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1 Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 2 Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Submitted 15 March 2002; accepted in final form 14 April 2003
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ABSTRACT |
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INTRODUCTION |
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;
Kommerell et al. 1976;
Optican et al. 1985) and in
monkeys with surgically induced paresis
(Optican and Robinson 1980;
Scudder et al. 1998). Because
of the conjugate oculomotor command conveyed to both eyes, eye movements are
necessarily smaller in the paretic, "weak" eye than in the normal
eye. When the normal eye is monocularly viewing, the subject makes saccades to
visible targets accurately, but when the subject is forced to use the weakened
eye by patching the normal eye, saccades initially undershoot the target.
However, saccades gradually increase in size until they are nearly accurate.
When the patch is switched and the normal eye is used again, saccades in this
eye initially overshoot the target, but adaptive mechanisms gradually restore
normal accuracy. The ability to adapt saccade size has also been
experimentally shown by displacing the target during the time that the human
or monkey subject is generating a saccade that would have acquired the target
("intrasaccadic target steps";
Deubel et al. 1986;
McLaughlin 1967;
Miller et al. 1981;
Scudder et al. 1998;
Straube et al. 1997).
Initially, saccades land near the original target and miss the displaced
target, but adaptation of saccade size and/or direction gradually produces
saccades that land near the displaced target.
A variety of evidence has led to the belief that the cerebellum
participates in the control of saccade size and direction. Lesions of the
posterior vermis that include lobule VII, especially unilateral lesions,
result in saccades that are markedly dysmetric (Aschoff and Cohen
1971,
1972;
Barash et al. 1999;
Optican and Robinson 1980;
Ritchie 1976; Selhorst et al.
1976a,b;
Takagi et al. 1998). Saccade
size may differ from target displacement by a factor of 2, indicating that the
cerebellar signals have a potent effect on the saccadic burst generator
located in the brain stem. Similar, transient deficits are produced in monkeys
and cats by local inactivation of the target area of lobule VII axons, that
is, the caudal fastigial nucleus. Inactivation of this part of the nucleus by
cooling (Vilis and Hore 1981)
or by injection of the GABA agonist, muscimol, results in saccades to the
contralesional side that are hypometric and saccades to the ipsilesional side
that are hypermetric (Goffart and Pelisson
1994,
1998;
Robinson et al. 1993).
Finally, microstimulation of lobule VII slightly before or during
contralaterally directed saccades has the ability to foreshorten these
saccades (Keller et al. 1983;
Ohtsuka and Noda 1991b).
Anatomical and physiological data support the hypothesis that saccade size
might be controlled by the cerebellum and, moreover, have suggested ways that
this might occur. Retrograde and anterograde tract tracing has shown that
fibers from the caudal fastigial nucleus project mainly contralaterally to the
pontine and mesencephalic reticular formations as well as to the superior
colliculus (Batton et al.
1977; Gonzalo-Ruiz et al.
1988,
1990;
Kurimoto et al. 1995;
May et al. 1990;
Sato and Noda 1991). Efferent
terminals seem to target the specific areas where saccade-related neurons are
located (Noda et al. 1990;
Scudder et al. 2000). These
neurons include the premotor "saccadic burst neurons," that is,
excitatory burst neurons (EBNs) and inhibitory burst neurons (IBNs), as well
as interneurons, that is, long-lead burst neurons (LLBNs) and midline
omnipause neurons (OPNs). EBNs, IBNs, and LLBNs exhibit a vigorous burst of
spikes preceding and during ipsiversive saccades, whereas OPNs exhibit a
cessation (pause) in their tonic firing at the same time (cf.
Fuchs et al. 1985;
Scudder et al. 2002). As
discussed in more detail later, the OPNs make inhibitory connections with EBNs
and IBNs (Curthoys et al.
1984; Nakao et al.
1980) and are thought to permit the discharge of these premotor
burst neurons by the cessation of tonic firing. Therefore OPNs probably
control both the onset and termination of premotor bursts. Given that saccade
size is determined by the number of spikes in these burst neurons
(Kaneko et al. 1981;
Keller 1974;
Scudder et al. 1988; Strassman
et al.
1986a,b;
van Gisbergen et al. 1981),
control of either the burst frequency and/or the burst duration would bring
about control of saccade size. The brain-stem connections of caudal fastigial
neurons are therefore well suited for this function.
Extracellular recording of cells in the caudal fastigial nucleus have
revealed further clues about how the cerebellum might control saccade size.
Saccade-related cells are found in a circumscribed area, which Noda and
colleagues have called the fastigial oculomotor region (FOR), and exhibit a
burst of spikes that precedes the onset of contraversive saccades by an
average 10–19 ms (Fuchs et al.
1993; Ohtsuka and Noda
1990,
1991a). The range of burst
leads is large but, nonetheless, the discharges seem well timed to affect the
discharges of the premotor burst neurons (EBNs and IBNs) on the contralateral
side while these latter neurons exhibit their maximal bursts (in their
"on-direction"; cf. Fuchs et
al. 1985). Because the vast majority of cerebellar nuclear
projections to the pons appear to be excitatory (Angaut and Sotello 1989;
Kitai et al. 1976;
Schwarz and Schmitz 1997;
Verveer et al. 1997), one
hypothesis is that the burst of FOR neurons during contraversive saccades
contributes to the on-direction burst in contralateral EBNs and IBNs, and
therefore to the production of force in agonist motoneurons and the reduction
of force in antagonist motoneurons, respectively. An effect on the onset
and/or offset of the OPN pause is also possible. FOR neurons also exhibit a
more delayed burst during ipsiversive saccades that seems to be best
correlated with the end of the saccade. Ohtsuka and Noda
(1991a) report that the burst
for individual neurons begins at a fairly fixed interval before saccade end
that averaged 31 ms, regardless of saccade size. By the contralateral
projection, this late burst could augment the late off-direction discharges of
EBNs and IBNs (Scudder et al. 1985; van
Gisbergen et al. 1981). Augmenting the off-direction discharges
would have the effect of "braking" the saccade
(Ohtsuka and Noda 1991a).
However, the tight relation of the FOR-neuron burst to saccade end would seem
to require a more secure mechanism, that is, indirect control of all burst
neurons by affecting the resumption of OPN firing.
Fastigial neurons also project to the superior colliculus and could affect
saccade size by this pathway. However, there are conflicting data regarding
the strength of this projection (reviewed by
Scudder et al. 2002) and
whether the projection is just to the "fixation neurons"
(Munoz and Wurtz 1993) in the
rostral colliculus (May et al.
1990) or is more widespread
(Batton et al. 1977;
Gonzalo-Ruiz et al. 1988,
1990;
Kurimoto et al. 1995).
Given that mechanisms are available for cerebellar control of saccade size
and that these mechanisms do exert powerful effects on saccade size, it stands
to reason that the cerebellum could mediate the adaptive processes described
above. Nonetheless, evidence for this hypothesis is meager. The fact that the
saccadic dysmetrias produced by chronic cerebellar lesions are enduring and
are not corrected by adaptation argues for this hypothesis. Goldberg et al.
(1993) extended this
conclusion by showing that monkeys with large electrolytic lesions including
the fastigial nuclei had no capacity to change saccade size when subjected to
intrasaccadic target displacements. Optican and Robinson
(1980) combined large lesions
of the monkey posterior cerebellum with muscle weakening in one eye. Monocular
viewing with the normal eye resulted in enduring hypermetria, as expected from
other binocular studies, but monocular viewing using the weakened eye did not
produce sufficient dysmetria for a critical test.
The current study attempted a direct test of the hypothesized role of the cerebellum in saccade adaptation by searching for the neural correlates of that adaptation. The discharges of neurons in the caudal fastigial nucleus of our monkeys were recorded extracellularly during ongoing adaptation produced by alternately patching a surgically weakened or normal unoperated eye. Our approach was to correlate a variety of FOR-neuron discharge parameters with saccade size as it changed to reveal those discharge parameters that were modified in a repeatable manner. We applied this approach consistently because the hypothesis is that adaptation functions to reduce the amplitude error (i.e., change saccade size) regardless of the precise neural mechanisms that mediate the change. As noted above, possible mechanisms include those that modulate EBN and IBN burst frequency and those that modulate burst duration, which also has the effect of modulating saccade duration. In fact, our results show that FOR-neuron discharges change during adaptation in multiple ways that can modify EBN and IBN burst frequency and duration, albeit not always in ways that maintain normal saccade amplitude–duration relationships.
A preliminary report based on a smaller sample of neurons has appeared as
an abstract (Scudder
1998).
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METHODS |
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Surgery
Monkeys were surgically prepared for eye movement recording during two
aseptic procedures in which they were deeply anesthetized with halothane (1.5%
in oxygen/nitrous oxide) after induction with ketamine. In the first surgery,
a magnetic search coil was sutured to the sclera of the right eye and three
acrylic lugs for the stabilization of the head were implanted as described
previously (Scudder et al.
1998). The front lug also served as the receptacle for a metal
stalk that held the eye patch. After training (see following text), monkeys
underwent a second surgery to weaken the eye muscles of the left eye, to
implant a search coil in the left eye, and to implant a recording chamber
directed at the fastigial nuclei. The medial and lateral recti were detached
from the globe and cut to about two-thirds their normal length. A length of
absorbable suture bridged the gap between the cut end of each muscle and the
original attachment of its tendon to help control the place where the cut
muscle would reattach to the globe. The second search coil was implanted in
the same manner as the first. The 20-mm-diameter recording chamber was placed
in a craniotomy over the midsagittal plane. It was aimed 5–7 mm
posterior to ear-bar zero and angled 20° posteriorly from stereotaxic
vertical. The recording chamber was attached to the bone with self-tapping
screws and dental acrylic. The chamber was filled with antibiotic gel and
covered with a cap. For the duration of the experiments, the antibiotic gel
was replaced daily and the dura cleaned with cotton swabs.
Behavioral apparatus and experimental tasks
Experiments began 3–4 wk after the second surgery. They were conducted in a dimly illuminated soundproof booth with the monkeys seated in a primate chair and their heads restrained. Surrounding their heads were two orthogonal pairs of magnetic induction coils that were used in conjunction with the implanted search coil for the measurement of eye movements (CNC Engineering). Eye movement signals were calibrated by having the monkey alternately fixate stationary targets at ±15° horizontal and vertical eccentricity.
Monkeys viewed a red, 0.3° target spot projected onto a textureless
white screen formed into a vertically oriented quarter cylinder and situated
75 cm in front of the monkey. The target spot was generated by a laser diode
and deflected by an X-Y mirror galvanometer system (General Scanning) under
computer control (PDP 11/73). The computer determined the target location,
monitored eye movements, and dispensed applesauce reward when on-target
conditions were met. For training, food-deprived monkeys were required to
fixate the target spot within an error "window" of 6° in all
directions to receive a dollop (about 0.1 ml) of applesauce. As performance
improved, the error window was reduced to 2° and monkeys were required to
fixate 
1.5 s after an on-target saccade.
One pattern of 16 possible targets located along 8 equally spaced
directions on 8°- and 15°-radius circles and with a central fixation
point was used to collect information about the relation between FOR-neuron
discharges and the size and direction of saccades. The fixation point and any
of the pseudorandomly chosen peripheral target locations were alternately
illuminated so that the monkey made saccades to and from the fixation point in
each of 8 directions. A 1.3- to 2.0-s period of fixation triggered the
illumination of the next target. A second pattern consisting of two possible
target locations separated horizontally by 20° was used to collect all
data relating to adaptation of saccade size and the correlated changes in FOR
neuron discharges. This pattern was used because it produced the most rapid
adaptation (Scudder et al.
1998) and thereby maximized the probability of obtaining
significant changes in a short period of time.
Long-term and short-term adaptation of saccade size was produced by forcing
the monkey to view the world through the eye having surgically weakened eye
muscles. Vision in the normal unoperated eye was blocked using an opaque rigid
patch that mated with a receptacle attached to the front acrylic lug on the
monkey's head. Reverse adaptation (recovery) was produced by patching the weak
eye. Monkeys were never allowed to experience binocular vision, either during
the experiments or when housed in the animal facility. By long term, we mean
that the monkeys would wear the patch on the same eye every day for 1 wk,
beginning on a Friday. When recordings began the following Monday, the monkey
had had sufficient time that saccades in the viewing eye could reach an
asymptotic value of saccadic gain (saccade amplitude/target-step amplitude;
Scudder et al. 1998), which we
will call the initial state. When a suitable neuron was isolated (see
following text), data from about 200 saccades were collected using first the
circular target pattern and then the two-target linear pattern. The eye patch
was then switched so the monkey viewed through the unadapted eye and data were
again collected using the two-target linear pattern. Further data from 100 to
200 saccades were collected 20 min after switching the patch, and every
10–20 min thereafter as the saccadic system adapted to the new viewing
condition. A few neurons were isolated long enough that adaptation slowed as
saccade gain approached its asymptotic value for the particular viewing eye
(0.8–0.95; Scudder et al.
1998). When this occurred, the target was then stepped
intrasaccadically to produce additional visual error. If the monkey was
viewing with the weakened eye, the target was stepped in the forward direction
3–4° (15–20% of the initial target step); if the monkey was
viewing with the normal eye, the target was stepped in the backward direction
3–4°.
If the neuron was lost after only a brief period of isolation (<20 min of adaptation), the patch was switched back to cover the original eye and we attempted to isolate a new neuron. If isolation was maintained for a longer time and then lost, the patch was switched to the original eye and the remainder of the experiment was used to return saccade size to its initial state. Regardless, the monkey was returned to its cage with the patch on the original eye so that saccade gain would return to the same initial state for the experiment the next day. After 1 or 2 wk of such sessions, the patch would be placed over the original viewing eye on Friday afternoon so that the monkey would enter the lab adapted to viewing with the opposite eye during the next set of experiments.
Neuronal recording
Neuronal action potentials were recorded with commercially available 0.005-in. tungsten microelectrodes with 15-µm exposed tips (Micro Probe, Potomac, MD). Electrodes were loaded into a 24/21-gauge concentric cannula assembly that protected the electrode as both were lowered into the brain and through the tentorium cerebelli. The outer 21-gauge cannula was 8 mm shorter than the inner 24-gauge cannula so that only the latter penetrated the tentorium. Electrodes were driven the last 10-mm to the fastigial nucleus with a Trent-Wells motorized hydraulic microdrive.
Neurons exhibiting discharges related to saccadic eye movements were
encountered 0.7–2.0 mm lateral to the midline in the most caudal
1–2 mm of the fastigial nucleus. The majority of neurons exhibited a
burst of spikes during saccades, and some had very pronounced bursts (peak
rates >500 spikes/s), which served as an unambiguous marker for the area.
Preliminary data were collected for all isolated saccade-related neurons using
the circular target pattern. Units selected for recording during adaptation
had to have had excellent, stable isolation throughout the preliminary data
collection. Neurons were also required to have a saccade-related response of
20 spike/s, and to have a stronger response during horizontal saccades
than during vertical saccades. Neurons failing the latter criteria were
rejected under the supposition that they might function to control vertical
and not horizontal saccades. Neurons meeting these criteria were tested during
short-term adaptation using the procedures described above.
Data collection and analysis
Neuronal signals were conventionally amplified and filtered (0.2–10 kHz). Most data were digitized on-line. Spikes were converted to TTL pulses with a simple Schmitt trigger, and were given a time stamp to the nearest 0.1 ms. The 4 eye channels (horizontal and vertical eye position for both eyes) as well as the 2 target channels were sampled every 4 ms. Data were also binary-encoded for storage on VCR tape (Vetter 4000A). Two cells were digitized off-line using the same program, but using the taped backup data. Seven other cells were digitized off-line, and spikes were detected in software using DataWave Experimenters Workbench. Temporal resolution for spike occurrence was again 0.1 ms, and the sampling rate for the eye and target channels was 4 ms.
Neuronal discharge parameters and saccade metrics were computed from the
digitized data using an interactive program similar to that used previously
(Scudder et al. 1988). The
user manually scrolled the data and placed a cursor near desired saccades. The
computer (Pentium-based) found peak velocity and independently searched
backward and forward in time for the first point where eye position reached
that occurring during fixation before and after the saccade, respectively.
Temporal resolution was improved by fitting the 4 adjacent persaccadic samples
with a second-order polynomial with the vertex forced through the steady-state
eye position. The time coordinate of the vertex was taken as the start or end
of the saccade. The computer marked these points and the user accepted them or
manually marked those that were in error (errors were usually in the vertical
channel where eye velocity could change direction in the middle of a
horizontal saccade). The user manually marked the approximate start and end of
bursts and/or pauses in the neuronal discharges. The computer used the spike
succeeding (preceding) the first mark as the onset of a burst (pause), and the
spike preceding (succeeding) the second mark as the end of the burst (pause).
From these marks and the eye positions at these marks, the computer determined
the amplitudes of the horizontal and vertical saccadic components, and
horizontal and vertical component durations. The computer also determined
latency from saccade onset to burst onset, burst duration, and other discharge
parameters. Because the firing rate of FOR neurons was frequently above the
resting level at saccade termination, and because subsequent spikes obviously
cannot affect the size of the terminated saccade, only spikes occurring
between burst onset and saccade termination were included in the computation
of number of spikes, average frequency (number of spikes/duration), and peak
frequency. The last was defined as the average frequency of the three
consecutive spikes spanning the shortest time interval.
As noted by Fuchs et al.
(1993), burst onset could not
always be marked with high reliability. In these cases, burst onset was
determined from averaged instantaneous frequency data. The interval between
successive spikes was assigned a frequency value equivalent to the reciprocal
of the interval. Frequency was averaged across saccades by aligning all data
on saccade onset. Burst onset was defined as the time when averaged frequency
crossed the criterion of one third the difference between resting rate and
peak burst frequency. For a given unit, the frequency criterion was determined
from the data at the start of adaptation, and this same absolute value was
applied to data acquired at all subsequent times. Measurements obtained with
this method usually differed by a few milliseconds from the averaged discharge
latency, but determinations at different times during adaptation were almost
always in the same rank order for the two methods. Among neurons with
well-defined burst onsets, the changes in burst onset during adaptation were
nearly identical for the two methods. Similarly, burst end was poorly defined
for some units and a graphical method was again used. Burst end was defined as
the time when firing rate had dropped to 40% of the difference between peak
rate and resting rate.
Saccades were excluded from the statistical analysis if the reaction times
were too short (<70 ms) or too long (>600 ms), if the monkey was not
initially on target (±1.5°), or if the saccade was clearly not
directed at the target. Saccades were also excluded if their durations
exceeded 3.5 times the average value reported by Fuchs
(1967) for a given size, or if
the saccade size was 3.5 SDs away from the mean for the particular data set
(about 0.3% of the data). Averaged saccade metrics (e.g., amplitude) and
discharge parameters were always computed separately for leftward and
rightward saccades. Measurements were statistically compared using Student's
t-test, and 2-tailed P values reported.
Data on saccade metrics after long-term adaptation were collected in association with the 28 neurons included in this study as well as with neurons that were not isolated long enough to be included. Means for each neuron were computed, and the average and SD of these means are reported. Preadaptation means and SDs of the discharge parameters (first section of RESULTS section) were obtained using the 20° target steps. Therefore some data were collected with the monkey adapted long term to using the normal eye and other data were collected with the monkey adapted long term to using the weak eye. The average saccade size for the combined data was 23.1 ± 4.4° (SD). Linear correlations were obtained between discharge and saccade parameters under two different circumstances, and the difference is important for understanding our findings. In the first circumstance, data were collected before short-term adaptation using the circle task, and the correlations describe how the discharges respond as saccade size and duration vary both naturally and to different size target steps. In the second, data were obtained during short-term adaptation, and the correlations describe how the discharges respond as saccade size changes because of adaptation. The process of obtaining the latter correlations are described more fully in the RESULTS.
Plots of average eye position versus time and averaged discharge rate were generated for illustrations. Instantaneous frequency was computed as described above, and eye position and frequency traces were aligned on saccade onset and averaged. Each data point corresponds to one 4-ms sample interval.
Anatomy and histology
At the completion of all experiments, monkeys were deeply anesthetized and perfused through the heart with buffered saline followed by buffered 4% paraformaldehyde. The fixed brain was sectioned coronally and sections were processed for neuroanatomical tracers (to be reported separately) and counterstained with Neutral Red. We confirmed that electrode tracks passed through the caudal pole of the fastigial nucleus, but we did not attempt to plot the location of recorded cells on individual tracks.
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RESULTS |
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5%. This
report focuses on these 28 neurons; 18 from monkey M, 7 from monkey S, and 3
from monkey G. Eighteen neurons were recorded during size increases, whereas
10 were recorded during size decreases. General features of included neurons: preadaptation data
The neurons used in this study were generally similar to those reported
elsewhere (Fuchs et al. 1993;
Ohtsuka and Noda 1990,
1991a). Averaged data from a
typical neuron are illustrated in Fig.
1 for 20° horizontal target steps. All the neurons exhibited a
burst of spikes during contraversive saccades that began on average 4.2
± 8.1 ms (SD, n = 28) before the onset of saccades averaging
23° (see METHODS). Although other investigators have emphasized
the early lead of this burst (18.5 ms,
Ohtsuka and Noda 1991a; 10.5
ms, Fuchs et al. 1993), the
burst began after saccade onset in 25% of our sample. In fact, one monkey (S)
had a predominance of such neurons, with a mean lead of –3.7 ms. The
peak discharge, which averaged 229 spikes/s for the full sample, nearly always
occurred during the saccade. Some neurons appeared to have two bursts: one
near saccade onset, and a second smaller burst before saccade end. For 7
neurons, the burst nearly always (>85% of saccades) ended before the
saccade ended, whereas for 7 other neurons, including that in
Fig. 1, the burst nearly always
(>85%) ended later than the saccade. The remaining 14 units exhibited
intermediate behavior, with some bursts ending before and some later than the
saccade. For the whole sample, the average end of the burst occurred at about
the end of the saccade. The burst was preceded by a 20–50% diminution in
firing rate in 8 units and was followed by a diminution in another 5, as
revealed in the averaged firing rate plots.
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All neurons also exhibited a burst of spikes during ipsiversive saccades.
For saccades averaging 23°, this burst began after saccade onset in all
but 4 neurons. The average latency, which is defined hereafter as ipsiversive
burst lag, was 23.9 ± 20.5 ms (SD, n = 28). Within neurons,
the variability (SD) of ipsiversive burst lag averaged 11.1 ms (range
5.1–27.4, n = 28). Expressed relative to the end of the
saccade, the average burst began 47.3 ± 18.8 ms (SD, n = 28)
before saccade end. Based on their finding that the average interval between
burst onset and saccade end was invariant regardless of saccade size, Ohtsuka
and Noda (1991a) argued that
the function of this burst is to terminate the saccade. We examined this
possibility by correlating ipsiversive burst lag against saccade duration as
the monkey made a spectrum of saccade sizes to the 8° and 15° target
steps. In our sample, there were only 4 neurons where the interval between
burst onset and saccade end was nearly invariant, but there were 2 other
neurons where the interval between saccade start and burst onset (burst lag)
was nearly invariant. In the majority of neurons, behavior was in between.
Overall, burst lag was significantly correlated with saccade duration in 24
neurons, but on average, increased 0.55 ± 0.27 ms (SD, n = 28)
for every 1-ms increase in saccade duration (average r = 0.68, range
0.07–0.98). This slope is considerably less than the 1.0 ms/ms slope
stipulated by Ohtsuka and Noda. The variability about this relation
(square-root of the error variance) was 9.0 ms (range 2.4–22.9).
Ipsiversive burst lag was also correlated with saccade size (1.22 ± 0.71 ms/deg, n = 28), but less well than with saccade duration (average r = 0.56, range 0.04–0.94). Thus the dependency on size could be a byproduct of the correlation between saccade size and saccade duration.
The ipsiversive burst was preceded by a full cessation of firing in 13
units, and a significant reduction (e.g., 50%) in another 7. The firing rate
at the end of the saccade remained elevated above the resting rate in most of
the neurons (22 of 28), and this was followed by a diminution or outright
pause in firing in 6 units. Overall, these discharge patterns fit within the
"burst," "pause-before-burst," and
"burst-before-pause" types described by Fuchs et al.
(1993). A small number of
neurons that exclusively paused were also encountered, but are not included in
this report.
Adaptation of saccade size
The process of adapting saccade size using the appropriate patching of the
paretic or normal eye is illustrated for monkey "M" in
Fig. 2, A–D.
Initially (Fig. 2A),
monkeys wore the patch over the weak eye and viewed the target with the normal
eye. Target steps elicited saccades in the normal eye (top traces)
that accurately acquired the target, but saccades measured in the nonviewing
weak eye were approximately half the size of the target step (bottom
traces). After recording initial saccade and neuronal-discharge data, the
patch was switched to cover the normal eye.
Figure 2B illustrates
typical eye movements recorded immediately thereafter. Saccades in the (now
viewing) weak eye were still severely hypometric, thereby requiring multiple
corrective saccades to finally acquire the target. Simultaneously, the initial
saccade measured in the (nonviewing) normal eye was still roughly equal to
target displacement (dotted line). Saccade size measured in both eyes began
increasing immediately (Scudder et al.
1998) and changed measurably over 20 min. Saccade size in the weak
eye ultimately reached an asymptotic value that undershot the target
(Scudder et al. 1998), but
this value was not achieved over the period that FOR neurons remained
isolated. Long-term asymptotic horizontal gains measured in the viewing weak
eye in monkeys M, G, and S were 0.85, 0.95, and 0.90, respectively. The
saccade in Fig. 2C
exhibits this long-term adapted gain. Horizontal gain measured in the
nonviewing normal eye was about 1.8. For 10 of the neurons, this was the
initial state of adaptation. Switching the patch to cover the weak eye
produced the eye movements illustrated in
Fig. 2D. Saccade size
was initially the same as that measured in the previous panel
(Fig. 2C), so that
saccades measured in the viewing normal eye severely overshot the target.
Saccade size decreased more rapidly than saccade size previously increased.
Long-term patching of the weak eye resulted in eye movements comparable to
those illustrated in Fig.
2A. Although this readaptation to use of the normal eye
is operationally a "recovery," we caution that this word carries
mechanistic implications that we believe do not apply to short-term adaptation
of saccade size. The vertical component of the saccades changed negligibly
during the patch-switching paradigm.
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In the long term, increases in saccade size produced by viewing with the weak eye were accomplished by increases in saccade duration and increases in saccade velocity. Measurements were made in the normal eye, and data from rightward and leftward saccades, which were somewhat but not significantly different, were combined. Long-term increases in saccade size for 20° target steps averaged 11.5° and were accompanied by an increased duration of 29.3 ms (67.7 ± 8.0 to 97.0 ± 13.7) and an increased peak velocity of 43°/s (548 ± 45 to 591 ± 68). These differences were significantly different (P < 0.02, n = 51). The change in duration was the dominant factor in increasing saccade size; the 62% change in saccade size was accomplished with a 43% increase in duration and an 8% increase in velocity. Adapted and unadapted "main sequence" parameters (Bahill 1975) were compared for 10° and for 15° saccades in the normal eye (values of maximal overlap for adapted and unadapted saccades using the circular target pattern). Adapted saccades had slightly, but significantly, smaller durations and velocities. For instance, unadapted and adapted durations for 15° saccades averaged 57.7 ± 5.5 (n = 45) and 50.9 ± 6.7 (n = 55) ms, respectively, whereas unadapted and adapted peak velocities were 519 ± 41 and 491 ± 42 deg/s. The smaller saccade durations and velocities associated with saccades of the same size imply that the basic shape of the velocity profiles must have changed.
Short-term changes in saccade size (those occurring during recording
sessions) were smaller than the long-term changes. For the 18 gain-increasing
experiments, saccade gain (weak eye) began at around 0.61 (range
0.43–0.76) and increased to 0.69. Saccade size (normal eye) began at an
average 22.5° and increased by 1.3–10.6°, with a mean increase
of 4.3°. Saccade size began at a value >20° because the muscle
weakening produced nonlinearities in the orbit
(Scudder et al. 1998) and
because adaptation had been attempted before the successful recording in some
electrode penetrations. For the 10 gain-decreasing experiments, saccade size
began at an average 25.5° and decreased by 1.3–13.2°, with a
mean decrease of 6.3°. All changes were statistically significant at
P < 0.01 or better.
As in the long term, short-term changes in saccade size were usually accomplished by changes in saccade duration and peak velocity, although there was considerable variability. In some cases, for instance, saccade duration changed negligibly and/or saccade velocity did not change or changed in the "wrong" direction (velocity decreased as size increased). In these cases, the shape of the velocity profiles must have changed during adaptation. To illustrate this, we plotted the averaged velocity profiles of rightward saccades recorded during a session in which saccade size, but not duration or peak velocity, had increased after 40 min of adaptation (Fig. 3). The 11% increase in saccade size was accomplished by a relative increase in velocity during the deceleration phase of the saccade. Similar results were obtained in two more conditions from two neurons where saccade duration and peak velocity changed negligibly (leftward and rightward saccades were separately averaged for a total of 56 conditions). For the remaining conditions, we computed the product of averaged peak velocity times averaged duration and compared the changes in this product during adaptation to the averaged changes in saccade size. If waveshape did not change, this product would scale directly with saccade size so that the percentage change in the product and the measured size would be equal. There was a gross inequality in 6 additional conditions; the percentage changes in this product were 2.5 to 4 times smaller than the percentage changes in saccade size. All these instances of unusually small increases in duration and peak velocity were obtained during gain-increasing experiments, and most (7/9) were obtained from one monkey (S). Both the long- and short-term data show that adapted saccade duration and peak velocity need not fall on the main sequence, and that these two parameters are not sufficient for characterizing all the changes that occur during adaptation.
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Changes in discharge patterns during adaptation
Based on the possible mechanisms mentioned in the INTRODUCTION by which FOR neurons might affect saccade size, the discharge onset time, discharge offset time, peak frequency, average frequency, and number of spikes were all considered important parameters to monitor during adaptation. One parameter exhibiting changes during adaptation was the burst lag for ipsiversive saccades. Because the ipsiversive burst was postulated to "brake" or truncate the saccade, earlier discharges should be associated with smaller saccades, just as they are in unadapted animals. Figure 4 illustrates this association for one neuron. Plots are averages of 54 and 44 saccades aligned on saccade onset. Before the experiment, the monkey had been wearing the patch on the normal eye so that switching the patch to the weak eye caused hypermetric saccades in the now viewing normal eye (Fig. 4, top). Saccade amplitude averaged 26 ± 1.6° in response to the 20°-target step. However, after 2 h of performing the saccadic tracking task, average saccade amplitude in the normal eye declined to 19.4 ± 1.7°, and there was a corresponding significant decrease in the average burst lag from 73.0 ± 14.5 to 60.1 ± 11.4 ms (P < 0.0001, n = 98).
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To quantify the results in this and in the other neurons, burst lag was plotted as a function of saccade size for all time points where data were collected. Figure 5 illustrates 8 such plots for 8 neurons selected to show the range of the data. For neurons plotted on the right-hand side, the monkey had previously been viewing with the weak eye, and data were collected after the patch was switched so that the normal eye became the viewing eye (Gain– condition). This is like Fig. 4, where initially overshooting saccades (size >20°) decreased in amplitude over time. Note that the size sometimes went below 19° (a normal saccade size to a 20° target) because of the use of backward intrasaccadic target steps (see METHODS). For neurons plotted on the left-hand side, the monkey had previously been viewing with the normal eye, and data were collected after the weak eye became the viewing eye (Gain+ condition). Gain increased during adaptation in these cases. Figure 5 illustrates that for some neurons, increasing saccade sizes were associated with increasing burst lags, although there were others where lag decreased. Among these is a neuron whose ipsiversive burst began before saccade onset (burst lag <0).
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To compare data from neurons with different magnitudes and directions of adaptation on an equal basis, discharge data were normalized to +1° change in saccade size. This is equivalent to computing the slope of the relationship between burst lag and saccade size. Neurons that behave according to the hypothesis that the ipsiversive burst acts to brake or terminate the saccade would exhibit increasing lags during gain-increasing experiments and decreasing lags during gain-decreasing experiments, but the same positive slopes in both cases. Therefore slope is the most appropriate measure for testing whether changes in burst parameters are consistent with the hypotheses outlined in the INTRODUCTION. Slopes of burst lag versus saccade size (measured using data from the normal eye regardless of which eye was viewing) were estimated using linear regression through averaged data points, as in Fig. 5. Correlation coefficients ranged from 0.08 to 0.99 (absolute value, and excluding neurons with 2 data points) and averaged 0.75. We include data yielding both statistically significant and nonsignificant (low or zero) slopes because the latter (e.g., no change) is a perfectly plausible outcome of these experiments. Figure 6 illustrates the results of this analysis, and confirms the conclusions drawn from Fig. 5. Sixty-four percent (18/28) of the neurons had positive slopes, and the mean slope (1.28 ± 3.0 ms/deg, n = 28) was significantly different from zero. Figure 6 also shows that neurons responded quite differently during gain-decreasing and gain-increasing experiments. For the gain-decreasing experiments, most neurons exhibited positive slopes, and the mean slope was significantly greater than zero (Table 1). For gain-increasing experiments, slopes were more uniformly distributed about zero, and the small positive average slope was not significantly different from zero.
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If ipsilateral burst lag exerts control over saccade duration, there should be a correlation between changes in these variables as adaptation progresses. Figure 7 shows this correlation for the sample of 28 neurons. Changes in burst lag relative to that at the start of adaptation are plotted against changes in saccade duration for all time points where data were collected. The slope of this relation was 0.64 and the correlation coefficient was 0.71 (P < 0.0001, n = 76). Some scatter is expected because ipsiversive burst lag is surely not the only determinant of saccade duration. In addition, 4 atypical "untuned neurons" (squares), to be described more fully later, almost align along a slope opposite to that of the rest of the sample. Elimination of these 4 neurons and elimination of data points where burst lag did not actually change (<2 ms) improved the correlation coefficient to 0.84 (P < 0.0001, n = 50) and changed the slope somewhat to 0.80.
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Analyses like those of Figs. 5 and 6 were conducted for other ipsiversive burst parameters. For the whole sample, number of spikes, average discharge frequency, and peak discharge frequency during ipsiversive saccades did not change significantly with adaptation (Table 1). However, this was due to opposing changes in gain-increasing and gain-decreasing experiments. Number of spikes, average frequency, and peak frequency were mostly positively correlated with saccade size in the former case, and negatively correlated in the latter case. Differences between these parameters for gain-increasing and gain-decreasing conditions were all statistically significant.
Changes in burst parameters during contraversive saccades are illustrated in Fig. 8 for one neuron recorded during a gain-increasing experiment. Preadaptation saccade size (top panel) recorded from the weak eye increased from 10.4 ± 1.4 to 12.4 ± 1.2° (postadaptation, bottom panel), a highly significant change (P < 0.0001, n = 101). Associated with that increase in saccade size was a significant increase in peak burst frequency from 254 ± 42 to 277 ± 47 spikes/s (P < 0.02), and a significant increase in burst duration from 54 ± 13 to 69 ± 15 ms (P < 0.0001). The increase in burst duration was mostly produced by a later termination of the burst. Changes in burst frequency and duration collectively produced a significant increase in number of spikes from 10.5 ± 2.5 to 13.1 ± 2.4 spikes (P < 0.0001).
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This pattern of changes was reflected in the sample as a whole. Burst
frequencies, burst onset- and end times, and number of spikes were regressed
against saccade size during adaptation, and the resulting slopes were
tabulated. Figure 9A
shows the most robust finding of this study: the number of spikes in the burst
was positively correlated with saccade size in all but one neuron, and the
mean slope (0.55 ± 0.44 spikes/deg, n = 28;
Table 1) was highly
significantly different from zero. Slopes associated with gain-increasing and
gain-decreasing experiments were similar but not identical
(Table 1). As in
Fig. 8, changes in the number
of spikes were produced by changes in burst duration and discharge frequency.
Figure 9B shows that
peak discharge frequency was positively correlated with saccade size in most
(21/28) neurons, and the mean value of the slope was significantly greater
than zero (Table 1). The mean
slope for gain-increasing experiments was greater than that for
gain-decreasing experiments, but not significantly (P 
0.25).
Burst duration was also strongly and positively correlated with saccade size
for most neurons. Figure
9C shows that the end of the burst, measured graphically
or by marking individual bursts (see METHODS), was positively
correlated with saccade size for 24 of 28 neurons and had a significant
positive mean. A caveat is that this change in burst end did not fully
contribute to the change in number of spikes because burst end occurred after
the end of the saccade for about half of all bursts (the spike count was
truncated at saccade end; see METHODS). So the changes in number of
spikes can loosely be attributed to three factors: 1) changes in peak
frequency, 2) changes in burst end for those neurons with shorter
bursts, and 3) changes in saccade duration acting on those neurons
with longer bursts. Finally, a fourth factor contributing to a change in
number of spikes was a moderate change in burst lead (0.54 ms/deg), which was
about 1/4th of the change in burst end, and in the complementary direction
(increased size was associated with earlier burst onset and later burst
end).
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Can all neurons contribute to size changes?
This study seeks to determine whether changes that occur in the discharges
of FOR neurons are appropriate for causing the changes in saccade size
observed during saccade adaptation. However, it is not necessarily true that
all saccade-related neurons are candidates for this function. For instance,
Sato and Noda (1991) raised
the possibility that some neurons preferentially or exclusively control
vertical saccades by showing that some caudal fastigial neurons are
retrogradely labeled from the mesencephalic reticular formation (the site of
the vertical burst generator) and not the pontine reticular formation.
Similarly, Noda et al. (1992)
found a separation of sites in the fastigial efferent pathways of the uncinate
fasciculus where microstimulation elicited vertical rather than horizontal
saccades. We attempted to obviate this possible problem by preselecting
neurons for study. Among neurons that do project to the pontine reticular
formation, not all may serve the same function. Scudder et al.
(2000) found that only a
fraction of fastigial neurons retrogradely labeled from the EBN and from the
IBN regions were double labeled, and there was a partial separation of neurons
projecting to each area. Consequently, we searched for criteria that might
isolate neurons that are poor candidates for participation in the adaptation
of horizontal saccades.
The discharges recorded during the circle task before adaptation were analyzed for directional characteristics using the model described earlier. That is, prototypical horizontal FOR neurons have an early burst containing more spikes for contraversive saccades and a later burst with fewer spikes for ipsiversive saccades. Two neurons had their longest lead and maximum number of spikes for downward saccades, whereas their longest lag and fewest spikes occurred during upward saccades. These two were classified as vertical neurons, and two others were classified as vertical-oblique. During adaptation, the number of spikes, burst duration, and peak frequency in the contraversive burst were all positively correlated with saccade size for all 4 neurons, and the slopes were within 1SD of the mean for the full sample. Similarly, for 3 of these neurons, burst lag for ipsiversive saccades was strongly positively correlated with saccade size during adaptation, whereas one vertical neuron exhibited negative correlations. In short, these neurons behaved much like the other 24 neurons with regard to encoding saccade size during adaptation.
Analysis based on the circle task also revealed 4 neurons that had minimal or no directional tuning based on burst latency and number of spikes. In addition, these cells had very poor (nonsignificant) preadaptation correlations between ipsiversive burst lag and saccade size or saccade duration; and finally, ipsiversive burst lag itself was close to zero or negative (the burst actually led saccade onset). These neurons would not appear to be good candidates for controlling saccade size according to the hypotheses stated in the INTRODUCTION, and in fact they were not. During adaptation, 2 of the neurons exhibited very small or negative correlations between number of spikes and contraversive saccade size, and 3 exhibited negative correlations between ipsiversive burst lag and ipsiversive saccade size. This latter point is illustrated in Fig. 10, which also illustrates the more general point that the best predictor of the change in ipsiversive burst lag during adaptation ("Lag Sensitivity") was the absolute burst lag that was recorded at the initiation of adaptation. These variables were related with a correlation coefficient of 0.57, which is significant at P < 0.005. Other variables were not significantly correlated with change in burst lag during adaptation. In fact, the preadaptation slope of the correlation between ipsiversive burst lag and saccade size was a poor predictor of the preadaptation slope (r = 0.19; P > 0.3).
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Elimination of the 4 untuned neurons from the sample averages produced minor (<10%) changes for most variables. However, the sensitivity of ipsiversive burst lag to saccade size increased 38% to 1.77 ms/deg. Sensitivity increased for both the gain-decreasing and the gain-increasing experiments, so that the mean for the latter approached significance (P = 0.10). The other significant change was a 44% reduction (to 1.88 spikes s–1 deg–1) in the sensitivity of contraversive peak discharge frequency to saccade size during gain-decreasing experiments. For gain-increasing experiments, sensitivity of peak frequency increased moderately (9%), so that the difference between gain-increasing and gain-decreasing experiments approached significance (P = 0.07). Elimination of the 4 vertical and oblique neurons produced little additional change in the average sensitivity of discharge parameters to adaptation of saccade size.
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DISCUSSION |
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An asymmetry in the mechanisms mediating gain increases and decreases is
consistent with the properties of synaptic plasticity. In the cerebellum, for
instance, where plasticity exists throughout the sequence of synapses from the
mossy fibers to the deep cerebellar nuclei
(Aizenman et al. 1998;
Armano et al. 2000;
Crepel and Jaillard 1991;
D'Angelo et al. 1999;
Hansel et al. 2001.
Morishita and Sastry 1996;
Ouardouz and Sastry 2000;
Salin et al. 1996), long-term
potentiation and long-term depression do not always coexist at the same
synapses or are more readily induced at some synapses than others. Long-term
potentiation and depression at the same synapse often occur at different rates
and are produced by distinctly different stimuli. Consequently, it is possible
that the changes in one set of synapses that mediate gain increases are not as
readily reversed, allowing a different set of synapses with more auspicious
properties to initially mediate the gain decreases.
Given the dichotomy in neuronal changes during gain-increasing versus gain-decreasing experiments, we had expected to see a dichotomy in the eye movement responses, with larger changes in saccade peak velocity and smaller changes in duration for gain increases compared with gain decreases. However, no significant differences were observed. A partial explanation might be found in the change in saccade waveshape, whereby the increase in velocity found during gain-increasing experiments occurred in the epoch after peak velocity. A second explanation is that changes in peak frequency probably also affect saccade duration using mechanisms that are described later.
Apparently, not all FOR neurons participate in the modification of saccade
size. The untuned neurons, whose bursts resembled the contraversive burst of
other neurons in all directions, were poor candidates for controlling saccade
size according to the mechanisms summarized in the INTRODUCTION and
described more fully later. In some ways, they behaved oppositely to the other
neurons during adaptation. On the other hand, one vertical and two oblique
neurons, which at first might seem to be poor candidates for controlling the
size of horizontal saccades, did participate in saccade adaptation. The
paradox can be resolved by noting that there are not discrete populations of
horizontal and vertical FOR neurons, but rather a continuum of best directions
(Fuchs et al. 1993;
Ohtsuka and Noda 1991a).
Consequently, many of the FOR neurons with off-vertical preferences might
nonetheless project to the horizontal burst neurons in the pons in addition to
projecting to vertical burst neurons in the mesencephalon. Such neurons could
have adaptively altered discharges during horizontal saccades and not have
altered discharges during vertical saccades because there can be separately
adapted horizontal and vertical inputs from the cerebellar cortex
(Deubel 1987;
Noda and Fujikado 1987).
In the remaining discussion, we consider the question of whether the changes in neuronal firing we observed during adaptation might cause the changes in saccade size. The question has two parts: 1) are there plastic changes occurring in the cerebellum that produce the changes in FOR-neuron firing, or do the cerebellar signals change as a byproduct of plastic changes occurring in structures that provide input to the cerebellum, and 2) are the changes in FOR-neuron discharges appropriate and sufficient to produce changes in saccade size.
The location of plastic synapses
To address the first question, we begin by considering the possible sites
that both provide input to the cerebellum and might undergo plastic changes.
Figure 11 shows a simplified
block diagram of the saccadic system that is based on known connections. We
have ignored cortical inputs from the frontal eye fields and parietal cortex,
which principally impinge on the superior colliculus and project more weakly
to the brain stem (Leichnetz and
Gonzalo-Ruiz 1987; Lynch et
al. 1985; Stanton et al.
1988). The superior colliculus is therefore regarded as a nodal
point for collecting inputs from the cortex and basal ganglia and, in turn,
issues the immediate saccadic command to the brain-stem saccadic burst
generator. The superior colliculus also projects heavily to the cerebellum by
way of nucleus reticularis tegmenti pontis (NRTP) and parts of the pontine
nuclei in both cats and monkeys (Batini et
al. 1978; Gerrits and Voogd
1987; Gonzalo-Ruiz and
Leichnetz 1990; Graham
1977; Harting
1977; Huerta and Harting
1982; Kawamura 1974; Scudder et al. 1996a;
Thielert and Thier 1993). The
neurons of the saccadic burst generator (EBNs, IBNs, and OPNs) do not project
to the cerebellum (Strassman et al.
1986a,b),
and their signals may reach the cerebellum indirectly only through the smaller
pathways originating in the pontine reticular formation and in raphe pontis
(Fig. 11, thin lines).
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This circuitry makes it unlikely that any plastic changes occurring in the
brain-stem burst generator make substantial contributions to the changes we
recorded in the FOR. Thielert and Thier
(1993) estimated that
afferents from the medial pontine reticular formation constitute only 5% of
the afferents to vermal lobule VII and VIc. In short, the feed-forward
pathways from the superior colliculus to the cerebellum are substantial,
whereas the feedback pathways from the brain-stem burst generator are
currently speculative and at best, considerably weaker. The small size of this
putative feedback pathway makes it difficult to explain how plasticity in the
burst generator could produce substantial changes in the discharge of FOR
neurons assuming it is combined with a much larger signal that is unchanged
during the adaptation paradigm. A case in point is ipsiversive burst lag,
which changed in excess of the changes in saccade duration during the
gain-decreasing experiments (3.2 vs. 2.9 ms/deg;
Table 1). Because OPN pause and
EBN and IBN burst durations covary one-to-one with saccade duration (cf.
Fuchs et al. 1985), it is hard
to see how weak feedback from these neurons could cause even an equal change
in burst lag, much less a greater change.
The strong inputs from the superior colliculus to the cerebellum by NRTP
suggest that plastic changes occurring in the colliculus could result in
changes in the discharge of cerebellar neurons, should such plastic changes
actually occur. However, Frens and van Opstal
(1997) found no evidence of
plastic changes occurring in the colliculus during short-term adaptation of
saccade size. These authors measured the discharge of neurons in the superior
colliculus before and after adaptation produced by backward intrasaccadic
steps of the target. For target steps of a constant size, the discharges of
these neurons did not change as saccade size decreased, even though in a
control experiment, they discharged less when monkeys made equivalently
smaller saccades to target steps of a smaller size.
Complementing the evidence that the altered discharges are not reflections
of plastic changes occurring in the brain stem or superior colliculus, there
is evidence that they could be the result of plastic changes occurring in the
cerebellum. Reiterating the point made in the INTRODUCTION, lesions
of the cerebellum produce enduring saccadic dysmetria (Aschoff and Cohen
1971,
1972;
Optican and Robinson 1980;
Ritchie 1976; Selhorst et al.
1976a,b;
Takagi et al. 1998). If there
were plastic mechanisms elsewhere in the brain, one would expect these
mechanisms to correct the dysmetria created by cerebellar lesions (unless
these mechanisms were completely dependent on signals from the cerebellum).
Note that the adaptation that we produced in a matter of hours could change
saccade size by a factor of almost 2, and that this ratio is comparable to the
short-term dysmetria produced by chemical inactivation of the fastigial nuclei
(Robinson et al. 1993). Hence,
it is difficult to argue that cerebellar lesions produce a dysmetria so
profound that it exceeds the capacity of extracerebellar plasticity to
compensate. A direct test of the capacity of cerebellar-lesioned animals to
adapt saccade size was made by Takagi et al.
(1998) and Barash et al.
(1999). Monkeys with bilateral
lesions of the posterior vermis, including lobule VII, tracked a target that
stepped backward intrasaccadically. Unlike in normal monkeys, this paradigm
did not produce decreases in saccade size. After a number of months, monkeys
did recover limited adaptive capabilities, but it seems clear that these
capabilities are different from those present in cerebellar-intact
animals.
Finally, another reason for believing that the plastic synapses mediating adaptation are located in the cerebellum is the extensive demonstration of cerebellar plasticity, as previously described. The wealth of plastic synapses makes it plausible that different sets of synapses mediate gain increases and gain decreases, thereby offering a ready explanation for our findings that differing neuronal changes are observed in each case.
How the observed cerebellar changes might affect saccade size
Figure 12A is a
simplified illustration of the probable projections of FOR neurons to
saccade-related neurons in the reticular formation. The crossed projection to
burst neurons (BN) includes both EBNs and IBNs. Moreover, there is a direct
crossed projection to OPNs. These projections have been strongly suspected on
anatomical grounds (Noda et al.
1990; Scudder et al.
2000) and have been confirmed electrophysiologically
(Scudder et al. 2000). In the
latter study, the FOR was activated by low-rate microstimulation, and its
effects on functionally identified neurons in the brain stem were measured
using poststimulus-time histograms. The vast majority of EBNs and IBNs were
directly excited at latencies of 1.3–2.2 ms, and a minority of OPNs were
similarly excited. These results are in accord with other anatomical and
physiological data showing that all, or nearly all, cerebellar nuclear
projections to the pons express excitatory neurotransmitters or are
excitatory, respectively (Angaut and Sotello 1989;
Kitai et al. 1976;
Schwarz and Schmitz 1997;
Verveer et al. 1997). Finally,
we hypothesize, as have others (Fuchs et
al. 1993), that there is also an indirect inhibitory projection
from the FOR to the OPNs. We envision that the excitatory pathway from FOR
neurons to OPNs is effective during ipsiversive saccades, and the inhibitory
pathway is effective during contraversive saccades. One way this could be
achieved is if the inhibitory pathway were the stronger, but was gated so that
it conveyed FOR signals only during saccades in one direction. Such gating
might be achieved if the interneuron in the fastigial-to-OPN pathway received
crossed inhibition (e.g., from IBNs) and/or excitation from (postdecussation)
superior-colliculus efferents on the same side (not illustrated).
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This circuitry is adequate to explain how the changes in FOR discharges observed in the present study could modify saccade size. First, we found that increased saccade size was associated with increased number of spikes in FOR neurons during contraversive saccades. Conversely, decreased saccade size was associated with a decreased number of spikes (positive slopes, Fig. 9A). Referring to Fig. 12A, increasing the number of spikes would directly increase the number of spikes in the on-direction bursts of EBNs and IBNs, thereby increasing the activity of agonist motoneurons and decreasing the activity of antagonist motoneurons. This would in turn increase saccade size, which is consistent with our data. A decreased number of spikes in FOR neurons would decrease EBN and IBN discharges, and decrease saccade size.
Second, we found that decreasing saccade size was associated with an earlier burst of FOR neurons during ipsiversive saccades. This earlier burst should advance the excitatory input from the FOR nucleus to EBNs and IBNs and increase the number of spikes in their off-direction discharges. The antagonist motoneurons would be excited earlier (by the EBNs), and the agonist motoneurons would be inhibited earlier (by the IBNs). Both effects would contribute to decreases in saccade size. Augmenting this effect was an increase in FOR-neuron peak frequency (Table 1; negative slope = frequency increase/size decrease). Antagonist and agonist motoneurons were not only excited or inhibited earlier, respectively, but they were excited or inhibited more. Again, this should help decrease saccade size. Curiously, the opposite changes were not seen during gain-increasing experiments. Ipsilateral burst lag in FOR neurons increased minimally, and peak frequency increased. The latter change would be expected to increase antagonist and decrease agonist activity, the opposite of that needed to increase saccade size. Evidently, ipsiversive burst lag is more susceptible to decreases than to increases, which may have a parallel in the nonreciprocal relationship between synaptic long-term potentiation and long-term depression as noted earlier.
In addition to controlling the firing rates of agonist and antagonist motoneurons, saccade size can be controlled by controlling discharge durations. Because EBN and IBN burst durations are regulated by the duration of the pause in OPN discharges, a powerful mechanism for controlling saccade size is to control OPN pause duration. There are both direct and indirect FOR connections that could help accomplish this.
The direct projection from the FOR to the OPNs
(Fig. 12A) conveys an
excitatory signal to the OPNs toward the end of ipsiversive saccades, which
could assist the resumption of firing in OPNs and help terminate the saccade.
Earlier bursts in FOR neurons should produce shorter OPN pauses and in turn
shorter duration and smaller amplitude saccades. As noted above, this is
consistent with our data. However, as also noted, the lack of changes in
ipsiversive burst lag during gain increases means that this mechanism was not
used in the latter case. An additional caveat is that electrophysiological
data show that this pathway is weak
(Scudder et al. 2000),
implying that the power of this mechanism for changing saccade size is also
weak.
Robinson and Fuchs (2001)
questioned whether onset time of the ipsiversive burst has sufficient
precision to serve as a mechanism for the control of saccade duration under
any circumstances. Although onset variability was somewhat high (9 ms for a
given duration), the summed discharge of all FOR neurons would be expected to
be much less variable. If there are 250 independent neurons in the FOR of
macaques (Sato and Noda 1991),
the standard error of the mean onset time would be only 0.6 ms. Moreover, the
argument presumes that the variability is pure noise. If the FOR is part of a
feedback network that acts to reduce errors produced elsewhere in the saccadic
system (cf. Scudder et al.
2002), some of the seeming variability is actually a signal that
increases the precision of saccades. In short, we believe the true error of
the aggregate ipsiversive burst onset is <0.6 ms, which is surely precise
enough to produce accurate saccades.
In the opposite direction (i.e., during contraversive saccades), the direct
excitation of OPNs by the early FOR discharge is undesirable. However, as
stated previously, we hypothesize that the direct excitation of OPNs is
overwhelmed by inhibition by an interneuron
(Fig. 12A). The
indirect inhibition of OPNs during contraversive saccades could potentially
affect OPN pause duration by affecting its onset and/or termination. The
finding that contraversive burst lead is positively correlated with saccade
size during adaptation is consistent with the idea that earlier FOR discharges
help produce earlier, and therefore longer OPN pauses. However, this mechanism
is apparently not consistently used, as shown by the fact that FOR burst onset
lagged contraversive saccade onset on average in one monkey, and considerably
lagged saccade onset during large head-free gaze shifts
(Brettler and Fuchs 2001).
Control of the resumption of OPN firing by the termination of the FOR burst,
on the other hand, is a potentially powerful mechanism that is consistent with
our data. That is, the end of the contraversive burst was positively
correlated with saccade size during adaptation for most neurons
(Fig. 9C) for both
gain increases and gain decreases.
There is yet a third mechanism by which FOR discharges might affect the
duration of OPN pauses and thereby saccade size. This is illustrated in
Fig. 12B, and hinges
on the existence of a "latch" neuron. Although proof of such a
neuron is lacking, it has long been suggested that there must be an inhibitory
neuron that prevents the OPNs from firing for the duration that EBNs and IBNs
are firing (cf. Fuchs et al.
1985; Robinson
1975; Scudder et al.
2002). This neuron is drawn as being different from the inhibitory
interneuron that receives FOR input, but this need not be so. The putative
latch neuron receives excitatory input from ipsilateral EBNs that is declining
toward the end of ipsiversive (on-direction) saccades, and also possibly
inhibitory input from contralateral IBNs, which is increasing. Firing of the
latch neuron, which is the difference between the EBN and IBN firing rates,
eventually declines to a level at which it is no longer able to inhibit firing
in the OPNs. Consequently, control of the EBN and IBN firing rates by FOR
neurons, as described above, also serve to control OPN pause duration. In the
current data, we found increased peak firing rate and increased duration of
the contraversive FOR burst in association with larger saccades during
adaptation. The increased FOR discharge should produce a stronger and longer
excitation of the latch neuron by the EBNs. This should, in turn, produce
longer and larger saccades, which agrees with what we found. Decreased FOR
firing rate and burst duration should be, and was, associated with smaller
saccades.
Similarly, an earlier and larger ipsiversive FOR burst was associated with smaller saccades, consistent with a putative earlier and stronger inhibition of the latch neuron by the IBNs. A later and smaller ipsiversive burst should have been associated with larger saccades, but this was not observed in our data, as noted previously.
Finally, the caudal fastigial nucleus also projects to the superior
colliculus, as noted in the INTRODUCTION. The specific collicular
neurons contacted by fastigial efferents are currently too uncertain to
advocate specific mechanisms for the control of saccade size, but we note that
powerful mechanisms may exist (cf. Scudder
et al. 2002). These mechanisms could prove to be as important as
those just discussed.
Quantitative assessment of FOR efficacy in the control of saccade size
Most of the observed changes in FOR discharge parameters are qualitatively
consistent with the proposed mechanisms by which FOR neurons might control
saccade size, but are not necessarily sufficient to cause the observed changes
in size. A rudimentary way to address this issue is to compare the number of
spikes in the FOR and EBN discharges during contraversive saccades. This
metric is relevant because there is a direct contribution of the FOR discharge
to the EBN and IBN discharges, as discussed above, and because EBN and IBN
number of spikes are directly proportional to saccade size. The relation
between EBN number-of-spikes and saccade size has a slope of around 1.3
spikes/deg (cf. Scudder 1988),
and the same relation between FOR discharges and saccade size has a slope of
0.55 spikes/deg (Table 1). To
properly compare these numbers, a correction must be made for the fact that
FOR peak firing rate is about 30% of the EBN peak rate (229/s vs.
750/s).1 For instance,
if the FOR provided all the input to EBNs, there would have to be a 3.3-fold
amplification of FOR discharge rate, possibly achieved by heavy convergence,
powerful synapses, or high EBN sensitivity to membrane depolarization. The
adjusted FOR sensitivity would be 1.8 spikes/deg. This example is, of course,
exaggerated because we know that EBNs also receive input from the superior
colliculus and long-lead burst neurons (reviewed by
Scudder et al. 2002). A more
reasonable estimation based on the finding that unilateral chemical
inactivation of FOR can cause up to a 50% dysmetria
(Robinson et al. 1993; C. A.
Scudder, unpublished observations) would be that the FOR provides 40% of the
input to EBNs. Therefore the FOR contribution to EBN firing would be 0.72
spikes/deg, which is less than the 1.3 spikes/deg needed to cause the observed
changes in saccade size. It does, however, exceed a lower estimate of EBN
discharge-size sensitivity (0.65 spikes/deg; computed from Table 2 in
van Gisbergen et al.
1981).
The above calculation partially excludes the effect of the putative control
of saccade duration by the FOR. To estimate the effect of this control on
saccade size based on an evaluation of each of the three mechanisms described
above would require many assumptions and modeling, which is beyond the scope
of this investigation. Rather, we presuppose that the FOR can control EBN and
IBN burst durations, and we ask what effect such changes have on saccade size.
We are interested in only that component of the EBN firing contributed by
noncerebellar inputs because the contribution of the FOR was taken into
account above. By definition, these noncerebellar inputs contribute the
remainder of the input to EBNs and IBNs; that is, 100%–40% = 60%. Using
the measurement of van Gisbergen et al.
(1981) that EBN firing rate is
about 500/s just before the end of the saccade, the FOR control of burst
duration accounts for 2.1 ms/deg x 60% x 500 spikes/s = 0.63
spikes/deg. When added to the direct contribution of FOR firing calculated
above (0.72 + 0.63 = 1.35 spikes/deg), the FOR appears to have adequate power
to control saccade size.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 The value of 229/s was obtained from the current data and represents the
mean peak frequency during 23° saccades for all 28 neurons; 750/s was
obtained from van Gisbergen et al.
(1981) for monkey EBNs during
20° saccades. 
Address for reprint requests: C. A. Scudder, 5716 SW Hamilton St., Portland, OR 97221 (E-mail: scudder{at}pitt.edu).
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