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The Journal of Neuroscience, April 1, 2000, 20(7):2657-2663
Cortical Processing of Human Somatic and Visceral Sensation
Q.
Aziz1,
D. G.
Thompson3,
V. W. K.
Ng1,
S.
Hamdy3,
S.
Sarkar3,
M. J.
Brammer2,
E. T.
Bullmore2,
A.
Hobson3,
I.
Tracey4,
L.
Gregory1,
A.
Simmons1, and
S. C. R.
Williams1
Departments of 1 Clinical Neurosciences, and
2 Biostatistics and Computing, Institute of Psychiatry,
London SE5 8AF, United Kingdom, 3 Department of
Gastroenterology, Hope Hospital, University of Manchester, Salford M6
8HD, United Kingdom, and 4 Oxford University Center for
Functional Magnetic Resonance Imaging of the Brain, John Radcliffe
Hospital, Oxford OX3 9DU, United Kingdom
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ABSTRACT |
Somatic sensation can be localized precisely, whereas localization
of visceral sensation is vague, possibly reflecting differences in the
pattern of somatic and visceral input to the cerebral cortex. We used
functional magnetic resonance imaging to study the cortical processing
of sensation arising from the proximal (somatic) and distal (visceral)
esophagus in six healthy male subjects. Esophageal stimulation was
performed by phasic distension of a 2 cm balloon at 0.5 Hz. For each
esophageal region, five separate 30 sec periods of nonpainful
distension were alternated with five periods of similar duration
without distension. Gradient echoplanar images depicting bold contrast
were acquired using a 1.5 T GE scanner. Distension of the proximal
esophagus was localized precisely to the upper chest and was
represented in the trunk region of the left primary somatosensory
cortex. In contrast, distension of the distal esophagus was perceived
diffusely over the lower chest and was represented bilaterally at the
junction of the primary and secondary somatosensory cortices. Different
activation patterns were also observed in the anterior cingulate gyrus
with the proximal esophagus being represented in the right midanterior
cingulate cortex (BA 24) and the distal esophagus in the perigenual
area (BA32). Differences in the activation of the dorsolateral
prefrontal cortex and cerebellum were also observed for the two
esophageal regions. These findings suggest that cortical specialization
in the sensory-discriminative, affective, and cognitive areas of the
cortex accounts for the perceptual differences observed between the two
sensory modalities.
Key words:
cerebral cortex; esophagus; somatic; visceral; functional
magnetic resonance imaging; sensation
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INTRODUCTION |
The perception of somatic and
visceral sensation is fundamentally different. Somatic sensation is
localized precisely to the site of origin, whereas visceral sensation
is vague, often referred to somatic structures and radiates to one or
other side of the body (Polland and Bloomfield, 1931 ; Cervero, 1985;
Ness and Gebhart, 1990).
Some of these differences can be explained on the basis of our
current knowledge of the projections of somatic and visceral spinal
afferents. For instance, the poor localization of visceral sensation
can be partially explained by the fact that visceral afferents,
which constitute <10% of the total afferent input to the spinal cord
have a much greater rostrocaudal distribution within the spinal cord
than somatic afferents (Polland and Bloomfield, 1931; Foreman et al.,
1984; Cervero, 1985; Ness and Gebhart, 1990; Sengupta and Gebhart,
1994). In addition, referral of visceral sensation to somatic
structures has been explained by the fact that most visceral afferents
synapse on spinal neurons that also receive projections from somatic
afferents (Polland and Bloomfield, 1931; Foreman et al., 1984; Sengupta
and Gebhart, 1994).
However, the perceptual differences between somatic and
vis- ceral sensation cannot be explained on the basis of spinal
innervation, because perception is largely dependent on cortical
processing. Animal data indicate differential cortical processing of
somatic and visceral sensation (Bruggemann et al., 1994), but
comparisons between the cortical processing of visceral and somatic
sensation in man remain unexplored.
The human esophagus is virtually unique in that it develops as both a
somatic and a visceral structure. It consists of striated muscle in its
proximal one-third and smooth muscle in its distal two-thirds and
differs in a number of ways in the innervation of the two regions
(Christensen and De Carle, 1974; Kahrilas, 1992). First, the proximal
(striated muscle) region has a denser spinal innervation than the
distal (smooth muscle) region. Second, vagal afferents from the
proximal region are largely myelinated, whereas those from the distal
region are unmyelinated (Christensen, 1984). Third, intramural
myenteric and submucous plexi are almost exclusive to the distal
esophagus allowing it a degree of autonomy from supraspinal control
(Christensen and De Carle, 1974; Christensen, 1984; Kahrilas, 1992).
Fourth, the quality of sensation experienced from these two regions is
different. Sensation arising from the proximal esophagus is localized
precisely to the upper sternum, in contrast, that arising from the
lower esophagus is perceived diffusely over the chest.
The human esophagus therefore provides a convenient neural system to
compare the cortical processing of somatic and visceral sensation from
the same anatomical organ. We therefore compared the cortical
representation of the proximal and distal regions of the human
esophagus using functional magnetic resonance imaging (fMRI).
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MATERIALS AND METHODS |
Subjects. Six right-handed healthy male subjects
(mean age of 33 years; range, 25-48 years) were studied. All were free
of esophageal symptoms, and all refrained from alcohol for at least 24 hr before the studies. Each subject underwent esophageal manometry to
identify the distance of the proximal and distal esophageal sphincters
from the incisors to accurately position the probe.
Informed, written consent was obtained from all subjects, and approval
from the local ethics committee was obtained before all studies.
Esophageal stimulation was performed by distending a 2-cm-long silicone
balloon with air. The balloon was mounted 15 cm from the tip of a
4-mm-diameter multilumen polyvinyl catheter (Wilson Cook; Letchworth,
Herts, UK). For proximal esophageal stimulation, the center of the
balloon was placed 3 cm distal to the upper esophageal sphincter,
whereas for the distal esophageal stimulation, its center was placed 5 cm proximal to the lower esophageal sphincter. During each study, the
balloon was repeatedly inflated with air using a purpose built pump
(Medical Physics Department, Hope Hospital, Salford, UK), which was
designed to operate in the strong magnetic field of the MR scanner. The
flow of air produced by the inflation pump was 12 l/min. The volume of
distension was adjusted for each subject to ensure that each inflation
produced a clearly perceptible but nonpainful sensation. The balloon
inflation frequency was 0.5 Hz.
Image acquisition. Gradient-echo echoplanar MR images
were acquired using a 1.5 T GE Signa System (General Electric,
Milwaukee, WI) fitted with Advanced Nuclear Magnetic Resonance (Woburn,
MA) hardware and software at the Maudsley Hospital (London, UK). A quadrate birdcage head coil was used for radio frequency transmission and reception. In each of 16 noncontiguous planes parallel to the
intercommissural anterior commissure-posterior commissure (AC-PC) plane, 100 T2*-weighted MR images depicting bold
contrast were acquired with an echo time (TE) of 40 msec and a
repetition time (TR) of 3600 msec. The slices had an in-plane
resolution of 3.1 mm, with a slice thickness of 7 mm and interslice
interval of 0.7 mm. Head movement was limited by foam padding within
the head coil and a restraining band across the forehead. During the same session, a 43 slice, high-resolution inversion recovery echoplanar image of the whole brain was acquired in the AC-PC plane with TE of 73 msec, inversion time (TI) of 180 msec, and TR of 16,000 msec.
The in-plane resolution was 1.5 mm, and the slice thickness was 3 mm with a 0.3 mm slice gap. The higher resolution image allowed
subsequent superimposition of area of activation from the lower
resolution bold images.
Image artifacts caused by subject movement during the course of the
functional study were minimized using a combination of cushions and
head straps, whereas those identified by subsequent postprocessing were
minimized using locally developed image realignment software (Friston
et al., 1996).
Generic brain activation mapping. The power of periodic
signal change at the (fundamental) ON-OFF frequency of stimulation was
estimated by iterated least squares fitting a sinusoidal regression model to the motion-corrected time series at each voxel of all images.
The fundamental power quotient (FPQ) i.e., fundamental power divided by
its SE was estimated at each voxel and represented in a
parametric map. Each observed fMRI time series was then randomly permuted 10 times, and FPQ was re-estimated after each permutation. This resulted in 10 parametric maps (for each subject at each plane) of
FPQ estimated under the null hypothesis that FPQ is not determined by
experimental design (Bullmore et al., 1996). All parametric maps were
then registered in the standard space of Talairach and Tournoux (1988),
as described elsewhere (Brammer et al., 1997). This was achieved in two
stages, using realignment algorithms similar to those previously used
for movement correction. First, the set of FPQ maps observed in each
subject is registered with that subject's high-resolution echo planar
imaging dataset, then registered and rescaled relative to a Talairach
template image.
Identical transformations were applied to the randomized FPQ maps
obtained for each subject. After spatial normalization, the observed
and permuted FPQ maps from each subject were identically smoothed with
a Gaussian filter (full-width, half-maximum, 7 mm) to accommodate
variability in gyral anatomy and error of voxel displacement during
normalization. Generic activation was then robustly determined by
computing the median value of FPQ at each voxel of the observed
parametric maps and comparing it to a null distribution of median FPQ
values computed from the randomized parametric maps. If the observed
median FPQ exceeded the critical value of randomized median FPQ, then
that voxel was considered generically activated with probability of
false positive activation, p < 0.0008. This
conservative threshold for activation was chosen to achieve acceptable
control over type 1 error despite the large number of tests conducted.
Generically activated voxels were colored and superimposed on the gray
scale Talairach template, to create generic brain activation maps
(GBAM) (Brammer et al., 1997). The coordinates for the activated
regions were then identified on the Talairach and Tournoux (1988) atlas
in sagittal, coronal, and axial sections. To determine the relationship
of esophageal representation over the primary somatosensory cortex with
the somatic homunculus, a comparison was made with the somatic
homunculus mapped in a recent human magnetoencephalography study
(Nakamura et al., 1998).
Comparison of proximal and distal esophageal brain activation
maps. To identify those voxels that demonstrated significant difference in standardized power of response to proximal and distal esophageal stimulation, the observed difference in the median FPQ
between the two experimental conditions was computed at each voxel.
Subjects were then randomly reassigned to one of two equal-sized groups, and the difference in median FPQ between randomized groups was
computed at each voxel. This process was repeated 64 times, and the
results were pooled over voxels to generate a null distribution for the
difference in median FPQ. For a two-tailed test of size p < 0.01, the critical values were the
100*p/2th and 100*(1  p/2)th percentiles
of the randomization distribution. Note that this more lenient
probability threshold was used to test for a differential power of
response between experiments only at those voxels that were
significantly activated in one or both of the GBAMs separately computed
for each experiment (Phillips et al., 1997; Curtis et al., 1998).
Protocol. At the start of each study, the balloon catheter
was passed perorally into the esophagus, and the balloon was positioned either in the proximal or the distal esophagus. The catheter was then
connected to the pump and the balloon repeatedly inflated, increasing
the volume of inflation in 1 ml increments to determine both the
sensory and pain thresholds for each individual. A value was then
determined that represented 50% of the difference between the sensory
and the pain threshold. For instance, if the sensory threshold was 5 ml
and the pain threshold 11 ml, then the volume used for the study was 8 ml. This method has been validated and described in detail in our
previous study (Hobson et al., 1998). It was confirmed that this
calculated volume produced a clearly perceptible but nonpainful
sensation in each subject. The subjects were also asked to mark the
site of radiation of esophageal sensation over the chest wall, and this
area was then measured. The subjects were then comfortably positioned
in the scanner, and a 5 min study was performed that was divided into
10 separate, 30 sec periods, of alternating nonpainful esophageal
sensation (ON) and no-sensation (OFF) (where the balloon remained
completely deflated). The order in which the two esophageal regions
were stimulated was randomized between subjects. After completion of
the process in one esophageal region, the balloon was repositioned in
the other esophageal region, and the procedure was repeated.
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RESULTS |
All subjects tolerated the study without difficulty. Proximal
esophageal sensation was localized precisely by each subject at a site
1-2 cm in area, in the midline over the lower neck and the upper
chest, whereas distal esophageal sensation was perceived as a vague
poorly localized sensation over an area of at least 5 cm in the lower
chest. The balloon volumes required to produce a definite sensation in
proximal and distal esophagus were 6 ± 2 and 9 ± 3 ml, respectively.
Brain activations
Proximal esophagus (Fig. 1)
The largest spatial extent of activation occurred over the upper
arm and chest area of the left primary sensory (S1) and motor cortices
(BA 1 and BA 4), the right insula, the right anterior midcingulate
gyrus (BA 24), the right dorsolateral prefrontal cortex (BA9), and the
left supplementary motor cortex (BA 6). Smaller clusters of activated
voxels were also seen bilaterally over inferior frontal gyrus (Broca's
area BA 44), the left dorsolateral prefrontal cortex (BA 9),
bilaterally over the premotor and supplementary motor cortices (BA 6),
and the left precuneus (BA 7), Table
1.
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Figure 1.
Brain activation after esophageal stimulation. The
figure shows the brain regions activated after stimulation of the
proximal (somatic) and the distal (visceral) regions of the esophagus.
a shows activation of the left cerebellum for the distal
but not for the proximal esophagus. b shows activation
of the right insula for both the proximal and the distal esophagus.
c shows activation of the right inferior frontal gyrus
for the proximal esophagus and the inferior part of the left primary
somatosensory cortex, the left secondary somatosensory cortex, the left
inferior frontal gyrus, and the right premotor cortex for the distal
esophagus. d shows activation of the right anterior
midcingulate gyrus, the left dorsolateral prefrontal cortex, the left
premotor and supplementary motor cortices, and the right premotor
cortex for the proximal esophagus, and the left premotor and
supplementary motor cortices for the distal esophagus. e
shows activation of the right dorsolateral prefrontal cortex, right
anterior midcingulate gyrus for the proximal esophagus and right
anterior cingulate gyrus, the right precuneus, left motor, premotor,
and supplementary cortices for the visceral esophagus. F
shows activation of the left motor and supplementary motor cortices,
the left primary somatosensory cortex, left precuneus and the right
premotor cortex, and supplementary cortex for the proximal esophagus,
and that of the right precuneus, the right premotor, and supplementary
cortices for the visceral esophagus.
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Distal esophagus (Fig. 1)
The largest spatial extent of activation occurred over the left
cerebellum, right anterior midcingulate gyrus (BA 24), left premotor
and supplementary motor cortex (BA 6), left inferior primary sensory
(gustatory) and secondary sensory (S2) cortices (BA 43), the left
inferior frontal gyrus (BA45), the perigenual part of the right
anterior cingulate gyrus (BA 32), and the right precuneus. Smaller
clusters of activated voxels were also seen at the right inferior
primary sensory and motor cortices (BA 1 and BA 4), left dorsolateral
prefrontal cortex (BA 46), right insula, (BA 7), and the premotor and
supplementary cortices bilaterally (Table
2).
Comparison of activation maps from proximal and distal esophagus
(Fig. 2)
Proximal esophageal stimulation produced greater activation over
the left upper arm and chest area of the primary
somatosensory/motor cortex, the right dorsolateral prefrontal
cortex (BA 9), and left inferior frontal gyrus (BA 44). In contrast,
distal esophageal stimulation produced greater activation of the left
cerebellum, the left dorsolateral prefrontal cortex (BA 46), inferior
(gustatory) part of the left primary sensory and motor cortex, and the
right anterior cingulate cortex (perigenual part, BA 32), (Table
3).
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Figure 2.
Three-dimensional brain representation of
esophageal sensation. The figure shows the brain loci that process
proximal (A) and the distal
(B) esophageal sensation, superimposed on
three-dimensionally rendered images of the brain. In comparison to the
distal esophagus, the proximal esophagus shows representation in the
more rostral regions of the primary somatosensory and motor cortex.
Furthermore, differential representation of the two esophageal regions
over the secondary somatosensory cortex, premotor, frontal, and
prefrontal cortices and the cerebellum is notable.
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DISCUSSION |
Our study shows fundamental differences in the cortical
representation of sensation arising from the proximal (somatic) and distal (visceral) esophagus, which correlate with perceptual
differences in sensation arising from the two regions. The
significantly greater activation of the chest area of the primary
somatosensory cortex during proximal in comparison to distal esophageal
stimulation could explain the better localization of sensation from the
somatic region of the esophagus.
This difference in somatosensory cortical representation may reflect
different cortical projections from the lateral thalamic neurons that
receive somatic and visceral afferent input. Animal electrophysiological studies show that thalamic neurons that receive somatotopically organized projections from the spinal cord also receive
nontopographically organized visceral spinal projection (Bruggemann et
al., 1994). It is therefore possible in humans that the thalamocortical
projections maintain this distribution, with somatic neurons projecting
somatotopically to the sensory homunculus, whereas visceral afferents
project either nontopographically or in a crudely topographic manner to
the caudal primary and secondary somatosensory cortices. It should be
noted, however, that a representation has been found in the rostral
hand region of primary somatosensory cortex of the squirrel monkey in
response to nociceptive stimulation of the distal esophagus, colon, and
urinary bladder (Bruggeman et al., 1997). In this study, cortical
activation to non-nociceptive stimulation was not consistently seen
probably because the animals were anesthetized and hence the cortical
excitability was diminished. In our current study, we have used
nonpainful esophageal stimulation, and it is possible therefore that
activation of additional more rostral regions of the primary
somatosensory cortex may have occurred if we had used a higher
stimulation intensity. This is, however unlikely, because in our
previous PET study (Aziz et al., 1997), we found a similar distribution
of cortical activation in the caudal primary somatosensory cortex for
both nonpainful and painful distal esophageal stimulation. It is
likely, therefore, that differences between our current study and that
performed by Bruggeman et al. (1997) are attributable to differences in
the species studied and the methods used.
It is of relevance to note that the proximal esophagus was represented
unilaterally over the left primary somatosensory cortex. In contrast,
the distal esophagus was represented bilaterally, although a larger
number of voxels were activated on the left in comparison to the right
hemisphere. Unilateral cortical representation of proximal esophagal
sensation has also been demonstrated in a study using
magnetoencephalography (Furlong et al., 1998), whereas a PET study of
distal esophageal sensation (Aziz et al., 1997) has shown bilateral but
asymmetric representation. Although the significance of this asymmetric
cortical representation of the esophagus remains unclear, it may
explain why esophageal pain, like that of myocardial pain, often
radiates to one or other side of the chest, mimicking angina pectoris
(Kramer and Hollander, 1955).
Our results also indicate that processing of visceral and somatic
sensation occurs differently in the anterior cingulate cortex. Although
the anterior midcingulate cortex (BA24) was activated in response to
both proximal and distal esophageal stimulation, the more rostral
perigenual part of the cingulate cortex (BA 32) was activated only in
response to distal stimulation. Perigenual cingulate cortical
activation has been reported in previous studies of visceral (Channer
et al., 1994; Aziz et al., 1997; Silverman et al., 1997) and somatic
pain (Derbyshire et al., 1997). Our study now shows that perigenual
cingulate activation also accompanies nonpainful visceral stimulation.
Whereas, the midcingulate cortex is largely responsible for response
selection, attention, and preparatory motor functions (Devinksy et al.,
1995; Vogt et al., 1996), the perigenual part of the cingulate cortex
is known to have direct connections with brainstem autonomic nuclei and
is involved in visceromotor control and regulation of autonomic and emotional responses to external stimuli (Devinksy et al., 1995; Vogt et
al., 1996). Because the autonomic and affective responses to visceral
stimulation are more intense than those to somatic stimulation
(Cervero, 1985), it seems plausible that these differences relate to
greater visceral afferent projection to the perigenual cingulate
cortex. This explanation, however, remains speculative as autonomic
responses to esophageal stimulation were not measured in our study.
We also found that the dorsolateral prefrontal cortex was activated
both by proximal and by distal esophageal stimulation. This region is
generally considered to be responsible for cognitive evaluation,
self-awareness, and attention (Dias et al., 1996; Frith and Dolan,
1996). It interacts closely with the anterior cingulate cortex and is
involved in behavioral control (Devinksy et al., 1995; Vogt et al.,
1996). Activation of this area is seen during somatic stimulation
(Hsieh et al., 1996; Derbyshire et al., 1997), and it has been
implicated in cognitive appraisal of the stimulus. Through its
connections to the limbic and other association cortices (Devinsky et
al., 1995; Vogt et al., 1996), it may also be responsible for
integrating motor responses to the stimulus.
The different activation patterns of the dorsolateral prefrontal cortex
to proximal and distal stimulation is intriguing. Functional
differences between the left and right dorsolateral prefrontal areas
have been observed in modulating emotions, motor behavior, and
attention (Ross et al., 1994), so it is possible that functional
specialization also exists for processing somatic and visceral sensation.
Activation of similar regions of the right insular cortex were seen
after both proximal and distal esophageal stimulation. The insula is
well recognized from both human and animal studies as an important
visceral sensory and motor area (Augustine 1996). Animal studies
suggest that the viscera are organized viscerotopically within the
insular cortex with gastrointestinal neurons located most rostrally and
cardiovascular neurons most caudally within the granular region. While
in our study, a small difference was seen in the representation of the
two esophageal regions in the insular cortex, the current resolution of
functional MRI is not sufficient to allow us to determine whether this
difference represents a true viscerotopic representation.
In addition to activating sensory areas, stimulation of either
esophageal region also activated motor, premotor, supplementary motor
cortices and the sensory associative cortex. This is not surprising as
sensory feedback from the esophagus is well known to modulate the motor
control of swallowing (Jean and Car, 1979; Hamdy et al., 1998).
Furthermore, esophageal motility was not recorded in our study because
of the technical limitations posed by using manometry equipment within
the MRI environment. Although it is possible that esophageal
distension may have evoked secondary peristaltic activity, which
contributed to the activation seen in the motor, premotor, and
supplementary motor cortices, the role of the cortex in mediating
secondary peristaltic activity remains hitherto unconfirmed.
The most robust difference seen between the proximal and the distal
esophagus was cerebellar activation that followed distal but not
proximal esophageal stimulation. The cerebellum forms an important part
of the sensorimotor integratory network but is not directly involved in
perception of sensation (Roland, 1993). In previously reported studies
of somatic sensation, cerebellar activation was observed only in
response to pain (Casey et al., 1994; Hsieh et al., 1996; Svensson et
al., 1997). Cerebellar activation, which overlaps with the activity
seen in our study, was also observed in a recent PET study of somatic
pain induced by capsaicin (Iadarola et al., 1998), a potent stimulator
of nonmyelinated C Fibers (Torebjork et al., 1992), whereas nonpainful
somatic sensation induced by activating myelinated A  fibers (Woolf
and Doubell, 1994) failed to produce cerebellar activation. The viscera
are innervated predominantly by nonmyelinated C fibers (Sengupta and
Gebhart, 1994), and these fibers mediate both painful and nonpainful
sensation (Cervero and Tattersall, 1986). Animal studies have shown
that distension of the smooth muscle esophagus in the non-noxious range
predominantly activates C fibers, (Sengupta et al., 1990). In contrast,
similar distension of the striated muscle esophagus predominantly
activates myelinated fibers (Satchell, 1984). It is possible therefore
to attribute differences in cerebellar activation for the two
esophageal regions in our study to a greater cerebellar projection of
C-fibers from the visceral than from the somatic esophagus.
Schnitzler et al. (1999) have recently used magnetoencephalography to
compare the cortical representation of the distal esophagus, median
nerve, and the lip. They observed that while median nerve and lip
stimulation activated both the primary and secondary somatosensory cortices, esophageal stimulation activated only the secondary somatosensory cortex. No differences in other cortical and subcortical areas were reported. They concluded that lack of esophageal afferent projection to the primary somatosensory cortex explains the poor spatial localization of visceral sensation.
Our results are in partial agreement with those of Schnitzler et al.
(1999), however, we have shown that not only do esophageal afferents
have a projection to the caudal part of the primary somatosensory
cortex, but also that there are differences in the processing of
somatic and visceral sensation in other cortical and subcortical areas.
It can be argued that with the current spatial resolution of fMRI, it
may not be possible to categorically differentiate between primary and
secondary somatosensory cortical activation and that the signal
observed in our study represents composite activation of the two
regions. However MEG studies (Furlong et al., 1998; Hecht et al., 1999)
suggest that esophageal stimulation activates two distinct dipoles
located in the primary and secondary somatosensory cortices. It is
likely therefore that the activation seen in our current study
represents two distinct foci in the primary and secondary somatosensory cortices.
In conclusion, differences occur in the processing of sensation arising
from somatic and visceral regions of the esophagus, particularly in the
primary somatosensory, limbic, and prefrontal cortices and in the
cerebellum. These findings indicate that the perception of somatic and
visceral sensations differs not only as a result of differences in the
spinal innervation of the two structures, but also because of
differences in the mode of cortical processing. This information may
help to explain differences in perception and autonomic responses
between visceral and somatic structures.
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FOOTNOTES |
Received Sept. 14, 1999; revised Dec. 29, 1999; accepted Jan. 20, 2000.
Dr. Q. Aziz is a Medical Research Council Clinician Scientist, Dr. V. Ng is a Wellcome Clinical Research Fellow, and Dr. S. Hamdy is a
Medical Research Council Research Training Fellow. We thank J. Suckling
(Institute of Psychiatry, London) for image analysis and Helen Navarro
(University of Manchester) for secretarial support.
Correspondence should be addressed to Dr. Qasim Aziz, Clinical Sciences
Building, Department of Gastroenterology, Hope Hospital, Stott Lane,
Salford M6 8HD, UK. E-mail: qaziz{at}fs1.ho.man.ac.uk.
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TOP
ABSTRACT
INTRODUCTION
