Because no detailed information exists regarding the topographic representation of swallowing musculature on the human cerebral cortex in health or disease, we used transcranial magnetic stimulation to study the cortical topography of human oral, pharyngeal and esophageal musculature in 20 healthy individuals and the topography of pharyngeal musculature in two stroke patients, one with and one without dysphagia. Our results demonstrate that swallowing musculature is discretely and somatotopically represented on the motor and premotor cortex of both hemispheres but displays interhemispheric asymmetry, independent of handedness. Following stroke, dysphagia appeared to be associated with smaller pharyngeal representation on the intact hemisphere, which increases in size with recovery of swallowing.

Changes in somatosensory input can remodel human cortical motor organization, yet the input characteristics that promote reorganization and their functional significance have not been explored. Here we show with transcranial magnetic stimulation that sensory-driven reorganization of human motor cortex is highly dependent upon the frequency, intensity, and duration of stimulus applied. Those patterns of input associated with enhanced excitability (5 Hz, 75% maximal tolerated intensity for 10 min) induce stronger cortical activation to fMRI. When applied to acutely dysphagic stroke patients, swallowing corticobulbar excitability is increased mainly in the undamaged hemisphere, being strongly correlated with an improvement in swallowing function. Thus, input to the human adult brain can be programmed to promote beneficial changes in neuroplasticity and function after cerebral injury.

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Removal of sensory input can induce changes in cortical motor representation that reverse when sensation is restored. Here we ask whether manipulation of sensory input can induce long-term reorganization in human motor cortex that outlasts the initial conditioning. We report that for at least 30 minutes after pharyngeal stimulation, motor cortex excitability and area of representation for the pharynx increased, while esophagus representation decreased, without parallel changes in the excitability of brainstem-mediated reflexes. Therefore increased sensory input can drive long-term cross-system changes in motor areas of the cerebral cortex, which suggests that sensory stimulation might rehabilitate dysphagia, a frequent consequence of cerebral injury.

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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 inhibitory (satiety) and stimulatory (orexigenic) factors from the gastrointestinal tract regulate food intake. In the case of the satiety hormone cholecystokinin (CCK), these effects are mediated via vagal afferent neurons. We now report that vagal afferent neurons expressing the CCK-1 receptor also express cannabinoid CB1 receptors. Retrograde tracing established that these neurons project to the stomach and duodenum. The expression of CB1 receptors determined by RT-PCR, immunohistochemistry and in situ hybridization in rat nodose ganglia was increased by withdrawal of food for Ն12 hr. After refeeding of fasted rats there was a rapid loss of CB1 receptor expression identified by immunohistochemistry and in situ hybridization. These effects were blocked by administration of the CCK-1 receptor antagonist lorglumide and mimicked by administration of CCK to fasted rats. Because CCK is a satiety factor that acts via the vagus nerve and CB1 agonists stimulate food intake, the data suggest a new mechanism modulating the effect on food intake of satiety signals from the gastrointestinal tract.