Significance of sensory inflow to the swallowing reflex

BRAIN RESEARCH

147

S I G N I F I C A N C E OF SENSORY I N F L O W TO T H E S W A L L O W I N G R E F L E X

A R T H U R J. MILLER

Department of Physiology, University of lllinois College of Medicine, School of Basic Medical Sciences, Chicago, Ill. 60612 (U.S.A.) (Accepted February 9th, 1972)

INTRODUCTION

Previous investigations of the complex time-locked sequence of muscular contractions of the buccopharyngeal component of swallowing have raised the question as to the importance of sensory input to this sequential order9,1~, 14,2°,55-57. Doty and Bosma 14 have mentioned that neither fixation of the hyoid bone at extreme positions, variation of the traction of the tongue, application of a local anesthetic to the pharyngeal mucosa, nor transection of different muscles affected the sequential pattern of swallowing in the 3 species studied. Filaretov and Filimonova 20 supported these findings demonstrating that motor fibers to the sternohyoid and thyrohyoid muscles continued to demonstrate rhythmic firing after motor paralysis, initiated with succinylcholine. Sumi reported 55 that, in the adult cat, single motoneurons of the nucleus ambiguus and hypoglossal nuclei did not change their discharge patterns after motor paralysis. Car and Roman 9 complemented these findings in the sheep demonstrating that stimulation of the frontal cortex continually evoked discharge patterns in the esophageal nerve branches after curarization of the animal. Investigations including aspiration or destruction of brain stem motor nuclei such as the motor trigeminaP 5 and hypoglossal nuclei 32, resulting in dysfunction of the denervated muscles, indicated no disruption of the sequence of contractions of other muscles still active in the reflex. Moreover, even though proprioceptors are present in joints, tendons, and muscles of the inframandibular regionZ-5,v,ag,zo,zs,27-29,33,46, 49, the classically studied muscle spindle afferent-gamma efferent control system has not been shown in muscles of the tongue, pharynx, and larynxl,S,20,33,39,45,47,4s,5s. Although much of the present data suggest a relative independence of the swallowing reflex from sensory inflow, the effects of a systematic and extensive deletion of sensory innervation on the complex sequence of muscular contraction has not been previously studied. This study applies, in particular, to both sensory and motor denervation at all anatomical levels of the reflex (i.e., tongue, supra- and infrahyoid regions, larynx, esophagus). This study includes recording from several muscles representative of the succeeding temporal phases of the swallow and the simultaneous recording of the discharge pattern of several cranial nerves. The importance of clarifying such a question is indicated in the recent work by Brain Research, 43 (1972) 147-159

148

A . J . MILLER

Ogura et al. 41, in which chronic unanesthetized dogs demonstrated serious impairment in normal swallowing with bilateral denervations of 3 cranial nerves, the hypoglossal, recurrent and superior laryngeal nerves. In addition, studies of individual electromyographic patterns of muscles contracting on materials of different consistency suggest proprioceptive or exteroceptive inputs can at least modify the EMG pattern n and possibly assist in determining the position of the bolus during succeeding stages of the swallow as suggested in human studies of abnormal swallowing al. METHODS

Experiments were conducted in 17 acutely prepared animals with partial denervations in 9 more animals. Following anesthetization with urethane, a tracheotomy was performed and artificial ventilation was administered during those procedures in which the animal was paralyzed with Flaxedil. Following intubation, a 3-5 cm ventral midline incision of the neck was made, the needed nerves exposed and placed on bipolar silver wire recording electrodes (interpolar distance 3-4 ram), and kept in a warm mineral oil pool which was formed by raising and extending the skin around the incision. Electromyographic recordings were taken by inserting two electrodes of 38gauge enamelled copper wire, with a 25-gauge hypodermic needle into the mylohyoid, posterior intrinsic tongue muscles, thyrohyoid, cricothyroid, middle pharyngeal, and inferior pharyngeal constrictor muscles 6. Electrodes were placed after surgical exposure of the muscles and their anatomical positions were rechecked after sacrificing the animal. Latencies were measured from the onset of the first stimulus pulse to the onset of mylohyoid EMG activity. Onset latencies of succeedingly active muscles were compared to onset of the mylohyoid EMG. Both electroneurograms and electromyograms were led through Tektronix 122 preamplifiers to be further amplified and displayed on normal sweeps of the Tektronix 565 cathode ray oscilloscope. Permanent records were recorded by a 7-channel Ampex FM 1300 tape recorder. Swallowing was evoked by electrical stimulation of the internal laryngeal nerve or by water droplets placed on the root of the tongue or posterior wall of the pharynx. For electrical stimulation, monophasic square wave pulses were used with 0.1-0.2 msec durations, peak voltages of 0.2-16.0 V, and frequencies of 20-40/sec. Current was measured across a 1 kf2 resistor in series with the stimulating electrode. RESULTS

For analysis, the buccopharyngeal phase was divided into 4 time segments with each time segment including muscles with similar onset latencies in their EMG activity (Fig. 1). Muscles were selected for recording based on the work by Doty and Bosma i4. As their work indicates, the onset of swallowing begins with the onset of excitation in the mylohyoid muscle. Within 0-40 msec of onset of mylohyoid contraction, hereafter called 'time segment I', activity begins in several muscles of the soft palate, Brain Research, 43 (1972) 147-159

SWALLOWING

149

REFLEX

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Fig. 1. Schematic representation of temporal sequence of muscular activity during the buccopharyngeal component of swallowing (adapted from Doty and Bosma14). Average duration of electromyograms (400 msec) of representative muscles is depicted, and activity is indicated by height of line above baseline. Inhibition prior to and following the excitatory phase is indicated in those muscles with some background activity. Muscles are grouped according to the onset of their activity referenced to the leading muscle, the mylohyoid. Muscles with similar latencies are grouped in 'time segments I, II, III, and IV'. Temporal sequence based on studies in the dog.

tongue and pharynx. Succeeding muscles contract with specified latencies ranging f r o m 40 to 360 msec; as indicated in this illustration, certain muscles overlap in their activity and begin contracting within similar time segments (designated by the R o m a n numerals I, II, III, IV). The duration of individual muscle contractions varies f r o m 250 to 500 msec depending on the preparation, and the total duration of the swallowing reflex rarely exceeds 700-900 msec.

(1) Muscle denervations The first series o f experiments, which involved 6 animals, consisted o f serial denervations o f particular muscles active in the swallowing reflex. Before and after the denervations, electromyographic recordings were m o n i t o r e d f r o m participating

Brain Research, 43 (1972) 147-159

A.J. MILLER

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Fig. 2. Effects of selective muscle denervation on the temporal sequence of muscular contractions during the buccopharyngeal phase of swallowing. Time segments (i.e., I, II, III, IV) include muscles with similar latencies to the onset of their excitatory activity. One neurogram from the hypoglossal nerve is shown with muscles of time segment I. The onset of the swallow is depicted by the dotted line. Results are taken from 1 experiment which was repeated in 6 animals. Sequence of selective denervation varied with each experiment and involved 3-5 successive denervations. muscles and electroneurograms were recorded from appropriate cranial nerve branches. Although the order of denervation was purposefully varied in each animal, Fig. 2 illustrates a representative protocol. Electromyographic recordings were taken from 6 muscles and a neurograln from one nerve. Swallowing was evoked by stimulation of the internal laryngeal nerve at an intensity sufficient to elicit 2-3 swallows within a 10 sec period. As seen in the first control records, the mylohyoid muscle and posterior tongue muscles are in time segment I, as they are among the first muscles to contract after onset of internal laryngeal nerve stimulation. Characteristically, the onset of activity in the mylohyoid is considered as the beginning of the reflex. The second major period of the sequence, time segment II, which consists of muscles beginning to contract within 45-100 msec after the onset of mylohyoid activity, is represented by the thyrohyoid and cricothyroid muscles. Time segment III includes muscles that contract at 130-145 msec and is represented by the middle constrictor. Time segment IV represents muscles whose activity begins 330-360 msec after the onset of activity in the mylohyoid, as shown by the inferior constrictor. In this preparation, neurogram recordings were made from the hypoglossal nerve; the appearance of hypoglossal neural activity generally preceded the onset of the posterior tongue electromyogram by 5-15 msec. Following control recordings, bilateral denervation of certain muscles was carried out in a series of steps. The first muscle denervated was the inferior constrictor. The inferior constrictor, one of 3 pharyngeal constrictors, contracts late in the buccoBrain Research, 43 (1972) 147-159

151

S W A L L O W I N G REFLEX

pharyngeal phase and continues the peristalic-like contractions initiated by the superior and middle constrictors. In this recording activation of the muscle was depicted by marked inhibition, a frequent but less common finding than an increase in activity approximately 330 msec after onset of the swallow. Motor innervation to the inferior constrictor is carried by fibers of the external laryngeal nerve and recurrent laryngeal nerve. Care was taken to preserve the external laryngeal nerve branches to the cricothyroid muscle. Following the bilateral nerve sections, the internal laryngeal nerve was restimulated and activity was recorded in the remaining intact muscles and one nerve. Despite the loss of contraction in both inferior constrictors, the sequential activation in all other recorded muscles remained the same. The mylohyoid continued to initiate the swallow and succeeding muscles followed within their given time periods. The posterior tongue muscles were the second group to be denervated. The posterior tongue contracts relatively early in the buccopharyngeal phase (time segment I) and consists of an extremely large complex of muscles which contract almost simultaneously. The hypoglossal nerve was sectioned after it curved rostrally and proceeded below the geniohyoid into the posterior tongue region. The nerve was sectioned bilaterally which effectively deleted activity in the entire tongue. Despite the loss of tongue movement, particularly that of the posterior tongue which is normally active in the reflex, stimulation of the internal laryngeal nerve continued to elicit the same sequential firing pattern in the remaining intact muscles and in the hypoglossal nerve as had been recorded initially. The final deletion of activity in this particular preparation was placed in the middle of the sequence of the buccopharyngeal phase. A muscle in time segment II, the thyrohyoid, whose contraction begins 45-100 msec after that of the mylohyoid, was bilaterally denervated. Stimulation of the internal laryngeal nerve continued to elicit sequential muscle contractions with the mylohyoid initiating the buccopharyngeal phase (time segment I), the cricothyroid still following the mylohyoid within the time segment II range of 40-100 msec, and the middle constrictor contracting within the third time segment of 130-145 msec. Although the procedure of denervations varied with each animal, recordings from the nerves and intact muscles exhibited results similar to those depicted in Fig. 2. The results were similar in all 6 cats regardless of the order of deletions or the temporal position of the particular muscles in the sequence.

(2) Muscle and mucosal denervation with gallamine paralysis In addition to the preceding selective denervations, other more extensive alterations of sensory inflow were carried out. Procedures varied in each of 7 animals but included combinations of extensive bilateral denervations of muscles active in swallowing, anesthesia of the oropharyngeal mucosa by a topically applied long-lasting anesthetic, and motor paralysis with the administration of Flaxedil. As indicated in Figs. 3 and 4, potential proprioceptive sensory inflow can proceed from at least 7 regions of the head and neck. The exteroceptive sensory input

Brain Research, 43 (1972) 147-159

152

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MILLER

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Fig. 3. Block diagram indicating potential proprioceptive and exteroceptive sensory inputs from anatomical regions active during swallowing. Innervation of particular muscles, joints, and mucosal regions and the central projections of primary afferent fibers are based on previous anatomical and physiological studies. Nerves which induce swallowing when stimulated are indicated by an arrowed s. In those experiments involving denervations of sensory input, solid black slanted lines indicate which nerves are sectioned, and dotted slanted lines indicate which sensory nerves are affected by mucosal anesthesia. Sensory input from the stylohyoid muscle, innervated by the facial nerve, is not shown; im nerve sections were carried out with this nerve. evoking swallowing in the cat is from peripheral receptive fields innervated by the trigeminal, glossopharyngeal, and vagal nerves25,37,zs,4z, 53. In the cat the most responsive areas 37 are the posterior wall and roof of the pharynx innervated by the glossopharyngeal nerve16, 31,44, and the region lateral and ventral to the base of the epiglottis innervated by the internal laryngeal nerve (internal branch of the superior laryngeal nerve)SL In contrast, stimulation of the soft palate and roof of the oral cavity, innervated by the trigeminal nerve, is relatively ineffective in inducing swallowing 87. Mapping the entire laryngeal mucosa innervated by the internal laryngeal and recurrent laryngeal nerves indicates that the glottis is the most effective site for eliciting the swallow 53. Total peripheral inflow proceeds through 4 cranial nerves as well as the dorsal roots of the first 3 cervical segments. Synaptic connections of sensory primary afferent fibers of the peripheral inputs have been recently postulated a4-a6. Pathways of motor output and involved motor nuclei are based on findings of active muscles in the reflex 14 as well as on single unit studies of certain cranial nerves active during swallowing 54-57. Swallowing was evoked by stimulating the internal laryngeal nerve with abovethreshold intensities for 5-15 sec periods and recordings were made from 2 to 3 muscles and 3-4 nerves in each animal. Latencies were averaged for 3-8 trials. Typical results are demonstrated by the animal illustrated in Fig. 5.

Brain Research, 43 (1972) 147-159

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Fig. 4. Block diagram indicating motor output of the swallowing reflex. Motor nuclei activated by the interneuronal system are indicated and muscles which contract during the buccopharyngeal phase are shown in their anatomical region. Muscles recorded from during this experimental study are preceded by an asterisk. Those muscles active during the first 0-40 msec of the swallow are indicated by a Roman numeral I. Nerves sectioned in the denervation series of experiments are indicated by solid black slanted lines. In this particular experiment, one electromyogram was recorded from the mylohyoid muscle, the leading active muscle in the swallow, and 3 neurograms were taken from the hypoglossal, cervical vagus, and recurrent nerves. The hypoglossal nerve contains motor fibers to the tongue muscles and has been shown to contain some sensory fibers21,4°, 50. The recurrent nerve contains motor fibers to some of the esophageal muscles, the inferior pharyngeal constrictor, and all of the laryngeal intrinsic muscles except the cricothyroid3,22, 39. The recurrent nerve also contains sensory fibers some of which innervate the laryngeal mucosa below the vocal cords. The cervical vagus contains fibers incorporated into the recurrent nervOV, 18 as well as additional motor and sensory fibers to the esophagus and trachea4,Z4A 2. Control records indicate that the hypoglossal unit activity can precede or follow the mylohyoid muscular activity with a range of - - 2 0 to %-10 msec (Fig. 5A1). Activity in the cervical vagus follows the onset of hypoglossal activity within 5060 msec and follows the ortset of mylohyoid muscular activity within 30-70 msec. The recurrent nerve shows corresponding latencies of 55-63 and 35-74 msec. In this particular preparation, Flaxedil was administered immediately after the control records and the remaining procedures were conducted during motor paralysis. In 4 of the animals, extensive denervations and mucosal anesthesia preceded the Flaxedil with results similar to those represented by this animal. After motor paralysis was complete, the internal laryngeal nerve was stimulated and recordings shown in Fig. 5A2 were made. Despite the loss of reflex movement, indicated by the flat base BraOz Research, 43 (1972) 147-159

154

A.J. MILLER EFFECT

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Fig. 5. The effects of extensive denervation on the sequential patterning of activity during the buccopharyngeal phase of swallowing. One electromyogram is recorded from the leading muscle, the mylohyoid; neurograms are recorded from 3 cranial nerves innervating muscles which contract in time sequences I, II, III, IV during swallowing (see summary diagram, Fig. 1). All recordings, except for the initial traces (A1) were made during neuromuscular paralysis. Experimental procedure is completed in one animal representative of results noted in 7 experiments.

line of the electromyogram, the neurograms o f the hypoglossal, cervical vagus and recurrent nerves continued to show the same patterns of activity as had been initially demonstrated in the control recordings. While paralysis was still evident as indicated by the lack of visible movement and the loss of the electromyogram, light touch and/or drops of water were applied to the dorsal surface of the tongue, stimuli sufficient to induce swallowing in the nonparalyzed animal (Fig. 5B1). Again, the pattern of neuronal activity did not vary from the control and the latencies o f the cervical vagus and recurrent nerve responses were similar to control values. Similar results were recorded in the sequential activity of the electromyograms of preparations not under paralysis in which natural stimuli evoked the entire complex reflex. While still paralyzed, a topical long-lasting anesthetic was applied to the oropharyngeal mucosa following subcutaneous administration of atropine (0.6 mg/kg) to decrease salivation. Subsequent natural stimulation no longer elicited a swallowing reflex discharge in the neurograms which indicated mucosal anesthesia (Fig. 5B2). However, stimulation of the internal laryngeal nerve continued to induce neuronal activity similar to the control records with latencies of 53-63 msec Brain Research, 43 (1972) 147-159

SWALLOWING REFLEX

155

in the cervical vagus and 57-67 msec in the recurrent nerve to the onset of activity in the hypoglossal nerve (Fig. 5C1). While still under motor paralysis and mucosal anesthesia, an extensive bilateral denervation was completed in this representative animal. The purpose of this denervation was to alter both motor output and sensory input from those muscles, joints and mucosal areas concerned with swallowing. The order of denervation varied with individual preparations but included the nerves indicated in Figs. 3 and 4. Three of the 4 suprahyoid muscles which cause the rostral movement of the hyoid bone early in swallowing were denervated by sectioning a branch of the inferior alveolar nerve and the branches of the ventral rami to these muscles. The action of all 4 infrahyoid muscles, which normally move the hyoid bone caudally after its previous rostral movement, was deleted by cutting branches of the ventral rami of the first 3 cervical nerves. One of the 3 pharyngeal constrictors, the inferior constrictor, was denervated, as well as all of the laryngeal intrinsic muscles active in glottic closure during the latter stages of the swallow, by sectioning the external laryngeal and recurrent nerves. Sectioning of the cervical vagus effectively eliminated activity in the esophageal skeletal muscles. Cutaneous input from 2 of 3 nerves known to elicit swallowing was also excluded by bilaterally sectioning the internal laryngeal and glossopharyngeal nerves. The internal laryngeal nerve is sensory to the laryngeal pharynx and the mucosa above the vocal cords while the glossopharyngeal nerve innervates the remainder of the pharynx to the level of the nasal pharynx. Sectioning of these two nerves, combined with sensory deletion of the mucosa innervated by mandibular and maxillary nerve branches with topical application of a long-lasting anesthetic, effectively denervated the mucosal areas from which swallowing was most readily elicited. These nerve sections combined with mucosal anesthesia deleted or altered sensory input from essentially all sources of proprioceptive and mucosal input associated with swallowing. Despite this extensive alteration, stimulation of the internal laryngeal nerve still evoked the same pattern of responses in the recorded neurograms as had been obtained in the original control recordings (Fig. 5C2). DISCUSSION

These results represent the first comprehensive demonstration that the persistent motor pattern of active muscles in swallowing does not depend on tonic peripheral sensory inflow. These data indicate that the buccopharyngeal component of the swallowing reflex proceeds despite alterations in the motor output to most of the active muscles, despite deletions of sensory input from the majority of muscles and joints active during swallowing, and after almost complete elimination of mucosal input from the oropharyngeal and laryngeal regions known to evoke swallowing. It demonstrates that in the anesthetized animal the reflexively elicited swallow need not depend on continued proprioceptive and exteroceptive input and suggests further study of individual muscle E M G and tension patterns following modification and alteration at successive anatomical levels of the swallow. It confirms previous suggesBrain Research, 43 (1972) 147-159

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h.J. MILLFR

tions that the patterned peripheral input, demonstrated in the optimum frequencies of electrical stimulation of the internal laryngeal nerve which evokes swallowing12,35, 36, 'triggers' the central nervous system to respond with a stereotyped motor output over a designated time span. When these specific sensory nerve fibers discharge in particular patterns adequate to initiate the swallow, the central neural control initiates the sequential motor response in the pertinent muscles regardless of their position, present activity, or possible sensory feedback. These findings suggest that swallowing, which is an example of a mammalian reflex organized at the brain stem leve11°,l~,3"%3a,37, consists of a 'prewired network' of neurons which control the activity of at least 8 cranial motor nuclei and motoneurons of the first 3 cervical ventral horns. Such an 'interneuronal center' could be a characteristic organization of the reticular formation at this level of the CNS and exist for brain stem control of reflexes involving a synergy of muscles of the head and neck region. Certain properties, possibly inherent in such organization which would separate swallowing from such classically studied reflexes as the flexion of the hind limb, include particular patterns of sensory input over specific nerves triggering a group of interneurons with a common threshold, a threshold level below which the interneurons as a group or center are inadequately excited, and the consistent stereotyped activation of motor nuclei anatomically situated over an extensive rostrocaudal axis by these interneurons when threshold is attained. Evidence of such complex networks have been obtained in invertebrates such as the mollusk in which an entire network of mutually interacting neurons possesses a threshold of excitability before it becomes active, and its threshold is different from that for any one cell59. In addition, command interneurons of the crayfish cord, when stimulated at certain frequencies, have been shown to sequentially coordinate activity of many motoneurons 26,a°. Such evidence in lower animals of neural networks which possess properties similar to that of swallowing's central control suggests further study of the swallowing reflex as a model of a complex mammalian nervous system organization at the brain stem level evoking certain patterned responses with specific patterned inputs. More importantly, such conceptual analysis of this reflex can be useful in understanding how to modify the central neural control of swallowing, how relevant sensory input facilitates or modifies this form of central control, and lead to further understanding of swallowing's interaction with other reflexes and motor responses organized at this level of the central nervous system; subject areas related to clinical applications and techniques in the pathology of the swallow. SUMMARY

These results indicate that selected denervation of muscles active during the buccopharyngeal phase of swallowing in the cat will not alter the sequence of electromyographic activity in the remaining active muscles. In addition, electroneurograms of 3 cranial nerves active during swallowing, the hypoglossal, vagus and recurrent, indicate the sequence of their activity remains intact despite extensive alteration of exteroceptive input from the oro-pharyngo-laryngeal mucosa, denervation of the Brain Research, 43 (1972) 147-159

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tongue, s u p r a h y o i d , i n f r a h y o i d , laryngeal, a n d e s o p h a g e a l regions, a n d the i n i t i a t i o n o f m o t o r paralysis. These d a t a suggest t h a t tonic p e r i p h e r a l inflow, either f r o m m u c o s a l surfaces e v o k i n g swallowing, or f r o m muscles a n d j o i n t s active d u r i n g the b u c c o p h a r y n g e a l phase is n o t essential to the sequence o f over 20 muscles o f the head a n d neck region c o n t r a c t i n g d u r i n g swallowing. The results suggest that this b r a i n stem reflex is pred o m i n a n t l y c o n t r o l l e d by a ' p r e w i r e d n e t w o r k ' o f n e u r o n s which activate several b r a i n stem a n d spinal c o r d m o t o n e u r o n a l p o o l s when ' t r i g g e r e d ' b y p a t t e r n e d p e r i p h eral input. ACKNOWLEDGEMENTS The a u t h o r wishes to t h a n k Dr. Jennifer S. B u c h w a l d whose g u i d a n c e a n d assistance were essential t h r o u g h all phases o f this work. W o r k was c o m p l e t e d while a p r e d o c t o r a l trainee o f the Brain R e s e a r c h Institute a n d the D e p a r t m e n t o f Physiology, U n i v e r s i t y o f California, Los Angeles.

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