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Prefrontal unit activity during delayed conditional discriminations in the monkey
Brain Research, 225 (1981) 51-65 Elsevier/North-Holland Biomedical Press
51
PREFRONTAL UNIT ACTIVITY DURING DELAYED CONDITIONAL DISCRIMINATIONS IN THE MONKEY
MASATAKA WATANABE Department of Psychology, Faculty of Letters, University of Tokyo, Bunkyo-ku, Tokyo, 113 (Japan) (Accepted April 2nd, 1981) Key words: monkey - - prefrontal unit activity - - delayed conditional discrimination - - spatial information processing - - non-spatial information processing - - conditional information processing
SUMMARY Single unit activity was recorded from the prefrontal cortex (principalis, arcuate and inferior convexity areas) of the monkey while the animal was performing a delayed conditional discrimination task. Sequential events of the task were as follows: instructional cue presentation, 1st delay, presentation of two pattern stimuli on left and right windows respectively as a discriminative cue, 2nd delay and choice response to the left or right window. The positive pattern was dependent on the instructional cue. In total, 424 units obtained from two monkeys showed a correlation with some aspects of the task. O f these 424 task-related units, 169 differentiated between the instructional cues and/or the discriminative cues. The majority of these differential units (n = 123) were found to be related to spatial information processing (related to the side of the response) while 19 differential units were related to non-spatial information processing (related to the color or pattern configuration of the cue). The activity of the remaining 27 differential units was considered to be related to both spatial and non-spatial information processing (related to both the instructional cue and the side of the response) and this type of unit was shown to be involved in conditional information processing. The results indicate that prefrontal units may be related to the meaning of the stimulus independent of its physical properties.
INTRODUCTION Unit activity in the prefrontal cortex has been studied in awake monkeys during performance on delayed response or delayed alternation tasks in order to investigate the neuronal correlates of these behaviors z,s. Many dorsolateral prefrontal units show 0006-8993/81/0000-0000/$02.50 © Elsevier/North-Holland Biomedical Press
52 changes in their discharge rate in relation to several aspects of these tasks. Some taskrelated units (differential delay units) show differential activity during the delay period on delayed response and delayed alternation tasks7,10,12. The possibility that these differential delay units are related to spatial short-term memory was proposed 1°. In our previous study on the delayed response task, two kinds of differential delay units were distinguished: one was related to the spatial location of the cue (cue-related differential delay unit), and the other was related to the direction of the animal's response (response-related differential delay unit) la. The activity of the latter types of differential delay unit was found to be conditional to the spatial cue. The unit activity which is considered to be conditional to the spatial cue was found also in the delayed alternation. The activity of differential delay units prior to the selection of a particular choice key was found to be related to the relative rather than the absolute position of two out of 4 horizontally situated keys 11 .These results suggest that the activity of prefrontal units is conditional to the task situation. On the other hand, prefrontal unit activity has not been fully studied in relation to non-spatial information processing. This study was therefore conducted to investigate how spatial and non-spatial aspects of the stimulus are processed in the prefrontal units and to analyze the 'conditional' nature of the prefrontal unit activity. The task situation employed in the present study was a 'delayed conditional discrimination'. The animal was required to respond differentially (respond to the right side or to the left side) to an identical cue or required to perform the same response to different cues depending on non-spatial instructions previously presented. Thus, different cues had the same meaning and an identical cue had different meanings to the animal depending on instructions. The major goal was to investigate those units which may show differential activity to some aspects of the stimulus presented, and to analyze to which aspects (physical properties or some other aspect such as the meaning) of the stimulus those units are related. 'Conditional units' which, depending on the instruction, showed different patterns of activity to the same cue, or the same pattern of activity to the different cues, were of special interest. Some parts of the present study have been presented in preliminary form 21,22. METHODS Two adult rhesus monkeys (Macaca mulatta) weighing 4.5-5.0 kg were trained in delayed conditional discrimination tasks using the approximation procedure. During the experiment the monkey was seated on a primate chair. The animal faced a test panel which contained two choice keys (each, 8 cm high and 6 cm wide) and a hold lever (5 cm wide and 5 cm protruded) situated 10 cm below the keys. The two choice keys, 5 cm apart, were located at the height of the monkey's eye approximately 40 cm in front of the animal. Each choice key could be illuminated from behind by a rear projection unit (Industrial Electronics Engineering, series 80). The apparatus was controlled by an electronic circuit. A schematic diagram of the sequence of events in the three delayed conditional discrimination tasks is shown in Fig. 1. The monkey was first trained on a 'color-pattern-I' task. The monkey had to
53 2ND
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Fig. 1. The sequence of events in the three delayed conditional discrimination tasks. Abbreviations: ITI, intertrial interval; IC, instructional cue; DC, discriminative cue. See text for details.
depress the hold lever to start a trial. After 5 s of holding (intertrial interval, ITI), either red or green lights were simultaneously presented on both choice keys for 1 s as an instructional cue (IC). The IC period was followed by a first delay period (1 s), and then two pattern stimuli were presented on the choice keys for 1 s as a discriminative cue (DC). The pattern stimuli were either a circle on the left key and stripes on the right key, or a circle on the right and stripes on the left. The D C period was followed by a second delay period (1.5-2.5 s, generally 2 s). If the monkey continued depressing the hold lever during all these periods (ITI, IC, 1st delay, D C and 2nd delay), white lights were then presented on both choice keys simultaneously as a go signal (GS). The correct key was the one that had had a circle on it if the IC had been red, and stripes if the IC had been green. I f the monkey pressed the correct key after the white lights were presented, the lights were turned off and a drop of fruit juice (0.2 ml) was given into the mouth as a reward. The re-run self-correction technique was employed. Thus, if the animal released the hold lever before the GS was presented, or if the animal made an error, the animal had to depress the hold lever again in order to restart a trial. The animal was allowed to use only one (preferred) hand. Two delay periods were introduced in this experiment to differentiate unitary firing changes related to the 3 events of the task; i.e., IC, D C and the choice response. The animal was trained on the task for about 1000 reinforced trials every day until reaching a criterion of better than 95 ~ correct responses in a daily session. Two control tasks were added after the unit recording was completed in one hemisphere of the first monkey. In a 'color-pattern-II' task, a plus and a square were used as D C stimuli. The positive pattern was the plus if the IC had been red and the square if it had been green. In a 'pattern-pattern' task, a plus or a square was presented as an IC on
54 CO LOR,
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Fig. 2. Twelve sequences of the three kinds of delayed conditional discrimination tasks. The small upward arrows indicate the positive side. both left and right choice keys. The positive pattern was the circle if plusses had been presented as an IC and the stripes if squares had been presented. As shown in Fig. 2, there were a total of 12 sequences o f l C s and DCs: from 1 to 4 in the 'color-pattern-l' task, from 5 to 8 in the 'color-pattern-II' task, and from 9 to 12 in the 'pattern-pattern' task. In each task the 4 sequences were presented in a predetermined semi-random schedule. It took about 4 months for the animal to master the color-pattern-I task, and an additional two months for the two other tasks. During the training and recording periods, the animals were deprived of water and received their entire fluid ration in the testing apparatus, except for their daily ration of fresh fruit. Monkey pellets were always available ad libitum in the home cage. On completion of the training, the animal was surgically prepared under sodium pentobarbital anesthesia (Nembutal 35 mg/kg, i.p.). A stainless steel cylinder (18 m m in diameter) as a microdrive receptacle and 4 bolts for head fixation were implanted at appropriate locations of the skull. The center of the cylinder was aimed at A -----28, L = 15 in the stereotaxic coordinate system. Details of the procedure have been described previously 2. Antibiotics (crystalline procaine penicillin G in oil, 20000 IU, i.m.) were administered every day for a week after the operation. Recording was started about 10 days after surgery. During the recording sessions, the animal's head was held rigidly by means of the implanted bolts, and a hydraulic microdrive was attached to the implanted cylinder. A glass-insulated platinum-iridium microelectrode similar to that described by Wolbarsht et al. 23 was used for unit recording. The unit action potentials were processed through a window discriminator and converted into square-wave pulses. Throughout the recording session, both unit discharges and shaped pulses were monitored on an oscilloscope to ensure reliability of the conversion. The unit activity, shaped pulses, and signals corresponding to the stimulus-response events of the task were all recorded on a magnetic tape, and also displayed on an inkwriter. Recorded data were later analyzed on a PDP-12 computer by utilizing a N I M H - L N P Neurophysiological Analysis Program. Raster displays, cumulative records and frequency histograms were used for graphic representation. Units were recorded in the principalis area, arcuate area, and inferior convexity area of the prefrontal cortex (A ~ 20-36, L ~ 10-20) while the animal was performing
55 the color-pattern-I task. Only when a task-related unit, especially the one which showed differential activity, was found, was the activity examined in the other two tasks so that the aspects of the stimulus to which the activity was related could be examined. At the end of the experiment, the monkeys were sacrificed and perfused with normal saline followed by 1 0 ~ formalin. Then the dura was removed and the location of the cylinder on the cortical surface was determined. The brain was extracted and fixed in 10 ~o formalin and later sectioned to match the tracks of the electrode penetrations. RESULTS
In the present experiment only those task-related units were examined which could be recorded for at least 24 trials (6 trials for each sequence) and showed marked changes in firing rate in association with one or more of the events of the colorpattern-I delayed conditional discrimination task. A total of 424 task-related units were obtained from 192 penetrations in 3 hemispheres of two monkeys. Out of 424 units, 169 units differentiated between cues or cue configurations (differential units), while the remaining 255 units did not show such differential activity (non-differential units). A unit was designated as a 'differential unit' when its activity observed at a certain phase of the task in one or two sequences was distinctively different from that observed in the other sequences. Those units which showed activity change at several phases and showed differential activity at one of these phases were classified into 'differential units'. Forty-seven differential units could be examined in all three tasks. TABLE I
( A ) Classification of units which did not show differential activity
I II III IV
S - R event units Reward units Delay units Unclassified units Total
N
%
150 19 52 34 255
58.8 7.5 20.4 13.3 100.0
( B) Classification of units which showed differential activity N I II III IV V
IC-related units DC-related units IC-DC-related units Impending-response-side-related units Choice-side-related units Total
%
10 9 27
5.9 5.3 16.0
87 36 169
51.5 21.3 100.0
56
Activity of non-differential units Non-differential units registered the occurrence of task events. For convenience the 255 non-differential units were classified into one of 4 types (stimulus-response event units, reward units, delay units and unclassified units) depending on the phase where distinct activity change could be observed on frequency histograms and raster displays, on correct trials in the color-pattern-I task (Table IA). Stimulus-response (S-R) event units (n = 150) showed increases or decreases in firing rate in relation to the onset of one or more of the stimuli (IC, DC and GS) and/or the response (release of the hold lever or depression of the choice key). Reward units (n = 19) exhibited increased or decreased firing when juice was delivered as a reward. Delay units (n = 52) showed sustained (increased or decreased) changes during the first (n = 6), second (n = 22) or both (n = 24) delay periods. In 9 of 52 delay units, sustained changes were observed during both the cue and the following delay periods. The remaining 34 units could not be classified into any of the three designated types. Most were combinations of the above categories.
Activity of differentia! units Differential units (n = 169) responded to a specific cue or cue configurations. The differential units were classified into one of 5 types (IC-related, DC-related, IC-DCrelated, impending-response-side-related, and choice-side-related) depending on both
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Fig. 3. Raster displays of the activity of the IC-related unit (A) and the DC-related unit (13). On the left side are shown 4 combinations of the IC and DC of the color-pattern-I task (sequences 1-4). For both units the dashed line indicates the time of the IC presentation and the solid line in the center indicates the time of the DC presentation. Black bars below the headings of IC and DC indicate the period when each cue was being presented, and GS indicates the time at which the 'go' signal was presented. Each row indicates one trial and each dot represents one spike discharge. Heavy dots after the GS presentation indicate the time of depression of the choice key. The second delay period was 2.3 s for (A) and 2.5 s for (B).
57 IC IC
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Fig. 4. Raster displays of the IC-DC related unit activity. Conventions are the same as in Fig. 3. In this unit, the second delay period was 1.7 s. the phase where differential activity was observed and the characteristics of the differential activity on correct trials in the color-pattern-I task (Table IB). IC-related units (n = 10) showed activity dependent on the difference in the IC. This could occur during the IC period (n = 1), during the first delay period (n = 8), or during the DC period (n = 1). An example of this type of unit, shown in Fig. 3A, exhibited a higher rate of firing when the green lights were presented (sequences 3 and 4) than when the red lights were presented (sequences 1 and 2) as an IC during the first delay period. DC-related units (n = 9) showed differential activity depending on the configuration of the two pattern stimuli; i.e., depending on whether DC was the circleright and stripes-left (sequences 1 and 3) or the circle-left and stripes-right (sequences 2 and 4). This could occur during the DC period (n = 7) or during both the DC and the second delay periods (n ~- 2). The example in Fig. 3B showed an increase in firing rate in sequence 1 and sequence 3 at the time of the DC presentation (the activity changes observed around the time of the response did not differentiate among the 4 sequences). IC-DC-related units (n = 27) showed specific activity depending on the combination of the IC and DC. Ten units showed such specificity at the time of the DC presentation, 7 units during the second delay period and the remaining 10 units throughout both periods. An example of this type of unit is shown in Fig. 4. This unit showed increased activity during the DC period (and in some trials during the second delay period), when a circle was presented on the left side and stripes were presented on the right only following red IC (sequence 2), and no noticeable change was observed in the other sequences. There were some variations in the specificity of the activity after the DC presentation in IC-DC-related units. In 10 units, the activity observed in one sequence
58
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Fig. 5. Raster displays of the activity of the impending-response-side-related unit (A) and the choiceside-related unit (B). For B, the center line indicates the time of the 'go' signal (GS) presentation. The unit activity around the IC presentation is not shown for this unit. Other conventions are the same as in Fig. 3. The second delay period was 1.7 s for A and 2.5 s for B. was different from that in the other 3 sequences, and no difference in activity was observed among the 3 sequences, as in Fig. 4. In 6 units, the activity observed in each of all 4 sequences was different from that in every other sequence. In the remaining 11 units, a specificity was observed for each of two sequences while the activity in the remaining two sequences was not distinguishable (e.g., Fig. 6). Impending-response-side-related units (n = 87) showed differential activity in relation to the side of the animal's response, at the time of the DC presentation (n = 14), during the second delay period ( n = 47) or throughout both periods (n = 26). The unit shown in Fig. 5A showed an increased firing rate after the IC presentation (in some trials even before the IC presentation) in all the 4 sequences. After the DC presentation, increased activity continued or further augmented activation was observed when the animal responded to the right side (sequences 1 and 4), while such activation was not observed when the animal responded to the left side (sequences 2 and 3). The differential activity was observed during both the D C and the second delay periods. Impending-response-side-related units showed a similar pattern of activity to different DCs (sequences 1 and 4, or 2 and 3; circle-right, stripes-left and circle-left, stripes-right), and showed different patterns of activity to the same D C (sequences 1 and 3; circle-right, stripes-left or sequences 2 and 4; circle-left, stripes-right), depending on the IC. Choice-side-related units (n = 36) showed differential activity at the time of choice depending on the side to which the animal responded. The example shown in Fig. 5B showed an activity change when the animal responded to the right side at the time of the response. The activity of differential units was examined in the color-pattern-II task and in the pattern-pattern task when such units could be held for a sufficient period of
59 time, in order to investigate what aspects of IC and D C were important for the observed differential changes in the color-pattern-I task. Only IC-DC-related units (n ---- 12) and impending-response-side-related units (n ----35) could be examined on these tasks. These came from the right hemisphere of the first monkey and from the left hemisphere of the second monkey. Fig. 6 shows an IC-DC-related unit on the three tasks. This unit showed a change in activity during the IC or during the first delay period in some trials, but the activity change did not differentiate among the 4 sequences of the color-pattern-I task. The activity of this unit after the D C presentation was not dependent on whether there was an activity change during the IC and the first delay periods. This unit exhibited the highest rate of firing in sequence 2, lowest activity in sequence 1, and moderate increased activity in sequence 3 and sequence 4 after the D C presentation in the original color-pattern-I task (Fig. 6A). ic
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Fig. 6. Raster displays of the IC-DC-related unit activity in the three delayed conditional discrimination tasks. A: activity in the color-pattern-I task; B: activity in the color-pattern-II task; C: activity in the pattern-pattern task. Conventions are the same as in Fig. 3. In this unit the second delay period was 2 s.
60 Correct C [
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Fig. 7. Example of the activity of the IC-DC-related unit on correct and erroneous trials in the colorpattern-I task. Each pulse represents a spike discharge. Other conventions are the same as in Fig. 3. Specific activity observed after the D C presentation in the color-pattern-I task was also observed in the other tasks (Fig. 6B, C) and the pattern of activity observed in sequence 5, 6, 7 or 8 in the color-pattern-II task and in sequence 9, 10, 11 or 12 in the pattern-pattern task was similar to that observed in sequence 1, 2, 3, or 4 in the colorpattern-I task although different ICs (red-green vs. plus-square) or different DCs (circle-stripes vs. plus-square) were used among the three different tasks. Thus, this type of unit showed similar patterns of activity to the different DCs (1 vs 5, 2 vs 6, 3 vs 7 and 4 vs 8) and showed different activity to the same DC (sequences 1 and 3, 2 and 4, 5 and 7, 6 and 8, 9 and 11, 10 and 12) depending on the IC. Impending-response-side-related units showed differential activity depending only on the side to which the animal responded regardless of the task. Thus, this type of unit showed a similar pattern of activity to sequences 1, 4, 5, 8, 9, and 12 or to sequences 2, 3, 6, 7, 10 and 11. Although activity on erroneous trials was not always obtained for all the 4 sequences of the color-pattern-I task for each unit because of the near perfect performance of the monkeys, some data were obtained for I C - D C - r e l a t e d units, impending-response-side-related units and choice-side-related units. Fig. 7 provides an example of the activity of an IC-DC-related unit on correct and erroneous trials. This unit is the same as in Fig. 6 and showed the highest rate of firing in sequence 2, lowest rate of firing in sequence 1 and moderate increased activity in sequence 3 and
61
A
B
C
Fig. 8. Locations of the penetration of differential units in the prefrontal cortex. Penetrations are projected on the surface of the left hemisphere. Following patterns indicate penetrations where each type of differential units were found. A: R, IC-related unit; A, DC-related unit; B: A, IC-DC-related unit; C: Q, impending-response-side-related unit; O, choice-side-related unit. sequence 4 after the D C presentation on correct trials. On erroneous trials, a large increment in firing rate was observed in sequence 4, but not in sequence 2 after the D C presentation. The activity on erroneous trials in sequence 3 was also different from that on correct trials in sequence 3. Thus, it was possible to predict the occurrence of errors from the activity of IC-DC-related units before the response was actually made, whenever the activity after the D C presentation was obviously different from that observed on correct trials. Impending-response-side-related units and choice-side-related units showed changes in activity depending on whether the animal responded to the left or to the right, irrespective of whether or not the response was correct. Thus, impendingresponse-side-related units showed the activity as if the positive pattern appeared on the right side (sequences 1 and 4) even if the positive pattern actually appeared on the left side (sequences 2 and 3) or vice versa on erroneous trials. Therefore it was also possible to predict the occurrence of errors from the activity of this type of units before the response. Differential units observed in this experiment were found in principalis, arcuate and inferior convexity areas of the prefrontal cortex. Each type of differential unit was found in each of these three areas and no distinct localization of each type of differential units was observed (Fig. 8). DISCUSSION Several kinds of differential units were found in the prefrontal cortex of the monkey during the performance of the task where different kinds of response (response to the right side or to the left side) to the same D C and same kind of response to different DCs were required depending on the instruction previously presented. There were three main findings in the present experiment. First, a small number of differential units were found which are considered to be related to non-spatial information processing. IC-related units may take part in coding or holding the information concerning the IC, and DC-related units may participate in
62 coding or holding the information concerning the DC. Furthermore 8 IC-related and 2 DC-related units which showed differential changes during the delay period may be related to non-spatial short-term memory. Second, a majority of differential units were related to spatial information processing. Impending-response-side-related units may be related to the recognition concerning which side is positive and/or related to its short-term memory or preparatory set for the impending response. Choice-side-related units may be associated with the initiation and execution of the pressing response of a particular choice key and/or its feedback. Similar units which are considered to be related to spatial information processing were observed in the previous studies on delayed response and delayed alternationT,10,12. It should be noted that the differential activity observed in these studies was shown to different spatial cues (including an internal cue in the case of delayed alternation). The impending-response-side-related units in the present study, however, showed differential activity independent of the physical properties of the DC. They showed differential activity to the same DC and showed the same pattern of activity to different DCs depending on the IC. This type of units may abstract only the spatial aspect of the DC (i.e., on which side the positive pattern is situated). This speculation is supported by the activity of these units on erroneous trials and by the similarity of their response across all three tasks. Third, the most interesting finding in the present study was the characteristics of the activity of IC-DC-related units. Their activity was dependent on information about both the IC and DC. Unlike impending-response-side-related units, however, these units showed IC dependent changes despite responses to the same side. Thus, these units are considered to be related to both spatial and non-spatial information processing. However, there is an alternative possibility. Because of the existence of impending-response-side-related units which indicate the side to be responded, it is not always necessary for the IC-DC-related units to recognize or hold the side of the impending response for the monkey to perform the task correctly. In that case, this type of unit may not so much be related to spatial information processing, but may be related to recognizing a D C in the context of a specific IC and/or related to holding what was recognized. Irrespective of whether or not this type of unit is related to spatial information processing, the activity was shown to be conditional to the instruction of the non-spatial cue, while the activity of response-related differential delay units in the previous study 13 had been shown to be conditional to the instruction of the spatial cue. The activity of IC-DC-related units on erroneous trials was interesting. For the unit shown in Fig. 7, the pattern of activity after the DC presentation on erroneous trials in sequence 4 was similar to that on correct trials in sequence 2, and was different from that on correct trials in sequence 3. Because ICs were different and DCs were same between sequence 2 and sequence 4, and ICs were same and DCs were different between sequence 3 and sequence 4, it could be deduced that these errors in sequence 4 were not caused by a fault in the recognition of the DC, but by recognizing the DC utilizing erroneously coded or maintained information concerning the IC. When a similar pattern of activity was observed on a correct trial in one sequence and on an
63 erroneous trial in the other sequence in the IC-DC-related units, the error was usually considered to be caused by recognizing a DC utilizing an erroneously coded or maintained instruction. Although some prefrontal units to be related to eye movement or eye fixation have been reported1, 2°, the possibility that some differential units, especially impending-response-side-related units, may be related to eye movement or eye fixation seems unlikely since no systematic eye movement or eye fixation was observed during the trials in this experiment.
Characteristics of information processing in the prefrontal cortex In the present experiment, the majority of differential units (impendingresponse-side-related units, choice-side-related units and possibly IC-DC-related units) were found to be related to spatial information processing, while a small number of differential units (IC-related units and DC-related units) were related to non-spatial information processing. The results are considered to be in accordance with many ablation studies in which prefrontally ablated monkeys could not learn or perform the delayed response and delayed alternation tasks (spatial tasks), while they could learn other discrimination tasks (non-spatial tasks). Thus, one of the most prominent functional roles of the prefrontal cortex may be spatial information processing. Another important feature of the prefrontal unit activity is that it is conditional to the task situation, and the prefrontal units respond to both spatial and non-spatial instruction. Finally, some prefrontal units may be related to the meaning of the stimulus. The activity of the impending-response-side-related units in the present study was not dependent on the physical properties of the DC, but was considered to abstract the spatial aspect of the DC (which side the positive pattern is presented). The activity of IC-DC-related units was also not determined by the physical properties of the IC and DC, but was considered to be related to the meaning of the cues derived from the task requirement (e.g., red lights have the same meaning as plusses), because similar patterns of differential activity were observed among the three kinds of tasks (Fig. 6). Although the activity of IC-related units and DC-related units could not be examined systematically in the color-pattern-II task and the pattern-pattern task, it was tentatively suggested that their activity was not dependent on the physical properties of the IC and DC. It seems that the activity of IC-DC-related units (and possibly IC-related units and DC-related units) reflects the consequence of learning that red lights and plusses, green lights and squares, circle and plus, stripes and square have the same significance to the animal. The units may categorize stimuli which have the same significance. Color sensitive differential activity of the prefrontal units has been reported on other task situations4,a, la. As has been suggested la, their unit activity may not reflect the color feature of the stimulus per se, but rather reflect some significance of the stimulus to the animal. Since no other areas of the brain were examined in this experiment, it is not possible to determine whether such unit activity as may be related to the meaning of the stimulus is specific to the prefrontal cortex. Although the task situation is not very
64 similar, unit activity of the posterior parietal or inferior temporal association cortices has been studied in awake behaving monkeys15,17,1s. In these studies, no unit has been reported which is considered to be related to the meaning of the stimulus. The unit activity of the posterior association cortices has been shown to be dependent on the physical features of the stimulus, although the features which trigger the unit activity are reported to be much more complex in these association cortices and the activity of these cortices is shown to be modified by attentional and situational variables 5,16. It has been reported that sustained activation of some prefrontal neurons (G neurons) during gaze of a small spot was little influenced by stimulus parameters, such as the size, intensity, and position of the light spot 2°. Similarly, some prefrontal units showed differential activity to an identical light spot depending on whether it was reward-related or not 6. These two studies indicate that the prefrontal unit activity is not dependent on physical properties of the stimulus but may be related to some attentional process. The present experiment suggests that the prefrontal unit activity may be related to the meaning of the stimulus. Thus, the prefrontal cortex may take part in information processing of a higher order than the other association cortices. Prefrontal units which show activity change at the time of the response or juice delivery have been reported in several task situations10,14,19 as in the present experiment. On the other hand, it has been reported that when the monkey was trained on both the spatial delayed response and the delayed matching to sample tasks, a substantial number of prefrontal units showed activity change at the time of the cue presentation or during the delay period only in association with one task situation t9. It may be these task-specific units which play an important role in the learning and performance of a certain task. And it may be IC-DC-related units, which are considered to be related to the recognition of the DC utilizing the information concerning the IC, that are essential for the correct performance of the conditional task in the present experiment, although their number is not large among taskrelated units. It is reported that the proportion of 'differential delay units', which are considered to play an important role in the performance of the delayed alternation, is about 5 ~ of recorded units in the dorsolateral prefrontal cortex TM. It may be the activity of these task-specific units that characterizes the functional roles of the prefrontal cortex which is considered to be related to higher mental activity in the human brain. If so, it is necessary to investigate the characteristics of the prefrontal unit activity in several task situations. Unit activity which is conditional to the task situation or which is related to the meaning of the stimulus is expected to be found in other task situations. ACKNOWLEDGEMENTS
The author expresses his gratitude to Dr. H. Niki of the University of Tokyo for his helpful advice during the experimental work and for his help in improving the manuscript. The author is also indebted to Dr. S. Nakajima of the Dalhousie University and Drs. M. Mishkin and R. Nakamura of N I M H for their comments on the manuscript. This study was supported by a grant from the Ministry of Education in Japan (No. 401029).
65 REFERENCES 1 Bizzi, E. and Schiller, P. H., Single unit activity in the frontal eye fields of unanesthetized monkeys during eye and head movement, Exp., Brain Res., 10 (1970) 151-158. 2 Evarts, E. V., A technique for recording activity of subcortical neurons in moving animals, Electroenceph. clin. Neurophysiol., 24 (1968) 83-86. 3 Fuster, J. M., Unit activity in prefrontal cortex during delayed-response performance: Neuronal correlates of transient memory, J. Neurophysiol., 36 (1973) 61-78. 4 Fuster, J. M., Cryogenic and microelectrode studies of the prefrontal cortex, Proc. Syrup. 5th Congr. Int. Primat. Soc., (1974) 445~-58. 5 Gross, C. G., Bender, D. B. and Gerstein, G. L., Activity of inferior temporal neurons in behaving monkeys, Neuropsychologia, 17 (1979) 215-229. 6 Kojima, S., Prefrontal unit activity in the monkey: Relation to visual stimuli and movements, Exp. Neural., 69 (1980) 110-123. 7 Kubota, K., Iwamoto, T. and Suzuki, H., Visuokinetic activities of primate prefrontal neurons during delayed-response performance, J. Neurophysiol., 37 (1974) 1197-1212. 8 Kubota, K. and Niki, H., Prefrontal cortical unit activity and delayed alternation performance in monkeys, J. Neurophysiol., 34 (1971) 337-347. 9 Kubota, K., Tonoike, M. and Mikami, A., Neuronal activity in the monkey dorsolateral prefrontal cortex during a discrimination task with delay, Brain Research, 183 (1980) 29-42. 10 Niki, H., Prefrontal unit activity during delayed alternation in the monkey. I. Relation to direction of response, Brain Research, 68 (1974) 185-196. 11 Niki, H., Prefrontal unit activity during delayed alternation in the monkey. II. Relation to absolute versus relative directions of response, Brain Research, 68 (1974) 197-204. 12 Niki, H., Differential activity of prefrontal units during right and left delayed response trials, Brain Research, 70 (1974) 346-349. 13 Niki, H. and Watanabe, M., Prefrontal unit activity and delayed response: Relation to cue location versus direction of response, Brain Research, 105 (1976) 79-88. 14 Niki, H. and Watanabe, M., Prefrontal and cingurate unit activity during timing behavior in the monkey, Brain Research, 171 (1979) 213-224. 15 Ridley, R. M., Hester, N. S. and Ettlinger, G., Stimulus- and response-dependent units from the occipital and temporal lobes of the unanesthetized monkey performing learned visual tasks, Exp. Brain Res., 27 (1977) 539-552. 16 Robinson, D. L., Goldberg, M. E. and Stanton, G. B., Parietal association cortex in the primate: sensory mechanisms and behavioral modulations, J. NeurophysioL, 41 (1978) 910-932. 17 Rolls, E. T., Judge, S. J. and Sanghera, M. K., Activity of neurons in the inferotemporal cortex of the alert monkey, Brain Research, 130 (1977) 229-238. 18 Rolls, E. T., Perrett, D., Thorpe, S. J., Puerto, A., Roper-Hall, A. and Maddison, S., Response of neurons in area 7 of the parietal cortex to objects of different significance, Brain Research, 169 (1979) 194-198. 19 Rosenkilde, C. E., Bauer, R. H. and Fuster, J. M., Single cell activity in ventral prefrontal cortex of behaving monkeys, Brain Research, 209 (1981) 375-394. 20 Suzuki, H. and Azuma, M., Prefrontal neuronal activity during gazing at a light spot in the monkey, Brain Research, 126 (1977) 497-508. 21 Watanabe, M., Prefrontal unit activity during delayed conditional discrimination in the monkey, Neurosci. Lett., Suppl. 2 (1979) $48. 22 Watanabe, M., Prefrontal unit activity and delayed conditional discrimination. In Y. Tsukada and B. E. Agranoff (Eds.), Neurobiological Basis of Learning andMemory, New York, 1980, Ch. 9, pp. 123-133. 23 Wolbarsht, M. L., MacNichol, E. F., and Wagner, H. G., Glass-insulated platinum microelectrode, Science, 132 (1960) 1309-1310.
51
PREFRONTAL UNIT ACTIVITY DURING DELAYED CONDITIONAL DISCRIMINATIONS IN THE MONKEY
MASATAKA WATANABE Department of Psychology, Faculty of Letters, University of Tokyo, Bunkyo-ku, Tokyo, 113 (Japan) (Accepted April 2nd, 1981) Key words: monkey - - prefrontal unit activity - - delayed conditional discrimination - - spatial information processing - - non-spatial information processing - - conditional information processing
SUMMARY Single unit activity was recorded from the prefrontal cortex (principalis, arcuate and inferior convexity areas) of the monkey while the animal was performing a delayed conditional discrimination task. Sequential events of the task were as follows: instructional cue presentation, 1st delay, presentation of two pattern stimuli on left and right windows respectively as a discriminative cue, 2nd delay and choice response to the left or right window. The positive pattern was dependent on the instructional cue. In total, 424 units obtained from two monkeys showed a correlation with some aspects of the task. O f these 424 task-related units, 169 differentiated between the instructional cues and/or the discriminative cues. The majority of these differential units (n = 123) were found to be related to spatial information processing (related to the side of the response) while 19 differential units were related to non-spatial information processing (related to the color or pattern configuration of the cue). The activity of the remaining 27 differential units was considered to be related to both spatial and non-spatial information processing (related to both the instructional cue and the side of the response) and this type of unit was shown to be involved in conditional information processing. The results indicate that prefrontal units may be related to the meaning of the stimulus independent of its physical properties.
INTRODUCTION Unit activity in the prefrontal cortex has been studied in awake monkeys during performance on delayed response or delayed alternation tasks in order to investigate the neuronal correlates of these behaviors z,s. Many dorsolateral prefrontal units show 0006-8993/81/0000-0000/$02.50 © Elsevier/North-Holland Biomedical Press
52 changes in their discharge rate in relation to several aspects of these tasks. Some taskrelated units (differential delay units) show differential activity during the delay period on delayed response and delayed alternation tasks7,10,12. The possibility that these differential delay units are related to spatial short-term memory was proposed 1°. In our previous study on the delayed response task, two kinds of differential delay units were distinguished: one was related to the spatial location of the cue (cue-related differential delay unit), and the other was related to the direction of the animal's response (response-related differential delay unit) la. The activity of the latter types of differential delay unit was found to be conditional to the spatial cue. The unit activity which is considered to be conditional to the spatial cue was found also in the delayed alternation. The activity of differential delay units prior to the selection of a particular choice key was found to be related to the relative rather than the absolute position of two out of 4 horizontally situated keys 11 .These results suggest that the activity of prefrontal units is conditional to the task situation. On the other hand, prefrontal unit activity has not been fully studied in relation to non-spatial information processing. This study was therefore conducted to investigate how spatial and non-spatial aspects of the stimulus are processed in the prefrontal units and to analyze the 'conditional' nature of the prefrontal unit activity. The task situation employed in the present study was a 'delayed conditional discrimination'. The animal was required to respond differentially (respond to the right side or to the left side) to an identical cue or required to perform the same response to different cues depending on non-spatial instructions previously presented. Thus, different cues had the same meaning and an identical cue had different meanings to the animal depending on instructions. The major goal was to investigate those units which may show differential activity to some aspects of the stimulus presented, and to analyze to which aspects (physical properties or some other aspect such as the meaning) of the stimulus those units are related. 'Conditional units' which, depending on the instruction, showed different patterns of activity to the same cue, or the same pattern of activity to the different cues, were of special interest. Some parts of the present study have been presented in preliminary form 21,22. METHODS Two adult rhesus monkeys (Macaca mulatta) weighing 4.5-5.0 kg were trained in delayed conditional discrimination tasks using the approximation procedure. During the experiment the monkey was seated on a primate chair. The animal faced a test panel which contained two choice keys (each, 8 cm high and 6 cm wide) and a hold lever (5 cm wide and 5 cm protruded) situated 10 cm below the keys. The two choice keys, 5 cm apart, were located at the height of the monkey's eye approximately 40 cm in front of the animal. Each choice key could be illuminated from behind by a rear projection unit (Industrial Electronics Engineering, series 80). The apparatus was controlled by an electronic circuit. A schematic diagram of the sequence of events in the three delayed conditional discrimination tasks is shown in Fig. 1. The monkey was first trained on a 'color-pattern-I' task. The monkey had to
53 2ND
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depress the hold lever to start a trial. After 5 s of holding (intertrial interval, ITI), either red or green lights were simultaneously presented on both choice keys for 1 s as an instructional cue (IC). The IC period was followed by a first delay period (1 s), and then two pattern stimuli were presented on the choice keys for 1 s as a discriminative cue (DC). The pattern stimuli were either a circle on the left key and stripes on the right key, or a circle on the right and stripes on the left. The D C period was followed by a second delay period (1.5-2.5 s, generally 2 s). If the monkey continued depressing the hold lever during all these periods (ITI, IC, 1st delay, D C and 2nd delay), white lights were then presented on both choice keys simultaneously as a go signal (GS). The correct key was the one that had had a circle on it if the IC had been red, and stripes if the IC had been green. I f the monkey pressed the correct key after the white lights were presented, the lights were turned off and a drop of fruit juice (0.2 ml) was given into the mouth as a reward. The re-run self-correction technique was employed. Thus, if the animal released the hold lever before the GS was presented, or if the animal made an error, the animal had to depress the hold lever again in order to restart a trial. The animal was allowed to use only one (preferred) hand. Two delay periods were introduced in this experiment to differentiate unitary firing changes related to the 3 events of the task; i.e., IC, D C and the choice response. The animal was trained on the task for about 1000 reinforced trials every day until reaching a criterion of better than 95 ~ correct responses in a daily session. Two control tasks were added after the unit recording was completed in one hemisphere of the first monkey. In a 'color-pattern-II' task, a plus and a square were used as D C stimuli. The positive pattern was the plus if the IC had been red and the square if it had been green. In a 'pattern-pattern' task, a plus or a square was presented as an IC on
54 CO LOR,
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Fig. 2. Twelve sequences of the three kinds of delayed conditional discrimination tasks. The small upward arrows indicate the positive side. both left and right choice keys. The positive pattern was the circle if plusses had been presented as an IC and the stripes if squares had been presented. As shown in Fig. 2, there were a total of 12 sequences o f l C s and DCs: from 1 to 4 in the 'color-pattern-l' task, from 5 to 8 in the 'color-pattern-II' task, and from 9 to 12 in the 'pattern-pattern' task. In each task the 4 sequences were presented in a predetermined semi-random schedule. It took about 4 months for the animal to master the color-pattern-I task, and an additional two months for the two other tasks. During the training and recording periods, the animals were deprived of water and received their entire fluid ration in the testing apparatus, except for their daily ration of fresh fruit. Monkey pellets were always available ad libitum in the home cage. On completion of the training, the animal was surgically prepared under sodium pentobarbital anesthesia (Nembutal 35 mg/kg, i.p.). A stainless steel cylinder (18 m m in diameter) as a microdrive receptacle and 4 bolts for head fixation were implanted at appropriate locations of the skull. The center of the cylinder was aimed at A -----28, L = 15 in the stereotaxic coordinate system. Details of the procedure have been described previously 2. Antibiotics (crystalline procaine penicillin G in oil, 20000 IU, i.m.) were administered every day for a week after the operation. Recording was started about 10 days after surgery. During the recording sessions, the animal's head was held rigidly by means of the implanted bolts, and a hydraulic microdrive was attached to the implanted cylinder. A glass-insulated platinum-iridium microelectrode similar to that described by Wolbarsht et al. 23 was used for unit recording. The unit action potentials were processed through a window discriminator and converted into square-wave pulses. Throughout the recording session, both unit discharges and shaped pulses were monitored on an oscilloscope to ensure reliability of the conversion. The unit activity, shaped pulses, and signals corresponding to the stimulus-response events of the task were all recorded on a magnetic tape, and also displayed on an inkwriter. Recorded data were later analyzed on a PDP-12 computer by utilizing a N I M H - L N P Neurophysiological Analysis Program. Raster displays, cumulative records and frequency histograms were used for graphic representation. Units were recorded in the principalis area, arcuate area, and inferior convexity area of the prefrontal cortex (A ~ 20-36, L ~ 10-20) while the animal was performing
55 the color-pattern-I task. Only when a task-related unit, especially the one which showed differential activity, was found, was the activity examined in the other two tasks so that the aspects of the stimulus to which the activity was related could be examined. At the end of the experiment, the monkeys were sacrificed and perfused with normal saline followed by 1 0 ~ formalin. Then the dura was removed and the location of the cylinder on the cortical surface was determined. The brain was extracted and fixed in 10 ~o formalin and later sectioned to match the tracks of the electrode penetrations. RESULTS
In the present experiment only those task-related units were examined which could be recorded for at least 24 trials (6 trials for each sequence) and showed marked changes in firing rate in association with one or more of the events of the colorpattern-I delayed conditional discrimination task. A total of 424 task-related units were obtained from 192 penetrations in 3 hemispheres of two monkeys. Out of 424 units, 169 units differentiated between cues or cue configurations (differential units), while the remaining 255 units did not show such differential activity (non-differential units). A unit was designated as a 'differential unit' when its activity observed at a certain phase of the task in one or two sequences was distinctively different from that observed in the other sequences. Those units which showed activity change at several phases and showed differential activity at one of these phases were classified into 'differential units'. Forty-seven differential units could be examined in all three tasks. TABLE I
( A ) Classification of units which did not show differential activity
I II III IV
S - R event units Reward units Delay units Unclassified units Total
N
%
150 19 52 34 255
58.8 7.5 20.4 13.3 100.0
( B) Classification of units which showed differential activity N I II III IV V
IC-related units DC-related units IC-DC-related units Impending-response-side-related units Choice-side-related units Total
%
10 9 27
5.9 5.3 16.0
87 36 169
51.5 21.3 100.0
56
Activity of non-differential units Non-differential units registered the occurrence of task events. For convenience the 255 non-differential units were classified into one of 4 types (stimulus-response event units, reward units, delay units and unclassified units) depending on the phase where distinct activity change could be observed on frequency histograms and raster displays, on correct trials in the color-pattern-I task (Table IA). Stimulus-response (S-R) event units (n = 150) showed increases or decreases in firing rate in relation to the onset of one or more of the stimuli (IC, DC and GS) and/or the response (release of the hold lever or depression of the choice key). Reward units (n = 19) exhibited increased or decreased firing when juice was delivered as a reward. Delay units (n = 52) showed sustained (increased or decreased) changes during the first (n = 6), second (n = 22) or both (n = 24) delay periods. In 9 of 52 delay units, sustained changes were observed during both the cue and the following delay periods. The remaining 34 units could not be classified into any of the three designated types. Most were combinations of the above categories.
Activity of differentia! units Differential units (n = 169) responded to a specific cue or cue configurations. The differential units were classified into one of 5 types (IC-related, DC-related, IC-DCrelated, impending-response-side-related, and choice-side-related) depending on both
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57 IC IC
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Fig. 4. Raster displays of the IC-DC related unit activity. Conventions are the same as in Fig. 3. In this unit, the second delay period was 1.7 s. the phase where differential activity was observed and the characteristics of the differential activity on correct trials in the color-pattern-I task (Table IB). IC-related units (n = 10) showed activity dependent on the difference in the IC. This could occur during the IC period (n = 1), during the first delay period (n = 8), or during the DC period (n = 1). An example of this type of unit, shown in Fig. 3A, exhibited a higher rate of firing when the green lights were presented (sequences 3 and 4) than when the red lights were presented (sequences 1 and 2) as an IC during the first delay period. DC-related units (n = 9) showed differential activity depending on the configuration of the two pattern stimuli; i.e., depending on whether DC was the circleright and stripes-left (sequences 1 and 3) or the circle-left and stripes-right (sequences 2 and 4). This could occur during the DC period (n = 7) or during both the DC and the second delay periods (n ~- 2). The example in Fig. 3B showed an increase in firing rate in sequence 1 and sequence 3 at the time of the DC presentation (the activity changes observed around the time of the response did not differentiate among the 4 sequences). IC-DC-related units (n = 27) showed specific activity depending on the combination of the IC and DC. Ten units showed such specificity at the time of the DC presentation, 7 units during the second delay period and the remaining 10 units throughout both periods. An example of this type of unit is shown in Fig. 4. This unit showed increased activity during the DC period (and in some trials during the second delay period), when a circle was presented on the left side and stripes were presented on the right only following red IC (sequence 2), and no noticeable change was observed in the other sequences. There were some variations in the specificity of the activity after the DC presentation in IC-DC-related units. In 10 units, the activity observed in one sequence
58
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Fig. 5. Raster displays of the activity of the impending-response-side-related unit (A) and the choiceside-related unit (B). For B, the center line indicates the time of the 'go' signal (GS) presentation. The unit activity around the IC presentation is not shown for this unit. Other conventions are the same as in Fig. 3. The second delay period was 1.7 s for A and 2.5 s for B. was different from that in the other 3 sequences, and no difference in activity was observed among the 3 sequences, as in Fig. 4. In 6 units, the activity observed in each of all 4 sequences was different from that in every other sequence. In the remaining 11 units, a specificity was observed for each of two sequences while the activity in the remaining two sequences was not distinguishable (e.g., Fig. 6). Impending-response-side-related units (n = 87) showed differential activity in relation to the side of the animal's response, at the time of the DC presentation (n = 14), during the second delay period ( n = 47) or throughout both periods (n = 26). The unit shown in Fig. 5A showed an increased firing rate after the IC presentation (in some trials even before the IC presentation) in all the 4 sequences. After the DC presentation, increased activity continued or further augmented activation was observed when the animal responded to the right side (sequences 1 and 4), while such activation was not observed when the animal responded to the left side (sequences 2 and 3). The differential activity was observed during both the D C and the second delay periods. Impending-response-side-related units showed a similar pattern of activity to different DCs (sequences 1 and 4, or 2 and 3; circle-right, stripes-left and circle-left, stripes-right), and showed different patterns of activity to the same D C (sequences 1 and 3; circle-right, stripes-left or sequences 2 and 4; circle-left, stripes-right), depending on the IC. Choice-side-related units (n = 36) showed differential activity at the time of choice depending on the side to which the animal responded. The example shown in Fig. 5B showed an activity change when the animal responded to the right side at the time of the response. The activity of differential units was examined in the color-pattern-II task and in the pattern-pattern task when such units could be held for a sufficient period of
59 time, in order to investigate what aspects of IC and D C were important for the observed differential changes in the color-pattern-I task. Only IC-DC-related units (n ---- 12) and impending-response-side-related units (n ----35) could be examined on these tasks. These came from the right hemisphere of the first monkey and from the left hemisphere of the second monkey. Fig. 6 shows an IC-DC-related unit on the three tasks. This unit showed a change in activity during the IC or during the first delay period in some trials, but the activity change did not differentiate among the 4 sequences of the color-pattern-I task. The activity of this unit after the D C presentation was not dependent on whether there was an activity change during the IC and the first delay periods. This unit exhibited the highest rate of firing in sequence 2, lowest activity in sequence 1, and moderate increased activity in sequence 3 and sequence 4 after the D C presentation in the original color-pattern-I task (Fig. 6A). ic
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2 SEC
Fig. 7. Example of the activity of the IC-DC-related unit on correct and erroneous trials in the colorpattern-I task. Each pulse represents a spike discharge. Other conventions are the same as in Fig. 3. Specific activity observed after the D C presentation in the color-pattern-I task was also observed in the other tasks (Fig. 6B, C) and the pattern of activity observed in sequence 5, 6, 7 or 8 in the color-pattern-II task and in sequence 9, 10, 11 or 12 in the pattern-pattern task was similar to that observed in sequence 1, 2, 3, or 4 in the colorpattern-I task although different ICs (red-green vs. plus-square) or different DCs (circle-stripes vs. plus-square) were used among the three different tasks. Thus, this type of unit showed similar patterns of activity to the different DCs (1 vs 5, 2 vs 6, 3 vs 7 and 4 vs 8) and showed different activity to the same DC (sequences 1 and 3, 2 and 4, 5 and 7, 6 and 8, 9 and 11, 10 and 12) depending on the IC. Impending-response-side-related units showed differential activity depending only on the side to which the animal responded regardless of the task. Thus, this type of unit showed a similar pattern of activity to sequences 1, 4, 5, 8, 9, and 12 or to sequences 2, 3, 6, 7, 10 and 11. Although activity on erroneous trials was not always obtained for all the 4 sequences of the color-pattern-I task for each unit because of the near perfect performance of the monkeys, some data were obtained for I C - D C - r e l a t e d units, impending-response-side-related units and choice-side-related units. Fig. 7 provides an example of the activity of an IC-DC-related unit on correct and erroneous trials. This unit is the same as in Fig. 6 and showed the highest rate of firing in sequence 2, lowest rate of firing in sequence 1 and moderate increased activity in sequence 3 and
61
A
B
C
Fig. 8. Locations of the penetration of differential units in the prefrontal cortex. Penetrations are projected on the surface of the left hemisphere. Following patterns indicate penetrations where each type of differential units were found. A: R, IC-related unit; A, DC-related unit; B: A, IC-DC-related unit; C: Q, impending-response-side-related unit; O, choice-side-related unit. sequence 4 after the D C presentation on correct trials. On erroneous trials, a large increment in firing rate was observed in sequence 4, but not in sequence 2 after the D C presentation. The activity on erroneous trials in sequence 3 was also different from that on correct trials in sequence 3. Thus, it was possible to predict the occurrence of errors from the activity of IC-DC-related units before the response was actually made, whenever the activity after the D C presentation was obviously different from that observed on correct trials. Impending-response-side-related units and choice-side-related units showed changes in activity depending on whether the animal responded to the left or to the right, irrespective of whether or not the response was correct. Thus, impendingresponse-side-related units showed the activity as if the positive pattern appeared on the right side (sequences 1 and 4) even if the positive pattern actually appeared on the left side (sequences 2 and 3) or vice versa on erroneous trials. Therefore it was also possible to predict the occurrence of errors from the activity of this type of units before the response. Differential units observed in this experiment were found in principalis, arcuate and inferior convexity areas of the prefrontal cortex. Each type of differential unit was found in each of these three areas and no distinct localization of each type of differential units was observed (Fig. 8). DISCUSSION Several kinds of differential units were found in the prefrontal cortex of the monkey during the performance of the task where different kinds of response (response to the right side or to the left side) to the same D C and same kind of response to different DCs were required depending on the instruction previously presented. There were three main findings in the present experiment. First, a small number of differential units were found which are considered to be related to non-spatial information processing. IC-related units may take part in coding or holding the information concerning the IC, and DC-related units may participate in
62 coding or holding the information concerning the DC. Furthermore 8 IC-related and 2 DC-related units which showed differential changes during the delay period may be related to non-spatial short-term memory. Second, a majority of differential units were related to spatial information processing. Impending-response-side-related units may be related to the recognition concerning which side is positive and/or related to its short-term memory or preparatory set for the impending response. Choice-side-related units may be associated with the initiation and execution of the pressing response of a particular choice key and/or its feedback. Similar units which are considered to be related to spatial information processing were observed in the previous studies on delayed response and delayed alternationT,10,12. It should be noted that the differential activity observed in these studies was shown to different spatial cues (including an internal cue in the case of delayed alternation). The impending-response-side-related units in the present study, however, showed differential activity independent of the physical properties of the DC. They showed differential activity to the same DC and showed the same pattern of activity to different DCs depending on the IC. This type of units may abstract only the spatial aspect of the DC (i.e., on which side the positive pattern is situated). This speculation is supported by the activity of these units on erroneous trials and by the similarity of their response across all three tasks. Third, the most interesting finding in the present study was the characteristics of the activity of IC-DC-related units. Their activity was dependent on information about both the IC and DC. Unlike impending-response-side-related units, however, these units showed IC dependent changes despite responses to the same side. Thus, these units are considered to be related to both spatial and non-spatial information processing. However, there is an alternative possibility. Because of the existence of impending-response-side-related units which indicate the side to be responded, it is not always necessary for the IC-DC-related units to recognize or hold the side of the impending response for the monkey to perform the task correctly. In that case, this type of unit may not so much be related to spatial information processing, but may be related to recognizing a D C in the context of a specific IC and/or related to holding what was recognized. Irrespective of whether or not this type of unit is related to spatial information processing, the activity was shown to be conditional to the instruction of the non-spatial cue, while the activity of response-related differential delay units in the previous study 13 had been shown to be conditional to the instruction of the spatial cue. The activity of IC-DC-related units on erroneous trials was interesting. For the unit shown in Fig. 7, the pattern of activity after the DC presentation on erroneous trials in sequence 4 was similar to that on correct trials in sequence 2, and was different from that on correct trials in sequence 3. Because ICs were different and DCs were same between sequence 2 and sequence 4, and ICs were same and DCs were different between sequence 3 and sequence 4, it could be deduced that these errors in sequence 4 were not caused by a fault in the recognition of the DC, but by recognizing the DC utilizing erroneously coded or maintained information concerning the IC. When a similar pattern of activity was observed on a correct trial in one sequence and on an
63 erroneous trial in the other sequence in the IC-DC-related units, the error was usually considered to be caused by recognizing a DC utilizing an erroneously coded or maintained instruction. Although some prefrontal units to be related to eye movement or eye fixation have been reported1, 2°, the possibility that some differential units, especially impending-response-side-related units, may be related to eye movement or eye fixation seems unlikely since no systematic eye movement or eye fixation was observed during the trials in this experiment.
Characteristics of information processing in the prefrontal cortex In the present experiment, the majority of differential units (impendingresponse-side-related units, choice-side-related units and possibly IC-DC-related units) were found to be related to spatial information processing, while a small number of differential units (IC-related units and DC-related units) were related to non-spatial information processing. The results are considered to be in accordance with many ablation studies in which prefrontally ablated monkeys could not learn or perform the delayed response and delayed alternation tasks (spatial tasks), while they could learn other discrimination tasks (non-spatial tasks). Thus, one of the most prominent functional roles of the prefrontal cortex may be spatial information processing. Another important feature of the prefrontal unit activity is that it is conditional to the task situation, and the prefrontal units respond to both spatial and non-spatial instruction. Finally, some prefrontal units may be related to the meaning of the stimulus. The activity of the impending-response-side-related units in the present study was not dependent on the physical properties of the DC, but was considered to abstract the spatial aspect of the DC (which side the positive pattern is presented). The activity of IC-DC-related units was also not determined by the physical properties of the IC and DC, but was considered to be related to the meaning of the cues derived from the task requirement (e.g., red lights have the same meaning as plusses), because similar patterns of differential activity were observed among the three kinds of tasks (Fig. 6). Although the activity of IC-related units and DC-related units could not be examined systematically in the color-pattern-II task and the pattern-pattern task, it was tentatively suggested that their activity was not dependent on the physical properties of the IC and DC. It seems that the activity of IC-DC-related units (and possibly IC-related units and DC-related units) reflects the consequence of learning that red lights and plusses, green lights and squares, circle and plus, stripes and square have the same significance to the animal. The units may categorize stimuli which have the same significance. Color sensitive differential activity of the prefrontal units has been reported on other task situations4,a, la. As has been suggested la, their unit activity may not reflect the color feature of the stimulus per se, but rather reflect some significance of the stimulus to the animal. Since no other areas of the brain were examined in this experiment, it is not possible to determine whether such unit activity as may be related to the meaning of the stimulus is specific to the prefrontal cortex. Although the task situation is not very
64 similar, unit activity of the posterior parietal or inferior temporal association cortices has been studied in awake behaving monkeys15,17,1s. In these studies, no unit has been reported which is considered to be related to the meaning of the stimulus. The unit activity of the posterior association cortices has been shown to be dependent on the physical features of the stimulus, although the features which trigger the unit activity are reported to be much more complex in these association cortices and the activity of these cortices is shown to be modified by attentional and situational variables 5,16. It has been reported that sustained activation of some prefrontal neurons (G neurons) during gaze of a small spot was little influenced by stimulus parameters, such as the size, intensity, and position of the light spot 2°. Similarly, some prefrontal units showed differential activity to an identical light spot depending on whether it was reward-related or not 6. These two studies indicate that the prefrontal unit activity is not dependent on physical properties of the stimulus but may be related to some attentional process. The present experiment suggests that the prefrontal unit activity may be related to the meaning of the stimulus. Thus, the prefrontal cortex may take part in information processing of a higher order than the other association cortices. Prefrontal units which show activity change at the time of the response or juice delivery have been reported in several task situations10,14,19 as in the present experiment. On the other hand, it has been reported that when the monkey was trained on both the spatial delayed response and the delayed matching to sample tasks, a substantial number of prefrontal units showed activity change at the time of the cue presentation or during the delay period only in association with one task situation t9. It may be these task-specific units which play an important role in the learning and performance of a certain task. And it may be IC-DC-related units, which are considered to be related to the recognition of the DC utilizing the information concerning the IC, that are essential for the correct performance of the conditional task in the present experiment, although their number is not large among taskrelated units. It is reported that the proportion of 'differential delay units', which are considered to play an important role in the performance of the delayed alternation, is about 5 ~ of recorded units in the dorsolateral prefrontal cortex TM. It may be the activity of these task-specific units that characterizes the functional roles of the prefrontal cortex which is considered to be related to higher mental activity in the human brain. If so, it is necessary to investigate the characteristics of the prefrontal unit activity in several task situations. Unit activity which is conditional to the task situation or which is related to the meaning of the stimulus is expected to be found in other task situations. ACKNOWLEDGEMENTS
The author expresses his gratitude to Dr. H. Niki of the University of Tokyo for his helpful advice during the experimental work and for his help in improving the manuscript. The author is also indebted to Dr. S. Nakajima of the Dalhousie University and Drs. M. Mishkin and R. Nakamura of N I M H for their comments on the manuscript. This study was supported by a grant from the Ministry of Education in Japan (No. 401029).
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