Download Mnemonic Coding of Visual Space in the Monkey`s Dorsolateral

JOURNALOFNEUROPHYSIOLOGY
Vol. 6 1, No. 2. February 1989. Printed
in U&4.
Mnemonic Coding of Visual Space in the Monkey’s
Dorsolateral Prefrontal Cortex
SHINTARO
FUNAHASHI,
Section of Neuroanatomy,
SUMMARY
AND
CHARLES
J. BRUCE,
AND
Yale University School of Medicine,
CONCLUSIONS
1. An oculomotor delayed-response task was used to examine
the spatial memory functions of neurons in primate prefrontal
cortex. Monkeys were trained to fixate a central spot during a
brief presentation (0.5 s) of a peripheral cue and throughout
a
subsequent delay period (l-6 s), and then, upon the extinction of
the fixation target, to make a saccadic eye movement to where the
cue had been presented. Cues were usually presented in one of
eight different locations separated by 45O. This task thus requires
monkeys to direct their gaze to the location of a remembered
visual cue, controls the retinal coordinates of the visual cues,
controls the monkey’s oculomotor
behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses.
2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding
the principal sulcus (PS) while
monkeys performed this task. An additional
31 neurons in the
frontal eye fields (FEF) region within and near the anterior bank
of the arcuate sulcus were also studied.
3. Of the 288 PS neurons, 170 exhibited task-related activity
during at least one phase of this task and, of these, 87 showed
significant excitation or inhibition
of activity during the delay
period relative to activity during the inter-trial interval.
4. Delay period activity was classified as div~tional
for 79% of
these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions
and were weak or absent for other cue directions. The remaining
2 1% were omnidirectional, i.e., showed comparable delay period
activity for all visual field locations tested. Directional
preferences, or lack thereof, were maintained across different delay intervals (l-6 s).
5. For 50 of the 87 PS neurons, activity during the delay period
was significantly elevated above the neuron’s spontaneous rate for
at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with
excitatory delay period activity were directional
and few (8%)
were omnidirectional.
Most (62%) neurons with purely inhibitory
delay period activity
directional, but a substantial minority
. . were
.
(38%) was ommdn-ectronal.
6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity
for other cue directions. These inhibitory responses were usually
strongest for, or centered about, cue directions roughly opposite
those optimal for excitatory responses.
7. The distribution
of preferred cue locations was examined
across the population of PS neurons having directional delay period activity. All possible cue locations were represented (left,
right, up, down, and obliques); however, preferred cue locations
in the contralateral
hemifield predominated.
8. Tuning curves were calculated by the Gaussian formula to
determine the directional specificity of delay period activity. The
mean tuning indices (7’J of PS neurons were 26.8” for excitatory
0022-3077/89
$1 SO Copyright
PATRICIA
S. GOLDMAN-RAKIC
New Haven, Connecticut 06510
delay period activity and 43S” for inhibitory
delay period activity.
9. Delay period activity was examined on trials in which the
monkey made large saccadic errors for cues in a neuron’s preferred direction. Delay period activity was either truncated or
absent altogether on such trials.
IO. Of the 3 1 FEF neurons examined, 22 exhibited task-related
activity: 17 had delay period activity and 10 showed directional
delay period activity. The mean tuning index (Td) of excitatory
directional delay period activity in the FEF was 27.4’.
I I. These results indicate that prefrontal neurons (both PS and
FEF) possess information
concerning the location of visual cues
during the delay period of the oculomotor
delayed-response task.
This information
appears to be in a labeled line code: different
neurons code different cue locations and the same neuron repeatedly codes the same location. This mnemonic
activity occurs
during the I- to 6-s delay interval-in
the absence of any overt
stimuli or movements-and
it ceases upon the execution of the
behavioral response. These results strengthen the evidence that
the dorsolateral
prefrontal cortex participates in the process of
working or transient memory and further indicate that this area of
the cortex contains a complete “memory”
map of visual space.
INTRODUCTION
The role of the prefrontal cortex, particularly the principal sulcal (PS) region, in spatial memory has been strongly
supported by lesion and developmental studies over the
past two decades (17, 28, 57). Studies of single neuron
activity in monkeys during performance of delayed-response tasks have also provided strong evidence of a prefrontal contribution to memory (4, 5, 15, 16,20,22, 37,4 1,
42, 46, 50-53). Although many types of neural activity
have been found in the prefrontal cortex, neurons that
show sustained activity during the delay period are particularly relevant to the issueof mnemonic processing. Usually
these neurons increase their discharge rates following the
brief cue presentation and continue firing tonically during
the delay period until the response is executed (5, 15, 20,
22, 52, 53). Such delay activity is often “directional” (44,
50-52) i.e., dependent on the left-right location of the cue
or response, with some neurons responding only in conjunction with “left” trials and others only with “right”
trials. Because experimental lesions of the dorsolateral prefrontal cortex profoundly affect the ability of monkeys to
perform spatial delayed-response tasks correctly ( 17, 28)
this delay activity has been assumed to be the cellular expression of a mnemonic code for the left-right direction of
the cue or, equivalently, of the impending response (17,
18, 28).
0 1989 The American
Physiological
Society
331
332
FUNAHASHI,
BRUCE, AND
In the present study we have explored further the properties of neural activity in the prefrontal cortex of monkeys
performing delayed-response tasks. We sought to determine if prefrontal neurons were capable of accessing and
maintaining activity reflecting the location of a target stimulus or motor response in any part of the visual field or if
they were particularly tuned to left-right categorization.
Further, we were interested in finding out if prefrontal
neurons code stimuli in both the contralateral and ipsilatera1 visual fields equally well. To answer these questions, it
was necessary to precisely control the retinotopic location
of the cues, a requirement that has not been met in most
previous studies. Accordingly, in the present study, we used
an oculomotor analogue of the classical, manual delayedresponse task, in which the monkeys were trained to maintain fixation during the cue presentation, and the visual cue
could be presented at multiple locations around the visual
field. This method allowed us to record the monkey’s direction of gaze throughout the task, and consequently to know
the precise retinotopic location of the peripheral visual cue.
In addition, the fixation requirement during the delay period insured comparable behavior in this period on every
trial and also made it difficult for the monkey to adopt
postural rather than mnemonic strategies to perform the
task. Similar oculomotor delay tasks have previously been
used for neurophysiological experiments in the frontal eye
fields (6), the posterior parietal cortex (30), the caudate
nucleus (32), and the substantia nigra (33) as well as in the
prefrontal cortex (37, 40). The present study, however, is
the first to explore the full perimetry of visual space with
this paradigm.
Preliminary results from this study have previously been
presented in abstract form (15).
METHODS
Subjects
Three adult rhesus monkeys (Maeaca mulatta, 3.2-5.3 kg, one
male and two females) served as subjects. Prior to surgery and
training they were adapted to a primate chair for 5- 10 days.
Surgical procedures
GOLDMAN-RAKIC
Behavioral techniques
The monkey sat in the primate chair during the experiment and
his head was fixed to the chair by the restraining receptacle. Recording and training sessionsusually lasted 2-3 h. A program on
the PDP- 1l/23 computer presented the visual stimuli, sampled
the monkey’s gaze coordinates as well as neuron activity, and
delivered rewards.
Visual stimuli were presented on a monochrome CRT (1g-in.,
RCA TC 1119) subtending 48 X 38” in visual angle using a
GRAPH- 11 graphics card (Pacific Binary Systems). The fixation
target was a small white spot (0.1’ diam.), usually presented at the
center of the CRT. The peripheral visual cues were filled white
squares (0.7 X 0.7”).
Gaze coordinates were obtained with Robinson’s search coil
method (56). The field coil and associated electronic equipment
were made by C-N-C Engineering, Seattle, WA. Details concerning the sampling and storage of the eye and neural signals are
given below.
The monkeys were rewarded with drops (0.2 ml) of lightly
sweetened water via an electronic metering pump (A741,
Waltham). Water was not available in the home cage; instead the
monkeys worked to satiety (150-250 ml) each day in the laboratory. They were given monkey chow immediately upon return to
their home cages and their intake of chow and body weight were
closely monitored.
Oculomotor delayed-response task
Figure
1 shows schematic drawings
of the oculomotor
delayed-
response task. Figure 1A depicts the timing of presentation of the
fixation target, peripheral cues, and reward. Figure 1B illustrates
records of horizontal and vertical eye movements and single
neuron activity on a typical trial of the oculomotor delayed-response task.
Following a 5-s inter-trial interval (ITI), the fixation target appeared at the center of the CRT. The monkey looked at the fixation target and maintained fixation for 0.75 s (the fixation period), whereupon the visual cue was presented for 0.5 s (the cue
period) at one of four or eight peripheral locations (13” eccentricA
Oculomotor
delayed-response
n-l
task
F
I
fixation
C
D
R
I I
II
target
peripheral cue
Monkeys were prepared for chronic single-neuron recording
using aseptic surgical technique and barbiturate anesthesia (pen-
tobarbital sodium, intravenous to effect). For the purpose of recording eye movements (see below), a search coil was placed
under the conjunctiva in one eye using the technique of Judge et
al. (38). To secure the implant, stainless steel’bolts with flattened
heads were run along slots in the skull with the bolt head under
the skull. The bolts, a connector for the search coil, and a stainless
steel receptacle for attaching the monkey’s head to the primate
chair were bound together with dental acrylic. Because dura exposed during the lengthy training period (usually 3-4 mo) would
thicken and impede the passageof electrodes, a second surgery to
install the recording cylinder was performed only after the monkey became proficient on the oculomotor delayed-response task.
Trephine holes (20 mm diam.) were made over the prefrontal
region and a stainless steel recording cylinder placed over the
hole. Additional acrylic was applied to bond the recording cylinder to the existing implant. Monkeys were given systemic antibiotics, fruits, and ad lib water and chow for 5-8 days following
each surgery.
reward
B An example
of an oculomotor
ITI
horizontal gaze
coordinate
delayed-response
, F ,C,
III
trial
D
, R,
I I
I I
vertical gaze
coordinate
neuron activity
10”
1 set
FIG. 1. A: temporal sequence of events in the oculomotor delayed-response task. B: eye movements and single neuron activity during an oculomotor delayed-response trial. ITI, intertrial interval; F, fixation period
(0.75 s); C, cue period (0.5 s); D, delay period (3 s); R, response period (0.5
9.
MEMORY
CODING
IN PREFRONTAL
ity). Stimulus location was randomized
over trials so that the
monkey could not predict where the cue would appear on any
given trial. A crucial feature of the task was that the monkey had
to maintain fixation throughout the cue period and also throughout the subsequent delay period. At the end of the delay period,
the fixation target was extinguished;
this was the “go” signal to
make a saccade. If the monkeys made a saccadic eye movement
within the next 0.5 s (the response period) to the location where
the cue had been presented, they were rewarded with a drop of
liquid. A correct response was defined as an eye movement that
fell within a window (6” diam.) around the cue location.
We usually used one fixed delay interval (3 s) during recording,
but longer delays (6 s) or combinations
of two (3 and 6 s) or three
(1.5, 3, and 6 s) different delays were sometimes used to examine
activity across different delay intervals. Many of these neurons
were also studied with other tasks (visual probe task, visually
guided saccade task, etc.): these results will be presented in a
future paper.
After analyzing the response properties of neurons, we sometimes employed microstimulation
through the recording microelectrode to determine whether the recording site was in the frontal eye fields, based on the criteria of Bruce et al. (7).
Single neuron activity was recorded with Parylene-coated
tungsten microelectrodes
(2-5 Mit at 1 kHz, Micro Probe) that
were advanced through the intact dura with a hydraulic microdrive (MO-95B, Narishige). Single neuron activity was amplified
1O,OOO-fold by a differential amplifier (MDA-4, BAK). This signal
passed through a low-pass filter to eliminate artifact from the
search coil driver and then to a window discriminator
(DIS- 1,
BAK) to isolate single neuron activity for the computer.
We
monitored both the raw activity signal and the window discriminator output simultaneously by an oscilloscope (5 1 10, Tektronix)
and an audio monitor. Usually one electrode track was explored
each recording session. Electrode tracks were separated on a
1-mm grid.
For the microstimulation,
trains of pulses were generated by a
biphasic pulse generator (BPG- 1, BAK). Each pulse was 0.2 ms in
duration, stimulation frequency was 330 Hz, and the train duration was 70 ms. The pulse generator output was connected to a
constant-current
stimulus isolation unit (BSI- 1, BAK). Current
was monitored by the voltage drop across a I-kft resistor in series
between the output of the isolation unit and the microelectrode.
Current tested ranged up to 200 PA.
A
Visually
guided
saccade
B
3.0
CORTEX
333
Data ucquisit ion
The on-line computer system, in addition to carrying out the
behavioral
paradigms, sampled neural and ocular signals and
stored these data in relation to task events on magnetic media.
Voltages from the phase-sensitive detector representing the horizontal and vertical eye coordinates were digitized every 2 ms (500
Hz). These signals were also electronically
differentiated to yield
horizontal and vertical eye velocity. The velocity signals were also
digitized and were used by the on-line computer
program to
identify each saccade that the monkey made via the algorithm of
van Gisbergen et al. (25).
Two types of data storage files were stored. Event bz&Gr files
contained the time of every event that the computer had access to,
including
the time of each discriminated
action potential, the
time, duration, and amplitude of each saccade, and the time of
events such as the appearance and disappearance of visual cues.
Individual event buffer files usually contained 50- 100 trials. AnaI~~~u~ bu&r files contained multiple records ( l-2-s epoches) of all
of the analogue signals being sampled, together with the discriminated action potentials and a code representing progress through
the task paradigm (see Fig. 1B).
Two types of computer-generated
displays were monitored
during the experiments. In one display, horizontal gaze, vertical
gaze, and overall eye velocity were displayed as scrolling traces on
a digital oscilloscope (1345A, Hewlett Packard). Discriminated
neuron activity was scrolled below these traces and tics representing on-line saccade recognition were placed on the velocity trace.
Superimposed on the scrolling display were two-dimensional
representations of gaze, visual stimuli, and the fixation window. In
the other display, rasters and histograms were viewed on the same
oscilloscope to observe the overall neural data collection.
Datu anaivsis
Using the stored event buffer files, we examined rasters and
histograms of neuron activity for each cue location. These rasters
and histograms were made with different alignment points including I) the onset of cue, 2) the start of the delay period, 3) the
end of the delay period, 4) the initiation of the saccadic eye movement during the response period, and 5) the appearance of the
fixation target. Rasters and histograms were examined on the
digital oscilloscope and copies were made using a digital plotter
(7470A, Hewlett-Packard).
Neural activity during the delay period was also analyzed quantitatively for all neurons recorded. The average discharge rate
C
s delay
6.0
s delay
20.
20
4
: --I-
*
20
----
** I”
- *
20
FIG. 2. The distribution
of eye positions following
the saccade in the visually guided saccade task (A), in the oculomotor
delayed-response
task with 3-s delay (B) and with 6-s delay (0 These plots contain both correct and incorrect
trials (if any).
All cue eccentricities
were 13”.
I
FUNAHASHI,
334
BRUCE,
AND
during the delay period was calculated for each trial, and then
overall mean discharge rates and standard deviations for each cue
location were computed. We tested for significant delay period
activity by comparing the mean discharge rate during the delay
period for all trials having a given cue direction versus the mean
discharge rate during the intertrial interval over all trials, using a
two-tailed unpaired Student’s t statistic and an alpha level of 0.05.
Differences in delay period activity across different cue locations
were evaluated using an analysis of variance (ANOVA).
1350
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GOLDMAN-RAKIC
Histological
After 2-8 mo of nearly daily recording sessions the monkeys
were killed with an overdose of pentobarbital
sodium and perfused with saline followed by buffered Formalin. The brains were
photographed.
Frozen coronal sections were taken and stained
with thionin.
Individual
recording sites that had been marked with electrolytic lesions (20 PA, lo- 15 s, tip negative) were identified. How450
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FIG. 3.
Directional
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sulcus neuron during the oculomotor
delayed-response
task. This
neuron (52 1 1, left hemisphere)
had strongly directional
delay period activity (fi’ = 48.35; df = 7, 68; P < 0.00 l), responding
only when the cue had been presented
at the bottom (270”) location.
It was suppressed during the delay when the cue was
presented in the upper visual field, and in all 3 cases delay period activity was significantly
below the IT1 rate (45”, l = 2.350,
df = 84, P < 0.025; 90”, t = 3.45 1, df = 85, P < 0.001; 135”, t = 2.607, df = 84, I-’ < 0.025). Visual cues were randomly
presented at 1 of the 8 locations indicated in the center diagram. All cue eccentricities
were 13” and all delay periods were 3 s.
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MEMORY
CODING
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PREFRONTAL
335
CORTEX
ever, the long duration of recording and large number of electrode
penetrations precluded identification
of most penetrations,
and
their locations in the brain were estimated from their microdrive
coordinates.
the distribution of saccade end points of one monkey in a
visually guided saccade task (Fig. 24, and in the 3-s (Fig.
2B) and 6-s delay conditions (Fig. 2C) of the oculomotor
delayed-response task. Although the distribution of saccade
end points is wider in the delay task than in the visually
RESULTS
guided saccade task, nearly all saccades end near the appropriate location, even with 6-s delays.
Task yerfimnance
.
The mean latencies for saccadic eye movements in the
responseperiod were 2 16.4 t 33.0 (SD) ms in the visually
All monkeys performed the oculomotor delayed-response task proficiently and the percentage correct was guided saccadetask, 298.3 t 34.4 ms in the 3-s delay task,
usually 90% or better for all cue locations. Figure 2 shows and 293.0 t 37.4 ms in the 6-s delay task. The difference in
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FIG. 4. Directional delay period activity
of a principal
sulcus neuron during the oculomotor
delayed-response
task. This
neuron (5 11 1, right hemisphere)
exhibited
directional
delay period activity (F = 25.23; df = 7, 56; P < 0.00 l), responding
only when the cue had been presented at locations in the upper quadrant
of the contralateral
visual field (90, 135, and 1800).
The strongest delay period activity occurred at the 135” location.
Visual cues were randomly
presented at 1 of the 8 locations
indicated in the center diagram.
All cue eccentricities
were 13” and all delay periods were 3 s.
IS
336
FUNAHASHI,
BRUCE,
AND
&w-al
mean latency between the visually guided saccade task and
each of the delay tasks was statistically
significant
(3-s
delay: t = 25.93, df = 454, P < 0.00 1; 6-s delay: t = 24.08,
df = 493, P < O.OOl), whereas that between the 3-s and
the 6-s delay tasks was not significant (t = 1.60, df = 477,
P > 0.05).
The mean duration
of saccadic eye movements
was
46.2 t 8.5 (SD) ms in the visually guided saccade task,
44.9 t 7.6 ms in the 3-s delay task, and 46.2 t 8.2 ms in the
6-s delay task. There were no significant differences in
mean saccade duration among the three tasks (ANOVA,
F = 1.982; df = 2, 706; P > 0.1).
900
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i
GOLDMAN-RAKIC
data base
We recorded from 3 19 neurons in the prefrontal cortex
of three rhesus monkeys while they performed the oculomotor delayed-response
task. As discussed in detail below,
288 of these neurons were from cortex within and surrounding the caudal half of the principal sulcus. We term
these PS (principal sulcus) neurons and most of this report
concerns their activity. The other 3 1 neurons were located
within and near the anterior bank of the arcuate sulcus and
were classified as frontal eye field (FEF) neurons. At some
sites this FEF classification was confirmed by low microstimulation thresholds (~50 pA) for the elicitation of sacD
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1
180'
270"
C
FIG. 5.
Directional
delay period activity of a principal
sulcus neuron. This neuron (5050, right hemisphere)
showed tonic
inhibitory
delay period activity only when the cue was presented at 90” (F = 4.870; df = 3, 39; P < 0.025). Visual cues were
randomly
presented at 1 of the 4 locations
indicated
in the center diagram.
All cue eccentricities
were 13” and all delay
periods were 3 s.
MEMORY
CODING
IN PREFRONTAL
cadic eye movements. Data concerning these 3 1 FEF
neurons is separately presented at the end of the RESULTS.
Of the 288 PS neurons thoroughly analyzed, most (170
neurons, 59% of total sample) had task-related activity in
that their average discharge rate during at least one phaseof
the delayed-response task differed significantly (P < 0.05, t
test) from their IT1 (InterTrial Interval) rate. Of these 170
neurons, 87 neurons (30% of total sample, 5 1% of total
task-related neurons) had significant de/a-v period activity.
For 33 (38%) of these neurons the delay period activity was
the only significant task-related activity, but most (54
neurons, 62%) also had significant activity in the task segments immediately preceding or following the delay period
337
CORTEX
(delay and cue periods: 11 neurons, 13%; delay and response periods: 32 neurons, 36%; delay, cue, and response
periods: 11 neurons, 13%). The remaining 83 task-related
neurons exhibited significant activity only in the cue period
(n = 12), only in the response period (n = 55) in both cue
and response periods (n = lo), or at reward presentation
(n = 6).
Directional
specifrcitv
. period activity
.
” of’delav
.
Most PS neurons with delay period activity showed a
significant increase or decrease in this activity relative to
their base-line discharge rate only when the cue had been
45O
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1 .O-6
FIG. 6.
Omnidirectional
delay period activity of a principal
sulcus neuron. This neuron (50 1 1, right hemisphere)
showed
tonic excitatory
delay period activity independent
of cue location (F = 0.63; df = 7,46; P > 0.1). Visual cues were randomly
presented at 1 of the 8 locations indicated in the center diagram.
All cue eccentricities
were 13” and all delay periods were 3 s.
I
l.
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FIG. 7.
Directional
tuning of 6 principal
sulcus neurons with delay period activity.
In each radial plot, the neuron’s
average discharge rate during the delay period for each cue location
is depicted by the radial eccentricity
of the plot in that
direction,
the standard deviation
of this rate is depicted by the radial line, and the neuron’s average IT1 discharge rate is the
radius of the circle. Asterisks (*) indicate cue directions
with statistically
significant
(t test, P < 0.05) differences
between
delay period activity
and the IT1 rate. A and B: 2 principal
sulcus neurons
(A: 504 1, right hemisphere;
B: 52 11, left
hemisphere)
with very specific directional
delay period activity (A, F = 10.12; df = 7,54; P < 0.00 1; B, F = 48.35; df = 7,68;
P < 0.00 1). They have a significant elevation of delay period activity for only 1 direction. Notice that there is significant
inhibition
of delay period activity for cue directions
roughly opposite the excitatory
directions.
C and D: 2 principal
sulcus
neurons (C: 5 1 1 1, right hemisphere;
D: 5066, right hemisphere)
with directional,
but broadly tuned, delay period activity (C,
F = 25.23; df = 7,56; P < 0.00 1; D, F = 3.80; df = 7,7 1; P < 0.005). Notice that for Cthe responses are excitatory
relative to
the IT1 rate whereas for D the only significant
responses are inhibitory.
E and F: 2 principal
sulcus neurons (E: 5011, right
hemisphere;
F: 5008, right hemisphere)
with omnidirectional
delay period activity (E, F = 0.63; df = 7, 46; P > 0.1; F, F =
1.26; df = 7, 65: P > 0.1). One of these is excitatory
(E) and the other inhibitory
(F).
338
MEMORY
CODING
IN
presented at one or a few among the 4 or 8 locations tested.
Of the 87 PS neurons with delay period activity, 69 (79%)
were directional,
i.e., a statistically
significant difference
(P < 0.05) in delay period discharge rates across different
cue locations.
Figure 3 shows directional activity in a PS neuron tested
with eight cue locations. Strong tonic excitatory activation
appeared throughout the delay period only when the cue
was presented at the downward
(270”) location. This response began - 100 ms after the cue presentation
and
ceased 130 ms after the initiation of the saccadic eye movement. Moreover, activity during the delay period was suppressed relative to the IT1 discharge rate for the three cue
locations in the upper (opposite)
visual field (45”, t =
2.350, df = 84, P < 0.025; 90”, t = 3.451, df = 85, P <
0.00 1; 135O, t = 2.607, df = 84, P < 0.025). This phenomenon of an excitation of delay period activity for one set of
cue locations and an inhibition of delay period activity for
other directions is discussed further below.
Figure 4 shows another PS neuron with directional activity that exhibited broader tuning than the neuron shown in
Fig. 3. The delay period activity was significantly elevated
for the three locations that span the upper quadrant of the
contralateral
visual field (90, 135, and 180”) with the
highest rate on 135’ trials. The activity ceased abruptly 170
ms after the initiation of the saccadic eye movement. For
the three cues spanning the opposite quadrant (lower ipsilateral, 270, 3 15, and 0”) this neuron’s activity was depressed below its ITI rate (see also Fig. 7C), although this
depression was not statistically significant for any individual direction.
Neurons with only inhibitory activity during the delay
period could also be directional. The neuron shown in Fig.
5 was suppressed during the delay period only when the cue
had been presented at the upper location (90”, t = 6.036,
df = 53, P < 0.001); there was no significant change in
activity during the delay period for the three other cue
locations tested.
The remaining 18 neurons (2 1%) with significant delay
period activity were classified as omnidirc~ctional
because
they responded similarly during the delay period regardless
of cue locations and the ANOVA
criterion for directional
selectivity was not met. Figure 6 shows an example of a PS
neuron with omnidirectional
delay period activity. The
tonic excitatory delay period responses for all locations was
significantly above the IT1 rate by individual t test and the
slight differences between locations were not statistically
significant.
To more concisely show directional specificity of directional delay period activity, we constructed polar plots that
1.
Response tIvpe of direct ion al und omnidirectional
delay period activit wv of. principal sz~lcus neurons
TABLE
Response
type
Directional
Omnidirectional
Total
Excitation
Inhibition
46
23
4
14
50
37
Total
69
18
87
PREFRONTAL
CORTEX
Distribution
for excitatory
of best
delay
cue directions
activity
(n=46)
45"
(1)
180"
(11)
315"
(4
225"
(2)
270"
(8)
Dis tribution
for inhibitory
of best
delay
cue directions
acti vity (n=23)
90”
(5)
180"
0"
(9)
(5)
315"
225"
(1)
(0)
270"
(3)
FIG. 8.
Distribution
of the preferred
directions
for delay period activity
of principal
sulcus neurons tested with the oculomotor
delayed-response
task. Length of radial lines is proportional
to the number of cells for which
that cue direction
gave the best delay period response: the cell counts are
also given beneath the directions.
Preferred
directions
were normalized
by
a right-hemisphere
convention:
the preferred
direction
of each left hemisphere neuron was mirror
reversed across the vertical meridian.
Top: this
plot summarizes
the preferred
directions
for the 46 neurons having excitatory directional
delay period activity.
Bottom:
this plot summarizes
the
preferred
directions
for the 23 neurons having inhibitory
directional
delay
period activity.
Note that 15 of the 46 neurons in the top plot also had
significant
inhibitory
delay period activity,
usually for cue directions
roughly opposite their best excitatory
direction.
The best inhibitory
direction for these neurons are not plotted in the hottom part, and hence the
neuron populations
comprising
the top and bottom plots are mutually
exclusive.
The overall preference
in both plots for directions
along the
horizontal
and vertical meridians,
as opposed to oblique directions,
is an
artifact because many neurons were only tested for four cue directions
(left, right, up, and down) and not for oblique directions.
depict the delay period discharge rate of a neuron as a
function of polar direction by plotting discharge rate as a
function of polar eccentricity.
The base-line (ITI) rate of
the neuron is shown on the plots by the radius of a circle,
the standard deviations of the delay period discharge for
each direction are shown by radial bars, and statistically
significant departures from the IT1 rate are indicated by
asterisks. Figure 7, B, C, and E, show polar plots for the
narrowly
tuned, broadly tuned, and omnidirectional
FUNAHASHI,
BRUCE,
AND
GOLDMAN-RAKIC
FIG. 9.
Directional
tuning of delay period
activity
for 2 principal
sulcus
neurons.
Plots show discharge rate during
the delay period for the 8 different
cue
directions,
with a Gaussian function
fit to
the data. A (521 1, left hemisphere)
shows
narrowly
tuned directional
activity
( Td =
19.7O, preferred
cue direction
= 270”) and
B (5077, right hemisphere)
shows broadly
tuned directional
activity
(T(, = 48.4”,
preferred
cue direction
= 135”).
20
10
1
I
180"
I
270"
cue
[5211.0]
0"
I
0
0”
90"
locat Ion
Excitatory e and inhihitorv * dduv- puiod
uctivit w
v
As evident from the polar plots in Fig. 7, we observed
instances of both elevation and depression of delay period
activity relative to a neuron’s base-line rate. To further
B
A
D
180"
270"
po77.01
neurons whose histograms were illustrated in the previous
three figures (Fig. 3, Fig. 4, and Fig. 6, respectively),
whereas Fig. 7, A, D, and c(‘, show three additional examples: another PS neuron with narrowly
tuned directional
delay period activity is shown in Fig. 7A. For this PS
neuron, the preferred cue direction was leftward (1 SOO),
whereas for most other cue directions, the discharge rate
during the delay period was suppressed below base line. A
neuron with directional delay period activity that was suppressed below base line when the to-be-remembered
cues
were in the upper-left quadrant of the visual field is shown
in Fig. 70. Finally, Fig. 7F shows a neuron with omnidirectional inhibition of delay period activity: comparable
inhibition occurred for all eight cue locations.
C
90”
understand the relation between the “sign” of this activity
and directional
specificity, we classified each neuron as
having either excitatory or inhibitory delay period activity
by the statistical criteria previously described. A neuron
was classified as excitatory (or inhibitory)
if delay period
rate for any cue direction was significantly elevated (or on/y
reduced) relative to the neuron’s ITI.
Table 1 shows the incidence of neurons for the different
combinations
of delay period response sign and directionality. As is evident from examining the Table, neurons
having excitatory delay period activity were more likely to
be directional (92%) than neurons with solely inhibitory
responses (62%). Furthermore,
we observed that directional tuning for inhibitory
delay period activity was
usually broader than that for excitatory directional activity.
The phenomenon
of a single neuron having both an
elevation of delay period activity for one set of directions
and depression of delay period activity for another set was
frequently encountered. Usually the best cue directions for
saccade
R
2os/s
0.5
C
FIG. 10.
The time course of excitatory
and inhibitory
delay period activity.
These
histograms
sum neural activity
at the preferred cue direction
for all 46 principal
sulcus neurons with excitatory
directional
delay period
activity
(A, B) and all 23
principal
sulcus neurons
with inhibitory
directional
delay period activity
(C’, D). A
and C’ were aligned at the cue presentation; B and D were aligned at the initiation
of the saccadic eye movements.
All delay
periods were 3 s.
s
saccade
D
R
2osi’s
MEMORY
CODING
IN
eliciting inhibitory responses were opposite to the best directions for eliciting excitatory responses. For 15 neurons
the criteria of having a statistically significant elevation of
delay period activity for at least one direction and a statistically significant inhibition of activity for at least one other
direction was met. However, several other neurons, such as
the ones illustrated in Figs. 4 and 7C, had delay period
discharge rates below base line for one or more directions
that did not meet our statistical criteria yet seemed genuine
because the inhibition was present for two or more adjacent directions opposite to the excitatory direction.
Distribution
of prefh-red
direct ions
.
To determine the distribution
of directional preferences
of delay period activity, we used the largest t statistic to
classify the preferred direction of each neuron as the cue
location where it showed the most prominent excitation or
inhibition. For analytical and graphic purposes, the preferred directions of left-hemisphere
neurons were transformed into mirror-image
directions, as if all neurons were
recorded from the right hemisphere. Among the 69 PS
neurons with directional delay period activity, 30 were
studied in the 4-cue condition and 39 were studied in the
8-cue condition.
As shown in Fig. 8, the majority
of
neurons with excitatory directional delay period activity
had preferred directions on the side contralateral
to the
hemisphere recorded from. This contralateral bias was statistically significant by a chi-square test (x2 = 8.758, df = 1,
P < 0.0 1). There was no statistical significance in the directional preference of inhibitory directional delay period activity (X2 = 1.667, df = 1, P > 0. l), although most inhibitory directions were also contralateral.
A
PREFRONTAL
Tuning ofL directional
where j‘(d) is discharge frequency, d is cue direction, and
the remaining terms are constants: B is the discharge rate
during the ITI, D is the best direction, R indexes delay
period response strength, and Td indexes tuning with respect to cue direction. The function was implemented by
fixing B at the average background discharge rate, and then
iteratively converging to the best least-squares solution for
R, D, and T’. This Gaussian approach has previously been
used to describe visual receptive fields and presaccadic
movement fields in the FEF (6).
We applied this Gaussian formula to all 69 PS neurons
that exhibited directional delay period activity. However,
we omitted 42 PS neurons because 30 PS neurons were
only studied with 4 cue directions and the Gaussian fits to 8
data points for 12 PS cells were poor. The remaining 27 PS
neurons had good fits based on 8 cue locations. Figure 9
shows the tuning curves obtained for two of these PS
neurons, one with narrowly tuned excitatory delay period
activity (Td = 19.7’, Fig. 9A) and another with broadly
tuned excitatory delay period activity ( Td = 48.4”, Fig. 9B).
Excitatory delay period activity tended to have narrower
tuning than inhibitory
delay period activity. The mean
tuning index (Td) was 26.8 t 14.2” (SD) (n = 22) for
neurons with significant excitatory delay period activity
versus 48.2 t 43.5O (n = 5) for neurons with only inhibitory delay period activity. These means are not significantly different (t = 1.985; df = 25; 0.05 < P < 0.1) proba-
D
IR
270 O
Il
I
l’
I
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II
I
I
delay period activit *v
To determine the directional specificity of delay period
activity, tuning curves were estimated using the Gaussian
function
.f(d) = B + R * e-l/2”dy~)/~d)2
1800
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CORTEX
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FIG. 1 1.
Directional
delay period activity
of a principal
sulcus
neuron (50 18, right hemisphere)
for 2 different
delay
durations
(3-s delay in A and 6-s delay in B), examined
sequentially
(3 s first, then 6 s). For each set of histograms
the visual
cues were presented randomly
at 1 of 4 locations
indicated (0” = right, 90” = up, 180” = left, and 270” = down). All cue
eccentricities
were 13 O.
III 111
l
II
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342
FUNAHASHI,
BRUCE,
bly because of the small number of inhibitory neurons that
could be fit and the large SD of inhibitory tunings.
Time course of dela wk)period act ivit w
c’
To further characterize the overall activity of PS neurons
during the oculomotor
delayed-response
task, we made
histograms
that summed activity across our sample of
neurons, selecting for each neuron the trials with cues in
that neuron’s preferred direction. Figure 10 shows these
composite histograms. Neurons with excitatory (n = 46)
and inhibitory (n = 23) directional delay period activity
were summed separately to prevent these activities from
canceling each other. The left pair of histograms (Fig. 10, A
and C) depict excitatory and inhibitory composite activities during the 3-s delay period, as well as during the fixation, cue, and response periods, and part of the ITI. For the
excitatory composite histogram the overall delay period
activity was 13.9 spikes/s, in comparison to 7.6 s/s during
the first 1.5 s of the histogram (the IT1 and fixation interval). For the inhibitory
composite histogram the overall
delay period discharge rate was 4.5 s/s, in comparison to
8.1 s/s during the ITI and fixation interval.
Thus PS
neurons with typical excitatory
directional
activity discharge at approximately
twice their base-line rate during
the delay period, whereas PS neurons with typical inhibitory directional activity discharge at approximately
onehalf their base-line rate.
The composite histograms also indicate the time course
of PS neuron activity during the delay period. Although
individual
neurons have a variety of temporal changes
during the delay period, these composite histograms indicate that overall PS neuron activity is well-maintained
during a 3-s delay. In fact, there is an increase in discharge
rate over the 3-s delay period in the excitatory composite
histogram ( 12.4, 14.9, and 14.5 s/s in the first, second, and
third second, respectively) and a decrease in the inhibitory
composite histogram (4.8, 4.7, and 3.9 s/s).
A phasic response is evident during the 0.5-s cue period
in the excitatory composite histogram (Fig. 1OA). The earliest indication of this response begins -70 ms following cue
onset (all latencies were estimated using a cumulative histogram of the same data, which is not shown); but individual neurons had a wide variety of latencies, and many did
not respond at all during the cue period. It should be noted
that many PS neurons having strong visual responses, but
lacking delay period activity, were not included in these
composite histograms.
Finally, the composite histograms
depict a phasic increase in activity during the response period for both the
excitatory and inhibitory activity. The latency of this activity is 180 ms following the disappearance of the fixation
target for the excitatory activity and 300 ms for the inhibitory activity. Since the typical saccade latency during the
oculomotor
delayed-response
task is -290 ms, it would
appear that the excitatory burst leads the saccade in the
excitatory composite histogram but follows the saccade in
the inhibitory composite histogram. Histograms aligned at
the saccade initiation (Fig. 10, B and n) support this interpretation: the additional burst of activity in the excitatory
composite begins -30 ms prior to the saccade initiation
AND
GOLDMAN-RAKIC
and ends -40 ms after the saccade initiation (Fig. 1OB). In
contrast, the increased discharge in the inhibitory composite begins -40 ms following the saccade initiation (which
is approximately
at the saccade termination)
and continues
for -0.5 s (Fig. lo@.
Eighteen PS neurons that exhibited directional delay period activity were tested either with two (3 and 6 s) or three
(1.5, 3, and 6 s) different delay durations. The monkeys
had little difficulty with any of these delay times and maintained a high level (>80%) of correct performance
at all
delays tested.
Varying the delay length over this range of values had
little effect on delay period activity. In particular, the directional preference was unchanged and the duration of excitation or inhibition expanded with longer delays. For example, Fig. 11A shows a neuron with tonic excitation during a 3-s delay period only when the cue was presented at
the 180’ location. Figure 11B shows the same neuron’s
A
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FIG. 12.
Directional
delay period activity of a principal
sulcus neuron
(5070, right hemisphere)
for three different
delay durations
(1 S-s delay in
A, 3-s delay in B, and 6-s delay in CT). The data are from an experiment
with 12 different
types of trials: 1.5, 3-, and 6-s delay durations
crossed
with 4 visual cue locations (0” = right, 90” = up, 180” = left, and 270” =
down). All cue eccentricities
were 13”. Only the 3 histograms
from the
preferred
direction
(180” location)
are shown.
MEMORY
Neuron
CODING
IN
PREFRONTAL
343
CORTEX
5018
correct
trials
3
error
u
!!!&
trial
’
e-k-!
Neuron
!
! ! It-u!!
!! !
5111
correct
trials
C
1
*j+*
2
UJ!f
D
R
fgj
H!
\
u
FIG. 13.
Discharges
of 2 principal
sulcus neurons with directional
delay period activity
during correct performance
of
the oculomotor
delayed-response
task and during
trials with
errors. For each trial depicted, discharge traces are shown on the
left and cue locations
and saccade directions
are shown on the
right. Top: this neuron’s
(5018, right hemisphere)
strongest
delay period activity was associated with leftward cue presentations. On the error trial, its discharge
ceased about midway
through
the delay period. Bottom:
this neuron’s
(5 111, right
hemisphere)
strongest delay period activity was associated with
cue presentations
in the upper-left
visual field. On the error
trial, its discharge in the delay period was absent.
3-###+#*
m
error
+
trial
t
:
! ! !!+S+t!
II IIaI
1111
Illl
I##+#+#
I
7-T
activity during the delayed-response task with a 6-s delay.
The tonic excitation still appeared only when the cue was
presented at 180’ and was maintained during the entire 6-s
delay period. With both delays, the tonic excitation ceased
at the initiation of the response. Eight other PS neurons
with tonic delay period activity were similarly tested with
different delay durations; all showed similar results, that is,
the response e panded to fill the entire delay.
Figure 12 sx ows another PS neuron tested across different delay durations. In this case, four cue locations (0, 90,
180, and 270”) at three different delay durations (1.5, 3,
and 6 s) were randomly intermixed. The rasters and histograms in Fig. 12 show neural activity during three different
delay durations for cues presented at 180”, the preferred
direction for this neuron. Notice that the activity in the first
1.5 s of the delay is very similar in all three conditions, that
is little or no change in activity relative to the preceding
fixation interval. Furthermore, the activity in the next 1.5 s
of the delay period is the same in the 3-s and 6-s delay
conditions, both showing a gradual rise in activity. This
result was obtained in six other PS neurons that increased
discharge rate during the delay. Likewise, two PS neurons
with gradually decreasing discharge rates during the delay
showed analogous patterning of activity when the delay
duration was changed.
Directional
delay period activity in error trials
Analysis of activity in error trials often aids the interpretation of delay period activity (5, 53, 54, 58,64-66). Therefore, we examined the activity when the monkeys made
errors on trials with the preferred cue direction for the
neuron being studied. For this analysis, failure to saccade
and misdirected saccades(i.e., ending outside the window)
were counted as errors; however, nearly all errors were
misdirected saccades.Premature saccadesmade during the
delay period did not count as errors. Of 69 PS neurons
A
Correct
trials
4Qsls
1s
B
Error
trials
C
D
R
FIG. 14.
Comparison
of delay period activity
for correct trials with
activity
for error trials. The first correct trial and the first error trial were
taken from each of the 9 principal
sulcus neurons
that had excitatory
directional
delay period activity and for which the monkey
made at least 1
error on a trial in the neuron’s preferred
direction.
The tophistogram
sums
the 9 correct trials and the bottom histogram
sums the 9 error trials.
344
FUNAHASHI,
BRUCE,
AND
exhibited directional
delay period activity, only 13 PS
neurons (9 excitatory and 4 inhibitory)
had one or more
such error trials. Nevertheless, these data indicate that the
responses of PS neurons during the delay period were significantly weaker on trials where the monkey made an
error during the response period.
Figure 13 shows examples of neural activity in both correct and error trials for two neurons with directional delay
period activity. The neuron shown at the top of the figure
had its strongest delay period activity with leftward (1 80°)
cue presentations.
For trials on which the monkey’s eventual saccade was to this location the neuron responded
tonically throughout the delay period. However, on the one
trial in which an error was made (saccade to upper right)
the neuron’s discharge ceased about midway through the
delay period. The neuron at the bottom of Fig. 13 showed a
similar pattern except that its delay period activity was
absent altogether on the one trial in which an error was
made.
To examine the error data as a whole we summed the
first error trial (usually the only one) across the nine excitatory neurons with an error trial in the neuron’s preferred
direction. This histogram was compared to a histogram
composed of the first correct trial (from the same event
buffer) of these nine neurons at their preferred direction.
Figure 14 shows these two histograms. The delay period
activity on the correct trials was significantly greater than
activity on the error trials by a paired t test (t = 2.76, df = 8,
P < 0.025).
A
GOLDMAN-RAKIC
Directional and omnidirectional
the frontal eye .fields
delay period activity e in
Of the 3 19 examined neurons, 3 1 were recorded from
the frontal eye fields (FEF), where low- (~50 PA) and intermediate-threshold
(between 50 and 100 PA) microstimulation generated saccadic eye movements (7). Of these 3 1
neurons, 22 showed task-related activity during the oculomotor delayed-response
task, with 17 (54.8%) having significant responses during the delay period ( 10 excitatory
and 7 inhibitory).
Of these 17 FEF neurons, 10 exhibited directional delay
period activity. Figure 15 provides an example of a neuron
with a preferred direction at 90”; this FEF neuron showed
tonic excitation during the delay period (see Fig. 15B) and
also exhibited presaccadic
excitation
at the time of response when the monkey made saccadic eye movements to
the cue location which was the neuron’s preferred direction
for delay period activity (see Fig. 15C). Like some PS
neurons, the delay period activity was suppressed when the
cue was presented at roughly opposite directions to its preferred direction (135, 180, and 225”).
Of the 10 FEF neurons with directional delay period
activity, 5 had preferred directions into the contralateral
hemifield, 4 preferred upward directions, and 1 preferred
ipsilaterally directed stimuli. The mean tuning index (Td)
was 27.4 t 20.0° (n = 7) for FEF neurons with excitatory
directional delay period activity. The three FEF neurons
with inhibitory directional delay period activity were very
broadly tuned.
D
**So
B
90”
D
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t
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uo503s.
000
.
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50sls
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5035.0-2
200
ms
FIG. 15.
Directional
delay period activity (F = 29.582; df = 7, 33; P < 0.00 1) of a frontal eye fields neuron. This neuron
(5035, right hemisphere)
had significant
tonic excitatory
delay period activity only when the cue was presented at the 45 and
90” locations
and was suppressed
during the delay when the cue was presented at roughly
opposite locations
(135”, t =
2.647, df = 43, P < 0.025; 180”. t = 3.158, df = 42, P < 0.005; 225”, t = 3.759, df = 46, P < 0.001). Visual cues were
presented
randomly
at 1 of the 8 locations.
All cue eccentricities
were 13” and all delay durations
were 3 s. A: radial plot
showing the directional
tuning of delay period activity. B and D: neuron’s delay period activity on the 90” trial and the 225”
trial, respectively.
C and E: activity aligned at the start of saccadic eye movements
at the response period on the 90” trial and
the 225” trial, respectively.
Note that this neuron had presaccadic activity for 90” saccades and postsaccadic
activity for 225”
saccades.
200
ms
MEMORY
CODING
IN
*I3 -I--
n
Directional
0
Omnidirectional
A
Both
Activity
__I--
Activity
,
FIG. 16. Tracings
of the dorsolateral
prefrontal
cortex showing
the
location of electrode penetrations
for the 3 monkeys
(monkq~.s 2,3, and 5)
studied. The perspective
of the tracings is approximately
normal
to the
dorsolateral
prefrontal
cortical surface, roughly midway between standard
lateral and dorsal views. Locations
of neurons with directional
delay period activity
(a), omnidirectional
delay period activity (m), and locations
where both types of activity
were found (A). Small &ts indicate
surface
locations of electrode penetrations
where neurons with delay period activity were not found. PS, principal
sulcus; AS, arcuate sulcus.
Cortical distribution of neurons with directional
omnidirectional
dela*v*period activity
in the prefrontal cortex
and
Recording sites in each hemisphere were located on reconstructions
of the dorsolateral prefrontal region. Most
electrode penetrations were in the dorsal and ventral banks
of the medial and posterior part of the principal sulcus and
also in the surrounding
regions of the principal sulcus
[Walker’s area 46 (63)]; however, in one hemisphere nine
penetrations were made in the prearcuate region bordering
the anterior bank of the arcuate sulcus where the frontal
eye fields are located.
Figure 16 illustrates the location of all penetrations and
also shows the location of neurons with directional and
omnidirectional
delay period activity in each of five hemispheres studied. We were unable to discern any clear localization or clustering of neurons with directional delay period activity and neurons with omnidirectional
delay period activity.
DISCUSSION
Memoryfields
of prefivntal
.
neurons
Prefrontal neurons with directionally selective delay period activity were first described in conjunction
with the
classical manual version of the delaved-response
task (50)
PREFRONTAL
CORTEX
345
and a related task, spatial delayed alternation (5 1, 52). Prefrontal neurons in previous studies were characterized as
directionally
selective because their delay period activity
was specific for the left- or right-of-center
locations of the
cues or the left or right direction of the manual response
(50-52). Similar selective delay period activity has been
observed in prefrontal neurons during performance of delayed discrimination
(22, 47, 58) and conditional response
(64) tasks. Although the overall percentage of neurons with
directionally
selective delay period activity in previous
studies of the prefrontal cortex was small [i.e., 6% of total
“task-related”
neurons in Niki (50); 13% in Niki (5 1); 19%
in Niki and Watanabe (53); 10% in Fuster et al. (22)], these
neurons are nevertheless reflective of central mnemonic
processes guiding the correct choice at the end of delay ( 18,
28, 50).
The present study differs from previous recording efforts
in that we employed fixation and perimetry in order to
extend the analysis of delay-related activity beyond the traditional two-choice (left and right) paradigms (5, 16,20,22,
37, 40-42, 45, 50, 53, 54, 58, 67). We found that the delay
period activity of prefrontal neurons codes the spatial coordinates of visual cues during a delayed-response
task and
thus provides a mnemonic code for direction over the full
perimetry of visual space, not for left-right direction alone.
Each neuron with directional delay period activity had a
“mnemonic”
receptive field: only when the cue was presented in that field did the neuron show excitation or inhibition during the subsequent delay period. Moreover, directional delay period activity expanded when the delay
was lengthened and faltered on occasional trials when
errors were made. Therefore, we propose that this area of
the visual field be termed the memory field of the neuron
analogous to the receptive fields of visual neurons or the
movement fields of oculomotor
neurons. Memory fields
may be the cellular expression of a working memory process (3) that allows mnemonic information
to guide behavior.
The mechanisms by which a memory field is constructed
are not known at present. It is highly relevant that the
caudal prefrontal areas around the principal sulcus and
prearcuate cortex are heavily interconnected
with the posterior parietal cortex (2, 9, 1 1, 35, 36, 55, 59) which is a
major center for processing of spatial vision (1, 49). Our
recent anatomic studies of the posterior parietal cortex ( 10)
indicate that visuotopic information may be transmitted to
posterior parietal areas from a recently described visual
area on the medial surface of the occipital lobe (area PO)
which receives a direct input from the striate cortex (12)
and where neurons are responsive to peripheral stimuli
( 13). The posterior parietal cortex also receives afferents
from the superior temporal sulcus, from area MT, from the
inferotemporal
cortex, and from other prestriate areas ( 10).
Thus we speculate that prefrontal neurons may access visuotopic information
via the parietoprefrontal
pathway,
although that information may be also available from other
cortical and subcortical sources.
Delay period activity has been reported for neurons in
several cortical or subcortical
structures
during performance of delayed-response
tasks, as well as in prefrontal
cortical areas. These cortical and subcortical structures in-
346
FUNAHASHI,
BRUCE,
elude the posterior parietal cortex (5, 30, 39) the inferotemporal cortex (23, 24), the cingulate cortex (54) the
basal ganglia (32, 33) the mediodorsal nucleus of the thalamus (2 l), and the hippocampus (67). Interestingly,
almost
all of these structures are reciprocally connected with the
prefrontal cortex (17, 29, 62). These data are compatible
with the idea that the mnemonic information
in the prefrontal cortex reflected by neurons with directional delay
period activity may be a result of the neural interaction
among these cortical and subcortical
structures
(28, 29)
and that many of these structures may be part of a distributed network of cortical and subcortical structures
dedicated to spatially guided behavior (29, 6 1).
Later-alit I17of. memorl?- .fields
Previous studies of prefrontal cortex in delay tasks have
not emphasized the laterality (left or right, contralateral
versus ipsilateral) of neuronal activity. In contrast, our
study found a predominance of neurons preferring contralateral cues for their delay period activation. Among the 69
PS neurons with directional delay period activity, one half
(49.3%) had memory fields centered in the visual field contralateral to the hemisphere where the neurons were located, only 17.4% had ipsilateral memory fields, and 17.4
and 15.9% had memory fields in upward and downward
directions, respectively. This result indicates that, although
the population of neurons in each hemisphere may be capable of coding cues over the entire visual field, the prefrontal neurons within each hemisphere code mainly contralateral locations. Accordingly,
these results provide evidence that memory for spatial location is lateralized, with
memories
for locations
in the right visual field coded
mainly in the left hemisphere and memories for left field
locations coded in the right hemisphere.
This physiological evidence of lateralization
of spatial
memory is supported by results from lesion studies. Fuster
and Alexander (19) observed a higher proportion of errors
to the contralateral side in monkeys with unilateral cryogenic depression of the dorsolateral prefrontal cortex. In a
study using the oculomotor delayed-response
task (15) we
found that monkeys with a unilateral surgical ablation in
the principal sulcus had marked difficulty making correct
saccadic eye movements
to remembered
visual targets
which had been presented in the visual field contralateral
to the lesioned hemisphere and only mild or no difficulty
making saccades to remembered targets which had been
presented in the ipsilateral visual field. A similar result was
obtained by Deng et al. for a unilateral lesion of the frontal
eye fields on a task requiring memory over a IOO-ms time
interval (14). Because the monkeys with unilateral prefrontal lesions made normal saccadic eye movements to
targets in both fields when their eye movements were visually guided, the difficulty of making saccades to remembered targets in the oculomotor
delayed-response
task
seems to reflect a mnemonic deficit, which we have termed
a “mnemonic
hemianopia”
( 15) or “mnemonic
scotoma.”
Incidence and specificit
. ev of. dela -v period activit _v
More research is still needed to know if the principal
sulcus region has one population of neurons with delay
AND
GOLDMAN-RAKIC
period activity specific for the oculomotor
delayed-response task and a separate population specific for manual
types of delay tasks. We saw no indication of an anatomic
subregion of the prefrontal
cortex particularly
dense in
neurons with directional delay period activity for the oculomotor task, and our sampling area largely overlapped
with the regions where neurons with directional activity on
manual types of delay tasks have been found (16, 22, 50,
5 1, 53). Thus it is possible that the same region of the
prefrontal cortex codes mnemonic representations
across
different types of delay tasks, and may even generalize
across both sensory (visual versus auditory) and response
(hand versus eye) modality. Some evidence favors such a
type of generalized
coding by individual
prefrontal
neurons, primarily the relatively high incidence of neurons
with directional delay period activity during the oculomotor task (40.5% of total “task-related”
neurons) obtained in
the present study. If there were separate populations
of
prefrontal neurons for mnemonic representations
in conjunction with eye movements and hand movements, then
both populations would be active during the conventional,
manual types of delayed-response
tasks because primates
invariably first direct their gaze with a saccade to stimuli
that are to be touched or grasped with the hand. Therefore,
previous studies should have found an even higher proportion of prefrontal neurons with delay period activity than
we found with the oculomotor
delay task. In fact, the reverse is the case, with 6-19% being the incidence of directional delay neurons from previous studies using the manual task, as reviewed earlier. Thus it is possible that the
same prefrontal neurons code delay period representations
for both oculomotor and manual response systems. On the
other hand, there is no anatomic evidence in primates that
would indicate that single neurons in the prefrontal cortex
have axon collaterals to both eye- and hand-movement
centers. Therefore, the question of “supramodal”
neurons
in the prefrontal cortex must remain open for future evaluation.
The higher proportion of prefrontal neurons with directional delay period activity may be explained by two other
differences between our study and most previous ones.
First, our use of four or eight cue locations increases the
number of responsive neurons relative to studies employing only two (left and right) cue locations; many of our
neurons with directional delay period activity responded
best to cues above or below the fixation point (see Figs. 3
and 4) and would have been classified as nondirectional
or
nonresponsive
if only the histograms for the left and right
cue locations are considered. Another important reason is
that other observers seem reluctant to attend to inhibitory
responses; however, neurons with on/y inhibitory responses
account for nearly one-half of our sample of neurons with
significant delay period activity and slightly over one-third
of the population of directional delay period neurons.
Inhihitorv e delab7
w period activitl?.
Inhibitory
delay period activity was much more prevalent than previous studies have indicated. Nearly one-half
of the neurons with significant delay period activity were
solely inhibitory. Inhibitory responses were less likely to be
MEMORY
CODING
IN PREFRONTAL
directional than excitatory ones; even so, nearly one-third
of the directional responses were classified as directional
because of selective inhibitory responses in the delay period. In addition, some neurons with excitatory delay period activity for particular cue locations had inhibitory activity for other cue locations, usually such inhibition being
strongest for, or centered about, cue directions opposite to
those optimal for excitatory responses.
These inhibitory responses may have several functions.
First, neurons with inhibitory omnidirectional
delay period
activity comprised 16% of all the PS cells with significant
delay period activity. We suggest that a tonic reduction in
activity over this prefrontal pathway during the delay period may help the monkey suppress all saccadic eye movements for the duration of the delay period. There is an
intense projection from the prefrontal cortex to the intermediate and deeper layers of the superior colliculus, the
collicular zones responsible for saccadic eye movements
(27, 48). A tonic reduction in activity over this pathway
may provide a mechanism whereby the prefrontal cortex
can prevent inappropriate
saccades; patients with frontal
lobe lesions have difficulty withholding
responses to salient
sensory stimuli (3 1). Another role for the inhibitory delay
period activity is suggested by the neurons with inhibitory
activity for directions opposite the excitatory
cues. For
these neurons inhibitory activity may be sharpening the
spatial tuning of excitatory delay period activity. Opposing
patterns of activity are reminiscent
of the complex response patterns of neurons in sensory and motor centers
that respond with excitation to one parameter of stimulation but are inhibited by the opposite or complementary
stimulation, e.g., the opponent vector organization of parieta1 neurons,
the color opponency
of visual cortical
neurons, and the reciprocal activation
of motor cortex
neurons by extension and flection. Our findings indicate
that mnemonic coding is organized on a common physiological principle.
We recorded neurons with memory fields from both the
principal sulcal (PS) region [Walker’s
area 46 (63)] and
from the frontal eye fields (FEF) region in and near the
anterior bank of the arcuate sulcus. Although the number
of FEF neurons sampled was small, several had directional
delay period activity similar to that of PS neurons and the
tuning of directional delay period activity was comparable
(mean Td = 26.8’ in PS and 27.4” in FEF). Furthermore,
the directional tuning of delay period activity in PS is comparable to the directional tuning of presaccadic movement
fields in FEF (mean Td of visuomovement
neurons =
3 1.3’ I, Ref. 6).
Bruce and Goldberg
(6) reported
that many FEF
neurons, particularly those having either tonic visual activity or visuomovement
activity, responded throughout a l-s
delay period preceding saccades into their visual or move’ All Td estimates of Bruce and Goldberg
(6) are inflated by a factor of
1.4 142 because of a program
error discovered
while completing
the present study. Thus their average Tci of 44.2” for visuomovement
neurons
should be 3 1.3”.
CORTEX
347
ment field. Our FEF results are in general agree with that
report and our PS results indicate that many prefrontal
neurons anterior to the FEF behave similarly in the context
of the delayed-saccade task.
The primary pathway of mnemonic information
pertinent to saccadic eye movements in the frontal lobe may be
from the PS to the FEF. We suggested in the previous
section that PS neurons could code mnemonic representations of previous stimuli and impending responses across
different delayed-response
tasks. The FEF may construct
appropriate
saccadic commands
based on these inputs
from the PS region. Other cortex, such as the supplementary motor area, may fabricate hand movements based on
similar PS inputs, with the context of the task potentiating
one or both of these motor-specific
cortical zones. Indeed,
Goldberg and Bushnell (26) found that FEF visual activity
was only enhanced in the context of eye movements, but
Bushnell et al. (8) found that the visual activity on the
surface of the inferior parietal lobule, which projects to the
PS region, was enhanced in the context of both eye and
hand movements.
On the other hand, the PS and FEF
regions also could function independently with respect to
the delayed-saccade task. Both areas receive visual inputs
from the temporal and parietal cortices (17, 62) and both
have direct projections to the superior colliculus (27, 34,
43, 48) as well as indirect projections there via the corticostriatal system (60, 6 1). The actual circuit for memory
guided behavior is probably complex, and at present, we
can only postulate that the PS region handles delay information for both saccades and for arm movements whereas
the FEF are specific for eye movements.
Oculomotor
dcla evcd-rcsponsc task
We used an oculomotor delayed-response
task to examine the functions of the primate prefrontal cortex, whereas
most information
about previous studies of spatial delayed-response
have been conducted in a Wisconsin General Test Apparatus
(WGTA),
in which freely moving
monkeys reach through the bars of a small cage to retrieve a
food reward manually after an imposed delay. Testing in a
WGTA precludes precise experimental
control over the
animal’s regard of visual stimuli as well as its behavior
during the delay period. In neurophysiological
experiments
modified
versions
of the
using behaving
monkeys,
WGTA-based
task, such as two-choice (left and right) paradigms, have been used. Although the monkey’s
head is
fixed and stimulus presentations and response movements
are more controlled in this situation, the monkey’s behavior during the delay period, especially its eye movements,
have still not been controlled. The question could be raised
as to whether, under these testing conditions, a monkey
really needs memory to perform correctly,
because he
could maintain an ocular or postural orientation
to the
appropriate response key throughout the delay period. Obviously, if a monkey looked at the prospective response
window
continuously
during this period, he would not
need to remember the correct cue location. Although investigators have sometimes recorded electrooculographic
data during task performance (21, 22, 37, 40, 65, 66) they
34%
FUNAHASHI,
BRUCE,
have not usuallv continuouslv monitored or controlled eve
movements during the collection of single neuron activity.
In this respect, the oculomotor delayed-response paradigm that we used has several advantages. First, the monkey’s behavior can be controlled more precisely during the
performance of the delayed-response task. Because the
monkey must maintain fixation of the center spot of light
during the delay period, and as there is no clue available
during this period to indicate the direction of the correct
response, the monkey is required to use working memory
to achieve a high level performance. Second, this paradigm
allows the use of multiple cue locations in the monkey’s
visual field in order to more rigorously test whether directionally selective activity of prefrontal neurons reflects
coding of specific spatial information
rather than just a
general preparatorv set. Finally, recording eye position
during the delay as-well as the latency, direction, and amplitude of the eye movement at the time of response allows
a more accurate analysis of correlations between prefrontal
single neuron activity and behavior. Thus the oculomotor
delayed-response task may be a powerful tool for analyzing
the mnemonic functions of the prefrontal cortex in both
neurophysiological
and ablation experiments.
The authors thank L. Ladewig and S. Morgenstern
for surgical assistance and animal preparation,
J. Coburn
and M. Pappy for histological
assistance, and J. Musco for photography.
The authors are also grateful to
D. Burman,
M. Chaffee,
T. Preuss, T. Sawaguchi,
and F. Wilson
for
reading an earlier draft and providing
constructive
comments.
This work was supported
by National
Institute of Mental Health Grants
MH-38546
and MH-00298
to P. S. Goldman-Rakic,
National
Eye Institute Grant
EY-04740
to C. J. Bruce, and by Jacob Javits Center
for
Excellence
in Neuroscience
Grant NS-22807.
Received
25 April
1988; accepted
in final
form
07 October
1988.
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