Enhancing neural activity to drive respiratory plasticity following cervical spinal cord injury (original) (raw)
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Rapid and robust restoration of breathing long after spinal cord injury
Nature Communications, 2018
There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (5HT) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via 5HT2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust pa...
Long-term reorganization of respiratory pathways after partial cervical spinal cord injury
European Journal of Neuroscience, 2008
High cervical spinal cord injury (SCI) interrupts bulbospinal respiratory pathways innervating phrenic motoneurons, and induces an inactivation of phrenic nerves (PN) and diaphragm. We have previously shown that the ipsilateral (ipsi) PN was inactivated following a lateral C2 SCI, but was spontaneously partially reactivated 7 days post-SCI. This phrenic reactivation depended on contralateral (contra) descending pathways, located laterally, that cross the spinal midline. We analysed here whether long-term post-lesional changes may occur in the respiratory network. We showed that ipsi PN reactivation was greater at 3 months compared with 7 days post-SCI, and that it was enhanced after acute contra phrenicotomy (Phx), which also induced a substantial reactivation of the ipsi diaphragm (not detected at 7 days post-SCI). At 3 months post-SCI (compared with 7 days post-SCI), ipsi PN activity was only moderately affected by ipsi Phx or by gallamine treatment, a nicotinic neuromuscular blocking agent, indicating that it was less dependent on ipsi sensory phrenic afferents. After an additional acute contra SCI (C1) performed laterally, ipsi PN activity was abolished in rats 7 days post-SCI, but persisted in rats 3 months post-SCI. This activity thus depended on new functional descending pathways located medially rather than laterally. These may not involve newly recruited neurons as retrograde labelling showed that ipsi phrenic motoneurons were innervated by a similar number of medullary respiratory neurons after a short and long post-lesional time. These results show that after a long post-lesional time, phrenic reactivation is reinforced by an anatomo-functional reorganization of spinal respiratory pathways.
Functional regeneration of respiratory pathways after spinal cord injury
Nature, 2011
Spinal cord injuries (SCI) often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. Unfortunately, the untoward effects of impaired breathing are a leading cause of SCI-related death, underscoring the importance of developing strategies to restore respiratory activity. Here we show that after cervical SCI, there is upregulation of the perineuronal net (PNN) associated chondroitin sulfate proteoglycans (CSPGs) around phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with Chondroitinase ABC (ChABC) can, by itself, promote plasticity of spared tracts and restore limited activity to the paralyzed diaphragm. However, when combined with application of a peripheral nerve autograft, ChABC treatment results in lengthy regeneration of serotonergic axons and other bulbospinal fibers with remarkable recovery of diaphragm function. Following recovery and initial transection of the bridge, there occurs an unusual, overall increased tonic diaphragmatic EMG activity, suggesting considerable remodeling of spinal cord circuitry after regeneration. This is followed by complete elimination of the restored activity proving that regeneration is critical for the return of function. Overall, these experiments present a way to profoundly restore function of a single muscle following debilitating CNS trauma, through both plasticity of spared tracts and regeneration of essential pathways. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Spinal circuitry and respiratory recovery following spinal cord injury
Respiratory Physiology & Neurobiology, 2009
Numerous studies have demonstrated anatomical and functional neuroplasticity following spinal cord injury. One of the more notable examples is return of ipsilateral phrenic motoneuron and diaphragm activity which can be induced under terminal neurophysiological conditions after high cervical hemisection in the rat. More recently it has been shown that a protracted, spontaneous recovery also occurs in this model. While a candidate neural substrate has been identified for the former, the neuroanatomical basis underlying spontaneous recovery has not been explored. Demonstrations of spinal respiratory interneurons in other species suggest such cells may play a role; however, the presence of interneurons in the adult rat phrenic circuit-the primary animal model of respiratory plasticity-has not been extensively investigated. Emerging neuroanatomical and electrophysiological results raise the possibility of a more complex neural network underlying spontaneous recovery of phrenic function and compensatory respiratory neuroplasticity after C2 hemisection than has been previously considered.
Restoration of respiratory muscle function following spinal cord injury
Respiratory Physiology & Neurobiology, 2005
Respiratory complications are a leading cause of morbidity and mortality in patients with spinal cord injury. Several techniques, currently available or in development, have the capacity to restore respiratory muscle function allowing these patients to live more normal lives and hopefully reduce the incidence of respiratory complications. Bilateral phrenic nerve pacing, a clinically accepted technique to restore inspiratory muscle function, allows patients with ventilator dependent tetraplegia complete freedom from mechanical ventilation. Compared to mechanical ventilation, phrenic nerve pacing provides patients with increased mobility, improved speech, improved comfort level and reduction in health care costs. The results of clinical trials of laparoscopically placed intramuscular diaphragm electrodes suggest that diaphragm pacing can also be achieved without the need for a thoracotomy and associated long hospital stay, and without manipulation of the phrenic nerve which carries a risk of phrenic nerve injury. Other clinical trials are being performed to restore inspiratory intercostal function. In patients with only unilateral phrenic nerve function who are not candidates for phrenic nerve pacing, combined intercostal and unilateral diaphragm pacing appears to provide benefits similar to that of bilateral diaphragm pacing. Clinical trials are also underway to restore expiratory muscle function. Magnetic stimulation, surface stimulation and spinal cord stimulation of the expiratory muscles are promising techniques to restore an effective cough mechanism in this patient population. These techniques hold promise to reduce the incidence of respiratory tract infections, atelectasis and respiratory failure in patients with spinal cord injury and reduce the morbidity and mortality associated with these complications.
Respiratory Motor Control Disrupted by Spinal Cord Injury: Mechanisms, Evaluation, and Restoration
Translational Stroke Research, 2011
Pulmonary complications associated with persistent respiratory muscle weakness, paralysis, and spasticity are among the most important problems faced by patients with spinal cord injury when lack of muscle strength and disorganization of reciprocal respiratory muscle control lead to breathing insufficiency. This review describes the mechanisms of the respiratory motor control and its change in individuals with spinal cord injury, methods by which respiratory function is measured, and rehabilitative treatment used to restore respiratory function in those who have experienced such injury.
Complete Restoration of Respiratory Muscle Function in Subjects With Spinal Cord Injury
American Journal of Physical Medicine & Rehabilitation, 2020
Objectives: To assess the safety and efficacy of complete restoration of respiratory muscle function in subjects with Spinal Cord Injury (SCI). Methods: This was an interventional study investigating three subjects maintained on a diaphragm pacing system who were implanted with the spinal cord stimulation (SCS) system to restore cough. Peak expiratory airflow and airway pressure generation were the primary physiologic outcome measures; an assessment of the degree of difficulty in raising secretions was the primary clinical outcome measure. Results: Mean peak expiratory airflow and airway pressure generation during spontaneous efforts were 1.7±0.2L/s and 31±7cmH 2 O respectively. When SCS was applied following pacing volume associated with the subject's maximum inspiratory effort and synchronized with the subject's maximum expiratory effort, peak expiratory airflow and airway pressure generation were 9.0±1.9 and 90±6cmH 2 O, respectively (p<0.05). Moreover, each subject experienced much greater ease in raising secretions and marked improvement in the ease in raising secretions compared to other methods. Conclusions: Complete restoration of respiratory muscle function can be safely and effectively achieved in the same individuals with SCI. SCS results in peak expiratory airflow and airway pressure generation characteristic of a normal cough while diaphragm pacing was successful in maintaining patients off mechanical ventilation.
Complete Restoration of Respiratory Muscle Function in Three Subjects With Spinal Cord Injury
American Journal of Physical Medicine & Rehabilitation, 2018
The aim of this study was to assess the safety and efficacy of complete restoration of respiratory muscle function in subjects with spinal cord injury. Methods: This was an interventional study investigating three subjects maintained on a diaphragm pacing system who were implanted with the spinal cord stimulation system to restore cough. Peak expiratory airflow and airway pressure generation were the primary physiologic outcome measures; an assessment of the degree of difficulty in raising secretions was the primary clinical outcome measure. Results: Mean peak expiratory airflow and airway pressure generation during spontaneous efforts were 1.7 ± 0.2 L/s and 31 ± 7 cmH 2 O, respectively. When spinal cord stimulation was applied after pacing volume associated with the subject's maximum inspiratory effort and synchronized with the subject's maximum expiratory effort, peak expiratory airflow and airway pressure generation were 9.0 ± 1.9 L/s and 90 ± 6 cmH 2 O, respectively (P < 0.05). Moreover, each subject experienced much greater ease in raising secretions and marked improvement in the ease in raising secretions compared with other methods. Conclusions: Complete restoration of respiratory muscle function can be safely and effectively achieved in the same individuals with spinal cord injury. Spinal cord stimulation results in peak expiratory airflow and airway pressure generation characteristic of a normal cough, whereas diaphragm pacing was successful in maintaining patients off mechanical ventilation.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
By 2 months after unilateral cervical spinal cord injury (SCI), respiratory motor output resumes in the previously quiescent phrenic nerve. This activity is derived from bulbospinal pathways that cross the spinal midline caudal to the lesion (crossed phrenic pathways). To determine whether crossed phrenic pathways contribute to tidal volume in spinally injured rats, spontaneous breathing was measured in anesthetized C2 hemisected rats at 2 months after injury with an intact ipsilateral phrenic nerve, or with ipsilateral phrenicotomy performed at the time of the SCI (i.e., crossed phrenic pathways rendered ineffective) (dual injury). Ipsilateral phrenicotomy did not alter the rapid shallow eupneic breathing pattern in C2 injured rats. However, the ability to generate large inspiratory volumes after either vagotomy or during augmented breaths was impaired if crossed phrenic activity was abolished. We also investigated whether compensatory plasticity in contralateral motoneurons would ...
Intermittent hypoxia induces functional recovery following cervical spinal injury
Respiratory Physiology & Neurobiology, 2009
Respiratory-related complications are the leading cause of death in spinal cord injury (SCI) patients. Few effective SCI treatments are available after therapeutic interventions are performed in the period shortly after injury (e.g. spine stabilization and prevention of further spinal damage). In this review we explore the capacity to harness endogenous spinal plasticity induced by intermittent hypoxia to optimize function of surviving (spared) neural pathways associated with breathing. Two primary questions are addressed: 1) does intermittent hypoxia induce plasticity in spinal synaptic pathways to respiratory motor neurons following experimental SCI? and 2) can this plasticity improve respiratory function? In normal rats, intermittent hypoxia induces serotonin-dependent plasticity in spinal pathways to respiratory motor neurons. Early experiments suggest that intermittent hypoxia also enhances respiratory motor output in experimental models of cervical SCI, (cervical hemisection) and that the capacity to induce functional recovery is greater with longer durations postinjury. Available evidence suggests that intermittent hypoxia-induced spinal plasticity has considerable therapeutic potential to treat respiratory insufficiency following chronic cervical spinal injury.