Download Role of the Human Anterior Cingulate Cortex in the Control of

JOURNALOF NEUROPHYSIOLOGY
Vol. 70, No. 2, August 1993. Printed
in U.S.A.
Role of the Human Anterior Cingulate Cortex in the Control
of Oculomotor, Manual, and Speech Responses:
A Positron Emission Tomography Sudy
TOMAS
PAUS,
Montreal
Neurological
SUMMARY
AND
MICHAEL
PETRIDES,
Institute,
McGill
ALAN
C. EVANS,
University, Montreal,
CONCLUSIONS
INTRODUCTION
Current advances in neuroimaging techniques, and in
particular the possibility of measuring changes in regional
cerebral blood flow (r CBF) by means of positron emission
tomography (PET) in human volunteers, have led to an
increased interest in the role of the cingulate cortex (Fig. 1)
in the control of human behavior. A number of interpretations have been proposed to account for changes in rCBF
observed in this region during the performance of various
cognitive and motor tasks. One of the first attempts to explain such changes was the notion of the “anterior attention
system” (Posner and Petersen 1990; Posner et al. 1988). It
was suggested that the anterior cingulate cortex (ACC) may
be involved in target detection (Posner and Petersen 1990)
and activated when “attention
to action” is required
ERNST
MEYER
(Posner et al. 1988). Furthermore, it was stressed that “although attention for action seems to imply motor acts, internal selections involved in detecting or noting an event
may be sufficient to involve attention in this sense” (Posner
et al. 1988). Other investigators also pointed out that the
high “attentional”
demands and/ or “response selection”
processes may underlie significant changes in rCBF in the
ACC obtained during the performance of the Stroop test
(Pardo et al. 1990) and voluntary generation of motor responses (Frith et al. 199 1).
In the present study, we set out to test a somewhat different view based on the demonstrated close relationship between the ACC, the motor system, and the prefrontal cortex
in the monkey (see below). We propose that the ACC is a
cortical region where a cognitive / motor “command”,
coming from a different cortical region (e.g., prefrontal cortex), is being modulated and “funneled” to the motor system. We further propose that this modulation takes place
within distinct, motor output-specific subregions of the
ACC, thus emphasizing the “motor” character of this region.
The prediction that rCBF changes in the ACC will map
onto distinct subregions, depending on the output modality, was based on the results of several recent neurophysiological and neuroanatomic
studies. These studies provide
evidence for the existence of a somatotopic organization of
the connections between the ACC and the primary motor
cortex (Dum and Strick 199 1; Morecraft and Van Hoesen
1992; Muakkassa and Strick 1979) and between the ACC
and the spinal cord (Dum and Strick 199 1). Such connectivity explains the fact that movements can be elicited by
electrical stimulation
of the ACC. Classical stimulation
studies (Hughes and Mazurowski 1962; Showers 1959) and
a more recent microstimulation
study (Luppino et al.
199 1) showed that there is a systematic relationship between the site of stimulation and the part of the body that
moves. In other words, a somatotopic organization of the
region was demonstrated consistent with its known anatomic connections. It should be noted at this point that the
ACC is not a morphologically
homogeneous region. It
comprises at least two cytoarchitectonic areas, Brodmann’s
areas 24 and 32. In the monkey, area 32 represents the
rostralmost part of the ACC, located rostra1 to the genu of
the corpus callosum (Barbas and Pandya 1989). Area 24 of
the monkey ACC can be further subdivided into ventral
0022-3077/93 $2.00 Copyright 0 1993 The American Physiological Society
453
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I. Two experiments were aimed at investigating the functional
organization
of the human anterior cingulate cortex (ACC) in
relation to higher-order
motor control.
2. The ‘50-labeled
H,O bolus method was used to measure
relative changes of regional cerebral blood flow (rCBF) in 18
healthy human subjects as they performed oculomotor,
manual,
or speech tasks.
3. Task-specific rCBF changes were obtained in distinct subregions of the ACC, depending on the output system employed. The
oculomotor
and the manual task-related foci were found in the
rostra1 and caudal regions of the ACC, respectively, whereas the
speech foci were localized within two cingulate subregions, the
intermediate dorsal and the rostra1 ACC.
4. In the manual tasks, two groups of activation foci could be
distinguished,
one just behind and the other just in front of the
vertical plane traversing the anterior commissure.
5. The above pattern of r CBF changes was observed only if
there was concomitant activation within the lateral prefrontal cortex (except for the posterior group of foci obtained in the manual
tasks).
6. The localization
of output-specific
rCBF changes within the
human ACC is consistent with the known somatotopic organization of the cingulate cortex in the monkey.
7. It is tentatively proposed that the ACC participates in motor
control by facilitating the execution of the appropriate responses
and/ or suppressing the execution of the inappropriate
ones. Such
a modulatory effect would be of particular importance when behavior has to be modified in new and challenging situations.
AND
Quebec H3A 2B4, Canada
T. PAUS,
M.
PETRIDES,
A. C. EVANS,
(subareas 24a and 24b) and dorsal (subareas 24c and 24d)
tiers ( Matelli et al. 199 1). The dorsal tier is buried within
the cingulate sulcus, whereas the ventral tier occupies the
cortex of the cingulate gyrus just above the corpus callosum. The dorsal tier of the cingulate cortex represents a
more differentiated, transitional
form of cortex having
some morphological
features in common with neocortical
areas 4 and 6 (Matelli et al. 199 1). The border between this
transitional portion of area 24 and true neocortex (area 6)
runs along the dorsal bank of the cingulate sulcus close to its
dorsal lip. It should be emphasized here that it is in the
dorsal tier of area 24, buried in the depth of the cingulate
sulcus, where the somatotopically
organized motor regions
were found in both neuroanatomic ( Dum and Strick 199 1;
Morecraft and Van Hoesen 1992) and neurophysiological
( Luppino et al. 199 1) studies.
At the behavioral level, the close interaction between the
ACC and the motor system can be seen in the following
studies. In the monkey, lesions to the rostralmost part ofthe
ACC were shown to reduce condition-specific vocal output,
but not to affect spontaneous vocalization emitted in a social group ( Aitken 198 1; Kirzinger and Jurgens 1982; Mac-
E. MEYER
Lean and Newman 1988; Sutton et al. 1974). In humans,
bilateral cingulate lesions give rise to akinetic mutism
(Barris and Schuman 1953; Jurgens and Von Cramon
1982; Nielsen and Jacobs 195 1). In the nonvocalization
domain, lesions to the medial frontal lobe, which often included both the neocortex (area 6 and 8) and the ACC,
were found to impair voluntary suppression of arm and eye
movements triggered from the contralateral hemispace
(Goldberg et al. I98 1; Paus et al. 199 1). Furthermore, a
close interaction between the ACC and the lateral prefrontal cortex, which should not be surprising in the light of an
extensive reciprocal connectivity between the two structures (Pandya et al. 198 1; Vogt and Pandya 1987), was
documented in the following studies. Increased glucose metabolism (Matsunami
and Kubota 1983) and task-related
changes in neuronal activity (Niki and Watanabe 1976)
have been observed within the ACC in monkeys performing a delayed-response task that is known to depend critically on the prefrontal cortex (see Goldman-Rakic
1987).
Lesions to the cingulate cortex impair acquisition of the
delayed-alternation
task, whereas performance of this task
is unaffected when learned preoperatively (Pribram et al.
1962 ). Thus the involvement of the ACC in the control of
behavior may depend critically on a close interaction with
both the prefrontal cortex and the motor system.
The PET technique, in combination with magnetic resonance imaging (MRI), allows direct localization of rCBF
changes that are thought to reflect changes in neuronal activity ( Raichle 1987). The following two questions were
asked in the present investigation. First, will the task-specific rCBF changes within the ACC be accompanied by concomitant changes in the prefrontal cortex? Second, will the
exact site of task-related modulation of neuronal activity in
the ACC (reflected by rCBF changes) follow a somatotopic
organization similar to that suggested by the monkey studies? The first question was explored by means of sensorimotor tasks designed to engage the prefrontal cortex differentially. The second question was addressed by employing
three different output systems, the oculomotor, manual,
and speech systems.
METHODS
Experiment 1
BLOOD-FLOW
MEASUREMENT.
PET scans were
obtained using the Scanditronix
PC-2048B tomograph,
which produces 15 image planes at an intrinsic resolution
of 5 X 5 X 6.5 mm (Evans et al. 199 1b). The distribution of
normalized cerebral blood flow was measured during each
60-s PET scan using the 150-labeled H,O bolus method
with averaged image subtraction (Fox et al. 1985b; Raichle
et al. 1983). For each subject, a high-resolution MRI study
(63 slices, 2 mm thick) was obtained from a Philips Gyroscan ( 1.5 T) and resliced for co-registration with the PET
data using a PIXAR 3-D computer (Evans et al. 1991a).
Interactive three-dimensional
image software was used to
establish an orthogonal coordinate frame on the basis of the
anterior commissure-posterior
commissure line as identified in the MRI image volume. These coordinates were
used to apply a linear resampling of matched MRI-PET
data sets into a standardized three-dimensional
coordinate
system (Talairach and Tournoux 1988). To overcome reCEREBRAL
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FG 1. Medial view of the left hemisphere
of the human (lop) and the
monkey
(bot!om)
brain. Three reference lines are depicted: AC-PC,
line
passing through
the anterior
and posterior
commissures;
VCA, line traversing the anterior
commissure
in the vertical plane; VCP, line passing
through the posterior commissure.
Botromphomgruph:
arrow indicates the
position
of the genu of the arcuate sulcus projected
onto the medial surface. Note that an uninterrupted
single cingulate sulcus is present only in
-60%
of cases in the human brain; 25% of cases show a double parallel
type (One et al. 1990). The human brain depicted in this figure is of the
latter type. CS, cingulate sulcus; PCS, paracingulate
sulcus (Smith 1907).
The scale is indicated
by the horizontal
line ( I cm) that is adjacent to the
human and the monkey
brains.
AND
HIJMAN
ANTEKIOR
Eight right-handed normal subjects ( 1 female, 7
male; 20-28 yr of age) participated
in this experiment.
Each subject underwent seven 60-s PET scans within a single session. Written informed consent was obtained in all
experiments in accordance with guidelines approved by the
Ethics Committee of the Montreal Neurological
Institute
and the Declaration of Human Rights, Helsinki, 1975.
ATE
COR?‘EX
355
one of three words in response to the specific word heard.
The auditory stimuli were three verbs (take, join, find), and
the responses were three pronouns (them, her, him). The
stimuli were presented through a pair of headphones. The
latency and accuracy of the verbal responses were measured
bv means of a voice trigger.
” In the overpracticed versions of the above tasks, the association between stimuli and responses had been established
in a training session administered the day before scanning
(900 trials per task). In the reversal versions, the same stimuli and responses were used as in the overpracticed
tasks,
but the subjects were assigned a new combination of stimulus-response associations. The sets of stimuli used in the
reversal and overpracticed
tasks, respectively, were counterbalanced across subjects. In the baseline scan, an asterisk
was flashed in the center of the screen. Scanning during the
overpracticed version of each task was always followed by
scanning in the corresponding
reversal task. The order of
the oculomotor,
manual, and speech tasks was counterbalanced across the subjects with the baseline scan following
either the first, second, or third pair of the sensorimotor
tasks. The stimulus-response
rate was constant in all tasks.
stimuli being presented every 2 s, with 60 stimuli presented
in total ( 30 stimuli during the actual scanning).
SU BJ ECTS.
PARADIGMS.
There were three pairs of sensorimotor tasks that diKered in terms of output modality. Each
pair comprised an overpracticed and a reversal version of
the task. In the baseline scan, the subjects were not required
to execute any responses other than fixating the center of
the screen.
&%MZU/ tcrsL~. In the manual task, one of three response
keys had to be pressed according to the particular visual
stimulus shown. Stimuli cuing the responses (simple geometric forms such as a cross or a circle) were presented for
200 ms inside an empty circle (0.5” diam) that was displayed permanently in the center of the screen. The three
response keys were arranged in a row; the subjects responded by pressing the keys with the second, third, or
fourth finger of their right hand. The latency and accuracy
of responses were recorded.
OC*ZI/OIMOZOI’ZLLS~.In the oculomotor
task, the subjects
were asked to make a direction-specitic
saccade, depending
on the particular visual stimulus presented. Eye movements were directed toward one of three squares (0.3” X
0.3”) arranged one above the other with a between-target
distance of 1.3O. The targets were displayed permanently
within the right hemitield at a distance of 5” from the center
of the screen. Stimuli cuing the responses (simple geometric forms such as a square or a triangle) were presented for
200 ms inside an empty circle (0.5” diam) that was displayed permanently in the center of the screen. The latency
and accuracy of oculomotor responses were recorded using
a Pupil/Cornea1
Reflection Tracker by ISCAN.
$XYY/Z USLL In the speech task, the subjects had to say
BEHAVIORAL
E~puim
en f 2
In this experiment, we used a different paradigm that
emphasized suppression of externally triggered motor programs and minimized the cognitive operations of the tasks
employed in experiment 1.
CEREBRAL.
BLOOD-FLOW
MEASIJRfiMEN’I‘.
In this experiment,
acquisition and analysis of the cerebral blood flow data
were identical to those used in experiment 1.
St JBJ ECI‘S.
Nine right-handed subjects (4 female, 5 male:
19-30 yr of age) underwent seven 60-s PET scans in a single
session.
BEII1AVIORAl.
PARADIGMS.
There were three pairs of tasks
that differed in terms of output modality (oculomotor,
manual, and speech). Each pair comprised a prostimulus
and an antistimulus
version of the task. The baseline scan
did not involve any sensory stimulation or the execution of
any kind of response. During all scans, the subjects were
blindfolded, except for the two oculomotor tasks.
:2~~rrz~/ Z&-S. In the manual task, the subjects were
asked to keep two levers pressed down using the second and
third fingers of their right hand. The pressure required
corresponded
approximately
to a force of 2 N. A tactile
stimulus (light touch) was delivered to the palmar side of
either of the two fingers by a solenoid moving up and down
(duration
of 100 ms). The subjects were required to lift
either the finger that was touched (prostimulus
task) or the
other one (antistimulus
task).
O~z&~rnoto~ faslis. In the oculomotor tasks, the subjects
were required to make a saccade either towJard (prostimulus task) or awav from (antistimulus
task) a visual stimulus
presented with& the right or left hemitield (Hallett 1978 ).
Each trial started with presentation of a fixation stimulus
(empty circle, 0.5” diam) in the center of the computer
screen. The fixation stimulus remained on the screen for
300 ms and was followed by a 200-ms gap ( blank screen)
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sidual anatomic variability persisting after the stereotactic
standardization,
PET images were smoothed with an 1%
mm Hanning filter. The PET data were normalized for
global cerebral blood flow and the mean state-dependent
change image volume obtained. For statistical analysis, the
mean state-dependent change volume was converted to a
t-statistic volume by dividing each voxel by the mean SD in
normalized cerebral blood flow for all intracerebral voxels
(Worsley
et al. 1992 ). Individual MRI images were subjected to the same averaging procedure such that composite
stereotactic image volumes, 128 X 128 X 80 voxels in extent and sampled at - 1.5 mm in each dimension,
dere
obtained for both t-statistic and MRI volumes (Evans et al.
1992). Anatomic and functional images were merged to
allow direct localization of f-statistic peaks on the MRI
images. These peaks were identified by an automatic peakdetection algorithm.
The peak distribution
was then
searched for significant signals using change-distribution
analysis and Z- score thresholding
(Fox et al. 1988). A
threshold for reporting a peak as significant was set at z
value of 2.17 (P < 0.03). Peaks with z value equal to or
higher than the threshold value are reported throughout the
present study. These peaks are referred to as either rCBF
changes or activation foci.
CINGlJi
456
T. PAUS, M. PETRIDES,
q
A. C. EVANS, AND E. MEYER
q
q
Overpractised
1000
400
t
*
Pro-stimulus
Anti-stimulus
r
300
200
0
50
s
t5
r
20
10
s
5
O
Speech
Manual
Oculomotor
Speech
Manual
Oculomotor
FIG. 2. Histograms illustrate the mean response latency for each of the 3 tasks, the mean of the within-subject response
variability, and the mean error rate (left panel: experiment 1; rightpanel: experiment 2). The means are based on data
obtained in the 60 trials of each task administered during the positron emission tomography (PET) session. Bars on the
histograms: mean + SE. In experiment 2, because of a technical failure, oculomotor data were obtained in only 6 subjects.
The statistical significance of the differences is based on a l-tailed paired t test with Bonferroni correction (*P < 0.05, **P <
0.01).
between the offset of the fixation and the onset ofthe peripheral stimulus. The gap was used to facilitate the execution of
saccades (Fischer and Breitmeyer 1987). The peripheral
stimulus (filled square, 0.3 by 0.3 ‘, duration of 200 ms)
was displayed 5’ to the left or the right of the fixation stimulus.
Speechtasks.In the speech tasks, the subjects heard two
letters (A or L) through a pair of headphones. In the prostimulus version of the task, the subjects were asked to respond by saying the letter that immediately
follows in the
alphabetic sequence ( A-“B”,
L-“M”).
In the antistimulus task, they were required to respond in the opposite way
by saying “M” when they heard the letter A and “B” for the
letter L.
The average rate of stimulus presentation was the same
for all tasks. The interstimulus interval was held constant
( 1.2 s) in the prostimulus versions of each task, but it varied
pseudorandomly ( 1.O, 1.2, or 1.4 s) in the antistimulus versions. There were 60 stimuli presented in each task. The
side of the visual stimulus (left or right hemifield), the location of the tactile stimulus (2nd or 3rd finger), and the type
of letter (A or L) alternated regularly in the prostimulus
versions, but were presented in a pseudorandom order in
the antistimulus version of each task. The predictability of
the stimuli in the prostimulus tasks was intended to reduce
the task requirements to those of a simple alternation of the
two possible responses.
Scanning in the prostimulus version of each task was always followed by scanning in the corresponding antistimulus one. The order of the oculomotor, manual, and speech
tasks was counterbalanced across all subjects. The baseline
scan followed either the first, second or third antistimulus
task. The latency and accuracy of motor responses were
measured. Eye movements were recorded by means of a
Pupil/Cornea1 Reflection Tracker (ISCAN) and the verbal
responses with a voice trigger device.
Experiment 3
This experiment is a replication of the speech part of
experiment 1. The procedure and the tasks (reversal and
overpracticed) were identical to those used in the original
study (see above). The only difference was the baseline
scan. In contrast to experiment 1, where the subject was
required in the baseline condition to fixate the center of the
screen, in this experiment the baseline procedure was identical to that used in experiment 2, i.e., the eyes were closed.
Eight right-handed normal subjects ( 5 female, 3 male; 1924 yr of age) participated in the experiment. Each subject
underwent six 60-s PET scans within a single session. Three
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100
HUMAN
TABLE
1.
ANTERIOR
CINGULATE
CORTEX
457
Stereotaxic coordinates of activation foci obtained in the reversal minus overpracticed subtraction
Region
Brodmann’s
Area
x
Y
Z
t
Z
30
25
32
17
27
18
-54
-50
-54
13
24
20
51
29
-3
39
40
31
3.1
3.0
3.8
3.1
2.8
3.0
4.2
3.4
2.9
2.4
2.3
2.9
2.4
2.2
2.3
3.2
2.6
2.2
13
8
-42
-47
-2
30
49
47
39
-6
3.3
3.0
4.3
4.0
3.2
2.5
2.3
3.3
3.0
2.4
58
22
22
6
20
49
3.7
3.9
4.3
2.2
2.3
2.6
Letter
Code
A. Ocukomotor subtraction
Right inferior
frontal sulcus
Left inferior
frontal sulcus
Left anterior
cingulate (rostral)
Right anterior cingulate (dorsal)
Right anterior cingulate (rostral)
Left inferior
frontal gyrus
Right intraparietal
sulcus
Left intraparietal
sulcus
Posterior cingulate or precuneus
(midline)
46/45
9145
24/32
32/8/6
32
47
7
7
23/3 1
38
-43
-3
5
7
-36
36
-39
0
A
B
B. Manual subtraction
inferior frontal sulcus
anterior ci ngulate (caudal)
intraparietal
sulcus
intraparietal
sulcus
putamen
9144
24/32
7
7
-47
-15
46
-35
-28
C. Speech subtraction
Left frontal
Left inferior
Left anterior
pole
frontal sulcus
cingulate (dorsal)
10
9145
3218
The anatomic
regions and Brodmann’s
areas listed in this and following
statistical values are reported
for each activation
focus.
of the six scans were unrelated to this study. Only activation
foci obtained on the medial wall of the frontal lobe are
reported here (see Table 7 and Figs. 3 and 5 ).
RESULTS
Experiment
1
Behavioral data obtained during the performance of the
overpracticed and the reversal versions of each task are
shown in Fig. 2.
Task-specific changes in rCBF were identified as the difference in rCBF between two scanning conditions. Two
types of subtractions were carried out. First, rCBF obtained
in the baseline scan was subtracted from that obtained either in the overpracticed or the reversal version of each
task. These subtractions will be referred to as the baseline
subtractions. Second, in the between-tasks subtractions,
rCBF obtained in the over-practiced task was subtracted
from that obtained in the reversal version of each task. The
coordinates of all activation foci (with the above-threshold
value of z) obtained in these subtractions are given in Tables l-3.
On the convexity of the frontal lobe, the reversal minus
overpracticed subtraction yielded a significant activation
focus within the left inferior frontal sulcus for each output
modality. The activation focus obtained from the manual
subtraction was caudal to that obtained from the oculomotor and the speech subtractions. For the oculomotor output
modality, changes in rCBF within the inferior frontal sulcus were bilateral. On the medial wall of the frontal lobe,
the same between-tasks subtraction yielded significant
changes in r CBF within the left anterior cingulate region for
each output modality. The most anterior focus was located
just above the genu of the corpus callosum (Fig. 6, focus A).
This was observed in the oculomotor subtraction. The most
-39
-42
-1
tables are based on the atlas by Talairach
and Tournoux
D
(1988).
Both 1 and z
posterior focus, buried in the depth of the cingulate sulcus
[ see also Talairach and Tournoux ( 1988 ), coronal section
taken at y = +8 mm depicted in Fig. 761, was detected in
the manual subtraction (Fig. 4, focus C). In the speech
subtraction, the activation focus (Fig. 5, focus D) was
found further dorsally in the vicinity of the paracingulate
sulcus. Even though the rCBF changes encroach on the
cortex of the medial frontal gyrus (area 8 ), a close relationship of the maximum of this focus to the paracingulate sulcus can be seen in Fig. 5 (inset). In the oculomotor subtraction, changes in r CBF were also detected within the right
ACC. One of these oculomotor foci was located in the rostral ACC (as was the focus in the left hemisphere), whereas
the second one was found further dorsally in the vicinity of
the paracingulate sulcus. The intermediate dorsal location
of the latter focus was similar to that obtained in the speech
subtraction.
In the reversal minus baseline subtraction, a similar pattern of rCBF changes was obtained within the left anterior
cingulate region. However, some differences with regard to
the precise localization of the activation foci in comparison
to those obtained in the between-tasks subtractions should
be noted. Thus the activation focus obtained in the manual
subtraction was located more closely to the midline (X = -4
mm) (Fig. 4, focus G), the rCBF changes yielded in the
speech subtraction extended into the cortex ventral to the
paracingulate sulcus (Fig. 5, focus H) with the maximum of
the activation again very close the this sulcus (Fig. 5, inset),
and, in the oculomotor subtraction, two foci were found
adjacent to the genu of the corpus callosum (Fig. 6, foci E
and F) . No significant r CBF changes were detected within
the intermediate dorsal ACC in the latter subtraction. None
of the foci observed within the inferior frontal sulcus in the
reversal minus overpracticed subtraction (see above) were
now seen. By contrast, changes in rCBF could be clearly
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
Left
Left
Right
Left
Left
458
TABLE
T. PAUS, M. PETRIDES,
2.
A. C. EVANS, AND E. MEYER
Stereotaxic coordinatesof activation foci obtained in the reversalminusbaselinesubtraction
Region
Brodmann’s Area
Left precentral sulcus
Right precentral sulcus
Left anterior cingulate (rostral)
Left anterior cingulate (rostral)
Left superior parietal lobule
Right intraparietal sulcus (caudal)
Left intraparietal sulcus
Right calcarine sulcus
Left middle occipital gyrus
Left lingual gyrus
6
6
24132
24
7
7
7
17
18
18
z
t
z
5
3
29
32
-61
-54
-44
-76
-83
-83
44
48
22
12
49
40
44
11
22
-11
4.6
3.2
3.9
3.8
6.1
4.5
5.1
4.7
3.8
5.7
3.0
2.2
2.6
2.5
4.0
3.0
3.4
3.1
2.6
3.8
-28
-37
-30
-21
49
49
44
15
-2
7.6
3.9
3.4
3.3
3.8
5.4
2.9
2.5
2.4
2.7
15
-23
-33
-13
49
3
11
0
4.8
7.7
6.5
5.3
2.2
3.6
3.0
2.4
Y
X
Letter Code
A. Oculomotor subtraction
-23
24
-8
-9
-19
35
-35
4
-21
-8
E
F
B. Manual subtraction
4
3216
7
-36
-4
43
1
-13
5
G
C. Speech subtraction
Left anterior cingulate (dorsal)
Right superior temporal sulcus
Left superior temporal sulcus
Left superior temporal sulcus
32/8
22
22
22
-4
59
-54
-58
identified in the primary motor regions. There was bilateral
activation within the depth of the precentral sulcus in the
oculomotor task. For the manual task, the left central region was activated.
TABLE
3.
H
In the over-practiced minus baseline subtraction, a different pattern of blood flow changes was observed within the
medial wall of the frontal lobe. In both oculomotor and
speech subtractions, significant changes of rCBF were
Stereotaxic coordinatesof activation foci obtained in the overpracticedminus baselinesubtraction
Region
Brodmann’s Area
Left precentral sulcus
Left superior frontal sulcus (caudai)
Left medial frontal gyrus
Left superior parietal lobule
Right superior parietal lobule
Right calcarine sulcus
Left superior/middle occipital gyrus
Left lingual gyrus
Left thalamus or corpus callosum
6
6
6
7
7
17
18/19
18
Left postcentral gyrus
Left central sulcus
Left anterior cingulate (caudal)
Right calcarine sulcus
Left lingual gyrus
Left substantia nigra
Left cingulum or corpus callosum
1
4
24132
17
18
Y
Z
t
Z
-1
-2
-4
-56
-57
-74
-88
-81
-26
45
51
60
53
53
12
20
-8
20
3.7
3.3
2.9
5.5
3.0
5.3
4.6
6.9
3.1
2.8
2.5
2.2
4.1
2.3
3.9
3.4
5.1
2.3
-21
-25
3
-71
-64
-23
30
33
51
39
11
0
-2
12
3.2
6.9
4.1
3.7
3.4
3.8
3.2
2.5
5.3
3.2
2.9
2.7
2.9
2.5
-11
-4
-2
-25
-19
-76
33
22
57
3
8
11
5.9
4.4
3.9
9.7
8.6
4.0
3.5
2.6
2.3
5.8
5.1
2.4
x
A. Oculomotor subtraction
-36
-20
-12
-24
25
4
-21
-11
-4
B. Manual subtraction
-51
-38
-8
7
-11
-16
-7
C. Speech subtraction
Left central sulcus
Right precentral gyrus
Left medial frontal gyrus (SMA)
Right superior temporal sulcus
Left superior temporal gyrus
Right calcarine sulcus
SMA, supplementary motor area.
4
4
6
22
22
17
-51
62
-4
58
-56
3
Letter Code
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
Left central sulcus
Left anterior cingulate (caudal)
Right intraparietal sulcus (rostral)
Right thalamus or corpus callosum
Left substantia nigra
HUMAN
TABLE
4.
ANTERIOR
CINGULATE
CORTEX
459
Stereotaxic coordinatesof activation foci obtainedin the antistimulusminusprostimulussubtraction
Region
Brodmann’s Area
x
Y
z
t
Z
Letter Code
8
10
-6
-64
-59
-81
-18
51
42
51
49
54
5
-6
3.5
3.4
3.2
3.7
3.9
3.4
5.0
2.4
2.4
2.2
2.6
2.7
2.4
3.5
J
10
49
-1
1
18
10
22
-64
-54
-68
38
24
49
49
0
45
38
45
51
62
3.0
2.7
3.6
3.2
3.4
2.9
3.2
3.0
3.5
3.3
2.4
2.2
2.8
2.6
2.7
2.3
2.6
2.4
2.8
2.7
48
39
-59
-68
-83
24
24
51
31
45
2.5
2.1
2.0
2.0
1.8
3.0
2.6
2.4
2.4
2.2
A. Oculomotor subtraction
Right anterior cingulate (caudal)
Right anterior cingulate (caudal)
Left anterior cingulate (caudal) or precental sulcus
Right superior parietal lobule
Precuneus (midline)
Right calcarine sulcus
Left substantia nigra
24132
32
2416
7
7
17
12
1
-15
17
0
7
-9
B. Manual subtraction
It middle frontal gyrus
It mediai frontal gyrus
precentral sulcus
nt precentral sulcus
It inferior frontal gyrus
anterior cingulate (caudal)
It anterior cingulate (dorsal)
It superior parietal lobule
it precuneus
nt precuneus/superior parietal lobule
9
9
6
6
45147
32
32
7
7
7
50
8
-39
39
34
-5
1
24
1
8
L
C. Speech subtraction
Right frontal pole/rostra1 middle frontal gyrus
Left frontal pole/rostra1 middle front. g.
Left inferior parietal lobule
Left precuneus
Precuneus/cuneus (midline)
9/10
9/10
7
7
7/19
found within the caudal and dorsal region of the left medial
frontal gyrus ( medial area 6). The activation focus obtained from the manual subtraction was localized within
the caudal left ACC (Fig. 4, focus I), as was the case in the
reversal minus overpracticed subtraction. Changes of rCBF
were also seen in the primary motor regions in all output
modalities.
Experiment
2
The behavioral findings obtained for all subjects are
shown in Fig. 2. In the prostimulus version of the oculomotor task, because of the predictability of the stimulus side,
the saccades appeared to be paced by the offset of the fixation rather than the onset of the peripheral stimulus. The
latency was 206 t 85 (SD) ms when measured from the
offset of the fixation and 6 t 85 ms from the onset of the
peripheral stimulus. The latter value is the one presented in
Fig. 2.
Task-specific changes in rCBF were identified as the difference in r CBF between two scanning conditions. As in
experiment 1, in the baseline subtractions the baseline scan
was subtracted from either the prostimulus or the antistimulus scan. In the between-tasks subtractions, normalized
subtractions are given in Tables 4-6.
On the convexity of the frontal lobe, the antistimulus
minus prostimulus subtractions yielded the following pattern of rCBF changes. In the oculomotor subtraction, there
were no activation foci. In the speech subtraction, activation was seen bilaterally in the frontal pole. In the manual
31
-32
-42
-4
0
subtraction, activation foci were found within the caudal
part of the right middle frontal gyrus, the left and right
precentral sulcus, and the right inferior frontal gyrus. On
the medial wall of the frontal lobe, significant changes in
rCBF were observed in the oculomotor and manual subtractions, but not in the speech one (see below for reanalyzed data). In the oculomotor task, one activation focus
was found at the border between the caudal and the intermediate portion of the anterior cingulate region. The other
activation focus (Fig. 6, focus J) was located more dorsally
but also more laterally from the midline and could be classified as falling within either the dorsal part of the caudal
ACC or the most ventral part of the neocortical portion of
the supplementary motor area (SMA). In the manual subtraction, two activation foci were observed within the anterior cingulate region, one located in its caudal portion in the
left hemisphere (Fig. 4, focus L) and one located within the
intermediate
dorsal portion of the ACC, close to the mid*.
line.
In the antistimulus minus baseline subtractions, significant rCBF changes were seen in the following regions of the
lateral frontal cortex: the primary motor regions (oculomotor and manual subtractions), the inferior frontal gyrus
(manual and speech subtractions), and the caudalmost
portion of the middle frontal gyrus (manual subtraction).
On the medial wall of the frontal lobe, an activation focus
was detected in the caudal portion of the left anterior cingulate region in the manual subtraction (Fig. 4, focus N). The
activation focus obtained in the oculomotor subtraction
was located at the border between the dorsal portion of the
caudal ACC and the ventral part of the neocortical SMA
(Fig. 6, focus AJ).
In the prostimulus minus baseline subtractions, only the
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
Rig
Rig
Lef
Rig
Rig
Lef
Rig
Rig
Rig
Rig
T, PAUS, M. PETRIDES,
460
TABLE
5.
A. C. EVANS, AND E. MEYER
Stereotaxic coordinatesqf activation foci obtained in the antistimulus minus basehe subtraction
Region
Brodmann’s Area
x
Y
t
z
Letter Code
A. Ocuk~motor subtraction
Right precentral sulcus/superior frontal sulcus
Left anterior cingulate (caudal)
Right intraparietal sulcus
Left intraparietal sulcus
Right calcarine sulcus
Right inferior occipital lobule
Left middle occipital lobule
Right inferior temporal gyrus (caudal)
Right inferior temporal sulcus (caudal)
6
3216
7
7
17
19
18
37
22
25
-9
27
-20
3
40
-28
47
52
-2
-59
-59
-85
-69
-85
-61
-52
53
53
47
48
6
-5
15
-11
9
4.8
5.4
5.6
4.8
9.4
3.8
3.7
3.7
3.6
2.9
3.2
3.3
2.9
5.4
2.3
2.3
2.3
2.2
-19
-2
-4
22
-44
-54
-30
-19
-18
51
56
48
-5
40
56
13
-2
-5
9.6
4.4
7.0
3.3
3.8
3.3
5.5
3.4
4.2
5.9
2.8
4.3
2.2
2.4
2.2
3.4
2.3
2.7
24
22
20
-21
-23
-2
-30
-8
-5
0
0
-3
-9
-11
3.6
3.2
3.0
5.9
5.4
4.5
4.9
2.6
2.3
2.2
4.4
4.0
3.3
3-7
I
M
B. Manual subtraction
4
6
24/6
47
7
7
42
22
-42
24
-5
38
38
-12
-54
-36
0
N
C. Speech subtract ion
Right inferior frontal gyrus
Left inferior frontal gyrus
Left inferior frontal gyrus
Left superior temporal gyrus
Right superior temporal sulcus
Right middle temporal gyrus
Tectum (midline)
47
47
47
22
21122
21
primary motor regions were activated on the lateral convexity of the frontal lobe (oculomotor and manual subtractions). In the speech subtraction, two activation foci were
observed within the right inferior frontal gyrus. On the medial wall of the frontal lobe, significant changes of r CBF
were observed in the oculomotor and manual subtractions.
The activation focus obtained in the oculomotor subtraction was localized quite dorsally within the caudal part of
the right medial frontal gyrus. The localization of rCBF
changes observed in the manual subtraction was the same
as that of the antistimulus minus baseline subtraction, i.e.,
the caudal part of the ACC (Fig. 4, focus 0).
In the speech antistimulus task, a clear difference in the
performance of individual subjects was noticed: four subjects passed the speech antistimulus task without making
any etiors (“passed” group), whereas the remaining five
subjects made 10% errors on average (“failed” group). The
PET data were then reanalyzed for each group separately.
The task subtraction yielded a significant r CBF change
within the dorsal intermediate ACC in the passed group
only ( Fig. 5, focus P) . Furthermore, the prostimulus minus
baseline subtraction performed in the failed group yielded
significant r CBF changes not only in the medial frontal
gyrus (SMA) but also in the intermediate ACC (Fig. 5,
focus Q).
DISCUSSION
An overview of the r CBF changes observed on the medial
wall of the fron tal lobes in all three experiments is provided
39
-34
-29
-60
64
59
0
in Fig. 3 and Table 7. Three main points emerge from this
summary of the data.
First, most of the activation foci obtained in the reversal
and/or antistimulus scans were located in the portion of
the medial wall that extends between and includes the cingulate and paracingulate sulci. This region has been referred to as the paralimbic zone by Sanides ( 1964) (see Fig.
3, inset) because it comprises cortex of a transitional type
that shares both limbic and neocortical morphological
features. This region includes Brodmann’s area 32 and the
dorsalmost part of area 24. This finding is consistent with
the localization of the cingulate motor areas in the dorsal
tier of area 24 of the monkey cingulate cortex (Dum and
Strick 199 1; Luppino et al. 199 1).
Second, somatotopic organization of the activation foci
could be seen in that the “manual” foci were located in the
caudalmost portion of the ACC (around the vertical plane
traversing the anterior commissure (VCA), the “oculomotor” foci obtained in experiment 1 were located in the rostral part of the ACC (close to the genu of the corpus callosum), and the “speech” foci were found in the middle portion of the ACC just anterior to the manual foci. In the
speech subtractions (experiments 1 and 3 ), additional activation was obtained also in the rostralmost portion of the
ACC, corresponding most likely to the face representation.
Thus the distinct localization of r CBF changes within the
human ACC is again consistent with the neuroanatomic
and neurophysiological
findings in the monkey, as alluded
to in the introduction and corroborated below.
Third, activation foci found almost exclusively in the
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
Left central sulcus
Right middle frontal gyrus (caudal)
Left anterior cingulate (caudal)
Right inferior frontal gyrus
Right intraparietal sulcus
Left superior parietal lobule
Left superior temporal gyrus
Left temporal insula
Nucleus ruber (midline)
HUMAN
ANTERIOR
CINGULATE
CORTEX
461
A. Oculomotor subtraction
Right precentral sulcus
Left precentral gyrus
Right medial frontal gyrus
Right intraparietal sulcus
Right calcarine sulcus
Left lingual gyrus
Left middle occipital gyrus
Right lingual gyrus
6
416
6
17
18
19
18
34
-44
3
27
1
-11
-27
24
-2
-6
-2
-54
-88
-83
-90
-76
48
44
60
45
8
-6
17
-8
3.4
3.3
3.7
3.7
7.5
5.7
3.7
4.8
2.4
2.3
2.6
2.6
5.0
3.8
2.6
3.3
48
49
11
9
15
-3
9.8
5.9
5.8
3.7
3.7
4.2
6.0
3.7
3.7
2.4
2.4
2.7
-5
5
5
2
-9
-11
3
3.2
2.9
7.0
6.7
5.1
4.0
3.7
2.6
2.3
5.6
5.3
4.1
3.2
3.0
B. IManual subtraction
4
2416
22
22
22
-43
-5
-50
63
58
0
-23
-7
-26
-37
-33
-18
0
C. Speech subtraction
Right inferior frontal gyrus
Right inferior frontal gyrus
Left superior temporal gyrus
Right superior temporal gyrus
Right middle temporal gyrus
Right tectum
Right thalamus
47
45147
22
22
21
38
28
-56
62
60
7
3
over-practiced and / or prostimulus scans were located more
dorsally in the caudal part of the medial frontal gyrus
( Brodmann’s area 6). Localization
of these oculomotor
and “speech/ face” foci is in agreement with the results of
other PET studies (eye movements: Fox et al. 1985a;
speech: Petersen et al. 1988 ) . It also demonstrates that both
the speech/ face and eye representations, located in the neocortical portion of the SMA, overlap to a great extent.
Before discussing in greater detail the above points, we
would like to comment on some results that might be
viewed as incongruent with the above interpretation of somatotopy. First, there is a difference between the rCBF
changes observed in the reversal (experiment 1) and the
antistimulus (experiment 2) oculomotor tasks (see Fig. 3).
It is possible that the lack of significant activation of the
rostra1 ACC during the performance of the antistimulus
task, which was observed in this region in the reversal task,
is related to the absence of concomitant activation of the
prefrontal cortex. The caudal localization of the rCBF
changes in the antistimulus subtractions might be related to
either involvement of the supplementary eye field (compare the localization of the foci obtained in these subtractions to those found in the overpracticed and prostimulus
ones) or to the tendency of subjects to make a simultaneous
head movement’
when required to move the eyes away
from a peripheral stimulus. Luppino and collaborators
( 199 1 ), using microstimulation
in the awake monkey, elicited neck and upper-trunk movements within the caudal
’ In a pilot study run after this experiment, both subjective reports from
subjects and electromyographic recording from neck muscles in the PET
setting provided evidence of an increase in neck muscle tension related to
the gaze response required in the antistimulus task.
22
18
-18
-23
-4
-30
-16
portion of the ACC, where forelimb movements were also
elicited. A second set of results that might be considered
incongruent with the somatotopic organization of the human ACC is the involvement of the intermediate, speechrelated portion of the ACC in the tasks requiring no overt
speech output ( see Table 7 B, activation foci K, V, and IV).
These changes in rCBF, observed in this region during the
manual (antistimulus,
focus IV) and oculomotor (reversal,
focus Vand antistimulus, focus K) tasks, may be related to
covert speech. This explanation is supported by the fact that
subjects noted the occurrence of covert speech more frequently during the more difficult reversal or antistimulus
tasks. Furthermore,
in the same subtractions, the “primary” activation foci were found in the expected regions,
i.e., the caudal and rostra1 ACC in the case of the manual
and oculomotor subtractions, respectively. In addition, the
“secondary” foci (K, I/, W) were not yielded by the respective “baseline” subtractions, whereas that was the case for
the primary foci. Zatorre et al. ( 1992) observed activation
of Broca’s area during the phonological analysis of words
heard, without any overt verbal responses. This strongly
suggests that “speech-related” regions could be activated
without actual motor output.
It should also be pointed out that an alternative interpretation of the data presented in this communication
might
be that there are multiple regions on the medial wall of the
frontal lobe where different output modalities are represented. Thus the intermediate
ACC (area 32) may be
viewed as a distinct region containing eye, hand, and speech
representations and involved in cognitive aspects of motor
control. The rostra1 ACC would then constitute an incomplete map containing only eye and face representations; no
significant r CBF changes were found here in the manual
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
Left central ‘sulcus
Left anterior cingulate (caudal)
Left superior temporal gyrus
Right superior temporal gyrus
Right superior temporal gyrus
Nucleus ruber (midline)
T. PAUS,
M.
PETRIDES,
A. C. EVANS,
AND
E. MEYER
I
MANUAL
FIG. 4. Merged
PET-MRI
sagittal slices of the left hemisphere,
depicting
activation
foci obtained
in the manual subtractions.
individual
foci. Distances from midline are in millimeters;
minus sign indicates left hemisphere.
C’: reversal minus ovcrpracticed
( 15).
minus prostimulus
(- 5). G: reversal minus baseline (-4).
I: overpracticed
minus baseline (-8).
N: antistimulus
minus baseline (-5).
minus baseline (-5).
Note that with the Scanditronix
PC-2048 tomograph
and the PET data analysis used in this study, a point source
would be detected as a focus with full width at half maximum
(FWHM)
of 18 mm. Therefore,
the spatial extent of the activation
foci N
necessarily imply an involvement
of the whole underlying
cortex. For that reason, we also present the position of the maximal
activation
respective subtractions
(foci N and 0. insrls). In L. additional
activation
can be seen in the parietal region.
Letters identify
L: antistimulus
0: prostimulus
of radioactivity
and 0 need not
obtained in the
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
FIG. 3. Activation
foci within the anterior cingulate region yielded by the manual (green),
the speech (red ). and the oculomotor
(yellow)
subtracr .
. ._-.
tions m experiments
l-3. Ihe toc~ located m either the left or nght hemisphere
were superimposed
on the sagittal section OI me averagea
MKI
(experiment
1) passing 2.7 mm to the left ofthe midline. Bottom k$ corner:
letters identify the individual
foci. Both the cingulate and paracingulate
sulci
are highlighted
by grey squares. Inset: (reprinted
with permission
from Sanides 1964) architectural
zones and principal
sulci of the medial wall of the
human frontal lobe (cm, sulcus callosomarginahs;
Pro, proisocortex;
PlZd, dorsal paralimbic
zone; FmZ, frontomotor
zone; PmZ, paramotor
zone; FpZ,
frontopolar
zone). Images, schematics,
and point locations are presented within the standardized
coordinate
space (Talairach
and Tournoux
1988).
HUMAN
TABLE
7.
Letter Code
ANTERIOR
CINGULATE
CORTEX
463
Stereotaxic coordinatesofactivationfici obtainedon the medial wall of thefiontal lobesin three PET experiments
Y
X
z
z
t
Subtraction
Output Modality
Brodmann’s Area
Interpretation
A. Rostra1 anterior cingulate cortex
A
B
E
F
x
Y
z*
-3
-8
-9
-4
-9
32
27
29
32
30
34
34
20
29
22
12
17
13
22
3.8
2.8
3.9
3.8
3.4
3.5
3.8
2.9
2.2
2.6
2.5
2.0
1.5
2.0
REV-OVR
REV-OVR
REV-BASE
REV-BASE
REV-OVR
REV-BASE
REV-OVR
Oculomotor
Oculomotor
Oculomotor
Oculomotor
Speech
Speech
Speech
24132
32
24132
24
24
24
24
Face
Face
Face
3218
32
32
24132
32
32
32
32
3218
32
32
Speech/vocalization
Speech/vocalization
Speech/vocalization
Speech/vocalization
Speech/vocalization
Speech/vocalization
Speech/vocalization
Speech/vocalization
Covert speech ?
Covert speech ?
Covert speech ?
24132
3216
24132
32
24123
24123
24132
3216
Arm
Arm
Arm
Arm
Arm
Arm
Head movement ?
Head/SEF ?
Eye
Eye
Eye
Eye
B. Intermediate anterior cingulate cortex
D
H
P
-1
-4
0
8
Q
3
5
-1
5
10
12
18
20
13
20
17
22
10
49
49
44
39
44
36
48
38
51
38
42
4.3
4.8
2.8
4.0
3.9
3.5
4.0
3.3
3.1
3.2
3.4
2.6
2.2
2.7
2.8
2.1
1.9
2.2
1.8
2.4
2.6
2.4
REV-OVR
REV-BASE
ANT-PRO
PRO-BASE
REV-OVR
REV-OVR
REV-BASE
REV-BASE
REV-OVR
ANT-PRO
ANT-PRO
Speech
Speech
Speech passed
Speech failed
Speech
Speech
Speech
Speech
Oculomotor
Manual
Oculomotor
C. Caudal anterior cingulate cortex
c
G
L
N
0
J
M
-15
8
5
3
-4
-8
-5
-5
-5
12
-- 9
10
-4
-7
8
-2
49
49
39
45
48
49
51
53
3.0
3.9
4.1
2.9
7.0
5.9
3.5
5.4
2.3
2.9
3.2
2.3
4.3
3.7
2.4
3.2
REV-OVR
REV-BASE
OVR-BASE
ANT-PRO
ANT-BASE
PRO-BASE
ANT-PRO
ANT-BASE
Manual
Manual
Manual
Manual
Manual
Manual
Oculomotor
Oculomotor
D. Medial frontal gyrus (supplementary motor area)
2
3
4*
-12
-4
3
-4
-2
-2
-1
-1
5*
6
5
4
1
60
57
60
60
58
62
2.9
3.9
3.7
5.2
4.7
3.3
2.2
2.3
2.6
3.1
2.6
1.8
OVR-BASE
OVR-BASE
PRO-BASE
OVR-BASE
REV-BASE
PRO-BASE
Oculomotor
Speech
Oculomotor
Speech
Speech
Speech failed
6
6
6
6
6
6
SEF
Speech/vocal/face
SEF
Speech/vocal/face
Speech/vocal/face
Speech/vocal/face
Experiment 1: reversal (REV), overpracticed (OVR), and baseline (Base) scans. Experiment 2: antistimulus (ANT), prostimulus (PRO), and baseline
(Base) scans. Experiment 3 (replication of experiment 1): REV, OVR, and Base scans. SEF, Supplementary Eye Field. * Activation foci obtained in
experiment 3 are marked with an asterisk. ? tentative interpretation of the given activation focus.
subtractions. Finally, the caudal portion of the medial frontal cortex contains representations for all the output modalities explored. However, it should be stressed that the neocortical portion of the SMA and the more ventrally located
caudal ACC probably do not constitute one homogeneous
region. The dorsal group of foci was found to be activated
mainly during the performance of the overpracticed and
the prostimulus tasks (oculomotor or speech), whereas the
ventral group was activated mainly during the reversal and
the antistimulus tasks (manual or oculomotor, the latter
only in experiment 2; see above). Changes in rCBF in the
caudal ACC yielded by both reversal (antistimulus)
and
overpracticed (prostimulus)
manual subtractions may be
related to the existence of the rostra1 and the caudal arm
representations within the ACC (see below).
The following discussion will concentrate on two issues.
First, the localization of the rCBF changes observed within
the human ACC will be examined in the context of findings
obtained in neuroanatomic and neurophysiological
studies.
Second, some functional
will be outlined.
considerations
regarding the ACC
Localization
As already pointed out, the medial wall of the primate
frontal lobe can be subdivided along the dorsoventral axis
into three general types of cortex. The dorsalmost region is
of the true neocortical type and comprises Brodmann’s
areas 6, 8, and 9 (in a caudorostral direction). The ventralmost part (the cortex of the cingulate gyrus, i.e., areas 24a
and 24b) lies above the corpus callosum and comprises cortex of the limbic type. Between these two regions lies a transitional type of cortex comprising Brodmann’s area 32 and
the dorsalmost part of area 24. Most of the activation foci
observed in all three experiments were found in this portion
of the ACC.
MANUAL
SYSTEM.
Changes of rCBF obtained in the manual subtractions in both experiments 1 and 2 were localized
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
R*
S*
T*
u*
V
w
K
22
15
T. PAUS,
M.
PETRIDES,
vco
A. C. EVANS,
UIA
AND
E. MEYER
SPEECH
_
.
.
.
.
-.
.-...--
.
.
.
_..
FIG. 6. Merged PET-MRI
sagittal shces of the left or the rtght hcmrsphcrc,
dcptctmg acttvatton
foci obtamed m the oculomotor
subtractions.
identify individual
foci. Distances from midline are in millimeters;
minus sign indicates left hemisphere.
.4 : reversal minus overpracticed
(-3).
reversal minus baseline (-8 and -9 for Eand F, respectively).
J: antistimulus
minus prostimulus
( 12). M: antistimulus
minus baseline (-9).
and M, a parietal and occipital activation
foci can also be seen. Caudally
located foci (J and 1211)were obtained in Experiment
2.
Letters
Eand F:
In E, F,
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
FIG. 5.
Merg
identify
the ind tvidual foci. Distances
from the mtdline
arc in milhmeters.
wtth the mmus sign tndicattng
tb-Ic IJ~
1L11 hc
18zm&phere.
D: reversal minus
overpraticed,
experiment
1 (~ 1 ). H: reversal minus basehne, experiment
1 ( -4) 1’. antrrtrmulus
mrnuz prostrmu lus, passed subgroup (.\- = 0, y =
10,F
44). Q: prostrmulus
minus baseline, fakd subgroup ( I ~ 7. 1’ = 12, 2 = 39). R and S: reversal menus overpractic- ed-1 ewneriment
- .~-.
3 (3 and 5 for R and S,
respecttvely).
Tand C’: reversal minus baseline. experiment
3 (~ 1 and 7 for Tand I’, respecttvely).
I: reversal minus overt aracticed. experiment
1I(-4).
Y: reversal minus baseline. experiment
1 ( -9). L: reversal minus overpracticcd.
experiment
3 (7). In\<>/\: posttton ofthe I,.~,,,...~.
n~v;fl~t
activation
for foci II
and H located in the ctctnity of the paracingulate
sulcus. In scctrons Q and 1’. tn additron to the focus In the anterior cingulate reg.-..,
.
.._
.._VC
rinn the nenr cortical
portion of the supplementary
motor area was also activated.
HUMAN
ANTERIOR
CORTEX
465
al. ( 1980). However, neither in our study nor in those studies could simultaneous activation of both neocortical and
cingulate arm representations be demonstrated. Such a finding would provide the most direct evidence for the existence
of multiple, distinct arm representations on the medial wall
of the human frontal lobe. Precisely such a pattern of r CBF
changes has recently been found in a PET experiment involving painful stimulation of the left forearm (Coghill et
al. 1992) .2 In this study, the painful (48°C) minus control
(35 “C) subtraction yielded three distinct activation foci on
the medial wall of the frontal lobe. These foci were located
close to the coronal plane defined by the VCA (Y coordinates: + 1, -4, and -6 mm, respectively), one above the
other (2 coordinates: +42, +54, and +66 mm above the
anterior commissure-posterior
commissure plane, respectively) (R. C. Coghill, personal communication).
Thus the
manual foci observed in the reversal and antistimulus tasks
were located in between the most ventral focus and the
intermediate one obtained in the “pain” study. The dorsalmost arm representation activated in the “pain” study did
not seem to be involved in our study.
In experiment I, the oculomotor
OCULOMOTOR
SYSTEM.
task subtraction yielded activation foci within the most anterior part of the ACC, just above the genu of the corpus
callosum. Connections between the frontal eye field (FEF),
representing a primary cortical region for the control of eye
movements3 and the cingulate cortex have not yet been
systematically explored. Nevertheless, in studies in which
retrograde tracers were injected either into the dorsocaudal
portion of Brodmann’s area 8 (Barbas 1988; Barbas and
Mesulam 198 1; Barbas and Pandya 1989) or into physiologically defined FEF (Huerta et al. 1987), labeled neurons
were identified within the rostra1 portion of the ACC, in
front of the genu of the corpus callosum. Furthermore, this
region is also known to send efferents to the supplementary
eye fields (Luppino et al. 1990) and to both the superior
colliculus (Leichnetz et al. 198 1) and the paramedian pontine reticular formation (Leichnetz et al. 1984). Thus the
neuroanatomic findings suggest that the rostralmost part of
the ACC (located around the genu of the corpus callosum)
may be concerned with oculomotor control, and as such
they are consistent with the localization of the oculomotor
foci observed in experiment 1.
SPEECH
SYSTEM.
In the classical study by Penfield and
Welch ( 195 1) , electrical stimulation of the medial surface
of the frontal lobe in epileptic patients yielded vocalization
(or speech arrest) not only from the neocortical portion of
2 Changes in rCBF observed on the medial wall of the frontal lobes
during the painful stimulation could be related to the necessity of suppressing a withdrawal response induced by the nociceptive stimulus.
3 Primary cortical areas involved in oculomotor control in humans
could be revealed by the baseline subtractions (see methods). In both
experiments, oculomotor baseline subtractions yielded rCBF changes in
the depth of the precentral sulcus or the caudalmost part of the superior
frontal gyrus. These findings are in agreement with what has been identified as the human FEF by Penfield and Rasmussen ( 1952) and Fox et al.
( 1985a). In nonhuman primates, the FEF is found along the anterior bank
of the arcuate sulcus, where it overlaps the posterior border of Brodmann’s
area 8 with area 6 (Stanton et al. 1989). Interestingly, rCBF changes were
found in the precentral sulcus not only in the oculomotor baseline subtractions but also in the manual between-tasks subtraction (experiment 2).
This finding agrees well with the fact that the FEF is adjacent to the hand
premotor region ( Rizzolati et al. 1988).
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
within the dorsal portion of the caudal ACC. In the rostrocaudal direction, the foci were localized from 10 mm in
front of the VCA (focus L) to 7 mm behind the VCA (focus
0). Along the dorsoventral axis, the foci were mapped onto
the region beginning ventrally at the level of the cingulate
sulcus (Fig. 4, focus I) and extending dorsally to the level
defined by the caudalmost part of the paracingulate sulcus
(Fig. 4, foci G and 0, see also Fig. 3). The localization of
this “hand’‘-related
area is consistent with the results of
classical stimulation studies carried out in epileptic patients
(Penfield and Jasper 1954; Penfield and Rasmussen 1952;
Penfield and Welch 195 1; Talairach and Bancaud 1966).
In those studies, movements could be elicited not only from
the medial frontal gyrus (medial area 6) but also from the
dorsal bank of the cingulate sulcus. Classical studies in nonhuman primates confirmed these findings (Penfield and
Welch 195 1; Woolsey et al. 1952). After these pioneering
studies, the concept of the SMA as a functionally homogeneous motor region containing one arm representation and
occupying primarily the medial portion of neocortical area
6 gradually evolved (see, e.g., Wiesendanger 1986). Recent
neurophysiological
and neuroanatomic studies have, however, provided ample evidence for the existence of multiple
arm representations on the medial wall of the monkey frontal lobe, located both dorsally within medial area 6 and
ventrally within the limits of the cingulate sulcus (but without encroaching upon the cortex adjacent to the corpus
callosum, i.e., the cingulate gyrus). For instance, projections to the cervical spinal cord and the arm area of the
primary motor cortex have been shown to originate not
only from the medial portion of area 6, but also from three
distinct subregions of the monkey cingulate cortex (Dum
and Strick 199 1). One group of projecting neurons has
been found in the region of area 24c just rostra1 to the coronal plane defined by the genu of the arcuate sulcus (see Fig.
1). The other two subregions are located caudal to this
plane. One extends for a considerable rostrocaudal distance
(8 mm) within the dorsal bank of the cingulate sulcus, and
the other, smaller, region is located on the ventral bank of
the sulcus (Dum and Strick 199 1). By means of cortical
microstimulation
in the awake monkey, Luppino et al.
( 199 1) elicited arm movements
(mostly contralateral
movements restricted to a single joint) from the caudal and
rostra1 medial area 6, as well as from two subregions of the
ACC located within the cingulate sulcus. A low-threshold
cingulate subregion was located caudal to the coronal plane
defined above (subarea 24d), and a high-threshold subregion was found rostra1 to this plane (subarea 24~). In another study, Shima et al. ( 199 1) recorded unit activity
within the cingulate cortex of monkeys performing either
externally triggered or self-paced wrist movements. Two
distinct arm representations within the cingulate sulcus ( 1
rostra1 and 1 caudal to the coronal plane defined by the
genu of the arcuate sulcus) were again demonstrated.
Thus, in the context of the monkey studies reviewed
above, we believe that the localization of the activation foci
obtained in our manual subtractions corresponds to the
ventral, i.e., cingulate, arm representation. In contrast, activation of the neocortical portion of the SMA, which most
likely corresponds to the dorsal arm representation found
in the monkey, has been demonstrated in PET studies by
Colebatch et al. ( 199 1). Fox et al. ( 1985a). and Roland et
CINGULATE
466
T. PAUS, M. PETRIDES,
A. C. EVANS, AND E. MEYER
Functional
considerations
Besides confirming the prediction related to the somatotopic organization of the ACC, our results emphasize the
importance of concomitant activation of the prefrontal cortex for such a somatotopy to emerge. This finding underscores the fact that the flow of information between, and
local computations
within, anatomically
interconnected
and functionally related cortical areas represent critical factors underlying the emergence of a specific pattern of r CBF
changes. This might be due to the fact that function-related
changes in metabolic activity occur at the level of nerve
terminals (synaptic events) rather than cell bodies (Sokoloff 1991).
The data obtained in experiment 1 provide a clear example of a specific activation pattern. In the oculomotor reversal minus overpracticed subtraction, concomitant activation was observed in the caudal part of the intraparietal
sulcus, the rostra1 portion of the inferior frontal sulcus, and
the rostra1 part of the ACC. By contrast, in the manual task
subtraction, the rostra1 intraparietal sulcus, the caudal inferior frontal sulcus, and the caudal ACC were coactivated.
This difference in the pattern of activated brain regions depending on the output system used is consistent with the
organization of corticocortical connections, not only between the primary motor regions and the ACC (see above)
but also between the intraparietal
sulcus and the lateral
frontal cortex. The rostralmost portion of the intraparietal
sulcus, which is related to the somatosensory system, is
linked to more caudal frontal areas, whereas the more posterior (visuomotor) intraparietal sulcus is connected to more
rostra1 frontal areas (Petrides and Pandya 1984).
The speech subtraction revealed rCBF changes within
the left inferior frontal sulcus, the left frontal pole (area
lo), the intermediate ACC (area 32), and the rostra1 ACC
(area 24). Area 32 is known to be closely interconnected
with both the prefrontal cortex and also the auditory association cortex4 ( Barbas 1988 ) . The dense connections with
the auditory cortex suggest that the intermediate ACC (area
32) may play a more specific role in the control of vocalization and speech (e.g., a feedback-type modulation).
On the
other hand, the connections with the prefrontal cortex
might also imply a close functional relationship between
the two regions. In contrast, the close relationship between
the rostra1 ACC (area 24) and the face representation of the
primary motor cortex points to a more basic role of this
region in motor control. This view is supported by a recent
neurophysiological
investigation
of the monkey ACC
showing that unit activity recorded from the rostra1 portion
of area 24 is related not only to vocalization but also to
orofacial movements, such as jaw opening or tongue protrusion (West and Larson 1992).
In the overpracticed and prostimulus tasks, the motor
responses were executed in a more automatic way. A different pattern of rCBF changes within the frontal cortex now
resulted. In addition to the primary motor cortical areas,
activation foci were obtained in the SMA or the inferior
frontal gyrus. This was the case in the oculomotor (SMA,
experiments 1 and 2) and the speech (SMA, experiments 1
and 3; inferior frontal gyrus, experiment 2) subtractions. By
contrast, in the manual overpracticed (or prostimulus)
minus baseline subtraction, task-specific activation remained localized to the dorsal portion of the caudal ACC.
The neocortical portion of the SMA that was found to be
activated in previous studies requiring finger movements
(Colebatch et al. 199 1; Fox et al. 1985a; Roland et al. 1980)
was probably not involved in this study. Two groups of
activation foci could be distinguished, however, within the
caudal cingulate region. One of those was located just behind and the other just in front of the vertical plane traversing the anterior commissure. The posterior group was obtained in the baseline subtractions (experiment 2), whereas
the two most anterior foci were found in the between-tasks
subtractions ( experiments 1 and 2) ( see Fig. 3 ) .
These two groups of manual foci may represent two functionally distinct subregions within the caudal ACC. This
suggestion would be consistent with the fact that there are
clear differences between the rostra1 and the caudal arm
representations of the monkey cingulate cortex. The stimu4 In both experiments 1 and 2, the speech baseline subtractions yielded
rCBF changes within the superior temporal gurus and/or sulcus.
Downloaded from http://jn.physiology.org/ by 10.220.33.4 on April 29, 2017
the SMA, but also from the dorsal bank of the cingulate
sulcus. The speech between-tasks subtraction in experiment 1 revealed a significant change in rCBF, the maximum of which was localized within the paracingulate sulcus (see Fig. 5, focus D). This is even more apparent in the
baseline subtraction using the same active condition (reversal minus baseline) (see Fig. 5, focus H) and in the replication study (Fig. 5, foci R-U). In experiment 2, a significant
rCBF change within this region was obtained in the passed
(antistimulus
minus prostimulus subtraction) and failed
(prostimulus minus baseline) group. Thus most of the activation observed in relation to speech was localized between
the cingulate and paracingulate sulci and extended in the
rostrocaudal direction from 22 mm (focus D) to 10 mm
(focus p)’ in front of the VCA ( see Fig. 3). The relative
position of hand- and speech-related foci, the latter being
located rostra1 to the former, is consistent with the results of
the PET study by Frith et al. ( 199 1) and, to some extent,
with the stimulation study by Fried et al. ( 199 1; see, e.g.,
patient 12).
Work with nonhuman primates has demonstrated that
vocalization can be elicited by electrical stimulation of the
rostra1 portion of the ACC [ for review, see Sutton and Jurgens ( 1988) and Vogt and Barbas ( 1988)]. This region
comprises area 32, the rostra1 portion of area 24, and the
subcallosal area 25. Neurons in this physiologically defined
vocalization region project directly to the periaqueductal
grey, a pontomesencephalic
phonation area ( Muller-Preuss
and Jurgens 1976). The rostralmost part of area 24 is linked
to the face representation of the primary motor cortex (Jurgens 1976; Morecraft and Van Hoesen 1992; Muakkassa
and Strick 1979). Reciprocal connections exist between
areas 24 and 32 (Vogt and Barbas 1988). As pointed out
above, area 32 in the human brain is not limited to the
rostra1 part of the ACC but extends caudally, occupying an
intermediate position between the dorsal tier of area 24 and
the neocortical areas 6,8, and 9. The intermediate group of
the speech-related activation foci obtained in our study is
most likely located within area 32, whereas the rostra1
group ( foci X-Z ), found in the same speech subtractions,
appears to be located in the rostralmost part of area 24.
HUMAN
ANTERIOR
CORTEX
467
in facilitation of the execution of the appropriate responses
and/or suppression of the inappropriate ones.
We thank the staff of the McConnell
Brain Imaging Center for technical
assistance, and Drs. A. Gjedde, G. Luppino,
and B. Milner for comments
on the manuscript.
This work was supported
by the McDonnell-Pew
Program in Cognitive
Neuroscience
and by the Medical Research Council (Canada)
Special Project SP-30 Grant (coordinator:
Dr. A. Gjedde).
Address for reprint requests: T. Paus, Montreal
Neurological
Institute,
3801 University
St., Montreal,
Quebec H3A 2B4, Canada.
Received
15 September
1992; accepted
in final form
17 March
1993.
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lation threshold for eliciting movement is lower in the cauda1 arm representation than in the rostra1 one (Luppino et
al. 199 1). Similarly, unit activity recorded from the caudal
arm region is not as complex as that recorded from the
rostra1 one (Shima et al. 199 I). The connectivity of these
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projections to the spinal cord, the primary motor cortex,
and the caudal part of the SMA (medial area 6aa). On the
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to the motor apparatus, whereas the anterior one is rather
involved in some aspects of higher-order motor control.
The results obtained in this study support the notion of a
multiplicity
of motor regions on the medial wall of the frontal lobe. These regions are organized in a distinct way in
terms of 1) the output system involved (somatotopy) and
2) the specific type of motor control exercised. The somatotopic organization reflects the existence of separate skeletal
and oculomotor channels linking different levels of the motor system (Alexander et al. 1990). The specific functional
contribution of a given region is probably related to its connectivity with nonmotor regions of the brain. A shift in the
activation pattern can be brought about by changing the
task requirements. In the present study, the human ACC
was activated mainly when the subject was forced to choose
from a set of competing responses, rather than relying on
well-established stimulus-response
associations (see also
Berman et al. 199 1; Corbetta et al. 199 1; Deiber et al. 199 1;
Frith et al. 199 1; Pardo et al. 1990; Raichle et al. 199 1).
Animal data concur with this notion in that both electrophysiological correlates of a specific behavior and the effect
of lesions to the ACC diminish as the animal becomes overtrained (Gabriel 1990; Pribram et al. 1962).
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such selection are carried out within the lateral prefrontal
cortex (Petrides 1989) and thence communicated
to the
ACC. The concomitant activation within the lateral prefrontal cortex and the ACC observed in this and other (see
above) PET studies is consistent with this view. Second,
there is the challenge brought about by the necessity to modify behavior in new and unpredictable situations. This may
activate nonspecific modulatory systems (e.g., the mesocortical dopaminergic system), which target, among other
regions, the ACC. We speculate that, at the level of the
ACC, subcortical nonspecific systems modulate the processing of cognitive information coming from the lateral prefrontal cortex. In this fashion, the ACC may contribute to
the funneling of cognitive commands to the motor structures. At the operational level, such a process would result
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