Anatomy and Physiology of the Primate Interstitial Nucleus ...€¦ · Anatomy and Physiology of the Primate Interstitial Nucleus of Cajal. II. Discharge Pattern of Single Efferent

Anatomy and Physiology of the Primate Interstitial Nucleus of Cajal.II. Discharge Pattern of Single Efferent Fibers

Y. DALEZIOS,1,2 C. A. SCUDDER,3 S. M. HIGHSTEIN,4 AND A. K. MOSCHOVAKIS1,2

1Department Basic Sciences, Faculty of Medicine, University of Crete, Crete, Greece 71110; 2Institute of Applied andComputational Mathematics, Foundation for Research and Technology-Hellas, Crete, Greece 71110; 3Eye and EarInstitute, Pittsburgh University, Pittsburgh, Pennsylvania 15213; and 4Department of Otolaryngology, WashingtonUniversity School of Medicine in St. Louis, St. Louis, Missouri 63110

Dalezios, Y., C. A. Scudder, S. M. Highstein, and A. K. Moscho- posterior commissure that deploys dense terminal fields invakis. Anatomy and physiology of the primate interstitial nucleus the contralateral NIC, the oculomotor nucleus, and the troch-of Cajal. II. Discharge pattern of single efferent fibers. J. Neuro- lear nucleus, a descending system that deploys terminalphysiol. 80: 3100–3111, 1998. Single efferent fibers of the intersti- fields in ipsilateral pontine and medullary nuclei and thetial nucleus of Cajal (NIC) were characterized physiologically and ventral horn of cervical spinal segments, and an ascendinginjected with biocytin in alert behaving monkeys. Quantitative

system that deploys terminal fields in ipsilateral mesence-analysis demonstrated that their discharge encodes a constellationphalic and diencephalic structures. The integrity of the firstof oculomotor variables. Tonic and phasic signals were relatedis crucial for normal velocity to position integration in theto vertical (up or down) eye position and saccades, respectively.vertical plane because after lesions of the posterior commis-Depending on how they encoded eye position, saccade velocity,

saccade size, saccade duration, and smooth-pursuit eye velocity, sure, the eyes can no longer be held at eccentric verticalfibers were characterized as regular or irregular, bi- or unidirection- eye positions (up or down) and the gain of the verticalally modulated, more or less sensitive, and reliable or unreliable. vestibuloocular response (VOR) is reduced and its phaseFurther, fibers that did not burst for saccades (tonic) and fibers advanced, particularly at lower stimulation frequenciesthe eye-position and saccade-related signals of which increased in (Partsalis et al. 1994). If the vertical eye-position-relatedthe same (in-phase) or in the opposite (anti-phase) directions were NIC signals are sent to the oculomotor complex via theencountered. A continuum of discharge properties was the rule.

posterior commissure, it should be possible to demonstrateWe conclude that NIC efferent fibers send a combination of eye-the existence of fibers that originate in the NIC, courseposition, saccade-, and smooth-pursuit-related signals, mixed inthrough the posterior commissure, and discharge in relationproportions that differ for different fibers, to targets of the verticalto vertical eye position. To test this, we studied the signalsneural integrator such as extraocular motoneurons.carried by oculomotor-related fibers in and near the posteriorcommissure of alert behaving squirrel monkeys and then

I N T R O D U C T I O N injected these same fibers with a tracer to establish the loca-tion of their cell bodies and the targets of their axons. HereThe interstitial nucleus of Cajal (NIC) is the largest andwe describe the signals that were carried by such fibers.most prominent of the cell groups of the medial longitudinalPreliminary versions of some of our results have appearedfasciculus (MLF). It contains at least two distinct cell classes,before (Moschovakis 1995; Moschovakis et al. 1997).namely large pyramidal or multipolar neurons and small- to

medium-size pyramidal, fusiform, or round cells (Zuk et al.M E T H O D S

1982). Several lines of evidence have implicated the NIC inUseful data were obtained from 14 adult squirrel monkeys ofoculomotor control and in particular in the process of velocity

either sex, weighing 500–950 g. Animals were treated in accor-to position integration in the vertical plane (for a review, see dance with the guidelines of the National Institutes of Health asMoschovakis 1997). First, lesions of the NIC prevent mon- stated in the Guide for the Care and Use of Laboratory Animalskeys and cats from holding eccentric gaze and impair their (DHEW Publication NIH85–23 1985) and with European Unionvertical vestibuloocular responses (Anderson et al. 1979; directive 86/609 (Presidential Decree 160/1991). The methodsCrawford et al. 1991; Fukushima et al. 1992; Helmchen et employed have been extensively described before (Moschovakis

et al. 1988, 1991a,b; Scudder et al. 1996a,b) . Briefly, the animalsal. 1998). Second, upward and downward medium lead burstwere prepared for recording under sterile conditions and pentobar-neurons terminate profusely within the NIC (Moschovakis etbital anesthesia (15 mg/kg). A stainless steel bolt was cementedal. 1990, 1991a,b). Finally, the discharge of NIC neuronson the occipital bone for head fixation, and preformed search coils,often encodes the vertical position of the eyes (Fukushima etmade of teflon-insulated stainless steel wire (Cooner) , were su-al. 1990; King and Leigh 1982; King et al. 1981).tured on the sclera of one or both eyes. In a second surgery 2 wkThree projection systems are known to arise from the later, a parietal craniotomy was performed, and part of the cortex

NIC (Kokkoroyannis et al. 1996): one directed through the was aspirated to place a plastic chamber over the exposed leftsuperior colliculus. The animals were alert and fully active withinhours after surgery and showed no obvious neurological deficits.The costs of publication of this article were defrayed in part by the

Two days after surgery animals were placed in a primate chairpayment of page charges. The article must therefore be hereby markedwith their heads fixed. Otherwise, they were free to move their‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact. body and limbs and appeared comfortable during the recording

3100 0022-3077/98 $5.00 Copyright q 1998 The American Physiological Society

J0070-8/ 9k2f$$de51 11-24-98 13:52:58 neupa LP-Neurophys

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DISCHARGE OF PRIMATE NIC FIBERS 3101

sessions. Glass micropipettes filled with either a 10% solution of neurons of the nucleus of the posterior commissurehorseradish peroxidase or a 5% solution of biocytin in 0.5 M KCl (Moschovakis et al. 1991a), of the downward medium leadand 100 mM tris(hydroxymethyl)aminomethane buffer (pH Å burst neurons of the NIC (Moschovakis et al. 1991b), or of7.4) , and beveled toõ1-mm tip diameter ( impedance: 40–80 MV) the long lead burst neurons located near the NIC (Scudderwere inserted into the brain stem through the superior colliculus, et al. 1996a). The remaining 84 fibers modulated their dis-and advanced toward the posterior commissure. Axon penetration

charge in relation to eye position and are the topic of thiswas signaled by a 30- to 80-mV DC shift and the presence of 5-report. Their intraaxonal injection with a tracer enabled usto 50-mV action potentials. We used the eye-coil method (Rob-to confirm the recording site of all fibers in our sample (27inson 1963) to record the instantaneous position of the eyes within the PC and 57 in the NIC) and the origin and projectiona resolution of 0.57. Eye position was digitized on-line at a sam-

pling rate of 2 ms, and the time between action potentials was of many of them. The trajectory of their axons has not beenmeasured with 100-ms resolution using the Spike2 software (Cam- completely reconstructed and will be the object of a futurebridge Electronics Design) running on a personal computer. Eye report. Preliminary results show that 39 of the 48 fibersvelocity was calculated off-line through software differentiation. recovered so far project through the PC, whereas the remain-

Digitized data were analyzed off-line. To evaluate the relation- der (n Å 9) descend via the MLF. The somata of all but 12ship between firing rate and eye position, we marked the beginning PC fibers were recovered, and their location in the NICand the end of segments during which the eyes were fairly station-

was ascertained. Because there were no differences betweenary (peak eye velocities õ107 /s) . These segments were ¢200recovered and not recovered fibers and somata in terms ofms long and did not include pre- and postsaccadic intervals. Thedischarge pattern, we describe them together as a singlecomputer stored the horizontal and vertical eye position at thegroup of NIC efferents.beginning (H1 and V1) and at the end (H2 and V2) of the segment,

the mean horizontal [H Å (H1 / H2) /2] and vertical [V Å (V1 /V2) /2] eye position as well as the intervals between all spikes Position-related dischargewithin the segment. An estimate of the regularity of neuronal dis-charge was obtained from the coefficient of variation (CV Å SD/ The fiber illustrated in Fig. 1A displayed tonic intersac-mean) of interspike intervals for spikes emitted while the eyes cadic activity and bursts that preceded saccades with anwere at or close to the primary position (within 27) . upward component, whether rightward or leftward. FigureTo evaluate the relationship between parameters of the bursts

1B is a plot of mean intersaccadic vertical eye position (V ;of NIC fibers and parameters of saccades, we first marked theabscissa) versus mean interburst frequency of discharge (F;beginning and the end of saccades and the beginning and the endordinate) for the same unit. The slope (3.5 spikes/s perof related bursts. The computer then stored values for the followingdegree of upward ocular deviation) and the correlation coef-variables: saccade latency (Lat) , saccade duration (Sd) , burst dura-

tion (Bd) , horizontal (DH) and vertical (DV ) eye displacement, ficient (r Å 0.96) of the linear regression between the twohorizontal (H

g m) and vertical (Vg m) peak eye velocity, peak firing variables are indicative of the sensitivity and of the reliability

rate (Fm), and the number-of-spikes in the burst (Nb) . Linear with which this fiber encoded the vertical position of theregressions between parameters of discharge and parameters of the eyes. The intercept (102 spikes/s) is indicative of the unit’smovement included those between Nb and DV (DH) , between Fm intensity of discharge when the animal was looking straightand V

g m (Hg m), and between Sd and Bd . To estimate the relationship ahead. The firing of this fiber was not correlated with thebetween the firing rate of NIC fibers and the mean eye velocity

mean horizontal position of the eyes between saccades (rightduring smooth-pursuit eye movements, we used a procedure pre-inset) . To get an indication of the regularity of its tonicviously employed by Skavenski and Robinson (1973). Briefly, wedischarge during intersaccadic intervals, we determined theselected segments during which the monkey pursued smoothly ancoefficient of variation (CV) of interspike intervals. Becauseobject of interest. For most neurons, we found several segments

during which the eyes moved at average velocities up to {607 /s. In the standard deviation of interspike intervals [SD(ISI)] in-these segments, we marked six interspike intervals symmetrically creased in proportion to the mean ISI (Fig. 1B, left inset) ,bracketing a certain eye position. The computer then stored the we evaluated the CV for positions within 27 of primaryhorizontal and vertical eye position that corresponded to the first position. Its value was low enough (0.06) to indicate that(H1 and V1) and to the last (H2 and V2) spike, the mean horizontal this unit was a regularly discharging one.[(H1 / H2) /2] and vertical [(V1 / V2) /2] eye position, the time Other burst-tonic responses were much less precise. Theof occurrence of the first ( t1) and of the last ( t2) spike, and the

fiber of Fig. 1C had a primary position firing rate of 66intervals between all seven spikes in the series. The average verticalspikes/s, increased its firing rate for downward eye posi-(horizontal) eye velocity during such segments then was estimatedtions, and decreased it for upward positions. The shalloweras the ratio (V2 0 V1) / ( t2 0 t1 ) [(H2 0 H1) / ( t2 0 t1)] . To estimateslope of the rate-position curve (2 spikesrs01

rdeg01) indi-the average frequency of a neuron’s discharge associated withvertical (horizontal) eye velocity, we subtracted the firing rate cates that this fiber was less sensitive to vertical eye positionattributed to the mean vertical (horizontal) eye position during the than the one of Fig. 1B, whereas the large scatter of the datasame segment (from the rate-position curve that had been estab- around the linear regression line indicates that this unit waslished previously for the same fiber) . less reliable in encoding the vertical position of the eyes

(r Å 0.67). The SD(ISI) of this unit obtained much highervalues than that of Fig. 1B for roughly the same values ofR E S U L T SmeanISI ( inset) . As a consequence, its CV was rather high(0.19), which underscores the irregularity of the tonic inter-One hundred and forty-one oculomotor-related efferent

fibers of the NIC were penetrated in and near the NIC and saccadic discharges of this fiber. As with the fiber of Fig.1B, the firing rate of this unit was not correlated with thethe PC of alert behaving squirrel monkeys. The intersaccadic

discharge of 57 fibers was not modulated with eye position mean horizontal eye position (Fig. 1C, right inset) .The eye-position-related discharge shown in Fig. 1 is typi-but rather was reminiscent of the upward medium lead burst


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DALEZIOS, SCUDDER, HIGHSTEIN, AND MOSCHOVAKIS3102

tion (up or down, left, or right) as well as the slopes, inter-cepts, and correlation coefficients of their rate-positioncurves. Most of them (n Å 61) modulated their tonic dis-charge only for vertical eye position. A small number ofunits (n Å 5) had an oblique on-direction as indicated bythe fact that their discharge was modulated for both verticaland horizontal eye position. Quantitative details of the rela-tionship between the firing rate of NIC fibers and the verticalposition of the eyes are summarized in Table 1. Figures 2Aand 3A plot rate-position linear regressions for our 35 up-ward and 31 downward NIC efferents, respectively. In gen-eral, the two variables were well correlated for both upward(Fig. 2A, inset) and downward (Fig. 3A, inset) cells. Thefrequency histograms of the slopes of these relationshipspeaked at 4 spikesrs01

rdeg01 (Fig. 2B) and about 03.5spikesrs01

rdeg01 (Fig. 3B) for upward and downwardunits, respectively, indicating similar sensitivities and con-siderable overlap (sign notwithstanding) for both types offibers. Also, the frequency histogram of the primary positionrate peaked at Ç90 spikes/s for upward units (Fig. 2C) andbetween 70 and 80 spikes/s for downward units (Fig. 3C) .

The slope of the rate-position curve and the primary posi-tion rate uniquely determine position threshold. In our sam-ple, this was equal to 046.4 { 52.77 (mean { SD) forupward and 42.97{ 45.67 for downward fibers, respectively.The majority of fibers were active well before primary posi-tion (Figs. 2D and 3D) . When its whole range is considered,the position threshold (T) of NIC fibers is related to theirvertical gain (kV ) through a power function of the form48rÉTÉ-0.81 (r Å 0.84; Fig. 2E) for upward cells and 28rT -0.71

(r Å 0.9; Fig. 3E) for downward cells. To enable compari-sons with previous samples, we also evaluated the relation-ship between vertical gain and position threshold when thelatter is restricted to less than {407. In this case, the twovariables are related linearly through an expression of theform kV Å 6.9 / 0.11T (r Å 0.72) for upward cells andkV Å 04.7 / 0.05T (r Å 0.45) for downward cells. Finally,few upward fibers had a CV ú0.1 (Fig. 2F) , and thus thepopulation as a whole can be thought of as regular. Althougha larger number of downward fibers had a CV ú0.1 (Fig.3F) , on average these were no less regular than upwardunits (1-tailed t-test , t Å 01.75, P õ 0.1) .

Other units (nÅ 12) modulated their discharge for upwardFIG. 1. A : oculomotor-related discharge pattern of a regular upward but little or not at all for downward deviations of the eyes.efferent fiber of the NIC. Traces from top to bottom illustrate the instanta-

Figure 4A illustrates the eye-position-related discharge ofneous horizontal and vertical eye position and the instantaneous firing rate.B : quantitative analysis of the relationship between the mean intersaccadic such a unit. As shown, upward deviation of the eyes wasfiring rate (ordinate) of the same unit and the mean intersaccadic vertical accompanied by increases of firing frequency; in contrast,eye position (abscissa) . , linear regression line through the data (s) the neuron did not fire less than Ç75 spikes/s whatever theobeys the expression F Å 3.5V / 102.3 (r Å 0.96). Insets, right and left :

depression of the eyes. The same point is made by the plotplots of horizontal eye position (abscissa) vs. firing rate (ordinate) andof Fig. 4B, which illustrates the relationship between themean interspike interval (meanISI; abscissa) versus standard deviation of

interspike intervals [SD(ISI); ordinate] . C : quantitative analysis of the mean intersaccadic vertical eye position (V) and the meanrelationship between the mean intersaccadic vertical eye position and the frequency of the same neuron’s discharge. There is an excel-mean intersaccadic firing rate of an irregular downward efferent fiber of lent linear relationship between the two variables when V isthe interstitial nucleus of Cajal (NIC). Plot layout as in B . Linear regression

restricted to upward positions. However, this cell had a veryline obeys the expression F Å 02.0V / 65.8 (r Å 0.67).small sensitivity (õ10% of the on-hemifield) for downwardeye positions (Fig. 4B) . It is for this reason that we refercal of the responses of 66 of the fibers we studied. The

discharge of 35 units increased for upward eye positions, to fibers of this sort as ‘‘unidirectionally modulated.’’ Norwas the same unit’s tonic intersaccadic discharge related towhereas the remaining (n Å 31) increased their discharge

for downward eye positions. Because vertical and horizontal horizontal eye position. The remaining six units modulatedtheir discharge for downward but little or not at all for up-eye position can covary due to sampling biases, we employed

multiple regression to estimate each unit’s preferred direc- ward eye positions. Quantitative details of the relationship


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TABLE 1. Relationship between the discharge of NIC efferent fibers and parameters of ocular movement

A. Position Related

Cell Type N kV, spikers01rdeg01 r F0, spikes/s CV

BidirectionalUp 35 3.4 { 1.5 (0.51–6.9) 0.89 { 0.12 (0.43–0.99) 97 { 25 (46–151) 0.09 { 0.06 (0.03–0.27)Down 31 03.0 { 2.0 (00.51–010.1) 0.86 { 0.14 (0.42–0.99) 82 { 30 (29–142) 0.12 { 0.07 (0.04–0.32)

UnidirectionalUp 12 3.1 { 1.1 (1.9–5.0) 0.84 { 0.14 (0.52–0.99) 74 { 31 (17–121) 0.16 { 0.06 (0.11–0.3)Down 6 02.4 { 0.6 (01.9–03.4) 0.88 { 0.08 (0.75–0.96) 91 { 33 (52–131.4) 0.12 { 0.05 (0.07–0.19)

B. Saccade Related

Cell ns ns G(Fm/Vg m), ns

Type N RV, spikes/deg r (N) Bd/Sd, s/s r (N) spike/s per deg/s r (N)

Up 38 0.5 { 0.3 (0.1–1.4) 0.81 { 0.11 (0.56–0.97) 0 0.9 { 0.2 (0.5–1.2) 0.84 { 0.12 (0.53–0.97) 2 0.45 { 0.36 (0.1–1.9) 0.71 { 0.16 (0.33–0.93) 2Down 27 00.7 { 0.5 (00.2–01.3) 0.75 { 0.13 (0.52–0.93) 4 0.94 { 0.2 (0.5–1.2) 0.87 { 0.1 (0.64–0.99) 0 0.6 { 0.3 (00.1–01.0) 0.73 { 0.13 (0.46–0.92) 11

C. Smooth Pursuit Related

Cell Type N FR/Vg sp, spike/s per deg/s r ns (N)

Up 36 0.8 { 0.4 (0.3–2.1) 0.77 { 0.15 (0.51–0.95) 12Down 31 00.8 { 0.6 (00.1–02.2) 0.76 { 0.16 (0.44–0.97) 14

Values are means { SD, ranges are in parentheses. N, number of units examined; kV, slope of the rate/position curve; r, regression coefficient; F0, firing rate at primary eye position; CV, coefficient ofvariation of interspike intervals at primary position; RV, slope of the relationship between number of spikes in the burst and vertical saccade size; ns (N), number of units that did not attain statisticalsignificance (P ú 0.05); Bd/Sd, slope of the relationship between burst duration (Bd) and saccade duration (Sd); G(Fm/V

g m), slope of the relationship between peak firing rate and peak vertical saccade velocity;FR/V

g sp, slope of the relationship between firing rate (FR) and smooth pursuit vertical eye velocity (Vg sp).

between the discharge of unidirectional fibers and eye posi- discharge usually was depressed or even ceased for down-tion are summarized in Table 1. ward saccades. To evaluate whether parameters of this unit’s

bursts were related to parameters of saccades, the numberof spikes in the burst (Nb ; ordinate) was plotted against theSaccade-related dischargesize of the upward component of saccades (DV ; abscissa)in Fig. 5B. There was an excellent linear relationship be-In addition to eye position, NIC efferent fibers usuallytween the two variables (r Å 0.97), whereas no relationshipmodulated their discharge for saccades. For example, thewas found between Nb and the size of the horizontal compo-fiber of Fig. 5A emitted bursts the intensity of which varied

in proportion to the size of upward saccades. In contrast, its nent of saccades (Fig. 5B, inset) . Further, an excellent corre-

FIG. 2. A : linear regression lines de-scribing the relationship between mean in-tersaccadic firing rate (ordinate) and verti-cal eye position (abscissa) for 35 bidirec-tionally modulated upward NIC units.Frequency histograms of the correlation co-efficients, slopes, and intercepts of theserelationships are illustrated in the inset, B,and C , respectively. D : percentage of fibersalready recruited (ordinate) when the eyereaches the downward position indicatedon the abscissa. E : plot of the slope of therate-position curves (ordinate) vs. positionthreshold (abscissa) . ●, different unit.

, least squares regression line thatobeys the expression indicated in the text.F : frequency histogram of the coefficientof variation (CV) of the same fibers.


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FIG. 3. Quantitative analysis of theeye-position-related discharge of 31 bidi-rectionally modulated downward NICunits. Plot layout as in Fig. 2.

lation (0.89) was found between the duration of this neu- to the duration of saccades (Sd ; Fig. 6C) . However, unlikethe fiber of Fig. 5, modulation of the peak frequency (Fm)ron’s bursts (Bd) and the duration of saccades (Sd ; Fig. 5C) .

Finally, the peak frequency during bursts (Fm) was well of its bursts could account for only Ç15% of the variance(r Å 0.4; Fig. 6D) of the peak velocity (Vg m) of the saccadesrelated (r Å 0.93) to the peak vertical velocity of accompa-

nying saccades (Vg m; Fig. 5D) . they accompanied.The saccade-related responses illustrated in Figs. 5 and 6As illustrated in Fig. 6A, the bursts that other fibers emit-

ted for saccades were much less intense. Here again, burst are typical of the pattern of discharge of the 65 burst-tonicunits we encountered. Thirty-eight of them emitted burstsintensity varied in proportion to the size of the upward com-

ponent of saccades, whereas the discharge was depressed or for upward saccades and 27 emitted bursts for downwardsaccades. Bursts preceded saccades by 4.3 { 3.3 ms on theceased for downward saccades. The bursts of such fibers

were less sensitive and often less precise in terms of the average (n Å 65). In the 40 cells where pauses for off-direction saccades could be consistently documented, pausesaccade metrics they encoded. Figure 6B plots the size of

the upward component of saccades (DV ; abscissa) against onset preceded saccade onset by 3.2{ 3.7 ms on the average.Figures 7 and 8 provide summary illustrations of the relation-the number of spikes in the bursts (Nb ; ordinate) of the fiber

illustrated in Fig. 6A. Although the two variables were well ships between saccade and burst parameters in upward (Fig.7) and downward (Fig. 8) units, respectively. Figures 7Acorrelated (r Å 0.9) , the slope of the linear relationship is

much more shallow (0.26 spikes/7) . Here again, no relation- and 8A are cumulative plots of the 38 upward and the 23downward linear regression lines between the number ofship was found between Nb and the size of the horizontal

component of saccades (Fig. 6B, inset) . The duration of spikes in the burst and the vertical size of saccades (upor down) that attained statistical significance (P õ 0.05).this fiber’s bursts (Bd) was also well correlated (r Å 0.81)

FIG. 4. A : eye-position-related dis-charge of a unidirectionally modulated up-ward NIC fiber. Segments of intersaccadicintervals have been arranged from down( left) to up (right) . B : quantitative analysisof the relationship between the mean inter-saccadic firing rate (ordinate) of the samefiber and the mean intersaccadic verticaleye position (abscissa) . , linear re-gression line through the data (s) thatobeys the expression F Å 4.9V / 76 (r Å0.89).


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FIG. 5. A : saccade-related dischargepattern of a burst-tonic NIC fiber that emit-ted strong bursts for upward saccades. Sac-cades are arranged from downward ( left) toupward (right) , and they have been movedvertically so that they all start (upward sac-cades) or end (downward saccades) at thesame vertical position. Note that differentcalibration bars apply to the instantaneousfiring rate that accompanies downward( left) and upward (right) saccades. B : plotof the number of spikes in the burst (Nb ,ordinate) vs. size of the vertical componentof saccades (DV, abscissa) . Linear re-gression line obeys the expression Nb Å0.56DV / 4.9 (r Å 0.97). Inset : plot ofNb (ordinate) vs. size of the horizontalcomponent of saccades (DH, abscissa) . C :plot of burst duration (Bd ; ordinate) vs. sac-cade duration (Sd ; abscissa) . Linear regres-sion line obeys the expression Bd Å0.88Sd / 6.96 (r Å 0.89). D : plot of peakfiring rate (Fm; ordinate) vs. peak saccadiceye velocity (V

g m; abscissa) . Linear regres-sion line obeys the expression Fm Å0.56V

g m / 168.8 (r Å 0.93).

Similarly, Figs. 7B and 8B are cumulative plots of the 36 obtain are summarized in Table 1. Note that relationshipsthat did not attain statistical significance (P õ 0.05) wereupward and the 27 downward statistically significant linear

regression lines of burst duration versus saccade duration. eliminated from the population averages of Table 1.It is important to note that the majority (n Å 50) of theThe fact that they cluster around the diagonal indicates that

burst duration was roughly equal to saccade duration for burst-tonic NIC fibers we encountered had the same on-direction for saccades and eye position. We refer to suchboth upward and downward cells. Finally, Figs. 7C and 8C

are cumulative plots of the 36 upward and the 16 downward units as in-phase units. Other fibers (n Å 15) behaved quitedifferently in that they had opposite on-directions for sac-statistically significant linear regression lines between peak

firing rate and peak saccade velocity. Frequency histograms cades and eye position and are for this reason referred to asantiphase units. Six antiphase units emitted bursts for upwardof the slopes and correlation coefficients of these relation-

ships are illustrated as insets in Figs. 7 and 8, whereas the saccades but increased their discharge for downward eyepositions. Another nine units emitted bursts for downwardrange, average, and standard deviation of the values they

FIG. 6. A : saccade-related discharge pattern of aburst-tonic NIC fiber that emitted weak bursts forupward saccades. Traces as in Fig. 5A. Note thefiring rate calibration bar. B : plot of the number ofspikes in the burst (Nb , ordinate) vs. size of thevertical component of saccades (DV, abscissa) . Lin-ear regression line obeys the expression Nb Å0.3DV / 3.8 (r Å 0.9) . Inset : plot of Nb (ordinate)vs. size of the horizontal component of saccades(DH, abscissa) . C : plot of burst duration (Bd ; ordi-nate) vs. saccade duration (Sd ; abscissa) . Linearregression line obeys the expression Bd Å 0.65Sd /20.3 (r Å 0.81). D : plot of peak burst firing fre-quency (Fm; ordinate) vs. peak saccadic eye velocity(V

g m; abscissa) . Linear regression line obeys the ex-pression Fm Å 0.1V

g m / 164.4 (r Å 0.4) .


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FIG. 8. Quantitative analysis of the saccade-related discharge of 27downward burst-tonic NIC units. Plot layout as in Fig. 7.FIG . 7. A : linear regression lines describing the relationship between

the number of spikes in the burst (Nb ; ordinate ) and the vertical sizeof saccades (abscissa ) for 38 upward burst-tonic NIC units. B : linear

saccades but increased their discharge for upward eye posi-regression lines describing the relationship between burst duration (ordi-tions.nate ) and saccade duration (abscissa ) for 36 upward burst-tonic NIC

fibers. Note that this plot contains fewer data points because the relation- Figure 9, provides a third example of the saccade-relatedship did not attain statistical significance in 2 units. C : linear regression discharge we encountered among efferent fibers of the NIC.lines describing the relationship between peak rate of discharge (ordi- Fibers such as this (n Å 19) neither burst nor paused fornate ) and the peak vertical velocity of saccades (abscissa ) for 36 upward

saccades and are for this reason referred to as tonic units.burst-tonic NIC units. This plot also contains fewer points because thelinear regression did not attain statistical significance in 2 units. Insets : Nevertheless, tonic fibers are not as distinct from burst fibersfrequency histograms of the slopes and the correlation coefficients of as our name would imply. The saccade-related bursts ofstatistically significant relationships. some burst-tonic neurons were small, whereas some tonic

neurons emitted small bursts or paused for some saccades,particularly large ones.


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vertical displacement of the eyes during saccades. Note thatparameters of discharge differ from one NIC unit to thenext, often significantly. Differences between units can bequalitative rather than quantitative. For example, Ç10% ofthe units demonstrated some sensitivity to the horizontalposition of the eyes. Also, Ç25% of the units modulatedtheir discharge in relation to upward or downward eye posi-tion, but not both. Finally, the discharge of Ç50% of thefibers was not affected by smooth pursuit, whereas Ç25%of the fibers did not emit any bursts for saccades.

Comparison with previous studies

The present study focuses on the output of the NIC,whereas previous work emphasized the response propertiesof cells located in the NIC regardless of whether they were

FIG. 9. Discharge pattern of an NIC fiber that emitted neither bursts norprojection neurons or not. NIC neurons previously were di-pauses for saccades and the firing rate of which was modulated with down-

ward eye position. Traces as in Fig. 5A. vided into burst-tonic (BT), irregular tonic (IrT), vestibu-lar-and-saccade (VSN), and burst (BN) neurons in the mon-key and into BT, VSN, and pitch neurons in the cat (re-Smooth-pursuit-related dischargeviewed in Moschovakis 1997). There are several reasons to

To evaluate whether the discharge of efferent NIC fibers think that it is the previously described BT neurons that theis related to smooth-pursuit eye movements, their firing rate fibers of the present study resemble most. First, the tonicwas studied for short segments (lasting for Ç7 ISIs) during discharge of the fibers we encountered was well correlatedwhich the monkey smoothly pursued a target of interest(novel objects and morsels of food that were displacedslowly in front of its eyes) . Figure 10 illustrates the relation-ship between the mean vertical velocity of the eyes (V

g sp )during such segments versus the mean firing rate (F) of afiber after correcting for changes in firing rate that wouldbe due to changes of eye position (from the rate-positioncurves of the same fibers) . As shown in Fig. 10A, the twovariables could be well correlated, in this case through theexpression F Å 0.64V

g sp 0 2.99 (r Å 0.95). Enough datawere available to carry out this analysis in 67 NIC efferentfibers (36 upward and 31 downward). Quantitative detailsabout the relationship between the discharge of NIC efferentsand the vertical velocity of the eyes during smooth pursuitare summarized in Table 1. About 60% of the fibers weexamined (24 upward and 17 downward) modulated theirdischarge in concert with the vertical velocity of the eyesduring smooth pursuit. Their on-direction for smooth-pursuiteye velocity was the same as their on-direction for eye posi-tion. The slope of the linear regression line could be as lowas 0.3 (00.1) spikes/s per deg/s or as high as 2.1 (02.2)spikes/s per deg/s for upward (downward) fibers (Fig.10B) . Correlation coefficients between F and V

g sp rangedfrom 0.51 to 0.95 for upward units and from 0.44 to 0.97for downward units (Fig. 10B, inset) . The remaining fiberswe tested (12 upward and 14 downward) did not modulatetheir discharge for vertical smooth-pursuit eye velocity.

D I S C U S S I O N

The present study demonstrates that the firing rate (F) ofefferent fibers of the NIC in alert, behaving monkeys is on FIG. 10. Quantitative analysis of the relationship between vertical eye

velocity and firing rate of NIC fibers during smooth-pursuit eye movements.the average related to the instantaneous vertical position (V )A : plot of the mean firing rate (F, ordinate) vs. mean vertical eye velocityand the smooth-pursuit vertical velocity (V

g sp ) of the eyes,(V

g sp , abscissa) for 1 unit. , least squares linear regression line throughthrough the expressionthe data (s) obeys the expression indicated in the text. B : frequency histo-gram of the slopes of the 41 such relationships that attained statisticalF Å 88 / 3.1rV / 0.8rV

g sp (1)significance. Inset : frequency histogram of the correlation coefficients ofthese relationships.Additionally, NIC fibers emit Ç0.6 spikes per degree of


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with the vertical position of the eyes during spontaneous vertical eye position. This property was first described forpursuit neurons and Ç30% of the vestibular-plus-eye-posi-saccades. Similar, excellent correlations between their tonic

discharge and vertical eye position were described pre- tion neurons of the primate vestibular nuclei (Chubb et al.1984). Similarly, many upward vestibular cells of the catviously for BT neurons in both the rhesus monkey (King et

al. 1981) and the cat (Fukushima et al. 1990). Further, the increase their rate with the upward deviation of the eyesand discharge at a constant rate for downward eye positionsaverage vertical position sensitivity of the fibers we encoun-

tered (cf. Eq. 1) is quite similar to that of previously re- (Iwamoto et al. 1990a). Horizontal cells also can behave ina similar manner; the discharge of Ç30% of the neurons ofcorded NIC BT cells in rhesus monkeys (2.6 spikesrs01

r

deg01) (King et al. 1981) and cats (3.9 spikesrs01rdeg01) the primate nucleus prepositus hypoglossi level off for off-

direction eye positions (McFarland and Fuchs 1992). Previ-(Fukushima et al. 1990). In contrast, primate IrT (King etal. 1981), primate VSN (Kaneko and Fukushima 1998), ous documentation of this phenomenon in NIC neurons has

been limited (e.g., Fig. 3D of Fukushima et al. 1990). More-feline VSN (Fukushima et al. 1995), and feline pitch (Fu-kushima et al. 1990) neurons display little if any relationship over, some NIC fibers had their saccade- and position-related

signals increase in opposite directions (antiphase units) . Thewith eye position, at least during spontaneous saccades.Second, the NIC fibers we encountered discharged at a existence of antiphase neurons had been predicted by a

model of the neural integrator ( the so called ‘‘rogue’’ cells)relatively high and regular rate when the animal was lookingstraight ahead. The average primary position firing rate of (Arnold and Robinson 1991) but previous documentation

of discharge patterns such as this was limited to gaze velocitythe fibers we encountered (cf. Eq. 1) agrees quite well withprevious descriptions of BT NIC neurons of rhesus monkeys cells of the primate group Y (Tomlinson and Robinson

1984), eye and head velocity cells of the primate medial(79 spikes/s) (King et al. 1981) and cats (75 spikes/s)(Fukushima et al. 1990). In contrast feline pitch neurons vestibular nucleus (Scudder and Fuchs 1992), and VSNs of

the feline (Fukushima et al. 1995) and the primate (Kaneko(mean: 34 spikes/s; Fukushima et al. 1990) and VSNs(mean: 40 spikes/s; Fukushima et al. 1995) discharge at a and Fukushima 1998) NIC. The present study demonstrates

that they are quite common among BT efferent fibers of thelower rate. The same is true of primate IrT neurons (Kinget al. 1981). Also the units we studied discharged at a rather NIC (they amount to Ç25% of the fibers in our sample) .regular rate as indicated by their relatively low CV (mean:0.09). Unfortunately, they cannot be compared with NIC To what extent can the discharge of vertical extraocularneurons of the rhesus monkey because there is no informa- motoneurons be attributed to the input they receive fromtion about the regularity of discharge of VSN, BT, and IrT NIC fibers?cells in this species. On the other hand, the CV of the unitswe studied is similar to that of feline NIC BT neurons (mean: Assuming linear summation of inputs, a provisional an-

swer can be had from comparisons between the discharge0.15) (Fukushima et al. 1990). In contrast, feline pitch neu-rons (mean CV: 0.61) (Fukushima et al. 1990) and feline pattern of NIC efferent fibers and that of vertical motoneu-

rons. In general, the rate-position curve of the NIC units weVSNs (mean CV: 0.5) (Fukushima et al. 1995) are quiteirregular. encountered is about two times shallower than that of vertical

motoneurons (King et al. 1981; Robinson 1970). Unless theFinally, the majority of the NIC efferent fibers we encoun-tered emitted bursts for vertical saccades. Consistent with NIC output is amplified, some of the position sensitivity of

vertical extraocular motoneurons must be due to sourcesprevious descriptions of BT units in both the cat and themonkey, parameters of their bursts (number of spikes in the other than the NIC, such as the vestibular nuclei (Chubb

and Fuchs 1982; Iwamoto et al. 1990a,b; McCrea et al. 1987;burst, duration, maximal rate of firing) were related to sac-cade parameters (saccade size, duration, and maximal eye Tomlinson and Robinson 1984). The importance of this

additional input is shown by the fact that pontine MLF le-velocity, respectively) . BT neurons are not the only NICcells that burst for saccades. More than half of the feline sions interrupting the ascending projections of vertical sec-

ondary vestibular neurons cause vertical gaze nystagmuspitch cells also burst for saccades and quick phases (Fuku-shima et al. 1990) as do VSNs (Fukushima et al. 1995) in (Evinger et al. 1977).

The same is probably true of the bursts of NIC efferentboth the cat and the monkey (Kaneko and Fukushima 1998).However, the latencies of VSN bursts are in the long-lead fibers. Even when the sample is restricted to fibers that burst

for saccades, these emit only Ç0.6 spikes/deg of verticalrange in both the cat (035 { 14 ms) (Fukushima et al.1995) and the monkey (32.5 { 21 ms) (Kaneko and Fuku- eye displacement, which is equal to about half of the saccadic

sensitivity of vertical oculomotoneurons (Hepp et al. 1989).shima 1998). They are thus much longer than the latenciesof NIC BT units documented in this study (04.0 { 3.4 ms), Again this implies that much of the burst of vertical extraoc-

ular motoneurons is due to sources other than the NIC, sucha previous study in the rhesus monkey (04.0 { 2.5 ms)(King et al. 1981), and a previous study in the cat (010 { as vertical medium lead burst neurons of the riMLF (King

and Fuchs 1979; Moschovakis et al. 1991a,b) . However, the3 ms) (Fukushima et al. 1990). To conclude, this extensivecomparison indicates that the NIC efferent fibers we encoun- fact that many NIC efferent fibers emit saccade-related bursts

could explain why human subjects generate hypometric ver-tered correspond to the previously described BT neurons ofthe NIC and not to its pitch, VSN, or IrT cells. tical saccades after lesions of the NIC (Fukushima 1991).

On the other hand, the slope of the rate-velocity curve ofBesides conventional, well-behaved, BT discharges, weobserved a number of less conventional discharge types. vertical oculomotoneurons (King et al. 1981) and the inten-

sity and regularity of discharge of presumed primate oculo-First we observed that Ç25% of the primate NIC efferentfibers encountered are not bidirectionally modulated with motoneurons (Robinson 1970) and trochlear motoneurons


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FIG. 11. Cross-correlation between variables describing NIC unit discharge. Correlation coefficients (r) and F ratios areshown for relationships which attained statistical significance (P Å 0.001 or better) . kV, slope of the rate-position curve; F0 ,firing rate at primary position; CV, coefficient of variation; Bi/Uni, bidirectional (Bi) or unidirectional (Uni) modulation offiring rate with vertical eye position; Lat, latency of saccade-related bursts; RV, slope of the relationship between the numberof spikes in the burst and the vertical displacement of the eyes; r(Bd/Sd) , correlation coefficient of the relationship betweenburst duration and saccade duration; G(Fm/Vm), slope of the relationship between maximal burst frequency and maximalsaccadic eye velocity; DF, neuron classes in which tonic and burst discharges increase in the same (DF Å 07) or in theopposite (DF Å 1807) directions.

(Fuchs and Luschei 1971) when the eyes are at primary distinct groups of neurons. To reduce the dimensions of theposition is similar to that of NIC efferent fibers. Accordingly, parameter space, we employed a principal component analysis.these aspects of motoneuronal discharge could be consider- Figure 11 illustrates the cross-correlation between the nineably influenced by the input they receive from the NIC. variables we studied and the results we obtained. Each one of

its boxes shows the location of each one of the units encoun-tered in the plane formed by two of the variables studied.Are there subpopulations of NIC efferent fibers?When one variable was discrete, such as in-phase/antiphase,we used analysis of variance (ANOVA) to compare the twoMuch of this study is devoted to a systematic explorationclasses in terms of the continuous variable. In the case whereof a large number of parameters describing the discharge pat-both variables were discrete, we used a x2 test.tern of NIC efferent fibers. Each one of these parameters can

Examination of Fig. 11 shows that several correlationsbe thought of as an axis of a multidimensional space, andwere significant. Burst latency (Lat) and Rv (the slope ofevery fiber in our sample can be described by its location inthe relation between vertical size and the number of spikesthis space. The question we wish to consider is whether the

units we studied fall into clusters corresponding to functionally in the burst) are related to several other variables. We found


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between the slopes and the correlation coefficients of theseanalyses rendered them redundant. We also did not includeany of the smooth-pursuit variables because vertical smooth-pursuit eye velocity was not related to the discharge ofÇ50% of the units in our sample. Suffice it to say thatsensitivity to vertical smooth-pursuit eye velocity was notcorrelated with any of the nine discharge parameters of Fig.11. Finally, we restricted the parameter space to continuousvariables and excluded units that had a zero value in anyone of these variables. Following these restrictions, therewere 45 BT units left in our sample; three factors weredetermined that accounted for almost 79% of the variancein this considerably restricted sample. The first factor (ac-counting for Ç45% of the variance) was related to parame-ters of saccade-related bursts ( i.e., latency, slope of the rela-tionship between Nb and saccade size, regression coefficientof the relationship between burst duration and saccade dura-tion, and slope of the relationship between maximal fre-quency and maximal saccadic velocity) . The second factor(accounting for Ç20% of the variance) was related to the

FIG. 12. Three-dimensional plot of parameters of discharge of 45 burst- regularity and intensity of discharge at primary position. Thetonic NIC efferent fibers (each sphere corresponds to 1 unit) . Three axes

third factor (accounting for Ç14% of the variance) wasof the plot correspond to the 3 factors extracted with the help of principalrelated to position sensitivity. These three factors (‘‘bursti-component analysis. Origin of each axis (0) corresponds to the mean of

the distribution of each factor, and increments are in units of standard ness,’’ ‘‘regularity,’’ ‘‘sensitivity’’) form the axes of thedeviation. Positive values indicate higher intensity, decreased regularity and three-dimensional plot of Fig. 12. As shown here, NIC effer-increased sensitivity, on the ‘‘burstiness,’’ ‘‘regularity,’’ and ‘‘sensitivity’’

ent fibers form a diffuse cloud one end of which is made ofaxes, respectively. To avoid clutter, some of the data points were removed.regular but relatively insensitive units that emit strong bursts.The cloud continues through units of average regularity and

that the earlier the onset of the bursts, the higher the fidelity sensitivity that also emit fairly strong bursts and ends withwith which they encoded saccade duration (r (Bd/Sd) , row 6), units that emit weak bursts and vary in terms of regularitythe higher the slope between their maximal frequency and and sensitivity. Although the absence of bursts did not allowthe maximal saccadic velocity (G (Fm/Vm) , row 7), and the us to extend the principal component analysis to tonic NIChigher the Rv (row 5). Also, fibers emitting weaker bursts units, these can be thought of as a continuation of the same(small Rv) were more irregular (high CV, column 3). This

cloud on a plane orthogonal to the ‘‘burstiness’’ axis andis consistent with a previous description of feline NIC BTlocated some distance away from its origin (such as theunits (Fukushima et al. 1990). Moreover, the higher the Rvregularity-sensitivity plane that forms the floor of Fig. 12).(column 6), the higher the fidelity with which the bursts of

To summarize, the efferent fibers of the NIC encode aNIC efferent fibers encoded saccade duration and the higherconstellation of oculomotor variables in terms of a complexthe slope between their maximal frequency and the maximalarray of discharge parameters. Each of these variables hasvelocity of saccades. The bursts of bidirectional units hadenough spread to serve as a basis for separating the unitslonger latencies than those of unidirectional units (columninto classes, but whatever the variable chosen, the gulf be-4) , whereas antiphase units discharged more irregularlytween the extremes always is occupied by fibers of interme-(higher CV) and emitted weaker bursts (shallower Rv) thandiate properties. Even using parameters of discharge thatin-phase units (row 8). Finally, the more reliably a neuron’sare inherently dichotomous to divide the population of NICbursts encoded saccade duration the higher the sensitivityefferent fibers into bi- and unidirectionally modulated unitswith which they encoded the maximal vertical velocity ofor into in-phase and antiphase units does not break the NICsaccades (column 7). With the exception of the good corre-efferent fibers into meaningful functionally distinct groupslation between F0 and CV, all other correlations were notbecause neither bidirectional nor antiphase units differ insignificant. Units which did not modulate their dischargeother respects much from units with antithetical properties.for saccades (tonic neurons) were analyzed separately. AnTherefore we conclude that NIC efferent fibers occupy aANOVA did not reveal differences between tonic and BTfunctional continuum in the parameter space that definesneurons in terms of regularity of discharge, firing rate attheir discharge. Further we conclude that each NIC efferentprimary position, and rate-position slope. The monkey verti-fiber sends a combination of eye-position, saccade-, andcal neural integrator therefore differs from the cat horizontalsmooth-pursuit-related signals to targets of the vertical neu-neural integrator, the tonic neurons of which are thought toral integrator ( including extraocular motoneurons) . To de-be more regular than BT neurons (Escudero et al. 1992).termine whether identical copies of these signals are sentFor our principal component analysis, we elected to ex-simultaneously to all targets of the NIC, we must knowclude the regression coefficients of the rate-velocity, rate-the trajectories and patterns of termination of functionallyposition, and Nb versus size curves as well as the gain ofidentified axons that arise from individual NIC neurons.the curve relating burst duration with saccade duration from

our cross-correlation analysis because the high correlations Their study will be the object of a future report.


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The expert technical assistance of P. Keller and the comments of two movements by mesencephalic burst neurons. J. Neurophysiol. 42: 861–876, 1979.anonymous reviewers are acknowledged gratefully.

This work was supported by Human Capital and Mobility Grant KING, W. M., FUCHS, A. F., AND MAGNIN, M. Vertical eye movement-related responses of neurons in midbrain near interstitial nucleus of Cajal.ERBCHRXCT-940559.

Address for reprint requests: A. K. Moschovakis, Dept. Basic Sciences, J. Neurophysiol. 46: 549–562, 1981.KING, W. M. AND LEIGH, R. J. Physiology of vertical gaze. In: FunctionalFaculty of Medicine, University of Crete, P.O. Box 1393, Crete, Greece

71110. Basis of Ocular Motility Disorders, edited by G. Lennerstrand, D. S. Zee,and E. L. Keller. Oxford: Pergamon, 1982, p. 267–276.

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