Psychopathology 1990:23:106-114

© 1990 S. Karger AG. Basel 0254-4962/90/0232-010652.75/0

Smooth Pursuit Eye Movements in Schizophrenia: Influences of Neuroleptic Treatment and the Question of Specificity1 13. Kiifferle, A. Friedmann, A. Topilz, P. Foldes, P. Anderer, M. Kulzer, K. Steinberger Psychiatric University Clinic. Vienna. Austria

The occurrence of eye movement dys­ functions in schizophrenia is well estab­ lished. The first report dates from 1908, when Diefendorf and Dodge, in a study of astonishingly high methodological standard, reported that schizophrenic patients showed impaired slow pursuit eye movements, an impairment that was not found in manic depressive patients. Twice in the following decades, similar observations were reported upon, but the nosological specificity was queried [Couch and Fox, 1934; White, 1938]. Although unaware of these former studies. Holzman et al. reported in 1973 that a large number of schizophrenic patients ex­

1 This study was supported in part by grant 'Jubi­ läumsfondsprojekt' 2921. from the Österreichische Nationalbank.

hibited smooth pursuit eye movement (SPEM) dysfunctions, and in a replication study including a number of first-degree rel­ atives 40% of these relatives also showed similar dysfunctions [Holzman et al.. 1974], Studies of normal monozygotic twin pairs and of psychotic monozygotic and dizygotic twin pairs showed that SPEM variability in itself is influenced by genetic factors [Holz­ man et al., 1980]. Since then, high preva­ lence of SPEM dysfunction has been con­ firmed by a series of independent studies using various techniques of measurement and scoring methods. Moreover, we were also able to trace such abnormalities in schizophrenics as compared to healthy con­ trols ar.d we found similar frequencies as Holzman et al. [1973; Saletu et al., 1986]. Especially the genetic findings support the assumption that SPEM may possibly

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Abstract. The authors investigated smooth pursuit eye movements (SPEMs) in 66 schizo­ phrenic and 40 major affective patients and 39 healthy controls. The results showed signif­ icant differences of both patient groups as compared to the controls. Schizophrenics with neuroleptic treatment in the preceding 2 years were significantly more disturbed than the controls, the affective patients and the untreated schizophrenics. Acute neuroleptic medica­ tion and neuroleptic treatment of a duration of 4-6 weeks appear not to significantly influence the quality of SPEMs.

serve as a trait marker for vulnerability to schizophrenia [Erlcnmeyer-Kimling and Cornblatt, 1987], According to the distribu­ tion of these traits within the families of schizophrenic patients, Holzman [1989] sug­ gests a model of genetic transmission that fits an autosomal dominant model, which he calls the ‘genetic latent trait model’. There are still some unsolved questions concerning the validity of dysfunctional SPEMs when serving as a marker in connec­ tion with schizophrenia. One of the main problems is the issue of nosological specific­ ity. Another one is the question of stability over time. In connection with the latter, the possible influence of medication on SPEM has to be considered. Further points of in­ quiry are whether there is any influence of chronicity, and also whether there is an inde­ pendence of psychotic productivity. Clarifi­ cation of these issues is imperative if dis­ turbed SPEM is to effectively serve as a trait marker. Diefendorf and Dodge [1908] failed to find the tracking impairment in patients with affective disorders. Couch and Fox [1934], however, reported that tracking dys­ function was not limited to schizophrenic patients. Some studies presented as a follow­ up to the work of Holzman et al. [1973] indi­ cated that a substantial percentage of pa­ tients with affective disorders also shows ab­ normalities in SPEM [Shagass et al., 1974; Klein et al., 1976; Lipton et al., 1980; Iacono et al., 1982], In quest of a possible explana­ tion, Levy et al. [1985] presented data dem­ onstrating a relationship between treatment with lithium carbonate and impaired SPEMs, a study limited by the small number of patients involved. The fact that abnormal eye tracking is more prevalent in chronic schizophrenics

107

[Holzman et al., 1974; Ccgalis and Sweeney, 1979] may reflect the tendency of chronic schizophrenics to have longer exposure to neuroleptic medication. According to stud­ ies by Holzman et al. [1975], single doses of neuroleptics lower than those generally re­ quired for therapeutic efficacy did not alter SPEMs. Data presented by Levy et al. [1983] gave evidence that treatment over a period of several weeks produced no change in SPEMs compared to performance during un­ medicated trials. Effects of prolonged neuro­ leptic treatment, however, are still a matter of discussion. In a first investiation, a double-blind clin­ ical trial comparing the effects of two differ­ ent neuroleptics (haloperidol and fluperlapine) in 20 schizophrenic patients where measurement of SPEMs was included, we found abnormal SPEMs by means of qualita­ tive evaluation in 55% of the schizophrenics as opposed to 10% of healthy controls, a result which is comparable to those of Holz­ man et al. [1973; Saletu et al., 1986], Com­ puter-assisted evaluation of the signal-tonoise (S/N) ratio proved to be statistically different, with higher values for the schizo­ phrenic group as expected. During neurolep­ tic treatment only minor changes occurred and, even after 4 weeks of treatment, the dif­ ference to the controls remained significant. There were high correlations between the measurements at different time periods. The patterns of SPEMs were often of striking similarity, examples are given in figure 1. Extrapyramidal side effects, which occurred in the haloperidol group only, did not seem to have a major effect on the quality of SPEMs, since there were no interdrug differ­ ences. In a following series of controlled treat­ ment studies using various neuroleptic sub-

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Smooth Pursuit Eye Movements in Schizophrenia

108

Kufferle/Friedmann/Topitz/F61des/Anderer/K.utzer/Steinberger

Fig. 1 . SPEMs prior (T|) and during (T2-T4) neuro­ leptic treatment in 2 schizo­ phrenic patients. Patient A. undisturbed. Patient B. dis­ turbed.

Patients and Methods Registration o f SPEMs Eye movements were registered by use o f an electro-oculograph (EOG) on a Beckman R 611 Poly­ graph. Horizontal eye movements were recorded with silver-silver chloride electrodes placed on the

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stances we continued to investigate SPEMs in schizophrenic patients before and during treatment in comparison to healthy controls to observe possible changes. In addition, SPEMs were also registered in a group of patients with affective disorders.

outer canthi o f both eyes. Vertical eye movements and eyeblinks were recorded with one electrode above and one electrode below the left eye. The ground electrode was attached to the middle o f the forehead. Horizontal and vertical EOG were ampli­ fied in AC mode (time constant 1 s). Low pass-fil­ tered signals (cutoff frequency: 15 Hz) were digitized

109

on-line by a Hewlett-Packard Vectra system (sam­ pling rate: 51.2 Hz). Subjects were seated 1.5 m from the pendulum, with head movements restrained by head rest. The frequency o f the horizontal sinusoidal pendulum was 0.4 Hz with an amplitude corresponding to ± 1 0 ° visual arc. The target was a light point with a diame­

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Smooth Pursuit Eye Movements in Schizophrenia

K.ufferlc/Fricdmann.'Topitz/F6ldes/Anderer/K.utzer/Steinberger

ter o f 2 cm. Subjects were instructed to watch the tar­ get at all times. Prior to the start of the pendulum they were aksed to focus a stationary target at the center for a 20-second period. Ten seconds after starting the pendulum, subjects were asked to follow with their eyes the movement of the pendulum as accurately as possible. The following 20 s were the first period of analysis. Thereafter, subjects were realerted. The fol­ lowing 20 s were the second period o f analysis. After a resting period o f 30 s the experiment was repeated, followed by a third and fourth period of analysis. The first step in processing the data was to calibrate the horizontal EOG to the pendulum amplitude of ± 10° of visual arc. Next, two global measures o f the subject’s overall tracking performance were calculated: the logarithm of the signal-to-noise ratio (In S/N) and the root-mean-square amplitude (RMS amplitude). The S/N ratio was calculated using spectral analysis. The data from the 12-bit data acquisition device were shifted up 4 bits before being loaded onto the PC FTT Processor Card (Ariel Corp.) to increase numerical sta­ bility. To prevent leakage o f spectral power, the data of a 20-second period were multiplied by a 25% cosine time window (tapering) before fast Fourier transforma­ tion. Subsequent spectral calculations were performed in floating point arithmetic in order to maintain preci­ sion. The frequency resolution was 0.05 Hz. The power in the frequency band 0.35-0.45 Hz (target frequency ± 0.05 Hz) was defined as the signal (S). The power in the frequency band 1.2-12 Hz was defined as noise (N). As usual, the logarithm o f the S/N ratio was used. For a subject following the movements o f the pendulum closely the S/N ratio would be high. For the period with the stationary target the logarithm o f the noise power was calculated. For a subject having only few saccadcs in this period the noise power would be low. The RMS amplitude was computed using the de­ viation between the curve describing the movement o f the pendulum and the curve describing the hori­ zontal movements o f the subject's eyes. These devia­ tion amplitudes were squared and averaged for time points with vertical FOG activity less than ± 50 pV. Taking the square root of this average yields the RMS amplitude. In contrast to the S/N ratio, this measure is not affected by vertical eye movements or eyeblinks. For a subject following the movements o f the pendulum smoothly and closely, the RMS amplitude would be low. For the period with the stationary tar­ get the RMS amplitude o f the curve describing the horizontal movements o f the subject's eyes was calcu­

lated for time points with vertical EOG activity less than ± 50 pV. The RMS amplitude is in this case equal to the standard deviation o f the signal. For a subject having only few saccades in this period the RMS amplitude would be low. To get further information on smooth pursuit tracking, saccadic eye movements greater than 1 ° of arc (in the absence o f vertical eye movements or blinks) were counted (total number o f saccadcs). In addition, the number o f saccadic intrusions, defined as pairs of small eye movements with an amplitude within I-2.5° o f arc, and the number o f large saccadic eye movements, defined as fast and irregular eye movements with an amplitude greater than 5° of arc. were calculated. Statistical analyses were performed using the av­ erage o f these measures for the 4 periods. In addition, the values obtained from the period with the highest S/N ratio were used in order to minimize the effect of attention, and these values are presented in the fol­ lowing data.

Patients and Controls The entire study population included in the re­ ported results consisted o f 66 schizophrenic patients. 40 patients with unipolar and bipolar major affective disorders and 39 healthy controls. The age and sex distribution can be seen in table I. In respect o f age. the groups were satisfactorily comparable. Diagnoses were reached according to ICD 9. All affective pa­ tients and most o f the schizophrenic patients also met the diagnostic criteria o f DSM III. The schizophrenic sample was split up into the following subgroups: subpopulation B consisted of 49 schizophrenic cases divided into 19 patients with pre­ dominantly positive symptoms and 30 patients with predominantly negative symptoms. This subdivision was based on ratings using the AMDP system [1981] and level o f severity o f the paranoid-hallucinatory syndrome and the apathy syndrome [Gebhardt et al.. I983J. Subpopulation C consisted of 50 schizo­ phrenic patients who already had received neurolep­ tic treatment during the course o f their illness within the last 2 years and 16 schizophrenic patients who had not been treated during the last 2 years. In case o f the schizophrenic patients, measure­ ments of SPEM were performed at different time peri­ ods: after a drugfree interval, 6 h after acute neurolep­ tic medication, and after 4 -6 weeks of treatment before and 6 h after neuroleptic morning medication.

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no

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Smooth Pursuit Eye Movements in Schizophrenia

When comparing the mean values of the In S/N as a quantitative measure of the accu­ racy of SPEMs, the group of 66 schizo­ phrenic patients showed the lowest In S/N values followed by the group of patients with affective disorders, whereas the controls ex­ hibited the highest values (table 2). The group differences, however, between schizo­ phrenics as a whole group and affectives did not reach significance. The In S/N values of both, the schizophrenic as well as the affec­ tive group, were significantly higher as com­ pared to controls (one-way analysis of vari­ ance, Duncan test, p > 0.05). Using RMS scores instead of In S/N values, similar re­ sults were obtained, and this was also the case for the following results. In 49 of the schizophrenic patients (sub­ population B) the psychopathological status was rated by means of AMDP [1981]. These patients were screened for participation in a program for the treatment of florid symp­ toms in productive states or in a program for the treatment of negative symptoms in resid­ ual states. According to the symptom scores the patients were classified as having one of the two AMDP syndromes presented by Gebhardt et al. [ 1983], These were: the para­ noid-hallucinatory syndrome (consisting of acoustic hallucinations, delusional mood, delusional perception, delusional thoughts, delusional ideas, delusional dynamics, syste­ matized delusions, delusions of reference, delusions of persecution, delusions of alien references, thought withdrawal and deper­ sonalization) and the apathy syndrome (con­ sisting of retarded thinking, circumstantial thinking, affective flattening, restricted af­ fect. avolition and social withdrawal). Com­ paring these two groups of schizophrenics

Table 1. Subjects 9

Schizophrenics Affectives Controls

10 10 10

56 30 29

Total Age

66 40 39

mean

range

29.13 33.50 29.63

19-54 18-55 21-46

Table 2. Comparison o f mean values o f In S/N at initial examination o f all subjects n

Schizophrenics Affectives Controls

66 40 39

In S/N mean

SD

3.97 4.29 5.03

0.73 0.84

1.20

One-way analysis o f variance: p 0.05. Duncan test: schizophrenics vs. affectives: NS: schizophrenics vs. controls: p ^ 0.05; affectives vs. controls: p 0.05.

with predominantly negative versus pre­ dominantly positive symptoms, no signifi­ cant intergroup differences could be ob­ served (table 3). When the whole group of schizophrenic cases was divided into patients who had not received neuroleptic treatment during the 2 years preceding the investigation of SPEMs and into patients who had neuroleptic pre­ medication during that time, the patients with neuroleptic therapy showed signifi­ cantly higher In S/N values as compared to affectives and healthy controls, and in addi­ tion as compared to schizophrenic patients without such neuroleptic premedication (ta­ ble 4). In contrast to affectives, who in most

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Results

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KüfTerle/Friedman n'Topitz/Foldcs/Andcrcr/Kutzer/Steinberger

Table 3. Comparison o f mean values o f Ln S/N at initial examination of subpopulation B n

ln S/N mean

Patients with predominanthly positive symptoms Patients with predominantly negative symptoms

SD

19

4.06

1.10

30

4.34

1.01

t test: NS: t value: 0.90.

the preceding 2 years, only minor and insig­ nificant changes occurred (table 5). A correlation of the ln S/N values ob­ tained at the 4 time periods under neurolep­ tic treatment (Pearson’s correlation) re­ vealed significant to highly significant corre­ lations in the group of schizophrenics with prior neuroleptic treatment during the pre­ ceding 2 years (table 6). This was also the case with schizophrenics without such neu­ roleptic pretreatment (table 7).

n

NL schizophrenics nNL schizophrenics Affectives Controls

50 16 40 39

ln S/N mean

SD

3.81 4.47 4.28 5.03

1.15 1.26 0.73 0.84

Schizophrenic subjects (subpopulation C): NL = patients with neuroleptic premedication: nNL = pa­ tients without neuroleptic premedication. One-way analysis o f variance: p =£ 0.05. Duncan test: NL vs. all: p 0.05: affectives vs. controls: p < 0.05: nNL vs. NL: p < 0.05: nNL vs. controls, affectives: NS.

instances had various premedications (ex­ cept lithium), the latter were statistically not different from the controls. As mentioned before, in all schizophrenic patients, after a drugfree interval, measure­ ments of SPEMs were made at consecutive time periods under neuroleptic treatment for 4-6 weeks. In both groups, i.e. patients who had received prior neuroleptic treatment and those who had not been treated during

Our results demonstrate that the accuracy of SPEMs. expressed quantitatively by means of ln S/N values, shows a significantly poorer quality in schizophrenic patients as compared to healthy controls. This is in agreement with the results of many studies conducted within the last two decades. We are also in agreement, on the other hand, with results proving that disturbed SPEMs can be seen also in patients with affective psychoses. Since a high percentage of the schizophrenics investigated in our study had received various psychopharmacological pretreatments during the 2-year period pre­ ceding SPEM measurements, which was also the case in a percentage of patients with affective psychoses, this could be one possi­ ble explanation for this finding. As already mentioned. Levy et al. [1985] suggested that treatment with lithium carbonate could pos­ sibly serve as an explanation for disturbed SPEMs in patients with affective psychoses. This assumption cannot serve as an explana­ tion in our case, since none of the affective patients included had been treated with lith­ ium before or had received lithium medica­ tion at the time of SPEM measurement.

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Discussion Table 4. Comparison o f mean values of ln S/N at initial examination o f all subjects

Smooth Pursuit Eve Movements in Schizophrenia

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Table 5. Mean values o f In S/N o f subpopulation C at four consecutive examinations (T 1-T 4)

T;

NL nNL

Tj

t4

n

mean SD

n

mean

SD

n

mean

SD

n

mean

SD

50 16

3.81 4.47

49

4.07 4.42

1.24 1.31

42 16

4.17 4.45

1.07 1.24

42 16

4.24 4.38

1.04 0.97

1.15 1.26

16

The influence of neuroleptic premedica­ tion on SPEM quality expressed in In S/N values cannot be ruled out by our results, since our schizophrenic cases, divided into patients with neuroleptic pretreatment in the 2 preceding years (75.7% of the patients be­ longed to that group) and into patients that were drugfree until the time of the first examination, showed significant differences, with less disturbances in the untreated group. However, this could also reflect cir­ cumstances immanent in the disease itself like chronicity, as suggested by several au­ thors. Testing SPEMs on consecutive occasions before and during neuroleptic treatment re­ vealed only minor changes. Correlations, moreover, between values after a drugfree interval, acute neuroleptic medication, and prolonged medication over 4-6 weeks were considerably high. This was also the case in patients who had not received neuroleptic medication until then. This appears to prove that such time-limited neuroleptic medica­ tion does not decisively influence the quality of SPEMs. It also demonstrates the high testretest quality of this parameter. The basis of dividing a subpopulation of the schizophrenic patients, in whom psycho­ pathology was rated in a standardized way by means of AMDP, into a group of patients with predominantly negative and a group

Table 6. Pearson’s correlations o f In S/N values T 1-T 4 of schizophrenics with neuroleptic premedica­ tion

T, t2

Tj T4

T,

t2

T,

0.65** 0.45* 0.45*

0.64** 0.57**

0.81**

T4

One-tailed significance: *p < 0 .0 T. **p

Smooth pursuit eye movements in schizophrenia: influences of neuroleptic treatment and the question of specificity.

The authors investigated smooth pursuit eye movements (SPEMs) in 66 schizophrenic and 40 major affective patients and 39 healthy controls. The results...
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