Identification of the Cerebral Loci Processing Human Swallowing With H215O PET Activation

Shaheen Hamdy,1,3 John C. Rothwell,1 David J. Brooks,2 Dale Bailey,2 Qasim Aziz,3 and David G. Thompson3

 1Medical Research Council Human Movement and Balance Unit, Institute of Neurology, London WC1N 3BG;  2Medical Research Council Cyclotron Unit, Hammersmith Hospital, London W12 0NN; and  3Department of Gastroenterology, Hope Hospital, University of Manchester, Salford M6 8HD, United Kingdom


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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; 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.

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). 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.

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.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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). 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.

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). 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.

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). 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.

Transmission scanning used a 150 MBq 137Cs (t1/2 = 30.2 yr; E = 0.662 keV) point source in single photon acquisition mode (DeKemp and Nahmias 1994; 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.

For each emission scan a bolus of ~185 MBq of H215O in 3 ml of normal saline was injected via the intravenous cannula over 20 s and then flushed with the automatic pump at a rate 10 ml/min. After a delay of 30 s emission data were acquired in a 90-s epoch, beginning 5 s before the raising phase of the radioactivity head curve, which records the whole brain net true count rate over time. The subject commenced the task 15 s before the onset of the raising phase to ensure that the performance of the task coincided with the maximum activity level of isotope in the brain.

A total of 12 emission scans were performed in each subject with 8 min between each scan to allow for radioactive decay. At the onset of each measurement mylohyoid EMG was recorded continuously until completion of the dynamic frame. Tasks were randomized between rest and 5-ml water swallows at frequencies 0.1, 0.2, and 0.3 Hz. Three scans were performed per task, the nature of each being communicated to the subject immediately before each recording. During swallowing, the water infusion was commenced at the designated rate, simultaneously with the visual cue, and continued until data acquisition was complete.

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).

Next, to determine the intensity for cortical stimulation in each subject, a preliminary mapping study was performed with 100% stimulator output. This allowed the sites evoking maximal EMG responses to be identified over each hemisphere. Next, a series of cortical stimulations was performed over these sites commencing at a subthreshold intensity and increasing by 5% steps until a threshold intensity was found that evoked EMG responses of >20 µV on >= 5 of 10 consecutive trials for each hemisphere. Full mapping for each hemisphere was then commenced at 120% threshold value, the stimulation coil being placed over each grid point in a random order. For all mapping procedures the point of stimulation used corresponded to the anterior bifurcation of the coil. Three stimuli were delivered to each scalp site at 15-s intervals. To avoid any inadvertent facilitation of the cortically evoked responses, all subjects were asked to avoid swallowing, coughing, or vocalizing during TMS. If any of these activities occurred during the recording of the evoked responses these were discarded, and the stimulation was repeated.


    DATA ANALYSIS
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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.



View larger version (18K):
[in this window]
[in a new window]
 
Fig. 1. The mylohyoid electromyographic activity recorded in 1 subject during positron emission tomography (PET) scanning for the conditions of rest and swallowing at 0.1, 0.2, and 0.3 Hz. It can be seen that during rest no swallowing occurred, whereas during the swallowing tasks the swallows occur in sequence at the same rate as the visually cue, with no aberrant activity between swallowing.


                              
View this table:
[in this window]
[in a new window]
 
Table 1. Group details of the cerebral loci with increased and decreased rCBF during volitional swallowing

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.



View larger version (98K):
[in this window]
[in a new window]
 
Fig. 2. The group mean Statistical Parametric Mapping (SPM{z}) maps of the areas of increased regional cerebral blood flow (rCBF) associated with swallowing are shown as 3 orthogonal projections through sagittal (side view), coronal (back view), and transverse (top view) views of the brain. A threshold of P < 0.001 was applied. A number of areas are activated, including regions corresponding to sensorimotor cortex, bilaterally, right insula, left cerebellum, left mesial frontal cortex, temporopolar cortex, and dorsal brain stem.



View larger version (47K):
[in this window]
[in a new window]
 
Fig. 3. Areas of increased rCBF during swallowing rendered onto normalized T1-weighted magnetic resonance imaging brain sections. The color scale indicates the z-score level for each locus depicted. In the sagittal section the cerebellar and dorsal brain stem loci activated by swallowing are demonstrated, in the transverse section the right and left sensorimotor cortex and right anterior insula loci active are shown, and in the coronal section the left mesial frontal and cingulate cortex and left temporo-amygdala loci are shown.

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.


                              
View this table:
[in this window]
[in a new window]
 
Table 2. Individual details of the cerebral loci showing increased rCBF during volitional swallowing

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.


                              
View this table:
[in this window]
[in a new window]
 
Table 3. Individual interhemispheric comparisons of increased rCBF within sensorimotor cortex during swallowing



View larger version (30K):
[in this window]
[in a new window]
 
Fig. 4. Comparison of (A) the transverse (top view) projection PET SPM{z} map for swallowing showing areas of increased rCBF with that of (B) transcranial magnetic stimulation (TMS)-generated scalp maps of the pharynx viewed from above, with the position of the cranial vertex marked X, in 1 individual (subject 2, Tables 3 and 4). A threshold of P < 0.001 was applied to the SPM{z} map, whereas in the TMS map the scale represents the percentage maximum response amplitude across hemispheres. It can be seen that the PET map regions corresponding to the lateral sensorimotor cortices are asymmetrically distributed, being much larger in the right hemisphere, and correspond closely to TMS map of the pharynx, being also right hemisphere lateralized.

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.


                              
View this table:
[in this window]
[in a new window]
 
Table 4. Individual TMS mapping data for pharynx in each hemisphere


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

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.


    ACKNOWLEDGMENTS

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.


    FOOTNOTES

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.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
DATA ANALYSIS
RESULTS
DISCUSSION
REFERENCES

0022-3077/99 $5.00 Copyright © 1999 The American Physiological Society