Vagal-dependent nonlinear variability in the respiratory pattern of anesthetized, spontaneously breathing rats

Physiological rhythms, including respiration, exhibit endogenous variability associated with health, and deviations from this are associated with disease. Specific changes in the linear and nonlinear sources of breathing variability have not been investigated. In this study, we used information theory-based techniques, combined with surrogate data testing, to quantify and characterize the vagal-dependent nonlinear pattern variability in urethane-anesthetized, spontaneously breathing adult rats. Surrogate data sets preserved the amplitude distribution and linear correlations of the original data set, but nonlinear correlation structure in the data was removed. Differences in mutual information and sample entropy between original and surrogate data sets indicated the presence of deterministic nonlinear or stochastic non-Gaussian variability. With vagi intact (n = 11), the respiratory cycle exhibited significant nonlinear behavior in templates of points separated by time delays ranging from one sample to one cycle length. After vagotomy (n = 6), even though nonlinear variability was reduced significantly, nonlinear properties were still evident at various time delays. Nonlinear deterministic variability did not change further after subsequent bilateral microinjection of MK-801, an N-methyl-D-aspartate receptor antagonist, in the Kölliker-Fuse nuclei. Reversing the sequence (n = 5), blocking N-methyl-D-aspartate receptors bilaterally in the dorsolateral pons significantly decreased nonlinear variability in the respiratory pattern, even with the vagi intact, and subsequent vagotomy did not change nonlinear variability. Thus both vagal and dorsolateral pontine influences contribute to nonlinear respiratory pattern variability. Furthermore, breathing dynamics of the intact system are mutually dependent on vagal and pontine sources of nonlinear complexity. Understanding the structure and modulation of variability provides insight into disease effects on respiratory patterning.