Psychiatry Research. 42:
I- 1I
Elsevier
Pursuit Eye Movement Compulsive Disorder
Dysfunction
John A. Sweeney, Donna R. Palumbo, M. Katherine Shear Received September 9, 1992.
in Obsessive-
James P. Halper, and
13, 1991; revised version received January
13, 1992; accepted
February
Abstract. Disturbances in neural circuitry including the basal ganglia and prefrontal cortex have been hypothesized to be a cause of obsessive-compulsive disorder (OCD). Because eye movements are often impaired in neurologic diseases affecting these brain areas, oculomotor functioning was assessed in 17 unmedicated patients with OCD and in 25 normal controls. As compared with control subjects, patients with OCD demonstrated low-gain (slow) pursuit eye movements and an increased frequency of square wave jerk intrusions, but no increase in anticipatory saccades. In addition, several OCD patients showed an unusual pattern of intrusive, brief epochs of high-gain (fast) pursuit lasting on the order of 50 to 130 msec. These epochs of fast pursuit moved the eyes ahead of the target being tracked, and were terminated by corrective reversal saccades. Studies of eye movement abnormalities may provide an informative neurophysiologic approach for studying disturbances in basal ganglia and frontal cortical function that have been observed in functional neuroimaging and neuropsychological studies of OCD. Key Words. compulsions,
Smooth pursuit eye tracking, basal ganglia, frontal cortex.
oculomotor
functioning,
obsessions,
Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and repetitive ritualistic behaviors that are distressing and debilitating for patients, and over which they have little control. The disorder is frequent in the population, with a lifetime prevalence of 2% to 3% (Robins et al., 1984). Neurobiological studies using a range of techniques are now being actively pursued in several laboratories to clarify the pathophysiology of OCD. One pathogenic model for OCD hypothesizes that abnormalities in basal gangliafrontal cortex interaction are involved in causing obsessive and compulsive symptoms (Baxter et al., 1987; Khanna, 1988; Model et al., 1989). Indirect support for this hypothesis comes from observations (Grimshaw, 1964; Pitman et al., 1987; Swedo et al., 1989~) of increased rates of obsessive and compulsive symptoms in
John A. Sweeney, Ph.D., is Assistant Professor of Psychiatry and Neurology at the University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, PA. Donna R. Palumbo, Ph.D., is Fellow of Psychology in Psychiatry; James P. Halper, M.D., is Assistant Professor of Psychiatry, and M. Katherine Shear, M.D., is Associate Professor of Clinical Psychiatry at Cornell University Medical College, New York, NY. (Reprint requests to Dr. J.A. Sweeney, Laboratories of Neuropharmacology, Dept. of Psychiatry, WPIC, 381 I O’Hara St., Pittsburgh, PA 15213-2593, USA.) 0165-1781/92/S05.00
@ 1992 Elsevier Scientific Publishers Ireland Ltd.
2
neuropsychiatric disorders that result primarily from basal ganglia disease (e.g., Tourette’s syndrome, Sydenham’s chorea, Huntington’s disease, and postencephalitic parkinsonism). The fact that psychosurgical lesions of orbital frontal cortex and anterior cingulum can markedly reduce obsessive and compulsive symptoms (Yaryura-Tobias and Neziroglu, 1983) also implicates this brain area in OCD. More direct evidence comes from studies using positron emission tomography (PET) that have demonstrated increased metabolic rates in the head of the caudate and orbital prefrontal cortex (Baxter et al., 1987, 1988, 1989; Nordahl et al., 1989; Swedo et al., 1989b).
Assessment of oculomotor function is a potentially informative strategy for investigating basal ganglia/ frontal cortical impairment in OCD. Disorders of smooth pursuit and saccadic eye movements are well documented in neurologic diseases affecting the basal ganglia such as Parkinson’s, Wilson’s, and Huntington’s diseases (Leigh and Zee, 1983; Gibson, 1988; Kuskowski, 1988). In these and other neuropsychiatric disorders, the study of eye movements can provide valuable information relevant to the localization, severity, and progression of disease processes. Oculomotor functioning in OCD has not been well characterized. One previous study assessed pursuit tracking in OCD (Siever et al., 1987); however, the purpose of that study was to investigate the effects of amphetamine challenge on pursuit. Patient and clinical group comparisons, and quantitative studies of the pursuit system, were not reported. Tien et al. (1991) recently presented evidence indicating an increased rate of errors on an oculomotor antisaccade task in OCD, suggesting a prefrontally mediated disturbance in response suppression. The aim of the present study was to determine whether a disturbance in the smooth pursuit eye movement system could be identified in nondepressed unmedicated patients with OCD. Methods Subjects. Seventeen outpatients who met DSWZZZ-R criteria (American Psychiatric Association, 1987) for OCD were recruited from the Anxiety Disorders Clinic at the Payne Whitney Clinic of New York Hospital. The average age of onset of OCD was 17.6 (SD = 8.2) and 53% of patients had an onset before the age of 18. The average duration of OCD was 16.0 years (SD = 9.1). All patients had a score > 14 on the Yale-Brown Obsessive-Compulsive Scale (YBOCS; Goodman et al., 1989), and none met DSM-III-R criteria for concurrent major depression. Patients with OCD had no history of psychotic symptoms, no known systemic or neurologic illness by history and physical examination, no prior treatment with electroconvulsive therapy, and no history of head trauma, substance dependence, or substance use in the 2 months before testing. OCD patients had received no psychotropic medication for at least 4 weeks before eye movement testing. Patients were rated by clinicians on the YBOCS and the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967) within 1 hour before eye movement testing. The average total YBOCS score was 12.9 (SD = 3.1) for obsessive symptoms and 14.0 (SD = 2.7) for compulsive symptoms. Their average HRSD score was 10.1 (SD = 4.3). Twenty-five control subjects were recruited from the hospital community. They did not differ significantly from the OCD patients in age (F= 1.82; df = 1,40; NS) or in sex ratio (~2 = 0.20, df= 1, NS). All subjects were between 18 and 50 years of age (see Table 1) and had not previously participated in eye movement studies.
3
Table 1. Demographic obsessive-compulsive
data and eye movement measures in patients disorder (OCD) and normal controls
Demographic data
OCD
Control
(n = 17)
(n = 25)
33.6
31.3
6.4
4.5
22-44
24-46
1215
1619
with
Significance
Age(yr) Mean SD Range Sex Imale/female\
Eye movement measures Pursuit gain
t=1.35,df=40,NS
x2=0.20.df=1.NS
OCD
Control
(n = 17)
(n = 25)
Mean
SD
Mean
SD
Significance
0.83
0.08
0.90
0.08
t = 2.86, df = 40, f~ < 0.007
Saccadic measures (per min) I Reversal # Square
saccades
7.3
6.6
3.1
3.0
wave jerks
7.5
3.7
5.1
4.7
1.4
2.6
2.0
3.7
78.9
22.6
66.6
19.7
# Anticipatory # Catch-up
saccades saccades
,$=7.91,df=l,p 6OO’/sec*. Those periods identified as saccades, as well as the 12 msec (3 samples) before and after the periods identified as saccades, were excluded from pursuit gain calculations to limit any influence that saccade-related velocity changes might have on pursuit-gain calculations. Recordings were manually edited for blinks, pauses after anticipatory saccades, and rare periods of gross inattention to the task. Pursuit of the first and last target oscillations was excluded, yielding a maximum of 6250 samples of pursuit (25 set of pursuit sampled at 250 Hz) for quantitative analysis. Average pursuit gain was calculated by dividing the average sample-to-sample velocity of pursuit eye movement activity by the target velocity. Constant velocity triangular waveform targets reverse direction abruptly at the endpoint of target excursion. Therefore, the eyes need to slow and reverse direction. This slow pursuit reduces average pursuit velocity, making average gain an underestimate of the capacity of the pursuit system to match the velocity of a steadily moving target. For this reason, pursuit slower than 20% of target velocity at the point of target reversal was excluded from pursuit gain calculations. Saccadic eye movements. An evaluation of saccadic eye movements during pursuit provides further information about pursuit performance. Saccades during pursuit are either corrective or intrusive in nature. Corrective saccades are typically forward-going movements that compensate for the eyes lagging behind the target; however, when fast pursuit takes the eyes ahead of the target, corrective reversal or backwardsaccades take the eyes in the opposite direction from target movement to refoveate the target. Intrusive saccades disrupt tracking by shifting the focus of the eyes away from the target. The most common intrusive saccades are called square wave jerks. During pursuit, square wave jerks begin with an intrusive saccade that typically diverts the eyes I”-3” of visual angle away from the target. The eyes remain displaced from the target for up to 400 msec, during which time pursuit continues until a corrective saccade refoveates the target (Abel and Ziegler, 1988). Another form of intrusive saccade that disrupts visual tracking is anticipatory saccades, wherein a saccade moves the eyes ahead of the target, after which pursuit velocity is immediately and markedly reduced as if the eyes move suddenly to where the target is expected and then wait for it there. The frequencies of anticipatory saccades and square wave jerks, and the number and average size of corrective saccades, were tabulated during the two 30-second trials that required pursuit of targets moving at a sinusoidal velocity. The total number of the different types of saccades that occurred during the two trials was obtained, and corrective saccade size was averaged across the two trials. During pursuit of the constant velocity target, the demand for abrupt reversal in pursuit direction at the end points of target excursion can elicit corrective saccades that are difficult to differentiate reliably from square wave jerks and anticipatory saccades, so intrusive saccades were not tabulated during that task. Reversal saccade frequency was also calculated during pursuit of the sinusoidal velocity targets. In addition, so that the frequency of reversal saccades could be directly studied in relation to pursuit gain during the same pursuit tracking interval, the frequency of reversal saccades was calculated during the constant velocity trial from which gain was computed. Studies in our laboratory with 100 consecutively studied psychiatric inpatients indicated that classifications of all types of saccades were made with reliability > 0.80. Data Analysis. Distributions of saccadic eye movement measures were skewed, particularly anticipatory saccades and square wave jerks. Therefore, the Kruskal-Wallis nonparametric group comparison procedure, with a x* statistic, was used to compare OCD patients and controls on all measures of saccadic frequency. For the same reason, Spearman’s rank-order correlations (p) were computed to assess associations of eye movement measures with clinical and demographic variables.
5
Results Patients with OCD had significantly reduced spursuit gain (t = 2.86, df = 40, p < 0.007; see Fig. 1 and Table 1). Fig. 2 presents the percentage of the full distribution of pursuit velocities maintained during pursuit of the constant velocity waveform for OCD and control subjects. The percentage of pursuit activity was tabulated in bins increasing in steps of 0.1 units of pursuit gain for each subject, and then averaged across subjects to provide an aggregate estimate for each subject group. Fig. 2 indicates that normal subjects have more pursuit activity close to target velocity, while OCD patients have both more slow and fast activity than healthy control subjects. It also illustrates the moderate reduction of gain in OCD patients.
Fig. 1. Average pursuit gain during visual tracking of a constant velocity target in patients with OCD and in normal controls.
w
E
. r*
** .a75
.*.t.
3
B PI
.
*t
f
5 .625
$-
...... + l
.15-
8
3
* 0
l
.*.t. .
.
I-
CONTROL tN=ZS)
OCD (N=17)
The target oscillated f IO’ at 16°1sec for 30 sec. OCD = obsessive-compulsive disorder.
Patients with OCD also had more frequent square wave jerk intrusions (x2 = 5.20, df = 1, p < 0.03). There was no increase in the frequency of anticipatory saccades (x2 = 0.15, df = 1, NS). Patients with OCD demonstrated more frequent reversal saccades during pursuit of targets moving at a sinusoidal velocity (x2 = 7.80, df = 1, p < O.OOS), and there was a similar trend during pursuit of the constant velocity target (~2 = 3.64, df = 1, p < 0.06). There was a trend for OCD patients to show more frequent catch-up saccades (t = 1.83, df = 40, p < 0.08). The between-group difference in mean catch-up saccade size was not significant. Fifty-nine percent of OCD patients had a reversal saccade frequency (during pursuit of targets with sinusoidal velocity) > 1 per 10 seconds, as opposed to 16% of controls (~2 = 8.35, df = 1, p < 0.004). To provide a preliminary description of rates of “abnormality” on the different eye movement measures, the percentage of patients with values more deviant than 95% of control cases was calculated. The findings were as follows: 35% of patients had abnormal gain and reversal saccade frequency,
6 Fig. 2. Distribution of point-by-point pursuit gain, averaged across subjects, for patients with OCD and normal controls
0.0
0.S
Point-to-Point
1.0
Gain of Pursuit Eye
15
20
YoYemsnt
Normal controls showed significantly (p < 0.05) more pursuit activity with gain between 0.90 and 1.O,and between 1.O and 1.I. Obsessive-compulsive disorder (OCD) patients showed significantly more pursuit activity with gain between 0.4 to 050.5 to 0.6 and 0.6 to0.7, and between 1.5 to 1.6,1.6 to 1.7, and 1.6 to 1.9.
and 29% had more frequent square wave jerks. Review of Fig. 1, which presents pursuit-gain scores, suggests that there may have been two outliers in the control group (29- and 3%year-old women) and one in the OCD group (a 37-year-old woman). The increased frequency of reversal saccades in OCD patients was unexpected. Reversal saccades compensate for fast pursuit, and it was expected that OCD patients would show slow pursuit. Visual inspection of pursuit records (see Figs. 3 and 4) in OCD patients indicated that many reversal saccades occurred after brief epochs of high velocity pursuit (approximately 1.5 to 2.0 times the target velocity) during which pursuit advanced ahead of the actual target location. Some saccades in the opposite direction from target motion can occur after predictive errors about target position (particularly around the point of reversal in pursuit of constant velocity oscillating targets), but these are not preceded by atypically high pursuit velocity. The duration of epochs of fast pursuit in the OCD patients was on the order of 50-130 msec. Pursuit velocity after these epochs returned to subjects’ typical velocity immediately after the corrective reversal saccade. We examined the relationship between average pursuit gain and reversal saccade frequency to determine whether a higher average pursuit gain was positively associated with the frequency of reversal saccades. Positive correlations were observed between pursuit gain and reversal saccade frequency during pursuit of targets with sinusoidal (p = 0.63, p < 0.007) and constant (p = 0.55, p < 0.03) velocity. The correlations were somewhat lower (p = 0.31, NS, and p = 0.47, p < 0.02, respectively) in the control group. These positive correlations indicate that reversal saccade frequency increases as a function of pursuit gain in OCD patients. This association is consistent with the interpretation that the reversal saccades were a compensation for fast pursuit rather than an independent abnormality of saccadic
7 disinhibition, and that the epochs of fast pursuit were not an atypical compensation for low gain pursuit (see Figs. 3 and 4). In contrast to these positive correlations, the Fig. 3. Examples of eye movement recordings from an OCD patient (including several reversal saccades) and a normal control during pursuit of a constant velocity target
The target oscillated across the central visual field (k loo) in the horizontal plane at 160/set. compulsive disorder.
OCD = obsessive-
Fig. 4. Example of eye movement recording from an OCD patient showing 2 epochs of high velocity pursuit (approximately 2 times target velocity) followed by corrective reversal saccades 275 m.wc.
I ?
pint of revcrsaf in dfmctiorl of rarga movement (at -10 dcgca)
Note that the duration of fast pursuit segments is < 130 msec, and that pursuit velocity after these segments returns to the typical velocity immediatety after the reversal saccades. OCD = obsessive-compulsive disorder.
8 association between gain and catch-up saccades was in the opposite direction (p = -0.43, p < 0.10) for patients and was nonsignificant for control subjects. Analyses for laterality effects (leftward vs. rightward eye movement) were conducted for each eye movement measure using the Wilcoxon Matched-Pairs test. There were no significant lateral asymmetries in the direction of reversal or anticipatory saccades, square wave jerks, or pursuit gain, either for OCD patients or normal controls. Correlational analyses revealed few significant associations between eye movement measures and clinical data from the OCD patients. There was a trend for severity of depression (HRSD scores) to be inversely associated with pursuit gain in the OCD patients (p = -0.44, p < 0.09). Although there were no group differences in anticipatory saccades, the frequency of these intrusive saccades was related to later onset (p = 0.51, p < 0.04) and briefer duration of illness (p = -0.54, p < 0.03) in OCD cases. Female patients with OCD had lower gain than male patients (t = 2.25, df = 15, p < 0.05) and more frequent anticipatory saccades (t = 2.86, df= 15, p < 0.05). However, there were only five female OCD patients, so these gender differences need to be interpreted with considerable caution. Age was not correlated with pursuit gain (p = -0.11, NS) or other eye movement measures in OCD patients, which probably reflected in large part the narrow age range of the sample. In the control group, there were trends for females to show more reversal saccades (t = 1.96, df = 23, p < 0.08) and for age to be related to lower pursuit gain (p = -0.39, p < 0.06).
Discussion The findings of this study provide the first demonstration of impaired pursuit eye movements in OCD patients. Unmedicated OCD patients demonstrated low gain (slow) pursuit. The reduction in pursuit gain was of a moderate severity (from 0.90 in controls to 0.83 in OCD patients). However, this difference in average pursuit velocity may somewhat underestimate the actual degree of disturbance of closedloop gain in OCD. Some OCD patients manifested brief periods offust pursuit that moved their eyes ahead of the target that they were tracking. The occurrence of brief high velocity pursuit epochs raised the estimate of the average velocity of pursuit activity, and therefore the average gain score somewhat overestimates typical pursuit performance in OCD patients. The patients with OCD also demonstrated an increased rate of square wave jerk saccadic intrusions. No association between pursuit disturbance and acute symptoms of OCD was observed in this sample. While the absence of an association suggests that the oculomotor abnormality is not state-related (i.e., governed by current levels of OCD symptomatology), the variance in OCD symptom severity was somewhat restricted because all patients were seeking treatment for acute symptoms. Longitudinal studies are needed to resolve the relationship between oculomotor disturbances and the current severity of OCD symptoms. The observation of disturbances in pursuit eye movements in OCD is consistent with a growing body of literature indicating that disturbances of motor control are associated with this illness-for example, tics and neurologic soft signs (Hollander et
9 al., 1990). In their implications for the pathophysiology of OCD, the findings of disturbed eye movements in the present study indirectly support the model that disturbances in the basal ganglia and frontal cortex are associated with this neuropsychiatric illness. This inference is consistent with PET studies indicating altered metabolic activity in these brain areas (Baxter et al., 1987, 1988, 1989; Nordahl et al., 1989; Swedo et al., 19896). The low gain pursuit observed in this sample of OCD patients is a common eye movement abnormality that occurs in schizophrenia (Clementz and Sweeney, 1990) and in a range of degenerative neurological disorders. It also occurs more frequently with aging (Leigh and Zee, 1983). While not specific to OCD, these disturbances in pursuit gain and increased saccadic intrusions, because they can be quantified and studied noninvasively, may provide a useful approach for assessing the onset, progression, and responsiveness to treatment of disturbances of brain-behavior systems in OCD. The observation of epochs of high gain pursuit is rare in normal subjects and in patients with neurologic diseases where quantitative eye movement studies have been performed. The typical pursuit disturbance in a broad range of neuropsychiatric disorders is slow pursuit, with the degree of slowing reflecting the degree of pathology. Unilateral brain lesions can be associated with fast pursuit away from the side of the lesion (Leigh and Zee, 1983), but to our knowledge, bilateral fast pursuit (whether as continuous high velocity pursuit or as brief epochs of fast activity) has not previously been reported in any other psychiatric or neurologic disorder. The novelty and unexpected nature of this observation require both conservative interpretation and replication. However, some possible causes of this abnormality can be considered. One possibility is that the epochs of fast velocity pursuit result from a disturbance in the use of perceptual feedback to control pursuit movements. Feedback about tracking accuracy facilitates predictive control of pursuit movements, maintaining an effective match between eye and target velocity. The possibility of a disturbance in the use of perceptual feedback is suggested by the fact that such feedback would be expected to obviate any tendency for patients to move their eyes much faster and ahead of an object of regard. The etiology and pathophysiologic significance of oculomotor disturbances in OCD remain to be delineated. The metabolic disturbances in basal ganglia and frontal cortex reported in patients with OCD might disrupt oculomotor control systems and cause the pursuit dysfunction that we observed in patients with OCD. From a cognitive vantage point, pursuit disturbance can be caused by distractibility or a problem in sustaining focal attention. Although our patients were tested in a quiet, dark chamber to reduce external distraction, internal distractions such as the obsessive ruminations characteristic of OCD might have influenced pursuit performance. Distractibility or lapses in attention, however, probably did not account for fast pursuit epochs, because distraction typically reduces rather than increases pursuit gain (Kaufman and Abel, 1986). Further studies using different eye movement testing strategies are needed to replicate and extend our observation of eye movement abnormalities in OCD. One
10 recent effort along these lines was a study by Tien et al. (1991), which reported a difficulty in suppressing responses to peripheral targets on an antisaccade task in OCD. Another approach would be to correlate eye movement abnormalities with other clinical assessments including functional neuroimaging. Such studies could assess cerebral metabolic activity during performance of eye movement tasks, and thereby directly determine whether cerebral metabolic disturbances in the basal ganglia and frontal cortex are associated with distinctive disturbances in oculomotor control that may be associated with OCD. Acknowledgments. This work was supported in part by grant MH-42969 and BRSG RR 05396 to Dr. Sweeney, and a grant from the Ciba Geigy Corporation to Dr. Shear. Part of this work was presented at the 1990 Annual Meeting of the American Psychiatric Association.
References Abel, L.A., and Ziegler, A.S. Smooth pursuit eye movements in schizophrenics-What constitutes quantitative assessment? Biological Psychiatry, 241747-761, 1988. American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: APA, 1987. Baxter, L.R.; Phelps, M.E.; Mazziotta, J.C.; Guze, B.H.; Schwartz, J.M.; and Selin, C.E. Local cerebral glucose metabolic rates in obsessive-compulsive disorder-A comparison with rates in unipolar depression and normal controls. Archives of General Psychiatry, 44:21 l-218, 1987. Baxter, L.R.; Schwartz, J.M.; Mazziotta, J.C.; Phelps, M.E.; Pahl, J.J.; Guze, B.H.; and Fairbanks, L. Cerebral glucose metabolic rates in nondepressed patients with obsessivecompulsive disorder. American Journal of Psychiatry, 145: 1560-l 563, 1988. Baxter, L.R.; Schwartz, J.M.; Phelps, M.E.; Mazziotta, J.C.; Guze, B.H.; Selin, C.E.; Gerner, R.H.; and Sumida, R.M. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Archives of General Psychiatry, 46:243-250, 1989. Clementz, B.A., and Sweeney, J.A. Is eye movement dysfunction a biological marker for schizophrenia? A methodological review. Psychological Bulletin, 108:77-92, 1990. Gibson, J.M. Do the basal ganglia have a role in the control of eye movements? In: Kennard, C., and Rose, F.C., eds. Physiological Aspects of Clinical Nemo-Ophthalmology. Chicago: Yearbook Medical Publishers, Inc., 1988. Goodman, W.K.; Price, L.H.; Rasmussen, S.A.; Mazure, C.; Fleischmann, R.L.; Hill, C.L.; Heninger, G.R.; and Charney, D.S. The Yale-Brown Obsessive-Compulsive Scale: I. Development, use and reliability. Archives of General Psychiatry, 46: 1006-1011, 1989. Grimshaw, L. Obsessional disorder and neurologic illness. Journal of Neurology, Neurosurgery and Psychiatry, 271229-23 1, 1964. Hamilton, M. Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology, 6:278-296, 1967. Hollander, E.; Schiffman, E.; Cohen, B.; Rivera-Stein, M.A.; Rosen, W.; Gorman, J.M.; Fyer, A.J.; Papp, L.; and Liebowitz, M.R. Signs of central nervous system dysfunction in obsessive-compulsive disorder. Archives of General Psychiatry, 47127-32, 1990. Kaufman, S.R., and Abel, L.A. The effects of distraction on smooth pursuit in normal subjects. Acta Otolaryngologica, 10:57-64, 1986. Khanna, S. Obsessive-compulsive disorder: Is there a frontal lobe dysfunction? Biological Psychiatry, 24:602-613, 1988. Kuskowski, M. Eye movements in progressive cerebral neurological disease. In: Johnston, C., and Pirozzolo, F., eds. Neuropsychology of Eye Movements. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. Leigh, R.J., and Zee, D. The Neurology of Eye Movements. New York: F.A. Davis, 1983.
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Model, J.G.; Mountz, J.M.; Curtis, G.C.; and Greden, J.F. Nemophysiologic dysfunction in basal gangliallimbic striatal and thalamocortical circuits as a pathogenic mechanism of obsessive compulsive disorder. Journal of Neuropsychiatry, 1:27-36, 1989. Nordahl, T.E.; Benkelfat, C.; Semple, W.E.; Gross, M.; King, A.C.; and Cohen, R.M. Cerebral glucose metabolic rates in obsessive-compulsive disorder. Neuropsychopharmacology, 2:3-28, 1989. Pitman, R.E.; Green, R.C.; Jenike, M.A.; and Mesulam, M.M. Clinical comparison of Tourette’s disorder and obsessive-compulsive disorder. American Journal of Psychiatry, 144:1166-1171, 1987. Robins, L.N.; Helzer, J.I.; Weissman, M.M.; Orvaschel, H.; Gruenberg, E.; Burke, J.D.; and Regier, M.D. Lifetime prevalence of specific psychiatric disorders in three sites. Archives of General Psychiatry, 41:949-958, 1984. Siever, L.J.; Insel, T.R.; Hamilton, J.; Nurnberger, J.; Alterman, 1.; and Murphy, D. Eye-tracking, attention and amphetamine challenge. Journal of Psychiatric Research, 21: 129135, 1987. Swedo, S.E.; Rapoport, J.L.; and Cheslow, D.L. High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s Chorea. American Journal of Psychiatry, 146:246-249, 1989a. Swedo, S.E.; Schapiro, M.B.; Grady, C.L.; Cheslow, D.L.; Lenard, H.L.; Kumar, A.; Friedland, R.; Rapoport, S.I.; and Rapoport, J.L. Cerebral glucose metabolism in childhoodonset obsessive-compulsive disorder. Archives of General Psychiatry, 465 18-526, 1989b. Tien, A.Y.; Machlin, S.; Pearlson, G.; and Blysma, F. Oculomotor function in OCD. Presented at the Annual Meeting of the American Psychiatric Association, New Orleans, LA, May 1991. Yaryura-Tobias, J.A., and Neziroglu, F.A. Obsessive-Compulsive Disorder. New York: Marcel Dekker, 1983. p. 197.
I- 1I
Elsevier
Pursuit Eye Movement Compulsive Disorder
Dysfunction
John A. Sweeney, Donna R. Palumbo, M. Katherine Shear Received September 9, 1992.
in Obsessive-
James P. Halper, and
13, 1991; revised version received January
13, 1992; accepted
February
Abstract. Disturbances in neural circuitry including the basal ganglia and prefrontal cortex have been hypothesized to be a cause of obsessive-compulsive disorder (OCD). Because eye movements are often impaired in neurologic diseases affecting these brain areas, oculomotor functioning was assessed in 17 unmedicated patients with OCD and in 25 normal controls. As compared with control subjects, patients with OCD demonstrated low-gain (slow) pursuit eye movements and an increased frequency of square wave jerk intrusions, but no increase in anticipatory saccades. In addition, several OCD patients showed an unusual pattern of intrusive, brief epochs of high-gain (fast) pursuit lasting on the order of 50 to 130 msec. These epochs of fast pursuit moved the eyes ahead of the target being tracked, and were terminated by corrective reversal saccades. Studies of eye movement abnormalities may provide an informative neurophysiologic approach for studying disturbances in basal ganglia and frontal cortical function that have been observed in functional neuroimaging and neuropsychological studies of OCD. Key Words. compulsions,
Smooth pursuit eye tracking, basal ganglia, frontal cortex.
oculomotor
functioning,
obsessions,
Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and repetitive ritualistic behaviors that are distressing and debilitating for patients, and over which they have little control. The disorder is frequent in the population, with a lifetime prevalence of 2% to 3% (Robins et al., 1984). Neurobiological studies using a range of techniques are now being actively pursued in several laboratories to clarify the pathophysiology of OCD. One pathogenic model for OCD hypothesizes that abnormalities in basal gangliafrontal cortex interaction are involved in causing obsessive and compulsive symptoms (Baxter et al., 1987; Khanna, 1988; Model et al., 1989). Indirect support for this hypothesis comes from observations (Grimshaw, 1964; Pitman et al., 1987; Swedo et al., 1989~) of increased rates of obsessive and compulsive symptoms in
John A. Sweeney, Ph.D., is Assistant Professor of Psychiatry and Neurology at the University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh, PA. Donna R. Palumbo, Ph.D., is Fellow of Psychology in Psychiatry; James P. Halper, M.D., is Assistant Professor of Psychiatry, and M. Katherine Shear, M.D., is Associate Professor of Clinical Psychiatry at Cornell University Medical College, New York, NY. (Reprint requests to Dr. J.A. Sweeney, Laboratories of Neuropharmacology, Dept. of Psychiatry, WPIC, 381 I O’Hara St., Pittsburgh, PA 15213-2593, USA.) 0165-1781/92/S05.00
@ 1992 Elsevier Scientific Publishers Ireland Ltd.
2
neuropsychiatric disorders that result primarily from basal ganglia disease (e.g., Tourette’s syndrome, Sydenham’s chorea, Huntington’s disease, and postencephalitic parkinsonism). The fact that psychosurgical lesions of orbital frontal cortex and anterior cingulum can markedly reduce obsessive and compulsive symptoms (Yaryura-Tobias and Neziroglu, 1983) also implicates this brain area in OCD. More direct evidence comes from studies using positron emission tomography (PET) that have demonstrated increased metabolic rates in the head of the caudate and orbital prefrontal cortex (Baxter et al., 1987, 1988, 1989; Nordahl et al., 1989; Swedo et al., 1989b).
Assessment of oculomotor function is a potentially informative strategy for investigating basal ganglia/ frontal cortical impairment in OCD. Disorders of smooth pursuit and saccadic eye movements are well documented in neurologic diseases affecting the basal ganglia such as Parkinson’s, Wilson’s, and Huntington’s diseases (Leigh and Zee, 1983; Gibson, 1988; Kuskowski, 1988). In these and other neuropsychiatric disorders, the study of eye movements can provide valuable information relevant to the localization, severity, and progression of disease processes. Oculomotor functioning in OCD has not been well characterized. One previous study assessed pursuit tracking in OCD (Siever et al., 1987); however, the purpose of that study was to investigate the effects of amphetamine challenge on pursuit. Patient and clinical group comparisons, and quantitative studies of the pursuit system, were not reported. Tien et al. (1991) recently presented evidence indicating an increased rate of errors on an oculomotor antisaccade task in OCD, suggesting a prefrontally mediated disturbance in response suppression. The aim of the present study was to determine whether a disturbance in the smooth pursuit eye movement system could be identified in nondepressed unmedicated patients with OCD. Methods Subjects. Seventeen outpatients who met DSWZZZ-R criteria (American Psychiatric Association, 1987) for OCD were recruited from the Anxiety Disorders Clinic at the Payne Whitney Clinic of New York Hospital. The average age of onset of OCD was 17.6 (SD = 8.2) and 53% of patients had an onset before the age of 18. The average duration of OCD was 16.0 years (SD = 9.1). All patients had a score > 14 on the Yale-Brown Obsessive-Compulsive Scale (YBOCS; Goodman et al., 1989), and none met DSM-III-R criteria for concurrent major depression. Patients with OCD had no history of psychotic symptoms, no known systemic or neurologic illness by history and physical examination, no prior treatment with electroconvulsive therapy, and no history of head trauma, substance dependence, or substance use in the 2 months before testing. OCD patients had received no psychotropic medication for at least 4 weeks before eye movement testing. Patients were rated by clinicians on the YBOCS and the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967) within 1 hour before eye movement testing. The average total YBOCS score was 12.9 (SD = 3.1) for obsessive symptoms and 14.0 (SD = 2.7) for compulsive symptoms. Their average HRSD score was 10.1 (SD = 4.3). Twenty-five control subjects were recruited from the hospital community. They did not differ significantly from the OCD patients in age (F= 1.82; df = 1,40; NS) or in sex ratio (~2 = 0.20, df= 1, NS). All subjects were between 18 and 50 years of age (see Table 1) and had not previously participated in eye movement studies.
3
Table 1. Demographic obsessive-compulsive
data and eye movement measures in patients disorder (OCD) and normal controls
Demographic data
OCD
Control
(n = 17)
(n = 25)
33.6
31.3
6.4
4.5
22-44
24-46
1215
1619
with
Significance
Age(yr) Mean SD Range Sex Imale/female\
Eye movement measures Pursuit gain
t=1.35,df=40,NS
x2=0.20.df=1.NS
OCD
Control
(n = 17)
(n = 25)
Mean
SD
Mean
SD
Significance
0.83
0.08
0.90
0.08
t = 2.86, df = 40, f~ < 0.007
Saccadic measures (per min) I Reversal # Square
saccades
7.3
6.6
3.1
3.0
wave jerks
7.5
3.7
5.1
4.7
1.4
2.6
2.0
3.7
78.9
22.6
66.6
19.7
# Anticipatory # Catch-up
saccades saccades
,$=7.91,df=l,p 6OO’/sec*. Those periods identified as saccades, as well as the 12 msec (3 samples) before and after the periods identified as saccades, were excluded from pursuit gain calculations to limit any influence that saccade-related velocity changes might have on pursuit-gain calculations. Recordings were manually edited for blinks, pauses after anticipatory saccades, and rare periods of gross inattention to the task. Pursuit of the first and last target oscillations was excluded, yielding a maximum of 6250 samples of pursuit (25 set of pursuit sampled at 250 Hz) for quantitative analysis. Average pursuit gain was calculated by dividing the average sample-to-sample velocity of pursuit eye movement activity by the target velocity. Constant velocity triangular waveform targets reverse direction abruptly at the endpoint of target excursion. Therefore, the eyes need to slow and reverse direction. This slow pursuit reduces average pursuit velocity, making average gain an underestimate of the capacity of the pursuit system to match the velocity of a steadily moving target. For this reason, pursuit slower than 20% of target velocity at the point of target reversal was excluded from pursuit gain calculations. Saccadic eye movements. An evaluation of saccadic eye movements during pursuit provides further information about pursuit performance. Saccades during pursuit are either corrective or intrusive in nature. Corrective saccades are typically forward-going movements that compensate for the eyes lagging behind the target; however, when fast pursuit takes the eyes ahead of the target, corrective reversal or backwardsaccades take the eyes in the opposite direction from target movement to refoveate the target. Intrusive saccades disrupt tracking by shifting the focus of the eyes away from the target. The most common intrusive saccades are called square wave jerks. During pursuit, square wave jerks begin with an intrusive saccade that typically diverts the eyes I”-3” of visual angle away from the target. The eyes remain displaced from the target for up to 400 msec, during which time pursuit continues until a corrective saccade refoveates the target (Abel and Ziegler, 1988). Another form of intrusive saccade that disrupts visual tracking is anticipatory saccades, wherein a saccade moves the eyes ahead of the target, after which pursuit velocity is immediately and markedly reduced as if the eyes move suddenly to where the target is expected and then wait for it there. The frequencies of anticipatory saccades and square wave jerks, and the number and average size of corrective saccades, were tabulated during the two 30-second trials that required pursuit of targets moving at a sinusoidal velocity. The total number of the different types of saccades that occurred during the two trials was obtained, and corrective saccade size was averaged across the two trials. During pursuit of the constant velocity target, the demand for abrupt reversal in pursuit direction at the end points of target excursion can elicit corrective saccades that are difficult to differentiate reliably from square wave jerks and anticipatory saccades, so intrusive saccades were not tabulated during that task. Reversal saccade frequency was also calculated during pursuit of the sinusoidal velocity targets. In addition, so that the frequency of reversal saccades could be directly studied in relation to pursuit gain during the same pursuit tracking interval, the frequency of reversal saccades was calculated during the constant velocity trial from which gain was computed. Studies in our laboratory with 100 consecutively studied psychiatric inpatients indicated that classifications of all types of saccades were made with reliability > 0.80. Data Analysis. Distributions of saccadic eye movement measures were skewed, particularly anticipatory saccades and square wave jerks. Therefore, the Kruskal-Wallis nonparametric group comparison procedure, with a x* statistic, was used to compare OCD patients and controls on all measures of saccadic frequency. For the same reason, Spearman’s rank-order correlations (p) were computed to assess associations of eye movement measures with clinical and demographic variables.
5
Results Patients with OCD had significantly reduced spursuit gain (t = 2.86, df = 40, p < 0.007; see Fig. 1 and Table 1). Fig. 2 presents the percentage of the full distribution of pursuit velocities maintained during pursuit of the constant velocity waveform for OCD and control subjects. The percentage of pursuit activity was tabulated in bins increasing in steps of 0.1 units of pursuit gain for each subject, and then averaged across subjects to provide an aggregate estimate for each subject group. Fig. 2 indicates that normal subjects have more pursuit activity close to target velocity, while OCD patients have both more slow and fast activity than healthy control subjects. It also illustrates the moderate reduction of gain in OCD patients.
Fig. 1. Average pursuit gain during visual tracking of a constant velocity target in patients with OCD and in normal controls.
w
E
. r*
** .a75
.*.t.
3
B PI
.
*t
f
5 .625
$-
...... + l
.15-
8
3
* 0
l
.*.t. .
.
I-
CONTROL tN=ZS)
OCD (N=17)
The target oscillated f IO’ at 16°1sec for 30 sec. OCD = obsessive-compulsive disorder.
Patients with OCD also had more frequent square wave jerk intrusions (x2 = 5.20, df = 1, p < 0.03). There was no increase in the frequency of anticipatory saccades (x2 = 0.15, df = 1, NS). Patients with OCD demonstrated more frequent reversal saccades during pursuit of targets moving at a sinusoidal velocity (x2 = 7.80, df = 1, p < O.OOS), and there was a similar trend during pursuit of the constant velocity target (~2 = 3.64, df = 1, p < 0.06). There was a trend for OCD patients to show more frequent catch-up saccades (t = 1.83, df = 40, p < 0.08). The between-group difference in mean catch-up saccade size was not significant. Fifty-nine percent of OCD patients had a reversal saccade frequency (during pursuit of targets with sinusoidal velocity) > 1 per 10 seconds, as opposed to 16% of controls (~2 = 8.35, df = 1, p < 0.004). To provide a preliminary description of rates of “abnormality” on the different eye movement measures, the percentage of patients with values more deviant than 95% of control cases was calculated. The findings were as follows: 35% of patients had abnormal gain and reversal saccade frequency,
6 Fig. 2. Distribution of point-by-point pursuit gain, averaged across subjects, for patients with OCD and normal controls
0.0
0.S
Point-to-Point
1.0
Gain of Pursuit Eye
15
20
YoYemsnt
Normal controls showed significantly (p < 0.05) more pursuit activity with gain between 0.90 and 1.O,and between 1.O and 1.I. Obsessive-compulsive disorder (OCD) patients showed significantly more pursuit activity with gain between 0.4 to 050.5 to 0.6 and 0.6 to0.7, and between 1.5 to 1.6,1.6 to 1.7, and 1.6 to 1.9.
and 29% had more frequent square wave jerks. Review of Fig. 1, which presents pursuit-gain scores, suggests that there may have been two outliers in the control group (29- and 3%year-old women) and one in the OCD group (a 37-year-old woman). The increased frequency of reversal saccades in OCD patients was unexpected. Reversal saccades compensate for fast pursuit, and it was expected that OCD patients would show slow pursuit. Visual inspection of pursuit records (see Figs. 3 and 4) in OCD patients indicated that many reversal saccades occurred after brief epochs of high velocity pursuit (approximately 1.5 to 2.0 times the target velocity) during which pursuit advanced ahead of the actual target location. Some saccades in the opposite direction from target motion can occur after predictive errors about target position (particularly around the point of reversal in pursuit of constant velocity oscillating targets), but these are not preceded by atypically high pursuit velocity. The duration of epochs of fast pursuit in the OCD patients was on the order of 50-130 msec. Pursuit velocity after these epochs returned to subjects’ typical velocity immediately after the corrective reversal saccade. We examined the relationship between average pursuit gain and reversal saccade frequency to determine whether a higher average pursuit gain was positively associated with the frequency of reversal saccades. Positive correlations were observed between pursuit gain and reversal saccade frequency during pursuit of targets with sinusoidal (p = 0.63, p < 0.007) and constant (p = 0.55, p < 0.03) velocity. The correlations were somewhat lower (p = 0.31, NS, and p = 0.47, p < 0.02, respectively) in the control group. These positive correlations indicate that reversal saccade frequency increases as a function of pursuit gain in OCD patients. This association is consistent with the interpretation that the reversal saccades were a compensation for fast pursuit rather than an independent abnormality of saccadic
7 disinhibition, and that the epochs of fast pursuit were not an atypical compensation for low gain pursuit (see Figs. 3 and 4). In contrast to these positive correlations, the Fig. 3. Examples of eye movement recordings from an OCD patient (including several reversal saccades) and a normal control during pursuit of a constant velocity target
The target oscillated across the central visual field (k loo) in the horizontal plane at 160/set. compulsive disorder.
OCD = obsessive-
Fig. 4. Example of eye movement recording from an OCD patient showing 2 epochs of high velocity pursuit (approximately 2 times target velocity) followed by corrective reversal saccades 275 m.wc.
I ?
pint of revcrsaf in dfmctiorl of rarga movement (at -10 dcgca)
Note that the duration of fast pursuit segments is < 130 msec, and that pursuit velocity after these segments returns to the typical velocity immediatety after the reversal saccades. OCD = obsessive-compulsive disorder.
8 association between gain and catch-up saccades was in the opposite direction (p = -0.43, p < 0.10) for patients and was nonsignificant for control subjects. Analyses for laterality effects (leftward vs. rightward eye movement) were conducted for each eye movement measure using the Wilcoxon Matched-Pairs test. There were no significant lateral asymmetries in the direction of reversal or anticipatory saccades, square wave jerks, or pursuit gain, either for OCD patients or normal controls. Correlational analyses revealed few significant associations between eye movement measures and clinical data from the OCD patients. There was a trend for severity of depression (HRSD scores) to be inversely associated with pursuit gain in the OCD patients (p = -0.44, p < 0.09). Although there were no group differences in anticipatory saccades, the frequency of these intrusive saccades was related to later onset (p = 0.51, p < 0.04) and briefer duration of illness (p = -0.54, p < 0.03) in OCD cases. Female patients with OCD had lower gain than male patients (t = 2.25, df = 15, p < 0.05) and more frequent anticipatory saccades (t = 2.86, df= 15, p < 0.05). However, there were only five female OCD patients, so these gender differences need to be interpreted with considerable caution. Age was not correlated with pursuit gain (p = -0.11, NS) or other eye movement measures in OCD patients, which probably reflected in large part the narrow age range of the sample. In the control group, there were trends for females to show more reversal saccades (t = 1.96, df = 23, p < 0.08) and for age to be related to lower pursuit gain (p = -0.39, p < 0.06).
Discussion The findings of this study provide the first demonstration of impaired pursuit eye movements in OCD patients. Unmedicated OCD patients demonstrated low gain (slow) pursuit. The reduction in pursuit gain was of a moderate severity (from 0.90 in controls to 0.83 in OCD patients). However, this difference in average pursuit velocity may somewhat underestimate the actual degree of disturbance of closedloop gain in OCD. Some OCD patients manifested brief periods offust pursuit that moved their eyes ahead of the target that they were tracking. The occurrence of brief high velocity pursuit epochs raised the estimate of the average velocity of pursuit activity, and therefore the average gain score somewhat overestimates typical pursuit performance in OCD patients. The patients with OCD also demonstrated an increased rate of square wave jerk saccadic intrusions. No association between pursuit disturbance and acute symptoms of OCD was observed in this sample. While the absence of an association suggests that the oculomotor abnormality is not state-related (i.e., governed by current levels of OCD symptomatology), the variance in OCD symptom severity was somewhat restricted because all patients were seeking treatment for acute symptoms. Longitudinal studies are needed to resolve the relationship between oculomotor disturbances and the current severity of OCD symptoms. The observation of disturbances in pursuit eye movements in OCD is consistent with a growing body of literature indicating that disturbances of motor control are associated with this illness-for example, tics and neurologic soft signs (Hollander et
9 al., 1990). In their implications for the pathophysiology of OCD, the findings of disturbed eye movements in the present study indirectly support the model that disturbances in the basal ganglia and frontal cortex are associated with this neuropsychiatric illness. This inference is consistent with PET studies indicating altered metabolic activity in these brain areas (Baxter et al., 1987, 1988, 1989; Nordahl et al., 1989; Swedo et al., 19896). The low gain pursuit observed in this sample of OCD patients is a common eye movement abnormality that occurs in schizophrenia (Clementz and Sweeney, 1990) and in a range of degenerative neurological disorders. It also occurs more frequently with aging (Leigh and Zee, 1983). While not specific to OCD, these disturbances in pursuit gain and increased saccadic intrusions, because they can be quantified and studied noninvasively, may provide a useful approach for assessing the onset, progression, and responsiveness to treatment of disturbances of brain-behavior systems in OCD. The observation of epochs of high gain pursuit is rare in normal subjects and in patients with neurologic diseases where quantitative eye movement studies have been performed. The typical pursuit disturbance in a broad range of neuropsychiatric disorders is slow pursuit, with the degree of slowing reflecting the degree of pathology. Unilateral brain lesions can be associated with fast pursuit away from the side of the lesion (Leigh and Zee, 1983), but to our knowledge, bilateral fast pursuit (whether as continuous high velocity pursuit or as brief epochs of fast activity) has not previously been reported in any other psychiatric or neurologic disorder. The novelty and unexpected nature of this observation require both conservative interpretation and replication. However, some possible causes of this abnormality can be considered. One possibility is that the epochs of fast velocity pursuit result from a disturbance in the use of perceptual feedback to control pursuit movements. Feedback about tracking accuracy facilitates predictive control of pursuit movements, maintaining an effective match between eye and target velocity. The possibility of a disturbance in the use of perceptual feedback is suggested by the fact that such feedback would be expected to obviate any tendency for patients to move their eyes much faster and ahead of an object of regard. The etiology and pathophysiologic significance of oculomotor disturbances in OCD remain to be delineated. The metabolic disturbances in basal ganglia and frontal cortex reported in patients with OCD might disrupt oculomotor control systems and cause the pursuit dysfunction that we observed in patients with OCD. From a cognitive vantage point, pursuit disturbance can be caused by distractibility or a problem in sustaining focal attention. Although our patients were tested in a quiet, dark chamber to reduce external distraction, internal distractions such as the obsessive ruminations characteristic of OCD might have influenced pursuit performance. Distractibility or lapses in attention, however, probably did not account for fast pursuit epochs, because distraction typically reduces rather than increases pursuit gain (Kaufman and Abel, 1986). Further studies using different eye movement testing strategies are needed to replicate and extend our observation of eye movement abnormalities in OCD. One
10 recent effort along these lines was a study by Tien et al. (1991), which reported a difficulty in suppressing responses to peripheral targets on an antisaccade task in OCD. Another approach would be to correlate eye movement abnormalities with other clinical assessments including functional neuroimaging. Such studies could assess cerebral metabolic activity during performance of eye movement tasks, and thereby directly determine whether cerebral metabolic disturbances in the basal ganglia and frontal cortex are associated with distinctive disturbances in oculomotor control that may be associated with OCD. Acknowledgments. This work was supported in part by grant MH-42969 and BRSG RR 05396 to Dr. Sweeney, and a grant from the Ciba Geigy Corporation to Dr. Shear. Part of this work was presented at the 1990 Annual Meeting of the American Psychiatric Association.
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Model, J.G.; Mountz, J.M.; Curtis, G.C.; and Greden, J.F. Nemophysiologic dysfunction in basal gangliallimbic striatal and thalamocortical circuits as a pathogenic mechanism of obsessive compulsive disorder. Journal of Neuropsychiatry, 1:27-36, 1989. Nordahl, T.E.; Benkelfat, C.; Semple, W.E.; Gross, M.; King, A.C.; and Cohen, R.M. Cerebral glucose metabolic rates in obsessive-compulsive disorder. Neuropsychopharmacology, 2:3-28, 1989. Pitman, R.E.; Green, R.C.; Jenike, M.A.; and Mesulam, M.M. Clinical comparison of Tourette’s disorder and obsessive-compulsive disorder. American Journal of Psychiatry, 144:1166-1171, 1987. Robins, L.N.; Helzer, J.I.; Weissman, M.M.; Orvaschel, H.; Gruenberg, E.; Burke, J.D.; and Regier, M.D. Lifetime prevalence of specific psychiatric disorders in three sites. Archives of General Psychiatry, 41:949-958, 1984. Siever, L.J.; Insel, T.R.; Hamilton, J.; Nurnberger, J.; Alterman, 1.; and Murphy, D. Eye-tracking, attention and amphetamine challenge. Journal of Psychiatric Research, 21: 129135, 1987. Swedo, S.E.; Rapoport, J.L.; and Cheslow, D.L. High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s Chorea. American Journal of Psychiatry, 146:246-249, 1989a. Swedo, S.E.; Schapiro, M.B.; Grady, C.L.; Cheslow, D.L.; Lenard, H.L.; Kumar, A.; Friedland, R.; Rapoport, S.I.; and Rapoport, J.L. Cerebral glucose metabolism in childhoodonset obsessive-compulsive disorder. Archives of General Psychiatry, 465 18-526, 1989b. Tien, A.Y.; Machlin, S.; Pearlson, G.; and Blysma, F. Oculomotor function in OCD. Presented at the Annual Meeting of the American Psychiatric Association, New Orleans, LA, May 1991. Yaryura-Tobias, J.A., and Neziroglu, F.A. Obsessive-Compulsive Disorder. New York: Marcel Dekker, 1983. p. 197.
