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Algorithms↗
Biomedical subjects
D Paydarfar
Publications and source records attributed to D Paydarfar.
High strength stimulation of the vagus nerve in awake humans: a lack of cardiorespiratory effects.
UNLABELLED: Vagus nerve stimulation is used to reduce the frequency and intensity of seizures in patients with epilepsy. In the present study four such patients were studied while awake. We analyzed the physiological responses to vagus nerve stimulation over a broad range of tolerable stimulus parameters to identify vagal A-fiber threshold and to induce respiratory responses typical of C-fiber activation. A-fiber threshold was determined by increasing stimulation current until laryngeal motor A-fibers were excited (frequency=30 Hz). With A-fiber threshold established, C-fiber excitation was attempted with physiologically appropriate stimulus parameters (low frequency and high amplitude). RESULTS: A-fiber thresholds were established in all patients, threshold currents ranged between 0.5 and 1.5 mA. Stimulation at lower frequency (2-10 Hz) and higher amplitudes (2.75-3.75 mA) did not produce cardiorespiratory effects consistent with C-fiber activation. It is possible that such effects were not observed because vagal C-fibers were not excited, because C-fiber effects were masked by the 'wakeful drive' to breathe, or because epilepsy or the associated therapy had altered central processing of the vagal afferent inputs.
Adult↗
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.
Aged↗
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.
Adult↗
Phase resetting of the respiratory oscillator by carotid sinus nerve stimulation in cats.
1. Stimulation of the carotid sinus nerve causes an increase in inspiratory (I) and expiratory (E) neural activities. If central respiratory oscillation is generated by an attractor-cycle process, an increase in its activity can be caused by a centrifugal perturbation of state. We evaluated this hypothesis by comparing the respiratory oscillator's phase responses to carotid sinus nerve stimulations in cats to the phase responses of an attractor-cycle oscillator, the Bonhoeffer-van der Pol (BvP) equations, subjected to centrifugal perturbations. 2. We recorded phrenic activity in seven anaesthetized, vagotomized, glomectomized, paralysed and servo-ventilated cats. Carotid sinus nerve (CSN) stimulation with 0.5-0.8 s electrical pulse trains increased the immediate cycle period and delayed the onset of breaths after stimulation in a highly predictable manner, with the exception that strong stimuli (25 Hz, 0.25-0.90 V) caused unpredictable responses when given at the I-E or the E-I transitions. The resetting plots exhibited focal gaps corresponding to these unpredictable responses, and the size of the gaps increased with increases in the strength of CSN stimulation. Type 0 resetting was not achieved despite the large perturbations in rhythm induced by CSN stimulation. 3. Centrifugal perturbations of the BvP oscillator resulted in phase responses which were similar to those found in the animal experiments. The BvP cycle had two critical phases at which phase resetting was highly irregular and neighbouring state trajectories were highly divergent. The resetting plots had focal gaps that increased in size with increases in the strength of perturbation. The gaps did not represent true discontinuity because at higher computational resolution the resetting plots appeared to be steep but smooth portions of topological Type 1 resetting curves. 4. These studies support the concept that brief carotid sinus nerve stimulations cause a transient outward displacement of the central respiratory state away from its attractor cycle, in contrast to the unidirectional displacements that accompany midbrain reticular or superior laryngeal nerve stimulations. The findings define particular geometrical relationships between oscillatory state trajectories of the rhythm generator and perturbed state trajectories induced by inputs to the oscillator. These relationships provide a framework for developing and testing the validity of neural models of the respiratory oscillator.
Animals↗
Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-1997. A 50-year-old woman with multiple sclerosis and an enlarging frontal-lobe mass.
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Astrocytoma↗
Sporadic apnea: paradoxical transformation to eupnea by perturbations that inhibit inspiration.
We speculate that sporadic apneas may be initiated and terminated by stochastic neural perturbations arising within or impinging upon the respiratory oscillator. A curious situation can then arise in which tiny perturbations that inhibit inspiration, paradoxically stimulate breathing. The plausibility of the hypothesis is supported by numerical analysis of a noisy attractor-cycle oscillator, and in studies of a preterm sleeping infant with sporadic apnea; low-level vibratory stimulation transformed the irregular apneic rhythm to eupnea.
Female↗
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)
Adult↗
Effect of mental activity on breathing in congenital central hypoventilation syndrome.
Congenital central hypoventilation syndrome (CCHS) is associated with hypoventilation during sleep, but breathing can be adequate during wakefulness. It has been assumed that in awake CCHS patients breathing is activated by the forebrain, even voluntarily (i.e. Ondine's Curse). We tested whether or not an abnormal breathing pattern can be provoked by intense mental concentration in CCHS patients as this would be expected to disturb any voluntary control over breathing if present. Breathing (inductance plethysmography), end-tidal PCO2) (PETCO2), arterial oxygen saturation (SaO2) and EEG were measured in 5 children with CCHS (aged 8-17 years) and 5 controls during 5 min periods while resting; reading; performing mental arithmetic and playing a hand-held "Nintendo" game. There were no significant differences between controls and CCHS (unpaired t-tests, P > 0.05) in mean breath duration, tidal volume, ventilation, SaO2 or PETCO2 during REST or the conditions of mental stimulation. Both groups increased ventilation during mental stimulation. Respiratory variability was not greater in CCHS in any condition. These data provide indirect evidence that CCHS patients do not require voluntary activation of every breath (they do not have Ondine's Curse) and suggest that mental concentration might stimulate the respiratory complex as part of a generalised CNS arousal.
Adolescent↗
Neural respiratory responses to cortically induced seizures in cats.
Seizure activity can lead to profound respiratory stimulation in spontaneously breathing animals with intact respiratory feedback mechanisms (Paydarfar et al., Am. J. Physiol. 260, R934, 1991). The present study was designed to test the hypothesis that peripheral respiratory feedback mechanisms are not important for the genesis of seizure-induced hyperpnea. Studies were performed in 16 anesthetized, vagotomized, glomectomized cats whose end-tidal PCO2 (PETCO2) was kept constant. Integrated phrenic nerve activity was used to represent respiration. Seizures were induced by injection of penicillin into the parietal cortex and electrocorticographic (ECoG) and biceps femoris nerve activities, arterial pressure, airway PCO2 and brain temperature were recorded continuously. Progressive seizure activity was associated with progressive increases of respiratory frequency and peak phrenic activity, despite constancy of PETCO2 and brain temperature. Patterns of entrainment were identified among ECoG spikes, biceps femoris nerve and phrenic nerve activities. Phrenic nerve activity became highly irregular during generalized ictal seizures and ceased to respond to changes of PETCO2. Acute intercollicular decerebration in all experiments resulted in normalization of respiratory rhythm even while ictal ECoG activity continued. We conclude that stimulation of breathing during seizures occurs in the absence of respiratory feedback mechanisms. The findings suggest that an important cause of the respiratory response is a feedforward mechanism, whereby activation of subcortical structures above medulla and pons results in stimulation of breathing.
Animals↗
Respiratory responses to focal and generalized seizures in cats.
We studied the effects on breathing of seizures induced by focal injection of penicillin G into the parietal cortex in 13 anesthetized cats. Electrocorticograms, ventilation, end-tidal PCO2, and intrapleural and arterial pressures were monitored; changes of these variables were related to the stages of motor seizure. The first respiratory responses, tachypnea and hyperpnea, usually occurred before any peripheral muscular contractions developed. Progression of the seizure was always accompanied by further tachypnea and hyperpnea. The hyperpnea associated with all stages of seizure activity resulted in hypocapnia, which was sustained even during prolonged tonic-clonic motor convulsions that caused a threefold increase of metabolic rate. The extreme tachypnea of tonic generalized convulsions led to increased end-expiratory lung volume because of dynamic hyperinflation associated with very short expiratory durations in the tonic phase. We suggest that the profound effects of seizures on respiration are by feedforward mechanisms from the cortical focus itself and from subcortical circuits, such as hypothalamus, that become involved during seizure propagation and generalization. Peripheral respiratory feedback mechanisms are not important for the genesis of seizure-induced hyperpnea.
Animals↗
Effects of electric fields on fibroblast contractility and cytoskeleton.
We used silicone rubber substrata and fluorescent staining of cytoskeletal components to study the mechanisms by which electrical voltage gradients cause reorientation of embryonic chick fibroblasts in tissue culture. No evidence was found for a direct stimulation of cell contractility, either parallel or perpendicular to the voltage gradient. Instead, there was a gradual weakening in cell contractility in the axis parallel to this gradient, accompanied by progressive retraction of lamellae oriented along this axis, apparently due to selective weakening of cell-substratum adhesions. The cells then elongated perpendicular to the electric field, and strengthened their contractility in that axis. Fluorescence microscopy showed that cytoplasmic actin stress fibers and microtubules oriented perpendicular to the imposed voltage gradient. Many more cases were observed in which cell morphology had reoriented, but the actin fibers had not, as compared to the converse (cytoskeleton oriented, but no morphology). This disparity further supports the interpretation that the redirection of cell contractility is a consequence of morphological reorientation, rather than its cause. We also studied the effects of reversing the polarity of the electric fields at constant intervals (of as long as 1 minute). Fibroblasts failed to orient in response to such alternating fields, even after long exposure, but these same cells did reorient in response to pulsed currents in a consistent direction separated by "rest periods" (with no current). This combination of results is more consistent with an electrophoretic mechanism than with one depending on voltage-induced changes in membrane permeabilities.
Actins↗
Herpes simplex labialis and trigeminal neuropathy.
Three patients had a transient trigeminal sensory disturbance associated with an ipsilateral herpes simplex (HS) labialis lesion. These cases support the theory that isolated trigeminal sensory disturbance may be caused by intermittent reactivation of HS virus in the trigeminal ganglion.
Adult↗
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.
Adenosine↗
Desynchronized respiratory rhythms and their interactions in cats with split brain stems.
1. The effects on activities and rhythms of the two opposing phrenic nerves (C5 roots) of mid-line sagittal splitting of the medulla were determined in anaesthetized or decorticate, vagotomized, paralysed and ventilated cats. 2. Splitting the medulla above the obex led to marked decreases of phrenic activity on both sides, but no desynchronization of the two phrenic rhythms occurred. Further splitting to more than 3 mm below the obex led to desynchronized phrenic rhythms in fourteen of the fifteen animals that survived the necessary surgery, although it was often necessary to increase respiratory drive by means of hypercapnia, stimulatory drugs or electrical stimulation of the mesencephalon to cause the rhythms to occur. 3. When only the brain stem had been split, the two desynchronized rhythms showed interactions that led to modulations of amplitude of phrenic bursts, both being larger when in phase than when out of phase. In addition each side modulated the rhythm of the opposite side, demonstrating a 'magnet' effect. 4. Both types of modulation were eliminated after additional splitting of the spinal cord at the level (C5-C6) of the phrenic motoneurone pools. 5. Potential explanations for the amplitude modulations include cross-over of activity from one phrenic motoneurone pool to the opposite side and cross-over from the medulla of one side to the opposite phrenic motoneurone pool at the phrenic level. 6. Since the rhythm generators were independent in our preparation and located in the split halves of the medulla and since peripheral sensory feed-back was not important in these paralysed animals, we propose that the phase modulations must be due to a corollary discharge, an afferent feed-back driven by phrenic motoneurone activity that crosses the mid-line at C5-C6, ascends to the brain and affects respiratory rhythm in the opposite medullary half.
Animals↗
Phase resetting of respiratory rhythm: effect of changing respiratory "drive".
We studied the effect of changing drive on resetting of respiratory rhythm in anesthetized cats and in a model (Van der Pol) of a limit-cycle oscillator. In cats, rhythm was perturbed by brief mesencephalic stimuli. Stimulus time in the cycle (old phases) and times of onset of rescheduled breaths (cophases) were measured. Previous study [Paydarfar and Eldridge, Am. J. Physiol. 252 (Regulatory Integrative Comp. Physiol. 21): R55-R62, 1987] showed distinct types of phase resetting that depended on strength of stimuli. In this study, stimulus strength was kept constant, but respiratory drive was changed by increasing PCO2, by stimulating carotid sinus nerve, or by cooling intermediate areas of ventral medulla. Type 0 (strong) resetting occurred when respiratory drive was low, type 1 (weak) resetting when drive was high, and a phase singularity when drive was intermediate. Phase-resetting patterns generated by the model showed the same behavior when a drive parameter was changed. The findings support the idea that continuous limit-cycle dynamics underlie generation of respiratory rhythm. Increased respiratory drive, by increasing size of the limit cycle, reduces functional effectiveness of the same perturbing stimulus in causing phase resetting.
Animals↗
Dynamics of medullary hydrogen ion and respiratory responses to square-wave change of arterial carbon dioxide in cats.
1. The dynamics of changes of medullary extracellular fluid (ECF) hydrogen ion concentration ([H+]) and respiration, measured as integrated phrenic nerve activity, were determined in anaesthetized, paralysed, vagotomized and glomectomized cats. ECF [H+] was measured directly by means of a small (2 mm diameter) glass pH electrode placed on the ventral surface of the medulla. The variables were measured continuously after a step change of arterial PCO2 produced by abruptly starting or stopping an infusion of hypercapnic fluid into the aortic arch. 2. Alteration of pH in the descending thoracic aorta at the onset or offset of infusion was complete within 1.5 s after the change began, indicating that it was nearly square wave in form. 3. In sixteen experiments, ECF [H+] began to fall within 2 s of offset of infusion, reflecting aortic-medullary circulation time. Thereafter, ECF [H+] decreased to a stable level over the next 5 min; the curve describing the decrease consisted of two exponential functions, one with a time constant (tau) of 9.5 +/- 0.6 s and a second with a tau of 53 +/- 3 s. 4. We interpret the findings at the offset of CO2 infusion in terms of CO2 wash-out from the medullary ECF. The slow function is associated with wash-out during stable medullary blood flow that develops after 1 min. The early fast function is associated with the decreasing medullary blood flow that occurs during the first minute after change from arterial hypercapnia to normocapnia. 5. We have estimated medullary blood flow using a mathematical model incorporating the two functions. The values obtained are consistent with those in the literature where other methods have been used. Changes of blood flow following the step change of CO2 are fairly rapid, half of the response occurring in 13 s. 6. The change of respiratory activity lags the change of stimulus expressed by [H+], throughout the recovery period and respiration requires up to 8 min to reach a stable level. We attribute this slow response to slow central neural respiratory dynamics, the respiratory after-discharge.
Action Potentials↗
Phase resetting and dysrhythmic responses of the respiratory oscillator.
This study explores resetting of respiratory rhythm by facilitatory perturbations. The midbrain reticular formation and periaqueductal gray matter were electrically stimulated to evoke facilitation of phrenic nerve activity in nine anesthetized, vagotomized, and glomectomized adult cats. The animals were paralyzed and servo-ventilated to keep end-tidal PCO2 constant. Brief midbrain stimuli were given at various times in the respiratory cycle and the times of onset of rescheduled breaths after stimulation were measured. A plot of phase resetting as a function of stimulus strength and time of delivery defined a helicoid surface. The axis of this helicoid identified a unique stimulus which, when given at the inspiratory-expiratory transition, resulted in unpredictable resetting of respiratory rhythm. This stimulus had a strength that was intermediate to that which identified types 1 and 0 resetting. In one experiment, the singular stimulus often initiated a breath having prolonged inspiratory activity; resumption of the normal rhythm was delayed significantly (P less than 0.01). We conclude that the dysrhythmias observed in this study represent the respiratory oscillator's phase singularity.
Animals↗