Sinusoidal eye movements from brain stem stimulation in the cat

Vi.viorr Rrs.

Vol.

8, pp. 1073-1079.

SINUSOIDAL STEM

Pergamon

Press 1968.

Printed in Great Britain.

EYE MOVEMENTS STIMULATION IN

FROM BRAIN THE CAT1

B. L. ZUBER Department of Information Engineering, University of Illinois at Chicago Circle and Department of Biomedical Engineering, Presbyterian-St. Luke’s Hospital, Chicago (Received 6 January 1968; in revised form 12 March 1968)

INTRODUCTION THE SINUSOIDAL input

is a basic tool in systems analysis and is very useful in the deter-

mination of the dynamical characteristics of both biological and non-biological systems. The usefulness of this tool could be extended if it were applicable to neurological systems at the level of the basic neuro-motor mechanisms. In the past systems analysis studies have generally considered the overall, intact neurological system as a “black box,” with only the system input and output available to the experimenter (e.g. STARK and YOUNG, 1964). Measuring the system output response to mathematically defined inputs may lead, through the use of linear systems analysis, to a mathematical description of the dynamic behavior of the system. The present paper represents part of a study involving breaking into the oculomotor black box with the hope of utilizing the techniques of systems analysis to dynamically characterize individual elements or small groups of neurological elements. The successful application of such techniques could lead to anatomical localization of specific dynamic characteristics that have been demonstrated but not localized in studies of an overall nature. In addition, one might hope to learn something about the organizational and signal handling aspects of the neurological elements subjected to investigation (PARTRIDGE, 1966; ZUBER,et al., 1967). This paper describes the application of a sinusoidal input at the level of the third nerve within the brain stem of the cat. The result of this stimulation has been horizontal sinusoidal eye movement with the medial rectus as the prime mover. The properties of the stimulus necessary to elicit these movements are described. The question of linearity is explored and some physiological and pharmacological properties of the system are briefly described. METHODS Cats are maintained on pentobarbital anesthesia (intravenous) at a level where cornea1 and lid reflexes are absent. A bipolar stimulating electrode consisting of two platinum wires within a cannula (tip separation approx. 0.6 mm) is stereo&u&ally aimed at the 1 This research was supported by the University of Illinois Research Board, the Public Health Service (NB-06487, NB-07777) and the W. Clement Stone Foundation. The author thanks Dr. L. Stark for encouragement and support, and Dr. A. Troelstra for critically reviewing the manuscript. 1073

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third nerve within the brain stem in anterior plane 4.5. After craniotomy the electrode is driven through the cerebrum toward the brain stem. Beginning at a point approximately one centimeter above the target, the stimulus (described below) is applied after every millimeter increase in depth of the electrode. The first physiological effects of stimulation occur about 5 mm above the target. These consist of bilateral pupillary dilatation with a superimposed sinusoidal component. Penetration is continued in 0.5 mm steps until an area is found from which clearly horizontal eye movement is elicited by stimulation. At this point, movement of the electrode by less than 0.5 mm may either change the direction of eye movement or obliterate it. Eye movements are monitored by a previously described method (STARK,et al., 1962; ZUBER, 1965) involving differential reflection of infrared light, in this case from the iris on either side of the constricted pupil. A specially constructed eye movement monitor is firmly attached to the stereotaxic frame. The pupil of the monitored eye is constricted with topically applied physostigmine to prevent the interference with eye movement recording caused by changes in pupillary area. As a starting point, a linear relationship has been assumed between frequency of firing in the third nerve and eye position. The stimulus, therefore, consists of trains of pulses with the frequency of the pulse train modulated sinusoidally. Figure 1 shows an example of the modulating waveform (of frequency F,,,) and the stimulus pulse train, the frequency of which (F,) is controlled by the level of the modulating waveform. The example shows F,varying between 50 pulses per set and 250 pulses per set with the modulating frequency, F,,,, equal to 10 c/s. There are then four crucial parameters associated with the stimulus: (1) the range of pulse frequency within the train; (2) the average value of Ft;(3) the frequency of the modulating waveform (F,,,); and (4) the intensity or magnitude of the stimulus pulses. The presence of a threshold for the production of sinusoidal eye movements is a clear property of this preparation. All experiments have been performed with slightly suprathreshold trains of pulses of magnitude 0.01 to 0.05 mA. Once the stimulating electrode has been localized to the appropriate brainstem area, the full oculomotor response may be elicited only by a stimulus with energy-per-pulse which is above a minimum level. Useful values of F,,, will, of course, depend upon the dynamics of the system itself. In the experiments described below, values of F,,, ranging from 0.5 to 20 c/s have been used. By far the most important stimulus parameter is F,-the frequency of pulses within the stimulus train. This is the true input to the system. In all experiments reported here the average value of Ft has been 100 pulses per set with F, varying within the range of 50-150 pulses per sec. Within this range the system appears to behave linearly in that a sinusoidal input produces a sinusoidal output waveform of the same frequency. If the limits of this range are significantly changed, the output waveform may become distorted. For example, if F,is modulated from 50 to 250 pulses per set, the output waveform becomes flattened at the top, indicating that the high frequency stimulation has driven the system into a region of saturation. The relationship between the development of tension and frequency of nerve stimulation in the extraocular muscles of the cat has been reported by COOPERand ECCLE~(1930, medial rectus) and BREININ(1962, lateral rectus). These two sets of data, if normalized, are virtually identical. Both studies show that the rate of tension development begins to decrease sharply as the stimulation frequency approaches about 200 pulses per sec. The curves of developed tension versus stimulation frequency may be closely approximated by a straight line within the stimulation frequency range of 50- 150 pulses per sec.

20MSEC

-

FIG. 1. An example of the stimutus.

Top trace is m~ulatin~ waveform which represents the variation in pulse frequency of the stirnub train (lower trace). In this example pulse frequency is sinusoidally modulated between SO-250 puke-s per set

[facing p. 1074

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Eye Movements from Brain Stem Stimulation in the Cat

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RESULTS 2 shows a plot of left eye position in degrees as a function of stimulation

frequency. In this experiment, the nerve was stimulated with steady pulse frequencies ranging Figure

STIMULUS FREQUENCY, Ft(PP8) FIG. 2. Static calibration showing extent of nasal deviation of the eye from the primary

position (ordinate) as a function of frequency of stimulation applied to the third nerve within the brain stem (abscii).

from 20 to 200 pulses per set while the resulting change in eye position was measured through a microscope equipped with a graduated ocular. A small piece. of thread was placed at the center of the cornea to provide a constant measuring point. The position of the thread relative to what was judged to be the primary position was measured during steady state after the onset of stimulation. Using the dimensions of the cat’s eyeball and simple triangulation this distance was converted into degrees of ocular rotation relative to the primary position, which is the variable plotted on the ordinate of Fig. 2. The filled circles in Fig. 2 represent the average values of ocular rotation at a given frequency of stimulation. The vertical lines show the range of the data points. The shape of the curve in Fig. 2 is quite similar to the tension frequency curves of COOPER and ECCLE~(1930) and BREININ (1962). Notice that the part of the curve corresponding to stimulation frequencies between 50-150 pulses per set may be closely approximated by a straight line. The static calibration curve of Fig. 2 serves to provide a quantitative basis for sinusoidal responses and represents additional experimental evidence for the assumption of linearity between eye position and frequency of firing in the third nerve. With low frequency sinusoidal modulation of F, between 50-150 pulses per set, we expect (and measure) a sinusoidal response with a peak-to-peak amplitude of approximately 12”. Assuming linearity this would correspond to a sensitivity of 0.12 deg/pulse per set within this range of stimulus frequencies. Figure 3 shows an average of twenty responses consisting of four cycles of a sinusoidal movement of the left eye at a frequency of 15 c/s. The modulating waveform is shown

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B. L. ZUBER

16 CPS Fm= ‘1:: CAT NO. 155 I( 0.05 SEC -I FIG. 3. The average sinusoidal eye movement (top trace) resulting from sinusoidal modulation of the stimulus pulse train between 50-150 pulses per second with a modulation frequency of 15 c/s. The phase lag is introduced by the nerve-muscle-eyeball system.

in the lower trace of the figure. Averaging was accomplished with a small average response computer (Nuclear Chicago 7100). The modulating waveform (F,,,) is representative of the time course of the true stimulus-the pulse train frequency. In this case the stimulus frequency was sinusoidally modulated between 50 and 150 pps. The eye movement follows the stimulus with a phase lag of slightly less than 180” introduced by the dynamics of the nerve-muscle system. As might be expected, only the ipsilateral eye moves and an increase in stimulus frequency causes the eye to move to the right (nasal). All movement is confined to the right of the primary position. These observations seem to confirm that the medial rectus is the prime mover for this eye movement. This has been further confirmed by the observation of EMG activation during stimulation (ZUBER, 1968). Responses such as that shown in Fig. 3 may be recorded using any value of F,,,within the range of 0.5-20 c/s. The amplitude of the response is, of course, a decreasing function of F,,,. As F,,, increases, the responses are seen to lag increasingly behind the stimulus. The amplitude and phase characteristics exhibited by this system may be adequately described as a first order lag (represented by a linear first order differential equation) with a time constant of 64 msec (ZUBER, 1968). If 0.5 mg decamethoniam bromide (ClO) is injected into the medial side of the ipsilateral orbit, eye movement is no longer elicited by brain stem stimulation. Electrical activity in the medial rectus may be seen to cease, and its disappearance follows the same time course as that of the disappearance of eye movement. During the hour following the application of the neuromuscular blocking agent, both electrical activity and ocular motility gradually return to the levels observed before the use of the drug. Cl0 has an effect on the extraocular muscles of the cat similar to that of succinylcholine (KATZ and EAKINS, 1967). This effect may be divided into two parts: a contracture, thought to result from direct depolarization of slow muscle fibers, and which increases base line tension in the muscle; and a depression of the twitch response of fast muscle fibers which is probably due to the interruption of neuromuscular transmission (BACH-Y-R.ITA and ITO, 1966). The twitch response resulting from electrical stimulation appears normal during contracture when small doses of Cl0 are used, but with larger doses both contracture and a depression of the twitch response are observed (KATZ and EAKINS, 1967). BACH-Y-RITA and ITO (1966) also observed that the depression of the twitch response lasted much longer than the contracture produced by intravenously administered succinylcholine, providing additional evidence that the two effects are produced by different mechanisms. Therefore, it is likely that the absence of eye movement on stimulation following the topical admin-

Sinusoidal Eye

Movementsfrom Brain Stem Stim~ation in the Cat

1077

istration of a relatively large dose of Cl0 may be attributed to the depression of the twitch response, probably caused by an interruption of neuromuscular transmission in the fast muscle fibers. Finally, the intraorbital administration of 0.5 mg of gallamine arsenide brings about a marked depression, but not obliteration, of both electrical activity in the medial rectus and eye movement caused by stimulation. Gallamine does not produce the contracture response observed with Cl0 or succinylcholine. These results are strong evidence in support of the normal functioning of the neuromuscular junction in these experiments.

DISCUSSION On stimulating neural structures with patterned inputs such as sinusoids certain assumptions regarding the neural code are implicit. The results of stimulation, specifically the shape of the output waveform may serve to justify the initial assumptions, and in doing so may provide new information about the details of the neural code normally used in the stim~ated structure. In the present case the initial assumption of a linear relationship between frequency of firing in the third nerve and eye position is seemingly justitled by the result indicating linearity of the static calibration curve within the range of input variables used, and by a sinusoidal output produced by a sinwoidal input. Linearity may not be a universal characteristic of peripheral neuromuscular systems. PARTRIDGE (1966), using similar stimulating techniques in an in sirU cat triceps surae nerve-muscle preparation, recorded non-linear responses of both load position and muscle force. These could not be linearized by decreasing input amplitudes. The use of patterned inputs and the fact that the final physiological output ofthe system-eye movement-is recorded, are considered crucial aspects of the experiments described above. While such variables as muscle tension may certainly be considered as outputs of the oculomotor system, they are not final outputs. Intermediate outputs are thus subject to further modification by more peripheral dynamic elements such as the dynamics imposed by the globe-orbit configuration. Using eye movement as the measured output in experiments such as those described above insures that all potentially limiting dynamic elements are present in the system being considered. The results of such experiments may also be more readily compared with studies involving the overall oculomotor system, since in those studies eye movement is usually the measured output. The use of mathemati~ly defined patterned inputs at the neural level of motor systems is of great potential value. The most crucial requirement is, of course, that of linearity. If this requirement is satisfied, the techniques of linear systems analysis may be applied to dynamically characterize these systems as well as to anatomically localize specific dynamic elements, and to more readily elucidate the code utilized in the neural pathways and elements of the system. The use of such inputs does not in the least obviate the need for the dynamic analysis of on-going neural activity recorded under more physiological conditions. Data resulting from electrical stimulation may only be properly interpreted in light of comparable data recorded from various points in the oculomotor system during physiologi~lly produced (e.g. visuaby initiated) eye movements.

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B. L. ZUBER REFERENCES

BACH-Y-RITA, P. and ITO, F. (1966). In viva studies on fast and slow muscle fibers in cat extraocular muscles. J. gen. Physiol. 49, 1177-l 198. BREININ, G. W. (1962). The Uectrophysiology of Extraocular Muscle. University of Toronto Press, Toronto. COOPER,S. and ECCLES,J. C. (1930). The isometric responses of mammalian muscles. J. Physiol., Lo&. 69, 377-385. KATZ, R. L. and EAIUNS, K. E. (1967). Pharmacological studies of extraocular muscles. Invest. Ophthal. 6, 261-268. PARTRIDC+E, L. D. (1966). Signal-handling characteristics of load-moving skeletal muscles. Am. J. Physiol. 210, 1178-1191. STARK, L. and YOUNG, L. R. (1964). Defining biological control systems. Ann. &‘.Y. Acad. Sci. 117, 426-442. STARK, L., Voss~us, G. and YOUNG, L. R. (1962). Predictive control of eye tracking movements. I.R.E. Trans. Hum. Fat. Elec., HFE3, 52-57. ZUBER, B. L. (1965). Physiological control of eye movements in humans. PH.D. Dissertation, MIT. ZUBER, B. L., REINHART,R. J. and BEUO, J. L. (1967). The final output pathways for oculomotor control in the cat. Proc. 20th Ann. Conf. Engineering in Medicine and Biol. 9, 7.2. ZUBER, B. L. (1968). Eye movement dynamics in the cat: The final motor pathway. Exptl Neural. 20, 255-260.

Abstract-Ipsilateral sinusoidal eye movements may be produced in the anesthetized cat by stimulating the third nerve within the brain stem. Stimulation has been of the form of trains of pulses with a sinusoidally modulated pulse frequency. Sinusoidal responses are observed over the modulation frequency range of 05 to 20 c/s. These responses are characterized by a threshold and are obliterated by neuromuscular blockmg agents. The sinusoidal output together with the results of static calibration indicate that the third nerve-medical rectus-eyeball system may be treated as a linear system for stimulus pulse frequencies between 50 and 150 pulses per second. Within this range the sensitivity of the system is approximately @12 degrees of eye movement/pulse per second. The static calibration curve of eye position versus stimulus frequency has the same shape as previously published curves of developed tension versus stimulation frequency.

R-n peut produire chez le chat anesthdsii des mouvements des yeux. ipsilattraux et sinusohiaux, en stimulant le troiaitmc nerf du faisceau c6r6bral. La stimulation comporte des trains de pulsations dont la f&quence est modul& sinusoi[dalement. On observe des r6ponsea sinuaohiales si la fr6quence de modulation varie entre 0,5 et 20 c/s. Ces reponses sont cara&ris&s par un seuil et sont supprim& par l’action d’agents de blocage neuromusculaire. La rdponse sinusoidale ainsi que le Cal&rage statique indiquent que le troisieme nerf-medical rectua-du syst&ne du globe oculaire fonctionne comme un systeme lineaire pour des frtquences du stimulus comprises entre 50 et 100 pulsations par seconde. Dans cet intervalle la sensibilite du syst&me eat voisine de 0,12 degr6 de mouvement de l’oeil/ pulsation par seconde. La courbe de calibrage statique de la position del’oeil en fonction de la fr6quence du stimulus a la m6me forme que lee courbes pr&demment publiees de la tension divelopp& en fonction de la fr6quence de stimulation.

Znaammenfaasaag-Gleichseitige, sinusfiirmige Augenbewegungen konnen in der betlubten Katze durch Reizung des d&ten Nervs innerhalb des Himstamms hervorgerufen werden. Die Reizung erfolgte tiber die Form der Pulsziige mit Hilfe einer sinusfljrmig modulierten Pulsfrequenz. Sinusformige Antworten werden iiber einen Modulations-Frequenzbereich von 0,5 bis 20 Hz beobachtet. Die Antworten sind durch eine Schwelle charakteristisiert Die sinusformige und werden durch neuromuskuhlre Blockienmgsagenzien geloscht. AusganpgriiBe in Verbindung mit der statischen Eichung weist darauf hin, daB das System “dritter Nerv-rectus medialis-Augapfel” fiJr Frequenzen des Pulsreizes von 50 bis 15O/sec, als lineares System betrachtet werden kann. Innerhalb dieses Bereiches ist die Empfindlichkeit des Systems etwa 0,12 Grad Augenbewegung/Puls pro Sekunde. Die stat&he Eichkurve von Augenlage zur Reizfrequenz hat die selbe Gestalt wie vorher veroffentlichte Kurven von auftretender Spannung zu Reizfrequenz.

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