Experimental Brain Research
Exp. Brain Res. 37, 581-593 (1979)
@ Springer-Verlag1979
Vestibular Nuclei Activity in the Alert Monkey During Suppression of Vestibular and Optokinetic Nystagmus* U.W. Buettner 1 and U. Biittner Department of Neurology, University of Ziirich, Rfimistr. 100, CH-8091 Zfirich, Switzerland
Summary. Single neurons were recorded in the vestibular nuclei of monkeys trained to suppress nystagmus by visual fixation during vestibular or optokinetic stimulation. During optokinetic nystagmus vestibular nuclei neurons exhibit frequency changes. With the suppression of optokinetic nystagmus this neuronal activity on average is attenuated by 40 % at stimulus velocities of 40~ At a stimulus velocity of 5~ responses are, under both conditions, close to threshold. For steps in velocity, suppression of vestibular nystagmus shortens the time constants of the decay of neuronal activity from 15-35 s to 5-9 s, while the amplitude of the response remains unchanged. The results are discussed in relation to current models of visual-vestibular interaction. These models use a feedback mechanism which normally operates during vestibular and optokinetic nystagmus, Nystagmus suppression interrupts this feedback loop. Key words: Vestibular nuclei - Alert monkey - Vestibular stimulation Optokinetic stimulation - Nystagmus suppression Vestibular nuclei neurons alter their discharge rate in response to large moving visual fields, which also elicit optokinetic nystagmus (Dichgans and Brandt, 1972; Azzena et al., 1974; Henn et al., 1974; Allure et al., 1976; Waespe and Henn, 1977a; Keller and Precht, 1978). Thus, changes in neuronal activity can be related either to the visual (optokinetic) stimulus or to the motor (nystagmus) response. During vestibular stimulation in the dark dominant time constants for vestibular nuclei neurons in the alert monkey and the accompanying nystagmus are always similar (Buettner et al., 1978), and longer than those of the vestibular nerve (Goldberg and Fernandez, 1971; Blanks et al., 1975; Schneider and Anderson, 1976) and of the vestibular nuclei in anesthetized or decerebrate preparations (Shimazu and Precht, 1965; Jones and Milsum, 1971; Shinoda and Yoshida, 1974; Schneider and Anderson, 1976). * Supported by the Swiss National Foundation for Scientific Research (SNF 3.233.77) and the Deutsche Forschungsgemeinschaft(U. W. Buettner, Bue 379/2) 1 Present address: NeurologischeUniversitfitsklinik, Liebermeisterstr. 18-20, D-7400 Tiibingen, Federal Republic of Germany Offprint requests to: Dr. U. Btittner (address see above)
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The question arises whether activity in the vestibular nuclei during vestibular or optokinetic nystagmus reflects motor output, a sensory input or a combination of both. Therefore, single neuron activity in the vestibular nuclei was investigated during optokinetic and vestibular stimulation with and without suppression of nystagmus.
Methods Two trained Rhesus monkeys (Macaca mulatta) were chronically prepared for single neuron recordings (for details see Buettner et al., 1978). Silver-silver chloride electrodes for measuring horizontal and vertical eye positions were implanted around the boney orbit. During experiments the monkey sat upright in a primate chair with his head fixed and tilted 25 ~ forward to bring the horizontal semicircular canals in the plane of rotation. A strain gauge for measuring head torque was mounted to the head holder. The limbs, except the arm for bar pressing (see below), were loosely restrained. Neuronal activity was recorded with varnished tungsten microelectrodes. The monkey in the primate chair was placed on a servo-controlled turntable. For vestibular stimulation he was rotated about a vertical axis in complete darkness using velocity trapezoids (acceleration 5-10~ 2, constant velocity 40-100~ for at least 50 s, deceleration 5-10~ For optokinetic stimulation a cylinder covered with vertical black and white stripes was rotated around the stationary monkey at velocities of 3-100~ For conflict stimulation the optokinetic cylinder and the turntable were coupled and rotated with the same parameters. Under this condition there is no relative movement between the monkey and the visual surround. Monkeys were trained to fixate a small spot of light using the paradigm of Wurtz (1969). The monkey pressed a bar to turn on the fixation light. After a variable time period (2-16 s) the light dimmed and he had to release the bar within 500 ms to be rewarded with a drop of water. The fixation light was attached to the turntable and rotated with the monkey to suppress vestibular nystagmus; when the monkey was stationary the fixation light allowed suppression of optokinetic nystagmus during rotation of the cylinder. During tests, when the monkey was allowed to have nystagmus, the fixation light was withdrawn from the monkey's sight. Neuronal activity, horizontal and vertical eye position, turntable and cylinder velocity, head torque and the intensity of the fixation light were stored on a FM magnetic tape recorder. At the end of all experiments recording sites were marked by small electrolytic lesions or the injection of neuroanatomical tracer substances. Animals were then perfused with formalin under an overdose of pentobarbital. Frozen sections of the brain, taken at least every 320 ~ were stained with cresyl violet and the recording sites were reconstructed. Instantaneous and average frequency (running average over 250-2,000 ms) was determined. Slow-phase nystagmus velocity was obtained by differentiating the horizontal eye position signal. For analysis, data were written out on a six-channel rectilinear oscillograph. Time constants of decay of neuronal activity and slow-phase nystagmus velocity after angular acceleration (vestibular stimulation) were determined as the time elapsed between maximal activity and the point at which activity had decreased to 1/e above baseline level. Neuronal activity during optokinetic stimulation was measured by averaging over a period of 20-30 s after a steady level of activity was reached.
Results Neurons, which receive their main input from the horizontal semicircular canals, were recorded in the vestibular nuclei of both sides of the brainstem. Anatomical reconstruction showed that recording sites were mostly in the rostral part of the vestibular nuclei complex. Results are based on the analysis of 57 neurons, which were specifically tested during suppression of optokinetic and/or vestibular nystagmus. Thirty-six (63%) neurons were activated during a c c e l e r a t i o n t o t h e i p s i l a t e r a l s i d e a n d w e r e c l a s s i f i e d as t y p e I ( D u e n s i n g a n d
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Neuronal Activity During Optokinetic Nystagmus and its Suppression All vestibular nuclei neurons respond to large moving visual fields, which elicit optokinetic nystagmus (Fig. 1). An activation occurs when the optokinetic cylinder moves in the direction opposite to an activating vestibular stimulus. Under these stimulus conditions, optokinetic and vestibular nystagmus beat into the same direction. When the optokinetic cylinder is rotated in the opposite direction neuronal activity decreases below spontaneous activity level. The activity changes persist during the whole period of optokinetic stimulation. A linear relation can be obtained between increase of neuronal activity and stimulus velocity up to velocities of 60~ At higher velocities neuronal activity tends to saturate (Figs. 3 and 4, Waespe and Henn, 1977a). When optokinetic nystagmus is suppressed, vestibular nuclei neurons are still activated or inhibited depending on the direction of stimulus motion (Fig. 1). In most neurons (80%) activity was reduced if nystagmus was suppressed (Figs. 1, 2, 3a, and 4). About 10% of the neurons responded in the same manner whether the monkey was allowed to have nystagmus or not. In the latter neurons the response to optokinetic stimulation remained unchanged after the transition from fixation suppression to nystagmus.
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A few neurons with a generally weak response during optokinetic nystagmus exhibited only a small, or no response during its suppression (Fig. 2). No obvious differences could be observed for the behavior of type I or II neurons, additionally modulated with eye movements or not. Neurons with a strong eye position signal were excluded from comparative analysis, although they also showed an activity increase during suppression, when a steady eye position was maintained. Neurons were most commonly investigated at a stimulus velocity of 40~ and quantitative measurements were confined to the activating direction. When activity at this stimulus velocity during optokinetic nystagmus is set at 100% (mean value: 23.2 imp/s above resting discharge), then during suppression of nystagmus, activity increase on average is attentuated to 5 9 % (mean value: 13.7 imp/s above resting discharge) (Fig. 2). Twenty-five neurons were also tested at optokinetic stimulus velocities of 3 ~ and 5~ Neuronal activation was small as expected with such low stimulus velocities. In every case activation was similar whether the monkey had nystagmus or suppressed it (Figs. 3 and 4). Fourteen neurons could be tested over the whole range of stimulus velocities between 5 ~ and 100~ A few neurons responded equally under both conditions, with and without nystagmus (Fig. 3B). The majority, however, showed this similar response only for velocities up to about 20~ above, activity was stronger during nystagmus than during its suppression (Figs. 3A and 4).
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Fig. 4. Averaged responses of 14 vestibular nuclei neurons (9 type I, 5 type II) to different velocities of optokinetic stimulation. Low stimulus velocities cause small activity changes under both conditions. At higher velocities the activity increase during optokinetic nystagmus is greater than that seen during nystagmus suppression. Both responses tend to saturate at stimulus velocities above 60~
Neuronal Activity During Vestibular Nystagrnus and its Suppression Vestibular nuclei neurons in the alert monkey respond to angular acceleration in a uniform way: depending on the direction and whether a type I or II neuron is tested, the activity increases, or decreases, and returns to the spontaneous activity level during constant velocity rotation with a time constant of 15-35 s. During deceleration a mirror-like activity pattern is observed (Figs. 5 and 6). This is seen for all vestibular nuclei neurons, regardless of whether or not they show an additional modulation with eye movements. Concomitant vestibular nystagmus shows the same behavior and declines with the same time constant (Fig. 5; Buettner et al., 1978). When vestibular nystagmus is suppressed by fixating a small spot of light, there is little change in the maximal firing rate at the end of acceleration: the activity in 80% of the neurons was reduced by less than 10%, for the remaining 20 %, reduction was between 10-30 %. During the period of rotation at constant velocity differences become prominent: with nystagmus suppression the activity returns faster to the spontaneous activity level, with a time constant between 5 and 9 s. This was found for all 31 neurons investigated. These short time constants occur only during nystagmus suppression and become much larger again during normal nystagmus response (Figs. 5 and 6). Another paradigm to suppress nystagmus is to expose the monkey to conflicting visual-vestibular stimulation by mechanically coupling the optokinetic cylinder to the turntable. During acceleration there is then no visual displacement and with accelerations below 10~ 2 all nystagmus is suppressed.
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This conflicting v i s u a l - v e s t i b u l a r stimulus a t t e n u a t e s the r e s p o n s e o f v e s t i b u l a r nuclei n e u r o n s a n d t i m e c o n s t a n t s a r e r e d u c e d to 3 - 4 s (Fig. 6, W a e s p e a n d H e n n , 1978). A few n e u r o n s c o u l d be i n v e s t i g a t e d u n d e r all t h r e e c o n d i t i o n s ( v e s t i b u l a r n y s t a g m u s in the d a r k , s u p p r e s s i o n o f v e s t i b u l a r n y s t a g m u s b y fixation o f a small s p o t o f light in d a r k n e s s , o r b y i n t r o d u c i n g v i s u a l - v e s t i b u l a r conflict). B o t h kinds o f n y s t a g m u s s u p p r e s s i o n s h o r t e n e d the t i m e c o n s t a n t s o f n e u r o n a l activity (conflicting s t i m u l a t i o n b e i n g m o r e effective t h a n fixation s u p p r e s s i o n ) , b u t w h e r e a s p e a k n e u r o n a l activity d u r i n g fixation s u p p r e s s i o n was n o t m u c h d i f f e r e n t f r o m t h e r e s p o n s e d u r i n g n y s t a g m u s , v i s u a l - v e s t i b u l a r conflict c o n s i d e r a b l y a t t e n u a t e d p e a k n e u r o n a l activity.
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Fig. 6. Response of a vestibular nuclei neuron (type I) to a velocity trapezoid during nystagmus in the dark (vestibular), nystagmus suppression in the dark (vestibular plus fixation), and rotation in the light with the cylinder fixed to the turntable (visual-vestibular conflict). In the latter condition there is no relative motion of the visual surround. Ordinate: Averaged neuronal response of 2-3 trials. Stimulus parameters are indicated. During nystagmus neuronal activity returns to spontaneous activity level with a time constant of 15 s after acceleration and 25 s after deceleration. Nystagmus slow-phase velocity showed the same time course with a similar asymmetry. Nystagmus suppression leads to a reduction of time constants to 5-6 s for both directions, whereas the maximal activity changes remain the same. During visual-vestibular conflict the response amplitudes are diminished and time constants are further reduced. No nystagmus occurred during visual-vestibular conflict stimulation
Discussion A t the outset we asked w h e t h e r n e u r o n a l activity in the v e s t i b u l a r nuclei is m o r e r e l a t e d to visual ( o p t o k i n e t i c ) a n d v e s t i b u l a r i n p u t or to o c u l o m o t o r ( n y s t a g m u s ) output. A l l n e u r o n s r e s p o n d e d in a similar way to the different e x p e r i m e n t a l paradigms, b u t their activity could n o t be r e l a t e d to simply o n e sensory or o n e m o t o r p a r a m e t e r . D u r i n g o p t o k i n e t i c s t i m u l a t i o n n e u r o n s were activated e v e n w h e n o p t o k i n e t i c n y s t a g m u s was suppressed, p r o v i n g that an i n p u t from the visual system o p e r a t e s i n d e p e n d e n t l y of the m o t o r response. O n the o t h e r hand, the p r e s e n c e or a b s e n c e of n y s t a g m u s was clearly reflected in n e u r o n a l activity. This leads to the u n e x p e c t e d result that only o n e synapse away from the vestibular n e r v e n e u r o n a l activity to the same sensory stimulus differs with the m o t o r b e h a v i o r of the animal.
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Optokinetic Stimulation Vestibular nuclei neurons still show consistent modulation of their activity during suppression of optokinetic nystagmus. This visually mediated response is small at low velocities, increases monotonically up to velocities of 40-60~ and tends to saturate at higher velocities (Fig. 4). If nystagmus is permitted, the increase in neuronal response is greater at velocities above 20~ but saturates also above 60~ It has not yet been determined which parameter the visually mediated responses of the vestibular nuclei neurons represent. An internally created signal about surround motion or retinal slip velocity have been suggested. The results in Fig. 4 cannot be explained by assuming that retinal slip velocity is the only effective parameter. Slip velocity during nystagmus probably does not exceed 10% of stimulus velocity up to 60~ (Cohen et al., 1977). Up to stimulus velocities of 20~ responses of vestibular nuclei neurons are similar during nystagmus and suppression although retinal slip is far greater during suppression. Furthermore, if the response differences for nystagmus and its suppression at higher stimulus velocities were due to a decreased responsiveness for high retinal slip velocities, the curve for nystagmus suppression should show a response peak at lower velocities. This was not found. Thus, responses of vestibular nuclei neurons during optokinetic nystagmus are not only determined by the visual input. Motor output (or an internal signal, see below) is also an important factor. The mode of interaction of these two parameters at the level of the vestibular nuclei is not known. When nystagmus takes place, neuronal activity is proportional to slow-phase nystagmus velocity over a wide range and independent of whether nystagmus was elicited by vestibular or optokinetic stimulation, or whether it is vestibular or optokinetic after-nystagmus (Waespe and Henn, 1977b).
Vestibular Stimulation If no fixation is required during vestibular stimulation, time constants of vestibular nuclei neurons range from 15-35 s, and are similar to those of slow-phase nystagmus velocity (Figs. 5, 6; Miles and Henn, 1976; Buettner et al., 1978). During suppression of vestibular nystagmus, time constants of vestibular nuclei neurons are shortened to 5-9 s, values only slightly larger than those found in the vestibular nerve (Goldberg and Fernandez, 1971) or the vestibular nuclei of the anesthetized monkey (Buettner et al., 1978). Skavenski and Robinson (1973) pointed out the differences between the vestibular nerve and nystagmus (VOR) response in alert animals and postulated a "low frequency compensation" in the brainstem to overcome these differences. Our single neuron recordings in the alert monkey show that this compensation can already be demonstrated in the vestibular nuclei. It is not yet clear, how and through which neuronal substrates this partial integration is achieved. Whatever the exact mechanism, fixation suppression or anesthesia (Buettner et al., 1978) cancel the "low frequency compensation". The signal recorded in
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the vestibular nuclei is then similar to that carried by the vestibular nerve. Keller and Daniels (1975) also found a vestibular signal still present in the vestibular nuclei during sinusoidal rotation of animals suppressing their nystagmus. For those neurons projecting to the oculomotor system this remaining vestibular modulation has to be cancelled, which requires additional information processing between the vestibular and the oculomotor nuclei (Fig. 7). A neuronal signal, which could take part in such information processing was recorded in the flocculus of the monkey (Lisberger and Fuchs, 1978), however, the exact location of interaction in the brainstem has yet to be determined. Another experimental paradigm to suppress nystagmus during vestibular stimulation is to introduce a visual-vestibular conflict by rotation of the animal together with its visual surround so that during vestibular stimulation no visual displacement takes place (Waespe and Henn, 1978). With accelerations up to 10~ 2 all nystagmus is suppressed. Under these conditions time constants of activity in vestibular neurons are shortened to about 3 - 4 s, and peak modulation is attenuated. This attenuation and pronounced shortening of time constants, which is different from the response when the monkey fixates a light spot in an otherwise dark environment, shows that changes in neuronal response cannot entirely be attributed to the lack of nystagmus. Rather, an additional effect from the retinal periphery must exist.
Models
Present physiological and anatomical knowledge is insufficient to explain all our results. However, models have been introduced to describe the nystag-
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mus response (Raphan et al., 1977; Robinson, 1977) during combined visual-vestibular stimulation, which can simulate some of our results and allow further specification of the role of the vestibular nuclei in transforming sensory information into motor behavior. Vestibular nuclei activity is determined by the vestibular nerve input, the visual input and a local feedback mechanism (Fig. 7). During vestibular stimulation, the feedback mechanism produces the longer time constant ("low frequency compensation", Skavenski and Robinson, 1973) of vestibular nuclei neurons. During optokinetic nystagmus this feedback mechanism is also activated and kept operating at a constant level by the continuous visual input. Therefore, over a wide range, a close correlation can be shown between neuronal activity in the vestibular nuclei and slow-phase velocity of both vestibular and optokinetic nystagmus. During optokinetic after-nystagmus, when all input ceases, the feedback mechanism, acting as a leaky integrator (Raphan et al., 1977), slowly discharges with its characteristic time constant. This feedback mechanism is independent of the actual execution of eye movements, since the time constants in the vestibular nuclei are not affected in monkeys with a horizontal gaze palsy caused by a lesion in the paramedian pontine reticular formation (Jaeger et al., 1979). In the model shown in Fig. 7, suppression of nystagmus by fixating a spot of light interrupts the feedback mechanism. The visual and vestibular nerve inputs, however, are still present in the vestibular nuclei. These remaining signals have to be cancelled by additional mechanisms between the vestibular and oculomotor nuclei. It should be emphasized that Fig. 7 only represents a simple scheme relevant to the results of our experiments. A more complete description would have to include more details and different mechanisms. The visual input can also act directly upon the oculomotor system, since vestibular nuclei neurons only increase their response up to stimulus velocities of 60~ (Fig. 4, Waespe and Henn, 1977a), whereas optokinetic nystagmus in the monkey follows velocities up to 180~ (Cohen et al., 1977). Also, if vestibular nystagmus is suppressed by a large visual field rotating together with the monkey (visual-vestibular conflict) neuronal responses are smaller than those seen in suppression of vestibular nystagmus by fixating a small spot of light (Fig. 6, Waespe and Henn, 1978). An internal comparator to estimate this conflict and accordingly weight these inputs has been suggested (Zacharias and Young, 1979).
Conclusions
Experimental results emphasize that the response of vestibular nuclei neurons cannot be related simply to sensory (vestibular or optokinetic) stimuli, but the presence or absence of the oculomotor response must also be taken into account. This stresses the complex multi-input information processing in the vestibular nuclei and its close reciprocal connection to the oculomotor system.
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Acknowledgements. The authors wish to thank Ms. Vappu Isoviita for technical assistance, Mr. V. Corti for building and maintaining part of the electronic equipment and Mr. J. Mttller for photography.
References Allum, J. H. J., Graf, W., Dichgans, J., Schmidt, C.L.: Visual-vestibular interactions in the vestibular nuclei of the goldfish. Exp. Brain Res. 26, 463-485 (1976) Azzena, G.B., Azzena, M.T., Marini, R.: Optokinetic nystagmus and the vestibular nuclei. Exp. Neurol. 42, 158-168 (1974) Blanks, R.H.I., Estes, M.S., Markham, C.H.: Physiological characteristics of vestibular first-oder canal neurons in the cat. II. Response to constant angular acceleration. J. Neurophysiol. 38, 1250-1268 (1975) Buettner, U.W., Bfittner, U., Henn, V.: Transfer characteristics of neurons in the vestibular nuclei of the alert monkey. J. Neurophysiol. 41, 1614-1628 (1978) Cohen, B., Matsuo, V., Raphan, T.: Quantitative analysis of the velocity characteristics of optokinetic nystagmus and optokinetic after-nystagmus. J. Physiol. (Lond.) 270, 321-344 (1977) Dichgans, J., Brandt, Th.: Visual vestibular interaction and motion perception. In: Cerebral control of eye movements and motion perception, Dichgans, J., Bizzi, E. (eds.). Bibl. Ophthal. Vol. 82, pp. 327-338. Basel: Karger 1972 Duensing, F., Schaefer, K.P.: Die Aktivitfit einzelner Neurone in Bereich der Vestibulariskerne bei Horizontalbeschleunigungen unter besonderer Berficksichtigung des vestibul/~ren Nystagmus. Arch. Psychiat. Nervenkr. 198, 225-252 (1958) Fuchs, A.F., Kimm, J.: Unit activity in vestibular nucleus of the alert monkey during horizontal angular acceleration and eye movement. J. Neurophysiol. 38, 1140-1161 (1975) Goldberg, J.M., Fernandez, C.: Physiology of peripheral neurons innervating semicircular canals of the squirrel monkey. I. Resting discharge and response to constant angular accelerations. J. Neurophysiol. 34, 635-660 (1971) Henn, V., Young, L.R., Finley, C.: Vestibular nucleus units in alert monkeys are also influenced by moving visual fields. Brain Res. 71, 144-149 (1974) Jaeger, J., Henn, V., Waespe, W., Hepp, K.: Neuronal activity in alert naonkeys with gaze paresis. How lesions of the pontine reticular formation change neuronal activity in the oculomotor and vestibular system. (Eur. Brain Behav. Soc. Paris 1979) Exp. Brain Res. 36, R 14 (1979) Jones, G.M., Milsum, J.H.: Frequency response analysis of central vestibular unit activity resulting from rotational stimulation of the semicircular canals. J. Physiol. (Lond.) 219, 191-215 (1971) Keller, E.L.: Behavior of horizontal semicircular canal afferents in alert monkey during vestibular and optokinetic stimulation. Exp. Brain Res. 24, 459-471 (1976) Keller, E.L., Daniels, P.D.: Oculomotor related interaction of vestibular and visual stimulation in vestibular nucleus cells in alert monkey. Exp. Neurol. 46, 187-198 (1975) Keller, E.L., Precht, W.: Persistence of visual response in vestibular nucleus neurons in cerebellectomized cat. Exp. Brain Res. 32, 591-594 (1978) Lisberger, S.G., Fuchs, A.F.: Role of primate flocculus during rapid behavioral modification of vestibulo-ocular reflex. 1. Purkinje cell activity during visually guided horizonaI smooth-pursuit eye movements and passive head rotation. J. Neurophysiol. 41, 733-763 (1978) Louie, A.W., Kimm, J.: The response of 8th nerve fibers to horizontal sinusoidal oscillation in the alert monkey. Exp. Brain Res. 24, 447-457 (1976) Miles, F.: Single unit firing patterns in the vestibular nuclei related to voluntary eye movements and passive head movements in conscious monkey. Brain Res. 71, 221-224 (1974) Miles, T. S., Henn, V.: Time constants of secondary vestibular neurons recorded from alert monkey. Pfltigers Arch. [SuppI.] 362, R 49 (1976) Raphan, T., Cohen, B., Matsuo, V.: A velocity storage mechanism responsible for optokinetic nystagmus (OKN), optokinetic after-nystagmus (OKAN) and vestibular nystagmus. In: Control of gaze by brain stem neurons, Baker, R., Berthoz, A. (eds.), pp. 37-47. Amsterdam: Elsevier 1977
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Robinson, D.A.: Vestibular and optokinetic symbiosis: An example of explaining by modelling. In: Control of gaze by brain stem neurons, Baker, R., Berthoz, A. (eds.), pp. 49-58. Amsterdam: Elsevier 1977 Schneider, L. W., Anderson, D. J.: Transfer characteristics of first and second order lateral vestibular neurons in gerbil. Brain Res. 112, 61-76 (1976) Shimazu, H., Precht, W.: Tonic and kinetic responses of cat's vestibular neurons to horizontal angular acceleration. J. Neurophysiol. 28, 1014-1028 (1965) Shinoda, Y., Yoshida, K.: Dynamic characteristics of responses to horizontal head angular acceleration in vestibulo-ocular pathways in the cat. J. Neurophysiol. 37, 653-673 (1974) Skavenski, A.A., Robinson, D.A.: Role of abducens neurons in vestibuloocular reflex. J. Neurophysiol. 36, 724-738 (1973) Waespe, W., Henn, V.: Neuronal activity in the vestibular nuclei of the alert monkey during vestibular and optokinetic stimulation. Exp. Brain Res. 27, 523-538 (1977a) Waespe, W., Henn, V.: Vestibular nuclei activity during optokinetic after-nystagmus (OKAN) in the alert monkey. Exp. Brain Res. 31), 323-330 (1977b) Waespe, W., Henn, V.: Conflicting visual-vestibular stimulation and vestibular nucleus activity in alert monkeys. Exp. Brain Res. 33, 203-211 (1978) Wurtz, R.H.: Visual receptive fields of striate cortex neurons in awake monkeys. J. Neurophysiol. 32, 727-742 (1969) Zacharias, G.L., Young, L.R.: Influence of combined visual and vestibular cues on human perception and control of horizontal rotation. Exp. Brain Res. (in press) (1979)
Received April 3, 1979
Exp. Brain Res. 37, 581-593 (1979)
@ Springer-Verlag1979
Vestibular Nuclei Activity in the Alert Monkey During Suppression of Vestibular and Optokinetic Nystagmus* U.W. Buettner 1 and U. Biittner Department of Neurology, University of Ziirich, Rfimistr. 100, CH-8091 Zfirich, Switzerland
Summary. Single neurons were recorded in the vestibular nuclei of monkeys trained to suppress nystagmus by visual fixation during vestibular or optokinetic stimulation. During optokinetic nystagmus vestibular nuclei neurons exhibit frequency changes. With the suppression of optokinetic nystagmus this neuronal activity on average is attenuated by 40 % at stimulus velocities of 40~ At a stimulus velocity of 5~ responses are, under both conditions, close to threshold. For steps in velocity, suppression of vestibular nystagmus shortens the time constants of the decay of neuronal activity from 15-35 s to 5-9 s, while the amplitude of the response remains unchanged. The results are discussed in relation to current models of visual-vestibular interaction. These models use a feedback mechanism which normally operates during vestibular and optokinetic nystagmus, Nystagmus suppression interrupts this feedback loop. Key words: Vestibular nuclei - Alert monkey - Vestibular stimulation Optokinetic stimulation - Nystagmus suppression Vestibular nuclei neurons alter their discharge rate in response to large moving visual fields, which also elicit optokinetic nystagmus (Dichgans and Brandt, 1972; Azzena et al., 1974; Henn et al., 1974; Allure et al., 1976; Waespe and Henn, 1977a; Keller and Precht, 1978). Thus, changes in neuronal activity can be related either to the visual (optokinetic) stimulus or to the motor (nystagmus) response. During vestibular stimulation in the dark dominant time constants for vestibular nuclei neurons in the alert monkey and the accompanying nystagmus are always similar (Buettner et al., 1978), and longer than those of the vestibular nerve (Goldberg and Fernandez, 1971; Blanks et al., 1975; Schneider and Anderson, 1976) and of the vestibular nuclei in anesthetized or decerebrate preparations (Shimazu and Precht, 1965; Jones and Milsum, 1971; Shinoda and Yoshida, 1974; Schneider and Anderson, 1976). * Supported by the Swiss National Foundation for Scientific Research (SNF 3.233.77) and the Deutsche Forschungsgemeinschaft(U. W. Buettner, Bue 379/2) 1 Present address: NeurologischeUniversitfitsklinik, Liebermeisterstr. 18-20, D-7400 Tiibingen, Federal Republic of Germany Offprint requests to: Dr. U. Btittner (address see above)
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The question arises whether activity in the vestibular nuclei during vestibular or optokinetic nystagmus reflects motor output, a sensory input or a combination of both. Therefore, single neuron activity in the vestibular nuclei was investigated during optokinetic and vestibular stimulation with and without suppression of nystagmus.
Methods Two trained Rhesus monkeys (Macaca mulatta) were chronically prepared for single neuron recordings (for details see Buettner et al., 1978). Silver-silver chloride electrodes for measuring horizontal and vertical eye positions were implanted around the boney orbit. During experiments the monkey sat upright in a primate chair with his head fixed and tilted 25 ~ forward to bring the horizontal semicircular canals in the plane of rotation. A strain gauge for measuring head torque was mounted to the head holder. The limbs, except the arm for bar pressing (see below), were loosely restrained. Neuronal activity was recorded with varnished tungsten microelectrodes. The monkey in the primate chair was placed on a servo-controlled turntable. For vestibular stimulation he was rotated about a vertical axis in complete darkness using velocity trapezoids (acceleration 5-10~ 2, constant velocity 40-100~ for at least 50 s, deceleration 5-10~ For optokinetic stimulation a cylinder covered with vertical black and white stripes was rotated around the stationary monkey at velocities of 3-100~ For conflict stimulation the optokinetic cylinder and the turntable were coupled and rotated with the same parameters. Under this condition there is no relative movement between the monkey and the visual surround. Monkeys were trained to fixate a small spot of light using the paradigm of Wurtz (1969). The monkey pressed a bar to turn on the fixation light. After a variable time period (2-16 s) the light dimmed and he had to release the bar within 500 ms to be rewarded with a drop of water. The fixation light was attached to the turntable and rotated with the monkey to suppress vestibular nystagmus; when the monkey was stationary the fixation light allowed suppression of optokinetic nystagmus during rotation of the cylinder. During tests, when the monkey was allowed to have nystagmus, the fixation light was withdrawn from the monkey's sight. Neuronal activity, horizontal and vertical eye position, turntable and cylinder velocity, head torque and the intensity of the fixation light were stored on a FM magnetic tape recorder. At the end of all experiments recording sites were marked by small electrolytic lesions or the injection of neuroanatomical tracer substances. Animals were then perfused with formalin under an overdose of pentobarbital. Frozen sections of the brain, taken at least every 320 ~ were stained with cresyl violet and the recording sites were reconstructed. Instantaneous and average frequency (running average over 250-2,000 ms) was determined. Slow-phase nystagmus velocity was obtained by differentiating the horizontal eye position signal. For analysis, data were written out on a six-channel rectilinear oscillograph. Time constants of decay of neuronal activity and slow-phase nystagmus velocity after angular acceleration (vestibular stimulation) were determined as the time elapsed between maximal activity and the point at which activity had decreased to 1/e above baseline level. Neuronal activity during optokinetic stimulation was measured by averaging over a period of 20-30 s after a steady level of activity was reached.
Results Neurons, which receive their main input from the horizontal semicircular canals, were recorded in the vestibular nuclei of both sides of the brainstem. Anatomical reconstruction showed that recording sites were mostly in the rostral part of the vestibular nuclei complex. Results are based on the analysis of 57 neurons, which were specifically tested during suppression of optokinetic and/or vestibular nystagmus. Thirty-six (63%) neurons were activated during a c c e l e r a t i o n t o t h e i p s i l a t e r a l s i d e a n d w e r e c l a s s i f i e d as t y p e I ( D u e n s i n g a n d
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Neuronal Activity During Optokinetic Nystagmus and its Suppression All vestibular nuclei neurons respond to large moving visual fields, which elicit optokinetic nystagmus (Fig. 1). An activation occurs when the optokinetic cylinder moves in the direction opposite to an activating vestibular stimulus. Under these stimulus conditions, optokinetic and vestibular nystagmus beat into the same direction. When the optokinetic cylinder is rotated in the opposite direction neuronal activity decreases below spontaneous activity level. The activity changes persist during the whole period of optokinetic stimulation. A linear relation can be obtained between increase of neuronal activity and stimulus velocity up to velocities of 60~ At higher velocities neuronal activity tends to saturate (Figs. 3 and 4, Waespe and Henn, 1977a). When optokinetic nystagmus is suppressed, vestibular nuclei neurons are still activated or inhibited depending on the direction of stimulus motion (Fig. 1). In most neurons (80%) activity was reduced if nystagmus was suppressed (Figs. 1, 2, 3a, and 4). About 10% of the neurons responded in the same manner whether the monkey was allowed to have nystagmus or not. In the latter neurons the response to optokinetic stimulation remained unchanged after the transition from fixation suppression to nystagmus.
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A few neurons with a generally weak response during optokinetic nystagmus exhibited only a small, or no response during its suppression (Fig. 2). No obvious differences could be observed for the behavior of type I or II neurons, additionally modulated with eye movements or not. Neurons with a strong eye position signal were excluded from comparative analysis, although they also showed an activity increase during suppression, when a steady eye position was maintained. Neurons were most commonly investigated at a stimulus velocity of 40~ and quantitative measurements were confined to the activating direction. When activity at this stimulus velocity during optokinetic nystagmus is set at 100% (mean value: 23.2 imp/s above resting discharge), then during suppression of nystagmus, activity increase on average is attentuated to 5 9 % (mean value: 13.7 imp/s above resting discharge) (Fig. 2). Twenty-five neurons were also tested at optokinetic stimulus velocities of 3 ~ and 5~ Neuronal activation was small as expected with such low stimulus velocities. In every case activation was similar whether the monkey had nystagmus or suppressed it (Figs. 3 and 4). Fourteen neurons could be tested over the whole range of stimulus velocities between 5 ~ and 100~ A few neurons responded equally under both conditions, with and without nystagmus (Fig. 3B). The majority, however, showed this similar response only for velocities up to about 20~ above, activity was stronger during nystagmus than during its suppression (Figs. 3A and 4).
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Neuronal Activity During Vestibular Nystagrnus and its Suppression Vestibular nuclei neurons in the alert monkey respond to angular acceleration in a uniform way: depending on the direction and whether a type I or II neuron is tested, the activity increases, or decreases, and returns to the spontaneous activity level during constant velocity rotation with a time constant of 15-35 s. During deceleration a mirror-like activity pattern is observed (Figs. 5 and 6). This is seen for all vestibular nuclei neurons, regardless of whether or not they show an additional modulation with eye movements. Concomitant vestibular nystagmus shows the same behavior and declines with the same time constant (Fig. 5; Buettner et al., 1978). When vestibular nystagmus is suppressed by fixating a small spot of light, there is little change in the maximal firing rate at the end of acceleration: the activity in 80% of the neurons was reduced by less than 10%, for the remaining 20 %, reduction was between 10-30 %. During the period of rotation at constant velocity differences become prominent: with nystagmus suppression the activity returns faster to the spontaneous activity level, with a time constant between 5 and 9 s. This was found for all 31 neurons investigated. These short time constants occur only during nystagmus suppression and become much larger again during normal nystagmus response (Figs. 5 and 6). Another paradigm to suppress nystagmus is to expose the monkey to conflicting visual-vestibular stimulation by mechanically coupling the optokinetic cylinder to the turntable. During acceleration there is then no visual displacement and with accelerations below 10~ 2 all nystagmus is suppressed.
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This conflicting v i s u a l - v e s t i b u l a r stimulus a t t e n u a t e s the r e s p o n s e o f v e s t i b u l a r nuclei n e u r o n s a n d t i m e c o n s t a n t s a r e r e d u c e d to 3 - 4 s (Fig. 6, W a e s p e a n d H e n n , 1978). A few n e u r o n s c o u l d be i n v e s t i g a t e d u n d e r all t h r e e c o n d i t i o n s ( v e s t i b u l a r n y s t a g m u s in the d a r k , s u p p r e s s i o n o f v e s t i b u l a r n y s t a g m u s b y fixation o f a small s p o t o f light in d a r k n e s s , o r b y i n t r o d u c i n g v i s u a l - v e s t i b u l a r conflict). B o t h kinds o f n y s t a g m u s s u p p r e s s i o n s h o r t e n e d the t i m e c o n s t a n t s o f n e u r o n a l activity (conflicting s t i m u l a t i o n b e i n g m o r e effective t h a n fixation s u p p r e s s i o n ) , b u t w h e r e a s p e a k n e u r o n a l activity d u r i n g fixation s u p p r e s s i o n was n o t m u c h d i f f e r e n t f r o m t h e r e s p o n s e d u r i n g n y s t a g m u s , v i s u a l - v e s t i b u l a r conflict c o n s i d e r a b l y a t t e n u a t e d p e a k n e u r o n a l activity.
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Fig. 6. Response of a vestibular nuclei neuron (type I) to a velocity trapezoid during nystagmus in the dark (vestibular), nystagmus suppression in the dark (vestibular plus fixation), and rotation in the light with the cylinder fixed to the turntable (visual-vestibular conflict). In the latter condition there is no relative motion of the visual surround. Ordinate: Averaged neuronal response of 2-3 trials. Stimulus parameters are indicated. During nystagmus neuronal activity returns to spontaneous activity level with a time constant of 15 s after acceleration and 25 s after deceleration. Nystagmus slow-phase velocity showed the same time course with a similar asymmetry. Nystagmus suppression leads to a reduction of time constants to 5-6 s for both directions, whereas the maximal activity changes remain the same. During visual-vestibular conflict the response amplitudes are diminished and time constants are further reduced. No nystagmus occurred during visual-vestibular conflict stimulation
Discussion A t the outset we asked w h e t h e r n e u r o n a l activity in the v e s t i b u l a r nuclei is m o r e r e l a t e d to visual ( o p t o k i n e t i c ) a n d v e s t i b u l a r i n p u t or to o c u l o m o t o r ( n y s t a g m u s ) output. A l l n e u r o n s r e s p o n d e d in a similar way to the different e x p e r i m e n t a l paradigms, b u t their activity could n o t be r e l a t e d to simply o n e sensory or o n e m o t o r p a r a m e t e r . D u r i n g o p t o k i n e t i c s t i m u l a t i o n n e u r o n s were activated e v e n w h e n o p t o k i n e t i c n y s t a g m u s was suppressed, p r o v i n g that an i n p u t from the visual system o p e r a t e s i n d e p e n d e n t l y of the m o t o r response. O n the o t h e r hand, the p r e s e n c e or a b s e n c e of n y s t a g m u s was clearly reflected in n e u r o n a l activity. This leads to the u n e x p e c t e d result that only o n e synapse away from the vestibular n e r v e n e u r o n a l activity to the same sensory stimulus differs with the m o t o r b e h a v i o r of the animal.
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Optokinetic Stimulation Vestibular nuclei neurons still show consistent modulation of their activity during suppression of optokinetic nystagmus. This visually mediated response is small at low velocities, increases monotonically up to velocities of 40-60~ and tends to saturate at higher velocities (Fig. 4). If nystagmus is permitted, the increase in neuronal response is greater at velocities above 20~ but saturates also above 60~ It has not yet been determined which parameter the visually mediated responses of the vestibular nuclei neurons represent. An internally created signal about surround motion or retinal slip velocity have been suggested. The results in Fig. 4 cannot be explained by assuming that retinal slip velocity is the only effective parameter. Slip velocity during nystagmus probably does not exceed 10% of stimulus velocity up to 60~ (Cohen et al., 1977). Up to stimulus velocities of 20~ responses of vestibular nuclei neurons are similar during nystagmus and suppression although retinal slip is far greater during suppression. Furthermore, if the response differences for nystagmus and its suppression at higher stimulus velocities were due to a decreased responsiveness for high retinal slip velocities, the curve for nystagmus suppression should show a response peak at lower velocities. This was not found. Thus, responses of vestibular nuclei neurons during optokinetic nystagmus are not only determined by the visual input. Motor output (or an internal signal, see below) is also an important factor. The mode of interaction of these two parameters at the level of the vestibular nuclei is not known. When nystagmus takes place, neuronal activity is proportional to slow-phase nystagmus velocity over a wide range and independent of whether nystagmus was elicited by vestibular or optokinetic stimulation, or whether it is vestibular or optokinetic after-nystagmus (Waespe and Henn, 1977b).
Vestibular Stimulation If no fixation is required during vestibular stimulation, time constants of vestibular nuclei neurons range from 15-35 s, and are similar to those of slow-phase nystagmus velocity (Figs. 5, 6; Miles and Henn, 1976; Buettner et al., 1978). During suppression of vestibular nystagmus, time constants of vestibular nuclei neurons are shortened to 5-9 s, values only slightly larger than those found in the vestibular nerve (Goldberg and Fernandez, 1971) or the vestibular nuclei of the anesthetized monkey (Buettner et al., 1978). Skavenski and Robinson (1973) pointed out the differences between the vestibular nerve and nystagmus (VOR) response in alert animals and postulated a "low frequency compensation" in the brainstem to overcome these differences. Our single neuron recordings in the alert monkey show that this compensation can already be demonstrated in the vestibular nuclei. It is not yet clear, how and through which neuronal substrates this partial integration is achieved. Whatever the exact mechanism, fixation suppression or anesthesia (Buettner et al., 1978) cancel the "low frequency compensation". The signal recorded in
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the vestibular nuclei is then similar to that carried by the vestibular nerve. Keller and Daniels (1975) also found a vestibular signal still present in the vestibular nuclei during sinusoidal rotation of animals suppressing their nystagmus. For those neurons projecting to the oculomotor system this remaining vestibular modulation has to be cancelled, which requires additional information processing between the vestibular and the oculomotor nuclei (Fig. 7). A neuronal signal, which could take part in such information processing was recorded in the flocculus of the monkey (Lisberger and Fuchs, 1978), however, the exact location of interaction in the brainstem has yet to be determined. Another experimental paradigm to suppress nystagmus during vestibular stimulation is to introduce a visual-vestibular conflict by rotation of the animal together with its visual surround so that during vestibular stimulation no visual displacement takes place (Waespe and Henn, 1978). With accelerations up to 10~ 2 all nystagmus is suppressed. Under these conditions time constants of activity in vestibular neurons are shortened to about 3 - 4 s, and peak modulation is attenuated. This attenuation and pronounced shortening of time constants, which is different from the response when the monkey fixates a light spot in an otherwise dark environment, shows that changes in neuronal response cannot entirely be attributed to the lack of nystagmus. Rather, an additional effect from the retinal periphery must exist.
Models
Present physiological and anatomical knowledge is insufficient to explain all our results. However, models have been introduced to describe the nystag-
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mus response (Raphan et al., 1977; Robinson, 1977) during combined visual-vestibular stimulation, which can simulate some of our results and allow further specification of the role of the vestibular nuclei in transforming sensory information into motor behavior. Vestibular nuclei activity is determined by the vestibular nerve input, the visual input and a local feedback mechanism (Fig. 7). During vestibular stimulation, the feedback mechanism produces the longer time constant ("low frequency compensation", Skavenski and Robinson, 1973) of vestibular nuclei neurons. During optokinetic nystagmus this feedback mechanism is also activated and kept operating at a constant level by the continuous visual input. Therefore, over a wide range, a close correlation can be shown between neuronal activity in the vestibular nuclei and slow-phase velocity of both vestibular and optokinetic nystagmus. During optokinetic after-nystagmus, when all input ceases, the feedback mechanism, acting as a leaky integrator (Raphan et al., 1977), slowly discharges with its characteristic time constant. This feedback mechanism is independent of the actual execution of eye movements, since the time constants in the vestibular nuclei are not affected in monkeys with a horizontal gaze palsy caused by a lesion in the paramedian pontine reticular formation (Jaeger et al., 1979). In the model shown in Fig. 7, suppression of nystagmus by fixating a spot of light interrupts the feedback mechanism. The visual and vestibular nerve inputs, however, are still present in the vestibular nuclei. These remaining signals have to be cancelled by additional mechanisms between the vestibular and oculomotor nuclei. It should be emphasized that Fig. 7 only represents a simple scheme relevant to the results of our experiments. A more complete description would have to include more details and different mechanisms. The visual input can also act directly upon the oculomotor system, since vestibular nuclei neurons only increase their response up to stimulus velocities of 60~ (Fig. 4, Waespe and Henn, 1977a), whereas optokinetic nystagmus in the monkey follows velocities up to 180~ (Cohen et al., 1977). Also, if vestibular nystagmus is suppressed by a large visual field rotating together with the monkey (visual-vestibular conflict) neuronal responses are smaller than those seen in suppression of vestibular nystagmus by fixating a small spot of light (Fig. 6, Waespe and Henn, 1978). An internal comparator to estimate this conflict and accordingly weight these inputs has been suggested (Zacharias and Young, 1979).
Conclusions
Experimental results emphasize that the response of vestibular nuclei neurons cannot be related simply to sensory (vestibular or optokinetic) stimuli, but the presence or absence of the oculomotor response must also be taken into account. This stresses the complex multi-input information processing in the vestibular nuclei and its close reciprocal connection to the oculomotor system.
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U.W. Buettner and U. Bfittner
Acknowledgements. The authors wish to thank Ms. Vappu Isoviita for technical assistance, Mr. V. Corti for building and maintaining part of the electronic equipment and Mr. J. Mttller for photography.
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Received April 3, 1979
