1Department of Physiology and 2Department of Radiology, Hirosaki University School of Medicine; and 3Division of Radiology, Hirosaki University Hospital, Hirosaki 036-8562, Japan
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ABSTRACT |
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Kurata, Kiyoshi, Toshiaki Tsuji, Satoshi Naraki, Morio Seino, and Yoshinao Abe. Activation of the Dorsal Premotor Cortex and Pre-Supplementary Motor Area of Humans During an Auditory Conditional Motor Task. J. Neurophysiol. 84: 1667-1672, 2000. Using functional magnetic resonance imaging (fMRI), we measured regional blood flow to examine which motor areas of the human cerebral cortex are preferentially involved in an auditory conditional motor behavior. As a conditional motor task, randomly selected 330 or 660 Hz tones were presented to the subjects every 1.0 s. The low and high tones indicated that the subjects should initiate three successive opposition movements by tapping together the right thumb and index finger or the right thumb and little finger, respectively. As a control task, the same subjects were asked to alternate the two opposition movements, in response to randomly selected tones that were presented at the same frequencies. Between the two tasks, MRI images were also scanned in the resting state while the tones were presented in the same way. Comparing the images during each of the two tasks with images during the resting state, it was observed that several frontal motor areas, including the primary motor cortex, dorsal premotor cortex (PMd), supplementary motor area (SMA), and pre-SMA, were activated. However, preferential activation during the conditional motor task was observed only in the PMd and pre-SMA of the subjects' left (contralateral) frontal cortex. The PMd has been thought to play an important role in transforming conditional as well as spatial visual cues into corresponding motor responses, but our results suggest that the PMd along with the pre-SMA are the sites where more general and extensive sensorimotor integration takes place.
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INTRODUCTION |
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In a conditional motor behavior,
desired motor responses are indicated by arbitrary sensory cues, such
as colors, which are not primarily associated with the responses. Such
behavior is extremely important in humans, because our actions are
frequently instructed and guided by arbitrary cues, like traffic
signals or language. In monkeys, it has been reported that the dorsal premotor cortex (PMd) is essential for performing conditional motor
behavior (Kurata and Hoffman 1994; Kurata and
Hoshi 1999
; Mitz et al. 1991
; Passingham
1985a
,b
; Petrides 1987
). The ventral premotor cortex (PMv) plays only a minor role in the behavior but
contributes to prism adaptation while reaching toward visuospatial targets (Kurata and Hoshi 1999
). As in monkeys, positron
emission tomography (PET) studies revealed that the PMd of
humans is activated during learning and performance of conditional
motor behavior (Deiber et al. 1997
; Grafton et
al. 1998
; Hazeltine et al. 1997
).
In those studies of humans and monkeys, visual stimuli were used as the
conditional cues. However, it is likely that cues with a nonvisual
modality, namely auditory cues, also guide conditional motor behavior.
Supporting this view, the activity of monkeys' PMd neurons was
reported to show sustained changes during the preparation period for
forthcoming movements following auditory instruction cues
(Kurata 1993; Weinrich and Wise 1982
;
Wise et al. 1996
). In humans, patients with premotor
(PM) lesions have deficits in conditional association of not only
visual, but also tactile and auditory stimuli with movements
(Halsband and Freund 1990
). Furthermore, the PMd is
activated when spatially (but not conditionally) presented auditory and
visual cues indicate the laterality of hand movements (Iacoboni
et al. 1998
). If the PMd is activated by arbitrary auditory
cues for conditional motor behavior, this indicates that the area may
play a more extensive role in sensorimotor integration than has
previously been considered. In addition to the PMd, we are particularly
interested in the presupplementary motor area (pre-SMA) of humans,
because this area is also activated during learning of conditional
visuomotor behavior (Deiber et al. 1997
) and visuomotor
associations (Sakai et al. 1999
).
Thus, the aim of this study was to measure the regional cerebral blood flow (rCBF) to examine whether the PMd and pre-SMA of humans play a role in conditional motor behavior with arbitrary auditory cues. We therefore compared functional magnetic resonance imaging (fMRI) scanned while performing two tasks; one required conditional association of auditory cues and appropriate motor responses, and the other combined the same movements and the same auditory cues, but without the conditional association.
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METHODS |
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Five healthy right-handed volunteers (3 males and 2 females,
21-26 years old) participated in this study. None had any history of
neurological or psychiatric disorders, and all gave informed consent
before the experiment. They were trained to perform an auditory
conditional motor task shortly before the scan. In the task, 330 or 660 Hz tones (100-ms duration) were randomly selected and presented to the
subjects every 1.0 s through earphones with a sound pressure level
equal to or greater than the maximal MRI noise level. The low and high
tones were the signals to initiate three successive opposition
movements of the right thumb and index finger or the right thumb and
little finger, respectively (Task 1). As a control task (Task 2), the
same subjects were asked to alternate the two opposition movements in
response to randomly selected tones presented at the same interval. In
our preliminary fMRI study, it was confirmed that cortical motor areas,
including the PMd and pre-SMA, were activated by the rate and number of taps. Each subject was naïve to Tasks 1 and 2 and practiced the tasks for about 3-5 min each immediately before the MRI scan. In the
experimental session, the two tasks were alternated for 30 s (30 trials), with an intervening rest period (Rest) of 30 s (30 tone
signals). In the Rest condition, the same tones were presented as in
the two tasks. Thus, one session consisted of four epochs (Task 1, Rest, Task 2, and Rest); six sessions were repeated in succession.
Throughout the six sessions, fMRI scans were taken continuously with a
whole-body 1.5 Tesla scanner (Siemens Magnetom Vision 4). A video
camera was used to monitor the subject's hand movements during the
scan. Straps around the forehead and jaw were used to minimize head
motion. Before obtaining the fMRI data, three sagittal T1-weighted
images around the midline and 10 horizontal T1-weighted images parallel
to the line between the anterior and posterior commissures were scanned
[repetition time (TR) = 300 ms, echo time (TE) = 14 ms, flip
angle (FA) = 90°, slice thickness = 3.0 mm, slice gap = 0.3 mm, imaging matrix = 256 × 256, and field of view
(FOV) = 256 × 256 mm] to identify the cortical areas with
reference to the central and precentral sulci, and a vertical line
traversing the anterior commissure (VCA line) in Talairach coordinates
(Talairach and Tournoux 1988). Five slices from the 10 T1 images were used to obtain fMRI images of the primary motor cortex
(MI), the primary somatosensory cortex (SI), PMd, SMA, and pre-SMA (see
Fig. 1). After identifying the cortical
sulci in the T1 images, each functional image was obtained using a
single-shot echo-planar imaging (EPI) sequence. Each set of functional
images consisted of five axial T2*-weighted images (TE = 66 ms,
FA = 90°, slice thickness = 3.0 mm, slice gap = 0.3 mm, an imaging matrix = 128 × 128, and FOV = 256 × 256 mm). Since a single-shot EPI sequence was used in each scan,
there was no TR. The acquisition time of a five-image set was 0.82 s. An image set was acquired every 3 s throughout the entire scan,
so that 10 sets were obtained in each 30 s epoch making up Task 1, Task 2, and Rest. Thus, 240 image sets were obtained for each subject during the six sessions, each set consisting of four epochs (Task 1, Rest, Task 2, and Rest). No event-related scans were attempted, so the
interval between the cue and the timing of the scan was not
synchronized in this study. After scanning the functional images, 50 T1-weighted images of the whole brain were collected (TR = 300 ms,
TE = 14 ms, FA = 90°, slice thickness = 3.0 mm, slice
gap = 0.3 mm, imaging matrix = 256 × 256, and FOV = 256 × 256 mm).
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Data were analyzed on a single subject basis. Using SPM96 for Windows
NT (Wellcome Department of Cognitive Neurology, London, UK) with Matlab
for Windows (v. 5.3, MathWorks, Sherborn, MA), fMRI time series data
were smoothed (full width at half-maximum = 4.00 mm) and analyzed.
No spatial normalization of the data were performed. The first five
scans were excluded from the analysis because of the nonequilibrium
state of magnetization. Constructing three delayed box-car functions
(delay = 6 s), Task 1 versus Task 2, Task 1 versus Rest, and
Task 2 versus Rest were compared using linear contrasts of [1, 0, 1], [1,
1, 0], and [0, 1,
1] for [Task 1, Rest, Task 2],
respectively. In the analysis, data from the two Rest conditions were
combined, and we applied a high-pass filter (cutoff period = 120 s, equivalent to the time for each session) with temporal
smoothing, no covariate of no interest, and no global normalization. We
also examined whether there was a statistically significant difference
between the Rest conditions after Task 1 and that after Task 2 using a
contrast of [1,
1] for [Rest after Task 1, Rest after Task 2] in
SPM96. To focus on significant activation in voxels, we measured
Z scores with the unit normal distribution, and created
{Z} maps consisting of the voxels with a threshold at
P < 0.005 (corrected for multiple comparisons)
throughout the analysis. The activated foci were located by
superimposing SPM{Z} onto the T1 images. The activated areas in the
mesial cortex immediately caudal and rostral to the VCA line and dorsal
to the cingulate sulcus are referred to as the SMA and pre-SMA,
respectively (Hikosaka et al. 1996
; Vorobiev et
al. 1998
). The x, y, and z
coordinates of the activated voxel in each region were also obtained
using SPM96.
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RESULTS |
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During scans, the subjects performed Task 1 correctly in more than
98% of the trials. Selection errors were only made in 2% of the
trials; these occurred when the scanner made a loud noise that
coincided with the auditory cues. No omission errors were observed
during Task 1. The subjects did not make any mistakes during Task 2. Figure 1 shows the brain regions of a representative subject that were
significantly activated during Task 1 versus Rest, Task 2 versus Rest,
and Task 1 versus Task 2. During Task 1 versus Rest, areas immediately
rostral and caudal to the left central sulcus were activated,
corresponding to the MI and SI, respectively. The left activated region
continued to the dorsal Brodmann's area 6 in the precentral
gyrus, and this area was regarded as the PMd (Freund
1991; Grafton et al. 1998
; Iacoboni et
al. 1998
; Wise et al. 1991
). On the left mesial
cortex (bottom left of Fig. 1), the left SMA, and pre-SMA were
activated (see METHODS for definition). The right pre-SMA
was also activated. Minor activation was observed in the PMd and MI of
the right hemisphere, but there were no activated areas in the
prefrontal cortex. Table 1 shows the
average location of constantly activated areas in the frontal cortex of
the five subjects, and the average number of pixels in each area.
Figure 1 and Table 1 indicate that the distribution and number of
activated voxels in each area were similar when comparing Task 1 versus
Rest or Task 2 versus Rest.
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When Task 1 and Task 2 were compared, however, preferentially activated regions were observed constantly in the left PMd and pre-SMA contralateral to the working hand (Fig. 1). In contrast, no preferentially activated regions were observed in the MI, SI, or SMA. Figure 2 shows averaged signals in the region of interest (ROI) within the left PMd during the three conditions. In the ROI, the signals observed were always greater in Task 1 than in Task 2. The signals observed in both Tasks 1 and 2 were significantly greater than those during Rest. Similar changes were observed in the pre-SMA. Of these, only the PMd and pre-SMA contralateral to the working hand constantly showed preferential activation during Task 1 in comparison with Task 2 in all the subjects (Table 1). Table 1 also shows that, in the PMd and pre-SMA, there were fewer pixels activated when Task 1 and Task 2 were compared than when Task 1 and Rest were compared.
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Since the two tasks were performed in a fixed order, the data could reflect nonspecific time effects. We examined this possibility by comparing the Rest conditions following Task 1 with that following Task 2 (see METHODS). However, no significantly activated pixels at P < 0.005 (corrected for multiple comparisons) were found in any part of the obtained images, including the PMd, pre-SMA, SMA, and MI. Figure 2 shows that the signal levels of the ROI in the PMd were similar during the two Rest conditions.
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DISCUSSION |
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Consistent with previous activation studies (Fink et al.
1997; Grafton et al. 1998
; Hazeltine et
al. 1997
; Iacoboni et al. 1998
), we found that
multiple regions in the frontal cerebral cortex, including the MI, PMd,
SMA, and pre-SMA, were activated during the two-finger movement tasks.
The main, and new, finding of this study is that, of the cortical
frontal motor areas activated, only the PMd and pre-SMA contralateral
to the working right hand were preferentially activated when auditory
conditional cues were presented to select a required movement. The PMd
and pre-SMA were more active in the conditional task (Task 1) than in
the control task (Task 2). The MI and SMA were more active during the
two tasks than during Rest, but they failed to show statistically significant difference in activity between the two tasks. The overall
number of auditory stimuli and movements executed in the two tasks over
the entire session matched. When combined with previous evidence that
the PMd and pre-SMA are activated when arbitrary or spatial visual cues
or spatial auditory cues are presented for motor selection (Fink
et al. 1997
; Grafton et al. 1998
;
Hazeltine et al. 1997
; Iacoboni et al.
1998
), and also activated when learning of visuomotor
association is in progress (Deiber et al. 1997
;
Hazeltine et al. 1997
; Sakai et al.
1999
), our results strongly suggest that the PMd and pre-SMA
play a more extensive, general role in sensorimotor integration than
has previously been thought. It is likely that the areas will also show
preferential activation when conditional cues with any other
modalities, such as somatosensory cues, are transformed into the
appropriate motor behavior. Our observations also imply that the PMd
and pre-SMA contain highly modifiable neural circuits, known as hidden
units (Churchland and Sejnowski 1992
; Fetz
1992
) that can switch connections between various inputs and
outputs for conditional motor behavior.
It has been reported that a number of neurons in the PMd of monkeys
showed sustained change after the presentation of visual and auditory
instruction cues, termed set-related activity (Boussaoud and
Wise 1993; di Pellegrino and Wise 1993
;
Kurata 1993
; Kurata and Hoffman 1994
;
Kurata and Wise 1988
; Weinrich and Wise
1982
). When arbitrary versus spatial visual cues indicated the
same movements, a number of set-related neurons showed higher
modulation of activity following the conditional cues than after the
spatial cues (Kurata and Hoffman 1994
; Kurata and
Wise 1988
). Furthermore, when muscimol was injected to
inactivate the area of the PMd where the set-related neurons were
densely located, the monkeys showed severe deficits in selecting
correct movement when conditional, but not spatial, cues were presented
(Kurata and Hoffman 1994
). Thus, it has been suggested
that the PMd contributes not only to preparation for the movements in
the conditional behavior, but also to selection of the movements
(Kurata and Hoffman 1994
; Kurata and Wise
1988
). This view is further supported by the preferential
activation of the human PMd during the conditional task used in this
study. In this study, the activated area of the PMd was rostrally
adjacent to the MI, a region termed the caudal PMd (PMdc)
(Grafton et al. 1998
; Iacoboni et al.
1998
; Matelli et al. 1985
). It was in the PMdc,
not the rostral PMd (PMdr), that preferential changes in neuronal
activity were observed in monkeys, and inactivation resulted in
behavioral deficits during conditional tasks. This is also where
activation during movement selection based on visual conditional cues
was found in humans (Grafton et al. 1998
). Although the
PMdr is reportedly activated when spatial auditory cues are presented for motor responses (Iacoboni et al. 1998
), we did not
confirm this in our study, perhaps due to the conditional nature of the auditory cues. In monkeys, the PMdr seems to be more involved in
oculomotor control than in limb movements (Fujii et al.
2000
; Mitz and Godschalk 1989
).
We found that the pre-SMA was more activated during the conditional
task than during the control task, in which the subjects were required
to select their finger movements internally. These results contrast
with a report that the pre-SMA is activated with self-initiated rather
than with visually triggered finger movements (Deiber et al.
1999). However, the difference in the results can be explained
by the design of the tasks. Deiber et al. (1999)
used a
visual cue as the only trigger without any conditional association,
whereas we used conditional auditory cues, not visual ones. The pre-SMA
of monkeys contains abundant neurons with phasic responses to visual
cue signals indicating the direction of forthcoming movements
(Matsuzaka et al. 1992
), and the human pre-SMA is
suggested to play a role in spatial visuomotor association
(Sakai et al. 1999
), which supports our findings.
In interpreting our data, preferential cortical activation resulting
from behavioral effects other than the conditional aspects of the tasks
should be considered. For example, visuospatial attention modulates
activity of the frontal motor areas in humans (Corbetta et al.
1993; Hazeltine et al. 1997
; Nobre et al.
1997
) and in monkeys (Boussaoud and Wise 1993
;
di Pellegrino and Wise 1993
). Although the location of
the areas modulated by visuospatial attention seems different in
previous studies from the areas activated in this study, whether the
PMd and other motor areas are modulated by auditory attention should be
examined directly in the future. The subjects in our study might have
been less attentive during the control task than during the conditional
task, or inhibition of conditional behavior could have occurred during
the control task. However, it was confirmed that the motor areas were
activated in the two tasks, and preferential activation was
consistently observed in the PMd and pre-SMA, but not in the MI and
SMA. Thus, it is more likely that specific changes do occur in the PMd
and pre-SMA during the conditional task.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the Ministry of Education, Science, and Culture of Japan (09268204, 10164205, and 11145203), "Research for the Future" Program (96L00206) by the Japan Society for the Promotion of Science, and Karouji Foundation.
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FOOTNOTES |
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Address for reprint requests: K. Kurata (E-mail: kuratak{at}cc.hirosaki-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 January 2000; accepted in final form 16 May 2000.
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REFERENCES |
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