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 Previous Article
The Journal of Neuroscience, September 1, 1999, 19(17):7679-7697
Reorganization in Primary Motor Cortex of Primates with
Long-Standing Therapeutic Amputations
Carolyn W.-H.
Wu and
Jon H.
Kaas
Department of Psychology, Vanderbilt University, Nashville,
Tennessee 37240
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ABSTRACT |
Intracortical microstimulation was used to investigate the
organization of primate primary motor cortex (M1) in three squirrel monkeys and two galagos years after the therapeutic amputation of an
injured forelimb or hindlimb. In two squirrel monkeys with forelimb
amputation, physiological results were correlated with the distribution
of corticospinal neurons after injections of tracers into the lower
cervical segments of the spinal cord. Distributions of labeled
corticospinal neurons helped identify the locations of the former
forelimb cortex in M1. Evoked movements from M1 ipsilateral to the
missing limb were not obviously different from M1 of normal controls.
Stimulation in the deefferented part of M1 contralateral to the missing
limb elicited movements of the remaining proximal muscles as well as
movements from adjacent body representations in all cases. Stimulation
in the deefferented forelimb cortex evoked shoulder stump, trunk, and
orofacial movements, whereas stimulation in the deefferented hindlimb
cortex evoked hip stump, trunk, and tail movements. Movements were
evoked from all sites in the deprived cortex, so that there were no
unresponsive zones. Minimal levels of current necessary to evoke these
movements varied from those in the normal range to those of much higher levels, with the average threshold higher than normal. Finally, multiunit recording from the two galagos revealed that the deprived portions of S1 were responsive to touch or taps on the stump and neighboring body parts.
Key words:
plasticity; microstimulation; frontal lobe; somatosensory
cortex; monkeys; prosimians
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INTRODUCTION |
Presently, we have only a limited
understanding of what happens to motor cortex in adult mammals after
the loss of some of the muscles this cortex controls. Much of what we
know comes from early studies that examined changes in the primary
motor cortex (M1) of rats after amputation of the forelimb or section
of the facial motor nerve (Sanes et al., 1988 , 1990; Donoghue et al., 1990). After these manipulations, the adjacent normal parts of the
representation in M1 appeared to have expanded to create a reorganized
field, and microstimulation in the deefferented portion of M1 evoked
movements of remaining body part at normal or lower than normal levels
of current. Findings consistent with this interpretation have been
obtained by transcranial magnetic stimulation of motor cortex in humans
with amputated limbs (Cohen et al., 1991; Pascual-Leone et al., 1996).
Although the results from this approach are less precise and open to
more interpretation than those from microstimulation, stump movements
were evoked from stimulation sites over deefferented motor cortex.
Similar but somewhat different results were obtained from a single
adult macaque monkey long after the loss of an arm (Schieber and Deuel,
1997). Although movements of the remaining shoulder girdle and arm
stump could be evoked by intracortical microstimulation (ICMS)
throughout the presumed deprived forelimb region of the contralateral
M1, higher stimulus currents were often needed than the opposite M1.
In the present study, we stimulated motor cortex in three squirrel
monkeys and two galagos years after amputations of a forelimb or
hindlimb. In each case, the animals had been injured to such an extent
that a therapeutic amputation was necessary. Our studies of motor
cortex with squirrel monkeys and galagos were aided by the fact that
these primates have only a short, shallow central sulcus, and motor
cortex is exposed on the dorsolateral surface of the cortex, which
allows a thorough systematic mapping. In addition, we used injections
of tracers into the cervical spinal cord of two squirrel monkeys with
forelimb loss to label corticospinal neurons related to forelimb
movements as an aid to identifying the forelimb portion of M1.
With these primates, we sought to determine the following questions.
First, what happens in the deefferented M1 after the loss of a limb?
Would there be a region of deefferented cortex where electrical
stimulation failed to evoke movements, or would adjacent body
representations invade the deefferented cortex? Second, would
stimulation thresholds in the deefferented cortex be normal or changed?
Third, would the nature of the reorganization vary with such factors as
species, age, and site of amputation? Finally, reorganization of
somatosensory cortex after amputation has been studied in monkeys
(Florence and Kaas, 1995) but not in prosimian galagos. Thus, we also
used microelectrode recording to determine whether primary
somatosensory cortex (S1) in galagos is reorganized in a manner
similar to the reorganization that occurs in monkeys.
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MATERIALS AND METHODS |
Microelectrodes were used to electrically stimulate many sites
in motor cortex of three adult squirrel monkeys and two galagos with
long-standing amputations of a limb. In an effort to determine the
organization of motor cortex related to the missing limb, cortex from
normal squirrel monkeys and galagos as well as cortex contralateral to
the intact limb of the amputees were used as comparison. Injections of
tracers in the lower cervical spinal cord of two forelimb-amputated
squirrel monkeys labeled corticospinal neurons in M1, which helped
identify the extent of cortex formerly devoted to the missing limb.
Animals. After an extensive search, we were able to obtain
three adult squirrel monkeys (Saimiri sciureus) and two
galagos (Galago garnetti) with long-standing therapeutic
amputations of a limb. Each of these monkeys had previously received
injury to a limb that was serious enough that the treatment was
surgical amputation of the limb. Except for one animal, all of them
received the amputation before they were adults. Each of these primates lived 4 or more years after the amputation (Table
1). Results were compared with those
obtained from two normal adult squirrel monkeys and four normal adult
galagos. All surgeries were performed under asceptic conditions, and
animals were cared for in accordance with the National Institutes of
Health Guide for the Care and Use of Laboratory Animals and
the guidelines of the Vanderbilt Animal Care and Use Committee.
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Table 1.
Summary of information on the squirrel monkeys and galagos
with long-lasting limb amputation used in this study
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Injection of tracers. Each of the two squirrel monkeys that
received spinal cord injections was premedicated with dexamethasone (2 mg/kg, i.m.) and Robinul (0.015 mg/kg, i.m.) and then anesthetized to
surgical levels with isofluorane gas. Because the motoneurons that
innervate hand muscles are exclusively located in the lower cervical
segments (Kuypers, 1981; Jenny and Inukai, 1983), these segments were
chosen for tracer injections. A short segment of the lower cervical
spinal cord was exposed after identifying vertebrae and dorsal root
entry zones (Hill, 1974; Stevens et al., 1981). The dura was opened on
both sides, and wheat germ agglutinin conjugated to horseradish
peroxidase (WGA-HRP, 2% in saline) was injected into segments C6-C7
(case 98-61) or C7-C8 (case 98-64). Two bilaterally symmetrical 0.5 µl injections were placed at the depths of the intermediate zone and
the ventral horn of the spinal cord gray matter of each side. The
injections were placed with a fine-tipped glass micropipette attached
to a 1 µl Hamilton syringe. The syringe entered the spinal cord at an
angle just lateral to the dorsal columns to avoid damage to the dorsal
column and the dorsolateral funiculus. The opening was closed, and
muscles as well as skin were sutured. Anesthesia was discontinued, and
recovery was rapid and uneventful. Normal movements of the hand were
observed after recovery from anesthesia. Postsurgical care included
treatment with antibiotics and analgesics.
Surgery and perfusion. In general, experimental procedures
followed those used previously in the laboratory (Preuss et al., 1996).
For the microstimulation and somatosensory recording sessions, each
monkey was anesthetized to surgical levels with an initial injection of
Telazol (Tiletamine HCl and Zolazepam HCl, Fort Dodge Laboratories
Inc.) of 10-20 mg/kg, i.m. Anesthesia was maintained by subsequent
injections of one-third of the initial dose as needed. The anesthetized
animals were placed in a stereotaxic apparatus for mapping. Some of the
body hair was clipped so that muscle movements could be easily observed.
For case 98-64, frontal cortex was exposed contralateral to the missing
limb under sterile conditions, and the cortex was kept moist with
sterile saline. After a microstimulation session, the cortex was
covered with sterile, absorbable gelatin film, and the bone flap was
replaced over cortex and cemented in place with dental acrylic. The
skin and muscle were sutured. Anesthesia was discontinued, and
antibiotics and analgesics were given as a precaution. One week later,
the spinal cord was injected, and 5 d later, motor cortex
contralateral to the intact limb was also stimulated as part of a
terminal procedure. In case 98-61, the spinal cord injections were
placed before cortical stimulation, and cortex was exposed and
stimulated bilaterally 6 d later. One squirrel monkey and two
galagos with amputation received no spinal cord injections, and motor
cortex was stimulated unilaterally contralateral to the missing limb.
In addition, microelectrode recordings were obtained from somatosensory
cortex in the two galagos with amputations. The motor cortex of two
normal squirrel monkeys and four galagos was stimulated unilaterally
for comparison. During the terminal sessions, cortex was protected with
silicone fluid to prevent dessication.
At the end of these stimulation sessions, reference lesion sites were
marked in cortex by passing a 10 µA DC current for 10 sec at several
depths in microelectrode penetrations. The animals were then given a
lethal dose of sodium pentobarbital. When they became areflexive, they
were perfused transcardially with PBS, followed first by a cold
solution of 4% paraformaldehyde and next by a mixed solution of 4%
paraformaldehyde and 10% sucrose. Blocks of brain and spinal cord were
removed and stored overnight in 30% sucrose at 5°C before cutting.
Motor mapping. Low-impedance tungsten microelectrodes
(0.9-1.1 M at 1 kHz, Microprobe, Inc.) were used to stimulate
cortex. For most of the M1 region, electrodes were lowered
perpendicularly to the brain surface and with a hydraulic microdrive to
a depth of ~1500 µm below the surface, approximating the level of
cortical layer V, from which movements can be elicited with the lowest levels of current (Stoney et al., 1968; Asanuma and Rosen, 1972; Sato
and Tanji, 1989). In addition, some stimulation sites were in cortex
along the medial wall of the cerebral hemisphere, which was reached by
deeper electrode penetrations that started on the dorsal surface
~1-1.5 mm from the midline. The microstimulation currents were
delivered in 60 msec trains, with a pulse duration of 0.2 msec and a
pulse frequency of 300 Hz. All penetration sites were first stimulated
with a current level that was likely to be above threshold (10-30
µA). If movements were reliably elicited, the current was gradually
reduced until movements no longer occurred. Threshold was defined as
the current level at which the last just noticeable movements were
observed. If a moderate level of stimulation failed to produce
movements, current level was increased to as high as 400 µA.
Unresponsive sites were defined as sites from which movements could not
be evoked at the current level of 400 µA. However, most sites
(>85%) in the explored cortex were responsive at levels well <60
µA. Because electrode displacements as small as 100 µm with
currents <30 µA can produce entirely different movements and
electromyographic responses (McGuinness et al., 1980; Strick and
Preston, 1982), the effective spread of current in the present study
was generally likely to be less than the distances between penetrations
(see Stoney et al., 1968; Nudo et al., 1990).
Movements were detected visually by two observers. Each responsive site
was characterized by visible body movements at the threshold current.
For convenience, movements were grouped into categories involving major
body parts (Table 2). In brief, the orofacial cortex included any movements involving the mouth and face.
The forelimb movements involved the actions of the muscle groups and
joints of the shoulder, arm, and hand. The trunk cortex included upper
and middle torso movements. Finally, the hindlimb cortex comprised
movements of the lower body, including the lower trunk, hip, leg, foot,
and tail. Within each main body representation, movements were
described using terminology commonly applied (Gould et al., 1986;
Preuss et al., 1996). Hand movements were assigned to sites that
included those for which wrist and digit movements were not clearly
dissociable. Similarly, foot movements included ankle and toe movements
that were not clearly dissociable. Arm and leg movement assignments
were made when the movement involved several sections of the limb.
To describe the ICMS results from amputees that received entire limb
removal up to the shoulder or hip joints, we further categorized the
limb movement into two subgroups. Within the forelimb cortex of the
normal control, movements elicited by activity of shoulder girdle were
defined as "shoulder" forelimb movements, and any movements
involving the rest of the forelimb were defined as "nonshoulder"
forelimb movements. The few sites (<8% in normal squirrel monkeys and
<13% in normal galagos) in the forelimb cortex from which axial body
movements were elicited, including neck, chest, or trunk, were referred
to as "nonlimb" movement sites. In the amputated animals,
contractions in both shoulder muscles and stump were observed in few
sites. Movements involving muscles of shoulder, and/or stump were
classified as "shoulder/stump" movements. Movements in hindlimb
cortex were similarly classified into the "hip," "nonhip," and
"tail" hindlimb movement categories for normal animals, as well as
"hip/stump," "nonhip," and "tail" for hindlimb-amputated animals.
Somatosensory recording sessions. In two galagos
microelectrode recordings were obtained from S1 in addition to the
motor cortex mapping. Multiunit activity was recorded in the middle layers (1000-1200 µm) of area 3b in the two limb-amputated galagos by advancing a low-impedance tungsten microelectrode (0.9-1.1 M at
1 kHz) perpendicular to the surface of the brain. The procedure for
somatosensory recordings was similar to that described elsewhere for
galagos (Sur et al., 1980). In brief, neuronal activity was recorded
during cutaneous stimulation of the body using fine probes and camel
hair brushes. Body parts were gently tapped, and joints were
manipulated when cutaneous stimuli failed to evoke neuronal activity.
At each recording site, the receptive field was defined as the skin
area from which near-threshold stimuli effectively evoked responses.
Neuronal responses were amplified, filtered, viewed on an oscilloscope,
and heard through a loudspeaker.
Histology and anatomical analysis. Blocks of brain that
contained frontal and adjoining parts of parietal cortex were cut on a
freezing microtome at 40-50 µm in the coronal plane. Sets of
one-in-six sections were stained for Nissl substance with cresyl violet
or were processed with tetramethylbenzidine to reveal WGA-HRP (Gibson
et al., 1984). Other sets of sections were processed for cytochrome
oxidase (Wong-Riley, 1979) or acetylcholinesterase (Geneser-Jensen and
Blackstad, 1971) to aid in the architectonic identification of motor
cortex. The cervical spinal cord was cut at 60 µm in the coronal
plane, and every one of six sections was processed for WGA-HRP or Nissl
substance. Some tissue was also processed with other histochemical and
immunocytochemical methods for subsequent analysis.
Injection sites in the spinal cord were defined as the zone that
contained the densest reaction product where labeled cells were masked
by the densely stained neuropil (Mesulam, 1978). The extents of the
injection sites and the transported tracer were determined under dark-
and bright-field illumination. Drawings of cortical sections were used
to reconstruct surface views of the cortical distribution of labeled
corticospinal neurons. These drawings included architectonic
boundaries, microlesions placed for reference, blood vessels, sulci
patterns, and other landmarks so that the electrophysiological results
could be related to the brain sections and the reconstructed surface view.
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RESULTS |
The effects of ICMS in M1 within and around the portion formerly
devoted to a missing limb were examined in three animals with forelimb
amputations, including two squirrel monkeys and one galago, as well as
two animals with hindlimb amputations, including one squirrel monkey
and one galago. In addition, two normal squirrel monkeys and four
galagos were used as a control group for comparison. We first describe
the ICMS results from the squirrel monkeys, followed by the ICMS
results from the galagos, and finally the somatosensory recording
results from two galagos.
In two forelimb-amputated squirrel monkeys, results were obtained from
cortex contralateral and ipsilateral to the missing limb. The portion
of cortex in both hemispheres devoted to the normal forelimb or the
missing limb was identified by ICMS results, by location relative to
brain surface landmarks, and by the distribution of labeled
corticospinal neurons projecting to the lower cervical spinal segments
that control forelimb muscles. Thus, results from cortex
ipsilateral to the missing limb served as one control. Another control
was to use identical methods to stimulate and map M1 as well as parts
of adjoining cortical fields in two normal squirrel monkeys. ICMS
results from one forelimb-amputated galago and two hindlimb-amputated
animals were compared with those from four normal animals of the same species.
ICMS mapping in squirrel monkeys
M1 of normal animals
M1 is located ~1-2 mm rostral to the short, shallow central
sulcus in squirrel monkeys (Fig. 1, also
see Figs. 2,
3, 6). Traditionally, M1 has been defined
by its overall somatotopic pattern of evoked movements at low threshold
of current and by its agranular cytoarchitectonic appearance with large
pyramidal cells in layer V (Gould et al., 1986; Donoghue et al., 1992;
Stepniewska et al., 1993; Preuss et al., 1996). In the present study,
M1 was delineated by noting elevation of thresholds for evoked
movements in cortex rostral and caudal to it. In addition, the
cytoarchitecture of the region defined as M1 was examined in coronal
brain sections in every case, and at least the bulk of the region
physiologically defined as M1 was clearly agranular M1.
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Figure 1.
Organization of motor cortex in a normal squirrel
monkey. Areas M1, PMD, and PMV are outlined on the dorsolateral surface
of the frontal lobe. The shallow central sulcus (CS) is
opened on the right, and the arcuate dimple
(AD) is on the bottom left. The frontal
eye field (FEF) and the estimated location of SMA
are indicated. Dots mark electrode penetration sites.
Next to each dot, the body movement evoked by electrical stimulation is
abbreviated (see Table 1 for abbreviations). The number
in parentheses next to each abbreviation indicates the
current used to evoke movements at threshold. Dotted
lines separate the forelimb region (shaded) from
orofacial, trunk, and hindlimb regions of M1. In the forelimb cortex of
M1, nonlimb movements could be elicited at few sites and are
highlighted with a white background. EM,
Eye movements.
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Figure 2.
Organization of M1 ipsilateral to an amputated
forelimb in a squirrel monkey (98-61). Conventions are as in Figure 1.
See Figure 6 for the position of M1 on a dorsolateral view of the
cerebral hemisphere.
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Figure 3.
Organization of M1 in cortex ipsilateral to an
amputated forelimb in a second squirrel monkey (98-64). Conventions are
as in Figure 1. See Figure 6 for the position of M1 on a dorsolateral
view of the cerebral hemisphere. Bi, Bilateral;
ip, ipsilateral.
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The major somatotopic organization of M1 is apparent from the
representative map of one of the normal squirrel monkeys shown in
Figure 1. The map corresponds to a surface view of cortex just rostral
to the central sulcus, with electrode penetrations marked. Next to each
penetration, the threshold level of current and the movement evoked
from the site at threshold are given. Results from our second
normal squirrel monkey (not shown) were similar to those shown in
Figure 1 (Table 3). The borders and the
estimated sizes of forelimb cortex [19.6 mm2 (see
Fig. 1) and 18.1 mm2 (results not shown)] of M1
from these two normal animals were similar. The details of the internal
organization within the specific body parts varied case by case, but
the global order was the same. The average threshold for each major
body movement from the two normal squirrel monkeys is shown in Table
3.
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Table 3.
Average current thresholds and frequencies for evoked
movements in M1 of control and amputated squirrel monkeys
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The first point to stress is that threshold levels in cortex caudal and
rostral to the region we define as M1 are higher than in M1. The M1 we
define in this manner corresponds closely to that identified by
electrical stimulation in other studies (Donoghue et al., 1992; Nudo et
al., 1992; Sanes and Donoghue, 1992). The second point is that the
characteristic global organization of M1 is apparent, with a zone of
cortex related to the leg and tail most medial, cortex involving the
trunk next, followed by a large, more lateral zone representing the
forelimb and digits, and finally the most lateral zone devoted to the
face and the mouth. There was no attempt to fully define the medial and
lateral borders of M1 physiologically. However, these borders were
delineated cytoarchitectonically in coronal brain sections. Third,
movements were evoked in a parallel topography at higher thresholds
from area 3a, as expected, and in different topography and at higher thresholds from regions rostral to M1 that correspond to the dorsal and
ventral premotor areas (PMD and PMV, respectively) (Preuss et al.,
1996; Wu et al., 1997), as well as the frontal eye field (Huerta et
al., 1986). Fourth, the results indicate that a given movement, of
digits, for example, often can be evoked from several discontinuous
locations in M1. The mosaic pattern of local organization of M1, first
stressed for M1 of owl monkeys (Gould et al., 1986), has been
repeatedly confirmed in squirrel monkeys (Donoghue et al., 1992; Nudo
et al., 1992, 1996; Sanes and Donoghue, 1992). Fifth, as it has been
described in earlier studies, suprathreshold levels of current
stimulation typically evoked movements in addition to those revealed by
low threshold levels of stimulation, and these additional movement
patterns were not always related to the movements of neighboring sites
(Sanes et al., 1990; Huntley and Jones, 1991; Nudo et al., 1996).
Finally, the internal organization of the forelimb cortex and hindlimb
cortex of M1 in our two normal squirrel monkeys did not differ notably
from previous descriptions of forelimb or hindlimb cortex (Gould et
al., 1986; Donoghue et al., 1992; Nudo et al., 1992; Preuss et al.,
1996) in New World monkeys, although some details differed, possibly
because of individual differences in monkeys or experimental
differences in procedures and movement detection. Additionally, details
of somatotopic organization and thresholds for evoked movements appear
to be modifiable by experience and motor training (Nudo et al., 1992;
Sanes and Donoghue, 1992) and even changes in limb position (Sanes et
al., 1992). Thus, normal organization is somewhat broadly defined, and
normal monkey studies under the same experimental conditions probably serve as the best comparison group for monkeys with amputations.
M1 contralateral to the intact limb of amputees
Although we used cortex contralateral to the intact limb as a
control for comparison to cortex contralateral to a missing limb, this
cortex may not be completely normal, and altered use of the intact limb
may have changed the organization of motor cortex (Nudo et al., 1992).
Yet, our physiological results from ipsilateral cortex did not reveal
any obvious difference from our normal controls. In both cases, cortex
contralateral and ipsilateral to the missing limb was mapped with large
numbers of closely spaced stimulation sites (Figs.
2-5). As
for the M1 of normal squirrel monkeys, the global organization of M1
contralateral to the intact limb of the two forelimb-amputated squirrel
monkeys proceeded from hindlimb to trunk to forelimb to orofacial
(Figs. 2, 3). The forelimb cortex appears to be normal in size (19.8 and 17.9 mm2 for cases 98-61 and 98-64, respectively) as well as in internal organization. Sites evoking digit
movements were scattered among those evoking hand, arm, and shoulder
movements. There was no significant difference in the percentage of
sites evoking hand, shoulder, and nonlimb movements in the forelimb
cortex between hemispheres from the normal animals and the hemispheres
contralateral to the intact forelimb (Table 3;  2 tests,
p > 0.05). Most importantly, the thresholds for
evoking these forelimb movements were similar between M1 contralateral to the intact limb and M1 of two normal controls (Table 3; t tests, p > 0.05). The same was true of the thresholds
for the movements in trunk and orofacial cortex. Thus, these
similarities indicate that M1 contralateral to the intact limb can be
used as an important comparison with M1 contralateral to a missing limb.
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Figure 4.
Organization of motor cortex contralateral to the
amputation of a limb at the level of the upper arm near the shoulder
joint in squirrel monkey case 98-61. Electrical stimulation evoked
movements throughout the forelimb cortex (gray
shading), with much of the cortex devoted to stump and shoulder
muscles. Moreover, sites evoking nonlimb movements (highlighted by a
white background) were significantly increased. In the
reorganized forelimb cortex, many sites required threshold currents
greater than the highest current threshold (25 µA) from the opposite
hemisphere; these high-threshold sites are outlined. Conventions are as
in Figures 1 and 3. See Figure 6 for the position of M1 on a
dorsolateral view of the cerebral hemisphere.
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Figure 5.
Organization of motor cortex contralateral to an
amputated limb at the level of the shoulder joint in squirrel monkey
98-64. Conventions are as in Figures 1, 3, and 4. See Figure 6 for the
position of M1 on a dorsolateral view of the cerebral hemisphere.
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In cortex contralateral to the missing limb, we wanted another way to
define the forelimb region of M1 in addition to electrical stimulation
of cortex, because the amputation would obviously alter the
electrophysiological results, changing somatotopy and possibly
stimulation thresholds. Thus, we injected the anatomical tracer WGA-HRP
bilaterally into the lower cervical spinal segments where corticospinal
afferents from the forelimb portion of M1 terminate (Kuypers, 1981;
Bortoff and Strick 1993; He et al., 1993; Maier et al., 1997; Wu and
Kaas, 1998) and motoneurons that innervate the forelimb muscles are
located (Jenny and Inukai, 1983; Rouiller et al., 1996). We were,
however, concerned that the spinal cord injections might impair spinal
cord function and reduce the effectiveness of motor cortex in evoking
movements. Thus, we looked for threshold and somatotopic changes in
cortex contralateral to the intact limb in the monkeys with
amputations, because both sides of the spinal cord had injections. As
described above, thresholds in the cortex contralateral to the intact
side were not significantly different from those in normal control cases (Table 3). Therefore, cortex contralateral to the intact limb
appeared to be normal, although we had injected tracers into the spinal cord.
The spinal cord injection sites were confined to the gray matter
covering a large portion of the intermediate zone and ventral horn
throughout lower cervical segments C6-C7 or C7-C8. The spread of
tracer involved the dorsal horn along the insertion track of the
micropipette tip. The cortical locations of neurons labeled by the
spinal cord injection in the two monkeys with forelimb loss were
similar in both hemispheres (Fig. 6). The
densest zones of label were found in the M1 forelimb cortex, and they
covered the entire subdivision. In agreement with early reports, the
labeled corticospinal neurons were found exclusively in cortical layer V, where they were distributed in an uneven pattern and constituted pyramidal neurons of various sizes (Murray and Coulter, 1981; Nudo and
Masterton, 1990; Dum and Strick, 1991a; Wu and Kaas, 1998). Because the
motoneuron pools that influence the control of distal forelimb muscles
are most heavily represented in the lower cervical segments where
tracer injections were placed, the uneven distribution of corticospinal
neurons was consistent with the mosaic patterns of organization
observed in the electrophysiological data. Labeled neurons were also
observed in the border zones medial and lateral to the forelimb cortex,
possibly from tracer injections involving the motoneurons of the medial
cell column throughout the lower cervical enlargement that innervate
the axial musculatures for shoulder and neck (Jenny et al., 1988;
Ueyama et al., 1990; our unpublished observations) and possibly
other motoneurons. However, the distribution extent of labeled neurons
was symmetrical in the two hemispheres, and the densest region of
labeled cortical neurons closely coincided with the forelimb cortex (He
et al., 1993; Wu and Kaas, 1998). Thus, this labeled region appears to be a suitable way of defining the forelimb cortex in monkeys with a
missing forelimb.
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Figure 6.
Locations of ICMS sites and labeled corticospinal
neurons after tracer WGA-HRP was placed in the lower cervical spinal
cord ipsilateral and contralateral to an amputated forelimb in two
squirrel monkeys. The large, dense focus of labeled neurons in each
hemisphere effectively indicates the forelimb region of M1 and is
confirmed by ICMS (see Figs. 2-5 for detailed mapping results).
Smaller foci of labeled neurons also mark forelimb regions of
subdivisions of somatosensory and premotor cortex. A,
Deefferented cortex is on the right. B,
Deefferented cortex is on the left.
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The extents of the forelimb cortex of M1 was judged to be comparable in
both hemispheres (19.8 and 17.9 mm2 for intact
cortex compared with 19.2 and 16.8 mm2 for
deefferented cortex in cases 98-61 and 98-64, respectively; also see
Fig. 6), and the same was true for the face and trunk cortex. Also, as
expected, the corticospinal neurons retrogradely labeled by the lower
cervical spinal cord injections were similarly distributed in the
forelimb portion of M1 in both hemispheres. Note also that in both
hemispheres injections equally labeled smaller numbers of neurons in
areas 3a and 3b of somatosensory cortex and in premotor cortex. The
great similarity in the location and extent of the main focus of
labeled neurons in all four hemispheres effectively indicates that the
procedure usefully identified the forelimb cortex, even after
long-standing amputation of the forelimb. There was no evidence from
these injections that long-standing forelimb loss alters the nature of
the corticospinal projections, although some changes, not revealed by
these methods, might have occurred.
M1 contralateral to the amputated limb
Overall, movements were evoked by ICMS throughout M1 contralateral
to the missing limbs in three limb-amputated squirrel monkeys. M1
contralateral to the amputated limb had a global organization similar
to M1 of normal control animals, so that mediolateral organization
proceeded from hindlimb to trunk to forelimb to face. However, the
patterns of movements and currrent thresholds for evoked movements in
the deefferented cortex were quite different from normal. In contrast,
ICMS sites located medial or lateral to deefferented cortex produced
normal patterns of movements at low current thresholds as typical of M1
cortex and were comparable with those observed in the normal cases as
well as the opposite hemisphere (compare Figs. 4, 5 with 1-3; also see
Table 3).
The portions of M1 cortex normally corresponding to the forelimb cortex
were revealed by the locations of dense concentration of labeled
corticospinal neurons. The densely labeled zones contralateral to the
amputated limbs were consistent with the forelimb cortex expected by
either relative location in M1 or position in the opposite hemisphere.
Within these regions, the internal organization of M1 was grossly
abnormal. However, movements were evoked from all sites, and no
unresponsive zones were found in the deeffferented cortex. A mixture of
shoulder, stump, trunk, and orofacial movements were elicited
throughout the regions at threshold levels ranging from normal to much
higher than normal currents (5-120 µA; see Figs. 4, 5). For
convenience, in Figures 4 and 5, we outlined the abnormally high
threshold values for sites that exceed the maximum threshold current of
any site in forelimb cortex of the opposite hemispheres.
Within the deefferented forelimb cortex, stimulation at ~80% of the
sites resulted in movements of the shoulder or stump, or both (referred
to as shoulder/stump movements), whereas stimulation at ~20%
of the sites resulted in movements of the trunk or face (referred to as
nonlimb movements). The deefferented portion of M1 had significantly
more shoulder/stump movement sites than shoulder movement sites in the
forelimb cortex of opposite hemispheres (case 98-61, 2 = 27.0; p < 0.001; case 98-64, 2 = 37.1; p < 0.001) and
significantly more nonlimb movements sites involving trunk and
orofacial muscles in the forelimb cortex than those in the forelimb
cortex of opposite hemispheres (case 98-61, 2 = 19.6; p < 0.001; case 98-64, 2 = 7.3; p < 0.01). Moreover, the current thresholds for
shoulder/stump movements in the deefferented hemisphere were
significantly higher than those for shoulder movements in the opposite
hemispheres (case 98-61, t87 = 6.9;
p < 0.001; case 98-64, t88 = 6.7; p < 0.001; see Table 3, Fig.
7). The current thresholds for nonlimb movements within the deefferented forelimb cortex were also
significantly higher than those for nonlimb movements within the
forelimb cortex of the opposite hemisphere (case 98-61, t31 = 4.5; p < 0.001; case
98-64, t22 = 5.4; p < 0.001; see Table 3) or higher than movements in trunk and orofacial
cortex of the opposite hemisphere (case 98-61, t35 = 5.0; p < 0.001; case
98-64, t19 = 5.7; p < 0.001; see Table 3, Fig. 8), as well as
movements in trunk and orofacial cortex medial and lateral to the
deefferented forelimb cortex (case 98-61, t37 = 5.3; p < 0.001; case 98-64, t20 = 5.6; p < 0.001; see Table 3, Fig. 8). Except for forelimb
cortex, the threshold levels for movements from the deefferented
hemispheres were not significantly different from those in the opposite
hemispheres or in controls (t tests, p > 0.05).
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Figure 7.
Frequency distribution of current thresholds for
evoked shoulder/stump movements from sites in M1 forelimb cortex
contralateral to the missing limb (filled
circles) and shoulder movements contralateral to the intact
limb (open circles) in monkeys 98-61 (A) and 98-64 (B). The
deefferented cortex exhibits a wide range of current thresholds that
was not observed in the opposite hemisphere.
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Figure 8.
Frequency distribution of current thresholds for
orofacial and trunk evoked movements in deefferent M1 forelimb cortex
(filled circles) and movements in face and trunk
cortex in M1 of the same and opposite hemispheres (open
circles) for squirrel monkey 98-61 (A)
and 98-64 (B). Current thresholds for the
orofacial and trunk cortex in the two hemispheres were not
significantly different; thus, data from the two hemispheres were
combined. Although the distribution of current thresholds for the
deefferented cortex overlap those for orofacial and trunk cortex; many
sites required much higher threshold levels.
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When the distributions of current thresholds for shoulder/stump
movements within deefferented cortex and normal shoulder movements in
opposite hemispheres were compared, it was clear that the distributions overlapped, but higher levels of current were required only in the
deefferented cortex (Fig. 7). In fact, the percentage of sites for
shoulder/stump movements with normal thresholds ( 25 µA) in the
deefferented hemisphere was not significantly different from the
percentage of sites with normal thresholds for shoulder movements in
the opposite hemisphere (case 98-61, 2 = 0.01;
p = 0.94; case 98-64, 2 = 0.85;
p = 0.36). It is likely that the sites eliciting
shoulder/stump movement with normal threshold in the deefferented
cortex correspond to sites that evoked shoulder movements before
amputation (as is the case for opposite hemisphere or control cases).
On the other hand, the high-threshold shoulder/stump movement sites
likely reflect sites that formerly evoked movements from the missing limb.
The loss of a hindlimb appears to result in changes in deefferented
hindlimb cortex that are comparable with those induced in deefferented
forelimb cortex by forelimb loss. In brief, throughout the deefferented
hindlimb cortex, no unresponsive sites were found, and electrical
stimulation resulted in movements of remaining body parts (Fig.
9). Usually, these movements were of the
stump or the tail but sometimes also of the lower trunk. Consequently, there was a significantly higher percentage of tail movement sites in
the deefferented hindlimb cortex than that in the normal animals (2 = 11.0; p < 0.001). Also, as in
the forelimb-amputated cases, current thresholds for evoking these
movements ranged from the normal range to much higher, with a
significantly higher average threshold level than in normal animals
(t52 = 7.7; p < 0.001).
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Figure 9.
Organization of motor cortex contralateral to a
hindlimb amputated at the hip joint in squirrel monkey (case 97-127).
Movements of the stump of the amputated limb, lower trunk, or tail were
evoked throughout the hindlimb portion of M1 (gray
shading). Current thresholds levels exceeding the maximum
current threshold in the normal control animals are
outlined. Sites eliciting tail movements are highlighted
by a white background. Stump movements were also evoked
from PMD and medial cortex judged to be SMA. The line at
the top left marks the medial wall of the cerebral
hemisphere, whereas the central sulcus (CS) is on the
right. Conventions are as in Figures 1 and 4. Top
right inset, Frequency distribution of current threshold in the
hindlimb amputee (filled circles) compared with
controls (open circles). A wider range of current
thresholds occurred in deefferented cortex.
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Effects of amputation on premotor cortex and area 3a
Area 3a is generally considered to be a somatosensory field within
the anterior parietal cortex. This area is activated by a relay of
muscle spindle afferents from the thalamus and is interconnected with
other fields in somatosensory cortex and primary motor cortex (for
review, see Kaas and Pons, 1988). Premotor area includes the PMD and
PMV, as well as the supplementary motor area (SMA). Movements can
be evoked from all of these fields (Preuss et al., 1996; Wu and Kaas,
1998) (for review, see Dum and Strick, 1991b). In addition to
stimulating M1, in the present cases, many electrode sites were in
premotor cortex and somatosensory area 3a, where movements were evoked
at somewhat higher current levels than in M1. In normal squirrel
monkeys (Fig. 1) and in cortex contralateral to the intact limb in two
forelimb-amputated squirrel monkeys (Figs. 2, 3), parts of areas PMD
and PMV produced forelimb movements, as did the part of area 3a just
caudal to the forelimb region of M1. In cortex contralateral to the
missing forelimb, stump or shoulder movements were produced from
many stimulation sites in PMD, PMV, and the forelimb portion of area 3a
(Figs. 7, 8). Current levels needed to evoke these movements were
higher than those for stump and shoulder sites in M1, but they were
often comparable with corresponding premotor and somatosensory sites in
normal cortex. However, some sites required much higher than normal
levels of current for evoked shoulder and stump movements in these
fields. Thus, this limited evidence from PMV, PMD, and area 3a suggests
that the changes that occurred in these fields were very comparable
with those in M1.
ICMS mapping in galagos
M1 of normal animals
The location and organization of motor cortex in galago is
known from recent studies using ICMS mapping, cytoarchitectonic features, and patterns of connections with area M1 and the spinal cord
(Fogassi et al., 1994; Wu et al., 1997; Wu and Kaas, 1998). In summary,
galago M1 is situated between anterior and posterior parts of frontal
sulcus (FSa and FSp, respectively), with orofacial movements
represented most laterally and hindlimb movements most medially,
extending deep into the medial wall (Fig.
10). The indentation between these two
frontal sulci caused by a large blood vessel separates the orofacial
from forelimb cortex. To serve as a control group, data from four
normal galagos were used to compare with the organization of M1 in the
limb-amputated galagos. Detailed maps obtained from these normal
galagos will be published elsewhere. The size of the forelimb cortex in
these galagos ranged from 5.6 to 7.9 mm2, with an
average of 6.4 mm2. As in squirrel monkeys,
movements evoked from galago M1 were restricted to small muscle groups
or joints contralateral to the stimulated hemisphere, and M1 contained
a complete body motor representation. However, the movements evoked in
galagos appeared to be less precise, involving more muscle groups at
some ICMS sites. For example, a single-digit or toe movement was evoked only in few sites in galagos, and movements involving single muscles were rarely observed. Such a difference in the motor organization of M1
forelimb cortex in these two primate species probably reflects their
behavioral differences, because galagos have less precise hand
movements than squirrel monkeys (Torigoe, 1985; Costello and Fragaszy,
1988; Larson et al., 1989).
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Figure 10.
Example of ICMS mapping result and motor
cortex organization in a normal galago. Area M1 of galagos is located
between two frontal sulci, FSa and FSp. Note that the forelimb cortex
is located above FSa and FSp. Conventions are as in Figure 1. Compare
with Figures 11 and 12.
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The average thresholds for evoked movements from different body cortex
in control galagos are summarized in Table
4. Although part of M1 hindlimb cortex in
galago extends into the medial wall (Wu and Kaas, 1998), we did not
include values from these sites because of the difficulty in ensuring
that the electrode was in layer V where the lowest thresholds are
obtained. Because the sites buried in the medial wall were not included
in the analysis, the total size of the hindlimb cortex was not
determined.
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Table 4.
Average current thresholds for evoked movements in M1 of
the control and amputated galagos (conventions as in Table 3)
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M1 contralateral to amputated limbs
The general topography in M1 of the forelimb-amputated galago was
remarkably similar to our observations in squirrel monkeys with
forelimb amputation (Fig. 11). The
orofacial, hindlimb, and trunk representations were not different from
those in controls, either in current thresholds (t tests,
p > 0.05) or patterns of evoked movements, and they
were found in locations predicted from control cases. Similar to
squirrel monkeys, there were no unresponsive sites in the deefferented
cortex, and the range of thresholds for evoked movements (5-80 µA)
was broader than in controls (2-25 µA). Within the expected location
of former forelimb cortex (i.e., cortex between FSa and FSp but above
the indention of the two sulci), there was a significant increase in
the number of sites from which nonlimb movements could be elicited
(2 = 52.2; p < 0.001). However,
the percentage of sites from which shoulder/stump movements could be
evoked was not different from that of normal shoulder movements in the
control cases (2 = 0.0; p = 0.99).
As in amputated squirrel monkeys, the current threshold for movements
were abnormally high at some sites compared with normal cortex for both
shoulder/stump movements (t36 = 5.1; p < 0.001) and nonlimb movements (compared with those
in the forelimb cortex of controls, t54 = 4.8; p < 0.001; compared with trunk and orofacial
cortex of controls: t52 = 8.3;
p < 0.001; compared with trunk and orofacial cortex
medial and lateral to the deefferented forelimb cortex,
t48 = 9.1; p < 0.001),
whereas the threshold in others are comparable with control cases
(t tests, p > 0.05; Tables 3, 4; Figs. 10,
11).
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Figure 11.
ICMS and somatosensory recording maps from the
hemisphere contralateral to the missing limb of the forelimb-amputated
galago (case 97-100). Inset at top left,
Portion of mapped cortex on a dorsolateral view of the cerebral
hemisphere. ICMS sites (smaller dots) were concentrated
in M1, whereas somatosensory recording sites (larger
dots) were concentrated between FSp and IPS where S1 is
normally located. Bottom left inset, Histograms
comparing the frequency distributions of current thresholds for
shoulder/stump (A) and nonlimb
(B) movements in deefferented forelimb cortex to
the shoulder movements in the forelimb cortex of control cases
(A) and average of face and trunk cortex in the
same hemisphere and control cases (B). Sites in
the deefferented cortex with current threshold exceeding the maximum
current threshold in control cases are outlined. Conventions for ICMS
are as in Figure 4. The receptive field of each somatosensory recording
site is indicated using the conventions described in Table 1. Responses
from the dorsal side of the body are indicated by
(d).
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The results of ICMS mapping in M1 of the galago with hindlimb
amputation exhibited remarkable similarity to the squirrel monkey hindlimb amputee as described above. The orofacial, trunk, and forelimb
cortex was not different from in controls either in current thresholds or patterns of evoked movements. Moreover, there was an
increase in the percentage of sites from which hip/stump and tail
movements could be elicited, and there was a wider distribution and a
significantly higher average threshold for these movements (Table 4;
Figs. 10, 12;
t58 = 4.5; p < 0.001).
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Figure 12.
ICMS and somatosensory recording maps from the
hemisphere contralateral to the missing limb of the hindlimb-amputated
galago (case 97-134). Bottom left inset, Histogram
showing the frequency distribution of current thresholds from
deefferented hindlimb cortex (filled circles)
compared with those from controls (open circles). See
Figures 9 and 11 for conventions.
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Somatosensory recording in limb-amputated galagos
In galagos, cortex located in FSp and intraparietal sulcus (IPS)
is vigorously responsive to cutaneous stimulation, exhibits typical
somatosensory koniocortex organization (Carlson and Welt, 1980; Sur et
al., 1980; Wu et al., 1995), and is therefore defined as a subdivision
of primary somatosensory cortex, area 3b. The somatosensory cortex
contralateral to the missing limb was mapped in two limb-amputated
galagos. In the region of area 3b where the forelimb and hindlimb
cortex is normally located, neurons at some recording sites responded
to the cutaneous stimulation. Sites where neurons did not respond to
light cutaneous stimulation often could be activated by more intense
stimulation produced by strokes or taps. In the deprived forelimb
cortex, neurons were largely activated by shoulder and stump
stimulation, with the majority clearly having cutaneous receptive
fields. However, some sites required more intense stimuli on the stump.
In addition, receptive fields from chest, neck, or the lower portion of
the face were observed in a few penetrations (Fig. 11). Similar
observations were made in the deprived hindlimb cortex (Fig. 12). In
short, stump and the lower body parts took over the majority of the
deprived cortex, and both normal and higher levels of stimulation were required for activating these neurons. In both limb amputees, neurons
in somatosensory cortex lateral or medial to the deprived region
responded normally to cutaneous stimuli and had normal sizes of
receptive fields.
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DISCUSSION |
The amputation of an injured limb directly severs most of the
afferents and efferents of that limb and undoubtedly produces a host of
related changes in the spinal cord, brainstem, and cortex (Calford and
Tweedale 1988; Florence and Kaas, 1995; Jones and Pons, 1998). Because
mammals with therapeutic amputations are rare and studies of humans
with amputations are limited, the motor and sensory effects of limb
amputations have not been extensively described. In the present study,
we addressed the issue of what happens to motor cortex after the loss
of a limb. More specifically, what are the consequences of electrical
stimulation at sites in motor cortex that would normally move that
limb? The answer was clear. Most of the sites throughout the forelimb
cortex of M1 were still related to that limb, in that they excited
muscles in the stump and shoulder. For some of these sites, the levels of current needed to evoke movements were similar to those needed to
evoke arm movements from normal cortex. However, many of the sites
required higher levels of current. Yet, there were no sites in the
deprived cortex where movements could not be evoked. In addition, the
small number of sites where movements of trunk or face could be evoked
increased significantly in deprived forelimb cortex. The results were
similar in both squirrel monkeys and prosimian galagos, and they
closely correspond to those reported for a single investigated macaque
monkey with a forelimb loss as a juvenile (Schieher and Deuel, 1997).
Results were also quite similar after the loss of a hindlimb in both a
squirrel monkey and a galago. Findings did not differ among individuals
with a limb loss as an adult or a juvenile. Finally, limited results from deprived portions of premotor cortex suggest that this cortex largely becomes devoted to stump and shoulder movements as well.
Although the results seem robust and general, they raise several
questions. Most notably, does the motor cortex of humans and other
mammals such as rats change in a comparable manner after limb loss?
What are the mechanisms of change?
M1 organization after limb amputation in humans and rats
The organization of motor cortex after long-standing limb
amputations in young and mature mammals has also been studied in humans
and rats. In humans, the results most comparable with those obtained in
the present experiments came from the direct stimulation of motor
cortex with surface electrodes in a patient 24 years after the
amputation of an arm as an adult (Ojemann and Silbergeld, 1995).
Stimulation of the portion of M1 that is normally devoted to hand and
finger movements evoked movements from the proximal muscles of the
missing limb (such as shoulder), except for a small region where no
movements were evoked with the current levels used. In an earlier study
of a patient 13 years after amputation of a leg above the knee (Woolsey
et al., 1979), stimulation of three sites thought to be in or near the
midline portion of M1 normally devoted to the leg produced stump
movement (one site) or hip movements (two sites). These limited results
suggest that the deprived cortex had become devoted to the remaining
muscles proximal to the missing limbs in these patients and that
current stimulation thresholds had increased for some of this cortex.
More extensive investigations of motor cortex in humans with
amputations have used the noninvasive technique of transcranial magnetic stimulation. By pulsing a small magnetic coil over different portions of the skull, current flow can be induced in different populations of neurons in motor cortex. In individuals studied after
long-standing limb amputations as adults, the general finding has been
that remaining muscles proximal to the stump can be activated from more
coil sites than the same muscles on the intact side (Hall et al.,
1990; Cohen et al., 1991; Chen et al., 1998). A reasonable
interpretation of this result is that movements from the remaining
muscles can be evoked from a larger than normal portion of M1, perhaps
most or all of the forelimb region.
According to this interpretation, M1 in humans reorganizes much as in
other primates. However, there was no evidence from the transcranial
magnetic stimulation experiments that sites within reorganized forelimb
cortex required higher than normal levels of current to evoke
movements. Instead, movements and muscle potentials were evoked in
remaining muscles proximal to the stump, compared with the same muscles
in the normal side, at similar or lower stimulus intensities, and
stimulation at a fixed suprathreshold level evoked larger muscle
potentials in these muscles (Cohen et al., 1991; Kew et al., 1994; Chen
et al., 1998). Although these results might indicate that sites in
reorganized motor cortex had normal or lower than normal thresholds,
this may not be the case. Stimulation with magnetic coils likely
involved larger populations of neurons than intracortical stimulation
with microelectrodes (Day et al., 1987, 1989; Topka et al., 1991), and
the convergence of many more active corticospinal projections in the
spinal cord motoneuron pools may produce the larger muscle response,
even if cortical sites of normal to higher than normal thresholds are involved.
The effects of forelimb amputation on the organization of motor cortex
have also been studied in developing (Donoghue and Sanes, 1987, 1988)
and mature rats (Sanes et al., 1990). One week to four months after
forelimb amputation in adult rats, shoulder movements were evoked by
ICMS over much of the forelimb region of cortex (Sanes et al., 1990).
As a result, the shoulder representation more than doubled in size.
Mean current thresholds for evoking shoulder movements in normal motor
cortex or altered motor cortex were not significantly different. Thus,
forelimb amputation in rats resulted in a reorganization of forelimb
cortex so that sites throughout evoked shoulder and stump movements.
Unlike monkeys and galagos, thresholds were normal rather than normal
to elevated.
We conclude that the major consequence of limb amputation for motor
cortex, regardless of species, is that sites throughout limb cortex
come to evoke shoulder and stump movements. Current thresholds for
evoking these movements from deprived portions of M1 clearly range from
normal to above normal in monkeys and galagos. The few unresponsive
sites obtained from directly stimulating motor cortex in one patient
suggest that thresholds may be raised in humans as well, but this
observation is countered by evidence for lower thresholds with magnetic
coil stimulation. In rats, thresholds appear to be normal. The time
course for this reorganization of M1 is uncertain, because stimulation
occurred at various but long times after amputation. The only
exception is that a single patient was stimulated with a magnetic coil
both before and three times within 11 months after an arm amputation
(Pascual-Leone et al., 1996). The results suggest that the
representation of muscles proximal to the stump enlarged slowly
over weeks to months. Nevertheless, changes in motor cortex detected by
magnetic coil stimulation during ischemic deefferentation of a
forelimb (Brasil-Neto et al., 1993; Ziemann et al., 1998a) suggest that
some reorganization can be very rapid.
The nature of the reorganization of M1
Given the consistency of the results across species,
one might ask how cortex has changed. Here we consider several
possibilities. First, the results could reflect residual upper arm and
shoulder movements at digit and wrist movement sites. Increasing the
levels of electrical stimulation at microelectrode sites in cortex does increase the magnitude of the response and the involvement of more
muscles (Sanes et al., 1990; Huntley and Jones, 1991; Nudo et al.,
1996). Possibly, some or many of the sites in the present experiments
where higher than normal levels of current were used to evoke stump
movements were sites where such movements could be evoked at higher
levels of current in normal animals. Such residual effects have been
described for the responses of neurons in the cochlear nucleus of cats
after partial cochlear lesions (Rajan and Irvine, 1998). However,
residual responses would not account for movements evoked at normal or
near-normal levels of stimulation or the observed increase in face and
trunk movement sites within forelimb cortex. Second, some or all of the
results could reflect potentiation of horizontal connections within
motor cortex (Huntley and Jones, 1991; Keller, 1993; Weiss and Keller, 1994; Huntley, 1997). A reduction of inhibition in motor cortex could unmask the effects of excitatory horizontal connections so that
stimulation at some sites activates patches of neurons at more distant
sites. Changes in the sensory activation of the cortex attributable to
loss of sensory afferents (Calford and Tweedale, 1988; Sanes et al.,
1992) or the reorganization in somatosensory cortex (this study;
Merzenich et al., 1984; Calford and Tweedale, 1988; Florence and Kaas,
1995; also see Jain et al., 1997) could alter the effectiveness of such
connections. The horizontal connections in M1 also can be strengthened
through long-term potentiation (Nudo et al., 1990; Hess and Donoghue,
1994; Hess et al., 1996; Rioult- Pedotti et al., 1998) or
activity-dependent reduction of GABA-related inhibition (Jacobs and
Donoghue, 1991; Ziemann et al., 1998b) (also see Dykes et al., 1984;
Hendry and Jones, 1986; Welker et al., 1989; Akhtar and Land, 1991;
Garraghty et al., 1991; Jones, 1993; Huntsman et al., 1994). Finally,
amputations may produce structural changes in the motor system,
including the possibility of the growth of new horizontal connections,
as has been shown in sensory systems (Darian-Smith and Gilbert,
1994; Das and Gilbert, 1995; Florence et al., 1998), the
expansion of terminal arbors of corticospinal axons, and the sprouting
of damaged peripheral nerves to innervate new muscle targets. We have
started to investigate some of these possibilities.
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FOOTNOTES |
Received April 5, 1999; revised May 20, 1999; accepted May 21, 1999.
This research was supported by National Institutes of Health Grant
NS16446 to J.H.K. We thank Drs. C. Collins, N. Jain, and I. Stepniewska
for helpful comments on this manuscript and N. Bichot and M. Feurtado
for assisting mapping sessions and surgeries. We are also grateful to
Judy Ives and Laura Trice for histological assistance.
Correspondence should be addressed to Dr. Jon H. Kaas, 301 Wilson Hall,
Department of Psychology, Vanderbilt University, Nashville, TN 37240.
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TOP
ABSTRACT
INTRODUCTION
