89
Psychiatry Research, 34~89-97
Elsevier
Smooth Pursuit Eye Tracking Symptoms in Schizophrenia Peter Kelly, Chris Rennie, and Russell Meares
Dysfunction
Evian Gordon,
and Negative
John Anderson,
Alan Howson,
Received August 24. 1989; revised version received May 16, 1990; accepted July 21, 1990. Abstract.
This study examined the hypothesis that negative symptoms are associated with abnormalities of smooth pursuit in schizophrenic patients. The pursuit eye movements of 25 subjects with schizophrenia and 25 matched normal control subjects were recorded using an infrared eye tracking system and quantified using the log of signal-to-noise ratio (In S/N). The severity of negative symptoms within the schizophrenic group was rated using the Scale for the Assessment of Negative Symptoms. Previous findings of pursuit abnormalities among schizophrenic patients as a group were replicated. There was, however, no significant association between the eye tracking dysfunction and the severity of negative symptoms. Key Words. Schizophrenia, eye tracking dysfunction, smooth pursuit abnormalities, negative symptoms, type II syndrome.
Smooth pursuit eye tracking dysfunction has been found in schizophrenic subjects in a large number of studies (Holzman et al., 1973, 1974; Shagass et al., 1974; Brezinova and Kendell, 1977; Pass et al., 1978; Salzman et al., 1978; Cegalis and Sweeney, 1979; Karson, 1979; May, 1979; Mialet and Pichot, 1981; Tomer et al., 1981; Iacono et al., 1982; Schmid-Burgk et al., 1982; Cegalis et al., 1983; Bartfai et al., 1983, 1985; Siever et al., 1986; Yee et al., 1987). These studies have found deviant eye tracking in 50-8670 of schizophrenic subjects, but in < 10% of normal control subjects (Lipton et al., 1983). Similar results have been found using a variety of stimulus types, recording methods, and means of quantification (Holzman et al., 1973, 1974; Shagass et al., 1974; Pass et al., 1978; Cegalis and Sweeney, 1979; Bartfai et al., 1983; Siever et al., 1986). The persistence of tracking abnormalities after the remission of acute symptoms (Holzman et al., 1973, 1974; Shagass et al., 1974; Iacono et al., 1981; Bartfai et al.,
Peter Kelly, M.B., B.S., is a Research Fellow of the New South Wales Institute of Psychiatry. Christopher Rennie, B.Sc., M.Biomed.Eng., is a medical physicist, the Department of Medical Physics, Westmead Hospital. Evian Gordon, B.Sc.(Hons.), M.B., B.S., Ph.D., is Senior Lecturer in Psychiatry, the University of Sydney, and Head of Cognitive Neuroscience Unit, Westmead Hospital. John Anderson, B.Pharm., M.Litt., is a research assistant, the Neuroscience Unit, Westmead Hospital. Alan Howson, M.A., is from the Department of Economics, Macquarie University. Russell Meares, M.D., D.P.M., F.F.A.N.Z.C.P., M.R.C.Psych., is Professor of Psychiatry, the University of Sydney. (Reprint requests to Dr. E. Gordon, Dept. of Psychiatry, Westmead Hospital, Sydney, New South Wales, Australia, 2145.) 01651781/90/$03.50
@ 1990 Elsevier Scientific
Publishers
Ireland
Ltd
90 1983) suggests that dysfunctional smooth pursuit may be a trait rather than a state variable in schizophrenia. It may also be a trait variable in schizotypal personality disorder (Siever et al., 1984). In contrast, tracking abnormalities may be a state variable in affective disorders (Lipton et al., 1983) and in central nervous system lesions (Corvera et al., 1973; Spooner et al., 1980; Leigh and Zee, 1983). One group has found eye tracking abnormalities in association with increased ventricular-brain ratios in schizophrenic subjects (Weinberger et al., 1981) while others have not (Bartfai et al., 1983; Siever et al., 1986). The negative, or type II schizophrenic, syndrome (Crow, 1980, 1985) is characterized by negative symptoms (narrowly defined as flattening of affect and poverty of speech), poor response to neuroleptics, and chronicity (Sommers, 1985). Objective assessment of this “subtype” of schizophrenia has been aided by the development of “dedicated” scales for use in rating negative symptoms (Lewine et al., 1983; Iager et al., 1985; Kay et al., 1987) of which the Scale for the Assessment of Negative Symptoms (SANS) of Andreasen (1984~) is the most widely used (Walker et al., 1988). Changes on computed tomography (CT) such as ventricular dilatation, and cerebellar and sulcal atrophy (Reveley, 1985), have been found in association with negative symptoms (Andreasen, 1982; Williams et al., 1985), as have components of the negative syndrome such as poor premorbid adjustment (Weinberger et al., 1980~; Williams et al., 1985), poor treatment response (Weinberger et al., 1980b; Kling et al., 1983), unfavorable outcome (Williams et al., 1985), and neuropsychological impairment (Golden et al., 1980; Keilp et al., 1988). In addition, negative symptoms are associated with neurological signs such as abnormal involuntary movements (Owens et al., 1980) and vulnerability for developing tardive dyskinesia (Waddington et al., 1987). In summary, it would seem that both a “subtype” of schizophrenia and a dysfunction in smooth pursuit eye tracking have been associated with structural brain damage. The type II syndrome and pursuit abnormalities may therefore be associated with each other. No previous study has used a rating scale of negative symptomatology to examine the relationship between negative symptoms and pursuit abnormalities. There have, however, been a number of studies suggesting a correlation between pursuit abnormalities and negative symptomatology. Holzman et al. (1974) found eye tracking dysfunction in 86% of chronic schizophrenic patients but in only 52Y0 of recently diagnosed patients. Two other studies have looked at poor premorbid adjustment and pursuit abnormalities (Bartfai et al., 1983; Siever et al., 1986). Both failed to find significant correlations, although the small size of the study groups (12 and 14, respectively) may have contributed to this failure. Bartfai et al. (1983, 1985) did find poor pursuit tracking associated with previous hospitalization and increasing age. Iacono (1988) found that the presence of pursuit abnormalities predicted poor outcome at 18-month followup in a group of first-episode schizophrenic patients. Simons and Katkin (1985) found an increased prevalance of abnormal pursuit in normal controls with high scores on a rating scale for physical anhedonia, a component of the negative syndrome in schizophrenic subjects. In this study, we explicitly examine the presence and severity of negative symptoms, as measured by the SANS as the index of the type II syndrome, and the
91 relationship schizophrenic
of this
measure
and normal
with
control
quantifications subjects.
of eye tracking
The experimental
dysfunction
hypotheses
were
in that
the mean log signal-to-noise ratio (In S/N) would be less in schizophrenic subjects than in normal controls; and that among schizophrenic subjects, the In S/N would be negatively correlated with the SANS score.
Methods Subjects. Fifty subjects were studied: 25 patients with a diagnosis of schizophrenia and 25 age-matched normal controls. All patients were aged between 17 and 52 (mean 30.3 years; SD 7.2). The mean age of onset of schizophrenia was 21.7 years (SD 5.5), and the mean duration of illness was 8.6 years (SD 5.3). Normal controls were matched for age (within 5 years) and sex. The mean age of normal control subjects was 28.5 years (SD 5.5 years). A two-sample t test performed to compare age between the two experimental groups showed no significant difference. There were 19 men and 6 women in each group. No subjects had significant preexisting medical conditions (such as epilepsy or head injury), family history of psychiatric disorder, or were on current nonpsychotropic medications. Six of the schizophrenic subjects were not on antipsychotic medication. Of the remaining subjects, the average daily dose of antipsychotic (expressed in mg of chlorpromazine equivalents) was 300 chlorpromazine equivalents, with a range of 100 to 800 daily. Subjects on lithium or barbiturates were excluded because of the influence of these drugs on smooth pursuit function. Diagnostic Measures. The schizophrenic subjects underwent a diagnostic interview using the schizophrenia and mania sections of the Composite International Diagnostic Interview Core Version (CIDI-C; Robins et al., 1987) to confirm lifetime diagnoses of schizophrenia according to DSM-III-R criteria (American Psychiatric Association, 1987). The interviews were performed by two of the investigators, who had been trained in the use of this instrument. Schizophrenic subjects also underwent an unstructured interview which dealt with social, recreational, and employment issues. The information obtained from the CIDI-C and the unstructured interview was used to complete the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1984~) and the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 19846). Intertester reliability of SANS and SAPS scores was not formally assessed. Final scores were obtained by averaging the two raters’ scores. The mean SANS score for schizophrenic subjects was 11.9 (SD 4.2), and the mean SAPS score was 7.2 (SD 4.3). Recording of Eye Tracking. The system used in this project consists of an optics assembly unit and a low-light television camera (used to record eye position) and a video screen directly above this (for presentation of stimuli). The optics assembly unit has a lamp which generates a beam of near-infrared light (of wavelength 700-l 100 nm). (The light was of sufficiently low intensity not to cause distraction to the subject.) A half-reflecting mirror set at 45’ to the camera’s optical axis resulted in a beam of light that was colinear with the camera’s line of sight. The image of the eye recorded by the camera was sampled at 50 Hz, and this digital image was then analyzed by a series of software algorithms that determined the cornea1 reflection and the pupil boundary. The relative position of the cornea1 reflection and the pupil center, after calibration, gave a linear output of eye gaze position corrected for individual variations. Eye coordinates could then be reported in digital form to a host computer. The host computer, an IBM-XT, was responsible for data acquisition and generation of the target stimuli. The error of resolution when determining eye position was approximately 0.75O of visual angle. The experiment was conducted in a room with stable light conditions throughout the session. The subjects were kept at a standard distance from the eye gaze monitor-60 cm from the eye to the center of the video screen. They were seated in a comfortable chair with adjustable height and a headrest.
92 The fixation point target was displayed on the screen and the subject was asked to fixate on it until the trial began. The subject was asked to try to blink as infrequently as possible during the trial. When the trial started, the target moved backward and forward across the screen along the horizontal plane with a sinusoidal velocity at a frequency of 0.4 Hz, subtending an angle of 15”. The eye tracking was recorded for 50 sec. Four such trials were undertaken. Data Analysis. Quantitative analysis of the data obtained from this paradigm used the log of the signal-to-noise ratio (In S/N) as proposed by Lindsey et al. (1978). Other indices of pursuit abnormality, such as gain, were not used because of the low sampling rate (50 Hz) of the technology used (Yee et al., 1987). The sine wave of best fit was subtracted from the subject’s actual eye tracking record. This subtraction waveform then underwent a Fast Fourier Transformation (FFT), and the contribution of the “power” of this subtraction waveform as a percentage of the total “power”in the eye tracking record was calculated. The frequency band that was examined in our quantification of eye tracking deviance was 0 Hz to 10 Hz as components of frequencies higher than 10 Hz seemed to make little or no contribution to the total power. In the In S/N measure, the total power in the subtraction waveform was defined as “noise,” and the subtraction of this percentage from 100% as “signal.” The “signal” score was then divided by the “noise” score and the logarithm to base e derived. This value was calculated for each of a subject’s four runs, and the highest score was used for between-group comparisons and for correlations with clinical status. Because the In S/N measures scores for schizophrenic subjects were found to be bimodally distributed, nonparametric techniques were used for subsequent analyses. Comparisons between schizophrenic subjects and normal controls on the In S/N measure used the Mann-Whitney U test, and the relationship between the In S/N scores and clinical variables was examined using the Spearman rank correlation coefficient.
Results The In S/N scores for the schizophrenic subjects were bimodally distributed, with 5 of the 25 subjects having markedly deviant eye tracking performance (all having scores below 3.0; mean 2.45). The remaining 20 schizophrenic subjects had near normal tracking performance (with the lowest score 3.62; mean 4.74). Table 1 lists the mean In S/N values for the schizophrenic group as a whole and for the normal control group. A Mann-Whitney U test (MWUT) demonstrated significant group differences between the schizophrenic group and normal controls (p = 0.031). A MWUT also demonstrated significant differences between the two groups of schizophrenic subjects delineated @ = O.OOl), but no difference between normal controls and the schizophrenic group with the better eye tracking performance.
Table 1. Group comparisons of the log of the signal-to-noise ratio (In S/N) scores In SIN Mean
SD
Schizophrenia
4.28
1.17
Normal controls
4.88
0.48
Group
Within the schizophrenic group, there were no significant differences on the MWUT between those who were and those who were not receiving antipsychotic medications (p = 0.70). Eight out of 25 schizophrenic subjects were drug free; in
93
addition, two out of the five subjects with the most deviant eye tracking performance were drug free. As mentioned above, 16 of the 50 subjects studied were women; there were no significant differences between men and women in eye tracking performance @ = 0.86). Table 2 contains the Spearman rank order correlation coefficients of the In S/N score and clinical variables among schizophrenic subjects. Of most importance, the correlation between the In S/N measure and the SANS score was -0.076. There were Table 2. Correlation coefficients of the log of the signal-to-noise S/N) with demographic and clinical variables Variable
Spearman rank order correlation
SANS
-0.076
SAPS
-0.38 0.016
Age Age of onset
SANS = Scale for the Assessment Symptoms.
Sianificance p > 0.05 p > 0.05 p > 0.05
-0.32
p > 0.05
0.18
p > 0.05
Duration of illness
Note.
ratio (In
of Negative Symptoms.
SAPS = Scale for the Assessment
of Positive
no other significant correlations, although the correlation between the SAPS score and In S/N almost achieved statistical significance. This seems to reflect the differing SAPS scores in the two groups of schizophrenic subjects (“deviant” group’s median = 11.0; “normal” group’s median = 5.5; MWUT significant at p = 0.032). Repeated MWUTs comparing SANS score, age, and duration of illness between the two schizophrenic groups failed to reveal statistical differences. Discussion
There was no significant association of eye tracking dysfunction with the severity of negative symptoms, as measured by SANS score, in this study. The Spearman Rank order correlation coefficient of the SANS and In S/N scores was -0.076. This preliminary finding suggests that pursuit dysfunction is not associated with the negative syndrome as measured by the SANS-despite the fact that pursuit abnormalities found in the schizophrenic group compared to normal controls replicated similar findings in earlier studies. If schizophrenia comprises two syndromes (Crow, 1980, 1985), each with different underlying pathologies, then it would seem appropriate to explore the possibility of specific vulnerability markers for these syndromes. That abnormalities of smooth pursuit may be markers of organic damage (Leigh and Zee, 1983) seems to have been established. In schizophrenia, eye tracking dysfunction would therefore more likely be associated with the negative, or type II syndrome, than the positive syndrome. A critical analysis of a number of study limitations is necessary in the assessment of these preliminary findings. The study had specific sample characteristics that require comment. The distinction between negative symptoms and the negative syndrome (Andreasen, 1985) is of particular relevance. This study examined subjects in
94 a cross-sectional manner. Although pursuit abnormalities appear to be stable over time in schizophrenic subjects, an important part of the definition of the type II syndrome is its natural history and prognosis. Typically, negative symptoms are longlasting and worsen over time (Crow, 1985). In a cross-sectional study, it is quite possible that a subject who will later develop a severe negative syndrome may be given a low score on current negative symptoms. The converse situation is also possible, although less likely (Carpenter et al., 1985). Previous research offers an important parallel in this regard. Earlier crosssectional studies (Bartfai et al., 1983; Siever et al., 1986) failed to find an association between poor premorbid adjustment, one component of the negative syndrome, and pursuit dysfunction. This contrasts with the findings of a longitudinal study (Iacono, 1988) of a positive association between poor outcome at 18-month followup (another component of the negative syndrome) and pursuit dysfunction. A longitudinal study of eye tracking abnormalities, in which multiple aspects of the negative syndrome were assessed serially, would be the most appropriate approach to the study of the interrelationships of these phenomena. The replication of group differences in pursuit abnormalities between schizophrenic patients and normal control subjects is notable in this study, since it may provide indirect evidence that the failure to confirm the specific hypothesis is unlikely to be merely the reflection of a difference in experimental paradigm between this and earlier studies. We have used one of the two usual means of recording eye movements (cf. Levin et al., 1982), a standard stimulus and experimental method (cf. Shagass et al., 1974; Iacono et al., 1982), and a widely accepted method of the quantification of global tracking performance (Lindsey et al., 1978). The demographic and historical characteristics of the schizophrenic subjects in this study may also have some bearing on the results. The group examined was comparatively young (mean age 30.3 years), with a mean duration of illness of 8.6 years. Only five subjects were hospitalized at the time of testing. Because the subjects were young and lived largely in the community, they were likely to have low negative symptom scores. However, there was a range of SANS scores within this population. Three subjects had SANS scores > 20, and five subjects had SANS scores between 15 and 20. These figures represent significant morbidity from negative symptoms within the population studied. It is unlikely, therefore, that the failure to confirm the experimental hypothesis arose from peculiarities in the distribution of negative symptoms within this population. In addition, the correlation between subject age and In S/N scores was only 0.018, indicating that age had no significant effect on the pursuit abnormalities found. Nor was there any significant correlation of tracking abnormalities with clinical variables, such as age of onset, duration of illness, and dosage of antipsychotic medication. It is important to note that the correlation between eye tracking abnormalities (In S/N) and positive symptoms (SAPS) almost achieved significance, and that there were significantly higher SAPS scores in those schizophrenic subjects in the group with more deviant tracking. Previous research (Holzman et al., 1973, 1974; Shagass et al., 1974, Iacono et al., 1981; Bartfai et al., 1983) has failed to find a relationship between tracking deviance and acute or positive symptoms in longitudinal studies,
95
which suggests differences in the composition of illness features in the subjects of this study. The negative correlation between SANS and SAPS scores in the schizophrenic group (Spearman rank order correlation coefficient = -0.367, p > 0.05) suggests that the population studied contained a high number of young patients with inversely correlated SANS and SAPS scores. Replication in other populations is thus clearly indicated. Despite the lack of support for the proposed association between negative symptoms and pursuit abnormalities in this study, further research is indicated. Future studies could incorporate the concurrent assessment of structural brain changes in schizophrenic subjects. The use of CT scans would address the objection that any discovered association between eye tracking dysfunction and the negative syndrome might merely reflect a shared association with organicity. In addition, Levin (1984a, 19846) has suggested that abnormalities of frontal lobe function underlie the negative syndrome in schizophrenia and also cause abnormalities of smooth pursuit. This hypothesis might be examined by tests of frontal lobe function, performed concurrently with the recording of eye movements and clinical assessment. Bartfai et al. (1985) found a positive association between poor eye tracking and poor performance on tests of frontal lobe function, such as the Trail-Making Test. The incorporation of these features into a longitudinal experiment examining negative and positive symptoms and eye tracking dysfunction may help illuminate the possible interrelationships among these disparate findings. Acknowledgments.
The New South Wales Institute of Psychiatry and IBM Australia
provided support. References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 1987. Andreasen, N. Negative symptoms in schizophrenia: Definition and reliability. Archives of General Psychiatry, 39:784-788, 1982. Andreasen, N. Scale for the Assessment
of Negative Symptoms.
of Iowa, 1984a. Andreasen, N. Scale for the Assessment of Positive Symptoms.
Iowa City: The University
Iowa City: The University of Iowa, 1984b. Andreasen, N.C. Positive vs. negative schizophrenia: A critical evaluation. Schizophrenia Bulletin, 11:380-389, 1985. Bartfai, A.; Levander, SE.; Nybkk, H.; Berggren, B.M.; and Schalling, D. Smooth pursuit eye tracking, neuropsychological test performance, and computed tomography in schizophrenia. Psychiatry Research, 1549-62, 1985. Bartfai, A.; Levander, S.E.; and Sedvall, G. Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients. Biological Psychiatry, 18:971-987, 1983. Brezinova, V., and Kendell, R.E. Smooth pursuit eye movements of schizophrenics and normal people under stress. British Journal of Psychiatry, 13059-63, 1977. Carpenter, W.T.; Heinrichs, D.W.; and Alphs, L.D. Treatment of negative symptoms. Schizophrenia Bulletin, 11440-452, 1985. Cegalis, J.A.; Hafez, H.; and Wong, P.S. What is deviant about deviant smooth pursuit eye movements in schizophrenia? Psychiatry Research, 10:47-58, 1983.
96
Cegalis, J.A., and Sweeney, J.A. Eye movements in schizophrenia: A quantitative analysis. Biological Psychiatry, 14: 14-26, 1979. Corvera, J.; Torres-Courtney, G.; and Topez-Rioz, G. The neurotological significance of alterations in pursuit eye movements and the pendular eye tracking test. Annals of Otology, Rhinology and Laryngology, 82:855-867, 1973. Crow, T.J. Molecular pathology of schizophrenia: More than one disease process? British Medical Journal, 280:66-68, 1980. Crow, T.J. The two syndrome concept: Origins and current status. Schizophrenia Bulletin, 11:471486, 1985. Golden, C.J.; Moses, J.A.; Zelazowski, R.; Graber, B.; Zatz, L.N.; Horvath, T.B.; and Berger, P.A. Cerebral ventricular size and neuropsychological impairment in young chronic schizophrenics: Measurement by the standardized Luria-Nebraska Neuropsychological Battery. Archives of General Psychiatry, 37:619-623, 1980. Holzman, P.S.; Proctor, L.R.; and Hughes, D.W. Eye tracking patterns in schizophrenia. Science, 181:179-181, 1973. Holzman, P.S.; Proctor, L.R.; Yasillo, N.J.; and Levy, D. Eye tracking patterns in schizophrenia. Science, 184: 1203-1204, 1974. Iacono, W.G. Eye movement abnormalities in schizophrenic and affective disorders. In: Johnston, C.W., and Pirozzolo, F.J., eds. Neuropsychology of Eye Movements. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. Iacono, W.G.; Peloquin, L.J.; Lumry, A.E.; Valentine, R.H.; and Tuason, V.B. Eye tracking in patients with unipolar and bipolar affective disorders in remission. Journal of Abnormal Psychology, 91:3544, 1982. Iacono, W.G.; Tuason, V.B.; and Johnson, R.A. Dissociation of smooth pursuit and saccadic eye tracking in remitted schizophrenics: An ocular reaction time task that schizophrenics perform well. Archives of General Psychiatry, 38:991-996, 1981. Iager, A.C.; Kirch, D.G.; and Wyatt, R.J. A negative symptom rating scale. Psychiatry Research, 16:27-36, 1985. Karson, C.G. Oculomotor signs in a psychiatric population: A preliminary report. American Journal of Psychiatry, 136:1057-1060, 1979. Kay, S.R.; Fiszbein, A.; and Opler, L.A. The positive and negative symptom scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13:261-276, 1987. Keilp, J.G.; Sweeney, J.A.; Jacobsen, P.; Solomon, C.; St. Louis, L.; Deck, M.; Frances, A.; and Mann, J.J. Cognitive impairment in schizophrenia: Specific relations to ventricular size and negative symptomatology. Biological Psychiatry, 24147-55, 1988. Kling, A.S.; Kurtz, N.; Tachiki, K.; and Orzeck, A. CT scans in subgroups of chronic schizophrenics. Journal of Psychiatric Research, 17:375-384, 1983. Leigh, R.J., and Zee, D.S. 77re Neurology of Eye Movements. Philadelphia: F.A. Davis, 1983. Levin, S. Frontal lobe dysfunctions in schizophrenia: I. Eye movement impairments. Journal of Psychiatric Research, 18:27-55, 1984a. Levin, S. Frontal lobe dysfunctions in schizophrenia: II. Impairments of psychological and brain functions. Journal of Psychiatric Research, 18:57-72, 19846. Lewine, R.J.; Fogg, L.; and Meltzer, H.Y. Assessment of negative and positive symptoms in schizophrenia. Schizophrenia Bulletin, 9:368-376, 1983. Lindsey, D.T.; Holzman, P.S.; Haberman, S.; and Yasillo, N.J. Smooth pursuit eye movements: A comparison of two measurement techniques for studying schizophrenia. Journal of Abnormal Psychology, 87:491-496, 1978. Lipton, R.B.; Levy, D.L.; Holzman, P.S.; and Levin, S. Eye movement dysfunctions in psychiatric patients: A review. Schizophrenia Bulletin, 9: 13-32, 1983. May, H.J. Oculomotor pursuit in schizophrenia. Archives of General Psychiatry, 36:827, 1979. Mialet, J.P., and Pichot, P. Eye tracking patterns in schizophrenia: An analysis based on the incidence of saccades. Archives of General Psychiatry, 38: 183-186, 198 1.
97 Owens, D.G.; Johnstone, E.C.; and Frith, C.D. Spontaneous involuntary disorders of movement: Their prevalence, severity and distribution in chronic schizophrenics with and without treatment with neuroleptics. Archives of General Psychiatry, 39:452-461, 1982. Pass, H.L.; Salzman, L.F.; Klorman, R.; Kaskey, G.B.; and Klein, R.B. The effect of distraction on acute schizophrenics’ visual tracking. Biological Psychiatry, 13587-593, 1978. Reveley, M.A. CT scans in schizophrenia. British Journalof Psychiatry, 146:367-371, 1985. Robins, L.N.; Wing, J.; and Helzer, J. Composite International Diagnostic Interview Core Version (CZDZ-C). Geneva: World Health Organization, 1987. Salzman, L.F.; Klein, R.H.; and Strauss, J.S. Pendulum eye-tracking in remitted psychiatric patients. Journal of Psychiatric Research, 14:121-126, 1978. Schmid-Burgk, W.; Becker, W.; Diekmann, V.; Jurgens, R.; and Kornhuber, H.H. Disturbed smooth pursuit and saccadic eye movements in schizophrenia. Archiv fur Psychiatric und Nervenkrankenheiten, 232:381-289, 1982. Shagass, C.; Amadeo, M.; and Overton, D.A. Eye-tracking performance in psychiatric patients. Biological Psychiatry, 9:245-260, 1974. Siever, L.J.; Coursey, R.D.; Alterman, 1,s.; Buchsbaum, MS.; and Murphy, D.L. Impaired smooth pursuit eye movement: Vulnerability marker for schizotypal personality disorder in a normal volunteer population. American Journal of Psychiatry, 141:1560-1566, 1984. Siever, L.J.; van Kammen, D.P.; Linnoila, M.; Alterman, I.; Hare, T.; and Murphy, D.L. Smooth pursuit eye movement disorder and its psychobiologic correlates in unmedicated schizophrenics. Biological Psychiatry, 21: 1167-l 174, 1986. Simons, R.F., and Katkin, W. Smooth pursuit eye movements in subjects reporting physical anhedonia and perceptual aberrations. Psychiatry Research, 14~275-289, 1985. Sommers, A. “Negative symptoms”: Conceptual and methodological problems. Schizophrenia Bulletin, 11:364-379, 1985. Spooner, J.W.; Sakala, S.M.; and Baloh, R.W. Effect of aging on eye tracking. Archives of Neurology, 37:575-576, 1980. Tomer, R.; Mintz, M.; Levy, A.; and Myslobodsky, M. Smooth pursuit pattern in schizophrenic patients during cognitive task. Biological Psychiatry, 16: 13 l-144, 198 1. Waddington, J.L.; Youssef, H.A.; Dolphin, C.; and Kinsella, A. Cognitive dysfunction, negative symptoms, and tardive dyskinesia in schizophrenia: Their association in relation to topography of involuntary movements and criterion of their abnormality. Archives of General Psychiatry, 44:907-912, 1987. Walker, E.F.; Harvey, P.D.; and Perlman, D. The positive/negative distinction in psychoses: A replication and extension of previous findings. Journal of Nervous and Mental Disease, 176:359-363, 1988. Weinberger, D.R.; Cannon-Spoor, E.; Potkin, S.G.; and Wyatt, R.J. Poor premorbid adjustment and CT scan abnormalities in chronic schizophrenia: An association with poor response to therapy. Archives of General Psychiatry, 37: 1 l-13, 1980a. Weinberger, D.R.; DeLisi, LE.; Neophytides, A.N.; and Wyatt, R.J. Familial aspects of CT scan abnormalities in chronic schizophrenic patients. Psychiatry Research, 4:65-7 1, 198 1. Weinberger, D.R.; Kleinman, J.E.; Luchins, D.J.; Bigelow, L.B.; and Wyatt, R.J. Cerebellar pathology in schizophrenia: A controlled post-mortem study. American Journal of Psychiatry, 137:359-361, 19806. Williams, A.O.; Reveley, M.A.; Kolakowska, T.; Ardern, M.; and Mandelbrote, B.M. Schizophrenia with good and poor prognosis: II. Cerebral ventricular size and its clinical significance. British Journal of Psychiatry, 146:239-246, 1985. Yee, R.D.; Baloh, R.W.; Marder, S.R.; Levy, D.L.; Sakala, SM.; and Honrubia, V. Eye movements in schizophrenia. Investigative Opthalmology and Visual Science, 28:366-374, 1987.
Psychiatry Research, 34~89-97
Elsevier
Smooth Pursuit Eye Tracking Symptoms in Schizophrenia Peter Kelly, Chris Rennie, and Russell Meares
Dysfunction
Evian Gordon,
and Negative
John Anderson,
Alan Howson,
Received August 24. 1989; revised version received May 16, 1990; accepted July 21, 1990. Abstract.
This study examined the hypothesis that negative symptoms are associated with abnormalities of smooth pursuit in schizophrenic patients. The pursuit eye movements of 25 subjects with schizophrenia and 25 matched normal control subjects were recorded using an infrared eye tracking system and quantified using the log of signal-to-noise ratio (In S/N). The severity of negative symptoms within the schizophrenic group was rated using the Scale for the Assessment of Negative Symptoms. Previous findings of pursuit abnormalities among schizophrenic patients as a group were replicated. There was, however, no significant association between the eye tracking dysfunction and the severity of negative symptoms. Key Words. Schizophrenia, eye tracking dysfunction, smooth pursuit abnormalities, negative symptoms, type II syndrome.
Smooth pursuit eye tracking dysfunction has been found in schizophrenic subjects in a large number of studies (Holzman et al., 1973, 1974; Shagass et al., 1974; Brezinova and Kendell, 1977; Pass et al., 1978; Salzman et al., 1978; Cegalis and Sweeney, 1979; Karson, 1979; May, 1979; Mialet and Pichot, 1981; Tomer et al., 1981; Iacono et al., 1982; Schmid-Burgk et al., 1982; Cegalis et al., 1983; Bartfai et al., 1983, 1985; Siever et al., 1986; Yee et al., 1987). These studies have found deviant eye tracking in 50-8670 of schizophrenic subjects, but in < 10% of normal control subjects (Lipton et al., 1983). Similar results have been found using a variety of stimulus types, recording methods, and means of quantification (Holzman et al., 1973, 1974; Shagass et al., 1974; Pass et al., 1978; Cegalis and Sweeney, 1979; Bartfai et al., 1983; Siever et al., 1986). The persistence of tracking abnormalities after the remission of acute symptoms (Holzman et al., 1973, 1974; Shagass et al., 1974; Iacono et al., 1981; Bartfai et al.,
Peter Kelly, M.B., B.S., is a Research Fellow of the New South Wales Institute of Psychiatry. Christopher Rennie, B.Sc., M.Biomed.Eng., is a medical physicist, the Department of Medical Physics, Westmead Hospital. Evian Gordon, B.Sc.(Hons.), M.B., B.S., Ph.D., is Senior Lecturer in Psychiatry, the University of Sydney, and Head of Cognitive Neuroscience Unit, Westmead Hospital. John Anderson, B.Pharm., M.Litt., is a research assistant, the Neuroscience Unit, Westmead Hospital. Alan Howson, M.A., is from the Department of Economics, Macquarie University. Russell Meares, M.D., D.P.M., F.F.A.N.Z.C.P., M.R.C.Psych., is Professor of Psychiatry, the University of Sydney. (Reprint requests to Dr. E. Gordon, Dept. of Psychiatry, Westmead Hospital, Sydney, New South Wales, Australia, 2145.) 01651781/90/$03.50
@ 1990 Elsevier Scientific
Publishers
Ireland
Ltd
90 1983) suggests that dysfunctional smooth pursuit may be a trait rather than a state variable in schizophrenia. It may also be a trait variable in schizotypal personality disorder (Siever et al., 1984). In contrast, tracking abnormalities may be a state variable in affective disorders (Lipton et al., 1983) and in central nervous system lesions (Corvera et al., 1973; Spooner et al., 1980; Leigh and Zee, 1983). One group has found eye tracking abnormalities in association with increased ventricular-brain ratios in schizophrenic subjects (Weinberger et al., 1981) while others have not (Bartfai et al., 1983; Siever et al., 1986). The negative, or type II schizophrenic, syndrome (Crow, 1980, 1985) is characterized by negative symptoms (narrowly defined as flattening of affect and poverty of speech), poor response to neuroleptics, and chronicity (Sommers, 1985). Objective assessment of this “subtype” of schizophrenia has been aided by the development of “dedicated” scales for use in rating negative symptoms (Lewine et al., 1983; Iager et al., 1985; Kay et al., 1987) of which the Scale for the Assessment of Negative Symptoms (SANS) of Andreasen (1984~) is the most widely used (Walker et al., 1988). Changes on computed tomography (CT) such as ventricular dilatation, and cerebellar and sulcal atrophy (Reveley, 1985), have been found in association with negative symptoms (Andreasen, 1982; Williams et al., 1985), as have components of the negative syndrome such as poor premorbid adjustment (Weinberger et al., 1980~; Williams et al., 1985), poor treatment response (Weinberger et al., 1980b; Kling et al., 1983), unfavorable outcome (Williams et al., 1985), and neuropsychological impairment (Golden et al., 1980; Keilp et al., 1988). In addition, negative symptoms are associated with neurological signs such as abnormal involuntary movements (Owens et al., 1980) and vulnerability for developing tardive dyskinesia (Waddington et al., 1987). In summary, it would seem that both a “subtype” of schizophrenia and a dysfunction in smooth pursuit eye tracking have been associated with structural brain damage. The type II syndrome and pursuit abnormalities may therefore be associated with each other. No previous study has used a rating scale of negative symptomatology to examine the relationship between negative symptoms and pursuit abnormalities. There have, however, been a number of studies suggesting a correlation between pursuit abnormalities and negative symptomatology. Holzman et al. (1974) found eye tracking dysfunction in 86% of chronic schizophrenic patients but in only 52Y0 of recently diagnosed patients. Two other studies have looked at poor premorbid adjustment and pursuit abnormalities (Bartfai et al., 1983; Siever et al., 1986). Both failed to find significant correlations, although the small size of the study groups (12 and 14, respectively) may have contributed to this failure. Bartfai et al. (1983, 1985) did find poor pursuit tracking associated with previous hospitalization and increasing age. Iacono (1988) found that the presence of pursuit abnormalities predicted poor outcome at 18-month followup in a group of first-episode schizophrenic patients. Simons and Katkin (1985) found an increased prevalance of abnormal pursuit in normal controls with high scores on a rating scale for physical anhedonia, a component of the negative syndrome in schizophrenic subjects. In this study, we explicitly examine the presence and severity of negative symptoms, as measured by the SANS as the index of the type II syndrome, and the
91 relationship schizophrenic
of this
measure
and normal
with
control
quantifications subjects.
of eye tracking
The experimental
dysfunction
hypotheses
were
in that
the mean log signal-to-noise ratio (In S/N) would be less in schizophrenic subjects than in normal controls; and that among schizophrenic subjects, the In S/N would be negatively correlated with the SANS score.
Methods Subjects. Fifty subjects were studied: 25 patients with a diagnosis of schizophrenia and 25 age-matched normal controls. All patients were aged between 17 and 52 (mean 30.3 years; SD 7.2). The mean age of onset of schizophrenia was 21.7 years (SD 5.5), and the mean duration of illness was 8.6 years (SD 5.3). Normal controls were matched for age (within 5 years) and sex. The mean age of normal control subjects was 28.5 years (SD 5.5 years). A two-sample t test performed to compare age between the two experimental groups showed no significant difference. There were 19 men and 6 women in each group. No subjects had significant preexisting medical conditions (such as epilepsy or head injury), family history of psychiatric disorder, or were on current nonpsychotropic medications. Six of the schizophrenic subjects were not on antipsychotic medication. Of the remaining subjects, the average daily dose of antipsychotic (expressed in mg of chlorpromazine equivalents) was 300 chlorpromazine equivalents, with a range of 100 to 800 daily. Subjects on lithium or barbiturates were excluded because of the influence of these drugs on smooth pursuit function. Diagnostic Measures. The schizophrenic subjects underwent a diagnostic interview using the schizophrenia and mania sections of the Composite International Diagnostic Interview Core Version (CIDI-C; Robins et al., 1987) to confirm lifetime diagnoses of schizophrenia according to DSM-III-R criteria (American Psychiatric Association, 1987). The interviews were performed by two of the investigators, who had been trained in the use of this instrument. Schizophrenic subjects also underwent an unstructured interview which dealt with social, recreational, and employment issues. The information obtained from the CIDI-C and the unstructured interview was used to complete the Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1984~) and the Scale for the Assessment of Positive Symptoms (SAPS; Andreasen, 19846). Intertester reliability of SANS and SAPS scores was not formally assessed. Final scores were obtained by averaging the two raters’ scores. The mean SANS score for schizophrenic subjects was 11.9 (SD 4.2), and the mean SAPS score was 7.2 (SD 4.3). Recording of Eye Tracking. The system used in this project consists of an optics assembly unit and a low-light television camera (used to record eye position) and a video screen directly above this (for presentation of stimuli). The optics assembly unit has a lamp which generates a beam of near-infrared light (of wavelength 700-l 100 nm). (The light was of sufficiently low intensity not to cause distraction to the subject.) A half-reflecting mirror set at 45’ to the camera’s optical axis resulted in a beam of light that was colinear with the camera’s line of sight. The image of the eye recorded by the camera was sampled at 50 Hz, and this digital image was then analyzed by a series of software algorithms that determined the cornea1 reflection and the pupil boundary. The relative position of the cornea1 reflection and the pupil center, after calibration, gave a linear output of eye gaze position corrected for individual variations. Eye coordinates could then be reported in digital form to a host computer. The host computer, an IBM-XT, was responsible for data acquisition and generation of the target stimuli. The error of resolution when determining eye position was approximately 0.75O of visual angle. The experiment was conducted in a room with stable light conditions throughout the session. The subjects were kept at a standard distance from the eye gaze monitor-60 cm from the eye to the center of the video screen. They were seated in a comfortable chair with adjustable height and a headrest.
92 The fixation point target was displayed on the screen and the subject was asked to fixate on it until the trial began. The subject was asked to try to blink as infrequently as possible during the trial. When the trial started, the target moved backward and forward across the screen along the horizontal plane with a sinusoidal velocity at a frequency of 0.4 Hz, subtending an angle of 15”. The eye tracking was recorded for 50 sec. Four such trials were undertaken. Data Analysis. Quantitative analysis of the data obtained from this paradigm used the log of the signal-to-noise ratio (In S/N) as proposed by Lindsey et al. (1978). Other indices of pursuit abnormality, such as gain, were not used because of the low sampling rate (50 Hz) of the technology used (Yee et al., 1987). The sine wave of best fit was subtracted from the subject’s actual eye tracking record. This subtraction waveform then underwent a Fast Fourier Transformation (FFT), and the contribution of the “power” of this subtraction waveform as a percentage of the total “power”in the eye tracking record was calculated. The frequency band that was examined in our quantification of eye tracking deviance was 0 Hz to 10 Hz as components of frequencies higher than 10 Hz seemed to make little or no contribution to the total power. In the In S/N measure, the total power in the subtraction waveform was defined as “noise,” and the subtraction of this percentage from 100% as “signal.” The “signal” score was then divided by the “noise” score and the logarithm to base e derived. This value was calculated for each of a subject’s four runs, and the highest score was used for between-group comparisons and for correlations with clinical status. Because the In S/N measures scores for schizophrenic subjects were found to be bimodally distributed, nonparametric techniques were used for subsequent analyses. Comparisons between schizophrenic subjects and normal controls on the In S/N measure used the Mann-Whitney U test, and the relationship between the In S/N scores and clinical variables was examined using the Spearman rank correlation coefficient.
Results The In S/N scores for the schizophrenic subjects were bimodally distributed, with 5 of the 25 subjects having markedly deviant eye tracking performance (all having scores below 3.0; mean 2.45). The remaining 20 schizophrenic subjects had near normal tracking performance (with the lowest score 3.62; mean 4.74). Table 1 lists the mean In S/N values for the schizophrenic group as a whole and for the normal control group. A Mann-Whitney U test (MWUT) demonstrated significant group differences between the schizophrenic group and normal controls (p = 0.031). A MWUT also demonstrated significant differences between the two groups of schizophrenic subjects delineated @ = O.OOl), but no difference between normal controls and the schizophrenic group with the better eye tracking performance.
Table 1. Group comparisons of the log of the signal-to-noise ratio (In S/N) scores In SIN Mean
SD
Schizophrenia
4.28
1.17
Normal controls
4.88
0.48
Group
Within the schizophrenic group, there were no significant differences on the MWUT between those who were and those who were not receiving antipsychotic medications (p = 0.70). Eight out of 25 schizophrenic subjects were drug free; in
93
addition, two out of the five subjects with the most deviant eye tracking performance were drug free. As mentioned above, 16 of the 50 subjects studied were women; there were no significant differences between men and women in eye tracking performance @ = 0.86). Table 2 contains the Spearman rank order correlation coefficients of the In S/N score and clinical variables among schizophrenic subjects. Of most importance, the correlation between the In S/N measure and the SANS score was -0.076. There were Table 2. Correlation coefficients of the log of the signal-to-noise S/N) with demographic and clinical variables Variable
Spearman rank order correlation
SANS
-0.076
SAPS
-0.38 0.016
Age Age of onset
SANS = Scale for the Assessment Symptoms.
Sianificance p > 0.05 p > 0.05 p > 0.05
-0.32
p > 0.05
0.18
p > 0.05
Duration of illness
Note.
ratio (In
of Negative Symptoms.
SAPS = Scale for the Assessment
of Positive
no other significant correlations, although the correlation between the SAPS score and In S/N almost achieved statistical significance. This seems to reflect the differing SAPS scores in the two groups of schizophrenic subjects (“deviant” group’s median = 11.0; “normal” group’s median = 5.5; MWUT significant at p = 0.032). Repeated MWUTs comparing SANS score, age, and duration of illness between the two schizophrenic groups failed to reveal statistical differences. Discussion
There was no significant association of eye tracking dysfunction with the severity of negative symptoms, as measured by SANS score, in this study. The Spearman Rank order correlation coefficient of the SANS and In S/N scores was -0.076. This preliminary finding suggests that pursuit dysfunction is not associated with the negative syndrome as measured by the SANS-despite the fact that pursuit abnormalities found in the schizophrenic group compared to normal controls replicated similar findings in earlier studies. If schizophrenia comprises two syndromes (Crow, 1980, 1985), each with different underlying pathologies, then it would seem appropriate to explore the possibility of specific vulnerability markers for these syndromes. That abnormalities of smooth pursuit may be markers of organic damage (Leigh and Zee, 1983) seems to have been established. In schizophrenia, eye tracking dysfunction would therefore more likely be associated with the negative, or type II syndrome, than the positive syndrome. A critical analysis of a number of study limitations is necessary in the assessment of these preliminary findings. The study had specific sample characteristics that require comment. The distinction between negative symptoms and the negative syndrome (Andreasen, 1985) is of particular relevance. This study examined subjects in
94 a cross-sectional manner. Although pursuit abnormalities appear to be stable over time in schizophrenic subjects, an important part of the definition of the type II syndrome is its natural history and prognosis. Typically, negative symptoms are longlasting and worsen over time (Crow, 1985). In a cross-sectional study, it is quite possible that a subject who will later develop a severe negative syndrome may be given a low score on current negative symptoms. The converse situation is also possible, although less likely (Carpenter et al., 1985). Previous research offers an important parallel in this regard. Earlier crosssectional studies (Bartfai et al., 1983; Siever et al., 1986) failed to find an association between poor premorbid adjustment, one component of the negative syndrome, and pursuit dysfunction. This contrasts with the findings of a longitudinal study (Iacono, 1988) of a positive association between poor outcome at 18-month followup (another component of the negative syndrome) and pursuit dysfunction. A longitudinal study of eye tracking abnormalities, in which multiple aspects of the negative syndrome were assessed serially, would be the most appropriate approach to the study of the interrelationships of these phenomena. The replication of group differences in pursuit abnormalities between schizophrenic patients and normal control subjects is notable in this study, since it may provide indirect evidence that the failure to confirm the specific hypothesis is unlikely to be merely the reflection of a difference in experimental paradigm between this and earlier studies. We have used one of the two usual means of recording eye movements (cf. Levin et al., 1982), a standard stimulus and experimental method (cf. Shagass et al., 1974; Iacono et al., 1982), and a widely accepted method of the quantification of global tracking performance (Lindsey et al., 1978). The demographic and historical characteristics of the schizophrenic subjects in this study may also have some bearing on the results. The group examined was comparatively young (mean age 30.3 years), with a mean duration of illness of 8.6 years. Only five subjects were hospitalized at the time of testing. Because the subjects were young and lived largely in the community, they were likely to have low negative symptom scores. However, there was a range of SANS scores within this population. Three subjects had SANS scores > 20, and five subjects had SANS scores between 15 and 20. These figures represent significant morbidity from negative symptoms within the population studied. It is unlikely, therefore, that the failure to confirm the experimental hypothesis arose from peculiarities in the distribution of negative symptoms within this population. In addition, the correlation between subject age and In S/N scores was only 0.018, indicating that age had no significant effect on the pursuit abnormalities found. Nor was there any significant correlation of tracking abnormalities with clinical variables, such as age of onset, duration of illness, and dosage of antipsychotic medication. It is important to note that the correlation between eye tracking abnormalities (In S/N) and positive symptoms (SAPS) almost achieved significance, and that there were significantly higher SAPS scores in those schizophrenic subjects in the group with more deviant tracking. Previous research (Holzman et al., 1973, 1974; Shagass et al., 1974, Iacono et al., 1981; Bartfai et al., 1983) has failed to find a relationship between tracking deviance and acute or positive symptoms in longitudinal studies,
95
which suggests differences in the composition of illness features in the subjects of this study. The negative correlation between SANS and SAPS scores in the schizophrenic group (Spearman rank order correlation coefficient = -0.367, p > 0.05) suggests that the population studied contained a high number of young patients with inversely correlated SANS and SAPS scores. Replication in other populations is thus clearly indicated. Despite the lack of support for the proposed association between negative symptoms and pursuit abnormalities in this study, further research is indicated. Future studies could incorporate the concurrent assessment of structural brain changes in schizophrenic subjects. The use of CT scans would address the objection that any discovered association between eye tracking dysfunction and the negative syndrome might merely reflect a shared association with organicity. In addition, Levin (1984a, 19846) has suggested that abnormalities of frontal lobe function underlie the negative syndrome in schizophrenia and also cause abnormalities of smooth pursuit. This hypothesis might be examined by tests of frontal lobe function, performed concurrently with the recording of eye movements and clinical assessment. Bartfai et al. (1985) found a positive association between poor eye tracking and poor performance on tests of frontal lobe function, such as the Trail-Making Test. The incorporation of these features into a longitudinal experiment examining negative and positive symptoms and eye tracking dysfunction may help illuminate the possible interrelationships among these disparate findings. Acknowledgments.
The New South Wales Institute of Psychiatry and IBM Australia
provided support. References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 1987. Andreasen, N. Negative symptoms in schizophrenia: Definition and reliability. Archives of General Psychiatry, 39:784-788, 1982. Andreasen, N. Scale for the Assessment
of Negative Symptoms.
of Iowa, 1984a. Andreasen, N. Scale for the Assessment of Positive Symptoms.
Iowa City: The University
Iowa City: The University of Iowa, 1984b. Andreasen, N.C. Positive vs. negative schizophrenia: A critical evaluation. Schizophrenia Bulletin, 11:380-389, 1985. Bartfai, A.; Levander, SE.; Nybkk, H.; Berggren, B.M.; and Schalling, D. Smooth pursuit eye tracking, neuropsychological test performance, and computed tomography in schizophrenia. Psychiatry Research, 1549-62, 1985. Bartfai, A.; Levander, S.E.; and Sedvall, G. Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients. Biological Psychiatry, 18:971-987, 1983. Brezinova, V., and Kendell, R.E. Smooth pursuit eye movements of schizophrenics and normal people under stress. British Journal of Psychiatry, 13059-63, 1977. Carpenter, W.T.; Heinrichs, D.W.; and Alphs, L.D. Treatment of negative symptoms. Schizophrenia Bulletin, 11440-452, 1985. Cegalis, J.A.; Hafez, H.; and Wong, P.S. What is deviant about deviant smooth pursuit eye movements in schizophrenia? Psychiatry Research, 10:47-58, 1983.
96
Cegalis, J.A., and Sweeney, J.A. Eye movements in schizophrenia: A quantitative analysis. Biological Psychiatry, 14: 14-26, 1979. Corvera, J.; Torres-Courtney, G.; and Topez-Rioz, G. The neurotological significance of alterations in pursuit eye movements and the pendular eye tracking test. Annals of Otology, Rhinology and Laryngology, 82:855-867, 1973. Crow, T.J. Molecular pathology of schizophrenia: More than one disease process? British Medical Journal, 280:66-68, 1980. Crow, T.J. The two syndrome concept: Origins and current status. Schizophrenia Bulletin, 11:471486, 1985. Golden, C.J.; Moses, J.A.; Zelazowski, R.; Graber, B.; Zatz, L.N.; Horvath, T.B.; and Berger, P.A. Cerebral ventricular size and neuropsychological impairment in young chronic schizophrenics: Measurement by the standardized Luria-Nebraska Neuropsychological Battery. Archives of General Psychiatry, 37:619-623, 1980. Holzman, P.S.; Proctor, L.R.; and Hughes, D.W. Eye tracking patterns in schizophrenia. Science, 181:179-181, 1973. Holzman, P.S.; Proctor, L.R.; Yasillo, N.J.; and Levy, D. Eye tracking patterns in schizophrenia. Science, 184: 1203-1204, 1974. Iacono, W.G. Eye movement abnormalities in schizophrenic and affective disorders. In: Johnston, C.W., and Pirozzolo, F.J., eds. Neuropsychology of Eye Movements. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. Iacono, W.G.; Peloquin, L.J.; Lumry, A.E.; Valentine, R.H.; and Tuason, V.B. Eye tracking in patients with unipolar and bipolar affective disorders in remission. Journal of Abnormal Psychology, 91:3544, 1982. Iacono, W.G.; Tuason, V.B.; and Johnson, R.A. Dissociation of smooth pursuit and saccadic eye tracking in remitted schizophrenics: An ocular reaction time task that schizophrenics perform well. Archives of General Psychiatry, 38:991-996, 1981. Iager, A.C.; Kirch, D.G.; and Wyatt, R.J. A negative symptom rating scale. Psychiatry Research, 16:27-36, 1985. Karson, C.G. Oculomotor signs in a psychiatric population: A preliminary report. American Journal of Psychiatry, 136:1057-1060, 1979. Kay, S.R.; Fiszbein, A.; and Opler, L.A. The positive and negative symptom scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13:261-276, 1987. Keilp, J.G.; Sweeney, J.A.; Jacobsen, P.; Solomon, C.; St. Louis, L.; Deck, M.; Frances, A.; and Mann, J.J. Cognitive impairment in schizophrenia: Specific relations to ventricular size and negative symptomatology. Biological Psychiatry, 24147-55, 1988. Kling, A.S.; Kurtz, N.; Tachiki, K.; and Orzeck, A. CT scans in subgroups of chronic schizophrenics. Journal of Psychiatric Research, 17:375-384, 1983. Leigh, R.J., and Zee, D.S. 77re Neurology of Eye Movements. Philadelphia: F.A. Davis, 1983. Levin, S. Frontal lobe dysfunctions in schizophrenia: I. Eye movement impairments. Journal of Psychiatric Research, 18:27-55, 1984a. Levin, S. Frontal lobe dysfunctions in schizophrenia: II. Impairments of psychological and brain functions. Journal of Psychiatric Research, 18:57-72, 19846. Lewine, R.J.; Fogg, L.; and Meltzer, H.Y. Assessment of negative and positive symptoms in schizophrenia. Schizophrenia Bulletin, 9:368-376, 1983. Lindsey, D.T.; Holzman, P.S.; Haberman, S.; and Yasillo, N.J. Smooth pursuit eye movements: A comparison of two measurement techniques for studying schizophrenia. Journal of Abnormal Psychology, 87:491-496, 1978. Lipton, R.B.; Levy, D.L.; Holzman, P.S.; and Levin, S. Eye movement dysfunctions in psychiatric patients: A review. Schizophrenia Bulletin, 9: 13-32, 1983. May, H.J. Oculomotor pursuit in schizophrenia. Archives of General Psychiatry, 36:827, 1979. Mialet, J.P., and Pichot, P. Eye tracking patterns in schizophrenia: An analysis based on the incidence of saccades. Archives of General Psychiatry, 38: 183-186, 198 1.
97 Owens, D.G.; Johnstone, E.C.; and Frith, C.D. Spontaneous involuntary disorders of movement: Their prevalence, severity and distribution in chronic schizophrenics with and without treatment with neuroleptics. Archives of General Psychiatry, 39:452-461, 1982. Pass, H.L.; Salzman, L.F.; Klorman, R.; Kaskey, G.B.; and Klein, R.B. The effect of distraction on acute schizophrenics’ visual tracking. Biological Psychiatry, 13587-593, 1978. Reveley, M.A. CT scans in schizophrenia. British Journalof Psychiatry, 146:367-371, 1985. Robins, L.N.; Wing, J.; and Helzer, J. Composite International Diagnostic Interview Core Version (CZDZ-C). Geneva: World Health Organization, 1987. Salzman, L.F.; Klein, R.H.; and Strauss, J.S. Pendulum eye-tracking in remitted psychiatric patients. Journal of Psychiatric Research, 14:121-126, 1978. Schmid-Burgk, W.; Becker, W.; Diekmann, V.; Jurgens, R.; and Kornhuber, H.H. Disturbed smooth pursuit and saccadic eye movements in schizophrenia. Archiv fur Psychiatric und Nervenkrankenheiten, 232:381-289, 1982. Shagass, C.; Amadeo, M.; and Overton, D.A. Eye-tracking performance in psychiatric patients. Biological Psychiatry, 9:245-260, 1974. Siever, L.J.; Coursey, R.D.; Alterman, 1,s.; Buchsbaum, MS.; and Murphy, D.L. Impaired smooth pursuit eye movement: Vulnerability marker for schizotypal personality disorder in a normal volunteer population. American Journal of Psychiatry, 141:1560-1566, 1984. Siever, L.J.; van Kammen, D.P.; Linnoila, M.; Alterman, I.; Hare, T.; and Murphy, D.L. Smooth pursuit eye movement disorder and its psychobiologic correlates in unmedicated schizophrenics. Biological Psychiatry, 21: 1167-l 174, 1986. Simons, R.F., and Katkin, W. Smooth pursuit eye movements in subjects reporting physical anhedonia and perceptual aberrations. Psychiatry Research, 14~275-289, 1985. Sommers, A. “Negative symptoms”: Conceptual and methodological problems. Schizophrenia Bulletin, 11:364-379, 1985. Spooner, J.W.; Sakala, S.M.; and Baloh, R.W. Effect of aging on eye tracking. Archives of Neurology, 37:575-576, 1980. Tomer, R.; Mintz, M.; Levy, A.; and Myslobodsky, M. Smooth pursuit pattern in schizophrenic patients during cognitive task. Biological Psychiatry, 16: 13 l-144, 198 1. Waddington, J.L.; Youssef, H.A.; Dolphin, C.; and Kinsella, A. Cognitive dysfunction, negative symptoms, and tardive dyskinesia in schizophrenia: Their association in relation to topography of involuntary movements and criterion of their abnormality. Archives of General Psychiatry, 44:907-912, 1987. Walker, E.F.; Harvey, P.D.; and Perlman, D. The positive/negative distinction in psychoses: A replication and extension of previous findings. Journal of Nervous and Mental Disease, 176:359-363, 1988. Weinberger, D.R.; Cannon-Spoor, E.; Potkin, S.G.; and Wyatt, R.J. Poor premorbid adjustment and CT scan abnormalities in chronic schizophrenia: An association with poor response to therapy. Archives of General Psychiatry, 37: 1 l-13, 1980a. Weinberger, D.R.; DeLisi, LE.; Neophytides, A.N.; and Wyatt, R.J. Familial aspects of CT scan abnormalities in chronic schizophrenic patients. Psychiatry Research, 4:65-7 1, 198 1. Weinberger, D.R.; Kleinman, J.E.; Luchins, D.J.; Bigelow, L.B.; and Wyatt, R.J. Cerebellar pathology in schizophrenia: A controlled post-mortem study. American Journal of Psychiatry, 137:359-361, 19806. Williams, A.O.; Reveley, M.A.; Kolakowska, T.; Ardern, M.; and Mandelbrote, B.M. Schizophrenia with good and poor prognosis: II. Cerebral ventricular size and its clinical significance. British Journal of Psychiatry, 146:239-246, 1985. Yee, R.D.; Baloh, R.W.; Marder, S.R.; Levy, D.L.; Sakala, SM.; and Honrubia, V. Eye movements in schizophrenia. Investigative Opthalmology and Visual Science, 28:366-374, 1987.
