Eye Movement Deficits After Ibotenic Acid Lesions of the Nucleus Prepositus Hypoglossi in Monkeys. I. Saccades and Fixation
Chris R. S. Kaneko
Department of Physiology and Biophysics and Regional Primate Research Center, University of Washington, Seattle, Washington 98195
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ABSTRACT |
Kaneko, Chris R. S. Eye movement deficits after ibotenic acid lesions of the nucleus prepositus hypoglossi in monkeys. I. Saccades and fixation. J. Neurophysiol. 78: 1753-1768, 1997. It has been suggested that the function of the nucleus prepositus hypoglossi (nph) is the mathematical integration of velocity-coded signals to produce position-coded commands that drive abducens motoneurons and generate horizontal eye movements. In early models of the saccadic system, a single integrator provided not only the signal that maintained steady gaze after a saccade but also an efference copy of eye position, which provided a feedback signal to control the dynamics of the saccade. In this study, permanent, serial ibotenic acid lesions were made in the nph of three rhesus macaques, and their effects were studied while the alert monkeys performed a visual tracking task. Localized damage to the nph was confirmed in both Nissl and immunohistochemically stained material. The lesions clearly were correlated with long-lasting deficits in eye movement. The animals' ability to fixate in the dark was compromised quickly and uniformly so that saccades to peripheral locations were followed by postsaccadic centripetal drift. The time constant of the drift decreased to approximately one-tenth of its normal values but remained 10 times longer than that attributable to the mechanics of the eye. In contrast, saccades were affected minimally. The results are more consistent with models of the neural saccade generator that use separate feedback and position integrators than with the classical models, which use a single multipurpose element. Likewise, the data contradict models that rely on feedback from the nph. In addition, they show that the oculomotor neural integrator is not a single neural entity but is most likely distributed among a number of nuclei.
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INTRODUCTION |
During the last 20 years, scientists have come to see that the nucleus prepositus hypoglossi (nph), which had been thought to be an accessory gustatory nucleus, is actually an oculomotor nucleus. Because of its anatomic proximity to the hypoglossal nucleus, the nph originally was assumed to serve a tongue motor function. This assumption was first questioned by Baker and Berthoz (1975)
, who suggested that the nph actually might serve a vestibular or oculomotor function because it projects directly to the oculomotor nucleus (Graybiel and Hartwieg 1974
). Electrophysiological studies substantiated the oculomotor projection as well as the vestibular input (Baker and Berthoz 1975
), and neural recordings from alert cats showed that nph neurons probably discharge for eye movements (Baker et al. 1975
). These results were corroborated by anatomic evidence of a prominent, direct projection of nph neurons to the abducens nucleus (Langer et al. 1986
; Maciewicz et al. 1977
).
A specific role for the nph in oculomotor function was suggested by Baker et al. (1981)
, who deduced, by process of elimination, that the neural integrator was located in the nph. They reasoned that the only major afferent to the abducens nucleus with an unknown function was the nph, and the only major missing input signal to the motoneurons that wasn't already associated with an anatomic locus was that from the oculomotor neural integrator (for discussion, see Fukushima et al. 1992
).
The neural integrator for vestibular and oculomotor signals is a hypothetical structure that converts velocity-coded input into position-coded commands that tonically activate ocular motoneurons to maintain steady eye position following eye movements (Robinson 1968
). For example, it is supposed to integrate, in the mathematical sense, the head velocity signal from the vestibular apparatus to produce compensatory eye position (e.g., Suzuki and Cohen 1966
) during the execution of the vestibulo-ocular reflex. More recent studies have supported the suggestion that the nph is the site of the neural integrator. The discharge of nph neurons is appropriate for integrating velocity signals to position-related discharge (i.e., tonic and burst-tonic discharge) (Lopez-Barneo et al. 1982
; McFarland and Fuchs 1992
), and the appropriate anatomic connections have been confirmed by a variety of techniques (Langer et al. 1986
; see Belknap and McCrea 1988
for review). In addition, lesion studies have correlated inactivation of the nph with loss of integrator function (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1986
).
Although the results of lesion studies suggested that the nph is the site of the oculomotor integrator, they were not definitive. The electrolytic lesions that Cheron et al. (1986)
placed in the nph region of cats unfortunately encroached on the medial vestibular nucleus and the abducens; they also interrupted portions of the medial longitudinal fasciculus and the numerous fibers that pass through the region carrying the signals for the vestibulo-ocular reflex (e.g., McCrea et al. 1987
), saccades (Hikosaka and Kawakami 1977
), and optokinetic velocity storage (Katz et al. 1991
). To circumvent this limitation, Cheron and Godaux (1987)
repeated their study using kainic acid, an excitatory neurotoxin that spares axons. Unfortunately, this technique produced neither permanent lesions nor long-lasting deficits, so it was impossible to pinpoint the actual cause of the transient oculomotor deficits observed in that study. Cannon and Robinson (1987)
attempted similar studies in monkeys using both kainic and ibotenic acid; they documented similar transient deficits but no permanent lesions. It is possible that the short-lasting deficits associated with neurotoxic lesions were due to the well-known transmitter mimetic effects of the neurotoxins. For example, ibotenate probably is decarboxylated rapidly in vivo to muscimol (e.g., Curtis et al. 1979
), a known
-aminobutyric acid (GABA) mimetic that is effective in nanomolar concentration and also inhibits the reuptake of GABA. Thus one might expect short-term stimulation of GABA receptors after the injection of ibotenate. Indeed, Straube et al. (1991)
used injections of the GABA agonist muscimol in the region to produce similar transient oculomotor deficits.
In addition to these technical constraints, which limited the conclusions that could be drawn from early lesion studies, the animals were not required to make targeting saccades. Thus there was no way of knowing the intended sizes of saccades (cf. Chu and Kaneko 1995
) and thereby determining what effects nph lesions had on saccades. Nor did the investigators present a quantitative analysis of the saccades, a procedure that might have revealed subtle deficits. Detailed assessment of the ability to make accurate saccades may be necessary before we can define the role of the integrator in saccade function. For example, Robinson's (1975) model of the saccade generator (Fig. 1A) uses the difference between desired eye position (i.e., the location of the target) and current eye position to drive the excitatory burst neurons (EBNs) until the eye is on target. EBNs, in turn, drive the motoneurons (MNs) to evoke the burst of action potentials that creates the pulse of force in the muscles that is necessary to overcome the viscous properties of the plant (i.e., the mechanical properties of the globe, its suspension and muscles). In the model, EBNs also drive the tonic neurons (
, Fig. 1A; currently identified as the nph) that integrate the eye velocity signal of the EBNs into an eye position signal; this eye position signal is fed to the MNs and maintains their tonic discharge against the elastic restoring forces of the plant. Other models use two integrators (e.g., Becker and Jürgens 1979
) in a variety of modified versions of Robinson's scheme. For example, in Scudder's (1988) version the integrator is separated into two components:
2 is composed of the long-lead burst neurons (LLBNs) that sum their inputs and integrate them (shown as a recurrent collateral) to get the eye on target, and
1 integrates eye velocity to hold the eye at its newly acquired fixation (Fig. 1B).

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| FIG. 1.
Examples of 2 distinct classes of model for the saccadic burst generator. A: Robinson's original, single-integrator, local-feedback model. B: Scudder's modification using a second integrator. Heavy lines, integrators and emphasize differences between the 2 classes regarding the hypothesized role of the neural integrator. Lines show connections of the various neural elements. , inhibitory endings; +, excitatory endings. EBN, excitatory burst neuron; IBN, inhibitory burst neuron; TN, tonic neuron; OPN, omnipause neuron; IFN, inhibitory feedback neuron; LLBN, long-lead burst neuron; , neural integrator.
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Comparison of even these simplified variations of the original models clearly shows that they make different predictions regarding the possible function of the nph in the generation of saccades. The Robinson model predicts two obvious deficits if the integrator is destroyed. First, the eye will not be able to maintain eccentric gaze and will drift back toward the center of the orbit. Such a result was observed after lesions of the nph in cats (Cheron and Godaux 1987
; Cheron et al. 1986
) and monkeys (Cannon and Robinson 1987
). Second, saccades should become hypermetric because there is no position feedback to the EBNs (Fig. 1A) to tell the system that the eye is on target. The previously reported data (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1996) do not allow an assessment of saccadic accuracy. The two-component integrator, such as that in Scudder's model, predicts that the only deficit will be an inability to maintain eccentric fixation because the second integrating function has been moved and attributed to other structures such as the LLBNs (
2 in Fig. 1B).
Because the two models make distinctly different predictions regarding the effect of nph lesions on saccades, I attempted to test the predictive validity of the models to understand how the nph might integrate saccadic command signals. Previous success with the neurotoxin ibotenic acid in a nearby oculomotor nucleus, the nucleus raphe interpositus (called OPN in Fig. 1 because it is the site of the omnipause neurons) (Büttner-Ennever et al. 1988
; Langer and Kaneko 1990
), suggested that ibotenic acid could produce permanent lesions in oculomotor structures (Kaneko 1996
). Permanent lesions would overcome one of the interpretational limitations of the previous investigations. In addition, work in our laboratory (e.g., McFarland et al. 1992
) suggested that the area could be identified by the characteristic discharge of its neurons in relation to saccades. Therefore it seemed likely that the lesions could be placed more precisely than had been done before and thus not compromise adjacent structures. Finally, the monkey nph has a distinct structure in its rostro-lateral margin, called the marginal zone (Langer et al. 1986
). Thus it should be possible to assess the damage in normal Nissl-stained material. Three pieces of evidence suggest that the marginal zone is the site of the output of the oculomotor neural integrator in monkeys: the marginal zone is the major afferent source to the abducens nucleus (Langer et al. 1986
; see also Belknap and McCrea 1988
), neurons in the marginal zone exhibit discharge appropriate for integrator function (McFarland and Fuchs 1992
), and lesions that include the marginal zone cause transient deficits in integrator function (Cannon and Robinson 1987
).
A related issue is whether the oculomotor integrator is a single multipurpose structure that subserves all oculomotor subsystems (Robinson 1968
) or whether its function is distributed among distinct anatomic nuclei. In the present experiment, I began to test these possibilities by comparing the ability to hold eccentric gaze in the dark with changes in the gain of saccades (i.e., saccade amplitude/target amplitude) in alert monkeys that had lesions of the nph. Preliminary portions of this work have been published in abstract form (Kaneko 1992a
,b
; Kaneko and Fuchs 1991
).
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METHODS |
The methods used in this experiment are similar to those described elsewhere (Kaneko 1996
). Three juvenile male rhesus macaques (Macaca mulatta) were chosen for tractability and an appetite for the reward medium (Gerber's applesauce). A scleral search coil (Fuchs and Robinson 1966
), a recording chamber, and stabilization lugs were implanted under aseptic surgical conditions. After 1 wk of recovery, the monkeys were trained to track saccadically a moveable, back-projected laser spot for food reward. Because they received all of their food initially as reward medium supplemented with protein powder and Stat, it was not necessary to deprive the animals for more than a portion of a day to motivate them to perform the tracking task. Within 1 wk they worked well enough to receive further supplements of monkey chow and fruit in their home cages. All experiments were performed in strict compliance with the Guide for the Care and Use of Laboratory Animals (Department of Health Education and Welfare publication No. NIH85-23 1985) and recommendations from the Institute of Laboratory Animal Resources and the Association for Assessment and Accreditation of Laboratory Animal Care International.
After the monkeys were prepared surgically and trained in the tracking task, the extent and location of the nph were mapped by the use of standard extracellular electrophysiological recording techniques. In all three animals, the nph was located on the basis of its position relative to the abducens nuclei and its characteristic discharge (McFarland and Fuchs 1992
; McFarland et al. 1992
), which consisted of burst-tonic (Luschei and Fuchs 1972
) discharge for ipsilateral saccades and fixation. The area was differentiated from neighboring structures that had similar discharge patterns (e.g., the rostrally adjacent abducens neurons) by the lack of a pause in activity for off-direction (contralateral) saccades, the large variability in the ratio of velocity to position sensitivity in adjacent neurons, the occasional presence of neurons with contralateral on-directions, and the ventrally adjacent burst-tonic neurons that had vertical on-directions, especially in caudal portions of the nph. The area was remapped before each injection, thereby ensuring that the injection was placed in an appropriate area.
After the mapping procedure, a lesion was made in a portion of the nph by the use of pressure injections of ibotenic acid, usually ~400 nL of 15 µg/µl in phosphate-buffered saline, pH 7.4 (Kaneko 1996
). In the first two monkeys, marking lesions were placed around the physiologically identified regions for later histological recovery and identification; the conspicuous marginal zone and the obvious injection sites observed in the first two animals made this procedure unnecessary in the last animal. Lesions were confirmed histologically on the basis of damage to the marginal zone and mechanical damage due to the injected volume, cell-death resulting from the neurotoxin, and previously placed marking lesions that bracketed the nucleus in the first two animals, monkeys Z and M. In the third animal, monkey R, a biomarker for assessment of minimal neurotoxicity indicated the maximal possible extent of the neural damage more precisely. Injection sites were revealed by immunohistochemical staining for glial fibrillary acidic protein (GFAP) in astrocytes; the extent of the neural damage was correlated with the proliferation of astrocytes (O'Callaghan 1991
). The staining technique uses a GFAP modification of standard peroxidase-antiperoxidase immunohistochemistry (Sternberger 1986
) and commercially available rabbit anti-GFAP (Sigma). Frozen sections were cut at 40 µm and treated with the following series of solutions made up in 0.01 M, phosphate-buffered saline with 1% normal goat serum, 0.25% Triton X-100, and 0.1% sodium azide (first two solutions only): 0.1 M l-lysine and rabbit anti-GFAP (1:160), goat anti-rabbit immnoglobulin G (1:400), rabbit peroxidase-antiperoxidase (1:200), and diaminobenzedine. The sections were rinsed several times between each step.
Because others had reported that excitatory neurotoxins were ineffective in the nph (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1986
), the feasibility of producing ibotenate lesions was ascertained by giving the first animal (monkey Z) a large (~1.5 µl) unilateral injection (Fig. 2). The other two animals received a series of more punctate (180-700 nL), separate unilateral injections on both sides (Figs. 3 and 4) so that the amount of damage could be titrated against the oculomotor deficits. Ibotenate was delivered via a pipette that was constructed of a glass tip pulled to a fine point and broken to an opening of ~30 µm. The pipette was glued to the outside end of a 30-gauge, insulated stainless steel tube and led through thick-walled, fine-gauge tubing to a solenoid-controlled pressure-delivery system. The entire system was filled with colored oil, and then ~1 µL of ibotenate was sucked up into the pipette tube. The movement of the ibotenate/oil interface was monitored so that the injected volume could be measured precisely (within ± 5 nL). The total injected volume was delivered in small aliquots during tens of minutes, thereby minimizing the possibility of mechanical damage and leakage of the ibotenate up the pipette shaft or into the ventricle.

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| FIG. 2.
Transverse, Nissl-stained section of the dorsal midline (- - -) region from the level just caudal to the abducens nuclei at the junction of the pons and medulla. Large ibotenic acid injection (*) on left side destroyed the cellular structure ( ) of the nucleus prepositus hypoglossi (nph) and marginal zone (M) while sparing the medial vestibular nucleus (mvn); compare left and right. Calibration: 1.0 mm. M, marginal zone; mlf, medial longitudinal fasciculus.
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| FIG. 3.
Transverse, Nissl-stained sections showing nucleus prepositus hypoglossi (nph) damage after ibotenic acid injections in monkey M. A: section ~1.25 mm caudal to abducens nucleus has damage () from closely spaced injections 3 (500 nL) and 4 (250 nL) in the right nph. B: section ~250 µm caudal to abducens nucleus shows damage () from injection 5 (360 nL). Note significant involvement of the marginal zone on the left while the right side appears uncompromised. Calibration: 1.0 mm.
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| FIG. 4.
Comparison of Nissl-stained and immunohistochemically stained sections from monkey R. A, C, and E: transverse, rostro-to-caudal Nissl sections from 700 µm, 1.1 mm, and 1.9 mm caudal to the posterior edge of the abducens nuclei. Damage is barely discernible in this Nissl-stained material. B, D, and E: immediately adjacent sections stained for glial fibrillary acidic protein (GFAP) reaction but not counterstained. More sensitive GFAP technique shows injection sites ( ) and suggests significantly more neural destruction. B: injection 3 (400 nL); D: injection 5 (430 nL); F: injection 7 (600 nL). Calibration: 1.0 mm. Lesion 8 and those on the right were concentrated more rostrally and dorsally. lvn, lateral vestibular nucleus.
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Within 1 day after each injection, saccadic data and postsaccadic drift, as well as drift in the dark, were recorded depending on when the animal recovered enough to track the target spot. Additional recordings were obtained from a few minutes after the injection and at increasing intervals of hours, days, and weeks until there were no further changes in the parameters of these or other eye movements. Saccades also were measured before each of the succeeding lesions. Saccadic parameters were recorded, digitized off-line, and analyzed with a home-made interactive program that identified saccades on the basis of an adjustable velocity criterion, marked the target and the onset, offset, and peak velocity of each saccade, and calculated the descriptive characteristics of the saccades (Kaneko 1996
). Each saccade was inspected and accepted, remarked, or rejected. Only saccades that began with the animal on target and only the initial (primary) saccade after a target step were used in the calculation of saccadic gain. As described in RESULTS, except for short periods immediately after the injections, only monkey Z had any difficulty tracking the target throughout its oculomotor range. All primary saccades were analyzed except those rare saccades that were obviously not targeting saccades, such as saccades in the wrong direction (e.g., left instead of right) or saccades with a latency that was too short (<~80 ms) or with an amplitude that was imprecise (i.e., <25% or >200% of the target step). When primary saccades did not end abruptly as judged by the failure of the velocity trace to return smoothly to zero, either the initial amplitude was used for the calculation of gain or the saccade was excluded from the analysis. Saccades that do not end abruptly have been characterized as having one of a variety of forms of postsaccadic drift. One form, glissades, has been hypothesized to be due to the mismatch between the saccadic pulse input and the fixation holding position (Easter 1973
) presumably created by the neural integrator from that pulse. In the analysis of saccadic gain, glissades were excluded so that the dynamic feedback function of the neural integrator could be studied in isolation. The measurement of postsaccadic drift in the dark was chosen because it is a more direct test of the isolated position integrator function and because the amplitude of glissades is too small to be measured reliably. Thus glissades following saccades made to visible targets in the dimly lit room and the shorter duration movements (Soetedjo and Kaneko 1995
) following saccades in the dark (dynamic overshoot) (Bahill 1975
) were excluded from the following analysis of drift and saccades.
The time constant for postsaccadic drift in the dark was calculated in one of two ways. For monkey Z, the drift was measured by hand from chart recordings, and the values were entered into a spread sheet, converted to a natural log scale, and fit by an exponential with the use of a linear least-square regression (Excel 1.5; Microsoft). For monkeys M and R, data were digitized, converted to ASCII (Igor) or binary (MatLab), and read into a software analysis package (Igor, Wavemetrics or MatLab, Math Works). The periods of drift were marked by hand and fit by the program with the use of an iterative minimum squared-error technique based on a single-exponential model. To measure the proportion of the neural integrator that was damaged by the nph injections, it was necessary to compare the calculated time constants with the mechanical time constant. The mechanical time constant is the amount of centripetal drift that is due to the mechanics of the plant itself, that is, the elastic restoring forces imposed by the suspensory apparatus and the muscles. The mechanical time constant of the globe was calculated with the use of Igor software to fit centripetal drift in lightly anesthetized monkeys M and R. The globe was deviated 20-45° laterally with the use of small forceps. The return time course for the horizontal movement after abrupt release was measured for
12 return movements of both directions, yielding an overall average time constant.
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RESULTS |
Anatomy
The output of the putative neural integrator is located in a distinct subregion, the marginal zone, of the nph at its rostro-lateral edge (M, Fig. 2, right) where it abuts the medial vestibular nucleus (Fukushima and Kaneko 1995
; for review, see Fukushima et al. 1992
). The large injection given to monkey Z in an attempt to maximize the chance of creating a long-lasting lesion was placed slightly deep to the left marginal zone. This lesion resulted in considerable mechanical damage owing to the volume of injected fluid (Fig. 2, *), even though the volume was similar to that used in other studies (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1986
). In addition to the mechanical damage, virtually the entire nph and marginal zone at this level were damaged (Fig. 2, arrows), and the medial portion of the medial vestibular nucleus (mvn) also may have been compromised along with the laterally and ventrally adjacent reticular formation. Specifically, the area symmetric to the marginal zone (M) appears acellular, and there are the beginnings of proliferation of microglia along the electrode track where the nph had been (darkened shaft above hole).
Although this result demonstrates the effectiveness of ibotenate in producing permanent neurotoxic lesions in this portion of the brain stem, the mechanical damage to the adjacent mvn as well as crossing fibers in the area caused by such large injections complicates interpretation of the associated behavioral deficits. In particular, the many axons projecting from vestibular and reticular neurons that carry saccadic signals to the abducens nucleus (e.g., Hikosaka and Kawakami 1977
; McCrea et al. 1987
) probably were damaged. For example, the lateral portions of the left medial longitudinal fasciculus were destroyed by the injection volume (Fig. 2, compare left and right sides). Therefore, smaller volumes were used in monkeys M and R (see methods) and were delivered during longer periods so that mechanical destruction would be limited. This also allowed a more complete destruction of the nph because injections could be placed along the rostral-caudal extent of the elongated nucleus and still be restricted to its medio-lateral boundaries.
Monkey M received five such smaller injections, two on the left and three on the right, with the results shown in Fig. 3. Two closely spaced injections of 500 and 250 nL in the body of the right nph resulted in considerable, but subtotal, destruction of the nph (Fig. 3A, right). The damage is indicated by the gliosis that shows up as a dense, dark stippling in the photomicrograph (; compare with Fig. 3B, right, and Fig. 2, right). Cell loss diminished with distance from the center of the injections (indicated by open arrows) and was slight in the medial margin of the mvn and in more rostral sections (Fig. 3B). Note that the nph on the left was relatively intact but showed some gliosis (darkening) due to the spread from a nearby injection on that side. Rostrally, a 360-nL injection destroyed the left marginal zone (Fig. 3B) but left a portion of the nph and the mvn intact on that side (compare with contralateral structures on the right). The smaller volumes (180 and 200 nL) used for the first two injections resulted in much less obvious cell loss even though they were associated with permanent behavioral deficits. In contrast, similar volumes were very effective when injected into the nearby nucleus raphe interpositus (Kaneko 1996
).
Because the damage associated with small volumes was not always obvious even in higher magnification micrographs, slightly larger quantities (350-700 nL) and more numerous injections (8) were used in monkey R, and sections were stained for GFAP in an attempt to reveal more subtle neural damage not readily discernible in Nissl-stained material. This monkey received the largest number of injections and experienced the most complete destruction of the rostral nph. Four injections were placed on each side, all within the rostralmost 2 mm of the nph. The rostral 0.5 mm of the nph was almost complete destroyed, especially on the right side. The damaged area did not seem to encroach on either the abducens nucleus immediately rostrally and laterally or the fiber tracts of the medial longitudinal fasciculus located ventrally and medially. A representative sample of these lesions is illustrated in Fig. 4, which also shows the maximal extent of damage as assessed by the GFAP reaction. The brownish reaction product from the GFAP processing is dark gray in the photomicrographs (Fig. 4, B, D, and F) and reveals damage that is not obvious in Nissl-stained material (Fig. 4, A, C, and E). On the basis of the GFAP material, the estimated largest extent of damage in monkey R included the entire nph but did not significantly encroach on the mvn laterally or the abducens rostrally. In the Nissl-stained material, the damage was less than complete (note the apparently intact neurons within the nph of each section). In summary, the nph of monkey R was affected over most of its rostral pole (Fig. 4, B, D, and F) but the damage was not complete (Fig. 4, A, C, and E).
Eye Movements
DRIFT.
Within minutes after the first portion of each injection was introduced, each monkey was unable to maintain eccentric gaze, especially in the ipsilateral hemifield, even in the light or with the aid of a fixation target. Gradually, a positional nystagmus developed so that attempts to look laterally of a "null position" (Straube et al. 1991
) resulted in drift back toward that null position. (Null position was estimated by taking the center of the zone toward which the eyes drifted after saccades lateral of that region; it was a zone of several degrees width rather than a fixed and exact eye position.) The null position moved contralaterally from the side of the injection site during the next several minutes and gradually recovered toward midline over the next several days. With subsequent injections, the width of the zone increased and was largest in the animals that had the most extensive damage, monkeys Z and R. In monkeys M and R, which received multiple injections, there was a tendency for injections on opposite sides to return the null position toward midline, though in monkey R, the null position consistently was biased toward the left. In monkey Z, which had a large lesion of the left nph, the deviation was initially so severe that the animal's eyes deviated to the extreme contralateral field (Fig. 5, left ordinate, 40° right); even after 1 mo, the gaze did not return to straight ahead but deviated ~25° to the right. In all three monkeys, the changes in null position were similar to those observed in other studies (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1986
).

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| FIG. 5.
Behavioral deficits after ibotenate injections into the nph and marginal zone of monkey Z. - , changes plotted in null position (left axis) during a period of several weeks. - , time constant (right axis) of drift in the dark.
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This gaze instability was permanent. Initially, saccades were followed by drift back toward the null position in both light and dark; this postsaccadic drift persisted in the dark even after many weeks and considerable retraining in the saccade task, which required fixation during intersaccadic intervals. Monkey R, for example, had a prelesion pattern of long intervals of stable fixation in the dark; drift, when present, was low-velocity and inconsistent (Fig. 6, top traces). The drift could be centripetal (first arrow) and centrifugal five saccades later (middle arrow). Similarly, one intersaccadic drift might be suggestive of centripetal drift (first arrow), whereas a succeeding drift from a more peripheral starting position might be insignificant (last arrow). After 141 days of recovery after the eighth lesion, however, this animal had a pronounced drift toward the null position (Fig. 6, solid line), which was displaced leftward from the midline (- - -).

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| FIG. 6.
Drift in the dark. Normal fixation in the dark is stable (top). Ibotenate injections cause permanent fixation instability (bottom) at 141 days following the 8th lesion in monkey R. - - -, straight-ahead gaze. Line in bottom traces, estimated null position.
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Because the rate of drift in the dark measures the time constant of the neural integrator (Cannon and Robinson 1987
; Cheron and Godaux 1987
; Cheron et al. 1986
), the fixation deficits were quantified with the use of an exponential fit to repeated episodes of drift. In an attempt to obtain drift from extreme eccentric positions, a peripheral fixation spot was turned off after the animal fixated it or the spot was flashed to attract the animal's gaze in the otherwise dark enclosure. Unfortunately, as soon as the spot was extinguished, the animal returned its gaze to near the null position in a single saccade so that most of the drift measurements were based on postsaccadic drift in the dark within plus or minus ~20° of the null position. To facilitate direct comparison with results of previous studies, I calculated the time constant of monkey Z's postsaccadic drift in the dark by fitting repeated individual trials with a single exponential and then averaging those responses (see METHODS). The results are plotted in Fig. 5 (triangles, right ordinate). The time constant, which was initially tens of seconds (i.e., no drift and near-perfect fixation in the dark), dropped immediately to a few hundred milliseconds and never recovered beyond 300 ms. Thus a large lesion of the rostral nph and surrounding area results in permanent damage that is correlated with inability to maintain eccentric gaze.
The time constant after punctate serial lesions decreased to 1.8 s in monkey M, which had limited nph damage (Fig. 3), and to 2.1 s in monkey R, which had extensive rostral nph damage (Fig. 4). The time course of these changes is shown in Fig. 7 for monkey M (left) and monkey R (right). After the first injection, the time constant dropped precipitously (bottom left of each plot) from its value of >20 s and remained at that low level throughout periodic retesting during recovery. Thereafter, each of the next several lesions caused only minor changes and modest further reduction. By the fourth lesion, there was an indication of some slight recovery from the minimum values seen after the third and fourth injections and eventually the time constant stabilized at a few seconds. The low values were consistent and permanent, as indicated by the similar magnitudes and lower standard deviations of the last several points (especially after lesion 8 in monkey R, Fig. 7, bottom right). Monkey R's "normal" drift, averaged from three separate days before any lesions, was 28 s (Fig. 7,
on ordinate). Thus damage to the nph caused at least a 10-fold reduction in the ability to maintain peripheral gaze. However, this greatly reduced time constant was still
20 times greater than the mechanical time constant of the plant even in the two animals with extensive nph damage [88 ± 51 (SD) ms and 103 ± 42 ms for monkeys M and R, respectively].

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| FIG. 7.
Time course of changes in time constant for postsaccadic drift in the dark. Values for monkey M ( ) on the left and monkey R ( ) on the right for each day they were measured after injections indicated by the number above the groups. on ordinate shows average normal time constant for monkey R. SDs are shown for each of the measurements. Inset: values after the 4th injection are shown on an expanded time scale.
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The time constant of the intersaccadic drift in the dark varied from trial to trial so that the standard deviations usually equaled or exceeded the average values. The variability associated with measurements of the time constant of drift in previous studies (Cannon and Robinson 1987
; Cheron and Godaux 1987
) has not been reported, so it is not known whether those measurements had similar variability. Several attempts were made to reduce the variability in the present study: 1) all poor fits were eliminated, as were all drift trajectories that were not monotonic; 2) the null position was estimated and used to constrain the final, asymptotic position for the fitting process; 3) a variety of asymptotic limits were considered; 4) the initial eye position was constrained to the normal oculomotor range (i.e., ± 30°); 5) impossibly extreme time constants (i.e., >100 s or <200 ms) were rejected from the calculations; and 6) only the longest periods of drift (>1.5 s) were used in the averages. Because none of these restrictions, either separately or in combination, significantly reduced the relative variability of the estimates or changed the trends or course of the changes in time constant, the results presented in Fig. 7 are averages of values constrained only to the oculomotor range with impossibly extreme values eliminated.
During the course of repeated injections in monkey R, peripheral gaze holding became so degraded that the animal could not fixate lateral target spots in the dimly lit enclosure. Pre- and postlesion fixation of a stationary target is shown in Fig. 8. Before the first lesion (thin black line), monkey R easily fixated the target within 0.5° for periods of several hundreds of milliseconds punctuated only by occasional saccades (clipped). After the eighth lesion (thick dark gray lines), fixation remained stable for leftward target positions (Fig. 8, bottom) but attempts at rightward fixation were characterized by small overshoots followed by centripetal drift (Fig. 8, top). When the target position was moved further lateral (at ~1,200 ms), the animal compensated by overshooting the target and drifting past it; this pattern indicates both the monkey's alertness and an attempt to refixate the target.

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| FIG. 8.
Instability of peripheral fixation in monkey R. Each panel shows target position (thin dashed gray line) and horizontal eye position before any injections (thin black line) and 141 days after the last injection (heavy solid dark gray line). After the last (8th) lesion, the monkey could not maintain peripheral gaze to the right even in dim light with a target spot (top), although leftward gaze was stable (bottom). Position traces are truncated to eliminate saccades.
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In addition to the horizontal drift, vertical fixation in the dark also was affected gradually and permanently by the lesions, especially in the two animals that received bilateral injections. Monkeys normally have an upward drift in the dark but the rate of drift increased progressively from several to many degrees per second.
SACCADES.
Permanent saccadic abnormalities were minimal. Within 24 h after an injection, the animals recovered the ability to make all eye movements, particularly saccades. Because it was clear in the initial sessions that they could not adequately track the target shortly after an injection (6 ± 2 h; n = 6), they were usually allowed to recover overnight in a dark room and tested the next day (mean 20 ± 6 h for the 13 lesions in monkeys M and R). The velocity, amplitude, and accuracy of saccades after a given injection depended on both the total amount of damage sustained up to that injection and the volume of that injection. In monkey Z, which had a large nph/reticular lesion (Fig. 2), the gaze positional nystagmus made independent assessment of saccades difficult. The large lesion was associated with inaccuracies in both vertical and horizontal saccades, but whereas vertical saccades returned substantially to normal within hours, horizontal saccades remained impaired. Qualitatively, and only for monkey Z, ipsilaterally directed saccades were inaccurate in proportion to amplitude of the movement into the ipsilateral hemifield; that is, monkey Z could not move its eyes normally in the ipsilateral field. The impression was that this was primarily a deficit in fixation ability and attendant positional nystagmus and not saccadic dysfunction per se. As the animal recovered, it made an increasing but still small number of targeting saccades during subsequent testing sessions. The gain (saccade size/target size) of those few saccades showed a slight elevation that was not statistically significantly different from normal owing to the large standard deviations of the measures. The lack of significant gain change contrasts sharply with the gross deficits in fixation capabilities.
Monkeys M and R received smaller injections that were not accompanied by obvious mechanical damage, suggesting that associated effects on saccades were due to nph damage and not fibers of passage. Figure 9 documents the minimal effects of nph damage on saccade metrics for monkey R, the animal with the most extensive nph loss. The pre- and postlesion peak velocity data overlay completely for these targeting saccades although the animal had a slight tendency to make larger rightward saccades before the lesions (
on the right). The scatter in the duration/size relation increased, as did the number of very long duration saccades after the lesions. The slope of the duration/size relation increased significantly (t-test for the difference between slopes, P < 0.001) from 1.49 to 1.97 ms/deg. The difference was due largely to a few (7 of 155) long-duration, large saccades. Monkey M showed even smaller differences in metrics before and after lesions. Again, pre- and postlesion peak velocities overlay, and there were larger saccades before the lesions. However, durations were more similar before and after lesions than for monkey R.

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| FIG. 9.
Metrics of horizontal saccades before and after nph lesions. Scatter plots of peak velocity (top) and duration (bottom) as a function of amplitude for normal, prelesion saccades ( ) and saccades after the last lesion ( ) in monkey R. In each plot, prelesion data are combined measurements from 5 sessions before injections were begun, and the postlesion data are taken from the last 2 sessions after the last injection (lesion 8, days 97 and 141).
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Saccadic gain also was affected only minimally in these two animals (Fig. 10). Monkey M showed a higher variability because the saccades were mostly oblique. Overall, monkey R had a slightly higher gain (thin gray line indicates a gain of 1.0). It is clear that the lesions in monkey M had little effect on saccadic gain, whereas gain increased slightly over the course of the experiment for monkey R (see DISCUSSION). Likewise, gain was little affected even immediately after an injection. The inset in Fig. 10 shows a typical time course for the fourth lesion in monkey R (gray dashed arrows). Gain was slightly elevated on day 1 postlesion (first point), depressed on day 2, and back to normal by day 6 (third and fourth points).

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| FIG. 10.
Saccadic gain as a function of time for monkeys M (left, ) and R (right, ). Abscissa: days after first collection of normal data. Numbers above each cluster indicate the lesion number. Lighter gray symbols (square for monkey M, dots for monkey R) at the left of each series show initial normal data. Clustered points are measurements after each injection; separations are periods during which the nph was remapped for the next injection. Each point is the mean ± SD of the horizontal component of all saccades (monkey M) or all purely horizontal saccades (monkey R) collected in each session.
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Although the gain changes were small, the increase in gain was statistically significant (P < 0.001, t-test for large sample difference between means) for each of the last days examined after lesions 6-8 in monkey R, from which large numbers of purely horizontal saccades were collected. These differences were not due to asymmetries in the saccade populations (e.g., more right than left saccades) or saccade size (e.g., more small saccades) because comparisons of restricted populations also were significantly different. The lack of a substantial change in gain might have been due to a slight variation in the population of saccades sampled (e.g., a higher proportion of small saccades that had higher gain in the "normal" sample), but reexamination of restricted samples of similar-size saccades revealed no consistent trends. For example, when only 9-11° saccades from the same populations illustrated in Fig. 9 were compared before and after lesions, the gains were equivalent: 1.06 ± 0.24 and 1.12 ± 0.05, respectively. In contrast, 4-6° as well as 19-21° samples were statistically significantly different (P < 0.001).
SACCADE/DRIFT INTERACTIONS.
Because nph neurons discharge both for eye position and for saccades, one might reasonably expect that damage to gaze holding must be accompanied by saccade deficits and vice versa. Ideally, to evaluate any parallel changes in drift and saccades, one should measure them simultaneously immediately after injections so that adaptive changes might be minimized. This was impossible because the ibotenate initiates a destructive process that requires an unknown duration for completion and because it was impossible to routinely estimate saccadic gain until the monkeys recovered enough from the injections to make targeting saccades. When performances in fully recovered conditions are compared (Figs. 7 and 10), drift and saccades do not appear to change in parallel. For example, comparison of prelesion saccades (Fig. 11A, left) with saccades during the last two sessions after the last lesion in monkey R (Fig. 11A, right) revealed no sign of drift after the 10° targeting saccades. Nevertheless, to examine the possibility of synchronous deficits in drift and saccadic gain more closely, I measured saccadic deficits in two additional ways. On one occasion, monkey M was able to track sporadically ~10 min after the beginning of the first injection (lesion 1 on the left side) and produced enough targeting saccades to form a basis for comparison. The saccadic gain and gaze-holding deficit for the few targeting saccades that were produced during this period are compared in Fig. 11B. Saccadic gain increased 5% above normal (1.02 ± 0.12 vs. 0.97 ± 0.07; P <0.001, t-test). The average time constant for postsaccadic drift after these same saccades (bottom inset) was 0.30 ± 1.78 s (n = 33), which represents a reduction of
6,000% (~20 vs. 0.3 s). It should be emphasized that these drifts are not equivalent to the measurements used to estimate gaze holding because they were taken when the animal had a fixation spot, not in the dark, and the animal still was suffering from the proximal effects of the injection.

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| FIG. 11.
Postsaccadic drift. A: all leftward targeting 10° saccades from monkey R before (left) and 97 and 141 d after the 8th injection (right). Note the lack of any sign of postsaccadic drift during the short ~25-ms period after saccades and the slightly increased average gain. For comparison, the averaged response of normal 10° leftward targeting saccades (heavy black dots) is superimposed on data obtained under both normal (left) and lesion (right) conditions (gray dots). B: saccadic gain measured immediately (10 min) after the first injection in monkey M during target tracking. Drift and saccadic gain were measured for the same data that included initial targeting saccades and the postsaccadic drift. Inset: example of 10° leftward saccades.
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Saccadic gain during drift in the dark also was estimated when a peripheral target spot was left on while the animals were coaxed to fixate laterally to induce long-duration drift segments. For four sessions in monkey R, the time constant of drift in those conditions could be compared with saccadic gain from the same sessions if it is assumed that the animal was attempting to fixate the peripheral target. An analysis of the few saccades from each of the four sessions (which are not the same as the ones used to estimate saccadic gain in the previous section) showed that the gain ranged from 0.58 to 0.65.
Even if nph damage affects gaze holding independently of saccades, a long-standing hypothesis (Easter 1973
) suggests that a change in the gaze-holding mechanism should lead to a mismatch between the saccade and the subsequent fixation, which is manifest as a glissade (Weber and Daroff 1972
). To check for this, I reexamined all normal saccades (n = 470) at high amplification and slower time scale, to magnify any postsaccadic movements, and counted the incidence of glissades for monkey R, which had the most extensive data. Under these conditions, movements of 0.2° were easily discernible. For the tally, the original definition of glissades (Weber and Daroff 1972
) had to be amended. Whereas the original definition applied only to monocular movements, I did not measure both eyes so that all slow movements (i.e., less than saccadic velocities; ~100°/s) that immediately followed the primary saccade were included. In addition, the original definition of glissades included only targeting movements, but I counted both backward and forward movements (i.e., opposite and in the same direction as the preceding saccade), even when they did not obviously move the eye toward the target, so that I could maximize the possibility of demonstrating mismatched saccade and fixation components. Postlesion glissades were always small and never exceeded 2° in amplitude no matter the size of the preceding saccade or the remaining targeting error. There was also no discernible pattern in the glissades that might be analogous to drift in the dark. That is, glissades could be forward or backward, away from or toward the target, and away from or toward the null-position regardless of their initial or final position. Before lesions, 67 of the 470 saccades (14%) were followed by an immediate, low-velocity drift, i.e., glissades. This percentage was virtually unchanged (17%, 50/291 after lesion 4; postlesion days 33, 42, and 54 combined) when there was a maximum gaze holding deficit (Fig. 7) but no change in saccadic gain (Fig. 10). For backward and forward glissades, the percentages were 5 and 9% under normal circumstances and 3 and 14% after lesion 4.

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| FIG. 12.
Glissades and dynamic overshoot. All 30° leftward saccades from before lesions (normal, left), 21 h after lesion 4 (middle), and 141 days after lesion 8 (right). Top row: eye position; bottom row: eye velocity. All saccades start at ~15° right. Eleven normal saccades show little if any postsaccadic movement, but half after lesion 4 and nearly all after lesion 8 show noticeable dynamic overshoot. Inset: heavy black saccade from right column, showing dynamic overshoot (light horizontal line shows final eye position) and glissade beginning at light vertical line. Dynamic overshoot is much larger than glissade and corresponds to saccade-like portion of postsaccadic movement seen more clearly in the velocity trace below.
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There were two instances that may have indicated a mismatch of saccade and fixation components. The first was an increase in the percentage of glissades in the first postlesion day for lesions 4-8. For example, 21 h after lesion 4, 44% (46/105) of saccades were followed by a glissade. Most of this increase was due to backward glissades, which followed 42% (44/105) of saccades; only 2% (2/105) was due to forward glissades. By 45 h, the percentages had returned to normal; 13% (13/103) total glissades, 6% (6/103) backward and 7% (7/103) forward. A more striking instance of apparent mismatch was associated with large leftward saccades that ended in the left peripheral field. Such saccades were followed by a large dynamic overshoot and sometimes a subsequent glissade (Fig. 12, inset at right). Dynamic overshoot was seen occasionally in the first session after lesion 4 (Fig. 12, middle traces) but was increasingly apparent in the first session after lesions 6-8. By the last testing day (141) after lesion 8, most large leftward saccades consistently displayed an overshooting component (Fig. 12, right), which was much larger than any of the glissades (inset). Smaller leftward saccades that ended more centrally showed only occasional overshoots and rightward saccades rarely showed any even for large amplitudes.
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DISCUSSION |
These results show that nph damage is most immediately associated with partial failure of the fixation-holding integrator, manifest as incessant regression of peripheral gaze toward the null position in the dark. The observation that the time constant was reduced drastically after the very first lesion most likely reflects the importance of the rostral nph as the output region of the nucleus. Apparently, the prominent reciprocal connections between the central and caudal portions of the nph on each side (Belknap and McCrea 1988
) are not enough to maintain the symmetry of the system because the null position often shifted contralaterally. These findings corroborate the hypothesis that the nph is at least a portion of the neural integrator for steady peripheral gaze (Baker et al. 1981
), and they substantiate the findings of similar studies (Cannon and Robinson 1987
; Cheron and Godaux 1987
) by adding the correlation between documented, restricted permanent neural damage and irreversible fixation deficits. In addition, they show that previous reports of complete integrator failure (i.e., time constant near 0 vs. ~2 s suggested here) after neurotoxin injections probably overestimated the role of the nph in the neural integration process and thus failed to reveal the possible contributions of other structures to the process. Indeed, although Cannon and Robinson (1987)
concluded that the neurotoxic lesions in their subjects were not permanent, the data in their Fig. 3 show clear damage to the nph (B) as well as the medial vestibular nucleus (A). Thus the recovery that they observed after their injections is quite similar to that reported here.
The results of these nph lesions are also consistent with previous findings on the nph. Physiological studies in alert monkeys showed that the majority of nph neurons discharge for ipsilateral eye movements (McFarland and Fuchs 1992
; McFarland et al. 1992
), and anatomic studies have shown that the majority of the nph output to the abducens from the marginal zone is contralateral (Belknap and McCrea 1988
; Langer et al. 1986
). Thus the predominant output of the nph apparently is inhibitory. The deviation of the eyes to the contralateral side after nph damage is consistent with the removal of tonic, contralateral inhibition, as are the asymmetric eye movements seen in monkeys Z and R. Monkey Z had a single large lesion, and its eyes remained deviated contralaterally throughout its postlesion survival. The most severe damage in monkey R was to the right rostral nph, including complete destruction of the output region, the marginal zone; damage in the nph was distributed more rostro-caudally (Fig. 4). This monkey could not fixate to the right even in the light with a target spot (Fig. 9), though its fixation of left hemifield targets was more normal. This result is concordant with the greater damage to the right nph, which resulted in proportionately more inhibition of rightward gaze from the relatively spared left nph, and also may explain the consistent dynamic overshoot of large leftward saccades (Fig. 12).
Deficits in the ability to maintain eccentric gaze were only roughly proportional to the amount of nph damage. Even the very large, single unilateral lesion in monkey Z and the extensive punctate series of lesions in monkey R did not reduce the centripetal drift to time constants approximating the mechanics of the globe. When a single exponential was used for the sake of comparison with previous studies, the estimated time constant in monkey Z showed an asymptotic value of ~400 ms (Fig. 5). This was still several times longer than the 100-ms time constant estimated for the mechanical restoring forces using similar methods (cf. Keller and Robinson 1971
). In monkey R, the mechanical time constant was measured as 103 ms and can be compared directly with the final value for drift in the dark (2.1 s). The difference between the final values for monkeys Z and R is probably attributable to the extensive damage in monkey Z, which included mechanical damage to fibers that course through the region.
Because destruction of the unilateral marginal zone in monkey Z and the damage to the entire nph in monkey R were nearly complete (Figs. 2 and 4) but the time constant was not reduced to the mechanical time constant, I suggest that inputs other than the nph are able to support eccentric gaze holding through adaptive increases in known extra-nph, eye-position inputs (e.g., vestibular neurons with eye-position sensitivity). The "longer-than-mechanical" time constant in the face of relatively complete nph destruction also suggests that the nph alone does not supply eye-position signals to all neurons that display that sensitivity. In other words, the nph does not seem to be the only input that maintains eccentric fixation even though it is very important. A corollary of this suggestion is that the oculomotor neural integrator is not localized exclusively within the nph but is distributed among nuclei, including the nph and vestibular nuclei, that supply substantial eye-position input to the motoneurons (Fukushima and Kaneko 1995
; for review, see Fukushima et al. 1992
).
In sharp contrast to these marked deficits in fixation ability, there was virtually no concomitant change in saccades. Even minor increases in saccadic gain were not seen until the nph was largely destroyed (Fig. 10), whereas fixation was affected immediately after the initial injection (Fig. 7). This result suggests that the only integrator function of the nph is to contribute to the gaze-holding integrator. Before this conclusion can be accepted, other explanations for the lack of saccadic changes must be considered. One possibility is that the integrator was not sufficiently damaged to affect saccades. Although this was clearly not true for saccades measured several weeks after injections, when fixation deficits were prominent, the saccadic deficits may have recovered owing to plastic or adaptive processes. The failure to observe parallel drift and saccadic gain changes immediately after a lesion (Fig. 11B) suggests that saccadic deficits are not masked by adaptive plasticity. This anecdotal observation also suggests that the two effects (saccadic gain and fixation stability) can be dissociated so that glissades cannot be considered to arise solely from a mismatch between the amplitude of the saccadic pulse (i.e., its gain) and the subsequent tonic fixation step. Indeed, the only obvious sign of mismatch occurs when the nph damage becomes more complete, as in the last lesions of monkey R. Then, the mismatch seems to be manifest as a dynamic overshoot as if the saccadic pulse gain has been increased adaptively but the fixation step is insufficient to match it.
Finally, the differential effects of nph lesions imply that a single integrator cannot account for the results. The magnitude of the saccadic changes that might result from damage to the neural integrator, estimated from digital implementation of Robinson's classic model and Scudder's modification (Kaneko 1989
, 1996
; APPENDIX) using the percentage of change calculated for the present data, confirms these qualitative suggestions. For these calculations, I assumed that the integrator gain decreased by ~90% in parallel with the >90% change in integrator time constant (from 28 to 2 s). If one reasonably assumes that the initial time constant is much larger than the 28 s estimated, the proportionate change also would be larger. On the other hand, if the integrator gain changes less than the time constant does due to, for example, adaptive changes in response to nph damage, then the integrator gain change would be smaller. Because an integrator gain change of as little as 25% results in a 21% increase in saccadic gain estimated by the Robinson model, the present results are not consistent with single-integrator models.
As mentioned, the data show that saccade gain is maintained, whereas fixation stability is reduced considerably. This finding has been interpreted as contradictory to the lack of postsaccadic drift, and to the assumption that the integrator gain is affected in parallel with the integrator time constant. There are several possible reasons why there is not a more obvious postsaccadic drift than the one illustrated in Fig. 8. First, even though the time constant has been reduced considerably, it still may be long enough to sustain initial eye position after a saccade. This possibility cannot be discounted, but it is hard to imagine how the time constant can be affected independently of the gain because both signals are carried by the same nph neurons. Second, because the target is illuminated continuously, the animals may have been able to suppress any drift and thus maintain steady postsaccadic fixation by predicting target position. Third, output from the nph may not be crucial for the maintenance of peripheral fixation if muscle tension is insensitive to the motor neuron discharge rate after a saccade, as it is in cat (Shall et al. 1997
). Fourth, muscle fibers that are connected serially may be able to compensate overall tension (and thus eye position) for lower input levels (Goldberg et al. 1997
) relayed from the nph via motoneurons. Finally, other sources, such as brain stem neurons that display position sensitivity, may be able to substitute for nph input to motoneurons. The dynamic overshoot (Fig. 12) seen for large leftward saccades in monkey R and the lack of parallel changes (Figs. 11B and 12) suggest that such compensation is accomplished independently for saccade gain and fixation.
For the two-integrator model, the simulations show that the gain of a 10° saccade actually would be expected to decrease slightly (from 0.98 to 0.84) after nph lesions. In contrast, Robinson's single-integrator model predicts that the gain of a 10° saccade would increase fourfold, from 1.02 to 4.32. Such simulations suggest that two-integrator models reflect the structure of the saccade generator more accurately than do single-integrator models. Unfortunately, neither type of model accounts for all the results of this study. For both types, the integrator is characterized not only by a time constant (nph, APPENDIX) but also by an integrator gain (IG, APPENDIX). In the double-integrator models, the decrease in observed saccadic gain is a function of the fact that a portion (~15%) of saccade signal is transmitted via the integrator. In physiological terms, the burst of action potentials in the burst tonic neurons that make up the nph and especially the marginal zone is an important saccadic input to the motoneurons. This fact, although obvious, is sometimes overlooked in discussions of the neural saccade generator. The predictions of each model depend on how much the integrator gain is assumed to have changed. They are not completely consistent with the two-integrator model, which predicts a small decrease in saccade gain rather than the small increase that actually was observed. We have begun simulations using more complete versions of these classes of models in the hope of resolving some of these issues. In particular, we have preliminary evidence that simulations that allow variations in the gain of the EBN input to motoneurons (DG, APPENDIX) can account for the trajectory of postsaccadic drift in the dark (which show an overshoot-like component) by increasing that gain (Soetedjo and Kaneko 1995
).
It is unlikely that the reason nph damage had no effect on saccades was that the lesions missed the appropriate region of the nph. The marginal zone (the output region of the nph) was affected severely in every case, and in the most thoroughly documented case (monkey R), it probably was destroyed completely. In addition, the ability to maintain peripheral gaze was affected. In both monkeys Z and R, the severe nph damage was associated with a positional nystagmus on the side contralateral to the most complete destruction even when the animal was presented with a fixation spot in the light. The GFAP material from monkey R suggests that the damage was much more extensive than could be estimated in the Nissl material from monkeys Z and M.
It is also improbable that technical problems contributed to the lack of saccadic abnormalities because such limitations would have resulted in greater, rather than smaller, saccade deficits. The first injection (monkey Z) was overlarge and affected a region ventral to the marginal zone. It included frank mechanical damage due to the volume displaced by the injected fluid and therefore affected axons in the region as well as cell bodies. The region ventral to the marginal zone may overlap the area that was shown to project to the site of EBNs in cats (Ohki et al. 1988
; cf. Fig. 1). If the saccadic effects were caused, at least in part, by damage to the "burster-driving neurons" of that region, one would expect hypometric contralateral saccades because the burst-driving neurons excite contralateral EBNs. Because targeting saccades were normal and rhesus macaques do not have horizontal burster-driving neurons (Kaneko and Fukushima 1993
), the results cannot be explained by damage to burster-driving neurons.
These results lead to the conclusion that the nph in general, and the marginal zone in particular, are not necessary for production of normal saccades, and thus they require modification of current models of the brain stem saccade generator. The most obvious modification is the addition of a second feedback integrator (Scudder 1988
) as originally suggested on the basis of behavioral (Becker and Jürgens 1979
) and clinical (Abel et al. 1978
) findings. A variety of alternatives have been suggested for the mechanism and site of the second integrator. However, models that require feedback of an eye position or velocity signal from the nph (e.g., van Gisbergen et al. 1981
) can be rejected on the basis of the current study, as can modifications that require the nph as a neural model of the oculomotor plant (e.g., Galiana 1991
). Models that place the superior colliculus within the feedback loop and require either velocity or position information from the neural integrator (e.g., Guitton et al. 1990
) also can be rejected because the interstitial nucleus of Cajal, which is the putative site of the neural integrator for vertical eye movements (see Fukushima and Kaneko 1995
; Fukushima et al. 1992
), does not project to the superior colliculus (Kokkoroyannis et al. 1996
).
Apparently, only feedback models that rely on other sites for the second integration remain viable. Scudder (1988)
hypothesized that the LLBNs located in the rostral pons are the second integrator (Fig. 1). Our anatomic finding that an area of the rostral pons supplies afferents to the OPNs (Langer and Kaneko 1990
) and our physiological finding that the same area contains LLBNs (Ling et al. 1989
) are consistent with the assumption that these neurons are important elements in saccade generation. On the other hand, recent attempts to test this notion have provided little support for such a scheme (Scudder et al. 1996a
,b
), although the results were inconclusive because the data were limited by the technical difficulty of the experiments. Another scheme (Optican 1995
) suggests that the integration is done within the superior colliculus via feedback from the burst generator (presumably the burst neurons). An anatomic substrate for such feedback or physiological evidence that burst neurons project to the colliculus is lacking, but some central mesencephalic, saccade-related neurons do project there (Moschovakis et al. 1991
). More recently, Optican and colleagues (1996) have moved the site to the caudal fastigial nucleus in the cerebellum.
Although my results show that the saccade system does not rely on the position-holding integrator in the nph for its function, they do not require the existence of a second, feedback integrator. In fact, they further limit the viability of the second integrator hypothesis because they virtually eliminate the nph as a possible source for either velocity or position feedback in the control of saccades. As mentioned above, alternative sites for the second integrator are the LLBN, collicular circuits, and/or fastigial circuits. Unfortunately, saccades do not require the colliculus (see Albano and Wurtz 1982
for review), and LLBNs apparently do not have the required anatomic connections (Scudder et al. 1996a
,b
). Likewise, our preliminary simulations indicate a predicted small decrease in saccadic gain (see above) rather than the slight but significant increase in gain that was observed in this study. Thus whether the source of the increase results directly or indirectly (i.e., adaptive mechanisms) from nph damage, it is in the wrong direction. These results, the results of OPN lesion studies (Kaneko 1996
) that demonstrated increased saccade latency instead of the decreased latency predicted by feedback models, and the failure of nph lesions to affect saccades, further decrease the probability that saccadic trajectory is controlled by local feedback. Similar considerations led Optican et al. (1996)
to move the local feedback function to the fastigal nuclei. However, the saccade-related discharge of those neurons is too variable to support such a function (Fuchs et al. 1993
). EBNs apparently do not project to the fastigial nuclei (Noda et al. 1990
), although LLBNs may (Noda et al. 1990
; Scudder et al. 1996a
,b
), and electrical stimulation of the area suggests that it is not in the feedback loop (Noda et al. 1991
). In a recent paper questioning the need for feedback to control saccades on these and other theoretical grounds, I outlined a parallel processing scheme that is consistent with current evidence but does not use feedback (Kaneko 1996
). The new model of Optican et al. (1996)
, which similarly distributes the inputs to the brain stem saccade generator, resembles my scheme if it is stripped of its feedback circuit.
The present data also suggest that the position integrator for saccades is not the same as the integrator for other oculomotor subsystems. Robinson (1968
, 1989)
has long championed the concept of a common integrator, but that notion has been questioned by Godaux and Laune (1983)
, who showed that xylidino-dihydrothiazin (Rompun) can affect integration in the vestibulo-ocular reflex while leaving saccades qualitatively unchanged. We recently provided data that suggested Godaux and Laune's initial interpretation may have been premature (Chu and Kaneko 1995
) because quantitative analyses of saccades do show a change in parallel with the vestibular changes. However, Mettens and colleagues (e.g., Mettens et al. 1994
) have produced compelling evidence consistent with multiple integrators: they demonstrated that injections of muscimol into the central medial vestibular nucleus affect gaze stability and vestibular imbalance. Those results, together with the present evidence, suggest that the oculomotor system uses multiple integrators that are not associated with unique nuclei.
If the oculomotor system uses multiple and/or distributed neural integrators, many new questions about oculomotor neural integration arise, as we have discussed more thoroughly elsewhere (Fukushima and Kaneko 1995
; Fukushima et al. 1992
). Perhaps the most important questions concern the extent to which the other oculomotor subsystems are subserved by unique integrators and the manner in which they are coordinated to provide a uniform position signal to the motoneurons. With respect to the latter issue, it should be pointed out that some subsystems may not require a velocity-to-position integrator. For example, models of the smooth-pursuit system include such a final integrator (e.g., Lisberger et al. 1987
; Robinson et al. 1986
), but it may not be necessary because smooth pursuit does not require an accurate eye position when it ends. Indeed, preliminary evidence suggests that nph lesions do not affect the gain or the phase of smooth pursuit (Lambert and Kaneko 1995
). Further analyses should reveal whether the nph is a common element to other integrative functions.
 |
ACKNOWLEDGEMENTS |
I am particularly indebted to Dr. R. Soetedjo, who wrote the MatLab programs used for estimation of the time constants of the exponential drift in the dark and was responsible for porting the models to MatLab. It is a pleasure to acknowledge the superb technical assistance of J. Balch and S. Usher and the editorial wizardry K. Elias. Drs. A. F. Fuchs, L. Ling, R. F. Robinson, and R. Soetedjo made useful comments on an earlier version of the manuscript.
This research was funded by National Institutes of Health Grants EY-06558 and RR-00166.
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APPENDIX |
The complete Matlab models are shown here. Figure A1 is the Robinson model and Figure A2 is the Scudder model. For both models, each subcomponent is enclosed by a thin-lined box, and its components are detailed in the enlargement of these boxes located at the end of the thin arrows (note that some arrows go behind other boxes). For example, the circuit used for the trigger (Fig. A1, left) and the third order model of the plant (Fig. A1, right) are shown in the boxes below the Robinson model. Numbered abbreviations (i.e., EBN1, IFN2, etc.) indicate left and right or horizontal and vertical duplication of similar elements, inputs, or outputs. Vertical rectangular boxes with + or
signs represent summing junctions and small boxes enclosing numbers represent inputs or constants. Circles enclosing numbers represent outputs. Plain numbers are either gains (when adjacent to or within triangles) or constants. Bold type indicates nonlinear functions that were written more easily as programming code and are listedbelow.
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[View Larger Version of this Image (23K GIF file)]
FIG. A1.

[View Larger Version of this Image (48K GIF file)]
FIG. A2.
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FOOTNOTES |
Address for reprint requests: Regional Primate Research Center, Box 357330, University of Washington, Seattle, WA 98195.
Received 15 November 1996; accepted in final form 24 June 1997.
 |
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