Abstract
Studies from human and non-human species have demonstrated a breakdown of functional corticocortical connectivity during general anesthesia induced by anesthetics with diverse molecular, neurophysiological, and pharmacological profiles. Recent studies have demonstrated that changes in long-range neural communication, and by corollary, functional connectivity, might be influenced by cross-frequency coupling (CFC) between the phase of slow oscillations and the amplitude of local fast oscillations. Phase-amplitude coupling (PAC) between slow oscillations and alpha rhythm during general anesthesia reveal distinct patterns depending on the anesthetic. In this study, we analyzed the effect of three clinically used anesthetics (propofol: n = 6, sevoflurane: n = 10, and ketamine: n = 8) with distinct molecular mechanisms on changes in PAC in the frontal cortex of rat. The loss of righting reflex was used as a surrogate for unconsciousness. PAC was calculated using the modulation index (MI) algorithm between delta (1–4 Hz), theta (4–10 Hz), low gamma (25–55 Hz), and high gamma (65–125 Hz) bands. A linear mixed model with fixed effects was used for statistical comparisons between waking, anesthetized, and post-anesthesia recovery epochs. All three anesthetics increased the coupling between delta and low gamma (p < 0.0001) as well as between theta and low gamma (p < 0.0001) oscillations, which returned to baseline waking levels during the post-anesthetic recovery period. In addition, a reversible reduction in high gamma power (p < 0.0001) was a consistent change during anesthesia induced by all three agents. The changes in delta-high gamma and theta-high gamma PAC as well as power spectral changes in delta, theta, and low gamma bandwidths did not show a uniform response across the three anesthetics. These results encourage the study of alternative PAC patterns as drug-invariant markers of general anesthesia in humans.
Highlights
MATERIALS AND METHODSLoss of connected consciousness is a functional outcome common to general anesthetics with diverse molecular, pharmacological, and neurophysiological effects
After averaging within target frequency bands across all rats, statistical analysis showed that, compared to the pre-anesthesia waking state, all three anesthetics induced a significant increase in delta-low gamma (p < 0.0001 for propofol, sevoflurane, and ketamine) and theta-low gamma (p < 0.0001 for propofol, sevoflurane, and ketamine) Phase-amplitude coupling (PAC) (Figures 3A,B, Tables 1–3)
Theta-high gamma PAC showed a significant increase during propofolinduced unconsciousness (p = 0.03 vs. waking) while there was a significant decrease in theta-high gamma PAC during sevoflurane (p = 0.004 vs. waking) and ketamine (p = 0.004 vs. waking) anesthesia (Figure 3D, Tables 1–3)
Summary
Loss of connected consciousness is a functional outcome common to general anesthetics with diverse molecular, pharmacological, and neurophysiological effects. Studies exploring PAC between slow oscillations and the alpha rhythm as a function of anesthetic-induced unconsciousness demonstrated agent specific effects; propofol increased the coupling while sevoflurane and ketamine did not induce significant changes (Purdon et al, 2013; Blain-Moraes et al, 2014, 2015). EEG data (750 s) corresponding to the freely moving pre-anesthesia baseline waking state, anesthetic-induced unconsciousness, and post-anesthetic recovery wakefulness were windowed into 30-s time bins. A linear mixed model with fixed effects was used for comparison of the MI (delta-low gamma, theta-low gamma, delta-high gamma, and theta-high gamma) and relative PSD (delta, theta, low gamma, and high gamma) between the following conditions: (1) pre-anesthesia baseline waking state, (2) anesthetic-induced unconsciousness (propofol, sevoflurane, ketamine), and (3) post-anesthetic recovery wakefulness. The statistical analyses were conducted using the programming and statistical language R (R Core Team, 2016)
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