J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

Journal ofNeurology, Neurosurgery, andPsychiatry, 1978, 41, 1024-1030

Disturbances of ocular movements and blinking in

JANICE R. STEVENS From the Departments of Neurology and Psychiatry, University of Oregon Health Sciences Center, Portland, Oregon, USA

S U M M A R Y Neurological examination and electroencephalograms and electro-oculograms, recorded by telemetry, from unmedicated patients with acute and chronic schizophrenia demonstrate a number of abnormalities of extraocular movement including staring, abnormai blink rate, absent glabellar , and increase in horizontal movements. As potential clues to the pathophysiology of schizophrenia, these disturbances are analysed in relation to anatomical substrate and dopamine modulation of ocular movement, rapid eye movement sleep, and the neurological disorders in which similar disturbances of ocular movement occur. by guest. Protected copyright.

In distinguishing dementia praecox from other consciousness; delusions, hallucinations, or formal forms of mental illness, Kraepelin (1913) called thought disorder; restricted affect; absence of signs attention to a number of ocular signs of the dis- and symptoms sufficient to make a diagnosis of order, including pupillary abnormalities, staring, affective illness or coarse brain disease. In ad- nystagmus, abnormal blinking, and blepharospasm. dition to the neurological examination, 36 of the Widespread use of neuroleptic medications has 55 medication-free patients and 12 normal control now induced a variety of neurological side effects subjects have had 2-24 hour electroencephalo- and sequelae which obscure the incidence of these grams (EEG) and electro-oculograms (EOG) signs and their relevance to the pathology of the recorded by radiotelemetry during which spontane- . Because these ocular signs may ous behaviour was recorded continuously by a provide clues to the pathology of the schizophrenia trained observer. Bipolar EEGs were recorded syndrome, it seemed worth while to document from tin or gold disc electrodes attached to the them carefully in medication-free patients. scalp with collodion at central-parietal (C3-P3; C4-P4) and temporal (T3-T5; T4-T6) positions Subjects and methods bilaterally. Lateral eye movement was recorded between electrodes placed at the outer canthus of Complete neurological examinations have been each eye. Vertical movements and blinks were performed on 45 patients who were free from recorded between electrodes placed immediately medication for periods of one month to four years, above and below one eye. Subjects wore a small

and 10 patients who had never received drugs or multiplexed 8-channel transmitter (weight 90 g, http://jnnp.bmj.com/ other physical treatment. Nine patients were seen Benton Instrument Company) held firmly to the within a year of diagnosis, 14 had been diagnosed head by a special cap. between one and five years, and the remaining 29 During the recording period, patients were in patients, longer than five years. The youngest their rooms or the dayroom within a radius of 40- patient was 17 years of age, the oldest, 49 years. 50 yards of the receiver antenna. They slept in their Thirty-one were men, 24 were women. own beds, and carried on their usual hospital The diagnosis was made by senior staff con- routine. Electroencephalographic and EOG signals

sensus and required the following five of the seven were recorded on a 7-channel FM tape recorder on September 30, 2021 criteria stipulated by Taylor and Abrams (1975): monitored by an ink-writing polygraph. Receiving illness duration greater than six monrths; clear and recording devices were centrally placed in a hallway near the ward dayroom. The polygraph Supported by National Institutes of Health Grant 18055. run at a of 15 mm second and Address for reprint requests: Department of Psychiatry, University of was speed per Oregon Health Sciences Center, Portland, Oregon 97201, USA. could be correlated continuously with ongoing Accepted 23 June 1978 behaviour and accelerated to 30 mm per second for )24 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

Disturbances of ocular inovemenits and blinking in schizophrenia 1025 more detailed examination during periods of A 17 year old boy avoided eye contact because unusual behaviour. Frequency modulated tape was "I'm afraid you'll read my thoughts." EEG accompanied recorded at 17 inches per second, and portions of No change in simultaneous these clinical events. the taped record were played back during be- havioural events of particular interest and for ALTERED BLINK RATE subsequent analysis. Behavioural observations Although both Kraepelin (1913) and Bleuler (1950) were recorded by a trained observer on a written remarked upon increased blinking in dementia log and were coded by number at the moment of praecox, quantitative studies of blinking in this occurrence on a time code placed on one channel illness are lacking. Abnormalities of blinking in of the tape recorder and polygraph, assuring exact this group of unmedicated schizophrenic patients correlation between EEG-EOG recording and fell into three categories: (1) decreased blinking, behavioural events. staring, and absent eye contact, most commonly seen in acute exacerbations of the disorder; (2) Results steady increase in blinking at rest in patients with chronic schizophrenia; (3) episodic paroxysms of Neurological examination of this group of patients rapid rhythmical blinking associated with demonstrated that, apart from the characteristic hallucinations, sudden impulsive acts, or deluded abnormalities of mental state and skeletal motor speech. activity (stereotyped behaviours, rocking, bizarre Sixteen patients demonstrated episodes of postures), the most common signs were dis- rhythmic or paroxysmal blinking at rates up to turbances of ocular contact and movement. These 2.5-3 per second, and seven patients, four of whom by guest. Protected copyright. included staring, abnormal blinking, saccades, and had never received neuroleptic treatment, dis- ocular pursuit. Prolonged telemetered EEG-EOG played absent or decreased blinking (0-1 per confirmed the clinical evidence of abnormal ocular minute). movements. Although slow or sharp activity ap- Eight patients showed abrupt change in blink peared over the left or right temporal region of rate during delusional excitement, while speaking one-third of these patients, these abnormalities in response to hallucinated voices, or during could not be associated with the clinical changes autistic reveries. nor with the appearance of abnormal ocular A 26 year old former college student, in hospital activity. In contrast, the oculomotor changes were for nine years with an unrelenting dementia frequently correlated with abnormalities of praecox, sat indolently in the dayroom of the perception and attention. hospital blinking steadily two and a half times per second. He reported that he was in a "waking ABNORMALITIES OF EYE CONTACT nightmare" of frightening sexual experiences A fixed penetrating stare directed into the (Fig. 1). A patient with acute catatonia who was studied examiner's , at a distant point, or avoidance before all treatment blinked only two to three and failure of eye contact were noted in 34 times per minute during the day, but exhibited patients. These signs were equally common in 2-10 second epochs of rhythmic blinking two and acutely and chronically ill individuals, and usually a half to three times per second associated with a responded promptly to neuroleptic treatment in posture of supplication or deep sighing respiration patients with acute psychosis. Interrogation of the at intervals during a sleepless night (Fig. 2). patient rarely provided a clear explanation for http://jnnp.bmj.com/ staring or diversion of gaze. A few individuals ABNORMAL BLINK (GLABELLAR) REFLEX indicated that staring or avoidance of eye contact In response to gentle taps of the glabella repeated was a response to perceptual change as indicated at one second intervals, most normal adults by the following examples: respond by single blinks to the first two to five taps, A 21 year old man with chronic paranoid schizo- then stop blinking unless stimulation is discon- phrenia, who stared fixedly at the examiner, tinued for 10-20 seconds, after which the response explained "your face is turning into an animal." returns and again habituates after repetition The mother of a 20 year old schizophrenic girl (Overend, 1896). Twelve of the 50 patients in this on September 30, 2021 reported: "when I go to the hairdresser I tell her study had no response to glabellar tap, six failed I'll be right back. When I come back an hour to habituate the reflex after 10 or more taps, and later and walk in she just stares at me like I'm a new person to her. At other times she stares at 14 patients displayed paroxysmal bursts of rapid her father like a stranger and shouts 'Get him out blinking to each tap on repetition. Absent blink of here, he's doing things to me. Who is he? Get reflex was most common in patients with acute him out!'" exacerbation of psychosis, while persistent or J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

1026 Janice R. Stevens

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j 2' 1. 4:02 pm Dozing No clinical sign 6 43 pm Eyes closed "My problem is think I'm not born. It's like a woking nightmare. Fig. 1 EEG-EOG by radiotelemetry in a 26 year old man shows steady rhythmic blinking which almost obliterates EEG on the top two panels. Note brief "spike" discharge at 4:02 pm from right parieto-occipital region while patient is dozing. No clinical signs detected. EEG shows asymmetrical temporal function with theta activity on the left, high voltage alpha spindles on the right as patient lies quietly with fluttering in a "waking nightmare." paroxysmal response was more characteristic of and looking in all directions for the source of chronic or less florid psychoses in patients with- auditory or visual stimuli imperceptible to the drawn from neuroleptics. Six of the 10 patients observer. Characteristically this was accompanied who had received no previous treatment had no by speech arrest or drivelling. In contrast to blink reflex to glabellar tap. Return and per- psychomotor seizures, which such ocular auto- sistence of the glabellar reflex was one of the matisms may resemble, the darting eye movements http://jnnp.bmj.com/ earliest effects of neuroleptic drug treatment in of the psychosis usually can be readily, if briefly, these patients. interrupted by speaking to or touching the patient. Although the patient can thus be made aware of LATERAL EYE MOVEMENTS the activity, an explanation is rarely forthcoming Abnormalities of three types were recorded: (1) (Fig. 2). rapid, irregular, searching movements; (2) spon- Seven patients, including three without previous taneous, rhythmic, horizontal saccades; (3) single, treatment, displayed episodes of sustained hori- sustained, lateral glances. zontal lateral oscillations of the eyes at rates of one on September 30, 2021 Darting, rapid, irregular searching movements to two per second lasting for 10-20 seconds. These were exhibited by 12 patients, and were observed rhythmic ocular movements resembled nystagmus most commonly during acute exacerbations of the in amplitude of excursion and return of eyes to illness or before all treatment. During such be- midposition after each lateral movement. Rarely haviour, patients appeared to be hypervigilant observed during conventional neurological ex- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

Disturbances of ocular movements and blinking in schizophrenia 1027

Acute catatonic, 21 year old a 12/30/76 Lights out, searching with eyes C3-P3

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C4 P4 --*_ T4 - T6 Fig. 2 Telemetered EEG-EOG Lat. eye .', .- > ,- , w , < from a 21 year old man with acute catatonia for three days Vert eye -* - with no previous treatment. Top: EEG is unremarkable in Stood up, darting loterol glonces sj50 uY dark room at night. Blinking occurs in showers accompanied by lateral eye movements. Middle: 11 am, lighted room. Patient is mute, statuesque, appears frightened. There are rapid, darting, searching, horizontal eye movements. 11 e, u le respon Bottom: midnight in lighted by guest. Protected copyright. room. Patient is unable to sleep or respond, and is blinking rhythmically and rapidly. EEG Mute, unoble to respond shows only low voltage fast activity.

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amination, spontaneous horizontal oscillations head remained flexed on the neck several inches usually occurred during autistic reveries or psycho- above the mattress ("psychological pillow"), and motor blocking. These episodes usually lasted for lateral eye movements continued for several hours less than 10 seconds, and continued for 30-60 until sleep supervened. in seconds severely disturbed patients, particularly http://jnnp.bmj.com/ those with intense delusory and hallucinatory IRREGULAR OCULAR PURSUIT experiences (Fig. 3). Using simple bedside examination of extraocular Unexplained single sustained lateral glances in- muscle function in which the patient was asked to terrupted the speech or attention of 14 patients, fix his eyes on the examiner's moving finger, flash- and, in their most extreme form, constituted a light, or the movement of his own finger, 24 continuous stereotyped automatism in two patients patients demonstrated one or more abrupt arrests with far advanced schizophrenia. or coarse saccades during each trajectory of A 37 year old man in hospital for nearly 20 horizontal ocular movement. Four patients, all on September 30, 2021 years after adolescent onset of schizophrenia stood with severe chronic were by the hour against the wall in the hospital day- schizophrenia, entirely room repeatedly turning his eyes from side to side unable to follow the moving object with the eyes, as though following a tennis match. Meanwhile he and two patients with previously untreated acute twisted his hands together steadily, flicking his schizophrenia repeatedly lost ocular contact with fingers, making signs to himself, smiling and the moving object as their eyes returned from laughing vacuously. On reclining at bedtime his pursuit to staring at the examiner's face. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

1028 Janice R. Stevens

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v.J..Qft. Masturbation contmninuc I;tnnc 6/3 9:34 pm Quiet, staring Muttering to sef Fig. 3 EEG-EOG recorded by telemetry from a 22 year old man demonstrates rhythmic I cps lateral saccades associated with spindled alpha activity during autistic reverie. Discussion The centres responsible for initiation and modulation of spontaneous blinking are poorly SPONTANEOUS BLINKING: CLINICAL AND defined. Van Buren (1963) reported rapid bursts EXPERIMENTAL STUDIES of blinking after stimulation of the caudate In contrast to normal control subjects, whose nucleus in man. Nashold (1969, 1970) elicited eye blink rates varied from 8-22 per minute (Zametkin closure and rhythmic lid flutter in response to et al., 1978), 17 patients in this series had resting stimulation ventral to the superior colliculus and blink rates in excess of 60 per minute. Sustained central grey matter, a region from which sensa- high blink rates were more common in patients tions of burning chest pain and intense emotional with previously treated chronic schizophrenia, reactions were also elicited. while blink rates of less than five per minute were found in five of six patients with catatonic schizo- LATERAL SACCADES AND GLANCES

phrenia. There are many studies of reflex blinking The darting glances displayed by these patients http://jnnp.bmj.com/ and the glabellar reflex in the literature, but very are strikingly similar to the ocular searching move- few address the clinical significance of spontaneous ments termed "checking" displayed by cats and blinking. Ponder and Kennedy (1928), in one of monkeys in strange environments, when intensely the few published studies of quantitative blink rate frightened, or after administration of amphetamine in man, noted that the rate of blinking tends to be and cocaine (Ellinwood, 1974). Sato (1977) remarkably constant in a given individual, and re- described visual searching movements after mains essentially unchanged by darkness, tempera- stimulation in the nucleus accumbens in cats. anaesthesia of or Similar movements are in ture, humidity, the , reported encephalitis, on September 30, 2021 deafferentation of the fifth cranial nerve. Observ- alcoholic encephalopathy, pretectal lesions, and ing that one of the earliest features of postence- temporal lobe seizures (Mayanagi and Walker, phalitic Parkinsonism was the almost complete 1974; Escueta et al., 1977). Shimazano et al. (1965) absence of blinking, Ponder and Kennedy proposed noted that, in contrast to normal subjects who that normal blinking depends on the integrity of characteristically increase horizontal saccades in the basal ganglia. response to external stimuli, patients with schizo- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

Disturbances of ocular movements and blinking in schizophrenia 1029 phrenia decrease or arrest rapid horizontal eye schizophrenia, and the auras and automatisms of movements in response to the same stimuli. These psychomotor epilepsy suggest that schizophrenia, investigators proposed that the increased horizontal like psychomotor epilepsy, is associated with ab- eye movements of schizophrenia, which they normal function in the limbic system (Stevens, termed "waking REM," do not simply reflect 1973). The dopamine innervation of the limbic arousal but represent a mechanism closely related system derives principally from the most medial to the psychotic state. units of the pars compacta of the substantia nigra We observed similar ocular movements after (SN), and from the ventral tegmental area (VTA, stimulation of the mesolimbic dopaminergic path- A10), located just medial and rostral to SN. From way in cats and in response to apomorphine and VTA, axons of the dopaminergic neurones of the other dopaminergic agents (Stevens et al., 1974; mesolimbic system ascend to the nucleus accum- Stevens and Livermore, 1978). These stereotyped bens, olfactory tubercle, nucleus of stria terminalis, responses were abolished by neuroleptic agents or diagonal band, lateral septum, and the central by elimination of visual stimuli, suggesting that nucleus of the amygdala (Ungerstedt, 1971). Ab- the ocular movements represent dopamine- normal electrical activity has been reported from mediated automatisms elicited by visual stimuli these regions in schizophrenic patients by Heath (Stevens et al., 1977). (1954), Hanley et al. (1970), and others. In keep- Wallach and Wallach (1964) described episodic ing with a more medial position in the forebrain, rapid regular horizontal oscillations of the eyes at the nucleus accumbens projects to more axial rates of 60-100 per minute in children and adults structures of the diencephalon and mesencephalon with severe forms of schizophrenia. Regularly than the caudate nucleus, including the para- by guest. Protected copyright. associated with severe thought disturbance, pre- median pontine reticular formation and tectum occupation with endogenous percepts, and a sense (Domesick et al., 1976), regions closely associated of personal dissolution, rhythmic lateral saccades with regulation of extraocular movement, arousal in their patients were also abolished by fixation of and attention. attention and by remission of the illness. Recur- Species specific stereotyped exploratory be- rence of rhythmic saccades coincided with haviours released by dopaminergic agents, consist- deterioration or recurrence of psychosis. ing of sniffing, licking, and chewing in rodents, depend on the integrity of the neostriatum OCULAR PURSUIT (Randrup and Munkvad, 1967), while increased First described and illustrated graphically in exploratory activity induced by these agents is patients with dementia praecox by Diefendorf and attributed to activation of the nucleus accumbens Dodge in 1908, interruption of smooth ocular and other components of the limbic pursuit movements has more recently been (Iversen, 1977). The disturbances in eye movement recorded again in a high percentage of patients demonstrated by schizophrenic patients are usually with schizophrenia and mania (Holzman et al., attributed to the heightened state of fear or 1973, 1976; Shagass et al., 1976). Savitsky and arousal associated with the acute psychosis. How- Winkelman (1947) described similar cogwheel ever, the occurrence of these disturbances in motion on deviation of the eyes in patients with patients with longstanding psychosis, the modula- disease of the corpus striatum, and Luria et al. tion of these signs by agents which alter central (1966) reported similar saccades in patients with dopamine function, and the appearance of similar

frontal lobe lesions and severe cognitive disorders. signs after stimulation of the mesolimbic dopa- http://jnnp.bmj.com/ Interruption in smooth pursuit can be overcome minergic system in experimental animals and partially by increasing the patient's attention to during temporal lobe seizures of man suggest that the task (Shagass et al., 1976). these ocular signs may represent abnormal function of the mesolimbic dopamine system. SCHIZOPHRENIA, DOPAMINE BLOCKADE, AND THE LIMBIC SYSTEM I express my appreciation to Dr John Lipkin, US Evidence that the effectiveness of neuroleptic Veterans Administration Hospital, Portland,

agents against the symptoms of schizophrenia is Oregon, to Dr Duane Denney, University of on September 30, 2021 related directly to the capacity of these agents to Oregon Health Sciences Center, Portland, Oregon, block dopamine receptors in the brain has impli- to Dr Richard Wyatt, National Institutes of cated central dopaminergic systems in the patho- Health, Washington, DC, to Dr Ernst Rodin, physiology of schizophrenia (Carlsson and Lafayette Clinic, Detroit, Michigan, to Dr Gerald Lindquist, 1963). Striking similarities between the Klerman, Eric Lindemann Mental Health Center, subjective disturbances and stereotypes of Boston, Massachusetts, and to the staffs and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.41.11.1024 on 1 November 1978. Downloaded from

1030 Janice R. Stevens patients of these hospitals. This study was sup- Nashold, B. S. (1970). Ocular reactions from brain ported by National Institutes of Health Grant stimulation in conscious man. Neuro-Ophthalmology, 18055. 5, 92-103. Overend, W. (1896). Preliminary note on a new References cranial reflex. Lancet, 1, 619. Ponder, E., and Kennedy, W. P. (1928). On the act Bleuler, E. (1950). Dementia Praecox or the Group of of blinking. Quarterly Journal of Experimental Schizophrenias, p. 22. Translated by J. Zinkin. Physiology, 18, 89-1 10. International Universities Press: New York. Randrup, A., and Munkvad, I. (1967). Stereotyped Carlsson, A., and Lindquist, M. (1963). Effect of activities produced by amphetamine in several chlorpromazine or haloperidol on the formation of animal species and man. Psychopharmacologia, 11, 3-methoxytyramine and normetanephrine in mouse 300. brain. A cta Pharmacologica et Toxicologica, 20, Sato, Mitsumoto (1977). 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Archives of General Psychiatry, 33, psychopharmacology of Monoamines and Their 121-125. Regulatory Enzymes, pp. 281-295. Edited by E. Shimazano, Y., Ando, K., Sakamoto, S., Tanaka, T., Usdin. Raven Press: New York. Eguchi, T., and Nakamura, H. (1965). Eye move- Escueta, A. V., Kunze, U., Waddell, G., Boxley, J., ments of waking subjects with closed eyes. A com- and Nadel, A. (1977). Lapse of consciousness and parison between normals and chronic schizophrenics. automatisms in temporal lobe epilepsy: a videotape Archives of General Psychiatry, 13, 537-543. analysis. Neurology (Minneapolis), 27, 144-155. Stevens, J. R. (1973). An anatomy of schizophrenia? Hanley, J., Berkhout, J., Crandall, W. R., Rickles, Archives of General Psychiatry, 29, 177-189. W. R., and Walter, R. D. (1970). Spectral character- Stevens, J. R., Wilson, K., and Foote, W. (1974). istics of EEG activity accompanying deep spindling GABA blockade, dopamine and schizophrenia: ex- in a patient with schizophrenia. Electroencepha- perimental studies in the cat. Psychopharmacologia, lography and Clinical Neurophysiology, 28, 90. 39, 105-119. Heath, R. G. (1954). Studies in Schizophrenia. Harvard Stevens, J. R., Livermore, A., and Cronan, J. (1977). University Press: Cambridge. Effects of deafening and blindfolding on ampheta- Holzman, P. S., Proctor, L. R., and Hughes, D. W. mine induced stereotypy in the cat. Physiology and (1973). Eye-tracking performance in psychiatric Behavior, 18, 809-812. schizophrenia. Science, 181, 179-181. Stevens, J. R., and Livermore, A. (1978). Kindling of Holzman, P. S., Levy, D. L., and Proctor, L. R. the mesolimbic dopamine system: animal model of (1976). Smooth pursuit eye movements, attention, psychosis. Neurology (Minneapolis), 28, 36-46. and schizophrenia. A rchives of General Psychiatry, Taylor, M. A., and Abrams, R. (1975). A critique of 33, 1415-1420. the St Louis psychiatric research criterion for Iversen, S. D. (1977). Striatal function and stereotyped schizophrenia. American Journal of Psychiatry, 132, 1276-1280. http://jnnp.bmj.com/ behavior. In Psychobiology of the Striatum, pp. Ungerstedt, U. (1971). Stereotaxic mapping of the 99-118. Edited by A. R. Cools, A. H. M. Lohman, monoamine pathways in the rat brain. Acta Physio- and J. H. L. van den Bercken. Elsevier/North- logica Scandinavica, Supplement 367, 1-48. Holland Biomedical Press: Amsterdam. Van Buren, J. M. (1963). Confusion and disturbance Kraepelin, E. (1913). Lectures on Clinical Psychiatry, of speech from stimulation in vicinity of the head of p. 24. William Wood and Company: New York. the caudate nucleus. Journal of Neurosurgery, 20, Luria, A. R., Karpov, B. A., and Yarbuss, A. L. 148-157. (1966). Disturbances of active visual perception with Wallach, M. B., and Wallach, S. S. (1964). Involuntary lesions of the frontal lobes. Cortex, 2, 202-212. eye movement in certain schizophrenics. 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