Visually-guided saccadic eye movements in adolescents at genetic risk for schizophrenia

SCHIZOPHRENIA RESEARCH ELSEVIER

Schizophrenia Research 25 ( 1997) 97-109

Visually-guided saccadic eye movements in adolescents at genetic risk for schizophrenia Herbert Schreiber a**, Gisela Stolz-Born a, Jan Born b, Johann Rothmeier ‘, Aribert Rothenberger d, Reinhart Jiirgens a, Wolfgang Becker a, Hans Helmut Komhuber a a University of Ulm, RKU Hospital, Department of Neurology and Neurophysiology Section, RKU Hospital, Oberer Eselsberg 45, D-89081 Ulm, Germany b University of Liibeck, Clinical Neuroendocrinology & Psychophysiology, Ratzeburgerallee 160, D-23562 Liibeck, Germany ’ Psychiatric Hospital Weissenau, 88214 Ravensburg- Weissenau, Germany ’ University of Gdttingen, Department of Child and Adolescent Psychiatry, D-37075 Giittingen, Germany Received 1 February

1996; accepted 9 January 1997

Abstract Visually-guided saccades of 21 offspring of schizophrenic parents and 21 individually matched controls were compared with regard to the frequency of occurrence of saccadic hypometria and hypermetria, non-fixations, and omissions of target jumps. Target steps ranged from 10 to 60”, and interstimulus intervals averaged 2.5 s; subjects were promised financial reward depending on performance. Recordings were carried out at the subjects’ homes. To screen for cognitive abilities and psychopathological behavior, subjects were tested by means of an intelligence scale and a behavioral checklist. With large target steps (40-60”), the high-risk group made significantly more grossly hypometric saccades (gain 10.8) than the control group; responses to small target steps ( 10-30”) exhibited a similar, albeit statistically not significant, trend. There were no significant differences with regard to the occurrence of hypermetria. Non-fixations scored marginally higher in the high-risks as compared to controls, but this was again not a significant difference. The incidence of omissions of saccades was very low in both groups. The results of the study suggest that subjects at genetic risk for schizophrenia may differ from controls by an increased incidence of conspicuously hypometric saccades. Clearly, this difference is not caused by a deficit of the saccadic motor circuitry proper; comparison to control data obtained with a similar experimental protocol suggests that it probably reflects an impaired internal control of saccades in the presence of distraction and stress. The relevance of saccades as indicators of a possible schizophrenic vulnerability is discussed. Keywords:

Eye movement;

Genetics: Psychopathology;

Saccades; Schizophrenia;

* Corresponding author. 0920-9964/97/$17.00 Q 1997 Elsevier Science B.V. All rights reserved PII SO920-9964(97)00011-X

Vulnerability

98

H. Schreiher

et al. ,’ Schi:ophrmicr

1. Introduction There is ample evidence that schizophrenic pathology is frequently accompanied by dysfunctions of eye movements, in particular of the smooth pursuit type (SPEM). Thus, a higher prevalence of abnormal SPEMs has been shown in schizophrenics compared to controls (Holzman et al., 1973; Holzman, 1985). The knowledge about a genetic disposition for schizophrenia (Gottesman and Shields, 1982) has stimulated research on eye movements as biological markers for the disease (Clementz and Sweeney, 1990; Szymanski et al., 1991). Whereas other psychiatric disorders tend also to be associated with pursuit deficits, schizophrenia appears to be the only disorder in which not only the manifestly ill but also their firstdegree relatives exhibit an increased occurrence of abnormal SPEMs compared to controls without any genetic load (Holzman et al., 1974; Abel et al., 1992). In contrast to SPEMs, there is less agreement as to whether saccadic eye movements are also affected by schizophrenic pathology. For visuallyguided saccades (e.g., tracking of simple target steps), several studies report normal latencies (Diefendorf and Dodge, 1908; Iacono et al., 198 1; Levin et al., 1981, 1982; Moser et al., 1990), accuracy (Levin et al., 1981, 1982; Yee et al., 1987; Ross et al., 1988) and peak velocity (Iacono et al., 1981; Levin et al., 1981, 1982; Yee et al., 1987) in schizophrenics. On the other hand, there are several reports showing a higher incidence of hypometric saccades (Becker et al., 1982; Cegalis et al., 1982; Mather and Putchat, 1983; Schmid-Burgk et al., 1982, 1983; Mackert and Flechtner, 1989; Moser et al., 1990; Schreiber et al., 1995) and of prolonged latencies (Schmid-Burgk et al., 1983; Yee et al., 1987; Mackert and Flechtner, 1989) in schizophrenic patients as compared to controls. Schwartz et al. ( 1995) have recently reported saccadic accuracy reduction to be more severe in patients with a positive family history of schizophrenia compared to those without, and they suggest the possibility of a genetic factor. An increased occurrence of hypometric saccades in adult first-order relatives of schizophrenic patients

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has been observed in this laboratory (Schreiber et al., 1995). Deficits of saccade accuracy may also be accentuated in tasks involving more complex visuospatial demands (Reischies et al., 1989), and may be particularly pronounced in tasks requiring a higher degree of internal control and volition (Fukushima et al., 1988, 1990; Thaker et al., 1989a,b; Hommer et al., 1991). For a review see Abel et al. (1992). Until now, very little is known about the characteristics of saccades in juveniles at genetic risk for schizophrenia. Only Mather (1985) has addressed this issue so far by comparing saccades in a group of adolescents with schizophrenic mothers to those of control subjects. In this study, the high-risks showed normal latencies, but made distinctly more corrective saccades than controls - an observation compatible with their earlier observation that schizophrenics also exhibited higher numbers and larger amplitudes of corrective saccades (Mather and Putchat, 1983). The higher frequency of corrective saccades in Mather’s study suggests that the subjects at risk produced more dysmetric saccades than her controls did. In the light of these findings it seems important to further investigate possible alterations of saccadic function in subjects with a genetic vulnerability to schizophrenia. In normal subjects, the undershoot of goal-directed saccades increases as a function of target distance (saccades typically undershoot their goal by 5-lo%, cf. Becker, 1989). Since target steps were limited to 30” in the study of Mather ( 1985 ), it appeared of interest to investigate the performance of subjects at risk also with larger target displacements, as these might enhance the contrast between the pathological and normal state. We therefore examined a group of adolescent offspring of schizophrenic parents and a group of individually matched controls with respect to the occurrence of dysmetric saccades, non-fixations and omissions during saccadic tracking of target jumps with amplitudes up to 60’. To screen for cognitive performance and evidence of psychopathology, oculomotor assessment was complemented by rating scales for cognitive performance and psychopathological behavior.

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2. Methods 2. I. Subjects

Forty-two adolescents, aged 10-l 8 years, took part in the investigation. Out of these, 21 were offspring of at least one schizophrenic parent and thus carried a genetic risk for schizophrenia. Three siblings had two schizophrenic parents. The parental diagnoses matched the DSM-III criteria for schizophrenia or schizoaffective psychosis (APA, 1980). Diagnoses were based on consensus of at least two psychiatrists and confirmed by clinical follow-up. The schizophrenic syndromes included the following subtypes: paranoid type (n= 14) schizoaffective type (n=6) and residual type (n= 2). Each subject at risk had been individually matched to a control subject without any family history of psychiatric illness. Matching criteria were age, sex, social background and education. A summary of demographic, cognitive and psychopathological group data is given in Table 1. Age matching was considered particularly important; the mean age (in years+SD) was identical in the high-risk (HRG, 13.0 + 2.6) and the control group (CG, 13.0f2.2), with the absolute value of the age difference within matched pairs averaging 3.4 months (refer to Fig. 3 for a comprehensive illustration of the age distribution in both groups). Each group included 11 female and 10 male subjects. The subjects’ education was rated on the basis of the four levels of the German school system ranging from low-grade classes ( 1) to grammar school (4). Educational scores (mean f SD) were very comparable between HRG (2.90 +0.9) and CG (2.68f0.8; for details refer to Table 1). Social background evaluation took into account whether the adolescent lived at home (i.e., with one or both biological parents), with foster parents or in foster homes. There were only five pairs in which social matching was not congruent. In all of these cases, the high-risk subject lived with foster parents (n = 3) or in foster homes (n =2), whereas the corresponding controls lived at home. None of the HRG and CG members had ever required psychiatric consultation or undergone neuroleptic treatment. Also, none of the subjects

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took any other medication at the time of the experiments. To screen for cognitive abilities, all subjects full ‘Hamburg-Wechsler performed a Intelligenztest’ (Bondy, 19&l), a German version of the Wechsler Intelligence Scales. Subjects under 14 years were presented with the version for children, the others completed the version for adults; results are summarized in Table 1. To uncover psychopathological behavior, we asked the parents to evaluate the child’s behavior with the Child Behavior Check List (CBCL; Achenbach and Edelbrock, 1983). CBCL evaluation of the highrisk children was obtained from the unaffected parent or from the foster parents. Twenty parents of controls and ten of the high-risks agreed to answer the CBCL. The others refused or did not send it back, probably because of the very personal questions of the checklist. In close relation to Achenbach ( 1989), we constructed a core version scrutinizing several psychopathological syndromes included in the CBCL. In addition, we developed five items for our scale on eating behavior and five items for the one on tic disturbance. Details of the CBCL results are summarized in Table 1. 2.2. Experimental

design and data analysis

Saccades were recorded at the subjects’ homes using a mobile system. Subjects sat in a darkened room and were presented with a luminous target ( LED) stepping randomly (pseudorandom sequence controlled by a microcomputer) between horizontal positions spaced 10’ and extending from 30” right to 30” left on a tangent screen. There was total of 109 steps which had amplitudes of 10, 20, 30, 40, 50, or 60”; the frequency of occurrence of these amplitudes decreased approximately linearly from n = 31 for 10” steps to n = 8 for 60” steps. Time epochs between target steps varied also pseudorandomly, with a mean of 2.5 s (range 2-3 s). Subjects viewed the screen from a distance of 100 cm while their heads rested on a chin support and were stabilized by a forehead holder. They were instructed to track the target ‘as rapidly and as exactly as possible’ and to accurately and permanently fixate at the current target position between steps without making concomitant head

100 Table 1 Demographic,

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mental

and psychopathological

Parameter

Age (years) Education (score) WIS (Full IQ)

et al. / Schizophrenia

characteristics HRG

of the high-risk

(n=21)

25 f 1997) 97-109

(HRG)

and control

group

(CG)

CG (n=21)

p value

mean

SD

mean

SD

13.0 2.90 116.4

2.6 0.92 16.0

13.0 2.68 116.7

2.2 0.83 11.7

CBCL

(summation

HRG

(N=

ns ns ns

of items)

10)

mean Total scale Summarized scales Externalizing Internalizing Subscales Eating disturbance Tics Attention deficit/hyperactivity Aggressive Anxious Depressive Somatic complaints Withdrawn Obsessive-compulsive Schizoid Delinquent

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CG (N= SD

mean

20)

p-value SD

22.4

11.4

11.1

16.9

0.003

13.6 9.9

8.0 5.8

6.6 4.1

8.7 6.4

0.03 0.002

0.5 0.0 2.3 6.3 1.1 1.7 0.7 2.6 1.6 0.9 1.1

0.7 0.0 1.9 3.4 2.2 1.4 0.9 2.5 1.1 1.0 1.7

0.1 0.1 2.3 3.5 0.8 1.0 0.4 1.1 0.7 0.6 0.4

0.4 0.2 2.7 4.0 1.1 1.8 0.7 1.6 1.3 1.8 1.3

0.02 ns

Comparison by Mann-Whitney U-test. WIS refers to the ‘Hamburg Wechsler Intelligenztest’, Intelligence Scales. Subjects under 14 years of age received the version for children, those over refers to the Child Behavior Checklist according to Achenbach and Edelbrock ( 1983).

movements. Careful observation confirmed that this instruction and the mechanical head stabilization prevented the subjects from making even small movements. Subjects were promised a financial reward for their participation. However, in order to enhance their motivation, they were told that inaccurate and slow reactions and non-fixations would reduce the amount of this reward. Eye movements were recorded by DCelectrooculography (EOG) using Ag-AgCl skin electrodes placed horizontally at the outer canthi of both eyes. For artifact recognition, especially eye blinks, the vertical EOG was recorded from one eye. The position of the visual target and both the horizontal and vertical eye position signals were written on a strip-chart recorder. For an initial calibration, the pen excursions of the

fI:o3 El4 ::05 0.009 ns ns

a German version of the Wechsler 14 years the version for adults. CBCL

recorder were adjusted to an amplitude of 4 cm peak to peak at the onset of a recording session while subjects tracked a sequence of 40” back and forth steps of the target. Saccades were analyzed off-line by two experienced observers (G.St-B.; J.R.), who had already participated in previous eye-movement experiments, but were blind with respect of the matching code of the present investigation. In the evaluation procedure, only few (up to 8%) of the saccadic reactions in a given experiment had to be rejected because of technical or physiological artifacts (drift, blinks, etc.); there was no correlation between the rejection rate and the size of the target steps. Using only artifact-free saccades, the following parameters were assessed: frequency of ( 1) hypometric (ho) saccadic reactions, (2) hyper-

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metric (he) reactions, (3) dysmetric (dys) reactions (sum of ho and he), (4) non-fixations (nf) and (5) omissions (om). A reaction was considered hypometric, if its primary saccade comprised at least 20% but less than 80% of the target step; the lower threshold of 20% reduced the risk of confounding responses to target steps with small ‘look-away’ saccades (non-fixations, cf. below), which happened to occur during the latent period of a pending reaction. The upper value of 80% reflects experience from previous work in our laboratory indicating that saccades with a gain of less than 0.8 are rare events in normal juveniles and adults. Obviously, we also could have recorded the magnitude of each saccade and could have calculated the mean accuracy and its dispersion; however, we felt that the resolution of the EOG recorded with our mobile equipment did not warrant such an approach which, in the large majority of reactions, would have required the measurement of quite small errors. Moreover, similar thresholds (75%) have been used in a parallel study on manifestly ill schizophrenic patients and adult first-degree relatives (Schreiber et al., 1995), and proved to be robust for detecting truely abnormal reactions. Similarly, a reaction was classified hypermetric, if it overshot the target by more than 10%. In calculating these percent amplitudes, we did not rely on the initial calibration because the subjects’ cameo-retinal potential would exhibit long-lasting changes after the room has been darkened at the outset of an experiment. Instead, we related the magnitude of the primary saccade to the size of the total eye displacement including all secondary saccades (‘correction saccades’) on the assumption that the final position would correspond to the target position; however, this assumption was always critically checked by consulting the initial calibration and by inspecting the records for periods of unstable fixation. Non-fixations were defined as look-away saccades deviating gaze by more than 5” during the interstep epochs, when subjects were supposed to quietly fixate. Finally, omissions were cases where the subjects did not at all respond to a given target step. The percent frequencies of hypometric, hypermetric and dysmetric saccadic reactions were

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assessed separately for each target step size (IO-600), but were also summarized under the form of a grand average across all step sizes. All frequencies were calculated as percent scores relative to the total number of artifact-free saccadic reactions.

3. Statistical analysis Analyses of variance (ANOVAs) were performed on the data set to evaluate group-related differences of hypometria, hypermetria, dysmetria, and non-fixations. Omissions were not statistically evaluated, since they were practically absent in the CG. ANOVAs proceeded from two repeated measures factors: (1) group (HRG, CC) and (2) amplitude of target step (10, 20,...,60”). To specify interaction effects, pairwise comparisons (contrasts) were performed between high risks and controls separately for any of the saccadic amplitudes. HRG and CG were treated as dependent groups because of the individual matching of children. Since five of the 21 high-risk children were siblings of another child examined, these children may not be considered statistically independent cases. However, the pattern of significant differences between high risks and controls reported here did not change if the degrees of freedom were adjusted to a number of 14 independent cases, representing the most conservative estimate of the degrees of freedom. Moreover, degrees of freedom were corrected after the Greenhouse-Geisser procedure. Finally, a possible dependence of high-risk related changes in saccadic eye movements on the age of the subjects was evaluated using (product moment) correlation analyses. A p-value co.05 was considered significant.

4. Results Results of the Hamburg Wechsler Intelligenztest (WIS) are summarized in Table 1. Total IQs (mean + SD) were almost congruent in both groups (116.4+1&O in HRG versus 116.7+11.7 in CC). Details of the CBCL results are also summarized in Table 1. The total scale and the compound

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scales for externalizing and internalizing behavior reflected more psychopathological signs in the high-risks than the controls. In the subscales, this held specifically true for eating disturbance, aggressive, depressive, withdrawn and obsessive-compulsive behavior. However, these Endings were only valid for inter-group comparisons, whereas the absolute CBCL scores of both groups lay within the normal range. Fig. 1 illustrates epochs of saccadic tracking by a control subject (A) and a risk subject (B). Both subjects exhibit a normal saccadic undershoot of about 5-10% on most of their reactions. However, the risk subject, in tracking one of the 50” steps, makes a grossly hypometric saccade (marked ho). Also, instead of quietly fixating between target steps, he occasionally looks away (marked nf). Note, however, that Fig. 1 is an example selected for illustrative purposes; it is not meant to indicate that gross hypometria and non-fixations would occur only in risk subjects. In fact, both phenomena do also occur in normal subjects, although

T-- A-

-

Fig. 1. Samples of original recordings from a control subject (A) and a subject at risk of schizophrenia (B). T, target position; EH, horizontal eye position (signal inverted with respect to target position); EV, vertical eye position (blink monitoring). nf, non-fixation; ho, hypometric reaction.

at a lower frequency as can be seen from Fig. 2, which summarizes the group means of the saccadic accuracy parameters. The frequency of hypometric saccades clearly increased in both the HRG and CG when larger amplitudes were required. However, this increase was larger in the high-risks as compared to controls (Group x Amplitude interaction, F( 5,100) = 3.2, p <0.05). Thus, whereas for small and intermediate target steps, saccadic accuracy exhibited no significant differences between groups, hypometria became significantly more frequent among the high-risks for saccades tracking steps of 40” (F( 1,20) =6.7, ~~0.025) and 60” (F( 1,20)= 5.0, ~~0.05). For steps of 50 and 30”, a similar, albeit statistically not signiEcant, tendency existed. Averaged across all step amplitudes, hypometric saccades (mean ) SE) were found in 10.4 + 1.3% of all reactions in the HRG as compared to 6.9 + 1.0% in CG (8’(1,20)=5.5,p
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Amplitudes

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(deg”)

Fig. 2. Frequencies (expressed as percent values) of hypometric (ho), hypermetric (he) and dysmetric (he) saccades for the various target displacements (10-60”) are illustrated for the HRG and CG groups (columns, mean across subjects; bars& 1 SE). Si@cant contrasts between groupsare indicated by asterisks (*p < 0.05; t p < 0.1).

group effect. Omissions (om) scored slightly higher in HRG (0.8&0.3%) than in CG where they were completely absent. However, given the very low incidence of this parameter in both groups, this difIerence would seem to be irrelevant. Product moment correlation coefficients between age and each of the saccade parameters were calculated separately for HRG and CC. In controls, the overall frequency of hypometric saccades (averaged across all target step ~plitud~) markedly decreased with increasing age (r= -0.62, p
5. Discussion The results of the present study suggest that subjects at genetic risk for schizophrenia may differ, as a group, from controls by a lower targeting accuracy of their visually-guided saccadic eye movements. Clearly, this difference emerges only when saccadic reactions to larger target displacements are considered. In the present study, adolescent offspring of ~~ophre~c parents exhibited a significantly higher frequency of grossly hypometric saccades than matched controls when tracking target steps of 40 to 60”, whereas there was no significant difference between the two groups for steps of 10 to 20”. A comparable accentuation of differences with large amplitudes has recently been reported by Schwartz et al. ( 1995) who found a significantly reduced accuracy in schizophrenics with a positive family history at amplitudes from 16 to 30”, but not for smaller ones. As pointed out in section 2, the individual members of the two groups were closely matched

104

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25 11997)

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0

lj

20 -

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Fig. 3. Relation between age and total percentage of hypometria in subjects at risk (filled dots) and controls (empty triangles). Small letters indicate matched pairs. In controls, the frequency of hypometria significantly decreased with age (r= - 0.62, solid line), whereas no such relationship can be seen in the high-risks (r= -0.04, dashed line).

for age and educational level. Moreover, their IQ levels were found to be highly comparable. Finally, none received a medication which could have influenced the results. Therefore, there is no evidence that the observed group differences could be due to artifacts or inadequate group sampling. Our study is compatible with the only other investigation of saccadic eye movements in adolescents at genetic risk for schizophrenia published so far (Mather, 1985). Mather reported an increased number of corrective saccades in a small group (N = 9) of offspring of schizophrenic parents tracking target displacements of 20-30”; her finding would suggest a higher incidence of hypometric reactions. The difference between the high-risk and control groups in that and the present study is all the more remarkable as an increased frequency of hypometric saccades during tracking of a visual target is not a universally acknowledged fact in manifest schizophrenics. While a considerable number of studies (Becker et al., 1982; Cegalis et al., 1982; Schmid-Burgk et al., 1982, 1983; Mather and Putchat, 1983; Mackert and Flechtner, 1989; Moser et al., 1990) suggest that an increased frequency of hypometric saccades might be a group trait of schizophrenic patients, and while Fukushima et al. (1990) recognize at least a ‘tendency of schizophrenics to make saccades of smaller amplitudes’, others found the saccades of

patients to be as accurate as those of normal controls (Levin et al., 1981, 1982; Yee et al., 1987). With regard to the incongruency of the abovementioned reports concerning saccadic tracking in schizophrenics, the question has to be raised as to whether methodological factors play a crucial role in revealing an impairment in schizophrenics and subjects at risk. Preliminary results of two other studies from our laboratory seem to support such an hypothesis. Indeed, using a procedure identical to the one presented in a parallel study from this laboratory, schizophrenic patients as well as their first-degree relatives were found to produce significantly more hypometric saccades than normal subjects (Schreiber et al., 1995). On the other hand, when the experimental procedures were changed in a later, third study comparing further groups of normal juveniles and juveniles at risk, we obtained much lower frequencies of hypometric saccades in both the risk and the control groups than in the two aforementioned studies (Jtirgens et al., in preparation). This later study differed in several respects from that of 1995 and the one reported here. (1) Experiments were carried out under strictly controlled laboratory conditions, not in a home environment. In particular, subjects were in complete darkness with only the target LED being visible, whereas in the subjects’ homes darkening was not always perfect and may have

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allowed for distraction by the visual background. (2) The pace of target stepping was slower (mean IS1 5 s instead of 2.5 s), and the range of step amplitudes was smaller (up to 40 instead of 60”). (3) Subjects were not sanctioned by reduced rewards for slow and inaccurate reactions, which may have created a state of stress and hyperarousal in the subjects participating in the present study. In summary, the study reported here put a higher load on the subjects in terms of attentional demand, of fending off distractive influences, and of motivational stress. We speculate that such conditions favour a higher frequency of dysmetric saccades in both the populations at risk and controls, albeit to a different degree so that the difference between the two groups becomes accentuated. Thus, we hypothesize that in order to discriminate groups at schizophrenic risk from controls, the experimental load has to be increased so as to drive the visuo-oculomotor system of the former to its limits which would be reached earlier than that of controls. Obviously, this view awaits confirmation by experiments varying the distractive load, the motivational level, and the pace, range and salience of target displacements in a given set in normal and risk samples. On the other hand, the cognitive demands in the present experiment were rather low. Subjects mainly had to yield to their visual grasp reflex. Cognition may have been involved in as much as keeping one’s sensory gates open for new target displacements and refraining from abandoning fixation during an IS1 requires a certain level of permanent conscious control of behaviour. To judge from the similar percentage of non-fixations in the controls and subjects at risk, and from the low frequency of omissions, the subjects at risk did not perform worse than the controls in this respect. We note, however, that the chance of observing non-fixations may have been low due to the short ISIS that were employed. A number of investigations have deliberately amalgamated cognitive demands into saccadic tracking tasks aimed at comparing schizophrenic patients to normal subjects. An example is the so-called antisaccade paradigm which calls for a saccade opposite to the displacement of a visual target into the ‘empty’ part of the visual field. With this paradigm,

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Fukushima et al. (1988, 1990), Thaker et al. (1989a), and Clementz et al. ( 1994) uncovered an increase of erroneous reactions towards the target in groups of schizophrenic patients, which means an impaired inhibition of the visual grasp reflex. In the study by Clementz et al., not only the schizophrenics but also their Erstdegree relatives made more errors on the antisaccade task, thus revealing its potential relevance for indicating a schizophrenic disposition. On the individual level of some of their schizophrenic patients, Fukushima et al. (1988) were also able to observe an association between low antisaccade performance and signs of frontal cortical atrophy on CT-scans. This observation has been conflrmed by a more recent study (Fukushima et al., 1994) indicating that schizophrenics and patients with frontal lesions share specific abnormalities on the antisaccade task. A related Iinding is the difficulty experienced by patients with frontal lobe lesions to suppress their visual grasp reflex (Guitton et al., 1985). Therefore, a dysfunction of the frontal eye field and the dorsomedial cortex may be a possible cause of saccade deficits in schizophrenics, a view that fits in within the ‘hypofrontality’ of these patients demonstrated during functional imaging tests (Buchsbaum et al., 1984, 1992; De Lisi et al., 1985; Weinberger et al., 1986; Andreasen et al., 1992). In a recent PET study, a lack of frontal eye field (FEF ) activation has also been reported for various saccadic tasks, including a reduced activity in dorsolateral frontal cortex specifically during a task requiring the suppression of distracting visual stimuli (Nakashima et al., 1994). It is important to realize that the hypometria observed in this study is fundamentally different from the hypometria occurring in a number of neurological diseases a&cting the cerebellum or the brain stem (for a review cf. Brandt and Btichele, 1983; Leigh and Zee, 1983). In these cases, because the lesions interfere with the saccadic motor circuitry, every single saccade of given amplitude and direction is a&&d in the same way, i.e., hypometria is a permanent phenomenon. Schizophrenia, in contrast, does not seem to interact with the saccadic motor circuitry proper since patients can, in principle, execute normometric saccades and actually do so in the majority of cases. Typically, they

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would produce only once in a while a conspicuously hypometric saccade; such an episodic hypometria does also occur in normal subjects, although at a much lower frequency. Thus, the site of dysfunction must be searched for above the level of the brain stem and cerebellum, conceivably at stages which select targets and which define desired amplitudes, i.e., in central decision and computing stages (Becker, 1989). In view of the hypofrontality hypothesis of schizophrenia (Weinberger, 1988), among the mesencephalic, diencephalic and cortical areas that constitute the substrate of these processes, the frontal eye fields (FEF) and principal sulcus (PS) would seem to be possible sites. Such a conclusion would be compatible with the aforementioned relation between frontal lobe dysfunction and impaired suppression of inappropriate saccades in schizophrenics suggested by Fukushima et al. ( 1988, 1990, 1994) and Clementz et al. (1994). Fig. 3 suggests an explanation in terms of a lack or late development of frontal lobe function. Indeed, this analysis of age dependence of hypometria scores showed that in the risk group accuracy did not improve with age, whereas it did in the control group in which the youngest subjects exhibited hypometria scores similar to the mean of the risk group, but older ones had clearly lower scores. Almost no data have been published, so far, on the development of accuracy of SPEMs in normal subjects of the age group considered here (lo-18 years). Cohen and Ross (1978) investigated responses to target steps of IO” in the presence and absence of distractor stimuli and found no difference in accuracy when comparing two groups of subjects with mean ages of 8.5 and 23.7 years, respectively. Their finding does not contradict the present results, however; when we restricted our correlation analysis to saccades evoked by IO’ steps, our controls showed no significant improvement of accuracy either. In a subsequent study in this laboratory using a roughly similar stimulus repertoire and involving juveniles of age 10-19, accuracy exhibited a significant decrease of scatter with age, whereas its mean value did not change. Clearly, our hypothesis of a maturation of saccadic function in normal adolescents which would be lacking in the risk group requires substantiation

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by further experiments. It would at least be compatible with the view of a frontal involvement, since the frontal cortex is still known to show substantial progress in myelinisation and function during adolescence (Yakovlev and Lecours, 1967; Stuss and Benson, 1986). On the other hand, one could argue that the older members of the risk group were closer to the age of possible onset of schizophrenic symptoms and that some may have actually entered a premorbid state. This touches on the question of whether hypometria is indeed a trait marker for vulnerability or whether it is linked to the actual onset, and eventually, manifestation of schizophrenia. Given the small number of subjects, we cannot exclude the latter possibility although we deem it less likely, because in 13 of the 18 subjects at risk, of 11 years or older, hypometria scores were larger than in their matched controls, which is a percentage distinctly higher than that expected to develop manifest schizophrenia at a later time (Gottesman and Shields, 1982). Alternatively, although present already during early life, the deficit causing impaired saccadic accuracy in high risk adolescents may be masked by the overall poor performance of younger children, and emerge as a differential factor between groups since saccadic accuracy continues to improve with age in normal controls. Finally, the lack of a developmental improvement in the HRG could also be due to a few cases with extreme hypometria frequencies. In fact, inspection of Fig. 3 reveals that the HRG subjects ‘j’, ‘m’, and ‘t’ present extreme deviations from the frequency of hypometria expected for similarly aged controls. These subjects might form a subgroup that is especially prone to develop manifest schizophrenia later on or will simply stand out by its inaccurate saccades without showing any other symptoms. It is, in fact, quite unlikely that all members of the HRG group should be prone to impairments of saccadic accuracy; since only a small percentage of them is likely to develop signs of schizophrenia, we would expect only a few of them to deviate from the normal maturation pattern of saccadic function. Again however, considering the small number of subjects in the different age groups, all of these considerations necessarily remain speculative. In light of the clear

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hints at an impairment of the normal development of saccadic accuracy in the high-risk adolescents, a more detailed analysis of the developmental dynamics of saccadic performance in further risk studies is indicated. In this context, the impairments of saccade performance in high-risk subjects observed in the present study might indicate an aspect of biological vulnerability. This is supported by the CBCL results in which the high-risks’ parents indicated more psychopathological signs for some CBCL subscales than those of controls. However, these differences were only valid for inter-group comparisons, whereas the absolute scores of the CBCL lay within the normal ranges for both groups. Re-inspection of the CBCL data suggested that the intergroup difference was due to a behaviorally ‘hypernormal’ group of controls as rated by their parents. Moreover, this data has to be carefully qualified since the data sets are incomplete for both samples. Especially, the limited number of CBCLs obtained from high-risks did not enable any exploration with regard to a possible subgroup of subjects showing extreme behavioral abnormalities in association with saccadic abnormalities. In fact, from the high-risks exhibiting extreme hypometria frequencies (j, m and t, in Fig. 3), a CBCL could be obtained only for one who displayed a moderately lower CBCL than his age-matched control. In any case, the reported deficits of saccadic accuracy have to be carefully related to schizophrenia, because psychophysiological variables such as saccades have a limited scope and evidently cannot account for all dimensions in the complex framework of schizophrenic vulnerability. Therefore, altered saccadic characteristics are likely to reflect only some aspects of the biological vulnerability associated with schizophrenia rather than to define the schizophrenic risk extensively. Clearly however, the present results justify further efforts aimed at defining saccadic characteristics in groups at genetic risk for schizophrenia and at clarifying their relation to vulnerable states of the disease. Finally, future research will also have to combine the investigation of saccades with studies of smooth pursuit performance in order to learn more about the specificity of these two different

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types of eye movements as possible indicators indicators of vulnerability.

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Acknowledgment

The authors are grateful to Mrs. Frey for excellent secretarial assistance.

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