Trends in Neurosciences
Volume 31, Issue 10, October 2008, Pages 538-547
Journal home page for Trends in Neurosciences

Review
Respiratory neuroplasticity and cervical spinal cord injury: translational perspectives

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Paralysis of the diaphragm is a severe consequence of cervical spinal cord injury. This condition can be experimentally modeled by lateralized, high cervical lesions that interrupt descending inspiratory drive to the corresponding phrenic nucleus. Although partial recovery of ipsilateral diaphragm function occurs over time, recent findings show persisting chronic deficits in ventilation and phrenic motoneuron activity. Some evidence suggests, however, that spontaneous recovery can be enhanced by modulating neural pathways to phrenic motoneurons via synaptic circuitries which appear more complex than previously envisioned. The present review highlights these and other recent experimental multidisciplinary findings pertaining to respiratory neuroplasticity in the rat. Translational considerations are also emphasized, with specific attention directed at the clinical and interpretational strengths of different lesion models and outcome measures.

Introduction

Among the more significant advances in spinal cord injury (SCI) research is growing recognition of the capacity for spontaneous recovery 1, 2. Intraspinal neuroplastic reserve in human subjects has been revealed by a range of outcome measures, and improvements can evolve months to years after trauma [3], even in cases of neurologically complete injury [4]. This has led to a greater appreciation for opportunities to therapeutically amplify natural recovery processes, as demonstrated by experimental studies 5, 6.

Although most attention to spinal cord neuroplasticity has centered on locomotor function, it is well established that a significant potential for spontaneous recovery also exists in another motor domain referred to here as the phrenic motor system. Approximately half of spinal injuries occur at cervical levels [7], and in those cases involving diaphragm dysfunction, intensive post-SCI care and management are usually required 8, 9, 10. Because such individuals are at risk of increased morbidity and mortality due to secondary pulmonary complications 8, 11, continuing development of strategies to improve respiratory function is necessary.

Respiration after cervical SCI has thus attracted increasing scientific attention largely through integration of SCI and respiratory neurobiology expertise. As with locomotion, current literature suggests that respiratory neuroplasticity might also be responsive to therapeutic intervention 12, 13, 14. In the present review, we first establish a clinical perspective with consideration of respiratory outcome measures, their interpretations and how some approaches might lend to clinical and laboratory application. Discussion then turns to recent experimental findings pertaining to mechanisms and neural substrates associated with phrenic motoneuron (PhMN) function and respiratory behavior after SCI. An additional emphasis of this review is on preclinical modeling considerations that can be pivotal in guiding future research and treatment approaches to optimize post-SCI respiratory neuroplasticity.

Section snippets

Clinical features of respiratory function following spinal cord injury

Respiratory compromise can result from trauma at any spinal segment from high cervical to midlumbar levels owing to impaired primary or accessory respiratory muscle activity 9, 11. A frequently cited example is injury sustained at high cervical levels which can result in diaphragm dysfunction due to interruption of bulbospinal respiratory drive to PhMN pools (C3–C5). In contrast, normal breathing and defensive mechanisms (e.g. cough) can be significantly compromised by more caudal trauma at

Outcome measures of respiratory function and preclinical studies

With expanding interest in applied SCI research, emphasis has been placed on the need for sensitive and quantitative outcome measures to demonstrate the efficacy of novel therapeutic approaches in preclinical investigations and future clinical trials [24]. Although a variety of neurological and functional tests have been discussed [25], little attention has been given to respiratory assessment with translational relevance. Table 1 summarizes available outcome measures with commentary on their

Experimental models of cervical SCI

The term ‘neuroplasticity’ is not commonly used in the clinical literature in association with recovery of respiratory function after SCI. Therefore, experimental demonstrations of this concept could facilitate future therapeutic developments. Essential to this are preclinical models approximating the human condition or capable of providing fundamental proof-of-principle information. Of all experimental cervical spinal lesion paradigms used to assess respiratory function after SCI (Figure 1;

Patterns of breathing after cervical SCI

Previous work suggests the CPP has little impact on breathing behavior during the first 5 weeks post-C2HMx [27]. Plethysmography studies of unanesthetized rats demonstrated that minute ventilation was maintained but with a rapid, shallow breathing pattern under room air (i.e. ‘quiet breathing’) conditions, similar to what is seen in humans (see above). Moreover, persistent deficits in ventilation were observed during conditions of increased respiratory drive, and parallel studies in

Enhancement of respiratory recovery

Whereas the clinical approach to respiratory dysfunction post-SCI has primarily focused on management and assisted ventilation, other approaches have been employed to enhance post-SCI pulmonary function such as respiratory muscle strengthening (reviewed in Ref. [60]). In addition, experimental evidence has shown that ipsilateral phrenic nerve activity post-C2HMx can be significantly enhanced by surgical 59, 61 or physiological 37, 39 approaches. Such findings suggest that chronic respiratory

Neural circuitry and respiratory recovery

To date, enhanced respiratory-related synaptic plasticity has been attributed to changes primarily at the level of the PhMN, as exemplified by neurophysiological studies 37, 76, Some synaptic plasticity might also entail respiratory-associated changes elsewhere in the cervical spinal cord, as well as at brainstem levels. Present neuroanatomical data indicate that the crossed axons mediating the CPP derive from decussating contralateral and recrossed ipsilateral axons from the ventral

Closing commentary: translational relevance of respiratory neuroplasticity models

Recent animal data, based upon the CPP model, continue to highlight the possibility that enhancement of phrenic neuroplasticity represents an achievable therapeutic target in SCI research. However, the pathology and cervical level of human contusions are often inconsistent with preservation of the neural substrate mediating the CPP (Figure 1). Therefore, from a clinical perspective, respiratory neuroplasticity as defined by the CPP might represent a biological phenomenon unique to a particular

Acknowledgements

Original research of the authors reported in this review was supported by NIH/NINDS RO1 NS054025, the Anne and Oscar Lackner Endowed Chair (P.J.R.) and a Craig H. Neilsen Postdoctoral Fellowship (M.A.L.). The authors also wish to thank Jeffrey Kleim for his helpful comments on the manuscript.

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