modify cognitive sensation such as pain, acting through higher centers [16]. Afferent information enters the NTS, where subdivisions of the NTS initiate and program sequencing of swallowing, modify ongoing motor activity, and activate reflexes involving the esophagus, esophageal sphincters, and airway [5, 17]. There is viscerotopic organization of the afferent input to the NTS [18, 19]. Although sympathetic nerves entering the spinal cord segments C1 to L3 also carry afferent sensory information from the esophagus [20, 21], their role in modulating SPG activity is unknown.
Oropharyngeal afferents enter primarily into two subnuclei of the NTS: the interstitial (NTSis) and the intermediate (NTSim); esophageal afferents enter into the subnucleus centralis (NTSce) [5, 6, 18,22–25]. Motor programming of the swallow sequence occurs within these subunits of the DSG [26]. Other NTS subnuclei presumably function in the relay to the VSG and to motor neurons, and in the pathways to affected activities such as respiration.
Motor
Motor function of muscles involved with the oropharyngeal stages is mediated by several cranial nerves (trigeminal, facial, hypoglossal, and vagus) [6]. Innervation of neck muscles through C1–C3 participates in a facilitative role. The striated muscle esophagus receives motor innervation from the nucleus ambiguus portion of the vagus nerve, although some control rests in the dorsal motor nucleus of the vagus (DMNV) in species with a smooth muscle esophagus, perhaps to inhibit the esophageal motor neurons. There is rostral to caudal myotopic organization within the nucleus ambiguus to coordinate output to the various striated muscles along the swallowing pathway [27–31]. The smooth muscle esophagus receives motor input from the DMNV, although a small number of fibers may arise in the nucleus ambiguus [32]. Specific locations exist within the DMNV for motor output to the esophageal body and LES, and for function of the LES, with excitation to the LES positioned distally and inhibition positioned rostrally [32–34].
Organization
Once the swallowing process is initiated at any stage, sequential activation of the neurons in the remaining portions of the swallowing pathway occurs [7, 18, 35]. Although sequential activation of neurons along the program is the basis for the eventual pattern of motor events in each peripheral location, inhibitory messaging is also present along the entire program circuitry. As swallowing proceeds down the esophagus, excitation decreases along the program pathway while inhibition correspondingly increases; this is also reflected in the concentration of excitatory and inhibitory neurotransmitters along the esophagus [36]. The decreasing excitation increases the role of sensory feedback to shape the activity of the central program depending on the bolus requirements (Figure 5.2). In the esophageal stage, sensory feedback may also be necessary to further excite the esophageal stage of the program for muscle contraction and peristalsis to occur [37–42].
Inhibition within and along the SPG serves at least two purposes: timing of peristalsis by progressively delaying excitation distally along the circuitry, and deglutitive inhibition of motor events to allow repetitive swallowing [36]. Excitation of neurons at any stage in the esophageal program circuitry shuts down activity in all neurons destined for more distal esophageal sites. Excitation at any peripheral level increases excitation at the corresponding level in the SPG while also increasing inhibition below that SPG level.
The oral‐to‐pharyngeal stage connection and the DSG‐to‐VSG motor neuron activation pathway are well established for the oropharyngeal stages of swallowing and appear fairly consistent among different species, regardless of the esophageal muscle type. It remains unknown if the connection of the pharyngeal stage to the esophageal circuitry from the DSG program in the NTSce to the motor neurons for the esophagus is direct or through a VSG [7, 35].
While there are numerous transmitter mechanisms within the SPG [35], only a few are responsible for the major actions. Excitation is mediated by excitatory amino acids such as glutamine and by the cholinergic system, while inhibition is through the action of gamma‐butyric acid (GABA) acting at the GABAA receptor. Nicotinic action is important for activation of premotor neurons in the programming and organizing portions of the SPG, while muscarinic action appears to couple the oropharyngeal with the esophageal stages of the SPG and activate motor neurons. At the level of the NTSce, two other transmitters are important in activation of the esophageal and LES neurons: nitric oxide (NO) and somatostatin. NO is involved with regulating esophageal contraction amplitude and LES tone and contraction [43, 44]. Other transmitters such as serotonin, norepinephrine, oxytocin, and vasopressin have modulatory roles and are likely also to influence other interrelated functions such as hunger, thirst, nausea, and sleep.
Figure 5.2 Excitation and inhibition in the swallowing network. (A) The swallowing network can be seen as a chain of neurons with excitatory (triangles) and inhibitory (dots) connections, and sensory feedback (broken lines). The power of excitatory inputs decreases along the chain; that of inhibitory inputs increases and can lead to long periods of inhibition of neurons controlling more distal parts of the tract. (B) The central pattern generator can be divided into an oropharyngeal network and an esophageal network. The esophageal network is first inhibited (dot) and then excited (triangle) to provide for successive activation of esophageal neurons. (C) Inhibitory–excitatory sequence recorded in an esophageal motor neuron in the sheep. (i) A single swallow was induced by stimulation of the superior laryngeal nerve (SLN). A biphasic inhibitory hyperpolarization was followed by a depolarization. (ii) When spiking occurs on the after‐depolarization, a contraction occurs following the inhibitory delay.
Source: Jean [7] with permissions of Springer Nature.
Cortical and supramedullary influences
Voluntary control of swallowing initiation resides in the dorsolateral and anterolateral regions of the sensory‐motor frontal cortex in primates, with bilateral representation, although one side, usually the left, is dominant [45–47]. Connections to the brainstem SPG and direct pathways to the motor neurons both exist. Cortical stroke on the dominant side results in dysphagia, recovery from which is associated with enhancement of cortical representation on the non‐dominant side [48]. Transcranial magnetic stimulation (TMS) of these cortical regions has demonstrated somatotopic organization serving different pharyngeal musculature and the upper striated muscle esophagus [49]. TMS directed at the cortex can stimulate swallowing in animals but not in humans [50].
Other cortical and supramedullary areas (cerebellum, nuclei in the pons, hypothalamus, basal ganglia) are also active during swallowing, as evident from neuroimaging in humans and neurophysiologic studies in animals. Generally, these areas control feeding behavior, mastication, and respiration, or accept peripheral afferent sensory input to modify swallowing at one or more central levels [51–54]. Consequently, strokes in many cortical areas and disorders like Parkinson’s disease can impact swallowing at many peripheral levels, including the esophagus [55, 56]. Therapeutic interventions directed at one or more of the central areas, such as TMS activation of the sensory feedback pathways, can be of value [57].
Oropharyngeal stage motor activity
The pharynx is an irregular muscular tube, with the superior, middle, and inferior constrictor muscles supported