Ivan M. Lang

Brain Stem Control of the Phases of Swallowing

The phases of swallowing are controlled by central pattern-generating circuitry of the brain stem and peripheral reflexes. The oral, pharyngeal, and esophageal phases of swallowing are independent of each other. Although central pattern generators of the brain stem control the timing of these phases, the peripheral manifestation of these phases depends on sensory feedback through reflexes of the pharynx and esophagus. The dependence of the esophageal phase of swallowing on peripheral feedback explains its absence during failed swallows. Reflexes that initiate the pharyngeal phase of swallowing also inhibit the esophageal phase which ensures the appropriate timing of its occurrence to provide efficient bolus transport and which prevents the occurrence of multiple esophageal peristaltic events. These inhibitory reflexes are probably partly responsible for deglutitive inhibition. Three separate sets of brain stem nuclei mediate the oral, pharyngeal, and esophageal phases of swallowing. The trigeminal nucleus and reticular formation probably contain the oral phase pattern-generating neural circuitry. The nucleus tractus solitarius (NTS) probably contains the second-order sensory neurons as well as the pattern-generating circuitry of both the pharyngeal and esophageal phases of swallowing, whereas the nucleus ambiguus and dorsal motor nucleus contain the motor neurons of the pharyngeal and esophageal phases of swallowing. The ventromedial nucleus of the NTS may govern the coupling of the pharyngeal phase to the esophageal phase of swallowing.

Gastrointestinal motor correlates of vomiting in the dog: Quantification and characterization as an independent phenomenon

The gastrointestinal motor correlates of vomiting were examined in 8 dogs. Each dog was chronically implanted with extramural strain gage force transducers distributed along the gastrointestinal tract. The following gastrointestinal motor responses accompanied vomiting activated spontaneously or after apomorphine administration (2.5-15 micrograms/kg, i.v.): (a) a retrograde peristaltic contraction (RPC), (b) a peri-RPC inhibitory period, (c) a post-RPC series of phasic contractions, and (d) a post-RPC inhibitory period. These same motor patterns occurred without the somatomotor responses associated with vomiting but sometimes with regurgitation under the following conditions: (a) spontaneously, (b) one-third of the time after low doses of apomorphine (2.5-5.0 micrograms/kg, i.v.), or (c) after the intragastric administration of hypertonic saline or a vinegar solution. We concluded that a set of gastrointestinal motor responses accompany vomiting and that this set of responses represents an independent phenomenon. This phenomenon was vagally mediated but only one phase, the RPC, was cholinergically mediated. Our results suggest that the vomiting center may consist of two functionally distinct parts that are activated sequentially: one controlling the gastrointestinal responses and the other the somatomotor responses.

Anatomy and Physiology of the Upper Esophageal Sphincter

The upper esophageal sphincter (UES) is composed of the cricopharyngeus (CP), thyropharyngeus (TP; inferior pharyngeal constrictor [IPC] in humans), and cranial cervical esophagus. All 3 muscles may at times function to maintain tone in the UES, but only the CP contracts and relaxes in all physiologic states consistent with the UES. The CP is a striated muscle composed of variable-sized small (25-35 microm) muscle fibers that are primarily type I (slow twitch), highly oxidative, and contain abundant (40%) endomysial elastic connective tissue. The fibers may attach to the connective tissue framework, forming a muscular net. In humans and rats, but not other animals, the CP has no median raphe. The optimum length of the CP for development of active tension is about 1.7 times resting length; therefore, in some respects the CP acts more like cardiac than striated muscle. A passive tone in the CP is present and increases through all degrees of stretch. The high compliance of the CP allows it to be opened by distraction of other muscles (e.g., geniohyoideus) or increased intraluminal pressure. The CP is innervated by branches of the vagus nerves: pharyngoesophageal (PE), superior laryngeal (SLN), and recurrent laryngeal (RLN); glossopharyngeal (GPN); and cervical sympathetics. Only the PE and SLN provide motor fibers to the CP. The GLN may be sensory; the sympathetics may innervate the mucosa, blood vessels, and glands; but no functional innervation by the RLN has been identified. Parasympathetic ganglia and various peptides (galanin, cGRP, VIP, neuropeptide Y, substance P, tyrosine hydroxylase) have been found in the CP, but their role in control of the CP is unknown. The motoneurons of the CP are found in the nucleus ambiguus, and the innervation is ipsilateral for animal species in which the CP has a median raphe. These motoneurons are topographically organized with other pharyngeal and laryngeal muscles and the striated muscle esophagus. Pharyngeal motoneurons often have a respiratory rhythm, but not a spontaneous background discharge. Therefore, the CP motoneurons may not generate CP tone. Various reflexes control the tone of the CP. Distension of the esophagus causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. Pressure on the pharyngeal mucosa contracts the CP and UES and is mediated by a glossopharyngo-vagal reflex. Inflation of the lungs causes contraction of the CP and UES, which is mediated by a vago-vagal reflex. The pharyngo-UES and pulmonary-UES reflexes may generate the respiratory rhythm often observed on UES pressure or electromyographic activity. The UES or CP also contracts with arousal or with changes in posture. All of these reflexes and responses and the passive elastic properties of the CP may contribute to the generation of tone in the CP and UES.

Effect of aging on the deglutitive oral, pharyngeal, and esophageal motor function.

Aging affects some members of the swallowing orchestra and spares the others. It seems that changes in the pharynx of the elderly are more of a positive nature than a negative one and reflect an adaptation to age-induced structural changes of the upper esophageal sphincter. In the esophagus, the positive change in deglutitive peristaltic amplitude and duration seem to revert to a negative one over the age of 90 years. In the upper esophageal sphincter, it appears that aging reduces the resting pressure, but spares its response to various stimuli. Considering the increasing elderly population and their medical needs, further normalcy data about various manometric aspects of deglutition is needed for physiologic studies as well as diagnostic and therapeutic purposes.

Characterization of the pharyngo-UES contractile reflex in humans

Preliminary human studies suggest the presence of an upper esophageal sphincter (UES) contractile reflex triggered by pharyngeal water stimulation. The purposes of this study were to further characterize this reflex and determine the threshold volume for its activation. We studied 10 healthy young volunteers by manometric technique before and after topical pharyngeal anesthesia. UES pressure responses to various volumes and temperatures of water injected into the pharynx were elucidated. At a threshold volume, rapid-pulse and slow continuous pharyngeal water injection resulted in significant augmentation of UES pressure in all volunteers. Threshold volume for inducing UES contraction averaged 0.1 +/- 0.01 ml for rapid-pulse injection and was significantly smaller than that for slow continuous injection (1.0 +/- 0.2 ml). UES pressure increase duration averaged 16 +/- 4 s. Augmentation of UES resting tone by injection of water with three different temperatures was similar. This augmentation was abolished after topical anesthesia. Conclusions were that stimulation of the human pharynx by injection of minute amounts of water results in a significant increase in resting UES pressure: the pharyngo-UES contractile reflex. The magnitude of pressure increase due to activation of this reflex is not volume or temperature dependent. Loss of pharyngeal sensation abolishes this reflex.Preliminary human studies suggest the presence of an upper esophageal sphincter (UES) contractile reflex triggered by pharyngeal water stimulation. The purposes of this study were to further characterize this reflex and determine the threshold volume for its activation. We studied 10 healthy young volunteers by manometric technique before and after topical pharyngeal anesthesia. UES pressure responses to various volumes and temperatures of water injected into the pharynx were elucidated. At a threshold volume, rapid-pulse and slow continuous pharyngeal water injection resulted in significant augmentation of UES pressure in all volunteers. Threshold volume for inducing UES contraction averaged 0.1 ± 0.01 ml for rapid-pulse injection and was significantly smaller than that for slow continuous injection (1.0 ± 0.2 ml). UES pressure increase duration averaged 16 ± 4 s. Augmentation of UES resting tone by injection of water with three different temperatures was similar. This augmentation was abolished after topical anesthesia. Conclusions were that stimulation of the human pharynx by injection of minute amounts of water results in a significant increase in resting UES pressure: the pharyngo-UES contractile reflex. The magnitude of pressure increase due to activation of this reflex is not volume or temperature dependent. Loss of pharyngeal sensation abolishes this reflex.

Gastrointestinal motor and myoelectric correlates of motion sickness

The objectives of this study were to characterize the digestive tract motor and myoelectric responses associated with motion sickness. Twenty-two cats (1.5-3.0 kg) were chronically implanted with force transducers and electrodes on the stomach and small intestine. Motion sickness was activated by vertical oscillation (VO) at +/-0.5 g and identified as salivation, licking, or vomiting. Vomiting was initiated chemically by UK-14304 (2.5-15 microg/kg iv) or CuSO4 (10-50 mg ig). We found that VO caused vomiting (45% of trials), a decrease in gastrointestinal (GI) motility (69% of trials), salivation or licking (59% of trials), bradygastria (39% of trials), retrograde giant contraction (RGC, 43% of trials), giant migrating contraction (GMC, 5% of trials), and defecation (18% of trials). The decrease in GI motility occurred with (62% of trials) or without (69% of trials) vomiting. Motion sickness was accompanied by bradygastria (52% of trials) and decreased GI motility (70% of trials). Similar events occurred after CuSO4 and UK-14304, but the incidences of responses after CuSO4 were less frequent, except for vomiting, RGC, and GMC. UK-14304 never caused GMCs or defecation. The magnitude and velocity of the RGC were the same during all emetic stimuli, and RGCs never occurred without subsequent vomiting. Supradiaphragmatic vagotomy (n = 1) or atropine (n = 2, 10 or 50 microg/kg iv) blocked the RGC, but not vomiting, due to VO. We concluded that 1) oculovestibular stimulation causes digestive tract responses similar to other types of emetic stimuli, 2) decreased GI motility and bradygastria may be physiological correlates of the motion sickness, and 3) motion sickness may not be dependent on any specific GI motor or myoelectric response.

An Intrinsic Neural Pathway for Long Intestino-Intestinal Inhibitory Reflexes

We studied the mechanisms of initiation and pathways for the propagation of intestino-intestinal inhibitory reflexes induced by close intraarterial injections of neostigmine in conscious dogs. Two or three T-shaped catheters were surgically implanted in the intestinal branches of the superior mesenteric artery to inject pharmacologic agents locally in 10-15-cm-long segments. Migrating myoelectric complexes were recorded by a set of 10 electrodes and strain-gauge transducers. Close intraarterial injection of neostigmine initiated strong contractions of long duration in the perfused segment that terminated phase III activity in progress 90-150 cm distal or proximal to the cannulated sites and stopped its further migration. Atropine or 4-diphenylmethoxy-N-methylpiperidine methiodide injected just before neostigmine administration through the same catheter blocked both the local contractile effects and the reflex inhibition of phase III activity. Pirenzepine or hexamethonium injected in a similar manner did not affect the local response to neostigmine but blocked the reflex inhibition of phase III activity. A transection and reanastomosis in the mid-small intestine blocked the reflex inhibition by close intraarterial injection of neostigmine beyond the transection site. Pirenzepine, atropine, or hexamethonium injected through a middle catheter also blocked the reflex inhibition of phase III activity beyond the site perfused with these cholinergic antagonists. Close intraarterial administration of 4-diphenylmethoxy-N-methylpiperidine methiodide at a middle site had no effect on reflex inhibition. We concluded that strong spasmodic contractions in the small intestine initiate an intestino-intestinal inhibitory reflex in both directions. This reflex is mediated through an intrinsic neural pathway involving nicotinic and M1 muscarinic receptors.

Deterioration of the Pharyngo‐UES Contractile Reflex in the Elderly

Objectives/Hypothesis Deterioration of aerodigestive tract reflexes such as the esophagoglottal and pharyngoglottal closure reflexes and pharyngeal swallow has been documented in the elderly. However, the effect of aging on the contractile response of the upper esophageal sphincter (UES) to pharyngeal water stimulation has not been studied. The aim of this study was to characterize the pharyngo‐UES reflex in the healthy elderly.

Pharyngoglottal closure reflex: identification and characterization in a feline model

Earlier studies in humans have shown that pharyngeal stimulation by water at a threshold volume induces a brief vocal cord adduction, i. e., pharyngoglottal closure reflex. The present study was undertaken to 1) develop a suitable animal model for physiological studies of this reflex and 2) delineate its neural pathway and effector organs. Studies were done in cats by concurrent videoendoscopy and manometry followed by electromyographic studies. At a threshold volume (0.3 +/- 0.06 ml), injection of water into the pharynx resulted in a brief closure of the vocal folds, closing the introitus to the trachea. Duration of this closure averaged 1.1 +/- 0.1 s. Bilateral transection of the glossopharyngeal nerve completely abolished this reflex but not swallows induced by pharyngeal water stimulation. The pharyngoglottal closure reflex is present in the cats. The glossopharyngeal nerve is the afferent pathway of this reflex, and the interarytenoid and lateral cricoarytenoid muscles are among its target organs.Earlier studies in humans have shown that pharyngeal stimulation by water at a threshold volume induces a brief vocal cord adduction, i.e., pharyngoglottal closure reflex. The present study was undertaken to 1) develop a suitable animal model for physiological studies of this reflex and 2) delineate its neural pathway and effector organs. Studies were done in cats by concurrent videoendoscopy and manometry followed by electromyographic studies. At a threshold volume (0.3 ± 0.06 ml), injection of water into the pharynx resulted in a brief closure of the vocal folds, closing the introitus to the trachea. Duration of this closure averaged 1.1 ± 0.1 s. Bilateral transection of the glossopharyngeal nerve completely abolished this reflex but not swallows induced by pharyngeal water stimulation. The pharyngoglottal closure reflex is present in the cats. The glossopharyngeal nerve is the afferent pathway of this reflex, and the interarytenoid and lateral cricoarytenoid muscles are among its target organs.

Response properties of the brainstem neurons of the cat following intra-esophageal acid–pepsin infusion

Studies in humans have documented that acute acid infusion into the esophagus leads to decrease in threshold for sensations to mechanical distension of the esophagus. It is not known whether acid infusion leads to sensitization of brainstem neurons receiving synaptic input from vagal afferent fibers innervating the esophagus. The aim of this study was to investigate the correlation of responses of vagal afferents and brainstem neurons after acute infusion of acid (0.1 N HCl)+pepsin (1 mg/ml) into the esophagus of cats. The vagal afferent fibers (n=20) exhibited pressure-dependent increase in firing to graded esophageal distension (5-80 mm Hg). Infusion of acid+pepsin into the esophagus produced a significant increase in ongoing resting firing of five of 16 fibers (31%) tested. However, their responses to graded esophageal distension did not change when tested 30 min after infusion. Pepsin infusion did not change the resting firing and response to esophageal distension (n=4). Twenty-one brainstem neurons were recorded that responded in an intensity-dependent manner to graded esophageal distension. Responses of 12 excited neurons were tested after intra-esophageal acid+pepsin infusion. Neurons exhibited a decrease in threshold for response to esophageal distension and increase in firing after acid+pepsin infusion. The sensitization of response after intra-esophageal acid remained unaffected after cervical (C1-C2) spinal transection (n=3). Results indicate that the esophageal distension-sensitive neurons in the brainstem exhibit sensitization of response to esophageal distension after acute acid+pepsin exposure. The sensitization of brainstem neurons is possibly initiated by increased spontaneous firing of the vagal afferent fibers to acid+pepsin, but not to sensitized response of vagal distension-sensitive afferent fibers to esophageal distension. Results also indicate that spinal pathway does not contribute to sensitization of brainstem neurons.