Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892
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ABSTRACT |
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Paré, Martin and Robert H. Wurtz. Progression in Neuronal Processing for Saccadic Eye Movements From Parietal Cortex Area LIP to Superior Colliculus. J. Neurophysiol. 85: 2545-2562, 2001. Neurons in both the lateral intraparietal area (LIP) of the monkey parietal cortex and the intermediate layers of the superior colliculus (SC) are activated well in advance of the initiation of saccadic eye movements. To determine whether there is a progression in the covert processing for saccades from area LIP to SC, we systematically compared the discharge properties of LIP output neurons identified by antidromic activation with those of SC neurons collected from the same monkeys. First, we compared activity patterns during a delayed saccade task and found that LIP and SC neurons showed an extensive overlap in their responses to visual stimuli and in their sustained activity during the delay period. The saccade activity of LIP neurons was, however, remarkably weaker than that of SC neurons and never occurred without any preceding delay activity. Second, we assessed the dependence of LIP and SC activity on the presence of a visual stimulus by contrasting their activity in delayed saccade trials in which the presentation of the visual stimulus was either sustained (visual trials) or brief (memory trials). Both the delay and the presaccadic activity levels of the LIP neuronal sample significantly depended on the sustained presence of the visual stimulus, whereas those of the SC neuronal sample did not. Third, we examined how the LIP and SC delay activity relates to the future production of a saccade using a delayed GO/NOGO saccade task, in which a change in color of the fixation stimulus instructed the monkey either to make a saccade to a peripheral visual stimulus or to withhold its response and maintain fixation. The average delay activity of both LIP and SC neuronal samples significantly increased by the advance instruction to make a saccade, but LIP neurons were significantly less dependent on the response instruction than SC neurons, and only a minority of LIP neurons was significantly modulated. Thus despite some overlap in their discharge properties, the neurons in the SC intermediate layers showed a greater independence from sustained visual stimulation and a tighter relationship to the production of an impending saccade than the LIP neurons supplying inputs to the SC. Rather than representing the transmission of one processing stage in parietal cortex area LIP to a subsequent processing stage in SC, the differences in neuronal activity that we observed suggest instead a progressive evolution in the neuronal processing for saccades.
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INTRODUCTION |
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The production of sensory guided movements entails a sequence of neural events distributed throughout the neural axis, and it is imperative that the processing hierarchy linking different brain regions be determined if we wish to understand fully their respective contributions within a functional circuit. To this end, a common approach has been to contrast results obtained in independent studies each performed in the distinct brain regions composing a distributed system. Such studies, however, generally permit only coarse comparisons, and experimental discrepancies render impractical the description of subtle but possibly significant differences between brain regions. A more rigorous alternative consists of performing a systematic comparison of the neuronal signals that are closely ordered within the neural sequence and collected under identical experimental conditions. The present study uses this approach to help elucidate the progression in processing linking two structures within perhaps the best-understood sensory-motor circuit in the primate brain, the visuo-saccadic system.
Neural pathways underlying the production of visually guided saccadic
eye movements extend through the visual cortex and converge in the
brain stem. One of these pathways involves the posterior parietal
cortex and the superior colliculus (SC), and a body of literature has
described their neuronal activation as transitional between sensory and
motor processing stages. Neurons within the SC intermediate layers
display, along with their typical visual and saccade-related
activation, a low-frequency "prelude" of activity that can precede
movement production considerably (Glimcher and Sparks
1992; Mohler and Wurtz 1976
; Munoz and
Wurtz 1995
; Sparks 1978
). Within the parietal
cortex, the lateral intraparietal (LIP) area contains a distinct
population of neurons with visual and saccade-related activation
(Andersen et al. 1987
) and projects to the SC
intermediate layers (Andersen et al. 1990
;
Asanuma et al. 1985
; Lynch et al.
1985
). A sustained low-frequency activity between visual
stimulation and saccade execution, resembling that of SC neurons, is a
prevailing characteristic of these parietal neurons (Barash et
al. 1991a
,b
; Colby et al. 1996
; Gnadt and
Andersen 1988
). Thus independent studies indicate a clear
overlap within the activity patterns of the SC and LIP neuronal
populations, and we previously showed that this was also the case for
the LIP neurons projecting to the SC (Paré and Wurtz
1997a
). These observations suggest that area LIP could account
for certain aspects of SC activation, particularly the low-frequency
activity. The key question is whether there are differences between the
activation of LIP and SC neurons, and if so, do they suggest a shift in
neuronal processing away from visual processing and toward saccade production?
To address this question, we directly compared signals in both brain
regions in two monkeys performing identical tasks and, most
importantly, we limited the comparison to neurons closely ordered
within the neural sequence by identifying antidromically the LIP
neurons projecting to SC. Using the well-known motor characteristics of
SC neurons as a reference to elucidate any progression in processing occurring between the LIP output and the SC, we concentrated our investigation on the neuronal activity that develops after target presentation but in advance of saccades. Understanding this activity is
a central issue because it may reveal the nature of covert processes
linking sensory representations and motor commands. One existing
hypothesis surmises that such delay activity represents a "motor
intention" or "preparatory process" (Dorris and Munoz 1998; Dorris et al. 1997
; Mazzoni et al.
1996
; Platt and Glimcher 1997
; Snyder et
al. 1997
). According to this motor preparation hypothesis, the activity's relationship with movement production must
be highly predictive when advance information is provided (Evarts et al. 1984
; Requin et al. 1991
),
and its intensity must be largely independent from sustained sensory
stimulation. Conversely, neuronal activity being unrelated to the
impending movement production and depending strongly on sensory
stimulation may rather simply construct a sensory
representation. Thus if there were a neuronal progression in the
processing leading to visually guided saccades, the dependence of this
neuronal activity on visual stimulation would gradually lessen while
the relation to the impending movement would gradually strengthen.
To examine whether there is such a progression in saccade processing between LIP and SC, we recorded neuronal samples during two behavioral tasks. We dissociated the timing of saccades from visual stimulation with a delayed saccade task to reveal the extent of any delay activity, and we manipulated advance response instruction with a delayed GO/NOGO saccade task to assess the extent to which this delay activity relates to the future production of a saccade. To determine whether the activity was independent of visual stimulation, variations of both tasks allowed us to compare the activity in advance of saccades guided either by a continuously present visual stimulus or by its remembered location. From area LIP to SC, we found a significant increase in the dependence of the delay activity on response instruction and a significant decrease in its dependence on sustained visual stimulation. These findings thus offer evidence of a progressive shift in saccade processing from area LIP to SC.
Brief reports have been presented elsewhere (Paré and
Wurtz 1997b; Sommer et al. 1997
).
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METHODS |
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Animal preparation
Two male rhesus monkeys (Macaca mulatta, 6-11 kg) were prepared for chronic recording of single neurons and eye position in a single surgical procedure carried out under general anesthesia and aseptic conditions. All animal care and experimental procedures were approved by the Institute Animal Care and Use committee and complied with Public Health Service Policy on the humane care and use of laboratory animals.
Just prior to the start of surgery, the animals were given an analgesic
(2.0 mg/kg im Flunixin meglumine), and a 10-day treatment of
antibiotics (25 mg/kg im Cefazolin) was initiated. They were also
premedicated with glycopyrrolate (15 µg/kg im). After induction of
anesthesia with ketamine HCl (10 mg/kg im) and diazepam (1 mg/kg im),
an endotracheal tube was positioned to permit subsequent gas
anesthesia, and an intravenous catheter was inserted in the saphenous
vein for fluids to maintain hydration. Anesthesia was continued with
isofluorane, and the monkey's head was fixed in a stereotaxic frame
throughout the surgery. Scleral search coils were inserted
subconjunctivally (Judge et al. 1980), and the connector leads were embedded in a dental acrylic implant that was firmly anchored to the skull by titanium screws inserted into drilled and
tapped holes. The implant also included a plastic (ULTEM resin) head-holding device and two plastic recording cylinders (18 mm diam),
each positioned over a trephined hole of identical dimension. The first
cylinder was directed toward the SC (15 mm above and 1 mm posterior of
stereotaxic zero) and was centered on the midline with its top tilted
42° posterior of vertical. The second cylinder was centered on the
stereotaxic coordinates P 5.0 and L 12.0 mm and tilted 30° lateral of
vertical to allow recordings from area LIP neurons.
Brain imaging procedure
Before the experiments began, an image of each monkey's brain was obtained using magnetic resonance imaging (MRI) technology. In preparation for being positioned within the MRI magnet (1.5 T GE SIGNA scanner), the animals were given an analgesic (0.1 mg/kg im Butorphanol) and premedicated with glycopyrrolate. Anesthesia was induced and maintained with ketamine HCl and diazepam. The animal's head was immobilized with a stereotaxic device (aluminum, brass, and plastic) positioned in the MR scanner to align the imaged sections with the stereotaxic planes. The MRI procedure was a fast SPGR T1-weigthed inversion recovery pulse sequence, and series of coronal and sagittal sections were obtained at 1-mm intervals. We positioned tungsten microelectrodes within the cylinders prior to the MRI scans and directed them near the SC and the lateral bank of the lateral intraparietal sulcus to delimit these brain regions and subsequently provide an anatomical reference to locate the relative position of the penetrations made during experimental sessions.
Experimental procedures
Animals were trained to execute visuooculomotor tasks for a
liquid reward. Behavioral paradigms, visual displays, and data acquisition were controlled by a personal computer running a UNIX-based real-time data acquisition system (REX) (Hays et al.
1982). Eye positions were monitored by the magnetic search coil
technique (Robinson 1963
). Single neurons were recorded
with tungsten microelectrodes (Frederick Haer, 1.0-2.0 M
at 1 kHz)
that were inserted into the brain via a sterile guide tube (13 gauge) positioned in the cylinder with the use of a grid system
(Crist et al. 1988
). The SC guide tube ended ~5 mm
above the surface of the SC, whereas the length of the LIP guide tube
was carefully measured and adjusted to allow the microelectrodes to
pass through the dura mater while avoiding damage to the cortical
tissue as much as possible. Neuronal signals were conventionally
amplified, filtered (band-pass 300 Hz to 5 kHz), and displayed on an
analog oscilloscope while being played on an audio monitor. They also
were transmitted to an additional computer acting as a digital
oscilloscope (50 kHz), where action potentials of single neurons were
isolated with the use of window discriminator software that excluded
action potentials that did not meet amplitude and time constraints.
Isolated action potentials, along with horizontal and vertical eye
position signals, were digitized at 1 kHz.
During the experiments, monkeys were seated in a primate chair with
their head restrained. They faced a vertical tangent screen (Crist and Robinson 1989) positioned exactly 57 cm in
front of their eyes, and for which they had an unobstructed view of
80° × 80° (±40° in any direction from straight-ahead). Visual
stimuli (<0.5° diam) were generated by a video projector (Sharp 850, 60 Hz) and back-projected onto the tangent screen. The colors of the
visual stimuli were blue (CIEx,y 0.15, 0.07;
luminance 0.3 cd/m2), red
(CIEx,y 0.61, 0.38; luminance 1.5 cd/m2), and green (CIEx,y
0.20, 0.75; luminance 2.0 cd/m2).
Fluid intake was controlled during training and recording sessions, during which the animals performed until satiated. Fruits and additional fluids were provided regularly. Animal weight, health status, and fluid intake were monitored closely under the supervision of the institute veterinarian.
Behavioral paradigms
All behavioral trials were initiated by the appearance of a visual stimulus, referred to as the fixation point, in the center of the screen. The monkey was required to look at the fixation point within 1,000 ms of its appearance. Once the eyes entered a computer-defined window (±1°) centered on the fixation point, the latter remained on for 500-800 ms (fixation period). If fixation was successful, one of the tasks described below proceeded; otherwise the trial was aborted. Because of the background illumination (0.1 cd/m2) of the video projector, the behavioral trials were performed only in partial darkness. During the inter-trial interval (randomized between 1,000 and 1,500 ms), the screen was illuminated with diffuse white light (0.6 cd/m2), and the monkey was not required to fixate.
DELAYED SACCADE TASK. Neurons initially were characterized with the delayed saccade task, which was designed to dissociate temporally the neuronal activity related to visual stimulation from that related to saccade initiation (Fig. 1A). After the initial fixation of a red fixation point, a green peripheral stimulus was presented, but the fixation point stayed illuminated for an additional 500- to 1,000-ms period of maintained fixation (delay period). The fixation point disappearance acted as the visual cue signaling the monkey to make a saccade to the stimulus within 500 ms and then maintain eccentric fixation on it to correctly perform the task and be rewarded. Two versions of the delayed saccade task were used to control for the possible contribution of the visual stimulus presence to the neuronal activation. In the visual version of the task, the peripheral stimulus remained present throughout the trial. In the memory (nonvisual) version, the stimulus was only briefly presented (100-ms flash), and the monkey had to make a saccade to the remembered location of the target.
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GO/NOGO SACCADE TASK. An additional instructed-delay saccade task with a GO/NOGO paradigm was designed to dissociate temporally the neuronal activity related to visual stimulation, response instruction, and behavioral response (Fig. 1B). First, the monkey was required to look at a blue fixation point. If fixation was maintained, a green peripheral stimulus then appeared (stimulus period). After 800-1,200 ms, the fixation point changed color to instruct the monkey that the peripheral stimulus will (green = GO instruction) or will not (red = NOGO instruction) become a saccadic target. After another 800-1,200 ms (instruction period), the fixation point turned back to its original blue color (choice period), the cue signaling the monkey to make a saccade to the stimulus location within 500 ms (GO) or maintain fixation for an additional 1,000 ms (NOGO) before being rewarded. Thus correct behavior in both GO and NOGO trials were rewarded, i.e., the reward procedure was symmetrical.
The above description of the task corresponds to the trials in which the instruction period followed the stimulus period; hereafter referred to as poststimulus instruction trials (Fig. 1B, top). We also used prestimulus instruction trials (Fig. 1B, bottom), wherein the instruction period preceded the stimulus period. In addition, visual and memory versions of the GO/NOGO saccade task were used to control for the possible contribution of the visual stimulus presence to the neuronal activation. The eccentric stimulus was visible either for 200 ms (memory version; Fig. 1B, black T) or until the end of the trial (visual version; Fig. 1B, gray T). Ten to 30 repetitions of each individual trial (visual and memory versions of pre- and poststimulus instruction trials) were randomly interleaved. Single-neuron recording experiments began after the performance of the two monkeys had reached 98% correct trials; we only considered either false alarms (targeting saccades in NOGO trials) or misses (absence of saccades in GO trials) as behavioral errors. This high performance level was maintained throughout the period that the neuronal data were collected. Early in the data collection, the first ten SC neurons were tested only with visual trials.RESPONSE FIELD MAPPING. We evaluated the general discharge properties of a neuron using the visual delayed saccade task and determined its response field (the neuron's movement field, or its visual receptive field if it had no saccade-related discharges) by varying systematically (step of 1°) the position of the visual stimulus. This was accomplished by graphically displaying on-line rasters and histograms of the spike occurrences aligned on the onset of the saccades made to each stimulus position. After the center of the response field (the target position for which neurons discharged optimally) was well defined, we collected data, first, in a block of randomized visual and memory delayed saccade trials and, second, in a block of GO/NOGO trials. In these blocks, the visual stimulus was presented with equal probability either in the center of the neuron's response field or at a position equidistant relative to the fixation point but in the diametrically opposite direction. The responses of all SC and LIP neurons were spatially selective, and no significant activity was therefore observed when the visual stimulus was presented outside the response field, except for some postsaccadic discharges. Consequently, we only analyzed quantitatively trials with the stimulus within the response field.
Neuronal identification techniques
Before the recordings in area LIP began, we first determined the
location of the SC and the organization of its topographical representation of saccades. The exact depth of the intermediate layers
that contain saccade-related neurons (~1-3 mm below the SC surface)
was delimited using tungsten microelectrodes to determine both the
presence of neuronal activity time locked to saccade onset and by the
ability to evoke saccades with stimulation trains of low-intensity
pulses (10 µA or less). We then identified area LIP physiologically
by the concentration of neurons with significant visual and
saccade-related activities within the lateral bank of the intraparietal
sulcus and studied only the neurons that were antidromically activated
from tungsten monopolar stimulating microelectrodes at predetermined
locations within the SC intermediate layer map of saccades. These
stimulating microelectrodes (Frederick Haer, impedance 50-100 k at
1 kHz) were moved with a microdrive during each session or held fixed
semi-chronically (1-5 wk) to the cylinder's grid with epoxy. The
electrical stimulus used for antidromic activation was a single
biphasic pulse (see Fig. 2A), whose duration was kept short (~0.15 ms for each phase) to optimize axon activation and minimize shock artifact. For each neuron, we
determined the threshold intensity to evoke LIP spike responses by SC
stimulation, the latency of the evoked responses, and whether the
responses could be collided with self-generated orthodromic action
potentials. The threshold intensity was defined as the intensity that
evoked a response on ~50% of the stimulus presentations. The
response latency was the interval from the onset of the stimulus (at
1.2 times threshold intensity) to the onset of the evoked action
potential. The collision test verified the antidromic nature of the
responses by triggering the stimulus after variable delays relative to
the occurrence of an orthodromic action potential. The antidromic
responses were abolished (collision, dashed trace in Fig.
2B) if the delay between the orthodromic action potential and the stimulus was within the collision interval (Lemon
1984
). Throughout the recording session, the occurrence of the
collision was monitored routinely (during the inter-trial interval) to
confirm the isolation.
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Data analysis
To visualize the collected data, rasters of neuronal discharges
and continuously varying spike density functions (MacPherson and
Aldridge 1979; Richmond et al. 1987
) were
aligned on specific events in the paradigms. To generate the spike
density function, a Gaussian pulse (
= 10 ms) was substituted
for each spike, and then all Gaussians were summed together to produce
a continuous function in time. Computer software determined the
beginning and end of each saccade using velocity and acceleration
threshold and template matching criteria (Waitzman et al.
1991
).
Several sampling epochs were considered for the analysis of the
neuronal activity, which was measured from the raw spike counts, with
only one exception. In the delayed saccade task, the activity of
neurons during fixation was measured by taking the mean discharge rate
during a 300-ms epoch within the fixation period, from 500 to 200 ms
before the target presentation (Fig. 1A, fix).
The stimulus activation was the mean discharge rate during the 50- to
150-ms interval after the visual stimulus presentation (Fig.
1A, stim). The delay activity was the mean
discharge rate displayed during the last 300-ms interval of the delay
period, ending at the fixation point disappearance (Fig. 1A,
delay). The presaccadic activity was the mean discharge rate
during the last 100 ms before saccade onset (Fig. 1A,
presac). This interval was employed to establish whether the
neurons had specific discharges that could contribute to the generation
of the saccade (Colby et al. 1996). The magnitude of the
saccade activity was determined as the peak rate of the saccade-related burst of activity found within ±20 ms from saccade initiation (not shown). We chose this temporal window because SC
neurons are known to discharge maximally at the beginning of saccades
(e.g., Dorris et al. 1997
), and we measured the peak discharge using the spike density functions constructed from rasters of
action potentials aligned on saccade onset.
In the GO/NOGO saccade task, the activity during fixation was the mean discharge rate during the final 300 ms during the fixation period (Fig. 1B, fix). The stimulus-related activity was the mean discharge rate during the 50- to 150-ms interval after the visual stimulus presentation (Fig. 1B, stim). The delay activity, after both the stimulus and the instruction had been presented, was estimated as the discharge rate displayed during the 300-ms interval before the response cue (Fig. 1B, delay). Two additional analysis epochs were computed for the sustained activity present: 1) when only the stimulus had been presented in the poststimulus instruction trials (Fig. 1B, stim-delay) and 2) when only the instruction had been provided in the prestimulus instruction trials (Fig. 1B, inst-delay). These epochs consisted of the last 300 ms of the instruction and the stimulus periods, respectively.
In both the delayed saccade task and the GO/NOGO saccade task, neurons significantly active in advance of saccade initiation were defined as those that had activity in the delay epoch significantly greater than their activity in the fixation epoch in either visual or memory trials (Wilcoxon signed rank test, P < 0.01). These were referred to as delay responsive neurons.
The majority of the data set composed nonnormal distributions as determined by the Kolmogorov-Smirnov test (P < 0.01), and we therefore conducted statistical comparisons within and between samples with the nonparametric Mann-Whitney U-test and Wilcoxon signed rank test, respectively. For comparisons of several samples, we used the nonparametric Kruskal-Wallis ANOVA, followed by an all-pairwise multiple comparison procedure (Student-Newman-Keuls of Dunn's method). Results of the statistical analyses were considered significant only if they exceeded a level of P < 0.01, except for the pairwise multiple comparison procedures (P < 0.05). All statistical tests were performed with the SigmaStat software (Jandel Scientific).
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RESULTS |
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Single-neuron recording in the two monkeys yielded sufficient data
from 102 neurons in the SC intermediate layers that displayed characteristic saccade (or delay) activity and 41 neurons in area LIP
that had peripheral excitatory response fields. All LIP neurons were
identified as output neurons projecting to the ipsilateral SC, wherein
stimulation produced antidromic activation (see Fig. 2) with an average
latency of 1.9 ms (range 0.8-6). The antidromic current threshold was
minimal for stimulation delivered within the intermediate layers
(Paré and Wurtz 1997a) and averaged 182 µA, with
90% of the neurons activated with a current <400 µA.
Discharge properties in the delayed saccade task
ACTIVITY PATTERNS.
In the delayed saccade task (see Fig. 1A), SC and LIP
neurons displayed a range of activity patterns that included a burst of
activity in response to visual stimulation, a sustained activity during
the delay period, and a presaccadic increase in activity. Figure
3 shows examples of these activity
patterns in the visual version of the task, i.e., when the visual
stimulus presented within a neuron's response field remained on from
its onset to the end of the trial. Within the SC sample, we observed
many neurons with two bursts of activity time locked to the onset of
either the visual stimulus or the saccade, along with a low-frequency sustained activation during the intervening delay period (Fig. 3A). A smaller subset of SC neurons showed only a sustained
delay activity without a clear burst of activity associated either with stimulus presentation or saccade execution (Fig. 3B).
Finally, we encountered several SC neurons whose primary discharge was a high-frequency saccade-related burst of activity (Fig.
3C), which occasionally could be preceded by a transient
stimulus-related response. These three example neurons were comparable
to those previously referred to as 1) "prelude bursters"
(Glimcher and Sparks 1992) or "buildup" neurons
(Munoz and Wurtz 1995
), 2) "quasi-visual" neurons (Mays and Sparks 1980
), and 3)
"saccade-related burst neurons" (Mays and Sparks
1980
) or "burst neurons" (Munoz and Wurtz
1995
).
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DEPENDENCE ON VISUAL STIMULUS PRESENCE. The LIP and SC neurons were also recorded in a memory version of the delayed saccade task, i.e., when the visual stimulus was only briefly presented and therefore absent during both the delay period and the saccade execution. The graphs in Fig. 4, C and D, depict the corresponding levels of activity for each of the LIP and SC neurons and reveal that they qualitatively resemble those observed in the visual version of the task (compare with Fig. 4, A and B). The statistical analysis of the LIP and SC activity in advance of saccades, however, demonstrates one major quantitative difference: the delay and presaccadic activity of LIP neurons, but not that of SC neurons, was significantly reduced in the absence of the visual stimulus (Table 1). This difference may indicate that LIP neurons are less involved in the early covert processes directly related to saccade production. To perform a meaningful comparison, however, one needs to compare quantitatively the normalized discharge properties of the LIP and SC neuronal samples. To do so, we chose not to use a ratio or contrast index based on mean discharge rates. This approach unfortunately relies on the assumption of normal population distributions, and this was often untenable in our data set (e.g., Fig. 5B). Rather, we opted for a nonparametric measure of the separation between the distributions of neuronal activity observed in visual and memory trials.
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Discharge properties in the GO/NOGO saccade task
We used the GO/NOGO saccade task (see Fig. 1B) to provide advance instruction about saccade production and to determine whether this manipulation modulates the subsequent delay activity of LIP and SC neurons. We shall first describe the neuronal responses observed in the version of the GO/NOGO saccade task in which the instruction was presented after the stimulus appearance, the poststimulus instruction trials.
POST-STIMULUS INSTRUCTION TRIALS.
Figure 7 illustrates the activity
patterns displayed by SC neurons in the visual version of the
poststimulus instruction trials of the GO/NOGO saccade task. Following
a GO instruction, most neurons (Fig. 7, A and B)
showed a rise of low-frequency sustained activity, which occurred with
a considerably longer latency than the earlier stimulus-related
activity (e.g., Fig. 7A). Such activation did not depend on
whether a neuron already displayed some delay activity or a presaccadic
increase in activity (compare Fig. 7, A and B).
The sustained activity following a NOGO instruction was greatly reduced
relative to that present in GO trials, and, of course, the burst of
activity that normally accompanied the GO-trial saccades did not occur
during the prolonged NOGO fixation period. A neuron that showed a
saccade-related burst of activity but lacked delay activity in the
delayed saccade task (see Fig. 3C) continued to burst only
for the saccades made in GO trials, remaining silent otherwise (Fig.
7C). We also found that 19% (13/69) of the SC neurons
classified as delay responsive neurons in the delayed saccade task no
longer displayed significant delay activity in the GO/NOGO saccade
task. This important change in neuronal activation could most probably
be attributed to the new behavioral context introduced by the randomly
interleaved NOGO trials. Relative to the delayed saccade task, the
probability of a saccade being produced was then reduced, and such a
manipulation has been shown to affect the excitability of SC neurons
(Basso and Wurtz 1998; Dorris and Munoz
1998
; Mohler and Wurtz 1976
).
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PRE-STIMULUS INSTRUCTION TRIALS. We showed that response instruction modulated the delay activity of both the LIP and SC neurons. In the experiments described so far, however, the instruction appeared after the presentation of the visual stimulus, thereby preventing us from determining whether it also modulated the stimulus activity. To address this issue, we had designed the GO/NOGO saccade task to include prestimulus instruction trials, in which the instruction was presented before the visual stimulus presentation (see Fig. 1B). Figure 12 shows the average LIP and SC neuronal activation during the performance of both the visual and the memory versions of these types of GO/NOGO trials. In both samples, the foveal instruction signal itself did not trigger any activation, but some activity occurred in anticipation of the visual stimulus in GO trials. Following the stimulus presentation, the initial burst of activity appeared slightly enhanced when preceded by a GO instruction.
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SC superficial layer neurons
In the course of this study, we also examined the activation of
nine additional SC neurons recorded presumably within the SC
superficial layers. In the delayed saccade task, these neurons lacked
significant presaccadic discharges and displayed a phasic discharge
time locked to the visual stimulus onset. Sustained delay activity
could also persist, but exclusively in the visual version of the
delayed saccade task. In the GO/NOGO saccade task, neither the
stimulus-related burst of activity of these neurons nor their sustained
activity was modulated by advance instruction about saccade production.
We excluded these "visual" neurons from our comparative study
because the SC superficial layers seem to receive negligible inputs
from area LIP, as indicated by anatomical (Lynch et al.
1985) and physiological (Paré and Wurtz
1997a
, 1998
) methods.
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DISCUSSION |
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We compared the activity of LIP neurons projecting to the SC with
that of neurons within the SC intermediate layers to assess the
differences in saccade processing between these two brain regions. An
examination of activity patterns in a delayed saccade task indicated
that LIP and SC neurons have an extensive overlap in their responses to
visual stimuli and in their sustained activity during the delay period,
as suspected from our previous study (Paré and Wurtz
1997a). LIP output neurons, however, discharged less strongly
than SC neurons during saccades, a difference perhaps reflecting
dissimilar intrinsic properties between the homogeneous cortical
pyramidal neurons and the morphologically heterogeneous SC neurons
(Moschovakis et al. 1988
). An analysis of the separation between activity associated with trials in which the visual stimulus presentation was either brief (memory trials) or sustained (visual trials) indicated that both the delay and the presaccadic activity levels of LIP neurons, but not of SC neurons, significantly depended on
sustained visual stimulation. The output of the LIP population thus
appears less directly devoted to saccade processing than the SC population.
An instructed saccade task with a GO/NOGO paradigm examined whether advance instruction about saccade production modulated the delay activity of these neuronal populations. In this task, both the LIP and the SC neurons discharged, on average, more strongly to a visual stimulus positioned in their response fields when it was specified to be a saccadic goal by a foveal color instruction than when the instruction indicated that no movement was requested. These results thus suggest that both neuronal populations could predict the production of an ensuing saccade, even though some level of activity persisted in NOGO trials. Nevertheless, when compared with SC neurons, individual LIP output neurons were significantly less dependent on the advance instruction; only a minority of LIP neurons was significantly modulated. Along with its dependence on visual stimulus presence, the delay activity of LIP neurons therefore continues to appear more remote from the processing for saccade production than that of SC neurons.
Altogether, this study indicates that the LIP neurons projecting to the SC comprise a heterogeneous subset of neurons whose general properties can only partially account for the neuronal activation of its downstream target structure. Indeed, the combined discharge properties predicted by our motor preparation framework (visual independence and instructional dependence of the neuronal activity in advance of saccades) was observed almost exclusively in the sample of SC neurons; the activity of the LIP neurons that project to the SC was more closely associated with a "visual representation." Accordingly, the differences in LIP and SC discharge properties suggest a progressive evolution in processing information associated with the production of saccades.
Visual dependence of neuronal activity
In its purest form, neuronal activity associated with saccades
must be independent from the sensory signals that trigger the movements. Converging evidence indicates that the saccade activity of
SC neurons generally is independent of the presence of a visual stimulus within their movement fields (e.g., Groh and Sparks
1996; Jay and Sparks 1987
; Mays and
Sparks 1980
; Munoz and Wurtz 1995
; Wurtz
and Goldberg 1971
). Nevertheless, differences can be observed when this activity is compared across conditions. For example, Mohler and Wurtz (1976)
described a small class of SC
neurons (the visually triggered movement cells) that discharge before saccades to a visual stimulus, but not before spontaneous saccades made
in the light or the dark. More quantitative studies further demonstrated that, although most SC neurons continue to discharge before saccades made in the absence of a visual stimulus, their activity does generally show signs of visual dependence (Edelman and Goldberg 1997
; Sparks and Porter 1983
).
Because this activity is so intimately linked to saccade execution, its
reduced level in nonvisual conditions may be related to the concurrent
reduction in saccade dynamics (Gnadt et al. 1991
;
White et al. 1994
). Measuring neuronal activity well in
advance of saccades, however, should not be confounding. Apart from our
study, the visual dependence of the SC delay activity has been
investigated only by Kojima et al. (1996)
, who found
that a minority of SC neurons had a significantly greater delay
activity either in the presence (12%) or the absence (14%) of a
visual stimulus in their movement fields. Our results indicated a
similar proportion of "memory"-dependent neurons (12%), but a
greater proportion of visual-dependent neurons (31%).
Very few analogous studies have been performed in area LIP. Our
previous paper was the first to demonstrate the strong visual dependence of the delay activity of LIP output neurons projecting to
the SC (Paré and Wurtz 1997a). This property
subsequently was recognized among nonidentified LIP neurons in
different experimental conditions (Gottlieb et al.
1999
). Our observation that the visual dependence of the delay
activity significantly diminishes from area LIP to SC therefore extends
the previous observations made in independent studies, and we interpret
this finding as indicating a progressive shift in saccade processing.
Influence of response instruction on neuronal activity
The manipulation of sensory information to instruct saccade
production allowed us to explore the transitional stage between the
sensory representation of the saccadic goal and the final achievement
of the goal. Such an instruction procedure has proved useful to others
who studied such covert processes often interpreted as "preparatory
set" or "motor preparation" (Evarts et al. 1984; Requin et al. 1991
). Our GO/NOGO saccade task is similar
to a GO/NOGO reaching task designed by Kalaska and Crammond
(1995)
, who investigated neuronal activity related to response
selection in both parietal and premotor cortex. Briefly, neuronal
responses in downstream premotor cortex were found to differentiate
between GO and NOGO instructions to a much greater degree than those
observed in upstream parietal cortex. These observations thus
interestingly paralleled the shift forward in movement processing
between area LIP and SC.
Somewhat closer to our study, Glimcher and colleagues studied the delay
activity of LIP and SC neurons with a saccade selection task, in which
a saccade to one of two peripheral visual stimuli is specified by the
color of the fixation stimulus (Glimcher and Sparks
1992; Platt and Glimcher 1997
). Data
independently collected from each neuronal population showed that
neurons generally discharged maximally if the cue dictated a saccade to
the stimulus within their response fields rather than outside. From the
available quantification, however, it can be estimated that SC neurons
were more strongly modulated by the advance instruction than LIP
neurons. Overall, the present activity modulation is qualitatively
comparable to that observed in this saccade selection task, despite the
distinction between the general and the selective inhibition of
movements associated with, respectively, GO/NOGO and selection tasks
(De Jong et al. 1995
). Using a two-alternative
force-choice visual discrimination task in which monkeys indicate their
choice by correctly directed saccades, Newsome and colleagues
(Horwitz and Newsome 1999
; Shadlen and Newsome
1996
) also recorded from two separate samples of LIP and SC
neurons. Differential activation was found to predict the upcoming
oculomotor decision in both brain regions, but no comparison is
currently available. Other independent studies limited their
quantitative investigations to activity patterns present in either area
LIP (e.g., Barash et al. 1991a
,b
; Colby et al.
1996
) or SC (e.g., Munoz and Wurtz 1995
) often
without comparable analyses. The ensemble of these studies thus
suggest, albeit qualitatively, that the LIP and SC neuronal populations
are functionally overlapping.
Further investigations of instructional influences on LIP and SC
neurons are available in studies that employed an anti-saccade task, in
which the fixation stimulus color specifies either a saccade to a
peripheral visual stimulus or a saccade directed diametrically away
from the stimulus. Neuronal data collected independently in area LIP
(Gottlieb and Goldberg 1999) and SC (Everling et
al. 1999
) again suggest that saccade instruction alters more
the SC than the LIP neurons, but the considerable differences between
the experimental designs and data analyses of these two studies
preclude any strong comparison. Moreover, the report by Gottlieb
and Goldberg (1999)
that the activation of most LIP neurons
encoded the location of the visual stimulus much more reliably than the
direction of the saccade did not refute the possibility that only those
neurons with distinct saccade-dependent activation reached the saccadic
system, including the SC. This possibility now seems unlikely given
that identified LIP output neurons show a similar range of properties
as do unidentified populations of LIP neurons.
Our observations that advance instruction about saccade production
modulates differently the delay activity of LIP output neurons and SC
neurons are therefore consistent with observations made on unidentified
neurons recorded in other instruction-based tasks. By using antidromic
activation, we have added the important finding that there is no
evidence for a motor preparation bias in the LIP neurons projecting to
the SC and that the influence of response instruction on neuronal
activity is enhanced from the LIP output to the SC. Insofar as the SC
delay activity represents a motor preparation signal, its strength
would not result from a signal already present in the output of
parietal cortex. This progressive evolution in neuronal signals appears
to be common within the saccadic system (Ferraina et al.
1999; Segraves and Goldberg 1987
; Sommer
and Wurtz 2000
), but it contrasts with the more abrupt stages
seen in visual motion processing (Ilg and Hoffmann 1993
;
Movshon and Newsome 1996
).
Interpretational limitations
Apart from the ubiquitous sampling biases, which more severely
affect physiological studies of unidentified neurons, the most serious
limitation about the validity of our conclusions arises from the fact
that our study did not limit the comparison to SC neurons receiving LIP
inputs. The discharge properties of some SC neurons did resembled that
of LIP output neurons (neurons with visually dependent and
instruction-independent delay activity), raising the prospect that the
cortical inputs could be restricted to a distinct sub-group of neurons
within the SC population. This would imply that any uniform sampling of
SC neurons could produce an apparent sequence of processing. This
hypothesis, however, is not supported by our preliminary finding that
the SC neurons orthodromically activated by LIP stimulation
can be either with or without delay activity, and those with delay
activity can be visually independent and instruction dependent
(Paré and Wurtz 1998). Thus the LIP projection is
rather unspecific, and it is reasonable to consider our sample of
unidentified SC neurons as putative targets. Accordingly, a progression
in saccade processing might emerge from a transformation of the LIP
signals within the SC neuronal ensemble via an intrinsic circuitry
(Munoz and Itsvan 1998
), nonlinear membrane properties
(Grantyn et al. 1983
), and complex dendritic trees
(Moschovakis et al. 1988
). Nevertheless, the observation
of an evolution in the discharge properties of LIP and SC neurons, by
itself, is not sufficient to reveal whether LIP inputs actually are
transformed within the SC. The differences between LIP and SC neurons
could be due to extra-parietal inputs possibly originating, for
example, from the frontal eye field (Everling and Munoz
2000
; Segraves and Goldberg 1987
; Sommer
and Wurtz 1998
, 2000
; see also Schlag-Rey
et al. 1992
).
Another intriguing sampling bias issue relates to the fact that the
response fields of LIP neurons, including the SC projection neurons,
have a three-dimensional configuration (Ferraina et al. 1999; Gnadt and Beyer 1998
; Gnadt and
Mays 1995
); whether SC neurons possess such a property is
currently unknown. The fixed-depth visual stimuli used in this study
thus might not have succeeded in optimally activating our neuronal
samples. Nevertheless, unless the activation in visual, memory, GO, and
NOGO trials each had a distinct tuning in depth, the differences
between LIP and SC neurons could not have been radically different from
what we showed. The exact influence of this factor on visual and
instructional dependencies, and particularly on the general properties
of SC neurons, nonetheless remains to be determined.
Our hypothesis of a progression in saccade processing assumes that
signals transmitted from area LIP to SC necessarily have something to
do with sensory-motor processing. It should be noted, however, that a
minor fraction of LIP output neurons have other or unidentified
properties (Paré and Wurtz 1997a), and these units
would need to be accommodated within future schemes. This could easily
be achieved for the LIP output neurons that show fixation-related
activity by assuming the hypothesized dual function of the SC in
fixation and saccade behaviors (Munoz and Wurtz
1993a
,b
). The remaining population of LIP output neurons that
we have previously identified as being unresponsive in visuo-oculomotor
tasks could, once we have characterized them fully, either be
pronounced developmental anomalies (if their low discharge rates do not
carry significant information) or significant players with a function
perhaps beyond sensory-motor processes.
Function of area LIP in saccade processing
Area LIP could be ideally suited to convert the product of visual
processing into oculomotor programs because it is anatomically interposed between visual cortical areas (Andersen et al.
1990; Baizer et al. 1991
; Morel and
Bullier 1990
) and saccadic centers (SC: Gnadt and Beyer
1998
; Lynch et al. 1985
; Paré and
Wurtz 1997a
, 1998
; frontal eye field:
Ferraina et al. 1999
; Schall et al.
1995
). The exact function of LIP in saccade processing,
however, remains controversial. Two main interpretations currently
implicate area LIP in either the planning of saccades (Andersen
et al. 1997
) or in the formation of an attention map of the
salient environment (Colby and Goldberg 1999
). Because
previous investigations might have focused on different neuronal
populations within the intraparietal sulcus region presumed to contain
area LIP, it has been particularly difficult to reconcile these
seemingly mutually exclusive hypotheses. The participation of LIP
neurons in saccade processing is presumably reflected in their
connectivity. We therefore reasoned that knowing the signals relayed by
the LIP output channels should help to clarify the saccadic role that
area LIP plays. Our original characterization of the signals conveyed
by the LIP output neurons projecting to the SC established that they
could influence saccade processing by means of a visual activation
frequently evolving into a presaccadic signal (Paré and
Wurtz 1997a
). The GO/NOGO saccade task offered an opportunity
to elucidate further the relation of this parietal output channel to
saccade processing, even though it was not specifically designed to
dissociate hypotheses based primarily on motor planning or
visuo-attentional mechanisms. Both hypotheses would predict that a GO
instruction should increase the LIP activity because of the concurrent
planning of the saccade and attentional relevance of the visual
stimulus. Our finding that the average LIP delay activity increased in
GO trials is therefore compatible with both hypotheses, but the lack of
a systematic modulation, along with the persistence of activity during
NOGO trials, does not lend strong support to either one. The
heterogeneity of the LIP neuronal properties implies either that a
single sensory-motor process cannot be attributed to this cortical
structure or that the signals carried by LIP output neurons do not
reflect a completed process. Hence area LIP does not impose
a planning or attention signal on SC neurons. In light of the potent
instructional influence on SC neurons, we submit that the moderate
modulation of the LIP output neurons represents an early stage in the
progressive formation of a decision specifying saccade production (cf.
Platt and Glimcher 1999
; Shadlen and Newsome
1996
). In this context, our study highlights the value of
comparing the processing taking place in interconnected brain regions
to understand their functional contributions.
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ACKNOWLEDGMENTS |
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We are grateful to the Laboratory of Diagnostic Radiology Research for magnetic resonance images. We also thank Drs. M. A. Sommer and D. P. Munoz, as well as our colleagues at the Laboratory of Sensorimotor Research, for helpful suggestions.
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FOOTNOTES |
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1 From the point of view of neurons receiving these inputs, it is impossible to distinguish which SC neurons had either lower or higher discharge rates in visual and memory trials. The influence of SC neuronal signals on downstream elements is reflected in both the proportion and the distribution of the significant visual/memory indexes.
Present address and address for reprint requests: M. Paré, Dept. of Physiology, Queen's University, Botterell Hall, Rm. 438, Kingston, Ontario K7L 3N6, Canada (E-mail: pare{at}biomed.queensu.ca).
Received 1 September 2000; accepted in final form 21 February 2001.
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REFERENCES |
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