swallowing Control.doc

Role of cerebral cortex in the control of swallowing
Shaheen Hamdy, M.R.C.P., Ph.D.

Key Points
· Swallowing is an essential gastrointestinal (GI) function that is under strong cerebral control.
· Swallowing is bilaterally but asymmetrically represented in the human motor cortex.
· Dysphagia after stroke may be a consequence of damage to the "dominant" swallowing hemisphere.
· Recovery of swallowing after dysphagic stroke appears to relate to compensation of function in the undamaged hemisphere.
· Therapies that can accelerate this compensatory process may help in the future to restore swallowing function in acute stroke.

Introduction
The process of swallowing is a complex neuromuscular activity that allows the safe transport of material from the mouth to the stomach for digestion without compromising the airway.1 Of course, this is a fairly simplistic description, as the act of swallowing requires a sophisticated integration of both central control and anatomic structures to produce the sensorimotor output that we call the swallow. This review focuses specifically on the role of the cerebral cortex in the regulations of swallowing, highlighting evidence from neurophysiologic studies in animals and humans, including recent advances in brain functional imaging. In addition, it examines inferential observations from lesions to the cortex that cause swallowing problems (dysphagia), and explores newer directions in the rehabilitation of swallowing after stroke.

Neurophysiologic Observations in Animals
The cortex has been strongly implicated in the control of swallowing. Numerous investigators have observed that stimulation of the cerebral cortex in different animal species is able to evoke the full swallowing sequence.2, 3 For example, in anesthetized sheep, swallowing can be evoked from a rostral region in the orbitofrontal cortex,4 whereas in primates the main cortical areas for eliciting a swallow appear to be dorsolateral and anterolateral frontal cortex, including an area known as the cortical masticatory area.5 Furthermore, it appears that, in animals, swallowing can be evoked by stimulation of both hemispheres,6 suggesting a bilateral, and possible equi-hemispheric contribution to cortical swallowing control. In addition, the corticofugal pathways to the brainstem have been mapped,7 demonstrating a definite route from cortex to the swallowing center in the brainstem. Damage to these fibers does not abolish the swallowing response completely, although marked dysphagia can occur. Indeed, anencephalic fetuses can still swallow,8 and lesions above the obex do not disturb the sequence of firing of the central pattern generator when evoked following superior laryngeal nerve (SLN) stimulation. However, these observation are based on experiments where SLN triggered swallowing has been studied in the artificial setting of the anesthetized animal. It is, therefore, likely that the cortex has a significant modulatory role in the control of the brainstem swallowing center and may have an initiating responsibility in the development of a voluntary swallow.
Functional Imaging of the Cerebral Cortex and Human Swallowing
The recent technologic advances in functional imaging of human brain have revolutionized our understanding of how the cerebral cortex operates in processing sensory and motor information. In particular, functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) have become established as useful methods for exploring the neuroanatomy of swallowing, within both cortical and subcortical structures (Table 1). There are a number of advantages and disadvantages associated with each technique. For example, fMRI allows a detailed investigation of the functional neuroanatomy of the human brain with a spatial resolution of 2 mm or less. Moreover, fMRI can be performed, unlike PET, using a single-event-related approach, which correlates cerebral activity with each task trial. The result is that improved functional information can be derived from such paradigms with potentially reduced motion-induced artifact. This may be advantageous for studying swallowing, where physiologic information about the complete functional swallow is desirable, and where motion-related problems inherent to the task are particularly likely during block trial designs using fMRI. Consequently, it seems likely that fMRI will supersede PET as the main functional imaging method for studying cerebral function as related to blood flow.

Table 1: Summary of the main cortical and sub-cortical activations associated with swallowing, as identified by functional brain imaging studies.
Brain region
PET
fMRI
MEG
PET, positron emission tomography; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalography.
Sensorimotor cortex

Insula

Anterior cingulate

Posterior cingulate

Supplementary motor cortex

Basal ganglia

Cuneus

Precuneus

Temporal pole

Orbitofrontal cortex

Cerebellum

Brainstem

Human brain imaging techniques such as PET and fMRI reflect changes in cortical function that are secondary consequences to alterations in regional cerebral blood flow, and have limited temporal resolution. Magnetoencephalography is a newer brain imaging modality that has started to resolve some of these limitations. It detects the postsynaptic magnetic fields generated by active populations of cortical neurons with millisecond temporal resolution and has a comparable spatial resolution to PET and fMRI. Nevertheless, until now, technical limitations in MEG data acquisition and analysis have restricted its use in exploring the cortical activation patterns during complex sensorimotor tasks such as swallowing. Finally, TMS is a non-invasive stimulation-based approach to studying central nervous system (CNS) function. Unlike the other brain imaging techniques, TMS does not rely on a task being performed; rather, it probes cortical pathways from motor cortex to muscles, via electromyography (EMG) recordings, building up a "map" of the cortical representation of a particular muscle or group of muscles. One advantage in the study of swallowing is that TMS can be used in patients with swallowing problems, because swallowing itself does not need to be performed, which is difficult in a scanner.
Functional Magnetic Resonance Imaging
Functional magnetic resonance imaging (fMRI) has been extensively used to investigate swallowing, and has good spatial resolution, of at least 2 mm, but the temporal resolution of a few seconds limits its use when studying deglutition. It was originally fraught with difficulties when used to assess brain signals associated with swallowing, because of large movement artifacts due to the swallow itself, especially in the inferior regions of the brain. Newer analysis techniques have allowed us to overcome these problems and obtain useful images.9 Traditional block trial studies require repeated swallows within short spaces of time, and this can induce inhibition of esophageal peristalsis, which may then mask some of the cortical activity that may otherwise be seen. Functional magnetic resonance imaging, unlike some of the other functional imaging modalities, may also be used with a single-event-related approach where the cerebral activity is correlated with each specific task. Event-related studies have advantages over block trial designs, especially with swallowing, as they can provide better functional information and are less likely to produce artifacts due to motion.
The simplest studies using functional imaging have looked at the areas of increased cortical activation during voluntary swallowing of either saliva or water, prompted by cues. Other studies have used a number of different techniques to investigate swallowing more thoroughly and to try to isolate the various neural components controlling each phase of deglutition, for example, using comparisons with tongue or hand movements and non-cued, involuntary swallowing (Figure 1). Although multiple regions are activated during swallowing, there appears to be some variability between subjects and between studies. During volitional swallowing the most consistent cortical activation is seen in the primary motor cortices and primary somatosensory cortices.10, 11, 12, 13, 14, 15 The greatest area of fMRI activation in the primary motor cortex is over the midinferior lateral portion of the precentral gyrus that corresponds with what is already known from direct cortical stimulation to be a region representing the face, tongue, and pharynx. This activation in the lateral precentral gyrus during swallowing tasks occurs dorsocaudally to the hand area.12
Figure 1: Voxelwise analysis of BOLD responses.

Responses are shown for a group of 14 subjects to (a) voluntary saliva swallow, (b) tongue elevation, and (c) voluntary finger-thumb opposition. Regions of significant activation are displayed on sagittal (left), coronal (middle), and axial (right) brain slices. Talairach-Tournoux plane coordinates are displayed above each image. (Source: Martin et al.11 with permission from the American Physiological Society.)
Most studies have also shown increased brain signal as measured using the Blood-Oxygen-Level-Dependent (BOLD) method in the majority of subjects during volitional swallowing in the anterior cingulate cortex (Brodmann Area (BA) 32,33), anterior insular cortex (BA 16), frontal operculum (BA 44), anteromedial temporal cortex (BA 21,22), superior premotor cortex (BA 6,8), and the precuneus. There is less consistently increased activation across subjects in the cerebellum, supplementary motor area, prefrontal cortex, posterior parietal cortex (BA 5), middle and inferior frontal gyri, cuneus, parietal opercula, motor association areas, sensorimotor integration areas, posterior cingulate (BA 23,31), basal ganglia, thalamus, and internal capsule.10, 11, 12, 13, 14, 15, 16 When fMRI is used specifically to look at the cerebellum and basal ganglia during volitional saliva swallowing, there is evidence of bilateral cerebellar activity more on the left, bilateral putamen, globus pallidus, and substantia nigra activation.15
Volitional swallowing results in activation of areas involved not only in the organization of a swallow itself, but also in the cue recognition and response and planning of the event. One method of differentiating these components is to study reflexive swallowing, which can be stimulated by injecting tiny amounts of water directly into the pharynx. Different swallowing tasks produce slightly different cortical maps. The areas most consistently and prominently activated in all tasks are the lateral precentral gyri, postcentral gyri, supplementary motor area, and insular cortex.12, 13, 14, 15, 16, 17 Reflexive swallowing induces bilateral activation concentrated in the primary somatosensory and motor cortices (BA 4,6), which is present in all subjects.16 When automatic saliva swallowing is compared to volitional saliva swallowing, there is more activation of the caudal anterior cingulate cortex during the reflexive swallow.17 Using visually cued go/no-go swallowing tasks during fMRI shows marked activation in the pericentral gyri and anterior cingulate cortex during the go condition, suggesting these areas are specifically involved in the act of swallowing. However, there is activation in the cuneus and precuneus during both go and no-go tasks, supporting the view that these areas are more concerned with processing of cues.18
By comparing the volitional movement of individual muscles involved in the swallow, such as the tongue, with those associated with the full swallow sequence, it may be possible to identify areas related more to the control of swallowing itself, rather than those linked more to motor planning. Tongue contraction alone produces bilateral signal increases within the sensorimotor cortex and operculum, as well as some activation in the supplementary motor area, putamen, thalamus, and cerebellum; there is also activation within the medulla corresponding to the regions known to contain the hypoglossal nuclei.19 Tongue movement and swallowing both produce activation of left lateral pre- and postcentral cortices, the anterior parietal cortex, and the anterior cingulate cortex. Tongue movements in these areas show a greater overall activation than that seen with volitional swallowing, perhaps because of a larger volitional component to tongue movement tasks compared with swallowing where much of the processing may be within the brainstem. Movements of the tongue also produce more activation than swallowing in the right pericentral gyri, supplementary motor area, premotor cortex, right putamen, and thalamus. Superimposed mapping of areas with increased activity suggests that only swallowing activates the most lateral extent of left pericentral and anterior parietal cortex, the rostral anterior cingulate cortex, precuneus, cuneus, middle frontal gyrus, and right parietal operculum. However, the main areas, where activation is stronger in swallowing than tongue elevation, are the precuneus and cuneus.11 Cortical activation in volitional swallowing also shares many regions with jaw clenching, lip pursing, and tongue rolling. Activation during all of the above functions can be found in anterior cingulate cortex, motor, and premotor cortices and occipital/parietal regions (BA 7,19,31).20 There is little agreement among studies about the activation of the insula, some having found it predominantly during swallowing tasks and others during both swallowing and tongue movement tasks.11, 16, 19
During volitional swallowing, the activation is usually bilateral, but with some areas having hemispheric dominance, 63% of subjects show left hemisphere dominance. This may be why some studies in stroke patients have shown a preponderance of left hemispheric lesions causing dysphagia.21 Most subjects show asymmetry of the postcentral gyrus activation (BA 4).11, 21 There also appears to be strong lateralization of increased activity in the midlateral precentral gyrus and somatosensory cortices (BA 1,2,3), supplementary motor area (BA 6), prefrontal cortex (BA 9,10), transverse temporal gyrus (BA 42), insula, operculum, cingulate gyrus, internal capsule, and premotor cortices.14, 15, 21 This dominance of one hemisphere is most often on the left, but if it is dominant on the right, then the lateralization is stronger. The asymmetry of activation may also vary depending on the type of swallow performed.21 In another study, of right-handed subjects, all had significantly more activation in the right insular than in the left.17
The cerebral regions that are most activated during dry swallowing in adults are similarly active in the brains of children. The main activation is seen in