1Medical Research Council Human Movement and
Balance Unit,
Hamdy, Shaheen,
John C. Rothwell,
David J. Brooks,
Dale Bailey,
Qasim Aziz, and
David G. Thompson.
Identification of the cerebral loci processing human
swallowing with H215O PET activation.
Lesional and electrophysiological data implicate a role for the
cerebral cortex in the initiation and modulation of human swallowing,
and yet its functional neuroanatomy remains undefined. We therefore
conducted a functional study of the cerebral loci processing human
volitional swallowing with 15O-labeled water positron
emission tomography (PET) activation imaging. Regional cerebral
activation was investigated in 8 healthy right handed male volunteers
with a randomized 12-scan paradigm of rest and water swallows (5 ml/bolus, continuous infusion) at increasing frequencies of 0.1, 0.2, and 0.3 Hz, which were visually cued and monitored with submental
electromyogram (EMG). Group and individual linear covariate analyses
were performed with SPM96. In five of eight subjects, the cortical
motor representation of pharynx was subsequently mapped with
transcranial magnetic stimulation (TMS) in a posthoc manner to
substantiate findings of hemispheric differences in sensorimotor cortex
activation seen with PET. During swallowing, group PET analysis
identified increased regional cerebral blood flow (rCBF)
(P < 0.001) within bilateral caudolateral sensorimotor cortex [Brodmann's area (BA) 3, 4, and 6], right anterior insula (BA
16), right orbitofrontal and temporopolar cortex (BA 11 and 38), left
mesial premotor cortex (BA 6 and 24), left temporopolar cortex and
amygdala (BA 38 and 34), left superiomedial cerebellum, and dorsal
brain stem. Decreased rCBF (P < 0.001) was also
observed within bilateral posterior parietal cortex (BA 7), right
anterior occipital cortex (BA 19), left superior frontal cortex (BA 8), right prefrontal cortex (BA 9), and bilateral superiomedial temporal cortex (BA 41 and 42). Individual PET analysis revealed asymmetric representation within sensorimotor cortex in six of eight subjects, four lateralizing to right hemisphere and two to left hemisphere. TMS
mapping in the five subjects identified condordant interhemisphere asymmetries in the motor representation for pharynx, consistent with
the PET findings. We conclude that volitional swallowing recruits
multiple cerebral regions, in particular sensorimotor cortex, insula,
temporopolar cortex, cerebellum, and brain stem, the sensorimotor
cortex displaying strong degrees of interhemispheric asymmetry, further
substantiated with TMS. Such findings may help explain the variable
nature of swallowing disorders after stroke and other focal lesions to
the cerebral cortex.
Both physiological and pathophysiological data strongly implicate
a role for cerebral cortex in the control of volitional human
swallowing. Direct stimulation of the brain surface of patients during
neurosurgery (Penfield and Boldery 1937 The recent technological advances in functional imaging of human brain
revolutionized our understanding of how the cerebral cortex operates in
processing sensory and motor information. In particular, positron
emission tomography (PET) has become established as the standard for
spatial localization of changes in neuronal activity during tasks
within both cortical and subcortical structures detected as changes in
regional cerebral blood flow (rCBF) (Aine 1995 The aim of our study was to therefore obtain precise whole brain
information on the functional neuroanatomy of swallowing with
H215O PET activation imaging, specifically
looking for individual motor cortex lateralization, and then to
characterize these motor cortex findings with TMS mapping.
Subjects
Eight healthy adult male volunteers (age 35-65 yr, mean age 48 yr) were studied. Handedness was determined in each subject with the
Edinburgh Handedness Inventory (Oldfield 1971 PET
EMG RECORDING OF SWALLOWING.
Mylohyoid EMG was used to monitor swallowing during each study. EMG
activity was detected with two pairs of bipolar silver-silver chloride
electrodes (Neuroline Medicotest UK; St. Ives, UK) with an
interelectrode distance of 2 cm, one positioned submentally over each
mylohyoid muscle on each side of the midline (Hamdy et al.
1997b PER ORAL WATER INFUSION.
To facilitate swallowing, sterile water was infused from a 1,000-ml
capacity fluid reservoir attached to a plastic infusion line, the
ending of which was placed into the oral cavity in the midline, 4 cm
from the incisors. The base of the fluid reservoir was sited 10 cm
above the mastoid process of each subject when lying supine in the
scanner. The infusion line was connected to a peristaltic pump (H. R. Flow Inducer, Watson-Marlowe, Falmouth; Cornwall, UK), which allowed
water to be infused continuously at rates of 30, 60, or 90 ml/min, thus
maintaining a constant bolus volume per swallow of 5 ml at the
frequencies of 0.1, 0.2, and 0.3 Hz, respectively.
PET SCANNING.
The scanner used was an EXACT three-dimensional (3D) HR++ tomograph
(CTI 966, PET Systems; Knoxville, TN). This is a very-high-sensitivity scanner that operates exclusively in 3D volumetric acquisition mode
(Bailey et al. 1998
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES
; Woolsey
et al. 1979
; Vogt and Vogt 1919
) and
transcranial magnetic stimulation (TMS) in awake healthy subjects
(Aziz et al. 1996
; Hamdy et al. 1996
)
demonstrated that areas of motor and premotor cortex are important in
the initiation and modulation of swallowing. This latter study also
suggested that the motor projections from cortex to pharynx and
esophagus are lateralized in the majority of subjects, a finding that
would be compatible with the frequent occurrence of dysphagia after
unilateral hemispheric stroke. Data from studies of dysphagia after
stroke (Barer 1989
; Gordon et al. 1987
;
Meadows 1973
) also indicate that other cortical and
subcortical regions, including the somatosensory cortex, frontal
operculum, and insula, are important in swallowing control, suggesting
that the functional organization of swallowing within the brain is
complex. However, most of this information is circumstantial, there
being no detailed description of the exact neuroanatomical
representation of swallowing function in the human cerebral cortex.
). Using
PET a spatial resolution of 4-8 mm can be attained (Aine
1995
; Hartshorne 1995
), depending on the
sensitivity of the scanner, and it is considered much less susceptible
to motion artifact, a problem often encountered with other noninvasive
imaging modalities, such as functional magnetic resonance imaging
(fMRI) (Aine 1995
). PET also has the advantage of being
able to measure the size of an area of metabolic change (Raichle
1987
), thus allowing interhemispheric comparisons of cerebral
function to be assessed.
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES
). None reported any
swallowing problems, and all gave informed written consent before each
of the studies performed. For PET, ethical approval was given by the
Imperial College School of Medicine, Hammersmith Hospitals' Research
Ethics Committee. Permission to administer radioactivity was obtained
from the Administration of Radioactive Substances Advisory Committee of
the Department of Health, UK. For TMS, ethical approval was given by
the Salford Health Authority Ethics Committee.
). The electrode pair was connected to a preamplifier (CED 1902, Cambridge Electronic Design; Cambridge, UK) with filter settings of
3-300 Hz. Response signals were then collected through a laboratory
interface (CED 1401 plus, Cambridge Electronic Design; Cambridge UK) at
a sampling rate of 4-8 kHz and fed into a 486Sx desktop computer for
immediate display, data collection, and analysis.
). The scanner has a 23.4-cm axial
field of view producing 95 reconstructed axial planes with a slice
spacing of 2.43 mm. The transaxial field of view is 62 cm.
Reconstruction is performed with the reprojection algorithm
(Kinahan and Rogers 1989
). The reconstructed resolution
is ~4.5 × 4.5 × 4.2 mm (full width half-maximum) with a
radial ramp filter with a cutoff of the Nyquist frequency (2.35 cycles/cm) and with a generalized Colsher z-filter. The in-plane
x-y voxel dimensions with a reconstruction zoom
of 2.5 are 2.03 mm. A specially designed lead shield was fitted to the
scanner to improve count rate performance by reducing photons from
outside the coincidence field of view.
; Karp et al. 1995
). The point
source is pumped hydraulically through 48 turns in a stainless steel
helix located just inside the detector radius. The data are acquired as
3D volumes and reconstructed after axial single slice rebinning
(Daube-Witherspoon and Muehllenher 1987
) with
two-dimensional (2D) filtered back projection and local threshold
segmentation and reassignment of attenuation coefficients. Transmission
scans for cerebral studies were acquired over 5 min.
TMS
EMG RECORDING DURING TMS.
The muscles of the pharynx were chosen to represent swallowing for TMS
mapping, as the corticopharyngeal projections activated have been
previously shown to correlate well with swallowing abnormalities and
their recovery after stroke (Hamdy et al. 1996, 1997a
).
Pharyngeal EMG responses were detected at rest with a 3-mm diameter
intraluminal catheter (Gaeltec, Dunvegan; Isle of Skye, Scotland)
(Hamdy et al. 1996
). One pair of bipolar platinum ring
electrodes was built into the catheter, the interelectrode distances
being 1 cm, which was connected to a preamplifier (CED 1902, Cambridge
Electronic Design; Cambridge, UK) with filter settings of 5 Hz to 2 kHz. Response signals were then collected through a laboratory
interface (CED 1401 plus) at a sampling rate of 4-8 kHz. A
solid-state, strain-gauge transducer was also incorporated into the
catheter between the electrode pair to enable the pharyngeal electrodes to be maintained in position.
MAGNETIC STIMULATION. Cortical magnetic stimulation was performed transcranially on each occasion with a commercially available magnetic stimulator (Magstim 200, MAGSTIM Company Limited, Whitland; Dyfield, Wales) connected to a 70-mm OD figure-of-8 coil that allowed focal stimulation of areas of the cortex up to a maximum intensity of 2.2 Tesla.
Experimental protocols
PET.
Before study each subject was asked to refrain from taking any
stimulants (e.g., caffeine or alcohol) for 12 h before the scan. Each
experiment was performed in the supine position, the subject lying
comfortably in a darkened quiet room and with his or her head firmly
secured within a molded head rest to reduce motion artifact. The EMG
recording electrodes were then applied to the mylohyoid muscles, after
which the water infusion catheter was inserted perorally. To ensure
that each subject swallowed on command and at a given rate, swallows
were visually cued with a purpose-built electronic light device
(Department of Medial Physics, MRC Cyclotron Unit, Hammersmith
Hospital; London), which could be programmed to flash (duration of
light source = 0.2 s) at frequencies of 0.1, 0.2, and 0.3 Hz.
The light was positioned immediately above and in front of the
subject's head, in the center of visual field. The subject's head was
then correctly aligned within the scanner, with laser lines located in
the gantry of the PET camera, after which the transmission scan was
conducted both to ensure that axial head positioning was within the
camera's field of view and to enable a measured correction of tissue
attenuation to be performed on the emission data. After this an
intravenous cannula was inserted in the subject's antecubital vein and
connected to an automated 15O-labeled water infusion.
TMS. To further substantiate the PET findings for sensorimotor cortex lateralization, posthoc, five of eight subjects subsequently underwent a bihemisphere mapping study of the pharynx with TMS.
For each study, the volunteer sat comfortably in a chair, the cranial vertex was marked on the scalp, and the pharyngeal catheter was inserted transnasally. To identify the sites for cortical stimulation, a 12 × 9 cm grid, with rows 2 cm apart anteroposteriorly and 1 cm apart mediolaterally, was constructed on a 1-mm-thick latex sheet and attached closely to the scalp. This grid, which comprised 70 stimulation points over each hemisphere, was oriented so that the most posterior and medial point on the grid was 2 cm posterior and 2 cm lateral to the cranial vertex, with the mediolateral rows perpendicular to the midsagittal plane (Hamdy et al. 1996 ![]() |
DATA ANALYSIS |
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PET
All calculations and image transformations were performed on a
Sun SPARC 5 workstation (Sun Computers Europe; Surrey, UK) with Analyze
version 7.0 image display software (BRU, Mayo Foundation; Rochester,
MN). Data were analyzed with Statistical Parametric Mapping software
(SPM 96, Wellcome Department of Cognitive Neurology, London)
implemented in Matlab (Mathworks; Sherborn, MA). After cropping the
image planes to retain brain data only, each subject's data images
were realigned and then transformed into standard stereotactic space
corresponding to the structure probability maps generated by the
Montreal Neurological Institute, Canada (Collins et al.
1996). Data were then smoothed with an isotropic Gaussian
kernal of 12 × 12 × 12 mm3 to increase the
signal-to-noise ratio. These normalized data could then be averaged
across subjects and scans or rendered onto a normalized T1-weighted MRI scan.
The technique of statistical parametric mapping was then used to
analyze the acquired data (Frackowiak and Friston 1994). The activity during each task was first averaged voxel by voxel after
normalization for differences in global blood flow to a mean of 50 ml · dl
1 · min
1, achieved by
analysis of covariance, with flow as the covariate. Task-specific
individual and group brain activations were then assessed by
statistical comparison with appropriate linear contrasts (weighting
each of the 4 conditions: rest and swallowing at 0.1, 0.2, and 0.3 Hz)
and included the effect of time on the subject as a confounding
variable, with the t statistic (Friston et al. 1991
). Consequently, regions of activation that demonstrated a linear relationship between frequency of swallowing to size of signal
would be preferentially identified. This generated
SPM{t} maps for the activations, which were subsequently
transformed into SPM{z} maps, which assessed the level
of significance as peak height and intervoxel clusters. Significance
was accepted if voxels survived an uncorrected threshold of
P < 0.001 (or P < 0.05, Bonferroni corrected).
TMS
First, the mean value of the three responses for each grid point
was calculated. Response amplitudes were measured as the maximum
peak-to-peak voltage of the EMG potential. Scalp maps, representing the
areas of response for pharynx, were generated for each hemisphere by
assigning to each grid point the calculated mean amplitude value of the
three EMG responses for each site. These amplitude values were then
imported into the Toolmaster product (Advanced Visual Systems; Waltham,
MA), for interpolation and plotting onto regular 2D grids (Hamdy
et al. 1996). A bilinear interpolation method was then
performed with the same search radius and smoothing factor for each
grid. Response values were then scaled by comparing each individual
response with the maxima (for either hemisphere). Each map created is
viewed from above, with the position of the cranial vertex marked X. The scale represents the percentage maximum response amplitude in each subject.
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RESULTS |
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All subjects were strongly right handed, with a mean handedness score of 95 ± 3% (mean ± SE).
PET
Swallowing was well tolerated by all subjects during PET, a representative example of the pattern of mylohyoid EMG activity recorded for each swallow condition being shown in Fig. 1. None of the subjects reported any difficulty in oromotor control while each bolus accumulated in the oral cavity between swallowing (as evidenced by a lack of any aberrant EMG activity between successive swallows) or the sensation of wanting to suppress the urge to swallow before the next cue. The brain areas showing significantly increased and decreased rCBF across the group are described subsequently and are shown in detail in Table 1.
|
|
AREAS OF INCREASED rCBF. A number of brain regions with increased rCBF were detected after group analysis and are shown in Fig. 2 as integrated projections through sagittal, coronal, and transverse views of the brain. To aid anatomic localization, these regions were rendered onto a normalized T1-weighted MRI scan in Fig. 3. These loci included right orbitofrontal cortex; left mesial premotor cortex and cingulate; right caudolateral sensorimotor cortex merging with right lateral premotor cortex; left caudolateral sensorimotor cortex merging with left lateral premotor cortex; right anterior insula, left temporopolar cortex merging with left amygdala; right temporopolar cortex; left medial cerebellum, which merged across the midline with the right medial cerebellum; and dorsal brain stem. Strongest activations (greatest z scores) were found to be in the sensorimotor cortices and cerebellum.
|
|
AREAS OF DECREASED rCBF. Regions with decreased rCBF were also consistently observed and were strongest within right prefrontal cortex, left superior premotor cortex, bilateral superiomedial temporal cortex, bilateral precuneus, and right anterior occipital cortex.
INDIVIDUAL DISTRIBUTION PATTERNS OF INCREASED rCBF DURING SWALLOWING. The individual patterns of increased activation for each subject are shown in Table 2. From these data, it is evident that sensorimotor cortex and cerebellum were activated in every subject, albeit with differing degrees of interhemispheric asymmetry. Of the other regions identified from the group analysis, individual analysis showed that the temporopolor cortex and amygdala, the mesial premotor cortex and cingulate, and the brain stem were activated in most subjects. By comparison, regions such as the right insula and orbitofrontal cortex were less consistently activated, being demonstrated in about one-half of the subjects after individual analysis. Interestingly, for virtually all regions recruited, the distribution of the activations was commonly asymmetric. Notably, only one-half of the subjects activated the primary visual cortex, in response to the visual cue, which was usually bilateral.
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INTERHEMISPHERIC ASYMMETRY IN rCBF WITHIN SENSORIMOTOR CORTEX. Despite the bilateral distribution of sensorimotor cortex activation seen when PET data were averaged across the group, individual data analysis revealed that clear asymmetries were present in a proportion of the subjects (Table 3). An example of this asymmetric sensorimotor representation is shown in Fig. 4A as an integrated projection through the transverse plane of the brain (subject 2, Table 3). Of the eight subjects, four had clearly stronger activation within the right hemisphere, whereas two had stronger activation within the left hemisphere.
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|
TMS
As previously described (Hamdy et al. 1996,
1997a
,b
) cortical stimulation evoked consistent and
reproducible motor responses in the pharynx from each hemisphere, with
biphasic or triphasic waveform morphologies. The mean thresholds for
evoking pharyngeal responses across the five subjects studied (equating
to subjects 1-5, Table 4) were similar
at 74 ± 10% and 76 ± 10% for the right and left
hemispheres, respectively. Mean response latencies were also similar at
8.8 ± 0.5 ms from the right hemisphere and 9.1 ± 0.5 ms
from the left hemisphere. The mean pharyngeal amplitudes and magnitudes
of representation for each hemisphere in each of the five subjects are
shown in Table 3, and a representative example of the comparison of PET
and TMS mapping data is shown as 2D maps in Fig. 4, A and
B. TMS mapping of pharynx identified the responsive area to
be in an anterolateral position with respect to the motor strip, the
best site for stimulation being 3 ± 2 cm anterior and 8 ± 3 cm lateral to the cranial vertex on each side. This site appeared
slightly anterior and medial to the best cortical activation area with
PET. However, in the three subjects who had stronger sensorimotor
activation in the right hemisphere with PET, there was correspondingly
greater motor representation for pharynx in the same (right) hemisphere
with TMS mapping, the number of responsive scalp sites being at least
double that of the left hemisphere. Furthermore, in the one subject who
had stronger sensorimotor activation in the left hemisphere, mapping
showed greater pharyngeal representation in the same (left) hemisphere, albeit with a lesser degree of asymmetry than with the right hemisphere differences described previously. By comparison, in the one subject with bilateral sensorimotor activation, mapping revealed a more symmetric pharyngeal motor representation between the two hemispheres.
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DISCUSSION |
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Swallowing involves a complex sequence of carefully timed muscular
contractions that transport food from the mouth to the stomach while
ensuring protection of the airway. The central regulation of reflex
swallowing depends on swallowing centers in the brain stem that receive
sensory input from the oropharynx and esophagus and together with local
peristaltic mechanisms control much of the swallowing sequence
(Jean 1990; Miller 1982
). However, the volitional initiation of swallowing requires the integrity of sensorimotor areas of the cerebral cortex. In conjunction with subcortical influences, these higher centers also modulate the pattern
of swallowing activity (Martin and Sessle 1993
).
Cerebral organization of swallowing based on human and animal data
Information concerning the functional organization of swallowing
within the human brain is sparse. Studies performed by Vogt and Vogt
(1919) and later by Penfield and Boldery (1937)
demonstrated that
intra-operative stimulation of the lateral aspect of the human motor
cortex could elicit swallowing movements. More recently, TMS was used
to map the normal pattern of motor cortex projections to a number of
swallowing muscles in healthy volunteers (Hamdy et al.
1996
). One important difference between this technique and
direct cortical stimulation is that with direct stimulation brain
tissue is usually stimulated with a train of several hundred stimuli at
a rate of 50-60 Hz (Penfield and Boldery 1937
;
Woolsey et al. 1979
) and can induce a full swallowing
cycle visible to the experimenter. However, because of the risk of
inducing epileptic seizures in awake subjects, TMS studies usually
employ only single pulses given several seconds apart with the
consequence that a full swallow is not evoked. Rather the TMS stimulus
evokes a simple EMG potential with a latency of ~8-10 ms, compatible
with a fairly direct and rapidly conducting pathway from motor cortex
via brain stem to the muscle. Mapping these projections demonstrates
that the various swallowing muscles are arranged somatotopically in the
motor cortex, with the oral muscles (mylohyoid) more lateral and the
pharynx and esophagus more medial. One interesting finding was that in
the majority of individuals the pharyngeal and esophageal projections
from one hemisphere tended to be larger than the other, i.e.,
asymmetric motor representation for swallowing musculature between the
two hemispheres, independent of handedness (Hamdy et al.
1996
).
Much of the information regarding the cerebral localization of human
swallowing relied on inference from studies of swallowing abnormalities
after cerebral injury (Alberts et al. 1992; Barer 1989
; Daniels and Foundas 1997
; Gordon et
al. 1987
; Meadows 1973
; Robbins and
Levine 1988
; Robbins et al. 1993
; Veis
and Logemann 1985
). From these reports, a rather diffuse
picture emerged of those areas of the brain considered important. For
example, lesions located in the thalamus (Alberts et al.
1992
), cerebellum (Alberts et al. 1992
), and
basal ganglia (Alberts et al. 1992
; Veis and Logemann 1985
) were associated with dysphagia in addition to
more expected sites such as pyramidal tracts (Robbins and Levine
1988
; Robbins et al. 1993
), frontal operculum
(Meadows 1973
), and the insula (Daniels and
Foundas 1997
). These data also tended to suggest that one or
other hemisphere may be dominant for swallowing. Indeed, one of the
earliest observations of a unilateral cerebral lesion producing
dysphagia was in 1898, when Bastian (1898)
reported on the case of a
human who was admitted to hospital with a hemiplegia and aphasia but
who also had transient "difficulty in deglutition." Later necropsy
revealed that apart from two limited lesions in the left hemisphere the
brain was healthy. More recently, Meadows (1973)
reported on six cases
of dysphagia. All of them confirmed unilateral lesions of the frontal
operculum region of the cerebral cortex, five of which affected the
right hemisphere. Since then a number of studies confirmed that
40%
of patients with unilateral hemispheric stroke may have swallowing
difficulties. There was an increased tendency for the pharynx to be
involved if the damage was limited to the right hemisphere
(Martin and Sessle 1993
; Robbins and Levine
1988
).
More extensive data on the suprabulbar regions important in the control
of swallowing were obtained from electrophysiological studies in
anesthetized animals (Bieger and Hockman 1976;
Car 1970
; Hockman et al. 1979
;
Jean 1990
; Martin and Sessle 1993
; Miller 1982
; Miller and Bowman 1977
;
Sumi 1969
; Woolsey et al. 1952
). These
indicated that considerable interspecies variation exists in the areas
of cortex that evoke swallowing. For example, in sheep, the
orbitofrontal gyrus appears important in swallowing control (Car
1970
), whereas in the cat (Bieger and Hockman
1976
), the rabbit (Sumi 1969
), and primates
(Martin and Sessle 1993
; Martin et al.
1997
; Miller and Bowman 1977
; Woolsey et
al. 1952
), the lateral precentral gyrus appears the best site
for evoking swallowing. Furthermore, in the primate at least, regions
immediately lateral and anterior (the cortical masticatory area) and
deep (insula) to the face primary motor cortex are also important
(Martin and Sessle 1993
; Martin et al.
1997
). Much less is known about the subcortical areas that
impinge on volitional swallowing. Work in the cat (Bieger and
Hockman 1976
) suggested that stimulation of areas including the
amygdala, hypothalamus, ventral tegmentum, substantia nigra, and basal
ganglia will facilitate swallowing and that stimulation of the ventral
cerebellar vermis can elicit swallowing itself (Hockman et al.
1979
).
Role of the sensorimotor cortex and lateralization in swallowing
Our study has now shown for the first time those brain regions
that are important in the control of human volitional swallowing. Our
observations indicate that swallowing has a multiregional cerebral
representation, most strong in caudal sensorimotor and lateral premotor
cortex, insula, temporopolar cortex and amygdala, cerebellum, and
dorsal brain stem. Broadly speaking, these finding are in keeping with
data previously reported from both human (Hamdy et al.
1996; Penfield and Boldery 1937
; Woolsey
et al. 1979
) and animal studies (Hockman et al.
1979
), with the lateral motor cortex being confirmed as having
the major role. The lateral motor cortex is traditionally described as
the site of representation for the tongue and more medially for the
face (Martin and Sessle 1993
; Martin et al.
1997
), and thus the observation that swallowing is also
represented in this region is not surprising. Furthermore, the finding
from the individual PET analysis that there is a bilateral and in most
cases asymmetric representation for swallowing in the sensorimotor
cortex would be compatible with the observation that 30-50% of
unilateral hemispheric stroke patients will develop dysphagia
(Barer 1989
). TMS mapping of the pharynx also
demonstrated that the best sites for activation would overlay
anterolateral motor cortex, albeit with a slightly more anterior
location than that found with PET. This most likely reflects the
problem of qualifying precisely the best point of stimulation within
the bifurcation of the coil so that an exact correspondence with the PET activation is perhaps not surprising. Furthermore, PET may incorporate activations related to tongue movement and sensory input
from the oropharynx and esophagus, which may have more caudal cortical
projection patterns. It is reassuring to note, however, that the
findings of sensorimotor cortex lateralization with PET were concordant
with the cortical motor representation findings from TMS mapping,
suggesting that the motor aspects of swallowing do indeed show some
degree of cortical asymmetry. Of interest is the possibility that
sensory cortex activation (BA 3) during PET may have shown parallel
lateralization for swallowing. Human studies (Penfield and
Boldery 1937
) demonstrated that the lateral aspects of the
somatosensory cortex can evoke swallowing, whereas studies in nonhuman
primates (Lin et al. 1998
) indicate that surface cooling
of areas of primary face somatosensory cortex, which when stimulated
evoke rhythmic jaw movements, can disrupt the normal pattern of
mastication and oropharyngeal movements. It might be speculated
therefore that the primary motor and sensory cortical representations
for swallowing are linked not only in terms of integrated function but
possibly also in terms of lateralization.
Role of supplementary motor area, anterior cingulate cortex, and attention in swallowing
We also observed that the left mesial premotor [or
supplementary motor area (SMA)] and cingulate cortex were consistently activated during swallowing. The SMA is thought to play an important role in mediating and preparing complex sequences of movement and in
its caudal apsects appears to have a somatotopic distribution for motor
movements with orofacial representation most anterior (Fried et
al. 1991). Consequently, this region may have an important function in the preparation for volitional swallowing, possibly in
conjunction with input from dorsal prefrontal cortex and insula. The
anterior cingulate is part of the paralimbic system and is important in
processing attention to volitional actions and sensory stimuli
(Vogt et al. 1994
). Activation of the anterior cingulate has been shown to occur with intense stimulation of the esophagus (Aziz et al. 1997
) as well as with changes in
gastrointestinal motility (Pandya and Van Hoesen 1976
).
Furthermore, connections between the insula and cingulate and amygdala
and cingulate were identified (Mesulam and Mufson 1982
;
Pandya and Van Hoesen 1976
), suggesting that it may play
a role in monitoring autonomic and vegetative functions. It could be
speculated therefore that anterior cingulate activation during
swallowing reflects the attentive aspect of performing the task of
repetitive swallowing.
With regard to the attention aspects of the task, it is important
to bear in mind that our paradigm utilized a visual cue to impose a
frequency-dependent order to the volitionally induced swallows. One
potential consequence of this approach is that the visual stimulus may
have influenced the degree and level of attention the subject directed
toward the task. Although it is impossible to state for certain how
this confounding variable may have altered the recruitment pattern of
cerebral activation seen during our swallowing paradigm, particularly
within the anterior cingulate cortex and SMA, it is reassuring to note
that in the group analysis the visual stimulus did not significantly
activate the primary visual cortex, being seen in only one-half of the
subjects during the individual analyses. This is probably because the
optimal light stimulus parameters for preferentially activating the
primary visual cortex utilize a frequency range of between 4 and 7 Hz (Mentis et al. 1997). By comparison, our study used a
much lower range of visual cue frequencies (0.1-0.3 Hz) with the
result that our light stimulus was probably ineffective in generating a
consistent neural response in the visual cortex. This strongly suggests
that most of the rCBF changes associated with each frequency-related condition were specific for swallowing, and any bias introduced by the
visual stimulus as a separate cerebral stimulus was minimal. Moreover,
because almost all the regions demonstrated to become active in our
study have been or can be specifically linked to areas of brain
previously shown, both in human and animal studies, to have a role in
swallowing, it seems likely that our paradigm was highly discriminating
for the specific task of swallowing.
Role of insular, temporal, and orbital cortices and amygdala in swallowing
Our data also indicate that the insula has an important role in
the control of swallowing. Previous stroke data implicated the anterior
insula as a common site of involvement in patients with dysphagia
(Daniels and Foundas 1997). Furthermore, the insula is
recognized to have a role in gastrointestinal motility and visceral
sensation, as stimulation studies in humans show that disturbances of
taste and defecation can be induced (Penfield and Faulk
1955
). Tracer studies in animals (Mesulam and Mufson 1982
; Mufson et al. 1981
; Shipley
1982
) demonstrated multiple connections between insula and
frontal, parietal, temporal, cingula, orbital, and paralimbic
structures as well brain stem regions including the nucleus tractus
solitarius (NTS), all of which were implicated in more autonomic
functions such as swallowing and respiration. This last observation
helps to explain some of the other activations seen in our study, i.e.,
within the temporopolar cortex, amygdala, and orbital cortex. It was
demonstrated in the mouse (Mesulam and Mufson 1982
) that
these latter regions have rich connections with the insula and appear
to comprise an integrated cerebral unit, with similar cytoarchitecture
and possibly function, although the precise behavioral implication of
this observation remains to be elucidated. Electrical stimulation of
these sites was demonstrated to produce a variety of somatomotor and
visceromotor responses, including inhibition of respiration, changes in
gastrointestinal motility and cardiovascular function, and olfactory
and behavioral responses (Kaada 1960
). It could
therefore be speculated that this insuloorbitotemporopolar unit may be
of specialized significance in the control of swallowing and other
visceromotor functions. In support of this possibility it is also
recognized that in animals the orbitofrontal cortex (Car
1970
) and amygdala (Bieger and Hockman 1976
) are
important in swallowing and feeding behavior and may therefore in
conjunction with the insula and temporopolar cortex be part of a
rudimentary cerebral swallowing network.
Role of cerebellum in swallowing
One of our novel observations was that of cerebellar
activation during swallowing and in particular that it was strongly
lateralized to the left cerebellar hemisphere and/or vermis. The
cerebellum has been shown in animals to be one of the sites from which
swallowing can be evoked (Hockman et al. 1979), but its
role in human swallowing was until now unclear. Certainly evidence from
stroke studies indicates that lesions in the cerebellum can induce
dysphagia (Alberts 1992
), although it is important to
bear in mind that because of the anatomy of its blood supply vascular
lesions in the cerebellum often involve brain stem structures, and so
unless detailed neuroimaging is performed concurrent brain stem damage may explain the dysphagia. Our data now provide evidence that the
cerebellum plays an important role in the regulation of human swallowing. In relation to the lateralization, it is interesting to
note that PET studies during speech demonstrated stronger activation within the right cerebellum compared with the left, in association with
cortical activation in the left hemisphere (Wise et al.
1991
). This would suggest that, if the left cerebellum is
important in swallowing, lateralization might be found within cortical
motor areas in the right hemisphere. Interestingly, although our group data showed bilateral sensorimotor cortex activation (albeit the highest z score in the right), it may be that clear motor
lateralization was obscured both by merging the mixed hemisphere
lateralization patterns seen in the individual data and by the fact
that the oral musculature active in swallowing may have a more
symmetric representation (Hamdy 1996
). It is noteworthy
that insula activation was clearly lateralized to the right hemisphere.
Role of the dorsal brain stem in swallowing
Dorsal brain stem activation is consistent with animal data
that have shown that the brain stem swallowing centers are located in
dorsal regions of the upper medulla and pons, surrounding the NTS. This
region was classically described in association with the adjacent
reticular formation and the cranial nerve motor nuclei V, VII, IX, X,
and XII as the site of the central pattern generator for swallowing
(Jean 1990; Miller 1982
) and is likely to
receive significant input from the cortex and subcortex as well as from peripheral afferents (Hockman et al. 1979
). Thus
activation of this region is in keeping with the concept that the
organization of swallowing is dependent on centers in the brain stem
being volitionally triggered by descending input from higher centers in
the cerebral cortex and subcortex to generate the swallowing reflex.
In conclusion, volitional swallowing in human has multiregional cerebral representation, strongest within sensorimotor cortex and cerebellum, each region showing hemispheric lateralization. These data provide the first description of the cerebral localization of functional swallowing in human, which should help in understanding the complex nature of swallowing problems commonly observed after focal brain damage.
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ACKNOWLEDGMENTS |
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We thank Drs. Richard Wise and Mike Samuel of the Department of Neurology, Medical Research Council (MRC) Cyclotron Unit, for helpful advice, and A. Blyth, D. Griffiths, and L. Schnorr of the MRC Cyclotron Unit for assistance. S. Hamdy is an MRC Clinical Training Fellow.
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FOOTNOTES |
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Address for reprint requests: D. G. Thompson, University Dept. of Medicine, Clinical Sciences Bldg., Hope Hospital, Eccles Old Road, Salford M6 8HD, UK.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 9 October 1998; accepted in final form 23 December 1998.
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REFERENCES |
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