David Paydarfar

Respiratory phase resetting and airflow changes induced by swallowing in humans.

1. Relationships between the timing of respiration and deglutition were studied in thirty awake healthy subjects at rest. Deglutition was monitored by submental electromyography, pharyngeal manometry and videofluoroscopy. Respiration was recorded by measurement of oronasal airflow and chest wall movement. Three types of deglutition were studied: injected bolus swallows, spontaneous swallows, and visually cued swallows of boluses previously placed in the mouth. 2. The effect of each swallow on respiratory rhythm was characterized by measurement of cophase, defined as the interval between the onset of deglutitive submental EMG activity to the onset of subsequent rescheduled inspirations. Cophase was determined for swallows initiated at different phases of the respiratory cycle. In all subjects deglutition caused phase resetting of respiratory rhythm. Cophase was largest for swallows initiated near the the inspiratory‐expiratory (E‐I) transition and smallest for swallows initiated near the expiratory‐inspiratory (E‐I) transition. The pattern of respiratory resetting by deglutition was topologically classified as type 0. This pattern was shown for swallows induced by bolus injection or visual cue, and for spontaneous swallows. 3. The incidence of spontaneous deglutition was influenced by the position of the swallow in the respiratory cycle. Few spontaneous swallows were initiated near the E‐I transition whereas most occurred from late inspiration to mid‐expiration. 4. Deglutition caused an abrupt decrease in airflow leading to an interval of apnoea, followed by a period of expiration. The duration of deglutition apnoea for spontaneous swallows was shorter than that for 5 ml bolus swallows, and was unaffected by the respiratory phase of swallow initiation. The period of expiration after swallowing was longest for swallows initiated at the I‐E transition, and shortest for E‐I swallows. 5. The intervals between bolus injection and the onset of deglutition apnoea, and the timing of swallowing events, were not significantly altered by the phase in the respiratory cycle at which swallowing was exhibited. 6. To quantify the relationship between bolus flow and respiration, we determined the latencies between cessation of inspiratory airflow and arrival of the bolus at the larynx (alpha), and between laryngeal bolus departure and resumption of inspiratory airflow (delta). Both values were dependent upon the respiratory phase of swallowing. The lowest values for alpha and delta were found for early‐inspiratory and late‐expiratory swallows, respectively. 7. We conclude that swallowing causes respiratory phase resetting with a pattern that is characteristic of the strong perturbations of an attractor‐cycle oscillator.(ABSTRACT TRUNCATED AT 400 WORDS)

Sensory Regulation of Swallowing and Airway Protection: A Role for the Internal Superior Laryngeal Nerve in Humans

During swallowing, the airway is protected from aspiration of ingested material by brief closure of the larynx and cessation of breathing. Mechanoreceptors innervated by the internal branch of the superior laryngeal nerve (ISLN) are activated by swallowing, and connect to central neurones that generate swallowing, laryngeal closure and respiratory rhythm. This study was designed to evaluate the hypothesis that the ISLN afferent signal is necessary for normal deglutition and airway protection in humans. In 21 healthy adults, we recorded submental electromyograms, videofluoroscopic images of the upper airway, oronasal airflow and respiratory inductance plethysmography. In six subjects we also recorded pressures in the hypopharynx and upper oesophagus. We analysed swallows that followed a brief infusion (4–5 ml) of liquid barium onto the tongue, or a sip (1–18 ml) from a cup. In 16 subjects, the ISLN was anaesthetised by transcutaneous injection of bupivacaine into the paraglottic compartment. Saline injections using the identical procedure were performed in six subjects. Endoscopy was used to evaluate upper airway anatomy, to confirm ISLN anaesthesia, and to visualise vocal cord movement and laryngeal closure. Comparisons of swallowing and breathing were made within subjects (anaesthetic or saline injection vs. control, i.e. no injection) and between subjects (anaesthetic injection vs. saline injection). In the non‐anaesthetised condition (saline injection, 174 swallows in six subjects; no injection, 522 swallows in 20 subjects), laryngeal penetration during swallowing was rare (1.4 %) and tracheal aspiration was never observed. During ISLN anaesthesia (16 subjects, 396 swallows), all subjects experienced effortful swallowing and an illusory globus sensation in the throat, and 15 subjects exhibited penetration of fluid into the larynx during swallowing. The incidence of laryngeal penetration in the anaesthetised condition was 43 % (P < 0.01, compared with either saline or no injection) and of these penetrations, 56 % led to tracheal aspiration (without adverse effects). We further analysed the swallow cycle to evaluate the mechanism(s) by which fluid entered the larynx. Laryngeal penetration was not caused by premature spillage of oral fluid into the hypopharynx, delayed clearance of fluid from the hypopharynx, or excessive hypopharyngeal pressure generated by swallowing. Furthermore, there was no impairment in the ability of swallowing to halt respiratory airflow during the period of pharyngeal bolus flow. Rather, our observations suggest that loss of airway protection was due to incomplete closure of the larynx during the pharyngeal phase of swallowing. In contrast to the insufficient closure during swallowing, laryngeal closure was robust during voluntary challenges with the Valsalva, Müller and cough manoeuvres under ISLN anaesthesia. We suggest that an afferent signal arising from the ISLN receptor field is necessary for normal deglutition, especially for providing feedback to central neural circuits that facilitate laryngeal closure during swallowing. The ISLN afferent signal is not essential for initiating and sequencing the swallow cycle, for co‐ordinating swallowing with breathing, or for closing the larynx during voluntary manoeuvres.

In vivo Magnetic Resonance Imaging and Surgical Histopathology of Intracardiac Masses: Distinct Features of Subacute Thrombi

We evaluated intracardiac masses in vivo, in situ and histologically to determine tissue properties revealed by magnetic resonance (MR) imaging. In 15 consecutive patients scheduled for cardiotomy, the cardiac chambers were studied preoperatively with MR imaging and echocardiography. Visual examination of one or more chambers was performed during cardiotomy for mitral valve replacement, aneurysmectomy, atrial septal repair and atriotomy. Six thrombi (1 atrial appendage, 5 ventricular) and 2 atrial myxomas were removed and subjected to histological analysis. All masses were detected preoperatively by MR imaging. The smallest was a subacute 3-mm mural clot in the left ventricle and was undetected by transesophageal and transthoracic echocardiography. The 3 subacute clots had homogeneously low MR signals, did not enhance with gadolinium and exhibited magnetic susceptibility effects; histopathology confirmed these clots to be avascular and laden with dense iron deposition related to hemoglobin breakdown products. The 3 organized clots had intermediate and heterogeneous MR signals and multiple areas of gadolinium enhancement. The 2 myxomas had low MR signals and gadolinium enhancement in the core and septal attachment; these areas had dense neovascular channels. Subacute thrombi appear to have MR features that are distinct from organized thrombi and myxomas, and MR images of subacute thrombi contrast sharply with normal cardiac structures, enabling detection of thin mural clots that may be echographically occult. These findings may be of value, because a subacute clot may be more likely than an organized thrombus to give rise to an embolus.

Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy.

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.

Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation

Breathing patterns in preterm infants consist of highly variable interbreath intervals (IBIs) that might originate from nonlinear properties of the respiratory oscillator and its input-output responses to peripheral and central signals. Here, we explore a property of nonlinear control, the potential for large improvement in the stability of breathing using low-level exogenous stochastic stimulation. Stimulation was administered to 10 preterm infants (postconceptional age: mean 33.3 wk, SD 1.7) using a mattress with embedded actuators that delivered small stochastic displacements (0.021 mm root mean square, 0.090 mm maximum, 30-60 Hz); this stimulus was subthreshold for causing arousal from sleep to wakefulness or other detectable changes in the behavioral state evaluated with polysomnography. We used a test-retest protocol with multiple 10-min intervals of stimulation, each paired with 10-min intervals of no stimulation. Stimulation induced an approximately 50% reduction (P = 0.003) in the variance of IBIs and an approximately 50% reduction (P = 0.002) in the incidence of IBIs > 5 s. The improved stability of eupneic breathing was associated with an approximately 65% reduction (P = 0.04) in the duration of O(2) desaturation. Our findings suggest that nonlinear properties of the immature respiratory control system can be harnessed using afferent stimuli to stabilize eupneic breathing, thereby potentially reducing the incidence of apnea and hypoxia.

Role of endogenous adenosine in recurrent generalized seizures

We induced generalized seizures by cortical injection of penicillin in anesthetized, paralyzed cats. After they had developed recurrent ictal-interictal ECoG cycling and fictive tonic-clonic motor convulsions (status epilepticus), we studied the effect of systemically administered neuropharmacological agents on the seizure cycling. Antagonists of adenosine receptors, theophylline and 8-cyclopentyltheophylline, increased the cycle period due to marked prolongation of duration of ictal discharge, often to more than 30 min. Dipyridamole, an inhibitor of adenosine reuptake, lengthened the interictal phase of the seizure with no effect on ictal duration. Antagonists of gamma-aminobutyric acid and opioid peptides had no effect on either ictal or interictal phases nor did the nonspecific neural excitant, doxapram. These findings suggest that a major mechanism of ictal-interictal cycling during status epilepticus is the alternating accumulation during the ictal phase and clearance during the interictal phase of the inhibitory neurochemical, adenosine.

Dysrhythmias of the respiratory oscillator

Breathing is regulated by a central neural oscillator that produces rhythmic output to the respiratory muscles. Pathological disturbances in rhythm (dysrhythmias) are observed in the breathing pattern of children and adults with neurological and cardiopulmonary diseases. The mechanisms responsible for genesis of respiratory dysrhythmias are poorly understood. The present studies take a novel approach to this problem. The basic postulate is that the rhythm of the respiratory oscillator can be altered by a variety of stimuli. When the oscillator recovers its rhythm after such perturbations, its phase may be reset relative to the original rhythm. The amount of phase resetting is dependent upon stimulus parameters and the level of respiratory drive. The long-range hypothesis is that respiratory dysrhythmias can be induced by stimuli that impinge upon or arise within the respiratory oscillator with certain combinations of strength and timing relative to the respiratory cycle. Animal studies were performed in anesthetized or decerebrate preparations. Neural respiratory rhythmicity is represented by phrenic nerve activity, allowing use of open-loop experimental conditions which avoid negative chemical feedback associated with changes in ventilation.In animal experiments, respiratory dysrhythmias can be induced by stimuli having specific combinations of strength and timing. Newborn animals readily exhibit spontaneous dysrhythmias which become more prominent at lower respiratory drives. In human subjects, swallowing was studied as a physiological perturbation of respiratory rhythm, causing a pattern of phase resetting that is characterized topologically as type 0. Computational studies of the Bonhoeffer-van der Pol (BvP) equations, whose qualitative behavior is representative of many excitable systems, supports a unified interpretation of these experimental findings. Rhythmicity is observed when the BvP model exhibits recurrent periods of excitation alternating with refractory periods. The same system can be perturbed to a state in which amplitude of oscillation is attenuated or abolished. We have characterized critical perturbations which induce transitions between these two states, giving rise to patterns of dysrhythmic activity that are similar to those seen in the experiments. We illustrate the importance of noise in initiation and termination of rhythm, comparable to normal respiratory rhythm intermixed with spontaneous dysrhythmias. In the BvP system the incidence and duration of dysrhythmia is shown to be strongly influenced by the level of noise. These studies should lead to greater understanding of rhythmicity and integrative responses of the respiratory control system, and provide insight into disturbances in control mechanisms that cause apnea and aspiration in clinical disease states. (c) 1995 American Institute of Physics.

A simple modification of the Hodgkin and Huxley equations explains type 3 excitability in squid giant axons

The Hodgkin and Huxley (HH) model predicts sustained repetitive firing of nerve action potentials for a suprathreshold depolarizing current pulse for as long as the pulse is applied (type 2 excitability). Squid giant axons, the preparation for which the model was intended, fire only once at the beginning of the pulse (type 3 behaviour). This discrepancy between the theory and experiments can be removed by modifying a single parameter in the HH equations for the K+ current as determined from the analysis in this paper. K+ currents in general have been described by IK=gK(V−EK), where gK is the membranes K+ current conductance and EK is the K+ Nernst potential. However, IK has a nonlinear dependence on (V−EK) well described by the Goldman–Hodgkin–Katz equation that determines the voltage dependence of gK. This experimental finding is the basis for the modification in the HH equations describing type 3 behaviour. Our analysis may have broad significance given the use of IK=gK(V−EK) to describe K+ currents in a wide variety of biological preparations.

Design principles for phase-splitting behaviour of coupled cellular oscillators: Clues from hamsters with 'split' circadian rhythms

Nonlinear interactions among coupled cellular oscillators are likely to underlie a variety of complex rhythmic behaviours. Here we consider the case of one such behaviour, a doubling of rhythm frequency caused by the spontaneous splitting of a population of synchronized oscillators into two subgroups each oscillating in anti-phase (phase-splitting). An example of biological phase-splitting is the frequency doubling of the circadian locomotor rhythm in hamsters housed in constant light, in which the pacemaker in the suprachiasmatic nucleus (SCN) is reconfigured with its left and right halves oscillating in anti-phase. We apply the theory of coupled phase oscillators to show that stable phase-splitting requires the presence of negative coupling terms, through delayed and/or inhibitory interactions. We also find that the inclusion of real biological constraints (that the SCN contains a finite number of non-identical noisy oscillators) implies the existence of an underlying non-uniform network architecture, in which the population of oscillators must interact through at least two types of connections. We propose that a key design principle for the frequency doubling of a population of biological oscillators is inhomogeneity of oscillator coupling.

Developmental aspects of the upper airway: report from an NHLBI Workshop, March 5-6, 2009.

The upper airway serves three important functions: respiration, swallowing, and speech. During development it undergoes significant structural and functional changes that affect its size, shape, and mechanical properties. Abnormalities of the upper airway require prompt attention, because these often alter ventilatory patterns and gas exchange, particularly during sleep when upper airway motor tone and ventilatory drive are diminished. Recognizing the relationship of early life events to lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI), with cofunding from the Office of Rare Diseases (ORD), convened a workshop of extramural experts, from many disciplines. The objective of the workshop was: (1) to review the state of science in pediatric upper airway disorders; (2) to make recommendations to the Institute to fill knowledge gaps; (3) to prioritize new research directions; and (4) to capitalize on scientific opportunities. This report provides recommendations that could facilitate translation of basic research findings into practice to better diagnose, treat, and prevent airway compromise in children.