Fast Reaction to Different Sensory Modalities Activates Common
Fields in the Motor Areas, but the Anterior Cingulate Cortex is
Involved in the Speed of Reaction
Naito, Eiichi, Shigeo Kinomura, Stefan Geyer, Ryuta Kawashima,
Per E. Roland, and Karl Zilles. Fast reaction to different sensory
modalities activates common fields in the motor areas, but the anterior
cingulate cortex is involved in the speed of reaction. J. Neurophysiol.
83: 1701–1709, 2000. We examined which motor areas would participate in the coding of a simple opposition of the thumb triggered by
auditory, somatosensory and visual signals. We tested which motor
areas might be active in response to all three modalities, which motor
structures would be activated specifically in response to each modality, and which neural populations would be involved in the speed of
the reaction. The subjects were required to press a button with their
right thumb as soon as they detected a change in the sensory signal.
The regional cerebral blood flow (rCBF) was measured quantitatively
with 15O-butanol and positron emission tomography (PET) in nine
normal male subjects. Cytoarchitectural areas were delimited in 10
post mortem brains by objective and quantitative methods. The images of the post mortem brains subsequently were transformed into
standard anatomic format. One PET scanning for each of the sensory
modalities was done. The control condition was rest with the subjects
having their eyes closed. The rCBF images were anatomically standardized, and clusters of significant changes in rCBF were identified.
These were localized to motor areas delimited on a preliminary basis,
such as supplementary motor area (SMA), dorsal premotor zone
(PMD), rostral cingulate motor area (CMAr), and within areas delimited by using microstructural i.e., cytoarchitectonic criteria, such as
areas 4a, 4p, 3a, 3b, and 1. Fields of activation observed as a main
effect for all three modalities were located bilaterally in the SMA,
CMAr, contralateral PMD, primary motor (M1), and primary somatosensory cortex (SI). The activation in M1 engaged areas 4a and 4p and
expanded into area 6. The activation in SI engaged areas 3b, 1, and
extended into somatosensory association areas and the supramarginal
gyrus posteriorly. We identified significant activations that were specific for each modality in the respective sensory association cortices,
though no modality specific regions were found in the motor areas.
Fields in the anterior cingulate cortex, rostral to the CMAr, consistently showed significant negative correlation with mean reaction time
(RT) in all three tasks. These results show that simple reaction time
tasks activate many subdivisions of the motor cortices. The information from different sensory modalities converge onto the common
structures: the contralateral areas 4a, 4p, 3b, 1, the PMD, and bilaterally on the SMA and the CMAr. The anterior cingulate cortex might
The costs of publication of this article were defrayed in part by the payment
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be a key structure which determine the speed of reaction in simple RT
tasks.
INTRODUCTION
Primates have three major motor zones: the primary motor
zone, the supplementary motor zone, and the premotor zone.
Further subdivisions of these zones have been prompted by
recent anatomic and physiological studies in monkeys and man
(Roland and Zilles 1996). The premotor zone (PM) is now
subdivided into at least two areas, a dorsal PMD and a ventral
PMV (Barbas and Pandya 1987; Crammond and Kalaska 1994;
Kurata and Hoffman 1994; Matelli and Luppino 1992; Matelli
et al. 1985). Similarly a subdivision of the supplementary
motor zone into a pre-SMA and SMA proper has been proposed (Luppino et al. 1991; Matsuzaka et al. 1992; Zilles et al.
1995). In addition to the three classic motor zones, a cingulate
motor zone was described that now is subdivided into a rostral
cingulate motor area (CMAr), a caudal cingulate motor area
(CMAc) (Dum and Strick 1991; Matelli et al. 1991; Shima et
al. 1991). Many of these motor areas have neurons that fire
when voluntary movements are triggered by sensory stimuli. In
the classical primary motor zone MI, the same neurons can be
triggered by somatosensory, visual and auditory stimuli
(Lamarre et al. 1983; Salinas and Romo 1998). In the SMA,
some neurons fire to all three modalities but with clear preferences for one sensory modality (Tanji 1994; Tanji and Kurata
1982). In the PMV and PMD, the majority of neurons fire
nondifferentially with respect to sensory modality (Kurata and
Tanji 1986). Little is known about the sensory preference of
neurons in the remaining motor areas. These studies raise the
question of how sensory information from different modalities
address the motor areas and which motor areas are active when
a movement is triggered by signals from different sensory
modalities.
In humans, activations of what has been hypothesized to be
MI, SMA, and PM have been described during various types of
voluntary movements, although there have been no systematic
studies of the activation of various motor areas when simple
voluntary movements are triggered by different sensory sig-
0022-3077/00 $5.00 Copyright © 2000 The American Physiological Society
1701
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EIICHI NAITO,1,2 SHIGEO KINOMURA,3 STEFAN GEYER,4 RYUTA KAWASHIMA,3 PER E. ROLAND,1 AND
KARL ZILLES5
1
Department of Neuroscience, Division of Human Brain Research, The Karolinska Institute, 171 77 Stockholm, Sweden;
2
Institute of Equilibrium Research, Gifu University School of Medicine, Gifu 500; 3Department of Nuclear Medicine and
Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980, Japan; 4Department of
Neuroanatomy and C. and O. Vogt Institute for Brain Research, University of Düsseldorf, D-40001 Düsseldorf; and
5
Institute of Medicine, Research Center Jülich, D-52425 Jülich, Germany
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NAITO, KINOMURA, GEYER, KAWASHIMA, ROLAND, AND ZILLES
METHODS
Subjects and physiological procedures
The study was approved by the Ethics Committee of the Karolinska
Hospital and the Radiation Safety Committee of the Karolinska Institute and Hospital, and carried out following the principles and
guidelines of the Declaration of Helsinki 1975. Nine healthy male
volunteers (aged 20 –32 yr) participated in the study. They were all
right-handed except for one ambidextrous person. The subjects rested
comfortably in a supine position and had their heads fixed to the
scanner by a stereotaxic helmet (Bergström et al. 1981), which also
was used for fixation during the magnetic resonance imaging (MRI)
scan. Each subject had a catheter placed into the right brachial vein for
tracer administration and another inserted, under local anesthesia, into
the left radial artery for the measurement of arterial radioisotope
activity and partial pressure of arterial CO2 (PaCO2). All subjects had
an electroencephalogram (EEG) recorded with four needle electrodes
located at the F3, F4, P3, and P4 positions according to the international 10/20 system (reference at Cz). The degree of ␣-blockade in the
EEG, indicating increased alertness, was assessed as the time period
of the PET measurement having faster activity than 14 Hz in the EEG
channels from the posterior leads. All subjects had predominant ␣
rhythm in the rest state. Eye movements were recorded with four
silver-disk electrodes, placed at the outer orbital canthuses (reference
at Cz). The arterial PaCO2 was measured twice during each PET scan.
The background illumination in all conditions was 0.27 cd/m2. The
subjects were adapted by a 9-min exposure to this level before each
PET scan. The order of the rest and test conditions was randomized
after a balanced randomized schedule.
Activation tasks
Four PET measurements were made on each subject. These were
rest, auditory reaction time (Aud-RT), somatosensory reaction time
(Som-RT), and visual reaction time (Vis-RT).
In rest, as defined by Roland and Larsen (1976), each subject was
instructed to keep his eyes closed and not to move. The subject held
a combined response key and somatosensory stimulator in his right
hand. The tip of the right index finger rested on a polyvinyl plate in
which a 11-mm-diam hole was drilled. The thumb in an opponent
position relative to the other fingers was resting on a mouse button
attached to the stimulator. The subjects received a warning 30 s before
the start of the injection of tracer that “the measurement would start in
30 s.” Before the actual measurement, sham injections (no tracer)
were made and all measurement procedures were performed to habituate the subjects to the scanning conditions. In the reaction time tasks,
the subjects got a similar warning. Thirty seconds later, 15O-butanol
was injected and the reaction time task started. This continued for
200 s.
In the auditory reaction time task, (Aud-RT), the subjects listened
to a pure tone of 530 Hz (baseline) at 80 dB (sound pressure level)
through earphones attached bilaterally inserted into the fixation helmet. The tone frequency changed abruptly to 1,530 Hz for 1,000 ms,
after which the frequency returned to baseline for a time period of
1,000 –3,000 ms. The subjects had their eyes open and fixated a 3°
visual angle yellow monochrome circle 0.8 cd/m2 displayed on a
video monitor. The task was to press the response key held in the right
hand with the thumb as soon as possible. The movement was a simple
thumb opposition.
In the visual reaction time task (Vis-RT), the subjects kept their
eyes open and fixated the yellow circle described in the preceding
paragraph. At random intervals ranging from 1,000 to 3,000 ms, the
luminance of the circle suddenly increased to 14.5 cd/m2 for 1,000 ms.
The task was to press the response key held in the right hand with the
thumb as soon as possible.
In the somatosensory reaction time task (Som-RT), a 2-mm-diam
stylus suddenly protruded through the 11-mm-diam hole and indented
the tip of the right index finger. The rise time to maximal amplitude
was 15 ms in free air. At interstimulus intervals ranging from 1,000 to
3,000 ms in a random manner, the stylus was not in contact with the
skin, but suddenly, controlled by a solenoid, the stylus indented the tip
of the index finger by 2.8 mm for 1,000 ms. During the somatosensory
reaction time task, the subjects had their eyes open and fixated on the
yellow circle. The task was to press the key as soon as possible when
the subject felt the indentation on his right index finger.
In all reaction-time tasks, reaction times between 121 and 500 ms
were included in the analysis, reaction times ⬎500 ms were discarded
(misses). The reason was that human subjects usually easily respond
to an external stimulus within 500 ms. The 500 ms was far longer than
each mean RT ⫹3 SD (see Table 1). Because reaction times of ⬍120
ms occur only as rare exceptions in adults (Woodworth and Schlos-
1. Physiological and response measurements during all
conditions for 9 subjects
TABLE
Rest
Aud-RT
Som-RT
Vis-RT
Alpha blockade, %
EEG
78.1 ⫾ 17.1 80.9 ⫾ 17
79.7 ⫾ 21.1 90.1 ⫾ 8.4
Global CBF,
⫺1
ml 䡠 100 ml 䡠
min⫺1
55.9 ⫾ 7
58.9 ⫾ 11.3 61.0 ⫾ 7.5 60.1 ⫾ 7.2
Correct response,
%
—
97.2 ⫾ 3.3 94.3 ⫾ 5.6 98.3 ⫾ 2.6
Mean reaction
time, ms
—
275.4 ⫾ 25.5 283.4 ⫾ 27.6 306.1 ⫾ 33.3
Values are means ⫾ SD. Aud-RT, Som-RT, and Vis-RT, auditory, somatosensory, and visual reaction times.
Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017
nals. As far as subdivision of motor zones in human is concerned, Dettmers et al. (1995), Jenkins et al. (1994), Kawashima et al. (1993), Paus et al. (1993), and Stephan et al.
(1995) have described activation of the cortex in or near the
cingulate sulcus. However, the human counterparts of the
primate CMAr and CMAc have not yet been identified due to
lack of anatomic evidence. Similarly the human counterparts of
PMV, PMD, and pre-SMA are also unidentified. First delineations of these areas based on combined architectonic and
transmitter receptor studies were reported recently (Zilles et al.
1995, 1996). The human primary motor area has been subdivided into two regions, areas 4a and 4p (Geyer et al. 1996). The
present study was undertaken to examine which of these many
motor areas would be activated in coding a simple motor
output triggered by sensory signals from somatosensory, auditory and visual modalities and which motor areas would be
specifically active in reaction to a signal from each sensory
modality.
It is not clear yet which neural substrates determine the
speed of reaction to stimuli. The length of the reaction time
(RT) is determined by many factors, such as attention, complexity of stimuli, conduction time of the signal, and so on. For
example, the RT is shorter when the subject pays attention to
a stimulus and a choice RT is longer than a simple RT. The
differences in RT between the sensory modalities set aside, it
is uncertain whether further prolongation of the RT would be
caused by the neuronal modulations in the sensory processing
stage or in the motor output stage. We therefore also examined
which neural structures would be involved in the speed of
reaction in a simple reaction time task and whether these
structures are engaged in the sensory processing stage or the
motor output stage.
MOTOR FIELDS OF THE HUMAN CEREBRAL CORTEX
berg 1951), responses ⬍120 ms were classified as false alarms. The
mean RT was calculated for 200 s of the RT recording. In the three
reaction time measurements, none of the subjects broke fixation. The
percent correct responses defined as [total stimuli ⫺ (false alarms ⫹
misses)] ⫻ 100/total stimuli, are shown in Table 1. Thus the differences between the rest and the reaction time conditions were open
eyes, fixation on the yellow circle, and the increased vigilance and
attention.
PET scanning, MRI scanning, and data processing
profiles by the Mahalanobis distance measure (Schleicher et al. 1999).
The Mahalanobis measure is a distance measure for multivariate
vectors (Mahalanobis et al. 1949). Maximal distances occur between
profiles that lie on opposite sites of an areal border (Schleicher et al.
1999). Borders between areas are defined at cross laminar planes
where the Mahalanobis measure is significant (Hotelling’s T2 test,
P ⬍ 0.05) (Schleicher et al. 1999) (For other applications and documentation of this method, see Amunts et al. 1996; Geyer et al. 1996,
1997; Larsson et al. 1999).
In addition to defining the borders between areas from neuronal
density profiles, borders also were determined on the basis of densities
of muscarinic M2 receptors and serotonin-2 (5-HT-2) receptors with
an similar approach as described in detail in Geyer et al. (1996, 1997).
The T2 measure showed statistically significance in exactly those
places where significant differences were found in the multivariate
(Mahalanobis) measures of neuronal densities (Geyer et al. 1996,
1997). In this way, areas 4a, 4p, 3a, 3b, and 1 were defined by
objective statistical measures in 10 brains. The images of the histological sections of each brain were corrected for distortions and
shrinking during the cutting and fixation by the software of Schormann et al. (1995) and subsequently matched with the 3D FLASH MR
images of the same brain. Each cytoarchitectural brain image then was
transformed into the standard anatomic format of the HBA (Shormann
et al. 1995). Subsequently the functional (PET) images were transformed into the standard anatomic format of the HBA. The accuracy
of the HBA software was described in Roland et al. (1994). In this
way, the cytoarchitectural brain images and the cluster images showing the statistically significant activations were transferred to the same
3D standard anatomic space.
The cytoarchitectural areas were filtered with a 5-mm Gaussian 3D
filter to have approximately the same spatial resolution as the cluster
images. The activated fields were then compared with the spatial
extent of each cytoarchitectural area defined as the 30% population
map of that area, i.e., the voxels in which that area can be found in
30% of the postmortem brains (Roland and Zilles 1998). We analyzed
which population threshold would maintain the criterion that adjacent
cytoarchitectural areas which abut in individual brains should also
abut in the map of cytoarchitectural areas made from the population
maps. A 30% threshold was found to fulfil this criterion without
producing overlaps between adjacent areas. Thus each cytoarchitectural area was represented as the volume corresponding to the volume
occupied by the 30% population map. Then the volumes of intersection between clusters and cytoarchitectural areas were calculated
(Tables 2– 4). The PMD, SMA, and CMAr were defined preliminarily
by Roland and Zilles (1996).
RESULTS
Psychophysiological measurements
The degree of ␣-blockade in the EEG was increased only
during the visual RT task, although the subjects had their eyes
open in all three tasks (Table 1; P ⬎ 0.2). The subjects fixated
the yellow monochrome circular spot in all three reaction time
tasks. The electrooculogram (EOG) showed only 0.2-Hz eye
blinks in all tasks. There was no significant correlation between
the percentage of ␣-blockade and the global cerebral blood
flow (gcbf; r ⫽ ⫺0.06 for Aud-RT, r ⫽ ⫺0.51 for Som-RT,
r ⫽ ⫺0.39 for Vis-RT, respectively). Neither was the global
blood flow correlated with the percentage of correct responses
nor the RTs. The RTs in individuals followed the same pattern
as the mean RTs. One-factorial ANOVA was done. The
ANOVA showed significant differences between three RTs
[F(2,12) ⫽ 4.14, P ⬍ 0.05]. A test by Ryan’s method for
multiple comparisons among means showed the visual reaction
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The methods for rCBF measurement were as described in a recent
study (Hadjikhani and Roland 1998). Each subject, equipped with a
stereotaxic helmet, had a magnetic resonance tomogram and PET. The
magnetic resonance tomogram was a spoiled gradient echo (SPGR)
sequence obtained with a 1.5 T General Electric Signa scanner, TE ⫽
5 ms, TR ⫽ 21 ms, flip angle ⫽ 50°, giving rise to a three-dimensional
(3D) volume of 128 ⫻ 256 ⫻ 256 isotropic voxels of 1 mm3 (field of
view 256 mm). The rCBF was measured with an eight-ring, 15-slice
PET camera (PC2048 –15B Scanditronix) in plane spatial resolution
of 4.5 mm and an interslice distance of 6.5 mm. 15O-butanol (70 mCi)
was injected intravenously as a bolus. The arterial input function was
monitored continuously, and the rCBF was calculated on the basis of
the data sampled from 20 to 80 s after injection (Roland et al. 1993).
The sinograms were reconstructed with a 4-mm Hanning filter. The
reconstructed images were subsequently filtered with a 5-mm 3D
isotropic Gaussian filter to yield a final full-width half-maximum of 6
mm for the images.
The images were anatomically standardized with the Human Brain
Atlas (HBA) (Roland et al. 1994). Each individual’s MRI of the brain
was transformed to the standard anatomic format of the HBA, and
subsequently the PET images were transformed with the HBA to
standard brain format. The anatomically standardized images had a
voxel size of 2 ⫻ 2 ⫻ 2 mm3. Statistical analysis was done with a
general linear model (GLM) (Ledberg et al. 1998). The design matrix
had subjects and tasks as factors. The main effect of reaction time was
contrasted to rest. Subsequently the RT of one modality was contrasted to the two other modalities. Both z threshold and cluster size
for significant activations in the whole brain (P ⬍ 0.05) were determined by 3,000 Monte Carlo simulations (Ledberg et al. 1998). This
simulation provided the thresholds z ⫽ 2.58, and cluster size ⫽ 712
mm3 in the whole brain. Correlation coefficients were calculated
between mean RT and rCBF voxel by voxel in each task. A t-test was
done according to the null hypothesis that the correlation coefficients
were equal to 0. The t-image had lower degrees of freedom, hence
only clusters ⬎800 mm3 having t ⬎2.5 were significant.
The activations covering the sensory-motor cortices were examined
for localization within the objectively cytoarchitecturally defined
areas 4a, 4p, 3a, 3b, and 1 (Geyer et al. 1996; Roland et al. 1997;
Schleicher et al. 1999). The cytoarchitectural regions were delineated
with observer-independent techniques in 10 post mortem brains by the
method described in detail by Schleicher et al. (1999). The areas were
delineated in cell-body-stained coronal sections of the post mortem
brains. The brains were fixed in 4% formalin or Bodian’s solution,
embedded in paraffin, serially cut into coronal sections 20 ␮m thick,
and stained for cell bodies (Merker 1983). Before the histological
procedures, high-resolution 3D FLASH MR images with a voxel size
of 1 ⫻ 1 ⫻ 1.17 mm were obtained from each brain.
The borders of areas 4a, 4p, 3a, 3b, and 1 were determined on each
60th section. The gray level index (GLI) was measured as an expression of the volume density of cell bodies with a computer-controlled
image analyzer (Schleicher et al. 1999). Profiles of the GLI were
measured from the border between layers I and II to the cortex/white
matter boundary. These profiles covered the whole cortical area (for
example area 4a) tightly spaced (200 ␮m) and define the cytoarchitecture in quantitative measures. The measured profiles at one crosslaminar sampling line are compared statistically with the neighboring
1703
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NAITO, KINOMURA, GEYER, KAWASHIMA, ROLAND, AND ZILLES
2. Main effects: active fields and their locations in all RT
tasks contrasted to the rest condition
TABLE
Coordinates of
Center of Gravity
Structures
Left hemisphere
MI, SI*
Area 4a
Area 4p
Area 3b
Area 1
SMA#
x
y
z
Volume, mm3
Mean z Value
38
⫺28
53
4493
845
139
854
896
1980
4.04
⫺2
0
52
4.22
times were significantly longer than the auditory and somatosensory RTs (t ⫽ 2.73, df ⫽ 12, P ⬍ 0.05 for Vis-RT vs.
Aud-RT; t ⫽ 2.15, df ⫽ 12, P ⫽ 0.053 for Vis-RT vs. Som-RT,
respectively; Table 1). The distribution of reaction times of
each of the three modalities was normal (Gaussian) or slightly
log-normal. In the calculation of means and SD, we have
assumed normal distributions. The longer RTs and occasional
misses occurred predominantly in the 10-s interval during
which the tracer was injected. In this case, we excluded all RT
data within this time interval from the analysis.
Main effects of RT tasks
We examined the main effect of doing a reaction time task
by contrasting the Aud-RT, Vis-RT, and Som-RT relative
blood flow measurements with the REST condition. Table 2
shows the two large active clusters observed in all three RT
modalities. One cluster covered the SMAs and part of the
CMAs bilaterally (Fig. 1B). The center of gravity was at y ⫽
0, meaning that both the caudal and rostral CMA were presumably active according to the parcellation of Roland and
Zilles (1996). The other cluster covered the contralateral sensory-motor cortices (Fig. 1A). The large field in the contralateral sensory-motor cortex engaged cytoarchitectural areas 4a,
4p, 3b, and 1. Rostrally it extended into the adjacent area 6
Activation patterns specific to each RT task
We also tested the hypothesis that there might be active
fields in the motor areas that are associated specifically with
only one RT modality. We compared the rCBF of a given RT
modality with the rCBF of the other two RT modalities. Table
3 shows that auditory RT task bilaterally activated the auditory
cortices and that the visual RT task activated the right visual
association cortex; however, no specific regions were active in
the somatosensory RT task. We could not find any modality
specific significant activation in the motor areas.
Correlation between rCBF and RT
We tested the hypothesis whether the rCBF of some cortical
areas might be correlated with the RTs. For all RT modalities
strong negative correlations appeared as fields located in the
anterior cingulate cortex (ACC) (r ⫽ ⫺0.95, df ⫽ 6, P ⬍ 0.01
for Aud-RT; r ⫽ ⫺0.97, df ⫽ 6, P ⬍ 0.01 for Som-RT; r ⫽
⫺0.93, df ⫽ 5, P ⬍ 0.01 for Vis-RT, respectively; Figs. 3 and
4, Table 4). The fields demonstrating the negative correlation
in somatosensory RT did not overlap with the fields associated
with visual RT and auditory RT, neither did the fields of visual
RT and auditory RT overlap. In addition, there were some
fields presumably specifically correlated with the Aud-RT,
Som-RT, and Vis-RT in different parts of the prefrontal cortex.
Table 4 shows the sizes and locations of these fields. Surprisingly mean rCBFs of the SMA cluster and the mean rCBF of
the SI-M1 cluster didn’t show any strong correlation between
the mean RT in any of the RT tasks (Table 4).
DISCUSSION
We have shown that simple RT tasks with reactions to
somatosensory, visual, and auditory stimuli activated the contralateral (left) PMD, M1, SI, SMA, and CMA bilaterally. The
large activation in the contralateral M1 and S1 engaged the
hand regions of the cytoarchitectural areas 4a, 4p, 3b, and 1.
FIG. 1. Common active fields for all three reaction
time (RT) tasks. Fields were superimposed on the
standard brain. A: horizontal section at z ⫽ 52. Bilateral activation of the supplementary motor area
(SMA). Activation also of the contralateral sensorymotor cortex (for details, see Fig. 2). B: sagittal section
at x ⫽ ⫺4, showing the SMA and rostral cingulate
motor area (CMAr) activation.
Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017
MI, primary motor cortex; SI, primary somatosensory cortex; SMA, supplementary motor area; CMA, cingulate motor area. * This is located in areas
4a, 4p, 3b, 1, and extending into area 6 anteriorly (1,351 mm3) and into the
somatosensoy association areas and supramarginal gyrus posteriorly (408
mm3). # This was bilateral and comprised the right as well as the left SMA and
CMA.
(Fig. 2). Caudally the field extended into the adjacent cortex
lining the postcentral sulcus and into the rostral and superior
part of the supramarginal gyrus. The somatosensory and visual
RT tasks also provided significant active fields in the same
locations when each RT was contrasted to the rest condition
(Table 3).
MOTOR FIELDS OF THE HUMAN CEREBRAL CORTEX
1705
negative correlation with the RT, but no such correlation was
found in the motor areas.
In all RT tasks, the subjects viewed a yellow circle on a
video monitor. In contrast, during the rest condition, the subjects had their eyes closed. This fundamental difference did
seem to affect the cortical activation pattern because there was
a small signal in visual area V1 (maximum Z value of 2.84 for
Som-RT contrasted to REST and 3.65 for Aud-RT contrasted
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FIG. 2. Engagement of cytoarchitectural areas 4a (red), 4p (black), 3b
(yellow), and 1 (green) by all 3 RT tasks. Horizontal section at z ⫽ 52.
Rostrally the activation extends into area 6 (PMD), caudally it extends into
somatosensory association areas. Area 3a was not activated.
Specific activations associated with each RT task appeared
only in sensory association cortices and not in the motor areas.
The rCBF in the anterior cingulate cortex showed significant
3. Active fields and their locations in each RT task
contrasted to the rest condition and specific active fields and their
locations in each RT task
TABLE
Coordinates of
Center of Gravity*
Structures
Each RT vs. rest
Aud-RT
Auditory cortex (L)
Auditory cortex (R)
Som-RT
MI, SI (L)
SMA (R)
Vis-RT
SI (L)
SMA (R)
Visual association (R)
Specific
Aud-RT
Auditory cortex (L)
Auditory cortex (R)
Vis-RT
Visual association (R)
Volume,
mm3
Mean z
Value
11
10
728
1936
3.15
3.03
⫺30
1
52
51
4176
1112
3.05
3.11
40
⫺1
⫺27
⫺35
⫺1
⫺53
51
53
⫺11
888
936
1464
3.18
3.09
3.1
49
⫺53
⫺25
⫺20
3
6
3864
2928
3.06
3.03
⫺31
⫺62
⫺11
2568
3.15
x
y
53
⫺59
⫺32
⫺28
39
⫺3
z
(L) indicates the left hemisphere and (R) indicates the right hemisphere.
* From Roland et al. (1994).
FIG. 3. Sagittal sections of the standard brain showing clusters of voxels
significantly negatively correlated with RT. A: auditory RT task. Sagittal
section at x ⫽ ⫺7. Activation of anterior cingulate cortex and the mesial part
of the superior frontal gyrus. B: somatosensory RT task. Sagittal section at x ⫽
⫺5. C: visual RT task. Sagittal section at x ⫽ 3. Fields demonstrating the
negative correlation with the somatosensory RT didn’t overlap with the fields
correlated with visual RT and auditory RT neither did the field correlated with
visual RT and the field correlated with auditory RT overlap.
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NAITO, KINOMURA, GEYER, KAWASHIMA, ROLAND, AND ZILLES
to the REST condition). This V1 signal was, however, not
statistically significant with the cluster-size method. No visual
association cortices were significantly active in the Aud-RT
and Som-RT tasks. Because we had only four conditions per
subject, but no repetitions, this could have reduced the sensitivity.
Because the subjects in all RT tasks held the response key in
their right hand, both in rest and during the RT tasks, the
somatosensory and motor activities associated with holding the
response key should have been cancelled out in the contrasts.
However, because the subjects responded to the stimuli by
pressing the button with their right thumb, the sensory-motor
cortices should be activated somatotopically. The active fields
in the motor areas (SMA, PMD, M1, CMA) might be due to
the preparation for movement, motor set, and movement execution. The present data do not permit one to distinguish
among these possible causes. The active fields in the primary
somatosensory cortex (SI) might be mainly due to the somatic
feedback by pressing the response button. Widener and Cheney
(1997) showed that microstimulation of areas 3b and 1 did not
produce significant postspike facilitation in spike-triggered averages of EMG activity during voluntary movement. This
result suggested that motor output effects from SI frequently
were absent or very weak compared with those of the primary
motor cortex. Neurons in area 3b and 1 showed a directionally
tuned activity during active digit and arm movements (Cohen
et al. 1994; Inase et al. 1989; Prud’homme et al. 1994). We
found activation in the finger-hand representation (Roland
1987a,b) of cytoarchitectural areas 4a, 4p (small), 3b, and 1.
Areas 4a and 4p have somatotopical representations of thumb
(Geyer et al. 1996) as have areas 3b and 1.
Activations in PMD and SMA
The activation in the premotor cortex can be classified as
belonging to PMD (Roland and Zilles 1996). The activation of
PMD as a main effect and the lack of any modality specific RT
activation in PMD is in accordance with a previous single-unit
TABLE
4. Cluster sizes and their locations in anterior cingulate
cortex
Coordinates of
Center of Gravity*
Structures
Aud-RT
Anterior cingulate (R)
Superior frontal (R)
(medial)
Som-RT
Anterior cingulate (R)
Orbitofrontal (L)
Vis-RT
Anterior cingulate (L)
Superior frontal (L)
Frontal pole (R)
Structures
Anterior cingulate
Aud-RT
Som-RT
Vis-RT
SMA
Aud-RT
Som-RT
Vis-RT
MI, SI
Aud-RT
Som-RT
Vis-RT
x
y
z
Volume,
mm3
Mean
t-Value
⫺7
20
34
1024
3.17
⫺8
47
20
2152
3.39
⫺5
6
26
10
25
⫺9
992
888
3.31
3.39
1
31
⫺18
15
37
65
27
25
6
1392
1104
1520
3.32
3.59
3.34
Correlation
Coefficients
df
P Value
⫺0.95
⫺0.97
⫺0.93
6
6
5
⬍0.01**
⬍0.01**
⬍0.01**
⫺0.4
⫺0.5
⫺0.7
6
6
5
⬎0.2
⬎0.2
⬎0.05
6
6
5
⬎0.2
⬎0.1
⬎0.1
0.35
0.57
0.61
Note that the region cerebral blood flow (rCBF) of the anterior cingulate
cortex consistently showed significant negative correlations with mean RT in
all RT tasks. The mean rCBF of the anterior cingulate cortex showed significant negative correlation with RT, and correlation coefficients between rCBF
and mean RT in clusters of the anterior cingulate, SMA, MI-SI. * From Roland
et al. (1994).
Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017
FIG. 4. Correlation between the normalized rCBF of the anterior cingulate
cortex (ACC) and log10 of the mean reaction time of each subject. Normalized
rCBF was calculated by dividing the absolute rCBF by the global cerebral
blood flow (gcbf). Note the strong negative correlation for all 3 modalities.
study showing that the majority of neurons in the PMD fire
nondifferentially with respect to sensory modality (Kurata and
Tanji 1986). Neurons of the PMD discharged more when a
stimulus instructs a limb movement than when the same stimulus instructs a shift in spatial attention or memory (Wise et al.
1992). Set-related neurons, showing sustained activity during
the delay period after presentation of instruction signals, are
predominantly located in the PMD (Kurata 1993; Kurata and
Hoffman 1994). Still other neurons in the PMD showed movement-related activity, which changed immediately before and
during a movement, after a trigger signal (Kurata 1993; Kurata
and Hoffman 1994). From this one may speculate that the
PMD activation was related to the set- and/or movementrelated neuronal activity but not by the attention to the stimuli.
The activation in the SMA is located in the SMA-proper
(Roland and Zilles 1996). Recently the human SMA-proper
was subdivided into two regions: rostral part of the SMA
(SMAr) and caudal part of the SMA (SMAc) (Vorobiev et al.
1998). The activation of SMA in the present study was located
in the mid (y ⫽ 0) part of the SMA (Roland and Zilles 1996).
However, this location was suggested by Picard and Strick
(1996) on the basis of a meta study of Talairach coordinates
from different imaging studies to be the “face” representation
of SMA. Obviously the claim of three medial motor areas
above the cingulate sulcus, pre-SMA, SMAr, and SMAc
(Vorobiev et al. 1998) must be supported by other results such
MOTOR FIELDS OF THE HUMAN CEREBRAL CORTEX
Activations in all three tasks
Our findings suggested that sensory information is processed
in each modality specific sensory association cortex and subsequently converges on the motor areas; SMA, CMA, PMD,
4a, and 4p. Neurons in the M1, SMA, and PMD of other
primates show set- and/or movement-related activities during
limb movements. Zhang et al. (1997) suggested that M1 belongs to a distributed network such that its neural activity
reflects the underlying network dynamics that translate a stimulus representation into a response representation via the activation and application of appropriate S-R mapping rule. It
therefore seems reasonable to describe the activation of these
fields as due to input from other cortical areas and subcortical
sectors processing the sensory stimuli which are relevant in a
motor context.
The auditory, somatosensory, and visual RT tasks activated
nearly all known subdivisions of the motor cortices despite the
simplicity of the motor task. This finding can be interpreted in
two ways. 1) All motor areas are being addressed by afferent
synaptic input from cortical and subcortical structures processing the sensory information. And 2) active fields in the motor
cortices arise as a consequence of synaptic activity originating
from the interconnections between the motor areas themselves
and the afferent input from subcortical motor sectors. This
explanation is to some extent favored by current knowledge
about the cortico-cortical connections of the motor cortices for
which only the somatosensory modality has direct access to the
primary motor cortex (areas 4a and 4p) (Darian-Smith et al.
1993; Stepniewska et al. 1993), whereas the premotor cortical
zone has connections with prefrontal, parietal and cingulate
areas that might process sensory information (Barbas and Pandya 1987; Jones and Powell 1969; Jones et al. 1978; Jürgens
1984; Lu et al. 1994; Muakkassa and Strick 1979; Pandya and
Vignolo 1971).
Correlation between rCBF in anterior cingulate and RT
We found active fields in the anterior cingulate cortex
(ACC), the superior frontal cortex, the orbitofrontal cortex, and
the frontal pole the rCBF of which showed significant negative
correlation with the RTs. The rCBF of the ACC was correlated
particularly strongly with the RTs. The greater the increase of
the rCBF in the ACC, the faster the response. Surprisingly,
there was no such strong correlation between RT and rCBF in
the motor cortices nor in the sensory areas. The cortical fields
correlated with Vis-RT, Som-RT, and Aud-RT did not overlap,
indicating parallel access to this sector of the ACC for the three
senses. The three ACC fields of correlation did not appear as
significantly activated in the main effect contrast probably
because of the range of rCBF in these regions (Fig. 4). The
three fields partly overlapped the position of the field intersection reported in Klingberg and Roland (1997). In that study, the
same part of the ACC was engaged in a simple auditory
working memory tasks and a simple visual working memory
task. When the two tasks were performed simultaneously, the
RTs increased considerably (Klingberg and Roland 1997). The
three fields were also very close to the part of the ACC (1, 24,
24) in which the rCBF was positively correlated with the rCBF
in the medial thalamus and midbrain tegmentum in a vigilance
task (Paus et al. 1997). Taken together, this indicates a role of
this particular sector of the ACC (y ⫽ 15–26) in the speed of
reaction. This sector seems functionally associated with the
midbrain reticular intralaminar thalamic system, known to be
modulating alertness and general attention in awake subjects
(Kinomura et al. 1996).
The technical help of J. Pedersen and W. Pulka was greatly appreciated.
This study was supported by the Volvo Foundation, the Swedish Medical
Research Council, and German Sonderforschungsbereich 194/Project A6. The
correlations between cytoarchitectures and functional fields were funded by
Biotech Grant Bio 96-0177 from the European Union. E. Naito was supported
by the Brain Science Foundation and the Naito Foundation in 1997.
Present address of E. Naito: Faculty of Human Studies, Kyoto University,
Sakyo-ku, Kyoto 606 8501, Japan.
Address for reprint requests: P. E. Roland, Department of Neuroscience,
Division of Human Brain Research, The Karolinska Institute, Berzelius vaeg 3,
171 77 Stockholm, Sweden.
Downloaded from http://jn.physiology.org/ by 10.220.32.246 on June 18, 2017
as differences in neuron or receptor densities and by a complete
(somatotopical) representation of the motor apparatus in single
subjects. Differences in the procedures for bringing data into
Talairach space may produce rather large variations in centers
of gravities or points of maximum activation (Roland et al.
1997). Direct stimulation of the SMA produce movements of
the hand and arm if the stimulation site is close to y ⫽ 0 (Buser
and Bancaud 1967; Chauvel 1976).
The SMA activation extended into the cingulate sulcus in
which several cingulate motor areas presumably exist in humans (Picard and Strick 1996) that are similar to the cingulate
motor areas described in monkeys (Dum and Strick 1991;
Galea and Darian-Smith 1994; Luppino et al. 1991; Roland and
Zilles 1996; Shima et al. 1991). The present activation was
located at a site predominantly activated by simple movements
of the hand (Dettmers et al. 1995; Kawashima et al. 1996;
Larsson et al. 1996; Schlaug et al. 1994; Stephan et al. 1995)
or arm in the meta study of Picard and Strick (1996). According to the localization of the main effect cluster (Fig. 1B), the
activation was located mainly in the caudal part of the cingulate motor zone, but a more definite parcellation of the human
cingulate motor zone is not yet available due to lack of anatomic and uniformly treated high quality functional data.
Some neurons in the SMA in monkeys fire to all three
modalities but with a clear preference for one sensory modality
(Matsuzaka et al. 1992; Tanji and Kurata 1982). SMA neurons
are more sensitive to the stimulus modality compared with PM
neurons. The present findings illustrate that in the SMA proper
and the PMD, the synaptic and neuronal activity associated
with responses to sensory signals is distributed roughly over
the same part of the cortex, making it impossible to distinguish
preferences in neuronal responses with respect to sensory modality within these areas with PET (and fMRI).
The large main effect activation in the sensory-motor region
posteriorly extended into the uppermost and rostral part of the
supramarginal gyrus. This part, laterally to the IPA functional
area (Roland et al. 1998) and posterior to the cortex lining the
postcentral sulcus (Bodegard et al. 1998) has been active in
previous studies in which subjects were in somatosensory
contact with objects and made a manual response (Bodegard et
al. 1998; Hadjikhani and Roland 1998; Ledberg and Roland
1998; Roland et al. 1998; Seitz et al. 1991).
1707
1708
NAITO, KINOMURA, GEYER, KAWASHIMA, ROLAND, AND ZILLES
Received 15 January 1999; accepted in final form 28 September 1999.
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