Hemisection of the cervical spinal cord rostral to the level of the phrenic nucleus interrupts descending bulbospinal respiratory pathways, which results in a paralysis of the ipsilateral hemidiaphragm. In several mammalian species, functional recovery of the paretic hemidiaphragm can be achieved by transecting the contralateral phrenic nerve. The recovery of the paralyzed hemidiaphragm has been termed the "crossed phrenic phenomenon." The physiological basis for the crossed phrenic phenomenon is as follows: asphyxia induced by spinal hemisection and contralateral phrenicotomy increases central respiratory drive, which activates a latent crossed respiratory pathway. The uninjured, initially latent pathway mediates the hemidiaphragm recovery by descending into the spinal cord contralateral to the hemisection and then crossing the midline of the spinal cord before terminating on phrenic motoneurons ipsilateral and caudal to the hemisection. The purpose of this study is to review work conducted on the crossed phrenic phenomenon and to review closely related studies focusing particularly on the plasticity associated with the response. Because the review deals with recovery of respiratory muscles paralyzed by spinal cord injury, the clinical relevance of the reviewed studies is highlighted.

Previous studies have shown that latent respiratory pathways can be activated by as phyxia or systemic theophylline administration to restore function to a hemidiaphragm paralyzed by C2 spinal cord hemisection in adult female rats. Based on this premise, electrophysiologic recording techniques were employed in the present investigation to first determine qualitatively whether latent respiratory pathways are activated spon taneously following prolonged post hemisection periods (4-16 weeks) without any therapeutic intervention. Our second objective in a separate group of hemisected an imals was to quantitate any documented functional recovery under the following stan dardized recording conditions: bilateral vagotomy, paralysis with pancuronium bro mide, artificial ventilation, and constant PCO 2 (maintained at 25 mmHg).

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.

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The phrenic nucleus of the adult albino rat was studied by utilizing the O-dianisidine method for the retrograde transport of horseradish peroxidase in conjunction with the zinc chromate modification of the Golgi technique. Application of HRP to the transected phrenic nerve in the neck labeled a column of phrenic motor neurons from C3 to C5 in the ipsilateral spinal cord. However, when HRP was applied to the phrenic nerve intrathoracically, labeled neurons were found from C3 to C6. The long axis of the column of phrenic neurons was oriented tangentially from rostral to caudal poles. There was a gradual shift of the column from posterior to anterior and from lateral to medial positions in the ventral horn. The peroxidase material was also used to localize impregnated phrenic motor neurons in the Golgi sections and to provide quantitative data on phrenic motor neurons. In Golgi-impregnated material two types of phrenic neurons were distinguished on the basis of dendritic morphology and orientation. These neurons were designated (1) large neurons with smooth, radially oriented dendrites, and (2) smaller neurons with varicose, tangentially oriented dendrites. Both types of neurons had a small number of spines and bulbous appendages issuing from the dendritic trunks and branches. The dendritic fields of adjacent phrenic neurons overlapped extensively with one another and with dendrites of more distally placed ventral horn motor neurons. In peroxidase-labeled sagittal sections the dendrites of phrenic neurons were primarily oriented in the rostrocaudal plane. The mean total number of peroxidase-labeled neurons in the phrenic nucleus was 415.75 +/- 18.36 cells. In sagittal sections the mean long axis diameter of phrenic cell bodies was 34.5 micrometers. In frontal sections the mean long axis diameter of phrenic cell bodies was 22.5 micrometers. Thus, from direct measurement, the phrenic neurons were 34% longer in the sagittal plane than in the frontal plane. In the present study each phrenic nucleus contributed fibers only to the ipsilateral phrenic nerve, and no evidence for peripheral crossing of fibers was found.

This review will focus on neural plasticity and recovery of respiratory function after spinal cord injury and feature the "crossed phrenic phenomenon" (CPP) as a model for demonstrating such plasticity and recovery. A very brief summary of the earlier literature on the CPP will be followed by a more detailed review of the more recent studies. Two aspects of plasticity associated with the CPP that have been introduced in the literature recently have been spontaneous recovery of ipsilateral hemidiaphragmatic function following chronic spinal cord injury and drug-induced persistent recovery of the ipsilateral hemidiaphragm lasting long after animals have been weaned from drug treatment. The underlying mechanisms for this plasticity and resultant recovery will be discussed in this review. Moreover, two new models involving the CPP have been introduced: a mouse model which now provides for an opportunity to study CPP plasticity at a molecular level using a genetic approach and light-stimulated induction of the CPP accomplished by transfecting mammalian cells with channelrhodopsin. Both models provide an opportunity to sort out the intracellular signaling cascades that may be involved in motor recovery in the respiratory system after spinal cord injury. Finally, the review will examine developmental plasticity of the CPP and discuss how the expression of the CPP changes in neonatal rats as they mature to adults. Understanding the underlying mechanisms behind the spontaneous expression of the crossed phrenic pathway either in the developing animal or after chronic spinal cord injury in the adult animal may provide clues to initiating respiratory recovery sooner to alleviate human suffering and eventually eliminate the leading cause of death in human cases of spinal cord injury.

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The hypothesis that excitatory drive is transmitted monosynaptically from bulbospinal medullary respiratory neurons to spinal respiratory motoneurons was tested by an ultrastructural analysis of the phrenic motoneuronal pool in the rat. Combined anterograde labeling of the principal inspiratory bulbospinal neuron population (ventral respiratory group) and retrograde labeling of the phrenic motoneuron pool demonstrated the presence of labeled synaptic profiles, indicating that at least some bulbospinal inspiratory neurons make monosynaptic contacts with phrenic motoneurons. The synaptic boutons of ventral respiratory group neurons that were labeled in the phrenic nucleus had asymmetrical membrane densities at sites of synaptic contact with labeled phrenic somal or dendritic profiles, supporting the notion that this bulbospinal pathway has excitatory contacts with phrenic motoneurons. The morphological types of labeled boutons included three of the eight previously identified bouton types in the phrenic nucleus (Goshgarian and Rafols: Journal of Neurocytology 13:85-109, 1984), including the "S"-terminal, the "NFs"-terminal, and the "F"-terminal. There was no conclusive evidence of labeled double synapses, indicating that this type of synaptic contact is not common in the intact bulbospinal pathway.