs of measures demonstrated low, and nonsignificant, test-retest reliability. Nonvisually guided saccadic accuracy and reflexive saccades during the antisaccade task also demonstrated low and nonsignificant test-retest reliability. Performance in the morning and afternoon was not significantly different, except for subjects having fewer (p < .05) saccades during pursuit and fixation in the morning.
Discussion These findings suggest that oculomotor function is stable across both morning and afternoon measurement times for a wide range of testing paradigms in medically and psychiatrically healthy subjects. This stability occurred in the face of a limited range of values for many paradigms, the possibility of practice effects, and the absence of control for usual
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caffeine intake which resulted in several subjects being tested on some occasions within 1-2 hours of caffeine intake and on other occasions within 6 hours of such intake. The stability of gain and saccadic frequency found in this study in normals is similar to that found by Campion et al (1992) in schizophrenic patients, although he only reported Pearson correlations. The few unreliable measures can be explained by a variety of factors. The number of reflexive (inappropriate) saccades made by our subjects in the antisaccade task was small (range 0°2) and may have limited our ability to assess reliability. In contrast, the range of premature reflexive saccades made during the memory-guided saccade task was larger (range 0-10), and this measure showed significant reliability. The reliability for accuracy of memory-guided saccades was poor, despite a reasonable range (0.86--1.0) of gain values. This may be due to the rapidity of this task, which presents new stimuli every 3 seconds and randomly varies the location of the new target. A more simplified task is being developed currently and may demonstrate better reliability. Two measures curiously demonstrated poor reliability only in the morning. Although initial pursuit velocity appeared to be a stable measure of open-loop gain, acceleration was not reliable for morning pairs of measures for the slowest (10°/sec) target speed. Similarly, the reliability for accuracy of saccades made to a target was poor for morning but good for afternoon measurements. The reason for the diurnal difference in reliability for these measures is not clear. It is possible that variability in alertness and ability to concentrate may be greater early in the morning compared with later in the afternoon. For most measures, it did not seem to matter whether patients were tested in the morning or late afternoon. We avoided testing in the early afternoon because of evidence that alertness reaches its lowest point during this time. However, saccadic frequency of all types was about 10% higher in the afternoon. The reason for this isolated finding is unclear, although the small variation is unlikely to be of functional significance. These findings, while reassuring, do not necessarily apply to patient groups (i.e., schizophrenia) with abnormal oculomotor function. Reliability needs to be separately determined for those groups. Nonetheless, these findings imply a basic stability to human oculomotor function and suggest that oculomotor function reflects basic underlying neurophysiologic traits or functions.
The authors acknowledgethe expert technical assistanceof Linda Floyd who managedcomputeranalysesof the oculomotordata.
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Table 1. M o r n i n g a n d A f t e r n o o n M e a s u r e m e n t s o f 7 0 c u i o m o t o r P a r a d i g m s i n E i g h t Healthy Subjects Mean + SD
ICC
AM
PM
AM
PM
AM--PM
Fixation Total saccades/sec Intrusive saccades/sec
.11 ± .t3 .04 ± .05
.14 ± .13" .06 ± .05"
.73b .71"
.87h .71"
.92" .83"
Visually guided saccades Mean latency (msec) 20° velocity (°/sec)
191 + 15 511 ± 55
194 ± 19 517 ± 51
.69° .95h
.61 ° .84"
.75" .94"
.93 ± . 10 1.61 ± .83" 1.26 ± ,58" .68 ± .48" .43 ± . 17 .61 ± .50-
.96" .88 ~ .81 b .87" .76" .83"
.94" .77 b .75" .71" .78" .85"
.97" .91 ~ .93 b .76 h .73" .85 h
36 38 2,8 3.9
.31 .56.82" .82 b
.83 b .74 ~' .96" .95"
.76 ~' .83" ,93" .96"
Closed-loop pursuit G a i n (eye speed/target speed) Total saccades/sec F o r w a r d saccades/sec Intrusive saccades/sec C a t c h - u p saccades/sec Square w a v e j e r k s / s e c
.93 1.43 I. 12 .60 .39 .41
+-. 10 ± .87 -+ .54 -+ .47 ± . 10 ± .40
O p e n - l o o p pursuit Initial acceleration ( 10 °/sec) Initial acceleration (20 °/sec) Initial velocity ( l0 °/secl Initial velocity (20 °/sec)
164 169 8.7 9.2
+- 26 + 36 ± 2.4 ± 3.5
157 165 8.1 9.2
= ± ± +
M e m o r y - g u i d e d saccades M e a n latency (msec) 20 ° velocity (°/sec) M e a n gain (eye amplitude/ target amplitude) Reflexive saccades (per 26 trials)
206 -+ 32 455 -+ 61
224 ± 34 469 - 54
.7Y' .7 I"
.69" .76 ~'
.67" .86"
.94 ± .05 2.94 ± 1.86
.97 ± .08 4.31 ± 3.20
.40 .86"
.06 .87"
.53 .7 I"
Antisaccade task Mean latency (msec) Reflexive saccades (per 20 trials)
149 + 146 .44 -+ .50
254 ± 96 .81 -+ .53
.78 ~' ,22
.80" -.30
.62" .15
193 ± 23 1.15 ± . 13 7.83 ± 3.3
202 ± 36 1.12 ± . 11 8.74 ± 2.6
.67" .38 .83"
.74 ~' ,69" .70"
.82 p' .82" .78"
Saccade to m o v i n g target Mean latency Mean accuracy (gain) Initial pursuit velocity
ICC = Intraclass correlation coefficient. Paired t tests used to compare AM and PM measures for each subject. "p < .05. ~'p < .01.
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