A brain stem generator for saccadic eye movements

T I N S - N o v e m b e r 1981

Vertebrate retinal horizontal cells Horizontal cells are a type of interneurone in the vertebrate retina, They are driven by the photoreceptor ceils (rods and three spectral classes of cone) through chemical synapses and, in response to light generate slow, graded hyperpolarizing and depolarizing electrical responses (Spotentials) 9. We have started an analysis of horizontal cell ionic mechanisms in the fish (roach, Rutilus rutilus) retina using ISMs. Fig. 3a is a chart recording showing the impalement of a red-sensitive L~-type unit with a double barrel K + liquid ion exchanger ISM. With this type of ISM, the m e m b r a n e potential (Era, in this case, - 3 9 m Y ) and the K + signal (upper trace) are recorded simultaneously from the same neurone. In these units, ak had an average value of about 60 mM ( a ~ 3.5 mM), and E~ was consistently more negative than Em by at least 20 mV. From these measurements, it is deduced that in the dark the L~-type horizontal cell membrane is permeable to other ion(s) 'x' with E~ more positive than E~. One candidate is CI , since in these units E o is more positive than Em by at least 15 m V (Fig. 3b). During synaptic blockage by light stimulation or application of 1-2 mM CoCk, the membrane potential tends towards EK, and at saturation E m = EK thereby showing that the non-synaptic conductance mechanisms of the horizontal cell m e m b r a n e is K + driven.

Invertebrate photoreceptors The intracellular K +, Cl-, Na +, Ca ~+ and H + levels have been measured in barnacle photoreceptors by Brown and coworkersS-~'~4'=L The dark-adapted photoreceptor was found to have a significant chloride permeability such that Cl- was distributed passively (Ecr = E~). The potassium equilibrium potential was in the range 70-80 m V negative whilst that for sodium was greater than + 6 0 inV. The lightevoked depolarization of the photoreceptor was accompanied by a decrease in the internal p H (a ~) and an increase in a ~ ~.~. It was suggested that changes in intracellular p H of the photoreceptor induced by light stimulation might modulate its sensitivity.

Molluscan neurones Several of the neurones in molluscs are unusually large, and, as a result, have been subject to extensive electrophysiological investigation with ISMs. Perhaps the best known is the correlation between a~, and the electrogenic sodium pump made by Thomas in 1969. (He later found, with a sharper microelectrode, that a~, was rather

283 lower than previously thought.) The intracellular CI- activity in both H and D cells of Helix aspersa was found to be about 8.3 raM, giving an E a of about - 5 8 m V (Ref. 12). The action of acetylcholine on these cells was to increase both the Na + and the CI- permeabilities. The intracellular p H of snail neurones was found by T h o m a s to be regulated by a mechanism that involves the simultaneous influx of Na + and H C O L and the effiux of C1- and H +. It was suggested that such a regulation might be mediated by a single membrane carrier with separate transport sites for each of these ions TM.

Acknowledgements We wish to thank R, C. Thomas and his students for teaching one of us (M.D.) the ISM technique. We also thank him, H. M. Brown, T. Gillett, R. W. Meech and W. R. Schlue for discussions and advice, the SRC for financial support and Guliz Onkal for technical assistance. Reading list 1 Armstrong, W. McD. and Garcia-Diaz, J.F. (1980) Fed, Proc. Fed. Am. Soe. Exp. Biol. 39, 2851-2859 2 Bailey, P. L. (1980) Analysis with Ion-selective Electrodes, 2nd edn, Heyden, London 3 Berridge, M. J. and Schlue. W. R. (1978) J. Exp. BioL 72, 203-216 4 BoRon, T. B. and Vaughan-Jones,R. D. (1977) J. Physiol. (London) 270, 801-833 5 Brown. H, M. (1976) J. Gen. PhysioL 68,

281-296 6 Brown, H. M. and Meech, R, W. (1979) J. Physiol. (London) 297, 73--93 7 Brown, H. M. and Owen, J.D. (1979) Ionselective Electrode Rev. t, 145-186 8 Coles, J. A. and Tsacopoulos, H. (1979) J. Physiol. (London) 290, 525-549 9 Djamgoz, M. B. A. and Ruddock. K. H. (1979) Vision Res. 19, 413~$18 1(I Green, R. and Giebisch,G, ( 1974) in Ion-selective Microelectrodes (Berman. H.J. and Herbert, N. C., eds), pp. 43-53, Plenum, New York ll Hinke. J. A. M. (1959) Nature (London) 184, 1257-1258 12 Neild, T. O. and Thomas, R. C. (1974) J, Physiol. (London) 242,453-470 13 O'Doherty, L, Garcia-Diaz,J. F. and Armstr
A brain stem generator for saccadic eye movements Albert F. Fuchs and Chris R. S. Kaneko The extremely rapid conjugate shiJ~s o f gaze called saccades are accomplished by a pulsestep change o f excitation in the extraocular muscles, Within the last several years, the premotoneuronal circuitry responsible for this innervation pattern has been studied intensively, and this paper summarizes our current understanding o f the brain stem mechanisms involved in generating the saccadic trajectory.

We scan our visual environment with saceadic eye movements, conjugate shifts of both eyes that aim each fovea at the object of interest. Saccades can be elicited by asking a subject to fixate a spot of light as it jumps from point to point. After the target jumps, a delay of 200-300 ms elapses before the eyes move. During this time, the CNS must identify the target, decide whether to move the eyes toward it, and initiate the saceade. Once the saccade is triggered, the eyes accelerate rapidly to m a x i m u m velocities exceeding 500 deg s -1 at mid-trajectory, and decelerate to bring the foveae accurately on to the target, usually with no overshoot or oscillations. Thus,

saccades are not only the fastest but also the best controlled movements of which the body musculature is capable. The central structures implicated in the control of eye m o v e m e n t s include parts of the thalamus, large areas of the cortex, the basal ganglia, the cerebellum and the superior colliculus. Unfortunately, it has been difficult to determine how these structures are involved in saccade generation, possibly because most of them seem to lie at the difficult, if exciting, interface between visual and motor events. On the other hand, neurons in the brain stem surrounding the various oculomotor nuclei have discharge patterns related primarily, O Elsevier/Norlh-Holland Biomedical Press 198 l 0378 - 5912/81/0000 - (K900/$02.75

284

TINS -November 1981

if not solely, to the eye movement. We describe here how these neurons interact to form the immediate premotor machinery for saccade generation.

Discharge of ocular motoneurons The neural basis of the saccade was first revealed in the discharge patterns of motoneurons innervating the extraocular muscles. As the best studied example, let us consider the behavior of abducens motoneurons, which innervate the lateral rectus muscle to produce a horizontal, lateral eye movement. In the monkey, experiments in our laboratory suggest that virtually every identified motoneuron has a similar discharge pattern, which consists of a regular firing rate during fixation and a burst of spikes during the saccade (Fig.

1A). The regular firing rate during fixation increases linearly with lateral eye position and the slope of the line varies from one motoneuron to another. In addition, different motoneurons are recruited into regular firing at different (threshold) lateral eye positions. In contrast, during lateral saccades, all motoneurons (except those with very high thresholds) exhibit a burst of spikes that begins, on average, 5-7 ms before the saccade and continues until just before the end of the saccade. For all saccades greater than 5 deg, burst duration is equal to saccade duration. The peak firing rate during the burst varies among motoneurons and at least partially reflects saccadic velocity~'. However, for saccades greater than 5 deg that begin and end lateral to the primary direction of gaze, virtu-

ally every motoneuron discharges at its maximum rate (at least 400-600 spikes s-t). These characteristics have led to the suggestion that motoneuron discharge can be modeled by a pulse of firing, which causes the eye to achieve rapid saccadic velocities+ and a step change in firing rate+ which serves to hold the eye in its lateral, eccentric position. The pulse of firing leads to a pulse of force generated by the extraocular muscles to overcome the viscous and elastic forces of the muscles, globe and suspensory ligaments. During medial saccades, most motoneurons exhibit a substantial decrease or complete cessation of firing rate, which again prccedes the saccade by about 5-7 ms and lasts until just before the end of the saccade, when the neuron resumes a steady discharge appro-

A Motoneuron

..... f

I

r f

\

f

\

"

E

B. Burst Neuron I

1

"

,"

~'

...........~

III

i . . . .

.......... ~++~"

IIIIII IBIIII +f++~':+~-

I

Ill ~

I

llr

L -r

71 lI '~ . . . . . . . . . . . . . . .

I illllliilll

i Iii

i

+,,.,

E C. Tonic Neuron

C D. Omnipause Neuron

1 second I ' ' ' '

i

I''

'

I

Fig. 1. Discharge patterns o f brain stem neurons whose firing rates are related to saccadic eye movements. The abducens motoneuron (.4) identified by spike.triggered averages o f EMG activity in the lateral rectus muscle exhibits a burst ofaction potentials (a pulse) for lateral (down deflection, middle trace) saccades and a steady firing rate (a step) which increases for more lateral positions of fixation. The burst neuron ( B ) discharges a burst ofaction potentials whose duration increases with saccade duration (compare the last two lateral saccades ) and probably generates the pulse in motoneur on firing. The tonic neuron ( C) discharges at a rate proportional to tateral eye position and could provide the step in motonearon firing. The omnipause neuron (D) fires at a high constant rate during fixation but pauses for saccades in all directions; it seems to provide tonic inhibition to burst netcrons between saccades+ For each neuron, the middle and bottom traces are horizontal and vertical eye position, respectively; downward deflections correspond to leftward and dowmvard movements. Calibration bars represent 30 deg and 1 s in IO0-ms intervals. (Figure retouched for clarity.)

285

T I N S - N o v e m b e r 1981

pilate to the new eye position. Therefore, the activity associated with medial saccades can also be modeled by a pulse-step change in firing rate.

TRIG

Midline !

The pons is the staging area for saccades

Where and how is the pulse-step of motoneuron firing generated? Several lines of evidence suggest that, in the monkey, the premotor apparatus for saccades lies in the paramedian pontine reticular formation (PPRF) 4. First, lesions in this area cause a complete, enduring paralysis of ipsilateral gaze, the only area outside the motor nuclei themselves where lesions produce such a catastrophic effect. Second, electrical stimulation in this area produces muscle activation at latencies of less than 3 msL Third, either the injection of an orthograde label into the PPRF or the injection of a retrograde label into the abducens nucleus reveals direct connections from the pons to the abducens nucleus 1. Finally, there are neurons in the PPRF whose discharge patterns are correlated specifically with the occurrence and trajectory of saccades. The generation of the saccadic pulse in motoneuron discharge has been attributed primarily to two groups of neurons, burst neurons and pause neurons, which were originally revealed in experiments on alert monkeys. The burst neuron emits a highfrequency (up to 1000 spikes s -1) burst of action potentials that begins, on average, 6-8 ms before the saccade and ends just before the eye lands on the target (Fig. 1B). Since this burst slightly precedes the saccadic burst in motoneurons, the duration of the saccade increases linearly with the duration of the burst, and burst neuron discharge is related exclusively to saccades, Luschei and Fuchs TM suggested that the pulse of firing in motoneurons was generated by burst neurons. A later suggestion that the motoneuron membrane itself can essentially differentiate a step input in presynaptic activity to produce a burst of the appropriate duration has not been substantiated. The pause neuron (Fig. 1D) has a complementary discharge pattern. When the animal is fixating a stationary target or making smooth eye movements to visual or vestibular stimuli, the pause neuron discharges at a relatively regular rate usually in excess of 100 spikess -~. About 10-12 ms before saccades in any direction, the omnidirectional pause neuron (OPN) exhibits a significant reduction and usually a complete cessation (a pause) in firing which lasts for the duration of the saccade; pause duration increases linearly with saccade duration. Since electrical stimulation

IIIIIIIIIILIIIII IIILIII

IIIII -% ~q

IIIIIIIIIn Pons

IIIIIIIIIIMIIl MIIIIIIIIlllllll IIIIIIIMIIIIIIIIIIIIIIIIII IIIllll Ill

Lateral Rectus

Eye

o/

/:

\

Fig. 2. Schematic representation of the circuitryand firing patterns of brain stem neurons involved in the generation of saccades. At lower left', a targetspot jumps to the side, causing neurons in both the pons and medMla to change their discharge rates to produce a saccade (0). The thick connections in the circmt diagram have been verified, whereas the thin connections arefrom a popular model of the saccadegenerator~. Firingpatter~ and operation of the model are described in the text. EBN, excitatoryburst neuron; IBN, inhibitory burst neuron; OPN, omnidirectional pause neuron; MN, motoneuron; TN, tonic neuron.

for several seconds at the site of OPNs prevents the occurrence of saccades while still allowing smooth eye movements to occur, Keller* suggested that OPNs provide a powerful tonic inhibition to burst neurons. A third group of brain stem neurons,. the tonic neurons (Fig. 1C), discharge steadily during fixation, firing at regular tonic rates which increase linearly with lateral eye position *'1°. The slope of the line and the threshold for steady firing varies from one tonic neuron to another. During a saccade, the tonic neuron changes its firing gradually between the pre- and postsaccadic rates and some may even discharge a weak burst. Therefore, Luschei and Fuchs ~° suggested that tonic neurons could provide the step component of the firing rate in motoneurons. Except for the OPNs, which form a relatively distinct midline group just rostral to the abducens nucleus, all the eyemovement-related neurons lie intermingled in the brain s t e m The connections of

these neurons have thus been almost impossible to unravel in the monkey. However, considerable progress has been made in elucidating the saccadic circuitry in the cat, in which intracellular recordings can be used in addition to behavioral experiments, extracellular recordings and modern anatomical tracers. When the retrograde tracer horseradish peroxidase (HRP) is injected into the abducens nucleus, it labels ipsilateral neurons just rostral, and contralateral neurons just caudal, to the abducens nucleus. The caudal neurons, which lie in the dorsomedial medullary reticular formation, discharge a burst of spikes for lateral saccades and produce monosynaptic inhibitory postsynaptic potentials (IPSPs) in contralateral abducens motoneurons 7. They are therefore called inhibitory burst neurons (IBNs), and they produce the pause in motoneuron firing for medial saccades. The rostral neurons exhibit a burst of spikes for lateral saccades, and some

286 produce spike-triggered field-potential averages at monosynaptic latencies in the ipsilateral abducens nucleus s. They are therefore called excitatory burst neurons (EBNs). Injection of an orthograde label into the OPN region produces terminal labeling in the EBN and IBN areas (Langer, T . P . and Kaneko, C. R. S., unpublished observations), and there is convincing circumstantial evidence that the monosynaptic connection of OPNs to IBNs is inhibitory TM.

A model that generates saccades How might these neurons produce a saccade? Early thinking on the saccade generator was dominated by the notion that saccades were preprogrammed or ballistic, since a h u m a n instructed to slow the trajectory of a 20-deg saccade succeeded only in breaking the movement up into a 'staircase' of smaller saccades, each of which had a duration and velocity appropriate for saccades of that size. However, recent experiments have shown that if a target undergoes a very large eccentric j u m p (greater than 61) deg) and returns to its starting position within 100 ms, the eye begins an eccentric saccade which then appears to turn around in midflight and return to its initial position 2. Furthermore, if a target is moved just before or during a saccade and then extinguished, the next saccade, which occurs 200 ms later, still lands accurately on the target 6. These two experiments suggest that not only can a saccade be modified in midflight, but it is controlled by a signal proportional to eye position rather than retinal error. On the basis of these observations, Robinson TMproposed a 'bang-bang' neural control system for the generation of saccades (Fig. 2) which incorporates the neurons and connections described above. As suggested earlier, the model assumes that the excitatory pulse and step of activity in motoneurons is generated by EBNs and tonic neurons (TNs), respectively. Since the most reliable relation of E B N discharge is that between the number of spikes in the burst and the size of the saccade, one needs only to count the number of spikes in the burst to determine how far the eye has moved. Counting the number of spikes is mathematically equivalent to integrating the area under the curve of instantaneous firing rate (i.e. the pulse) which provides the rapid change in TN firing rate. There|brc, the EBN excites a TN (or nest of TNs) which, by way of recurrent connections to itself and other neurons (shown only schematically in Fig. 2), integrates the pulse input to provide a neural replica, ON, of eve position. To make a saccade, the

T I N S - N o v e m b e r 1981

EBN is strongly excited by some input proportional to the desired target position, T, which causes the EBN to begin discharging at its m a x i m u m rate. The problem of how to turn the EBN off at precisely the correct time to stop the eye and produce an accurate saccade is solved by inhibiting the EBN with the neural re plica of eye position so that when the eye reaches the target (i.e. 0~ = T) the inhibitory feedback cancels the excitatory input and the EBN stops discharging. Controlling the saccadic trajectory by an efference copy signal proportional to eye position neatly accounts for the precise timing of normal saccades, and also explains why the slower saccades in the drowsy animal, which have both lower velocities and longer durations, still reach the target accurately. Finally, since the EBN must have a low threshold to respond rapidly and maximally to produce the high saccadic velocities, but must not respond to synaptic noise and generate unwanted saccades, the EBN is strongly inhibited by OPNs between saccades. Just before and during a saccade, the OPN would be inhibited to allow the saccade to occur. The inhibitory feedback from the EBN prevents the O P N from resuming its discharge before the end of the saccade. Because all of the neurons in the model lie close together, it has been impossible to determine the validity of Robinson's TM burst generator model. Furthermore, since the transient changes in activity of the various neurons are closely synchronized with the saccade and consequently with each other, sorting out putative connections and causal relations based on timing has not been successful. However. at least two predictions of the model have been tested. First, the local feedback connection suggests that the instantaneous firing rate of an EBN should be proportional to the error remaining between actual eye position and desired eye position (i.e. target position). This is true in at least some EBNs TM. Second, if OPNs provide tonic inhibition of EBNs, it should be possible, during a saccade, to reactivate OPNs artificially by electrical stimulation and interrupt the saccade in midflight. Not only are saccades interrupted in midflight after only 14-15 ms, but the duration of the interruption is equal to the duration of the stimulus train, indicating that OPN activity can provide a sensitive control of saccade duration ~. Furthermore, the interrupted saccades eventually land accurately on target as predicted by the local feedback modeP.

Reading list l Baker, R. and Berthoz, A. (eds) (1977) Dev.

Inputs to the saccade generator The brain stem burst generator requires two kinds of signals from higher structures

A. F. buchs and C. R. S. Kaneko are at the Regional Primate Research ('enter, University of Woa$hington, 1-421 tleahh Sciences Building, Seattle. WA 98195, U.S.A

associated with visual processing. First, the E B N must have an excitatory input (T) that represents the location of the target in space and not the location of the target on the retina since, for example, if the eye is displaced by electrical stimulation of the brain just before a saccade to a visual target, the saccade nevertheless brings the eye to the correct target location ~'. How and where T is created is still unknown. Second, an inhibitory trigger input must disable the O P N inhibition to allow the E B N to respond to the excitatory input, T. The superior colliculus, which projects to the PPRF, has been implicated as a possible source of the trigger signal since lesions there cause an increase in saccadic reaction times TM. Other classical oculomotor structures (e.g. the frontal eye fields) also project to the PPRF and could be involved in some phase of saccade production. A s our understanding of the brain stem mechanisms involved in generating the saccade improves, we may soon be able to proceed to the difficult problem of what these suprabulbar structures are doing to transform the visual target perception into the motor c o m m a n d that initiates a saccade.

Neuro~ci. l

2 Becker, W. and Jiirgens, R. (1974) in Basic Mechanisms of Ocular Motility and their Clinical Implications (Lennerstrand, G. and Baeh-y-Rita,

P., eds), pp. 519-524, PergamonPress,New York 3 Becker, W., King, M. W., Fuchs, A. F., Jiirgens, R., Johanson, G. W. and Kornhuber, H. (1981) Dev. Neurosci. 12, 30=~7 4 Cohen, B.andHenn, V. (1972)Bibl. OphthalmoL 82, 36-.55 5 Fuchs, A. F. and Becker, W. (eds) (1981)Dev. Neurosci. 12

6 Hallett, P. E. and Lightstone,A. D. (1976) Vision Re~. 16, 99-106 7 Hikosaka. O., lgusa, Y., Nakao, S. and Shimazu, H. (1978) Exp. Brain Res. 33,337-352 8 lgusa, Y., Sasaki,S. and Shimazu,H. (1980)Brain Res. 182, 451-456 9 Keller,E. L. (1974)J. NeurophysioL 37,316-332 10 Luschei. E. S. and Fuchs, A. F. (1972) J. Neurophysiol. 35, 445-461 I 1 Mays,L. E. and Sparks, D. L. (1980)Science,208, 1163-1165 12 Nakao, S., Curthoys, 1. S. and Markham, C. H. (1980)Exp. Brain Res. 40, 283-293 13 Robinson, D. A. (1975) in Basic Mechanisms of Ocular Motility and Their Clinical Implications

(Lennerstrand, G. and Bach-y-Rita,P., eds), pp. 337-378, Pergamon Press, New York 14 Robinson, D. A. (1970)J. Neurophysiol. 33, 393-404 15 van Gisbergen, J. A. M., Robinson, D. A. and Gielen, S. (1981)J. Neurophysiol. 45,417-442 16 Wurtz, R. H. and Goldberg, M. E. (1972) .I. Neurophysiol. 35, 587-596