JOURNALOF NEUROPHYSIOLOGY Vol. 42, No. 5, September 1979. Printed
in U.S.A.
Neural Correlates of Nystagmus in Abducens Nerve V. HONRUBIA,
D. B. REINGOLD,
C. G. Y. LAU,
AND
P. H. WARD
Division of Heud und Neck Surgery (Otolaryngology) cud Brcrirl Resecwh Institlrte, UCLA School of Medicine, Los Angeles, Ccclifbrnk 90024; and Ncrtioncrl EJY Institute, Nationd Institutes of Heulth, Bethesdu, Muryland 20205
SUMMARY
AND
CONCLUSIONS
I. The firing rates of action potentials of abducens nerve single fibers were recorded in the cat’s orbit during a variety of vestibular and optokinetic stimulations. 2. Comparison was made of the neural firing rates associated with agonist and antagonist responses during slow and fast components of vestibular and optokinetic nystagmus. It was found that the relationship between the motoneuron firing rates and the eye motion was independent of the reflex with which they were associatedvestibular or optokinetic, or the type of response-agonist or antagonist. No neurons were observed that responded only during the fast or only during the slow nystagmus phase. Motoneuron firing rates were proportional to both velocity and position of the eye in a ratio of 1 (spike/s)/(deg/s) to 7.2 (spikesls)ldeg. The behavior of the motoneurons was compatible with the hypothesis that their firing rates are sufficient to overcome both elastic and viscous forces by which the muscles and ligaments hold the eye in the orbit. 3. For low-frequency head rotations, eye displacement and neural responses showed a small phase angle difference. At higher frequencies, however, while the eyes maintained a fixed relationship to the head rotation, the neural responses showed an increasing phase lead. One component of this phase lead compensated for the phase lag introduced by the orbital mechanics. The other was modeled as a constant delay of approximately 70 ms, which may be accounted for by neuromuscular transmission and transduction. INTRODUCTION
To maintain vision during sinusoidal angular acceleration of the head at the center 1282
frequency of the vestibular system’s response, the eye executes two basic types of counterturning movements. For head displacements of 20” of peak amplitude or less, the eye movement reflects the trajectory of the head displacement. However, for larger head displacements, when the maximum rotation that the eyes can produce is smaller than that of the head, compensation is achieved by means of nystagmus. Visual fixation is achieved during the slow component, even when the amplitude of the nystagmus is small, since, at this time, the eye velocity is proportional to the velocity of the head, but in the opposite direction (e.g., Refs. 5,22,27). Likewise, during rotation of the visual surrounding-optokinetic stimulation -a nystagmus is induced whose slow component, in the direction of the visual surrounding, has the velocity of the visual stimulus (e.g., Refs. 11, 18). In this way the space around the head is visually monitored by the eye, with small angular deviations within the orbit interrupted by fast components in the opposite direction, which are too quick and brief for vision. The first quantitative evidence on the relationship between eye movements induced by physiological stimulation of the semicircular canals (vestibular stimulation) and firing rates of abducens motoneurons was obtained in alert monkeys by Skavenski and Robinson (27). They measured the relationship between the amplitude and velocity of eye movements with the motoneuron firing rate during slow components of vestibular nystagmus and during the production of purely compensatory sinusoidal eye movements. Quantitatively the behavior of abdutens motoneurons in primates following vestibular stimulation was found to be similar to that discovered earlier during visually guided motions (20). Within a reasonable range of angular eye deviations, the firing
0022-3077/79/0000-OOOO$O 1.25 Copyright 0 1979 The American Physiological Society
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NEURAL
CORRELATES
rate of the motoneurons, Fmn, is approximately given by the equation Fmn
= k(8 - 0,,) + r(dldr)(8
- 0,)
OF NYSTAGMUS
motor function (8, 20, 27).
1283
discovered
in
primates
(1)
where 8 is the eye’s angular position in the orbit, & is the orbital eye position or threshold beyond which the motoneuron is active -the on-region, and constants /i and r’ relate the frequency of ocular motoneuron firing to the position and velocity, respectively, of the eye movement. Important observations in this study were that no significant difference existed in the value of the coefficients /i and I’ during agonist or antagonist movement resulting from either visual or vestibular reflex activation, and that no neurons were found whose activity was limited to the production of the saccadic quick phase of nystagmus. The existing information obtained from experiments on cats is at variance with that from primates in that among cat’s motoneurons there appear to be some that are associated with production of either slow or fast components (1, 9, 10, 16, 19, 30). However, the relationship between the cat’s ocular motoneuron firing rates and eye movement during each phase of nystagmus has not been studied with the precision and detail used in primates. Whether this functional aspect of the vestibulooculomotor system in the cat is similar to that in primates is not known. Since much basic information on vestibuloocular functions and structures is being derived from studies in cats (2, 15, 25), it is important to know if, in these animals, the firing rate of ocular motoneurons follows the same principles as in monkeys. This report describes the results of quantitative measurements of abducens motoneuron neural activity during vestibular- and visual(optokinetic) induced nystagmus in alert cats. Simultaneous recordings were made of action potentials in single fibers of the abducens nerve dissected within the right orbit and of electrooculographically monitored movements of the left eye. Statistical information about the correlation between the eye movement and the ocular motoneuron firing rates was obtained using digital computer programs developed for this purpose. Findings of this study were compared with those from earlier experiments in alert monkeys to determine the applicability to the cat of basic principles of vestibulo-visual-oculo-
METHODS
Animul
prepuration
Under general anesthesia with fast-acting Fluothane, an acrylic cap was mounted on the skull of adult cats that had been screened for normal optokinetic and vestibular reflexes. The cap allowed the head to be fastened rigidly in place, assuring precise control of the animal’s motion and recording of nerve impulses during strong angular accelerations. By means of surgical methods similar to those of Ward (28), after enucleation of the eye globe, branches of the right sixth nerve were exposed where they enter the lateral rectus muscle. Operative sites, except in the immediate vicinity of the nerve, were infiltrated with long-lasting Xylocaine in an oil base. Normal body temperature and liquid supply were maintained with the aid of a heating pad and electrolytes injected intraperitoneally. The animal was allowed 6- 12 h for recovery from anesthesia. It was then wrapped in towels and placed in a soundproof chamber in a fixation box mounted on an Inland Controls model 800 rateof-motion table in such a way that the animal’s head was on the vertical axis of rotation and its lateral semicircular canals were horizontal. Each animal, after its recovery from anesthesia, was alert and able to eat and drink, showed no signs of undue stress, and responded well to being talked to and played with. During recordings, the animal was kept alert by being petted frequently. Occasionally, from the outside, the investigator talked to it loudly or made noise with the hands, keys, or other objects. Vestibular stimuli, in the form of angular accelerations about a vertical axis passing through the center of the head, were delivered to the animal in the dark with minimal excitation of visual, otolithic, and cervical proprioceptive reflexes. An Inland model 403 servocontroller regulated the instantaneous angular velocity of the rate table in response to sinusoidal control signals from a precision function generator. Stimulus frequencies ranged from 0.05 to 3.0 Hz.
Recording und culihrution procedures Individual nerve branches of the right orbit’s sixth nerve, previously dissected from the muscle and denuded of perineurium, were meticulously dissected until a thin fascicle was left containing a nerve fiber whose action potential could be distinctly recorded. Dissection was facilitated by the use of stainless steel needles electrolytically sharpened. The fascicle with the isolated
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1284
COUNTS
HONRUBIA,
REINGOLD,
LAU,
AND
WARD
“I]
I
125
II
INSTANT. FREQ.
12pLk--
III
COUNTS
30;]_*\___
I
INSTANT. FREQ.
’
‘2&llllld., lb- -- -
II
125
III
0
FIG. 1. Computer display of experimental data. Shown in I is a reproduction of eye-position data sampled at 100 samples per second. In 11 the occurrence of a spike is indicated by vertical lines whose height is proportional to the instantaneous frequency. Shown in III are changes in firing frequency of action potentials calculated at the instant when the eye-position value was sampled in I.
fiber was grasped between the jaws of a springalligator-forceps electrode mounted on a multidirectional micromanipulator. Action potentials were amplified differentially and displayed on an oscilloscope where they could be continuously monitored by the experimenter to allow him to evaluate the stability of the recordings, even while the animal was undergoing rather strong angular accelerations. The amplified nerve action potentials were recorded on FM tape and transmitted to an audio monitor and a rate meter whose output was displayed on a strip-chart recorder. Simultaneously, DC recordings of the horizontal movement of the contralateral eye were made using subcutaneous platinum needle electrodes. The electrooculographically monitored eye movements were differentially amplified, displayed on a chart, and recorded on the same FM tape. After the nerve fibers were isolated, a constant-velocity (loo/s) optokinetic stimulus was applied to the preparation to verify the feasibility of the singlefiber recording and to judge the quality of the nystagmus response on the basis of our past experience with nystagmus recordings. If judged satisfactory, the animal was left alone inside the booth and testing was initiated with the use of different optokinetic and vestibular stimuli, the latter administered in complete darkness. Eye movements were evaluated in terms of the number of computer counts obtained from the analogto-digital conversion of the electrooculograms at the rate of 102.4 counts/V. Although electrooculographic recordings of optokinetic nystagmus were available for calibration of eye movements, they were not used because it had been shown earlier in cats (12) that the velocity of the slow component of nystagmus induced by monocular,
in contrast to binocular, optokinetic stimulation was less than that of the optokinetic stimulus, and the precise difference had not been adequately ascertained. The method chosen instead for quantification of data referring to eye position in “counts” allowed a comparison of neural responses associated with different types of eye movements produced during brief vestibular or optokinetic tests. Comparison could also be made of neural responses associated with eye movements obtained in tests separated by intervals of a few seconds, since the magnitude of the electrooculographic voltages for a given eye movement could not change substantially in such a short time. Neural responses were also evaluated in relationship to the stimulus characteristics, which were constantly monitored by recording the output of the calibrated tachometer of the rotating device.
Methods of unalysis Unit responses were obtained from the nerve leads by conventional window circuitry and verified by the existence of a minimum interspike interval and the distribution of spike heights. Pulses corresponding to unit action potentials and the analog record of eye movements were simultaneously digitized with the use of a PDP- 11 computer, and a program was written to display both the eye position and the nerve-firing frequency as functions of time, as shown in Fig. 1. The reproduced data correspond to the responses obtained during angular accelerations of 0.1 Hz at 6O”/s peak velocity. The eye-position display (I) consists of data values indicating the voltage of the electrooculographic record sampled at uniform intervals of time (100 samples/s). The nerve-
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NEURAL
CORRELATES
firing record (II) was constructed by plotting vertical bars at the times of occurrence of the spikes, the height of the bars indicating the instantaneous frequency of firing (ordinate) computed as the reciprocal of the interspike interval. During the first section of the record (Fig. 1, top) the fast component of the nystagmus is moving from left to right (upward) and the slow component from right to left; consequently, the right abducens nerve shows an increase in activity (agonist) during the fast component and a decrease of activity (antagonist) during the slow component. The opposite is true during the next section of the record. The method that proved best in our experiments for comparing the two-time series was to calculate the nerve-firing frequency at the instants when the eye-position value was sampled by computing the inverse of the interspike interval that bracketed the time for which the value was to be calculated, as shown in III. In this way we had in the first record (I) information about eye position, and in the third (III) the instantaneous nerve-firing frequency, sampled at uniform intervals and capable of being compared to eye position point by point. Segments of data selected for analysis were those containing action potentials only. During nystagmus, the individual fast and slow components could be identified with the aid of a sensor on the screen of the computer display terminal and analyzed separately to test hypotheses pertaining to the relationship of sixth nerve activity to particular features of eye movement. Additional analysis of nystagmus movements could be performed using programs described elsewhere (26). For analysis of quasi-sinusoidal eye movements or neural responses, gain and phase values in relation to the sinusoidal vestibular stimulus were obtained with the use of a finite Fourier transform of the average cycle of the response. The nerve spike rate channel in many instances, however, resembled a clipped sinusoid and was analyzed as such. The phase estimate produced by the Fourier transform could be used directly as an estimate of phase angle of the neural signal. The gain estimates, however, were biased by the clipping and had to be corrected. The relationship used to calculate the actual peak amplitude of a sinusoid from which a signal had been produced by clipping was as follows: if h is the clipped peak-to-peak amplitude and f is the fraction of a cycle remaining after the clipping, then the unclipped peak-to-peak amplitude is H = 2h/ (1 - cosnf). Another approach used later was to reflect and translate the unclipped half-cycleand curve-fit the data as if a whole cycle were available. Both methods produced similar results for the estimation of the peak amplitude of the
OF NYSTAGMUS
response, but the latter method allowed analysis of the data.
1285
additional
RESULTS
Vestibularlv * induced eve w movements The firing frequency of abducens neurons, following activation of the vestibuloocular reflex, was monitored while the neuron participated in the production of agonist or antagonist fast and slow components (see Figs. 1 and 2A, B, C). The firing frequency during the agonist slow component increased steadily with the eye displacement, then decreased 60-80 ms before the beginning of the fast component. This decrease was usually sudden, sometimes gradual, until the firing ceased altogether. During agonist fast components, firing rates associated with a given eye position appeared greater than during the corresponding position in the adjacent slow components. Furthermore, the greater the eye velocity during the fast component, the greater the initial burst of activity, suggesting that both position and velocity of displacement are significant in the production of action potentials. Following the high-frequency bursts of neural activity during the agonist fast component, the motoneurons continued firing during most of the subsequent slow component. A strong impression was obtained that action potentials were more often recorded when the right lateral rectus muscle was relaxing during the slow componentantagonistically activated- than when it was contracting- agonistically activated. It was later on in the study that this observation became understandable following a reevaluation of the relation between the position of the eye in the orbit and the direction of the slow-component movement. We took into consideration recent findings that showed that, during a train of nystagmus, the mean eye position is in the same side of the orbit where the fast component is directed. As a consequence, at the end of the agonist fast component the firing frequency in the nerve fiber is high because the eye is positioned in the orbit well into the on-side of the motoneuron region of activity. Firing continues during the subsequent slow component even though the neuron is activated antagonistically because the lateral rectus is still con-
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1286
HONRUBIA,
100
()I amI A,-,0’
REINGOLD,
,I- IId.1.1A I
LAU,
#’
10
AND
WARD
em .a-I 20
I
30
SECONDS and motoneuron activity. In each pair of traces, the top trace represents the electroFIG. 2. Eye movement oculographic recording of eye movement, and the bottom trace represents the corresponding oculomotor firing frequency. In A, B, and C‘, the animal was rotated at the frequency of 0.1 Hz at peak velocities of 30, 60, and 12O”/s. respectively. D shows data obtained during spontaneous eye movements: E, during nystagmus eye movements after impulsive acceleration.
tracted, maintaining the eye on the fast-component side of the orbit (4, 13, 14, 17). There are substantial differences in time relationships between firing rates and fastcomponent movements because of the variability in the duration, amplitude, and velocity of the fast phases. In general, the occurrence in time of the maximum rate of firing associated with the production of agonist fast components preceded by 40 to 60 ms the time at which the maximum amplitude of the fast components was reached. On the other hand, the delay between the initiation of the burst of neural activity and the initiation of the fast movement was only about lo-30 ms. This interval was difficult to estimate accurately because of the gradual nature of the changes in firing and eye movements and the limited sampling rate of digitation. It positively can be said that the firing rate does not reach its maximum instantly.
Several spikes always occur before the maximum firing frequency is attained during a fast component. In seven fibers, neural activity was recorded during several cycles of 0. l-Hz stimuli at different peak magnitudes of velocity. An example is shown in Fig. 2A, B, and C where velocities of 30, 60, and 12O”/s, respectively, were used. These records made it possible to compare neural responses associated with agonist and antagonist movements for a large sample of eye velocities. Indeed, the velocity of the eye during the slow component changed sinusoidally during the cycle, as can be appreciated merely by inspection of the records. As would have been expected, the peak eye velocity increased almost three-fold with increasing stimulus magnitude. During the quantification of these relationships, we tested the hypothesis that the firing rate represents
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NEURAL
CORRELATES
OF NYSTAGMUS
the driving force acting on the muscles necessary to overcome not only elastic, but also viscous forces restraining the ocular globe in the orbit. The transfer function selected to describe this relationship during nystagmus was the simplified one (eyuation I) proposed by Robinson (20) on the basis of measurements of visually guided movements. This implies that the firing rate of the nerve fibers-reflects in proportions r and k, the velocity and position, of the eye movement, respectively. By simplifying equation I we have: Fmn
= k(4
+ T$)
= k(l
+ ST)@(S)
= [I/Q1
+ sT)]F(s)
Ch I
0 200 0
200
sw
0
55 ANTAGONIST
AGONIST
127
a n
(3)
where F(s) and Q(s) are the Laplace transforms of Fmn and 6, respectively, and s is a complex variable, which for the present purpose can be identical to jo (o = 2rf, the frequency of rotation) in radians per second. The eye deviation expressed in terms of the motoneuron firing frequency, both in transform notation, is Q(s)
200
g 7 g
(2) t-
where T = r/k and 8 - & = 4. In Laplace transform notation, F(s)
1287
iif 5
b=2.43 +_0.04
-El9
--10.4
INCJ
FRQ
66.9
27g
INST
FRQ 7g.3
l20
?-
2
8
(4)
The significance of these equations can be evaluated by comparing experimental and transformed data as shown in Fig. 3. The computer-produced data at the top of the figure, for the purpose of analysis, are divided into four channels. The electrooculographic output is shown in channel I. Channel II shows the firing rate as predicted by transforming the channel I nystagmus data according to equution 3. Channel III shows the actual instantaneous frequency of firing of the motoneuron as recorded during the experiment. Channel IV show the results of transforming channel III data according to equcrtion 4. The first two scatter plots in the middle of the figure show the results of comparing data of channel I with those from channel IV. The left plot corresponds to nystagmus obtained during the half-cycle of stimulation when the abducens nerve was controlling the slow-component antagonist displacement of the eye (i.e., the neuron’s frequency of firing decreased during the slow component). The plot on the right corresponds to the time when the neuron was firing agonistically during slow components.
FIG. 3. Relationship between motoneuron activity and vestibular-induced eye movement. I, eye movement recorded by EOG. III, recorded motoneuron firing frequency. II and IV, predicted firing frequency and eye position, respectively, as described in text. The lower four plots show the correlation between the various channels as indicated.
In the scatter plots in the bottom row, a comparison is made of the data in channels III and II. In the computation of the regression lines, the data of the channel containing the neural response were shifted forward by 70 ms. During preliminary analysis of the data it was observed that this shift produced the best visual superposition of recordings from the two channels. This delay was accepted as representative of the time necessary for development of muscular force and, hence, eye displacement. Later during the quantification of the relationship between the two channels, the data were routinely shifted by this amount. The high value of the correlation coefficient (r) of the scatter plots indicates the fitness of the least-squares line computed through the data points. The value of the correlation coefficient
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1288
HONRUBIA,
REINGOLD,
1. Time constants and relative sensitivities of abducens nerve jibers during vestibular and optokinetic slow components
TABLE
VAGVAN,
Fiber No.
T
Y
I 2 3 4 5 6 II 12 17 20 21 23 24 25 26 27 28 29 30 31
0.15 0.15 0.15 0.15 0.20 0.20 0.10 0.17 0.17 0.10 0.14 0.10 0.16 0.15 0.17 0.10 0.08 0.15 0.12 0.08
0.92 0.91 0.90 0.80 0.97 0.72 0.86 0.89 0.89 0.93 0.90 0.99 0.90 0.91 0.94 0.95 0.91 0.89 0.96 0.74
VAGOAG,
%
70
2.6 23.6 1.6 11.3 2.7 -27.6
-26.7 - 17.2 -32.2 -20.0 23.5
-4.5
-35.5
16.2 8.7 3.5
13.1 22.5 28.4
20.0 14.6 1.5 - 11.8 - 11.3 19.4 -25.3
30.8 30.0 40.3 10.1 -4.2 0.3 5.3
Values for individual fibers of the time constants (T) and correlation coefficients (r) obtained during comparison of eye movements with neural responses in the abducens nerve. In the fourth column are values in percentages of the difference in sensitivity of the neural responses during vestibular-induced agonist versus antagonist slow components. In the fifth column are the same values during comparison of vestibular versus optokinetic agonist slow components.
was used to estimate objectively the magnitude of the time constants T of the transfer function that best describes the data. Starting with an initial guess value, the magnitude of T was increased iteratively in small steps of 0.025 s and the computer program returned the value of T, which maximized the sum of the coefficients of linear correlations for data between channels III and II and between I and IV, using for each fiber the data collected when the neuron was participating in slow-component antagonist movements. The values of T for each of 20 fibers are indicated in Table 1, together with the value of the correlation coefficient of the regression line obtained from comparison of data in channel I with channel IV. The mean value of T was 0.139 t 0.03 s. This is not different from the value of monkey motoneurons (20, 27).
LAU,
AND
WARD
In 17 fibers neural responses were recorded during both agonist and antagonist slow component reactions and, therefore, it was possible to evaluate whether the fiber sensitivity differed when one or the other type of slow component was being produced. This was done by comparing the slopes (b) of the regression line through the plots of eye-movement data (channel I) with filtered nerve response (channel IV). The mean percentage differences between the slope values (b) obtained during agonist and antagonist neural activity, expressed as: [(ago) - (antag)]/[(ago) + (antag)] x 100, indicate that the sensitivity of the average neuron was only 2.6 t 15 .O% greater during agonist than during antagonist activity. Statistically, therefore, the rate of change in firing frequency of the abducens motoneurons appears to bear the same mathematical relationship to the eye movement whether they are contributing to the contraction or relaxation of the muscle. During rotations with higher frequencies, the compensatory eye movement shows a sinusoidal trajectory associated with sinusoidal modulation of the frequency of action potentials in the motor fiber (Figs. 4 and 5). Average poststimulus time histograms were obtained for neural responses during several cycles at either 0.8 or 1.0 Hz in 18 fibers. The change in frequency of the neural response during a cycle was used to obtain estimates of the sensitivity of the fiber to these stimuli specified as the ratio of the peak change in the firing frequency to the peak head velocity (Table 2). Values ranged from 0.28 to 4.2 (spikes/s)/(deg/s) with bimodal distribution with maxima at 0.5 and 1S. Information about the amplitude and phase relationships between the displacement of the head and eye movement and about the neural response for stimulus frequencies ranging from 0.1 to 3.0 Hz was obtained from 12 fibers (Figs. 6 and 7). Even though the stimulus magnitude was kept relatively low to produce purely sinusoidal compensatory movements, nystagmus did appear at times, making it difficult to obtain estimates from poststimulus time histograms of the amplitude of each of the two classes of responses: eye movements and neural firing rates -even more so during rotations at low frequencies (0.1-0.2 Hz).
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NEURAL
CORRELATES
OF NYSTAGMUS
0.05 Hz
0.4 Hz
0.1 Hz
0.8 Hz
FIG. 4. Eye movements and neural responses during head rotation In each group of traces, the top trace represents the eye movement recorded motoneuron firing frequency, and the lower trace represents head velocity.
However, in these cases, phase estimates could still be made by measuring the time interval between maximum table deviation and the times at which the slope changed sign in the response of interest. Phase estimates mostly during these low frequencies were computed manually from an average of the measurements in at least four cycles. The eye movement, in the frequency range for which data were collected, maintained a practically constant out-of-phase relationship with the head rotation, therefore compensating almost perfectly for the angular deviation of the head (Fig. 6, filled circles in the upper plot). On the contrary, the phase relationship between the neural response (firing frequency) and the head position was more dependent on the frequency of rotation (Fig. 6, open circles at the top). At low frequencies (~0.1 Hz), the neural responses of the right abducens nerve were out of phase with the head position. In other .x ,I\* ) the freqluency nc GAmm raorhd3A VV”ldS VI 111111g lb/abllbU a maximum value at the time of maximum deviation of the head to the left. However, this phase lag decreased with increasing fre-
1289
at various frequencies as indicated. by EOG,
the middle
trace represents
quency of rotation. Consequently, between the neural response and the eye movement, there was an increasingly larger phase difference as the frequency of rotation was increased. The difference in angular position 0.2 Hz i
0.8Hz.:
.,
.~ __.’ .../ .._.: _ . . . ““’
\
__.
a.
.--..’
.
----
0.4 Hz k
,_V”“.“.
.. .: .-.: * .* ._.-.
.-. “‘. . -.
-.-
1.0 Hz ; .:‘e-...* ’*.‘+”:.. “0. -.-. ..’.-’ ?
-. .. . :e ..:.....‘.:a..,. ..... . ..“’ ..“”
FIG. 5. Average eye movement and neural responses for different stimulus frequencies. In each group, the top trace represents the average of several cycles of eye movement, together with the sinusoidal curve fitted by means of a fast Fourier transform program. Lower trace represents the average of several cycles of neural response data.
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HONRUBIA,
1290
2. Sensitivity abducens nerve
of 19fibers
TABLE
REINGOLD,
LAU,
I 2 3 4 5 7 8 9 IO 12 14 16 18 29 20 21 30 31 32
4.20 1.60 0.96 1.20 1.00 1.13 0.34 2.90 2.75 1.12 0.28 0.66 0.54 0.67 0.90 0.76 2.00 2.90 0.60
Values expressed as the ratio over peak head velocity.
between the neural fibers and the eye the lower graph of Illustrated in Fig.
of firing
WARD
the change in amplitude of the eye movement and of the neural response as a function of the frequency of head rotations of equal peak velocity. All values were normalized relative to the magnitude of the response at 1.0 Hz rotation. Neural response measurements are indicated at the top of Fig. 7 (open circles) and eye movement measurements at the bottom (filled circles). For frequencies below 1.5 Hz, the amplitude of the eye movement varied inversely with frequency, approximately at a rate of 6 dB/octave, suggesting that at lower frequencies the gain of the reflex remains constant. This conclusion is based on the fact that since the stimulus was one of a constant peak velocity, the change in the amplitude of eye motion followed the change in head angular rotation. However, the data suggest that, at higher frequencies, there is an increase in gain with frequency because the amplitude of eye movement decreases at a lower rate than that of head rotation. The neural response showed a steady decrease in amplitude with increasing frequency, but the rate of decline was less than that seen between the decrease of the magnitude of the eye movement and that of the head. This indicates a steady increase in gain
of
Spikes. s-l/ deg. s-l
Fiber No.
AND
frequency
response for each of the movement is plotted in Fig. 6 (filled triangles). 7 is the relation between
n
-90 0
8 -180
l
B
0 0
8
ir B t
0
l
8 0
8
8
830
8
0
0 8 3
l
i !
b l
l
l l
l
A
I 0.1
I
I
0.2
0.4
I
I
I
0.6 0.8 1.O
FREQUENCY
I
I
1 .5 2.0
1
3.0
Hz
FIG. 6. Phase relationship between head position and position of the eye, and head position and neural Abscissa is the frequency of rotational stimulus; ordinate is the phase difference. Phase difference neural activity and head position is represented by open circles, that between eye position and head is represented by filled circles. The phase difference between the neural activity and eye position, by subtracting the latter from the former, is represented by filled triangles.
activity. between position obtained
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NEURAL
CORRELATES
OF NYSTAGMUS
1291
in the relationship between the neural response and the head rotation as a function of frequency. Visually guided eye movements Neural responses during optokinetic nystagmus were found to have the same characteristics as in nystagmus produced by vestibular stimulation. Shown in Fig. 8 is an example of recordings obtained from one fiber during clockwise and counterclockwise optokinetic stimulation of different velocities (I = 15, II = 10, and III = 7.5”/s). As was the case in vestibular nystagmus, the fibers continued to fire during both fast and slow components. Particularly striking in this fiber is the change in frequency of firing at a constant rate during the long slow components of nystagmus while the eye velocity remained practically constant. The quantitative relationships between eye motion and firing frequency were studied following the procedures used for vestibular nystagmus. The data analyzed in Fig. 9 were obtained during optokinetic stimulation with loo/s velocity of counterclockwise drum rotation. The motoneuron activity was greatest during the agonist fast component when the eye was brought in the direction of the incoming optokinetic stimulus (toward the right) and thereafter decreased in frequency at a constant rate, as can be seen by comparing channel I (eye position) and channel IV (the measured instantaneous firing frequency). Transformation of channel I by equation 3 using a time constant of 0.17 s, found to be the best in this fiber, resulted in a predicted firing frequency (channel II) that was greater during the fast than during the slow component because of the proportion of eye velocity (0.17) that was added to the record during the quick phase of the nystagmus. The scatter plots at the bottom of Fig. 9 show, from left to right, the relationship between the predicted eye movement (channel III) and the actual electrooculographic record (channel I), the correlation between the predicted frequency (channel II) and the actual frequency (channel IV), and finally the comparison between the actual recorded frequency of firing (channel IV) and the actual eye record (channel I). In this last scatter plot, it can be seen that during the long slow components,
i 0
8 0
0
8
i?
0
0
; 0
Q
0 0 .
8
I
0
l
1.o
t
.
l
l
. 0.4 1
l
1
1
I
0.1
0.2
0.4
III
II
0.6 0.8 1.0
FREQUENCY
1.5 2.0
1
3.0
Hz
FIG. 7. Amplitude response as a function of stimulus frequency. The neural response is represented by open circles and the eye movement response by filled circles, both normalized with respect to response at 1.0 Hz.
when the eye velocity remained constant, the data points are grouped along a straight path shown by their heavy clustering. During the fast components, however, the frequency of firing changed faster, so that the eye position and the data points show a curvilinear trajectory. In 17 fibers the sensitivity of the neuron to vestibular agonist (VAG) slow-component movements was compared with the optokinetic agonist (OAG) slow-component activity (Table 1). The mean percentage difference was 4.2 t 24.5, showing therefore no significant difference in the activity of the fiber during production of either vestibular or optokinetic nystagmus (P e 0.1). However, in individual cases differences were substantial. In nine fibers differences were greater than 20%. Neural responses associated with spontaneous eye movements in the light were recorded in 10 fibers. Two basic types of firing patterns were observed, as shown in Fig. 10. One class of fibers showed steady firing frequency in proportion to the steady eye position (Fig. 10A). In four fibers of this type, the coefficient of variation in the interspike interval during steady eye position
Downloaded from www.physiology.org/journal/jn by ${individualUser.givenNames} ${individualUser.surname} (129.081.226.078) on January 12, 2019
1292
HONRUBIA,
REINGOLD,
LAU,
AND
WARD
0. K.N. cw
c-cw
w
\
VESTI BULAR
t
I
5 set
FIG. 8. Motoneuron activity during Records in rows I, II, and 111 represent in clockwise (CW) and counterclockwise recorded by EOG, and the lower trace
optokinetic responses (C-CW) represents
nystagmus to optokinetic directions. neural firing
was less than 10% (Fig. 10A). Other fibers, however, showed greater fluctuations in the interspike interval (Fig. 10B). Two fibers appeared to behave differently from the rest,
(OKN) and vestibular-induced eye movement. stimulation at 15, 10, and 7.5”/s, respectively, In each group, the top trace is eye movement frequency.
seemingto code the eye position with quanta1 changes of firing frequency (Fig. IOC). At any given position, the fiber fired in doublets or triplets. The value of the shortest inter-
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FREQ
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-10.6
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SMPL
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0
200
INST
FREQ
FIG. 9. Analysis of optokinetic nystagmus and neural response. I represents the optokinetic nystagmus recorded by EOG; 11 is the predicted neural response, and III the predicted eye movement as explained in the text; IV is the actual neural firing frequency. Scatter plots show correlations between indicated pairs of data channels.
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NEURAL
CORRELATES
OF
NYSTAGMUS
1293
32
msec
100
Neural firing patterns from fibers of the abducens nerve during spontaneous eye movements. In each FIG. 10. pair of traces, the top trace reproduces the eye movements recorded by EOG, the lower trace shows the neural firing frequency. A and B correspond to fibers with steady firing frequency in proportion to steady eye position, but with different coefficients of variation, C to fibers with quanta1 changes in firing frequency for the steady eye position.
regardless of what aspect of the movements the innervated external rectus muscle is involved with. The similarities between vestibular- and optokinetic-induced neural responses observed in this study indicate that there are DISCUSSION no neurons responsible specifically for the Based on the previous information, Fig. 11 production of one type of reflex. Furthermore, they suggest that the strength of depicts the relationship of two different synaptic connections in each neuron for nysmagnitudes (A and B) of head displacement tagmus production is the same for visual and (oh) with the resulting right eye movement vestibular input since, if there were more (Rt 0e) and the firing rate of an idealized right abducens motoneuron (Rt VI N) whose neurons connected to the labyrinthine pathbehavior is similar to that shown in Fig. 1. ways than to pathways responsible for the production of optokinetic nystagmus, the In A the eye movement is compensatory, contribution of a single neuron to a given whereas in B , representing a larger stimulus, would be different for it takes the form of nystagmus. The nystag- eye movement than for optokinetic-induced mus pattern is such that the eye during the vestibularfast component is displaced toward the eye movements, which is not the case. All neurons examined participate equally periphery of the orbit. In all cases, the eye motion results from the contraction as well in producing slow and fast components. However, apparent exceptions to this rule as the relaxation of the muscles in an active, may be found because the firing frequency tightly coupled tonic process. The threshold of firing for the neuron is presumed to occur is slightly dependent on the eye velocity, at an eye position - 10” from the center of the although chiefly dependent on the eye position; indeed, the ratio of the two effects is orbit and its firing rate holds the same mathe1.O (spike/s)/(deg/s) to 7.2 (spikes/s)/deg matical relationship to the eye movement spike interval changed proportionally to the eye position, and during stationary eye position showed a narrow range of dispersion for each of the peaks (Fig. IOC, left).
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HONRUBIA,
REINGOLD,
LAU,
AND
WARD
DEGREES
A
60 40 F
8h
-40 -60 t
Rt.PI
N
-I
0
2.5
5.0
7.5
10.0
0
2.5
5.0
7.5
10.0
SECONDS FIG 11. Graphic representation of ments (ee), and abducens motoneuron selected: a smaller one (A) that results results in a nystagmus reaction. In the In the bottom graphs two ordinates are to the predicted eye position associated time in seconds.
relationships between head sinusoidal motion (oh), right eye movefiring rates (VI N). Two magnitudes of head angular deviation have been in a sinusoidal compensatory eye movement, and a larger one (B) that top four graphs the ordinate indicates degrees of oh and tie movement. shown: one corresponding to firing rates (impulses/second) and the other with steady motoneuron firing rates. The abscissa in all graphs indicates
(T = l/7.2 or 0.14). Thus, in some instances, particularly during large fast components with maximum velocities of several hundred degrees per second, it may be found that the occurrence of motoneuron firing is limited to one phase of nystagmus. For example, as shown in Fig. 2C, the motoneuron responds very actively due to the agonist fast-component velocity because the eye is on the right side of the orbit. Then it ceases firing during the subsequent antagonist slow component when the eye, going toward the left, reaches the threshold position. During the other half-cycle of rotation (Fig. 2C, where the slow component brings the eye from the left side of the orbit to the center), we may get the opposite impression. The right abducens nerve starts firing when the eye reaches the on-region, gradually increasing firing frequency due to the low velocity of the eye. During the subsequent antagonist fast component, the motoneuron may cease firing before reaching its threshold position due to the inhibitory effect of the
eye's high velocity, rather than gradually dimini shing as the ey e enters the off-region. Because of the special pattern of the nystagmus trajectory and the role of eye velocity in determining motoneuron firing rates, investigations, particularly those concerned with unidirectional nystagmus such as that induced by unilateral labyrinthine lesion, unidirectional angular acceleration, or electrical stimulation of the vestibular nerve, would probably lead to the conclusion that certain neurons control only one phase of nystagmus and that there exist two or three classes of nerve fibers involved in the production of nystagmus. The use of sinusoidal rotation, during which the eye changes sides of the orbit each half-cycle, and quantitative techniques have facilitated an understanding of the role of eye velocity in modulating motoneuron firing. During low-frequency rotation, the eye displacement and the neural response showed only a small difference in phase angle (= lo”), thus confirming the observa-
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NEURAL
CORRELATES
tions and postulates of Robinson (21, 22) that an integration must have taken place in the neural signal arriving at the motoneuron from the vestibular end organ to compensate for the 90’ phase lead shown by the vestibular primary afferent fibers (6). At higher frequencies, while the eyes maintained a fixed relationship to the head rotation ( 1800), making fixation on a visual target possible, the neural response showed increased gain and phase leads similar to those shown in the vestibular nerve. It appears as if the necessary integration of the signal to produce adequate compensatory eye movements were left to the orbital mechanics. For most of the high frequencies, however, it is unlikely that the low pass characteristics of the orbital ligaments could compensate for this phase angle difference. For example, in the lower scatter plot of Fig. 6 (solid line), the predicted phase lead resulting from a time constant of 0.14 s, according to equation I, gives phase angle differences between eye movement and neural response of 19 and 41” at 0.4 and 1.0 Hz, respectively. The difference between these predictions and the experimental values of 50 t 20 and 61 t 21” at 0.4 and 1.0 Hz can be reconciled by a fixed signal transmission delay between abducens nerve fibers and external rectus muscle of approximately 70 ms, which, if added to the 0.14-s time constant, produces the dashed line in Fig. 6, with phase angle differences of 29 and 60’ at 0.4 and 1.0 Hz, respectively. The magnitude of this delay is different from that observed in monkeys between the initiation of bursts of activity in abducens motoneurons and the initiation of voluntary saccades: 6-8 ms (8,20), a discrepancy that could be explained by several factors. Saccade velocity, the main factor contributing to the burst of activity, has been found to depend on the amplitude of the motion (3,7, 29). It is likely that amplitude and velocity of the fast component during nystagmus are also related (24). However, the amplitude and, therefore, the velocity of fast components are only a fraction of those during large-amplitude voluntary saccades. Largeamplitude saccades, soon after their initiation, reach velocities sufficiently high to draw the motoneuron firing rate toward saturation (20). But monkey saccades of an amplitude comparable to that of the quick
OF
NYSTAGMUS
1295
component of cat’s vestibular nystagmus (5-20”) are of shorter duration (25-40 ms) than the cat’s quick phases (100-150 ms) (7, 12,20). Consequently, during the slower fast components, the burst of activity should be neither as strong nor as sudden as that during saccades. A significant part of the 70-ms delay must be due to the complex neuromuscular transduction process; when the abducens nerve is electrically stimulated directly there is a delay of 20-30 ms between the electrical stimulation and initiation of muscle contraction or of eye movement (1, 30, 31). The rest of the time is required to develop adequate forces to bring the eye to the intended position. It may be then that the difference in the pattern of firing during saccades and quick phases is in part due to species differences and in part to different characteristics of eye movements. The sensitivity of the cat’s motoneurons is of the same order of magnitude as that in monkeys (20, 27). If we use a value of 0.8 for the gain of the VOR in cats (23), the sensitivity figures of Table 2 as representative of the neural responses to rotation of 1 .O Hz, and 0.14 s for T, we can, using eyuation 2, obtain the absolute values of k and Y. The value of k varied from 1.2 to 18.2 (spikes/s)/deg. The value of Y varied from 0.16 to 2.5 (spikes/s)/(deg/s) of eye velocity. For a typical fast component of 15” amplitude, reaching a maximum velocity of 150%, the firing rates vary during the quick phase anywhere between 18 and 273 spikes/s due to change in position, and between 24 and 375 spikes/s due to a change in velocity. While there are considerable differences in the amount of firing that a neuron may produce during nystagmus, all behave quantitatively in the same manner. The principles controlling the cat’s abducens motoneurons are the same as those for primates in visually and vestibularly guided eye movements. ACKNOWLEDGMENTS
We sincerely thank Ms. Marilyn Oreck for editorial aid, Mr. Warren Kumley for help in programming, and Mr. Leonard Jones for help with the care of animals and performance of experiments. This study was supported by National Institutes of Health Grants NS 09823 and NS 08335. Received 13 July 27 March 1979.
1978;
accepted
in
final
form
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HONRUBIA,
1296
REINGOLD,
LAU,
AND
WARD
REFERENCES P. Neurophysiology of eye movements. in: The Control oj’Eyc Movements, edited by P. Bach-y-Rita, C. C. Collins, and J. E. Hyde. New York: Academic, 1971, p. 7-45. BAKER, R. AND BERTHOZ, A. Organization of vestibular nystagmus in oblique oculomotor system. J. Neurophysiol. 37: 195-217, 1974. BALOH, R. W., SILLS, A. W., KUMLEY, W. E., AND HONRUBIA, V. Quantitative measurement of saccade amplitude, duration, and velocity. Neurology 25: 1065-1070, 1975. CHUN, K.-S. AND ROBINSON, D. A. A model of quick phase generation in the vestibuloocular reflex. Biol. Cyhern. 28: 209-221, 1978. DOHLMAN, G. On the mechanism of transformation into nystagmus on stimulation of the semicircular canals. Acta Oto-Laryngol. 26: 425-442, 1938. FERNANDEZ, C. AND GOLDBERG, J. M. Physiology of peripheral neurons innervating semicircular canals of the squirrel monkey. II. Response to sinusoidal stimulation and dynamics of peripheral vestibular system. J. Neurophysiol. 34: 661-684, 1971. FUCHS, A. F. Saccadic and smooth pursuit eye movements in the monkey. J. Physiol. London 191: 609-63 1, 1967. FUCHS, A. F. AND LUSCHEI, E. S. Firing patterns of abducens neurons of alert monkeys in relationship to horizontal eye movement. J. Neurophysiol. 33: 382-392, 1970. HENN, V. AND COHEN, B. Eye muscle motor neurons with different functional characteristics. Brain Res. 45: 561-568, 1972. HENN, V. AND COHEN, B. Quantitative analysis of activity in eye muscle motoneurons during saccadic eye movements and positions of fixation. J. Neurophysiol. 36: 115-126, 1973. HONRUBIA, V., DOWNEY, W. R., MITCHELL, D. P., AND WARD, P. H. Experimental studies on optokinetic nystagmus. II. Normal humans. Acta OtoLaryngol. 65: 441-448, 1968. HONRUBIA, V., JENKINS, H. A., AND WARD, P. H. Computer analysis of induced vestibular and optokinetic nystagmus. Ann. Otol. Rhinol. Laryngol. 80, Suppl. 3: 34-42, 1971. HONRUBIA, V., BALOH, R. W., LAU, C. G. Y., AND SILLS, A. W. The patterns of eye movements during physiologic vestibular nystagmus in man. Trans. Am. Acad. Ophthalmol. Otolaryngol. 84: 339-347, 1977. LAU, C. G. Y., HONRUBIA, V., ANDBALOH, R. W. The pattern of eye movement trajectories during physiological nystagmus in humans. In: Vestibular Mechanisms in Health and Disease, edited by J. D. Hood. New York: Academic, 1978, p. 37-44. BACH-Y-RITA,
15. MAEDA, M., SHIMAZU, H., Nature of synaptic events in neurons at slow and quick nystagmus. J. Neurophysiol.
AND SHINODA, Y. cat abducens motophase of vestibular 35: 279-296, 1972.
16. MCINTYRE, A. K. The quick component of nystagmus. J. Physiol. London 97: 8-16, 1939. 17. MELVILL JONES, G. Predominance of anticompensatory oculomotor response during rapid head rotation. Aerospace Med. 35: 965-968, 1964. 18. NELSON, G. P. AND STARK, L. Optokinetic nystagmus in man. Q. Prog. Rep. Res. Lab. Electr. MIT. 66: 366-369, 1962. R. J. AND ZUBER, B. L. Abducens 19. REINHART, nerve signals controlling saccadic eye movements in the cat. Brain Res. 34: 331-344, 1971. D. A. Oculomotor unit behavior in the 20. ROBINSON, monkey. J. Neurophysiol. 33: 393-404, 1970. 21 ROBINSON, D. A. Models of oculomotor neural organization. In: The Control oj‘ Eye Movements, edited by P. Bach-y-Rita, C. C. Collins, and J. E. Hyde. New York: Academic, 1971, p. 519-538. 22 ROBINSON, D. A. Oculomotor control signals. In: Basic Mechanisms oj’ Ocular Motility and Their Clinical Implications, edited by G. Lennerstrand and P. Bach-y-Rita. New York: Pergamon, 1975, p. 337-378. 23 ROBINSON, D. A. Adaptive gain control of vestibuloocular reflex by the cerebellum. J. Neurophysiol. 39: 954-969, 1976. 24 RON, S., ROBINSON, D. A., AND SKAVENSKI, A. A. Saccades and the quick phases of nystagmus. Vision Res. 12: 2015-2022, 1972. 25. SHI MAZU, H. Vestibulo-oculomotor relations: dynamic responses. Prog. Brain Res. 37: 493-506, 1972. 26. SILLS, A. W., HONRUBIA, V., AND KUMLEY, W. E. Algorithm for the multi-parameter analysis of nystagmus using a digital computer. Aviat. Space Environ. Med. 46: 934-942, 1975. 27. SKAVENSKI, A. A. AND ROBINSON, D. A. Role of abducens neurons in vestibuloocular reflex. J. Neurophysiol. 36: 724-738, 1973. 28. WARD, P. H. Neurophysiological correlates of nystagmus. Laryngoscope 83: 1859- 1896, 1973. 29. WESTHEIMER, G. The mechanism of saccadic eye movement. Arch. Ophthalmol. 52: 710-724, 1954. 30. YAMANAKA, Y. AND BACH-Y-RITA, P. Conduction velocity in the abducens nerve correlated with vestibular nystagmus in cats. Exp. Neurol. 20: 143- 155, 1968. 31. ZUBER, B. L. Eye movement dynamics in the cat: the final motor pathway. Exp. Neurol. 20: 255-260, 1968.
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in U.S.A.
Neural Correlates of Nystagmus in Abducens Nerve V. HONRUBIA,
D. B. REINGOLD,
C. G. Y. LAU,
AND
P. H. WARD
Division of Heud und Neck Surgery (Otolaryngology) cud Brcrirl Resecwh Institlrte, UCLA School of Medicine, Los Angeles, Ccclifbrnk 90024; and Ncrtioncrl EJY Institute, Nationd Institutes of Heulth, Bethesdu, Muryland 20205
SUMMARY
AND
CONCLUSIONS
I. The firing rates of action potentials of abducens nerve single fibers were recorded in the cat’s orbit during a variety of vestibular and optokinetic stimulations. 2. Comparison was made of the neural firing rates associated with agonist and antagonist responses during slow and fast components of vestibular and optokinetic nystagmus. It was found that the relationship between the motoneuron firing rates and the eye motion was independent of the reflex with which they were associatedvestibular or optokinetic, or the type of response-agonist or antagonist. No neurons were observed that responded only during the fast or only during the slow nystagmus phase. Motoneuron firing rates were proportional to both velocity and position of the eye in a ratio of 1 (spike/s)/(deg/s) to 7.2 (spikesls)ldeg. The behavior of the motoneurons was compatible with the hypothesis that their firing rates are sufficient to overcome both elastic and viscous forces by which the muscles and ligaments hold the eye in the orbit. 3. For low-frequency head rotations, eye displacement and neural responses showed a small phase angle difference. At higher frequencies, however, while the eyes maintained a fixed relationship to the head rotation, the neural responses showed an increasing phase lead. One component of this phase lead compensated for the phase lag introduced by the orbital mechanics. The other was modeled as a constant delay of approximately 70 ms, which may be accounted for by neuromuscular transmission and transduction. INTRODUCTION
To maintain vision during sinusoidal angular acceleration of the head at the center 1282
frequency of the vestibular system’s response, the eye executes two basic types of counterturning movements. For head displacements of 20” of peak amplitude or less, the eye movement reflects the trajectory of the head displacement. However, for larger head displacements, when the maximum rotation that the eyes can produce is smaller than that of the head, compensation is achieved by means of nystagmus. Visual fixation is achieved during the slow component, even when the amplitude of the nystagmus is small, since, at this time, the eye velocity is proportional to the velocity of the head, but in the opposite direction (e.g., Refs. 5,22,27). Likewise, during rotation of the visual surrounding-optokinetic stimulation -a nystagmus is induced whose slow component, in the direction of the visual surrounding, has the velocity of the visual stimulus (e.g., Refs. 11, 18). In this way the space around the head is visually monitored by the eye, with small angular deviations within the orbit interrupted by fast components in the opposite direction, which are too quick and brief for vision. The first quantitative evidence on the relationship between eye movements induced by physiological stimulation of the semicircular canals (vestibular stimulation) and firing rates of abducens motoneurons was obtained in alert monkeys by Skavenski and Robinson (27). They measured the relationship between the amplitude and velocity of eye movements with the motoneuron firing rate during slow components of vestibular nystagmus and during the production of purely compensatory sinusoidal eye movements. Quantitatively the behavior of abdutens motoneurons in primates following vestibular stimulation was found to be similar to that discovered earlier during visually guided motions (20). Within a reasonable range of angular eye deviations, the firing
0022-3077/79/0000-OOOO$O 1.25 Copyright 0 1979 The American Physiological Society
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NEURAL
CORRELATES
rate of the motoneurons, Fmn, is approximately given by the equation Fmn
= k(8 - 0,,) + r(dldr)(8
- 0,)
OF NYSTAGMUS
motor function (8, 20, 27).
1283
discovered
in
primates
(1)
where 8 is the eye’s angular position in the orbit, & is the orbital eye position or threshold beyond which the motoneuron is active -the on-region, and constants /i and r’ relate the frequency of ocular motoneuron firing to the position and velocity, respectively, of the eye movement. Important observations in this study were that no significant difference existed in the value of the coefficients /i and I’ during agonist or antagonist movement resulting from either visual or vestibular reflex activation, and that no neurons were found whose activity was limited to the production of the saccadic quick phase of nystagmus. The existing information obtained from experiments on cats is at variance with that from primates in that among cat’s motoneurons there appear to be some that are associated with production of either slow or fast components (1, 9, 10, 16, 19, 30). However, the relationship between the cat’s ocular motoneuron firing rates and eye movement during each phase of nystagmus has not been studied with the precision and detail used in primates. Whether this functional aspect of the vestibulooculomotor system in the cat is similar to that in primates is not known. Since much basic information on vestibuloocular functions and structures is being derived from studies in cats (2, 15, 25), it is important to know if, in these animals, the firing rate of ocular motoneurons follows the same principles as in monkeys. This report describes the results of quantitative measurements of abducens motoneuron neural activity during vestibular- and visual(optokinetic) induced nystagmus in alert cats. Simultaneous recordings were made of action potentials in single fibers of the abducens nerve dissected within the right orbit and of electrooculographically monitored movements of the left eye. Statistical information about the correlation between the eye movement and the ocular motoneuron firing rates was obtained using digital computer programs developed for this purpose. Findings of this study were compared with those from earlier experiments in alert monkeys to determine the applicability to the cat of basic principles of vestibulo-visual-oculo-
METHODS
Animul
prepuration
Under general anesthesia with fast-acting Fluothane, an acrylic cap was mounted on the skull of adult cats that had been screened for normal optokinetic and vestibular reflexes. The cap allowed the head to be fastened rigidly in place, assuring precise control of the animal’s motion and recording of nerve impulses during strong angular accelerations. By means of surgical methods similar to those of Ward (28), after enucleation of the eye globe, branches of the right sixth nerve were exposed where they enter the lateral rectus muscle. Operative sites, except in the immediate vicinity of the nerve, were infiltrated with long-lasting Xylocaine in an oil base. Normal body temperature and liquid supply were maintained with the aid of a heating pad and electrolytes injected intraperitoneally. The animal was allowed 6- 12 h for recovery from anesthesia. It was then wrapped in towels and placed in a soundproof chamber in a fixation box mounted on an Inland Controls model 800 rateof-motion table in such a way that the animal’s head was on the vertical axis of rotation and its lateral semicircular canals were horizontal. Each animal, after its recovery from anesthesia, was alert and able to eat and drink, showed no signs of undue stress, and responded well to being talked to and played with. During recordings, the animal was kept alert by being petted frequently. Occasionally, from the outside, the investigator talked to it loudly or made noise with the hands, keys, or other objects. Vestibular stimuli, in the form of angular accelerations about a vertical axis passing through the center of the head, were delivered to the animal in the dark with minimal excitation of visual, otolithic, and cervical proprioceptive reflexes. An Inland model 403 servocontroller regulated the instantaneous angular velocity of the rate table in response to sinusoidal control signals from a precision function generator. Stimulus frequencies ranged from 0.05 to 3.0 Hz.
Recording und culihrution procedures Individual nerve branches of the right orbit’s sixth nerve, previously dissected from the muscle and denuded of perineurium, were meticulously dissected until a thin fascicle was left containing a nerve fiber whose action potential could be distinctly recorded. Dissection was facilitated by the use of stainless steel needles electrolytically sharpened. The fascicle with the isolated
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1284
COUNTS
HONRUBIA,
REINGOLD,
LAU,
AND
WARD
“I]
I
125
II
INSTANT. FREQ.
12pLk--
III
COUNTS
30;]_*\___
I
INSTANT. FREQ.
’
‘2&llllld., lb- -- -
II
125
III
0
FIG. 1. Computer display of experimental data. Shown in I is a reproduction of eye-position data sampled at 100 samples per second. In 11 the occurrence of a spike is indicated by vertical lines whose height is proportional to the instantaneous frequency. Shown in III are changes in firing frequency of action potentials calculated at the instant when the eye-position value was sampled in I.
fiber was grasped between the jaws of a springalligator-forceps electrode mounted on a multidirectional micromanipulator. Action potentials were amplified differentially and displayed on an oscilloscope where they could be continuously monitored by the experimenter to allow him to evaluate the stability of the recordings, even while the animal was undergoing rather strong angular accelerations. The amplified nerve action potentials were recorded on FM tape and transmitted to an audio monitor and a rate meter whose output was displayed on a strip-chart recorder. Simultaneously, DC recordings of the horizontal movement of the contralateral eye were made using subcutaneous platinum needle electrodes. The electrooculographically monitored eye movements were differentially amplified, displayed on a chart, and recorded on the same FM tape. After the nerve fibers were isolated, a constant-velocity (loo/s) optokinetic stimulus was applied to the preparation to verify the feasibility of the singlefiber recording and to judge the quality of the nystagmus response on the basis of our past experience with nystagmus recordings. If judged satisfactory, the animal was left alone inside the booth and testing was initiated with the use of different optokinetic and vestibular stimuli, the latter administered in complete darkness. Eye movements were evaluated in terms of the number of computer counts obtained from the analogto-digital conversion of the electrooculograms at the rate of 102.4 counts/V. Although electrooculographic recordings of optokinetic nystagmus were available for calibration of eye movements, they were not used because it had been shown earlier in cats (12) that the velocity of the slow component of nystagmus induced by monocular,
in contrast to binocular, optokinetic stimulation was less than that of the optokinetic stimulus, and the precise difference had not been adequately ascertained. The method chosen instead for quantification of data referring to eye position in “counts” allowed a comparison of neural responses associated with different types of eye movements produced during brief vestibular or optokinetic tests. Comparison could also be made of neural responses associated with eye movements obtained in tests separated by intervals of a few seconds, since the magnitude of the electrooculographic voltages for a given eye movement could not change substantially in such a short time. Neural responses were also evaluated in relationship to the stimulus characteristics, which were constantly monitored by recording the output of the calibrated tachometer of the rotating device.
Methods of unalysis Unit responses were obtained from the nerve leads by conventional window circuitry and verified by the existence of a minimum interspike interval and the distribution of spike heights. Pulses corresponding to unit action potentials and the analog record of eye movements were simultaneously digitized with the use of a PDP- 11 computer, and a program was written to display both the eye position and the nerve-firing frequency as functions of time, as shown in Fig. 1. The reproduced data correspond to the responses obtained during angular accelerations of 0.1 Hz at 6O”/s peak velocity. The eye-position display (I) consists of data values indicating the voltage of the electrooculographic record sampled at uniform intervals of time (100 samples/s). The nerve-
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NEURAL
CORRELATES
firing record (II) was constructed by plotting vertical bars at the times of occurrence of the spikes, the height of the bars indicating the instantaneous frequency of firing (ordinate) computed as the reciprocal of the interspike interval. During the first section of the record (Fig. 1, top) the fast component of the nystagmus is moving from left to right (upward) and the slow component from right to left; consequently, the right abducens nerve shows an increase in activity (agonist) during the fast component and a decrease of activity (antagonist) during the slow component. The opposite is true during the next section of the record. The method that proved best in our experiments for comparing the two-time series was to calculate the nerve-firing frequency at the instants when the eye-position value was sampled by computing the inverse of the interspike interval that bracketed the time for which the value was to be calculated, as shown in III. In this way we had in the first record (I) information about eye position, and in the third (III) the instantaneous nerve-firing frequency, sampled at uniform intervals and capable of being compared to eye position point by point. Segments of data selected for analysis were those containing action potentials only. During nystagmus, the individual fast and slow components could be identified with the aid of a sensor on the screen of the computer display terminal and analyzed separately to test hypotheses pertaining to the relationship of sixth nerve activity to particular features of eye movement. Additional analysis of nystagmus movements could be performed using programs described elsewhere (26). For analysis of quasi-sinusoidal eye movements or neural responses, gain and phase values in relation to the sinusoidal vestibular stimulus were obtained with the use of a finite Fourier transform of the average cycle of the response. The nerve spike rate channel in many instances, however, resembled a clipped sinusoid and was analyzed as such. The phase estimate produced by the Fourier transform could be used directly as an estimate of phase angle of the neural signal. The gain estimates, however, were biased by the clipping and had to be corrected. The relationship used to calculate the actual peak amplitude of a sinusoid from which a signal had been produced by clipping was as follows: if h is the clipped peak-to-peak amplitude and f is the fraction of a cycle remaining after the clipping, then the unclipped peak-to-peak amplitude is H = 2h/ (1 - cosnf). Another approach used later was to reflect and translate the unclipped half-cycleand curve-fit the data as if a whole cycle were available. Both methods produced similar results for the estimation of the peak amplitude of the
OF NYSTAGMUS
response, but the latter method allowed analysis of the data.
1285
additional
RESULTS
Vestibularlv * induced eve w movements The firing frequency of abducens neurons, following activation of the vestibuloocular reflex, was monitored while the neuron participated in the production of agonist or antagonist fast and slow components (see Figs. 1 and 2A, B, C). The firing frequency during the agonist slow component increased steadily with the eye displacement, then decreased 60-80 ms before the beginning of the fast component. This decrease was usually sudden, sometimes gradual, until the firing ceased altogether. During agonist fast components, firing rates associated with a given eye position appeared greater than during the corresponding position in the adjacent slow components. Furthermore, the greater the eye velocity during the fast component, the greater the initial burst of activity, suggesting that both position and velocity of displacement are significant in the production of action potentials. Following the high-frequency bursts of neural activity during the agonist fast component, the motoneurons continued firing during most of the subsequent slow component. A strong impression was obtained that action potentials were more often recorded when the right lateral rectus muscle was relaxing during the slow componentantagonistically activated- than when it was contracting- agonistically activated. It was later on in the study that this observation became understandable following a reevaluation of the relation between the position of the eye in the orbit and the direction of the slow-component movement. We took into consideration recent findings that showed that, during a train of nystagmus, the mean eye position is in the same side of the orbit where the fast component is directed. As a consequence, at the end of the agonist fast component the firing frequency in the nerve fiber is high because the eye is positioned in the orbit well into the on-side of the motoneuron region of activity. Firing continues during the subsequent slow component even though the neuron is activated antagonistically because the lateral rectus is still con-
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1286
HONRUBIA,
100
()I amI A,-,0’
REINGOLD,
,I- IId.1.1A I
LAU,
#’
10
AND
WARD
em .a-I 20
I
30
SECONDS and motoneuron activity. In each pair of traces, the top trace represents the electroFIG. 2. Eye movement oculographic recording of eye movement, and the bottom trace represents the corresponding oculomotor firing frequency. In A, B, and C‘, the animal was rotated at the frequency of 0.1 Hz at peak velocities of 30, 60, and 12O”/s. respectively. D shows data obtained during spontaneous eye movements: E, during nystagmus eye movements after impulsive acceleration.
tracted, maintaining the eye on the fast-component side of the orbit (4, 13, 14, 17). There are substantial differences in time relationships between firing rates and fastcomponent movements because of the variability in the duration, amplitude, and velocity of the fast phases. In general, the occurrence in time of the maximum rate of firing associated with the production of agonist fast components preceded by 40 to 60 ms the time at which the maximum amplitude of the fast components was reached. On the other hand, the delay between the initiation of the burst of neural activity and the initiation of the fast movement was only about lo-30 ms. This interval was difficult to estimate accurately because of the gradual nature of the changes in firing and eye movements and the limited sampling rate of digitation. It positively can be said that the firing rate does not reach its maximum instantly.
Several spikes always occur before the maximum firing frequency is attained during a fast component. In seven fibers, neural activity was recorded during several cycles of 0. l-Hz stimuli at different peak magnitudes of velocity. An example is shown in Fig. 2A, B, and C where velocities of 30, 60, and 12O”/s, respectively, were used. These records made it possible to compare neural responses associated with agonist and antagonist movements for a large sample of eye velocities. Indeed, the velocity of the eye during the slow component changed sinusoidally during the cycle, as can be appreciated merely by inspection of the records. As would have been expected, the peak eye velocity increased almost three-fold with increasing stimulus magnitude. During the quantification of these relationships, we tested the hypothesis that the firing rate represents
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NEURAL
CORRELATES
OF NYSTAGMUS
the driving force acting on the muscles necessary to overcome not only elastic, but also viscous forces restraining the ocular globe in the orbit. The transfer function selected to describe this relationship during nystagmus was the simplified one (eyuation I) proposed by Robinson (20) on the basis of measurements of visually guided movements. This implies that the firing rate of the nerve fibers-reflects in proportions r and k, the velocity and position, of the eye movement, respectively. By simplifying equation I we have: Fmn
= k(4
+ T$)
= k(l
+ ST)@(S)
= [I/Q1
+ sT)]F(s)
Ch I
0 200 0
200
sw
0
55 ANTAGONIST
AGONIST
127
a n
(3)
where F(s) and Q(s) are the Laplace transforms of Fmn and 6, respectively, and s is a complex variable, which for the present purpose can be identical to jo (o = 2rf, the frequency of rotation) in radians per second. The eye deviation expressed in terms of the motoneuron firing frequency, both in transform notation, is Q(s)
200
g 7 g
(2) t-
where T = r/k and 8 - & = 4. In Laplace transform notation, F(s)
1287
iif 5
b=2.43 +_0.04
-El9
--10.4
INCJ
FRQ
66.9
27g
INST
FRQ 7g.3
l20
?-
2
8
(4)
The significance of these equations can be evaluated by comparing experimental and transformed data as shown in Fig. 3. The computer-produced data at the top of the figure, for the purpose of analysis, are divided into four channels. The electrooculographic output is shown in channel I. Channel II shows the firing rate as predicted by transforming the channel I nystagmus data according to equution 3. Channel III shows the actual instantaneous frequency of firing of the motoneuron as recorded during the experiment. Channel IV show the results of transforming channel III data according to equcrtion 4. The first two scatter plots in the middle of the figure show the results of comparing data of channel I with those from channel IV. The left plot corresponds to nystagmus obtained during the half-cycle of stimulation when the abducens nerve was controlling the slow-component antagonist displacement of the eye (i.e., the neuron’s frequency of firing decreased during the slow component). The plot on the right corresponds to the time when the neuron was firing agonistically during slow components.
FIG. 3. Relationship between motoneuron activity and vestibular-induced eye movement. I, eye movement recorded by EOG. III, recorded motoneuron firing frequency. II and IV, predicted firing frequency and eye position, respectively, as described in text. The lower four plots show the correlation between the various channels as indicated.
In the scatter plots in the bottom row, a comparison is made of the data in channels III and II. In the computation of the regression lines, the data of the channel containing the neural response were shifted forward by 70 ms. During preliminary analysis of the data it was observed that this shift produced the best visual superposition of recordings from the two channels. This delay was accepted as representative of the time necessary for development of muscular force and, hence, eye displacement. Later during the quantification of the relationship between the two channels, the data were routinely shifted by this amount. The high value of the correlation coefficient (r) of the scatter plots indicates the fitness of the least-squares line computed through the data points. The value of the correlation coefficient
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1288
HONRUBIA,
REINGOLD,
1. Time constants and relative sensitivities of abducens nerve jibers during vestibular and optokinetic slow components
TABLE
VAGVAN,
Fiber No.
T
Y
I 2 3 4 5 6 II 12 17 20 21 23 24 25 26 27 28 29 30 31
0.15 0.15 0.15 0.15 0.20 0.20 0.10 0.17 0.17 0.10 0.14 0.10 0.16 0.15 0.17 0.10 0.08 0.15 0.12 0.08
0.92 0.91 0.90 0.80 0.97 0.72 0.86 0.89 0.89 0.93 0.90 0.99 0.90 0.91 0.94 0.95 0.91 0.89 0.96 0.74
VAGOAG,
%
70
2.6 23.6 1.6 11.3 2.7 -27.6
-26.7 - 17.2 -32.2 -20.0 23.5
-4.5
-35.5
16.2 8.7 3.5
13.1 22.5 28.4
20.0 14.6 1.5 - 11.8 - 11.3 19.4 -25.3
30.8 30.0 40.3 10.1 -4.2 0.3 5.3
Values for individual fibers of the time constants (T) and correlation coefficients (r) obtained during comparison of eye movements with neural responses in the abducens nerve. In the fourth column are values in percentages of the difference in sensitivity of the neural responses during vestibular-induced agonist versus antagonist slow components. In the fifth column are the same values during comparison of vestibular versus optokinetic agonist slow components.
was used to estimate objectively the magnitude of the time constants T of the transfer function that best describes the data. Starting with an initial guess value, the magnitude of T was increased iteratively in small steps of 0.025 s and the computer program returned the value of T, which maximized the sum of the coefficients of linear correlations for data between channels III and II and between I and IV, using for each fiber the data collected when the neuron was participating in slow-component antagonist movements. The values of T for each of 20 fibers are indicated in Table 1, together with the value of the correlation coefficient of the regression line obtained from comparison of data in channel I with channel IV. The mean value of T was 0.139 t 0.03 s. This is not different from the value of monkey motoneurons (20, 27).
LAU,
AND
WARD
In 17 fibers neural responses were recorded during both agonist and antagonist slow component reactions and, therefore, it was possible to evaluate whether the fiber sensitivity differed when one or the other type of slow component was being produced. This was done by comparing the slopes (b) of the regression line through the plots of eye-movement data (channel I) with filtered nerve response (channel IV). The mean percentage differences between the slope values (b) obtained during agonist and antagonist neural activity, expressed as: [(ago) - (antag)]/[(ago) + (antag)] x 100, indicate that the sensitivity of the average neuron was only 2.6 t 15 .O% greater during agonist than during antagonist activity. Statistically, therefore, the rate of change in firing frequency of the abducens motoneurons appears to bear the same mathematical relationship to the eye movement whether they are contributing to the contraction or relaxation of the muscle. During rotations with higher frequencies, the compensatory eye movement shows a sinusoidal trajectory associated with sinusoidal modulation of the frequency of action potentials in the motor fiber (Figs. 4 and 5). Average poststimulus time histograms were obtained for neural responses during several cycles at either 0.8 or 1.0 Hz in 18 fibers. The change in frequency of the neural response during a cycle was used to obtain estimates of the sensitivity of the fiber to these stimuli specified as the ratio of the peak change in the firing frequency to the peak head velocity (Table 2). Values ranged from 0.28 to 4.2 (spikes/s)/(deg/s) with bimodal distribution with maxima at 0.5 and 1S. Information about the amplitude and phase relationships between the displacement of the head and eye movement and about the neural response for stimulus frequencies ranging from 0.1 to 3.0 Hz was obtained from 12 fibers (Figs. 6 and 7). Even though the stimulus magnitude was kept relatively low to produce purely sinusoidal compensatory movements, nystagmus did appear at times, making it difficult to obtain estimates from poststimulus time histograms of the amplitude of each of the two classes of responses: eye movements and neural firing rates -even more so during rotations at low frequencies (0.1-0.2 Hz).
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NEURAL
CORRELATES
OF NYSTAGMUS
0.05 Hz
0.4 Hz
0.1 Hz
0.8 Hz
FIG. 4. Eye movements and neural responses during head rotation In each group of traces, the top trace represents the eye movement recorded motoneuron firing frequency, and the lower trace represents head velocity.
However, in these cases, phase estimates could still be made by measuring the time interval between maximum table deviation and the times at which the slope changed sign in the response of interest. Phase estimates mostly during these low frequencies were computed manually from an average of the measurements in at least four cycles. The eye movement, in the frequency range for which data were collected, maintained a practically constant out-of-phase relationship with the head rotation, therefore compensating almost perfectly for the angular deviation of the head (Fig. 6, filled circles in the upper plot). On the contrary, the phase relationship between the neural response (firing frequency) and the head position was more dependent on the frequency of rotation (Fig. 6, open circles at the top). At low frequencies (~0.1 Hz), the neural responses of the right abducens nerve were out of phase with the head position. In other .x ,I\* ) the freqluency nc GAmm raorhd3A VV”ldS VI 111111g lb/abllbU a maximum value at the time of maximum deviation of the head to the left. However, this phase lag decreased with increasing fre-
1289
at various frequencies as indicated. by EOG,
the middle
trace represents
quency of rotation. Consequently, between the neural response and the eye movement, there was an increasingly larger phase difference as the frequency of rotation was increased. The difference in angular position 0.2 Hz i
0.8Hz.:
.,
.~ __.’ .../ .._.: _ . . . ““’
\
__.
a.
.--..’
.
----
0.4 Hz k
,_V”“.“.
.. .: .-.: * .* ._.-.
.-. “‘. . -.
-.-
1.0 Hz ; .:‘e-...* ’*.‘+”:.. “0. -.-. ..’.-’ ?
-. .. . :e ..:.....‘.:a..,. ..... . ..“’ ..“”
FIG. 5. Average eye movement and neural responses for different stimulus frequencies. In each group, the top trace represents the average of several cycles of eye movement, together with the sinusoidal curve fitted by means of a fast Fourier transform program. Lower trace represents the average of several cycles of neural response data.
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HONRUBIA,
1290
2. Sensitivity abducens nerve
of 19fibers
TABLE
REINGOLD,
LAU,
I 2 3 4 5 7 8 9 IO 12 14 16 18 29 20 21 30 31 32
4.20 1.60 0.96 1.20 1.00 1.13 0.34 2.90 2.75 1.12 0.28 0.66 0.54 0.67 0.90 0.76 2.00 2.90 0.60
Values expressed as the ratio over peak head velocity.
between the neural fibers and the eye the lower graph of Illustrated in Fig.
of firing
WARD
the change in amplitude of the eye movement and of the neural response as a function of the frequency of head rotations of equal peak velocity. All values were normalized relative to the magnitude of the response at 1.0 Hz rotation. Neural response measurements are indicated at the top of Fig. 7 (open circles) and eye movement measurements at the bottom (filled circles). For frequencies below 1.5 Hz, the amplitude of the eye movement varied inversely with frequency, approximately at a rate of 6 dB/octave, suggesting that at lower frequencies the gain of the reflex remains constant. This conclusion is based on the fact that since the stimulus was one of a constant peak velocity, the change in the amplitude of eye motion followed the change in head angular rotation. However, the data suggest that, at higher frequencies, there is an increase in gain with frequency because the amplitude of eye movement decreases at a lower rate than that of head rotation. The neural response showed a steady decrease in amplitude with increasing frequency, but the rate of decline was less than that seen between the decrease of the magnitude of the eye movement and that of the head. This indicates a steady increase in gain
of
Spikes. s-l/ deg. s-l
Fiber No.
AND
frequency
response for each of the movement is plotted in Fig. 6 (filled triangles). 7 is the relation between
n
-90 0
8 -180
l
B
0 0
8
ir B t
0
l
8 0
8
8
830
8
0
0 8 3
l
i !
b l
l
l l
l
A
I 0.1
I
I
0.2
0.4
I
I
I
0.6 0.8 1.O
FREQUENCY
I
I
1 .5 2.0
1
3.0
Hz
FIG. 6. Phase relationship between head position and position of the eye, and head position and neural Abscissa is the frequency of rotational stimulus; ordinate is the phase difference. Phase difference neural activity and head position is represented by open circles, that between eye position and head is represented by filled circles. The phase difference between the neural activity and eye position, by subtracting the latter from the former, is represented by filled triangles.
activity. between position obtained
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NEURAL
CORRELATES
OF NYSTAGMUS
1291
in the relationship between the neural response and the head rotation as a function of frequency. Visually guided eye movements Neural responses during optokinetic nystagmus were found to have the same characteristics as in nystagmus produced by vestibular stimulation. Shown in Fig. 8 is an example of recordings obtained from one fiber during clockwise and counterclockwise optokinetic stimulation of different velocities (I = 15, II = 10, and III = 7.5”/s). As was the case in vestibular nystagmus, the fibers continued to fire during both fast and slow components. Particularly striking in this fiber is the change in frequency of firing at a constant rate during the long slow components of nystagmus while the eye velocity remained practically constant. The quantitative relationships between eye motion and firing frequency were studied following the procedures used for vestibular nystagmus. The data analyzed in Fig. 9 were obtained during optokinetic stimulation with loo/s velocity of counterclockwise drum rotation. The motoneuron activity was greatest during the agonist fast component when the eye was brought in the direction of the incoming optokinetic stimulus (toward the right) and thereafter decreased in frequency at a constant rate, as can be seen by comparing channel I (eye position) and channel IV (the measured instantaneous firing frequency). Transformation of channel I by equation 3 using a time constant of 0.17 s, found to be the best in this fiber, resulted in a predicted firing frequency (channel II) that was greater during the fast than during the slow component because of the proportion of eye velocity (0.17) that was added to the record during the quick phase of the nystagmus. The scatter plots at the bottom of Fig. 9 show, from left to right, the relationship between the predicted eye movement (channel III) and the actual electrooculographic record (channel I), the correlation between the predicted frequency (channel II) and the actual frequency (channel IV), and finally the comparison between the actual recorded frequency of firing (channel IV) and the actual eye record (channel I). In this last scatter plot, it can be seen that during the long slow components,
i 0
8 0
0
8
i?
0
0
; 0
Q
0 0 .
8
I
0
l
1.o
t
.
l
l
. 0.4 1
l
1
1
I
0.1
0.2
0.4
III
II
0.6 0.8 1.0
FREQUENCY
1.5 2.0
1
3.0
Hz
FIG. 7. Amplitude response as a function of stimulus frequency. The neural response is represented by open circles and the eye movement response by filled circles, both normalized with respect to response at 1.0 Hz.
when the eye velocity remained constant, the data points are grouped along a straight path shown by their heavy clustering. During the fast components, however, the frequency of firing changed faster, so that the eye position and the data points show a curvilinear trajectory. In 17 fibers the sensitivity of the neuron to vestibular agonist (VAG) slow-component movements was compared with the optokinetic agonist (OAG) slow-component activity (Table 1). The mean percentage difference was 4.2 t 24.5, showing therefore no significant difference in the activity of the fiber during production of either vestibular or optokinetic nystagmus (P e 0.1). However, in individual cases differences were substantial. In nine fibers differences were greater than 20%. Neural responses associated with spontaneous eye movements in the light were recorded in 10 fibers. Two basic types of firing patterns were observed, as shown in Fig. 10. One class of fibers showed steady firing frequency in proportion to the steady eye position (Fig. 10A). In four fibers of this type, the coefficient of variation in the interspike interval during steady eye position
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1292
HONRUBIA,
REINGOLD,
LAU,
AND
WARD
0. K.N. cw
c-cw
w
\
VESTI BULAR
t
I
5 set
FIG. 8. Motoneuron activity during Records in rows I, II, and 111 represent in clockwise (CW) and counterclockwise recorded by EOG, and the lower trace
optokinetic responses (C-CW) represents
nystagmus to optokinetic directions. neural firing
was less than 10% (Fig. 10A). Other fibers, however, showed greater fluctuations in the interspike interval (Fig. 10B). Two fibers appeared to behave differently from the rest,
(OKN) and vestibular-induced eye movement. stimulation at 15, 10, and 7.5”/s, respectively, In each group, the top trace is eye movement frequency.
seemingto code the eye position with quanta1 changes of firing frequency (Fig. IOC). At any given position, the fiber fired in doublets or triplets. The value of the shortest inter-
E *“1 20;,ich --Ch
141
164
2 n
s CtL Ll-
t9-
2 > u-l 11
16.8
104
I NST
FREQ
III m:
m - rJ
::.,’;.I.‘. \..: . *.., ..,.” .. . .’ ,.,\:: ‘... .:” ‘1’; .. .,:-;,;;.!II . .’ ..f:,..‘!(1‘_ ‘, &.: y, ;r/l:.-..-.-
-10.6
231
SMPL
DAT
150
0
200
INST
FREQ
FIG. 9. Analysis of optokinetic nystagmus and neural response. I represents the optokinetic nystagmus recorded by EOG; 11 is the predicted neural response, and III the predicted eye movement as explained in the text; IV is the actual neural firing frequency. Scatter plots show correlations between indicated pairs of data channels.
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NEURAL
CORRELATES
OF
NYSTAGMUS
1293
32
msec
100
Neural firing patterns from fibers of the abducens nerve during spontaneous eye movements. In each FIG. 10. pair of traces, the top trace reproduces the eye movements recorded by EOG, the lower trace shows the neural firing frequency. A and B correspond to fibers with steady firing frequency in proportion to steady eye position, but with different coefficients of variation, C to fibers with quanta1 changes in firing frequency for the steady eye position.
regardless of what aspect of the movements the innervated external rectus muscle is involved with. The similarities between vestibular- and optokinetic-induced neural responses observed in this study indicate that there are DISCUSSION no neurons responsible specifically for the Based on the previous information, Fig. 11 production of one type of reflex. Furthermore, they suggest that the strength of depicts the relationship of two different synaptic connections in each neuron for nysmagnitudes (A and B) of head displacement tagmus production is the same for visual and (oh) with the resulting right eye movement vestibular input since, if there were more (Rt 0e) and the firing rate of an idealized right abducens motoneuron (Rt VI N) whose neurons connected to the labyrinthine pathbehavior is similar to that shown in Fig. 1. ways than to pathways responsible for the production of optokinetic nystagmus, the In A the eye movement is compensatory, contribution of a single neuron to a given whereas in B , representing a larger stimulus, would be different for it takes the form of nystagmus. The nystag- eye movement than for optokinetic-induced mus pattern is such that the eye during the vestibularfast component is displaced toward the eye movements, which is not the case. All neurons examined participate equally periphery of the orbit. In all cases, the eye motion results from the contraction as well in producing slow and fast components. However, apparent exceptions to this rule as the relaxation of the muscles in an active, may be found because the firing frequency tightly coupled tonic process. The threshold of firing for the neuron is presumed to occur is slightly dependent on the eye velocity, at an eye position - 10” from the center of the although chiefly dependent on the eye position; indeed, the ratio of the two effects is orbit and its firing rate holds the same mathe1.O (spike/s)/(deg/s) to 7.2 (spikes/s)/deg matical relationship to the eye movement spike interval changed proportionally to the eye position, and during stationary eye position showed a narrow range of dispersion for each of the peaks (Fig. IOC, left).
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HONRUBIA,
REINGOLD,
LAU,
AND
WARD
DEGREES
A
60 40 F
8h
-40 -60 t
Rt.PI
N
-I
0
2.5
5.0
7.5
10.0
0
2.5
5.0
7.5
10.0
SECONDS FIG 11. Graphic representation of ments (ee), and abducens motoneuron selected: a smaller one (A) that results results in a nystagmus reaction. In the In the bottom graphs two ordinates are to the predicted eye position associated time in seconds.
relationships between head sinusoidal motion (oh), right eye movefiring rates (VI N). Two magnitudes of head angular deviation have been in a sinusoidal compensatory eye movement, and a larger one (B) that top four graphs the ordinate indicates degrees of oh and tie movement. shown: one corresponding to firing rates (impulses/second) and the other with steady motoneuron firing rates. The abscissa in all graphs indicates
(T = l/7.2 or 0.14). Thus, in some instances, particularly during large fast components with maximum velocities of several hundred degrees per second, it may be found that the occurrence of motoneuron firing is limited to one phase of nystagmus. For example, as shown in Fig. 2C, the motoneuron responds very actively due to the agonist fast-component velocity because the eye is on the right side of the orbit. Then it ceases firing during the subsequent antagonist slow component when the eye, going toward the left, reaches the threshold position. During the other half-cycle of rotation (Fig. 2C, where the slow component brings the eye from the left side of the orbit to the center), we may get the opposite impression. The right abducens nerve starts firing when the eye reaches the on-region, gradually increasing firing frequency due to the low velocity of the eye. During the subsequent antagonist fast component, the motoneuron may cease firing before reaching its threshold position due to the inhibitory effect of the
eye's high velocity, rather than gradually dimini shing as the ey e enters the off-region. Because of the special pattern of the nystagmus trajectory and the role of eye velocity in determining motoneuron firing rates, investigations, particularly those concerned with unidirectional nystagmus such as that induced by unilateral labyrinthine lesion, unidirectional angular acceleration, or electrical stimulation of the vestibular nerve, would probably lead to the conclusion that certain neurons control only one phase of nystagmus and that there exist two or three classes of nerve fibers involved in the production of nystagmus. The use of sinusoidal rotation, during which the eye changes sides of the orbit each half-cycle, and quantitative techniques have facilitated an understanding of the role of eye velocity in modulating motoneuron firing. During low-frequency rotation, the eye displacement and the neural response showed only a small difference in phase angle (= lo”), thus confirming the observa-
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NEURAL
CORRELATES
tions and postulates of Robinson (21, 22) that an integration must have taken place in the neural signal arriving at the motoneuron from the vestibular end organ to compensate for the 90’ phase lead shown by the vestibular primary afferent fibers (6). At higher frequencies, while the eyes maintained a fixed relationship to the head rotation ( 1800), making fixation on a visual target possible, the neural response showed increased gain and phase leads similar to those shown in the vestibular nerve. It appears as if the necessary integration of the signal to produce adequate compensatory eye movements were left to the orbital mechanics. For most of the high frequencies, however, it is unlikely that the low pass characteristics of the orbital ligaments could compensate for this phase angle difference. For example, in the lower scatter plot of Fig. 6 (solid line), the predicted phase lead resulting from a time constant of 0.14 s, according to equation I, gives phase angle differences between eye movement and neural response of 19 and 41” at 0.4 and 1.0 Hz, respectively. The difference between these predictions and the experimental values of 50 t 20 and 61 t 21” at 0.4 and 1.0 Hz can be reconciled by a fixed signal transmission delay between abducens nerve fibers and external rectus muscle of approximately 70 ms, which, if added to the 0.14-s time constant, produces the dashed line in Fig. 6, with phase angle differences of 29 and 60’ at 0.4 and 1.0 Hz, respectively. The magnitude of this delay is different from that observed in monkeys between the initiation of bursts of activity in abducens motoneurons and the initiation of voluntary saccades: 6-8 ms (8,20), a discrepancy that could be explained by several factors. Saccade velocity, the main factor contributing to the burst of activity, has been found to depend on the amplitude of the motion (3,7, 29). It is likely that amplitude and velocity of the fast component during nystagmus are also related (24). However, the amplitude and, therefore, the velocity of fast components are only a fraction of those during large-amplitude voluntary saccades. Largeamplitude saccades, soon after their initiation, reach velocities sufficiently high to draw the motoneuron firing rate toward saturation (20). But monkey saccades of an amplitude comparable to that of the quick
OF
NYSTAGMUS
1295
component of cat’s vestibular nystagmus (5-20”) are of shorter duration (25-40 ms) than the cat’s quick phases (100-150 ms) (7, 12,20). Consequently, during the slower fast components, the burst of activity should be neither as strong nor as sudden as that during saccades. A significant part of the 70-ms delay must be due to the complex neuromuscular transduction process; when the abducens nerve is electrically stimulated directly there is a delay of 20-30 ms between the electrical stimulation and initiation of muscle contraction or of eye movement (1, 30, 31). The rest of the time is required to develop adequate forces to bring the eye to the intended position. It may be then that the difference in the pattern of firing during saccades and quick phases is in part due to species differences and in part to different characteristics of eye movements. The sensitivity of the cat’s motoneurons is of the same order of magnitude as that in monkeys (20, 27). If we use a value of 0.8 for the gain of the VOR in cats (23), the sensitivity figures of Table 2 as representative of the neural responses to rotation of 1 .O Hz, and 0.14 s for T, we can, using eyuation 2, obtain the absolute values of k and Y. The value of k varied from 1.2 to 18.2 (spikes/s)/deg. The value of Y varied from 0.16 to 2.5 (spikes/s)/(deg/s) of eye velocity. For a typical fast component of 15” amplitude, reaching a maximum velocity of 150%, the firing rates vary during the quick phase anywhere between 18 and 273 spikes/s due to change in position, and between 24 and 375 spikes/s due to a change in velocity. While there are considerable differences in the amount of firing that a neuron may produce during nystagmus, all behave quantitatively in the same manner. The principles controlling the cat’s abducens motoneurons are the same as those for primates in visually and vestibularly guided eye movements. ACKNOWLEDGMENTS
We sincerely thank Ms. Marilyn Oreck for editorial aid, Mr. Warren Kumley for help in programming, and Mr. Leonard Jones for help with the care of animals and performance of experiments. This study was supported by National Institutes of Health Grants NS 09823 and NS 08335. Received 13 July 27 March 1979.
1978;
accepted
in
final
form
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HONRUBIA,
1296
REINGOLD,
LAU,
AND
WARD
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![[Right abducens nerve palsy revealing pansinusitis].](/assets/img/hold.png)
