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JOURNALOFNEUROPHYSIOLOGY
Vol. 74, No. 3, September 1995. Printed in U.S.A.
Modulation of Muscle Responses Evoked by Transcranial Magnetic
Stimulation During the Acquisition of New Fine Motor Skills
ALVARO PASCUAL-LEONE, NGUYET DANG, LEONARDO G. COHEN, JOAQUIM P. BRASIL-NETO,
ANGEL CAMMAROTA, AND MARK HALLETT
Human Cortical Physiology Unit, Human Motor Control Section, Medical Neurology Branch, National Institute of
Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
SUMMARY AND CONCLUSIONS
1. We used transcranial magnetic stimulation (TMS ) to study
the role of plastic changes of the human motor system in the INTRODUCTION
acquisition of new fine motor skills. We mapped the cortical motor
areas targeting the contralateral long finger flexor and extensor
muscles in subjects learning a one-handed, five-finger exercise on .
Playing the piano demands orderly, sequential control of
individual finger movements and a high degree of bimanual
the piano. In a second experiment, we studied the different effects
of mental and physical practice of the same five-finger exercise on
the modulation of the cortical motor areas targeting muscles in-
volved in the task.
coordination. Even when given information about the hand
position, the finger motions, the sequence of keys to press,
and the duration and velocity of each key press, a novice
would still be unable to play even the simplest piano sonata.
The piano student must understand the demands of the task,
develop a cognitive representation of it, and initiate a first,
centrally guided response. At first, his or her limbs will move
slowly, with fluctuating accuracy and speed, and success will
require visual, proprioceptive, and auditory feedback. With
practice, the pianist can refine each single movement, link
the different movements with the desired timing, and attain
stability and fluency in the ordered sequence. Only then can
the pianist shift his or her attention from the mechanical
details of the performance to its artistic interpretation.
2. Over the course of 5 days, as subjects learned the one-handed,
five-finger exercise through daily 2-h manual practice sessions, the
cortical motor areas targeting the long finger flexor and extensor
muscles enlarged, and their activation threshold decreased. Such
changes were limited to the cortical representation of the hand
used in the exercise. No changes of cortical motor outputs occurred
in control subjects who underwent daily TMS mapping but did not
practice on the piano at all (control group 1) .
3. We studied the effect of increased hand use without specific
skill learning in subjects who played the piano at will for 2 h each
day using only the right hand but who were not taught the five-
finger exercise (control group 2) and who did not practice any
specific task. In these control subjects, the changes in cortical motor
outputs were similar but significantly less prominent than in those
occurring in the test subjects, who learned the new skill.
4. In the second experiment, subjects were randomly assigned
to a physical practice group, a mental practice group, or a control
group. Subjects in each practice group physically or mentally prac-
ticed the five-finger piano exercise independently for 2 h daily for
5 days. The control group did not practice the exercise. All subjects
had daily TMS mapping of the cortical motor areas targeting the
long finger flexor and extensor muscles.
5. Over the course of 5 days, mental practice alone led to sig-
nificant improvement in the performance of the five-finger exercise,
but the improvement was significantly less than that produced by
physical practice alone. However, mental practice alone led to the
same plastic changes in the motor system as those occurring with
the acquisition of the skill by repeated physical practice.
6. We conclude that acquisition of the motor skills needed for
the correct performance of a five-finger piano exercise is associated
with modulation of the cortical motor outputs to the muscles in-
volved in the task. This rapid modulation may occur through an
increase of synaptic efficacy in existing neural circuits (long-term
potentiation) or unmasking of existing connections due to disinhi-
bition.
7. Mental practice alone seems to be sufficient to promote the
modulation of neural circuits involved in the early stages of motor
skill learning. This modulation not only results in marked perfor-
mance improvement but also seems to place the subjects at an
advantage for further skill learning with minimal physical practice.
Acquisition of new fine motor skills may demand modifi-
cation of the nervous system to accommodate the new proce-
dures (Jenkins et al. 1990; Kaas 1991; Merzenich et al.
1990). The primary motor cortex (M 1) may have a central
role in skill learning considering the flexibility in the associa-
tions of sensory inputs to Ml neurons and in the associations
between Ml, spinal neurons, and somatic musculature ( Aou
et al. 1992; Iriki et al. 1989; Kaas 1991). Studies using
noninvasive imaging and neurophysiological techniques
have demonstrated skill-associated nervous system plasticity
in humans. In blind subjects, for example, proficient Braille
reading is associated with enlargement of the cortical senso-
rimotor representation of the reading finger ( Pascual-Leone
et al. 1993; Pascual-Leone and Torres 1993), and in normal
subjects, learning of a complicated sequence of voluntary
finger movements is associated with changes in the slow
cortical DC potentials (Niemann et al. 199 1) and transient
increases in regional cerebral blood flow in the cerebellum
and striatum (Seitz et al. 1990).
In the present study we used transcranial magnetic stimu-
lation (TMS ) to study the cortical motor areas targeting
the contralateral long finger flexor and extensor muscles in
subjects learning a one-handed, five-finger exercise on the
piano. In a second experiment we studied the different effects
of mental and physical practice on the acquisition of the
1037
1038 PASCUAL-LEONE ET AL.
same five-finger exercise and on the modulation of the corti-
cal motor areas targeting muscles involved in the task.
METHODS
Subjects
We used different subjects for each experiment. In experiment
1, we studied 18 subjects who were randomly assigned to a test
group or one of two control groups. Each group consisted of three
men and three women who were matched for age (mean age, 44
yr; range, 38-5 1 yr). In experiment 2, we studied 15 subjects who
were randomly assigned to a physical practice group, a mental
practice group, or a control group. Each group consisted of three
men and two women who were matched for age (mean age, 32 yr;
range, 19-42 yr). All subjects were right-handed, as determined by
the Oldfield questionnaire (Oldfield 197 1) . None of the subjects
had experience playing the piano or any other musical instrument.
None of them knew how to typewrite using all fingers. None of
them had jobs or were involved in daily activities that demanded
skilled, fine-finger movements. All subjects had normal findings
on neurological and general physical examinations. The protocol-
was approved by the Institutional Review Board, and all subjects
gave their written informed consent for the study. The transcranial
magnetic stimulator was used under an Investigational Device Ex-
emption from the Food and Drug Administration.
Experiment 1
In experiment 1, subjects performed the one-handed, five-finger
exercise on a Yamaha electronic piano keyboard interfaced with a
Macintosh IIci computer. The exercise consisted of the following
sequence of finger movements (and notes): thumb (C), index
finger (D), middle finger (E), ring finger (F), little finger (G),
ring finger (F), middle finger (E), index finger (D) . A metronome
marked a rhythm of 60 beats per minute, and the subjects were
asked to match the thumb and little finger movements to the beat,
intercalating the movements of the other fingers between the beats.
The subjects were asked to try to perform the sequence of finger
movements fluently, without pauses, and without skipping any key,
and to pay particular attention to keeping the interval between the
individual key presses constant and the duration and velocity of
each key press the same.
On day 1, baseline TMS mapping of the cortical motor areas
targeting the long finger flexor and extensor muscles bilaterally
was done according to the technique described below. Subjects
were then randomly assigned to a test group or to one of two
control groups. Only subjects in the test group were taught the
five-finger exercise. Thereafter, they practiced the exercise for 2 h
daily on days l-5, had their performance tested, rested for 20-30
min, and had TMS mapping of the motor cortex.
The performance was tested by recording 20 sequential repeti-
tions of the exercise on the computer with the use of a sequencing
software package (Vision, Opcode, Menlo Park, CA) that allowed
the analysis of the exact sequence of key presses, the interval
between key presses, and the duration and velocity of each key
press. Any key pressed out of order was considered an error, so
more than one error was possible during each sequence. The antici-
pated interval between key presses was 0.25 s given that a rhythm
of 60 beats per minute was marked by a metronome for each four
intervals. After each daily test, the subjects were given feedback
about their performance, as well as tips on how to improve.
Control group 1 had daily TMS mapping only. Control group
2 played the piano at will for 2 h each day with the use of only
the right hand, rested for 20-30 min, and had daily TMS mapping.
Subjects in control group 2 could play anything they wanted on
the piano but were asked to press only one key at a time, therefore
executing individual finger movements in self-generated se-
quences. They were asked not to repeat a given sequence. On day
5, control groups 1 and 2 were also taught the exercise, and their
performance on the test was recorded as for the test subjects.
All practice sessions were performed in the laboratory and were
supervised by one of the investigators. Subjects were asked not to
rehearse the task at home.
Experiment 2
In experiment 2, all subjects were taught the same five-finger
exercise as in experiment 1. Baseline TMS mapping of their cortical
motor areas targeting the long finger flexor and extensor muscles
was done according to the technique described below. Thereafter,
the subjects were randomly assigned to a physical practice group,
a mental practice group, or a control group.
Subjects in each practice group physically or mentally practiced
the exercise independently for 2 h daily for 5 days. The control
group did not practice the exercise but had daily TMS mapping.
Subjects were asked not to rehearse the task at home. During
the practice session, subjects in the physical practice group were
encouraged to repeatedly perform the exercise on the keyboard
and were free to select their own strategy. Subjects in the mental
practice group were asked to sit in front of the piano and try to
visualize their fingers performing the exercise and to imagine the
sound. They were not allowed to touch the piano keys or to rehearse
the exercise by moving the fingers in the air. To assure that they
were indeed not moving their fingers, electromyographic (EMG)
activity from the long finger flexor and extensor muscles was moni-
tored continually with the use of pairs of surface EMG electrodes
taped to the skin over the belly of the muscle and displaying the
activity on an oscilloscope at a sensitivity of 20 pV/div. After the
1st lo-15 min, all subjects were able to follow the instructions
without difficulty. The mental practice group had a single 2-h
physical practice session at the end of day 5. The results of task
performance and TMS mapping following this physical practice
session are reported as day 5’.
The performance of all subjects was tested daily by 20 sequential
repetitions of the exercise in the same fashion as described for
experiment 1. TMS mapping was performed 20-30 min after the
test. Therefore performance assessment and TMS mapping were
Metronome beats (60 beatdmin)
w+++++++++++++
FIG. 1.
Experiment 1: example of the performance in the 5finger exer-
cise on days 1 and 5 in a representative test subject. Arrows and dashed
lines mark the metronome beats. Bars illustrate the different notes (finger
movements) with the thumb being the lowest row of bars and the little
finger the highest. The length of the bar represents the duration of each key
press. Circles highlight the errors in the sequence performance. Comparison
between &~ys 1 and 5 illustrate the large number of errors, the highly
variable key press durations, and the frequent deviations from the metro-
nome on &y 1.
CORTICAL MOTOR OUTPUTS IN ACQUISITION OF MOTOR SKILLS 1039
i
- --
20
IN
i
_--_-_
T T
15- 1
IO-
5
0 I \
P
I
Days 1 ‘2 3 4 5 Colntrol Cor;trol
Test Group Group 1 Group 2
FIG.
2. Experiment I : interval between key presses and number of se-
quence errors for all subjects (mean 2 SD) in the 20-sequence test (5
finger piano exercise) over the course of 5 days’ learning. Dashed line
indicates the anticipated interval of 0.25 s between key presses (see text
for details).
the same in all three groups, which differed only in the learning
conditions.
Transcranial magnetic stimulation and mapping technique
We used a Cadwell MES-10 magnetic stimulator equipped with
an &shaped coil, which was held flat on the scalp with the intersec-
tion of its two “wings” centered over a defined scalp position; the
handle of the coil was held horizontally, tangentially to the sub-
ject’s head, pointing occipitally. This technique allows relatively
focal stimulation (Cohen et al. 1990; Maccabee et al. 1990). The
brain structures stimulated might be inferred from models of the
induced electric fields (Roth et al. 199la,b; Tofts 1990). However,
this approximation might be affected by the existence of bends in
the course of fibers that lower their threshold (Maccabee et al.
1993). In any case, overlay of TMS maps onto the magnetic reso-
nance image of the subject’s brain suggests that the motor re-
sponses are evoked from activation of the primary motor cortex
(Levy et al. 1991; Wassermann et al. 1992).
For cortical mapping, scalp positions 1 cm apart were stimulated
successively, following the technique described by Wassermann et
al. ( 1991), and we calculated contour maps of the probability of
evoking a motor potential with a peak-to-peak amplitude of at least
50 PV in the contralateral muscles according to the stimulated scalp
position. Eight single stimuli were given at each scalp position. On
average, a stimulus was delivered every 3-5 s. Each contour map
represents 25 scalp positions (1 cm apart) arranged in a 5 X 5
grid around the “optimal” scalp position, which was marked on
the subject’s scalp with indelible ink. The mark, which remained
throughout the 5-day experiment, was used as a reference point
for the daily mapping. The optimal scalp position was the one from
which TMS elicited motor evoked potentials (MEPs) of maximal
amplitude in the contralateral finger flexor or extensor muscles.
We have previously shown that optimal scalp positions determined
in this manner project onto the posterior bank of the precentral
sulcus and seem to represent activation of the primary motor cortex
(Wassermann et al. 1992). The stimulus intensity was 110% of
the subject’s threshold on each particular day. Motor threshold was
defined by the method of limits. In each subject we determined
threshold as the average result from six series of stimuli, three
with ascending stimulation intensities and three with descending
stimulation intensities. The order of these six series of stimuli was
randomly varied across subjects. For the ascending series we began
stimulation at an intensity at which TMS did not evoke any identi-
fiable MEPs in 10 trials. Thereafter, we increased the stimulation
intensity in steps of 1% of the stimulator output. At each new
intensity we applied 10 stimuli. Threshold intensity was defined
as the lowest stimulation intensity at which TMS evoked 25 MEPs
of z5O-pV peak-to-peak amplitude. For the descending series we
first stimulated at an intensity at which TMS evoked MEPs of
250 PV peak-to-peak amplitude in 10 of 10 trials. Thereafter, we
decreased the stimulation intensity in steps of 1% of the stimulator
output. At each new intensity we applied 10 stimuli. Threshold
intensity was defined as the lowest stimulation intensity at which
Trained Hand
Finger
Flexors
Finger
Extensors
Finger
Flexors
Finger
Flexors
Finger
Extensors
:ontrol
Day 1 Day 2 Day 3 Day 4 Day 5
FIG.
3. Experiment I: representative examples of the cortical motor
output maps for the long finger flexor and extensor musles on days I-5 in
a test subject (trained and untrained hand) and a subject from control group
2. Each map is based on 25 measured points.
1040 PASCUAL-LEONE ET AL.
5
1
Finger extensors Finger extensors
- lo
C 1 Finger flexors
8 5-
5
Q O-
-5 -
-lO-
-15-
-2o-
t I , , 1
1 2 3 4 5
Day
Finger flexors
T
Day
TMS evoked 25 MEPs of r50-PV peak-to-peak amplitude. There-
fore the threshold in any given session represents the average value
from six separate determinations and expresses the lowest stimulus
intensity that evoked from the optimal scalp position motor poten-
tials with a peak-to-peak amplitude of at least 50 PV in 250% of
the trials.
Mapping was performed with the subjects at rest. The absence
of spontaneous, background EMG activity was documented by
continuous EMG monitoring that was presented to the subjects by
loudspeaker and on an oscilloscope at 20 PV per division. Subjects
were instructed to relax the target muscles completely achieving
auditory silence and a flat line on the oscilloscope. EMG activity
was recorded with a Dantec Counterpoint electromyograph with
the use of pairs of surface EMG electrodes taped to the skin over
the belly of the superficial finger flexor and extensor muscles in
the forearm. This recording setup was not selective for movements
of any particular digit but rather allowed monitoring of flexion-
extension activity of all fingers.
In both experiments the experimenter performing the TMS map-
ping was unaware of the group to which a given subject belonged
in order to avoid biasing of the results.
RESULTS
Experiment 1
Over the course of the 5 days, the test group’s playing
skill improved markedly (Figs. 1 and 2). By day 5, the
number of errors in the sequence of key presses clearly
decreased, and the subiects correctlv completed at least 18
of the 20 sequential repktitions of the exercise. The variabil-
ity of the . interval between key r presses decreased, as illus-
trated by the narrowing of the standard deviation. The im-
_ _
provement in accuracy is illustrated by the decrease in the
mean interval between key presses to 0.25 s, which corre-
FIG.
4. Experiment I : change in motor threshold, ex-
pressed as a percentage of change from baseline thresh-
old, and in number of scalp positions on the stimulation
grid from which motor evoked potentials (MEPs) could
be produced in the finger flexor and extensor muscles
with a probability of 260% in all subjects over the course
of 5 days. Values are given as means + SD. Filled circles,
trained hand of test subjects; open circles, untrained hand
of test subjects; filled diamonds, control group I; stippled
squares, control group 2.
sponds with the interval specified by the rhythm of 60 beats
per minute marked by the metronome.
Concurrently with this improvement in performance, the
threshold for activation of the finger flexor and extensor
muscles contralateral to the side of TMS decreased steadily
over the course of the 5 days, but only for the hand being
trained. In addition, the size of the cortical output map for
both muscle groups increased (Figs. 3 and 4). The increase
in the size of the maps was independent of the threshold
changes, because daily mapping of each muscle was per-
formed at 110% of the subject’s threshold on that day, thus
controlling the effects of threshold changes across days.
As predicted, skill learning did not take place in the con-
trol subjects. Control groups I and 2 performed the exercise
on day 5 with the same accuracy as the test subjects on day
I (Fig. 2). In control group I, daily motor mapping with
TMS did not affect the threshold for activation of the finger
flexor and extensor muscles or the size of their cortical repre-
sentation (Fig. 4). In control group 2, increased daily use
of the hand by random piano playing resulted in a slight
decrease in the threshold for TMS activation of the finger
flexor and extensor muscles and in some increase in the size
of the cortical representation for both muscle groups (Figs.
3 and 4). However, these changes were significantly smaller
[P < 0.001, analysis of variance (ANOVA)] than in the
test subjects.
Experiment 2
Over the course of 5 days, both practice groups showed
progressive improvement in their playing skills, as illustrated
by a decrease in the number of sequence errors and a reduc-
tion in the variability (standard deviation) of the interval
CORTICAL MOTOR OUTPUTS IN ACQUISITION OF MOTOR SKILLS 1041
between key presses (Fig. 5). Accuracy increased in all
practice subjects, as illustrated by a decrease in the mean
interval between key presses to 0.25 s. However, the physical
practice group showed a significantly greater reduction (P <
0.001, ANOVA) in the number of sequence errors and a
trend toward greater accuracy than did the mental practice
group. The control group’s performance did not improve.
Concurrently with the improvement in performance, the
threshold for activation of the finger flexor and extensor
muscles by TMS to the contralateral scalp decreased steadily
over the course of the 5 days in the physical and mental
practice groups. In addition, even though the threshold de-
crease was taken into account, the size of the cortical repre-
sentation for both muscle groups increased equally for both
practice groups
but
did not increase for the control group
(Figs. 6 and 7).
Therefore mental practice alone led to significant fine mo-
tor skill learning but did not result in as much performance
improvement as physical practice alone. However, mental
practice alone led to the same plastic changes in the motor
system as those occurring with the acquisition of a skill by
repeated physical practice. By the end of day 5, the changes
in the cortical motor outputs to the muscles involved in the
2
0.5,
8
ii
ii! 0.4-
P
2
Y
5 0.3-
!i
$
P 0.2-
z
5
I O.l-
25-
20 -
15-
IO-
5-
o-
I t
1 2 3 4 5 5
Days
FIG.
5. Experiment 2: interval between key presses and number of se-
quence errors for all subjects (mean t SD) in the 20-sequence test (5-
finger piano exercise) over the course of 5 days’ learning. Dashed line
indicates the anticipated interval between key presses (0.25 s). Arrows
indicate the level of performance between the physical and mental practice
groups at the end of day 5 or day 5’ (see text for details). Filled circles,
physical practice group; open circles, mental practice group; stippled
squares, control group; stippled circle, mental practice group on day 5’.
Finger
flexors
Finger
extensors
Finger
flexors
Finger
extensors
Mental Practice
Day 1 Day 2 Day 3 Day 4 Day 5
SOL 100
Probability (“A)
2cr;l
FIG.
6. Experiment 2: representative examples of the cortical motor
output maps for the long finger flexor and extensor muscles on days I-5
in a subject from each group. Each map is based on 25 measured points.
task did not differ between the physical and the mental prac-
tice groups (Fig. 5). However, the mental practice group’s
performance was at the level of that occurring with only 3
days’ physical practice. After a single 2-h physical practice
session, the mental practice group’s performance improved
to the level of 5 days’ physical practice (Fig. 5).
DISCUSSION
Neurophysiological correlates
of
motor skill acquisition
Recently, studies using noninvasive neurophysiological
and imaging techniques have suggested that even the adult
human nervous system is capable of reorganizing after in-
jury, with the probable purpose of minimizing deficits and
producing recovery of function (Cohen et al. 1991b, 1993;
Pascual-Leone et al. 1992). These findings confirm in hu-
mans the growing body of evidence suggesting the flexible
nature of connections in the nervous system of adult animals
(Kaas 1991).
The nervous system of animals may also undergo changes
according to the patterns of use, thereby providing a substrate
for the acquisition of new skills (Jenkins et al. 1990; Merzen-
ich et al. 1990). The sensorimotor representation of the pre-
1042 PASCUAL-LEONE ET AL.
5
1
Finger extensors
g -5 -
0
E
8
-10..
g 10
C 1
F ‘lnger flexors
-20 I r I I r t
1 2 3 4 5
Day
Finger extensors
Finger flexors
3
Day
ferred hand in monkeys is more elaborate than that of the
nonpreferred hand (Nudo et al. 1992)) and training can result
in distortions of body surface and movement representations
that lead to behavioral gains (Jenkins et al. 1990). Motor
cortical representation of a body part expands after selec-
tively increased activity (Humphrey et al. 1990; Sanes et al.
1992)) and differential stimulation of a restricted skin sur-
face in a finger pad of adult monkeys leads to a reorganiza-
tion of its somatosensory cortical representation, especially
when stimulation has a functional significance (Recanzone
et al. 1992a-d). In humans, a recent positron emission to-
mography study (Seitz et al. 1990) found that learning of
a complicated sequence of voluntary finger movements is
associated with increases in regional cerebral blood flow
(r CBF) in the cerebellum and that acquisition of the motor
skill results in an increase of r CBF in the striatum. Relative
increases in r CBF have been shown to occur in the primary
motor area, the supplementary motor area, and the thalamus
as subjects learned a pursuit rotor task (Grafton et al. 1992).
Finally, changes in slow cortical negative DC potentials dur-
ing the acquisition of a complex finger motor task (Niemann
et al. 1991) also suggest a dynamic modulation of the corti-
cal representation of movement control during skill learning.
In the present study we found that acquisition of the motor
skills needed for the correct performance of a five-finger
piano exercise is associated with modulation of the cortical
motor outputs to the muscles involved in the task. The corti-
cal sensorimotor representation of a specific body part, as
demonstrated, for example, by TMS mapping, may depend
on the momentary level of excitability of the intracortical
network that targets it. Extensive intracortical axonal collat-
erals provide inputs to many different movement representa-
tions of a given body part, and their pattern of recruitment
5
FIG.
7. Experiment 2: change in motor threshold, ex-
pressed as a percentage of the baseline threshold, and in
number of scalp positions from which MEPs could be pro-
duced in the long finger flexor and extensor muscles with
a probability of ~60% in all subjects (mean 5 SD) over
the course of 5 days. Filled circles, physical practice group;
open circles, mental practice group; stippled squares, con-
trol group.
may determine the execution of complex movements (Hunt-
ley and Jones 1991). In addition, neuronal networks tar-
geting different body parts overlap widely and even share
in part common neuronal elements (Schieber 1992). The
neuronal elements in such networks may maintain a flexible
balance based on demand and competition by their targets.
Removal of a target, as in amputation or peripheral deaffer-
entation, may result in the “takeover” of neuronal elements,
formerly activated primarily as part of the network targeting
the removed target, by neighboring networks targeting
neighboring body parts. This would explain the reorganiza-
tion of the motor outputs targeting muscles proximal to the
stump of an amputated limb (Cohen et al. 1991a) or to an
ischemic sensorimotor block (Brasil-Neto et al. 1992,
1993). Conversely, increased use and enhanced sensory
feedback of a body part, especially if coupled with functional
gain for the subject, may lead to a shift of the balance of
intracortical networks toward that body part. Cortical net-
works underlying coordinated finger movements show a
movement gradient across digits from the most prominently
activated digit, which may depend on corticocortical or sub-
corticocortical projections (Amassian et al. 1989). Learning
and practice may modulate the cortical outputs by strength-
ening such a gradient.
Modulation of motor cortical outputs may result from the
establishment or unmasking of neuronal connections. The
rapid time course of the motor output modulation, by which
a certain region of motor cortex can increase its influence
on a motoneuron pool, suggests the unmasking of existing
neuronal connections, which may be due to decreased inhibi-
tion or increased synaptic efficacy (long-term potentiation)
( Asanuma and Keller 1991; Iriki et al. 1989; Jacobs and
Donoghue 1991) . Such flexible modulation may represent a
CORTICAL MOTOR OUTPUTS IN ACQUISITION OF MOTOR SKILLS 1043
first stage in learning and could lead to structural changes in
the intracortical and subcortical networks as the skill becomes
overlearned and automatic. For example, Greenough et al.
(Greenough 1984; Greenough et al. 1985) have shown that
motor training is associated with changes in the dendritic
branching patterns of motor and sensory cortical cells in-
volved in the performance of the task. Sprouting may account
for plastic changes in such situations, as likely occurred in
monkeys deafferented for 10 years (Pons et al. 199 1) , and
represents the correlate of long-standing ‘ ‘memories.’ ’
Learning-associated modulation of motor cortical outputs
may result from changes in synaptic efficacy in the motor
cortex itself (Jacobs and Donoghue 1991). However, our
results do not allow ruling out that the observed plastic
changes are driven by changes in the activity of other cortical
areas or subcortical structures, for example, the premotor
cortex or the cerebellum. Discharge patterns of Purkinje cells
change during motor learning (Gilbert and Thach 1977; Oja-
kangas and Ebner 1992)) which could lead to changes in
cortical excitability via cerebellothalamocortical projections.
A large proportion of cells in the premotor cortex in the
monkey show a learning-dependent change in activity during
the acquisition of visuomotor associations (Mitz et al.
1991) , which could modulate primary motor cortex activity
via corticocortical projections. Even a shift in the segmental
excitability of appropriate spinal levels could account for
the observed changes in the motor outputs. For example,
an excitatory input to a-motoneurons from suprasegmental
levels or increased fusiform drive could bring the motoneu-
rons close to firing level without overtly causing background
EMG. Further studies are needed to define the level of the
observed plasticity.
The changes in cortical motor outputs that we observed
during TMS do not necessarily reflect the cortical activation
pattern evoked during task performance, because TMS was
applied while the subject was at rest, not performing the
trained task. Therefore they must indicate a longer-lasting
change possibly due to long-term synaptic potentiation (Asa-
numa and Keller 1991; Iriki et al. 1989; Jacobs and Do-
noghue 199 1) . We show that the “momentary level of excit-
ability,’ ’ a fixed time after performance of the task (20 min
to -3 h), rises progressively over the course of 5 days for
the cortical outputs to muscles involved in the task as the
subject’s performance improves. Further practice may even-
tually lead to new changes in the cortical motor outputs
as the task becomes overlearned and correct performance
eventually may become ‘ ‘automatic’ ’ ( Pascual-Leone et al.
1994). An important issue raised by our findings is the
apparent lack of a plateau in the modulation of cortical out-
puts during learning. We believe that this apparent lack of
plateau is likely an artifact of the duration of our study
design. Our assumption would be that if we would continue
with the training of the task used in the present study for
longer than a week, there would be a plateau of the cortical
output changes and even possibly a return of cortical thresh-
olds to baseline as the skill becomes overlearned.
Effect of manual and mental practice
Mental practice is the imagined rehearsal of a motor act
with the specific intent of learning or improving it, without
overt movement output. Mental practice can be viewed as
a virtual simulation of behavior by which the subject devel-
ops and ‘ ‘internally’ ’ rehearses a cognitive representation of
the motor act. When confronted with a new motor task, the
subject must develop a cognitive representation of it and
initiate a centrally guided response, which secondarily can
be improved by the use of sensorimotor feedback. Mental
practice may accelerate the acquisition of a new motor skill
by providing a well-suited cognitive model of the demanded
motor act in advance of any physical practice (McBride and
Rothstein 1979; Mendoza and Wichman 1978; White et al.
1979). Mental practice has found wide acceptance in the
training of athletes (Denis 1985; Suinn 1984), and several
famous instrumental musicians have used mental practice in
the learning and rehearsal of new compositions (Schonberg
1987, 1988).
Studies of r CBF suggest that the prefrontal and supple-
mentary motor areas, basal ganglia, and cerebellum are part
of the network involved in the mental simulation of motor
acts (Decety and Ingvar 1990; Ingvar and Philipson 1977;
Roland et al. 1980, 1982, 1987; Roland and Friberg 1985).
Therefore mental simulation of movements activates some
of the same central neural structures required for the perfor-
mance of the actual movements. In doing so, mental practice
alone seems to be sufficient to promote the modulation of
neural circuits involved in the early stages of motor skill
learning. This modulation not only results in marked perfor-
mance improvement but also seems to place the subjects at
an advantage for further skill learning with minimal physical
practice. The combination of mental and physical practice
leads to greater performance improvement than physical
practice alone (McBride and Rothstein 1979; White et al.
1979), a phenomenon for which our findings provide a phys-
iological explanation. Mental imaging of movements recre-
ates the effects of physical practice on the modulation of the
central motor system and may, therefore, be an important
adjunct not only for the learning of new motor skills but
also for the maintenance of motor skills in temporarily im-
mobilized patients and
neurological disorders. in the rehabilitation of patients with
We thank B. J. Hessie for skillful editing.
Present addresses: A. Pascual-Leone, Unidad de Neurobiologia, De-
partamento de Fisiologia, Universidad de Valencia, Valencia 46010, Spain;
J. P. Brasil-Neto, Laboratorio de Neurobiologia, Departamento de Ciencias
Fisiologicas, Universidade de Brasilia, Brasilia 709 10, Brazil.
Address for reprint requests: M. Hallett, Clinical Director, NINDS, Bldg.
10, Rm. 5N226, National Institutes of Health, Bethesda, MD 20892.
Received 21 April 1993; accepted in final form 28 April 1995.
REFERENCES
AMASSIAN,
V. E., CRACCO, R. Q.,
AND MACCABEE,
P. J. Focal stimulation
of the human cerebral cortex with magnetic coil: a comparison with
electrical stimulation. Electroencephalogr. Clin. Neurophysiol. 74: 401-
416, 1989.
Aou, S. A.,
WOODY,
C. D.,
AND BIRT,
D. Increases in excitability of
neurons of the motor cortex of cats after rapid acquisition of eye blink
conditioning. J. Neurophysiol. 12: 560-569, 1992.
ASANUMA,
H.
AND KELLER,
A. Neuronal mechanisms of motor learning in
mammals. Neuroreport 2: 217-24, 199 1.
BRASIL-NETO,
J. P.,
COHEN,
L. G.,
PASCUAL-LEONE,
A.,
JABIR,
F. K.,
WALL,
R. T.,
AND HALLETT,
M. Rapid reversible reorganization in human motor
PASCUAL-LEONE ET AL.
system following transient deafferentation. Neurology 42: 1302- 1306,
1992.
BRASIL-NETO,
J. P.,
VALLS-SOL&
J.,
PASCUAL-LEONE,
A.,
CAMMAROTA,
A.,
AMASSIAN,
V. E., CRACCO, R.,
MACCABEE,
P., CRACCO, J.,
HALLETT,
M.,
AND COHEN,
L. G. Rapid modulation of human cortical motor outputs
following ischaemic nerve block. Brain 116: 5 11-525, 1993.
COHEN,
L. G.,
BANDINELLI,
S.,
FINDLAY,
T. W.,
AND HALLETT,
M. Motor
reorganization after upper limb amputation in man. Brain 114: 615 -627,
1991a.
COHEN,
L. G.,
BRASIL-NETO,
J. P.,
PASCUAL-LEONE,
A.,
AND HALLETT,
M.
Plasticity of cortical motor output organization following deafferentation,
cerebral lesions, and skill acquisition. Adv. Neural. 63: 187-200, 1993.
COHEN,
L. G.,
ROTH,
B. J.,
NILSSON,
J., DANG, N.,
BANDINELLI,
S.,
PANIZZA,
M.,
FRIAUF,
W.,
AND HALLETT,
M. Effects of coil design on delivery of
focal magnetic stimulation. Technical considerations. Electroencepha-
logr. Clin. Neurophysiol. 75: 350-357, 1990.
COHEN,
L. G.,
ROTH,
B. J.,
WASSERMANN,
E. M.,
TOPKA,
H.,
FUHR,
P.,
SCHULTZ,
J.,
AND HALLEY,
M. Magnetic stimulation of the human cere-
bral cortex, an indicator of reorganization in motor pathways in certain
pathological conditions. J. Clin. Neurophysiol. 8: 56-65, 199 1 b.
DECETY,
J.
AND INGVAR,
D. H. Brain structures participating in mental
simulation of motor behavior: a neuropsychological interpretation. Acta
Psychol. 73: 13-34, 1990.
DENIS,
M. Visual imagery and the use of mental practice in the development
of motor skills. Can. J. Appl. Sport Sci. 10: 4S-16S, 1985.
GILBERT,
P. F. C.
AND THACH,
W. T. Purkinje cell activity during motor
learning. Brain Res. 128: 309-328, 1977.
GRAFTON,
S. T.,
MAZZIOTTA,
J. C.,
PREsTY,
S.,
FRISTON,
K. J.,
FRACKOWIAK,
R. S. J.,
AND PHLEPS,
M. E. Functional anatomy of human procedural
learning determined with regional cerebral blood flow and PET. J. Neu-
rosci. 12: 2542-2548, 1992.
GREENOUGH,
W. T. Structural correlates of information storage in the mam-
malian brain: a review and hypothesis. Trends Neurosci. 7: 229-233,
1984.
GREENOUGH,
W. T.,
LARSON,
J. R.,
AND WITHERS,
G. S. Effects of unilateral
and bilateral training in a reaching task on dendritic branching of neurons
in the rat motor-sensory forelimb cortex. Behav. Neural Biol. 44: 301-
314, 1985.
HUMPHREY,
D. R., OIU, X. O.,
CLAVEL,
P.,
AND O’DONOGHUE,
D. L.
Changes in forelimb motor representation in rodent cortex induced by
passive movements Sot. Neurosci. Abstr. 16: 422, 1990.
HUNTLEY,
G. W.
AND JONES,
E. G. Relationship of intrinsic connections
to forelimb movement representations in monkey cortex: a correlative
anatomic and physiological study. J. Neurophysiol. 66: 390-413,
1991.
INGVAR,
D. H.
AND PHILIPSON,
L. Distribution of the cerebral blood flow
in the dominant hemisphere during motor ideation and motor perfor-
mance. Ann. Neural. 2: 230-237, 1977.
IRIKI,
A.,
PAVLIDES,
C.,
KELLER,
A.,
AND ASANUMA,
H. Long-term potentia-
tion of motor cortex. Science Wash. DC 245: 1385-1387, 1989.
JACOBS,
K. M.
AND DONOGHUE,
J. P. Reshaping the cortical motor map by
unmasking latent intracortical connections. Science Wash. DC 25 1: 944-
947, 1991.
JENKINS,
W. M.,
MERZENICH,
M. M.,
AND RECANZONE,
G. Neocortical
representational dynamics in adult primates: implications for neuropsy-
chology. Neuropsychologia 28: 573-584, 1990.
KAAS,
J. H. Plasticity of sensory and motor maps in adult mammals. Annu.
Rev. Neurosci. 14: 137-167, 1991.
LEVY,
W. J.,
AMASSIAN,
V. E.,
SCHIMD,
U. D.,
AND JUNGREIS,
C. Mapping
of motor cortex gyral sites non-invasively by transcranial magnetic stimu-
lation in normal subjects and patients. In: Magnetic Motor Stimulation:
Basic Principles and Clinical Experience, edited by W. J. Levy, R. Q.
Cracco, A. T. Barker, and J. Rothwell. Amsterdam: Elsevier, 1991, p.
51-75.
MACCABEE,
P. J.,
AMASSIAN,
V. E.,
EBERLE,
L.,
AND
CRACCO, R. Q. Mag-
netic coil stimulation of straight and bent amphibian and mammalian
peripheral nerve in vitro: locus of excitation. J. Physiol. Land. 460: 201-
219, 1993.
MACCABEE,
P. J.,
EBERLE,
L.,
AMASSIAN,
V. E., CRACCO, R. Q.,
RUDELL,
A. P.,
AND JAYACHANDRA,
M. Spatial distribution of the electric field
induced in volume by a round and figure ‘8’ magnetic coils: relevance
to activation of sensory nerve fibers. Electroencephalogr. Clin. Neuro-
physiol. 76: 131-141, 1990.
MCBRIDE, E. R.
AND ROTHSTEIN,
A. L. Mental and physical practice and
the learning and retention of open and closed skills. Percept. Mot. Skills
49: 359-365, 1979.
MENDOZA,
D. W.
AND WICHMAN,
H. ‘Inner’ darts: effects of mental practice
on performance of dart throwing. Percept. Mot. Skills 47: 1195- 1199,
1978.
MERZENICH,
M. M.,
F&CANZONE,
G. H.,
JENKINS,
W. M.,
AND
GRAJSKI,
K. A. Adaptive mechanisms in cortical networks underlying cortical con-
tributions to learning and nondeclarative memory. Cold Spring Harbor
Symp. Quant. Biol. 55: 873-887, 1990.
MITZ,
A. R.,
GODSCHALK,
M.,
AND WISE,
S. P. Learning-dependent neuronal
activity in the premotor cortex: activity during the acquisition of condi-
tional motor associations. J. Neurosci. 11: 1855- 1872, 1991.
NIEMANN,
J.,
WINKER,
T.,
GERLING,
J.,
LANDWEHRMEYER,
B.,
AND JUNG,
R. Changes in slow cortical negative DC-potentials during the acquisi-
tion of a complex finger motor task. Exp. Brain Res. 85: 417-422,
1991.
NUDO,
R. J.,
JENKINS,
W. M.,
MERZENICH,
M. M.,
PREJEAN,
T.,
AND
GRENDA,
R. Neurophysiological correlates of hand preference in primary
motor cortex of adult squirrel monkeys. J. Neurosci. 12: 2918-2947,
1992.
OJAKANGAS,
C. L.
AND EBNER,
T. J. Purkinje cell complex and simple
spike changes during a voluntary arm movement learning task in the
monkey. J. Neurophysiol. 68: 2222-2236, 1992.
OLDFIELD,
R. C. The assessment and analysis of handedness: the Edinburgh
inventory. Neuropsychologia 9: 97 - 113, 197 1.
PASCUAL-LEONE,
A.,
CAMMAROTA,
A.,
WASSERMANN,
E. M.,
COHEN,
L. G.,
AND HALLETT,
M. Modulation of motor cortical outputs to the reading
hand of Braille readers. Ann. Neural. 34: 33 -37, 1993.
PASCUAL-LEONE,
A.,
COHEN,
L. G.,
AND HALLETT,
M. Noninvasive evalua-
tion of plastic changes in human motor system. Trends Neurosci. 15:
13-15, 1992.
PASCUAL-LEONE,
A.,
GRAFMAN,
J.,
AND HALLETT,
M. Modulation of cortical
motor output maps during the development of implicit and explicit knowl-
edge. Science Wash. DC 263: 1287-1289, 1994.
PASCUAL-LEONE,
A.
AND TORRES,
F. Plasticity of the sensorimotor cortex
representation of the reading finger in Braille readers. Brain 116: 39-
52, 1993.
PONS,
T. P.,
GARRAGHTY,
P. E.,
OMMAYA,
A. K.,
KASS,
J. H.,
TAUB,
E.,
AND MISHKIN,
M. Massive cortical reorganization after sensory deafferen-
tation in adult macaques. Science Wash. DC 252: 1857- 1860, 199 1.
RECANZONE,
G. H.,
JENKINS,
W. M., HRADEK, G. T.,
AND MERZENICH,
M. M. Progressive improvement in discriminative abilities in adult owl
monkeys performing a tactile frequency discrimination task. J. Neuro-
physiol. 67: 1015-1030, 1992a.
RECANZONE,
G. H.,
MERZENICH,
M. M.,
AND JENKINS,
W. M. Frequency
discrimination training engaging a restricted skin surface results in an
emergence of a cutaneous response zone in cortical area 3a. J. Neurophys-
iol. 67: 1057-1070, 1992b.
RECANZONE,
G. H.,
MERZENICH,
M. M.,
JENKINS,
W. M.,
GRAJSKI,
K. A.,
AND DINSE,
H. R. Topographic reorganization of the hand representation
in cortical area 3b owl monkeys trained in a frequency-discrimination
task. J. Neurophysiol. 67: 1031-1056, 1992~.
RECANZONE,
G. H.,
MERZENICH,
M. M.,
AND SCHREINER,
C. E. Changes in
the distributed temporal response properties of SI cortical neurons reflect
improvements in performance on a temporally based tactile discrimina-
tion task. J. Neurophysiol. 67: 107 1- 1091, 1992d.
ROLAND,
P. E.,
ERICKSSON,
L.,
STONE-ELANDER,
S.,
AND WIDEN,
L. Does
mental activity change the oxidative metabolism of the brain? J. Neu-
rosci. 7: 2373-2389, 1987.
ROLAND,
P. E.
AND FRIBERG,
L. Localization of cortical areas activated by
thinking. J. Neurophysiol. 53: 1219-1243, 1985.
ROLAND,
P. E.,
LARSEN,
B.,
LASSEN,
N. A.,
AND SIUNHOJ,
E. Supplementary
motor area and other cortical areas in organization of voluntary move-
ments in man. J. Neurophysiol. 43: 118- 136, 1980.
ROLAND,
P. E.,
MEYER,
E.,
SHIBASAKI,
T.,
YAMAMOTO,
Y. L.,
AND THOMP-
SON,
C. J. Regional cerebral blood flow changes in cortex and ganglia
during voluntary movements in normal human volunteers. J. Neurophys-
iol. 48: 467-478, 1982.
ROTH,
B. J.,
COHEN,
L. G.,
AND HALLETT,
M. The electric field induced
during transcranial magnetic stimulation. Electroencephalogr. Clin. Neu-
rophysiol. Suppl. 43: 268-278, 1991a.
ROTH,
B. J.,
SAYPOL,
J. M.,
HALLETT,
M.,
AND COHEN,
L. G. A theoretical
CORTICAL MOTOR OUTPUTS IN ACQUISITION OF MOTOR SKILLS 1045
calculation of the electric field induced in the cortex during magnetic
stimulation. Electroencephalogr. Clin. Neurophysiol. 8 1: 47-56,
1991b.
SANES, J. N., WANG, J., AND DONOGHUE, J. P. Immediate and delayed
changes of rat motor cortical output representation with new forelimb
configurations. Cereb. Cortex 2: 141- 152, 1992.
SCHIEBER, M. H. Widely distributed neuron activity in primary motor cortex
area during individuated finger movements. Sot. Neurosci. Abstr. 18:
504, 1992.
SCHONBERG, H. Great Pianists. St. Louis, MO: Fireside Books, 1987.
SCHONBERG, H. The Virtuosi. New York: Vintage-Random House, 1988.
SEITZ, R. J., ROLAND, E., BOHM, C., GREITZ, T., AND STONE-ELANDER, S.
Motor learning in man: a positron emission tomographic study. Neurore-
port 1: 57-60, 1990.
SUINN, R. M. Imagery and sport. In: Imagery and Sport, edited by W. F.
Straub and J. M. Williams. Lansing, NY: Sport Science Associates, 1984.
TOFTS, P. S. The distribution of induced currents in magnetic stimulation
of the nervous system. Phys. Med. Biol. 35: 1119-l 128, 1990.
WASSERMANN, E. M., MCSHANE, L. M., HALLETT, M., AND COHEN, L. G.
Noninvasive mapping of muscle representations in human motor cortex.
Electroencephalogr. Clin. Neurophysiol. 85: 1 - 12, 199 1.
WASSERMANN, E. M., WANG, B., TORO, C., ZEFFIRO, T., VALLS-SOL& J.,
PASCUAL-LEONE, A., AND HALLETT, M. Projecting transcranial magnetic
stimulation (TMS ) maps into brain MRI. Sot. Neurosci. Abstr. 18: 939,
1992.
WHITE, C. A., ASHTON, R., AND LEWIS, S. Learning a complex skill: effect
of mental practice, physical practice and imagery ability. Znt. J. Sports
Psychol. 10: 71-78, 1979.
