Disruption of frontal-parietal communication by ketamine, propofol, and sevoflurane

Abstract

Introduction: Directional connectivity from anterior to posterior brain regions (or "feedback" connectivity) has been shown to be inhibited by propofol and sevoflurane. In this study the authors tested the hypothesis that ketamine would also inhibit cortical feedback connectivity in frontoparietal networks.

Methods: Surgical patients (n = 30) were recruited for induction of anesthesia with intravenous ketamine (2 mg/kg); electroencephalography of the frontal and parietal regions was acquired. The authors used normalized symbolic transfer entropy, a computational method based on information theory, to measure directional connectivity across frontal and parietal regions. Statistical analysis of transfer entropy measures was performed with the permutation test and the time-shift test to exclude false-positive connectivity. For comparison, the authors used normalized symbolic transfer entropy to reanalyze electroencephalographic data gathered from surgical patients receiving either propofol (n = 9) or sevoflurane (n = 9) for anesthetic induction.

Results: Ketamine reduced alpha power and increased gamma power, in contrast to both propofol and sevoflurane. During administration of ketamine, feedback connectivity gradually diminished and was significantly inhibited after loss of consciousness (mean ± SD of baseline and anesthesia: 0.0074 ± 0.003 and 0.0055 ± 0.0027; F(5, 179) = 7.785, P < 0.0001). By contrast, feedforward connectivity was preserved during exposure to ketamine (mean ± SD of baseline and anesthesia: 0.0041 ± 0.0015 and 0.0046 ± 0.0018; F(5, 179) = 2.07; P = 0.072). Like ketamine, propofol and sevoflurane selectively inhibited feedback connectivity after anesthetic induction.

Conclusions: Diverse anesthetics disrupt frontal-parietal communication, despite molecular and neurophysiologic differences. Analysis of directional connectivity in frontal-parietal networks could provide a common metric of general anesthesia and insight into the cognitive neuroscience of anesthetic-induced unconsciousness.

Figure 1

Schematic illustration of transfer entropy. Symbolic transfer entropy measures the causal influence of source signal X on target signal Y, and is based on information theory. The information transfer from signal X to Y is measured by the difference of two mutual information values, I[Y^F; X^P, Y^P] and I[Y^F; Y^P], where X^P, Y^P and Y^Fare, respectively, the past of source and target signals and the future of target signal. The difference corresponds to information transferred from the past of source signal X^P to the future of target signal Y^Fand not from the past of the target signal itself. The average overall vector points measures the information transferred from the source signal to the target signal. The vector points are symbolized with the rank of their components: ex) a vector point (30,78,51) is symbolized to (1,3,2) with the rank of components in ascending order.

Figure 2

The relative power spectrum for ketamine, propofol and sevoflurane. The relative powers for each frequency band, (A) delta (0.1–4Hz), (B) theta (4–8Hz), (C) alpha (8–13Hz), (D) beta (13–25hz) and (E) gamma (25–35hz), are presented. Error bar denotes the standard error for each 10 s electroencephalogram epoch over 30 subjects. The blue shade indicates induction of anesthesia (from 5 to 7 minutes). The time spans for propofol and sevoflurane anesthesia were rescaled to match with the time of ketamine. Red color indicates the increase of relative power after anesthetic-induced unconsciousness, whereas blue color indicates the decrease of relative power. The relative power of alpha and gamma demonstrated different responses among the three anesthetics. Six substates (B1, B2, B3 in baseline state and A1, A2 and A3 in anesthesia) are denoted.

Figure 3

The relationship of gamma waves between electroencephalography and electromyography. (A) Gamma wave of 2 s-long electroencephalogram epoch. (B) Gamma wave of 2 s-long electromyogram epoch. (C) Scatter plot of two gamma waves of 5 min-long electroencephalogram and electromyogram during ketamine anesthesia. No correlations were identified using Pearson correlation coefficient. EEG= electroencephalogram; EMG = electromyogram

Figure 4

The feedback (FB) and feedforward (FF) connectivity measured by normalized symbolic transfer entropy (NSTE) between (A) frontal and parietal regions, (B) frontal and temporal regions and (C) left and right hemispheres. The FB/FF asymmetry is shown between (D) frontal and parietal regions, (E) frontal and temporal regions and (F) left and right hemispheres. The positive value of asymmetry indicates that the FB connectivity is dominant over the FF connectivity. The mean and standard error over 30 subjects are denoted. The ‘Ket’ in blue shade indicates the ketamine injection for 2 minutes. Only the FB connections of rostral-caudal connectivity show significant reduction, whereas the horizontal connectivity across hemispheres did not.

Figure 5

Distinct connectivity response of the frontal-parietal network at different scales. The mean feedback/feedforward (FB/FF) connectivity over 30 subjects is demonstrated for (A) a short time scale (τ=1), (B) a longer time scale (τ=20), and (C) various time scales (τ=1, 3, 5, 10, 15, 20). The shorter time scales (τ=1, 3 and 5) are denoted with filled squares and the longer time scales (τ=10, 15 and 20) are denoted with empty circles. The corresponding asymmetries of FB and FF connectivity are presented for (D) τ=1, (E) τ=20 and (F) various delay times (τ=1, 3, 5, 10, 15, 20). The ‘ket’ denotes the period of ketamine administration. Error bar reflects standard error over 30 subjects.

Figure 6

A common neural correlate of anesthetic-induced unconsciousness. The inhibition of asymmetry between the feedback (FB) and feedforward (FF) connectivity is a common feature found across three heterogeneous anesthetics. The FB (red)/FF (blue) connections (A–C) and their asymmetry (D–F) in the frontal-parietal network are shown for (A & D) ketamine (n=30), (B & E) propofol (n=9), (C & F) sevoflurane (n=9). The means and standard errors are denoted at each window. Anesthetic administration is highlighted with blue shading. Six substates (B1, B2, B3 in baseline state and A1, A2 and A3 in anesthesia) are denoted. Note that the timeline of propofol and sevoflurane induction has been rescaled for the purpose of comparison with ketamine induction.