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Saccadic intrusions into smooth pursuit in patients with schizophrenia or affective disorder and normal controls
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Saccadic Intrusions into Smooth Pursuit in Patients with Schizophrenia or Affective Disorder and Normal Controls Lee Friedman, Larry A. Abel, John A. Jesberger, Amjad Malki, and Herbert Y Meltzer
Two types of saccadic intrusions into smooth pursuit eye tracking, anticipatory saccades (AS), and square wave jerks (SWJ), were measured in 23 patients with schizophrenia, 16 patients with affective disorder, and 21 normal controls. Constant velocity (5 ° and 20°/sec) predictable targets were employed. High resolution infrared oculography was employed to record eye movements. Although most subjects had at least one SWJ, there were no significant group differences, and the highest individual rates of SWJ were seen in the normal control group. On the other hand, AS were never seen in normals, but were present in 25%-44% of patients with either schizophrenia or affective disorder. Both patient groups had significantly more AS than controls, but the two patient groups were not significantly different.
Introduction In a recent publication in this journal, we reported on smooth pursuit performance in patients with schizophrenia or affective disorder and normal controls (Abel et al 1991). In that paper, measures related to the pursuit system, that is, gain (eye velocity/target velocity) and rate of corrective catch-up saccades (CUS), were presented. In the present report, measures of saccadic intrusion, that is, square wave jerk (SWJ) rate, and anticipatory saccade (AS) rate, are reported. An SWJ can occur during either pursuit or fixation and consists of a pair of small saccades, in opposite directions, separated by approximately 200 msec (Daroff 1977; Sharpe et al 1982). When an SWJ intrudes into pursuit, the direction of the initial saccade is independent of target motion, and during the SWJ pursuit continues virtually uninterrupted (Jesberger et al 1989 unpublished observations). Several studies of the incidence of SWJ in schizophrenia have employed small samples and reported only general observations, rather than statistical tests of measured rates between groups. For example Levin et al (1982) reported SWJ (termed "saccadic intrusions," see Weinreb 1983) in three of From the Laboratory of Biological Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, and Cleveland Veterans AdministrationHospital (LF, JAJ, HYM), Cleveland, Ohio; Department of Ophthalmology, Indiana University (LAA) Indianapolis, Indiana; and Department of Biomedical Engineering, University of Akron (AM); Akron, Ohio. Address reprint requests to Lee Friedman, PhD., Departmentof Psychiatry, Case Western Reserve University and University Hospitals of Cleveland, Hanna Pavilion, Rm B-68, 2040 Abington Road, Cleveland, OH 44106. Received August 2, 1991; revised March 5, 1992. © 1992 Sociietyof Biological Psychiatry
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six patients with schizophrenia, although in a subsequent study Levin et al (1988) reported no SWJ in any of five patients included in their report. Moser et al (1990) also reported no SWJ in 10 patients with schizophrenia. However, Clementz et al (1990) did statistically test measured rates of SWJ. These authors reported that SWJ rates did not differ in patients with schizophrenia compared to nonschizophrenic groups, which included normal controls and first degree relatives of patients with schizophrenia. An AS is a large saccade that takes the eyes ahead of target (Whicker et al 1985). These are followed by a period of fixation, which ends either when the target catches up to the eye, or when another saccade brings the eye back to target. AS (misidentified as macro square wave jerks) have been reported before in two of 19 (11%) "psychotic" patients (Andersson 1984) although the diagnostic criteria for this patient group was not detailed. Similarly, Moser et al (1990) reported finding only "a few anticipatory saccades" in 10 schizophrenic patients. Two prior studies have statistically compared AS rates in patients with schizophrenia to control groups (Clementz et al 1990; Grove et al 1991). Clementz et al (1990) found no evidence for increased rates of AS compared to nonschizophrenic groups including normal controls and first-degree relatives of patients with schizophrenia. These authors did report that the relatives of patients with schizophrenia had higher rates of AS than normal controls, which is consistent with the earlier report of Whicker et al (1985) who reported AS ~li 50% to 88% of parents of patients with schizophrenia. Grove et al (1991) found ao differences between patients with schizophrenia and controls, but there is a reason to question if the appropriate statistical analysis of AS rate was performed. Frequency distributions of AS rates are typically extremely skewed, and thus statistical tests which are not based on the assumption of normality must be employed. Grove et al (1991) do not mention the skewness of the distribution, but the means and standard deviations of their patient and control groups indicate that these distri~.~utions were also very highly skewed (controls: mean - 0.44, standard deviation 1.20; patients: mean - 1.50, standard deviation -- 3.28). Nonetheless, Grove et al (1991) compare patients with controls with a parametric t-test. Thus their conclusions must be questioned. A number of studies have reported alterations (mostly elevations) in saccade rates during smooth pursuit in schizophrenia (for review, see Friedman et al 1991), but most studies have not discriminated between corrective and intrusive saccades. Corrective saccades are a normal adaptation of the ocular motor system to low or high pursuit gain, and thus are not, in and of themselves, an indication of tracking abnormality--these saccades can only be evaluated in association with measures of smooth pursuit gain. Saccadic intrusions serve no apparent useful purpose, and their presence in smooth pursuit may be an indication of an abnormality in saccadic inhibition, independent of low gain.
Methods
Subjects All patients in this study were recruited from the research wards of the Psychiatry Service of the Cleveland Veterans Administration Medical Center. There were 23 patients with schizophrenia, 16 patients with affective disorder, and 21 normal controls. Normal controis were recruited by advertisement, primarily from hospital staff. Prospective controls were excluded if they had a history of psychiatric or neurologic disease, if they had a first-degree relative with psychiatric illness, or if they had a significant ophthalmologic
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condition (not including myopia or hyperopia). The mean ages ~_+SD) of each group were: (1) patients with schizophrenia, 37.4 years (_+9.0); (2) patients with affective disorder, 49.6 years ( _+11.8); and (3) normal controls, 37.5 years ( _+10.9). All of the subjects were men. All patients were assigned a Research Diagnostic Criteria (RDC) diagnosis using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) (Endicott and Spitzer 1978; Spitzer and Endicott 1978). The diagnosis was reached by consensus by a multidisciplinary team that was familiar with the patient, after a review of the SADS-L. Eleven schizophrenic and 12 affective disordered patients were unmedicated; the remainder received conventional doses of typical neuroleptics or antidepressants. None were receiving lithium, as this has previously been reported to impair smooth pursuit performance (lacono et al 1982; Levy et al 1985; Holzman et al 1991). Five patients had previously been exposed to lithium, however. None of the patients had received benzodiazepines in the 24 h before recording, as these drugs have been shown to affect smooth pursuit (Abel and Hertle 1988).
Procedure A detailed description of the procedures and apparatus has been presented in the previous report (Abel et ai 1991). Briefly, the testing protocol was as follows: Subjects were seated in a chair with their heads stabilized by a chin and head rest, and a strap across the brow. Eye movements were recorded binocularly, by infrared oculography. Stimuli were generated using a computer-controlled mirror galvanometer, which reflected a bright red laser spot onto a curved arc. The target laser spot moved at a constant velocity from 15° (to the left) to + 15° (to the right) and back again. There were 10 complete cycles per task. Target speeds were 5°/sec and 20°/sec. -
Scoring Rules Scoring Rules for Square Wave Jerks (SWJ). An SWJ was defined as an intrusion into smooth pursuit consisting of a small initial saccade in either direction immediately followed by a short period of continued pursuit and terminated by another small saccade in the opposite direction of the first. One saccade must have been at least 0.5 °, one saccade must have been at least 1.0°. (We have noticed some unambiguous SWJ with a slight asymmetry in the amplitude of the two saccades, which may be related to variations in gain between the pursuit portion of the SWJ and the surrounding pursuit.) Both must have been less than 5°, to distinguish SWJ from Macro SWJ (Dell'Osso et al 1975). The second saccade must have followed the first by at least 150 msec but no more than 450 msec. Pursuit must have continued between the saccades. The direction of an SWJ does not depend on the direction of target motion. An event that occurred at the transition between tracking and fixation was not scored as an SWJ. To be scored, the square wave jerk must have been preceded and followed by smooth eye movements. Sometimes SWJ occurred contiguously, such that the second saccade of the first SWJ was also the first saccade of the second SWJ. In order for the second event to be classifie¢[ as an SWJ, the first saccade of this second SWJ must cross the line of pursuit. These ew~nts were counted, and a rate was computed by dividing by the total tracking time, in rain. The interrater reliability for scoring of SWJ at 5°/sec was 0.94, but at 20°/sec it was 0.61 [intraclass correlation coefficients (ICC), based on 3 raters, 20 re-
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cordings] (Bartko and Carpenter 1976). Therefore, only SWJ rates at the slower target speed were analyzed.
Scoring Rules for Anticipatory Saccades (AS). An AS was defined as a large saccadic intrusion that took the eye ahead of target for at least 250 msec. The intrusion may have been made up of more than one saccade as long as there was no return to target position. The ar~,~litude of the saccade must have been greater than 5°. In cases in which the event was maL.e up of multiple saccades at least one of them must have met this criterion. The gain of the postsaccade fixation segment(s) must have been less than one-half of the gain of the preceding pursuit segment. An AS must have been in the direction of target motion. These events were counted, and a rate was computed by dividing by the total tracking time, in min. The interrater reliability for scoring of AS at 5°/see was 0.98, and at 20°/sec it was 0.97 (ICCs, as above). Therefore, AS rates are reported at both target speeds. All probability values for the correlations are two-tailed.
Results Age. Although the group of patients with affective disorder was significantly older than the other two groups (F - 8.1, df - 2,57; p < 0.001; Duncan's test, p < 0.05) there were no significant correlations between saccadic intrusions and age for any group. Medication Status. To test for an effect of medication, medicated patients with either schizophrenia or affective disorder were compared to unmedicated patients on all three eye-tracking variables. No significant effects and no trends were evident.
Group Differences in Saccadic Intrusions As is evident from Table l, assumptions of parametric statistics were generally violated by the data. None of the frequency distributions met criteria for normality and none of the sets of group data met assumptions of homogeneity of variance. Therefore, nonparametric statistics, including Spearman rank order correlation coefficients (rs), were employed, except where noted. Most patients had no AS. Therefore, for correlational analyses, in order to avoid undue influence of a few subjects with a large number of AS, patients were classified into those who had AS and those who did not have AS at a particular target speed (point-biserial correlations).
SWJ Rate. There were no statistically significant differences between the three groups on SWJ rate (Table 1). In fact, the subjects with the two highest SWJ rates were in the normal control group. At least one SWJ was seen in all normals, 83% of patients with schizophrenia, and more than 94% of patients with affective disorder.
AS Rate at S°/sec. No AS were seen in normals at this target speed (Table 1). Of patients with schizophrenia, 26% had AS, and of patients with affective disorder, 44% had AS at this target speed. Both patient groups had significantly more AS than controls, but the two pattent groups were not significantly different from each other. AS Rate 20°/sec. No AS were seen in normals at this target speed, either (Table 1). Of patients with schizophrenia, 26% had AS, and of patients with affective disorder 25%
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Table 1. Saccadic Instrusions--Group Comparisons Square wave jerk rate (per rain) (So/sec)° Number
n
at0(%)
Min
Max
Med
IQR b Normality"
21 23 16
0(0.0) 4(17.4) I(6.3)
0.56 0.00 0.00
51.67 30.00 22.22
4.44 7.22 5.00
13.61 16.11 7.22
< 0.01 < 0.01 0.02
X2 0.03
Normal controls Schizophrenics Affecfive disorders
p-value d 0.983
Anticipatory saccade rate (per rain) (S°/see)" Number n
at0(%)
Min
Max
Med
IQR
Normality
21 23 16
21(100.0) 0.00 17(73.9) 0.00 9(56.3) 0.00
0.00 3.33 17.22
0.00 0.00 0.00
0.00 0.56 1.39
-<0.01 <0.01
X2 10.07
Normal controls Schizophrenics Affectivedisorders
p-value 0.007 * **
Anticipatory saccade rate (per rain) (20°lsee) * Number n
at0(%)
Min
Max
Meal
IQR
Normality
21 23 16
21(100.0) 0.00 17(73.9) 0.00 12(75.0) 0.00
0.00 36.67 36.67
0.00 0.00 0.00
0.00 3.33 2.50
m <0.01 < 0.01
Xz 6.34
Normal controls Schizophrenics Affective disorders
p-value 0,042 * *
'Tne test for homogeneity of variance between groups on this variable was statistically significant, indicating that the groups have different variances, which violates an assumption of parametric statistics (Levene statistic = 3.9, p = 0.03) ~'lnterquartile range. 'Indicates the probability value for the Shapiro-Wilks test for normality of the distribution. A significant value indicates a significant departure from normality, thus violating an assumption of parametric statistics. Rased on Kruskal.Wallis I.way ANOVA. 'A test for homogeneity of variance could not be computed for these variables, since there was no variance in the normal group. Obviously, in this case, the homogeneity of variance assumption of parametric statistics would be violated. *Significantlydifferent from normal controls, p < 0.02, based on Mann-Whitney U test. **Significantlydifferent from normal consols, p < 0,002,
had AS at this target speed. As was the case at the slower target speed, both patients groups had significantly more AS than controls, but the two patient groups were not significantly different from each other.
Correlational Analyses Relationship between AS at 5°/sec and 20°/sec. Three patients with schizophrenia had AS at both target speeds, 3 had AS just at 5°/see and 3 just at 20°/sec. Two patients with affective disorder had AS at both target speeds, 5 has AS just at 5°/sec and 2 just at 20°/sec. Phi coefficients of association were in the range of 0.07 to 0.32 with proportional reduction in error estimates (Lambda) (Goodman and Kruskal 1954) of 0.0. In other words, there was little or no evidence in support of the notion that patients who had AS at one target speed had AS at another target speed. Relationship between SWJ Rate andAS. SWJ rate was not correlated with the presence of 1 or more AS in any group at any target speed.
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Table 2. Percentages of Saccade Types (5°/sec)° Percentage CUS All Groups Normal controls Schizophrenia Affective disorder
72 75 70 69
(24) (25) (27) (19)
Percentage SWJ 27 25 28 26
(24) (25) (27) (18)
Percentage AS 2 (7) 0 (0) 1 (3) 5 (12)
aValues are mean (SD) percentage of all saccadic activity.
Relationship between Saccadic Intrusions and Gain or CUS Rate. Gain and CUS rate measures were available on these subjects (Abel et al 1991). AS rate at 20°/see was negatively correlated with gain within the group of patients with affective disorder (rs - 0 . 6 6 , p < 0.01), but not within the group of patients with schizophrenia. Within the schizophrenia group, there was a significant negative correlation between catch-up saccade rate at 5°/see and SWJ rate at 5°/see (rs -- - . 4 2 , p < 0.05). Since 14 correlation coefficients were calculated in this section, none of the correlation coefficients would be statistically significant if a correction for the number of tests is conducted.
Saccade Percentages Several earlier studies have not discriminated between CUS, AS, and SWJ, but rather have reported total saccade counts (e.g., Mather et al 1989). Therefore, it is of interest to determine what percentages of all saccades are CUS, AS, and SWJ. Table 2 presents the mean percentage of each saccade type for all groups combined and for each diagnostic category. In this calculation, SWJ have been counted as two saccades. Approximately 10% of all saccades are CUS, 25%-28% are SWJ and less than 5% are AS. These findings were characteristic of all three groups.
Discussion The main findings of this study were: (I) that patients with schizophrenia or affective disorder have increased rates of AS compared to normal controls but do not differ from each other; (2) that neither patients with schizophrenia or patients with affective disorder have abnormal SWJ rates. In this study, AS were found in 26% of patients with schizophrenia and 25%-44% of patients with affective disorder, but not in normal subjects. The occurrence of AS was not significantly different in the two patient groups, indicating they are not specific for either disorder. AS were observed in some patients at both target speeds; in others they were found only at one target speed. In patients with affective disorder but not patients with schizophrenia, gain and AS were negatively correlated at the high target speed, suggesting that in affective disorder, AS may be a response to the increased position error that accumulates with low gain. The notion that AS are generally infrequent events that occur in psychiatric patients is consistent with the report of Andersson (1984) and Moser et al (1990). Although Clementz et al (1990) found no evidence for increased rates of AS in patients with schizophrenia compared to nonschizophrenic groups including normal controls and first-degree relatives of patients with schizophrenia, they did report that the relatives of patients with schizophrenia had higher rates of AS than normal controls.
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Similarly, Whicker et al (1985) reported AS in 50% to 88% of parents of patients with schizophrenia. These latter reports are consistent with other reports of abnormal smooth pursuit tracking, assessed globally, in asymptomatic family members of patients with schizophrenia (for review, see Holzman 1987). Anticipatory saccades are also found in normal a i,ing (Kaufman and Abel 1986; Fletcher and Sharpe 1988), alcohol abuse (Andersson 1984), and Alzheimer-type dementia (Fletcher and Sharpe 1988; Jones et al 1983). Anticipatory saccades have also been reported in Pick's disease (Hutton et al 1987), which is ch&"acterized pathologically by severe atrophy of the frontal and temporal poles, with sparing of the motor and sensory cortex and the first temporal convolution (Katzman 1984). Aside from the association with Pick's disease, AS have not been associated with focal brain lesions although such an association may have been missed, as many workers have not distinguished these events from other saccadic intrusions. There is an association between the occurrence of AS and the presence of visual, but not auditory or verbal, distraction (Kaufman and Abel 1986). However, they are not simply due to a general failure of attention, as they occur during successful smooth pursuit performance, and as they are always in the direction of target motion. Taken together, these facts suggest that they are most likely an indication of a failure of involuntary visual attention, possibly involving frontal 1o~ areas (Crowne 1983; Stark 1983). Alternatively, they may reflect a failure of brain systems involved in the inhibition of saccadic activity, such as the frontal eye fields and the substantia nigra (Guitton et al 1985; Thaker et al 1989). Two of the normal subjects in this study had very high SWJ rates (above 40/min), although the median rate in this study (4.4/min) for normals was similar to the mean rate reported by Herishanu and Sharpe (1981)(4.7/min). Most previous normative data were collected during fixation, not smooth pursuit, so it is possible that some normal subjects have high SWJ rates only during pursuit. However, the rate of SWJ during fixation is highly correlated with the rate during pursuit (Friedman et al 1992). Regardless of whether these two normal subjects with the highest rates of SWJ were included or not, there were no significant differences between the normals and patients in this study, in agreement with Moser et al (1990) and the more recent report from Levin et al (1988) but not their earlier work (Levin et ai 1982). Coesidering that SWJ were not correlated with gain or AS in any group, and that SWJ rates were not elevated in schizophrenia or affective disorders or parents of patients with schizophrenia (Whicker et al 1985) these events are not likely to be significantly related to the disease process of schizophrenia. Furthermore, this suggests that defective tracking is not simply caused by a failure to inhibit small saccadic intrusions. This research was supported by grants from the USPHS (MH 47574, MH 41684, and MH 41594), the Scottish Rite Schizophrenia Research Program, an unrestricted grant to Indiana University by Research to Prevent Blindness, the Sawyer Foundations, and by the Department of Veterans Affairs. HYM is a recipient of a USPHS Research Career Scientist Award (MH 47808).
References Abel LA, Hertle RW (1988): Effects of psychoactive drugs on ocular motor behavior. In Johnston CW, Pirozzolo FJ (ads), Neuropsychology of Eye Movements. Hillsdale, NJ: Erlbaum; pp 81114.
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Abel LA, Friedman L, Jesberger JA, Malki A, Meltzer HY (1991): Quantitative assessment of smooth pursuit gain and catch-up saccades in schizophrenia and affective disorders. Biol Psy. chiawy 29:1063-1072. Andersson SE (1984): Eye tracking and attention in alcohol abusers and psychotic patients. In Gale AG, Johnson F (eds), Theoretical and Applied Aspects of Eye Movement Research. Amsterdam, North Holland: Elsevier, pp 489-496. Bal~kOJJ, Carpenter WT Jr (1976): On methods and theory of reliability. J Nerv MeritDis 183:307317. Clementz BA, Sweeney JA, Hirt M, Haas G (1990): Pursuit gain and saccadic intrusions in firstdegree relatives of probands with schizophrenia. J Abnorm Psychol 99:327-335. Crowne DP (1983): The frontal eye field and attention. Psychol Bull 93:232-260 Daroff RB (197'7): Ocular oscillations. Ann Otol Rhinol Laryn8ol 86:102-107. Dell'Osso IF, Troost BT, Daroff RB (1975): Macro square wave jerks. Neurology 25:975-979. Endicott J, Spitzer RL (1978): A diagnostic interview: The schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35:837-844. Fletcher WA, Sharpe JA (1988): Smooth pursuit dysfunction in Alzheimer's disease. Neurology 38:272-277. Friedman L, Jesberger JA, Meltzer HY (1991): A model of smooth pursuit performance illustrates the relationship between gain, catch-up saccade rate, and catch-up saccade amplitude in normal controls and patients with schizophrenia. Biol Psychiatry 30:537-556. Friedman L, Jesberger JA, Meltzer HY (1992): Catch-up saccade amplitude is related to squarewave jerk rate. Invest Opthalmol I/is $ci. Goodman LA, Kruskal WH (1954): Measures of association for cross classification. Journal of the American Statistical Association, 49:732-764. Guitton D, Buchtel HA, Douglas RM (1985): Frontal lobe lesions in man create difficulties in supressing reflexive glances and in generating goal directed saccades. Exp Brain Res 58:455472. Herishanu YO, Sharpe JA (1981): Normal square wave jerks. Invest Ophthalmol Vis Sci 20:268272. Holzman PS (1987): Recent studies of psychophysiology in schizophrenia. Schizophr Bull 13:4975. Holzman PS, O'Brian C, Watemaux C (1991): Effects of lithium treatment on eye movements. Biol Psychiatry 29:1001-1015. Hutton JT, Dippel RL, Sung JH (1987): Eye tracking in Pick Disease as contrasted to Alzheimer Disease. Neuro-ophthalmology 7:159-164. lacono WG, Peloquin l.J, Lumry AE, Valentine P,J-I, Tuason VB (1982): Eye tracking in patients with unipolar affective disorders in remission. J Abnorm Psycho! 91:35-44. Jones A, Friedland RP, Koss B, Stark L, Thompkins-Ober BA (1983): Saccadic intrusions in Alzheimer-type dementia. J Neurol 229:189-194. Katzman R (1984): The dementias. In Rowland LP (ed), Merrit's Textbook of Neurology. Philadelphia: Lea & Febiger. Kaufman SR, Abel LA (1986): The effects of distraction on smooth pursuit eye movements in normal subjects. Acta Otolaryngoi 102:--64. Levin S, Jones A, Stark L, Merrin EL, Holzman PS (1982): Identification of abnormal patterns in eye movements of schizophrenic subjects. Arch Gen Psychiatry 39:1125-1130. Levin S, Luebke A, Zee Ds, Hain TC, Robinson DA, Holzman PS (1988): Smooth pursuit eye movements in schizophrenics: Quantitative measurements with the search-coil technique. J Psychiatr Res 22:195-206. Levy DL, Doms E, Shanghnessy R, et al (1985): Pharmacological evidence for specificity of pursuit dysfunction to schizophrenia. Arch Gen Psychiatry 42:335-341.
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Mather JA, Neufeld RWJ, Merskey H, Russell NC (1989): Release of saccades in schizophrenics: Inattention or inefficiency? Eur Arch Psychiatry Neurol Sci 239:23-26. Moser A, Kompf D, Arolt V, Resch T (1990): Quantitative analysis of eye movements in schizophrenia. Neuro-ophthamology 10:73-80. Sharpe JA, Herishanu YO, and White OB (1982): Cerebral square wave jerks. Neurology 32:--62. Spitzer RL, Endicott J (1978): NIMH Clinical research branch collaborative program on the psychobiology of depression: Schedule for Affective Disorders and Schizophrenia-Lifetime Version, 3rd ed. New York: New York State Psychiatric Institute, Biometrics Research Division. Stark L (1983): Abnormal patterns of normal eye movements in schizophrenia. Schizophr Bull 9:55-71. Thacker GK, Nguyen JA, Tamminga CA (1989): Increased saccadic distractability in tardive dyskinesia: Functional evidence for subcortical GABA dysfunction. Biol Psychiatry, 5:49-59. Weinreb HJ (1983): Saccadic intrusions in schizophrenia: Identity with square wave jerks. Arch Gen Psychiatry 40:1343. Whicker L, Abel LA, Deli'Osso LF (1985): Smooth pursuit eye movements in the parents of schizophrenics. Neuro-ophthalmology 5:1-8.
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Saccadic Intrusions into Smooth Pursuit in Patients with Schizophrenia or Affective Disorder and Normal Controls Lee Friedman, Larry A. Abel, John A. Jesberger, Amjad Malki, and Herbert Y Meltzer
Two types of saccadic intrusions into smooth pursuit eye tracking, anticipatory saccades (AS), and square wave jerks (SWJ), were measured in 23 patients with schizophrenia, 16 patients with affective disorder, and 21 normal controls. Constant velocity (5 ° and 20°/sec) predictable targets were employed. High resolution infrared oculography was employed to record eye movements. Although most subjects had at least one SWJ, there were no significant group differences, and the highest individual rates of SWJ were seen in the normal control group. On the other hand, AS were never seen in normals, but were present in 25%-44% of patients with either schizophrenia or affective disorder. Both patient groups had significantly more AS than controls, but the two patient groups were not significantly different.
Introduction In a recent publication in this journal, we reported on smooth pursuit performance in patients with schizophrenia or affective disorder and normal controls (Abel et al 1991). In that paper, measures related to the pursuit system, that is, gain (eye velocity/target velocity) and rate of corrective catch-up saccades (CUS), were presented. In the present report, measures of saccadic intrusion, that is, square wave jerk (SWJ) rate, and anticipatory saccade (AS) rate, are reported. An SWJ can occur during either pursuit or fixation and consists of a pair of small saccades, in opposite directions, separated by approximately 200 msec (Daroff 1977; Sharpe et al 1982). When an SWJ intrudes into pursuit, the direction of the initial saccade is independent of target motion, and during the SWJ pursuit continues virtually uninterrupted (Jesberger et al 1989 unpublished observations). Several studies of the incidence of SWJ in schizophrenia have employed small samples and reported only general observations, rather than statistical tests of measured rates between groups. For example Levin et al (1982) reported SWJ (termed "saccadic intrusions," see Weinreb 1983) in three of From the Laboratory of Biological Psychiatry, Case Western Reserve University, University Hospitals of Cleveland, and Cleveland Veterans AdministrationHospital (LF, JAJ, HYM), Cleveland, Ohio; Department of Ophthalmology, Indiana University (LAA) Indianapolis, Indiana; and Department of Biomedical Engineering, University of Akron (AM); Akron, Ohio. Address reprint requests to Lee Friedman, PhD., Departmentof Psychiatry, Case Western Reserve University and University Hospitals of Cleveland, Hanna Pavilion, Rm B-68, 2040 Abington Road, Cleveland, OH 44106. Received August 2, 1991; revised March 5, 1992. © 1992 Sociietyof Biological Psychiatry
0006-3223/92/$O5.00
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six patients with schizophrenia, although in a subsequent study Levin et al (1988) reported no SWJ in any of five patients included in their report. Moser et al (1990) also reported no SWJ in 10 patients with schizophrenia. However, Clementz et al (1990) did statistically test measured rates of SWJ. These authors reported that SWJ rates did not differ in patients with schizophrenia compared to nonschizophrenic groups, which included normal controls and first degree relatives of patients with schizophrenia. An AS is a large saccade that takes the eyes ahead of target (Whicker et al 1985). These are followed by a period of fixation, which ends either when the target catches up to the eye, or when another saccade brings the eye back to target. AS (misidentified as macro square wave jerks) have been reported before in two of 19 (11%) "psychotic" patients (Andersson 1984) although the diagnostic criteria for this patient group was not detailed. Similarly, Moser et al (1990) reported finding only "a few anticipatory saccades" in 10 schizophrenic patients. Two prior studies have statistically compared AS rates in patients with schizophrenia to control groups (Clementz et al 1990; Grove et al 1991). Clementz et al (1990) found no evidence for increased rates of AS compared to nonschizophrenic groups including normal controls and first-degree relatives of patients with schizophrenia. These authors did report that the relatives of patients with schizophrenia had higher rates of AS than normal controls, which is consistent with the earlier report of Whicker et al (1985) who reported AS ~li 50% to 88% of parents of patients with schizophrenia. Grove et al (1991) found ao differences between patients with schizophrenia and controls, but there is a reason to question if the appropriate statistical analysis of AS rate was performed. Frequency distributions of AS rates are typically extremely skewed, and thus statistical tests which are not based on the assumption of normality must be employed. Grove et al (1991) do not mention the skewness of the distribution, but the means and standard deviations of their patient and control groups indicate that these distri~.~utions were also very highly skewed (controls: mean - 0.44, standard deviation 1.20; patients: mean - 1.50, standard deviation -- 3.28). Nonetheless, Grove et al (1991) compare patients with controls with a parametric t-test. Thus their conclusions must be questioned. A number of studies have reported alterations (mostly elevations) in saccade rates during smooth pursuit in schizophrenia (for review, see Friedman et al 1991), but most studies have not discriminated between corrective and intrusive saccades. Corrective saccades are a normal adaptation of the ocular motor system to low or high pursuit gain, and thus are not, in and of themselves, an indication of tracking abnormality--these saccades can only be evaluated in association with measures of smooth pursuit gain. Saccadic intrusions serve no apparent useful purpose, and their presence in smooth pursuit may be an indication of an abnormality in saccadic inhibition, independent of low gain.
Methods
Subjects All patients in this study were recruited from the research wards of the Psychiatry Service of the Cleveland Veterans Administration Medical Center. There were 23 patients with schizophrenia, 16 patients with affective disorder, and 21 normal controls. Normal controis were recruited by advertisement, primarily from hospital staff. Prospective controls were excluded if they had a history of psychiatric or neurologic disease, if they had a first-degree relative with psychiatric illness, or if they had a significant ophthalmologic
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condition (not including myopia or hyperopia). The mean ages ~_+SD) of each group were: (1) patients with schizophrenia, 37.4 years (_+9.0); (2) patients with affective disorder, 49.6 years ( _+11.8); and (3) normal controls, 37.5 years ( _+10.9). All of the subjects were men. All patients were assigned a Research Diagnostic Criteria (RDC) diagnosis using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) (Endicott and Spitzer 1978; Spitzer and Endicott 1978). The diagnosis was reached by consensus by a multidisciplinary team that was familiar with the patient, after a review of the SADS-L. Eleven schizophrenic and 12 affective disordered patients were unmedicated; the remainder received conventional doses of typical neuroleptics or antidepressants. None were receiving lithium, as this has previously been reported to impair smooth pursuit performance (lacono et al 1982; Levy et al 1985; Holzman et al 1991). Five patients had previously been exposed to lithium, however. None of the patients had received benzodiazepines in the 24 h before recording, as these drugs have been shown to affect smooth pursuit (Abel and Hertle 1988).
Procedure A detailed description of the procedures and apparatus has been presented in the previous report (Abel et ai 1991). Briefly, the testing protocol was as follows: Subjects were seated in a chair with their heads stabilized by a chin and head rest, and a strap across the brow. Eye movements were recorded binocularly, by infrared oculography. Stimuli were generated using a computer-controlled mirror galvanometer, which reflected a bright red laser spot onto a curved arc. The target laser spot moved at a constant velocity from 15° (to the left) to + 15° (to the right) and back again. There were 10 complete cycles per task. Target speeds were 5°/sec and 20°/sec. -
Scoring Rules Scoring Rules for Square Wave Jerks (SWJ). An SWJ was defined as an intrusion into smooth pursuit consisting of a small initial saccade in either direction immediately followed by a short period of continued pursuit and terminated by another small saccade in the opposite direction of the first. One saccade must have been at least 0.5 °, one saccade must have been at least 1.0°. (We have noticed some unambiguous SWJ with a slight asymmetry in the amplitude of the two saccades, which may be related to variations in gain between the pursuit portion of the SWJ and the surrounding pursuit.) Both must have been less than 5°, to distinguish SWJ from Macro SWJ (Dell'Osso et al 1975). The second saccade must have followed the first by at least 150 msec but no more than 450 msec. Pursuit must have continued between the saccades. The direction of an SWJ does not depend on the direction of target motion. An event that occurred at the transition between tracking and fixation was not scored as an SWJ. To be scored, the square wave jerk must have been preceded and followed by smooth eye movements. Sometimes SWJ occurred contiguously, such that the second saccade of the first SWJ was also the first saccade of the second SWJ. In order for the second event to be classifie¢[ as an SWJ, the first saccade of this second SWJ must cross the line of pursuit. These ew~nts were counted, and a rate was computed by dividing by the total tracking time, in rain. The interrater reliability for scoring of SWJ at 5°/sec was 0.94, but at 20°/sec it was 0.61 [intraclass correlation coefficients (ICC), based on 3 raters, 20 re-
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cordings] (Bartko and Carpenter 1976). Therefore, only SWJ rates at the slower target speed were analyzed.
Scoring Rules for Anticipatory Saccades (AS). An AS was defined as a large saccadic intrusion that took the eye ahead of target for at least 250 msec. The intrusion may have been made up of more than one saccade as long as there was no return to target position. The ar~,~litude of the saccade must have been greater than 5°. In cases in which the event was maL.e up of multiple saccades at least one of them must have met this criterion. The gain of the postsaccade fixation segment(s) must have been less than one-half of the gain of the preceding pursuit segment. An AS must have been in the direction of target motion. These events were counted, and a rate was computed by dividing by the total tracking time, in min. The interrater reliability for scoring of AS at 5°/see was 0.98, and at 20°/sec it was 0.97 (ICCs, as above). Therefore, AS rates are reported at both target speeds. All probability values for the correlations are two-tailed.
Results Age. Although the group of patients with affective disorder was significantly older than the other two groups (F - 8.1, df - 2,57; p < 0.001; Duncan's test, p < 0.05) there were no significant correlations between saccadic intrusions and age for any group. Medication Status. To test for an effect of medication, medicated patients with either schizophrenia or affective disorder were compared to unmedicated patients on all three eye-tracking variables. No significant effects and no trends were evident.
Group Differences in Saccadic Intrusions As is evident from Table l, assumptions of parametric statistics were generally violated by the data. None of the frequency distributions met criteria for normality and none of the sets of group data met assumptions of homogeneity of variance. Therefore, nonparametric statistics, including Spearman rank order correlation coefficients (rs), were employed, except where noted. Most patients had no AS. Therefore, for correlational analyses, in order to avoid undue influence of a few subjects with a large number of AS, patients were classified into those who had AS and those who did not have AS at a particular target speed (point-biserial correlations).
SWJ Rate. There were no statistically significant differences between the three groups on SWJ rate (Table 1). In fact, the subjects with the two highest SWJ rates were in the normal control group. At least one SWJ was seen in all normals, 83% of patients with schizophrenia, and more than 94% of patients with affective disorder.
AS Rate at S°/sec. No AS were seen in normals at this target speed (Table 1). Of patients with schizophrenia, 26% had AS, and of patients with affective disorder, 44% had AS at this target speed. Both patient groups had significantly more AS than controls, but the two pattent groups were not significantly different from each other. AS Rate 20°/sec. No AS were seen in normals at this target speed, either (Table 1). Of patients with schizophrenia, 26% had AS, and of patients with affective disorder 25%
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Table 1. Saccadic Instrusions--Group Comparisons Square wave jerk rate (per rain) (So/sec)° Number
n
at0(%)
Min
Max
Med
IQR b Normality"
21 23 16
0(0.0) 4(17.4) I(6.3)
0.56 0.00 0.00
51.67 30.00 22.22
4.44 7.22 5.00
13.61 16.11 7.22
< 0.01 < 0.01 0.02
X2 0.03
Normal controls Schizophrenics Affecfive disorders
p-value d 0.983
Anticipatory saccade rate (per rain) (S°/see)" Number n
at0(%)
Min
Max
Med
IQR
Normality
21 23 16
21(100.0) 0.00 17(73.9) 0.00 9(56.3) 0.00
0.00 3.33 17.22
0.00 0.00 0.00
0.00 0.56 1.39
-<0.01 <0.01
X2 10.07
Normal controls Schizophrenics Affectivedisorders
p-value 0.007 * **
Anticipatory saccade rate (per rain) (20°lsee) * Number n
at0(%)
Min
Max
Meal
IQR
Normality
21 23 16
21(100.0) 0.00 17(73.9) 0.00 12(75.0) 0.00
0.00 36.67 36.67
0.00 0.00 0.00
0.00 3.33 2.50
m <0.01 < 0.01
Xz 6.34
Normal controls Schizophrenics Affective disorders
p-value 0,042 * *
'Tne test for homogeneity of variance between groups on this variable was statistically significant, indicating that the groups have different variances, which violates an assumption of parametric statistics (Levene statistic = 3.9, p = 0.03) ~'lnterquartile range. 'Indicates the probability value for the Shapiro-Wilks test for normality of the distribution. A significant value indicates a significant departure from normality, thus violating an assumption of parametric statistics. Rased on Kruskal.Wallis I.way ANOVA. 'A test for homogeneity of variance could not be computed for these variables, since there was no variance in the normal group. Obviously, in this case, the homogeneity of variance assumption of parametric statistics would be violated. *Significantlydifferent from normal controls, p < 0.02, based on Mann-Whitney U test. **Significantlydifferent from normal consols, p < 0,002,
had AS at this target speed. As was the case at the slower target speed, both patients groups had significantly more AS than controls, but the two patient groups were not significantly different from each other.
Correlational Analyses Relationship between AS at 5°/sec and 20°/sec. Three patients with schizophrenia had AS at both target speeds, 3 had AS just at 5°/see and 3 just at 20°/sec. Two patients with affective disorder had AS at both target speeds, 5 has AS just at 5°/sec and 2 just at 20°/sec. Phi coefficients of association were in the range of 0.07 to 0.32 with proportional reduction in error estimates (Lambda) (Goodman and Kruskal 1954) of 0.0. In other words, there was little or no evidence in support of the notion that patients who had AS at one target speed had AS at another target speed. Relationship between SWJ Rate andAS. SWJ rate was not correlated with the presence of 1 or more AS in any group at any target speed.
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Table 2. Percentages of Saccade Types (5°/sec)° Percentage CUS All Groups Normal controls Schizophrenia Affective disorder
72 75 70 69
(24) (25) (27) (19)
Percentage SWJ 27 25 28 26
(24) (25) (27) (18)
Percentage AS 2 (7) 0 (0) 1 (3) 5 (12)
aValues are mean (SD) percentage of all saccadic activity.
Relationship between Saccadic Intrusions and Gain or CUS Rate. Gain and CUS rate measures were available on these subjects (Abel et al 1991). AS rate at 20°/see was negatively correlated with gain within the group of patients with affective disorder (rs - 0 . 6 6 , p < 0.01), but not within the group of patients with schizophrenia. Within the schizophrenia group, there was a significant negative correlation between catch-up saccade rate at 5°/see and SWJ rate at 5°/see (rs -- - . 4 2 , p < 0.05). Since 14 correlation coefficients were calculated in this section, none of the correlation coefficients would be statistically significant if a correction for the number of tests is conducted.
Saccade Percentages Several earlier studies have not discriminated between CUS, AS, and SWJ, but rather have reported total saccade counts (e.g., Mather et al 1989). Therefore, it is of interest to determine what percentages of all saccades are CUS, AS, and SWJ. Table 2 presents the mean percentage of each saccade type for all groups combined and for each diagnostic category. In this calculation, SWJ have been counted as two saccades. Approximately 10% of all saccades are CUS, 25%-28% are SWJ and less than 5% are AS. These findings were characteristic of all three groups.
Discussion The main findings of this study were: (I) that patients with schizophrenia or affective disorder have increased rates of AS compared to normal controls but do not differ from each other; (2) that neither patients with schizophrenia or patients with affective disorder have abnormal SWJ rates. In this study, AS were found in 26% of patients with schizophrenia and 25%-44% of patients with affective disorder, but not in normal subjects. The occurrence of AS was not significantly different in the two patient groups, indicating they are not specific for either disorder. AS were observed in some patients at both target speeds; in others they were found only at one target speed. In patients with affective disorder but not patients with schizophrenia, gain and AS were negatively correlated at the high target speed, suggesting that in affective disorder, AS may be a response to the increased position error that accumulates with low gain. The notion that AS are generally infrequent events that occur in psychiatric patients is consistent with the report of Andersson (1984) and Moser et al (1990). Although Clementz et al (1990) found no evidence for increased rates of AS in patients with schizophrenia compared to nonschizophrenic groups including normal controls and first-degree relatives of patients with schizophrenia, they did report that the relatives of patients with schizophrenia had higher rates of AS than normal controls.
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Similarly, Whicker et al (1985) reported AS in 50% to 88% of parents of patients with schizophrenia. These latter reports are consistent with other reports of abnormal smooth pursuit tracking, assessed globally, in asymptomatic family members of patients with schizophrenia (for review, see Holzman 1987). Anticipatory saccades are also found in normal a i,ing (Kaufman and Abel 1986; Fletcher and Sharpe 1988), alcohol abuse (Andersson 1984), and Alzheimer-type dementia (Fletcher and Sharpe 1988; Jones et al 1983). Anticipatory saccades have also been reported in Pick's disease (Hutton et al 1987), which is ch&"acterized pathologically by severe atrophy of the frontal and temporal poles, with sparing of the motor and sensory cortex and the first temporal convolution (Katzman 1984). Aside from the association with Pick's disease, AS have not been associated with focal brain lesions although such an association may have been missed, as many workers have not distinguished these events from other saccadic intrusions. There is an association between the occurrence of AS and the presence of visual, but not auditory or verbal, distraction (Kaufman and Abel 1986). However, they are not simply due to a general failure of attention, as they occur during successful smooth pursuit performance, and as they are always in the direction of target motion. Taken together, these facts suggest that they are most likely an indication of a failure of involuntary visual attention, possibly involving frontal 1o~ areas (Crowne 1983; Stark 1983). Alternatively, they may reflect a failure of brain systems involved in the inhibition of saccadic activity, such as the frontal eye fields and the substantia nigra (Guitton et al 1985; Thaker et al 1989). Two of the normal subjects in this study had very high SWJ rates (above 40/min), although the median rate in this study (4.4/min) for normals was similar to the mean rate reported by Herishanu and Sharpe (1981)(4.7/min). Most previous normative data were collected during fixation, not smooth pursuit, so it is possible that some normal subjects have high SWJ rates only during pursuit. However, the rate of SWJ during fixation is highly correlated with the rate during pursuit (Friedman et al 1992). Regardless of whether these two normal subjects with the highest rates of SWJ were included or not, there were no significant differences between the normals and patients in this study, in agreement with Moser et al (1990) and the more recent report from Levin et al (1988) but not their earlier work (Levin et ai 1982). Coesidering that SWJ were not correlated with gain or AS in any group, and that SWJ rates were not elevated in schizophrenia or affective disorders or parents of patients with schizophrenia (Whicker et al 1985) these events are not likely to be significantly related to the disease process of schizophrenia. Furthermore, this suggests that defective tracking is not simply caused by a failure to inhibit small saccadic intrusions. This research was supported by grants from the USPHS (MH 47574, MH 41684, and MH 41594), the Scottish Rite Schizophrenia Research Program, an unrestricted grant to Indiana University by Research to Prevent Blindness, the Sawyer Foundations, and by the Department of Veterans Affairs. HYM is a recipient of a USPHS Research Career Scientist Award (MH 47808).
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