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Early Expression of Smooth-Pursuit Eye Movement Abnormalities in Children of Schizophrenic Parents
Early Expression of Smooth-Pursuit Eye Movement Abnormalities in Children of Schizophrenic Parents RANDAL G. ROSS, M.D., DANIEL HOMMER, M.D., ALLEN RADANT, M.D., MARGARET ROATH, M.S.W., AND ROBERT FREEDMAN, M.D.
ABSTRACT Objective: Disordered smooth-pursuit eye movements (SPEM) and, specifically, small anticipatory saccades that disrupt
SPEM have been hypothesized to be a marker of genetic vulnerability to schizophrenia. This study compares SPEM in children of schizophrenic parents with normally developing control children to assess whether SPEM abnormalities are also present in a subset of at-risk children. Method: With infrared oculography, SPEM was examined in 13 children of schizophrenic parents and 19 normally developing controls (aged 6 to 15 years). Measures of smooth-pursuit gain and root mean square error were used in addition to more specific measures of catch-up saccades and anticipatory saccades. Results: Children of schizophrenic parents differed from normally developing controls on gain and root mean square error, but not on catch-up saccades. Small anticipatory saccades were significantly more frequent in the at-risk group. The percentage oftotal eye movements due to anticipatory saccades identified 54% of the at-risk group (compared with none of the control group) as performing more than two standard deviations above (worse than) the control mean. Conclusions: The presence of increased anticipatory saccades is evidence for an oculomotor dysfunction that may
be a phenotype of the genetic risk for schizophrenia, expressed years prior to the possible development of clinical illness. J. Am. Acad. Child Ado/esc. Psychiatry, 1996, 35(7):941-949. Key Words: eye movements, smooth pursuit, schizophrenia, children, at-risk, endophenotype.
Almost 90 years ago, Diefendorf and Dodge (1908) first noted that adult patients with schizophrenia had difficulties with tasks that required smooth-pursuit eye movements (SPEM). This finding was replicated by Couch and Cox in the 1930s (1934), independently rediscovered by Holzman et al. in the 1970s (1973), and then consistently replicated over the past 20 years in a number of laboratories (e.g., Abel and Ziegler, 1988; Abel et al., 1991; Friedman et al., 1991, 1992; Holzman et al., 1984, 1988; Iacono and Lykken, Accepted August 9, 1995. Dr. Ross and Ms. Roath are Assistant Professors and Dr. Freedman is a Professor, University ofColorado HealthSciences Center, Denver. Dr. Hommer is Section Chief,NationalInstitute ofAlcohol Abuseand Alcoholism, Bethesda, MD. Dr. Radant is Assistant Professor, University of Washington, Seattle. Thisresearch wasfUnded bya NARSADJuniorInvestigator Award (R. G.R.), by the University of Colorado Developmental Psychobiology Research Group Endowment Fund provided by the Grant Foundation, by The Veterans Administration MedicalResearch Service, and by USPHSgrants MH15442, MH44212, and MH38321. Reprintrequests to Dr. Ross, Box C268-71, 4200 E. 9th Avenue, Denver, CO 80262; e-mail: [email protected] 0890-8567/96/3507-0941$03.00/0©1996 by the American Academy of Child and Adolescent Psychiatry.
1979a,b; Pass et al., 1978; Radant and Hommer, 1992). SPEM measurements are currently being used to address at least two questions in the study of schizophrenia: (1) Do abnormalities in SPEM reflect underlying cognitive or neurobiological deficits in schizophrenia? (2) Do SPEM abnormalities help identify carriers of the genetic risk for schizophrenia? Global measures of smooth-pursuit tracking have included qualitative rating systems (e.g., Holzman et al., 1973; Iacono and Lykken, 1979a,b; Keefe et al., 1989; Salzman et al., 1978; Siever et al., 1982) and quantitative global measures such as root mean square (RMS) error, signal-to-noise ratio, and smooth-pursuit gain (see Clementz and Sweeney, 1990, for a review). A quantitative measure of pure smooth-pursuit gain (eye velocityltarget velocity during periods when only the smooth-pursuit mechanism is used) has been developed, patterned after proposals by several authors (e.g., Abel and Ziegler, 1988; Clementz and Sweeney, 1990; Radant and Hommer, 1992). Irrespective of the global measure of SPEM used, most authors have consistently found that schizophrenic subjects perform worse than
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normal controls (see Levy et al., 1993, for a review). Impaired smooth pursuit is also found in schizotypal (Keefe et al., 1989; Siever et al., 1990), but not other personality disorders (Siever et al., 1990), which suggests that impaired smooth pursuit may OCCut in the full range of schizophrenic spectrum disorders. In addition to the impaired smooth pursuit found in schizophrenic subjects, smooth pursuit has been examined in unaffected relatives of schizophrenic probands. In twins discordant for schizophrenia, SPEM abnormalities are more highly correlated in monozygotic than dizygotic twins (Holzman et al., 1980); SPEM abnormalities are found at high rates in nonaffected adult relatives of schizophrenic probands (Blackwood et al., 1991; Clementz et al., 1990, 1992; Grove et al., 1991, 1992; Holzman, 1989; Holzman et al., 1984, 1988; Iacono et al., 1992; Levy et al., 1983), in adult children of schizophrenic probands (D . Rosenberg, personal communication, September 29, 1994), and in older adolescent children of schizophrenic probands (Mather, 1985). In addition, in adult relatives of schizophrenic probands, SPEM abnormalities are correlated with negative symptomatology (Clementz et al., 1990). Many authors have used these results to suggest that SPEM abnormalities may be a marker for biological vulnerability to schizophrenia, even in subjects who never develop the full clinical disorder (Blackwood et al., 1991; Clementz and Sweeney, 1990; Erlenmeyer-Kimling, 1987; Grove et al., 1991, 1992; Holzman, 1989; Holzman et al., 1988; Rund and Landro, 1990). In other words, SPEM abnormalities may represent an endophenotype of the genetic risk for schizophrenia. The application of SPEM analysis to children and younger adolescents would be useful, both (1) because inclusion of an additional generation (and generally the largest generation ) in family studies would facilitate genetic linkage analysis of abnormal SPEM, and (2) because identification of children at increased genetic risk for schizophrenia might help in understanding the developmental pathways associated with schizophrenia. Unfortunately, the assessment of SPEM in children and adolescents has, to this point, been problematic. There is a large developmental component to SPEM performance, such that normally developing control children perform as poorly as adults with schizophrenia , making separation of developmental effects from atrisk for schizophrenia effects unclear (Ross et al., 1993).
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Thus, to date, family studies of SPEM have generally excluded children younger than 15 to 18 years of age. More recently, however, we have completed a normal developmental study of SPEM (Ross et al., 1993), suggesting that developmental changes in SPEM may be due to a different type of error than that hypothesized to represent genetic risk for schizophrenia (see below). Historically, in schizophrenia research, the tracking of objects moving in a predictable manner through visual space has generally been termed "smooth-pursuit eye movements" (SPEM). However, this is somewhat of a misnomer as visual tracking of this type actually involves the coordination of two types of eye movements, smooth-pursuit and saccades (see Clementz and Sweeney, 1990, for a review). Smooth pursuit refers to slow-velocity eye movements which function to maintain the image of a moving stimulus on the fovea by matching eye velocity to target velocity. If, however, eye velocity and target velocity are mismatched, there becomes, over time, an increasingly large mismatch between foveal gaze and target location. The eye then generates a "saccade"; a high-velocity eye movement that rapidly moves the eye to bring the image of a stimulus from the periphery back onto the fovea. Smooth-pursuit gain may decrease (worsen; that is, have slower eye velocity than target velocity) because of at least two possible causes. First, the smooth-pursuit system may inaccurately match eye velocity to target velocity, the eye may fall behind the target, and a "catch-up" saccade may be employed to return gaze to the target. Alternatively, the subject may "anticipate" target movement by initiating a saccade which takes gaze ahead of the target and then decrease eye velocity in order to allow the target to catch up. In the first case the deficit is in the smooth-pursuit system (corrected for by the saccadic system), and in the second case in the system that inhibits context-inappropriate saccades (and corrected for by the smooth-pursuit system). A large portion of the SPEM deficit in schizophrenia can be attributed to primarily small (mean amplitude of approximately 2°) anticipatory saccades, where the critical identifying feature is slowed postsaccadic smooth-pursuit velocity (Abel et al., 1991; Litman et al., 1994). Anticipatory saccades move gaze ahead of the target and can be distinguished from another type of saccade, square-wave jerks, based on postsaccadic pursuit velocity. Anticipatory saccades have immediate compensatory postsaccadic slowed pursuit,
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whereas square-wave jerks are followed by normalvelocity parafoveal pursuit (Abel and Ziegler, 1988). Parents ofschizophrenic probands who themselveshave an ancestral history of schizophrenia also have an increase in this type of primarily small anticipatory saccade (Ross et al., 1994). Thus, primarily small anticipatory saccades,when identified by slowed postsaccadic velocity, may be the phenotype most associated with genetic risk for schizophrenia. Because most of the developmental changes in SPEM are due to an ageassociated decrease in catch-up saccades, with no agerelated changes in anticipatory saccades (Ross et al., 1993), elevation of anticipatory saccadesmay be observable in children, with little concern that the elevated values due to schizophrenic risk will be obscured by developmental variability. This study compared SPEM in 6- to 15-year-old children of schizophrenic parents with SPEM in normally developing controls. Because children of schizophrenic parents are at increased risk for later developing schizophrenia (Schulsinger, 1976), presumably due to inheriting schizophrenia-vulnerability genes (Gottesman and Bertelsen, 1989; Tienari et al., 1989), this group of children was designated an "at-risk" group. Because catch-up saccades are age-related and not highly associated with genetic vulnerability to schizophrenia, we hypothesized that catch-up saccadeswould have a high variability within this sample but that no differences in catch-up saccades would exist between the at-risk and control groups. Conversely, since anticipatory saccades are associated with genetic risk for schizophrenia and do not change as a child ages, we hypothesized that anticipatory saccades would disrupt SPEM to a higher degree in the at-risk than in the control group. Because children in the at-risk group vary in the amount of genetic vulnerability to schizophrenia which they will have inherited from their schizophrenic parent, we hypothesized that the increase in anticipatory saccades in the at-risk group would be primarily due to a subset of that group.
including the Denver Veterans Hospital and Medical Center, the University of Colorado Psychiatry Outpatient Program, and a parent education group for mothers with schizophrenia (Waldo et al., 1987). All proband parents met DSM-III-R(American Psychiatric Association, 1987) criteria for schizophrenia and completed either a Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Endicott and Spitzer, 1978) or Structured Clinical Interview for DSM-III-R-Patient Edition (Spitzer et al., 1990) to confirm the diagnosis. Once the proband parent was identified, the parents were asked whether their 6- to 15-year-old children would be willing to participate in this study. All children tested, except one, currently lived in the custody of their proband parents, although several of the children had intermittently lived in alternative arrangements, often as a result of the involvement of social services (with temporary placement in foster homes). All parents gave written consent for participation and all child and adolescent subjects gave written and/or oral assent. Child and adolescent subjects were paid $15 for participation. Parents were not paid for child participation. Nineteen normally developing 6- to l S-year-old control children were recruited through advertisements. Children were excluded from the normally developing group for a personal history of major psychiatric or neurological disorders or if any first-degree family member had ever received a diagnosis of psychosis. First-degree relatives were not screened for nonpsychotic psychiatric disorders. Consent/assent and subject payment procedures were identical with those used for the at-risk group. Children in the at-risk group did not differ from children in the control group on age (mean age ± SD: at-risk group 127 ± 28 months versus control group 133 ± 24 months; t = 0.64, not significant) or ratio of male to female subjects (percentage male: at-risk group 38.5% versus control group 47.4%; X2 = 0.25, not significant). Children in the at-risk group did have significantly lower scaled scores on the Vocabulary (mean ± SD: at-risk 9.3 ± 2.6 versus control 11.9 ± 2.8; t = 2.5, P < .02) and Block Design (mean ± SD: at-risk 9.3 ± 2.5 versus control 12.9 ± 3.3; t = 2.5, P < .02) subtests of the WISC-III (Weschler, 1991). Previous studies of 53 normally developing children have failed to demonstrate any consistent correlation between WISC-III subtest scores and performance on any SPEM measures (unpublished data).
Eye Movement Procedure
The experimental group consisted of 13 children ofschizophrenic parents; the children were aged 6 to 15 years. We recruited them by first identifying the parent with the schizophrenia diagnosis. These proband parents were recruited from a variety of sources
Children were allowed to tour the eye movement laboratory prior to initiating the procedure, and actual eye movement procedures were generally done after cognitive and demographic forms were completed by the child. All children were allowed to ask questions and to take as much time as needed between aspects of the procedure. Children appeared relaxed and nonstressed by the experience. Subjects were seated 43 ern in front of a video monitor on which a small target was displayed against a black background in an otherwise dark room. The subject's head was stabilized with a bite bar and head rest. We have found that the quality of eye movement recording in children is greatly improved by the addition of a chair with two critical features: first that the chair can be raised and lowered over a broad enough height range to allow for wide variabilities in children's height, and second that the chair "locks" so that the child cannot swivel in his or her seat. Raising the chair high enough so that the child has to crouch slightly in the seat in order to bite onto the bite bar also decreases head movement and improves the overall quality of the eye movement recording. Horizontal eye movements were recorded using an
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METHOD
Subjects
ROSS ET AL.
infrared photoelectric limbus detection eye-tracking device (Eyetrac model 210, Applied Sciences Laboratories, Waltham, MA), which is accurate to within 0.25° of visual angle and has a time constant of 4 milliseconds. The analog output of the device is sampled at 1,000 Hz using a 12-bit analog-to-digital converter. There are no reported data assessing left-right differences in the dependent eye movement measures employed in this study, but, since disconjugate gaze should be absent in most subjects, both eyes should be tracking the target in a similar manner . Our experience has suggested that minimizing calibration time decreases the time these young subjects must maintain head position and improves the quality ofthe recording. Therefore, data were collected only from the eye for which the most rapid and accurate calibration could be obtained.
Smooth-Pursuit Eye Movement Task The target moved horizontally back and forth over 30° with a constant velocity of l2o/second and a lA-second fixation period between ramps, a "trapezoidal pattern." Children were told to " keep your eyes on the target wherever it goes." Figure 1 shows an example of the performance of two children on a portion on this task.
Eye Movement Analysis All eye movement data were analyzed with a computerized pattern recognition program , SEMAS (Seattle Eye Movement Analysis
9 y/o female normal control
4 seconds
Data Analysis
10 y/o female
at-risk for schizophrenia
4 seconds Fig. 1 Smooth-pursuit qe movements in cwo children, a 9-year-old normally developing control female and a IO-year-old female who, as the child of a schizophrenic parent, is at increased genetic risk for later developing schizophrenia. Dotted lines represent target motion; solid lines represent visual gaze of the subjects.
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System). This analysis system has been described elsewhere (Radant and Hommer, 1992; Ross er al., 1993) and will be briefly described here. Gain for a given interval of smooth pursuit is defined as mean eye velocity divided by target velocity. Overall smoothpursuit gain is defined as the mean gain, weighted for time, of all intervals of true smooth pursuit (Abel et al., 1991). Intervals defined as saccades are not included in computing smooth-pursuit gain. Although theoretical optimal performance on this task is defined as gain equal to 1.0 (i.e., eye velocity = target velocity), most children have mean eye velocity less than target velocity. The resulting mismatch must be compensated for by saccadicmovement. Saccades are classified on the basis of apparent function . The two types of saccades focused on in this analysis are catch-up and anticipatory saccades. Catch-up saccades function to significantly reduce error between foveal gaze and target location. Saccades that are in the same direction as target motion and begin and end behind the target are catch-up saccades. Saccades that are in the same direction as target motion but that begin behind target location and end ahead of target location are classified as catchup saccades if postsaccadic position error is :550% of presaccadic position error (that is, the saccade functions to dramatically decrease the mismatch between visual gaze and target location). Classification of anticipatory saccades is based on proposals by Abel and Ziegler (1988). Anticipatory saccades must (1) be in the direction of target motion, (2) either begin and end ahead of target location or increase position error by 100%, and (3) be followed by a 50millisecond interval of eye velocity less than 75% of target velocity. For all saccades, a nonlinear relationship exists between saccadic amplitude and the maximum eye velocity reached during the saccade (termed the main sequence) (Bahill et al., 1975). In reviewing individual records, we have noted saccades which full outside the main sequence. These saccadesare rare (most recordings have none; only one record had more than one), oflong duration (80 to 110 milliseconds for a 10° to 15° saccade), and of unclear functional significance in the tracking task. Saccades of greater than 60 milliseconds' duration have therefore been discarded for this analysis. Figure 2 shows a short segment of a record containing examples of smooth pursuit, a catch-up saccade, and an anticipatory saccade.
Data are presented and examined in three ways: Task Performance. Task performance on this smooth-pursuit tracking task was measured using two techniques: smooth-pursuit gain (e.g., Radant and Homrner, 1992) and RMS error (e.g., Clementz and Sweeney, 1990). Smooth-pursuit gain is mean eye velocity divided by target velocity during periods when the smoothpursuit system is employed; optimal performance occurs when eye velocity equals target velocity or a smooth-pursuit gain of 1.0. RMS error is the square root of the average of the square of the distance from the target position to eye position at each artifactfree time point; optimal performance would have eye position and target position match at all times or an RMS error of O. Since previous studies of SPEM in family members of schizophrenia have used both of these techniques for measuring smooth-pursuit performance, both analyses were included here for comparison with previous studies. Frequency of Saccadic Subtypes. A measure often used by other investigators (e.g., Abel et al., 1991; Clementz and Sweeney, 1990; Radant and Hommer, 1992) is the frequency of saccadic subtypes. Data will be presented in this format to allow for comparison with previous studies.
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Contribution of Saccadic Subtypes to Total Pursuit Tracking. Frequency data fail to address questions about differences in saccadic amplitude. A given number of large anticipatory saccades would cause much more mismatch between eye and target position (and hence more compensatory slowing of smooth pursuit) than would the same number ofsmall saccades. This emphasizes the importance of examining amplitude data along with frequency data. To assess the full impact of saccades during ongoing pursuit, we measured the total distance covered by each saccadic type (catch-up and anticipatory) and divided by the total distance covered by artifactfree eye movements. This produces the percentage of artifact-free eye movements due to each type of saccade, providing a measure of the full impact of each type of saccade on ongoing pursuit .
question . This approach of determining whether each subject is "abnormal" may also be appropriate as, even within the at-risk group, not all children will be expected to have inherited the full biological risk for schizophrenia. Because of concerns about the influence of development over a IO-year age span, all comparisons between groups were performed with chronological age as a covariant. Because the normally developing control group scored higher on tests of cognitive functioning (the Vocabulary and Block Design subtests of the WISC-I1I), subtest standardized scores were also used as covariants. Results of statistical analyses did not differ as a result of whether or not covariants were included in the analyses. Only results with covariants are included here.
Statistical Analysis There are three dependent measures ofinterest: task performance, catch-up saccades (which represent error due to the smooth-pursuit system), and anticipatory saccades (which represent error due to the inabiliry to inhibit context-inappropriate saccades). Each dependent measure is calculated in two ways. Task performance is measured by smooth-pursuit gain and RMS error. Catch-up saccades and anticipatory saccades are measured both the by frequency of their occurrence and by their contribution to total eye movement. Comparisons between groups will be made in two ways. First, groups will be compared by using analyses of covariance. Second, groups will be compared to determine whether the at-risk group members are more likely to be described as "abnormal," with abnormaliry being defined as values greater than two standard deviations poorer than mean performance of the normal group . One rationale for studying SPEM in at-risk children is to determine whether abnormalities in SPEM can be used as an endophenotype for genetic risk for schizophrenia, and determining whether at-risk children perform more frequently as "abnormal" addresses this
RESULTS
Table 1 summarizes the comparisons between the at-risk and normally developing groupS. Smooth-pursuit gain and RMS error significantly differed between at-risk and control children. In addition, if one defines abnormality as two standard deviations poorer than the control mean, at-risk children were significantly different in their likelihood of being defined as abnormal for either measure (Table 2). When examining the possible sources of error , both measures of catchup saccades showed no significant difference between the groups, and at-risk children were not significantly different in their likelihood of being defined as abnormal (Tables 1 and 2). In direct contrast to the results with catch-up saccades, and as hypothesized, measures of anticipatory saccades were significantly increased in the at-risk group. For example, the percentage of total eye movements due to anticipatory saccades was both increased in the at-risk group (Table 1) and more likely to define subjects in the at-risk group as abnormal (Table 2). Figure 3 (anticipatory saccades as a percentage of total eye movement) graphically demonstrates both the low variability and the lack of age effects in the normally developing control group as well as the 7 of 13 atrisk children (54%) who fell more than two standard deviations above the control mean. DISCUSSION
Fig. 2 Smooth-pursuit eye movements: analysisof saccadic subtypes. This segment shows smooth pursuit (sp), a catch-up saccade (cs), and an ant icipatory saccade (as).
Abnormalities in SPEM were first proposed by Holzman et al. (1980) to be a potential endophenotype of the genetic risk for schizophrenia. In comparing atrisk to normally developing controls, we found that global task measures of gain and RMS error were significantly worse in at-risk than control children and
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400 milliseconds
ROSS ET AL.
TABLE 1 Mean Values::!:: Standard Deviations for Smooth-Pursuit Eye Movement Measures
Task measures Gain RMS error Catch-up saccades No.lsecond Mean amp % Total Anticipatory saccades No.lsecond Mean amp" % Total
p
Control Group
At-Risk Group
F
0.920 ::!:: 0.079 1.431 ::!:: 0.944
0.820::!:: 0.163 2.612 ::!:: 1.323
4.8 4.8
.04 .04
0.721 ::!:: 0.306 1.767 ::!:: 0.493 10.4 ::!:: 5.3
0.855 ::!:: 0.515 2.081 ::!:: 0.776 13.6 ::!:: 8.6
0.9 1.4 1.6
NS NS NS
0.061 ::!:: 0.079 1.609 ::!:: 1.032 0.744 ::!:: 0.994
0.272 ::!:: 0.252 2.192 ::!:: 1.324 5.347 ::!:: 5.993
10.7 1.7 12.1
.004 NS .002
Note: Gain = smooth-pursuit gain; RMS = root mean square; Mean amp = mean amplitude; % Total = percentage of total eye movement due to that particular type of saccade; NS = not significant. F values are results from analyses of covariance with age and WISC subscale scores as covariates. a For anticipatory saccades, mean amplitude is calculated only for those subjects who exhibited anticipatory saccades: n = 9 controls and 9 at-risk subjects.
identified as abnormal 31% to 62% of the at-risk compared with 5% to 11% of control children. When we examined the types of errors which may have contributed to poor tracking, measures of catch-up saccadesdid not significantly differ between the groups. TABLE 2 Number and Percentage of Subjects in Each Group with "Abnormal" Performance on Smooth-Pursuit Eye Movement Measures At-Risk Group No.
%
%
~
~
~
~
14
m
•
•
11 12
o u p
4 8
30.8 61.5
1 2
5.3 10,5
.07 .004
; :ll 10 >.'"
2 2 2
15.4 15.4 15.4
0 1 1
0.0 5.3 5.3
NS NS NS
7 2 7
53.8 22.2 53.8
1 1 0
5.3 11.1 0.0
.004 NS .0005
•
~
se .s~ 'O;g
8
~
4
6
~ GI
a..
2
•
•
GI C Cl ca
Note: "Abnormal" is defined as worse performance than two standard deviations poorer than the control mean. Gain = smoothpursuit gain; RMS = root mean square; Mean amp = amplitude; % Total = percentage of total eye movement due to that particular rype of saccade; NS = not significant. Probabiliry (p) values are based on Fisher's Exact Test with comparisons between the control and at-risk group for each variable. a For anticipatory saccades, mean amplitude values are based on only those subjects who exhibited anticipatory saccades: n = 9 controls and 9 at-risk subjects.
946
•
16
"0
GI
Task measures Gain RMS error Catch-up saccades No.lsecond Mean amp % Total Anticipatory saccades No.lsecond Mean amp" % Total
18 , . . - - - - - - - - - - - - - - - ,
.s
Control Group No.
In contrast, in about half of at-risk children, anticipatory saccadeswere more frequent and covered a greater percentage of total eye distance. Examination of thirteen 9- to 12-year-old children with attention deficit disorder did not produce a similar distribution of
···············tI·-6;·····!· lh 6. A
o
6. 6.. 6
7
8
6.. 9
~4'"
10 11 12 13 14 15 16
Age in years Fig. 3 Anticipatory saccades (percentage of total eye movements) as a function of age. The at-risk group (solidcircles) are children of schizophrenic parents (aged 6 to 15 years; n = 13); the control group (open triangles) are normally developing children (aged 6 to 15 years; n = 19). The dotted line represents two standard deviations above the control mean. Seven (54%) of the 13 at-risk children compared with 0 (0%) of the control children performed more than two standard deviations higher (worse) than the control mean.
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elevated anticipatory saccades (unpublished data), further suggesting at least some specificity of the finding to genetic risk for schizophrenia. Children were placed in the at-risk group solely on the basis of parental diagnosis; none of the children demonstrated nor did any parent report any child to have symptoms suggestive of psychotic disorders. The increase in anticipatory saccades does not seem to have been directly associated with the presentation of schizophrenic symptoms, but instead was associated with the parental diagnosis of schizophrenia. Anticipatory saccades may therefore be an indicator of genetic risk, even in young children. These results must be considered preliminary because of the relatively small sample size and the significantly poorer performance on tests of cognitive functioning in the at-risk group. We have found no consistent relationship between cognitive test scores and eye movement variables in this group, and covarying for cognitive test results does not change the results of this study; however, replicating this study with more cognitively matched controls will be necessary.Since we did not screen for family histories of nonpsychotic psychiatric disorders, the control group may contain children at increased genetic risk for non psychotic psychiatric disorders. Even with this possible confounding factor, there were no outliers in the control group. Additional studies incorporating control groups specifically identified on the basis on parental history of nonpsychotic psychiatric disorders will also be required to fully assess the specificity of increased anticipatory saccades to genetic risk for schizophrenia. The eye movement difficulty in schizophrenics and their children involves, in part, the intrusion of primarily small saccades onto otherwise accurate smooth pursuit. These saccades are in the direction of ongoing smooth-pursuit movement, and disruption of tracking accuracy is immediately compensated for by slowed smooth-pursuit movement. In posterior cortical lesions, SPEM are severely impaired and tracking is done primarily with saccades (Thurston et al., 1988). In children of schizophrenic parents, the smooth-pursuit system is intact; however context-inappropriate saccades intrude. Thus, a possible model of the pathophysiology is the loss of inhibitory control over behavior based on expected target motion. The brain region responsible for the inhibitory control is unknown, but it may involve saccadic inhibition ("fixation") neurons in the superior colliculus (Munoz and Wurtz, 1993) that are
controlled by a thalamic gating circuit (Matsumura et al., 1992), which in turn receives cortical input via the basal ganglia (Hikosaka et al., 1993). The frontal eye fields may be a critical cortical center (O'Driscoll et al., 1995; Suzuki and Azuma, 1977), although other regions of the frontal lobe have also been proposed (Bon and Lucchetti, 1992). The finding of this abnormality in childhood, before higher cortical functions are fully developed, supports further consideration of both cortical and subcortical sites of pathophysiology in schizophrenia.
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Clinical Relevance
The identification of a potential marker of genetic risk for schizophrenia in children may be useful in locating the gene (or genes) responsible for genetic risk, and it may eventually improve diagnostic and prognostic evaluations. However, reporting that anticipatory saccades are increased during smooth-pursuit tasks in a subset of children of schizophrenic parents does little to explain what that deficit may mean cognitively or behaviorally. There is little direct evidence to tie an increase in anticipatory saccades to any specific cognitive functioning, but one can speculate that anticipatory saccades represent a problem in selection of attentional focus. One classic feature of smooth-pursuit tasks is their predictability. The target's future behavior (velocity, direction, and location) is easily predictable. The subject, therefore, has access to at least two bits of information about the target: where it currently is and where it will be at later time points. Since the task instructions are to maintain visual gaze on the current location of the target, the at-risk child's increased tendency to shift gaze to a later target location suggests problems in either (1) remembering task instructions, or (2) using task instructions to select task-appropriate behavior (that is, to keep visual gaze and presumably attention on the current target). Difficulties in selecting taskappropriate attentional focus would lead to high rates of task-inappropriate attentional shifts and may explain the high rates of attention deficit disorder symptoms in children of schizophrenic subjects (Marcus et al., 1987; Mednick, 1970; Rieder and Nichols, 1979). Further work in this area may help clarify whether genetic vulnerability for schizophrenia is an etiological pathway to attention deficit disorder, may help identify
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subgroups with different symptomatology and prognosis, and may eventually lead to more etiologically specific intervention strategies. This study provides evidence that the use of SPEM in the examination of children of schizophrenic parents is productive. SPEM analysis in children may provide evidence useful both in family genetic risk studies and in the study of the developmental course of schizophrenia. However, further research is necessary to elucidate fully the relationship between SPEM, genetic risk for schizophrenia, and developmentally frameworked symptom presentation.
REFERENCES Abel L, Friedman L, ]esberger], Malki A, Meltzer HY (1991), Quanrirarive assessmenr of smooth pursuit gain and catch-up saccades in schizophrenia and affective disorders. Biol Psychiatry 29: 1063-1072 Abel L, Ziegler A (1988), Smooth pursuit eye movements in schizophrenics: what constitutes quantitative assessmenr? Biol Psychiatry 24:747-761 American Psychiatric Association (1987), Diagnostic and Statistical Manual ofMental Disorders, 3rd edition-revised (DSM-III-R). Washington, DC: American Psychiatric Association Bahill AT, Clark MR, Stark L (1975), The main sequence, a tool for studying human eye movemenrs. Math Biosci 24:191-204 Blackwood DHR, Sr Clair OM, Muir W), Duffy ]C (1991), Auditory P300 and eye tracking dysfunction in schizophrenic pedigrees. Arch
Gen Psychiatry 48:899-909 Bon L, Lucchetti C (1992), The dorsomedial fronral cortex of the macaca monkey: fixation and saccade-related activity. ExpBrainRes 89:571-580 Clementz BB, Grove WM, Iacono WG, Sweeney ]A (1992), Smoothpursuit eye movemenr dysfunction and liability for schizophrenia: implications for genetic modeling. J Abnorm Psycholl01:117-129 Clementz BB, Sweeney]A (1990), Is eye movemenr dysfunction a biological marker for schizophrenia? A methodological review. Psychol Bull 108:77-92 Clementz BB, Sweeney]A, Hirt M, Haas G (1990), Pursuit gain and saccadic inrrusions in first-degree relatives of probands with schizophrenia. J
Abnorm PsychoI99:327-335 Couch RH, Cox]C (1934), Photographic study of ocular movements in menral disease. Arch Neurol Psychiatry 34:556-578 Diefendorf AR, Dodge R (1908), An experimenral study of the ocular reaction on the insane from photographic records. Brain 31:451-489 Endicotr ], Spitzer RL (1978), A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch GenPsychiatry 35:837-844 Erlenmeyer-Kimling L (1987), Biological markers for the liability to schizophrenia. In: Biological Perspectives ofSchizophrenia, Helmchen H, Henn FA, eds. S. Chichester, England: John Wiley & Sons Limited, pp 33-56 Friedman L, ]esberger ]A, Meltzer HY (1991), A model of smooth pursuit performance illustrates the relationship between gain, catch-up saccade rate, and catch-up saccades amplitude in normal controls and patients with schizophrenia. Biol Psychiatry 30:537-556 Friedman L, ]esberger ]A, Meltzer HY (1992), Effect of rypical antipsychotic medication and clozapine on smooth pursuit performance in patients with schizophrenia. Psychiatry Res 41:25-36 Gottesman II, Bertelsen A (1989), Confirming unexpressed genotypes for schizophrenia, Arch Gen Psychiatry 46:867-872 Grove WM, Clementz BA, Iacono WG, Katsanis ] (1992), Smooth pursuit ocular motor dysfunction in schizophrenia: evidence for a major gene.
Am J Psychiatry 149:1362-1368 Grove WM, Lebow BS, Clementz BA, Cerri A, Medus C, Iacono WG (1991), Familial prevalence and coaggregation of schizorypy indicators: a multitrait family study. J Abnorm Psychol100:115-121
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Hikosaka 0, Masahiro M, Miyashita N (1993), Effects of caudate nucleus stimulation on substantia nigra cell activity in monkey. Exp Brain
Res 95:457-472 Holzman PS (1989), The use of eye movemenr dysfunctions in exploring the genetic transmission of schizophrenia. Eur Arch Psychiatr Neurol
Sci 239:43-48 Holzman PS, Kringlen E, Levy DL, Haberman S] (1980), Deviant eye tracking in twins discordant for schizophrenia. Arch Gen Psychiatry 37:627-631 Holzman PS, Kringlen E, Matthysse S et al. (1988), A single dominant gene can accounr for eye tracking dysfunction and schizophrenia in offspring of discordant twins. Arch Gen Psychiatry 45:641-647 Holzman PS, Proctor LR, Hughes OW (1973), Eye tracking patterns in schizophrenia. Science 181: 179-181 Holzman PS, Solomon CM, Levin S, Waternaux CS (1984), Pursuit eye movement dysfunctions in schizophrenia. Arch Gen Psychiatry 41:136-139 Iacono WG, Lykken DT (1979a), Eye tracking and psychopathology. Arch Gen Psychiatry 36: 1361-1369 Iacono WG, Lykken DT (1979b), Electo-oculographic recording and scoring of smooth pursuit and saccadic eye tracking: a parametric study using monozygotic twins. Psychophysiology 16:94-107 Iacono WG, Moreau M, Beiser M, Fleming ]AE, Lin TY (1992), Smoothpursuit eye tracking in first-episode psychotic patients and their relatives.
J Abnorm Psychol101:104-116 Keefe RSE, Siever L], Mohs RC et al. (1989), Eye tracking, schizophrenic symptoms, and schiwrypal personality disorder. Eur Arch Psychiatr
Neurol Sci 239:39-42 Levy DL, Holzman PS, Matthysse S, Mendell NR (1993), Eye tracking dysfunction and schizophrenia: a critical perspective. Schizophr Res 19:461-536
Levy DL, Yasillo N], Dorus E et al. (1983), Relatives of unipolar and bipolar patients have normal pursuit. Psychiatry Res 10:285-293 Litman RE, Hommer OW, Radant A, Clem T, Pickar 0 (1994), Quantitative effects of rypical and arypical neuroleptics on smooth pursuit eye tracking in schizophrenia. Schizophr Res 12: 107-120 Marcus ], Hans SL, Auerbach ]G, Mirsky AF, Aubrey A (1987), Review of the NIMH Israeli Kibbutz-City Study and the Jerusalem Infant Developmenr Study. Schizophr Bull 13:425-438 Mather ]A (1985), Eye movements of teenage children of schizophrenics: a possible inherited marker of susceptibiliry to the disease. J Psychiatr
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Matsumura M, Kojima], Gardiner TW, Hikosaka (1992), Visual and oculomotor functions of monkey subthalamic nucleus. J Neurophysiol 67:1615-1631 Mednick SA (1970), Breakdown in individuals at high risk for schizophrenia: possible predispositional perinatal factors. Ment Hyg 54:50-63 Munoz DP, Wurtz RH (1993), Fixation cells in monkey superior colliculus II. Reversible activation and deactivation. J Neurophysiol 20:576-589 O'Driscoli GA, Alpert NM, Matthysse SW, Levy DL, Rauch SL, Holzman PS (1995), Functional neuroanatomy of antisaccade movements investigated with positron emission tomography. Proc Natl Acad Sci USA 92:925-929 Pass HL, Salzman LF, Klorrnan R, Kaskey GB, Klein RH (1978), The effect ofdistraction on acute schizophrenics' visual tracking. BiolPsychia-
try 13:587-593 Radant AD, Hommer OW (1992), A quanritative analysis of saccades and smooth pursuit during visual pursuit tracking: a comparison of schizophrenics with normals and substance abusing conrrols. Schizophr
Res 6:225-235 Rieder RO, Nichols PL (1979), Offspring ofschizophrenics III: hyperactivity and neurological soft signs. Arch Gen Psychiatry 36:665-674 Ross RG, Harris], Cullum CM et al. (1994), Smooth pursuit eye movements in parenrs of pro bands with schizophrenia: an obligate carrier approach. Soc Neurosci Abstr 20: 1262 Ross RG, Radant AD, Hommer OW (1993), A developmenral study of smooth pursuit eye movements in normal children from 7 to 15 years of age. JAm Acad Child Adolesc Psychiatry 32:783-791
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Rund BR, Landro NI (1990), Information processing: a new model for understanding cognitive disturbances in psychiatric patients. Acta Psychiatr Scand 8 I :305-316 Salzman LF, Klein RH, Strauss JS (1978), Pendulum eye-tracking in remitted psychiatric patients. J Psychiatr Res 14:121-126 Schulsinger H (1976), A ten-year follow-up of children of schizophrenic mothers. Acta Psychiatr Scand53:371-386 Siever LJ, Haier RJ, Coursey RD et al. (1982), Smooth pursuit eye tracking impairment. Arch Gen Psychiatry 39:1001-1 005 Siever LJ, Keefe R, Bernstein DP et al. (1990), Eye tracking impairment in clinically identified patients with schizorypal personality disorder.
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Suzuki H, Azuma M (1977), Prefrontal neuronal activity during gazing at a lighr spor in rhe monkey. Brain Res 126:497-508 Thurston SE, Leigh RJ, Crawford T, Thompson A, Kennard C (1988), Two distinct deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Ann NeuroI23:266-273 Tienari P, Lahti I, Sorci A, Naarala M, Moring J, Wahlberg KE (1989), The Finnish adoptive family study of schizophrenia: possible joint effects of genetic vulnerability and family environment. Br J Psychiatry 155(suppl 5):29-32 Waldo MC, Roath M, Levine W, Freedman R (1987), A model program to teach parenting skills to schizophrenic mothers. Hosp Community
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Spitzer RL, Williams JBW, Gibbon M, First MB (1990), Structured Clinical Interview for DSM-III-R-Patient Edition. Washington, DC: American Psychiatric Press
Weschler 0 (1991), Weschler Intelligence Scale for Children-Third Edition. San Antonio, TX: Harcourt Brace Jovanovich
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ABSTRACT Objective: Disordered smooth-pursuit eye movements (SPEM) and, specifically, small anticipatory saccades that disrupt
SPEM have been hypothesized to be a marker of genetic vulnerability to schizophrenia. This study compares SPEM in children of schizophrenic parents with normally developing control children to assess whether SPEM abnormalities are also present in a subset of at-risk children. Method: With infrared oculography, SPEM was examined in 13 children of schizophrenic parents and 19 normally developing controls (aged 6 to 15 years). Measures of smooth-pursuit gain and root mean square error were used in addition to more specific measures of catch-up saccades and anticipatory saccades. Results: Children of schizophrenic parents differed from normally developing controls on gain and root mean square error, but not on catch-up saccades. Small anticipatory saccades were significantly more frequent in the at-risk group. The percentage oftotal eye movements due to anticipatory saccades identified 54% of the at-risk group (compared with none of the control group) as performing more than two standard deviations above (worse than) the control mean. Conclusions: The presence of increased anticipatory saccades is evidence for an oculomotor dysfunction that may
be a phenotype of the genetic risk for schizophrenia, expressed years prior to the possible development of clinical illness. J. Am. Acad. Child Ado/esc. Psychiatry, 1996, 35(7):941-949. Key Words: eye movements, smooth pursuit, schizophrenia, children, at-risk, endophenotype.
Almost 90 years ago, Diefendorf and Dodge (1908) first noted that adult patients with schizophrenia had difficulties with tasks that required smooth-pursuit eye movements (SPEM). This finding was replicated by Couch and Cox in the 1930s (1934), independently rediscovered by Holzman et al. in the 1970s (1973), and then consistently replicated over the past 20 years in a number of laboratories (e.g., Abel and Ziegler, 1988; Abel et al., 1991; Friedman et al., 1991, 1992; Holzman et al., 1984, 1988; Iacono and Lykken, Accepted August 9, 1995. Dr. Ross and Ms. Roath are Assistant Professors and Dr. Freedman is a Professor, University ofColorado HealthSciences Center, Denver. Dr. Hommer is Section Chief,NationalInstitute ofAlcohol Abuseand Alcoholism, Bethesda, MD. Dr. Radant is Assistant Professor, University of Washington, Seattle. Thisresearch wasfUnded bya NARSADJuniorInvestigator Award (R. G.R.), by the University of Colorado Developmental Psychobiology Research Group Endowment Fund provided by the Grant Foundation, by The Veterans Administration MedicalResearch Service, and by USPHSgrants MH15442, MH44212, and MH38321. Reprintrequests to Dr. Ross, Box C268-71, 4200 E. 9th Avenue, Denver, CO 80262; e-mail: [email protected] 0890-8567/96/3507-0941$03.00/0©1996 by the American Academy of Child and Adolescent Psychiatry.
1979a,b; Pass et al., 1978; Radant and Hommer, 1992). SPEM measurements are currently being used to address at least two questions in the study of schizophrenia: (1) Do abnormalities in SPEM reflect underlying cognitive or neurobiological deficits in schizophrenia? (2) Do SPEM abnormalities help identify carriers of the genetic risk for schizophrenia? Global measures of smooth-pursuit tracking have included qualitative rating systems (e.g., Holzman et al., 1973; Iacono and Lykken, 1979a,b; Keefe et al., 1989; Salzman et al., 1978; Siever et al., 1982) and quantitative global measures such as root mean square (RMS) error, signal-to-noise ratio, and smooth-pursuit gain (see Clementz and Sweeney, 1990, for a review). A quantitative measure of pure smooth-pursuit gain (eye velocityltarget velocity during periods when only the smooth-pursuit mechanism is used) has been developed, patterned after proposals by several authors (e.g., Abel and Ziegler, 1988; Clementz and Sweeney, 1990; Radant and Hommer, 1992). Irrespective of the global measure of SPEM used, most authors have consistently found that schizophrenic subjects perform worse than
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normal controls (see Levy et al., 1993, for a review). Impaired smooth pursuit is also found in schizotypal (Keefe et al., 1989; Siever et al., 1990), but not other personality disorders (Siever et al., 1990), which suggests that impaired smooth pursuit may OCCut in the full range of schizophrenic spectrum disorders. In addition to the impaired smooth pursuit found in schizophrenic subjects, smooth pursuit has been examined in unaffected relatives of schizophrenic probands. In twins discordant for schizophrenia, SPEM abnormalities are more highly correlated in monozygotic than dizygotic twins (Holzman et al., 1980); SPEM abnormalities are found at high rates in nonaffected adult relatives of schizophrenic probands (Blackwood et al., 1991; Clementz et al., 1990, 1992; Grove et al., 1991, 1992; Holzman, 1989; Holzman et al., 1984, 1988; Iacono et al., 1992; Levy et al., 1983), in adult children of schizophrenic probands (D . Rosenberg, personal communication, September 29, 1994), and in older adolescent children of schizophrenic probands (Mather, 1985). In addition, in adult relatives of schizophrenic probands, SPEM abnormalities are correlated with negative symptomatology (Clementz et al., 1990). Many authors have used these results to suggest that SPEM abnormalities may be a marker for biological vulnerability to schizophrenia, even in subjects who never develop the full clinical disorder (Blackwood et al., 1991; Clementz and Sweeney, 1990; Erlenmeyer-Kimling, 1987; Grove et al., 1991, 1992; Holzman, 1989; Holzman et al., 1988; Rund and Landro, 1990). In other words, SPEM abnormalities may represent an endophenotype of the genetic risk for schizophrenia. The application of SPEM analysis to children and younger adolescents would be useful, both (1) because inclusion of an additional generation (and generally the largest generation ) in family studies would facilitate genetic linkage analysis of abnormal SPEM, and (2) because identification of children at increased genetic risk for schizophrenia might help in understanding the developmental pathways associated with schizophrenia. Unfortunately, the assessment of SPEM in children and adolescents has, to this point, been problematic. There is a large developmental component to SPEM performance, such that normally developing control children perform as poorly as adults with schizophrenia , making separation of developmental effects from atrisk for schizophrenia effects unclear (Ross et al., 1993).
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Thus, to date, family studies of SPEM have generally excluded children younger than 15 to 18 years of age. More recently, however, we have completed a normal developmental study of SPEM (Ross et al., 1993), suggesting that developmental changes in SPEM may be due to a different type of error than that hypothesized to represent genetic risk for schizophrenia (see below). Historically, in schizophrenia research, the tracking of objects moving in a predictable manner through visual space has generally been termed "smooth-pursuit eye movements" (SPEM). However, this is somewhat of a misnomer as visual tracking of this type actually involves the coordination of two types of eye movements, smooth-pursuit and saccades (see Clementz and Sweeney, 1990, for a review). Smooth pursuit refers to slow-velocity eye movements which function to maintain the image of a moving stimulus on the fovea by matching eye velocity to target velocity. If, however, eye velocity and target velocity are mismatched, there becomes, over time, an increasingly large mismatch between foveal gaze and target location. The eye then generates a "saccade"; a high-velocity eye movement that rapidly moves the eye to bring the image of a stimulus from the periphery back onto the fovea. Smooth-pursuit gain may decrease (worsen; that is, have slower eye velocity than target velocity) because of at least two possible causes. First, the smooth-pursuit system may inaccurately match eye velocity to target velocity, the eye may fall behind the target, and a "catch-up" saccade may be employed to return gaze to the target. Alternatively, the subject may "anticipate" target movement by initiating a saccade which takes gaze ahead of the target and then decrease eye velocity in order to allow the target to catch up. In the first case the deficit is in the smooth-pursuit system (corrected for by the saccadic system), and in the second case in the system that inhibits context-inappropriate saccades (and corrected for by the smooth-pursuit system). A large portion of the SPEM deficit in schizophrenia can be attributed to primarily small (mean amplitude of approximately 2°) anticipatory saccades, where the critical identifying feature is slowed postsaccadic smooth-pursuit velocity (Abel et al., 1991; Litman et al., 1994). Anticipatory saccades move gaze ahead of the target and can be distinguished from another type of saccade, square-wave jerks, based on postsaccadic pursuit velocity. Anticipatory saccades have immediate compensatory postsaccadic slowed pursuit,
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whereas square-wave jerks are followed by normalvelocity parafoveal pursuit (Abel and Ziegler, 1988). Parents ofschizophrenic probands who themselveshave an ancestral history of schizophrenia also have an increase in this type of primarily small anticipatory saccade (Ross et al., 1994). Thus, primarily small anticipatory saccades,when identified by slowed postsaccadic velocity, may be the phenotype most associated with genetic risk for schizophrenia. Because most of the developmental changes in SPEM are due to an ageassociated decrease in catch-up saccades, with no agerelated changes in anticipatory saccades (Ross et al., 1993), elevation of anticipatory saccadesmay be observable in children, with little concern that the elevated values due to schizophrenic risk will be obscured by developmental variability. This study compared SPEM in 6- to 15-year-old children of schizophrenic parents with SPEM in normally developing controls. Because children of schizophrenic parents are at increased risk for later developing schizophrenia (Schulsinger, 1976), presumably due to inheriting schizophrenia-vulnerability genes (Gottesman and Bertelsen, 1989; Tienari et al., 1989), this group of children was designated an "at-risk" group. Because catch-up saccades are age-related and not highly associated with genetic vulnerability to schizophrenia, we hypothesized that catch-up saccadeswould have a high variability within this sample but that no differences in catch-up saccades would exist between the at-risk and control groups. Conversely, since anticipatory saccades are associated with genetic risk for schizophrenia and do not change as a child ages, we hypothesized that anticipatory saccades would disrupt SPEM to a higher degree in the at-risk than in the control group. Because children in the at-risk group vary in the amount of genetic vulnerability to schizophrenia which they will have inherited from their schizophrenic parent, we hypothesized that the increase in anticipatory saccades in the at-risk group would be primarily due to a subset of that group.
including the Denver Veterans Hospital and Medical Center, the University of Colorado Psychiatry Outpatient Program, and a parent education group for mothers with schizophrenia (Waldo et al., 1987). All proband parents met DSM-III-R(American Psychiatric Association, 1987) criteria for schizophrenia and completed either a Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Endicott and Spitzer, 1978) or Structured Clinical Interview for DSM-III-R-Patient Edition (Spitzer et al., 1990) to confirm the diagnosis. Once the proband parent was identified, the parents were asked whether their 6- to 15-year-old children would be willing to participate in this study. All children tested, except one, currently lived in the custody of their proband parents, although several of the children had intermittently lived in alternative arrangements, often as a result of the involvement of social services (with temporary placement in foster homes). All parents gave written consent for participation and all child and adolescent subjects gave written and/or oral assent. Child and adolescent subjects were paid $15 for participation. Parents were not paid for child participation. Nineteen normally developing 6- to l S-year-old control children were recruited through advertisements. Children were excluded from the normally developing group for a personal history of major psychiatric or neurological disorders or if any first-degree family member had ever received a diagnosis of psychosis. First-degree relatives were not screened for nonpsychotic psychiatric disorders. Consent/assent and subject payment procedures were identical with those used for the at-risk group. Children in the at-risk group did not differ from children in the control group on age (mean age ± SD: at-risk group 127 ± 28 months versus control group 133 ± 24 months; t = 0.64, not significant) or ratio of male to female subjects (percentage male: at-risk group 38.5% versus control group 47.4%; X2 = 0.25, not significant). Children in the at-risk group did have significantly lower scaled scores on the Vocabulary (mean ± SD: at-risk 9.3 ± 2.6 versus control 11.9 ± 2.8; t = 2.5, P < .02) and Block Design (mean ± SD: at-risk 9.3 ± 2.5 versus control 12.9 ± 3.3; t = 2.5, P < .02) subtests of the WISC-III (Weschler, 1991). Previous studies of 53 normally developing children have failed to demonstrate any consistent correlation between WISC-III subtest scores and performance on any SPEM measures (unpublished data).
Eye Movement Procedure
The experimental group consisted of 13 children ofschizophrenic parents; the children were aged 6 to 15 years. We recruited them by first identifying the parent with the schizophrenia diagnosis. These proband parents were recruited from a variety of sources
Children were allowed to tour the eye movement laboratory prior to initiating the procedure, and actual eye movement procedures were generally done after cognitive and demographic forms were completed by the child. All children were allowed to ask questions and to take as much time as needed between aspects of the procedure. Children appeared relaxed and nonstressed by the experience. Subjects were seated 43 ern in front of a video monitor on which a small target was displayed against a black background in an otherwise dark room. The subject's head was stabilized with a bite bar and head rest. We have found that the quality of eye movement recording in children is greatly improved by the addition of a chair with two critical features: first that the chair can be raised and lowered over a broad enough height range to allow for wide variabilities in children's height, and second that the chair "locks" so that the child cannot swivel in his or her seat. Raising the chair high enough so that the child has to crouch slightly in the seat in order to bite onto the bite bar also decreases head movement and improves the overall quality of the eye movement recording. Horizontal eye movements were recorded using an
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METHOD
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infrared photoelectric limbus detection eye-tracking device (Eyetrac model 210, Applied Sciences Laboratories, Waltham, MA), which is accurate to within 0.25° of visual angle and has a time constant of 4 milliseconds. The analog output of the device is sampled at 1,000 Hz using a 12-bit analog-to-digital converter. There are no reported data assessing left-right differences in the dependent eye movement measures employed in this study, but, since disconjugate gaze should be absent in most subjects, both eyes should be tracking the target in a similar manner . Our experience has suggested that minimizing calibration time decreases the time these young subjects must maintain head position and improves the quality ofthe recording. Therefore, data were collected only from the eye for which the most rapid and accurate calibration could be obtained.
Smooth-Pursuit Eye Movement Task The target moved horizontally back and forth over 30° with a constant velocity of l2o/second and a lA-second fixation period between ramps, a "trapezoidal pattern." Children were told to " keep your eyes on the target wherever it goes." Figure 1 shows an example of the performance of two children on a portion on this task.
Eye Movement Analysis All eye movement data were analyzed with a computerized pattern recognition program , SEMAS (Seattle Eye Movement Analysis
9 y/o female normal control
4 seconds
Data Analysis
10 y/o female
at-risk for schizophrenia
4 seconds Fig. 1 Smooth-pursuit qe movements in cwo children, a 9-year-old normally developing control female and a IO-year-old female who, as the child of a schizophrenic parent, is at increased genetic risk for later developing schizophrenia. Dotted lines represent target motion; solid lines represent visual gaze of the subjects.
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System). This analysis system has been described elsewhere (Radant and Hommer, 1992; Ross er al., 1993) and will be briefly described here. Gain for a given interval of smooth pursuit is defined as mean eye velocity divided by target velocity. Overall smoothpursuit gain is defined as the mean gain, weighted for time, of all intervals of true smooth pursuit (Abel et al., 1991). Intervals defined as saccades are not included in computing smooth-pursuit gain. Although theoretical optimal performance on this task is defined as gain equal to 1.0 (i.e., eye velocity = target velocity), most children have mean eye velocity less than target velocity. The resulting mismatch must be compensated for by saccadicmovement. Saccades are classified on the basis of apparent function . The two types of saccades focused on in this analysis are catch-up and anticipatory saccades. Catch-up saccades function to significantly reduce error between foveal gaze and target location. Saccades that are in the same direction as target motion and begin and end behind the target are catch-up saccades. Saccades that are in the same direction as target motion but that begin behind target location and end ahead of target location are classified as catchup saccades if postsaccadic position error is :550% of presaccadic position error (that is, the saccade functions to dramatically decrease the mismatch between visual gaze and target location). Classification of anticipatory saccades is based on proposals by Abel and Ziegler (1988). Anticipatory saccades must (1) be in the direction of target motion, (2) either begin and end ahead of target location or increase position error by 100%, and (3) be followed by a 50millisecond interval of eye velocity less than 75% of target velocity. For all saccades, a nonlinear relationship exists between saccadic amplitude and the maximum eye velocity reached during the saccade (termed the main sequence) (Bahill et al., 1975). In reviewing individual records, we have noted saccades which full outside the main sequence. These saccadesare rare (most recordings have none; only one record had more than one), oflong duration (80 to 110 milliseconds for a 10° to 15° saccade), and of unclear functional significance in the tracking task. Saccades of greater than 60 milliseconds' duration have therefore been discarded for this analysis. Figure 2 shows a short segment of a record containing examples of smooth pursuit, a catch-up saccade, and an anticipatory saccade.
Data are presented and examined in three ways: Task Performance. Task performance on this smooth-pursuit tracking task was measured using two techniques: smooth-pursuit gain (e.g., Radant and Homrner, 1992) and RMS error (e.g., Clementz and Sweeney, 1990). Smooth-pursuit gain is mean eye velocity divided by target velocity during periods when the smoothpursuit system is employed; optimal performance occurs when eye velocity equals target velocity or a smooth-pursuit gain of 1.0. RMS error is the square root of the average of the square of the distance from the target position to eye position at each artifactfree time point; optimal performance would have eye position and target position match at all times or an RMS error of O. Since previous studies of SPEM in family members of schizophrenia have used both of these techniques for measuring smooth-pursuit performance, both analyses were included here for comparison with previous studies. Frequency of Saccadic Subtypes. A measure often used by other investigators (e.g., Abel et al., 1991; Clementz and Sweeney, 1990; Radant and Hommer, 1992) is the frequency of saccadic subtypes. Data will be presented in this format to allow for comparison with previous studies.
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Contribution of Saccadic Subtypes to Total Pursuit Tracking. Frequency data fail to address questions about differences in saccadic amplitude. A given number of large anticipatory saccades would cause much more mismatch between eye and target position (and hence more compensatory slowing of smooth pursuit) than would the same number ofsmall saccades. This emphasizes the importance of examining amplitude data along with frequency data. To assess the full impact of saccades during ongoing pursuit, we measured the total distance covered by each saccadic type (catch-up and anticipatory) and divided by the total distance covered by artifactfree eye movements. This produces the percentage of artifact-free eye movements due to each type of saccade, providing a measure of the full impact of each type of saccade on ongoing pursuit .
question . This approach of determining whether each subject is "abnormal" may also be appropriate as, even within the at-risk group, not all children will be expected to have inherited the full biological risk for schizophrenia. Because of concerns about the influence of development over a IO-year age span, all comparisons between groups were performed with chronological age as a covariant. Because the normally developing control group scored higher on tests of cognitive functioning (the Vocabulary and Block Design subtests of the WISC-I1I), subtest standardized scores were also used as covariants. Results of statistical analyses did not differ as a result of whether or not covariants were included in the analyses. Only results with covariants are included here.
Statistical Analysis There are three dependent measures ofinterest: task performance, catch-up saccades (which represent error due to the smooth-pursuit system), and anticipatory saccades (which represent error due to the inabiliry to inhibit context-inappropriate saccades). Each dependent measure is calculated in two ways. Task performance is measured by smooth-pursuit gain and RMS error. Catch-up saccades and anticipatory saccades are measured both the by frequency of their occurrence and by their contribution to total eye movement. Comparisons between groups will be made in two ways. First, groups will be compared by using analyses of covariance. Second, groups will be compared to determine whether the at-risk group members are more likely to be described as "abnormal," with abnormaliry being defined as values greater than two standard deviations poorer than mean performance of the normal group . One rationale for studying SPEM in at-risk children is to determine whether abnormalities in SPEM can be used as an endophenotype for genetic risk for schizophrenia, and determining whether at-risk children perform more frequently as "abnormal" addresses this
RESULTS
Table 1 summarizes the comparisons between the at-risk and normally developing groupS. Smooth-pursuit gain and RMS error significantly differed between at-risk and control children. In addition, if one defines abnormality as two standard deviations poorer than the control mean, at-risk children were significantly different in their likelihood of being defined as abnormal for either measure (Table 2). When examining the possible sources of error , both measures of catchup saccades showed no significant difference between the groups, and at-risk children were not significantly different in their likelihood of being defined as abnormal (Tables 1 and 2). In direct contrast to the results with catch-up saccades, and as hypothesized, measures of anticipatory saccades were significantly increased in the at-risk group. For example, the percentage of total eye movements due to anticipatory saccades was both increased in the at-risk group (Table 1) and more likely to define subjects in the at-risk group as abnormal (Table 2). Figure 3 (anticipatory saccades as a percentage of total eye movement) graphically demonstrates both the low variability and the lack of age effects in the normally developing control group as well as the 7 of 13 atrisk children (54%) who fell more than two standard deviations above the control mean. DISCUSSION
Fig. 2 Smooth-pursuit eye movements: analysisof saccadic subtypes. This segment shows smooth pursuit (sp), a catch-up saccade (cs), and an ant icipatory saccade (as).
Abnormalities in SPEM were first proposed by Holzman et al. (1980) to be a potential endophenotype of the genetic risk for schizophrenia. In comparing atrisk to normally developing controls, we found that global task measures of gain and RMS error were significantly worse in at-risk than control children and
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400 milliseconds
ROSS ET AL.
TABLE 1 Mean Values::!:: Standard Deviations for Smooth-Pursuit Eye Movement Measures
Task measures Gain RMS error Catch-up saccades No.lsecond Mean amp % Total Anticipatory saccades No.lsecond Mean amp" % Total
p
Control Group
At-Risk Group
F
0.920 ::!:: 0.079 1.431 ::!:: 0.944
0.820::!:: 0.163 2.612 ::!:: 1.323
4.8 4.8
.04 .04
0.721 ::!:: 0.306 1.767 ::!:: 0.493 10.4 ::!:: 5.3
0.855 ::!:: 0.515 2.081 ::!:: 0.776 13.6 ::!:: 8.6
0.9 1.4 1.6
NS NS NS
0.061 ::!:: 0.079 1.609 ::!:: 1.032 0.744 ::!:: 0.994
0.272 ::!:: 0.252 2.192 ::!:: 1.324 5.347 ::!:: 5.993
10.7 1.7 12.1
.004 NS .002
Note: Gain = smooth-pursuit gain; RMS = root mean square; Mean amp = mean amplitude; % Total = percentage of total eye movement due to that particular type of saccade; NS = not significant. F values are results from analyses of covariance with age and WISC subscale scores as covariates. a For anticipatory saccades, mean amplitude is calculated only for those subjects who exhibited anticipatory saccades: n = 9 controls and 9 at-risk subjects.
identified as abnormal 31% to 62% of the at-risk compared with 5% to 11% of control children. When we examined the types of errors which may have contributed to poor tracking, measures of catch-up saccadesdid not significantly differ between the groups. TABLE 2 Number and Percentage of Subjects in Each Group with "Abnormal" Performance on Smooth-Pursuit Eye Movement Measures At-Risk Group No.
%
%
~
~
~
~
14
m
•
•
11 12
o u p
4 8
30.8 61.5
1 2
5.3 10,5
.07 .004
; :ll 10 >.'"
2 2 2
15.4 15.4 15.4
0 1 1
0.0 5.3 5.3
NS NS NS
7 2 7
53.8 22.2 53.8
1 1 0
5.3 11.1 0.0
.004 NS .0005
•
~
se .s~ 'O;g
8
~
4
6
~ GI
a..
2
•
•
GI C Cl ca
Note: "Abnormal" is defined as worse performance than two standard deviations poorer than the control mean. Gain = smoothpursuit gain; RMS = root mean square; Mean amp = amplitude; % Total = percentage of total eye movement due to that particular rype of saccade; NS = not significant. Probabiliry (p) values are based on Fisher's Exact Test with comparisons between the control and at-risk group for each variable. a For anticipatory saccades, mean amplitude values are based on only those subjects who exhibited anticipatory saccades: n = 9 controls and 9 at-risk subjects.
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•
16
"0
GI
Task measures Gain RMS error Catch-up saccades No.lsecond Mean amp % Total Anticipatory saccades No.lsecond Mean amp" % Total
18 , . . - - - - - - - - - - - - - - - ,
.s
Control Group No.
In contrast, in about half of at-risk children, anticipatory saccadeswere more frequent and covered a greater percentage of total eye distance. Examination of thirteen 9- to 12-year-old children with attention deficit disorder did not produce a similar distribution of
···············tI·-6;·····!· lh 6. A
o
6. 6.. 6
7
8
6.. 9
~4'"
10 11 12 13 14 15 16
Age in years Fig. 3 Anticipatory saccades (percentage of total eye movements) as a function of age. The at-risk group (solidcircles) are children of schizophrenic parents (aged 6 to 15 years; n = 13); the control group (open triangles) are normally developing children (aged 6 to 15 years; n = 19). The dotted line represents two standard deviations above the control mean. Seven (54%) of the 13 at-risk children compared with 0 (0%) of the control children performed more than two standard deviations higher (worse) than the control mean.
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SPEM IN AT-RISK CHILDREN
elevated anticipatory saccades (unpublished data), further suggesting at least some specificity of the finding to genetic risk for schizophrenia. Children were placed in the at-risk group solely on the basis of parental diagnosis; none of the children demonstrated nor did any parent report any child to have symptoms suggestive of psychotic disorders. The increase in anticipatory saccades does not seem to have been directly associated with the presentation of schizophrenic symptoms, but instead was associated with the parental diagnosis of schizophrenia. Anticipatory saccades may therefore be an indicator of genetic risk, even in young children. These results must be considered preliminary because of the relatively small sample size and the significantly poorer performance on tests of cognitive functioning in the at-risk group. We have found no consistent relationship between cognitive test scores and eye movement variables in this group, and covarying for cognitive test results does not change the results of this study; however, replicating this study with more cognitively matched controls will be necessary.Since we did not screen for family histories of nonpsychotic psychiatric disorders, the control group may contain children at increased genetic risk for non psychotic psychiatric disorders. Even with this possible confounding factor, there were no outliers in the control group. Additional studies incorporating control groups specifically identified on the basis on parental history of nonpsychotic psychiatric disorders will also be required to fully assess the specificity of increased anticipatory saccades to genetic risk for schizophrenia. The eye movement difficulty in schizophrenics and their children involves, in part, the intrusion of primarily small saccades onto otherwise accurate smooth pursuit. These saccades are in the direction of ongoing smooth-pursuit movement, and disruption of tracking accuracy is immediately compensated for by slowed smooth-pursuit movement. In posterior cortical lesions, SPEM are severely impaired and tracking is done primarily with saccades (Thurston et al., 1988). In children of schizophrenic parents, the smooth-pursuit system is intact; however context-inappropriate saccades intrude. Thus, a possible model of the pathophysiology is the loss of inhibitory control over behavior based on expected target motion. The brain region responsible for the inhibitory control is unknown, but it may involve saccadic inhibition ("fixation") neurons in the superior colliculus (Munoz and Wurtz, 1993) that are
controlled by a thalamic gating circuit (Matsumura et al., 1992), which in turn receives cortical input via the basal ganglia (Hikosaka et al., 1993). The frontal eye fields may be a critical cortical center (O'Driscoll et al., 1995; Suzuki and Azuma, 1977), although other regions of the frontal lobe have also been proposed (Bon and Lucchetti, 1992). The finding of this abnormality in childhood, before higher cortical functions are fully developed, supports further consideration of both cortical and subcortical sites of pathophysiology in schizophrenia.
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Clinical Relevance
The identification of a potential marker of genetic risk for schizophrenia in children may be useful in locating the gene (or genes) responsible for genetic risk, and it may eventually improve diagnostic and prognostic evaluations. However, reporting that anticipatory saccades are increased during smooth-pursuit tasks in a subset of children of schizophrenic parents does little to explain what that deficit may mean cognitively or behaviorally. There is little direct evidence to tie an increase in anticipatory saccades to any specific cognitive functioning, but one can speculate that anticipatory saccades represent a problem in selection of attentional focus. One classic feature of smooth-pursuit tasks is their predictability. The target's future behavior (velocity, direction, and location) is easily predictable. The subject, therefore, has access to at least two bits of information about the target: where it currently is and where it will be at later time points. Since the task instructions are to maintain visual gaze on the current location of the target, the at-risk child's increased tendency to shift gaze to a later target location suggests problems in either (1) remembering task instructions, or (2) using task instructions to select task-appropriate behavior (that is, to keep visual gaze and presumably attention on the current target). Difficulties in selecting taskappropriate attentional focus would lead to high rates of task-inappropriate attentional shifts and may explain the high rates of attention deficit disorder symptoms in children of schizophrenic subjects (Marcus et al., 1987; Mednick, 1970; Rieder and Nichols, 1979). Further work in this area may help clarify whether genetic vulnerability for schizophrenia is an etiological pathway to attention deficit disorder, may help identify
ROSS ET AL.
subgroups with different symptomatology and prognosis, and may eventually lead to more etiologically specific intervention strategies. This study provides evidence that the use of SPEM in the examination of children of schizophrenic parents is productive. SPEM analysis in children may provide evidence useful both in family genetic risk studies and in the study of the developmental course of schizophrenia. However, further research is necessary to elucidate fully the relationship between SPEM, genetic risk for schizophrenia, and developmentally frameworked symptom presentation.
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