Multivariate Determinants of Phrenic Motor Facilitation (pLTF and pMF) via Machine Learning

Acute intermittent hypoxia-induced Phrenic long-term facilitation (pLTF) is a well-known form of respiratory motor plasticity. This form of respiratory motor plasticity falls under the umbrella term Phrenic Motor Facillitaion (pMF), which also includes pharmacologically induced plasticity. Understanding the mechanisms of pLTF and pMF represent opportunities for therapeutic targets for spinal cord injury or amyotrophic lateral sclerosis. Given the limitations of expressing pMF as a percent, we employed Gradient Boosted Decision Trees and SHAP analysis to establish confirmed determinants and find novel or non-linear determinants of respiratory plasticity via percent-based (%) and absolute (Δ) changes in pLTF and pMF. We induced pLTF via acute intermittent hypoxia (n=75) and pMF via pharmacologic intervention (n=39) under a single anesthetic and data-gathering protocol to find our results. Hypoxia-induced phrenic response (Δ hypoxic PNA) was the primary predictor of ΔpLTF, while Δ maximal PNA exerted a lesser influence in our analysis. Similarly, %pLTF was most strongly influenced by % hypoxic PNA but was also influenced by baseline (BL) phrenic nerve activity and the hypoxia-evoked blood pressure response (Δ hypoxic BP). Notably, calculating percent change in pLTF versus absolute change in pLTF presents certain limitations. Each animal has a unique level of baseline phrenic nerve activity, so calculation via percent change can conceal or misrepresent the overall magnitude of respiratory motor plasticity. For ΔpMF, BL PNA was the strongest positive correlate, while body mass, which reflects rat age, was inversely correlated to ΔpMF. Rat body mass was strongly inversely correlated with %pMF, while BL PNA and BL respiratory frequency (RF) exerted some influence. Similarities in determinant variables for pMF and pLTF indicate the two phenomena exhibit overlapping mechanisms of action, while the differing variables in each measure of respiratory motor plasticity shows the unique sensitivities of pLTF and pMF. This study provides a comprehensive evaluation of respiratory motor plasticity, discovering new determinants while validating previous research regarding pLTF. Better understanding its mechanism could further research into new therapies for increasing respiratory drive. All financial support was provided by the Marian University Wood College of Medicine. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.