Blink rate in childhood schizophrenia spectrum disorder

Blink Rate in Childhood Schizophrenia Spectrum Disorder Rochelle Caplan and Donald Guthrie

Spontaneous blink rate, a putative measure of dopamine function, was measured in schizophrenic, schizotypal, and normal children, aged 5.6-13.2 years during three diferent cognitive tasks. Unlike that of schizophrenic adults, the blink rate of the schizophrenic children who were not on neuroleptics was significantly lower than that of the normal children, There were no statistically significant differences, however, in the blink rates of the neuroleptic-treated schizophrenic children and the normal children. The schizophrenic and schizotypal children had similar spontaneous blink rates, Within each diagnostic group, the blink rate was lowestfor listening, intermediate for conversation, and highest for verbal recall, These findings highlight the need to examine the relationship between age, blink rate, and dopamine function in childhood.onset schizophrenia spectrum disorder,

Key Words: Blinks, schizophrenia, schizotypal personality disorder, childhood, formal thought disorder, speech

Introduction Central nervous system dopamine activity that involves both DI and D: receptors underlies spontaneous blink rates in humans (Blin et al 1990) and in animals (Ellsworth et al 1991; Lawrence and Redmond 1991; Karson et al 1981a). Studies of blink rate in patients with dopamine dysfunction, such as schizophrenia (Helms and Godwin 1985; Karson et ai 1981b; 1983, 1984, 1990; Kleinman etal 1984; MacLean et al 1985; Stevens 1978), Parkinson's disease (Hall 1945; Karson et al 1984; Ponder and Kennedy 1928), Tourette syndrome (Bonnet et al 1982; Cohen et al 1980), Huntington's disease (Karson et al 1984), and tardive dyskinesia (Karson et al 1983; Stevens 1978), suggest that measure-

From the Departments of Psychiatry(RC, DO) and Biostatistics (DO), and the Mental Retardation Center (DO), Universityof California, Los Angeles, Address reprint requests to Dr. R. Caplan, Neuropsychiatric Institute, Room 48-B, 760 Westwood Plaza, Los Angeles, CA 90024. Supported by National Institute of Mental Health grant KOI-MH00538. Received May 3,1993; revised October 8,1993. © ! 994 Society of Biological Psychiatry

ment of spontaneous blink rates is a noninvasive technique to study dopamine function, Schizophrenic adolescents (Karson et al 1986a) and adults (MackeR et al 1990) who have not been treated with neuroleptics have significantly higher blink rates than normal subjects. Treatment of schizophrenic adults with neuroleptics is associated with a decrease in spontaneous blink rate (Karson et al 1983). Regarding the relationship between clinical symptoms and spontaneous blink rate, the blink rate of schizophrenic patients correlates with the severity of blunted affect, a negative sign of schizophrenia (Kitamura et ai 1984). A decrease in Brief Psychiatric Rating Scale (BPRS) measures of anxiety, hostility/suspicion, and unusual thought content are associated with a reduction in the blink rate of schizophrenic adults (Mackert et al 1990). From the information-processing perspective, blinks do not occur in a random manner (Fogarty and Stem 1989; Orchard and Stem 1991; Stem et al 1984). For example, performance on a visual (i.e., reading or mental arithmetic) or auditory task (i.e., listening) is associated with a decrease in the spontaneous blink rate of normal (Stem et al 1984) 0006-3223/94/$07.00

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and schizophrenic subjects (Karson et al 1981a). This enables the subject to focus on the ongoing task and to process the information in an efficient manner. Increased blink rates, however, occur during the motor act of speaking (Hall 1945; yon Cramon and Schuri 1980) and during a task that demands a high level of activation and processing flow (Stem et al 1984). Spontaneous blink rate also reflects anxiety, arousal, and alertness in normal adults (Harris et al 1960; Monster et al 1978; Ponder and Kennedy 1928). From the developmental perspective, infants blink infrequently and the blink rate increases during childhood and adolescence to reach adult rates by the age of 20 years (Zametkin et al 1979). To date there have been no studies of blink rates across different cognitive tasks in normal or schizophrenic children. During the past decade several studies have demonstrated that schizophrenic children have similar clinical features (Green et al 1984; Russell et al 1989), thought processing deficits (Arboleda and Holzman 1985; Caplan et al 1990b, 1992), and information processing impairments (Asamow and Sherman 1984; Strandburg et al 1992) as schizophrenic adults. We, therefore, hypothesized that, like schizophrenic adults, schizophrenic children who were not on neuroleptics would have significantly higher blink rates than normal children. Schizophrenic children on neuroleptics, however, would have significantly lower blink rates than normal children. In addition, as demonstrated in schizophrenic adults (Kitamura et al 1984), we postulated that schizophrenic children with low blink rates would score high on negative signs of thought disorder in childhood, such as illogical thinking and discourse deficits (Caplan et ai, in press). Schizophrenic children with fast blink rates, however, would have high loose associations scores, a positive formal thought disorder sign in childhood schizophrenia (Caplan et al 1990a). Finally, the spontaneous blink rate of schizophrenic children would be low for a listening task, intermediate for a conversation task, and high for a story recall task.

Methods and Materials

Subjects The study included 30 (25 boys, 5 girls) schizophrenic, 13 (9 boys, 4 girls) schizotypal, and 52 (43 boys, 9 girls) normal children, aged 5.6-13.2 years. Table 1 presents the mean age, intelligence quotient (IQ), socioeconomic status, and ethnicity of the three groups of children. We address the full-scale IQ differences (FSlQs~h,,~h,~,jc---90, SD - 12.60; FSIQs~bj~o~ - 98, SD --- 19.38; FSIQ~om~ - 110, SD -13.09) between the two patient groups and the normal group in the data analysis section of this paper. At the time of testing, 50% of the schizophrenic group and 54% of the schizotypal group were on neuroleptic medication. The remainine children had not received neumlep-

Table 1. Demographic Data on Schizophrenic, Schizotypal, and Normal Children Demographic variables

Schizophrenic

Schizotypal

Normal

30

13

53

Range Mean

7.4-12.3 10.3 (SD - 1.53)

7.3-11.7 9.5 (SD -- 1.37)

5.6-13.2 9.3 (SD -- 2.39)

Full-scale IQ

90 (SD = 12.6)

98 (SD = 19.38)

110 (SD = 13.09)

77 15 8 0 0

57 6 16 19 2

8 23 46 15 8

6 48 33 13 0

N Chronological age (yr)

Ethnicity (%) Anglo Black Hispanic Asian Other

70 13 13 0 4

Socioeconomicst~us(Hollingshead)(%) i 3 !1 37 III 33 IV 20 V 7

tics for at least 1 month prior to their participation in the study. The age ranges of the schizophrenic subjects on and off medication were 7.4-12.3 and 8.5-12.2 years, respectively. The schizotypal subjects on and off neuroleptics were aged 9.0-11.2 and 7.3-11.7 years, respectively. Information on the duration and dosage of the neuroleptics was not available for this study. Seventy percent of the schizophrenic children and 61% of the schizotypal children were inpatients at the time of the study. Most of the schizophrenic and schizotypal children were from middle class Caucasian families (Table 1). More normal children, however, were from bilingual Asian and Hispanic families. We address the ethnic heterogeneity of the normal subjects in the Results section. The schizophrenic and schizotypal subjects were recruited from the UCLA Neuropsychiatric Institute's Inpatient and Outpatient Child Services, as well as from two Los Angeles schools for the emotionally disturbed. The children were diagnosed by the Diagnostic Unit of UCLA Childhood Psychoses Clinical Research Center with the Interview for Childhood Disorders and Schizophrenia (ICDS) by a research team blind to the present formal thought disorder data (Russell et al 1989). In addition to questions from the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) (Puig-Antich and Chambers 1978) and Diagnostic Interview for Children and Adolescents (DICA) (Herjanic and Campbell 1977), ~is reliable interview (Kappa - 0.89) includes questions that ensure an adequate assessment of schizophrenia and schizotypal personality disorder. To be included in the study, the

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children had to meet DSM-UI (APA 1987) criteria for schizophrenia or schizotypal personality disorder. The mean age of onset of psychotic symptoms was 6.9 years (SD = 1.98) in the schizophrenic group. Most of the children continued to be psychotic at the time of their participation in this study. The milder psychotic-like symptoms of the schizotypal children did not meet DSM-III criteria for schizophrenia (Russell 1992). Due to the nonspecificity of the earlier symptoms of the schizotypal children, we were unable to document a clear age of onset for this group of children. At follow-up, these children were found to have long-term maladaptive behaviors (Asarnow and Ben-Meir 1988). Children with a neurological, language, or hearing disorder were excluded from the study. We recruited the normal subjects from four Los Angeles schools and from the community via advertisements in a local newspaper. We screened the normal children for neurological, psychiatric, language, or hearing disorders through a telephone conversation with the parent. We excluded children from the normal sample if they manifested symptoms of these disorders either at the time of the study or in the past. To the best of our knowledge, none of the children in the study had ophthalmologic problems that affected blink rate. We obtained informed consents from the parent and the child after advising them on the study's procedures.

Procedures BLINKRATE. Two independent raters with no knowledge about the children's diagnosis counted the number of blinks and computed blink rates per minute from three sections of the videotaped Story Game (Caplan et al 1989): listening, conversation, and verbal recall. The child listened to an audiotaped story, responded to a series of standardized open-ended questions on the story, and retold two stories that he/she heard during the Story Game. Using the zoom-in feature, the videocamera focused on the child's face throughout the testing.In addition to counting the number of blinks, the raters timed these three tasks from predetermined points in the Story Game protocol and subtracted down time during which the child's eyes were obscured from the rater's vision because the child moved. The duration of the listening and verbal recall conditions was 1.57-1.62 and 1.271.62 minutes, respectively. The raters coded blinks during 3 minutes of the conversation condition. The interrater agreement (intraclass correlation coefficient) (Mitchell 1979) on the blink rate of 32 children was 0.95, 0.92, and 0.96 for the listening, conversation, and memory tasks, respectively. The intraclass correlation coefficients for the duration of the listening and verbal recall conditions in these 32 children were 0.90 and 0.93, respectively.

R. Caplanand D. Guthrie

FORMAL THOUGHT DISORDER AND DISCOURSE MEASURES. Using the Kiddie Formal Thought Disorder Rating Scale (K-FFDS) (Caplan et -,d 1989, 1990b), two additional raters coded the speech samples elicited from the entire Story Game. The Story Game involves a narrative chosen from four given topics in addition to the previously described conversation and verbal recall conditions. The scores derived from the K-FTDS ratings were frequency counts of illogical thinking and loose associations divided by the number of sentences (clauses) made by the child. The chance-corrected interrater agreement, Kappa (Fleiss 1973), for 27 schizophrenic, schizotypal, and normal children was 0.78 (SE = 0.03) and 0.66 (SE = 0.01) for illogical thinking and loose associations, respectively. COHESIONANDREFERENCEPATTERNS. Two blind, independent raters rated transcripts of the Story Game using Caplan et al' s (1992) modificatiotl for children of Halliday and Hassan's (1976) analysis of cohesion. To control for the variation in the number of clauses (sentences) elicited from each child during the entire Story Game, the raters divided the cohesion (i.e., referential cohesion, conjunction, lexical cohesion, and ellipsis) and reference pattern frequency scores (i.e., exophora) by the total number of clauses. The interrater agreement (mean generalizability coefficient) (Mitchell 1979) of the cohesion and reference pattern scores in 20 schizophrenic and normal children was 0.94 for referential cohesion, 0.99 for conjunction, 0.89 for lexical cohesion, 0.70 for ellipsis, and 0.72 for exophora. PSYCHOLOGICALTESTING. A clinical psychologist administered the Wexler Intelligence Scale for Childrenm Revised (WISC-R) to all children. DATA ANALYSIS. After subtracting the down time, the mean time for the listening, conversation, and memory conditions were 2.31 (SD = 0.34), 2.87 (SD = 0.40), and 1.52 (SD = 0.58) minutes, respectively, for all children in the study. To compute blink rates, we first determined if the duration of each of these three conditions was symmetrically distributed in the schizophrenic, schizotypal, and norreal groups. The blink rates exhibited some distributional skewness. All statistical inferences were based, therefore, on square-root transformed data. We, however, report untransformed mean blink rate values. Due to the known effect of neuroleptics on blink rates (Karson et el 1983), we subdivided the schizophrenic and schizotypal groups by their neuroleptic status (i.e., on or off neuroleptics). To compare blink rates across the listening, conversation, and verbal recall conditions, we computed a two-way repeated measures analysis of covariance (ANCOVA) with diagnosis/neuroleptic status as the inter-

Blinks in Childhood Schizophrenia

subject and testing condition (i.e., listening, conversation, or verbal recall) as the intrasubject classification variables. These analyses were executed with a general mixed linear model including both fixed and random components (SAS Institute, 1992 PROC MIXED) to allow for both variation among subjects and for experimental error. Preliminary computations using standard analysis of variance for repeated measures had indicated that necessary covarlance assumptions were not valid, thus the more general approach was used. Use of the general mixed linear model yields nonstandard values for the degrees of freedom in some tests. These degrees of freedom are based on the relevant maximum likelihood ratio statistics. The two patient groups had lower full-scale IQ scores than the normal groups (Table 1). We, therefore, covaried out full-scale IQ from the analysis of variance (ANOVA) after ascertaining that there was a linear relationship between blink rate and full-scale IQ in all three diagnostic groups. To determine if our findings were a function of age (Zametkin et 81 1979), amount of speech (yon Cramon and Schuri 1980), and formal thought disorder, we covaried out these variables from the ANOVA after determining that they have a linear relationship with blink rate. Within all groups, we examined the relationship among blink rate, formal thought disorder, and discourse measures using Spearman correlation coefficients for the continuous variables (i.e., illogical thinking and discourse measures) and t tests for the parametric variables (i.e., loose associations). Results

Blink Rates We conducted a two-way repeated measures ANCOVA with diagnosis (i.e., schizophrenic children on and off neuroleptics, schizotypal children on and off neuroleptics, norreal children) and condition (i.e., listening, conversation, verbal recall) as classification variables and full-scale IQ, chronological age, utterances per minute, and illogical thinking as covariates. The ANCOVA demonstrated a main effect for diagnosis [F (4, 208) = 5.33, p < 0.001] and condition IF (2, 208) = 19.53, p < 0.001] with interaction between condition and diagnosis [F (8, 208) = 2.49, p <

0.011. We found a significant effect for chronological age [F (1, 208) = 11.34, p < 0.001], but not for the other covariates. In the normal subjects, blink rate correlated with age only in the listening condition ( r - 0.28; p < 0.04). In the medicated (r = 0.1-0.26, p < 0.2-0.6) and unmedicated patient groups (r = -0.17 to 0.32, p < 0.1--0A4), however, we found no statistically significant correlation between age and blink rates. We also found no statistically significant differences in the blink rates of the normal group that were attributable

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231

Table 2. Mean Blink Rate by Diagnosis/Neuroleptic Status and Condition Condition Diagnosis/ neuroleptic status Normal Schizophrenic Off On Schizotypal Off On

Listening

Conversation

Recall

N

Mean

SD

Mean

SD

Mean

SD

53

10.4

8.20

14.0

7.44

19.7

10.61

14 16

5.7 9.0

3.40 5.99

9.2 15.0

6.80 7.54

10.4 16.7

5.95 9.77

8 5

7.2 11.1

4.80 9.34

8.5 4.4 10.59 6.96

9.5 12.6

3.51 6.31

to ethnicity [F (3, 47) = 0.25-2.33, p < 0.8], or gender (t (50) = 0.02 to-0.59]. Planned contrasts demonstrated that the nonmedicated schizophrenic children [F (I, 208) -- 7.62-21. I, p < 0.006] had statistically significant lower blink rates compared to the normal children for the listening, conversation, and verbal recall conditions. The normal children and the schizophrenic children on neuroleptics, however, had similar blink rates in the three conditions [F (1,208) = 0-.2.31, p < 0.95]. The nonmedicated schizophrenic children had significantly lower blink rates than the medicated schizophrenic children [F (1,208) = 4.54-10.65, p < 0.005]. With the exception of verbal recall [F (1,208) = 7.99, p < 0.001], there were no significant differences in the blink rates of the schizophrenic and schizotypal children with similar drug status. In each of the three diagnostic groups the blink rate was low for listening, intermediate for conversation, and high for verbal recall (Table 2). In the normal children there were statistically significant differences in the blink rates across all three conditions [F (1,208) = 17.5-76.33, p < 0.001]. The blink rates of the medicated and nonmedicated schizophrenic subjects during verbal recall and conversation were significantly higher than those in the listening condition IF (1,208) = 7.85-20.18,p < 0.001]. We found no significant differences of blink rate by condition in the schizotypal subjects on and off medication.

Blink Rates, Formal Thought Disorder, and Discourse Deficits Table 3 presents the mean formal thought disorder and discourse measures of the schizophrenic, schizotypal, and normal subjects. For each of the three conditions, we found no statistically significant correlations of blink rates with illogical thinking (r = -0,32 to 0.13), referential cohesion (r = -0.26 to 0.27), conjunction (r = -0.06 to 0.38), lexical cohesion (r = 0.54-0.57), ellipsis (r = 0.49-0.43), or exophora (r = -0.11-0.43) in the patient subgroups. The medicated (t = 0.31 to-l.04) and unmedicated patients (t =-1.39

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R. Caplan and D. Guthrie

to --0.82) with and without loose associations had similar blink rates.

Discussion The results of this study suggest that similar to schizophrenic (Karson et :!! 1981) and normal adults (Stem et al 1984), schizophrenic children appear to modulate their spontaneous blink rates during different cognitive tasks. Three additional findings imply that the spontaneous blink rate of schizophrenic children differ from those of schizophrenic adults. First, schizophrenic children appear to have lower, not higher, blink rates compared with normal peers. Second, schizophrenic children on neuroleptics might have significantly higher blink rates than unmedicated schizo. phrenic children. Third, we found no association of positive or negative measures of thought disorder with the spontaneous blink rate of schizophrenic children. From the clinical perspective, this is the first study to demonstrate that DSM-III diagnosed schizophrenic children might differ from normal children on a biological measure. By demonstrating similar blink rates in the schizophrenic and schizotypal children, the results of this study highlight the biological similarity of these two disorders in childhood. This finding adds to previously described similarities in the phenomenology (Russell 1992), course of illness (Asarnow and Ben-Meir 1988) and formal thought disorder scores (Caplan et al 1990b) of schizophrenic and schizotypal children. The retrospective nature of the neuroleptic status of the children in this study, however, limits the generalizability of our findings in two ways. First, the decision to prescribe neuroleptics to some of the schizophrenic and schizotypal subjects could reflect differences in the acuteness and/or clinical severity of the patient samples. Based on measures of clinical severity available to us in this study, formal thought disorder and discourse deficits (Table 3), the schiz-

ophrenic children on neuroleptics had somewhat lower loose associations scores, but more discourse deficits than the unmedicated schizophrenic subjects. We cannot rule out clinical differences between the medicated and nonmedicated subgroups of schizophrenic children. However, the decision to treat the children with neuroleptics was made irrespective of their blink rates. Second, in schizophrenic adults the relationship between reduction in blink rate and decrease in unusual thought content, a positive sign of schizophrenia was found when these patients were treated with neuroleptics (Mackert et al 1990). Similarly, the correlation between blink rate and blunted affect, a negative sign of schizophrenia was also thought to represent a neuroleptic effect (Kitamura et al 1984). Owing to the retrospective nature of our study, we were unable to measure the association of neuroleptic induced change in blink rate, positive signs, and negative signs of schizophrenia. Furthermore, the lack of a statistically significant relationship between these signs of schizophrenia and blink rate could have reflected the small sample size (N = 16) of the medicated subjects. From the developmental perspective, Zametkin et al (1979) reported that the spontaneous blink rate of children "during quiet conversation" (p. 454) increases with age. We demonstrated an association between age and blink rate only in the normal children during the listening condition. We found no age-related changes, however, in the schizophrenic and schizotypal children. Further study is needed to determine if onset of schizophrenia during middle childhood impacts the developmental increase of spontaneous blink rate with age. Finally, Dt and D= receptors play a role in both schizophrenia (Fitton and Heel 1990; Losonczy et al 1987) and in spontaneous blink rate (Ellsworth et al 1991). Current theories postulate that schizophrenia involves abnormalities of brain development that impact the development of dopamine and other neuromodulatory systems (Weinberger

Table3. MeanFormalThoughtDisorderand DiscourseMeasuresby Diagnosisand NeumlepticStatus Diagnosisb SZ on

SZ off

SZT on

SZT off

Normal

Thought discourse"

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

lilogic~ thinking Loose associations Referential cohesion Conjunctions Lexical cohesion Ellipsis Exophora Utterances/minute

0,27 0.09 0,42 0.37 0,54 0.49 0,37 14.8

0,22 0,15 0,14 0.18 0, ! 7 0,07 0,13 6.25

0,22 0,13 0,53 0,57 0,57 0,43 0,42 12,9

0,14 0, I ! 0,11 0,17 0,16 0,05 0,13 4,82

0,21 0,01 0,51 0,52 0,58 0,47 0,44 14,0

0,19 0,02 0,11 0, ! 0 0, I0 0, i I 0,13 3,67

0,35 0,05 0,48 0,48 0.58 0.50 0.35 ! 3,4

0.13 0.06 0.18 0.25 0.25 0.04 0.08 3.08

0.14 0.00 0.64 0.68 0.64 0.47 0.35 13.7

0.19 0.02 0.15 0.20 0.2 I 0.09 0.12 5.38

"Thoughtdisorder= formalthoughtdisorderand discomsemeasures, bSZ= schizoFhrenic,SZT= schizotypal,on ::on neuroleptics,off= offneumleptics,

Blinks in Childhood Schizophrenia

et al 1992). The findings of our study underscore the need for additional studies to determine if the lower blink rate of unmedicated schizophrenic children is associated with abnormalities in the development of the dopamine system.

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WethankJamesT. McCracken,M.D.,forhis commentson earlierversions of this paper. We also thank Amy Mo, NatashaWheeler, Scou Komo,and WandaCox for theirtechnicalassistance.

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