- Email: [email protected]
Abnormal saccadic eye movements associated with positive family history schizophrenics
,,
B R IE F R E P O R T
Abnormal Saccadic Eye Movements Associated with Positive Family History Schizophrenics Barry D. Schwartz, Beth A. O'Brien, William J. Evans, Barbara E. McDermott, Frederic J. Sautter Jr., and Daniel K. Winstead Key Words: Schizophrenia, a b n o r m a l eye m o v e m e n t s , saccades, family history BIOL PSYCHIATRY 1995;38:487--491
Introduction Information processing and attention deficits are hallmarks of schizophrenia. These deficits are characterized by a dysfunction of the oculomotor and visual spatiotemporal information processing systems. Dysfunction of smooth pursuit eye movement occurs with a higher frequency in schizophrenics and in their first-degree relatives than in the normal population (Holzman et al 1974; Matthysse et al 1986; Levy et al 1993). Dysfunction of the saccadic eye movement system has also been observed in schizophrenia, although these findings are not as consistent. Schizophrenics show deficits compared to normals in fixational saccade amplitude (Schmidt-Burgk et al 1983; Ross et al 1988; Moser et al 1990), in saccade amplitude to remembered targets (Hommer et al 1991; Fukushima et al 1990a), and in peak saccade velocity at larger amplitudes (Cegalis et al 1982), despite findings of normal saccade latency and velocity (Ross et al 1988; Moser et al 1990; Levin et al 1982). Increased latencies and errors on antisaccade tasks (Fukushima et al 1988, 1990a, b;
From the Department of Psychiatry and Neurology, Tulane University School of Medicine, New Orleans, LA (BDS, WJE, BEM, FJS, DKW); Veterans Administration Medical Center, New Orleans, LA (BDS, BAO, WJE, DKW); and Department of Psychology, Tulane University, New Orleans, LA (BAO, WJE). Address reprint requests to Barry D. Schwartz, 1415 Tulane Avenue, Tulane University School of Medicine, Department of Psychiatry and Neurology, New Orleans, LA 70112. Received March 30, 1994; revised February 21, 1995.
© 1995 Society of Biological Psychiatry
Thaker et al 1989; Clementz et al 1994) and increased saccadic intrusions during fixation (Fukushima et al 1990a; Matsue et al 1986; Mialet and Pichot 1981) suggest that schizophrenics have an inability to suppress saccadic eye movements to peripheral targets (Fukushima et al 1990a). Some investigators have suggested a heterogeneous cause of schizophrenia (Tsung et al 1990). Murry et al (1985) support a division of schizophrenia into genetic and nongenetic subtypes, and they suggest that indicators specific to these subtypes can be elucidated through studies of positive and negative family history schizophrenics. Others support the family history research strategy as useful (Lyons et al 1989a, b; Lewis et al 1987), despite arguments of potential misclassification (Kendler 1987) and for a lack of statistical power (Eaves et al 1986). Lyons et al (1989a) cite a large number of studies that have demonstrated significant differences between familial and nonfamilial schizophrenics on various clinical and biological parameters. A well-established relationship exists between a genetic component of schizophrenia and dysfunction of smooth pursuit eye movements. Although the relationship between a genetic component of schizophrenia and dysfunctional saccadic eye movements is not well-established, Clementz et al (1994) report increased antisaccade errors in schizophrenics and their first-degree relatives. This provides evidence of saccade performance deficits in a genetic subtype of schizophrenia, but it remains unclear if saccadic deficits will occur in a nongenetic subtype. Saccade gain, velocity, and latency were assessed for positive and for negative family history schizophrenics as well as for nonschizophrenic controls to determine if genetic and environmental contributions to schizophrenia are related to saccade abnormalities. 0006-3223/95/$09.50 SSDI 0006-3223(95)00193-K
488
Brief Report
BIOL PSYCHIATRY 1995;38:487-491
Method Subjects All subjects in the clinical group met Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised, (DSM-III-R) criteria for schizophrenia (APA 1987), as well as the following additional criteria: (1) no gross organic brain disease or cognitive dysfunction; (2) no history of electroconvulsive therapy; (3) no significant history of head trauma; (4) normal or corrected to normal vision (i.e., at least 20/30 as assessed by Snellen acuity); and (5) right hand dominance, to control for laterality effects (Oldfield 1971). All subjects were able to cooperate and to understand the procedures of the study. Thirty-nine schizophrenics and 18 nonschizophrenics participated in the study. Twenty-one of the schizophrenics were family history-positive (FH +) and 18 were family history-negative (FH-). The positive and negative family history schizophrenics were recruited over several years in order to obtain an approximately equal number of each type. Analysis of variance revealed that the control group was significantly older than the F H group. The mean ages for each of the groups was 29.7 + 1.7 years for the controls, 25.3 + 1.3 years for the F H - schizophrenics, and 21.7 _+ 0.8 years for the FH + schizophrenics. Age effects upon saccade metrics have not been observed with this age range (Carter et al 1983). There were no significant differences for the groups' medication status when converted to chlorpromazine equivalents (means of 417 and 326 mg for FH + and F H schizophrenics, respectively; p > 0.2), nor was there a significant difference in their clinical status as determined on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (p > 0.2). Family history was determined through interviews with family members using either Structured Clinical Interview for DSMIII-R (SCID) procedures (Spitzer et al 1987) or a semistructured family history interview that obtains information from relatives about DSM-III-R diagnoses in other relatives (Mannuzza et al 1985). At least two relatives of each patient were diagnosed using the SCID. Any diagnosis of first- or second-degree relatives was based on information obtained from at least two relatives who had direct contact with that relative. The mean number of relatives diagnosed vs. family size for FH + schizophrenics was 4.6 of 5.2 first-degree relatives and for F H schizophrenics 5.1 of 5.6 first-degree relatives. For seconddegree relatives, a mean of 8.6 of 12.3 relatives were diagnosed for FH + schizophrenics and a mean of 9.3 of 13.8 relatives were diagnosed for F H - schizophrenics. Hospital chart information, when available, was used to complement diagnosis.
Procedure Subjects were seated 122 cm from a light-emitting diode (LED) light bar with their heads stabilized in a chin rest. A pseudorandom sequence of 60 saccade targets was presented to each subject. Target amplitudes ranged between 5 and 30 degrees, with 2-3 degree increments. The interstimulus interval was 1.25
s. Horizontal eye movements were recorded using DC-electrooculography with silver-silver chloride electrodes placed at the outer canthus of each eye. Testing commenced only after the measured electrode offset potential was less than 20 millivolts. Recordings were analyzed with microcomputer-based ENG MASTR software (ICS Medical Corporation, Schaumburg, IL). The system bandwidth was 0 - 3 0 Hz.
Eye Movement Analysis A threshold of 90 degrees/s was used to detect a saccade. Eye movement latency was computed as the time between target movement and the point when the eye's velocity reached 90 degrees/s. The maximum velocity is defined as the largest difference between three successive eye position samples between saccade onset and offset. Final eye position was defined as the first stopping point of the eye for at least 75 ms. Saccade gain was determined as the ratio of eye movement amplitude to target amplitude. Saccades were excluded from the analysis if the latency was less than 75 ms, greater than 600 ms, or if the maximum velocity was less than 108 degrees/s.
Results Saccade peak velocity-amplitude data was fit to the equation: V = Vmax(1 -
e-AMI'/C),
where V is the measured peak velocity, Amp is the measured saccade amplitude, Vmax is the asymptotic peak velocity, and C is the rate of approach. Vmax and C were then compared for the three groups using a multivariate analysis of variance. The analysis revealed a significant effect of V~,,x (F(2,53) = 3.26, p < 0.05), but C was not significant. Subsequent Neuman-Keuls comparisons revealed Vm~x for the FH + group to be significantly lower than the control group (p < 0.05); other Vmax between group comparisons did not differ significantly (see Fig. 1). Mean VmaX values for FH +, F H - , and control groups were 402, 429, and 458 dens, respectively. Saccade latency and gain measures were submitted to repeated measures analyses of covariance (ANCOVAs) with a between factor of group and a covariate of saccade amplitude. The latency analysis revealed that groups did not differ in saccade latency across different amplitudes. The saccade gain analysis revealed that groups did differ across saccade amplitudes. To determine on which amplitudes groups differed, saccade gain measures were analyzed for targets between 5 and 10 degrees, 11 and 15, 16 and 20, 21 and 25, and 26 and 30 degrees. A group by amplitude analysis of variance (ANOVA) revealed a significant interaction of group by amplitude (p = 0.03). Subsequent Newman-Keuls comparisons show significantly lower saccade gain for the FH + group compared with the other two groups for targets between 5 and 10 degrees (p < 0.05) (see Table 1). With targets between 16 and 30 degrees, both the FH +
Brief Report
BIOL PSYCHIATRY
489
1995;38:487-491
Saccade M a x i m u m Velocity by Group 600 550 ~ 500 450 400 O
. .55 Y551
350
;> 300 /t) '/ ))t
250 200
:!!
"'a.. FH"
[
0
0
"o. FH+
5 10 15 20 AMPLITUDE (deg)
25
Figure 1. Peak saccade velocity by saccade amplitude for positive and negative family history schizophrenic and control groups.
and FH- groups eye showed significantly lower gain than controls (p < 0.05).
Discussion Schizophrenics with a positive family history showed lower peak saccade velocities over target eccentricity compared with conTable 1. Saccade Percentage Gain Means and Standard Deviations (in Parentheses) for Positive and Negative Family History Schizophrenics and Controls Gain Target eccentricity (Degrees)
Positive
Negative
Control
5-10
80.8 (10.5)" 83.6
87.6 (9.7)" 85.8
85.1 (6.8) ~ 86.2
11-15 16-20 21-25 26-30
(8.1)"
(8.9)"
(5.6)°
78.5 (7.8)" 74.7 (12.6)" 74.7 (10.8)"
81.0 (9.9)" 76.9 (9.7)" 77.2 (10.8)"
85.8 (5.5) b 84.8 (5.5) b 84.5 (6.0)"
For each row, means with different subscript letters differ at p < 0.05.
trois. This group also had lower saccade gain for small-amplitude targets (between 5 and 10 degrees) in comparison with both FHschizophrenics and controls. With higher eccentricity targets (between 16 and 30 degrees) both schizophrenic groups showed lower gain than controls. Saccade latency did not differ between the three groups at any amplitude; however, the saccade threshold of 90 degrees/s may have resulted in decreased latency sensitivity to small-amplitude saccades. These findings indicate that although both schizophrenic groups produce inaccurate saccades: those with a positive family history experience decreased gain across a wider range of visual angle, as well as having decreased peak velocity. This suggests that a genetic subtype of schizophrenia is related to more pervasive oculomotor deficits that may not be limited to smooth pursuit deficits, but may also include saccade irregularities. Hallett (1978) suggests that saccades to briefly presented targets are initiated by transient-type mechanisms. Transient afferents directly from the retina and via the visual cortex innervate the dorsal superior colliculus, an area ascribed the function of visual attention and that may contribute to sensorymotor efference from the ventral superior colliculus (Breitmeyer 1984). Discharge rates of ventral SC cells are related to the dynamics of saccades and to motor error, where SC lesions in primates lead to slightly increased saccade latencies and mildly hypometric saccades (Leigh and Zee 1991). Lesions of the magnocellular layer of the lateral geniculate nucleus, composed primarily of transient neurons, result in a number of eye movement abnormalities including delayed saccade latency and decreased pursuit speed (Page et al 1994). Schwartz and Winstead (1982) have proposed that schizophrenics have a neurophysiological deficit that is reflected by dysfunctional activation of the transient channel. This view is supported by Merritt and Balogh (1989) and Schuck and Lee (1989). A dysfunction of transient channel inputs to the brain circuitry involved in the accurate generation of saccadic eye movements (e.g., to the ventral SC either through the dorsal SC or through other areas such as the visual or parietal cortex) could be expected to result in disruption of saccade dynamics, as is presently seen in the FH + schizophrenics. A number of other neurophysiological deficits, however, including cerebellar lesions could also result in similar deficits. A neurophysiological deficit in familial schizophrenics is supported by previous family history studies that have shown relatively increased neurologic abnormalities in this group of schizophrenics (Lyons et al 1989a), and by studies supporting familial schizophrenia as a neurointegrative defect (Fish et al 1992). The familial-nonfamilial subtyping strategy has been challenged along the lines of misclassification and statistical power. In the present study the possibility of misclassification is minimized by including assessments of first- and second-degree relatives. Furthermore, differences on the saccade measures were primarily found between the FH + schizophrenics and the controls, where the FH + group is not at risk for misclassification. In terms of statistical power, a large number of studies have demonstrated differences between FH + and FH schizophrenics and a recent Monte Carlo simulation study has shown that this strategy does demonstrate reasonable statistical power (Lyons et
490
BIOL PSYCHIATRY
Brief Report
1995;38:487-491
al 1989b). The present findings suggest that a genetic contribution to schizophrenia is related to saccade dysfunction.
This work was supported by the Department of Veterans Affairs.
References American Psychological Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised. Washington, DC: American Psychological Association Press. Breitmeyer BG (1984): Visual Masking: An Integrative Approach. New York: Oxford University Press, p. 313. Carter JE, Obler L, Woodward S, Albert ML (1983): The effect of increasing age on the latency for saccadic eye movements. J Gerontol 38(3):318-320. Cegalis JA, Sweeney JA, Dellis EM (1982): Refixation saccades and attention in schizophrenia. Psychiatr Res 7:189-198. Clementz BA, McDowell JE, Zisook S (1994): Saccadic system functioning among schizophrenia patients and their firstdegree biological relatives. J Abnorm Psychol 103(2):277287. Eaves IA, Kendler KS, Schulz SC (1986): The familial sporadic classification: Its power for the resolution of genetic and environmental etiological factors. J Psychiatr Res 20:115130. Fish B, Marcus J, Hans SL, Auerbach JG, Perdue S (1992): Infants at risk for schizophrenia--sequelae of a genetic neurointegrative defect--a review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry 49:221-235. Fukushima J, Fukushima K, Morita N, Yamashita I (1990a): Further analysis of the control of voluntary saccadic eye movements in schizophrenic patients. Biol Psychiatry 28: 943-958, Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I (1990b): Voluntary control of saccadic eye movements in patients with schizophrenic and affective disorders. J Psychiatr Res 24:9-24. Fukushima J, Fukushima K, Chiba T, Tanaka S, Yamashita l, Kato M (1988): Disturbances of voluntary control of saccadic eye movements in schizophrenic patients. Biol Psychiatry 23:670-677. Hallet PE (1978): Primary and secondary saccades to goals defined by instructions. Vision Res 18:1279-1296. Holzman PS, Proctor LR, Levy DL, Yasillo N J, Meltzer HY, Hurt SW (1974): Eye-tracking dysfunctions in schizophrenic patients and their relatives. Arch Gen Psychiatry 31:143-151. Hommer DW, Clem T, Litman R, Pickar D (1991): Maladaptive anticipatory saccades in schizophrenia. Biol Psychiat~ 30: 779 -794. Kendler KS (1987): Sporadic vs. familial classification given etiological heterogeneity: I. Sensitivity, specificity, and positive and negative asymmetry. Gen Epidemiol 4:313-330. Leigh RJ, Zee DS (1991): The Neurology of Eye Movement. edition two. Philadelphia: F.A. Davis, p. 96. Levin S, Jones A, Stark L, Merrin EL, Holzman PS (1982): Saccadic eye movements of schizophrenic patients measured by reflected light technique. Biol Psychiatry 17(11):12771287.
Levy DL, Holzman PS, Matthysse S, Mendell NR (1993): Eye tracking dysfunction and schizophrenia: A critical perspective. Schizophr Bull 19(3):461-536. Lewis SW, Reveley AM, Reveley MA, Chitkura B, Murray RM (1987): The familial/sporadic distinction as a strategy in schizophrenia research. Br J Psychiatry 151:306-313. Lyons MJ, Kremen WS, Tsuang MT, Faraone SV (1989a): Investigating putative genetic and environmental forms of schizophrenia: Methods and findings. Int Rev Psychiatry 1:259-276. Lyons MJ, Faraone SV, Kremen WS, Tsuang MT (1989b): Familial and sporadic schizophrenia: A simulation study of statistical power. Schizophr Res 2:345-353. Mannuzza S, Fyer AJ, Endicott J, Klein DF, Robins LN (1985): Family Informant Schedule and Criteria (FISC). New York: Anxiety Disorders Clinic, New York State Psychiatric Institute. Matsue Y, Okuma T, Saito H, Aneha S, Ueno T, Chiba H, Matsuoka H (1986): Saccadic eye movements in tracking, fixation, and rest schizophrenics and normal subjects. Biol P~vchiat~ 21:382-389. Matthysse S, Holzman PS, Lange K (1986): The genetic transmission of schizophrenia: Application of Mendelian latent structure analysis to eye tracking dysfunctions in schizophrenia and affective disorders. J Psychiatr Res 20:57-76. Merritt RD, Balogh DW (1989): Backward masking spatial frequency effects among hypothetically schizotypal individuals. Schizophr Bull 15:573-583. Mialet JP, Pichot P (1981): Eye-tracking patterns in schizophrenia. Arch Gen Psychiatry 38:183-186. Moser A, Kompf D, Arolt V, Resch T (1990): Quantitative analysis of eye movements in schizophrenia. Neuro-Ophthalmology 10(2):73-80. Murry RM, Reveley AM, Reveley MA, Sure E, Lewis S (1985): Genetic and environmental influences in schizophrenia. In Hafner H, Gattaz WF (eds), Search for the Causes of Schizophrenia, Vol II. New York: Springer-Verlag, pp. 120122. Oldfield RC (1971): The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9:97-113. Page WK, King WM, Merigan W, Maunsell J (1994): Magnocellular or parvocellular lesions in the lateral geniculate nucleus of monkeys cause minor deficits of smooth pursuit eye movements. Vision Res 34(2):223-239. Ross DE, Ochs AL, Hill MR, Goldberg SC, Pandurangi AK, Winfrey CJ (1988): Erratic eye tracking in schizophrenic patients as revealed by high-resolution techniques. BioI Psychiatr3, 24:675-688. Schmidt-Burgk W, Becker W, Jurgens R, Kornhuber HH (1983): Disturbed smooth pursuit and saccadic eye movements in schizophrenia. Arch Psychiatr Nervenkrankh 232:381-389. Schuck JR, Lee RG (1989): Backward masking, information processing, and schizophrenia. Schizophr Bull 15:491-500.
Brief Report
Schwartz BD, Winstead DK (1982): Visible persistence in acute and chronic schizophrenics. Biol Psychiatry 17:1377-1387. Spitzer RL, Williams JB, Gibbons M (1987): Structured Clinical Interview for DSM-III-R (SCID). New York: Biometric Research Department, New York State Psychiatric Institute. Thaker G, Kirkpatrick B, Buchanan RW, Ellsberry R, Lahti A,
BIOL PSYCHIATRY 1995;38:487-49]
491
Tamminga C (1989): Oculomotor abnormalities and their clinical correlates in schizophrenia. Psychopharmacol Bull 25(3):491-497. Tsung MT, Lyons MJ, Faraone SV (1990): Heterogeneity of schizophrenia--conceptual models and analytic strategies. Br J Psychiatry 156:17-26.
B R IE F R E P O R T
Abnormal Saccadic Eye Movements Associated with Positive Family History Schizophrenics Barry D. Schwartz, Beth A. O'Brien, William J. Evans, Barbara E. McDermott, Frederic J. Sautter Jr., and Daniel K. Winstead Key Words: Schizophrenia, a b n o r m a l eye m o v e m e n t s , saccades, family history BIOL PSYCHIATRY 1995;38:487--491
Introduction Information processing and attention deficits are hallmarks of schizophrenia. These deficits are characterized by a dysfunction of the oculomotor and visual spatiotemporal information processing systems. Dysfunction of smooth pursuit eye movement occurs with a higher frequency in schizophrenics and in their first-degree relatives than in the normal population (Holzman et al 1974; Matthysse et al 1986; Levy et al 1993). Dysfunction of the saccadic eye movement system has also been observed in schizophrenia, although these findings are not as consistent. Schizophrenics show deficits compared to normals in fixational saccade amplitude (Schmidt-Burgk et al 1983; Ross et al 1988; Moser et al 1990), in saccade amplitude to remembered targets (Hommer et al 1991; Fukushima et al 1990a), and in peak saccade velocity at larger amplitudes (Cegalis et al 1982), despite findings of normal saccade latency and velocity (Ross et al 1988; Moser et al 1990; Levin et al 1982). Increased latencies and errors on antisaccade tasks (Fukushima et al 1988, 1990a, b;
From the Department of Psychiatry and Neurology, Tulane University School of Medicine, New Orleans, LA (BDS, WJE, BEM, FJS, DKW); Veterans Administration Medical Center, New Orleans, LA (BDS, BAO, WJE, DKW); and Department of Psychology, Tulane University, New Orleans, LA (BAO, WJE). Address reprint requests to Barry D. Schwartz, 1415 Tulane Avenue, Tulane University School of Medicine, Department of Psychiatry and Neurology, New Orleans, LA 70112. Received March 30, 1994; revised February 21, 1995.
© 1995 Society of Biological Psychiatry
Thaker et al 1989; Clementz et al 1994) and increased saccadic intrusions during fixation (Fukushima et al 1990a; Matsue et al 1986; Mialet and Pichot 1981) suggest that schizophrenics have an inability to suppress saccadic eye movements to peripheral targets (Fukushima et al 1990a). Some investigators have suggested a heterogeneous cause of schizophrenia (Tsung et al 1990). Murry et al (1985) support a division of schizophrenia into genetic and nongenetic subtypes, and they suggest that indicators specific to these subtypes can be elucidated through studies of positive and negative family history schizophrenics. Others support the family history research strategy as useful (Lyons et al 1989a, b; Lewis et al 1987), despite arguments of potential misclassification (Kendler 1987) and for a lack of statistical power (Eaves et al 1986). Lyons et al (1989a) cite a large number of studies that have demonstrated significant differences between familial and nonfamilial schizophrenics on various clinical and biological parameters. A well-established relationship exists between a genetic component of schizophrenia and dysfunction of smooth pursuit eye movements. Although the relationship between a genetic component of schizophrenia and dysfunctional saccadic eye movements is not well-established, Clementz et al (1994) report increased antisaccade errors in schizophrenics and their first-degree relatives. This provides evidence of saccade performance deficits in a genetic subtype of schizophrenia, but it remains unclear if saccadic deficits will occur in a nongenetic subtype. Saccade gain, velocity, and latency were assessed for positive and for negative family history schizophrenics as well as for nonschizophrenic controls to determine if genetic and environmental contributions to schizophrenia are related to saccade abnormalities. 0006-3223/95/$09.50 SSDI 0006-3223(95)00193-K
488
Brief Report
BIOL PSYCHIATRY 1995;38:487-491
Method Subjects All subjects in the clinical group met Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised, (DSM-III-R) criteria for schizophrenia (APA 1987), as well as the following additional criteria: (1) no gross organic brain disease or cognitive dysfunction; (2) no history of electroconvulsive therapy; (3) no significant history of head trauma; (4) normal or corrected to normal vision (i.e., at least 20/30 as assessed by Snellen acuity); and (5) right hand dominance, to control for laterality effects (Oldfield 1971). All subjects were able to cooperate and to understand the procedures of the study. Thirty-nine schizophrenics and 18 nonschizophrenics participated in the study. Twenty-one of the schizophrenics were family history-positive (FH +) and 18 were family history-negative (FH-). The positive and negative family history schizophrenics were recruited over several years in order to obtain an approximately equal number of each type. Analysis of variance revealed that the control group was significantly older than the F H group. The mean ages for each of the groups was 29.7 + 1.7 years for the controls, 25.3 + 1.3 years for the F H - schizophrenics, and 21.7 _+ 0.8 years for the FH + schizophrenics. Age effects upon saccade metrics have not been observed with this age range (Carter et al 1983). There were no significant differences for the groups' medication status when converted to chlorpromazine equivalents (means of 417 and 326 mg for FH + and F H schizophrenics, respectively; p > 0.2), nor was there a significant difference in their clinical status as determined on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (p > 0.2). Family history was determined through interviews with family members using either Structured Clinical Interview for DSMIII-R (SCID) procedures (Spitzer et al 1987) or a semistructured family history interview that obtains information from relatives about DSM-III-R diagnoses in other relatives (Mannuzza et al 1985). At least two relatives of each patient were diagnosed using the SCID. Any diagnosis of first- or second-degree relatives was based on information obtained from at least two relatives who had direct contact with that relative. The mean number of relatives diagnosed vs. family size for FH + schizophrenics was 4.6 of 5.2 first-degree relatives and for F H schizophrenics 5.1 of 5.6 first-degree relatives. For seconddegree relatives, a mean of 8.6 of 12.3 relatives were diagnosed for FH + schizophrenics and a mean of 9.3 of 13.8 relatives were diagnosed for F H - schizophrenics. Hospital chart information, when available, was used to complement diagnosis.
Procedure Subjects were seated 122 cm from a light-emitting diode (LED) light bar with their heads stabilized in a chin rest. A pseudorandom sequence of 60 saccade targets was presented to each subject. Target amplitudes ranged between 5 and 30 degrees, with 2-3 degree increments. The interstimulus interval was 1.25
s. Horizontal eye movements were recorded using DC-electrooculography with silver-silver chloride electrodes placed at the outer canthus of each eye. Testing commenced only after the measured electrode offset potential was less than 20 millivolts. Recordings were analyzed with microcomputer-based ENG MASTR software (ICS Medical Corporation, Schaumburg, IL). The system bandwidth was 0 - 3 0 Hz.
Eye Movement Analysis A threshold of 90 degrees/s was used to detect a saccade. Eye movement latency was computed as the time between target movement and the point when the eye's velocity reached 90 degrees/s. The maximum velocity is defined as the largest difference between three successive eye position samples between saccade onset and offset. Final eye position was defined as the first stopping point of the eye for at least 75 ms. Saccade gain was determined as the ratio of eye movement amplitude to target amplitude. Saccades were excluded from the analysis if the latency was less than 75 ms, greater than 600 ms, or if the maximum velocity was less than 108 degrees/s.
Results Saccade peak velocity-amplitude data was fit to the equation: V = Vmax(1 -
e-AMI'/C),
where V is the measured peak velocity, Amp is the measured saccade amplitude, Vmax is the asymptotic peak velocity, and C is the rate of approach. Vmax and C were then compared for the three groups using a multivariate analysis of variance. The analysis revealed a significant effect of V~,,x (F(2,53) = 3.26, p < 0.05), but C was not significant. Subsequent Neuman-Keuls comparisons revealed Vm~x for the FH + group to be significantly lower than the control group (p < 0.05); other Vmax between group comparisons did not differ significantly (see Fig. 1). Mean VmaX values for FH +, F H - , and control groups were 402, 429, and 458 dens, respectively. Saccade latency and gain measures were submitted to repeated measures analyses of covariance (ANCOVAs) with a between factor of group and a covariate of saccade amplitude. The latency analysis revealed that groups did not differ in saccade latency across different amplitudes. The saccade gain analysis revealed that groups did differ across saccade amplitudes. To determine on which amplitudes groups differed, saccade gain measures were analyzed for targets between 5 and 10 degrees, 11 and 15, 16 and 20, 21 and 25, and 26 and 30 degrees. A group by amplitude analysis of variance (ANOVA) revealed a significant interaction of group by amplitude (p = 0.03). Subsequent Newman-Keuls comparisons show significantly lower saccade gain for the FH + group compared with the other two groups for targets between 5 and 10 degrees (p < 0.05) (see Table 1). With targets between 16 and 30 degrees, both the FH +
Brief Report
BIOL PSYCHIATRY
489
1995;38:487-491
Saccade M a x i m u m Velocity by Group 600 550 ~ 500 450 400 O
. .55 Y551
350
;> 300 /t) '/ ))t
250 200
:!!
"'a.. FH"
[
0
0
"o. FH+
5 10 15 20 AMPLITUDE (deg)
25
Figure 1. Peak saccade velocity by saccade amplitude for positive and negative family history schizophrenic and control groups.
and FH- groups eye showed significantly lower gain than controls (p < 0.05).
Discussion Schizophrenics with a positive family history showed lower peak saccade velocities over target eccentricity compared with conTable 1. Saccade Percentage Gain Means and Standard Deviations (in Parentheses) for Positive and Negative Family History Schizophrenics and Controls Gain Target eccentricity (Degrees)
Positive
Negative
Control
5-10
80.8 (10.5)" 83.6
87.6 (9.7)" 85.8
85.1 (6.8) ~ 86.2
11-15 16-20 21-25 26-30
(8.1)"
(8.9)"
(5.6)°
78.5 (7.8)" 74.7 (12.6)" 74.7 (10.8)"
81.0 (9.9)" 76.9 (9.7)" 77.2 (10.8)"
85.8 (5.5) b 84.8 (5.5) b 84.5 (6.0)"
For each row, means with different subscript letters differ at p < 0.05.
trois. This group also had lower saccade gain for small-amplitude targets (between 5 and 10 degrees) in comparison with both FHschizophrenics and controls. With higher eccentricity targets (between 16 and 30 degrees) both schizophrenic groups showed lower gain than controls. Saccade latency did not differ between the three groups at any amplitude; however, the saccade threshold of 90 degrees/s may have resulted in decreased latency sensitivity to small-amplitude saccades. These findings indicate that although both schizophrenic groups produce inaccurate saccades: those with a positive family history experience decreased gain across a wider range of visual angle, as well as having decreased peak velocity. This suggests that a genetic subtype of schizophrenia is related to more pervasive oculomotor deficits that may not be limited to smooth pursuit deficits, but may also include saccade irregularities. Hallett (1978) suggests that saccades to briefly presented targets are initiated by transient-type mechanisms. Transient afferents directly from the retina and via the visual cortex innervate the dorsal superior colliculus, an area ascribed the function of visual attention and that may contribute to sensorymotor efference from the ventral superior colliculus (Breitmeyer 1984). Discharge rates of ventral SC cells are related to the dynamics of saccades and to motor error, where SC lesions in primates lead to slightly increased saccade latencies and mildly hypometric saccades (Leigh and Zee 1991). Lesions of the magnocellular layer of the lateral geniculate nucleus, composed primarily of transient neurons, result in a number of eye movement abnormalities including delayed saccade latency and decreased pursuit speed (Page et al 1994). Schwartz and Winstead (1982) have proposed that schizophrenics have a neurophysiological deficit that is reflected by dysfunctional activation of the transient channel. This view is supported by Merritt and Balogh (1989) and Schuck and Lee (1989). A dysfunction of transient channel inputs to the brain circuitry involved in the accurate generation of saccadic eye movements (e.g., to the ventral SC either through the dorsal SC or through other areas such as the visual or parietal cortex) could be expected to result in disruption of saccade dynamics, as is presently seen in the FH + schizophrenics. A number of other neurophysiological deficits, however, including cerebellar lesions could also result in similar deficits. A neurophysiological deficit in familial schizophrenics is supported by previous family history studies that have shown relatively increased neurologic abnormalities in this group of schizophrenics (Lyons et al 1989a), and by studies supporting familial schizophrenia as a neurointegrative defect (Fish et al 1992). The familial-nonfamilial subtyping strategy has been challenged along the lines of misclassification and statistical power. In the present study the possibility of misclassification is minimized by including assessments of first- and second-degree relatives. Furthermore, differences on the saccade measures were primarily found between the FH + schizophrenics and the controls, where the FH + group is not at risk for misclassification. In terms of statistical power, a large number of studies have demonstrated differences between FH + and FH schizophrenics and a recent Monte Carlo simulation study has shown that this strategy does demonstrate reasonable statistical power (Lyons et
490
BIOL PSYCHIATRY
Brief Report
1995;38:487-491
al 1989b). The present findings suggest that a genetic contribution to schizophrenia is related to saccade dysfunction.
This work was supported by the Department of Veterans Affairs.
References American Psychological Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised. Washington, DC: American Psychological Association Press. Breitmeyer BG (1984): Visual Masking: An Integrative Approach. New York: Oxford University Press, p. 313. Carter JE, Obler L, Woodward S, Albert ML (1983): The effect of increasing age on the latency for saccadic eye movements. J Gerontol 38(3):318-320. Cegalis JA, Sweeney JA, Dellis EM (1982): Refixation saccades and attention in schizophrenia. Psychiatr Res 7:189-198. Clementz BA, McDowell JE, Zisook S (1994): Saccadic system functioning among schizophrenia patients and their firstdegree biological relatives. J Abnorm Psychol 103(2):277287. Eaves IA, Kendler KS, Schulz SC (1986): The familial sporadic classification: Its power for the resolution of genetic and environmental etiological factors. J Psychiatr Res 20:115130. Fish B, Marcus J, Hans SL, Auerbach JG, Perdue S (1992): Infants at risk for schizophrenia--sequelae of a genetic neurointegrative defect--a review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. Arch Gen Psychiatry 49:221-235. Fukushima J, Fukushima K, Morita N, Yamashita I (1990a): Further analysis of the control of voluntary saccadic eye movements in schizophrenic patients. Biol Psychiatry 28: 943-958, Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I (1990b): Voluntary control of saccadic eye movements in patients with schizophrenic and affective disorders. J Psychiatr Res 24:9-24. Fukushima J, Fukushima K, Chiba T, Tanaka S, Yamashita l, Kato M (1988): Disturbances of voluntary control of saccadic eye movements in schizophrenic patients. Biol Psychiatry 23:670-677. Hallet PE (1978): Primary and secondary saccades to goals defined by instructions. Vision Res 18:1279-1296. Holzman PS, Proctor LR, Levy DL, Yasillo N J, Meltzer HY, Hurt SW (1974): Eye-tracking dysfunctions in schizophrenic patients and their relatives. Arch Gen Psychiatry 31:143-151. Hommer DW, Clem T, Litman R, Pickar D (1991): Maladaptive anticipatory saccades in schizophrenia. Biol Psychiat~ 30: 779 -794. Kendler KS (1987): Sporadic vs. familial classification given etiological heterogeneity: I. Sensitivity, specificity, and positive and negative asymmetry. Gen Epidemiol 4:313-330. Leigh RJ, Zee DS (1991): The Neurology of Eye Movement. edition two. Philadelphia: F.A. Davis, p. 96. Levin S, Jones A, Stark L, Merrin EL, Holzman PS (1982): Saccadic eye movements of schizophrenic patients measured by reflected light technique. Biol Psychiatry 17(11):12771287.
Levy DL, Holzman PS, Matthysse S, Mendell NR (1993): Eye tracking dysfunction and schizophrenia: A critical perspective. Schizophr Bull 19(3):461-536. Lewis SW, Reveley AM, Reveley MA, Chitkura B, Murray RM (1987): The familial/sporadic distinction as a strategy in schizophrenia research. Br J Psychiatry 151:306-313. Lyons MJ, Kremen WS, Tsuang MT, Faraone SV (1989a): Investigating putative genetic and environmental forms of schizophrenia: Methods and findings. Int Rev Psychiatry 1:259-276. Lyons MJ, Faraone SV, Kremen WS, Tsuang MT (1989b): Familial and sporadic schizophrenia: A simulation study of statistical power. Schizophr Res 2:345-353. Mannuzza S, Fyer AJ, Endicott J, Klein DF, Robins LN (1985): Family Informant Schedule and Criteria (FISC). New York: Anxiety Disorders Clinic, New York State Psychiatric Institute. Matsue Y, Okuma T, Saito H, Aneha S, Ueno T, Chiba H, Matsuoka H (1986): Saccadic eye movements in tracking, fixation, and rest schizophrenics and normal subjects. Biol P~vchiat~ 21:382-389. Matthysse S, Holzman PS, Lange K (1986): The genetic transmission of schizophrenia: Application of Mendelian latent structure analysis to eye tracking dysfunctions in schizophrenia and affective disorders. J Psychiatr Res 20:57-76. Merritt RD, Balogh DW (1989): Backward masking spatial frequency effects among hypothetically schizotypal individuals. Schizophr Bull 15:573-583. Mialet JP, Pichot P (1981): Eye-tracking patterns in schizophrenia. Arch Gen Psychiatry 38:183-186. Moser A, Kompf D, Arolt V, Resch T (1990): Quantitative analysis of eye movements in schizophrenia. Neuro-Ophthalmology 10(2):73-80. Murry RM, Reveley AM, Reveley MA, Sure E, Lewis S (1985): Genetic and environmental influences in schizophrenia. In Hafner H, Gattaz WF (eds), Search for the Causes of Schizophrenia, Vol II. New York: Springer-Verlag, pp. 120122. Oldfield RC (1971): The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9:97-113. Page WK, King WM, Merigan W, Maunsell J (1994): Magnocellular or parvocellular lesions in the lateral geniculate nucleus of monkeys cause minor deficits of smooth pursuit eye movements. Vision Res 34(2):223-239. Ross DE, Ochs AL, Hill MR, Goldberg SC, Pandurangi AK, Winfrey CJ (1988): Erratic eye tracking in schizophrenic patients as revealed by high-resolution techniques. BioI Psychiatr3, 24:675-688. Schmidt-Burgk W, Becker W, Jurgens R, Kornhuber HH (1983): Disturbed smooth pursuit and saccadic eye movements in schizophrenia. Arch Psychiatr Nervenkrankh 232:381-389. Schuck JR, Lee RG (1989): Backward masking, information processing, and schizophrenia. Schizophr Bull 15:491-500.
Brief Report
Schwartz BD, Winstead DK (1982): Visible persistence in acute and chronic schizophrenics. Biol Psychiatry 17:1377-1387. Spitzer RL, Williams JB, Gibbons M (1987): Structured Clinical Interview for DSM-III-R (SCID). New York: Biometric Research Department, New York State Psychiatric Institute. Thaker G, Kirkpatrick B, Buchanan RW, Ellsberry R, Lahti A,
BIOL PSYCHIATRY 1995;38:487-49]
491
Tamminga C (1989): Oculomotor abnormalities and their clinical correlates in schizophrenia. Psychopharmacol Bull 25(3):491-497. Tsung MT, Lyons MJ, Faraone SV (1990): Heterogeneity of schizophrenia--conceptual models and analytic strategies. Br J Psychiatry 156:17-26.