Abnormal Access of Axial Vibrotactile Input to Deafferented
Somatosensory Cortex in Human Upper Limb Amputees
JOHN J. M. KEW, 1,2 PETER W. HALLIGAN, 3 JOHN C. MARSHALL, 3 RICHARD E. PASSINGHAM, 1,4
JOHN C. ROTHWELL, 2 MICHAEL C. RIDDING, 2 C. DAVID MARSDEN, 2 AND DAVID J. BROOKS 1,2
1
Medical Research Council Cyclotron Unit, Hammersmith Hospital, London W12 0HS; 2 Medical Research Council
Human Movement and Balance Unit, Institute of Neurology, London WC1N 3BG; 3Neuropsychology Unit, Radcliffe
Infirmary, and Rivermead Rehabilitation Centre, Oxford OX1 4XD; and 4 Department of Experimental Psychology,
University of Oxford, Oxford OX1 3UD, United Kingdom
INTRODUCTION
The dramatic results of a study on the functional effects
of long-term, extensive deafferentation of the primary so-
matosensory cortex (S1) in adult primates (Pons et al. 1991)
have reopened the debate about the extent to which the cortex
of fully developed mammals can reorganize. In the light of
these findings a reappraisal of the upper spatial limit of
cortical reorganization has been necessary. In their studies
on monkeys with longstanding total deafferentation of the
S1 hand/arm area, Pons et al. (1991) showed that neurons
throughout the deafferented S1, rather than remaining unresponsive, became responsive to cutaneous stimuli delivered
to the face. These results unexpectedly demonstrated a spatial extent of cortical reorganization that was 1 order of
magnitude greater than any encountered before. At the time,
researchers could only speculate on the perceptual correlates
of this large-scale reorganization.
Curious perceptual phenomena had been recognized in
human amputees with phantom limbs for over a century
(Cronholm 1951; Katz 1992; Mitchell 1872). It had been
established that in some amputees, stimulation of areas of
skin adjacent, and sometimes distant (Case 13 of Cronholm
1951), to the amputation reproducibly elicited sensations in
the phantom limb. However, it was not until referred phantom sensations were reexplored and reevaluated in a systematic way that their significance started to become apparent.
Ramachandran et al. (1992a,b) reported two human upper
limb amputees in whom stimuli applied to the lower face
ipsilateral to the amputation were referred to the phantom
limb in an apparently topographic manner. These findings
were later replicated and extended independently (Halligan
et al. 1993, 1994), and similar perceptual mislocalizations
were subsequently reported in lower limb amputees (Aglioti
et al. 1994a) and patients who had undergone mastectomy
(Aglioti et al. 1994b). Ramachandran et al. (1992a,b) postulated that the referred phantom sensations reported by their
amputees could represent the perceptual correlate of the
physiological ‘‘facial remapping’’ demonstrated by Pons et
al. (1991) in primates, and hypothesized that similar remapping should be demonstrable in these subjects (Yang et al.
1994). Studies with magnetic source imaging, a technique
combining magnetic resonance imaging of brain anatomy
with magnetoencephalographic localization of functional activity, have recently provided evidence in support of this
hypothesis (Elbert et al. 1994; Knecht et al. 1996; Yang et
al. 1994). However, although the changes reported in these
studies were dramatic, with shifts of S1 facial sites into the
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Kew, John J. M., Peter W. Halligan, John C. Marshall, Richard
E. Passingham, John C. Rothwell, Michael C. Ridding, C. David Marsden, and David J. Brooks. Abnormal access of axial
vibrotactile input to deafferented somatosensory cortex in human
upper limb amputees. J. Neurophysiol. 77: 2753–2764, 1997. We
studied two human subjects with total deafferentation of one upper
limb secondary to traumatic multiple cervical root avulsions. Both
subjects developed a phantom limb and underwent elective amputation of the paralyzed, deafferentated limb. Psychophysical study
revealed in each subject an area of skin in the pectoral region
ipsilateral to the amputation where vibrotactile stimulation (VS)
elicited referred sensations (RS) in the phantom limb. Positron
emission tomography was then used to measure regional cerebral
blood flow changes during VS of the pectoral region ipsilateral to
the amputation with RS and during VS of a homologous part of
the pectoral region adjacent to the intact arm without RS. A voxelbased correlation analysis was subsequently used to study functional connectivity. VS of the pectoral region adjacent to the intact
arm was associated with activation of the dorsal part of the contralateral primary somatosensory cortex (S1) in a position consistent
with the S1 trunk area. In contrast, VS of the pectoral region
ipsilateral to the amputation with RS was associated with activation
of the contralateral S1 that extended from the level of the trunk
representation ventrally over distances of 20 and 12 mm, respectively, in the two subjects. The area of S1 activated during VS of
the digits in a normal control subject was coextensive with the
ventral S1 region abnormally activated during VS of the ectopic
phantom representation in the two amputees, suggesting that the
deafferented digit or hand/arm area had been activated by sensory
input from the pectoral region. Correlation analysis showed an
abnormal pattern of intrinsic connectivity within the deafferented
S1 hand/arm area of both amputees. In one subject, the deafferented S1 was functionally connected with 3 times as many S1
voxels as the normally afferented S1. This abnormal functional
connectivity extended in both the rostrocaudal and ventrodorsal
dimensions. The results demonstrate that sensory input delivered
to the axial body surface may gain access to the S1 hand/arm area
in some humans who have suffered extensive deafferentation of
this area. The findings are consistent with the hypothesis that deafferentation of an area of S1 may result in activation of previously
dormant inputs from body surfaces represented in immediately
adjacent parts of S1. The results also provide evidence that changes
in functional connectivity between these adjacent areas of the cortex play a role in the somatotopic reorganization.
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KEW ET AL.
deafferented hand/arm area on the order of 15–30 mm, their
overall spatial extent could not be determined because of
limitations imposed by the imaging technique, and the results
did not allow any firm conclusions about the route by which
the reorganized facial input gained access to the deafferented
cortex. The objective of the present study was to provide
greater insight into the cortical substrate of referred phantom
sensations by using positron emission tomography (PET) to
study reorganized patterns of activation and connectivity in
the deafferented S1 of human amputees with ectopic representations of the phantom limb.
METHODS
(Fox et al. 1987). In accordance with the findings of Meyer et al.
(1991), subjects were instructed to direct attention toward the
stimulus throughout each scan to maximize the rCBF changes
induced by the sensory paradigm. Subjects were also instructed to
close the eyes during all stimulation conditions.
Psychophysical study
Before the PET study, both amputees were subjected to a detailed somatosensory examination to determine the spatial extent
of the cutaneous area from which RS in the phantom limb could
be obtained. In addition to the vibrotactile stimulus a second stimulus, firm pressure stimulation (PS) of the skin with a probe, was
employed to determine whether the extent of the ectopic phantom
representation was specific to the mode of stimulation.
Subjects
Sensory activation paradigm
The somatosensory paradigm consisted of the application of a
vibrotactile stimulus (series 200 vibrotactile stimulator and TPO
25 power oscillator, Ling Dynamic Systems, Royston, UK). The
stimulus frequency was set at 100 Hz, with a stimulus amplitude
of 2 mm. The stimulus was applied throughout the period of data
acquisition in each PET scan. This type of vibrotactile stimulation
(VS) paradigm has been shown to induce robust and reproducible
regional cerebral blood flow (rCBF) responses in the human S1
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PET study
In the two amputees studied the stimulus was applied to two
corresponding regions of the trunk: one in the upper pectoral region
ipsilateral to the amputated upper limb from which the most consistent and intense referred phantom sensations had been obtained in
the psychophysical study (the optimal site); the other in a homologous part of the upper pectoral region ipsilateral to the normal
intact arm from which no referred phantom sensations could be
obtained. In the normal subject, the stimulus was delivered to a
part of the right upper pectoral region corresponding to that stimulated in the amputees, and to the fingers of the right hand, to map
the normal somatotopic representation of these body parts in S1.
A ball applicator was used for pectoral stimulation in all three
subjects. A bar applicator was used for the simultaneous stimulation of all four fingers of the right hand in the normal subject.
Measurement of rCBF
Measurements of rCBF at rest and during VS were made with
the use of PET. Scans were performed with the use of a CTI/
Siemens 953B PET scanner (CTI, Knoxville, TN) operating in
three-dimensional mode with septa retracted, allowing simultaneous acquisition of a 31-transaxial-plane three-dimensional image
volume (Spinks et al. 1992). Images were reconstructed with a
Hanning filter with a cutoff frequency of 0.5 cycles per pixel,
giving a spatial resolution in the reconstructed image of 8.5 1
8.5 1 4.3 mm full width at half maximum (FWHM). Twelve
dynamic scans were performed in each subject during repeated 2min infusions of H2 15O administered via an antecubital vein canula
at a flow rate of 10 ml/min. Data were acquired for 165 s after
the start of each infusion. Measured attenuation correction of the
emission scans was made with the use of transmission scans performed with three external 68Ge rod sources.
In the amputees, four scans were performed in the resting state
(condition A), four during stimulation of the pectoral region ipsilateral to the intact arm (condition B), and four during stimulation
of the pectoral region ipsilateral to the amputated arm with referred
phantom sensations (condition C).
In the normal subject, four scans were performed in the resting
state (condition A), four during stimulation of the right pectoral
region (condition B), and four during stimulation of the right
fingers (condition C). Scans were conducted with eyes closed and
ears plugged in a counterbalanced sequence (ABCCBAABCCBA)
to avoid order and time effects.
Image analysis
Image analysis was performed on a SUN Sparcstation 2 (Sun
Microsystems Europe, Surrey, UK) with the use of interactive
image display software (ANALYZE, Biodynamics Research Unit,
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Subject 1 was a 31-yr-old male who sustained multiple left-sided cervical nerve root avulsions as a result of a motorcycle accident in 1980. Myelography confirmed avulsion of all cervical roots between C5 and T 1 . The subject was left with a paralyzed,
anesthetic left arm that was subsequently amputated above the
elbow in 1982, and a left Horner’s syndrome. Subject 1 became
aware of a phantom left arm and hand, which was supernumerary
to the paralyzed arm, within a few weeks of the original injury.
The experience of the phantom limb had remained complete. In the
hand, the thumb and the index and middle fingers were particularly
prominent. The subject had noticed intermittent ‘‘telescoping’’ of
the hand toward the stump, and had become aware of two areas
on the body surface tactile stimulation of which elicited referred
sensations (RS) in the phantom limb. The first was a large area
centered around the left upper chest and pectoral region, from
which RS in the thumb and forearm could be elicited. The second
was smaller and centered around the left upper scapula; stimulation
here induced referred pain in the medial aspect of the phantom
forearm. The subject had had an unsuccessful trial of a myoelectric
arm and was using a body-powered prosthesis at the time of the
study.
SUBJECT 2. Subject 2 was a 49-yr-old male who sustained multiple, myelographically proven right-sided cervical nerve root avulsions (C5 –T 1 ) as a result of a motorcycle accident in 1963. The
subject was left with a paralyzed, anesthetic right arm that was
subsequently amputated above the elbow four months after the
injury. Subject 2 had become aware of a phantom right arm immediately after the injury. In the early postinjury period this was felt
to be contained within the paralyzed, anesthetic limb while the
subject was awake, but during drowsiness the phantom limb would
drift out of the paralyzed limb to become supernumerary. The
phantom limb had gradually telescoped to the extent that the phantom hand was felt to be attached to the amputation stump. The
subject had become aware that RS in the phantom hand could be
elicited by tactile stimulation of the right pectoral region. The
subject used a cosmetic prosthesis.
SUBJECT 3. Subject 3, a healthy 31-yr-old male with no history
of neurological injury, was employed as a control subject.
SUBJECT 1.
ABNORMAL ACCESS OF VIBROTACTILE INPUT TO DEAFFERENTED S1 IN AMPUTEES
Statistical analysis
Global cerebral blood flow across the 12
scans was normalized to a value of 50 ml per 100 g per min with
the use of a voxel-based analysis of covariance (Friston et al.
1990). Adjusted mean rCBF maps were derived for each of the
three experimental conditions. Planned comparisons between rCBF
at rest and rCBF during stimulation of the pectoral region ipsilateral to the intact or amputated arm were then performed. Significant
changes in the distribution of rCBF between the rest condition and
each stimulation condition were identified by statistical parametric
mapping (Friston et al. 1991b). The significance of the mean
change in rCBF at each voxel location was determined with the
use of the adjusted error variance generated by the analysis of
covariance to compute the t statistic. The t distribution was transformed into a Gaussian distribution before projection in three orthogonal planes as a statistical parametric map (SPM). By the use
of this approach it is possible to specify the location of a region
of functionally activated brain to within a few millimeters (Fox et
al. 1986; Mintun et al. 1986).
In subjects 1 and 3 the significance threshold was set at the
conventional level of P õ 0.05 per plane after application of a
Bonferroni-like correction for multiple, nonindependent comparisons; this threshold corresponded to a Z score of ¢3.75. An uncorrected significance threshold of P õ 0.01 (corresponding to a Z
score of ¢2.33) was, however, necessary to demonstrate quantitatively smaller rCBF responses in the contralateral S1 during VS
of the right pectoral region in subjects 1 and 3. Although not
significant by conventional (Bonferroni-corrected) criteria traditionally used in PET activation studies, these responses were felt
to be of clear physiological relevance. To facilitate interpretation
of the results, these responses will be referred to as ‘‘low-amplitude
rCBF increases.’’ Because these data were obtained with the use
of an exploratory (albeit hypothesis-led) approach, it is appropriate
to report them descriptively in the text, but not in tabular or SPM
format.
Because of quantitatively smaller rCBF increases in subject 2
during both stimulation conditions, use of a conventional (Bonferroni-corrected) significance threshold resulted in the detection of
very few rCBF responses. Detection of rCBF responses was improved by the use of an uncorrected significance threshold of P õ
0.01 (corresponding to a Z score of ¢2.33 as above), and all
results in this subject were therefore thresholded at this level.
ACTIVATION STUDY.
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To determine the magnitude of the rCBF changes between the
resting and active states, percentage changes in rCBF at voxels of
maximal significance were determined from the statistical maps.
CONNECTIVITY STUDY. To determine the functional connectivity
within cortical regions of interest, rCBF at a reference voxel location was correlated across all 12 scans within each subject. The
confounding effects of global activity were removed with the use
of linear regression to produce adjusted activity values for each of
the 12 scans. An SPM of the correlation coefficient between activity at the reference voxel and all remaining voxels was constructed
after the correlation coefficient was transformed to the normal
distribution with the use of Fisher’s Z transformation. The resulting
SPM of the Z score was thresholded at P õ 0.001 (uncorrected);
across a series of 12 scans, with 10 degrees of freedom, this corresponded to a voxel-to-voxel correlation of R Å 0.823. The theory
behind this analysis is that if two or more voxels are functionally
connected, rCBF at these two voxels should be mutually correlated
within a subject across different brain conditions.
RESULTS
Psychophysical study
Subject 1 was found to have a large ectopic phantom
representation over the left anterior thorax in the pectoral
region ipsilateral to the amputation (Fig. 1A). This phantom
extended mediolaterally between the sternum and the nipple,
and superiorly from 5 cm below the nipple to the level of
the clavicle. The ectopic representation was more extensive
inferiorly, superiorly, and medially during VS than during
PS (Fig. 1A). However, there was considerable overlap of
VS and PS sites. Furthermore, the wider spatial distribution
of VS sites may simply have reflected stimulus spread. A
second ectopic representation of the phantom limb was found
over the left posterior thorax in the upper scapular region
close to the midline (Fig. 1B). This site was more clearly
responsive to PS than VS. The subject’s face was carefully
explored with both stimuli but no ectopic phantom representation was found.
The optimal site for stimulation was found to be the first
left intercostal space 4 cm from the midline. RS elicited
from this site consisted of paresthesias spreading down the
medial aspect of the phantom forearm, into the hand, and
diffusely into the fingers. Gentle movement of the ball applicator elicited more intense RS than a stationary stimulus.
This moving stimulus was therefore used for stimulation of
the optimal site in the PET study. For control purposes, a
similar moving stimulus was applied to the opposite (right)
pectoral region in the PET study in this subject.
Subject 2 was found to have a smaller ectopic representation of the phantom hand in the right pectoral region ipsilateral to the amputation, superior and lateral to the nipple (Fig.
2). A second, even smaller ectopic representation, which
the subject had not previously noticed, was found just proximal to the stump in an area of skin in which there was
some remaining cutaneous sensation. The ectopic phantom
representation in the pectoral region was responsive to both
VS and PS. However, phantom sensations elicited by stimulation of this region were much more intense with VS than
with PS, to the extent that VS of the optimal site induced
vibratory phantom sensations that were of sufficient intensity
to cause extinction of the vibratory sensation at the point of
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Mayo Clinic, Rochester, MN). Image matrix manipulations were
performed with the use of PROMATLAB (Mathworks, Natick,
MA). Correction for the effects of movement of the subject’s head
between scans was made by aligning scans 2–12 with scan 1 with
the use of Automated Image Registration (AIR) software (Woods
et al. 1992). This technique uses anatomic information in the PET
images to calculate the linear and angular displacements needed
to align the images. It is based on the assumption that if two image
sets are accurately aligned, then the value of any voxel in one
image set is related to the value of the corresponding voxel in
another image set by a single multiplicative factor [R]. If the image
sets are misaligned, this multiplicative factor is no longer constant
but varies from voxel to voxel throughout the image. The alignment
algorithm iteratively moves the two image sets relative to one
another until this voxel-to-voxel variation, expressed in terms of
the SD of [R] across all voxels, is minimized. This technique has
been shown to confine movement errors to 0.6–0.7 mm.
The images were standardized by transformation into a conventional stereotactic space (Friston et al. 1989, 1991a) and smoothed
with a Gaussian filter of 20 mm FWHM. This resulted in a normalized set of 26 images per scan with an interplane distance of 4
mm, corresponding directly to the brain sections in the atlas of
Talairach and Tournoux (1988).
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KEW ET AL.
application. RS were elicited from the ectopic representation
proximal to the stump by PS but not by VS.
The optimal site for stimulation lay near the axilla in the
lateral pectoral region adjacent to the amputated arm. This
site was situated 5 cm lateral and 8 cm superior to the nipple.
Stationary VS applied to this area was found to elicit an
intense, diffuse vibratory sensation in the subject’s phantom
hand. A stationary rather than a moving stimulus was therefore used for stimulation of the optimal site in the PET study
in this subject.
PET activation study
SUBJECT 1. VS of the subject’s right pectoral region (ipsilateral to the intact arm) was associated with significant
(P õ 0.05, Bonferroni-corrected) activation of the second
somatic sensory cortex (SII) bilaterally and of the contralateral anterior thalamus. Additional low-amplitude rCBF increases (significance threshold P õ 0.01, non-Bonferronicorrected) were also present in the contralateral S1 60 mm
(coordinates: X Å 08, Y Å 042, Z Å 60; rCBF increase
2.8%; Z score 1.8) and 68 mm (coordinates: X Å 014,
Y Å 42, Z Å 68; rCBF increase 2.8%; Z score 2.7) above
the intercommissural (AC-PC) plane.
VS of the subject’s left pectoral region (ipsilateral to amputated arm, and source of referred phantom sensations) was
associated with significant (P õ 0.05, Bonferroni-corrected)
activation of SII and thalamus bilaterally. In addition, significant activation was seen in the contralateral S1, primary
motor cortex (M1), superior posterior parietal cortex (PPC),
and anterior cingulate cortex (Brodmann area 32). The large
focus of activation in S1 and M1 extended in the ventro-
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dorsal (Z ) dimension from /36 to /68 mm relative to the
AC-PC plane.
The cortical areas activated at a conventional threshold of
significance (P õ 0.05, Bonferroni-corrected) in this subject
during the two stimulation conditions are shown in quantitative form in Table 1 and in the form of an SPM in Fig. 3.
SUBJECT 2. The results in subject 2 replicated those in subject 1, although, as already stated, the overall rCBF changes
were less significant. VS of the subject’s left pectoral region
(ipsilateral to intact arm) was associated with low-amplitude
rCBF increases (significance threshold P õ 0.01, non-Bonferroni-corrected) in the contralateral posterior insula and
SII and the ipsilateral SII. However, there were no significant
rCBF increases in the contralateral S1.
VS of the subject’s right pectoral region (ipsilateral to
amputated arm, and source of referred phantom sensations)
was associated with low-amplitude rCBF increases (significance threshold P õ 0.01, non-Bonferroni-corrected) in SII
bilaterally, the contralateral S1, and the ipsilateral posterior
insula. The S1 rCBF increases extended in the ventrodorsal
(Z ) dimension from /44 to /64 mm relative to the AC-PC
plane.
The cortical areas activated at a significance threshold of
P õ 0.01 (non-Bonferroni-corrected) in this subject during
the two stimulation conditions are shown in quantitative
form in Table 2 and in the form of an SPM in Fig. 4.
SUBJECT 3. VS of the normal subject’s right fingers was
associated with significant (P õ 0.05, Bonferroni-corrected)
activation of the contralateral S1 and M1, which extended
in the ventrodorsal (Z ) dimension from /36 to /64 mm
relative to the AC-PC plane, and of the contralateral superior
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FIG . 1. A: anterior ectopic phantom representation
in the pectoral region ipsilateral to the amputation in
subject 1. Left: cutaneous sites from which referred
sensations (RS) were elicited in the phantom limb by
pressure stimulation (PS) of the skin. Right: cutaneous
sites from which RS were elicited in the phantom limb
by vibrotactile stimulation (VS) of the skin. B: posterior ectopic phantom representation in the upper scapular region ipsilateral to the amputation in subject 1.
Left: cutaneous sites from which RS were elicited in
the phantom limb by PS of the skin. Right: cutaneous
sites from which RS were elicited in the phantom limb
by VS of the skin.
ABNORMAL ACCESS OF VIBROTACTILE INPUT TO DEAFFERENTED S1 IN AMPUTEES
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FIG . 2. A: anterior ectopic phantom representation in subject 2. RS in
the phantom fingers and forearm were elicited by PS in 2 small regions of
the stump. RS in the phantom hand were elicited by both PS and VS of
the upper pectoral region ipsilateral to the amputation. B: posterior ectopic
phantom representation in subject 2. RS in the phantom thumb and hand
were elicited by PS alone in 2 small regions of the stump.
PPC (Table 3, Fig. 5). Low-amplitude rCBF increases (significance threshold P õ 0.01, non-Bonferroni-corrected)
were also present in the contralateral posterior insular cortex
(coordinates: X Å 036, Y Å 012, Z Å 12; rCBF increase
2.5%; Z score 3.6) and SII (coordinates: X Å 046, Y Å
012, Z Å 20; rCBF increase 2.1%; Z score 3.5).
VS of the subject’s right pectoral region was associated
with significant (P õ 0.05, Bonferroni-corrected) activation
of the contralateral SII and adjacent mid-insular cortex, and
the more ventral aspects of the ipsilateral anterior cingulate
cortex (Brodmann area 24; Table 3). Low-amplitude rCBF
increases (significance threshold P õ 0.01, non-Bonferronicorrected) were also present in the contralateral S1 at 56
mm (coordinates: X Å 036, Y Å 030, Z Å 56; rCBF increase
2.8%; Z score 2.7) and 60 mm (coordinates: X Å 016,
Y Å 026, Z Å 60; rCBF increase 1.1%; Z score 2.9) relative
to the AC-PC plane.
Thus two distinct patterns of cerebral activation were pres-
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1. Cortical areas significantly activated during VS of
the right and left pectoral regions in subject 1
TABLE
Talairach Coordinates
Area
VS right pectoral
region
L thalamus
R SII
L SII
VS left pectoral
region with RS
R thalamus
L thalamus
R SII
L SII
R anterior cingulate*
R SI
R MI
R PPC
X
Y
Z
Percent
Change
in rCBF
06
42
036
08
026
032
8
12
20
2.2
3.5
2.7
4.8
4.8
4.2
4
04
42
048
10
34
32
36
022
014
024
024
32
032
022
038
4
8
8
20
28
56
60
60
3.3
3.8
4.0
3.5
2.9
8.3
9.8
6.4
4.5
5.3
4.3
4.4
6.3
4.4
4.4
5.1
Z
Score
P õ 0.05, Bonferroni corrected. VS, vibrotactile stimulation; rCBF, regional cerebral blood flow; R, right; L, left; SII, 2nd somatic secondary
cortex; RS, referred sensations in the phantom limb; SI, primary somatosensory cortex; MI, primary motor cortex; PPC, superior posterior parietal
cortex (Brodmann area 5). * Brodmann area 32.
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ent in the amputees depending on which pectoral region was
stimulated.
1) VS of the pectoral region ipsilateral to the intact arm:
similar patterns of activation were observed in the two amputees during VS of the pectoral region ipsilateral to the intact
arm (without RS) and in the normal control subject during
VS of the right pectoral region. Activation of the contralateral SII was common to all three subjects, the SII activation
foci lying at a similar ventrodorsal (Z ) level relative to the
AC-PC plane (compare Tables 1–3). Additional ipsilateral
SII activation was present in both amputees. Differences
in the patterns of activation included contralateral anterior
thalamic activation in one amputee (subject 1) and ipsilateral
anterior cingulate activation in the normal control subject.
Low-amplitude rCBF increases were present in the dorsal
S1 of one amputee (subject 1) and the normal control subject. These activation foci also lay at a similar ventrodorsal
(Z ) level, with one focus common to both subjects lying at
/60 mm relative to the AC-PC plane. It is important to note
that no S1 activation was present ventral to a level of /56
mm relative to the AC-PC plane in either of these subjects
even at an uncorrected significance level of P õ 0.01.
2) VS of the pectoral region ipsilateral to the amputated
arm: the two amputees showed similar patterns of cerebral
activation during VS of the pectoral region ipsilateral to the
amputated arm (with RS). Bilateral activation of SII was
again common to both subjects. One point of difference,
however, was the presence of bilateral thalamic activation
in subject 1. Activation of the contralateral S1 was also
present in both subjects, but under this stimulation condition
the S1 activation foci extended ventrally to levels of /36
and /44 mm (relative to the AC-PC) in subjects 1 and 2,
respectively. Given that the most ventral of the S1 activation
foci mapped in subject 1 and the normal control subject
during VS of the pectoral region ipsilateral to the intact arm
(without RS) lay at a level of /56 mm, it can be seen that
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the S1 foci during VS of the pectoral region ipsilateral to
the amputated arm (with RS) extended ventrally to distances
of 20 and 12 mm beyond the normal S1 pectoral representation in subjects 1 and 2, respectively. The results in the
normal control subject showed that this more ventrally situated area of S1 (extending from /36 to /56 mm relative
2. Cortical areas significantly activated during VS of
the right and left pectoral regions in subject 2
TABLE
Talairach Coordinates
Area
X
VS left pectoral
region
R SII/posterior
insula
L SII
VS right pectoral
region with RS
L SII
L SI
R SII/posterior
insula
Y
Z
Percent
Change
in rCBF
Z
Score
34
036
018
02
16
04
3.1
3.1
3.1
3.0
042
030
024
034
20
64
3.3
3.7
3.0
3.0
28
018
16
3.6
3.9
P õ 0.01, non-Bonferroni corrected. For abbreviations, see Table 1.
/ 9k11$$my11 J181-6
to the AC-PC plane) was activated exclusively by VS of the
contralateral fingers. This suggests that VS of the pectoral
region ipsilateral to the amputated arm was associated with
activation of not only the contralateral S1 pectoral representation (dorsal to /56 mm relative to the AC-PC plane) but
also the contralateral S1 finger (or hand/arm) representation
(ventral to /56 mm relative to the AC-PC plane). Furthermore, it appears that the entire S1 finger representation was
activated during this stimulation condition in subject 1. Considering that both these subjects reported RS in the phantom
limb during this stimulation condition, it is probable that the
S1 hand/arm activation is the cortical correlate of these RS.
Connectivity study
SUBJECT 1. The Talairach coordinates used to study the connectivity of the normally afferented and deafferented S1
hand/arm representations were derived from the PET activation study. The voxel of maximal significance in the contralateral S1 during VS of the subject’s left pectoral region
(with referred phantom sensations) was assumed to lie
within the deafferented hand/arm representation. This assumption was supported by the results obtained in the normal
subject showing that VS of the fingers was associated with
activation of this same area of S1 (compare Tables 1 and
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FIG . 3. Significant increases in regional cerebral blood flow (rCBF) in subject 1 during VS of the right and left pectoral
regions. Sagittal, coronal, and transverse projections of the statistical parametric maps (SPMs) are shown. Voxels at which
a significant increase in rCBF occurred are displayed in black within the standardized stereotactic grid system of Talairach
and Tournoux (1988); nonsignificant voxels are displayed in white. VAC and VPC: vertical orientation lines transecting the
anterior and posterior commissures. The significance threshold was set at P õ 0.05 after application of a Bonferroni-like
correction for the number of planes analyzed. The images were smoothed with a Gaussian filter to 8 mm full width at half
maximum (FWHM) for display purposes. VS of the subject’s right pectoral region (ipsilateral to the intact arm) was
associated with significant activation of the 2nd somatic sensory cortex (SII) bilaterally and of the contralateral anterior
thalamus. VS of the subject’s left pectoral region (ipsilateral to the amputated arm, with RS in the phantom limb) was
associated with significant activation of SII and thalamus bilaterally, and of the contralateral primary somatosensory cortex
(S1) and primary motor cortex [M1; extending in the ventrodorsal (Z ) dimension from /36 to /68 mm relative to the
intercommissural (AC-PC) plane], superior posterior parietal cortex (PPC), and anterior cingulate cortex (Brodmann area
32). Thal, thalamus; Ant Cing, anterior cingulate cortex.
ABNORMAL ACCESS OF VIBROTACTILE INPUT TO DEAFFERENTED S1 IN AMPUTEES
2759
3 and Figs. 3 and 5). The coordinates used to study the
connectivity of the normally afferented S1 were the mirror
coordinates of those determined for the deafferented S1 (sign
of X coordinate reversed to transfer voxel location from right
to left hemisphere).
The intrinsic connectivity of the subject’s normally afferented left S1 hand/arm representation (coordinates: X Å
034, Y Å 032, Z Å 56) extended from 44 to 60 mm above
the AC-PC plane. The intrinsic connectivity of the subject’s
deafferented right S1 hand/arm representation (coordinates:
3. Cortical areas significantly activated during VS of
the right fingers and the right pectoral region in the normal
subject (subject 3)
TABLE
Talairach
Coordinates
Area
VS right fingers
L SI
L PPC
VS right pectoral
region
L SII
L mid-insula
R anterior cingulate*
X
Y
Z
Percent
Change
in rCBF
038
02
030
046
56
64
7.9
3.6
6.5
3.8
040
038
8
08
08
0
16
12
28
3.2
2.5
2.5
3.9
4.9
5.1
Z
Score
P õ 0.05, Bonferroni corrected. For abbreviations, see Table 1. * Brodmann area 24.
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X Å 34, Y Å 032, Z Å 56) extended from 40 to 68 mm above
the AC-PC plane. The reference voxel in the deafferented
representation was functionally connected with Ç3 times
as many S1 voxels as the reference voxel in the normally
afferented representation (725 compared with 250 voxels)
(Fig. 6). This abnormal connectivity extended in both the
rostrocaudal and ventrodorsal dimensions. The subject’s
deafferented right S1 hand/arm area also showed abnormal
connectivity with the ipsilateral ventral S1 between 20 and
32 mm (face area).
Thalamic connectivity was not explored in this subject,
despite significant thalamic activation, because it was not
possible to specify the location of the main sensory nucleus
of the thalamus.
SUBJECT 2. The voxel of maximal significance in the contralateral S1 during VS of the subject’s right pectoral region
(with referred phantom sensations) was located at Talairach
coordinates X Å 030, Y Å 034, Z Å 64. This location,
which was used to study the connectivity of the deafferented
S1, was situated dorsal to that in subject 1. By analogy with
the results of the PET activation study in the normal subject,
this voxel was located at or near the junction between the
S1 hand/arm and pectoral representations. As in subject 1,
the coordinates used to study the connectivity of the normally afferented S1 were the mirror coordinates of those
determined for the deafferented S1.
The intrinsic connectivity of the subject’s normally afferented right S1 hand/arm representation (coordinates: X Å
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FIG . 4. Significant increases in rCBF in subject 2 during VS of the left and right pectoral regions. Conventions of SPMs
as in Fig. 3. Because of a lower overall magnitude of rCBF response in this subject, the significance threshold was set at
P õ 0.01 without a correction for the number of planes analyzed. The images were smoothed with a Gaussian filter to 8
mm FWHM for display purposes. VS of the subject’s left pectoral region (ipsilateral to the intact arm) was associated with
significant activation of the contralateral posterior insular cortex and SII and of the ipsilateral SII. VS of the subject’s right
pectoral region (ipsilateral to the amputated arm, with RS in the phantom limb) was associated with significant activation
of SII bilaterally, the contralateral S1 [extending in the ventrodorsal (Z ) dimension from /44 to /64 mm relative to the
AC-PC plane], and the ipsilateral posterior insula. Post insula, posterior insular cortex.
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FIG . 5. Significant increases in rCBF in the normal control subject (subject 3) during VS of the right fingers. Conventions of SPMs as in Fig. 3.
Significance threshold was set at P õ 0.05, with a Bonferroni-like correction, and the images were smoothed with a Gaussian filter to 8 mm FWHM.
Significant activation was present in the contralateral S1 and M1 [extending
in the ventrodorsal (Z ) dimension from /36 to /64 mm relative to the
AC-PC plane] and in the contralateral PPC.
30, Y Å 034, Z Å 64) extended from 44 to 64 mm above
the AC-PC plane. The intrinsic connectivity of the subject’s
deafferented left S1 hand/arm representation (coordinates:
X Å 030, Y Å 034, Z Å 64) extended from 40 to 64
mm above the AC-PC plane. Because of abnormal confluent
connectivity between the deafferented S1 and other cortical
areas, quantification of the intrinsic connectivity of the deafferented hand/arm representation in S1 per se was not possible in this subject. However, inspection of the SPM of the
correlation coefficient clearly showed that the intrinsic connectivity of the deafferented S1 hand/arm representation was
much more extensive than that of its normally afferented
counterpart (Fig. 7). This abnormal connectivity extended
in both the rostrocaudal and the ventral dimensions. The
subject’s deafferented left S1 hand/arm representation also
showed abnormal connectivity with the ipsilateral ventral S1
between 28 and 32 mm (face area), similar to that seen in
subject 1.
DISCUSSION
Normal somatotopic organization of S1
The results obtained in the control subject confirm that
VS of the digits is associated with significant blood flow
responses in the human S1 that extend ventrodorsally from
/36 to /64 mm relative to the AC-PC plane. The results
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Activation of SII by VS
The role of SII in vibratory processing is well established.
McIntyre et al. (1967) were the first to show that evoked
potentials from Pacinian corpuscles could be recorded in SII
of the cat. Single-cell recordings have confirmed that neurons with Pacinian-like responses to high-frequency vibration ( ú128 Hz) are relatively common in SII of primates
(Robinson and Burton 1980) and cats (Bennett et al. 1980).
In fact, in the cat, there appears to be a greater proportion
of neurons responsive to Pacinian input in SII than in S1
(Bennett et al. 1980; Fisher et al. 1983). It has also been
shown that SII neurons display phase-locking of impulse
activity to the vibratory stimulus waveform when the frequency of cutaneous vibration is in the range of 100–300
Hz (Ferrington and Rowe 1980), although the majority of
SII neurons activated by tactile stimuli appear to have a
bandwidth of 10–100 Hz (Bennett et al. 1980; Robinson
and Burton 1980).
Coactivation of the contralateral S1 and SII was present
during VS of the fingers and pectoral region in the normal
subject. The vibratory stimulus frequency of 100 Hz used
in the studies lies toward the lower end of the bandwidth
for Pacinian neurons in both S1 (Mountcastle et al. 1969)
and SII (Ferrington and Rowe 1980). It is, therefore, not
surprising that such a stimulus should coactivate these two
somatosensory areas. Indeed, similar coactivation of S1 and
SII was reported by Fox et al. (1987) in normal human
subjects during vibration of the fingers at a frequency of
130 Hz.
Reorganization of S1 following deafferentation
The results obtained in subject 1 leave little doubt that
VS of the subject’s ectopic phantom limb representation in
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also show that the most significant rCBF response within
the S1 finger representation lies at a dorsal (Z ) level of 48
mm above the AC-PC plane. These findings replicate those
of Fox et al. (1987) and Meyer et al. (1991), who each
used a vibrotactile stimulus similar to that employed in the
present study to show that the finger area in S1 was located
at a mean vertical (dorsal) distance above the AC-PC plane
of 47 mm.
S1 blood flow responses during VS of the pectoral region
were of lower magnitude and significance in comparison
with those mapped during VS of the fingers. Two observations from the present study indicate that the S1 pectoral or
trunk representation is situated dorsal to the finger representation. First, in the normal subject low-amplitude rCBF increases to VS of the pectoral region were present in the
contralateral S1 at a level of 56–60 mm above the AC-PC
plane. Second, in one amputee (subject 1), similar blood
flow responses to VS of the contralateral pectoral region
were present in the normally afferented S1 at levels of 60
and 68 mm above the AC-PC plane. The evidence therefore
suggests that the pectoral, or trunk, representation in S1 is
located at a dorsal level of Ç60 mm above the AC-PC plane,
whereas the center of the finger representation is located
more ventrally at a level of 48 mm. The finding of a more
dorsal location of the trunk representation in S1 is consistent
with the findings of Penfield and Rasmussen (1950) and of
Woolsey et al. (1979) in humans.
ABNORMAL ACCESS OF VIBROTACTILE INPUT TO DEAFFERENTED S1 IN AMPUTEES
2761
the left pectoral region ipsilateral to the amputation was
associated with significant activation of not only the contralateral S1 pectoral representation, but also of the more
ventrally located contralateral S1 finger representation. By
analogy with the pattern of activation obtained during VS of
the fingers in the normal subject, this abnormal S1 activation
extended throughout the entire S1 hand representation. Furthermore, the rCBF response in the deafferented S1 finger
representation of subject 1 during VS of the ectopic phantom
limb representation was of equivalent magnitude to that in
the S1 finger representation of the normal subject during VS
of the fingers.
The results observed in subject 2, although less striking
than those in subject 1, are again consistent with abnormal
access of axial vibratory input to the deafferented S1. Several
factors may have contributed to the variability between the
two subjects with amputations. The overall rCBF changes
in subject 2, which were less pronounced than those in subject 1, may have occurred as a result of individual differences
in the extent of radioactive tracer uptake. In addition, it is
possible that the different magnitudes of rCBF response
were influenced by differences in stimulus presentation. In
subject 1, a moving vibratory stimulus was employed,
whereas in subject 2, the vibratory stimulus was stationary.
It is likely that a moving stimulus is a more optimal source
of activation. Finally, intrinsic within-subject variability
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needs to be considered. Because of variability between individuals, most PET activation studies employ averaged data
gathered from a number of subjects. Group averaging is used
to improve the statistical significance of the activation in
such studies. However, this approach was not possible in
this study because amputees reporting ectopic phantom representations are rare and the two subjects in our study had
amputations on different sides. Under such circumstances,
it is not possible to perform intersubject averaging. Variability in control subjects is an important issue for future studies.
However, the activations observed in subject 3 are in keeping
with previous normative studies of the relative neurophysiological localization of the stimulated areas (Fox et al. 1987;
Meyer et al. 1991). There is, furthermore, considerable similarity between the overall patterns of activation in the two
amputees and that in the control subject during VS of the
pectoral region ipsilateral to the intact arm.
By contrast, the large-scale changes observed during VS
of the pectoral region ipsilateral to the amputated arm (involving shifts of the S1 trunk representation into the deafferented S1 hand/arm areas spanning 20 and 12 mm in the
2 subjects, respectively) are consistent with the results of
previous magnetic source imaging studies in amputees. In
those studies, shifts of the S1 facial dipole into the deafferented S1 hand/arm representation of between 15 and 30 mm
have been recorded (Elbert et al. 1994; Yang et al. 1994).
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FIG . 6. Pattern of intrinsic and extrinsic connectivity of the normally afferented left S1 hand/arm area (Talairach coordinates: X Å 034, Y Å 032, Z Å 56) and the deafferented right S1 hand/arm area (Talairach coordinates: X Å 34, Y Å 032,
Z Å 56) of subject 1. Voxels showing functional connectivity (voxel-to-voxel rCBF correlation across scans of R ¢ 0.823;
significance P õ 0.001 uncorrected at 10 degrees of freedom) with the reference voxel are displayed in black within the
standardized stereotactic grid system of Talairach and Tournoux (1988); voxels showing no functional connectivity are
displayed in white. Conventions of SPMs otherwise as in Fig. 3. Reference voxel in the deafferented right S1 hand/arm
representation was intrinsically connected with Ç3 times as many S1 voxels as the reference voxel in the normally afferented
representation (725 compared with 250 voxels). The subject’s deafferented S1 hand/arm area also showed abnormal connectivity with the ipsilateral ventral S1 (face area), the ipsilateral insular cortex, the anterior cingulate cortex (areas 24 and 32)
bilaterally, and the contralateral ventral premotor cortex (area 6). The subject’s normally afferented left S1 hand/arm area
showed extrinsic connectivity that was limited to a small number of voxels in lateral visual association (VA) cortex (Brodmann
area 19) bilaterally. Premotor, ventral premotor cortex.
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KEW ET AL.
In conjunction with the psychophysical results, it is difficult
to escape the conclusion that this abnormal S1 activation
reflects abnormal access of axial (pectoral) vibratory input
to the deafferented S1 finger and hand/arm areas.
The findings above raise two additional questions. What is
the route via which the reorganized pectoral input is allowed
access to the deafferented cortex? What mechanism mediates
this reorganization? There are several possible routes by
which this reorganized input may gain access to the deafferented cortex, including reorganized thalamocortical and reorganized corticocortical pathways. A number of animal
(Garraghty et al. 1991; Gilbert and Wiesel 1992; Jones
1993) and human (Brasil-Neto et al. 1993) studies have
concluded that deafferentation-induced reorganization of this
kind may take place at a cortical rather than a thalamic or
spinal level. For example, although arborizations of individual thalamocortical neurons can be quite extensive, on the
order of 2–3 mm (Jones 1993), it has been suggested that
their unmasking is probably not sufficient to account for
the large-scale cortical reorganization found in some studies
(Pons et al. 1991). In addition, if alterations in thalamocortical input were to explain the reorganization of the cortex,
changes in g-aminobutyric acid (GABA) immunoreactivity
(see below) should remain confined to those cortical layers
(specifically layer IV) that receive this input, and this has
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been shown not to be the case; in fact, all layers of S1 show
reduced staining for GABA after peripheral deafferentation,
suggesting that this affects the intrinsic inhibitory circuitry
of the cortex (Garraghty et al. 1991). Furthermore, the observation that discrete retinal lesions in primates result in an
initial unresponsive zone in the corresponding striate cortex
that rapidly regains responsiveness to visual input from the
perilesion retina, whereas a large permanent unresponsive
zone remains in the corresponding lateral geniculate nucleus,
provides further evidence of reorganization at a cortical
rather than a thalamic level following deafferentation, at
least in the visual system (Gilbert and Wiesel 1992).
The results of neurophysiological studies in human subjects have been in agreement with these findings in animals.
Temporary forearm deafferentation by ischemic nerve block
has been shown to be associated with increases in the size of
motor evoked potentials elicited from muscles immediately
proximal to the block by transcranial magnetic stimulation,
but not by transcranial electrical stimulation or spinal electrical stimulation (Brasil-Neto et al. 1993). Because transcranial magnetic stimulation is thought to excite M1 pyramidal
neurons presynaptically, whereas transcranial electrical stimulation excites these neurons directly, this finding is likewise
consistent with a modulation of inhibitory neuronal networks
within the cortex following deafferentation. Having said this,
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FIG . 7. Pattern of intrinsic and extrinsic connectivity of the normally afferented right S1 hand/arm area (Talairach
coordinates: X Å 30, Y Å 034, Z Å 64) and the deafferented left S1 hand/arm area (Talairach coordinates: X Å 030, Y Å
034, Z Å 64) of subject 2. Conventions of SPMs as in Fig. 6. Because of abnormal confluent connectivity between the
deafferented S1 and other cortical areas, quantification of the intrinsic connectivity of the deafferented hand/arm representation
in S1 was not possible in this subject. Nevertheless, the intrinsic connectivity of the deafferented S1 hand/arm representation
could be seen to be much more extensive than that of its normally afferented counterpart. The subject’s deafferented left S1
hand/arm representation also showed abnormal connectivity with the ipsilateral ventral S1 (face area), paracentral lobule
(medial area 5), inferior parietal lobule (area 40), and dorsal premotor cortex (area 6). The subject’s normally afferented
right S1 hand/arm representation showed extrinsic connectivity that was mainly confined to a small number of voxels in the
ipsilateral mesial and lateral visual association cortex (Brodmann areas 18 and 19). PCL, paracentral lobule; IPL, inferior
parietal lobule.
ABNORMAL ACCESS OF VIBROTACTILE INPUT TO DEAFFERENTED S1 IN AMPUTEES
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the present study. However, we and others have previously
provided evidence that limb amputations acquired by human
subjects in adult life are accompanied by marked alterations
in the excitability of the deafferented M1 to transcranial
magnetic stimulation (Cohen et al. 1991; Kew et al. 1994),
and that similar increased excitability of the deafferented S1
and PPC may be important in the genesis of phantom limb
perceptions (Kew et al. 1994). A plausible substrate for
these changes is a modulation of GABAergic inhibition
within the deafferented cortex (Kew et al. 1994). Although
such modulation has yet to be demonstrated directly in humans, it has been confirmed clearly in animal studies. Functional deafferentation of monkey visual cortex by unilateral
enucleation, eyelid suture, or intraocular injection of tetrodotoxin has been shown to result in a 50% reduction in the
number of neurons immunoreactive for GABA and its synthesizing enzyme glutamic acid decarboxylase in ocular
dominance columns subserving the deprived eye (Hendry
and Jones 1986, 1988; Jones 1990). Similar reductions in
glutamic acid decarboxylase immunoreactivity have been
observed in the S1 barrel cortex of rodents after whisker
removal (Welker et al. 1989), and in primates, deafferentation of an area of S1 by peripheral nerve section leads to a
dramatic (75%) local reduction in the number of GABAimmunoreactive neurons (Garraghty et al. 1991). It has been
suggested that this deafferentation-induced localized loss of
GABAergic inhibitory neurons may allow functional access
of normally suppressed, subthreshold inputs to the deafferented cortex (Garraghty et al. 1991; Jones 1993). The presence of such inputs has been inferred from studies of pharmacological manipulation of cortical GABAergic inhibition
in both S1 (Dykes et al. 1984) and M1 (Jacobs and Donoghue 1991). These inputs are likely to be intracortical
and may originate from long-range horizontal collaterals of
pyramidal neurons situated in regions of primary cortex adjacent to the deafferented zone (DeFelipe et al. 1986; Huntley
and Jones 1991; Jones 1993). Such horizontal collaterals
are known to extend for ¢6 mm (Jones 1993).
The present results could be interpreted in a similar way:
vibrotactile input gaining access to the S1 pectoral representation via thalamocortical afferents would then be relayed
into the deafferented S1 hand/arm representation via longrange horizontal collaterals unmasked by local deafferentation-induced modulation of GABAergic inhibition. This hypothesis is currently tenable and is amenable to testing by
further PET studies with the use of the benzodiazepine antagonist 11C-flumazenil to measure levels of cortical GABAA
binding.
We thank the volunteers for participation; Dr. Sellaiah Sooriakumaran
for help in recruiting the subjects; Dr. Karl Friston for statistical guidance;
colleagues in the Medical Research Council Cyclotron Unit Radiochemistry
and PET methods sections; and G. Lewington, A. Williams, and A. Blyth
for assistance with the PET scanning.
This work was supported by the Medical Research Council.
Address for reprint requests: P. Halligan, Rivermead Rehabilitation Centre, Abingdon Rd., Oxford OX1 4XD, UK.
Received 6 March 1996; accepted in final form 9 January 1997.
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