Intermittent phrenic afferent activation induces phrenic motor plasticity.

Approaches such as electrical stimulation of the phrenic neuromuscular system are currently used in humans to manage breathing impairments. We recently showed that electrical stimulation of the diaphragm muscle induces phrenic afferent-dependent plasticity. These findings highlight the need to better understand the mechanisms of afferent-mediated plasticity to guide and improve the development of novel therapies using electrical stimulation. Here, we tested the hypothesis that intermittent activation of large-diameter phrenic afferents induces phrenic motor plasticity, which, like other forms of plasticity, is pattern sensitive. We delivered inspiratory-triggered electrical stimulation using a narrow pulse width (0.1 ms) to preferentially activate large-diameter afferents, to one phrenic nerve in an intermittent (5, 5-min episodes) or sustained (25 min) pattern, and recorded contralateral motor output for 60 min after stimulation. We show that intermittent, but not sustained, inspiratory-triggered stimulation elicits a long-lasting increase in contralateral phrenic motor amplitude. Our data suggest that, unlike laminectomy controls, phrenic motor plasticity is not observed in rats receiving a left, C3-C6 dorsal rhizotomy before intermittent stimulation. Thus, this form of plasticity requires phrenic afferent activation, as dorsal rhizotomy eliminates phrenic afferent activity from reaching the cervical spinal cord. We also see an enhanced hypercapnic response following both intermittent and sustained stimulation. Finally, our results demonstrate that contralateral phrenic motor amplitude progressively increases during and after repeated episodes of stimulation. Our results indicate that intermittent activation of large-diameter afferents induces a novel form of respiratory motor plasticity that we have termed phrenic afferent-induced plasticity (pAIP).