Biomedical subjects

James Duffin

Publications and source records attributed to James Duffin.

12 recordsLinked to original sources

PubMed2003

Connections between respiratory neurones in the neonatal rat transverse medullary slice studied with cross-correlation.

In the transverse medullary slice prepared from neonatal rats the hypoglossal nerve rootlets exhibit a bursting 'respiratory' rhythm as do neurones in the pre-Bötzinger complex (PBC). We used cross-correlation analysis of the rhythmic multiunit discharges recorded from hypoglossal nerve rootlets, hypoglossal nucleus neurones and PBC neurones to investigate the connections between these groups. All cross-correlograms computed between left and right hypoglossal nerves, and between hypoglossal neurones and contralateral hypoglossal nerves, displayed central peaks with broad half-amplitude widths (mean +/- S.D. of 29.6 +/- 10.4 and 37.3 +/- 6.0 ms, respectively), which we interpreted as evidence for activation from a common source. Five of the 18 cross-correlograms computed between left and right PBC neurones displayed peaks either side of time zero with narrower half-amplitude widths (mean +/- S.D. of 9.3 +/- 1.9 ms) superimposed on broader central peaks, which we interpreted as evidence for mutual excitation and common activation, respectively. Cross-correlograms computed between PBC neurones and contralateral hypoglossal neurones or nerves did not display consistent features, but some of those computed between PBC and ipsilateral hypoglossal neurones (two of eight) or nerves (two of five) displayed peaks with broad half-amplitude widths (mean +/- S.D. of 36.8 +/- 6.9 ms), offset from time zero by 6 ms (except for one at 18 ms), which we interpreted as evidence for excitation of hypoglossal neurones and motoneurones by PBC neurones. We concluded that rhythm is synchronised between left and right sides by mutual excitatory connections between left and right PBC neurones. The rhythm is transmitted to ipsilateral hypoglossal neurones by a paucisynaptic pathway. Both hypoglossal neurones and PBC neurones receive a common activation from as yet unidentified sources.

Animals↗

PubMed2003

Inhibitory connections among rostral medullary expiratory neurones detected with cross-correlation in the decerebrate rat.

Expiratory neurones, with a decrementing firing pattern during the first phase of expiration (E-DEC) and located in the rostral ventrolateral medulla, are thought to be involved in the network generating respiratory rhythm, which also includes expiratory neurones with augmenting firing patterns (E-AUG). We used cross-correlation to detect their synaptic interconnections and connections to phrenic motoneurones in 32 vagotomised, decerebrate, paralysed and ventilated male rats. Pairs of neurones were recorded extracellularly with glass-insulated tungsten microelectrodes and the whole phrenic nerve with bipolar silver wire electrodes. Of the 79 cross-correlograms computed between pairs of E-DEC neurones, 8 (approximately 10%) showed evidence for inhibitory connections. Of the 67 cross-correlograms computed between E-DEC and E-AUG neurones, 5 (7.5%) showed evidence for a monosynaptic inhibition of the E-AUG neurone by the E-DEC neurone, while 3 (4.5%) showed evidence for a monosynaptic inhibition of the E-DEC neurone by the E-AUG neurone. An inhibitory connection from E-DEC neurones to phrenic motoneurones was detected in 5 (approximately 2%) of the cross-correlograms, and from E-AUG neurones to phrenic motoneurones in 4 (approximately 3.7%). These results are the first demonstration that network models of rhythm generation in the rat involving reciprocal inhibition between E-DEC and E-AUG neurones could have a neurophysiological basis, and the first to demonstrate that phrenic motoneurones are inhibited during the early phase of expiration by E-DEC neurones.

Animals↗

PubMed2003

CO2 does not affect passive exercise ventilatory decline.

Breathing increases abruptly at the start of passive exercise, stimulated by afferent feedback from the moving limbs, and declines toward a steady-state hyperpnea as exercise continues. This decline has been attributed to decreased arterial CO2 levels and adaptation in afferent feedback; however, the relative importance of these two mechanisms is unknown. To address this issue, we compared ventilatory responses to 5 min of passive leg extension exercise performed on 10 awake human subjects (6 men and 4 women) in isocapnic and poikilocapnic conditions. End-tidal Pco2 decreased significantly during poikilocapnic (Delta = -1.5 +/- 0.5 Torr, P < 0.001), but not isocapnic, passive exercise. Despite this difference, the ventilatory responses to passive exercise were not different between the two conditions. Using the fast changes in ventilation at the start (5.46 +/- 0.40 l/min, P < 0.001) and end (3.72 +/- 0.33 l/min, P < 0.001) of passive exercise as measures of the drive to breathe from afferent feedback, we found a decline of 68%. We conclude that the decline in ventilation during passive exercise is due to an adaptation in the afferent feedback from the moving limbs, not a decline in CO2 levels.

Adolescent↗

PubMed2003

Adaptation in the respiratory control system.

Exposure to hypoxia, whether for short or prolonged periods or for repeated episodes, produces alterations in the ventilatory responses. This review presents evidence that these adaptations are likely to be mediated by adaptations in the respiratory chemoreflexes, particularly the peripheral chemoreflex, and proposes models of respiratory control explaining the observed changes in ventilation. After a brief introduction to the respiratory control system, a graphical model is developed that illustrates the operation of the system in the steady state, which will be used later. Next, the adaptations in ventilatory responses to hypoxia that have been observed are described, and methods of measuring the alterations in the chemoreflexes that might account for them are discussed. Finally, experimental data supporting the view that changes in the activity of the peripheral chemoreflex can account for the ventilatory adaptations to hypoxia are presented and incorporated into models of chemoreflex behaviour during exposures to hypoxia of various durations.

Adaptation, Physiological↗

PubMed2002

The respiratory effects of two modes of passive exercise.

We monitored gas exchange and muscle activity during two commonly used modes of passive leg exercise as a means of assessing the degree of passivity associated with these techniques. Additionally, we measured the rapid changes in ventilation at the start and end of the passive exercise to assess changes that occur in the fast exercise drive to breathe during passive exercise. We monitored seven subjects at rest and during 5 min of passive exercise using (1) cycling movements performed on a tandem bicycle and (2) leg extension movements performed in a chair apparatus. The increase in measured parameters from rest to passive exercise were all higher while using the tandem bicycle compared to the chair apparatus: ventilation [3.09 (0.63) versus 0.35 (0.38) l x min(-1)], leg muscle electromyogram [8.3 (1.6) versus 1.6 (0.6) microV], carbon dioxide production [0.092 (0.018) versus -0.002 (0.001) l x min(-1)] and oxygen consumption [0.158 (0.046) versus -0.008 (0.007) l x min(-1)]. Passive exercise on the tandem bicycle was also associated with a significantly larger fast exercise drive to breathe at both the start and end of motion, compared to the chair apparatus [start: 5.59 (0.74) versus 3.08 (0.79) l x min(-1), end: 3.38 (0.79) versus 1.75 (0.54) l x min(-1)]. The fast exercise drive to breathe at the end of exercise was significantly smaller (60%) than at the start for both modes. We conclude that passive exercise on an upright bicycle contains a significant active component that contributes both neural and metabolic influences toward the physiological adjustments observed. Furthermore, we conclude that adaptation occurs in the fast exercise drive to breathe accompanying passive limb movement.

Adult↗

PubMed2002

Changes in respiratory control after three hours of isocapnic hypoxia in humans.

Despite the obvious role of hypoxia in eliciting respiratory acclimatisation in humans, the function of the peripheral chemoreflex is uncertain. We investigated this uncertainty using 3 h of isocapnic hypoxia as a stimulus (end-tidal PCO2, 0.5-1.0 mmHg above eucapnia; end-tidal PO2, 50 mmHg), hypothesising that this stimulus would induce an enhancement of the peripheral chemoreflex ventilatory response to hypoxia. Current evidence conflicts as to whether this enhancement is mediated by an increase in the sensitivity or a decrease in the threshold of the peripheral chemoreflex ventilatory response to carbon dioxide. Employing a modified rebreathing technique to assess chemoreflex function, we found evidence of the latter in nine healthy volunteers (six male, three female). Testing consisted of pairs of isoxic rebreathing tests at high and low levels of oxygen, performed before, immediately after and 1 h after a 3 h isocapnic hypoxic exposure. No parameters changed significantly in the high-oxygen rebreathing tests. In the low-oxygen rebreathing tests there were no changes in non-chemoreflex ventilatory drives, or in the sensitivity to carbon dioxide, but the carbon dioxide response threshold decreased (approximately 1.5 mmHg) immediately after exposure, and the decrease persisted for 1 h (one-way repeated-measures ANOVA; P < 0.05). We repeated the protocol in five of the original nine volunteers, but this time exposing them to isocapnic normoxia. No trends or significant changes were observed in any of the rebreathing test parameters. These findings demonstrate that in the earliest stages of acclimatisation, there is a decrease in the threshold of the peripheral chemoreflex response to carbon dioxide, which persists for at least 1 h after the return to normoxia. We suggest that ventilatory acclimatisation to hypoxia results from this decreased threshold, reflecting an increase in the activity of the peripheral chemoreflex.

Acclimatization↗

PubMed2002

Central and peripheral chemoreflexes in panic disorder.

Klein (Arch Gen Psychiatry, 50, 1993, 306-317) has suggested that panic disorder patients have a false suffocation alarm that may be associated with a lowered threshold for carbon dioxide detection. We compared the thresholds and sensitivities of the central and peripheral chemoreflexes between panic disorder patients and age- and sex-matched healthy volunteers to test this aspect of the hypothesis. We used a modified version of Read's rebreathing technique in 11 panic disorder patients and 10 healthy volunteers to examine the peripheral and central chemoreflex characteristics in these two populations. Subjects were examined during three rebreathing tests: training, hyperoxic (central chemoreflex alone) and hypoxic (combined central and peripheral chemoreflex). Panic symptoms were retrospectively assessed between groups using a DSM-IV derived Panic Symptom Scale. Comparisons of panic disorder patients with agoraphobia and healthy volunteers showed no significant differences in sensitivities or thresholds. Klein's hypothesis is not supported by these data. If a false suffocation alarm exists, its triggering may not be implemented within the respiratory chemoreflexes.

Adult↗

PubMed2002

Effects of tryptophan depletion on central and peripheral chemoreflexes in man.

Klein (Arch. Gen. Psychiatry 50, 306-317, 1993) suggests that panic attacks are the result of a defective 'suffocation alarm' threshold that presents with carbon dioxide (CO(2)) hypersensitivity, exaggerated ventilatory response and panic in panic disorder (PD) patients. Serotonergic deficiencies enhance this ventilatory response in PD patients, as per 'suffocation alarm' theory predictions, suggesting that serotonin (5-HT) normalizes the ventilatory response. Other research supports a serotonin system-mediated stimulation of ventilation. Knowledge of 5-HT's role on ventilatory output and its neurophysiological sources impacts on the 'suffocation alarm' theory validity and predictive value. We used tryptophan depletion (TRP-) in concert with a modified Read rebreathing test to determine the effect of deficient serotonergic modulation on the central and peripheral chemoreflex threshold and sensitivity of response to CO(2) in 11 healthy men. TRP- did not affect central or peripheral chemoreflex threshold or sensitivity of response to CO(2). However, basal ventilation was significantly elevated during TRP-. In contrast to 'suffocation alarm' theory predictions, decreased 5-HT neurotransmission does not significantly affect the respiratory chemoreflex response to CO(2), impacting on non-chemoreflex drives to breathe. Panic associated respiratory abnormalities may be related to defective 5-HT modulation of non-chemoreflex drives to breathe, unrelated to any respiratory chemoreflex abnormality.

Adult↗

PubMed2002

Acetazolamide and respiratory chemosensitivity to CO(2) in the neonatal rat transverse medullary slice.

Hypoglossal nerve rootlets in the transverse medullary slice prepared from neonatal rats exhibit a bursting 'respiratory' rhythm that increases in frequency with CO(2), presumably due to activation of chemosensitive cells such as the central chemoreceptors. Carbonic anhydrase is associated with areas of central chemoreception and we propose a hypothesis for its involvement in the chemoreception process. We tested this hypothesis by blocking its activity with acetazolamide in six slice preparations. However, the addition of 1 mM acetazolamide dissolved in dimethyl sulphoxide to the superfusing bathing solution produced no alteration in the bursting frequency response of the slice to CO(2). We concluded that the chemoreception process producing the CO(2) response of the superfused, transverse medullary slice does not involve carbonic anhydrase.

Acetazolamide↗

PubMed2002

Caudal expiratory neurones in the rat.

The main source of expiratory drive to respiratory muscles in the rat is thought to be the caudal expiratory neurones. However, their projections to the spinal cord and the coordination of the population activity with the respiratory cycle are largely unknown. We examined their bulbospinal projections using antidromic activation, and the coordination of their activity using cross-correlation. Of 76 expiratory neurones examined, 40% projected to the C2 segment of the spinal cord, all unilaterally and all but 4 to the contralateral side. Thirteen contralateral axons were located in the ventromedial funiculus, when activation thresholds were less than 25 microA. For 29 neurones, the mean (+/- SEM) conduction velocity, calculated from the single-point activation and a measure of the direct distance between recording and stimulating electrodes, was 7.4 +/- 0.4 m/s. We calculated 88 cross-correlograms from ipsilateral pairs of expiratory neurones recorded on the same side of the medulla, and 176 contralateral pairs recorded from opposite sides of the medulla. All of the latter were featureless, but 23% of cross-correlograms for ipsilateral pairs displayed broad peaks at time zero, which we interpreted as due to activation of both neurones from a common source. We conclude that in the adult rat, approximately half of the caudal expiratory neurones project unilaterally and contralaterally to the spinal cord and, although common activation serves to coordinate some of the ipsilateral population, we suggest that neither common activation nor excitatory cross-connections exist as sufficient means for coordinating left and right populations to the same respiratory rhythm.

Animals↗

PubMed2002

Cerebral blood flow responses to changes in oxygen and carbon dioxide in humans.

This study characterized cerebral blood flow (CBF) responses in the middle cerebral artery to PCO2 ranging from 30 to 60 mmHg (1 mmHg = 133.322 Pa) during hypoxia (50 mmHg) and hyperoxia (200 mmHg). Eight subjects (25 +/- 3 years) underwent modified Read rebreathing tests in a background of constant hypoxia or hyperoxia. Mean cerebral blood velocity was measured using a transcranial Doppler ultrasound. Ventilation (VE), end-tidal PCO2 (PETCO2), and mean arterial blood pressure (MAP) data were also collected. CBF increased with rising PETCO2 at two rates, 1.63 +/- 0.21 and 2.75 +/- 0.27 cm x s(-1) x mmHg(-1) (p < 0.05) during hypoxic and 1.69 +/- 0.17 and 2.80 +/- 0.14 cm x s(-1) x mmHg(-1) (p < 0.05) during hyperoxic rebreathing. VE also increased at two rates (5.08 +/- 0.67 and 10.89 +/- 2.55 L min(-1) m mHg(-1) and 3.31 +/- 0.50 and 7.86 +/- 1.43 L x min(-1) x mmHg(-1)) during hypoxic and hyperoxic rebreathing. MAP and PETCO2 increased linearly during both hypoxic and hyperoxic rebreathing. The breakpoint separating the two-component rise in CBF (42.92 +/- 1.29 and 49.00 +/- 1.56 mmHg CO2 during hypoxic and hyperoxic rebreathing) was likely not due to PCO2 or perfusion pressure, since PETCO2 and MAP increased linearly, but it may be related to VE, since both CBF and VE exhibited similar responses, suggesting that the two responses may be regulated by a common neural linkage.

Adult↗

PubMed2001

Bilateral coordination of inspiratory neurones in the rat.

Inspiratory activity on the left and right sides must be coordinated to be effective. We used cross-correlation to examine the hypothesis that the coordination of left and right medullary inspiratory neurones is produced by excitation from common sources and by midline-crossing excitatory connections among these neurones. In adult rats, a total of 185 contralateral pairs of inspiratory neurones ( n=370) were recorded extracellularly, and classified, according to their firing pattern, as augmenting ( n=262), constant ( n=82) or decrementing ( n=26). Of the 262 augmenting inspiratory neurones, 98 were classified as phrenic premotor neurones by cross-correlation with phrenic nerve discharge. The 185 cross-correlograms showed little evidence of common activation, or midline-crossing excitatory connections. Of the 45 cross-correlograms for pairs of augmenting neurones, only 4 (approximately equal to 9%) indicated a common activation, and only one a monosynaptic connection. Of the 45 for pairs of augmenting and phrenic premotor neurones, only 9 (20%) showed a common activation, and only 2 a monosynaptic excitatory connection. Of the 19 pairs of phrenic premotor neurones, 5 from the same rat showed high-frequency oscillations, and 1 a monosynaptic excitatory connection. Cross-correlograms for pair combinations of other types of neurones also exhibited few features. We suggest that, in the adult rat, although both common activation and excitatory cross-connections exist as a means for coordinating left and right ventral group inspiratory neurones to the same respiratory rhythm, they are insufficient to account for it.

Animals↗