M. Beth Zimmer

Effect of Spinal Cord Injury on the Respiratory System: Basic Research and Current Clinical Treatment Options

Abstract Summary: Spinal cord injury (SCI) often leads to an impairment of the respiratory system. The more rostral the level of injury, the more likely the injury will affect ventilation. In fact, respiratory insufficiency is the number one cause of mortality and morbidity after SCI. This review highlights the progress that has been made in basic and clinical research, while noting the gaps in our knowledge. Basic research has focused on a hemisection injury model to examine methods aimed at improving respiratory function after SCI, but contusion injury models have also been used. Increasing synaptic plasticity, strengthening spared axonal pathways, and the disinhibition of phrenic motor neurons all result in the activation of a latent respiratory motor pathway that restores function to a previously paralyzed hemidiaphragm in animal models. Human clinical studies have revealed that respiratory function is negatively impacted by SCI. Respiratory muscle training regimens may improve inspiratory function after SCI, but more thorough and carefully designed studies are needed to adequately address this issue. Phrenic nerve and diaphragm pacing are options available to wean patients from standard mechanical ventilation. The techniques aimed at improving respiratory function in humans with SCI have both pros and cons, but having more options available to the clinician allows for more individualized treatment, resulting in better patient care. Despite significant progress in both basic and clinical research, there is still a significant gap in our understanding of the effect of SCI on the respiratory system.

Regulation of cardiac rhythm in hibernating mammals

The dramatic fall in heart rate exhibited by mammals entering hibernation begins before there is any noticeable fall in body temperature. The initial, progressive decrease in heart rate is the result of a cyclic parasympathetic activation that induces skipped beats and regular asystoles as well as slows the even heart beat. As body temperature subsequently falls, the parasympathetic influence is progressively withdrawn and periods of parasympathetic and sympathetic dominance alternate and give rise to regular periods of arrhythmia (tachycardia followed by bradycardia), and occasional long asystoles or periods of highly irregular cardiac activity. Superimposed on this is a vagally-mediated, respiratory sinus arrhythmia that is accentuated in species that breathe episodically. These events give way to a uniform heart rate in deep hibernation at low temperatures where both parasympathetic and sympathetic tone appear absent. The complete absence of tone is not a function of reduced temperature but is reflective of the state of deep, steady state hibernation. The elevation in heart rate that accompanies the onset of arousal is the result of dramatic increases in sympathetic activation that precede any increases in body temperature. As body temperature then rises, sympathetic influence is slowly withdrawn. Arrhythmias are also common during natural arousals or shifts from lower to warmer hibernation temperatures as periods of parasympathetic and sympathetic dominance again alternate en route to re-establishing a steady state in euthermia. The mechanism behind, and the biological significance of, cardiac changes mediated through orchestrated arrhythmias remain unknown.

Effect of spinal cord injury on the neural regulation of respiratory function

Injury at any level of the spinal cord can impair respiratory motor function. Indeed, complications associated with respiratory function are the number one cause of mortality in humans following spinal cord injury (SCI) at any level of the cord. This review is aimed at describing the effect of SCI on respiratory function while highlighting the recent advances made by basic science research regarding the neural regulation of respiratory function following injury. Models of SCI that include upper cervical hemisection and contusion injury have been utilized to examine the underlying neural mechanisms of respiratory control following injury. The approaches used to induce motor recovery in the respiratory system are similar to other studies that examine recovery of locomotor function after SCI. These include strategies to initiate regeneration of damaged axons, to reinnervate paralyzed muscles with peripheral nerve grafts, to use spared neural pathways to induce motor function, and finally, to initiate mechanisms of neural plasticity within the spinal cord to increase motoneuron firing. The ultimate goals of this research are to restore motor function to previously paralyzed respiratory muscles and improve ventilation in patients with SCI.

Spinal Activation of Serotonin 1A Receptors Enhances Latent Respiratory Activity After Spinal Cord Injury

Abstract Background/Objective: Hemisection of the cervical spinal cord results in paralysis of the ipsilateral hemidiaphragm. Removal of sensory feedback through cervical dorsal rhizotomy activates latent respiratory motor pathways and restores hemidiaphragm function. Because systemic administration of serotonin 1A receptor (5HT1A) agonists reversed the altered breathing patterns after spinal cord injury (SCI), we predicted that 5HT1A receptor activation after SCI (C2) would activate latent crossed motor pathways. Furthermore, because 5HT1A receptors are heavily localized to dorsal horn neurons, we predicted that spinal administration of 5HT1A agonists should also activate latent motor pathways. Methods: Hemisection of the C2 spinal cord was performed 24 to 48 hours, 1 week, or 16 weeks before experimentation. Bilateral phrenic nerve activity was recorded in anesthetized, vagotomized, paralyzed Sprague-Dawley rats, and 8-OH-DPAT (5HT1A agonist) was applied to the dorsal aspect of the cervical spinal cord (C3-C7) or injected systemically. Results: Systemic administration of 8-OH-DPAT led to a significant increase in phrenic frequency and amplitude, whereas direct application to the spinal cord increased phrenic amplitude alone. Both1 systemic and spinal administration of 8-OH-DPAT consistently activated latent crossed phrenic activity. 8-OH-DPAT induced a greater respiratory response in spinal injured rats compared with controls. Conclusion: The increase in crossed phrenic output after application of 8-OH-DPAT to the spinal cord suqgests that dorsal horn inputs, respiratory and/or nonrespiratory, may inhibit phrenic motor output, especially after SCI. These findings support the idea that the administration of 5HT1A agonists may be a beneficial therapy in enhancing respiratory neural output in patients with SCI.

The conditional nature of the Central Rhythm Generator and the production of episodic breathing

Episodic breathing patterns have been observed in species of all vertebrate classes under certain conditions and/or at certain times in development. This breathing pattern can be considered part of a continuum between no breathing and continuous breathing. In birds and mammals it is also generally part of a developmental continuum in which episodic breathing occurs early in development and rarely in adults. Production of this pattern appears to be an intrinsic property of the medullary rhythm generating mechanism (possibly due to interactions between different rhythm generating sites) that is stabilized by pontine or midbrain inputs and, in intact animals, is primarily regulated by afferent inputs from chemoreceptors and pulmonary stretch receptors; i.e. there is a hierarchy of control. In all cases, episodes appear to be produced by quantal expression of a fundamental rhythm. At present NO, GABA(A) and glycine mediated processes, and possibly mu-opioid receptor mediated processes, are implicated in the clustering of breaths into episodes. The inter-breath interval, which may occur at either the end of the inspiratory or the expiratory phase in different species, is the primary regulated variable in this pattern. The biological significance of clustering breaths into episodes may relate to reducing the oxidative cost of breathing, enhancing gas exchange or minimizing oxidative damage to tissues.

Effects of Changing Ambient Temperature on Metabolic, Heart, and Ventilation Rates during Steady State Hibernation in Golden‐Mantled Ground Squirrels (Spermophilus lateralis)

To determine whether metabolic rate is suppressed in a temperature‐independent fashion in the golden‐mantled ground squirrel during steady state hibernation, we measured body temperature and metabolic rate in ground squirrels during hibernation at different Tas. In addition, we attempted to determine whether heart rate, ventilation rate, and breathing patterns changed as a function of body temperature or metabolic rate. We found that metabolic rate changed with Ta as it was raised from 5° to 14°C, which supports the theory that different species sustain falls in metabolic rate during hibernation in different ways. Heart rate and breathing pattern also changed with changing Ta, while breathing frequency did not. That the total breathing frequency did not correlate closely with oxygen consumption or body temperature, while the breathing pattern did, raises important questions regarding the mechanisms controlling ventilation during hibernation.

Spinal cord injury in neonates alters respiratory motor output via supraspinal mechanisms.

Upper cervical spinal cord injury (SCI) alters respiratory output and results in a blunted respiratory response to pH/CO2. Many SCI studies have concentrated on respiratory changes in neural function caudal to injury; however few have examined whether neural plasticity occurs rostral to SCI. Golder et al. (2001a) showed that supraspinal changes occur to alter respiratory output after SCI. Furthermore, Brown et al. (2004) showed that neural receptors change rostral to a thoracic SCI. We hypothesized that SCI in neonates will alter supraspinal output, show a blunted response to pH and alter receptor protein levels in the medulla. On postnatal day 0/1, a C2 SCI surgery was performed. Two days later, neonates were anesthetized and brainstem-spinal cords removed. Respiratory-related activity was recorded using the in vitro brainstem-spinal cord preparation and the superfusate pH was changed (pH 7.2, 7.4 and 7.8). The respiratory-like frequency was significantly reduced in SCI rats indicating supraspinal plasticity. Increasing the pH decreased respiratory-like frequency and peak amplitude in injured and sham controls. Increasing the pH increased burst duration and area in sham controls, whereas in injured rats, the burst duration and area decreased. Western blot analysis demonstrated significant changes in glutamate receptor subunits (NR1, NR2B and GluR2), adenosine receptors (A1, A2A), glutamic acid decarboxylase (65) and neurokinin-1 receptors in medullary tissue ipsilateral and contralateral to injury. These data show that supraspinal plasticity in the respiratory system occurs after SCI in neonate rats. The mechanisms remain unknown, but may involve alterations in receptor proteins involved in neurotransmission.

GABA, not glycine, mediates inhibition of latent respiratory motor pathways after spinal cord injury

Previous work has shown that latent respiratory motor pathways known as crossed phrenic pathways are inhibited via a spinal inhibitory process; however, the underlying mechanisms remain unknown. The present study investigated whether spinal GABA-A and/or glycine receptors are involved in the inhibition of the crossed phrenic pathways after a C2 spinal cord hemisection injury. Under ketamine/xylazine anesthesia, adult, female, Sprague-Dawley rats were hemisected at the C2 spinal cord level. Following 1 week post injury, rats were anesthetized with urethane, vagotomized, paralyzed and ventilated. GABA-A receptor (bicuculline and Gabazine) and glycine receptor (strychnine) antagonists were applied directly to the cervical spinal cord (C3-C7), while bilateral phrenic nerve motor output was recorded. GABA-A receptor antagonists significantly increased peak phrenic amplitude bilaterally and induced crossed phrenic activity in spinal-injured rats. Muscimol, a specific GABA-A receptor agonist, blocked these effects. Glycine receptor antagonists applied directly to the spinal cord had no significant effect on phrenic motor output. These results indicate that phrenic motor neurons are inhibited via a GABA-A mediated receptor mechanism located within the spinal cord to inhibit the expression of crossed phrenic pathways.

Physiological Society Symposium – Vagal Control: From Axolotl to Man

Autonomic events associated with entrance into hbernation are primarily mediated by the parasympathetic nervous system while those associated with arousal from hibernation are primarily sympathetically mediated. During deep hibernation, both sympathetic and parasympathetic tone are greatly reduced or absent. Within this context, the pattern of autonomic influence on cardiorespiratory control is intriguing. The dramatic fall in heart rate exhibited by mammals entering hibernation begins before there is any noticeable fall in body temperature and is due to a cyclic vagal activation that induces skipped beats and regular asystoles, and also slows the even heart beat. As body temperature subsequently falls, the vagal influence is progressively withdrawn and periods of vagal and sympathetic dominance alternate and give rise to regular periods of arrhythmm (tachycardia followed by bradycardia). Superimposed on this is a vagally mediated, respiratory sinus arrhythmia. As metabolic rate and body temperature fall, breathing frequency slows, depending on species, either by a prolongation of the pause between breaths, or by a waxing and waning of breathing frequency giving rise to discrete periods of apnoea interspersed by periods of continuous breathing. In such cases, the waxing and waning, and resulting episodic pattern, appear to be due to alternating positive and negative influences, possibly arising from vagal-pontine interactions acting on the medullary respiratory centres. The respiratory sinus arrhythmia is accentuated in these species. While advances have been made in describing the overt changes in autonomic control of cardiorespiratory processes during hibernation, the mechanisms behind, and the biological significance of cardiac and respiratory changes mediated through orchestrated arrhythmias and apnoeas, remain enigmatic.

Spontaneous crossed phrenic activity in the neonatal respiratory network.

Hemisection of the cervical spinal cord causes paralysis of the ipsilateral hemidiaphragm in adult rats. Activation of a latent crossed phrenic motor pathway can restore diaphragmatic function, although structural changes take place before the pathway can be activated. Since mechanisms are employed to eliminate non-functional projections during development, we predicted that this latent neural pathway might be active during development. Therefore, we examined the effect of spinal hemisection (C2) on respiratory-like activity bilaterally using the brainstem--spinal cord preparation from neonatal rats (0-4 days). Spontaneous crossed phrenic activity (respiratory-like activity recorded from the ipsilateral C4 or C5 ventral roots following C2 hemisection) was observed in an age-dependent manner; younger preparations exhibited more than older preparations. Increasing drive (increasing [K+] or superfusion of theophylline) either increased or induced crossed phrenic activity. Hemisection caused no change in the frequency, the burst area, duration or peak amplitude contralateral to hemisection. Unlike adult rats, this study shows that crossed phrenic activity is present in the in vitro respiratory network of neonatal rats suggesting that a crossed neural pathway may be functionally active in neonates.