Determinants of transdiaphragmatic pressure in dogs

We measured the transdiaphragmatic pressure (Pdi) during bilateral phrenic nerve stimulation and evaluated the determinants of its change with lung volume, chest wall geometry, and respiratory system impedance in supine dogs. Four rows of radiopaque markers were sewn onto muscle bundles of the costal and crural diaphragm between their origin on the central tendon and their insertion on the rib cage and spine. The length of the diaphragm (L) was determined from the projection images of marker rows using biplane fluoroscopy. Measurements were made at lung volumes between total lung capacity and functional residual capacity before and after the infusion of Ringer lactate solution into the abdominal cavity. In contrast to relaxation, during tetanic stimulation the active lengths of the muscle bundles were similar at all volumes, but the diaphragm assumed different shapes. Although the small differences in active muscle length with volume and liquid loads are consistent with only small changes in muscle force output, Pdi varied by a factor of greater than or equal to 5. There was no single L/Pdi curve that fitted all data during 50-Hz stimulations. We conclude that under these experimental conditions Pdi is not a unique measure of the force produced by the diaphragm and that lung volume, chest wall geometry, and respiratory system impedance are important determinants of the mechanical efficiency of the diaphragm as a pressure generator.     

Effect of respiratory muscle tension on lung volume.

The chest wall is modeled as a linear system for which the displacements of points on the chest wall are proportional to the forces that act on the chest wall, namely, airway opening pressure and active tension in the respiratory muscles. A standard theorem of mechanics, the Maxwell reciprocity theorem, is invoked to show that the effect of active muscle tension on lung volume, or airway pressure if the airway is closed, is proportional to the change of muscle length in the relaxation maneuver. This relation was tested experimentally. The shortening of the cranial-caudal distance between a rib pair and the sternum was measured during a relaxation maneuver. These data were used to predict the respiratory effect of forces applied to the ribs and sternum. To test this prediction, a cranial force was applied to the rib pair and a caudal force was applied to the sternum, simulating the forces applied by active tension in the parasternal intercostal muscles. The change in airway pressure, with lung volume held constant, was measured. The measured change in airway pressure agreed well with the prediction. In some dogs, nonlinear deviations from the linear prediction occurred at higher loads. The model and the theorem offer the promise that existing data on the configuration of the chest wall during the relaxation maneuver can be used to compute the mechanical advantage of the respiratory muscles.     

The role of lung afferent system in respiratory control during head-down tilt

The role of lung receptors in respiratory control during acute head-down tilt (AHDT, -30 degrees) was investigated in anesthetized, tracheostomized rats. The results show that AHDT increased the mechanical respiratory load, slowed inspiratory flow, reduced the end expiratory lung volume, tidal volume and minute ventilation. On the other hand, during AHDT a significant rise in inspiratory swings of oesophageal pressure was recorded indicated a compensatory increase in inspiratory muscle contraction force. These effects were reduced after transaction of the vagus nerve. It was also shown that respiratory response on added mechanical load was reduced during AHDT as compared with the value in horizontal position. This deference disappeared after vagotomy. The data obtained suggested that afferent information from lung receptors take part in compensation of respiratory effects of AHDT. The cause of reduction in respiratory response to loading during AHDT involves weakness of lung reflexes evoked by volume changes.     

Effects of aging on sensation of respiratory force and displacement

The psychophysical technique of magnitude production was used to evaluate the sensation of inspiratory force and inspired volume in young and older subjects. Inspiratory force was generated during a static inspiratory maneuver against a closed airway. The exponent of the power function relationship between airway pressure and sensation intensity during force scaling was not significantly different between young and older subjects. In contrast, the exponents for the magnitude production of inspired volume were significantly greater in the older compared with the young group. We also assessed the effects of age on the relative importance of force and displacement signals on the sensation of inspired volume. Subjects attempted to reproduce a control tidal volume while breathing against a series of inspiratory resistive and elastic loads. In both groups error in tidal volume reproduction increased progressively as the severity of the load increased. During moderate and severe loading the error in the older subjects was significantly greater than in the young group. Correspondingly, the peak inspiratory airway pressures at tidal volume reproduction against these loads were significantly smaller in the older compared with the young subjects. The results suggest that in older subjects cues related to respiratory muscle force are more important than volume in the sensation of lung volume changes. In young subjects the sensation of lung volume changes is based to a greater degree on signals of volume or displacement.     

A Closed-Loop Model of the Respiratory System: Focus on Hypercapnia and Active Expiration

Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal “expiratory” muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O₂ and CO₂) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO₂ level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model can be used for simulation of closed-loop control of breathing under different conditions including respiratory disorders.     

A two-component simulation model to teach respiratory mechanics

Interactive learning has been proven instrumental for the understanding of complex systems where the interaction of interdependent components is hard to envision. Due to the mechanical properties and mutual coupling of the lung and thorax, respiratory mechanics represent such a complex system, yet their understanding is essential for the diagnosis, prognosis, and treatment of various respiratory disorders. Here, we present a new mechanical model that allows for the simulation of respiratory pressure and volume changes in different ventilation modes. A bellow reflecting the "lung" is positioned within the inverted glass cylinder of a bell spirometer, which is sealed by a water lock and reflects the "thorax." A counterweight attached to springs representing the elastic properties of the chest wall lifts the glass cylinder, thus creating negative "pleural" pressure inside the cylinder and inflating the bellow. Lung volume changes as well as pleural and intrapulmonary pressures are monitored during simulations of spontaneous ventilation, forced expiration, and mechanical ventilation, allowing for construction of respiratory pressure-volume curves. The mechanical model allows for simulation of respiratory pressure changes during different ventilation modes. Individual relaxation curves constructed for the lung and thorax reflect the basic physiological characteristics of the respiratory system. In self-assessment, 232 medical students passing the physiology laboratory course rated that interactive teaching at the simulation model increased their understanding of respiratory mechanics by 70% despite extensive prior didactic teaching. Hence, the newly developed simulation model fosters students' comprehension of complex mechanical interactions and may advance the understanding of respiratory physiology.     

Flow and volume dependence of expiratory resistance in anesthetized cats

In five anesthetized paralyzed cats, mechanically ventilated with tidal volumes of 36-48 ml, the isovolume pressure-flow relationships of the lung and respiratory system were studied. The expiratory pressure was altered between 3 and -12 cmH2O for single tidal expirations. Isovolume pressure-flow plots for three lung volumes showed that the resistive pressure-flow relationships were curvilinear in all cases, fitting Rohrer's equation: P = K1V + K2V2, where P is the resistive pressure loss, K1 and K2 are Rohrer's coefficients, and V is flow. Values of K1 and K2 declined with lung inflation, consistent with the volume dependence of pulmonary (RL) and respiratory system resistances (Rrs). During lung deflation against atmospheric pressure, RL and Rrs tended to remain constant through most of expiration, resulting in a nearly linear volume-flow relationship. In the presence of a fixed respiratory system elastance, the shape of the volume-flow profile depended on the balance between the volume and the flow dependence of RL and Rrs. However, the flow dependence of RL and Rrs indicates that their measured values will be affected by all factors that modify expiratory flow, e.g., respiratory system elastance, equipment resistance, and the presence of respiratory muscle activity.     

Spinal stiffness changes throughout the respiratory cycle.

Posteroanterior stiffness of the lumbar spine is influenced by factors, including trunk muscle activity and intra-abdominal pressure (IAP). Because these factors vary with breathing, this study investigated whether stiffness is modulated in a cyclical manner with respiration. A further aim was to investigate the relationship between stiffness and IAP or abdominal and paraspinal muscle activity. Stiffness was measured from force-displacement responses of a posteroanterior force applied over the spinous process of L2 and L4. Recordings were made of IAP and electromyographic activity from L4/L2 erector spinae, abdominal muscles, and chest wall. Stiffness was measured with the lung volume held at the extremes of tidal volume and at greater and lesser volumes. Stiffness at L4 and L2 increased above base-level values at functional residual capacity (L2 14.9 N/mm and L4 15.3 N/mm) with both inspiratory and expiratory efforts. The increase was related to the respiratory effort and was greatest during maximum expiration (L2 24.9 N/mm and L4 23.9 N/mm). The results indicate that changes in trunk muscle activity and IAP with respiratory efforts modulate spinal stiffness. In addition, the diaphragm may augment spinal stiffness via attachment of its crural fibers to the lumbar vertebrae.     

Flow and volume dependence of respiratory mechanical properties studied by forced oscillation

The influence of inspiratory and expiratory flow magnitude, lung volume, and lung volume history on respiratory system properties was studied by measuring transfer impedances (4-30 Hz) in seven normal subjects during various constant flow maneuvers. The measured impedances were analyzed with a six-coefficient model including airway resistance (Raw) and inertance (Iaw), tissue resistance (Rti), inertance (Iti), and compliance (Cti), and alveolar gas compressibility. Increasing respiratory flow from 0.1 to 0.4 1/s was found to increase inspiratory and expiratory Raw by 63% and 32%, respectively, and to decrease Iaw, but did not change tissue properties. Raw, Iti, and Cti were larger and Rti was lower during expiration than during inspiration. Decreasing lung volume from 70 to 30% of vital capacity increased Raw by 80%. Cti was larger at functional residual capacity than at the volume extremes. Preceding the measurement by a full expiration rather than by a full inspiration increased Iaw by 15%. The data suggest that the determinants of Raw and Iaw are not identical, that airway hysteresis is larger than lung hysteresis, and that respiratory muscle activity influences tissue properties.     

Interrupter technique for measurement of respiratory mechanics in anesthetized cats

In six spontaneously breathing anesthetized cats (pentobarbital sodium, 35 mg/kg ip), airflow, changes in lung volume, and tracheal and esophageal pressures were measured. Airflow was interrupted by brief airway occlusions during relaxed expirations (elicited via the Breuer-Hering inflation reflex) and throughout spontaneous breaths. A plateau in tracheal pressure occurred throughout relaxed expirations and the latter part of spontaneous expirations indicating respiratory muscle relaxation. Measurement of tracheal pressure, immediately preceding airflow, and corresponding volume enabled determination of respiratory system elastance and flow resistance. These were partitioned into lung and chest wall components using esophageal pressure. Respiratory system elastance was constant over the tidal volume range, divided approximately equally between the lung and chest wall. While the passive pressure-flow relationship for the respiratory system was linear, those for the lung and chest wall were curvilinear. Volume dependence of chest wall flow resistance was demonstrated. During inspiratory interruptions, tracheal pressure increased progressively; initial tracheal pressure was estimated by backward extrapolation. Inspiratory flow resistance of the lung and total respiratory system were constant. Force-velocity properties of the contracting inspiratory muscles contributed little to overall active resistance.     

A Method for Numerical Simulation of Single Limb Ground Contact Events: Application to Heel-Toe Running

The objective of this work was to develop a method to simulate single-limb ground contact events, which may be applied to study musculoskeletal injuries associated with such movements. To achieve this objective, a three-dimensional musculoskeletal model was developed consisting of the equations of motion for the musculoskeletal system, and models for the muscle force generation and ground contact elements. An optimization framework and a weighted least-squares objective function were presented that generated muscle stimulation patterns that optimally reproduced subject-specific movement data. Experimental data were collected from a single subject to provide initial conditions for the simulation and tracking data for the optimization. As an example application, a simulation of the stance phase of running was generated. The results showed that the average difference between the simulation and subject's ground reaction force and joint angle data was less than two inter-trial standard deviations. Further, there was good agreement between the model's muscle excitation patterns and experimentally collected electromyography data. These results give confidence in the model to examine musculoskeletal loading during a variety of landing movements and to study the effects of various factors associated with injury. Limitations were examined and areas of improvement for the model were presented.     

Desmin modulates lung elastic recoil and airway responsiveness

Desmin is a structural protein that is expressed in smooth muscle cells of both airways and alveolar ducts. Therefore, desmin could be well situated to participate in passive and contractile force transmission in the lung. We hypothesized that desmin modulates lung compliance, lung recoil pressure, and airway contractile response. To test this hypothesis, respiratory system complex impedance (Zin,rs) at different positive end-expiratory pressure (PEEP) levels and quasi-static pressure-volume data were obtained in desmin-null and wild-type mice at baseline and during methacholine administration. Airways and lung tissue properties were partitioned by fitting Zin,rs to a constant-phase model. Relative to controls, desmin-null mice showed 1) lower values for lung stiffness and recoil pressure at baseline and induced airway constriction, 2) greater negative PEEP dependence of H and airway resistance under baseline conditions and cholinergic stimulation, and 3) airway hyporesponsiveness. These results demonstrate that desmin is a load-bearing protein that stiffens the airways and consequently the lung and modulates airway contractile response.     

Modelling motor units in 3D: influence on muscle contraction and joint force via a proof of concept simulation

Functional heterogeneity is a skeletal muscle’s ability to generate diverse force vectors through localised motor unit (MU) recruitment. Existing 3D macroscopic continuum-mechanical finite element (FE) muscle models neglect MU anatomy and recruit muscle volume simultaneously, making them unsuitable for studying functional heterogeneity. Here, we develop a method to incorporate MU anatomy and information in 3D models. Virtual fibres in the muscle are grouped into MUs via a novel “virtual innervation” technique, which can control the units’ size, shape, position, and overlap. The discrete MU anatomy is then mapped to the FE mesh via statistical averaging, resulting in a volumetric MU distribution. Mesh dependency is investigated using a 2D idealised model and revealed that the amount of MU overlap is inversely proportional to mesh dependency. Simultaneous recruitment of a MU’s volume implies that action potentials (AP) propagate instantaneously. A 3D idealised model is used to verify this assumption, revealing that neglecting AP propagation results in a slightly less-steady force, advanced in time by approximately 20 ms, at the tendons. Lastly, the method is applied to a 3D, anatomically realistic model of the masticatory system to demonstrate the functional heterogeneity of masseter muscles in producing bite force. We found that the MU anatomy significantly affected bite force direction compared to bite force magnitude. MU position was much more efficacious in bringing about bite force changes than MU overlap. These results highlight the relevance of MU anatomy to muscle function and joint force, particularly for muscles with complex neuromuscular architecture.

     

Breathing pattern of anesthetized humans during pancuronium-induced partial paralysis

We investigated the breathing patterns of 17 subjects anesthetized with enflurane before and after partial muscle paralysis produced by pancuronium bromide. In the face of significant muscle weakness produced by pancuronium, breathing patterns are characterized by decreases in both tidal volume and respiratory frequency. The decreased tidal volume corresponded to the decrease in occlusion pressure, indicating that the decreased tidal volume results solely from a decreased contractile force of the respiratory muscles. The decreased respiratory frequency was due to prolongation of both inspiratory and expiratory time without changing the ratio of the inspiratory time to the total breath time. Withdrawal of phasic vagal influence by airway occlusion before partial muscle paralysis revealed that an active Breuer-Hering inflation reflex was operative in only 8 of all 17 subjects. Since the contribution of the Breuer-Hering inflation reflex alone does not seem to account for the consistent decrease in respiratory frequency, some other mechanisms modulating respiratory frequency might be involved in the characteristic breathing patterns during partial muscle paralysis under enflurane anesthesia.     

A study of the muscle force waveform using a population stochastic model of skeletal muscle

A population stochastic model based on the differing properties and the independent activation of motor units is used to describe the production of force in the contracting skeletal muscle. Detailed force predictions of the model concerning a hand muscle are obtained by computer simulation. General features of the force signal are established analyticaly on the basis of the general properties of the neuromuscular system which the population model takes into account. The results show that the asynchronous activity of motor units and the distribution of their filtering and firing properties at various levels of muscle contraction are esponsible, at least partially, for the main features of the muscle force waveform, including tremor.     

Links between the mechanics of ventilation and spine stability

Spine stability is ensured through isometric coactivation of the torso muscles; however, these same muscles are used cyclically to assist ventilation. Our objective was to investigate this apparent paradoxical role (isometric contraction for stability or rhythmic contraction for ventilation) of some selected torso muscles that are involved in both ventilation and support of the spine. Eight, asymptomatic, male subjects provided data on low back moments, motion, muscle activation, and hand force. These data were input to an anatomically detailed, biologically driven model from which spine load and a lumbar spine stability index was obtained. Results revealed that subjects entrained their torso stabilization muscles to breathe during demanding ventilation tasks. Increases in lung volume and back extensor muscle activation coincided with increases in spine stability, whereas declines in spine stability were observed during periods of low lung inflation volume and simultaneously low levels of torso muscle activation. As a case study, aberrant ventilation motor patterns (poor muscle entrainment), seen in one subject, compromised spine stability. Those interested in rehabilitation of patients with lung compromise and concomitant back troubles would be assisted with knowledge of the mechanical links between ventilation during tasks that impose spine loading.     

Fatigue and non-fatigue mathematical muscle models during functional electrical stimulation of paralyzed muscle

Electrical muscle stimulation demonstrates potential for preventing muscle atrophy and restoring functional movement after spinal cord injury (SCI). Control systems used to optimize delivery of electrical stimulation protocols depend upon the algorithms generated using computational models of paralyzed muscle force output. The Hill–Huxley-type model, while being highly accurate, is also very complex, making it difficult for real-time implementation. In this paper, we propose a Wiener–Hammerstein system to model the paralyzed skeletal muscle under electrical stimulus conditions. The proposed model has substantial advantages in identification algorithm analysis and implementation including computational complexity and convergence, which enable it to be used in real-time model implementation. Experimental data sets from the soleus muscles of 14 subjects with SCI were collected and tested. The simulation results show that the proposed model outperforms the Hill–Huxley-type model not only in peak force prediction, but also in fitting performance for force output of each individual stimulation train.     

Integrated approach for in vivo evaluation of respiratory muscles mechanics

The respiratory muscles constitute the respiratory pump, which determines the efficacy of ventilation. Any functional disorder in their performance may cause insufficient ventilation. This study was designed to quantitatively explore the relative contribution of major groups of respiratory muscles to global lung ventilation throughout a range of maneuvers in healthy subjects. A computerized experimental system was developed for simultaneous noninvasive measurement of inspired/expired airflow, mouth pressure and up to 8 channels of EMG surface signals from major respiratory muscles which are located near the skin (e.g., sternomastoid, external intercostal, rectus abdominis and external oblique) during various respiratory maneuvers. Lung volumes values were calculated by integration of airflow data. Hill's muscle model was utilized to calculate the forces generated by the muscles from the acquired EMG data. Analysis of EMG measurements and respiratory muscles forces revealed the following characteristics: (a) muscle activity increased with increased breathing effort, (b) inspiratory muscles contributed to inspiration even at relatively low flow rates, while expiratory muscles are recruited at higher flow rates, (c) the forces generated by the muscle depended on the muscle properties as well as on their EMG performance and (d) the pattern of the muscle's force curves varied between subjects, but were generally consistent for the same subject regardless of breathing effort.     

Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1^G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1^G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.     

A phenomenological model and validation of shortening-induced force depression during muscle contractions

History-dependent effects on muscle force development following active changes in length have been measured in a number of experimental studies. However, few muscle models have included these properties or examined their impact on force and power output in dynamic cyclic movements. The goal of this study was to develop and validate a modified Hill-type muscle model that includes shortening-induced force depression and assess its influence on locomotor performance. The magnitude of force depression was defined by empirical relationships based on muscle mechanical work. To validate the model, simulations incorporating force depression were developed to emulate single muscle in situ and whole muscle group leg extension experiments. There was excellent agreement between simulation and experimental values, with in situ force patterns closely matching the experimental data (average RMS error <1.5 N) and force depression in the simulated leg extension exercise being similar in magnitude to experimental values (6.0% vs. 6.5%, respectively). To examine the influence of force depression on locomotor performance, simulations of maximum power pedaling with and without force depression were generated. Force depression decreased maximum crank power by 20–40%, depending on the relationship between force depression and muscle work used. These results indicate that force depression has the potential to substantially influence muscle power output in dynamic cyclic movements. However, to fully understand the impact of this phenomenon on human movement, more research is needed to characterize the relationship between force depression and mechanical work in large muscles with different morphologies.