Pharyngoesophageal motility reflex mechanisms in the human neonate: importance of integrative cross-systems physiology

Abstract

Swallowing is a critical function for survival and development in human neonates and requires cross-system coordination between neurological, airway, and digestive motility systems. Development of pharyngoesophageal motility is influenced by intra- and extrauterine development, pregnancy complications, and neonatal comorbidities. The primary role of these motility reflex mechanisms is to maintain aerodigestive homeostasis under basal and adaptive biological conditions including oral feeding, gastroesophageal reflux, and sleep. Failure may result in feeding difficulties, airway compromise, dysphagia, aspiration syndromes, and chronic eating difficulties requiring prolonged tube feeding. We review the integration of cross-systems physiology to describe the basis for physiological and pathophysiological neonatal aerodigestive functions.

INTRODUCTION

In the human neonate, difficulties are commonly noted with eating, swallowing, and airway protection and can be multifactorial (1, 2). Eating generates swallowing and airway protection, which are distinct but codependent functions in humans. Swallowing and airway protective functions are also closely interdependent from the point of airway safety, to keep the airway introitus clear of any liquid or particulate matter. Deglutition is a sequential process involving neurosensory communications and neuromotor reflexes and behaviors, which facilitates ingestion of nutrients involving anterograde bolus movement and peristalsis from mouth to stomach and beyond. The basis for peristalsis lies in Starling’s law of the intestine, in which, the ascending peristaltic contraction forces bolus propulsion and descending relaxation facilitates distal bolus transit, ensures clearance, and provides accommodation to normalcy (3). The development of peristaltic pharyngoesophageal motility reflex mechanisms in preterm and full-term born human neonates is a process in continuum and not yet completely understood. The sensory-motor effects of stimulus-response relationships are multifactorial and dependent on intrauterine and extrauterine development and influenced by comorbidities with airway, pulmonary, digestive motility, and neurological systems. The ensuing pathologies lead to increasing burden of aerodigestive diseases in infants and can culminate in technology dependence in maintaining airway and digestive functions at the extreme end of the severity spectrum (4, 5). In this review article, we describe 1) neonatal pharyngoesophageal anatomy and physiology relevant to feeding, swallowing, and airway functions; 2) testing modalities to investigate cross-system interactions during feeding, swallowing, and airway functions; and 3) utilization of a systematic integrative physiology approach to determine pathophysiological aerodigestive mechanisms.

ANATOMY AND PHYSIOLOGY OF FEEDING, SWALLOWING, AND AIRWAY FUNCTIONS IN NEONATES

The fetus begins swallowing of amniotic fluid by ∼14–16 wk of gestation (6). During this process, the amniotic fluid from the amniotic sac is swallowed by the fetus. Fetal breathing movements contribute to the efflux of fetal lung fluid (∼5 mL/breath) into the amniotic fluid, but about half the effluent is swallowed and the rest enters the amniotic fluid compartment. Given that fetal breathing occurs 20–30 min each hour, the contribution of fetal breathing to overall amniotic fluid is significant. Increase in amniotic fluid volume out of proportion to the degree of gestation may signify fetal swallowing and gastrointestinal motility deficits (7). Subsequent swallowing and propulsion of amniotic fluid via pharyngeal-esophageal motility ensures a unidirectional bolus transit in the fetus that continues until full-term birth (37–42 wk of gestation). Thereafter, the interactive roles of individual organ-systems, i.e., airway-lung and pharynx-esophagus function, in parallel, ex utero. These upper aerodigestive tract structures are designed to serve multiple functions including breathing, swallowing, airway protection, and speech. Thus a healthy fetus is prepared for independent airway and digestive functions as evidenced by spontaneous breathing and safe direct breast or bottle feeding.

Neurophysiology of the Aerodigestive Tract

Normal swallowing physiology is dependent on cross-system communication between the oral cavity, foregut (from the pharynx to stomach), and cardiorespiratory and neurological systems. The foregut comprises striated muscle proximally [pharynx, upper esophageal sphincter (UES), and proximal esophagus] and transitions to smooth muscle distally. The UES high pressure zone is generated by the cricopharyngeus (the main muscle), proximal cervical esophagus, and inferior pharyngeal constrictor and is innervated by 1) the cranial nerve X via the pharyngoesophageal, superior laryngeal and recurrent laryngeal branches; 2) the cranial nerve IX; and 3) the sympathetic nerves via the cranial cervical ganglion (8). The distal esophagus and lower esophageal sphincter (LES) are composed of circular and outer longitudinal muscle with myenteric plexus in between. The LES circular muscle tone is augmented by diaphragmatic crura, intra-abdominal esophagus, and gastric sling fibers. The laryngeal muscles are innervated by cranial nerve X via superior laryngeal nerve (cricothyroid, levator palatini, and constrictors of pharynx) and recurrent laryngeal nerve (intrinsic laryngeal muscles). The airway and esophagus have common innervations, in that the foregut afferents are derivatives of cranial nerve X and dorsal root ganglions with cell bodies in the nodose ganglion (9). The sensory impulses are relayed to the nucleus tractus solitarius in the dorsomedial medulla oblongata; the esophageal sensory signals are integrated in the subnucleus centralis where they terminate. From the nucleus tractus solitarius, the signals activate airway motor neurons in the nucleus ambiguous and the dorsal motor nucleus of the cranial nerve X. The vagus nerve (cranial nerve X) contains fibers that activate cholinergic (excitatory) neurons and noncholinergic (nitric oxide and vasoactive intestinal polypeptide) neurons that participate in contractile and relaxation functions, respectively, at the esophageal level resulting in peristalsis and sphincteric coordination. The cross-system responses involve sensory output from pharynx or esophagus with airway motor response resulting in glottal closure reflexes.

Normal Swallowing Function Physiology

Human neonates are unique to study because their swallowing and aerodigestive behaviors are very specific and differ from adult and animal populations. Data from human adults cannot be extrapolated as maturational changes contribute to acquisition of feeding and aerodigestive milestones (2). Additionally, adults can comprehend and follow verbal directions to carry out voluntary eating and swallowing tasks. They can retain a bolus in oral cavity, chew or drink a variety of solids and liquids of varying volumes, and evoke bolus transit primarily by a solitary swallow for each bolus while maintaining airway protection. In contrast, young infants ingest and transport liquids via repetitive sucking-swallowing-breathing rhythms. Thus oral pharyngoesophageal motility evaluation protocols in the infant centers around maximal infant cooperation, reproducibility of events, and examination of reflexes and their coordination. Although some airway-digestive-neurological reflex testing protocols (using stimulants as infusions) can be carried out in both populations, pharyngoesophageal motility responses differ between infants and adults (10). In animal models, underlying comorbidities cannot be replicated; thus human infant studies are needed to study translational effects.

Neurosensory and neuromotor regulation of reflexes that facilitate swallowing and airway protection, along with aspiration prevention mechanisms in human infants, are highlighted in this section. There are a number of excitatory reflexes at the level of pharynx, esophagus, and larynx that prevent pulmonary aspiration and occur at rest (basal swallowing) (10–13) and during and adaptive provocation as in esophageal stimulation (12, 14–21), pharyngeal stimulation (11, 22–27), and oral feeding challenge states (1, 28–30). To briefly summarize, two types of swallowing patterns exist: 1) one that involves the pharynx (voluntary or involuntary) termed pharyngeal swallowing, and 2) one that does not involve the pharynx (involuntary). Pharyngeal swallowing is characterized by deglutition apnea (a surrogate marker of glottal closure and cessation of air flow), pharyngeal peristalsis, UES relaxation, esophageal peristalsis, and LES relaxation. During deglutition apnea, a brief inhibition in respiration occurs due to a break in inspiration or expiration and is a normal phenomenon during pharyngeal swallow (31). This concept is the foundation for pharyngoesophageal motility in the neonate.

Normal pharyngoesophageal motility responses (Fig. 1) and cross-system neurological and cardiorespiratory responses under different testing conditions in the infant population are shown (Fig. 2). Note, pharyngeal swallowing can occur during basal resting state (Fig. 1A) or under adaptive conditions such as oral feeding (Fig. 1B), esophageal provocation (Fig. 1, C and D), or pharyngeal provocation (Fig. 1, E and F). Adaptive swallowing reflexes are present in preterm born infants and exist by 33 wk of postmaturational age, and undergo further extrauterine maturation and differentiation during postnatal life (9, 10, 20, 21, 24) and are explained as follows below.

Figure 1.

Normal pharyngoeesophageal motility in human neonates. Depicted are esophago-pressure topography plots generated by high-resolution impedance manometry methods. The x-axis represents time (sec). Colors represent pressures or muscle activity at each anatomic level of the foregut (Px, pharynx; UES, upper esophageal sphincter; ESO, esophagus; LES, lower esophageal sphincter; Sto, stomach; Inf, infusion) with blue signifying low pressures (0 mmHg) and purple signifying high pressures (100 mmHg). Impedance lines are shown in white and represent bolus transit. Decrease in impedance represents liquid while increase represents air. Note the following signature pattern characteristics in A–F. During resting state, basal swallow or primary peristalsis occurs spontaneously (such as a salivary swallow) and is characterized by pharyngeal contraction, UES relaxation followed by postdeglutitive contraction, esophageal body contraction, and LES relaxation (A). During oral feeding, multiple rhythmic pharyngeal contractions are observed along with esophageal peristaltic contractions and LES relaxation (B). In response to spontaneous esophageal stimulation [as in the case of gastroesophageal reflux (GER)], secondary peristalsis (SP) is characterized by UES contraction to protect the airway from bolus entry while esophageal peristalsis and LES relaxation allows for bolus clearance (C), while esophago-deglutition reflex is similar to basal swallow wherein the pharyngeal and esophageal components contract while the upper and lower esophageal sphincters relax to facilitate bolus clearance (D). In response to pharyngeal stimulation (as in the case of bolus from the oral cavity, secretions, or proximal GER), pharyngo-UES contractile reflex (PUCR) (E), or pharyngeal reflexive swallowing may occur (F); in this example, there are 8 pharyngeal contractions (multiple-pharyngeal reflexive swallowing) and a terminal esophageal peristaltic contraction. Note in A–F restoration of aerodigestive homeostasis results only after swallowing associated complete peristalsis ensues.

Figure 2.

Integration of pharyngoesophageal and airway protection reflexes in human infants. UES, upper esophageal sphincter; LES, lower esophageal sphincter; C, contraction; D, delayed; DA, deglutition apnea; GER, gastroesophageal reflux; I, incomplete; M, multiple; P, prolonged; R, relaxation; •, not present; ✓, present; +, increase; −, decrease.

Provocation-induced reflexes.

Although, responses are dependent on stimulus volume and media, in general normal response to esophageal provocation [as in the case of gastroesophageal reflux (GER)] includes either secondary peristalsis (Fig. 1C), or esophagodeglutition reflex (EDR) (Fig. 1D). These reflexes prevent the bolus ascent and favor bolus descent to ensure esophageal clearance and may also result in arousal or sleep state changes indicating hierarchical cortical activation. Note, along with secondary peristalsis, the UES contraction is noted, termed the esophago-UES-contractile reflex, which prevents proximal spread of the refluxate, thus protecting the airway. Magnitude of UES contractility is variable and decreases significantly during sleep. Concurrently, esophageal peristalsis and LES relaxation reflex response facilitate anterograde bolus clearance by minimizing the downstream resistance to bolus flow. Changes in sleep patterns correlated with esophageal stimulation, wherein sleep patterns changed and arousals occur (13, 16).

Upon pharyngeal provocation (as in the case of secretions or proximal GER), a solitary pharyngeal reflexive swallow (PRS) can be activated with minute amounts of stimuli similar in appearance to EDR. Air is a weaker stimulus while liquids are more potent stimuli in inducing pharyngeal reflexive swallowing, with threshold volumes ranging from 0.1 to 0.3 mL (32). PRS reflex is the most frequent response in neonates, although pharyngo-UES contractile reflex can also occur (Fig. 1E). As pharyngeal stimulus dose increases, multiple pharyngeal swallows with terminal clearance (Fig. 1F) and slightly longer deglutition apnea should occur (23, 24, 32). With maturation, deglutition apnea duration, number of pharyngeal peaks, pharyngeal rhythm variability, and heart rate drop frequency and severity decrease (22–24).

In neonates, the laryngeal muscles are major effectors involved with stimulatory reflexes preventing aspiration. The protective function of the larynx involves aspiration-aborting reflexes attributed to the glottic zone. The glottal closure in neonates can be activated upon esophageal stimulation, the esophagoglottal closure reflex, or during pharyngeal provocation, the pharyngoglottal closure reflex (25, 32, 33). This airway protective mechanism can occur independently or with swallowing and occurs in any breathing phase (inspiration, expiration, or interphase), which ensures protection against predeglutitive, deglutitive, or postdeglutitive aspiration (25, 32, 33). The esophagoglottal closure reflex can be associated with UES contractile reflex and/or LES relaxation reflex response and prevents aspiration due to retrograde GER (32). Laryngeal adduction augments aspiration prevention, while esophageal peristalsis clears the stimulus. The pharyngoglottal closure reflex increases airway agility and favors the airflow from airway to outside, thus preventing inhalation of bolus contents in the vicinity of pharyngeal airway.

Oral feeding rhythms.

Infant oral feeding activity is driven by feeding provider-infant participation and interpersonal communication, which depend on the recognition and interpretation of cues, taking appropriate action to provide appropriate feeding method in a timely manner. Utilization of an infant oral feeding readiness scale may be predictive of infant engagement (34). Infants that are awake, alert or fussy during care, bring hands to the mouth, exhibit rooting behavior, or take a pacifier are likely to participate in oral feeding (34). We have noted that successful oral feeders have rhythmic suck-swallow-breathing sequences along with esophageal peristalsis and lower esophageal sphincter relaxation with minimal fluid loss (1, 29). Additionally, compared with provocation-induced reflexes, pharyngeal contractile vigor is lower (28). Hence, these patterns point to efficient mature and efficient oral feeding skills. This is also supported by another study of oral feeding rhythms in preterm infants wherein pharyngeal contractile vigor was greater, while pharyngeal contraction frequency and activity were lesser along with lesser UES relaxation magnitude and volume intake (30). Differing attributes may be related to intra- and extrauterine maturation as well as feeding opportunities.

INVESTIGATIVE MODALITIES TO EXAMINE CROSS-SYSTEM NORMAL AND ABNORMAL INTERACTIONS DURING SWALLOWING AND FEEDING

It is important to understand the neuroanatomic basis for neurological-airway-digestive motility functions. Multimodal investigations can be utilized to evaluate these functions and symptoms/signs in the neonatal and infant population. This is accomplished by interrogation of the effects of stimulus on local, regional, and remote organs and explanation of the behaviors that were concerned to be “troublesome symptoms,” which indeed are an association with the method of restoring normalcy (22–24, 35–37). We have unraveled the physiological basis of neonatal aerodigestive and eating problems using novel methods that aided in characterization of sensory-motor aspects of pharyngeal-esophageal motility and its relationships with airway and cardiac rhythms. Described are the investigative modalities to examine the neonatal neuro-aerodigestive physiology and pathophysiology. Historically, using pneumohydraulic, micromanometric, water perfusion methods using multichannel measurements and sleeve sensors, basal manometry of pharyngeal-esophageal motility has been characterized by us and others to measure the pharynx, upper esophageal sphincter; proximal, middle, and distal esophagus; and stomach regions (10, 15, 38–40). During gastroesophageal reflux (GER), refluxed material ascending proximally may lead to laryngeal penetration and airway aspiration leading to injury or infection; this is the basis for “the reflux theory” (41). Alternatively, the responses (reflexes) triggered by refluxed material can activate vagally mediated pharyngeal, esophageal, and upper and lower esophageal sphincteric and airway reflex mechanisms (42); this is the basis for “the reflex theory” (41). Therefore, to complement basal motility, a custom-built silicone catheter was designed for infants utilizes infusions for direct provocation to the midesophagus and/or pharynx to test adaptive reflexes to simulated biological events (retrograde or anterograde bolus of varying characteristics) of varying media (air: for mechanosensitive stimulation; sterile water: osmosensitive stimulation; and apple juice: chemosensitive stimulation) and dose volumes (0.1 – 5.0 mL to examine stimulus magnitude effects) (10, 11, 15, 17). Specifically, the provocation was used to characterize changes in motility, and in the process several reflexes were discovered at different regions of pharynx-UES-esophageal body-lower esophageal sphincter regions upon stimulus loci (Fig. 2). Reflexes include esophagodeglutition reflex, secondary peristalsis, pharyngeal glottal closure reflex, esophagoglottal closure reflex, UES relaxation reflex, UES contractile reflex, esophageal peristalsis, and LES relaxation reflex (10, 11, 14, 15, 17, 18, 21). Sensory-motor metrics of each of these reflexes include stimulus sensory threshold, response latency, response frequency, response magnitude for contractile and relaxation functions, and occurrence of cross-systems responses (10, 11, 14, 15, 17, 18, 21–24, 43). However, water perfusion manometry can be cumbersome for easy adaptability. Limitations include time intensive catheter placement (∼15–30 min utilizing pull-through technique dependent on infant cooperation), extensive expertise needed for system setup, catheter selection and placement, and low resolution (1 sensor per esophageal segment totaling 7 channels).

As manometry technology has advanced, high-resolution manometry (HRM) has largely replaced traditional water-perfusion manometry methods in the research realm and is used for clinical diagnostic needs to evaluate motility disorders across the age spectrum (44, 45). HRM allows researchers to measure luminal pressure changes simultaneously within the pharynx and UES with a contiguous representation of pressure propagation along the catheter. Normative basal data in adults are available using Chicago Classification, with the latest version utilizing multiple rapid swallow and multiple rapid drink challenge to assist to identify esophagogastric junction outflow obstruction (45). Strengths of HRM include 1) quick catheter placement (<15 min); 2) more closely spaced pressure sensors (25 sensors spaced 1 cm apart) that permit measurement of esophago-pressure topography utilizing multiple dimensions (pressure, time, and now length) allowing for detailed evaluation of proximal and distal pharyngeal segments, and distal esophageal segments (smooth muscle); and 3) integration of impedance technology to examine bolus movement coupled with changes in pressurization across the pharyngeal-esophageal column; 4) capability of provocative testing (26, 43); 5) multisystemic evaluation (22, 23); 6) capability to include video-fluoroscopy studies (46, 47); 7) oral feeding challenge testing to measure pharyngeal rhythms and video recording to measure normal and abnormal behaviors (35); and 8) and identification of esophageal abnormalities (hiatal hernia, achalasia, jackhammer esophagus, and hypomotility). Comparison of esophago-pressure topography and conventional line plots are shown in Fig. 3. Major drawback of high-resolution manometry methodology is the absence of normative data and lack of automation with analysis for the developing infant population; hence interpretation and recommendations can be a problem if providers lack experience with this technology for infant use.

Figure 3.

Comparison of esophageal pressure topography (EPT) and conventional line plots. Px, pharynx; UES, upper esophageal sphincter; ESO, esophagus; LES, lower esophageal sphincter; Sto, stomach; Resp, respiration; Inf, infusion. The left side depicts the foregut mapped from the pharynx to the stomach and corresponding sensor positions of the high-resolution manometry (HRM) catheter in both EPT and conventional line plot views for esophageal infusion-induced secondary peristalsis (A) and esophagodeglutition (B) reflex responses. For the conventional line plots, the x-axis represents time (sec) and the y-axis represents pressure (mmHg). This is similar to water perfusion manometry methods, except in HRM there are more pressure sensors spaced more closely together yielding “high resolution.” The EPT view on the other hand also takes esophageal length into account with the x-axis representing time (sec) and the y-axis representing length (cm) and the colors representing pressure (mmHg). Thus metrics are often measured in mmHg·cm·s and is a measure of overall contractile vigor or magnitude of sphincter relaxation. The nasal thermistor measures respiration in the conventional view with upstroke indicating inhalation and downstroke indicating exhalation.

In addition to motility responses, cross-system organ system functions can be evaluated via concurrent time-synchronized testing modalities: 1) respiratory inductance plethysmography and nasal airflow thermistor to detect changes in respiratory rhythms (11, 22, 23, 25, 26, 33, 36); 2) ultrasonography (25, 33, 48) or videofluoroscopy to evaluate airway protection; 3) continuous electrocardiography to evaluate cardiac heart rate and sympathetic/parasympathetic changes (22, 23); 4) pulse oximetry to evaluate oxygen saturation; 5) continuous electroencephalography or near infrared spectroscopy to detect cortical responses (12, 13, 16); and 6) video recording to evaluate infant behaviors and/or symptoms (35). Importantly, these methods have led to discovery of cardiorespiratory and neurological responses associated with swallowing and/or GER and may include the following: prolonged respiratory changes and apnea (24, 36), glottal closure reflexes (25, 33), heart rate decrease (22, 23), vagal activation (13, 16, 49), and symptoms (22, 23, 35) (Fig. 2).

IMPORTANCE OF AN INTEGRATIVE PHYSIOLOGY APPROACH TO DETERMINE PATHOPHYSIOLOGICAL MECHANISMS

In this section, we highlight the importance of integrative physiology in determining pathophysiological mechanisms. The integrative physiological approaches clarify the findings under optimal feeding and crib-side testing conditions and the ability to perform follow up studies the risk of transportation or exposure to radiation. Our approaches have proven to be safe in examining high-risk infants convalescing on positive pressure ventilation and/or high-flow oxygen supplementation. These approaches can be applied in the setting of evaluation of swallowing abnormalities or of aerodigestive problems.

Swallowing Abnormalities

A summary of potential abnormal pharyngoesophageal motility responses in the infant population is shown in Fig. 2. Selected abnormal pharyngoesophageal motility and cross-system interaction examples during resting or adaptive states are shown in Fig. 4. When swallowing dysfunction occurs, symptoms are likely as an adaptive mechanism and may be protective in cases of peristaltic failure to return to homeostasis. This is evident with cough, which is frequently triggered by nonpropagating swallow but then clears the airway of contents and returns to aerodigestive normalcy (37). If final clearance does not occur, younger infants may be susceptible to heart rate drop resulting in bradycardia (22, 23).

Figure 4.

Normal and abnormal pharyngoesophageal motility responses in infants during basal (rest) and adaptive (provocation and oral feeding) states. Note these examples were generated using water perfusion manometry methods with concurrent methodologies to evaluate cross-system interactions between the airway, digestive, neurological, and cardiac systems. A: basal swallow. Bottom: infants referred for apparent life-threatening events have prolonged spontaneous respiratory events and gasping associated with multiple swallowing events, decreased upper esophageal sphincter (UES) protection, and inadequate peristaltic clearance. Adapted from Hasenstab and Jadcherla (36) with permission from Elsevier. B: esophageal provocation-induced responses. Top: an example of a normal secondary peristalsis response to esophageal infusion wherein sleep state was preserved during UES contraction, esophageal body peristalsis, and lower esophageal sphincter (LES) relaxation, without respiratory change, cardiac change, or symptoms. Bottom: failed esophago-deglutition responses resulting in cortical arousal, prolonged respiratory changes, and prolonged motility response. Adapted from Jadcherla et al. (13). C: pharyngeal provocation-induced responses. Top: a normal multiple pharyngeal swallow response with terminal clearance and minimal change in cardiorespiratory rhythms. Bottom: a response resulting in bradycardia (low heart rate) with prolonged respiratory change, increased number of pharyngeal peaks, and esophageal dysmotility. Adapted from Hasenstab-Kenney et al. (22). D: oral feeding. Top: pharyngoesophageal motility is coordinated with sucking and breathing rhythms during normal oral feeding. Abnormal responses are absence of pharyngoesophageal motility rhythms during oral feeding (Bottom) or uncoordinated motility responses along with prolonged respiratory pauses, decompensation, or bradycardia (not pictured). PE, proximal esophagus; DE, distal esophagus; ME, middle esophagus. Adapted from Jadcherla et al. (29).

Other motility abnormalities may be at a regional anatomic level such as peristaltic or sphincteric dysfunction or at a central level such as sensory-motor issues. Multiple peristaltic responses, polymorphic waveforms, hypercontractility (aka “nutcracker”), absent or prolonged inhibition, and absent or prolonged contraction may be indicative of poor clearance or sensory-motor issues or due to comorbid factors. Multiple pharyngeal swallowing abnormalities may include, absence of multiple peaks indicating hyposensitivity, prolonged deglutition apnea beyond pharyngeal activity indicating airway hypersensitivity or incoordination, or higher than normal contractions indicating poor clearance or hypersensitivity. Prolonged deglutitive inhibition can be a troublesome pathological sign, and restoration of aerodigestive normalcy is of importance (22, 23, 36).

The UES, an important barrier, allows anterograde bolus clearance and protects against the entry of gastroesophageal refluxate into the aerodigestive tract. If tone is too low, the infant is at risk of aspiration due to retrograde GER. If tone is too high and unable to adequately relax, the infant is at risk of anterograde aspiration. Abnormal UES function may include poor relaxation or absence of relaxation termed “achalasia” indicating potential issues with anterograde clearance or absent contraction indicating poor proximal protection against esophageal provocation If LES tone is too low or relaxes for prolonged periods of time, the infant is at risk for GER events. If LES tone is too high and does not adequately relax, achalasia may occur. If LES and crural diaphragm are separated, then hiatal hernia can occur. Thus cortical hierarchical development is a process in continuum in health and is modified in the presence of comorbidities. In such scenarios, exaggeration (maladaptation) or absence (maldevelopment) of reflexes ensues and therefore the genesis of troublesome symptoms.

Additional Consideration of Subject Factors Favoring Dysregulation

Dysregulation of aerodigestive functions is common in neonatal period, which extends into infancy. Structural anomalies such as congenital birth defects and chromosomal syndromes are associated with maldevelopment of aerodigestive apparatus and therefore its functions. Premature birth is associated with multisystemic illness (1, 2, 50) and therefore problems with maldevelopment and or maladaptation of reflexes. Hypoxic-ischemic encephalopathy and neonatal stroke involve cerebral cortical, basal ganglia, thalamus, cerebellum, and or brain stem regions, and all these entities signal central neurological effects leading to maladaptation of aerodigestive functions (51, 52). Inflammation in the foregut as in gastroesophageal reflux disease (GERD) or airway and chronic lung disease may be associated with malfunction of nerve-muscle interactions at contiguous or cross-systems level (37, 53). Thus the foundations of these difficulties involve the central and enteric reflexes, neuromuscular apparatus involved with deglutition, swallowing and airway protection, as well as cardiorespiratory rhythm patterns (9). Three major systems are at play in the development of such symptoms: 1) central and enteric nervous system, 2) airway and pulmonary systems, and 3) oropharyngeal and esophagogastric apparatus (9). Hence, characterization of integrative physiology of cross-systems (neurological, airway, and upper foregut) is a necessary step in advancing our understanding of the feeding problems in infancy.

Neonates are at risk for gastroparesis and therefore delayed gastric emptying, weak integrity of GE junction, ineffective esophageal motility, hypertensive esophageal contractions, LES dysfunction, and autonomic dysfunctions are some of the potential mechanisms. Maldevelopment, malfunction, and/or maladaptation of cross-systems interactions may result in dysphagia, chronic airway problems, speech difficulties, gastroesophageal reflux disease (GERD), sleep disturbances, chronic feeding difficulties, and overall quality of life impairment. Patient characteristics also impact swallowing function. For example, preterm (<37 wk of gestation) birth or perinatal illness (airway, pulmonary, neurological, digestive, and sepsis) complicates the process of independent breathing and eating, and such infants in the neonatal intensive care unit are dependent on artificial support systems for feeding via intragastric feeding and breathing via various respiratory support measures (4, 5). Upon either partial or total recovery, infants have abnormal eating, swallowing, and airway regulatory issues, and the presence of aerodigestive symptoms and signs can be perplexing to the parents and health care providers. Pharyngeal-esophageal pathologies may coexist or lead to pulmonary complications. Esophageal pathologies may cause or worsen pulmonary disorders by affecting alveolar, smaller and larger tubular airways, laryngeal, pharyngeal, and sinus regions. All these pathologies can complicate changes in regional functions and ultimately in respiratory mechanics due to variability in lung disease (4, 5).

Regardless of reasons for underlying pathophysiology such as swallowing dysfunction or comorbid factors, oral feeding success is possible even in critical care infants via utilization of translational approaches: specifically, evidence-based physiological evaluation along with multidisciplinary and individualized management strategies (1, 29). Management strategies may include treatment of underlying comorbidities, feeding modifications (nipple flow, gavage feeding, posture changes, and caloric density), swaddling, cue-based feeding, pacifier oro-motor stimulation, cheek and chin support, maintaining airway position during sucking pauses, allowing additional time for suck-swallow breathe organization and pacing, and/or use of pharmacological therapies (1, 29).

FUTURE DIRECTIONS FOR CLINICAL AND TRANSLATIONAL RESEARCH

Additional research is needed in understanding the maturational changes in UES and LES functions under different conditions of health. Changes in pharyngeal and esophageal provocation-induced reflexes with maturation under comorbid conditions need to be ascertained so that appropriate diagnostic and therapeutic targets can be developed to modify pathologies. The esophageal and pharyngeal stimulatory effect on autonomic behaviors and sleep patterns is an important area that needs further clarity in health and disease. In particular, the roles played by GERD, dysphagia, perinatal asphyxia, and chronic lung disease are all of importance as the final common manifestations in all these conditions are related to eating and swallowing difficulty, airway adaptation, and the presence of troublesome symptoms. Any of these entities can result in long-term tube-feeding methods and chronic respiratory supports. Design of clinical trials in these populations of interest must have a strong physiological basis for integrative biology (43, 53), and future work must include placebo in clinical trials so that the effects of therapeutic agents can be adequately tested.

SUMMARY

The frequency of elicitation and further advancement of sensory-motor aspects of pharyngoesophageal motility reflex mechanisms in the premature and full-term born human neonate continue to develop with growth and maturation. The development of sensory-motor effects is multifactorial and is dependent on birth gestation, pregnancy complications, extrauterine development, and neonatal comorbidities associated with airway, pulmonary, digestive, and neurological systems. The significance of spontaneous and stimulus-induced pharyngeal-esophageal reflexes in modulating aerodigestive and pharyngoesophageal-upper esophageal sphincter-lower esophageal sphincter motility functions to maintain homeostasis is described in this review article. Specific functions of these reflexes are airway protection at rest, sleep, and activity, pharyngeal and esophageal clearance, prevention of gastroesophageal reflux and homeostasis after that, and regulatory behaviors during oral feeding. Importantly, the use of investigative process to examine the integration of cross-systems physiology is explained to describe the physiological basis for neonatal aerodigestive functions and symptoms/signs.

GRANTS

This work was supported in part from the National Institute of Diabetes and Digestive and Kidney Diseases Grants R01-DK-068158 and R01-DK-122171.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Z.S. and K.A.H. prepared figures; Z.S., K.A.H., and S.R.J. drafted manuscript; Z.S., K.A.H., and S.R.J. edited and revised manuscript; Z.S., K.A.H., and S.R.J. approved final version of manuscript.