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The effect of cerebellectomy on the cat's vestibulo-ocular integrator
Brain Research, 71 (1974) 195-207
195
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Colloque C.N.R.S. no. 226 Comportement moteur et activit~s nerveuses programm6es Aix-en-Provence, 7-9 sept. 1973
T H E E F F E C T OF C E R E B E L L E C T O M Y ON T H E CAT'S VESTIBULO-OCULAR INTEGRATOR
D A V I D A. ROBINSON
Department of Ophthalmology, The Johns Hopkins University, School of Medicine, Baltimore, Md. 21205 (U.S.A.)
SUMMARY
(1) Cat eye movements during fixation with vision, attempted fixation in the dark and during rotatory nystagmus were examined before and after cerebellectomy. (2) After cerebellectomy most eye movements such as saccades, optokinetic and vestibular nystagmus superficially appeared to return to normal. (3) However, the cats were unable to maintain a steady eye position in the dark. Eye drift came from two sources; a post-saccadic slip of the eye back to some neutral point and a slow wandering of that neutral point. (4) The post-saccadic slip was exponential in shape and had a time constant of 1.3 sec. (5) The interpretation of post-saccadic slip is that the vestibulo-ocular integrator is located in the pons but it is a leaky integrator with a time constant of only 1.3 sec. The cerebellum somehow improves this integrator's performance by raising its time constant above 20 sec. (6) The fact that the leaky integrator affected both saccades and vestibular nystagmus is evidence that the integrator is shared by the saccadic and vestibular systems. (7) The wandering neutral point is regarded as a form of internal noise that is released by cerebellectomy. (8) It appears that one oculomotor function of the cerebellum is to use extraretinal knowledge of eye position to try and prevent the eyes from drifting about in very dim illumination when the normal optokinetic mechanism becomes inadequate. It is suggested that a single cerebellar mechanism is involved since it could simulta-
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neously account for the attenuation of neutral point drift and the increase in the integrator time constant.
, RI~SUMI~
(1) Chez le chat les mouvements des yeux pendant la fixation lors de la vision, pendant la tentative de fixation dans le noir et pendant le nystagmus rotatoire ont 6t6 examin6s avant et apr6s c6r6bellectomie. (2) Apr6s c6r6bellectomie la plupart, des mouvements des yeux tels que saccades, nystagmus optocin6tique et labyrinthique semblent retourner pratiquement ~t la normale. (3) Cependant, dans le noir, les chats ne sont pas capables de maintenir leurs yeux dans une position fixe. La d6viation des yeux rel6ve de deux sources: un retour post-saccadique des yeux h u n point neutre; et un lent mouvement de d6rive de ce point neutre. (4) La d6viation post-saccadique des yeux est d'allure exponentielle avec une constante de temps de 1,3 sec. (5) L'explication de la d6viation post-saccadique est que l'int6grateur oculovestibulaire est localis6 dans le pont mais c'est un int6grateur '~ fuite' dont la constante de temps est de 1,3 sec. Le cervelet am61iore en quelque sorte les qualit6s de cet int6grateur en portant sa constante de temps ~t une valeur sup6rieure b~20 sec. (6) Le fait que cet int6grateur affecte aussi bien les mouvements saccadiques que le nystagmus labyrinthique, indique que cette fonction int6gratrice est partag6e par les syst6mes saccadique et vestibulaire. (7) Le mouvement de d6rive du point neutre est consid6r6 comme une forme de bruit de fond interne, lib6r6 par la c6r6bellectomie. (8) I1 semble qu'une des fonctions oculomotrices du cervelet soit d'utiliser l'information extrar6tinienne concernant la position des yeux pour essayer d'emp6cher les yeux de d6river lors des illuminations faibles, ceci, lorsque le m6canisme optocin~tique normal devient insuffisant. Nous sugg~rons que le ph~nom6ne relive d'un seul et m~me m6canisme c6r6belleux puisqu'il peut ~t la fois expliquer la diminution de la d6viation du point neutre et l'augmentation de la constante de temps de l'int6grateur.
The vestibulo-ocular reflex maintains clear vision during head movements by quickly and exactly changing the position of the eye in the head to compensate for changes of the position of the head. This sequence of actions is shown in Fig. 1. The position of the visual axis in space, 0s(t), is the difference between eye position in the head, 0(t), and head position in space, H(t). If 0s is not to change when H changes, the signal 0(t) must exactly cancel H(t) and so must be an exact copy of it. But it is head acceleration, not position, which excites the semicircular canals. There-
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SCC
Fig. 1. The flow of signals in the vestibulo-ocular reflex. EOM, the dynamics of the extraocular muscles and globe suspensory tissues; H(t), head position in space; ~I, head acceleration; mlf, direct vestibulo-oculomotor fibers ascending in the medial longitudinal fasciculus; NI, a neural integrator
which must exist to make eye movements compensatory for head movements; OMN, oculomotor nucleus; SCC, semicircularcanals; VN, vestibular nucleus; O, eye position in the head; 08, the position of the visual axis in space. The main function of this reflex is to retrieve a signal proportional to H by doubly integrating I~, once in the SCC and once in the NI.
fore, the main dynamic activity of this reflex is to recover the head position signal from head acceleration by integrating the latter twice. The first integration is performed by the semicircular canals. This is implicit in the overdamped pendulum model of the cupula proposed by Steinhausen in 19332a. It has been shown explicitly by observing that the discharge rates of primary and secondary vestibular afferent fibers are proportional to head velocity1°,15 over the bandwidth of physiological head movements. The second integration cannot occur in the final common path because the firing rates of oculomotoneurons are proportional to eye position for head movement frequencies up to about 1.0 Hz ~1. Therefore, there must exist a neural network somewhere between the vestibular and oculomotor nuclei which converts a head velocity signal into a head position signal. During rotatory nystagmus, for example, it is this integrator which creates the slow phases. Since the integrator is the major signal processing element in the central pathways of the vestibulo-ocular reflex, its location is of some importance. The integrators for horizontal eye movements may lie in the paramedian pontine reticular formation. This idea is supported by the work of Cohen and his collaborators4, 6 involving electrical stimulation and lesions and also by single unit recordings in the pontine reticular formation in behaving monkeys 14. However, none of this evidence is conclusive. Recently, R. H. S. Carpenter 3 provided evidence that the integrator was in the cerebellum. This was surprising since chronic, partial or total removal of the cerebellum has never been reported to abolish vestibular nystagmus (see Dow and Manni 9 for a review). Yet, if, in Fig. 1, the integrator were removed, nystagmus could not be produced. Carpenter sinusoidally rotated decerebrate cats and measured the gain and phase of the resulting sinusoidal eye movements. Cerebellectomy caused a phase advance and a marked gain decrease that became more pronounced at lower frequencies. This is the result one would expect if the integrator were removed. The reflex did not entirely disappear because of remaining pontine pathways (e.g. the medial longitudinal fasciculus (mlf)) but their contribution was negligible compared
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to that of a presumed parallel path through the cerebellum. Consequently the integrator appeared to be in the cerebellum. I undertook this research to try and resolve this dilemma. The cats in this study were not decerebrate. The result seems to be a compromise. Chronic cerebellectomy did not remove the integrator but did greatly degrade its performance. This in turn did affect the vestibulo-ocular reflex but in ways too subtle to be seen on gross examination. Therefore, it seems incorrect to put the entire integrator in the cerebellum. Instead, there seems to be a rather poor integrator in the pons and cerebellar circuitry, somehow, greatly improves its performance. Eye movements were measured by implanting a coil of wire on the cat's eyeball and placing the cat in alternating magnetic fields. The method is described in detail elsewhere 11. It has a sensitivity of 3 min arc and a bandwidth of 1 kHz. A platform was attached to the cat's skull by 3 stainless steel bolts. The cat was restrained in a close-fitting box and its head immobilized by fastening the platform to a shelf extending from the box. The cat was supported in the magnetic field coil frame which could rotate about a vertical axis. Head (frame) angular velocity was measured by a tachometer generator. Eye velocity was obtained by differentiating eye position over the bandwidth 0-16 Hz. The cats were anesthetized with sodium pentobarbital and, under aseptic conditions, cerebellectomy was done by aspiration through a hole trephined over the posterior fossa. The entire cerebellum was removed. The peduncles were transected so as to remove the cerebellar nuclei and spare the lateral vestibular nuclei. The superior and lateral peduncles were fully visualized so that any fragments of flocculus left in the ventrolateral corners of the fossa must have been very small. Histology is not yet available. Four intact and 4 cerebellectomized adult cats were studied. After cerebellectomy, most eye movements such as saccades, optokinetic and vestibular nystagmus appeared, superficially, to return to normal. However, there was one striking abnormality; the cat's eyes drifted about in the dark in a very unusual manner. Normal cats
N o r m a l cats can hold their eyes quite steady in the dark (Fig. 2B). The cats were kept alert by strange noises. Horizontal eye velocity (between saccades) was sampled 3 times/sec and velocity histograms over 10 sec intervals were constructed. Mean drift rates over 10 sec were typically 18.0 min arc/sec. The more rapid velocity fluctuations had a standard deviation of 30 min arc/sec. The illustration in Fig. 2B was deliberately chosen to show a large mean drift rate. When the cat could see (Fig. 2A) its eye drift became much less. Using the ability of the retina to detect very slow drift velocities, the optokinetic system, through negative feedback to the eye muscles, reduces this drift to small values to better stabilize images on the retina s. Horizontal drift with vision was measured with a much higher sensitivity (3 min arc in position, 1.5 min arc/sec in velocity) than shown in Fig. 2A. The records have not yet been analyzed but their inspection showed that mean eye drift during any fixation interval was less than 0.3 rain arc/sec with more
CEREBELLECTOMYAND THE VESTIBULO-OCULARREFLEX
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Fig. 2. Some eye movements of the intact cat. A: fixation and saccades with vision; vertical eye position above, horizontal below. B: the same but in total darkness. C: the lowest trace shows head velocity when the cat is suddenly rotated in darkness, the upper trace shows the resulting horizontal nystagmus. The middle trace is horizontal eye velocity. U, D, L and R are up, down, left and right.
rapid peak fluctuations within 1 sec intervals of about 20 min arc/sec. When the cats were suddenly rotated at a constant velocity in the dark (Fig. 2C), nystagmus resulted whose initial slow phase velocity was nearly equal and opposite to head velocity. The ratio of the former to the latter is the (high frequency) gain of the vestibulo-ocular reflex. The gain was measured by applying about 20 velocity steps over the range of ± 10 to q- 80 deg/sec. In 4 normal cats the gains and their standard deviations were 0.95 ± 0.13, 0.83 ± 0.12, 0.99 ± 0.10 and 0.83 ± 0.11. Cerebellectomized cats
Two cats were first observed on the first postoperative day, the other two on the second day. The following characteristics were observed then and changed slowly, if at all, over subsequent months. The animals looked about and made saccades which covered the normal range of size and speed. In the dark, the eyes drifted between saccades at velocities that could momentarily exceed 10 deg/sec (Fig. 3B). This drift appeared to come from two sources. When the cat made a saccade toward the periphery, its eyes slipped back toward a more central position, following an approximately exponential time course. That is, the cats could not hold their eyes in the deviated position to which the saccade took them. This is similar to gaze or gaze-effort nystagmus seen clinically in patients with certain pontine or cerebellar lesions. The second source of drift appeared to come from the fact that the neutral point to which the eyes returned was not stable. It was clearly not mechanical but neural in origin. If it drifted left then post-saccadic slip to the left was increased, slip
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D . A . ROBINSON
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Fig. 3. Some eye movements of the cerebellectomized cat. A: fixation and saccades with vision. Note the large vertical eye slip and the initial post-saccadic horizontal slip (arrows) before optokinetic stabilization is complete. B: eye drift in the dark. After each saccade, the eye slips back toward some shifting neutral point. C: eye position and velocity during the low velocity phase of postrotatory nystagmus. Note the curvature in the slow phases and the exponential decay of eye velocity.
to the right decreased or even reversed. If the neutral point wandered outside the oculomotor range (about 20 deg in any direction) for some period, then the slip was always in one direction, broken by saccades in the opposite direction, and the cat appeared to have spontaneous nystagmus during that period. It is probably impossible to accurately separate the two sources of eye drift in the dark but a subjective estimate of neutral point drift is that it slowly wandered over a range of about + 30 deg from its long-time average value. The rate of drift was small and seldom appeared to exceed 1 or 2 deg/sec. Two cats had fairly persistent spontaneous nystagmus in the dark, primarily horizontal. In one cat, slow phase velocity could reach a maximum of 24 deg/sec. This nystagmus was compatible with the interpretation that the neutral point had developed a bias that placed it, on the average, outside the oculomotor range. Nevertheless, the neutral point still continued to drift about, and caused great variability in the intensity of the nystagmus. It often wandered into the oculomotor range (no spontaneous nystagmus) and out the other side (reversal of nystagmus). Conse-
CEREBELLECTOMY AND THE VESTIBULO-OCULAR REFLEX
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quently, the cats with spontaneous nystagmus were not considered qualitatively different from those without. The neutral point did not drift much in 1 or 2 sec and post-saccadic eye slip could usually be approximately described by, t
0 = 00e
T
(1)
where 0 is eye position (vertical or horizontal component), 00, an initial deviation from the neutral point, and T, the time constant of the movement. T may be found by measuring eye velocity 01 at time tl and 02 at tz within the same movement and applying, T
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T was measured for about 15 vertical post-saccadic slipping movements in each cat and 15 horizontal post-saccadic slipping movements in the two cats without spontaneous nystagmus. The mean value and standard deviation of these measurements was 1.30 -4- 0.55 sec. There was no significant difference between vertical and horizontal values of T for any one cat. There were differences between cats; the smallest mean value of T for any one cat was 0.74 sec, the largest was 1.71 sec. Because eye drift contained a deterministic component (post-saccadic slip), histograms of velocity are not very instructive but do permit a gross comparison with intact cats. Mean eye drift in a 10-sec interval was as high as 2.4 deg/sec (in cats without spontaneous nystagmus) and the standard deviations were typically 1.75 deg/ sec. Thus, roughly speaking, eye drift in the dark from all sources increased by a factor of 3: 1 after cerebellectomy. The optokinetic reflex in these cats was more or less intact. It attempts to stop eye drift from any source once vision is available (Fig. 3A). However, post-saccadic slip still occurred and it was at least 0.5 sec before the optokinetic system could catch the eye and diminish or stop this high velocity source of slip (see arrows, Fig. 3A). But even during longer periods of fixation the eye still slipped considerably in the light. Mean horizontal slip velocities and standard deviations in 10-sec intervals were typically 0.18 ± 0.68 deg/sec. Thus, cerebellectomy also interfered considerably with the stability of fixation with vision. The cat's vertical optokinetic system is very poor and saturates at velocities around 2-5 deg/sec (unpublished observations). This means that vertical post-saccadic slip is much less attenuated by visual feedback than the horizontal slip. The result is that cats often appear, as in Fig. 3A, to have unabated vertical slip even in the light. From 1 to 4 days after surgery, quick phases of nystagmus were sometimes abnormal in size and frequency but then returned to approximately preoperative values. When slow phases occurred with high velocities and short durations they also appeared normal but when they occurred with small velocities and long durations, as in Fig. 3C, a pronounced curvature could be seen in them. The slow phase velocity appeared to be decaying more or less exponentially with time. Equation (2) was applied to about 15 such slow phases in each cat during rotatory, post-rotatory or
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spontaneous nystagmus. The time constant was 1.03 ~ 0.34 sec. This was not considered different from the value of T found for post-saccadic slip. The gains of the vestibulo-ocular reflex in the 4 cerebellectomized cats were 1.21 ~_ 0.19, 1.34 ± 0.17, 0.48 ± 0.07 and 0.66 ± 0.11. All these numbers are outside the range for normal cats. The fact that the eye movements a cat can make are grossly unaffected by removal of the cerebellum certainly accounts for the general opinion voiced by Dow and Manni 9 that the cerebellum seems to have little to do with eye movement control. All of the basic machinery for making saccadic, optokinetic and vestibular eye movements appears to lie in the brain stem proper, not in the cerebellum, at least in the cat. The cerebellum again appears, as it often does, in a regulatory role. Fortunately, the vestibulo-ocular reflex is a simple, elemental, sensory-motor reflex. Its sensory end organ is simple, one-dimensional and its dynamics are fairly well understood 10. Its central data processing is limited to a simple integration '~1. Its effector muscles are free from external mechanical disturbances and thus have no stretch reflex la and their dynamics are well described is. This simplicity allows even subtle changes brought about by cerebellectomy to be measured so that the regulatory effects of the cerebellum can at least be described if not clearly understood.
The leaky integrator The major effect of cerebellectomy observed in this study is to convert the neural integrator of Fig. 1 into a leaky integrator. If Rl(t) is the signal at the input of such an integrator and R2(t) is the output, they are related by, dR2 d~ +
R2 Y -- R1
(3)
where T, the time constant, is a measure of the integrator's leakiness. If T is infinite, the integrator is not leaky. If its output, which is proportional to eye position, is set at some value, the eye will stay in that position indefinitely, or until a new input c o m m a n d occurs. If T is not infinite, an eccentric eye position will not be maintained and the eye will drift back to a neutral position with the exponential time course of equation (1). How large is T in the intact cat? If T were 20 sec and the eye were 10 deg from the neutral point, the return eye drift in the dark would be about 30 min arc/sec. This is somewhat larger than what one actually sees in the cat so we can only estimate that T is normally greater than 20 sec. A similar study in man by Becker z gave a mean time constant of about 20 sec. Looked at in this light, cerebellectomy has made a large change in the vestibulo-ocular reflex by dropping the integrator time constant to only 1.3 sec from a normal value in excess of 20 sec.
Is the integrator in the cerebellum? Are these results compatible with those of Carpenter3? They are qualitatively but not quantitatively. If R1 and R2 in equation (3) are sine waves of amplitudes R1 and R2, then the gain of the leaky integrator (R2/R1) at the frequency f is
CEREBELLECTOMY AND THE VESTIBULO-OCULAR REFLEX
R2 R1
T
203
(4)
V/(2~rfT) 2 + 1
At high frequencies the leaky integrator behaves like a perfect integrator (i.e. (R~/R 1) ----(1/2ztf)). At low frequencies it does not (i.e. (R2/R1) = T). The boundary between these two regions is the frequency 1/(2ztT). If T is 1.3 sec, that frequency is 0.12 Hz. The cats in this study were not systematically rotated sinusoidally as in Carpenter's study because they could and did make quick phases and this introduces an intrinsic non-linearity which negates the benefits of frequency domain analysis. However, if it had been possible to do so, this value of T would predict that the gain of the vestibulo-ocular reflex would begin to decrease below 0.12 Hz and be only a tenth normal at 0.012 Hz. While Carpenter also found a gain that decreased with decreasing frequency after cerebellectomy, he found the gain already a tenth normal at 0.1 Hz, a much greater effect than would be predicted by the present results. Put another way, Carpenter's results could be better approximated if T had been about 0.13 sec rather than 1.3 sec. However, an important difference in technique is that Carpenter apparently studied his cats within a few hours after cerebellectomy; the cats in this study were first observed the next day. There appear to be two alternative hypotheses to explain the difference observed. The first assumes that the integrator is in the cerebellum. Its removal would result in an immediate loss of integrator action. Within 24 hours, some remaining part of the nervous system would detect this loss and learn to partially compensate for it. It would do so with limited success, achieving a time constant of only 1.3 sec. Subsequent passage of time apparently would lead to no further improvement. The second hypothesis assumes that there exists a native, pontine, leaky integrator with a time constant of 1.3 sec. Circuits through the cerebellum would somehow improve the operation of the integrator, raising its apparent time constant above 20 sec. The sudden withdrawal of massive, tonic cerebellar influep.ces throughout the brain stem would completely derange the normal operation of any complex polysynaptic system such as the neural integrator and it would appear, initially, not to work. Within 24 h, intrinsic readjustments in nerve thresholds would partially restore operating levels and the leaky integrator would resume operation. I think the latter alternative is more probable. It is very unlikely that data processing nerve nets in the pons would not be seriously disrupted immediately after the removal of tonic cerebellar activity. Also, the cats in this study were immobile and mostly slept off the effects of anesthesia during the first 24 h. They, therefore, had no vestibular and little or no visuo-oculomotor experience during this time. It seems unlikely that the dormant brain would create a new oculomotor integrator before the system was challenged by the demands of visuo-motor experience. It is also odd, were this the case, that subsequent to the first day when the system finally is challenged, no further improvement in the time constant takes place. For these reasons it seems more reasonable to put the integrator in the brain stem. However, this integrator is of poor quality. It is barely adequate for eye movement control even when assisted by visual feedback through the optokinetic system. The contribu-
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tion of the cerebellum in improving the integrator performance is considerable and the cerebellum may certainly be considered an important element in the nonvisual stabilization of the oculomotor control system. However, the data produced by this study do not appear to support the interpretation of Carpenter that the integrator is entirely within the cerebellum.
Noise, drift and its suppression From a broad, functional view, the cerebellum appears to assist the cat, a nocturnal predator, in holding its eyes still in very dim light. Under such a condition, ocular stability is very important for clear vision yet, at the same time, the optokinetic system may not operate adequately since the illumination may be insufficient to stimulate its retinal slip detectors. Consequently the nervous systems of animals with a need for visual stability in dim light may have developed a non-retinal method of achieving it. The need for active stabilization points to the often unrecognized fact that any control system, neural or otherwise, is subject to noise. This noise is especially disturbing in an open-loop system like the vestibulo-ocular reflex which contains integrators. Such an arrangement allows very small fluctuations in the tonic levels of nerve net activity from any source, such as variations in metabolism, to result in large drifting movements of the eyes. It is almost certain that some neural circuit monitors and automatically adjusts for such fluctuations. This circuit appears to lie in the cerebellum since cerebellectomy releases this noise in the form of neutral point drift. The cerebellum could utilize feedback to stop eye drift arising from any source. If eye drift was reported to the cerebellum from muscle stretch afferents, or a corollary discharge, and it, in turn, sent the amplified signal to the integrator input in the form of negative, velocity feedback, then any attempted eye drift would be attenuated by a factor equal to the gain of the feedback loop. This would attenuate neutral point drift by that factor. Since post-saccadic slip would also be attenuated by the same amount, it would make the apparent integrator time constant go up by that factor. The most attractive feature of the hypothesis is that it would account for both major findings in this study with only one assumption. It is suggestive that Carpenter found the same loss of integrator action simply by cooling the cerebellum s . From his illustration, the vermis, near the primary fissure, was probably best cooled and the flocculi cooled little if at all. This part of the vermis is one of the few areas of the cerebellum where eye movements may be easily produced by electrical stimulation 5,z° and it is known to receive the projections of extraocular muscle stretch receptors 1,1z. Thus, it is possible that feedback could originate from the muscle stretch receptors and that the pathway passes through the vermis, lobes V-VII. Carpenter has correctly pointed out that removal of such a negative feedback loop, by cerebellectomy, would cause a large increase in the gain of the vestibuloocular reflex, just the opposite of what is observed. However, head velocity is a signal readily available to the cerebellum since it arrives there on both primary and secondary vestibular fibers, and the cerebellum may calculate not just eye velocity alone but
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the difference between actual eye velocity and that required by the semi-circular canal signals. If that were the signal fed back, then only inappropriate (noisy) eye drift would be attenuated by the feedback and appropriate eye velocities would not be affected. If this were the case, cerebellectomy would not be expected to alter the gain of the vestibulo-ocular reflex. This hypothesis is slightly more complex but, on the other hand, is not incompatible with the presumed data processing capabilities of the cerebellum. The theory that the cerebellum acts as it does on the oculomotor integrator by feedback is an attractive possibility that should be explored further. The integrator is shared Finally, the fact that during rotatory nystagmus, slow phase velocity, after cerebellectomy, decays exponentially with the same time constant as the eye velocity during post-saccadic slipping, allows us to conclude that the neural integrator of the vestibulo-ocular reflex is also shared by the saccadic system. All models of the saccadic system17 incorporate a neural integrator whose function is to hold the eye in the position to which the saccade has taken it. It is very reasonable to suppose that the vestibular and saccadic systems share a final common integrator rather than each having an independent one. In fact the conclusion is nearly unavoidable on theoretical grounds. Each quick phase must reposition the eye in the orbit. It can only do this by resetting the operating level of the integrator. Therefore the integrator participates in both the slow and fast components of nystagmus. Since there is no reason to believe that quick phases and saccades are not generated by the same mechanism1~, it follows that the integrator is also used for saccades. The results of these experiments confirm this idea. How do saccades (or quick phases) rapidly alter the operating level of the integrator? Fig. 4 shows a simple hypothesis. A major component of a saccade is a pulse of high frequency discharges in the oculomotor neurons 16. Similar pulses, perfectly time-locked to saccades are also seen in the brain stems of alert monkeys, especially in the pontine reticular formation7,14, 22. The most reasonable hypothesis is that saccades and quick phases are generated by a neural pulse generator. If this pulse is applied to the integrator input, its effect is to rapidly alter the integrator output from one level to another. This output is called a step. The combination of a step from the neural integrator and a pulse directly relayed to the motoneurons produces the pulse-step needed to create a saccade. Other arrangements are possible, of course, but they are invariably more complicated. The scheme of Fig. 4 is at least the simplest consistent with all the known facts. The dashed lines in Fig. 4B illustrate the post-saccadic slip that occurs when the neural integrator is made leaky by cerebellectomy. Fig. 4C illustrates the neural signals that make up the entire sequence of rotatory nystagmus in response to a step in head velocity. The dashed lines show the exponential curvature introduced in the slow phases by a leaky integrator. Fig. 4A also illustrates a few known (solid lines) and hypothetical (dashed lines) connections between the ports and the cerebellum. The cerebellum receives a vestibular input from the semicircular canals and vestibular nuclei and from extraocular muscle stretch receptors. It projects back directly by Purkinje cell fibers to the vestib-
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I). A. ROBINSON
CRBLM A
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Fig. 4. A: an extension of Fig. 1. A neural pulse generator, NPG, is added to make saccades and nystagmus quick phases. System noise and drift from all sources are represented by the noise generator n(t). Several of the more obvious cerebello-pontine connections are shown that might be utilized in the non-visual cerebellar control of eye drift noise. CRBLM, cerebellum; ec, a hypothetical efference copy signal of eye position; FN, fastigial nucleus; LI, leaky neural integrator; sa, stretch afferents from extraocular muscles. B: the signals that may appear in various parts of A, during a saccade with a nearly perfect integrator (solid lines) or a leaky integrator (dashed lines). C: as in B but for several slow and quick phases of nystagmus. The leaky integrator (dashed lines) introduces curvature in the slow phases. ular nuclei a n d b o t h directly a n d relayed t h r o u g h the fastigial nucleus to the p o n t i n e reticular f o r m a t i o n . These connections are m o r e t h a n a d e q u a t e to subserve the h y p o thetical f e e d b a c k circuit p r o p o s e d here. A n obvious extension o f this research is to localize t h a t p a r t o f the cerebellum responsible a n d further localize the afferent a n d efferent fibers t h a t mediate this p a r t i c u l a r type o f cerebellar regulation o f eye movements. I t h a n k A. R. Friendlich a n d G. L. Savage for technical assistance and A. L. M c C r a c k e n for p r e p a r a t i o n o f the manuscript. This investigation was s u p p o r t e d by Research G r a n t 5 R01 EY00598 f r o m the Eye Institute o f the N a t i o n a l Institutes o f Health, Bethesda, Md., U.S.A.
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1 BAKER, R., PRECHT, W., AND LLIN.~S, R., Mossy and climbing fiber projections of extraocular muscle afferents to the cerebellum, Brain Research, 38 (1972) 440-445. 2 BECKER, W., AND KLEIN, H. M., Accuracy of saccadic eye movements and maintenance of eccentric eye positions in the dark, Vision Res., 13 (1973) 1021-I034. 3 CARPENTER,R. H. S., Cerebellectomy and the transfer function of the vestibulo-ocular reflex in the decerebrate cat, Proc. roy. Soc. B, 181 (1972) 353-374. 4 COHEN, B., Vestibulo-ocular relations. In P. BACH-Y-RITAAND C. C. COLLINS(Eds.), The Control of Eye Movements, Academic Press, New York, 1971, pp. 105-148. 5 COHEN,B., GOTO, K., SHANZER,S., AND WEISS, A. H., Eye movements induced by electric stimulation of the cerebellum in the alert cat, Exp. NeuroL, 13 (1965) 145-162. 6 COrIEN,B., AND KOMATSUZAKI,A., Eye movements induced by stimulation of the pontine reticular formation: evidence for integration in oculomotor pathways, Exp. Neurol., 36 (1972) 101-107. 7 COHEN, B., AND HENN, V., Unit activity in the pontine reticular formation associated with eye movements, Brain Research, 46 (1972) 403-410. 8 COLLEWIJN,H., AND VAN DER MARK, F., Ocular stability in variable visual feedback conditions in the rabbit, Brain Research, 36 (1972) 47-57. 9 Dow, R. S., AND MANNI, E., The relationship of the cerebellum to extraocular movements. In M. B. BENDER(Ed.), The Oculomotor System, Hoeber, New York, 1964, pp. 280-292. 10 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 (1971) 661-675. 11 FUCHS, A. F., AND ROBINSON,D. A., A method for measuring horizontal and vertical eye movement chronically in the monkey, J. appl. Physiol., 21 (1966) 1068-1070. 12 FucrIS, A. F., AND KORNHUaER, H. H., Extraocular muscle afferents to the cerebellum of the cat, J. Physiol. (Lond.), 200 (1969) 713-722. 13 KELLER, E. L., AND ROBINSON, D. A., Absence of a stretch reflex in extraocular muscles of the monkey, J. Neurophysiol., 34 (1971) 908-919. 14 LUSCHEI, E. S., AND FUCHS, A. F., Activity of brain stem neurons during eye movements of alert monkeys, J. Neurophysiol., 35 (1972) 445-461. 15 MELVILLJONES, G., AND MILSUM, J. H., Characteristics of neural transmission from the semicircular canal to the vestibular nuclei of cats, J. Physiol. (Lond.), 209 (1970) 295-316. 16 ROBINSON,D. A., Oculomotor unit behavior in the monkey, J. NeurophysioL, 33 (1970) 393-404. 17 ROBINSON,D. A., Models of the saccadic eye movement control system, Kybernetik, 14 (1973) 71-83. 18 ROBINSON,D. A., AND KELLER, E. L., The behavior of eye movement motoneurons in the alert monkey, Bibl. ophthal. (Basel), 82 (1972) 7-16. 19 RON, S., ROBINSON,D. A., AND SKAVENSKI,A. A., Saccades and the quick phases of nystagmus, Vision Res., 12 (1972) 2015-2022. 20 RON, S., AND ROBINSON, O. A., Eye movements evoked by cerebellar stimulation in the alert monkey, J. NeurophysioL, 36 (1973) 1004-1022. 21 SKAVENSKI,A. A., AND ROBINSON, D. A., Role of abducens neurons in the vestibulo-ocular reflex, 3". Neurophysiol., 36 (1973) 724-738. 22 SPARKS,D. L., AND TRAVIS, R. P., JR., Firing patterns of reticular formation neurons during horizontal eye movements, Brain Research, 33 (1971) 477-481. 23 STEINHAUSEN,W., Ober die Beobachtung der Cupula in den Bogengangsampullen des Labyrinths des lebenden Hechts, Pfliigers Arch. ges. Pt, Fsiol., 232 (1933) 500-512.
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© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Colloque C.N.R.S. no. 226 Comportement moteur et activit~s nerveuses programm6es Aix-en-Provence, 7-9 sept. 1973
T H E E F F E C T OF C E R E B E L L E C T O M Y ON T H E CAT'S VESTIBULO-OCULAR INTEGRATOR
D A V I D A. ROBINSON
Department of Ophthalmology, The Johns Hopkins University, School of Medicine, Baltimore, Md. 21205 (U.S.A.)
SUMMARY
(1) Cat eye movements during fixation with vision, attempted fixation in the dark and during rotatory nystagmus were examined before and after cerebellectomy. (2) After cerebellectomy most eye movements such as saccades, optokinetic and vestibular nystagmus superficially appeared to return to normal. (3) However, the cats were unable to maintain a steady eye position in the dark. Eye drift came from two sources; a post-saccadic slip of the eye back to some neutral point and a slow wandering of that neutral point. (4) The post-saccadic slip was exponential in shape and had a time constant of 1.3 sec. (5) The interpretation of post-saccadic slip is that the vestibulo-ocular integrator is located in the pons but it is a leaky integrator with a time constant of only 1.3 sec. The cerebellum somehow improves this integrator's performance by raising its time constant above 20 sec. (6) The fact that the leaky integrator affected both saccades and vestibular nystagmus is evidence that the integrator is shared by the saccadic and vestibular systems. (7) The wandering neutral point is regarded as a form of internal noise that is released by cerebellectomy. (8) It appears that one oculomotor function of the cerebellum is to use extraretinal knowledge of eye position to try and prevent the eyes from drifting about in very dim illumination when the normal optokinetic mechanism becomes inadequate. It is suggested that a single cerebellar mechanism is involved since it could simulta-
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neously account for the attenuation of neutral point drift and the increase in the integrator time constant.
, RI~SUMI~
(1) Chez le chat les mouvements des yeux pendant la fixation lors de la vision, pendant la tentative de fixation dans le noir et pendant le nystagmus rotatoire ont 6t6 examin6s avant et apr6s c6r6bellectomie. (2) Apr6s c6r6bellectomie la plupart, des mouvements des yeux tels que saccades, nystagmus optocin6tique et labyrinthique semblent retourner pratiquement ~t la normale. (3) Cependant, dans le noir, les chats ne sont pas capables de maintenir leurs yeux dans une position fixe. La d6viation des yeux rel6ve de deux sources: un retour post-saccadique des yeux h u n point neutre; et un lent mouvement de d6rive de ce point neutre. (4) La d6viation post-saccadique des yeux est d'allure exponentielle avec une constante de temps de 1,3 sec. (5) L'explication de la d6viation post-saccadique est que l'int6grateur oculovestibulaire est localis6 dans le pont mais c'est un int6grateur '~ fuite' dont la constante de temps est de 1,3 sec. Le cervelet am61iore en quelque sorte les qualit6s de cet int6grateur en portant sa constante de temps ~t une valeur sup6rieure b~20 sec. (6) Le fait que cet int6grateur affecte aussi bien les mouvements saccadiques que le nystagmus labyrinthique, indique que cette fonction int6gratrice est partag6e par les syst6mes saccadique et vestibulaire. (7) Le mouvement de d6rive du point neutre est consid6r6 comme une forme de bruit de fond interne, lib6r6 par la c6r6bellectomie. (8) I1 semble qu'une des fonctions oculomotrices du cervelet soit d'utiliser l'information extrar6tinienne concernant la position des yeux pour essayer d'emp6cher les yeux de d6river lors des illuminations faibles, ceci, lorsque le m6canisme optocin~tique normal devient insuffisant. Nous sugg~rons que le ph~nom6ne relive d'un seul et m~me m6canisme c6r6belleux puisqu'il peut ~t la fois expliquer la diminution de la d6viation du point neutre et l'augmentation de la constante de temps de l'int6grateur.
The vestibulo-ocular reflex maintains clear vision during head movements by quickly and exactly changing the position of the eye in the head to compensate for changes of the position of the head. This sequence of actions is shown in Fig. 1. The position of the visual axis in space, 0s(t), is the difference between eye position in the head, 0(t), and head position in space, H(t). If 0s is not to change when H changes, the signal 0(t) must exactly cancel H(t) and so must be an exact copy of it. But it is head acceleration, not position, which excites the semicircular canals. There-
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SCC
Fig. 1. The flow of signals in the vestibulo-ocular reflex. EOM, the dynamics of the extraocular muscles and globe suspensory tissues; H(t), head position in space; ~I, head acceleration; mlf, direct vestibulo-oculomotor fibers ascending in the medial longitudinal fasciculus; NI, a neural integrator
which must exist to make eye movements compensatory for head movements; OMN, oculomotor nucleus; SCC, semicircularcanals; VN, vestibular nucleus; O, eye position in the head; 08, the position of the visual axis in space. The main function of this reflex is to retrieve a signal proportional to H by doubly integrating I~, once in the SCC and once in the NI.
fore, the main dynamic activity of this reflex is to recover the head position signal from head acceleration by integrating the latter twice. The first integration is performed by the semicircular canals. This is implicit in the overdamped pendulum model of the cupula proposed by Steinhausen in 19332a. It has been shown explicitly by observing that the discharge rates of primary and secondary vestibular afferent fibers are proportional to head velocity1°,15 over the bandwidth of physiological head movements. The second integration cannot occur in the final common path because the firing rates of oculomotoneurons are proportional to eye position for head movement frequencies up to about 1.0 Hz ~1. Therefore, there must exist a neural network somewhere between the vestibular and oculomotor nuclei which converts a head velocity signal into a head position signal. During rotatory nystagmus, for example, it is this integrator which creates the slow phases. Since the integrator is the major signal processing element in the central pathways of the vestibulo-ocular reflex, its location is of some importance. The integrators for horizontal eye movements may lie in the paramedian pontine reticular formation. This idea is supported by the work of Cohen and his collaborators4, 6 involving electrical stimulation and lesions and also by single unit recordings in the pontine reticular formation in behaving monkeys 14. However, none of this evidence is conclusive. Recently, R. H. S. Carpenter 3 provided evidence that the integrator was in the cerebellum. This was surprising since chronic, partial or total removal of the cerebellum has never been reported to abolish vestibular nystagmus (see Dow and Manni 9 for a review). Yet, if, in Fig. 1, the integrator were removed, nystagmus could not be produced. Carpenter sinusoidally rotated decerebrate cats and measured the gain and phase of the resulting sinusoidal eye movements. Cerebellectomy caused a phase advance and a marked gain decrease that became more pronounced at lower frequencies. This is the result one would expect if the integrator were removed. The reflex did not entirely disappear because of remaining pontine pathways (e.g. the medial longitudinal fasciculus (mlf)) but their contribution was negligible compared
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to that of a presumed parallel path through the cerebellum. Consequently the integrator appeared to be in the cerebellum. I undertook this research to try and resolve this dilemma. The cats in this study were not decerebrate. The result seems to be a compromise. Chronic cerebellectomy did not remove the integrator but did greatly degrade its performance. This in turn did affect the vestibulo-ocular reflex but in ways too subtle to be seen on gross examination. Therefore, it seems incorrect to put the entire integrator in the cerebellum. Instead, there seems to be a rather poor integrator in the pons and cerebellar circuitry, somehow, greatly improves its performance. Eye movements were measured by implanting a coil of wire on the cat's eyeball and placing the cat in alternating magnetic fields. The method is described in detail elsewhere 11. It has a sensitivity of 3 min arc and a bandwidth of 1 kHz. A platform was attached to the cat's skull by 3 stainless steel bolts. The cat was restrained in a close-fitting box and its head immobilized by fastening the platform to a shelf extending from the box. The cat was supported in the magnetic field coil frame which could rotate about a vertical axis. Head (frame) angular velocity was measured by a tachometer generator. Eye velocity was obtained by differentiating eye position over the bandwidth 0-16 Hz. The cats were anesthetized with sodium pentobarbital and, under aseptic conditions, cerebellectomy was done by aspiration through a hole trephined over the posterior fossa. The entire cerebellum was removed. The peduncles were transected so as to remove the cerebellar nuclei and spare the lateral vestibular nuclei. The superior and lateral peduncles were fully visualized so that any fragments of flocculus left in the ventrolateral corners of the fossa must have been very small. Histology is not yet available. Four intact and 4 cerebellectomized adult cats were studied. After cerebellectomy, most eye movements such as saccades, optokinetic and vestibular nystagmus appeared, superficially, to return to normal. However, there was one striking abnormality; the cat's eyes drifted about in the dark in a very unusual manner. Normal cats
N o r m a l cats can hold their eyes quite steady in the dark (Fig. 2B). The cats were kept alert by strange noises. Horizontal eye velocity (between saccades) was sampled 3 times/sec and velocity histograms over 10 sec intervals were constructed. Mean drift rates over 10 sec were typically 18.0 min arc/sec. The more rapid velocity fluctuations had a standard deviation of 30 min arc/sec. The illustration in Fig. 2B was deliberately chosen to show a large mean drift rate. When the cat could see (Fig. 2A) its eye drift became much less. Using the ability of the retina to detect very slow drift velocities, the optokinetic system, through negative feedback to the eye muscles, reduces this drift to small values to better stabilize images on the retina s. Horizontal drift with vision was measured with a much higher sensitivity (3 min arc in position, 1.5 min arc/sec in velocity) than shown in Fig. 2A. The records have not yet been analyzed but their inspection showed that mean eye drift during any fixation interval was less than 0.3 rain arc/sec with more
CEREBELLECTOMYAND THE VESTIBULO-OCULARREFLEX
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Fig. 2. Some eye movements of the intact cat. A: fixation and saccades with vision; vertical eye position above, horizontal below. B: the same but in total darkness. C: the lowest trace shows head velocity when the cat is suddenly rotated in darkness, the upper trace shows the resulting horizontal nystagmus. The middle trace is horizontal eye velocity. U, D, L and R are up, down, left and right.
rapid peak fluctuations within 1 sec intervals of about 20 min arc/sec. When the cats were suddenly rotated at a constant velocity in the dark (Fig. 2C), nystagmus resulted whose initial slow phase velocity was nearly equal and opposite to head velocity. The ratio of the former to the latter is the (high frequency) gain of the vestibulo-ocular reflex. The gain was measured by applying about 20 velocity steps over the range of ± 10 to q- 80 deg/sec. In 4 normal cats the gains and their standard deviations were 0.95 ± 0.13, 0.83 ± 0.12, 0.99 ± 0.10 and 0.83 ± 0.11. Cerebellectomized cats
Two cats were first observed on the first postoperative day, the other two on the second day. The following characteristics were observed then and changed slowly, if at all, over subsequent months. The animals looked about and made saccades which covered the normal range of size and speed. In the dark, the eyes drifted between saccades at velocities that could momentarily exceed 10 deg/sec (Fig. 3B). This drift appeared to come from two sources. When the cat made a saccade toward the periphery, its eyes slipped back toward a more central position, following an approximately exponential time course. That is, the cats could not hold their eyes in the deviated position to which the saccade took them. This is similar to gaze or gaze-effort nystagmus seen clinically in patients with certain pontine or cerebellar lesions. The second source of drift appeared to come from the fact that the neutral point to which the eyes returned was not stable. It was clearly not mechanical but neural in origin. If it drifted left then post-saccadic slip to the left was increased, slip
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Fig. 3. Some eye movements of the cerebellectomized cat. A: fixation and saccades with vision. Note the large vertical eye slip and the initial post-saccadic horizontal slip (arrows) before optokinetic stabilization is complete. B: eye drift in the dark. After each saccade, the eye slips back toward some shifting neutral point. C: eye position and velocity during the low velocity phase of postrotatory nystagmus. Note the curvature in the slow phases and the exponential decay of eye velocity.
to the right decreased or even reversed. If the neutral point wandered outside the oculomotor range (about 20 deg in any direction) for some period, then the slip was always in one direction, broken by saccades in the opposite direction, and the cat appeared to have spontaneous nystagmus during that period. It is probably impossible to accurately separate the two sources of eye drift in the dark but a subjective estimate of neutral point drift is that it slowly wandered over a range of about + 30 deg from its long-time average value. The rate of drift was small and seldom appeared to exceed 1 or 2 deg/sec. Two cats had fairly persistent spontaneous nystagmus in the dark, primarily horizontal. In one cat, slow phase velocity could reach a maximum of 24 deg/sec. This nystagmus was compatible with the interpretation that the neutral point had developed a bias that placed it, on the average, outside the oculomotor range. Nevertheless, the neutral point still continued to drift about, and caused great variability in the intensity of the nystagmus. It often wandered into the oculomotor range (no spontaneous nystagmus) and out the other side (reversal of nystagmus). Conse-
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201
quently, the cats with spontaneous nystagmus were not considered qualitatively different from those without. The neutral point did not drift much in 1 or 2 sec and post-saccadic eye slip could usually be approximately described by, t
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T was measured for about 15 vertical post-saccadic slipping movements in each cat and 15 horizontal post-saccadic slipping movements in the two cats without spontaneous nystagmus. The mean value and standard deviation of these measurements was 1.30 -4- 0.55 sec. There was no significant difference between vertical and horizontal values of T for any one cat. There were differences between cats; the smallest mean value of T for any one cat was 0.74 sec, the largest was 1.71 sec. Because eye drift contained a deterministic component (post-saccadic slip), histograms of velocity are not very instructive but do permit a gross comparison with intact cats. Mean eye drift in a 10-sec interval was as high as 2.4 deg/sec (in cats without spontaneous nystagmus) and the standard deviations were typically 1.75 deg/ sec. Thus, roughly speaking, eye drift in the dark from all sources increased by a factor of 3: 1 after cerebellectomy. The optokinetic reflex in these cats was more or less intact. It attempts to stop eye drift from any source once vision is available (Fig. 3A). However, post-saccadic slip still occurred and it was at least 0.5 sec before the optokinetic system could catch the eye and diminish or stop this high velocity source of slip (see arrows, Fig. 3A). But even during longer periods of fixation the eye still slipped considerably in the light. Mean horizontal slip velocities and standard deviations in 10-sec intervals were typically 0.18 ± 0.68 deg/sec. Thus, cerebellectomy also interfered considerably with the stability of fixation with vision. The cat's vertical optokinetic system is very poor and saturates at velocities around 2-5 deg/sec (unpublished observations). This means that vertical post-saccadic slip is much less attenuated by visual feedback than the horizontal slip. The result is that cats often appear, as in Fig. 3A, to have unabated vertical slip even in the light. From 1 to 4 days after surgery, quick phases of nystagmus were sometimes abnormal in size and frequency but then returned to approximately preoperative values. When slow phases occurred with high velocities and short durations they also appeared normal but when they occurred with small velocities and long durations, as in Fig. 3C, a pronounced curvature could be seen in them. The slow phase velocity appeared to be decaying more or less exponentially with time. Equation (2) was applied to about 15 such slow phases in each cat during rotatory, post-rotatory or
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spontaneous nystagmus. The time constant was 1.03 ~ 0.34 sec. This was not considered different from the value of T found for post-saccadic slip. The gains of the vestibulo-ocular reflex in the 4 cerebellectomized cats were 1.21 ~_ 0.19, 1.34 ± 0.17, 0.48 ± 0.07 and 0.66 ± 0.11. All these numbers are outside the range for normal cats. The fact that the eye movements a cat can make are grossly unaffected by removal of the cerebellum certainly accounts for the general opinion voiced by Dow and Manni 9 that the cerebellum seems to have little to do with eye movement control. All of the basic machinery for making saccadic, optokinetic and vestibular eye movements appears to lie in the brain stem proper, not in the cerebellum, at least in the cat. The cerebellum again appears, as it often does, in a regulatory role. Fortunately, the vestibulo-ocular reflex is a simple, elemental, sensory-motor reflex. Its sensory end organ is simple, one-dimensional and its dynamics are fairly well understood 10. Its central data processing is limited to a simple integration '~1. Its effector muscles are free from external mechanical disturbances and thus have no stretch reflex la and their dynamics are well described is. This simplicity allows even subtle changes brought about by cerebellectomy to be measured so that the regulatory effects of the cerebellum can at least be described if not clearly understood.
The leaky integrator The major effect of cerebellectomy observed in this study is to convert the neural integrator of Fig. 1 into a leaky integrator. If Rl(t) is the signal at the input of such an integrator and R2(t) is the output, they are related by, dR2 d~ +
R2 Y -- R1
(3)
where T, the time constant, is a measure of the integrator's leakiness. If T is infinite, the integrator is not leaky. If its output, which is proportional to eye position, is set at some value, the eye will stay in that position indefinitely, or until a new input c o m m a n d occurs. If T is not infinite, an eccentric eye position will not be maintained and the eye will drift back to a neutral position with the exponential time course of equation (1). How large is T in the intact cat? If T were 20 sec and the eye were 10 deg from the neutral point, the return eye drift in the dark would be about 30 min arc/sec. This is somewhat larger than what one actually sees in the cat so we can only estimate that T is normally greater than 20 sec. A similar study in man by Becker z gave a mean time constant of about 20 sec. Looked at in this light, cerebellectomy has made a large change in the vestibulo-ocular reflex by dropping the integrator time constant to only 1.3 sec from a normal value in excess of 20 sec.
Is the integrator in the cerebellum? Are these results compatible with those of Carpenter3? They are qualitatively but not quantitatively. If R1 and R2 in equation (3) are sine waves of amplitudes R1 and R2, then the gain of the leaky integrator (R2/R1) at the frequency f is
CEREBELLECTOMY AND THE VESTIBULO-OCULAR REFLEX
R2 R1
T
203
(4)
V/(2~rfT) 2 + 1
At high frequencies the leaky integrator behaves like a perfect integrator (i.e. (R~/R 1) ----(1/2ztf)). At low frequencies it does not (i.e. (R2/R1) = T). The boundary between these two regions is the frequency 1/(2ztT). If T is 1.3 sec, that frequency is 0.12 Hz. The cats in this study were not systematically rotated sinusoidally as in Carpenter's study because they could and did make quick phases and this introduces an intrinsic non-linearity which negates the benefits of frequency domain analysis. However, if it had been possible to do so, this value of T would predict that the gain of the vestibulo-ocular reflex would begin to decrease below 0.12 Hz and be only a tenth normal at 0.012 Hz. While Carpenter also found a gain that decreased with decreasing frequency after cerebellectomy, he found the gain already a tenth normal at 0.1 Hz, a much greater effect than would be predicted by the present results. Put another way, Carpenter's results could be better approximated if T had been about 0.13 sec rather than 1.3 sec. However, an important difference in technique is that Carpenter apparently studied his cats within a few hours after cerebellectomy; the cats in this study were first observed the next day. There appear to be two alternative hypotheses to explain the difference observed. The first assumes that the integrator is in the cerebellum. Its removal would result in an immediate loss of integrator action. Within 24 hours, some remaining part of the nervous system would detect this loss and learn to partially compensate for it. It would do so with limited success, achieving a time constant of only 1.3 sec. Subsequent passage of time apparently would lead to no further improvement. The second hypothesis assumes that there exists a native, pontine, leaky integrator with a time constant of 1.3 sec. Circuits through the cerebellum would somehow improve the operation of the integrator, raising its apparent time constant above 20 sec. The sudden withdrawal of massive, tonic cerebellar influep.ces throughout the brain stem would completely derange the normal operation of any complex polysynaptic system such as the neural integrator and it would appear, initially, not to work. Within 24 h, intrinsic readjustments in nerve thresholds would partially restore operating levels and the leaky integrator would resume operation. I think the latter alternative is more probable. It is very unlikely that data processing nerve nets in the pons would not be seriously disrupted immediately after the removal of tonic cerebellar activity. Also, the cats in this study were immobile and mostly slept off the effects of anesthesia during the first 24 h. They, therefore, had no vestibular and little or no visuo-oculomotor experience during this time. It seems unlikely that the dormant brain would create a new oculomotor integrator before the system was challenged by the demands of visuo-motor experience. It is also odd, were this the case, that subsequent to the first day when the system finally is challenged, no further improvement in the time constant takes place. For these reasons it seems more reasonable to put the integrator in the brain stem. However, this integrator is of poor quality. It is barely adequate for eye movement control even when assisted by visual feedback through the optokinetic system. The contribu-
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tion of the cerebellum in improving the integrator performance is considerable and the cerebellum may certainly be considered an important element in the nonvisual stabilization of the oculomotor control system. However, the data produced by this study do not appear to support the interpretation of Carpenter that the integrator is entirely within the cerebellum.
Noise, drift and its suppression From a broad, functional view, the cerebellum appears to assist the cat, a nocturnal predator, in holding its eyes still in very dim light. Under such a condition, ocular stability is very important for clear vision yet, at the same time, the optokinetic system may not operate adequately since the illumination may be insufficient to stimulate its retinal slip detectors. Consequently the nervous systems of animals with a need for visual stability in dim light may have developed a non-retinal method of achieving it. The need for active stabilization points to the often unrecognized fact that any control system, neural or otherwise, is subject to noise. This noise is especially disturbing in an open-loop system like the vestibulo-ocular reflex which contains integrators. Such an arrangement allows very small fluctuations in the tonic levels of nerve net activity from any source, such as variations in metabolism, to result in large drifting movements of the eyes. It is almost certain that some neural circuit monitors and automatically adjusts for such fluctuations. This circuit appears to lie in the cerebellum since cerebellectomy releases this noise in the form of neutral point drift. The cerebellum could utilize feedback to stop eye drift arising from any source. If eye drift was reported to the cerebellum from muscle stretch afferents, or a corollary discharge, and it, in turn, sent the amplified signal to the integrator input in the form of negative, velocity feedback, then any attempted eye drift would be attenuated by a factor equal to the gain of the feedback loop. This would attenuate neutral point drift by that factor. Since post-saccadic slip would also be attenuated by the same amount, it would make the apparent integrator time constant go up by that factor. The most attractive feature of the hypothesis is that it would account for both major findings in this study with only one assumption. It is suggestive that Carpenter found the same loss of integrator action simply by cooling the cerebellum s . From his illustration, the vermis, near the primary fissure, was probably best cooled and the flocculi cooled little if at all. This part of the vermis is one of the few areas of the cerebellum where eye movements may be easily produced by electrical stimulation 5,z° and it is known to receive the projections of extraocular muscle stretch receptors 1,1z. Thus, it is possible that feedback could originate from the muscle stretch receptors and that the pathway passes through the vermis, lobes V-VII. Carpenter has correctly pointed out that removal of such a negative feedback loop, by cerebellectomy, would cause a large increase in the gain of the vestibuloocular reflex, just the opposite of what is observed. However, head velocity is a signal readily available to the cerebellum since it arrives there on both primary and secondary vestibular fibers, and the cerebellum may calculate not just eye velocity alone but
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the difference between actual eye velocity and that required by the semi-circular canal signals. If that were the signal fed back, then only inappropriate (noisy) eye drift would be attenuated by the feedback and appropriate eye velocities would not be affected. If this were the case, cerebellectomy would not be expected to alter the gain of the vestibulo-ocular reflex. This hypothesis is slightly more complex but, on the other hand, is not incompatible with the presumed data processing capabilities of the cerebellum. The theory that the cerebellum acts as it does on the oculomotor integrator by feedback is an attractive possibility that should be explored further. The integrator is shared Finally, the fact that during rotatory nystagmus, slow phase velocity, after cerebellectomy, decays exponentially with the same time constant as the eye velocity during post-saccadic slipping, allows us to conclude that the neural integrator of the vestibulo-ocular reflex is also shared by the saccadic system. All models of the saccadic system17 incorporate a neural integrator whose function is to hold the eye in the position to which the saccade has taken it. It is very reasonable to suppose that the vestibular and saccadic systems share a final common integrator rather than each having an independent one. In fact the conclusion is nearly unavoidable on theoretical grounds. Each quick phase must reposition the eye in the orbit. It can only do this by resetting the operating level of the integrator. Therefore the integrator participates in both the slow and fast components of nystagmus. Since there is no reason to believe that quick phases and saccades are not generated by the same mechanism1~, it follows that the integrator is also used for saccades. The results of these experiments confirm this idea. How do saccades (or quick phases) rapidly alter the operating level of the integrator? Fig. 4 shows a simple hypothesis. A major component of a saccade is a pulse of high frequency discharges in the oculomotor neurons 16. Similar pulses, perfectly time-locked to saccades are also seen in the brain stems of alert monkeys, especially in the pontine reticular formation7,14, 22. The most reasonable hypothesis is that saccades and quick phases are generated by a neural pulse generator. If this pulse is applied to the integrator input, its effect is to rapidly alter the integrator output from one level to another. This output is called a step. The combination of a step from the neural integrator and a pulse directly relayed to the motoneurons produces the pulse-step needed to create a saccade. Other arrangements are possible, of course, but they are invariably more complicated. The scheme of Fig. 4 is at least the simplest consistent with all the known facts. The dashed lines in Fig. 4B illustrate the post-saccadic slip that occurs when the neural integrator is made leaky by cerebellectomy. Fig. 4C illustrates the neural signals that make up the entire sequence of rotatory nystagmus in response to a step in head velocity. The dashed lines show the exponential curvature introduced in the slow phases by a leaky integrator. Fig. 4A also illustrates a few known (solid lines) and hypothetical (dashed lines) connections between the ports and the cerebellum. The cerebellum receives a vestibular input from the semicircular canals and vestibular nuclei and from extraocular muscle stretch receptors. It projects back directly by Purkinje cell fibers to the vestib-
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I). A. ROBINSON
CRBLM A
SCC
/
V~
LI
H(1)~
!
NPG SACCADES
B
LI
LI
Fig. 4. A: an extension of Fig. 1. A neural pulse generator, NPG, is added to make saccades and nystagmus quick phases. System noise and drift from all sources are represented by the noise generator n(t). Several of the more obvious cerebello-pontine connections are shown that might be utilized in the non-visual cerebellar control of eye drift noise. CRBLM, cerebellum; ec, a hypothetical efference copy signal of eye position; FN, fastigial nucleus; LI, leaky neural integrator; sa, stretch afferents from extraocular muscles. B: the signals that may appear in various parts of A, during a saccade with a nearly perfect integrator (solid lines) or a leaky integrator (dashed lines). C: as in B but for several slow and quick phases of nystagmus. The leaky integrator (dashed lines) introduces curvature in the slow phases. ular nuclei a n d b o t h directly a n d relayed t h r o u g h the fastigial nucleus to the p o n t i n e reticular f o r m a t i o n . These connections are m o r e t h a n a d e q u a t e to subserve the h y p o thetical f e e d b a c k circuit p r o p o s e d here. A n obvious extension o f this research is to localize t h a t p a r t o f the cerebellum responsible a n d further localize the afferent a n d efferent fibers t h a t mediate this p a r t i c u l a r type o f cerebellar regulation o f eye movements. I t h a n k A. R. Friendlich a n d G. L. Savage for technical assistance and A. L. M c C r a c k e n for p r e p a r a t i o n o f the manuscript. This investigation was s u p p o r t e d by Research G r a n t 5 R01 EY00598 f r o m the Eye Institute o f the N a t i o n a l Institutes o f Health, Bethesda, Md., U.S.A.
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