W24989j92 55,oO + 0.00 Copyright C 1992 Pergamon Press Ltd

Vision Res. Vol. 32, No. 6, pp. 1~9-1014, 1992 Printed in Great Britain. All rights reserved

Minireview Abnormalities of Smooth Pursuit and Saccadic Control in Schizophrenia and Affective Disorders L. A. ABEL,* S. LEVIN,?

P. S. HOLZMAN~

Receitled I7 October 1991

Smooth pursuit abnormalities have heen reported in patients with schizophrenia and their first-degree relatives, suggesting that abnormal tracking may serve as a biological marker for ~h~ophrenia. Recent studies in schizophrenic patients have found reduced pursuit gain, low initial acceleration and abnormal gain-corrective saccade interactions. Impaired saccadic initiation has heen noted in anti-saccade tasks and in predictive saccade ge~ration, as has saccadic h~rne~Ia. WhiL a~o~aIities have been found in affective disorder patients, studies of their firstdegree relatives suggest that abnormalities during pursuit are more closely associated with schizophrenia. Identification of specific defects allows informed specuiation ahout tkeir neural substrates and suggests possible relation~i~ between the ocular motor defects and other cognitive and perceptual abnormalities associated with the major psychiatric disorders. Schizophrenia

Eye movements

Smooth

pursuit

INTRODUCTION Because of a burgeoning interest, on the part of psychopathologists and neuroscientists, in the usefulness of eye movement abnormalities in genetic and pathophysiologic studies of major mental illnesses, we present here a brief review of the principal empirical findings and our assessment of the major issues in this field. We wish to illustrate to the vision reseach community how recent studies in this field have advanced our understanding of the mechanisms underlying these disorders. Although eye movements of patients with schizophrenia and manic depressive illness were recorded in one of the earliest clinical studies of ocular motility (Diefendorf & Dodge, 1908), agreement about the precise nature of the defects found in these patients has remained elusive. Modern studies of eye movements in major mental disorders began with the work of Holzman et al. (Holzman, Proctor & Hughes, 1973) who described smooth pursuit abnormalities in 50-80% of schizophrenics and in 40% of their first-degree relatives, compared to about 8% of the normal population (Holzman, Proctor, Levy, Yasillo, Meltzer & Hurt, 1974; Holzman, Kringlen, Levy & Proctor, 1977; Holzman, Solomon, Levin & Waternaux, 1984). *Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202-5175. U.S.A. Kate of McLean Hospital and Harvard University, Boston. U.S.A. department of Psychology, Harvard University and McLean Hospital, Boston. U.S.A.

Saccades

The early work of Holzman and his colleagues evaluated pursuit eye movements by classifying electroo~ulographic tracings as either normal or abnormal, or used a 4 or 5 point rating scale (Benitez, 1970). But qualitative evaluation had the fundamental shortcoming that it was a global assessment and could neither identify nor quantify the specific factors that made eye tracking abnormal. For example, either low pursuit gain or frequent saccadic intrusions could give rise to equivalent qualitative ratings, yet reflect different etiologies of eye tracking dysfunction (Abel & Ziegler, 1988). Other quantitative measures were subsequently introduced to circumvent the subjectivity of rating scales, including the natural logarithm of the signal-to-noise ratio (Lindsey, Holzman, Haberman & Yasillo, 1978) and the rootmean-square error (RMSE) (Iacono & Lykken, 1979). Although these measures are quantitative, neither indicates with any specificity how the eye fails to follow the target (Abel & Ziegler, 1988). Although the nature of defective pursuit in schizophrenic patients remained unidentified, numerous studies replicated the basic findings of abnormal eye tracking in schizophrenic patients and of their first-degree relatives (Holzman et al., 1974, 1977, 1984; Holzman, Kringlen, Levy & Haberman, 1980; Iacono, Bassett & Jones, 1988; Hoizman, 1989; Clementz, Sweeney, Hirt & Haas, 1990). It became clear that the eye tracking abnormalities could not be ascribed to anti-psychotic medication (Holzman, Levy, Uhlenhuth, Proctor & Freedman, 1975; Holzman, 1985) or to ordinary

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inattention or lack of motivation (Holzman, Levy & Proctor, 1976; Lipton, Frost & Hoizman, 1980; van den Bosch. 1984; Holzman, 1985). Lithium salts, however, were shown to produce eye tracking dysfunctions (facono, Peloquin, Lumry, Valentine & Tuason, 1982: Levy, Dorus, Shaughnessy, Yasillo, Pandey, Janicak. Gibbons. Gaviria & Davis, 1985; Holzman, O’Brian & Waternaux, 1991), particularly in bipolar disorder patients. With the introduction of i.r. recording techniques, and the collaboration between ocular motor scientists, neurologists, and psychologists. a more precise understanding of the nature of the defects began to develop. QUANTITATIVE Sl-UDlES Smooth pursuit

Recent quantitative studies have documented several distinct pursuit abnormalities in psychiatric patients. particularly in schizophrenic patients. Low pursuit gain (the ratio of eye velocity to target velocity) was first identified in a group of schizophrenics by Levin. Jones. Stark, Merrin and Holzman (1982), but no statistical comparisons with a control group were made. Significant reductions in gain in schizophrenic patients vs normals when tracking predictable targets were described in several studies (Schmid-Burgk, Becker. Diekmann. Jurgens & Kornhuber. 1982; Yee. Baloh. Marder, Levy, Sakala & Honrubia, 1987; Levin. Luebke. Zee. Hain, Robinson & Holzman. 1988; Litman. Hommer, Clem, Rapaport. Pato & Pickar. 1989; Allen. Matsunaga, Hacisalihzade & Stark. 1990: Clementz ct al.. 1990; Moser, Kompf, Arolt & Resch. 1990; Abel, Friedman, Jesberger, Malki & Meltzer. 1991). The average magnitude of these reductions was about IO-25% below normal levels. While a bidirectional gain reduction is a non-specific ocular motor abnormality, recent studies have used stimuli more complex in order to define the pursuit defect in schizophrenics. Levin et al. (1988) used both predictable triangular wave and non-predictable stepramp targets to study 5 schizophrenic patients and 5 controls. Using both small and large field targets. they found that steady-state gain was reduced in patients in all test conditions. The greatest difference between groups was found for the fastest, small field step-tramp stimulus. Initial acceleration to the step-ramp target was also significantly reduced in the patient group. With triangle wave targets, the patients also showed less prediction of the turnaround point in the trajectory. as indicated by a significantly longer interval between direction reversals of eye and target movement. The authors interpreted these findings to indicate that schizophrenic patients were less able to anticipate target motion. even though they. like normal subjects, showed improved performance with predictable stimuli. Defective anticipation was also reported in response to a very different stimulus by Allen et al. ( 1990). In this study, both pure sinusoidal and a sum-of-sines target were presented to schizophrenic patients and normal

controls. In addition to a gam reoucnon tor sInusoIda stimuli. gains were also lower for the patients :-lt each of the frequencies contained in the sum-of-sines target. but less SO than for the individual sinusoids. The unpredictable target also elicited “!ook ahead” saccades. as subjects tried to anticipate future target positIon: schizophrenic patients made fewer of these than did controls. The authors suggested rhat the reduction 11~ saccades reflected yet another example of the reduced capacity of schizophrenic patients to anticipate the course of the target. Such anticipation is an integral part of pursuit behavior (Kowler. Martins & Pavel. 1984’1. Although the patients. like normal subjects. constructed an internal representation of target motion and used this internal model to anticipate future target location. they did so differently from normal subjects. Such failure to anticipate has been ascribed to impaired frontal lobe functioning (Levin et al.. 1988). which has been previously proposed as the site of a range of defects in schizophrenic patients. These speculations are consistent with those offered by Goldman-Rakic (1987) concerning deficits in “working memory” that reflect dysfunctions in the dorsolateral prefrontal cortex. and with the recent empirical findings of Park and Holzman (1993). Smooth pursuil --sac*cadic interac~icm.\

Following ;1 smoothly movmg target requires more than the smooth pursuit system alone. When pursuit gain falls below 1.O. corrective catch-up saccades (CUS) return the image of the target to the fovea. It seems logical to assume that as pursuit becomes increasingly impaired, the rate of CUS generation increases. Indeed. this assumption. at least implicitly. underlies those studies that used saccade frequency as :I measure of pursuit integrity (Mather. Neufield, Merskey & Russell, 1989: Van Gelder. Anderson. Herman. Lebedev & Tsui, 1990). If the relation between gain and CUS rate were fixed and linear. the simple counting of CL’S could substitute for the more laborious measurement of gain. If. however. some subjects tolerate greater position error before correcting, a given gain could elicit fewer. but larger, CUS. Abel et (11.(Abel. Friedman, Jesberger & Meltzer. 1988: Abel ct (II.. 1991) have addressed these issues. For C set targets normal. schizophrenic, and affective disorder subject groups had virtually the same garns, but both patient groups showed significantly lower CUS rates. They also reported the expected significant negative correlation between gain and CUS in normal subjects. and a lower but still statistically significant correlation In schizophrenic patients. Patients with major affective disorders. however, did not show a significant gain--CUS rate correlation. These studies suggest that the saccadic systems of patients and normals may respond in different ways to the error accumulated during pursuit. and that a simple counting of CUS does not yield an unambiguous measure of pursuit integrity. Interaction between the pursuit and saccadic systems during tracking in different subject groups requires further stud!

MINIREVIEW

Attempts to identify the nature of the eye tracking abnormality in psychiatric patients have led a number of ~uv~sti~~t~rsto examine saccades observed during execution of a smooth pursuit task. Most~ et ai. (I9903 examined both gain and the frequency of ~orr~tive and intrusive saccades in schizophrenic patients. They noted that the saccade rate included mostly catch-up, and not intrusive, saccades. They also found a significant increase in saccade rate and a decrease in saccade amplitude in their s~hjzophreni~ patients when compared with normal subjects. Patients also had signi~~antly lower gain. Clementz et aI. (1990) examined square wave jerks (SWJ) and anticipatory saccades (AS) in schizophrenic patients, first-degree relatives, and controls. SWJ did not di~erentiate any of the groups. AS, however, o~~rred significantly more frequently in the relatives, particularly relatives who had some sch~zotypal traits, although the patients themselves showed no elevation in the number of AS. Whicker, Abel and Dell’Osso (1985) had previously reported the prominence of AS in the relatives of ~h~~ophre~i~ patients. Holzman et af. (19911, in a Ion~itudi~aI repeated measures design, examined the effect of lithium salts on several aspects of smooth pursuit perfo~an~e in bipolar patients. quantitative measures included average gain, catch-up and back-up saccades, double saccadic pulses (DSP), SWJ, and AS. They also rated the tracings qualitatively. The quali~t~ve ratings showed that lithium, at levels of I.0 mEq/l, degraded smooth pursuit in 9 of 1I patients. Gain tended to be lower after lithium treatment, but the reduction did not reach conventional levels of statistical si~i~can~e. The total number of all saccades was s~gni~cantly greater when patients were on lithium. The CUS rate increased as gain decreased. DSP also increased during lithium treatment. SWJ and AS showed no group or groin-by-t~rne differences. Thus, in addition to the modest gain decreases, lithium treatment appeared to potentiate the generation of saccades but without a predilection as to type. Several investigators have also examined performance of schizophrenic patients snd controls on a range of saccadic tasks, with normal latency, accuracy, and vefocity being reported in several studies ffacono, Tuason & Johnson, 1981; Levin et al.. 1982; Yee ef al., 1987). Schmid-Burgk, Becker, Jwrgens and Kornhuber (1983), however, reported that more schizophrenic patients than alcoholic or normaf subjects undershot the target by more than 25%. The most frequently observed saccadic ab~o~ality is impairment on an “anti-saccade” task, where subjects are required to look in an equal and opposite direction from a laterally displaced target. Performance has been found to be impaired by frontal lobe damage (Guitton, Bu~htel & Douglas, f985) and in H~nt~n~t0n.s disease, presumably due to degeneration in the basal ganglia &asker, Zee, Hain, Folstein & Singer, 1987; Tian, Zee, Folstein & Lasker, 1990). One study found that 6 of 12

1011

patients with s~hi~ophren~a performed abno~~lly on this task; 5 of these 6 showed atrophy of the frontal cortex upon CT scan (Fukushima, Fukushima, Chiba, Tanaka, Yamashita & hato, f988). A similar result was reported by Thaker, Kirkpatrick, Buchanan, Ellsberry, Lahti and Tamminga (1989). The anti-saccade deficit was exacerbated in patients with tardive dyskjnes~a (TD), raising the possibility that some of the deficit could be medication-related. Fukushima et al. (19881, howparkinsonisms ascribable to neuroever, stated that “. . . A schizophrenic anti-saccade leptics were not noted”, impaj~ent was described in another study by Thaker, Nguyen and ~~rnrn~nga f1989), which found that although non-TD patients did significantly worse on the task than controls, the performance of TD patients was, in turn, s~gni~~~~y worse than non-TD patients. Other defects of saccadic programming have been observed. Hommer, Radant and Nickolo~ tl990) found that when target timing went from u~pr~i~table to predictable and back to unpredictable, schizophrenic patients had difficulty with the second transition, and made excessive numbers of premature saccades, This result may be another indicator of impai~~nt in the saccadic inhibition function of the frontal eye fieids. Schizophrenic patients, however, were able to adapt to the predictable pattern of saccadic target presentation in the same way as normals. Patients with Huntington’s disease who performed a similar task, however, were unable to team the repetitive, predictable target motion. Genetic hplications

Much evidence supports the view that at least the vulnerability to schizophrenia is genetically transmitted. ~ono~goti~ (MZ) twins have about a 45% and dizygotic (DZ) twins about a. 10% concordance for clinical schizophrenia (Gottesman, Shields & Hanson, 1982). Adoption studies show that schizophrenia tends to run in the bioiogical but not the adoptive Families of offspring born to a schizophrenic mother (Kety, Rosenthal, Wender 6%S~hulsing~r~ i 975). About 4- 10% of the biological first-degree relatives of a schizophrenic patient have the disease, in contrast to c 1% of the adoptive first-degree relatives, These numbers, while quite consistent with a genetic ro’le in the transmission of the disease, are too low to be consistent with single gene Mendelian models of transmission. The finding of eye tracking abnormalities in about 45% of the first-degree relatives of schizophrenic patients suggested that these ocular motor dysfunctions may be associated with a genetic predisposition to schizophrenia. TWO studies of twins discordant for schizophrenia showed that among the clinically discordant twins, pursuit abnormalities were twice as concordant among the MZ as among the DZ twins (Holzman et al., 1977, l%W. These studies suggested that, in rhe absence of clear dja~nosable CNS disease, there appears eo be a significant genetic contribution to eye tracking performance. Studies of the prevalence of eye tracking abnormalities in the families of patients consistently

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reported that from 30 to 45% of the biological firstdegree relatives of schizophrenics show tracking disturbances, compared with 2-12% of family members of patients with bipolar disorder (Holzman et al.. 1974, 1984; Levy, Yasillo, Dorus, Shaughnessy, Gibbons, Peterson, Janicak, Gaviria & Davis, 1983). These studies suggest that while eye tracking abnormalities may occur in many kinds of disease, neurological as well as psychiatric, these abnormalities occur in the unaffected biological relatives of schizophrenics and not of any other psychiatric patient. In a family prevalence study (Holzman et al., 1984) and two early twin studies (Holzman er al., 1977. 1980) a number of schizophrenic patients with normal pursuit eye movements had clinically non-schizophrenic relatives with impaired pursuit. To account for these paradoxical findings, Matthysse. Holzman and Lange (1986) postulated that there is a latent trait which is not directly observable, but which can cause either schizophrenia or abnormal pursuit eye movements, or both. It is the latent trait that is to be regarded as genetically transmitted, rather than the manifest traits of schizophrenia or abnormal tracking. The idea behind the model is that the transmission pattern of the latent trait may be closer to that of a Mendelian gene with high penetrance than either of the manifest traits alone. The latent trait may be regarded as a disease process in the brain that can independently invade one region or another and gives rise to different symptoms depending on which region or system is affected. Since impaired pursuit is much more common than schizophrenia. Matthysse et al. (1986) postulated that the disease process is more likely to invade the smooth pursuit system than the systems involved in schizophrenia. DISCUSSION

The early qualitative reports of poor performance on tracking tasks by schizophrenic patients have now been augmented in recent years by studies focused on specific measures of the function of the smooth pursuit and saccadic systems, as well as their interactions. These studies have reported a number of identifiable, reproducible abnormalities of pursuit and saccadic performance, thus making it possible to identify the underlying neural substrates. Relating the ocular motor defects to perceptual and cognitive abnormalities should advance our understanding of the neurobiology and perhaps the genetics of schizophrenia. The consistency of the early, qualitative findings led to the formulation of a modified Mendelian latent trait model for the transmission of schizophrenia, and is currently employed, at least as a heuristic aid, in several ongoing studies of chromosomaf linkage analysis. utilizing molecular genetic techniques. The psychiatric research community has now moved beyond the use of global qualitative scores, to examine specific aspects of smooth pursuit and saccadic function. and in this effort, much has been accomplished toward integrating this field into the broader one of eye move-

ment research. As noted m the Introduction, reduced smooth pursuit gain, although non-specific in origin. has been a frequently reproduced finding. The disparity between normal and schizophrenic subjects’ performance increases with increasing target speed (Levin 6’1of., 1988; Abe1 er al., 1991). implying that the defect does not reflect a fixed gain reduction. A similar disparity was noted for initial acceleration in response to step-ramp targets (Levin er al., 1988). Defects in pursuit initiation with step-ramps have been described in monkeys with lesions of middle temporal cortex (Newsome. Wurtz, Dursteler & Mikami, 1985; Lisberger. Morris & Tychsen, 19871 and in humans with lesions of the homologous region (Leigh. 1989). Psychophysical and imaging studies are needed to determine whether functioning of this region appears to be impaired In schizophrenic patients. and perhaps in their relatives. A larger body of investigations suggests that frontal lobe functioning is defective in schizophrenic patients. The reductions in anticipation of pursuit target motion may arise from such defects (Levin et uf.. 1988: .4llen c’f al., 1990). Lesions of the frontal eye fields (FEF) have been shown to reduce pursuit gain in monkeys (Lynch. 1989). but reduced gain has been associated with so many different brain abnormalities that attribution to one neuroanatomical site in particular is problematic. The perseveration of errors in predictive tracking ma) also be related to frontal lobe abnormalities (Hommer & Radant. 1989). Other evidence of frontal lobe Involvement comes from studies of the saccadic system. which report Impaired performance in anti-saccade tasks, a defect seen in patients with frontal lobe lesions. Interpreting results of anti-saccade tasks is complicated by several factors. First. failure to suppress inappropriate saccddes on this task implicates the pathway linking the FEF and the substantia nigra pars reticulata. but provides no more precise localization. Second. the anti-saccade task is more difficult than the usual saccade task. In schizophrenic patients, and in patients with degenerative CNS disease. deficits with specific functional significance must be distinguished from poor performance that is referable to the difficulty of the task itself. a phenomenon referred to by psychopathologists as “generalized deficit” (Chapman & Chapman, 1973). There is yet a third complication: even if the rmti-saccade task is Impaired in patients with FEF lesions (or lesions of the basal ganglia). one cannot infer that all patients with anti-saccade deficits therefore have FEF (or hasa! ganglia) pathology. These issues underscore the importance of obtaining anti-saccade data on patients with 21 broad array of CNS disease and of controlling for task difficulty. The presence of anti-saccade performance decrements in unaffected relatives would strengthen the importance of the finding in schizophrenics. There have been differences between schizophrenic and affective disorder patients reported in catch-up saccade generation (Abel et al.. I991), but such differences are without a known anatomical source. Both the medial temporal cortex and the FEF are possible

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locations for the requisite interaction between pursuit and saccadic systems, but the limited state of current knowledge about programming of corrective saccades makes ascribing a specific substrate very risky. The specificity of eye movement abno~alit~es to schizophrenia is stiI1 under active investigation. The early qualitative studies found statistically greater numbers of people with poor pursuit among the relatives of schizophrenic patients than among the relatives of patients with affective disorders. Thus, although patients with affective disorders may show an elevated prevalence of pursuit dysfunctions (and a significant proportion of those dysfunctions may reflect the effects of lithium treatment}, the speci~city of these dysfunctions may best be assessed by looking at the f&M/y unit. Abnormal eye pursuit tends to aggregate in the families of schizophrenic patients, and for the most part, in those family members who themselves have never suffered from clinical schizophrenia, but not in relatives of affective disorder patients. The relation between eye movement dysfunctions and other co-familial traits (such as schizophrenia spectrum disorders and traits, thought disorder, attentional disturbances~ and the question of whether the relatives of schizophrenics show the same kind of eye tracking impai~ent as the patients, require further study, Quantitative study of ocular motor function in patients with major psychiatric disorders has in recent years provided insights into the genetics and neural substrates of these diseases. By refining these investigations we can anticipate additional insights into their underlying pathology. REFERENCES Abel, L. A. & Ziegler, A. S. (1988). Smooth pursuit eye movements in schizophrenia: What constitutes quantitative assessment? ~i~~~gjeul Ps~c!mzfrJJ, 24, 747-763. Abel, L. A., Friedman. L.. Jesberger. J. & Meitzer. H. Y. (f988). Reiatjonship between catch-up saccade frequency and smooth pursuit gain in schizophrenics and normals. SocierJ~.for Neuroscirnee Abstracts, 14, 796. Abel, I.. A., Friedman, L., Jesberger, J., Malki, A. & Meltzer, H. Y. (199 i 1.Quantitative assessment of smooth pursuit gain and catch-up saccades in schizophrenia and affective disorders, Biological f?~~hiatry, 2% 1063-1072. Alien, J. S.. Matsunga, K., Hacisaiihzade, S. & Stark, L. (1990). Smooth pursuit eye movements of normal and schizophrenic subjectstrackingan unpredictable target. Biolugical ~s&rt~rry, 2~. 705-720. Benitez, J. 1. (1970). Eye tracking and optokinetic tests: ~j~gnostic significance in peripheral and central vestibuiar tests. ~r~r~~~~~.~~~ 80, 834-848. van den Bosch. R. J. (1984). Eye tracking impairment: Attentionai and psychometric correlates in psychiatric patients, Journal qf Psychiorric Research, 18. 277-286.

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structure analysis to eye trackmg dysfuncttons m schlzophrerua and affective disorders. Journal of Psychiatric Research, 20, 57.-65. Moser, A.. Kompf, D.. Arott, V & Resch, 7 (1990). Quantitative analysis of eye movements in schizophrenia. Neuro-ophrhnlmologv, IO. 73-80. Newsome, W. T., Wurtz, R. H., Dursteler. M. K. & Mlkami. A. (1985).

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Acknowledgemena-This study was supported by U.S. Public Health Servtce Grants MH 31340 and MH 31154. by the Scottish Rite Schizophrenia Research Foundation, and by an unrestricted grant to the Department of Ophthalmology, Indiana University, by Research to Prevent Blindness Inc. The authors would like to express their warm appreciation to Deborah L. Levy. Ph D. for her help with the manuscript.