Contribution of the spontaneous crossed-phrenic phenomenon to inspiratory tidal volume in spontaneously breathing rats

Spinal cord hemisection at C2 (C2HS) severs bulbospinal inputs to ipsilateral phrenic motoneurons causing transient hemidiaphragm paralysis. The spontaneous crossed-phrenic phenomenon (sCPP) describes the spontaneous recovery of ipsilateral phrenic bursting following C2HS. We reasoned that the immediate (next breath) changes in tidal volume (VT) induced by ipsilateral phrenicotomy during spontaneous breathing would provide a quantitative measure of the contribution of the sCPP to postinjury VT. Using this approach, we tested the hypothesis that the sCPP makes more substantial contributions to VT when respiratory drive is increased. Pneumotachography was used to measure VT in anesthetized, spontaneously breathing adult male rats at intervals following C2HS. A progressive increase in VT (ml/breath) occurred over an 8 wk period following C2HS during both poikilocapnic baseline breathing and hypercapnic respiratory challenge (7% inspired CO2). The sCPP did not impact baseline breathing at 1–3 days postinjury since VT was unchanged after ipsilateral phrenicotomy. However, by 2 wk post-C2HS, baseline phrenicotomy caused a 16 ± 2% decline in VT; a comparable 16 ± 4% decline occurred at 8 wk. Contrary to our hypothesis, the phrenicotomy-induced declines in VT (%) during hypercapnic respiratory stimulation did not differ from the baseline response at any postinjury time point (all P > 0.11). We conclude that by 2 wk post-C2HS the sCPP makes a meaningful contribution to VT that is similar across different levels of respiratory drive.

Influence of vagal afferents on supraspinal and spinal respiratory activity following cervical spinal cord injury in rats

C2 spinal hemisection (C2HS) interrupts ipsilateral bulbospinal pathways and induces compensatory increases in contralateral spinal and possibly supraspinal respiratory output. Our first purpose was to test the hypothesis that after C2HS contralateral respiratory motor outputs become resistant to vagal inhibitory inputs associated with lung inflation. Bilateral phrenic and contralateral hypoglossal (XII) neurograms were recorded in anesthetized and ventilated rats. In uninjured (control) rats, lung inflation induced by positive end-expired pressure (PEEP; 3–9 cmH2O) robustly inhibited both phrenic and XII bursting. At 2 wk post-C2HS, PEEP evoked a complex response associated with phrenic bursts of both reduced and augmented amplitude, but with no overall change in the mean burst amplitude. PEEP-induced inhibition of XII bursting was still present but was attenuated relative to controls. However, by 8 wk post-C2HS PEEP-induced inhibition of both phrenic and XII output were similar to that in controls. Our second purpose was to test the hypothesis that vagal afferents inhibit ipsilateral phrenic bursting, thereby limiting the incidence of the spontaneous crossed phrenic phenomenon in vagal-intact rats. Bilateral vagotomy greatly enhanced ipsilateral phrenic bursting, which was either weak or absent in vagal-intact rats at both 2 and 8 wk post-C2HS. We conclude that 1) compensatory increases in contralateral phrenic and XII output after C2HS blunt the inhibitory influence of vagal afferents during lung inflation and 2) vagal afferents robustly inhibit ipsilateral phrenic bursting. These vagotomy data appear to explain the variability in the literature regarding the onset of the spontaneous crossed phrenic phenomenon in spontaneously breathing (vagal intact) vs. ventilated (vagotomized) preparations.

Invited Review: The crossed phrenic phenomenon: a model for plasticity in the respiratory pathways following spinal cord injury

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.