Blink rate and stereotyped behavior: Evidence for dopamine involvement?

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BRIEF REPORTS

Blink Rate and Stereotyped Behavior: Evidence for Dopamine Involvement? William E. MacLean, Jr., Mark H. Lewis, William A. Bryson-Brockmann, David N. Ellis, Robert E. Arendt, and Alfred A. Baumeister

Introduction Clinical observations, as well as animal studies, suggest that spontaneous eye-blink rates are determined, at least in part, by the activity of central dopamine pathways (Karson 1983). A levodopa-reversible decrease in spontaneous eyeblink rate is a well-established early sign of Parkinson's disease (Ponder and Kennedy 1928; Hall 1945; Karson et al. 1982, 1984), and Tourette's syndrome and schizophrenia have been reported to be associated with elevated blink rates that can be reversed with antipsychotic drug treatment (Stevens 1978; Cohen et al. 1980). Experimentally, administration of dopamine antagonists to nonhuman primates decreased spontaneous eye-blink rates, whereas dopamine agonists significantly increased blinking in a dosedependent fashion (Karson et al. 1981c; Casey et al. 1980; Karson 1983). Moreover, diazepam, clonidine, phenylephrine, phentolamine, or LSD failed to alter the spontaneous blink rate, suggesting that the effect is not due to nonspecific activation or sedation (Karson 1983). On the From Peabody College, Vanderbilt University, Nashville, TN (W.E.M., W.A.B.-B., D.N.E., R.E.A., A.A.B.), and the Department of Psychiatry, University of Medicine and Dentistry of New Jersey, School of Ostoopathie Medicine, Camden, NJ (M.H.L.). Supported in part by PHS Grants HD13344 and HDO7226. Address r~print requests to Dr. William E. MacLean, Jr., P.O. Box 158, PeabodyCollege, VanderbiltUniversity, Nashville,TN 37203. Received June 3, 1985; revised July 5, 1985.

© 1985 Society of Biological Psychiatry

basis of these and other experiments, it can be concluded that dopaminergic activity controls, at least in part, the frequency of eye blinking. If spontaneous eye-blink rate reflects the activity of central nervous system (CNS) dopamine systems, then this measure, which appears to be reliable and easy to quantify, would provide a useful way to assess noninvasively CNS dopaminergic involvement in specific aberrant behaviors. Thus, we attempted to quantify the spontaneous eye-blink rates of mentally retarded persons who exhibited excessive stereotyped behavior. Stereotyped mannerisms are rhythmical motor behaviors that occur frequently in severely mentally retarded, autistic, or blind persons (Lewis and Baumeister 1982). Such behavior typically takes the form of body rocking, head rolling, or complex hand movements. Although the pathophysiology or etiology of such behavior is not well understood, animal studies and clinical observations support the hypothesis of perturbations in dopaminergic activity or altered receptor sensitivity in the nigrostriatal dopamine pathway (Ellinwood 1967, 1969; Kramer et al. 1967; Randrup and Munkvad 1967; Rylander 1971; Lewis and Baumeister 1982). Our initial hypothesis was that the excessive stereotyped behavior observed in institutionalized mentally retarded persons was due to dopaminergic hyperactivity, and this neurobiolog-

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ical state would be reflected in increased spontaneous eye-blink rates.

Methods

Subjects Twenty residents of a local developmental center who were identified by institutional staff as exhibiting excessive stereotyped behavior served as subjects. After obtaining informed consent from the residents and their parents or legal guardians, potential subjects were observed in their typical environments to ensure that they engaged in moderate to high rates of stereotyped behavior, such as repetitive body rocking, head rolling, or complex hand movements. Ten of the subjects engaged in both repetitive body rocking and one other stereotyped mannerism, typically a complex hand movement. Five subjects engaged in body rocking exclusively, whereas the stereotyped behavior of five other subjects was limited to complex hand movements. Only residents whose eyes were visible for at least 75% of the initial observation period were selected as subjects. In addition, residents who had received antipsychotic medication within 3 months of the initiation of the study were excluded from further participation. This decision followed the finding that antipsychotics reduce the spontaneous eye-blink rates of schizophrenic patients (Karson et al. 1981a). The subjects selected were severely or profoundly mentally retarded males and females between the ages of 21 and 60 years (mean 36.85 years), who had no known visual impairments. Subjects had been residents of the developmental center for at least 3 years. Their diagnoses were varied, with most of the residents classified as mentally retarded due to unknown prenatal influence (Grossman 1977). Twenty residents who were matched on age, sex, and level of retardation served as control subjects.

Setting and Apparatus All observations were conducted through oneway glass that separated an observation booth

from an experimental room (2.9 m x 2.4 m x 2.6 m) located at the developmental center. Observational data were collected using an electronic data collector (DATAMYTE 900, Electro/General Corp., Minnetonka, MN) that permitted continuous entry of behavior codes and assigned a real-time value to each code. Following observation sessions, stored data were transmitted through an acoustic phone coupler to an interactive computer for statistical analysis.

Procedures Each subject was escorted to a chair facing the one-way observation window and was informed that the experimenter would return in a few minutes. Before any observation was taken, the subject was allowed 5 min to adapt to the experimental environment. At this point, a 5-min observation was attempted. If a subject's eyes were out of the observer's visual range for more than 4 consecutive seconds, data collection was immediately terminated. Another observation period was begun as soon as the subject's eyes were again within the observer's visual range. This sequence was repeated until a total of 5 min of data were collected. Each session lasted approximately 20 min and was conducted at approximately the same time of day for each subject. At least three of these daily sessions were conducted on at least three separate days, yielding a minimum of 15 min of data. Additional sessions were needed for some stereotypy subjects in order to obtain at least 2 min of stereotyped behavior for analysis.

Data Analysis Rates of eye blinking, defined as the simultaneous closure of the upper and lower eyelids of both eyes, and the percent of time engaged in stereotyped behavior, were analyzed for differences. Two observers were present during all data collection. Observer 1 recorded the occurrence of eye blinks while Observer 2 scored the occurrence of stereotypy. A third observer was present to assess interobserver agreement for 68% of the subjects. An algorithm devised by

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MacLean et al. (in press) was used to compare directly the times of the secondary observer's data entries to those of the primary observer. An agreement was registered only if the reliability observer's data entry was within 2 sec of the primary observer's data entry. Interobserver agreement was computed by dividing the total number of agreements by the total number of agreements-plus-disagreements for both stereotyped behavior and eye blinks. Results Interobserver agreement for both stereotyped behavior and spontaneous eye blinking was above 84% across reliability sessions. The mean numbers of spontaneous eye blinks for experimental and control subjects are presented in Table 1. The data for this comparison reflect eye-blink rates recorded during periods of no stereotyped behavior. A two-factor ANOVA indicated no statistically significant main effects for groups (F = 1.04, df = 1,36, p > 0 . 0 5 ) or for sex (F = 1.0, df = 1,36, p > 0.05). The groups by sex interaction was highly significant, however (F = 10.68, df = 1,36, p < 0.01). Post hoc comparisons (Tukey's HSD) indicated that males who engaged in stereotypy exhibited significantly lower blink rates than did male controls (p < 0.01). Blink rates for females who exhibited stereotyped mannerisms were not significantly different than female controls, who also exhibited low Table 1. Spontaneous Eye-Blink Rates a (Mean Blinks/Minute ± SD) for Stereotypy versus Control Subjects Stereotypy subjects Male Mean 6.00b SD 3 . 6 2 n 10 Female M e a n 10.35 SD 6 . 6 9 n 10

Control subjects

14.69 7.46 10 6.33 5.24 10

"Eye-blink rates were recorded during periods of no stereotyped behavior. bStatistically different from same sex controls (p <: 0.01).

blink rates. Indeed, female control subjects were found to blink significantly less than male control subjects (p < 0.01). A Pearson product-moment correlation was computed to determine the relationship between stereotyped behavior and spontaneous eye blinking. As can be seen in Figure 1, a statistically significant inverse correlation was found between time spent engaged in stereotypy and eye blinking (r = - 0 . 4 7 , df = 18, p < 0.05). This relationship was largely due to the influence of female subjects (r = - 0 . 4 8 ) , as there was a limited range of blink rates among the males and, so, a low correlation between time spent in stereotypy and blink rate (r -- - 0.33). No significant correlation was found between chronological age and blink rate (r = 0.13, df = 38, p > 0.05). Because of the sex differences observed in the data, menses records were inspected for all female subjects. A significant point biserial correlation was found between blink rate and menses (r = 0.42), i.e., female subjects exhibiting a regular menstrual cycle were found to have higher blink rates than irregular or amenorrheic subjects (t = 1.81, df = 18, p < 0.05, onetailed). Additionally, almost twice as many females in the stereotypy group were found to have regular menstrual cycles as was noted for control females, although a chi-square test failed to yield a statistically significant difference [X2(1,n = 20) = 1.82, p > 0.05). In order to test whether initiation of stereotyped movements altered spontaneous blinking, blink rates during periods of body rocking, other stereotyped behavior, and no stereotyped behavior were recorded. Correlated t-tests indicated no significant difference in blinking between periods of no stereotyped behavior and periods of body rocking (t = 1.00, df = 14, p > 0.05) or periods of other stereotyped behavior (t = 1.34, df = 14, p > 0.05), although most subjects showed an increase in blink rate during stereotypy. Little difference could be observed in the blink rates for those subjects exhibiting both body rocking and other stereotyped movements while engaging in those behaviors.

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Figure 1. Relationship between the frequency of eye-blinks per minute and the percent of time engaged in stereotyped behavior (N = 20).

Discussion The spontaneous eye-blink rates of mentally retarded patients who engaged in excessive stereotyped behavior were compared with rates observed in matched controls. Male stereotypy subjects exhibited significantly lower rates of spontaneous blinking than same-sex controls, suggesting decreased dopaminergic activity, and possibly dopamine receptor supersensitivity, in these subjects. Indeed, the rates observed in male stereotypy subjects are comparable to the blink rates reported for patients with advanced Parkinson's disease (Karson et al. 1982). Female body rockers, however, did not differ from same-sex controls in blink rate. Female control subjects were found to have blink rates significantly lower than those observed for male controls and somewhat lower blink rates than female stereotypers. The low blink rate observed in this group appeared to be related to the higher percentage of amenorrheic subjects. This finding suggests that gonadal steroids, particularly estrogen, determine, at least in part, blink rate. There is ample evidence in the literature that estrogen modulates dopamine activity, including dopamine receptor sensitivity. This may well explain the sex differences observed here (e.g., Joyce et al. 1984). No significant

relationship was found between age and blink rate, a result that confirms previous reports (Zametkin et al. 1979; Mueser et al. 1984). Initially, we included nonretarded controls in our experimental design. However, it was quickly apparent that it would not be possible to obtain similar data, due to increased reactivity on the part of this group to the experimental setting. Indeed, their blink rates were typically elevated, perhaps reflecting the influence of anxiety (Tecce et al. 1978). Informal observations in other less reactive settings were confounded by potential subjects engaging in other tasks, such as reading, looking out the window, and so on. Contrary to our initial hypothesis, stereotyped behavior was inversely related to spontaneous blink rate; i.e., the greater the percent of time engaged in stereotyped behavior, the lower the blink rate. These data support the idea that stereotyped behavior may involve decreased concentrations of nigrostriatal dopamine, with subsequent increased postsynaptic receptor sensitivity. Finally, no significant difference was observed in blink rates recorded during periods of stereotyped activity versus periods during which no stereotyped behavior was observed. This result differs from the work of Obrist et al. (1970),

Brief Reports

who reported that blink rate, as well as electromyogram and heart rate, increased with somatic activity. However, we have also observed that stereotyped behavior also fails to increase heart rate significantly (Lewis 1980). The authors wish to thank Jon Tapp for technical support, Bonnie Beck for assistance in data collection, and Dr. Daniel E. Casey for helpful preliminary discussions.

References Casey DE, Gerlach J, Christenson E (1980): Behavioral aspects of GABA~lopamine interrelationships in the monkey. Brain Res Bull 51(Suppl 2):269-273. Cohen DJ, Detlor J, Young JB, Shaywitz BA (1980): Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen Psychiatry 37:1350-1357. Ellinwood EH Jr (1969): Amphetamine psychosis: A multidimensional process. Semin Psychiatry 1:208-226. Ellinwood EH Jr (1967): Amphetamine psychosis: I. Description of the individuals and process. J Nerv Ment Dis 144:273-282. Grossman HJ (ed) (1977): Manual on Terminology and Classification. Washington, DC: American Association on Mental Deficiency. Hall A (1945): The origin and purposes of blinking. Br J Ophthalmol 29:445-467. Joyce J N, Montero E, Van Hartesveldt C (1984): Dopaminemediated behaviors: Characteristics of modulation by estrogen. Pharmacol Biochem Behav 21:791-800. Karson CN (1983): Spontaneous eye-blink rates and dopaminergic systems. Brain 106:643~553. Karson CN, Freed WJ, Kleinman JE, Bigelow LB, Wyatt RJ (1981a): Neuroleptics decrease blinking in schizophrenic subjects. Biol Psychiatry 16:679-682. Karson CN, Staub RA, Kleinman JE, Wyatt RJ (1981b): Blink rates and receptor supersensitivity. Neuropharmacology 20:91-93. Karson CN, Staub RA, Kleinman JE, Wyatt RJ (t981c): Drag effect on blink rates in rhesus monkeys: Preliminary studies. Biol Psychiatry 16:249-254. Karson CN, LeWitt PA, Calne DB, Wyatt RJ (1982): Blink rates in Parkinsonism. Ann Neurol 12:580-583.

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Karson CN, Bums S, Lewitt PA, Foster NL, Newman RP (1984): Blink rates and disorders of movement. Neurology 34:677~o78. Kramer JC, Fischman VS, Littlefield DC (1967): Amphetamine abuse pattern and effects of high doses taken intravenously. JAMA 201:305-309. Lewis MH (1980): The Effects of Stereotyped Behavior on Responsivity and Other Measures of Autonomic Function. Unpublished doctoral dissertation, Peabody College, Vanderbilt University. Lewis MH, Baumeister AA (1982): Stereotyped mannerisms in mentally retarded persons: Animal models and theoretical analyses. In Ellis NR (ed), International Review of Research in Mental Retardation. Vol. 11. Orlando, FL: Academic, pp 123-161. MacLean WE Jr, Tapp JT, Johnson WL (in press): Alternate methods and software for calculating interobserver agreement for continuous observation data. J Behav Assess. Mueser KT, Dysken MW, Sussman S, Lyons JS, Davis JM (1984): Development of tolerance to neuroleptic-induced decreases in blink rate. Biol Psychiatry 19:617-621. Obrist PA, Webb RA, Sutterer JR, Howard JL (1970): The cardiac-somatic relationship: Some reformulations. Psychophysiology 6:569-587. Ponder E, Kennedy WP (1928): On the act of blinking. Q J Exp Physiol 18:89-110. Randrup A, Munkvad I (1967): Stereotyped activities produced by amphetamines in several animal species and man. Psychopharmacologia 11:300-310. Rylander G (1971): Stereotypy in man following amphetamine abuse. In deBanker SB (ed), The Correlation of Adverse Effects in Man with Observations in Animals. Amsterdam: Excerpta Medica, International Congress Series 220. Stevens JR (1978): Eye-blink and schizophrenia: Psychosis or tardive dyskinesia? Am J Psychiatry 135:223-226. Tecce JJ, Savignano-Bowman J, Cole JO (1978): Drug effects on contingent negative variation and eyeblinks: The distraction-arousal hypothesis. In Lipton MA, DiMascio A, Killam KF (eds), Psychopharmacology: A Generation of Progress. New York: Raven Press, pp 745-748. Zametkin AJ, Stevens JR, Pittman R (1979): Ontogeny of spontaneous blinking and of habituation of the blink reflex. Ann Neurol 5:453457.