Spatial Processing in the Monkey Frontal Eye Field. II. Memory Responses

Marc M. Umeno1,2 and Michael E. Goldberg1,3

 1Laboratory of Sensorimotor Research, National Eye Institute, Bethesda, Maryland 20892;  2Department of Physics, The American University, Washington 20016; and  3Department of Neurology, Georgetown University School of Medicine, Washington, DC 20007


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Umeno, Marc M. and Michael E. Goldberg. Spatial Processing in the Monkey Frontal Eye Field. II. Memory Responses. J. Neurophysiol. 86: 2344-2352, 2001. Monkeys and humans can easily make accurate saccades to stimuli that appear and disappear before an intervening saccade to a different location. We used the flashed-stimulus task to study the memory processes that enable this behavior, and we found two different kinds of memory responses under these conditions. In the short-term spatial memory response, the monkey fixated, a stimulus appeared for 50 ms outside the neuron's receptive field, and from 200 to 1,000 ms later the monkey made a saccade that brought the receptive field onto the spatial location of the vanished stimulus. Twenty-eight of 48 visuomovement cells and 21/32 visual cells responded significantly under these circumstances even though they did not discharge when the monkey made the same saccade without the stimulus present or when the stimulus appeared and the monkey did not make a saccade that brought its spatial location into the receptive field. Response latencies ranged from 48 ms before the beginning of the saccade (predictive responses) to 272 ms after the beginning of the saccade. After the monkey made a series of 16 saccades that brought a stimulus into the receptive field, 21 neurons demonstrated a longer term, intertrial memory response: they discharged even on trials in which no stimulus appeared at all. This intertrial memory response was usually much weaker than the within-trial memory response, and it often lasted for over 20 trials. We suggest that the frontal eye field maintains a spatially accurate representation of the visual world that is not dependent on constant or continuous visual stimulation, and can last for several minutes.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Monkeys and humans can easily make eye movements to remembered targets (Hikosaka and Wurtz 1983). They can do it even in a double-step task where another saccade intervenes between the disappearance of the target that evokes the saccade and the eye movement necessary to acquire it (Hallett and Lightstone 1976; Mays and Sparks 1980). Neurons in the frontal eye field (Bruce and Goldberg 1985), prefrontal cortex (Funahashi et al. 1989), and lateral intraparietal area (LIP) (Barash et al. 1991; Goldberg et al. 1990) show evidence of a visual-memory signal, responding in a tonic manner to briefly flashed targets. This activity occurs even in a fixation task in which monkeys do not make a saccade to the stimulus that evokes the response (Colby et al. 1996). Neurons in the frontal eye field (Goldberg and Bruce 1990), superior colliculus (Mays and Sparks 1980), and LIP (Barash et al. 1991; Goldberg et al. 1990) all discharge appropriately before saccades in a double-step task. They discharge before saccades into their movement fields even though there is a dissonance between the retinal location of the stimulus and the saccade necessary to acquire the target.

Recent experiments have suggested that such spatially accurate presaccadic activity can occur because some neurons in these areas are capable of two different kinds of nonclassical visual responses. The first is a predictive visual response: neurons in LIP (Duhamel et al. 1992), the superior colliculus (Walker et al. 1995), and the frontal eye field (Umeno and Goldberg 1997) respond to targets that will be brought into their receptive fields by an impending saccade, even if the stimulus never appears in their visual receptive fields as determined in a fixation task. The predictive visual response occurs before the saccade. If the stimulus remains illuminated after the saccade moves it onto the retinal receptive field, there is a reafferent response that reinforces the initial predictive response.

The majority of neurons in LIP only discharge after the saccade brings a stimulus into the receptive field. The simple assumption is that this postsaccadic response is merely a reafferent response. However, in LIP, for many neurons, there is a visual-memory response that contributes to postsaccadic activity. If a stimulus flashes at the spatial location that will enter the receptive field as a result of a saccade but disappears before the saccade, the neurons discharge after the saccade in response to the flashed target (Duhamel et al. 1992) (see Fig. 1 for a diagram of this experiment). Although the response occurs after the saccade, it is a response to a stimulus that appeared only before the saccade in a retinal location outside the receptive field as determined in a fixation task. If the only component of the postsaccadic response was visual reafference, the cell would be expected to remain silent because the saccade does not bring the stimulus into the receptive field. The stimulus vanished before the saccade began. If the additional postsaccadic signal were a postsaccadic movement response, one would expect to see it after every saccade regardless of whether or not a stimulus had recently flashed. Instead LIP neurons exhibiting spatially accurate memory responses discharge after only those saccades that bring the spatial location of a recently vanished stimulus onto the receptive field. Similar spatially accurate visual memory responses were demonstrated in the intermediate gray layers of the monkey superior colliculus (Walker et al. 1995).

In these experiments, we asked if a similar memory response was present in the frontal eye field of the monkey. We found two different kinds of memory responses: a short-term within-trial memory response that resembles that seen in LIP and the superior colliculus and a longer-term intertrial memory response that has not been previously described. A preliminary report of these results has been presented in abstract form (Umeno and Goldberg 1998).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Surgical and physiological methods were described in a recent report (Umeno and Goldberg 1997). All animal protocols were approved by the Animal Care and Use Committee of the National Eye Institute and certified to be in compliance with the Public Health Service Guide for the Care and Use of Laboratory Animals.

Behavioral methods

Monkeys were trained on a number of baseline tasks all of which have been described previously. Cells were characterized first using either visually guided or the memory-guided delayed saccade tasks (Hikosaka and Wurtz 1983). In the latter, the monkey was required to hold its gaze on a fixation point, and during this fixation, a peripheral visual stimulus (a red light-emitting diode) appeared in the spatial position of the receptive field; it was extinguished after a fixed period of time, usually 50 ms. When the fixation point disappeared, the monkey made a saccade to the location of the now-vanished visual stimulus. If the monkey made a saccade within a window of 25% of the desired saccade amplitude around the target location, the light reappeared after the saccade, and the monkey was rewarded for holding fixation at that location for 100 ms. This task enabled us to characterize presaccadic frontal eye field neurons according to the classification of (Bruce and Goldberg 1985) as visual, visuomovement, or movement. Visual cells responded in a time-locked manner to the onset of the visual stimulus in their receptive fields and were silent during the saccade. Movement cells were silent during the stimulus presentation and responded just before saccades to their movement fields. Visuomovement cells responded to the visual stimulus and before the saccade.

We then studied presaccadic neurons in two tasks designed to show the effects of saccades on the neuron's receptive field: the flashed stimulus task and the continuous stimulus task (Fig. 1). In both tasks, the monkey held its gaze on a fixation light, FP1. In the flashed stimulus task, a visual stimulus (STIM) appeared for 50 ms at a location outside of the neuron's receptive field. We call the receptive field location during this first fixation the current receptive field (CRF). After a pseudorandom interval between 800 and 1,000 ms, FP1 disappeared, and a saccade target, FP2, appeared at a location chosen so that when the monkey made a saccade to it, the eye movement brought the spatial location of the now-vanished STIM into the neuron's receptive field. We call the spatial location that will be brought into the receptive field the future receptive field (FRF) because that spatial location will occupy the receptive field of the neuron after the saccade. The FRF stimulus was always located so that the cell never responded to it either when it appeared during fixation or before the saccade when the monkey made a memory-guided saccade directly to it. The monkey then had to make a second saccade to FP3 after another 500 ms. This second saccade was never made to the location of STIM or to any part of the neuron's receptive field. For some, but not all, receptive field locations the second saccade removed STIM from the neuron's receptive field. The continuous stimulus task was identical to the flashed stimulus task except that STIM remained illuminated for the duration of the trial (Umeno and Goldberg 1997).



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Fig. 1. Flashed stimulus task. Left: traces depicting fixation points (FP1, FP2, FP3), stimulus (STIM), and an idealized eye trace. Right: cartoon of physical arrangement of stimuli and receptive fields. CRF and ---: current receptive field, i.e., the location in space of the receptive field when the monkey fixates FP1. FRF and - - -: FRF, i.e., the location in space of the receptive field after the saccade from FP1 to FP2. The monkey begins the trial by fixating FP1, and during this interval, a stimulus (STIM) flashes in the FRF. FP1 disappears and a 2nd fixation point (FP2) appears after the disappearance of the fixation point, and the monkey makes a saccade to it. Subsequently a 3rd fixation point (FP3) appears and FP2 disappears, and the monkey makes a second saccade. Note that the monkey does not make a saccade to the stimulus in the FRF. In the no-saccade control, the monkey fixates and the stimulus appears in the FRF but the monkey continues to fixate and does not make the saccade. In the saccade control, the monkey makes the saccade from FP1 to FP2, but no stimulus appears in the future receptive field (FRF).

We used two types of control experiments for activity evoked in the flashed stimulus task. The no-stimulus control task was a saccade task in which the monkey made a saccade from FP1 to FP2 but no stimulus appeared while the monkey fixated; in an alternate version, a stimulus appeared on the screen but it was in neither the current nor the FRF and never entered the neuron's receptive field during the trial. In the no-saccade control task, the monkey fixated and the stimulus appeared at STIM, but the monkey made no saccade. In an alternate version of this task (the null saccade control), the monkey made a saccade that did not move the spatial location of STIM into the receptive field. For experiments in which the saccade signal appeared more than 400 ms after the appearance of STIM and at several different times, we did not always run the no-saccade control because there was no consistent response to the stimulus at these long latencies. For most of these experiments, we ran the trial types in blocks with the no-saccade and no-stimulus tasks performed first and followed by the flashed stimulus task and continuous stimulus task. For some experiments, all four tasks were run in a randomly interleaved fashion after they had first been run in blocks.

Data analysis methods

We determined each neuron's visual latencies and discharge frequency off-line, using a series of data analysis programs written in C running on a Silicon Graphics workstation. We rejected trials in which the monkey failed to earn a reward. We smoothed the eye position traces using a finite impulse response filter with a low-pass roll-off of 3 dB at 53.7 Hz. To determine the beginning and end of saccades, we digitally differentiated eye position traces using a differentiating finite impulse response filter with a 3-dB roll-off at 211.9 Hz, and computed when the velocity rose above a value, usually 50°/s. We chose this relatively high value to reject microsaccades and fixation breaks automatically. We used 15°/s as the value to determine the end of the saccade. We verified the computer's estimate of saccade beginning and end by visual inspection of the traces. We found that we rarely had to adjust the computer's estimate of saccade beginning, although occasionally the computer would pick up a saccade before the fixation point went out, in which case we found the next saccade, or the monkey made too slow a saccade and the computer failed to identify any, in which case we lowered the velocity criteria for that trial only. We computed rasters, histograms, cumulative histograms, and spike density probability functions (Richmond et al. 1987) synchronized on stimulus onsets and offsets and saccade beginnings and ends from the accepted trials, using a binwidth of 2 ms. We calculated spike discharge frequency as the average in the 100 ms following the onset of the burst. We defined the beginning of the burst as the first inflection point in the cumulative histogram after the appearance of the stimulus or the signal to make the saccade. To find this point, we computed the cumulative histogram by adding all of the spikes in a given 2- or 4-ms bin and then differentiating it using the same finite impulse response filter that we used for the eye position trace. We defined the beginning of the burst as 10 ms before the differentiated cumulative histogram value was greater than a value usually set at 12.5 spikes/s/trial. The cursor placement was verified by inspection to ensure that the program did not pick out a burst that began before the fixation point went out.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The data set in this report is the same as that in the previous report (Umeno and Goldberg 1997). We recorded from three hemispheres of two awake behaving Rhesus monkeys and used the delayed or visually guided saccade tasks to classify presaccadic neurons into visual (32 cells) and visuomovement (48 cells). We found two different sorts of visual memory---a short-term spatial memory that occurred in a single trial and a longer-term memory that lasted for as long as 30 trials.

Short-term spatial memory

We tested the responses of the 80 visually responsive neurons using the flashed stimulus task. This task exposed the neurons to a stimulus that flashed only in the FRF, the spatial location that would lie in the neuron's receptive field after the saccade. The stimulus never appeared in the visual receptive field of the neuron as determined in the delayed saccade task. A majority [61% (49/80)] of the visually responsive cells responded in the flashed stimulus task, i.e., the cell responded around the time of the saccade to a stimulus that appeared only in the FRF. We did not test movement cells in the flashed stimulus paradigm: these cells never responded to the stimulus in the continuous stimulus task before or after the saccade because the monkey never made a saccade to the stimulus (Umeno and Goldberg 1997). Given that there was no response to a sustained stimulus, it was extremely unlikely that the cells, which had no visual response even to a stimulus in their movement field, would respond to a transient, irrelevant stimulus outside their movement fields.

VISUOMOVEMENT NEURONS. We studied 48 visuomovement cells, of which 28 responded in the flashed stimulus task (58%). Visuomovement cells responded to the appearance of the stimulus in a saccade task and also discharged before the beginning of the saccade (Fig. 2A). The neuron illustrated did not show a predictive effect in the continuous stimulus task: the neuron discharged only after the saccade, with latency comparable to the latency of the neuron's response to the appearance of the visual stimulus (the on-response; Fig. 2B). Note that the STIM did not appear in any part of the current receptive field: the latency of the response was prolonged relative to the absolute appearance of the stimulus, and the response was best synchronized to the saccade and not to the stimulus appearance. If the STIM had been capable of driving the cell itself, one would have expected it to do so with latency similar to its response to the stimulus when it appeared in the current receptive field (Fig. 2A). Nonetheless, the neuron did respond in the flashed stimulus task: when the stimulus appeared and disappeared in the FRF, the neuron discharged after the saccade that brought the spatial location of the vanished stimulus into the receptive field (Fig. 2C). The activity was not a response to the saccade alone: when the monkey made the identical saccade in the no-stimulus control task where there was no stimulus flashed in the future receptive, the cell did not discharge (Fig. 3A). The activity was not a response to the stimulus flashed at that location: When the monkey made a saccade that moved the spatial location of the same flashed stimulus from one location outside the receptive field to another location outside the receptive field, there was no discharge (Fig. 3B). The monkey was unlikely to be preparing a saccade to the stimulus in the FRF because the monkey always had to make a second saccade to another fixation point in the interval after the first saccade. The computer randomly interleaved the trials illustrated in Figs. 2 and 3. We define this response to a stimulus that only appeared in the current receptive field but whose spatial location lies in the FRF as a short-term spatial memory response.



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Fig. 2. Response of a visuomovement cell in the continuous and flashed stimulus tasks. A: response of the cell in the visually guided saccade task. Left: raster diagram of neuronal response in 8 successive trials. Each black dot is a neuronal discharge. Successive trials are synchronized on target appearance (left) and saccade beginning (right). The histograms sum the activity in the trials displayed in the raster above. Tick marks under the histogram are 100 ms apart. Horizontal (H) and vertical (V) eye position and fixation point (FP) and stimulus (STIM) traces are below. The right is a cartoon of the geometric arrangement of the saccade, receptive field, fixation point, and target. The cell begins to discharge when the stimulus appears, and continues until the monkey makes the saccade. B: continuous stimulus task: the monkey makes a saccade that brings a stimulus into the FRF. The cell discharges after the saccade. C: flashed stimulus task: the stimulus appears and disappears in the FRF before the monkey makes the saccade. The cell fires after the saccade with the same latency as when the saccade brought the physical stimulus into the FRF.



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Fig. 3. Control experiments for the neuron shown in Fig. 2. Cartoon, rasters, histograms, and traces as in Fig. 2. Rasters synchronized on the beginning of the saccade. A: no-stimulus control. The monkey makes the same saccade as in the flashed-stimulus task in the previous figure, but the stimulus is not present. There is no postsaccadic response, 6 trials. B: null saccade control. The monkey makes a saccade that fails to bring the stimulus into the receptive field. The cell does not respond. Only 3 trials are shown here, but Fig. 4 addresses this issue in a more detailed way for the same neuron.

This short-term spatial memory response was not merely a nonspecific expansion of the receptive field around the time of the saccade. The cell had a negligible response when the flashed stimulus location (STIM A) was outside both the current and FRFs (Fig. 4A). When the stimulus appeared closer to the center of the FRF (STIM B), the cell showed a slight increase in response (Fig. 4B). When the flashed stimulus location was in the center of the FRF (STIM C), the cell fired robustly (Fig. 4C). Varying the delay period between stimulus flash and the saccade in randomly interleaved trials between 150 and 1,100 ms did not affect the response of the cell (Fig. 5) for the neuron shown, but for other neurons, the stimulus had to appear close to the onset of the saccade target.



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Fig. 4. Spatial selectivity of short-term memory response. In A-C, the monkey makes the same saccades, from FP1 to FP2 to FP3, but the stimulus appears at different locations that were pseudorandomly interleaved from trial to trial. A: stimulus outside the FRF. B: stimulus at the border of the receptive field. C: stimulus in receptive field. Cartoon shows the spatial relation of the various stimuli. All rasters synchronized on the beginning of the saccade.



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Fig. 5. Time course of short-term memory response. Short-term memory response to a stimulus flashed for 50 ms at 1,100, 900, 450, and 100 ms before the fixation point disappeared as the signal to make the saccade. Rasters synchronized on saccade beginning. Histograms sum the activity of the rasters above.

Fifty-eight percent (28/48) of the visuomovement cells demonstrated short-term spatial memory. Of course for a cell to qualify as short-term memory response, the neuron could not respond to the stimulus when it appeared in the FRF as the target for a saccade. Furthermore, the neuron could not respond during or after the saccade when there was no stimulus present---except for cells with intertrial memory, which, as described in the following text, respond when no stimulus is present after the monkey has had sustained exposure to a stimulus in the FRF. In all of the experiments, the stimulus that evoked the response from the neuron was completely irrelevant to the animal's behavior.

VISUAL NEURONS. Sixty-six percent (21/32) of the visual cells exhibited short-term spatial memory responses (Fig. 6). The neuron illustrated fired 78 ms after a visual stimulus appeared its receptive field (Fig. 6A, left) and had no burst before the saccade to the location of that stimulus (Fig. 6A, right). The cell responded at the time of the saccade in the flashed stimulus task (Fig. 6B, right) but gave no response to the appearance of the stimulus in the FRF (Fig. 6B, left). Because this cell discharged before the beginning of the saccade in the continuous stimulus task, it also had a predictive response in the continuous stimulus task (not shown). The cell also did not discharge in association with the identical saccade when saccade brought no stimulus into the receptive field (Fig. 6C).



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Fig. 6. Short-term spatial memory in a visual cell. Each panel shows the activity of the neuron synchronized on stimulus appearance (left) and saccade beginning (right). Rasters, histograms, stimulus and eye movement traces, and cartoon as in Fig. 2. A: memory-guided saccade task: visual response to the appearance of the stimulus (left raster, synchronized on stimulus appearance) but no presaccadic burst (right raster, synchronized on saccade onset) in the memory guided saccade task. B: flashed stimulus task: no response to the appearance of the stimulus (left raster, synchronized on stimulus onset) and perisaccadic response when the monkey brings the spatial location of the vanished stimulus into the receptive field (right raster, synchronized on beginning of saccade). The burst precedes the saccade. C: no-stimulus control: no response when the monkey makes the same saccade without a properly situated stimulus in the no-stimulus control task (raster synchronized on saccade beginning).

SAMPLE POPULATION CHARACTERISTICS. There was a continuous distribution of latencies from saccade onset, ranging from -48 to 272 ms (Fig. 7). The amplitude of the short-term spatial memory response was almost inevitably less than the visual on response as measured in the delayed saccade task (Fig. 8).



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Fig. 7. Latency of short-term memory response during flashed stimulus task vs. visual on-response latency. Abscissa: visual on-response latency. Ordinate: latency from saccade beginning. open circle , the latency of a single neuron; ---, the saccade beginning.



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Fig. 8. Magnitude of short-term memory response versus visual on response. open circle , the response of one neuron. Abscissa: visual on response. Ordinate: short-term memory response. ---, x = y.

Intertrial spatial memory

Short-term spatial memory responses occur within a single trial. We used the interleaved experimental paradigm to demonstrate effects between trials. We first ran the no-saccade and no-stimulus control experiments in blocks and then studied the response of the neuron in the flashed and continuous stimulus paradigms, also run in blocks. For 60 visually responsive frontal eye field neurons, we then randomly interleaved trials of all four sorts. At this point, the monkey had already become accustomed to the stimuli shown in the task. Immediately before the interleaved paradigm, the monkey had done a block of flashed or continuous stimulus trials in which a stimulus or the spatial location of a recently flashed stimulus had been brought into the receptive field by a saccade. None of the cells studied had responded in either the no-stimulus or the no-saccade control tasks. Surprisingly, 21 (35%) of these cells, which had previously been silent during the initial no-stimulus control task when it was performed before the flashed or continuous stimulus tasks, now responded during the no-stimulus control task when it was interleaved with continuous stimulus trial. A visuomovement cell that demonstrates this effect is illustrated in Figs. 9 and 10. Note that the cell had a significant anticipatory response (Bruce and Goldberg 1985) (Fig. 9A): it responded after the saccade to the fixation point but before the stimulus appeared; this anticipatory response was less than the visual on response. The cell illustrated had both a visual (Fig. 9B) and movement response (Fig. 9C) during the delayed saccade task. When the monkey performed the delayed saccade task in a block of trials, with the stimulus always in the same place, the cell began to discharge after the monkey had achieved fixation but before the saccade target appeared on the screen. When the monkey performed the no-stimulus control task before any continuous-stimulus or flashed-stimulus trials, the cell was silent (Fig. 10A). The cell exhibited a marked predictive response during the continuous stimulus task, discharging before the identical saccade when that saccade would bring the stimulus into the receptive field (Fig. 10B). We then randomly interleaved no-stimulus trials and stimulus trials, with the monkey always making the same saccade. When we presented stimuli in the cell's FRF during some of the trials, the cell registered a brisk predictive response (Fig. 10C), which was then reinforced by the reafferent response to the stimulus in the receptive field after the saccade. Surprisingly, even though previously the cell did not discharge during the saccade control task when that task had been run before any continuous stimulus trials, the same saccade with no stimulus in the FRF now elicited a significant response, differing from the response in the continuous stimulus task only in latency (Fig. 10D). We interpreted this response as an intertrial memory response: the cell responded as if the stimulus, present on the majority of recent trials, were still present on the current trial.



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Fig. 9. Responses of visuomovement cell with intertrial memory. Cartoon, rasters, histograms, and eye and stimulus traces as in Fig. 2. A: activity synchronized on saccade to fixation point at the beginning of each trial (vertical line). B: activity synchronized on appearance of saccade target. C: activity synchronized on beginning of saccade. Note that the cell has both a visual and a presaccadic response.



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Fig. 10. Predictive visual response in a cell with intertrial memory response. Same neuron as in Fig. 9. Cartoon, rasters, histograms, and eye position and stimulus traces same as in Fig. 2. All rasters synchronized on the beginning of the saccade. A: no-stimulus control task run in a block before any continuous stimulus trials: the neuron did not discharge. B: continuous stimulus task run in a block: the visuomovement cell fired consistently before the beginning of the saccade. C: interleaved continuous stimulus task: the cell fires similarly to B. D: interleaved no-stimulus control trials: now the cell also discharges during trials in which no stimulus is present, showing an intertrial-memory response to a stimulus that appeared in a previous trial.

The intertrial memory response often took a long time to disappear, as long as 30 trials (roughly 1.5 min). Figure 11 shows the forgetting curves for two cells with intense intertrial memory activity.



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Fig. 11. Forgetting curves for 2 neurons. The monkey performed consecutive saccade-control trials, in which the monkey made the same saccade that evoked the response but no stimulus present, were made consecutively until the intertrial response returned to background, or the cell was lost. Ordinate: neuronal activity in the immediate postsaccadic period for each single trial. Abscissa: trial number in the forgetting sequence.

Thirty-five percent (21/60) of the neurons had intertrial memory activity, i.e., their activity in the no-stimulus interleaved task was significantly greater (P < 0.05 by t-test) than the background activity measured in one of the control tasks performed before any flashed or continuous stimulus trials had occurred (Fig. 12). For all cells, the intertrial memory response was less than the visual on-response. Unlike the short-term memory responses, no intertrial memory response began before the beginning of the saccade (Fig. 13). This was true even for neurons that demonstrated predictive responses in the continuous stimulus task.



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Fig. 12. Relationship of visual responses and intertrial memory responses to background activity. Visual on-response () and intertrial response (open circle ) plotted against background activity as determined in a no-stimulus control task before any continuous stimulus or flashed stimulus task was performed, for each cell with a statistically significant intertrial response. Straight lines connect activity for each cell in the 2 conditions. Diagonal straight line is x = y.



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Fig. 13. Latency of intertrial memory response compared with latency of visual on-response. Abscissa: visual on-response latency. Ordinate: latency from saccade beginning. black-triangle, a single neuron.

TONIC RESPONSES. Of the 80 visually responsive cells examined, 20 discharged longer than the stimulus duration (300 ms) in the delayed saccade task. Every one of these cells had at least one of a short-term memory response, intertrial memory response or a predictive response.

COMBINATIONS OF NONCLASSICAL VISUAL RESPONSES. Sixty-two (78%) of the visually responsive cells tested had at least one kind of nonclassical visual response (predictive, short-term spatial memory, intertrial spatial memory responses) demonstrated in the flashed stimulus or continuous stimulus task. Table 1 shows the different combinations of these effects found in this population. Note that the most common response type to be found alone was the short-term memory response. The table only included those cells for which all three types of response were tested.


                              
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Table 1. Distribution of nonclassical visual and memory responses


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In these experiments, we have demonstrated two different forms of visuospatial memory in the monkey frontal eye field: a within-trial short-term spatial memory response and a longer-term, intertrial memory response. The within-trial memory response resembles those demonstrated in the monkey lateral intraparietal area (LIP) (Duhamel et al. 1992) and superior colliculus (Walker et al. 1995). In the course of these experiments, however, we found a rather unexpected effect: a low-frequency discharge that occurred when the monkey revisited a fixation location where, for a block of trials in the recent past, a stimulus had appeared in the receptive field of the neuron. This intertrial spatial memory effect required a number of trials to disappear. We will discuss these phenomena in the context of their relationship to visual processing and to their resemblance to other demonstrations of memory in the monkey brain.

Short-term spatial memory as a visual phenomenon

Visual memory has been demonstrated in the frontal eye fields (Bruce and Goldberg 1985) and also in a number of other areas of the monkey brain, including the prefrontal (Funahashi et al. 1989; Fuster and Alexander 1971), inferotemporal (Fuster and Jervey 1981), and parietal cortices (Colby et al. 1996; Gnadt and Andersen 1988) and the substantia nigra pars reticulata (Hikosaka and Wurtz 1983). In these areas, the memory is manifest by a tonic, continuing response to a stimulus that appeared transiently during a fixation task. Although in some of these areas the activity was first demonstrated in the context of a delayed saccade task, in the frontal eye fields (Bruce and Goldberg 1985) and in LIP (Colby et al. 1996), the saccade is not necessary for the tonic visual response. In these experiments, we demonstrated a new property of the visual memory response in the frontal eye field. The stimulus need not appear in the receptive field of the neuron as determined in a simple fixation or delayed-saccade task. Instead, neurons with a visual response can respond after a saccade to a stimulus that appeared briefly before the saccade when that saccade brings the spatial location of the vanished stimulus into the visual receptive field of the neuron. This effect depends not on the trajectory of the saccade, nor on the absolute spatial location of the target, but instead on the combination of the two: the saccade must bring the spatial location of the vanished stimulus into the receptive field of the neuron. This effect resembles the predictive visual response described previously (Umeno and Goldberg 1997), but it can occur in neurons that do not demonstrate a predictive response, neurons that discharge after but not before a saccade brings a stimulus into their receptive field.

Because the frontal eye field is primarily dedicated to the generation of purposive eye movements, one could argue that the spatial memory is actually a premotor discharge signaling a saccade that is canceled elsewhere in the brain. Such cancellation could occur at the level of the fixation neurons in the superior colliculus (Munoz and Wurtz 1993) or the omnipause neurons in the dorsal raphé (Buttner-Ennever et al. 1988). However, we never saw a predictive response on a movement neuron (Umeno and Goldberg 1997); these neurons require that the monkey actually make the saccade, and it would be unlikely for them to respond to a transient stimulus when they failed to response to the onset of a more sustained stimulus. In addition, the task was designed so that the monkey predictably made a saccade to a stimulus outside the receptive field immediately after the saccade that evoked the memory response. It would be difficult to argue that the response was due to an active planning of the saccade to the spatial location of the target when the monkey could predict that its next saccade would be to a different target. Therefore the within-trial memory response must be a property of the visual processing of the frontal eye field or its afferents. Similar within-trial memory responses have been demonstrated in LIP, an area with a strong reciprocal projection to the frontal eye field.

The stimuli with which we demonstrated both the short-term and intertrial responses were irrelevant to the monkey's task, and it is natural to assume that the stimuli were therefore irrelevant to the monkey. This may not be the case. Flashed stimuli are inevitably salient. Neurons in LIP respond far more intensely when a saccade brings recently flashed irrelevant stimuli onto the receptive field of a neuron than they do when the same saccade brings the same stimulus onto the receptive field when it has been stable in the environment (Gottlieb et al. 1998; Kusunoki et al. 2000). Because LIP has a strong projection to the frontal eye field, it would not be surprising if the short-term response resulted from the salience of the task-irrelevant stimulus. The maintenance of the memory response in the intertrial memory phenomenon may also have to do with the salience of the stimuli. The visual environment of the monkeys in these experiments consisted only of three dots in a sea of darkness rather than the complex visual environment of everyday life. It could be that a task-irrelevant stimulus is not irrelevant to the monkey when it is one of only three stimuli that the monkey ever sees. Certainly the response to a possible saccade target in the superior colliculus varies inversely with the number of possible stimuli (Basso and Wurtz 1998). Similarly, the responsiveness of visual neurons to stable stimuli in a natural environment brought into their receptive fields by saccades is marginal (Burman and Segraves 1994). If one assumes that the role of the visual mechanism in the frontal eye field is to provide a spatially accurate map of salient stimuli that are plausible oculomotor targets, then in the experimental environment that we have used, the irrelevant stimuli can evoke intertrial and short-term responses because, given the sparseness of the environment, they cannot help but be salient.

It is important to emphasize that short-term spatial memory is not an explicit spatial representation. The neurons describe the distance and direction of the stimulus from the fovea, i.e., a vector, rather than the absolute spatial location of the stimulus in supraretinal coordinates. As the eyes move, the ensemble of neurons representing a given stimulus moves. This enables the frontal eye field to maintain a spatially accurate representation of possible saccade targets despite a moving eye. The shift of representation, of course, would be expected if the stimulus were still present; in short-term spatial memory the ensemble representing the trace of the stimulus shifts around the time of the saccade even though the stimulus never appeared in the receptive fields of the postsaccadic ensemble.

This short-term spatial memory, although unlikely to be a saccadic signal per se, is immensely useful to the saccadic system. By automatically updating the frontal eye field's representation of the remembered world, the phenomenon facilitates spatially accurate saccades to the spatial locations of stimuli that flashed briefly before intervening saccades without requiring an explicit representation of target position in some supraretinal coordinate system.

The short-term memory resembles the predictive response and may share some of its underlying neural processing. However, the majority of neurons with short-term memory responses do not have predictive responses. The predictive and memory responses can be modeled by assuming that the visual system has access to a signal describing the change in eye position (Quaia et al. 1998). In the predictive response, the change in eye position must be signaled by a corollary discharge from the oculomotor system because it comes before the eye actually moves. The change in eye position signal for those neurons that have short-term memory responses after the saccade could arise from a proprioceptive signal of the new eye position.

Intertrial memory

The time interval of memory is greater than a visual fixation. The studies quoted in the preceding text have all demonstrated within-fixation mnemonic responses and not responses that lasted for longer intervals. In these experiments, however, we have demonstrated that once a spatial location becomes established as associated with a visual stimulus, activity referable to that stimulus remains for a number of trials after the stimulus has vanished. Spatial memory responses have been demonstrated in the hippocampus of the rat (O'Keefe 1999) and monkey free to move in space (Eifuku et al. 1995). These neurons discharge when the animal occupies a certain place, and the nature of the place can be established by cues of many modalities. This hippocampal memory can be considered a cognitive memory for location. The memory that we have described in these experiments is more likely to be a more specialized form of memory, a memory for trajectory. Unlike the hippocampal neurons, which are probably independent of eye position, the frontal neurons are dependent on the establishment of a vector between eye fixation and target location. Once the visual location of a target has been established, the presence of that target is no longer necessary for the guidance of eye movements to its spatial location, and monkeys can performed saccades to the location of a target that appeared only on previous trials (Bruce and Goldberg 1985). We suggest that the intertrial mechanism that we have established can provide the substrate for the memory that allows the performance of such learned saccades. Like the predictive visual responses (Umeno and Goldberg 1997) and the within-trial memory responses, intertrial memory responses are a property of visual processing. They are seen on visual and visuomovement neurons and not movement neurons, and they occur despite the fact that the monkey does not make a saccade to the spatial location of the vanished stimulus that evokes the response.

The intertrial memory may be responsible for some component of the anticipatory response. Neurons in the frontal eye field have often have increased activity before the appearance of the stimulus when the monkey performs a block of saccade trials (Bruce and Goldberg 1985). Although the original interpretation was that the monkey was anticipating the appearance of the saccade target, this activity could actually be an intertrial memory response. We discovered neurons with intertrial memory that also showed anticipatory responses (Fig. 9).

The three nonclassical visual responses that we have demonstrated in this and the preceding paper (Umeno and Goldberg 1997) are distributed in a way that suggests that they are generated independently. Clearly many cells with memory responses do not have the latency advance that is the hallmark of the predictive responses. It is curious that cells with predictive or intertrial responses do not have short-term responses but that may be due to an inability to respond to transient task-irrelevant stimuli.

These results suggest that whenever a monkey achieves a visual fixation, the frontal eye field develops a representation of potential saccade targets based on the animal's recent experience. These targets include present and recently vanished objects, evoked by visual and memory responses. However, this representation of potential saccade targets is far earlier in the saccadic processing chain than the actual decision to make a saccade.


    FOOTNOTES

Address for reprint requests: M. E. Goldberg, Laboratory of Sensorimotor Research, National Eye Institute, Bldg. 49, Rm. 2A50, Bethesda, MD 20892-4435 (E-mail: meg{at}lsr.nei.nih.gov).

Received 5 October 2000; accepted in final form 31 July 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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0022-3077/01 $5.00 Copyright © 2001 The American Physiological Society