Neuromuscular Physiology Research Articles

Chronic acetylcholinesterase overexpression induces multilevelled aberrations in mouse neuromuscular physiology.

Chronic overexpression of the acetylcholine-hydrolysing enzyme acetylcholinesterase (AChE) is a notable consequence of exposure to anticholinesterase drugs or poisons. However, the physiological consequences for the resultant neuromuscular disfunction have not yet been carefully analysed. Here we report detailed dissection of the different components of neuromuscular function in transgenic mice previously shown to display motor fatigue and altered muscle morphology as a consequence of neuronal overexpression of AChE-S, the synaptic AChE variant. Transgenic diaphragm muscle presented exaggerated fatigue as a combined consequence of neurotransmission fading and muscle mechanical malfunctioning. In a tetanic stimulation protocol, transgenic muscles rapidly fatigued to a larger extent than wild-type muscles, when stimulated either directly or via the phrenic nerve. AChE overexpression involved moderate but significant aberrations of synaptic transmission with higher quantal content (measured at 0.2 mM Ca(2+), 2.3 mM Mg(2+)). Furthermore, treatment with the anti-cholinesterase physostigmine revealed a higher amplitude and half-decay time of the transgenic quantal postsynaptic response. Our observations imply that elevated levels of neuronal AChE-S are expected to cause muscle exhaustion due to a combination of modest, multilevelled aberrations in synaptic transmission, muscle function and morphology.

Multiple motor unit recordings of laryngeal muscles: the technique of vector laryngeal electromyography.

To display time-series firing rate and recruitment data for multiple, simultaneously active motoneurons activating human laryngeal muscles. These data provide specific information about how laryngeal muscle force is being controlled by the central nervous system at the level of the lower motoneuron. A quadrifilar needle electrode was used to record multi-channel myoelectric signals from thyroarytenoid muscle of normal subjects during tasks ranging from quiet breathing to a short sentence. Motor unit action potentials of the signal space were identified and tracked throughout task productions using pattern recognition and Precision Decomposition software. We present the first recordings and analyses of multiple motor unit activations in the larynx. The firing times and mean firing rates are plotted for each identified motor unit, which reveal recruitment and decruitment information and the database from which common firing statistics across motor units may be derived. This study provides new information about neuromuscular physiology of the larynx. Specifically, the results reveal the ordered recruitment and firing patterns of multiple motor units and the existence of common drive from the central nervous system. The technique may prove fundamental to understanding various neuromuscular pathologies such as laryngeal spasm and to assist clinical prognosis of laryngeal paresis and the diagnosis of certain neurogenic disorders.

The Utah paradigm of skeletal physiology: what is it?

SummaryAn elegant design stratagem for an organ intended to carry loads for life without fracturing, rupturing or wearing out would make those loads determine the organ's strength. It seems load-bearing mammalian bones, joints, fascia, ligaments and tendons do exactly that. Physiologists begin to understand how they do it, and that led to the Utah paradigm of skeletal physiology. Those adaptations occur in two major steps. The first step creates the genetically predetermined newborn skeleton with its anatomical relationships and biologic machinery. The second step adds to the first one all postnatal adaptations to mechanical and other challenges that would affect an organ's strength, size, architecture and composition. During postnatal growth, increasing loads make tissue-level biologic mechanisms correspondingly increase the strength of such organs. Mechanical strain-dependent signals help to control that process, which muscle strength, muscle anatomy and neuromuscular physiology strongly influence. Its problems seem to cause or help to cause numerous skeletal and some extraskeletal disorders. A Table in the article lists examples of them.This article summarizes salient features of the Utah paradigm, which includes both facts and some meanings inferred from them. Other times and people must resolve any questions about those meanings and about the devils that can lie in the details. Parenthetically, instead of the accuracy of the facts on which that paradigm stands, the above questions usually concern the different meanings people can infer from facts, and whether particular facts and ideas would be relevant to a particular issue.

Prednisolone-induced muscle dysfunction is caused more by atrophy than by altered acetylcholine receptor expression.

Large doses of glucocorticoids can alter muscle physiology and susceptibility to neuromuscular blocking drugs by mechanisms not clearly understood. We investigated the effects of moderate and large doses of prednisolone on muscle function and pharmacology, and their relationship to changes in muscle size and acetylcholine receptor (AChR) expression. With institutional approval, 35 Sprague-Dawley rats were randomly allocated to receive daily subcutaneous doses of 10 mg/kg prednisolone (P10 group), 100 mg/kg prednisolone (P100 group), or an equal volume of saline (S group) for 7 days. A fourth group of rats was pair fed (food restricted) with the P100 rats for 7 days (FR group). On Day 8, the nerve-evoked peak twitch tensions, tetanic tensions, and fatigability, and the dose-response curves of d-tubocurarine in the tibialis cranialis muscle were measured in vivo and related to muscle mass or expression of AChRs. Rate of body weight gain was depressed in the P100, FR, and P10 groups compared with the S group. Tibialis muscle mass was smaller in the P100 group than in the P10 or S groups. The evoked peak twitch and tetanic tensions were less in the P100 group than in the P10 or S groups, however, tension per milligram of muscle mass was greater in the P100 group than in the S group. The 50% effective dose of d-tubocurarine (microg/kg) in the tibialis muscle was smaller in the P10 (33.6 +/- 5.4) than in the S (61.9 +/- 5.0) or the P100 (71.3 +/- 9.6) groups. AChR expression was less in the P10 group than in the S group. The evoked tensions correlated with muscle mass (r(2) = 0.32, P < 0.001), however, not with expression of AChR. The 50% effective dose of d-tubocurarine did not correlate with muscle mass or AChR expression. Our results suggest that the neuromuscular dysfunction after prednisolone is dose-dependent, and derives primarily from muscle atrophy and derives less so from changes in AChR expression. The mechanisms by which chronic glucocorticoid therapy alters neuromuscular physiology and pharmacology are unclear. We suggest that the observed effects are dose-dependent and derive primarily from muscle atrophy and derive less from changes in acetylcholine receptor expression.

Hand grip dynamometry does not correlate with anthropometric measures of nutritional status in survivors of prolonged critical illness

Prolonged critical illness results in malnutrition and functional impairment. Impaired muscle function has several possible explanations in these patients such as reduced muscle mass, myopathy and neuropathy. There are no data regarding the relation between anthropometric measures and measures of muscle strength following critical illness. In other populations mid arm muscle circumference (MAMC, a measure of lean body mass) and muscle strength measured by hand grip dynamometry (HGD, a simple measure of muscle function) correlate. We have investigated the relation between anthropometric measures of nutritional status and muscle strength using HGD in patients attending our Intensive Care follow up clinic. Thirty patients who spent more than 4 days in Intensive Care (median stay 9.25 days (range 4.4–58.9)) were studied 3 months following ICU discharge. Height, weight, body mass index (BMI), triceps skinfold thickness (TSF), mid arm circumference (MAC) and MAMC were measured using standard anthropometric techniques. Pre-illness weight and BMI were determined retrospectively from patient records or recollection. HGD was measured with a single spring hand grip dynamometer. Quality of life was assessed using the SF-36 questionnaire. A total of 64% of patients had failed to regain the weight recorded prior to admission to ICU; 39% had a persistent weight loss of >10% (mean pre-illness BMI 24.3 (SEM 0.60), 3 month BMI 23.3 (0.51),P Our findings demonstrate marked loss of muscle mass and functional ability using established methods in about one third of patients 3 months following prolonged critical illness. However, unlike other populations MAMC did not correlate with HGD. This may be because (1) factors other than muscle mass contribute to functional impairment following critical illness such as neuropathy and myopathy (2) HGD is too insensitive or effort-dependent in this population. Evaluation of neuromuscular physiology should be included in studies of functional recovery from critical illness. More rigorous measures of functional ability are needed in order to understand and improve recovery from prolonged critical illness.

Neuromechanical interaction in human snoring and upper airway obstruction

The fact that snoring and obstructive apnea only occur during sleep means that effective neuromuscular functioning of the upper airway during sleep is vital for the maintenance of unimpeded breathing. Recent clinical studies in humans have obtained evidence demonstrating that upper airway neural receptors sense the negative pressure generated by inspiration and "trigger," with a certain delay, reflex muscle activation to sustain the airway that might otherwise collapse. These findings have enabled us to propose a model in which the mechanics is coupled to the neuromuscular physiology through the generation of reflex wall stiffening proportional to the retarded fluid pressure. Preliminary results on this model exhibit three kinds of behavior typical of unimpeded breathing, snoring, and obstructive sleep apnea, respectively. We suggest that the increased latency of the reflex muscle activation in sleep, together with the reduced strength of the reflex, have important clinical consequences.

Nondepolarizing neuromuscular blocking drugs in the intensive care unit: a clinical review.

The use of nondepolarizing neuromuscular blocking drugs (NDNMBDs) via continuous infusion in the intensive care unit (ICU) is gaining in popularity. Several new NDNMBDs have been developed recently; these drugs vary in their elimination, metabolism, and half-lives. A review of the recent English language literature was done, with those articles relevant to the ICU being incorporated into this paper. The six most frequently used NDNMBDs, consisting of atracurium, cisatracurium, doxacurlum, pancuronium, rocuronium, and vecuronium, were reviewed. The neuromuscular junction and impulse transmission, clinical monitoring, clinical pharmacology, the elimination and metabolism, the adverse reactions, and the drug interactions of these NDNMBDs are reviewed. The use of NDNMBDs is progressively increasing in ICUs. Proper understanding of normal neuromuscular physiology, clinical pharmacology, and drug interactions is essential to optimize patient care and to minimize the risk of adverse reactions.

The clinical limits of myasthenia gravis and differential diagnosis

The question of the limits of the clinical diagnosis of myasthenia gravis is in part one of definitions superimposed on the evolution in our understanding of normal and abnormal neuromuscular junction anatomy, physiology, and pharmacology, complemented by new knowledge of the immunopathogenic events that take place at the neuromuscular junction in the most common form of myasthenia gravis, acquired autoimmune myasthenia gravis. [1,2] In the past, myasthenia gravis was used to describe a series of disorders, most of them quite uncommon or rare, in which there appeared to be a defect in neuromuscular function based on abnormal neurophysiology and on pharmacologic responses to agents that enhanced or inhibited neuromuscular transmission, acting either presynaptically or postsynaptically. In 1982, we still classified myasthenia gravis as generalized vs. ocular, but in the generalized category we included congenital myasthenia gravis. It was recognized that congenital myasthenia gravis comprised several different disorders that did not appear to be immunologically mediated but that did appear to involve the neuromuscular junction based on the clinical picture, neurophysiology, and/or response to cholinesterase inhibitory drugs. [3] Through the work of several investigators, principally Dr. Andrew Engel and his collaborators (reviewed by Dr. Engel in this supplement and elsewhere [4]), we now understand that congenital myasthenia includes several disorders involving different presynaptic and postsynaptic defects. Some of these have very different neurophysiologic findings from those of classic autoimmune myasthenia gravis, even using traditional clinical neurophysiologic testing. It is of interest that we classified the Lambert-Eaton myasthenic syndrome (LEMS) as a clearly different myasthenic syndrome, although some of the congenital forms of myasthenia are just as clearly presynaptic as LEMS, albeit not immunologically mediated, which we now know is true of LEMS. Should we now reserve the term myasthenia gravis for the acquired, immunologically mediated postsynaptic disorder, be it generalized or …

The mechanisms of action of antiprotozoal and anthelmintic drugs in man

The mechanisms of action of antiprotozoal and anthelmintic drugs are reviewed according to: (1) drugs interfering with metabolic processes; (2) drugs interfering with reproduction and larval physiology; and (3) drugs interfering with neuromuscular physiology of parasites.

A spinal circuitry simulator as a teaching tool for neuromuscular physiology.

Many concepts in neuromuscular physiology can be difficult for instructors to teach and for students to understand. The behaviors of various components in neuromuscular systems do not always interact in obvious ways, and the function of hundreds of components can be very different from the function of just one or two "representatives." In this paper, a simulator is presented that can model both small and large spinal circuitry systems thus allowing students to explore the dynamic functional implications of the static circuitry diagrams that are common in many neuroscience textbooks. The simulator brings to life many concepts in neuromuscular physiology and permits students to explore such concepts without extensive supervision. The benefits and drawbacks of using this kind of simulator in the classroom are discussed, based on initial field tests with undergraduate and graduate students as well as input from the literature. It was found that such a simulation can be very useful as a teaching tool if it is used properly with the right audience.

The goal of treatment for motor impairment is not to “normalize” but to “functionalize” through facilitative modulation and enabling context

AbstractAdaptations occurring in the central nervous system (CNS) in the presence of pathology arenotuniformly “good” for the organism when viewed in a functional context. A functional reordering of CNS priorities can be produced by allowing restructuring of the external context or through modification of neuromuscular physiology or anatomy designed to reduce the inherent restriction of functional movement in upper motor neuron syndrome. In fact, volitional control can often be “unmasked” through such interventions. Therapeutic interventions should not be directed toward “normalization” of motor patterns but should permit a functional reordering of CNS priorities that would otherwise not be possible.

FMRFamide-related peptides (FaRPs) in nematodes: occurrence and neuromuscular physiology.

The occurrence of classical neurotransmitter molecules and numerous peptidic messenger molecules in nematode nervous systems indicate that although structurally simple, nematode nervous systems are chemically complex. Thus far, studies on one nematode neuropeptide family, namely the FMRFamide-related peptides (FaRPs), have revealed an unexpected variety of neuropeptide structures in both free-living and parasitic species. To date 23 nematode FaRPs have been structurally characterized including 12 from Ascaris suum, 8 from Caenorhabditis elegans, 5 from Panagrellus redivivus and 1 from Haemonchus contortus. Ten FaRP-encoding genes have been identified in Caenorhabditis elegans. However, the full complement of nematode neuronal messengers has yet to be described and unidentified nematode FaRPs await detection. Preliminary characterization of the actions of nematode neuropeptides on the somatic musculature and neurones of A, suum has revealed that these peptidic messengers have potent and complex effects. Identified complexities include the biphasic effects of KNEFIRFamide/KHEYLRFamide (AF1/2; relaxation of tone followed by oscillatory contractile activity) and KPNFIRFamide (PF4; rapid relaxation of tone followed by an increase in tone), the diverse actions of KSAYMRFamide (AF8 or PF3; relaxes dorsal muscles and contracts ventral muscles) and the apparent coupling of the relaxatory effects of SDPNFLRFamide/SADPNFLRFamide (PF1/PF2) to nitric oxide release. Indeed, all of the nematode FaRPs which have been tested on somatic muscle strips of A. suum have actions which are clearly physiologically distinguishable. Although we are a very long way from understanding how the actions of these peptides are co-ordinated, not only with those of each other but also with those of the classical transmitter molecules, to control nematode behaviour, their abundance coupled with their diversity of structure and function indicates a hitherto unidentified sophistication to nematode neuromuscular intergration.

Neuromuscular physiology and pharmacology of parasitic flatworms

The trematode and cestode flatworms include numerous parasitic forms of major medical and economic importance. A better knowledge of the neuromuscular physiology of these animals could lead to development of new control measures against these parasites. Since these animals are near the stem from which all other animals have evolved, better knowledge of these animals could also yield valuable information about the early evolution of nerve and muscle systems in the animal kingdom. This review focuses on what is known about the characteristics of the somatic muscle in these animals. The anatomy of the muscles is described along with a review of current information about their electrophysiology, including descriptions of the ion channels present. Also included is a summary of recently acquired data concerning the nature of serotonin, peptide, acetylcholine and glutamate receptors on the membranes of the muscles.

Computer-based waveform subtraction for measuring refraction of neuromuscular transmission

The study demonstrated that computer-based waveform subtraction is a viable approach for the accurate determination of the refractory periods (RPs) of the neurally-evoked compound electromyograms (ncEMGs) and the refraction of neuromuscular transmission. Computer-based waveform subtraction can easily extract the R2 waveform from the complex ncEMGs and calculate accurate R2/R1 ratios. The method is more accurate and useful than the traditional "eyeballing," which is the current method used. In the ncEMGs with twin stimuli, the interstimulus interval determines the time relationship between R2 and the R1. A short interstimulus interval obscures the R2 by the downward deflection of the R1. The emergence of the R2 is then delayed. Furthermore, the downward deflection elevates the baseline of the R2 waveform, making the measurement of the R2 amplitude difficult and unreliable by the traditional method. By use of computer-based waveform subtraction, the progression of R2 becomes smooth as the interstimulus intervals increase. The accurate R2 and the R2/R1 ratios are then available, and are suitable for evaluating the refraction of neuromuscular transmission. Applying the accurate R2/R1 in the study of neuromuscular physiology and pharmacology, a "dose-response" curve can be drawn and be used to investigate drug effects of many anesthetics and neuromuscular blocking drugs. In this study, the computer-based waveform subtraction resulted in an accurate dose response curve, similar to the traditional method but with a smaller refractory area.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

Principles and Practice of Anesthesiology

Anaesthetic approach to the health patient anaesthetic approach to the patient with medical problems anaesthetic care patient safety monitoring inhalation anaesthesia intravenous sedation and analgesia regional anaestheia/analgesia and pain autonomic and neuromuscular physiology concurrent drugs.

Neurological rehabilitation.

Increasingly, neurologists are participating in the rehabilitation of disorders of the nervous system. Compelling reasons why neurologists, especially those with academic interests, should become involved in rehabilitation include the opportunity to observe patients in the recovery phases of their illnesses and to study issues relating to functional recovery, exposure to patients (such as those with spinal cord injury) who are often not seen by neurologists in the acute phase, and the opportunity to help establish a scientific base for rehabilitation medicine. Many areas of investigation can contribute to the scientific basis of neurological rehabilitation. Among the most promising are regeneration in the central (CNS) and peripheral nervous systems, adaptive mechanisms following CNS injury, computational neuroscience, neuromuscular physiology of chronic denervating conditions (e.g., the post-polio syndrome), and outcome studies of both physical and pharmacological therapeutic modalities. While there may be financial advantages to involvement in neurological rehabilitation, these are probably overestimated and interest in this field would continue to grow without them. There is a need for enhanced training in this subspecialty, including the development of dual certification programs in neurology and rehabilitation medicine.

A NEW FOUR-PARAMETER THRESHOLD MODEL FOR THE PLASMA ATRACURIUM CONCENTRATION-RESPONSE RELATIONSHIP

The plasma concentration of atracurium and the electromyographic depression of the first response of the train-of-four (T1:T0) were measured during and after recovery from a 10-min infusion of atracurium 0.25 mg kg-1 in 14 patients anaesthetized with 66% nitrous oxide and 0.9% isoflurane (end-tidal) in oxygen. A standard pharmaco-dynamic model was fitted to the data; a small but consistent discrepancy was found between the time and rate of onset of depression of the ratio T1:T0 and the predictions of the standard biophase model of best fit to the data. This discrepancy is reduced by the inclusion of a threshold term (CPss theta) in the model to represent the greatest steady state plasma concentration which would just fail to evoke an effect. The values of CPss theta correlated significantly with the values of CPss50 (r = +0.627; P less than 0.02). The estimates of CPss50 and keo from the two models are very similar; the estimate of gamma, the slope of the concentration-response curve, was less in the threshold model. The relationship of the present threshold model to existing knowledge of neuromuscular physiology is discussed.

Acoustic myography for investigating human skeletal muscle fatigue

Sounds produced during voluntary isometric contractions of the quadriceps muscle were studied by acoustic myography (AMG) in five healthy adults. With the subject seated, isometric force, surface electromyography (EMG), and AMG were recorded over rectus femoris, and the EMG and AMG signals were integrated (IEMG and IAMG). Contractions lasting 5 s each were performed at 10, 25, 50, 60, 75, and 100% of maximum voluntary contraction (MVC) force. Fatigue was then induced by repeated voluntary contractions (10 s on, 10 s off) at 75% MVC until only 40% MVC could be sustained. After 15 min of rest, the different force levels were again tested in relation to the fresh MVC. Both before and after fatiguing activity the relationships between force and IEMG [r = 0.99 +/- 0.01 (SD), n = 10] and force and IAMG (r = 0.98 +/- 0.02) were linear. After activity, however, the slopes of the regression lines for force and IEMG increased (P less than 0.01) but those for force and IAMG remained the same (P greater than 0.05). The present results clarify the relationship between AMG and isometric force in fatigued muscle without the problem of fatigue-induced tremor, which hampered previous studies of prolonged activity. This study contributes to the validation of AMG and shows that it is a potentially useful method for noninvasive assessment of force production and fatigue. Further studies to establish the origin of AMG activity are required before AMG can be accepted for use in neuromuscular physiology or rehabilitation.

Plate and screw fixation in the management of mandible fractures

The use of compression plates and screws in the management of mandibular fractures is a reliable method of producing rigid internal fixation and a functionally stable fracture site. Early mandibular function is possible, resulting in a decrease in intermaxillary fixation time, improved oral hygiene and nutrition, and maintenance of normal neuromuscular physiology. Compression osteosynthesis results in primary bone healing, which has been shown to hasten osseous regeneration. With adherence to strict technical details and the use of sound clinical judgment, compression plate and screw techniques provide for a predictable method in the treatment of mandible fractures.

ZPT-related distal axonopathy: Behavioral and electrophysiologic correlates in rats

These experiments examined the relationship between behavioral and electrophysiologic signs of neuromuscular dysfunction in rats with zinc pyridinethione (ZPT)-induced neurotoxicity. ZPT added to the diet of adult rats at 50 ppm produced a moderate (approximately 200 g) reduction in forelimb and hindlimb grip strength which occurred during the second week of dosing. Other behavioral tests of peripheral nervous system toxicity were affected inconsistently. Electrophysiologic changes included a marked (maximum 95%) reduction of indirect muscle-evoked potential (M-wave) and a decrement (maximum 30%) during repetitive M-wave elicitation. Electrophysiologic changes were greater in hindlimb than in forelimb. Needle electromyography revealed denervation potentials in ZPT-treated rats which appeared after M-wave changes and recovered faster than did M-wave amplitude. Caudal nerve conduction velocity was unaffected, indicating that peripheral neurotoxic effects were confined to the neuromuscular junction. When ZPT exposure was discontinued, grip strength recovered in about 1 week. In contrast, electrophysiologic measures required 42 days to recover completely. These results indicate that deficits in neuromuscular junction physiology are a sensitive index of ZPT-related distal axonopathy.