Download Dissociation of Mnemonic Coding and Other Functional Neuronal

Dissociation of Mnemonic Coding and Other Functional Neuronal
Processing in the Monkey Prefrontal Cortex
SYNNÖVE CARLSON, PIA RÄMÄ, HEIKKI TANILA, ILKKA LINNANKOSKI, AND HEIKKI MANSIKKA
Department of Physiology, Institute of Biomedicine, 00014-University of Helsinki, Helsinki, Finland
sensory stimulation. These results indicate that most prefrontal
neurons firing selectively during the delay phase of the DA task
are highly specialized and process only task-related information.
INTRODUCTION
The importance of the principal sulcus (PS) area in the
dorsolateral prefrontal cortex (PFCdl) in spatial short-term
mnemonic functions has been well documented in monkeys
(for reviews see Fuster 1989; Goldman-Rakic 1987). Lesions in this cortical region produce inability to perform
delayed response (DR) tasks (Butters and Pandya 1969;
Funahashi et al. 1993a; Goldman 1971; Goldman and Rosvold 1970; Goldman et al. 1971; Jacobsen 1936; Mishkin
1957; Mishkin and Pribram 1955) but do not disrupt the
ability to perform various visual discrimination tasks (Fuster
1989; Goldman 1971; Mishkin et al. 1969; Passingham 1972,
1975; Petrides and Iversen 1976). Electrophysiological studies in the PFCdl of monkeys have revealed delay-related
neuronal activity during the performance of DR and delayed
alternation (DA) tasks in manual (Carlson et al. 1990; Fuster
1973; Fuster and Alexander 1971; Kojima and GoldmanRakic 1984; Kubota and Niki 1971; Niki 1974a–c) and
oculomotor (Funahashi et al. 1989–1991; Joseph and Barone 1987) tasks. This delay-related activity exhibits crosstemporal sensory-motor integration including short-term
memory and motor preparation (Fuster and Alexander 1971;
Fuster et al. 1982; Niki 1974a–c; Quintana et al. 1988).
Many neurons in PFCdl have been shown to respond to the
visual cue or in relation to the response period of the DR
task (e.g., Funahashi et al. 1990; Fuster 1973; Niki 1974c).
Neurons changing their firing rate toward the end of the
delay period of the task have been suggested to be coupled
to preparatory motor activity (Funahashi et al. 1993b; Niki
1974a–c; Niki and Watanabe 1976; Quintana and Fuster
1992). The delay period activity has also been suggested to
be related to short-term memory (Fuster 1973; Fuster and
Alexander 1971; Kubota and Niki 1971), especially because
in a subpopulation of prefrontal neurons the delay-related
neuronal activity is spatially selective (Funahashi et al. 1989;
Kojima and Goldman-Rakic 1982, 1984; Niki 1974a–c).
Furthermore, although many neurons fire in relation to the
response period in the oculomotor DR task, the majority of
the spatially selective neurons in the PFCdl code the cue
location during the delay period rather than the direction of
the impending response in an antisaccade task, indicating
that the delay activity is related to the remembering of the
cue location and not to preparation for a movement (Funahashi et al. 1993b).
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Carlson, Synnöve, Pia Rämä, Heikki Tanila, Ilkka Linnankoski, and Heikki Mansikka. Dissociation of mnemonic coding
and other functional neuronal processing in the monkey prefrontal
cortex. J. Neurophysiol. 77: 761–774, 1997. Single-neuron activity
was recorded in the prefrontal cortex of three monkeys during the
performance of a spatial delayed alternation (DA) task and during
the presentation of a variety of visual, auditory, and somatosensory
stimuli. The aim was to study the relationship between mnemonic
neuronal processing and other functional neuronal responsiveness
at the single-neuron level in the prefrontal cortex. Recordings were
performed in both experimental situations from 152 neurons. The
majority of the neurons (92%) was recorded in the prefrontal
cortex. Nine of the neurons were recorded in the dorsal bank of
the anterior cingulate sulcus and two in the premotor cortex. Of
the total number of neurons recorded in the prefrontal area, 32%
fired in relation to the DA task performance and 39% were responsive to sensory stimulation or to the movements of the monkey
outside of the memory task context. Altogether 42% of the recorded
neurons were neither activated by the various stimuli nor by the
DA task performance. Three types of task-related neuronal activity
were recorded: delay related, delay and movement related, and
movement related. The majority of the task-related neurons (n Å
33, 73%) fired in relation to the delay period. Of the delay-related
neurons, 26 (79%) were spatially selective. The number of spatially selective delay-related neurons of the whole population of
recorded neurons was 18%. Twelve task-related neurons (27%)
fired in relation to the response period of the DA task. Five of
these neurons changed their firing rate during the delay period and
were classified as delay/movement-related neurons. Contrary to
the delay-related neurons, less than half (42%) of the responserelated neurons were spatially selective. The majority (70%) of
the delay-related neurons could not be activated by any of the
sensory stimuli used and did not fire in relation to the movements
of the monkey. The remaining portion of the delay-related neurons
was activated by stationary and moving visual stimuli or by visual
fixation of an object. In contrast to the delay-related neurons, the
majority (66%) of the task-related neurons firing in relation to
the movement period were also responsive to sensory stimulation
outside of the task context. The majority of these neurons responded to visual stimulation, visual fixation of an object, or
tracking eye movements. One neuron gave a somatomotor and
another a polysensory response. The majority (n Å 37, 67%) of
all neurons responding to stimulation outside of the task context
did not fire in relation to the DA task performance. The majority
of their responses was elicited by visual stimuli or was related to
visual fixation of an object or to eye movements. Only six neurons
fired in relation to auditory, somatosensory, or somatomotor stimulation. This study provides further evidence about the significance
of the dorsolateral prefrontal cortex in spatial working memory
processing. Although a considerable number of all DA task-related
neurons responded to visual, somatosensory, and auditory stimulation or to the movements of the monkey, most delay-related neurons engaged in the spatial DA task did not respond to extrinsic
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CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA
METHODS
Three female monkeys (Macaca arctoides) weighing 6–8 kg
were used in the experiment. The animals were housed in individual cages with the other monkeys of the colony. The monkeys
were deprived of water during the night preceding the recording
day. They were rewarded with juice or water during the recordings,
which started in the morning. The monkey’s liquid intake and
weight were carefully monitored daily and extra water was given
after the experiment, if necessary. The monkey had free access to
food. The maintenance of the monkeys and all procedures of the
study were carried out according to the Finnish law and statutes
governing animal experimentation. The Finnish Ministry of Agriculture had approved of the study and granted permission to perform it.
Test panel and DA task performance
All monkeys were trained to perform a DA task in three directions: to the right, to the left, and upward. The test panel consisted
of a central hold bar and three pairs of response bars that were
located on the right and left sides of the hold bar and above it.
The test panel was in front of the monkey within the hand’s reach
(Fig. 1). The distance between the five horizontally located bars
was 12 cm. The lower and upper bars of the vertically oriented
pair were 11 and 9 cm above the central hold bar. Above each bar
there was a light-emitting diode, which was red above the central
bar and green above the response bars.
The trial began when the light-emitting diode above the central
bar came on and the monkey started to hold it. The monkey was
required to hold the central bar continuously throughout the delay
period, which was gradually prolonged to 5.3 s during the training
period. At the end of the delay, the light-emitting diode above the
central bar went off and the green light-emitting diodes above one
pair of the response bars turned on. In the first trial, the monkey
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could touch either one of the bars and was rewarded with a drop
of juice. In the next trials, only touching the bar of the pair that
had not been touched in the previous trial was rewarded. The
monkeys were trained until they mastered the task correctly in 80–
100% of daily trials. They were allowed to work daily until they
had received juice reward to satiety (300–500 trials per day).
Erroneous responses were not rewarded and the trial started from
the beginning again.
Surgery
A stainless steel recording cylinder (diameter 18.7 mm) was
implanted onto the skull under general anesthesia (pentobarbital
sodium, 25 mg/kg iv). The center of the cylinder was stereotactically aimed at the center of the PS. The stereotaxic coordinates
of the centers of the cylinders were A30–A32 and L14–L15 in
four hemispheres and A35 and L8 in one hemisphere. In the same
operation a halo fixation device was screwed onto the skull. The
halo could be attached to the primate chair during the recordings.
When the recordings of one hemisphere were completed, the cylinder and the halo were removed and the wound was closed. The
cylinder was later implanted on the other hemisphere and the halo
was attached. The skin around the cylinder was cleaned daily with
iodine detergent, the cylinder was rinsed with sterile saline, and
chloramphenicol ocular drops were applied to it.
Recording techniques and data analysis
Extracellular single-cell activity was recorded with glass-coated
tungsten microelectrodes (exposed tips of 20–50 mm, impedances
of 0.4–1.5 MV at 1 kHz) with the use of a hydraulic micromanipulator (Narishige MO-9B). With the microdrive coordinate system
the penetrations were made at a minimum distance of 1 mm apart
from each other. The microdrive coordinates were logged and each
penetration was also marked on a chart that was a 10-fold enlargement of the coordinate system. The amplified ( 11,000) and filtered
(passband 300–4,000 Hz) neuronal activity was monitored with
an oscilloscope, stored on a magnetic tape (Akai GX-630D-SS),
and recorded with a pen recorder. The single-cell activity was
converted to transistor-transistor logic pulses by a window discriminator. The recording method has been described in detail earlier
(Carlson et al. 1990). Horizontal electrooculogram and electromyogram of the triceps brachii muscle were recorded with Ag-AgCl
skin electrodes. When the functional responsiveness of the neurons
was studied, the cellular activity was also computerized on-line
and perievent time rasters and histograms were produced. For this
purpose timing pulses of the presentation of visual and auditory
stimuli were produced manually and the occurrence of cutaneous
stimulation was marked by a probe with an electronic circuitry that
produced a signal ( /5 V) when the probe was in contact with the
skin of the monkey.
Both hemispheres were studied in two monkeys and the left
hemisphere was studied in one of the monkeys. Single-cell activity
was recorded while the monkey performed the DA task ( Ç20 trials
in each of the 3 directions), after which the functional properties
of the same neuron were studied. When possible, the basal activity
was recorded after the task performance for 60 s. The data recorded
during the DA task was analyzed off-line from the stored magnetic
tape. Rasters and histograms were produced by aligning the data
from different possible triggering points (start of delay, end of
delay, receiving of reward).
The functional properties of the neurons were studied with a
method first introduced by Hyvärinen (1981). The method was
later further developed in our laboratory and has been described
in detail by Tanila et al. (1992). Furthermore, to provide a homogenous background for the presentation of visual stimuli and to enable
more accurate determination of visual receptive fields of neurons,
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Prefrontal neurons have also been reported to respond to
various types of auditory (Azuma and Suzuki 1984; Tanila
et al. 1992), visual (Pigarev et al. 1979; Tanila et al. 1992),
and multisensory (Tanila et al. 1992; Vaadia et al. 1986;
Watanabe 1992) stimuli in monkeys not performing memory
tasks. Bimodal responses to both visual and auditory stimulation have been recorded in monkeys (Ito 1982; Vaadia et
al. 1986; Watanabe 1992) and in humans (Clarke et al.
1995). Electrophysiological recordings in the prefrontal cortex showed that although many neurons responded to some
type of sensory stimulation, almost half (48%) of the recorded neurons remained unresponsive to such stimulation
(Tanila et al. 1992). It has been proposed that the neurons
in the PFCdl that do not respond to any external stimulation
may represent a neuronal population that is engaged in mnemonic processing and other cognitive functions (Tanila et
al. 1992).
The aim of this work was to study whether, on the singlecell level, there is dissociation between mnemonic coding
and other functional neuronal processing, that is, whether or
not the same single neurons that are engaged in the DA
task performance also respond to various types of visual,
auditory, or somatosensory stimuli or to the movements of
the monkey. It was hypothesized that neurons that participate
in mnemonic functions do not respond to sensory stimulation
or in relation to movements outside the task performance,
whereas neurons that are not engaged in mnemonic processing are functionally responsive.
DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX
763
a covered semicircular screen was constructed during the course
of the study. The functional properties of the neurons were classified in the following way. 1) Visual/oculomotor: the neuronal
response was time locked to the presentation of visual stimuli
(stationary or moving objects varying in shape, color, and size) or
saccades, to tracking or spontaneous eye movements, or visual
fixation of an object. The correlation of the neuronal activity to
spontaneous or elicited eye movements was monitored with horizontal electrooculogram and observation of vertical eye movements. 2) Auditory: the response was related to the presentation
of auditory stimuli (complex natural sounds varying in pitch and
intensity, clicks, rustles, steps, and human voice). 3) Somatosensory: the neurons responded to blowing, light touching, or pinching
of the skin and passive movements of the joints. 4) Motor: the
neuron fired in relation to movements but not to eye movements
per se. The monkey was enticed to reach and grasp objects with
its hands and legs and to put pieces of food into its mouth, after
which also chewing and licking could be observed. If the neuron
responded to more than one type of sensory stimulation it was
classified as polysensory. If the neuron did not respond to any of
the afore mentioned stimuli it was classified as nonfunctionally
responsive (F0 ).
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Statistical analysis
The responsiveness of the neurons during different phases of
the task performance (delay period, movement period) to the six
different target locations was first evaluated visually independently
by the investigators. The neurons that were classified as task related
(T/ ) or as having a functional response (F/ ) were further analyzed statistically with the use of two-way analysis of variance.
Because there is no intertrial period in the DA task (the previous
trial is followed immediately by the next trial), the neuronal activity in each trial over all trials to the same target location was
studied statistically in the following way. 1) To study the delay
period activity, neuronal firing during a 1 or 2-s time period at the
beginning of the delay and at the end of the delay were compared.
2) To study the delay/movement-related activity, neuronal firing
during a 1 or 2-s time period at the beginning of the delay period
was compared with the neuronal activity during a similar time
period counted backward from the touching of the target bar (this
period consists of the end of the delay and the movement periods).
3) Movement-related neuronal activity was studied for neuronal
activity during the time period between the release of the hold bar
and touching of the target bar (movement period) and compared
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FIG . 1. Task-related (T/ ) neuron firing spatially selectively during the delay phase. Each pair of rasters and histograms
represents the firing of the neuron in 1 target location. Vertical (V1, V2), left (L1, L2), and right (R1, R2) refer to the
locations of the target bars. 1, raster; 2, histogram; 3, receiving of reward; 4, touching the target bar; 5, solid lines indicate
the time of holding the central bar. Diagram at right: drawing from the histological coronal section corresponding to the
level where the neuron was recorded. Dot: location of the neuron. Diagram at left: test panel. There were significant main
effects of the target location [2-way analysis of variance (ANOVA): F(5,84) Å 4.34, P õ 0.005] and the phase of the task
[F(1,84) Å 48.87, P õ 0.0001]. This neuron increased its firing significantly during the 1st part of the delay period at R1
[t(16) Å 6.67, P õ 0.0001], R2 [t(16) Å 4.34, P õ 0.001], and V1 [t(16) Å 3.84, P õ 0.005].
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TABLE 1. Number and percentage of neurons recorded in
different cortical regions in three macaque monkeys
Area
n
Percent
2. Classification of neurons according to their
responsiveness to the DA task performance and to stimulation
outside of the task context
TABLE
PFCdl
PFCl
PFCm
PS
Cin
FEF
Pm
Total
98
65
1
1
8
5
15
10
9
6
18
12
2
1
151*
100
PFCdl, dorsolateral prefrontal cortex; PFCl, lateral prefrontal cortex;
PFCm, medial prefrontal cortex; PS, principal sulcus; Cin, cingulate sulcus;
FEF, frontal eye fields; Pm, premotor cortex. *The total number of recorded
neurons is 151, instead of 152, because the location of 1 neuron was not
identified.
Histology
At the end of the recording of the first hemisphere, marking
electrodes were inserted with the micromanipulator and left in the
brain for later verification. At the end of the recordings, anodal
direct current (60 mA, 30 s) was passed through the recording
electrode to mark a few penetrations. The monkey was killed with
an overdose of pentobarbital and the brain was fixed with intracardial perfusion of 0.9% saline followed by 10% Formalin. The brain
was photographed. Frozen 30-mm coronal sections were cut and
stained with 0.25% cresyl violet. The electrolytic lesions and the
tracks of the marking electrodes were identified. The locations of
the other penetrations in relation to the marked ones were reconstructed from their microdrive coordinates. For the construction of
the brain maps from the histological sections, an average map from
the brains of five monkeys (3 monkeys from this study and 2 from
an earlier study) was produced according to the method described
in an earlier report from this laboratory (Tanila et al. 1993). The
recording sites were marked on the map according to their relative
location to the PS and arcuate sulcus. The following classification
of anatomic locations was used: the PS, areas 46 above the PS and
9 as PFCdl, area 46 below the PS as lateral prefrontal cortex, the
medial parts of area 9 as medial prefrontal cortex, the anterior part
of the cingulate sulcus, area 8 as frontal eye fields (FEF), and the
dorsal part of area 6 as premotor cortex.
RESULTS
Altogether 152 neurons were studied in three macaque
monkeys both during the DA task and for their functional
responsiveness. The number of neurons recorded in different
regions is shown in Table 1. Nine neurons were recorded in
the anterior part of the cingulate sulcus and two neurons were
recorded in the premotor cortex. The neuronal responses of
these 11 units are described at the end of the RESULTS section.
The neurons that showed a distinct pattern of discharge during some phase of the task were classified as T/, and the
others were classified as non-task related (T0 ). Same neurons were classified as F/ when they responded to sensory
stimulation (visual, auditory, or somatosensory) or when
their firing was time locked to the movements of the monkey.
If there was no relationship between the neuronal firing and
the sensory stimulation and/or the movements of the mon-
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Percent
18
27
37
59
141
12.8
19.2
26.2
41.8
100
DA, delayed alternation; T/, task related; T0, non-task related; F/,
functionally responsive; F0, non-functionally responsive.
key, the neuron was classified as F0. Altogether 31.9% (45
of 141) of the recorded neurons were classified as T/. Of
these T/ neurons, 40.0% (n Å 18) were also F/ (T/F/ ).
Thirty-seven (26.2%) neurons were F/ but their firing was
not related to the task performance (T0F/ ). Of the total
number of recorded neurons, 41.8% were classified as T0F0
neurons (Table 2), which means that the firing of these
neurons was related neither to the task performance nor to
external stimulation or to the movements of the monkey.
T/F/ and T/F0 neurons
Of the total number of recorded neurons, 12.8% (n Å 18)
were classified as T/F/ neurons, whereas 19.2% (n Å 27)
of the neurons were classified as T/F0 neurons (Table 2).
Most of the T/F/ neurons gave visual/oculomotor responses (n Å 16, 88.9%). In one neuron, visual/oculomotor
response was elicited by stationary stimuli, but in most visual/oculomotor neurons the response was elicited by moving stimuli either in the whole visual field (n Å 4) or in the
side contralateral to the recordings (n Å 2). Two neurons
responded only when the monkey was presented with a novel
stimulus (or a stimulus not used for a while). In seven
T/F/ visual/oculomotor neurons the activity was clearly
related either to eye movements or to fixation of a visual
object. Five of these neurons gave inhibitory responses when
the monkey fixated a visual object presented either in the
visual field contralateral to the side of the recordings (n Å
1) or anywhere in the visual field (n Å 4). One neuron gave
an excitatory response when the monkey fixated a visual
object presented anywhere in the visual field. The discharge
of one visual/oculomotor neuron was related to moving
stimuli and tracking eye movements. Only 2 T/ neurons of
18 responded to other than visual stimulation (Table 3).
TABLE
3.
Distribution of functional responses of T/ and T0
neurons
VisOkm
SomMot
88.9
16
5.55
1
T/F/
Percent
n
T0F/
Percent
n
70.3
26
16.2
6
Aud
8.10
3
Poly
Total
5.55
1
100
18
5.4
2
100
37
VisOkm, visual/oculomotor; SomMot, somatomotor; Aud, auditory;
Poly, polysensory. For other abbreviations, see Table 2.
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with the neuronal activity of a similar time period at the beginning
of the delay period. The main effects of the ‘‘target location’’ and
‘‘phase of the task’’ factors were analyzed. If there was a significant
main effect (P õ 0.05) a post hoc analysis was performed (unpaired t-test). For the statistical evaluation of the functional responsiveness of the neurons, the neuronal activity during the presentation of the stimulus over all trials was compared with baseline
neuronal activity during a similar time period.
T/F/
T/F0
T 0 F/
T 0 F0
Total
n
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T/ neurons were further classified according to the
phase of the task at which the change in the firing rate
occurred. The DA task can be divided into distinct timelocked periods. The trial starts when the monkey starts to
hold the central bar. The monkey has to keep in mind the
spatial location of the previously touched response bar
( delay period ) . At the end of the delay period the monkey
has to stop holding the central bar and touch the response
bar ( response period ) . Neurons that showed a distinct
pattern of discharge during some phases of the delay period were classified as delay-related neurons ( Fig. 1 ) ,
whereas neurons firing in relation to the response period
were classified as movement-related neurons ( Fig. 2 ) .
Neurons that showed a response both during the delay
and response periods were classified as delay /movementrelated neurons ( Fig. 3 ) . Cue-related neurons were not
involved in the classification because there is no cue period in the DA task as in the DR task.
Most of the T/ neurons showed delay-related activity
(n Å 33 of 45, 73.3%) that was spatially selective in 26 of
33 neurons (78.8%, Table 4). The mean percentages of
movement-related and delay/movement-related neurons
were 15.6% (n Å 7) and 11.1% (n Å 5) (Table 4). Of the
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delay-related neurons, 69.7% (n Å 23 of 33) were F0 (Table
5). These neurons make up 16.3% of the total number of
neurons recorded (23 of 141 neurons). Those 10 delayrelated neurons that were F/ were all classified as visual/
oculomotor neurons. Two of the visually responsive neurons
gave visual responses only when the monkey was presented
with a novel stimulus. The four other delay-related visually
responsive neurons gave responses to visual stationary stimuli ( n Å 1) or to moving visual stimuli either in the whole
visual field (n Å 2) or in the side contralateral to the recording (n Å 1). Four visual/oculomotor neurons gave inhibitory responses when the monkey fixated an object regardless of the direction of gaze (n Å 3) or in the side
contralateral to the recording (n Å 1).
Contrary to the delay-related neurons, the majority of neurons that fired in relation to the movement period were F/. Of
the movement-related and delay/movement-related neurons,
71.4% (n Å 5 of 7) and 60.0% (n Å 3 of 5), respectively,
were F/ (Table 5). Three of the movement-related neurons
gave visual/oculomotor responses (Fig. 4). Responses to somatomotor (n Å 1) and polysensory (n Å 1) stimulation
were also elicited. All delay/movement-related neurons gave
responses to visual/oculomotor stimulation.
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FIG . 2. T/ neuron firing in relation to the movement phase of the task. There were significant main effects of the target
location [2-way ANOVA: F(5,106) Å 18.36, P õ 0.0001] and the phase of the task [ F(1,106) Å 146.23, P õ 0.0001].
Although there was significant spatial tuning of the firing of the neuron during the response period [1-way ANOVA: F(5,53)
Å 14.20, P õ 0.0001], the firing increased its rate significantly in all target locations [e.g., L2: t(18) Å 4.17, P õ 0.0005].
Other conventions as in Fig. 1.
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CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA
T0F/ and T0F0 neurons
The majority of the recorded neurons (n Å 96) did not
change their activity in relation to the task performance, and
61.5% of them were defined as F0. Thirty-seven of the T0
neurons were F/ (Table 3). T0F/ neurons were mostly
responsive to visual/oculomotor stimulation (n Å 26,
70.3%). Moving visual stimuli (Fig. 5) elicited responses
4. Distribution of T/ neurons into different classes
according to their responsiveness during the delay and
movement phases of the DA task and their spatial selectiveness
in the whole visual field (n Å 6) or in the side contralateral
to the recording (n Å 2). The receptive field of one neuron
responding to moving stimuli could not be identified. Visual
responses were also elicited by stationary stimuli presented
anywhere in the visual field (n Å 1) or in the side contralateral to the recording (n Å 1). Two neurons that gave responses in the contralateral side of the recordings responded
only to novel stimuli. Four neurons responded to the closing
TABLE
T/
Total
Delay
Percent
n
Motor
Percent
n
D/M
Percent
n
Spatial
73.3
33
78.8
26
15.6
7
28.6
2
11.1
5
60.0
3
Total number of T/ neurons Å 45. D/M, delay/movement-related neurons. For other abbreviations, see Table 2.
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TABLE 5. Classification of different types of T/ neurons
according to their responsiveness to stimulation outside
of the task context
Delay
Percent
n
Motor
Percent
n
D/M
Percent
n
F0
VisOkm
69.7
23
30.3
10
28.6
2
42.9
3
40.0
2
60.0
3
For abbreviations, see Tables 2–4.
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SomMot
14.3
1
Aud
Poly
14.3
1
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FIG . 3. T/ neuron firing spatially selectively during the delay and movement phases of the task. There were significant
main effects of the target location [2-way ANOVA: F(3,66) Å 11.32, P õ 0.0001] and the phase of the task [ F(1,66) Å
19.35, P õ 0.0001]. The neuron increased its firing rate toward the end of the delay and during the response period of the
task at locations R1 [t(12) Å 4.51, P õ 0.001] and R2 [t(18) Å 3.25, P õ 0.005]. Other conventions as in Fig. 1.
DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX
767
of the eyelids or to changes in illumination in the laboratory
(Fig. 6). Seven visual/oculomotor responses were related
to visual fixation. The responses were either inhibitory or
excitatory to visual stimuli presented anywhere in the visual
field (n Å 3) or in the side contralateral to the recordings
(n Å 2). The receptive field of two fixation-related neurons
could not be identified. Two neurons fired in relation to the
presentation of an object or to eye movements toward the
object. Neurons in the T0F/ group also responded to somatomotor (n Å 6, 16.2%), auditory (n Å 3, 8.10%, Fig. 7, A
and B), or polysensory (n Å 2, 5.4%) stimulation. Somatomotor responses were elicited by the monkey’s own contralateral hand movements (n Å 4), by chewing (n Å 1), or
by pressing the midthigh (n Å 1), which gave a response
bilaterally. The response was stronger on the contralateral
side (Fig. 8).
Distribution of the recorded neurons in the prefrontal
cortex
The distribution of the recorded neurons in different cortical areas is shown in Table 1. Figures 9, A and B, and 10
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illustrate the regional distribution of T/ and T0 neurons,
respectively. Both T0 and T/ neurons were rather evenly
distributed over the recorded area. Eighteen neurons were
located in the FEF. Seven of these were T/ neurons and
three were spatially selective. Two T/ FEF neurons were
activated during the movement period of the DA task and
the rest were activated during the delay phase. Three of the
T/ neurons were also F/ and were classified as visual/
oculomotor. Six other FEF neurons were also F/ but had
no relation to the task performance (T0F/ ). Except for one
neuron, all other T0F/ neurons in the FEF were responsive
to visual/oculomotor stimulation. The one exception was a
neuron that fired in relation to the monkey’s hand movement.
The sparse auditory responses (3 neurons) were recorded in
the anterior parts of the area studied. Of the seven somatomotor
neurons, one was located in the inferior bank of the PS, one
in the medial prefrontal cortex, four in the prefrontal region
above the PS, and one in FEF. Of the four polysensory neurons,
one was in the lower bank of the PS, two on the dorsal side of
the PS, and one in the premotor cortex. The visually responsive
neurons were scattered around the whole recorded area.
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FIG . 4. Example of a visual/oculomotor neuron responding to the presentation of a visual stimulus at 4 locations in the
visual field. The neuron increased its firing rate during the presentation of the visual stimulus. The responses are presented
at 4 locations: right [t(16) Å 12.48, P õ 0.0001], left [t(18) Å 6.10, P õ 0.0001], upward [t(18) Å 14.82, P õ 0.0001],
and downward [t(18) Å 6.28, P õ 0.0001]. The increased firing was most likely related to visual fixation of an object.
Diagram in the middle: drawing from the histological section corresponding to the level at which the neuron was recorded.
Dot: location of the neuron. Horizontal lines below the histogram: presentations of the stimulus.
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CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA
Task-related activity and functional responsiveness of
cingulate and premotor neurons
Nine neurons were located in the upper bank of the anterior part of the cingulate sulcus. Three of these neurons were
spatially tuned T/F0 neurons and fired in relation to the
delay (1 neuron) or delay/movement phase (2 neurons) of
the DA task. Only one cingulate neuron was F/ (T0F/ )
and responded to visual stimulation in the contralateral visual
field. The other five T0 neurons were F0. Two neurons (1
FIG . 6. Top histogram: change of illumination elicited a visual response [t(18) Å 5.60,
P õ 0.0001]. The lights in the laboratory were
turned on and left on at the beginning of the
horizontal lines illustrated below the histogram.
Bottom histogram: presentation of an visual object did not activate the neuron. The location
of the neuron is shown in the diagram at right
from the corresponding histological section.
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FIG . 5. Example of a neuron responding to the presentation of a visual stimulus moving in depth in front of the
monkey [ forward vs. backward motion: t(18) Å 18.41, P
õ 0.0001]. Raster and histogram illustrate the firing rate
during 10 trials of stimulus presentation. Top histogram:
visual stimulus approached the monkey during the period
indicated by horizontal bars below the histogram. Bottom
histogram: visual stimulus retreated from the monkey. Diagram at top left: drawing from the histological section
corresponding to the level where the neuron was recorded.
Dot: location of the neuron.
DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX
769
T0F0 and 1 T/F/ ) were located in the anterior part of
the premotor cortex. The T/F/ neuron fired in relation to
the movement phase of the DA task. The neuron gave a
complex functional response to both visual stimulation and
the hand movement of the monkey.
DISCUSSION
In the present work we studied both functional (motor-related and sensory responsive neurons outside of the task context) and working memory (neurons firing in relation to DA
task) properties of single neurons in the prefrontal cortex of
macaque monkeys. Of the total number of recorded neurons,
32% fired in relation to the DA task performance, 39% were
functionally responsive to sensory stimulation or to the movements of the monkey, and 42% responded neither to the task
nor to the various stimulations. Independent of the neuronal
discharge during the task performance, the functionally activated neurons were mainly responsive to visual stimulation.
The majority (60%) of the neurons firing in relation to
the spatial working memory task did not respond to external
sensory stimuli or to the movements of the monkey. The
two main findings of the present study are the following. 1)
The great majority (70%) of the neurons that fired selectively during the delay phase of the DA task could not be
activated by any of the various stimuli used in this study.
2) The majority of all F/ neurons did not fire in relation to
the working memory task performance and thus possess
other than mnemonic functions.
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The delay-related neurons represent the neuronal population that in many previous studies has been suggested to be
engaged in the neuronal processing of working memory (for
reviews see Funahashi and Kubota 1994; Fuster 1989; Goldman-Rakic 1987, 1995). The present study demonstrates
that the majority of these neurons do not process sensory
information that is not relevant to the performance of mnemonic tasks. In contrast to the delay-related neurons, 66%
of the task specific neurons firing during the movement phase
could also be activated by sensory stimulation or movements
of the monkey not related to the task context.
Neuronal firing during the DA task
The present study again demonstrates that there is a population of neurons in the PFCdl that is engaged in the processing of working memory task performance. About a third
of the neurons (32%) recorded in this work fired in relation
to the DA task.
The recordings were conducted mainly in the PFCdl in
Walker’s areas 46 and 9 (Walker 1940) extending from the
lower lip of PS to the dorsal convexity of the PFCdl (Table
1). Because lesion studies have indicated that the cortex in
and around the PS is the most important area for spatial DR
and DA performances and lesions sparing this area have
little if any effect on such task performance (Goldman and
Rosvold 1970; Goldman et al. 1971; Mishkin 1957), most
electrophysiological studies concerning spatial working
memory processing in the PFCdl have therefore been con-
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FIG . 7. A: raster and histogram represent the
response of a neuron to 11 presentations of an
auditory stimulus [t(20) Å 5.22, P õ 0.0001].
The stimulus was a short click presented contralaterally 607 to the right in front of the monkey.
The monkey was sitting inside a hemifield, which
hindered it from seeing the presentation of the
stimulus. B: neuronal firing (1) to 2 presentations
of the auditory stimulus (2) illustrated together
with the horizontal electrooculogram (3). The firing was not related to eye movements. Other conventions as in Fig 4.
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CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA
FIG . 8. Pressing of the contralateral (A) and ipsilateral (B)
midthigh elicited a response [A: t(18) Å 11.58, P õ 0.0001; B:
t(18) Å 7.10, P õ 0.0001]. The location of the neuron is shown
in the diagram at right from the corresponding histological section.
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Funahashi et al. 1989; Niki 1974a,b). In these studies the
number of spatially selective delay-related neurons of all
neurons recorded was between 5–18% (Niki 1974a,b) and
24% (Funahashi et al. 1989).
Twelve neurons fired in relation to the response period,
and five of these changed their firing rate significantly also
during the delay period. These neurons were not spatially
selective (5 of 12 neurons, 42%) as frequently as the delay
neurons. This proportion is smaller than in the study by
Funahashi et al. (1991), who reported that 34% of the neurons recorded in the oculomotor DR task changed their firing
rate in relation to saccadic eye movements and that ú90% of
the neurons were spatially selective. The number of neurons
firing in relation to the movement phase in the present work
was in the same range (27%). In the present study, the
monkeys responded with a hand movement and the results
of several studies indicate—although there may be subareal
differences in the prefrontal cortex that may have obscured
this phenomenon—that the prefrontal cortex has a lower
representation of hand-movement-related neurons than of
eye-movement-related neurons (Funahashi et al. 1989, 1990,
1993b; Tanila et al. 1992, 1993). It is important to point
out that although the horizontal and occasionally the vertical
electrooculogram was recorded, the eye movements of the
monkeys were not controlled here in the way they were in
studies in which oculomotor DR tasks were used (Funahashi
et al. 1989–1991) and the task performance did not require
the monkey to maintain fixation during the delay period.
The movement period thus invariably includes both hand
and eye movements because the monkey tends to make a
saccade toward the target location just before the hand movement. The movement period related neuronal firing cannot
therefore be dissociated from hand and eye movements in
this testing paradigm, and, on the basis of the present study,
it is not possible to draw conclusions about the motor nature
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ducted in the dorsal and ventral banks of PS and in the
adjacent PFCdl (e.g., Funahashi et al. 1989–1991; Kojima
and Goldman-Rakic 1984; Kubota and Niki 1971; Niki
1974a–c). However, electrophysiological studies have also
demonstrated delay-related neuronal activity in the prefrontal cortex dorsolateral convexity above PS (Fuster 1973;
Quintana et al. 1988), suggesting that prefrontal areas outside PS are also involved in spatial working memory processing. Other prefrontal cortex areas have also recently been
shown to be engaged in working memory processing. An
electrophysiological study by Wilson et al. (1993) conducted in the ventrolateral prefrontal cortex and a lesion
study by Petrides (1995) comprising the mid-dorsal prefrontal cortex indicate that these areas are involved in nonspatial
mnemonic processing, suggesting that subareas of the prefrontal cortex are functionally specialized for different aspects of mnemonic processing.
The DA task differs from the DR task in several important
aspects. The DR task has clearly distinguishable cue, delay,
and response periods. The DA task does not have a distinguishable cue period, although it is possible that the monkeys
use proprioceptive cues produced by their own movements
to solve the task (Gentile and Stamm 1972; Goldman and
Rosvold 1970; Wagman 1968), or, in this study, may even
have looked at the next correct target because the eye movements were not controlled. Therefore in the DA task one
cannot record a cue response in the same sense as in the DR
task. The spatial selectiveness of a given neuron can only
become evident during the delay and the response period.
The majority (73%) of the T/ neurons fired in relation to
the delay period and of 79% (26 of 33) of these neurons
were spatially selective. The total number of spatially selective delay-related neurons was thus 18%. This finding is in
line with earlier reports in which DA or DR tasks have been
used to study neuronal activity in the prefrontal cortex (e.g.,
DISSOCIATION OF FUNCTIONS IN THE PREFRONTAL CORTEX
processing and other functional neuronal responsiveness in
the prefrontal cortex. For this purpose the monkeys were
trained to master a DA task and single-cell responses were
recorded during this task performance. The monkeys were
also trained to accept another kind of recording situation in
which they were presented with various types of stimuli and
were not required to respond to them. This experimental
situation allowed us to study the responsiveness of single
neurons both under a rather strictly controlled behavioral
situation and during presentation of a variety of stimuli to
the monkey.
The majority (70%) of the neurons firing selectively during the delay phase of the DA task did not respond to extrinsic sensory stimulation or to the movements of the monkey.
As a comparison, the number of F0 neurons was small
among the T/ neurons that fired in relation to the response
period: 29% of movement-related and 40% of neurons firing
in relation to both the delay and movement phases of the
task. This finding is significant because it has been suggested
that the delay-related neuronal firing during DR and DA
tasks represents mnemonic coding (Fuster 1989; GoldmanRakic 1987, 1995).
Funahashi et al. (1990) recorded prefrontal cortex neurons
during an oculomotor DR task for several target locations.
They also studied some of these neurons during a visuospatial task in which visual stimuli were presented in the same
locations as in the oculomotor DR task but the monkey was
not required to memorize the stimulus location. Funahashi
et al. found that several neurons responded similarly to the
cue presentations in both tasks and argued that the responses
to cues in the oculomotor DR and visuospatial task reflect
the same underlying visual responsiveness of the neuron.
The authors suggested that the spatial visual information
arriving at the prefrontal neurons is registered in the cuerelated neurons, then fed forward to cue-delay-related neurons that in turn feed the information to delay neurons. The
fact that so many of the delay-related neurons of the present
study could not be activated by external stimulation is in
line with the above suggestion. It is likely that the delay
of the movement-related prefrontal cortex neurons during
DA task performance. However, in other studies in which
manual versions of DR were used (Kojima and GoldmanRakic 1982, 1984; Niki 1974c) or DA tasks (Niki 1974a),
the number of movement-related neurons that were spatially
selective has been in the same range (45%) (Niki 1974a)
as in the present study or even much lower (10–13%) (Kojima and Goldman-Rakic 1982, 1984). Another reason for
the high number of spatially selective movement-related
neurons recorded in the oculomotor DR task by Funahashi
et al. (1989, 1991) is that those researchers used eight target
locations, compared with only two or six in the other manual
versions of the working memory tasks.
Functional responsiveness of DA task-related neurons
Our main interest in this work was to study on the singleneuron level the relationship between mnemonic neuronal
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FIG . 10. Regional distribution of non-task-related (T0 ) neurons and
their responsiveness to stimulation outside of the task context. Six T0
neurons were located in the anterior cingulate cortex (not illustrated). Five
of them were nonfunctionally responsive and 1 responded to visual stimulation. One T0 nonfunctionally responsive neuron was recorded in the premotor cortex (not illustrated). Other conventions as in Fig. 9.
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FIG . 9. A: regional distribution of the T/ neurons and their responsiveness outside of the task context. Open circles: non-functionally responsive. V, visual/oculomotor response; S, somatomotor response; A, auditory
response; P, polysensory response. The locations of the neurons are projected to the lateral surface of the prefrontal cortex. Three non-functionally
responsive T/ neurons were recorded in the anterior cingulate sulcus and
1 functionally responsive neuron (P) was recorded in the premotor cortex
(not illustrated). B: areal distribution of the delay-related neurons. White
bars: total number of neurons recorded in the corresponding subarea. Black
bars: delay-related neurons.
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CARLSON, RÄMÄ, TANILA, LINNANKOSKI, AND MANSIKKA
Functional responsiveness of T0 neurons
T0 neurons were responsive to a variety of stimuli: in
addition to visual stimuli, responses were elicited by auditory, somatomotor, and polysensory stimuli. Some of the
visually responsive neurons were rather ‘‘primitive’’ in their
nature. Four neurons responded repetitively to a change in
the overall level of illumination (see Fig. 6) or to the covering or uncovering of the eyes. Seven neurons fired in relation to visual fixation of the monkeys.
The functional properties of prefrontal cortical neurons
have been studied earlier with different types of testing pro-
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cedures and methods. In the study by Pigarev et al. (1979)
the monkeys were anesthetized during the recordings. Despite the anesthesia, a variety of visual responses could be
recorded in the posterior parts of the prefrontal cortex. Vaadia et al. (1986) recorded neurons in the posterior parts of
the prefrontal cortex responding during auditory and visual
localization tasks. Ito (1982) used a simple reaction time
task with auditory and visual stimuli and found neurons
responsive to both types of stimuli. Watanabe (1989) studied
neuronal responses during a go/no-go discrimination task
and reported that the prefrontal cortex has a role in cognitive
functions related to the coding of posttrial events. Watanabe
( 1990) also recorded prefrontal neurons during a stimulusreward association task and found many cue-related responses that were related to the significance of the cue
(whether it signaled the receiving of a reward or not) rather
than to the physical properties of the cue.
In addition to its role in the neuronal processing of spatial
working memory, the prefrontal cortex exhibits functional
responsiveness to many kinds of visual stimuli and to a
lesser extent to somatosensory and auditory stimuli and
movements. The majority of the neurons responsive to such
stimuli in the present study did not have a role in mnemonic
processing and, vice versa, neurons engaged in spatial working memory processing only seldom responded to sensory
stimulation that is not relevant to the task performance. Wilson et al. (1993) have recently shown that the inferior convexity in the ventrolateral prefrontal cortex contains neurons
responsive to pattern visual stimuli and to faces (Wilson
et al. 1993). Many of these visually responsive neurons
expressed delay-related activity with selective responsiveness to pattern memoranda, suggesting that the prefrontal
cortex contains specialized subareas for the remembering of
the spatial location and the identity of visual objects. The
recordings in the present study were located more dorsally
on the prefrontal cortex than in the above mentioned study,
which may explain why complex visual stimuli in our work
were not effective in arousing visual responses in most of
the delay-related neurons. The results of the present study
thus support the idea that the prefrontal cortex is functionally
specialized. For fully understanding the behavioral role of
the prefrontal cortex, the multiplicity of the functions of the
prefrontal cortex needs to be further studied.
We thank K. Lauren and P. Kilpiö for technical assistance.
This study was supported by The Paulo Foundation, The Finnish Cultural
Foundation, and The Kordelin Foundation.
Present address of H. Tanila: Dept. of Neuroscience and Neurology,
University of Kuopio, Canthia, P.O. Box 1627, 70211 Kuopio, Finland.
Address for reprint requests: S. Carlson, Dept. of Physiology, Institute of
Biomedicine, P.O. Box 9, 00014-University of Helsinki, Helsinki, Finland.
Received 1 May 1996; accepted in final form 3 October 1996.
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