Cortical Evoked Potentials Preceding Voluntary ...

(Accepted 1 April 1984)

Cortical evoked potentials preceding voluntary saccadic eye movements*

Neuroophthalmology Downloaded from informahealthcare.com by Nyu Medical Center on 01/11/15 For personal use only.

JOEL M. WEINSTEINI, GLENN R. WILLIAMS3, ARLENE V. DRACK3, THOMAS M. STANK3 and CAREY D. BALABAN2 Departments of Ophthalmology and Neurology1, Anatomy2, School of Medicine3, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, PA, USA

ABSTRACT. An antecedent potential (AP) and a positive spike (SP) potential that precede saccades have been described in normal human subjects using evoked potential techniques. These responses can be recorded over parietal cortex (P3, P4) with linked ear reference. The AP-SP was examined in two patients with progressive supranuclear palsy (PSP) and in two patients with congenital ocular motor apraxia. The response was grossly abnormal in both PSP patients and in one of the congenital ocular motor apraxia patients. This indicates that pre-saccadic cortical activity may be altered in these patients. Thus, these potentials may be of diagnostic value in the evaluation of supranuclear disorders of ocular motility. Key words: saccade; evoked potential; progressive supranuclear palsy; ocular motor apraxia

INTRODUCTION Cortical control of saccadic eye movements has been investigated in both primates (Lynch e f al., 1977; Bushnell et al., 1981; Goldberg & Bushnell, 1981; Schiller et al., 1980) and in humans (Guitton et al., 1982; Sharpe et al., 1979; Daroff & Hoyt, 1971; Cogan, 1965; Luria et al., 1963). In normal human subjects pre-saccadic discharges originating in the frontal and parietal lobes have been identified using averaged electroencephalographic recordings (evoked potential techniques) (Kurtzberg &

*

Reprinr requesis and correspondence to: Joel M . Weinstein, M.D., Division of Ophthalmology, The Milton S. Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA.

Neuro-ophthalmology 1984, Vol. 4, NO. 3,pp. 169-176 0Aeolus Press Amsterdam 1984

Vaughn, 1982; Armington, 1978; Becker et al., 1972). Three components of this eye movement potential (EMP) have been described (Kurtzberg & Vaughn, 1982) (Fig. 1): (1) A slow negative shift (SNS) centered over the frontal cortex, (2) an antecedent potential (AP) centered over the parietal cortex, and (3) a sharp spike potential (SP) centered over the posterior parietal and rostra1 occipital cortex. The SNS begins about 600 msec before the saccade. The AP begins 100-250 msec before the saccade, and the SP precedes the saccade onset by 10-40 msec and peaks at about the time of onset of the saccade (Fig. 1). To our knowledge, this potential has not been investigated in patients with neurologic disorders affecting saccadic eye movements.

169

J . M. Weinstein et al. ~

SP


T

Fig. 1. Eye movement potential (EMP) in a normal subject. SNS - slow negative shift, AP - antecedent potential, SP - spike potential, arrow - onset of eye movement.

This report describes two patients with progressive supranuclear palsy (PSP) who displayed grossly abnormal pre-saccadic eye movement potentials. Two patients with congenital ocular motor apraxia were also studied. One patient had grossly abnormal potentials. A less severely affected patient, though, had a normal EMP waveform. These results suggest that there is altered cortical pre-saccadic activity in patients with PSP and in some patients with congenital ocular motor apraxia, and that the EMP may be of diagnostic value in patients with supranuclear eye movement disorders. MATERIALS AND METHODS Evoked potential recordings were obtained using standard techniques (Kurtzberg & Vaughn, 1982). EEG electrodes were placed bilaterally over the left and right posterior parietal cortices at sites P3 and P4 (International 10/20 system). Linked ears served as reference and the chip as ground. The EEG amplifier band pass was set at 1-100 Hz with 10 K. Horizontal eye movements were recorded using standard electro-oculographic (EOG) techniques and in-

170

~

~

strumentation (Tracoustics RV275). EOG electrodes were placed at the inner and outer canthi of the left eye. The EOG band pass was 0-30 Hz. Eye position and velocity were recorded on an electrostatic chart. The differentiated EOG signal (eye velocity) was used to trigger the EEG signal averager (Nicolet CA- 1000). The mid-signal trigger was set for recording and averaging EEG activity 250 msec before and 100 msec after the eye movement trigger. Epochs containing potentials that exceeded a preset voltage (25 or 50 pv) were presumed to represent artifacts and were excluded from the averaged record. EEG activity was digitized and the averaged potential was monitored on-line. The amplitude of the SP was calculated for both rightward and leftward saccades over each parietal lobe. In general, 100 saccades evoked EMPs of consistent morphology and amplitude in normal subjects. Recordings which did not produce a recognizable waveform after 100 saccades were continued until 200-250 saccades had been performed. The subject was seated and was instructed to perform saccades at will between two light-emitting diodes (LED's) 10" apart. The LED's were positioned straight ahead (primary position) and 10" to the right (for rightward saccades) or left (for leftward saccades). EMP recordings were obtained from 20 normal right-handed subjects (ages 22-36), two patients with progressive supranuclear palsy, and two patients with congenital ocular motor apraxia. Eye movement recordings Normal subjects A prominent AP-SP complex was recorded over both parietal lobes for both

Saccadic evokedpotentials TABLE 1. EMP spike potential amplitudes in 20 normal subjects (mean ? S.E.) SP Amplitude (pv) Recording site


L Parietal(P,) R Parietal (P4)

Saccades to L

Saccades to R

6.3 5 .80 7.1 f .88

6.8 f .59 5.4 f .57

rightward a n d leftward saccades in all normal subjects. Mean SP amplitude and standard error for these recordings are summarized in Table 1 (20 normal subjects were studied).

Progressive supranuclear palsy

were grossly slow and the eyes could not be voluntarily moved more than 10" above or below the midline. Horizontal saccades were grossly slow, and right and left conjugate gaze were limited to 20" to the right or left. Attempted refixation movements larger than 10" resulted in multiple hypometric saccades. Most eye movements of less than 10" were also achieved by multiple hypometric saccades (Fig. 2). The fast phase of optokinetic nystagmus was absent for either horizontally or vertically moving targets. Spontaneous 'square-wave jerks' were present. Vestibulo-ocular movements were full in all directions. The EMP recording for rightward saccades displayed a broad positive wave over the right parietal cortex instead of the sharp AP-SP complex (Fig. 2). This broadened peak was attenuated over the left parietal cortex. No definite pre-saccadic response was observed for leftward saccades.

Case 1. A 70-year-old right-handed woman had noted difficulty with voluntary gaze, vertical worse than horizontal, over the past two years. Disorders of movement (bradykinesia, episodic retropulsion) and cognitive function as well as mild pseudobulbar signs were considered by a neuro- Congenital ocular motor apraxia logic consultant to be consistent with PSP. Case 3. An 8-year-old right-handed girl The eyes could not voluntarily move more was followed since the age of six months than 10" above or below the midline, and with the diagnosis of congenital ocular voluntary horizontal movements were motor apraxia. At the age of about six limited to 20" to the right or left. Sponmonths, she began making typical rapid taneous horizontal 'square-wave jerks' were head jerks during attempted refixation. Inpresent. Vestibulo-ocular movements were itially, she was unable to move the eyes unimpaired in all directions. Voluntary sacmore than 5-10" beyond the midline in cades were grossly slow in all directions and any direction. Gradually, her head jerks the fast phase of optokinetic nystagmus was disappeared and the amplitude of her eye absent. Refixation movements of larger movements increased. By age eight, than 5" were composed of multiple horizontal eye movements of nearly full hypometric saccades. The EMP recording amplitude could be achieved, but saccades shows no pre-saccadic response over either larger than 8-10' were hypometric (Fig. 2). parietal lobe for saccades in either direction Attempted horizontal smooth pursuit was (Fig. 2). punctuated by numerous 'catch-up' sacCase 2. A 67-year-old right-handed cades. The fast phase of optokinetic nyswoman had noted difficulty with downward tagmus was absent. Eye movements in the gaze for one year. Cognitive function was vertical plane were grossly normal. The intact but a movement disorder consistent EMP recording showed a sharp SP for both with PSP was present. Vertical saccades rightward and leftward saccades over both

171

J. M. Weinstein et al. PATIENT

EOQ

EMP Saccadar to R


NORMAL

SWX.d.8

to L

10.[

CASE 1

CASE 2

CASE 3

CASE 4

Fig. 2. Eye movement potential (EMP) and electrooculograph (EOG)in a normal subject and four patients (see text). For each subject, top two EMP recordings are right parietal (P3) and bottom two recordings are left parietal (P4). Arrow - onset of eye movement.

172

parietal lobes, despite hypometria of some saccades (Fig. 2). Although the waveforms were of normal morphology, the amplitude of these potentials (saccades to R: 3.3 pv at P3, 4.0 pv at P4; saccades to L: 2.5 pv at P3, 1.7 pv at P4) was slightly below the 95% confidence interval for 20 normal subjects.

Saccadic evoked p o ten tials redirecting visual attention toward objects of interest in the peripheral visual field (Lynch et al., 1977). One population of neurons, saccade cells, show pre-saccadic histograms which are similar to the AP-SP spike complex of the EMP. These neurons are insensitive to purely visual stimulation but discharge vigorously prior to saccades directed to behaviorally relevant (i.e., reward related) stimuli in the visual periphery (Motter & Mountcastle, 1981). These characteristics have led one group of investigators to conclude that area 7 'executes a matching function between the neural signals of the nature of objects and the internal drive state of the organism' (Lynch et al., 1977). Although further work is needed to characterize the origin and physiologic significance of the EMP, the resemblance of the spike potential to the pre-saccadic discharges of saccade neurons in area 7 in alert monkeys is striking. Both potentials begin 40-50 msec before the onset of an eye movement, and peak around the time of onset of the eye movement. These similarities suggest that the human pre-saccadic spike potential (SP) represents a discharge from a population of neurons similar to the saccade related neurons described in the posterior parietal area of sub-human primates. Although the central pathways involved DISCUSSION in the generation of the EMP are not known, Recent studies in alert monkeys have experimental studies have shown that area 7 provided insight into the contribution of of the posterior parietal lobe derives visual neurons in the posterior parietal cortex to input from the ipsilateral pulvinar (Trojavoluntary, behaviorally motivated eye nowski & Jacobson, 1976). This information movements (Lynch et al., 1977; Bushnell et is relayed from the superficial layers of the al., 1981). The studies of Lynch et al. suggest (ipsilateral) superior colliculus which that area 7a in the posterior parietal cortex receives visual input from retinal ganglion contains neurons which are involved in cells and occipital cortex. This is of parti21-year-old right-handed man was referred for evaluation of strabismus. An alternating esotropia had been present since the age of approximately six months. For the first four years of life, refixation eye movements were accomplished by typical head turning maneuvers. This behavior gradually diminished during childhood. There was a history of hyperactivity and learning disability. Visual acuity was 20120 in each eye and a 20 diopter alternating esotropia was present. On attempted refixation, he was unable to move the eyes more than 10" away from the midline in the horizontal plane. This was accomplished through multiple small (2-3") saccades. The maximum saccadic amplitude was 7'. On rare occasions, spontaneous eye movements resulted in full conjugate horizontal deviation to either side. The fast phase of optokinetic nystagmus was absent. Vertical saccades were grossly slow and hypometric but full upward and downward excursions could be performed. Vestibulo-ocular movements were normal. The saccades during the EMP recording session were hypometric (Fig. 2). The EMP record displayed a broad peak of pre-saccadic activity over both parietal lobes for rightward saccades, which was similar to the responses in Case 2. No well-defined pre-saccadic discharges were observed over either cortex for leftward saccades, but some post-saccadic discharges were observed.


Case 4. A

173


J . M . Weinstein et al.

cular interest because neurons in the human pulvinar fire in association with saccades (Straschill & Takahashi, 1981), and left posterior pulvinar resection in a patient resulted in deficiencies in search and scanning performance during eye movements directed to the contralateral hemifield (Ogren et al., 1984). However, the role of this tecto-fugal visual pathway in the generation of the EMP requires further study of patients with discrete lesions of parietal afferent pathways. The significance of the abnormal EMP in patients with progressive supranuclear palsy is unclear. This neurodegenerative disorder, first described by Steele et al. (1964), is characterized clinically by onset in the fifth to seventh decade of (1) a movement disorder similar to Parkinson's disease but without tremor, (2) a disorder of equilibrium and balance in which the patient typically falls backwards, (3) pseudobulbar palsy, (4) a characteristic form of dementia, and (5) a progressive supranuclear gaze disorder, typically affecting vertical gaze before horizontal (Steele et al., 1964; Hynd et al., 1982; Chu et al., 1979). Pathologic studies in patients with PSP have shown prominent changes in the superior colliculi (Behrman et al., 1969; Oppenheimer et al., 1976). Other sites of damage include the periaqueductal gray matter, the basal ganglia, the dentate nucleus, the subthalamic nuclei, the brain stem reticular formation, and the oculomotor nuclei (Behrman et al., 1969; Oppenheimer et al., 1976; Jellinger et al., 1980). The cerebral cortex is remarkably spared in this disorder (Behrman et al., 1969; Oppenheimer et al., 1976; Jellinger et al., 1980). This suggests that the abnormal pre-saccadic discharge may represent disruption of eye-movemen t

174

related ascending pathways to the parietal cortex. Congenital ocular motor apraxia is a stereotyped disorder characterized by absence of voluntary horizontal eye movements with relative preservation of vertical and random horizontal eye movements (Cogan & Adams, 1953). The fast phases of both optokinetic and vestibular nystagmus are absent. Refixation is accomplished through characteristic head thrusts which take the eyes beyond the fixation target. During the head thrust there is deviation of the eyes in the opposite direction due to the vestibulo-ocular reflex. While the eyes fixate on a target, they return to 1" position by a slow rotation of the head in the opposite direction. The literature does not support a single discrete focus of CNS damage in congenital ocular motor apraxia (Cogan & Adam, 1953; Zaret et al., 1980; Orrison & Robertson, 1979; Smith et al., 1969; Lyle, 1961; Hirt et al., 1967). Indeed, the syndrome may represent the final common pathway for lesions at a number of sites in the CNS. Previous pathologic and radiologic studies have implicated a variety of lesions including agenesis of the corpus callosum with a porencephalic cyst (Smith et al., 1969), a hamartoma of the foramen of Munro with a dilated left ventricle, familial macrocephaly (all described by Smith et al., 1969), a large cystic tumor involving the rostra1 brain stem and posterior third ventricle (Zaret et al., 1980) and cerebellar hypoplasia (Hirt et al., 1967). Radiologic studies were not indicated in our patients and we cannot comment upon any structural abnormalities. However, the grossly abnormal EMP in our more severely affected patient, and the attenuated EMP in our less severely affected patient suggest that


Saccadic evoked potentials

pre-saccadic parietal activity is altered in some patients with congenital ocular motor apraxia. We have attempted to minimize certain technical problems in the testing procedure due to properties of saccades in these patients. Because the saccadic amplitude and velocity can be variable in patients, it is possible that the trigger pulse (saccadic velocity) occurs at a variable time after the onset of the attempted saccade. Such desynchronization could result in inaccurate averaging of EEG activity that is closely time-locked to the onset of eye movements. In order to avoid this problem, the velocity amplifier gain and the trigger level must be adjusted such that triggering occurs only for saccades of maximum velocity. As described in previous studies (Chu et al., 1979; Troost & Daroff, 1977) our patients with PSP made hypometric saccades with peak velocities of about 65% of normal values, but with normal velocity-amplitude relationships. By choosing a velocity trigger level near the maximum value for each patient, a homogeneous population of velocities (and amplitudes) was selected. In the patient with the most heterogeneous population of saccades (Case 4), triggering occurred within a 9 msec window (35-44 msec after the eye movement). This 9 msec range in trigger onset, compared to a 5 msec

range in normals, clearly cannot account for the broadened SP in this patient, which begins 80 msec before the eye movement. Square wave jerks were of insufficient velocity to trigger the averager. Finally, the normal morphology of the EMP waveform obtained in Case 3, despite horizontal eye movements similar to the three abnormal patients, provides further evidence that these adjustments minimize desynchronization of averaged potentials. We do not believe that the abnormal potentials in our patients are due to predominance of or an admixture of saccades of small amplitude. Prior studies have shown that saccades as small as 7' produce spike potentials of approximately 3.0 pv, or about 50% of the amplitude produced by 10" saccades (Armington, 1978). Thus, the markedly abnormal waveforms in our patients probably represent changes in cortical pre-saccadic activity. This suggests that recordings of pre-saccadic cortical activity may be of value in the diagnosis of disorders of ocular motility. ACKNOWLEDGEMENT This research was supported in part by a grant from the Pennsylvania Lions Eye Research Foundation. We are indebted to Nicolet Biomedical and Patrick Mulvanny, Ph.D. for technical advice and for the generous loan of equipment.

REFERENCES ARMINGTON, J. C.: Potentials that precede small saccades. In: Visual Psychophysics and Physiology ( J . C . Armington, J. Krauskopf and B. R. Wooten, eds.), pp. 363-372. Academic Press, New York 1978 BECKER, W., HOEHNE, D., IWASE, K. & KORNHUBER, H.: Bereitschaftspotential, pramotorische Positivierung und andere Himpotentiale, bei sakkadischen Augenbewegungen. Vision Res. I2:42 1-436, 1972 BEHRMAN, S., CARROLL, J. D., JANOTA, I. & MATTHEWS, W. B.: Progressive supranuclear palsy: clinico-pathological study of four cases. Bruin 92:663-678, 1969

175


J. M . Weinstein et al. BUSHNELL, M. C., GOLDBERG, M. E. & ROBINSON, D. L.: Behavioral enhancement of visual responses in monkey cerebral cortex. I. Modulation in posterior parietal cortex related to selective visual attention. J. Neurophysiol. 46:755-772, 1981 CHU, F. C., REINGOLD, D. B., COGAN, D. G. & WILLIAMS, A. C.: The eye movement disorders of progressive supranuclear palsy. Ophthalmology 86:422-430, 1979 COGAN, D. G. & ADAMS, R. D.: A type of paralysis of conjugate gaze (ocular motor apraxia). Arch. Ophthal. 50:434-442, 1953 COGAN, D. G.: Ophthalmic manifestations of non-occipital cerebral lesions. Brit. J. Ophthal. 49:28 1-297, 1965 DAROFF, R. B. & HOYT, W. F.: Supranuclear disorders of ocular control systems in man. In: The Controlof Eye Movements (P. Bach-y-Rita, C. C. Collins and J. E. Hyde, eds.), pp. 175-235.Academic Press, New York 1971 GOLDBERG, M. E. & BUSHNELL, M. C.: Behavioral enhancement of visual responses in monkey cerebral cortex. 11. Modulation in frontal eye fields specifically related to saccades. J.Neurophysiol. 46:773-787, 1981 GUITTON, D., BUCHTAL, H. A. & DOUGLAS, R. M.: Disturbances of voluntary saccadic eye movement mechanisms following discrete unilateral frontal lobe removals. In: Functional Basis of Ocular Motility Disorders (G. Lennerstrand, D. S. Zee and E. Keller, eds.), pp. 497-499. Pergamon Press 1982 HIRT, H. R., KRAVER, B. & WIESER, D.: Die kongenitale oculomotorische Apraxia. Dtsch. Z. Nervenheilk. 191:342-359. 1967 HYND, G. W., PIROZZOLO, F. J. & MALETTA, G. J.: Progressive supranuclear palsy. Int. J. Neurosci. 16~87-98.1982 JELLINGER,’ K., RIEDERER, P. & TOMONAGA, M.: Progressive supranuclear palsy: Clinico-pathological and biochemical studies. J. neural Transmiss. Suppl. 16: 11 1-128, 1980 KURTZBERG, D. & VAUGHN, H. G.: Topographic analysis of human cortical potentials preceding self-initiated and visually triggered saccades. Brain Res. 243: 1-8, 1982 LURIA, A. R., PRAVIDA-VINARSKAYA, E. N. & YARBUS, A. L.: Disorders of ocular movement in a case of simultagnosia. Brain 86:219-228, 1963 LYLE, D. J.: A discussion of ocular motor apraxia with a case presentation. Trans. Amer. ophthal. SOC.59:274-285, 1961 LYNCH, J. C., MOUNTCASTLE, V. B., TALBOT, W. H. & YIN, T. C. T.: Parietal lobe mechanisms for directed visual attention. J. Neurophysiol. 40:362-389, 1977 MOTTER, B. C. & MOUNTCASTLE, V. B.: The functional properties of the light-sensitive neurons of the posterior parietal cortex studied in waking monkeys: Foveal sparing and opponent vector organization. J . Neurosci. 1:3, 1981 OGREN, M. P., MATEER, C. A. & WYLER, A. R.: Alterations in visually related eye movements following left pulvinar damage in man. Neuropsychologia 22: 187-196, 1984 OPPENHEIMER, R., BLACKWOOD, W. & CORSELLIS, J. A. N. (eds.): Diseases of the basal ganglia, cerebellum, and motor neurons. In: Greenfield’s Neuropafhology,pp. 616-618. Year Book Medical Publishers, Inc., Chicago, IL 1976 ORRISON, W. W. & ROBERTSON, W. C.: Congenital ocular motor apraxia: A possible disconnection syndrome. Arch. Neurol. 36:29-31, 1979 SCHILLER, P. H., TRUE, S. D. & CONWAY, J. L.: Deficits in eye movement following frontal eye field and superior colliculus ablations. J . Neurophysiol. 44: 1175- 1189, 1980 SHARPE, J. A., LO, A. W. & RABINOVITCH, H. E.: Control of the saccadic and smooth pursuit systems after cerebral hemidecortication. Brain 102:387-403, 1979 SMITH, J. L., cited by F. B. Walsh and W. F. Hoyt: Clinical Neuro-ophthalmology, 3rd edn., p. 213. Williams & Wilkins Co., Baltimore 1969 STEELE, J. C., RICHARDSON, J. C. & OLSZEWSKI, J.: Progressive supranuclear palsy. Arch. Neurol. 10:333-359, 1964 STRASCHILL, M. & TAKAHASHI, H.: Changes of EEG and single unit activity in the human pulvinar associated with saccadic gaze shifts and fixation. In: Progress in Oculomotor Research (A. F. Fuchs and W. Becker, eds.), p. 225. Elsevier/North-Holland, Amsterdam 1981 TROJANOWSKI, J. Q. & JACOBSON, S.: A real and laminar distribution of some pulvinar cortical efferents in rhesus monkey. J. comp. Neurol. 169:371-392, 1976 TROOST, B. T. & DAROFF, R. B.: The ocular motor defects in progressive supranuclear palsy. Ann. Neurol. 2:397-403, 1977 ZARET, C. R., BEHRENS, M. M. & EGGERS, H. M.: Congenital ocular motor apraxia and brainstem tumor. Arch. Ophthal. 98:328-330, 1980

176