Ketamine, Propofol, and the EEG: A Neural Field Analysis of HCN1-Mediated Interactions

Abstract

Ketamine and propofol are two well-known, powerful anesthetic agents, yet at first sight this appears to be their only commonality. Ketamine is a dissociative anesthetic agent, whose main mechanism of action is considered to be N-methyl-d-aspartate (NMDA) antagonism; whereas propofol is a general anesthetic agent, which is assumed to primarily potentiate currents gated by γ-aminobutyric acid type A (GABAA) receptors. However, several experimental observations suggest a closer relationship. First, the effect of ketamine on the electroencephalogram (EEG) is markedly changed in the presence of propofol: on its own ketamine increases θ (4-8 Hz) and decreases α (8-13 Hz) oscillations, whereas ketamine induces a significant shift to beta band frequencies (13-30 Hz) in the presence of propofol. Second, both ketamine and propofol cause inhibition of the inward pacemaker current I h, by binding to the corresponding hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) subunit. The resulting effect is a hyperpolarization of the neuron's resting membrane potential. Third, the ability of both ketamine and propofol to induce hypnosis is reduced in HCN1-knockout mice. Here we show that one can theoretically understand the observed spectral changes of the EEG based on HCN1-mediated hyperpolarizations alone, without involving the supposed main mechanisms of action of these drugs through NMDA and GABAA, respectively. On the basis of our successful EEG model we conclude that ketamine and propofol should be antagonistic to each other in their interaction at HCN1 subunits. Such a prediction is in accord with the results of clinical experiment in which it is found that ketamine and propofol interact in an infra-additive manner with respect to the endpoints of hypnosis and immobility.

Keywords: EEG; HCN1; anesthesia; drug interaction; infra-additivity; ketamine; neural field theory; propofol.

Figure 1

Experimentally described EEG power spectral changes induced by ketamine and propofol. (A) A single bolus dose of ketamine (0.25 mg/kg) is associated with resting α activity being transiently replaced by θ band activity. Data shown is the mean power spectral density (PSD) of EEG recorded in three subjects from a Cz-A1/A2 (vertex-linked ears) montage. Figure adapted and used with permission from Kochs et al. (1996). (B) Average spectra of EEG recorded during two sequential target concentrations of propofol in a single subject. BL = baseline, M = 1.25 μg/ml propofol, H = 2.5 μg/ml propofol. α band EEG recorded from parietal (P4) and occipital (O2) electrodes reveals minimal changes in peak frequency with increasing propofol concentration. At medium propofol concentrations (M) the α rhythm shifts to central and frontal areas (figure not shown) without any significant change in frequency. Figure adapted and used with permission from Feshchenko et al. (2004). (C) Fifteen minutes after the administration of a ketamine bolus (1 mg/kg; bold line labeled B), in the presence of a steady state target controlled propofol level (3.5 μg/ml; thin line labeled A), peak α band EEG activity is markedly shifted to higher frequencies. Data shown is mean PSD recorded at Fp1-A1, with an Fpz reference, from nine subjects undergoing elective abdominal surgery. Figure used with permission from Tsuda et al. (2007).

Figure 2

Eigenspectra of 10 parameter sets. The panels show eigenspectra estimated with Eq. 11 from 10 different parameter sets in Bojak and Liley (2005). These 10 sets are selected for the behavior of their α peak frequency under hyperpolarization, see text and Figures 3B,D.

Figure 3

Parameterization of the hyperpolarization effects of propofol and ketamine. (A) Shift of the α peak frequency, average over all 1,627 sets estimated as described below Eq. 11. (B) Likewise, but averaged over the 10 sets shown in Figure 2, which were selected for having large up (Δf > 1.6 Hz) and down (Δf < −0.8 Hz) shifts of α peak frequency, as well as a lack of shift for some large hyperpolarizations (|Δf(−3.7 mV, ≤4.3 mV)| < 0.4 Hz). (C) Blue contours indicate areas where 4, 7, or 10 sets have the required down-shift. A blue arrow points to the midpoint of this area, and drug effect parameters for Eq. 12 and Eq. 13 derived from this are listed in blue text. Likewise, parameters are derived for up-shift in red and a lack of shift in green. (D) These are the same results as in (B), but now plotted against normalized propofol P and ketamine K concentrations using the drug effect parameters found in (C).

Figure 4

Estimated α peak frequency shifts. Shifts of the α peak frequency for normalized propofol P and ketamine K concentrations estimated as described below Eq. 11, using the hyperpolarizations in Eq. 12 and Eq. 13. Either all 1,627 (gray) or the 10 selected sets (red) are used to compute quantile bands, as indicated by the legend. The median value is shown by a thick black or red line, respectively. There are four phases of drug variation, as indicated by the titles and dotted lines, quantified by bars below the main panel: first, P = 0 → 1.2 linearly, while K = 0. Then K = 0 → 1.4 linearly, while P = 1.2. Next P = 1.2 → 0, while K = 1.4. Finally, K = 1.4 → 0, while P = 0. No pharmacodynamics has been modeled here, so every (P, K) combination yields an independent “steady state” result. Hence for example an increase of P at high K is shown by the third phase viewed from right to left.

Figure 5

Power spectral densities for Set III under drug variations. (A) PSDs for increasing normalized propofol concentration from none (thinnest green line) to 1.2 (thickest green line). (B) PSDs for increasing normalized ketamine concentration from none (thinnest blue line) to 1.4 (thickest blue line). (C) PSDs for increasing normalized ketamine concentration from none (thinnest red line) to 1.4 (thickest red line), while normalized propofol concentration is held constant at 1.2. (D) Comparison of the PSDs representing the highest normalized concentrations from (A) in green, (B) in blue, and (C) in red. The black curve is the PSD without drugs. In all four panels the dotted line represents the position of the α peak of this curve.

Figure 6

Power spectral densities for all 10 selected parameter sets under drug variation. We use here the same four phases of drug variation as in Figure 4, as indicated by the dotted lines and quantified by bars below the main panels: first, P = 0 → 1.2 linearly, while K = 0. Then K = 0 → 1.4 linearly, while P = 1.2. Next P = 1.2 → 0, while K = 1.4. Finally, K = 1.4 → 0, while P = 0. Every panel corresponds to 1 of the 10 selected parameter sets, as indicated by a white roman numeral. The PSD for one specific (P, K) combination is indicated in the panel by a colored vertical line corresponding to frequencies from 0 to 20 Hz. Colors here indicate decibels of the PSD, with dark red corresponding to large, green to medium and dark blue to small values. (The “jet” colormap of Matlab has been mapped for each panel individually, to the full range of PSD decibel values shown in the panel.) A white dashed line indicates the α peak frequency in the absence of drugs.