Department of Medical Physics and Biophysics, University of Nijmegen, 6500 HB Nijmegen, The Netherlands
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ABSTRACT |
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Chaturvedi, Vivek and Jan A. M. van Gisbergen. Perturbation of combined saccade-vergence movements by microstimulation in monkey superior colliculus. This study investigated the role of the monkey superior colliculus (SC) in the control of visually (V)-guided combined saccade-vergence movements by assessing the perturbing effects of microstimulation. We elicited an electrical saccade (E) by stimulation (in 20% of trials) in the SC while the monkey was preparing a V-guided movement to a near target. The target was aligned such that E- and V-induced saccades had similar amplitudes but different directions and such that V-induced saccades had a significant vergence component (saccades to a near target). The onset of the E-stimulus was varied from immediately after V-target onset to after V-saccade onset. E-control trials, where stimulation was applied during fixation of a V-target, yielded the expected saccade but no vergence. By contrast, early perturbation trials, where the E-stimulus was applied soon after the onset of the V-target, caused an E-triggered response with a clear vergence component toward the V-target. Midflight perturbation, timed to occur just after the monkey initiated the movement toward the target, markedly curtailed the ongoing vergence component during the saccade. Examination of pooled responses from both types of perturbation trials showed weighted-averaging effects between E- and V-stimuli in both saccade and fast vergence components. Both components exhibited a progression from E- to V-dominance as the E-stimulus was delayed further. This study shows that artificial intervention in the SC, while a three-dimensional (3D) refixation is being prepared or is ongoing, can affect the timing (WHEN) and the metric specification (WHERE) of both saccades and vergence. To explain this we interpret the absence of overt vergence in the E-controls as being caused by a zero-vergence change command rather than reflecting the mere absence of a collicular vergence signal. In the perturbation trials, the E-evoked zero-vergence signal competes with the V-initiated saccade-vergence signal, thereby giving rise to a compromised 3D response. This effect would be expected if the population of movement cells at each SC site is tuned in 3D, combining the well-known topographical code for direction and amplitude with a nontopographical depth representation. On E-stimulation, the local population would yield a net saccade signal caused by the topography, but the cells coding for different depths would be excited equally, causing the vergence change to be zero.
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INTRODUCTION |
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This study was designed to investigate the
involvement of the monkey superior colliculus (SC) in binocular
refixations to targets in three-dimensional (3D) visual (V)-space
requiring combined saccade-vergence responses. It is well known from
previous electrophysiological studies that the SC is involved in the
control of saccades (for review see Sparks and Mays
1980; Wurtz 1996
) through its connections with
saccadic burst cells (see Munoz and Wurtz 1995
;
Sparks 1978
) and its association with the omnipause
neurons (OPNs) in the brain stem (Buttner-Ennever and Horn
1994
; Gandhi and Keller 1997
;
Raybourn and Keller 1977
). In contrast relatively little
is known about the neuronal circuitry controlling vergence movements at
the premotor and higher levels. This has made it rather difficult to
understand the neural mechanisms controlling eye movements that are
composed of both directional and depth components. An early suggestion by Yarbus (1967)
was that the saccadic and vergence systems function rather independently of each other. Investigators long had the tendency
to study each oculomotor subsystem in isolation from the other and the
finding that saccade and vergence responses have strongly contrasting
dynamics lent some credibility to the Yarbus concept. Early modeling
studies (for overview see Collewijn et al. 1995
), by
emphasizing these distinctions, helped reinforce the conviction that
the two systems are quite different in nature. It is commonly accepted
that the saccadic system (classically defined as the system that causes
the eyes to move equally in the same direction to fixate a target of
interest in the frontal plane) does not process its inputs
continuously. The saccadic system is normally suppressed by tonic pause
cell activity that must be inhibited before a saccade can be made
(gating). Saccadic eye movements are much too fast to allow sensory
feedback during the movement. In contrast to this intermittent
behavior, however, the vergence system (which moves the eyes in
opposite directions in the horizontal plane to maintain binocular
alignment when gaze is shifted between targets at different distances)
was often portrayed as a continuous system relying on V-feedback.
As a sign that insights are changing a more recent suggestion regarding
the control of 3D gaze shifts proposed that saccades and fast vergence
have a shared gating system for movement initiation (Mays and
Gamlin 1995, 1996
; Zee et al. 1992
). Common
gating would be reflected in a strong temporal (WHEN)
coupling between the latencies of saccade and fast vergence responses.
The finding that pure vergence movements can be slowed down by
electrical (E)-stimulation in the OPN region suggests that pause
neurons can indeed affect the vergence system, directly or indirectly (Mays and Gamlin 1996
). These studies suggest that there
is a greater degree of interaction between the two subsystems than was
previously perceived.
Arguing further against thinking in terms of independent subsystems, it
has been shown that binocular refixations, made up of combined
version-vergence eye movements, are not simply linear summations of the
required components executed in isolation (Collewijn et al.
1995, 1997
; Enright 1984
, 1986
; Erkelens
et al. 1989
; Maxwell and King 1992
;
Oohira 1993
). The vergence component, when combined with
a saccade, is substantially faster than a normal pure vergence response, which implies that sensory feedback would be unlikely in this
case. A recent study provided strong evidence for a shared saccade-vergence target selection system, where the metrics
(WHERE) of the saccadic and vergence components of planned
movements are jointly determined (Chaturvedi and Van Gisbergen
1998
). In line with this idea, this study explores to what
extent the SC, generally held to be a saccadic control center, may also
be involved in the control of vergence movements.
Possible role of SC in neural control of vergence eye movements
For the sake of clarity, three different possible scenarios (see Fig. 1) regarding the involvement of the SC in vergence control will now be developed. One extreme point of view (the "noninvolvement" hypothesis), shown in Fig. 1A, entertains the view that saccades and vergence are implemented by entirely separate control systems. This implies dedicated WHERE and WHEN mechanisms for each distinct oculomotor subsystem. Because the SC is obviously heavily involved in saccadic control, simple logic implies that this view precludes its involvement in vergence movements. Any artificial intervention in the colliculus would only affect the conjugate response and have no vergence effect whatsoever.
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An alternative idea (the "indirect involvement" hypothesis), shown
in Fig. 1B, is that saccades and vergence have a shared WHEN system (Mays and Gamlin 1995, 1996
;
Zee et al. 1992
). As for the dedicated WHERE
system, the scenario of indirect involvement entails that the SC
specifies only the metric of saccadic eye movements, leaving
vergence-dedicated WHERE control to some other neural
center (Judge and Cumming 1986
; Mays
1984
; Mays et al. 1986
). The postulated
WHEN coupling in both systems may be implemented through
gating by omnipause cells further downstream. Accordingly, the indirect
involvement hypothesis implies that collicular microstimulation may
indirectly have an effect on vergence initiation but not on its metrics.
A third possibility to be considered (the "direct involvement"
hypothesis) is that the SC is involved in the WHEN and
WHERE mechanisms of both saccade and vergence subsystems
(see Fig. 1C). A number of electrophysiological studies
(Bacon et al. 1998; Billitz and Mays
1997
; Dias et al. 1991
; Gnadt and Beyer
1998
; Jiang et al. 1996
; Mays
1996
) proposed that the SC may indeed have some involvement
with eye movements in depth. If this view is correct, stimulating in
the SC in principle should affect not only the onset of saccade and
vergence responses but also bias their metrics.
It occurred to us that a suitable and effective way of testing the 3D colliculus hypothesis would be to intervene artificially in the SC by E-stimulation. We carried out microstimulation perturbation experiments in the caudal SC with the intention of studying the initiation (WHEN) and metric-specification (WHERE) mechanisms of 3D eye movements. Before we explain the logic behind this approach, we briefly review earlier SC stimulation studies.
Earlier E-stimulation studies in SC
Neurons in the deeper layers of the caudal SC burst for saccadic
eye movements in a limited range of directions and amplitude (Sparks and Mays 1980; Sparks et al.
1976
; Wurtz and Goldberg 1972
). High-frequency
stimulation at caudal collicular sites elicits short-latency
fixed-vector saccades (Schiller and Stryker 1972
; Robinson 1972
) by recruiting the brain stem
burst neurons that are normally kept silent by omnipause cell
inhibition (Raybourn and Keller 1977
). Glimcher and
Sparks (1993)
have shown that low-frequency E-stimulation in the caudal
region of the monkey SC, before the initiation of a V-guided saccade,
can influence the metrics (direction and amplitude) of the ensuing
target-directed response. They suggest, in agreement with results from
previous studies (Becker and Jurgens 1979
;
Glimcher and Sparks 1992
; Sparks and Mays
1983
), that signals specifying the metrics of saccades develop
gradually after target presentation. Sparks and Mays (1983)
used
high-frequency stimulation in caudal collicular sites to elicit an
E-induced saccade before an impending V-guided saccade and found that
the metrics of the E-saccade could be altered by target location. The
degree to which the saccade was dominated by the E- or the V-stimulus
depended on the time interval between target onset and stimulation
onset. They suggested that stimulation of the SC caused the V-induced motor error signal, which was being specified at the time, to be expressed.
Possible outcomes of combined EV-stimulation
To explore the three hypotheses outlined previously (see Fig. 1) we applied a similar paradigm in a 3D V-task to see if the V-specified vergence signal that is presumably building up would manifest itself in the E-triggered response in a similar way to the saccadic signal described previously. In our experiments we perturbed the system by applying E-stimulation at a time when the monkey was preparing or just initiated a 3D refixation to a newly presented target. Our goal was to see whether any effects on the vergence component along with the expected change in the saccade response could be demonstrated.
On the basis of results found previously in the frontal plane
(Sparks and Mays 1983), the saccadic vector can be
expected to exhibit a gradual change in its metrics from purely E- to
more V-dominated when the E-stimulus is applied later and later in the
trial. However, one would still expect an E-effect in late-stimulation trials where the monkey just initiated the V-guided response itself so
that V-dominance will not reach the 100% level (Schlag-Rey et
al. 1989
). In other words, the expected effect of the
perturbation on the saccadic system involves both a WHEN
and WHERE aspect; saccadic responses can be triggered
prematurely, and even when they are not (in the case of self-initiated
movements) their metrical properties are affected by the E-stimulus. In
the case of vergence, predictions are different for each model. First,
if one takes the view that the SC is a saccade-related area
(noninvolvement), one would not expect any vergence component as a
result of premature stimulation. Alternatively, the indirect
involvement hypothesis, which rests on the assumption of common gating,
suggests the possibility that a premature E-triggered vergence response
toward the V-stimulus may emerge. Finally, if the SC is involved in the
control of the WHEN and WHERE systems of both
saccades and vergence (hypothesis 3), one would expect not only a
vergence response resulting from premature stimulation but also when
E-stimulation is applied to ongoing self-initiated movements.
This study illustrates the actual effect of the combined E- and V-stimulation on the initiation and metric specification of binocular refixations. The results show that the WHEN and WHERE control, for both saccadic and vergence systems, is closely related and can be manipulated by artificial intervention in a stereotyped fashion.
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METHODS |
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Animal preparation and neurophysiological procedures
SUBJECTS. The experiments were performed in two adult male rhesus monkeys (monkeys I and II), weighing 8-9 kg, that were trained to accurately fixate and follow V-targets presented in 3D V-space. The animals were water deprived and received a liquid reward after each correct trial. All surgical and experimental procedures were approved by the university committee for the use of experimental animals.
To prepare the animals for chronical neurophysiological experiments, three separate sterile surgical procedures were performed. We first fitted a solid cement cap to the skull to allow rigid fixation of the head of the monkey during experiments (for details, see Melis and Van Gisbergen 1996RECORDING OF NEURONAL ACTIVITY.
Extracellular activity in the SC was recorded with glass-coated
tungsten microelectrodes (impedance 0.5-1.2 M) inside a transdural guide tube. After amplification and filtering the electrode signal was
fed into a level detector for spike detection.
Experimental procedures and setup
BINOCULAR EYE POSITION RECORDING AND CALIBRATION.
Two-dimensional (2D) binocular eye positions were recorded with the
double magnetic induction technique (Bour et al. 1984). Two alternating perpendicular magnetic fields (horizontal: 30 kHz;
vertical: 50 kHz) induced eye position-dependent currents in the
implanted eye rings, which in turn induced secondary currents in
sensitive pickup coils that were mounted directly in front of each eye
(interocular distance: 3.5 cm). A nulling coil, placed some distance
away from each eye on a rigid manipulator, electronically canceled the
primary (eye position independent) signal component induced by the
magnetic fields. After amplification and demodulation by lock-in
amplifiers (PAR 128A), the raw horizontal and vertical eye position
signals were low-pass filtered (
3 dB at 200 Hz; 4th-order Bessel
filter), sampled with 12-bit resolution at 500 Hz per channel, and
stored for off-line analysis (details are described subsequently). The
resolution of the recording technique was ~0.2° for eccentricities
up to 25°. Careful inspection revealed that cross talk between the
signals from the two eyes was negligible (<1° error for large
horizontal angles) for our purposes. This was confirmed by other
investigators who were using the same technique in cat studies
(Malpeli 1998
).
STIMULUS PRESENTATION AND DATA ACQUISITION. Experiments were performed while the monkey sat, head fixed, in a primate chair. Light emitting diodes (LEDs; diameter 5 mm), positioned on a large circular board at a distance of 125 cm from the monkey, were used as V-targets to guide eye movements. The central LED was aligned with the cyclopean eye of the monkey. A number of LEDs were positioned on an adjustable perspex rod, roughly at eye level and closer to the monkey, thereby enabling the presentation of V-targets at various locations in the depth plane. Target presentation and stimulus timing were controlled by a PC. All experimental paradigms required the monkey to fixate a V-target before other targets were presented. For each trial, data recording always started 300 ms before the offset of this initial fixation point (FP) and continued for 2 s.
Perturbation paradigm
The objective of the perturbation paradigm was to elicit a saccade by E-microstimulation in the caudal region of the SC while the monkey was preparing a saccade to a V-target. The paradigm exploited the fact that, when a combination of E-stimulation and V-evoked activity occurs at different sites in the collicular map, the system may generate a saccade whose timing is related to E-stimulation onset, whereas its metrics may also reflect a V-guided influence, depending on relative timing of the E- and the V-stimulus. We tested whether 3D refixations were similarly affected, especially with regard to vergence metrics. To gauge the relative effects of the two stimuli in various temporal combinations, we recorded two control responses, i.e., an E-elicited eye movement (see Fig. 2A) and a purely V-evoked eye movement (see Fig. 2B). To determine the compromising character of the saccadic response in the forthcoming experimental paradigm we ensured that these controls clearly differed from each other in direction. The location of the FP was chosen freely in 3D space in these experiments, but once chosen it remained unchanged throughout the session.
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To record the E-induced binocular eye movement (E-control), an
E-stimulation pulse train was applied in the deep layers of the caudal
SC while the monkey was fixating an LED. The FP was extinguished on
stimulation, and after the E-saccade the monkey was rewarded. The pulse
train (duration 50 ms; frequency 500 Hz) consisted of constant current
biphasic pulses (BAK, Model BPG-1) with a duration of 0.2 ms.
Initially, the threshold value for evoking saccades was determined by
finding the current intensity where 90% of all stimulations led to a
saccadic response. Experiments were then conducted with a
suprathreshold current level of up to twice this value (between 20 and
70 µA) such that most saccades had a fixed amplitude. The E-control
paradigm was repeated at the end of the experiment.
To obtain the purely V-guided control response, the monkey first had to fixate the FP. Directly after FP offset, a V-target was presented at one of a number of selected positions in 3D space, and the monkey made a V-guided binocular refixation (V-control) to the target. Care was taken to position the V-targets with respect to the fixation plane in either a far plane (requiring diverging eye movements) or a near plane (requiring convergence responses) such that there was a clear 3D directional difference between the E- and the V-response in both direction (Fig. 3A) and depth (Fig. 3B). An attempt was made to align both near and far targets such that refixations from the FP to these target LEDs required V-responses with saccades of roughly the same direction and amplitude. After choosing the target positions, a third set of experiments was started where fixation and depth-plane (both near and far) targets were randomly interleaved and where 30% of the trials required refixations with a vergence component.
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To explore the effect of combined E- and V-stimulation (see Fig.
2C), in some of these 3D trials (20%), denoted as
EV-trials, a stimulation pulse train was applied at various short
delays () after the presentation of the V-target to induce a
premature binocular eye movement. The onset time of the stimulation
pulse train was varied from immediately after target onset to after V-saccade onset. E-triggered EV-responses were usually followed by a
later V-guided response to the V-target, which corrected for the
E-perturbation. E-stimulation generally only occurred when either the
near or far target was presented. To minimize the possibility of
predictive behavior during the V-guided refixations, a number of
V-catch trials (where the FP was extinguished and no target was
presented), stimulation catch trials (where no target was presented and
stimulation was applied at FP offset), and eccentric targets, located
along the four perpendicular axes in the far plane, were incorporated
in each experimental session and presented at random times. The monkey
was only rewarded at the end of the trial if correct fixation of the
presented target was achieved. The monkey was rewarded in the catch
trials and in the control E-trials if the fixation target was correctly
attended to. Whenever the monkey did not fulfill a requirement set in
our paradigm, the FP or target disappeared immediately and no reward
was given. All experiments were done under dim lighting conditions.
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RESULTS |
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E- and V-control responses
The perturbation experiments in this study were designed to
investigate the involvement of the monkey SC in binocular refixations to targets in 3D V-space requiring combined saccade-vergence responses. The basic idea was to evaluate the effect of E-stimulation at one SC
site on the 3D eye movement elicited by the V-target at another
location in the SC map. As described previously (see Fig. 3) the E- and
V-controls differed from each other in direction and depth, similar to
the examples from a typical site shown in Fig.
4. The two panels on the left show both
control responses projected together in the frontal and depth planes,
respectively, whereas the three right-hand panels illustrate their
corresponding time-courses. We aligned the LED target (tgt) in 3D space
such that there was a clearly discernible difference in the vertical component of the two controls, keeping the magnitude of their horizontal components roughly similar. The V-response shown here, directed toward a near target, has a vergence component that can be
separated into a fast intrasaccadic vergence phase and a subsequent slower movement. The eye movement generated on E-stimulation
(E-response) is purely saccadic, and no evident vergence response is
elicited. The slight divergence displacement during the E-saccade can
be attributed to transient divergence (Collewijn et al. 1988,
1995
; Maxwell and King 1992
;
Oohira 1993
; Zee et al. 1992
).
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Qualitative observations
TEMPORAL ASPECTS. To introduce the analysis of the data, examples of EV-responses are depicted in Fig. 5, where the onset of the stimulation pulse train occurred at early, intermediate, and late stages after V-target presentation. The saccadic time courses are presented in Fig. 5 in the top plots, and the vergence components are presented in the bottom panels. By inspecting the time course of the vertical component of the combined EV-trials relative to the E- and V-responses (controls) we can evaluate how saccadic displacement changes as a consequence of E-stimulation. As will become clear, saccade behavior showed no surprises and conformed to the expectations formulated previously.
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METRICAL ASPECTS. To make this distinction we now reinspect the component displacements of the binocular refixations to compare them with the predictions put forward by each hypothesis. The notion of indirect involvement (see Fig. 1B) suggests that the E-stimulus causes a train of events that allows a V-induced vergence signal to be expressed prematurely but without adding any vergence WHERE contribution. Accordingly, if this view is correct, one should find averaging of E- and V-induced effects in the saccadic component but not in the vergence signal. As a corollary, V-induced movements that were E-perturbed in midflight in their saccadic component should not show any vergence effects.
The direct involvement viewpoint proposes that the E-stimulus not only triggers a premature movement but also produces saccadic and vergence WHERE signals. These E-induced WHERE signals then compete with the V-induced WHERE signals, yielding a compromise (averaging) response. That E-controls do not show any net vergence does not necessarily mean that they have no effect on vergence-metrics specification. A possibility that should be considered instead is that the absence of an overt vergence component in the E-control signifies a desired vergence change of zero amplitude rather than simply the absence of a vergence WHERE signal at the SC level (see DISCUSSION). If the E-stimulus would indeed induce such a zero-vergence change command, one can see how averaging may play an equally important role in the vergence response as in the saccadic response. As a consequence, collicular E-stimulation applied in midflight during a V-triggered 3D refixation should prevent the vergence response from reaching completion and becoming as "full-blown" as it might otherwise become. As will become clear from the following analysis, it appears that the experimental data are in accordance with the direct involvement hypothesis. If the vergence traces in Fig. 5, bottom panels, are scrutinized with these perspectives in mind, it becomes obvious that there is a gradual increase in the influence of the V-stimulus when the E-stimulus is given later and later in the trial. This trend toward V-dominance can be expected if indeed the vergence WHERE signal needs some time to build up. It is reasonable to assume that this WHERE signal will have reached an advanced state when the 3D refixation, whether E-triggered or initiated by the monkey, starts in the range of normal V-latencies. The crucial distinction between the two remaining hypotheses that we are now exploring is whether such late responses (see Fig. 5, right panels) show a full-blown fast vergence movement as in the V-controls. Actually it is clear that the E-triggered response is not close to being equal in magnitude to the V-controls. This is illustrated further in Fig. 6, where the trajectories of all three E-triggered EV-trials and controls (as seen in Fig. 5) are depicted in both the frontal and depth planes. As explained previously, this result may signify that a degree of averaging occurs between the E- and V-related signals and that the E-locus in the SC contributes an explicit zero-vergence change signal. In the further analysis, to be presented subsequently, we will investigate this suggestion in a quantitative manner with data from all sites. As a prelude to this quantitative treatment, it is important to ask what happens when the E-stimulus is given at a time when the monkey already initiated the eye movement.
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MIDFLIGHT PERTURBATION EFFECTS. In Fig. 7 we present three examples of V-initiated responses where E-stimulation is applied in midflight after onset of the binocular refixation. It is a crucial finding that such a late E-stimulus perturbs not only the saccadic but, remarkably enough, also the vergence component. In each case the saccade time course closely follows the V-control until stimulation onset, after which the response deviates from its initial V-guided path toward the E-control. Interestingly, there is also a corresponding disturbance to the vergence response, temporally linked to the saccadic perturbation, where the V-guided vergence component breaks off its initial target-directed trajectory and diverges temporarily. As soon as the saccade picks up where it left off then so does the vergence. This is seen clearly in the spatial trajectories of the trials in Fig. 7, A and C, which are shown in Fig. 8.
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Quantitative analysis of metrical perturbation effect
In this analysis, it is important to keep track of how the binocular refixations in the E-triggered EV-trials, the V-stimulus and the E-stimulus, are temporally related to one another. Because E-stimulation was applied at a number of discrete delays relative to the V-stimulus, we obtained E-triggered responses over an extensive time period of target signal buildup, ranging from zero (E-stimulation at V-target onset) to nearly complete (V-latency range). When the E-stimulation was applied at a late point in time, the V-guided response could begin before stimulation onset so that in these cases E-latency (saccade onset with respect to E-stimulation onset) was negative. When E-stimulation occurred at a relatively early stage, all EV-responses were E-initiated, having rather constant E-latency values of ~20-30 ms. As one would predict, when E-delays (time between V-stimulus onset and E-stimulation onset, see Fig. 2C) were made long enough to enter the domain of V-latencies, the probability of getting a V-triggered EV-response increased sharply. To understand the additive effects of E- and V-stimulation, it is useful to consider how the characteristics of EV-responses develop both as a function of their timing relative to the V-stimulus (V-latency) but also as a function of E-latency. We will now proceed to present data, considered from either perspective.
METRICAL DEPENDENCE ON V-LATENCY.
We present the entire range of EV-responses in Fig.
9, where the component displacements are
now plotted as a function of V-saccade latency. Saccade amplitudes are
depicted in Fig. 9A, and intrasaccadic vergence is shown
in Fig. 9B. The mean control values for E-stimulation
and V-guided refixations are also shown. If we first inspect the
saccadic component in Fig. 9A we can see that
E-triggered EV-responses () only attain roughly up to halfway completion. These EV-responses are fully E-dominated when their V-latencies are short (e.g., ~100 ms). The V-influence increases when
the E-stimulus is delayed such that V-latency is prolonged. However,
for long V-latencies we do not see complete V-dominance, at best a
compromise between the two influences. This averaging effect continues
to be present in the V-triggered EV-responses (
), which show a large
degree of scatter in saccadic displacement. Similar conclusions can be
drawn for the intrasaccadic vergence as a function of V-latency, shown
in Fig. 9B. Here a compromising phenomenon is also seen
for both E- and V-triggered EV-responses, and it is apparent that
metrically the latter set of data points can range almost anywhere
between E- and V-domination. E- and V-triggered EV-responses show a
marked degree of overlap. A much clearer picture emerges if one
analyzes how the interplay of competing E-stimulus and V-stimulus
effects depends on the time shift between the E-stimulus and response
onset (E-latency).
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METRICAL DEPENDENCE ON E-LATENCY. This point is illustrated in Fig. 10 where each rapid component of the binocular refixation is plotted as a function of E-latency, linking the displacement in each component with its latency relative to the E-stimulus onset. A great deal of information is contained in this plot, and we start by considering the saccadic behavior, shown in Fig. 10A. Notice that EV-responses with the longest positive E-latencies, obtained by very early E-stimulation, are indistinguishable from the E-controls (top dotted line). The other extreme, responses that are fully V-dominated (indistinguishable from V-controls, indicated by the bottom dotted line), are those V-triggered movements where the E-stimulus came too late to affect the movement at all, that is, after saccade offset. In between these two extremes there is a gradual transition of data points, which are observed to be at an intermediate stage of displacement when E-latency is zero. Because it seems reasonable to assume that the V-buildup signals reached the V-control level in all V-triggered EV-responses (i.e., negative E-latencies), the fact that the intercept value does not equal the V-control level indicates that the E-stimulus must be exerting a metrical effect on ongoing V-initiated movements. As previously noted, this is the critical distinction between hypotheses 2 and 3. Figure 10 shows that the E-triggered saccades become more and more V-affected as the E-latency diminishes toward zero. This clear change from E- to V-dominance continues further as E-latencies become increasingly negative. The picture that emerges therefore is one of an averaging process that blends the evoked E- and V-signals, causing a gradual trend of data points that link the E-control response to the V-control response.
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QUANTITATIVE EVALUATION OF HYPOTHESES.
To gain a quantitative measure for each site that characterizes the
important relationship between the metrics of the responses and the
E-latencies, we applied a linear regression analysis to the data points
within a selected temporal window. By choosing only the responses that
make the transition from the E- to the V-control lines (roughly between
±40 and 40ms) we were able to gauge the intercept of the
EV-responses on the dashed line in Fig. 10 representing zero
E-latency. For the site shown in Fig. 10A, the
intersection point is roughly midway between the E-control and
V-control lines. This provides strong evidence that the two regions of
activity (E- and V-activated) still compete strongly with each other
after the V-guided refixation was initiated. To ascertain to what
extent the picture emerging from Fig. 10, favoring hypothesis 3, is
representative we provide a quantitative overview of all sites (see
Table 1).
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Similarities in saccade and vergence perturbation effects
CORRELATED PERTURBATION EFFECTS. If the basic idea behind direct involvement is correct, the possibility has to be considered that the proposed involvement of the SC in both saccades and vergence may cause functional linkages between the WHERE signals of the two oculomotor subsystems by the introduction of a common noise source. To assess whether such couplings can in fact be demonstrated, we further examined the perturbation data from Table 1. What causes the variability in P values is not known (see DISCUSSION for a suggestion), but it is clear that if the scatter in saccadic P values strongly correlates to the variation in vergence P values, this would support the idea that these causes work equally on both subsystems. We compare P indices for saccades and vergence for all the sites, from both monkeys, in Fig. 11. The best-fit line has nearly a unity slope and a correlation coefficient that is highly significant (P < 0.01), showing that the perturbation effects in the saccade and vergence components of the binocular response covary and, interestingly, that they are about equally strong.
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ANALYSIS OF TRIAL-TO-TRIAL VARIABILITY.
The plots in Fig. 10 show that there is a linear relationship between
the degree of perturbation and E-latency both for saccades and
vergence. This strong relation with E-latency was observed for almost
all sites, as shown by the data presented in Table 2 for both saccadic and vergence
components. There also appears to be a considerable degree of scatter
in displacement for the V-triggered responses that are perturbed in
midflight. Given that a trial-to-trial variation exists in the relative
effects of the V- and E-activity, one wonders whether this scatter in
the saccadic and the vergence component is also correlated. In other
words, if the V-effect in a particular trial is especially small or
large in the saccadic component, relative to the fit curve, would the corresponding vergence component then show concordant variations? To
explore the possibility that a common noise source is affecting the
metrical effects in both components on a trial-by-trial basis we
plotted the various component displacements against each other in Fig.
12. Of course, if the trial-by-trial
scatter were independent in both subsystems, one would still expect the
two components to be correlated in this plot because of their shared
dependency on E-latency (shown in Fig. 10). The impression at first
glance is that the very strong relationship between the conjugate and disconjugate responses of each binocular refixation is unlikely to be
merely an epiphenomenon of the shared latency dependence. As Table 2
shows, a high degree of metrical correlation between saccades and
vergence was seen for all sites. In more than two-thirds of the sites,
85% or more of the variability in vergence can be accounted for on
this basis. To determine the contribution of trial-to-trial
variability, it is necessary to filter out the latency contribution
with partial correlation analysis. After this was done (see Table 2),
we see that a substantial correlation remains in the majority of sites.
This means that the trial-to-trial variability, causing scatter about
the metric-latency relationship (see Fig. 10), is not independent for
the saccadic and vergence components. To illustrate, in one-half of the
sites 50% of this variability can be ascribed to this common noise
factor (see Table 2).
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Vergence changes are not on epiphenomenon of varying saccade duration
In our analysis, we concentrated on intrasaccadic vergence as a clearly defined signal for comparison with the saccade behavior. However, this means that the following caveat has to be considered. One might argue that modification of the saccade metrics by the E-stimulus might, by virtue of the amplitude-duration relationship of saccades, influence the time-window in which rapid vergence can express itself. Although our experimental setup was expressly designed to sidestep this potential problem, by attempting to keep the amplitude of the saccade vector nearly constant (see METHODS), it was inevitable that saccades would vary in amplitude and therefore also in duration. The question to be answered now is to what extent these unintended duration effects may have determined intrasaccadic vergence displacement indirectly. To illustrate the problem, we examined this issue for the responses shown in Fig. 12. The data points depicted in Fig. 13 show the intrasaccadic vergence as a function of saccade duration. It appears that there is only a weak relationship between the two parameters, which in this site would only account for some 22% in the variance of the vergence component (r2 = 0.22). To gauge how significant a role saccade duration plays in causing the metrical correlation with the vergence signal, we performed a partial correlation analysis for all sites by controlling for the influence of saccade duration. If the strong correlation in Fig. 12 were an epiphenomenon of variations in saccade duration, it would be lost after performing this further statistical analysis. What becomes clear from Table 2 is that the strong correlation between the saccade and vergence displacements, as seen for all sites, cannot be unduly considered to be an epiphenomenon of varying saccade duration. The r2 values in the column on the righthand side of Table 2 reflect the genuine relation between the metrics of saccades and vergence after controlling for saccade duration effects. The relationship between the saccade and vergence metrics clearly remains very strong.
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DISCUSSION |
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We undertook neurophysiological experiments in the SC to learn more about the neural substrate of combined saccade-vergence eye movements. The oculomotor system was perturbed by E-stimulation in the SC at a time when the monkey was preparing, or just initiated, a 3D refixation to a newly presented target. Our goal was to see whether any effects on vergence, besides the expected changes in saccade responses, could be demonstrated. Results from our perturbation paradigm have shown not only the occurrence of premature E-triggered (and V-directed) vergence responses but also the weighted averaging of the two sets of stimuli (E and V) as a function of stimulation onset for both sets of components. Furthermore, data from V-triggered EV-responses show that the vergence response reveals a highly similar degree of perturbation as the corresponding saccadic portion.
Absence of vergence in E-induced refixations
To differentiate between the E- and V-triggered portions of
EV-responses in the perturbation paradigm, the experiment was designed
such that separate E- and V-stimulation yielded control responses with
clearly distinct saccade and vergence directions (see Fig. 4). The
results indicate that the greatest part of the required convergence, in
the V-controls, takes place during the fast intrasaccadic phase. The
E-control trials consistently yielded the saccade expected on the basis
of the stimulated site in the SC motor map but did not exhibit any
vergence response. This data are in line with findings recently
presented by Billitz and Mays (1997), who observed that stimulation of
caudal and rostral sites, while a monkey fixated a distant target, did
not lead to any vergence effects. If interpreted in a straightforward
manner as a sign that the SC is only involved with saccade control,
this fact would lead one to believe that E-stimulation, applied in
conjunction with a V-target in 3D EV-trials, will only interfere with
the required saccadic response, leaving vergence unaffected. It is evident from our results (see Figs. 10 and 11 and Table 1) that this
explanation has become untenable.
Rejection of noninvolvement hypothesis
Yarbus' (1967) suggestion that refixations in 3D space are a
result of distinct and independent oculomotor subsystems and neurophysiological work indicating that saccades and vergence responses
may be coded in different areas of the brain (Judge and Cumming
1986
; Mays 1984
; Mays et al.
1986
) provides a basis for the noninvolvement hypothesis,
outlined in the INTRODUCTION. If, as in this proposal, each
subsystem is considered to be an independent entity, then no room is
left for a common WHEN and/or WHERE control
mechanism for the two components. On the basis of the results from
previous studies (Glimcher and Sparks 1993
;
Sparks and Mays 1983
) one would expect, in the
perturbation paradigm, that the saccadic response shows a gradual
change in displacement between the two sets of controls as the onset
time of the E-stimulus is delayed. A specific prediction from the
noninvolvement model is a zero-vergence response (as seen in the
E-control) for all positive E-latencies (i.e., cases where the
E-stimulus is applied before any V-triggered response occurs). In
addition, a full convergence response, unmitigated by the E-stimulus,
should occur when a V-guided response is initiated toward the near
target, in other words, when E-latencies are negative.
Because both vergence predictions are in conflict with the data, the model must be discarded. Next we will evaluate the second model that can account for the subset of our experimental results showing that (V-directed) vergence is elicited prematurely as a result of the E-stimulation in the SC. This novel result (see Fig. 5) shows that, by intervening in the SC during the time period of V-signal buildup, one can affect not only the saccadic response but also the vergence response.
Evaluation of indirect-involvement model
PREMATURE E-TRIGGERED VERGENCE RESPONSES. E-stimulation, in the indirect involvement model, opens the gate for both sets of components (in whichever state of preparation they may be). If we assume that the vergence signal is built up gradually, this model can explain why the V-directed vergence signal is able to manifest itself prematurely after application of the E-stimulus in the SC.
Our results show how varying the delay of the E-stimulus can reveal the magnitude of the gradually increasing V-contribution to the saccadic component. What we see in Fig. 10A is that when stimulation is applied shortly after V-target presentation the saccade elicited is strongly reminiscent of that seen during the E-control. When stimulation occurs later but nevertheless before a V-guided response, the E-triggered saccade is being increasingly influenced by the V-signal. Because, apparently, V-signal buildup occurs gradually over time, the V-influence becomes stronger as the onset of the E-stimulus is delayed. These observations are very similar to what was described earlier by Sparks and Mays (1983)E-PERTURBATION OF V-TRIGGERED 3D RESPONSES.
In the case of saccades, it was well established that E-stimulation in
midflight causes a perturbing effect on the V-guided response
(Schlag-Rey et al. 1989). In other words, a full-blown saccade response will only be observed if the E-stimulus is delayed until after saccade completion. This is also evident from our data
presentation in Fig. 10A. If we stimulated earlier, we
observed that the saccade only reached roughly halfway completion by
the time the V-latency range was reached. Not only does the saccade response intersect the zero latency axis far below V-control level (see
Fig. 10A) but it continues to be influenced by the
E-stimulus when the response is V-guided.
Direct involvement model
It has become clear that the explanation put forward previously by
Glimcher and Sparks (1993), on how combined EV-stimulation leads to a
compromise between competing signals in the frontal plane, can be
extended to the realm of 3D space. How these newly found temporal and
metrical effects can be reconciled with the direct involvement model
will now be discussed.
To understand what this means we must consider that the SC may actually be involved in the coding of 3D information. However, it does appear difficult at first glance to reconcile this notion with the zero-vergence response obtained during E-controls. As a prelude to a discussion on how this issue may be resolved, we provide an overview of the classical collicular scheme and subsequently present suggestions on possible revisions of this model.
Indirect evidence for 3D colliculus
The SC was always considered to be a saccadic control center receiving input signals from 2D neural structures and projecting information to regions that handled conjugate signals. This picture was modified somewhat lately, on the basis of new studies that shed new light on 3D information processing, upstream and downstream of the SC. We present some of this evidence.
Signals reflecting stimulus location in 3D space were found not only in
various regions of the monkey visual cortex (for review see
Trotter 1995) but also in the parietal cortex
(Colby et al. 1993
; DeAngelis et al.
1998
; Roy et al. 1992
; Sakata et al.
1997
). The lateral intraparietal area (LIP) has cells with 3D
tuning curves (Gnadt and Mays 1995
), and it was
demonstrated that these "saccade-related" neurons, tuned for a 3D
volume of space, project depth-related as well as directional
information to the SC (Gnadt and Beyer 1998
). Although
it has long been known that the SC of the cat has a large proportion of
binocular cells (Berman et al. 1975
), it is only since
very recently that a systematic study was done to determine that cells
in the superficial layers of the cat SC can have binocular receptive
fields with various types of coarse disparity-sensitivity profiles
(Bacon et al. 1998
). Dias et al. (1991)
previously
reported on broadly tuned disparity-selectivity in the superficial
layers of the SC of the opossum. Because binocular disparity provides
one of the principal cues for converting the 2D retinal images into a
3D percept, these studies suggest that the SC has access to vital
information for mediating vergence eye movements.
Although it may come as a surprise to learn that the SC, often
portrayed as a bastion of saccadic control, may have a broader role,
there is reason to think that the same may apply to so-called saccadic
burst cells downstream of the SC. A recent neurophysiological study
(Zhou and King 1998) has shown, in a radical departure
from the classical scheme of separate saccadic and vergence control systems, that binocular fast eye movements may be controlled separately for each eye. They show that saccadic burst cells at the premotor level, previously thought to code conjugate signals, are actually monocular in nature. This indicates that the idea of a binocular version and vergence system is probably oversimplified. It now appears
that depth movements could be attributed at least partly to unequal
saccades caused by a disconjugate saccadic control of each eye
separately. This new finding, that the population of burst cells
contains a 3D code, raises interesting questions about the SC, which is
a major source of input to this population and is classically regarded
as a 2D structure. We propose that this may be less of an enigma if the
SC also contains a 3D code (see Fig. 1C), a possibility that
finds strong support in this paper.
Further support was provided by recent findings that relate the SC to
changes in accommodation. This is interesting because accommodation and
vergence control are considered to be closely related (Carpenter
1988). Sawa and Ohtsuka (1994)
reported an increase in
accommodation when the rostral collicular region in the anesthetized
cat was stimulated. An anatomic study established, furthermore, that
rostral neurons project to accommodation-related areas (Sato and
Ohtsuka. 1996
). More recently, Billitz and Mays (1997)
, in the
monkey, elicited a relaxation in accommodation, and they observed
divergence response when microstimulation was applied in the deeper
layers throughout the colliculus, during a near fixation task. Another
interesting study indicated that the rostral area of the SC in the
alert cat contains neurons that are modulated (i.e., the cell discharge
pauses or increases) during vergence eye movements (Jiang et al.
1996
). E-stimulation in the deeper layers of the cat rostral SC
was reported to induce disconjugate eye movements and even pure
vergence (Jiang et al. 1996
).
Whether the newly discovered vergence effects described in this paper are a direct reflection of signal processing inside the SC or whether they arise indirectly cannot be determined at this moment. Assuming the former, we now discuss a hypothetical collicular coding scheme that seems to allow a simple interpretation of our findings.
3D movement coding scheme for colliculus
The SC is commonly divided into superficial and deeper layers. Although neurons in the superficial layers are activated by visual stimuli in their receptive field, neurons in the deeper layers are mainly involved in orienting eye movements. The latter only fire for eye movements into their movement field that delineates the range of saccade vectors for which a particular cell is activated. Movement fields are topographically laid out in a motor map, and suprathreshold E-stimulation at a specific point elicits saccades with reproducible vectors, a specific amplitude and direction but no depth component. We now propose how this model can be revised, considering the recent literature and our experimental data.
Gnadt and Beyer (1998) described depth-related signals carried from
area LIP to the SC. This suggests that deeper layer movement cells have
access to depth information that is needed to code eye movements in 3D
space. Each specific location in the motor map of the SC contains a
group of movement cells that share the same direction preference (in
the frontal plane). We propose a new scenario where they would also
have a preferred depth component, different for each cell. Thus, if
within this group the neurons are randomly intermingled (no
topographical code for depth, only for direction), then it becomes
quite straightforward to understand that any indiscriminate activation
by local E-stimulation yields a fixed 2D (horizontal and vertical
components) saccade vector but a net depth command signal that equals
zero. The latter should not be confused with simply the absence of a
vergence signal.
To directly relate this hypothesis to our results we refer to the
scheme shown in Fig. 14. In the
classical picture of a 2D colliculus, site X is activated by
E-stimulation and leads to a saccade that is directed upward. Cells at
site Y are excited when a saccade of similar amplitude is made in the
downward direction toward the location of the V-stimulus (Van
Gisbergen et al. 1987). In the case of simultaneous E- and
V-activation a compromise response occurs, which can be thought of as
the result of a weighted average of the two sets of signals that were
built up at the different sites thus far. The result is a saccade that
is directed somewhere between the E- and the V-saccades, depending on
the timing of the E-stimulus, and its current strength.
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The new idea of a 3D colliculus is presented in a similar way in Fig. 15. The two sites are activated in the same fashion as described for the 2D situation. Additionally, however, each neuron codes for its own preferred depth. The broad distribution of depth vectors, with an evenly ordered range of converging and diverging components, is shown for both sites X and Y (Fig. 15A). In the next step (Fig. 15B) we depict what would happen during control situations and combined EV-responses. The horizontal and vertical components of the controls are identical with the classical situation. However, if, based on population coding, a weighted average is taken of all the depth directions coded by the population of cells at location X, as would be expected during E-stimulation, then one would obtain a zero-vergence signal. This desired zero-vergence command can cause vergence perturbation unlike the 2D colliculus. As explained in Fig. 15, far-right bottom diagram, the final outcome in EV-responses would again be a weighted average of the signal carried by the population of E-activated neurons and the population of V-activated cells, just as was described for the case of direction (the saccadic component). The latter set of cells provides for the occurrence of a locally represented saccade vector and a vergence component that enables the eyes to fixate the near target. The population of E-activated cells emphatically demands a 3D movement with zero vergence, and it is this insistence on a zero-vergence movement that, according to the proposal, causes the disturbance in the vergence component of EV-responses.
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It is interesting that Gnadt and Beyer (1998) left open this
possibility of a 3D colliculus as a consequence of their findings that
area LIP neurons send depth-related signals to the SC. They briefly
mention that previous studies may not have adequately tested for this
possibility and that E-stimulation at a particular site may "recruit
neurons across a range of depth sensitivities that are embedded within
the map." It is clear that only single-unit studies showing that SC
movement cells are actually tuned in depth will provide clarification,
and in the absence of these results the present interpretation of our
findings can only be preliminary.
Further evaluation of 3D colliculus model
It is interesting to reflect for a moment on two other aspects of the results that were not yet discussed in terms of the model. First, we found that the perturbation effects varied in strength from site to site but were generally approximately equal for the saccade and vergence component (see Fig. 11). If, depending on the position of the electrode and on current intensity, the strength of the E-vector signal varies from site to site, this will have similar consequences for its direction and its depth component. It is this vector strength that will determine the perturbation effect in the weighted averaging process that also takes into account the V-vector. Similarly, the V-vector will have its direction fixed by the location of the target but its strength will be time dependent, varying with the time since target onset. It is quite feasible that the time course of this buildup may vary somewhat from trial to trial, thereby causing a fluctuation around the mean behavior. In this way, it can be understood, in principle, why the trial-to-trial variability was to a considerable extent common to the saccadic and the vergence component (see Table 2). If the specification of the saccade and vergence components would take place at different centers, such couplings would be less easy to comprehend.
Indirect support for the idea of a vergence-related colliculus comes
from a study where the midbrain was damaged (Lawler and Cowey
1986). Monkeys with large collicular lesions were observed to
have a dramatic misalignment of their visual axes, suggesting diplopia.
It was suggested that the perceptual impairments that followed as a
consequence of this pathology were due to faulty vergence eye
movements. Of course, one cannot exclude the possibility that these
lesions indirectly affected other neural regions that may have been
involved in vergence control.
As mentioned previously, decisive evidence to test our hypothesis
will have to come from single-unit studies that investigate depth-related activity in the deeper layers of the SC. To our knowledge
there was until now only one preliminary study on the question as to
whether SC burst neurons are involved in vergence control (Mays
1996). Initial results appear to indicate that firing rates are
modified when convergence components occur in conjunction with
saccades. It is not clear as yet whether that is due to a change in the
velocity of the 3D response, compared with similar amplitude saccades
in the frontal plane, or whether the SC is truly involved in coding
depth movements.
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CONCLUSION |
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The neurophysiological perturbation experiments revealed two distinct effects of SC-stimulation on vergence in the presence of a V-target, involving the initiation (WHEN) and the metric-specification (WHERE) systems that were not expressed when E-stimulation was applied in isolation. Although our results are partly compatible with the notion of a common gating system to saccades and vergence, it is clear that this is not an elaborate-enough scheme to explain all the previously described phenomena. To make better sense of the results, we interpret the absence of an overt vergence effect on E-stimulation in the SC as a command specifying a zero-vergence change rather than as the mere absence of a vergence signal. In the perturbation trials, this zero signal competes with the V-related vergence signal, thereby causing a perturbation with averaging characteristics. This effect would be expected if the population of movement cells at each SC site is tuned in 3D, combining the well-known topographical code for direction with a nontopographical depth representation. On E-stimulation, the local population would yield a net saccade signal because of the topography, but the cells coding for different depths would be excited equally, causing the vergence change to be zero.
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ACKNOWLEDGMENTS |
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We thank S. Gielen for providing useful comments and F. van der Werf for doing the histology. We gratefully acknowledge the experimental and technical assistance of C. van der Lee, T. van Dreumel, H. Kleijnen, V. Langeveld, G. van Lingen, and W. Corbeek. We also thank H. Arndts, M. Faassen, A. Peters, and F. Philipsen for animal care.
This study was supported by the Foundation for Life Sciences and the Netherlands Organization for Scientific Research.
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FOOTNOTES |
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Address for reprint requests: J.A.M. Van Gisbergen, 231 Dept. of Medical Physics and Biophysics, University of Nijmegen, P.O. Box 9101, 6500HB Nijmegen, The Netherlands.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 28 September 1998; accepted in final form 13 January 1999.
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REFERENCES |
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