Electroencephalographic effects of ketamine on power, cross-frequency coupling, and connectivity in the alpha bandwidth

Abstract

Recent studies of propofol-induced unconsciousness have identified characteristic properties of electroencephalographic alpha rhythms that may be mediated by drug activity at γ-aminobutyric acid (GABA) receptors in the thalamus. However, the effect of ketamine (a primarily non-GABAergic anesthetic drug) on alpha oscillations has not been systematically evaluated. We analyzed the electroencephalogram of 28 surgical patients during consciousness and ketamine-induced unconsciousness with a focus on frontal power, frontal cross-frequency coupling, frontal-parietal functional connectivity (measured by coherence and phase lag index), and frontal-to-parietal directional connectivity (measured by directed phase lag index) in the alpha bandwidth. Unlike past studies of propofol, ketamine-induced unconsciousness was not associated with increases in the power of frontal alpha rhythms, characteristic cross-frequency coupling patterns of frontal alpha power and slow-oscillation phase, or decreases in coherence in the alpha bandwidth. Like past studies of propofol using undirected and directed phase lag index, ketamine reduced frontal-parietal (functional) and frontal-to-parietal (directional) connectivity in the alpha bandwidth. These results suggest that directional connectivity changes in the alpha bandwidth may be state-related markers of unconsciousness induced by both GABAergic and non-GABAergic anesthetics.

Keywords: anesthetic mechanisms; anesthetic-induced unconsciousness; consciousness; general anesthesia; ketamine.

Figure 1

Group spectral analysis. (A) Spectrogram and (B) baseline-normalized spectrogram of frontal channels (F3 and F4) demonstrate a decrease in alpha power during and after ketamine-induced unconsciousness. LOC, loss of consciousness.

Figure 2

Phase-amplitude coupling analysis. Top panel: Frontal phase-amplitude coupling across baseline and induction/unconscious epochs. Bottom panel: Modulation indices (blue line) of each minute of data in baseline and induction/unconscious epochs; values are significant at p = 0.05 above the red line. LOC, loss of consciousness.

Figure 3

Coherence analysis. (A) Average frontoparietal coherence across 28 participants in baseline resting and ketamine-induced unconscious states (error bars indicate standard deviation). No significant differences are observed in coherence between conditions. (B) Average coherence across all channel combinations in baseline rest and ketamine-induced unconscious states, represented on a channel grid (left) and on an axial view of the brain (right). On the brain network, both color and size of the edges represent strength of coherence.

Figure 4

Phase lag index analysis. (A) Difference in PLI between baseline and ketamine-induced unconscious states represented for all bandwidths, across all participants. The largest decreases in PLI are observed in the alpha bandwidth. (B) Average frontoparietal PLI values for experimental data and surrogate data (error bars indicate standard deviation). Frontoparietal PLI significantly decreases (as indicated by ^*) between states in the experimental data; no phase-locking is observed in the surrogate dataset. (C) Average difference in PLI between baseline and unconscious states across all channel combinations, represented on a channel grid (left), and on the axial view of the brain (right). Color and size of edges in the brain network represent the difference in PLI between baseline and unconscious states. Large decreases in PLI are observed between frontoparietal channel combinations.

Figure 5

Directed phase lag index analysis. (A) Difference in frontoparietal dPLI between baseline rest and ketamine-induced unconscious states, represented across six frequency bandwidths and all participants. The largest decreases in dPLI occur in the alpha bandwidth. Note that a dPLI value of 0.5 indicates neither phase lag nor phase lead relationship. (B) Average frontoparietal dPLI values for each state in experimental and surrogate data (error bars indicate standard deviation). Frontoparietal dPLI significantly decreases during ketamine-induced unconsciousness (as indicated by ^*). Surrogate data demonstrate no phase-lead/phase-lag relationship in either state. (C) Average dPLI values across all channel combinations in baseline and unconscious states. Only dPLI values greater than 0.55 are represented on the axial brain network. In this network, color, and size of the edges indicate the dPLI value between two nodes; arrows indicate the direction of phase lead and lag.