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The Journal of Neuroscience, May 1, 1998, 18(9):3443-3450
Mechanisms of Cortical Reorganization in Lower-Limb Amputees
Robert
Chen,
Brian
Corwell,
Zaneb
Yaseen,
Mark
Hallett, and
Leonardo G.
Cohen
Human Cortical Physiology Unit, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
20892-1430
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ABSTRACT |
The human motor system undergoes reorganization after amputation,
but the site of motor reorganization and the mechanisms involved are
unknown. We studied the site and mechanisms of motor reorganization in
16 subjects with traumatic lower-limb amputation. Stimulation at
different levels in the CNS was used to determine the site of
reorganization. The mechanisms involved were evaluated by measuring the
thresholds for transcranial magnetic stimulation (TMS) and by testing
intracortical inhibition and facilitation. With TMS, the threshold for
muscle activation on the amputated side was lower than that of the
intact side, but with transcranial electrical stimulation there was no
difference in motor threshold between the two sides. TMS at the maximal
output of the stimulator activated a higher percentage of the motor
neuron pool (%MNP) on the amputated side than on the intact side. The
%MNP activated by spinal electrical stimulation was similar on the two
sides. Paired TMS study showed significantly less intracortical
inhibition on the amputated side. Our findings suggest that motor
reorganization after lower-limb amputation occurs predominately at the
cortical level. The mechanisms involved are likely to include reduction of GABAergic inhibition.
Key words:
amputation; motor reorganization; mechanisms of
plasticity; human; transcranial magnetic stimulation; motor cortex
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INTRODUCTION |
The motor system undergoes
reorganization after peripheral nerve lesions (Donoghue et al., 1990 ;
Sanes et al., 1990), spinal cord injuries (Levy et al., 1990; Topka et
al., 1991), cortical lesions (Jenkins and Merzenich, 1987; Benecke et
al., 1991; Cohen et al., 1991b; Weiller et al., 1992; Nudo et
al., 1996), amputations (Hall et al., 1990; Cohen et al., 1991a; Fuhr
et al., 1992; Kew et al., 1994; Ridding and Rothwell, 1995), and
transient deafferentation induced by ischemia (Brasil-Neto et al.,
1992, 1993). The changes after spinal cord injury and transient
deafferentation are more prominent with the target muscle at rest
than during voluntary activation (Topka et al., 1991; Ridding and
Rothwell, 1995). Using ischemic deafferentation of the forearm as a
model for short-term plasticity in humans, we recently showed that
plastic changes in the deafferented motor cortex can be upregulated by
transcranial magnetic stimulation (TMS) to the deafferented cortex and
downregulated by TMS to the contralateral motor cortex (Ziemann et al.,
1998). Although experiments in animals have shown that reorganization can occur at multiple levels, including the cortex (Pons et al., 1988;
Recanzone et al., 1992; Merzenich and Jenkins, 1993; Darian-Smith and
Gilbert, 1994, 1995), thalamus (Garraghty and Kass, 1991; Pons et al.,
1991; Nicolelis et al., 1993), brainstem (Pons et al., 1991; Florence
and Kaas, 1995), and spinal cord (Carp and Wolpaw, 1994; Florence and
Kaas, 1995), the site of motor reorganization in humans is not known.
Whereas animal studies have shown that GABAergic (Hendry and Jones,
1986; Welker et al., 1989; Jacobs and Donoghue, 1991), glutaminergic
(Anwyl, 1991; Garraghty et al., 1993; Conti et al., 1996), and
cholinergic mechanisms (Juliano et al., 1991) are involved in different
forms of cortical plasticity, the mechanisms of human plasticity are
also unclear. Understanding of these mechanisms is crucial to the
design of rational strategies to modulate plasticity and to enhance
recovery of function.
Studies with TMS may provide insights into the mechanisms of plasticity
in humans. The motor threshold (MT) is influenced by changes in
voltage-gated ion channels (Ziemann et al., 1996b; Chen et al., 1997),
whereas intracortical inhibition tested by paired pulse TMS (Kujirai et
al., 1993) is related to GABAergic mechanisms (Ziemann et al.,
1996a,b). In the present study, we examined the site of motor
reorganization with stimulation at different levels of the CNS and
studied the mechanisms involved with testing for MT and with paired
pulse TMS in subjects with lower-limb amputation.
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MATERIALS AND METHODS |
We studied 14 subjects (10 men and 4 women), aged 25-76 (mean,
52.2) years, with unilateral amputation and two subjects, aged 48 and
60 years, with bilateral amputation of the lower limbs. The amputations
were above the knee in nine subjects and below the knee in seven
subjects. The right leg was amputated in seven subjects, and the left
leg was amputated in seven others. Amputation had occurred 7 months to
53 years (mean, 13.7 years) earlier. A prosthesis was used by 13 of the
16 subjects. The reasons for amputation were gunshot wound or explosion
(six subjects), peripheral vascular disease (four), motor vehicle or
industrial accident (three), osteosarcoma (one), chondrosarcoma (one),
and chronic osteomyelitis (one). None of the subjects had any
neurological disorders, and all had normal findings on the neurological
examination, except one subject who had mild distal sensory loss in the
intact lower limb. All subjects gave their written informed consent for the study, and the protocol was approved by the Institutional Review
Board.
Recordings. A surface EMG was recorded from the quadriceps
femoris muscle bilaterally with silver-silver chloride electrodes. For
below-knee amputees, the electrodes were placed on the anterior aspect
of the midthigh overlying the quadriceps muscle and on the muscle
tendon just above the patella. For above-knee amputees, the electrodes
were placed at the midpoint between the stump and the inguinal ligament
overlying the quadriceps muscle and at the stump. On the intact side,
the electrodes were placed in symmetrical positions. The signals were
filtered (bandpass, 50 Hz-2 KHz), amplified, displayed (Counterpoint
electromyograph; Dantec, Skovlunde, Denmark), and stored in a
laboratory computer for off-line analysis. The peak-to-peak amplitudes
of motor-evoked potentials (MEPs) were measured.
Transcranial magnetic stimulation. TMS was delivered through
a 9 cm circular coil and two Magstim 200 stimulators connected via a
Quadconnect module (Magstim, Dyfed, UK). The circular coil was used
because in preliminary studies MEPs could not always be elicited from
the quadriceps muscle with the more focally stimulating eight-shaped
coil (Cohen et al., 1990), even at 100% of the output of the
stimulator. When viewed from above, the current direction in the
circular coil is counterclockwise (side A) for stimulation of the left
hemisphere and clockwise (side B) for stimulation of the right
hemisphere. The induced current therefore flows in a
posterior-to-anterior direction for both hemispheres. The site of
activation by TMS depends on the direction of the current induced in
the brain. Posteroanterior current used in the present study predominately activates pyramidal tract neurons transynaptically via
cortical interneurons, producing indirect corticospinal waves (I-waves)
at threshold intensity (Werhahn et al., 1994; Kaneko et al., 1996;
Nakamura et al., 1996). The coil was initially centered on the vertex
and then moved in 1 cm steps in the anteroposterior and mediolateral
directions to determine the optimal scalp position for eliciting MEPs
from each quadriceps muscle. The optimal positions were marked on the
scalp to ensure identical coil placement throughout the study. The MT
and maximum MEP amplitudes were measured in all subjects. MT was
determined at rest to the nearest 1% of the output of the stimulator
and was the minimum intensity required to evoke an MEP of >50 µV in
at least 5 of 10 trials. The maximum MEP amplitude was the largest of
three MEPs evoked at 100% of the output of the stimulator. Muscle
relaxation was monitored with audio feedback at a sensitivity of 50 µV/division, and trials with background facilitation were
excluded.
Paired TMS studies. We used the paired TMS technique, which
measures changes in the test MEP amplitude caused by a subthreshold conditioning stimulus, to study intracortical inhibition and
facilitation (Kujirai et al., 1993; Ziemann et al., 1996c; Nakamura et
al., 1997b).
Nine subjects with unilateral amputation and two with bilateral
amputation participated in the paired TMS studies. Both the amputated
and the intact sides were tested in seven unilateral amputees. In two
unilateral amputees, only the amputated side was tested, because the MT
on the intact side was too high for paired TMS. The paradigm used was
similar to that described by Kujirai et al. (1993). Because the
paradigm using paired TMS and a circular coil to study lower-limb
muscles has not been described, we also studied seven normal subjects
(five men and two women), aged 31-53 (mean, 39.3) years. The
subthreshold conditioning stimulus was set at 80% of the resting MT
(Kujirai et al., 1993), because it is in the middle of the range of
conditioning stimulus intensities that stable intracortical inhibition
is observed. In another study of 12 normal subjects, conditioning
stimulus intensities from 60-90% of the resting MT did not change
intracortical inhibition in the quadriceps femoris muscle (R. Chen and
L. Cohen, unpublished observations). The intensity of the
suprathreshold test stimulus was adjusted to produce MEPs of ~0.3 mV
peak-to-peak amplitude and was usually 110-120% of the MT. Single
test pulses and paired stimuli with interstimulus intervals (ISIs) of
2, 4, 6, 8, 10, 15, and 30 msec were delivered 6 sec apart in a
pseudorandom order controlled by a laboratory computer. For each ISI,
10 trials were recorded, and test MEP amplitudes were expressed as a
percentage of the mean amplitude of the test MEP given alone.
The average inhibition and facilitation were determined as the mean
test MEP amplitude of the inhibitory ISIs (2 and 4 msec) and the
facilitatory ISIs (10 and 15 msec) for the amputated and intact sides
of the amputees and for the normal subjects. The maximum degree of
inhibition and facilitation achieved at any ISI on each side was also
assessed.
Effects of subthreshold TMS on spinal excitability. Although
in upper-limb muscles the subthreshold conditioning stimulus (80% of
the resting MT) does not change spinal excitability (Kujirai et al.,
1993; Ziemann et al., 1996c), the effects of the subthreshold conditioning pulse on the spinal excitability of lower-limb muscles are
unknown. We therefore studied the effects of the subthreshold conditioning pulse on quadriceps motor neuron excitability with Hoffmann's reflexes (H-reflexes) in six normal subjects (three men and
three women), aged 28-66 (mean 49.3) years, and in three amputees (one
man and two women), aged 39-70 years. The conditioning stimulus was
TMS at 80% of the MT. The test stimulus was either suprathreshold TMS
to produce MEPs of ~0.3 mV or electrical stimulation of the femoral
nerve at the inguinal fold capable of eliciting H-reflexes with
consistent amplitudes. For the suprathreshold TMS test stimulus, ISIs
of 2 msec (inhibitory) and 10 msec (facilitatory) were used. For
femoral nerve stimulation (FNS), the cathode was a 1 cm metallic sphere
mounted on a frame that was attached to the upper thigh by Velcro
straps. The cathode was firmly fixed at the optimal position for
eliciting H-reflexes at the level of the inguinal ligament. The anode
was a 3 cm metal plate attached to the posterior thigh. The stimulus
duration was 1 msec, and the stimulus intensity was adjusted to elicit
H-reflexes with amplitudes of ~5% of the compound muscle action
potential (CMAP), because the degree of facilitation and inhibition of
test H-reflexes is dependent on the size of the control H-reflexes
(Meinck, 1980). Three ISIs were studied: (1) 0 msec, with the
conditioning TMS and FNS arriving at the spinal cord simultaneously
(ISI = TMS latency  H-reflex latency); (2) 2 msec, with the
conditioning TMS arriving at the spinal cord 2 msec before the FNS
(ISI = 2 msec + TMS latency H-reflex latency), which
corresponds to the inhibitory ISI in the paired TMS study; and (3) 10 msec, with the conditioning TMS arriving at the spinal cord 10 msec
before the FNS (ISI = 10 msec + TMS latency H-reflex
latency), which corresponds to the facilitatory ISI in the paired TMS
study. Ten trials were performed for the single-test stimulus and each
ISI in random order.
Transcranial electrical stimulation. Transcranial electrical
stimulation (TES) of the motor representations for both upper-limb (Day
et al., 1987; Amassian et al., 1990; Thompson et al., 1991; Nakamura et
al., 1996) and lower-limb (Edgley et al., 1997; Nakamura et
al., 1997a) muscles predominately activates pyramidal tract neurons
directly, producing direct waves (D-waves) at threshold intensity. TES
was performed using a Digitimer D180 high-voltage electrical stimulator
(Digitimer Ltd., Welwyn Garden City, UK). Gold-plated electrodes, 1 cm
in diameter, were placed at CZ as the anode and at
FZ as the cathode (international 10-20 system). Because
TES is painful, some subjects did not participate. MT, which required
multiple stimuli, was determined in seven subjects, and maximum MEP
amplitude was measured in 13 subjects. MT was determined at rest to the
nearest 2% of the maximum output of the stimulator and was the minimum
stimulus intensity required to evoke an MEP of >50 µV in two
consecutive trials. Maximum MEP amplitude was determined at 100% of
the output of the stimulator (750 V; time constant, 100 µsec).
Spinal electrical stimulation. Spinal electrical stimulation
(SES), which stimulates descending tracts in the spinal cord, was used
to test spinal excitability. SES was performed in 13 subjects. A
Digitimer D180 stimulator, with the cathode placed at the C-7 level and
the anode placed 10 cm below, was used. The maximum amplitude evoked at
100% of the output of the stimulator was determined. MT was not
measured because of the discomfort associated with the procedure.
Femoral nerve stimulation. The CMAP was determined by
supramaximal electrical stimulation of the femoral nerve at the
inguinal ligament. The maximum MEPs obtained by TMS, TES, and SES were expressed as a percentage of the CMAP to provide an estimate of the
%MNP activated (Fuhr et al., 1992).
Statistical analysis. The Wilcoxon signed ranks test was
used to compare the MT, maximum amplitude, %MNP activated, and
inhibition and facilitation in the paired TMS study on the amputated
and intact sides. The Mann-Whitney U test was used to
compare the difference in inhibition and facilitation between amputees
and normal subjects in the paired TMS study. Differences were
considered significant if p < 0.01 (Bonferroni
correction to account for multiple comparisons).
The relationship between clinical information and the extent of
reorganization was tested with analysis of covariance (ANCOVA). The
factors in the ANCOVA model were time from amputation, type of
amputation (above or below the knee), and use of prosthesis. The
dependent variables were the ratio of the amputated to the intact sides
for measurements that were significantly different between the two
sides. Differences were considered significant if p < 0.05.
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RESULTS |
Thresholds to TMS and TES
MTs for TMS were lower on the amputated side (76.1 ± 2.8%;
mean ± SEM) than on the intact side (88.5 ± 2.3%)
(p = 0.001) in every subject. MTs for TES were
similar on both sides (amputated side, 65.3 ± 8.8%; intact side,
67.7 ± 8.8%) (Fig. 1).
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Figure 1.
Motor threshold for transcranial magnetic
stimulation (A; n = 14) and
transcranial electrical stimulation (B;
n = 7). Each line represents one
subject, and each error bar represents 1 SEM.
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Maximum MEP amplitude to TMS, TES, SES, and FNS
Maximum MEP amplitudes were not significantly different on the
amputated and intact sides for TMS (amputated side, 474 ± 126 mV;
intact side, 319 ± 78 mV) and TES (amputated side, 626 ± 186 mV; intact side, 740 ± 306 mV). With SES, the maximum
amplitude was lower on the amputated side (638 ± 300 mV) than on
the intact side (1823 ± 1059 mV), but the differences were not
statistically significant. The femoral CMAP was significantly smaller
on the amputated side (2630 ± 423 mV) than on the intact side
(5773 ± 934 mV) (p = 0.001) (Fig.
2A).
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Figure 2.
A, Maximum amplitudes produced by
TMS (n = 14), TES (n = 13), SES
(n = 13), and FNS (n = 14).
B, Percentage of motor neuron pool activated with TMS
(n = 14), TES (n = 13), and SES
(n = 13). MEP, Motor-evoked
potential; TMS, transcranial magnetic stimulation;
TES, transcranial electrical stimulation;
SES, spinal electrical stimulation; FNS,
femoral nerve stimulation. Asterisks indicate a
significant difference between the amputated and intact sides. Error
bar indicates 1 SEM.
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Percentage of motor neuron pool activated
A significantly larger %MNP was activated by TMS on the amputated
side (21.6 ± 4.4%) than on the intact side (6.4 ± 1.6%) (p = 0.001). TES showed a nonsignificant trend
toward a larger %MNP recruited on the amputated side (26.0 ± 6.5%) than on the intact side (11.9 ± 2.8%). The %MNP
activated by SES was similar on both sides (amputated side, 25.8 ± 9.7%; intact side, 23.8 ± 8.9%) (Fig.
2B).
Paired TMS studies
The results of the paired TMS studies for the normal subjects and
the intact side of the amputees were similar, and both showed inhibition at ISIs of 2 and 4 msec, followed by facilitation at ISIs of
10-30 msec (Fig. 3). The amputated side
showed more facilitation at all ISIs from 2 to 30 msec compared with
the intact side and with normal subjects (Fig. 3). At the inhibitory
ISIs of 2 and 4 msec, the test MEP amplitude on the amputated side
(240 ± 121% of control) was significantly larger compared with
the intact side (60.1 ± 7.6%) (p = 0.01, Wilcoxon signed ranks test) and with normal subjects (59.6 ± 7.5%) (p = 0.01, Mann-Whitney U
test) (Fig. 4A). The
difference in the test MEP amplitude between the amputees' intact side
and normal subjects was not significant. At the facilitatory ISIs of 10 and 15 msec, the facilitation of the test MEP was greater on the
amputated side (384 ± 154%) compared with the intact side
(285 ± 78.2%) and with normal subjects (296 ± 40.8%), but
the differences were not significant (Fig. 4A). The
maximum inhibition obtained on the amputated side (MEP amplitude, 81.1 ± 14.2% of control) was less than that on the amputees'
intact side (38.2 ± 6.7%) and in normal subjects (32.7 ± 7.3%) (Fig. 4B). The difference in the test MEP
amplitude between the amputated and intact sides was not significant
(p = 0.02, Wilcoxon signed ranks test), but the
difference between the amputated side and normal subjects was
significant (p = 0.01, Mann-Whitney
U test). The maximum facilitation was larger on the
amputated side (620 ± 254%) compared with the intact side
(308 ± 81.3%) and with normal subjects (345 ± 43.7%), but
the differences were not significant (Fig. 4B).
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Figure 3.
Paired TMS study. Interstimulus interval (ISI) of
0 represents the MEP amplitude of the test pulse alone, which is
defined as 100%. Each point represents an average of 11 subjects for the amputated side, seven subjects for the intact side,
and seven normal subjects. On the intact side and in normal subjects,
there was inhibition at ISIs of 2 and 4 msec and facilitation at ISIs
of 6-30 msec. On the amputated side, there was more facilitation than
on the intact side at all ISIs. Error bar indicates 1 SEM.
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Figure 4.
A, Average MEP amplitude for
inhibitory ISIs of 2 and 4 msec and facilitatory ISIs of 10 and 15 msec. B, Maximum inhibition and facilitation among all
ISIs. The asterisk indicates a significant difference
between the amputated and intact sides, and plus signs
indicate a significant difference between the amputated side and normal
subjects.
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Without the conditioning pulse, the test MEP amplitude was similar on
both sides (amputated side, 209 ± 55 mV; intact side, 277 ± 65 mV).
Effects of subthreshold TMS on femoral H-reflex
In all six normal subjects, paired TMS trials showed inhibition of
the test MEP at the ISI of 2 msec (MEP amplitude, 32 ± 2.9% of
control) and facilitation at the ISI of 10 msec (MEP amplitude, 351 ± 37.3% of control), but there was no change in the H-reflex amplitude at any ISIs (101 ± 4.9% at 0 msec, 93.7 ± 10%
at 2 msec, and 113.4 ± 7.9% at 10 msec) (Fig.
5A).
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Figure 5.
A subthreshold conditioning TMS was followed by
either a suprathreshold test TMS (paired TMS) or electrical stimulation
of the femoral nerve to elicit an H-reflex (femoral H-reflex). The ISI
indicated for the femoral nerve H-reflex study reflects the potential
arrival time of the stimuli at the spinal cord. The actual ISIs between
TMS and femoral nerve stimulation were adjusted in each subject
according to the TMS and H-reflex latencies. A, Results
from six normal subjects. There was significant inhibition of the TMS
test response at the ISI of 2 msec and facilitation at the ISI of 10 msec, but the femoral H-reflex amplitude was unchanged at all ISIs.
B, Results from the amputated side of three lower-limb
amputees. Each line represents one subject. The TMS test
responses were inhibited (2 amputees) or facilitated (1 amputee) at the
ISI of 2 msec and was facilitated at the ISI of 10 msec. The femoral
H-reflex amplitude was unchanged at all ISIs.
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On the amputated side of the three amputees, paired TMS at 2 msec
resulted in inhibition of the test MEP in two of them (42.3 and 62.8%)
and facilitation (275%) in one of them. All three amputees showed
facilitation of the test pulse at the ISI of 10 msec (171, 174, and
600%). Again, there was no change in the amplitude of the H-reflex at
any ISIs (95.5, 97.8, and 105% at 0 msec; 98.1, 96.2, and 102% at 2 msec; and 102, 94.4, and 117% at 10 msec) (Fig. 5B). The
intact side was also studied in one amputee (the resting MT was too
high for paired TMS in the two other amputees). The test MEP was
inhibited at the ISI of 2 msec (65.8%) and facilitated at the ISI of
10 msec (180%), but the H-reflex amplitude was unchanged at the ISI of
0 msec (118%), 2 msec (106%), and 10 msec (115%), which is similar
to the results in the six normal subjects.
Relationship between clinical information and
physiological measurements
There were no significant effects of the time from amputation,
type of amputation (above or below the knee), or use of prosthesis on
any of the physiological measurements that were significantly different
between the amputated and intact sides (TMS threshold, %MNP activated
by TMS, and average inhibition at ISIs of 2 and 4 msec in paired TMS
studies).
| |
DISCUSSION |
Site of motor reorganization
The recruitment of a similar %MNP by SES, which activates
descending tracts in the spinal cord, on the amputated and intact sides
indicates that spinal excitability, as measured with the present
techniques, is largely unchanged after amputation. These findings point
to supraspinal sites for motor reorganization. The MT for TMS was lower
on the amputated side than on the intact side, but TES thresholds were
similar on both sides. Recent studies recording spinal volleys in
monkeys (Edgley et al., 1997) and humans (Nakamura et al., 1997a)
clarified the site of activation for TMS and TES of the leg motor
representation. Recordings from the lumbosacral cord of anesthetized
monkeys revealed that, at the threshold for recording responses from
the surface of the spinal cord, more D-waves were elicited by TES than
by TMS, and that TMS evoked a higher proportion of I-waves (Edgley et
al., 1997). Recordings from the thoracic epidural space in awake humans also showed that TMS (with posteroanterior current direction) over the
leg motor area had a lower threshold for I-waves than D-waves (Nakamura
et al., 1997a). These studies indicate that stimulation of the leg
motor area by TMS at threshold intensity with posteroanterior current
direction used in the present study results in predominately
transynaptic activation of pyramidal neurons, whereas TES leads to
predominately direct activation of pyramidal tract axons. The different
findings for TMS and TES thresholds therefore suggest that a major part
of motor reorganization after lower-limb amputation occurs at the
cortical level.
The %MNP activated by both TMS and TES was higher on the amputated
side than on the intact side, with a bigger difference for TMS. Because
the TMS threshold was lower on the amputated side, the recruitment of a
higher %MNP was likely caused by higher stimulus intensity as a ratio
to TMS threshold. There may also be a more rapid rise in MEP amplitude
with increasing TMS intensities on the amputated side (Ridding and
Rothwell, 1997). At high intensities, TES activates pyramidal tract
neurons not only directly, but also transynaptically (Day et al., 1989;
Rothwell et al., 1991; Edgley et al., 1997). The trend toward a higher
%MNP activated by maximal TES on the amputated side is likely the
result of increased transynaptic activation of pyramidal tract neurons
at high stimulus intensities. MEPs to SES and CMAPs were smaller on the
amputated side than on the intact side, probably because of muscle
atrophy on the amputated side (Fuhr et al., 1992). Therefore, our
results are consistent with the interpretation that motor
reorganization after amputation predominately takes place at the
cortical level.
Differences in the reorganization of the somatosensory and
motor systems
The somatosensory pathway from the periphery to the cortex
involves synapses in the spinal cord, the dorsal column nuclei in the
brainstem, and the thalamus. Reorganization of the somatosensory system
can occur at both cortical (Merzenich and Jenkins, 1993; Darian-Smith
and Gilbert, 1994, 1995) and subcortical (Florence and Kaas,
1995; Davis et al., 1998) sites. On the other hand, the corticospinal
pathway from the motor cortex to muscles requires only synapses in the
spinal cord. Therefore, there are fewer subcortical sites in the motor
system than in the somatosensory system at which reorganization can
take place.
After amputation, areas of the somatosensory cortex that were
responsive to the missing inputs became responsive to stimulation of
neighboring body parts (Pons et al., 1991; Flor et al., 1995; Florence
and Kaas, 1995). The somatosensory cortex has specific projections to
layers II and III of the motor cortex that are closely connected to
motor output neurons in layer V (Kenko et al., 1994a,b). Stimulation of
the somatosensory cortex can induce long-term potentiation (LTP) in the
motor cortex (Sakamoto et al., 1987), and projections from the
somatosensory cortex to the motor cortex are important in the
acquisition of motor skills (Pavlides et al., 1993). Therefore,
reorganization in the motor cortex may be secondary to changes in the
somatosensory cortex.
Mechanisms underlying changes in TMS threshold
The MT for TMS was lower for the amputated side, a finding
consistent with reduced threshold for evoking limb movements by intracortical electrical stimulation of the motor cortex after amputation or nerve lesion in rats (Donoghue and Sanes, 1988; Sanes et
al., 1990). Because drugs that increase GABAergic inhibition do not
alter the MT for TMS (Ziemann et al., 1996a,b), modulation of GABAergic
mechanisms cannot explain changes in the MT. However, drugs that block
voltage-gated sodium channels raise the MT without changes in
intracortical inhibition or facilitation (Ziemann et al., 1996b; Chen
et al., 1997). One possible mechanism therefore involves changes in
sodium channels, which have been implicated in other forms of
plasticity (Carp and Wolpaw, 1994; Halter et al., 1995).
Other potential mechanisms, particularly those that may mediate
long-term reorganization, should also be considered. These include LTP
(Garraghty and Muja, 1996; Dykes, 1997), which has been demonstrated in
the motor cortex (Hess and Donoghue, 1994). Because our subjects'
lower limbs were amputated months to years previously, structural
alterations in synaptic size or shape or the formation of new synapses
may also be involved (Kaas, 1991; Keller et al., 1992; Darian-Smith and
Gilbert, 1994).
Mechanisms underlying intracortical inhibition
and facilitation
We found that intracortical inhibition is significantly reduced on
the amputated side compared with the intact side or normal subjects. In
previous TMS studies of intracortical inhibition and facilitation, only
upper-limb muscles were examined with an eight-shaped coil (Kujirai et
al., 1993; Ziemann et al., 1996c). Now, with the quadriceps femoris
muscle and a circular coil, we show that a conditioning stimulus
sufficient to cause inhibition and facilitation did not change spinal
excitability, as tested by H-reflexes in both normal subjects and
amputees. This finding further suggests that the inhibition and
facilitation observed in our experimental paradigm were also mediated
by intracortical mechanisms.
Because drugs that enhance GABAergic inhibition increase
intracortical inhibition but have no effect on MT for TMS
(Ziemann et al., 1996a,b), the reduction of intracortical
inhibition may be attributed to decreased GABAergic inhibition. Several
lines of evidence indicate that modulation of GABAergic inhibition
plays an important role in cortical plasticity. GABA is the most
important inhibitory neurotransmitter in the brain (Jones, 1993). Rapid reorganization of the motor cortex within hours after motor nerve injury (Sanes et al., 1988; Donoghue et al., 1990; Huntley, 1997) may
be mediated by unmasking of latent excitatory synapses attributed to
reduction of GABAergic inhibition (Jacobs and Donoghue, 1991). Deafferentation of the somatosensory thalamus (Ralston et al., 1996),
somatosensory cortex (Welker et al., 1989; Garraghty et al., 1991), and
visual cortex (Hendry and Jones, 1986) also led to a reduction in the
number of neurons containing GABA or its synthetic enzyme glutamic acid
decarboxylase, which in some studies persisted for >5 months (Hendry
and Jones, 1986; Garraghty et al., 1991; Ralston et al., 1996). Our
findings are consistent with the results of these animal studies and
suggest that reduction of GABAergic inhibition participates in plastic
changes after amputation in humans. In addition, reduction of
intracortical inhibition may also be related to strengthening of
facilitatory connections owing to mechanisms such as enhancement of
glutaminergic transmission, LTP, and axonal sprouting (Keller
et al., 1992; Darian-Smith and Gilbert, 1994).
Amputation versus short-term plasticity caused
by deafferentation
Ischemic nerve block in humans induces reorganization of the motor
system within minutes, and the plastic changes are substantially enhanced by TMS of the deafferented cortex (Ziemann et al., 1998). Similar to the findings in amputees, ischemic nerve block with TMS of
the deafferented cortex leads to reduction of intracortical inhibition
(Ziemann et al., 1998), suggesting that modulation of GABAergic
inhibition is involved in plastic changes after both short-term
(ischemic nerve block) and long-term (amputation) deafferentation. On
the other hand, MT for TMS was reduced after amputation (Hall et al.,
1990; Cohen et al., 1991a) but not after ischemic nerve block
(Brasil-Neto et al., 1993; Ridding and Rothwell, 1997; Ziemann et al.,
1998), suggesting that changes in MT may require longer-lasting deafferentation. The timing for changes in MT in humans is similar to
the changes in threshold for evoking forelimb movements by intracortical electrical stimulation of the motor cortex after nerve
lesion in the rat, because the thresholds are reduced with long-term
(weeks to months) (Sanes et al., 1990) but not with short-term (within
hours) (Huntley, 1997) reorganization. These findings are compatible
with the hypothesis that reduction in GABAergic inhibition induces a
permissive state in the cortex that then allows long-term changes to
occur (Dykes, 1997). The long-term changes likely involve an increase
in synaptic efficacy within the motor cortex and may include mechanisms
such as LTP and axonal sprouting (Keller et al., 1992; Darian-Smith and
Gilbert, 1994).
In conclusion, the present study suggests that the motor reorganization
after human lower-limb amputation occurs predominately at the cortical
level and is likely mediated by different mechanisms, including
modulation of GABAergic inhibition.
| |
FOOTNOTES |
Received Nov. 19, 1997; revised Feb. 13, 1998; accepted Feb. 17, 1998.
We thank Dr. Shari DeSilva and Dr. Peter Gorman for referring some of
the subjects in this study, Dr. Mary Kay Floeter for technical advice,
Dr. Ulf Ziemann and Dr. John Rothwell for helpful comments, and B. J. Hessie for skillful editing.
Correspondence should be addressed to Dr. Leonardo G. Cohen, Building
10, Room 5N234, 10 Center Drive, MSC-1430, National Institute of
Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD 20892-1430.
| |
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T. D Sanger, R. R Garg, and R. Chen
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L. G Cohen
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M. H. Schieber
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R. Chen and R. Garg
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M. Hallett
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Top
Abstract
Introduction
