Search PubMed⌕ Search

Biomedical subjects

T A Sears

Publications and source records attributed to T A Sears.

At least 55 records · Page 3Linked to original sources
PubMed1982

Variations in the time course of the synchronization of intercostal motoneurones in the cat.

1. Synchronization of intercostal motoneurones was studied by the construction of cross-correlation histograms which related the firing times of paired groups of efferent inspiratory or expiratory discharges recorded from filaments of the external or internal nerves of anaesthetized or decerebrate cats.2. The principal feature of the histograms was always a central peak but the time course of the central peak showed considerable variation. Three forms of synchronization were defined on the basis of the time course of the central peak: (i) short-term synchronization (Sears & Stagg, 1976), where the peak was narrow, extending over about +/-3 ms but sometimes with weak shoulders to about +/-5 ms; (ii) broad-peak synchronization where the peak was wider than this (often +/-20 ms or more) but where there were no strong periodicities; (iii) high-frequency oscillation (h.f.o) synchronization, which was named from the related phenomena in medullary and phrenic recordings (Cohen, 1979), where there were periodic peaks on either side of the central peak with a frequency in the range 60-120 Hz. Combinations of these forms of synchronization were seen in some histograms.3. When different animals were compared, broad peak synchronization was seen in association with light anaesthesia and with polysynaptic excitation of the motoneurones from muscle spindle afferents.4. In individual animals, additional anaesthesia depressed both broad peak and h.f.o. synchronization.5. Raising P(A, CO2), which increased the respiratory drive to the motoneurones, favoured short-term or h.f.o. synchronization at the expense of broad-peak synchronization.6. In three decerebrate animals only short-term or h.f.o. synchronization was seen.7. Spinal cord lesions above or below the segments of interest promoted broad-peak synchronization, even with high P(A, CO2) or deep anaesthesia.8. We conclude: (i) that short-term synchronization, due mainly to the branching of presynaptic axons, is generated mainly by those axons which transmit the respiratory drive, that drive providing most of the excitation of the motoneurones in moderately deep anaesthesia; (ii) that h.f.o. synchronization arises from the periodic synchronization of the discharges in these same presynaptic axons; (iii) that broad-peak synchronization is generated by the activity of other presynaptic neurones whose discharges are also synchronized, but aperiodically, these neurones most likely including spinal cord interneurones which are active in light anaesthesia or when released by spinal cord lesions.9. These conclusions are supported by comparisons between intracellular recordings from inspiratory motoneurones in animals showing different forms of motoneurone synchronization, the comparison including the measurements of ;average common excitation' (a.c.e.) potentials (Kirkwood & Sears, 1978).

Action Potentials↗
PubMed1982

The spatial distribution of synchronization of intercostal motoneurones in the cat.

1. The three different types of synchronization of intercostal motoneurones which were described in the preceding paper (Kirkwood, Sears, Tuck & Westgaard, 1982) were studied for motoneurones of the same segment or for different segmental separations (up to five segments) and for motoneurones on opposite sides of the same segment.2. The strength of synchronization declined with segmental separation for all three categories, although the rate of decline was more variable for broad-peak synchronization than for the two other types. Short-term synchronization was undetectable for separations greater than three or four segments but clear peaks were still visible in the cross correlation histograms for high-frequency oscillation (h.f.o.) or broad-peak synchronization at a segmental separation of five. Synchronization between motoneurones on opposite sides of the cord was generally weak although less so for broad-peak or h.f.o. components.3. The decline in strength of short-term synchronization with segmental separation could not be explained by temporal dispersion of impulses in presynaptic axons.4. A time shift was observed in the position of the cross-correlation histogram peak which was dependent on segmental separation and equivalent to a mean descending conduction velocity of 28 m/s in the assumed common input. This figure is similar to the mean conduction velocity of bulbospinal respiratory neurones derived from published values.5. We conclude that the short-term synchronization in these preparations is generated by the bulbospinal respiratory neurones and that the majority of their axons do not branch to make strong synaptic connexions to motoneurones over more than three to four segments.6. Interpretations of the different distributions of the other types of synchronization are discussed.

Action Potentials↗
PubMed1982

Effect of glutamate, aspartate and related derivatives on cerebellar purkinje cell dendrites in the rat: an in vitro study.

1. The responses of Purkinje cells to short duration (pulse) ionophoretic applications of L-aspartate (L-asp), L-glutamate (L-glu), N-methyl DL-aspartate (NMDLA) and quisqualic acid in their dendritic fields were studied in vitro on sagittal slices of lobules IX and X of the adult rat cerebellum.2. Pulse application of L-asp or L-glu evoked transient and dose-dependent increases in the firing rate of the simple spikes recorded extracellularly as single units. When the ionophoretic electrode was positioned in the dendritic field of the Purkinje cells, the lowest thresholds for L-glu and L-asp mediated excitations of the cells were as low as 25 and 35 pC respectively, with a latency for maximal responses as brief as 7 ms.3. In intracellular recordings these excitatory responses consisted of depolarizations of up to 18 mV in amplitude and with depolarizing slopes up to 0.52 mV/ms. They were generally unaccompanied by changes in cell input resistance in contrast to the marked decrease which occurred in response to steady applications of large doses of L-asp and L-glu.4. The spatial distribution of the excitatory sites confirmed that the dendritic sensitivity to L-glu was greater than that of the soma and showed that the same was true for L-asp. In 34% of cells the sensitivity for L-asp declined markedly in the upper region of the molecular layer, whereas it remained high for L-glu; no such differential sensitivity was detected in the remaining 66% of cells.5. Inhibitory responses, antagonized by 10(-5) M-bicuculline in the bath, were also induced in Purkinje cells by L-glu and L-asp when the ionophoretic electrode was withdrawn from the excitatory sites by as little as 8 mum and up to 40 mum upward or downward along the track of parallel fibres or positioned as far as 250 mum laterally.6. Whenever it was applied in the molecular layer, the pulse application of NMDLA elicited no excitatory response in Purkinje cells recorded extra or intracellularly. However, slow depolarizations accompanied by a slight increase in cell input resistance were obtained with steady applications of 20-50 nA of the drug for 20-30 s.7. In contrast, pulse application of quisqualic acid appeared to have the same type of fast excitatory effect on Purkinje cells as L-asp and L-glu, but its potency was greater and its action more prolonged. Furthermore, its steady application led to an abrupt and marked decrease in cell membrane resistance.8. The excitatory effects of L-asp, L-glu and quisqualic acid were antagonized by L-glutamic acid diethyl ester more consistently than by D-alpha-aminoadipate, suggesting together with previous observations that L-asp and L-glu act on Purkinje cells via quisqualic acid rather than via NMDLA receptors.

2-Aminoadipic Acid↗
PubMed1981

A quantitative ultrastructural study of dorsal root regeneration.

Regeneration in rat lumbo-sacral dorsal roots was studied 5-71 days following crush lesions. Wallerian degeneration occurred up to 20 days. At 11 days degenerating myelin was found in both Schwann cells and macrophages. Myelination was first observed 4 mm central to the crush at 7 days, and myelin became compact when the mesaxon exhibited 3.5 turns about the axon (about 11 days post-operatively). At 71 days, 69% of all fibres were myelinated, compared with 36% in normal roots. An example of 2 axons myelinating within the same Schwann cell occurred at 20 days. In normal roots curvilinear relationships were found between axon diameter and fibre diameter, myelin thickness and axon diameter, and between g and fibre diameter. In contrast, linear relationships between these parameters occurred in post-operative roots up to 71 days. Curvilinearity returned at 71 days. Alterations in the relationship between axon diameter and myelin thickness during regeneration indicated that myelin growth lagged behind axon growth throughout, but was more noticeable in larger calibre fibres. By 71 days, larger fibres exhibited disproportionately thin myelin, whilst small fibres possessed abnormally thick myelin compared to normal fibres of similar calibre. Regeneration was limited by axons failing to make successful central synaptic connections and by the poor metabolic response of dorsal root ganglion cells to sectioning of their central processes.

Animals↗
PubMed1981

Conduction in regenerating dorsal root fibres.

Rat dorsal roots were crushed and recordings of compound action potentials and single fibre longitudinal currents were made 12-85 days later from the regenerating portions. Maximum conduction velocities rose from 1.3 m/s at day 10 to 25.7 m/s by day 41 and single fibre velocities varied from 1.2 m/s at 12 days postcrush to 23.8 m/s at 85 days. Many fibres appeared to conduct continuously in the early stages, although the resolution of the technique was insufficient to exclude saltatory conduction over short internodes. Two fibres showed internodes of about 200 microns at 9 and 13 days of regeneration, suggesting that "nodal" regions may be formed before significant myelination. At 27 days post-crush and later, internodes were 300-425 microns in length. Many regenerating fibres had branches, both retrograde and orthograde. Reduced conduction velocities in rostral portions of regenerating fibres suggested tapering.

Animals↗
PubMed1981

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.

1. 4-Aminopyridine (4AP) and tetraethylammonium ions (TEA), which block voltage-dependent potassium channels in other nerve membranes, have been used to study nerve conduction in fibres of normal rat spinal roots and those demyelinated with diphtheria toxin. The pharmacological actions have been compared with those of temperature. 2. Both TEA and 4AP increased the amplitude and duration of the monophasically recorded compound action potentials of non-myelinated fibres in normal rat dorsal roots. Enhancement of the action potential amplitude by 4AP was maximal near 1 mM, and was not readily reversed by washing. At concentrations up to 50 mM the action of TEA was weaker and reversible. 3. In normal dorsal and ventral roots TEA (20 mM) and 4AP (5 mM) had only a mildly depressant action on the compound action potentials of myelinated fibres. Whereas the slight reduction in peak amplitude and increase in width was also found in a single fibres treated with TEA, none was discerned in single fibres exposed to 4AP over a wide temperature range. 4. It is concluded that voltage-dependent potassium channels occur in significant numbers in mammalian non-myelinated fibres, but not at nodes of Ranvier. 5. Spinal roots previously treated with diphtheria toxin to cause demyelination were studied by longitudinal current analysis. Fibres affected by diphtheria toxin had a late phase of outward current, either restricted to nodes or, in the case of continuous conduction, distributed along internodes, and this outward current was specifically blocked by 4AP. 6. Both 4AP and TEA increased the temperature at which conduction block occurred in most single demyelinated fibres, so that in some cases fibres blocked at physiological temperatures were enabled to conduct. 4AP was more potent than TEA, but less consistent in its effect. 7. It is concluded that potassium channels are present at widened nodes and in internodal axolemma exposed by demyelination. Their presence enables TEA and 4AP to overcome conduction block in some demyelinated nerve fibres.

4-Aminopyridine↗
PubMed1981

Recurrent inhibition of intercostal motoneurones in the cat.

1. The external and internal intercostal nerves of a single intercostal space were stimulated in anaesthetized paralysed cats with dorsal roots cut in the corresponding spinal cord segment. 2. Extracellular recording in the ventral horn revealed single units which fired short high frequency bursts of spikes at short latency to stimulation of either or both of the two nerves at stimulus strengths appropriate to the activation of alpha motor axons. These units were deduced to be Renshaw cells. 3. Small (0.1-0.2 mV) hyperpolarizing potentials of duration up to 50 msec were recorded intracellularly in both inspiratory and expiratory motoneurones of the same segment. Latencies and thresholds were appropriate for disynaptic i.p.s.p.s evoked by collaterals of alpha motor axons. 4. The changes in probability of firing following the stimuli were examined for inspiratory alpha motoneurones by constructing post-stimulus histograms of efferent discharges recorded from filaments of the external intercostal nerve of the segment stimulated and from other segments. 5. A period of reduced probability of firing of up to 24 msec duration, corresponding in all respects to disynaptic inhibition from alpha motor axon collaterals, was seen in the segment stimulated and up to three segments distant, though declining in intensity with distance. Either nerve could evoke such inhibition although that evoked from the internal intercostal nerve was stronger, as were the intensities of the Renshaw cell discharges. 6. We conclude that recurrent inhibition, via Renshaw cells which have axons up to 30 mm in length, is present for intercostal motoneurones. Arguments are adduced to show that although the effects from stimulating any one segmental nerve may be relatively weak, the over-all effect resulting from the widely spread projections of the Renshaw cells concerned is an inhibition comparable intensity with that seen in many hind limb motor nuclei.

Action Potentials↗
PubMed1980

Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The use of a potassium-blocking agent to prolong action potentials may seem surprising because we previously found tetraethylammonium chloride (TEA), another potassium blocker, ineffective on normal rat myelinated fibres, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels. On the other hand, 4AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre, might further resemble its unmyelinated terminals by responding to 4AP. In testing this hypothesis, we have found that both TEA and 4AP prolong action potentials of demyelinated and unmyelinated fibres, and both facilitate conduction in fibres blocked by demyelination. 4AP is effective at lower concentrations, and is the more promising for clinical use, as it has already been used with beneficial effects in the treatment of Eaton-Lambert syndrome and myasthenia gravis.

Action Potentials↗
PubMed1978

Muscle activity during chest wall restriction and positive pressure breathing in man.

The effects of sustained constriction of the rib cage (RCC), constriction of the abdomen (AC) and of breathing against a positive pressure of 10 cms of water (PPB) were studied in four normal subjects with moderate constant hypercapnia. Intercostal electrical activity (Eic) was measured by implanted wire electrodes and diaphragmatic electrical activity (Edia) by oesophageal electrodes. There was no fixed relation between Edia and VT. VT was unaltered during AC and RCC: Edia was unaltered during AC but increased during RCC. The response to PPB without constriction varied: three subjects increased end-expiratory VL with increase in Edia and inspiratory Eic. One subject initially, and one subject after training, maintained end-expiratory VL constant with no change in Edia and an increase in expiratory Eic. When PPB was applied during AC and RCC there was an increase in Edia proportional to end-expiratory lung volume. The overall response to distortion was determined by voluntary choice, but muscle electrical activity reflected chest wall configuration: when the diaphragm was shorter and at a mechanical disadvantage its electrical activity increased. This was compatible with a reflex with afferent information from diaphragm tendon organ and muscle spindle receptors.

Action Potentials↗
PubMed1978

The synaptic connexions to intercostal motoneurones as revealed by the average common excitation potential.

1. The hypothesis is advanced that the joint occurrence of unitary e.p.s.p.s evoked in motoneurones by branches of common stem presynaptic fibres causes, on average, transient depolarization in one motoneurone at the time of discharge in another motoneurone of the same pool. 2. The hypothesis was tested in anaesthetized, paralysed cats by averaging the naturally occurring synpatic noise of thoracic inspiratory motoneurones with an averager triggered by spikes from other inspiratory motoneurones. These spikes were obtained as efferent discharges in nerve filaments supplying the proximal regions of the external intercostal muscles. 3. A transient depolarization centred around the time of the trigger spikes was consistently observed and was designated the average common excitation (a.c.e.) potential. 4. The peak depolarization lay between -1.0 and +4.6 msec (mean +0.7 msec) with respect to the trigger spikes and the rise times of its most prominent component ranged from 4 to 16 msec (mean 8.4 msec). 5. The amplitudes of the a.c.e. potentials ranged from 6 to 104 muV (mean 32 muV) when the trigger spikes were derived from a filament in the same segment as the relevant motoneurones, and from 3 to 42 muV (mean 19 muV) when the filament was two segments rostral to the motoneurone. 6. Cells innervating the proximal region of the intercostal space gave larger a.c.e. potentials than those innervating more distal regions and also showed larger central respiratory drive potentials. 7. A.c.e. potentials were observed for either alpha or gamma spikes as triggers. The potentials were usually smaller for the gamma than for the alpha spikes, the mean ration being about 0.6. The presence of the a.c.e. potentials from the gamma spikes was taken as evidence for alpha-gamma coactivation by common presynaptic axons. 8. A theory is developed which quantitatively accounts for the main features of both the a.c.e. potential and the short term synchrony observed by Sears & Stagg (1976). 9. The theory includes the proposition that the raised probability of firing of a motoneurone due to a unitary e.p.s.p. has a time course which may be described by the sum of the e.p.s.p. time course and its time differential. Thus, via the measurements, the theory predicts at least to a first approximation the expected probability of firing due to e.p.s.p.s of various shapes and sizes.

Action Potentials↗
PubMed1978

On the transmission of the stimulating effects of carbon dioxide to the muscles of respiration.

1. Electromyography was used to measure the response of the diaphragm and intercostal muscles to CO2 in artificially ventilated decerebrate cats. 2. Hypocapnia produced tonic activity in either inspiratory or expiratory muscles or both, according to the preparation. 3. A graded effect of CO2 on both rhythmic and tonic activity was observed and for the latter this could be seen at as low as 10 torr PA,CO2. 4. In one human subject tonic firing of expiratory motoneurones was also induced by hypocapnia and this activity showed a graded increase with increasing (CO2. 5. A saggital incision of the medulla aimed at interrupting inspiratory bulbospinal axons abolished activity in inspiratory muscles and at eupnoeic levels of CO2 converted the activity of expiratory muscles from a periodic to a topic firing pattern. 6. Following such lesions the threshold for rhythmic excitation of expiratory muscles was elevated and this revealed that the graded effect of CO2 on tonic expiratory activity extends to as high as 60 torr. 7. The tonic activation of respiratory muscles in response to CO2 ceased after cervical cord transection or when the saggital incision in the medulla was extended caudally to the first cervical segment. 8. It is concluded that the CO2 dependent activation of spinal respiratory motoneurones is conveyed by bulbospinal axons which decussate in the vicinity of the obex and that this activation can be rhythmic or tonic. 9. It is suggested that the rhythmic excitation of expiratory muscles derives from a periodic inhibition of expiratory bulbospinal neurones which are subjected to a tonic CO2 dependent excitation which is continuously variable over the physiological range.

Action Potentials↗
PubMed1978

The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination.

1. Longitudinal action currents were recorded from single undissected myelinated nerve fibres in intact, perfused ventral roots of normal rats and ones treated with diphtheria toxin to produce demyelination. 2. Closely spaced recording electrodes (120 micron), signal averaging and the use of a calibrating current throught the root permitted membrane currents to be determined over 240 micron lengths of nerve. Contour plotting was used to plot membrane current density as a function of space and time. 3. The previous result of Rasminsky & Sears (1972) of delayed saltation in demyelinated nerve fibres was confirmed. 4. In addition a new phenomenon of continuous conduction was observed, along distances of up to 1 1/2 times the afferent internodal distance. The continuous spatial distribution of inward current in these cases showed that electrical excitability was distributed along the internodes. 5. Internodal excitability was also revealed in demyelinated fibres by extra foci of inward current judged to be internodal on the basis of the spacing of the other (nodal) foci. 6. Continuous conduction occurred at velocities in the range of 1.1-2.3 m/sec or roughly 1/20th-1/40th of the velocities expected for normal stretches of the same fibres. 7. The continuous conduction was attributed to conduction along lengths of demyelinated axon. This was supported by estimates of 0.86 and 1.5 muF/cm2 for membrane capacity from the foot of a continuously conducted action potential. 8. The implications of internodal electrical excitability in demyelinated nerve fibres are discussed in relation to (a) recent estimates of the density of sodium channels in intact and homogenized normal nerves, (b) the pathophysiology of demyelinating disease.

Action Potentials↗
PubMed1978

Mechanics of the human diaphragm during voluntary contraction: statics.

We related diaphragm electromyographic activity (Edi) to transdiaphragmatic pressure (Pdi) in man during graded inspiratory efforts. Estimates of rib cage and abdominal volume displacements were based on their anteroposterior (AP) diameter changes. The diaphragm was assumed to contract isometrically when subjects performed inspiratory efforts against a closed airway at specified abdominothoracic configurations, increasing Edi and Pdi while holding lung volume and rib case and abdominal AP diameters constant. The relationship between Pdi and Edi depends primarily on abdominothoracic configuration rather than lung volume. For equal increments in lung volume, the Pdi developed at constant Edi is four to eight times more sensitive to changes in abdominal than in rib cage AP diameter. We demonstrate an isofunctional state of the diaphragm at different lung volumes, when increases in lung volume and rib cage AP diameter are compensated for by slight decreases in abdominal AP diameter, resulting in a constant relationship between Edi and Pdi. We conclude that diaphragm shortening is reflected more directly in abdominal displacement than in lung volume change.

Abdominal Muscles↗
PubMed1978

Mechanics of the human diaphragm during voluntary contraction: dynamics.

We determined the static, isometric relationship between diaphragmatic EMG (Edi) and transdiaphragmatic pressure (Pdi) in man at specified abdominothoracic configurations, assessed with magnetometers. During inspiratory airflow, measurements of Edi and Pdi were taken as the respiratory system passed through the same configuration as obtained during the static isometric contractions, allowing a comparison of static and dynamic contractions of the diaphragm at a given length and curvature. When voluntary inspiratory maneuvers are performed with no associated outward displacement of the abdominal wall, or with slight inward displacement, the Pdi developed dynamically is the same as that developed statically at a given Edi. When outward movement of the abdominal wall occurs during inspiratory airflow, the Pdi developed dynamically depends on the rate of abdominal displacement, not on overall inspiratory airflow rate. We conclude that the velocity of shortening of the diaphragm increases directly as the rate of abdominal displacement. We construct a pressure-flow analogue of the force-velocity relationship for the diaphragm and discuss the functional implications of these observations in relation to spontaneous breathing.

Adult↗