BJA Advance Access published online on July 9, 2007
British Journal of Anaesthesia, doi:10.1093/bja/aem175
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Ketamine increases the frequency of electroencephalographic bicoherence peak on the 
spindle area induced with propofol
1 Department of Anesthesiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
2 Department of Anesthesiology, Kyoto First Red Cross Hospital, Kyoto, Japan
3 Department of Anesthesiology, Osaka University Graduate School of Medicine, Osaka, Japan
* Corresponding author: Department of Anesthesiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kamigyo-ku, Kyoto 602-0841, Japan. E-mail: zukko{at}koto.kpu-m.ac.jp
Accepted for publication May 18, 2007.
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Abstract |
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Background: The reticular and thalamocortical system is known to play a prominent role in spindle wave activity, and the spindle wave is related to the sedative effects of anaesthetics. Recently, bispectral analysis of the EEG has been developed as a better method to indicate nonlinear regulation including the thalamocortical system linking to the cortical area. In the present study, in order to explore the interference of ketamine with the nonlinear regulation of the sub-cortical system, we examined the effect of ketamine on spindle
waves through the bispectral analysis. Methods: The study included 21 patients. Anaesthesia was induced and maintained using a propofol-TCI system (target-controlled infusion, with target concentration 3.5 µg ml–1). An A-2000 BIS monitor was used and the raw EEG signals were collected via an RS232 interface on a personal computer. Bicoherence, the normalized bispectrum, and power spectrum were analysed before and after i.v. administration of 1 mg kg–1 racemic ketamine.
Results: Propofol caused peaks in both power and bicoherence spectra, with average frequencies of 10.6 (SD 0.9) Hz and 10.7 (1.0) Hz, respectively. The addition of ketamine significantly shifted each peak to frequencies of 14.4 (1.4) Hz and 13.6 (1.5) Hz, respectively [P<0.05, mean (SD)].
Conclusions: Ketamine shifted the peaks of bicoherence induced by propofol to higher frequencies. This suggests that ketamine changes the spindle rhythms through the modulation of the nonlinear sub-cortical reverberating network.
Keywords: anaesthetics i.v., ketamine; monitoring, depth of anaesthesia; monitoring, electroencephalogrophy; neurophysiology; sleep
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Introduction |
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The spindle oscillation is a waxing and waning field potential lasting for 1–3 s at
frequency of 7–14 Hz, which is characterized by high-frequency bursts of action potentials followed by a period of quiescence. This activity is known to emerge from the intrinsic properties of thalamic neurons and their inter-connectivity. During spindles, GABAergic thalamic reticular (RE) neurons generate rhythmic (7–14 Hz) spike bursts superimposed on a depolarizing envelope, which are transmitted to the thalamocortical relay (TC) neurons. The TC neurons have an intrinsic ability to generate a burst of action potentials following inhibition by the RE cells, the so-called post-inhibitory rebound burst. The burst is transmitted to the cortex where it induces rhythmic excitatory postsynaptic potentials, which are the origin of EEG spindle oscillations.1–5
It is known that propofol causes a strong frontal-central rhythm, and the characteristics of the waves resemble spindle waves.6–8 In a previous study, we found that ketamine shifted the spindle waves of 10 Hz frequencies to 
5 Hz higher frequencies, suggesting the possibility that ketamine interacts with the spindle oscillations induced by a GABA agonist.9 However, the method we employed was power spectral analysis based on the assumption that the signal arises from a linear process, thereby ignoring potential nonlinear interactions between components of the signals. Thus, although ketamine appeared to affect the frequency of spindle wave, we could not access the effect of ketamine on the nonlinear regulations of thalamocortical networks.
Bicoherence, a power-independent measure of bispectral analysis, has been developed to detect nonlinear cross-frequency (CF) phase coupling. In the nonlinear modulation such as seen in the reverberant circuits, phase angles of input components are passed onto the output components,10 and the phases are expected to be coupled with each other between input signals and output signals in quadratic form. Bicoherence is a powerful candidate for determining the reverberating configuration linking RE and TC circuits.
In a previous study, Hagihira suggested that the high bicoherence peak in the -frequency represents the activities of the spindle wave.11 If the increased peak-frequency of spindle waves induced by ketamine is accompanied by disappearance of its bicoherence peak, the modification of the frequency is considered to be due to the change of area of rhythm source. However, if the bicoherence peak simultaneously changes without vanishing, it suggests that modification is caused by the same reverberant source, that is, RE and TC neurons. We are interested in whether ketamine blocks the quadratic phase coupling of waves or not, because we think that this will contribute to understanding how and where ketamine modifies the spindle activities.
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Methods |
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Protocol
The institutional ethics committee approved the present study, and informed consent was obtained from all patients. The study included 21 patients (aged 23–62 yr; ASA physical status I or II) who were undergoing non-cranial surgery. None of the patients had any neurological or psychiatric disease. Patients were not pre-medicated. In the operating room, EEG monitoring with the ASPECT A-2000 BIS monitor (version 3.3, Aspect Medical Systems, Natick, MA, USA) was started, and EEG data were continuously collected. Anaesthesia was induced with propofol, using a TCI (computer-assisted target-controlled infusion) system (Terumo, TE-371, Tokyo, Japan).12 After the TCI system achieved the target effect-site concentration of propofol (3.5 µg ml–1) on the display, tracheal intubation, facilitated by vecuronium 0.15 mg kg–1, was performed. Anaesthesia was maintained with TCI-propofol (3.5 µg ml–1) and oxygen 30% in air, and vecuronium 0.08 mg kg–1 h–1 was administered to obtain muscle relaxation during surgery. At 20 min after the tracheal intubations, patients received a racemic ketamine bolus 1 mg kg–1 administered intravenously. This dose is considered as appropriate to obtain the anaesthetic effect.13 EEG analyses (bispectral analysis, power spectral analysis, and EEG indexes) were performed at 5 min before and 15 min after ketamine injection to examine ketamine-induced activation of EEG under propofol. The time for EEG-analysis was determined by considering the time when the maximal effect of ketamine on
frequency appeared in our previous study9 14 15 (Fig. 1). All measurements were performed before surgery started, and no other hypnotic or analgesic drugs were used during this period.
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Data acquisition and analysis
A BIS sensor (Aspect Medical Systems) consisting of three EEG-electrodes was applied to the forehead. The electrode impedance was checked every 10 min and was maintained at 5 k
or less throughout the study. All binary data packets containing raw EEG wave signals (converted from analogue to digital at 128 Hz frequency) were continuously recorded via an RS232 interface on a personal computer (CF02, Panasonic, Osaka, Japan) using the Bispectrum Analyzer BIS A2000 version (BSA Ver3.22B2).11 16 17 The procedure for collections of EEG waves and BIS values, and the methods for calculation of SEF95 (spectral edge frequency: the frequency below which 95% of the power in the spectrum resides) were the same as described in our previous study. Briefly, the low-pass filter was set at 50 Hz and we discarded signals below 0.5 Hz. BIS values were calculated by the A-2000 from the preceding 1-min period of EEG recording and were extracted to a personal computer directly from the A-2000. The SEF95 was calculated using our BSA software as the averaged over 1 min. Detailed power spectral analysis was performed before and after injection of ketamine, from the preceding 1 min of EEG signals using a 2-s epoch, with each epoch overlapped by 75%, and averaged over 1 min, and then recorded from 0.5 to 47.0 Hz at 0.5-Hz intervals. Thereafter, the power spectra were converted to a normalized form, i.e. the ratio of the individual power to total power within the frequency range from 0.5 to 47.0 Hz at 0.5-Hz intervals. The raw bicoherence values were computed from three consecutive minutes of artifact-free signals at the same points as the power spectral analysis. The signals were divided into a series of 2-s epochs, with each epoch overlapped by 75%. After applying Blackman's window function, the Fourier transform of each epoch was computed. The raw bicoherence values were calculated, using the following equations:10 11 16 17
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Here, the subscript j refers to the epoch number, Xj ( f1) is a complex value calculated with Fourier transformation of the jth epoch, and Xj* ( f1) is the conjugate of Xj ( f1). We then defined aBIC( f1, f2) as the average of bicoherence values (total, 11 points) in the area across the diagonal plot, and calculated aBIC( f1, f2) every 0.5 Hz from 2.0 to 23.0 Hz, using the following equation:11 16
aBIC( f1, f2)={BIC( f1, f2)+2[BIC( f1, f2–0.5)+BIC( f1+0.5, f2–0.5)+BIC( f1+0.5, f2–1.0)+BIC( f1+1.0, f2 – 1.0)+BIC( f1+1.0, f2–1.5)]}/11.
Here, BIC ( f1, f2) is a raw bicoherence value that is calculated as described earlier. These computations of BIC( f1, f2) and aBIC( f1, f2) were performed using MATLAB Ver. 6.5.1 (The Math Works Inc., MA, USA) and Borland C++ Ver. 5.02J (Borland International Inc., Tokyo, Japan) software.
The EEG parameters SEF95 and BIS were compared with the Wilcoxon signed-rank sum test between points before and after injection of ketamine. The haemodynamic parameters and shifts in mean spindle peaks in power and bicoherence spectra were analysed with the paired t-test, because the distributions were regarded as the normality assumption by the Shapiro–Wilk normality test. Data were statistically analysed using Statview version II, software and are presented as mean (SD), or median and 25, 75% percentiles. Findings of P<0.05 were considered significant.
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Results |
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The background characteristics of the 21 patients (9 men and 12 women) were as follows: age 48.1 (12.6) yr; weight 60.4 (10.6) kg, and duration of anesthesia 260.5 (137) min. The haemodynamic parameters of systolic and diastolic blood pressure (SBP and DBP, respectively) and heart rate (HR) did not differ significantly between the points of data measurements before and after injection of ketamine [HR: 66.8 (13.7) bpm vs 65.7 (12.2) bpm; SBP: 111.6 (18.0) mm Hg vs 116.6 (20.3) mm Hg; DBP: 65.0 (12.5) mm Hg vs 68.2 (13.1) mm Hg; P>0.05]. EEG variables BIS and SEF95 (median and 25, 75% percentiles), were significantly increased from 42.7 (39.8, 49.5) and 14.9 Hz (13.9 Hz, 16.9 Hz) to 64.1 (62.4, 66.1) and 20.9 Hz (20.2 Hz, 21.2 Hz), after injections of ketamine (P<0.05).
Figure 2 represents the raw EEG and the corresponding power spectrum in a conscious person without propofol in closed-eye condition (Fig. 2A), and also represents the spindle EEGs and their power spectra which are observed during propofol anaesthesia before and after injection of ketamine (Fig. 2B and C). In the conscious human, the raw EEG had no spindle oscillations, in contrast to the spindles seen under the propofol anaesthesia. Conspicuous peaks were not found in the power spectrum. Before injection of ketamine during propofol anaesthesia, sleep spindles of around 10 Hz were predominant (B). After the administration of ketamine, the -peak shifts remarkably to a higher frequency on the power spectrum (shown by arrows). The power of the high frequency area (
-range) also increased.
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Figure 3 shows the average bicoherence (aBIC) in the same patients as in Figure 2, both in the oblique view and in the vertical view. In the conscious condition, the bicoherence plot indicated no remarkable peaks (Fig. 3A). During propofol anaesthesia, a bicoherence peak at around 10 Hz appeared. We again found a remarkable shift of the
bicoherence peak to a higher frequency with administration of ketamine.
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Figure 4 shows the average normalized power spectra of 21 superimposed cases, 5 min before and 15 min after injection of ketamine during propofol-TCI. Addition of ketamine shifted the spindle peaks on the power spectrum to higher frequency, resulting in peaks at about 15 Hz instead of 10 Hz.
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Figure 5 shows the average aBIC values of 21 superimposed cases around the diagonal lines ( f1=f2), before and after injection of ketamine. Addition of ketamine shifted the spindle peaks of aBIC to higher frequency, resulting in peaks at about 15 Hz instead of 10 Hz, similar to the changes found in the power spectrum.
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Table 1 summarizes the changes in spindle peak frequencies in both power and aBIC spectra. The values of power and aBIC, where spindle peaks appeared, were also summarized. Ketamine, respectively, increased the peak frequencies in both power and bicoherence spectra (P<0.05). However, the values of normalized power where spindle peaks appeared did not change significantly. The aBIC of spindle peaks, decreased slightly after injection of ketamine (P<0.05).
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Discussion |
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In the present study, BIS and SEF95 were significantly increased by ketamine. The result coincided with the findings of previous reports.18 However, the effect of ketamine on the spindle wave has not been well described. For the first time, this research shows that ketamine increases the
peak frequency, and that the bicoherence peak simultaneously shifts. There are some reports indicating the changes of spindle frequency according to the depth of sleep, the neural mechanism, or both. The mean frequency of spindles was reported typically to decrease along with deepening sleep in each natural sleep cycle.19 Another report showed that the sleep spindles frequencies seen in frontal brain regions changed due to the altered pathological neural mechanisms regulating sleep spindles activity.20 However, there are no reports regarding the ketamine-anaesthesia related changes concerning the spindle frequency.
Since the rhythm of a spindle wave is known to be generated by the reticular neurons and thalamo-cortico- thalamic reverberating network, a spindle wave is regarded as having the self-modulated characteristics. That is, it is considered that the modulated components as well as the original components exist in the same EEG signal. Bicoherence is a signal processing technique capable of tracking the changes in such a re-entry loop as the RE and TC system, investigating the phase relationships between two frequencies (input signals: f1, f2) by introducing a third factor (a certain output signal: f1+f2) and by quantifying the quadratic phase-coupling between them.10 The result indicates that the output signal ( f1+f2, 20 Hz) from the thalamocortical system included the components of intermodulation products (IMP: a signal component produced by multiplication of input signal components), and indicates that these output signal components were generated, as the result of nonlinear modulation (quadric phase coupling) of two input signal components (10 Hz). That is, phases of input 10 Hz components were coupled with each other in quadratic form. In other words, we can predict the existence of a certain re-entry loop, where 10 Hz components reverberate. Similarly, after addition of ketamine, 14 Hz components were quadratically coupled with each other. Thus, we hypothesized that the reverberating feature contributes to the reason why peaks in EEG bicoherence appear around the diagonal lines ( f1=f2). Although a theoretical link between neural network physiology in the cerebral cortex and frequency coupling had not been sufficiently established,21 a certain reverberating system may contribute to the high bicoherence values. Some current theories hypothesized that the strong EEG phase relationships are inversely related to the number of independent EEG pacemakers in the brain.10 22 Yousif and Denham4 demonstrated that the nonlinear dynamics of the thalamocortical feedback circuit are intrinsically capable of maintaining the synchronized oscillatory behaviour in the spindle range of frequencies. Sarnthein and colleagues23 suggested that the tight coupling of the thalamocortical re-entry loop is reflected by high thalamocortical coherence in humans. These findings are consistent with our speculation that the growth of bicoherence in the frequency of spindle waves indicates greater EEG synchronization driven by the RE nucleus. If the genesis of the observed oscillation is driven by thalamic RE, TC systems, or both, the high peak in the bicoherence spectrum would appear at the frequency of the , 
, or both areas, because the EEG spikes are reverberating around the RE and TC circuits, and the phases of the corresponding waves should be coupled with each other.
We found that ketamine shifts the peak on the power spectrum to an 4 Hz higher frequency when administered concurrently with propofol. Simultaneously, we found that ketamine shifts the -peak on the bicoherence spectrum in the same way. The result probably shows that the origin of the oscillatory rhythms was the same reverberating network, but the frequency of the rhythms alone changed after injection of ketamine. It suggests that the modulation of spindle frequency depends on the modulation of the nature of the origin, that is, the thalamic RE and TC drives. While anesthetic effects of N-methyl-D-aspartate (NMDA) receptor antagonism are reported to depend directly on cortical mechanisms,24 25 we speculated that the result is the evidence that ketamine affected thalamic drive. Spindle waves are characterized by prolonged inhibitory postsynaptic potentials in TC cells, and the oscillations are effective in eliminating the synaptic transmissions of incoming volleys.1 We think that ketamine modulates unresponsiveness and unconsciousness, and can intervene in the consciousness through the thalamic pathway.
Although the direct target site of ketamine could not be determined, the modulations of membrane conductance and of the hyperpolarization kinetics in TC and RE neurons, which results from various ionic currents with different voltage dependencies and different kinetics of activation/inactivation, can contribute to the change of spindle frequency.5 26–28 Ketamine is not simply an NMDA blocker, but has actions on a variety of ligand-gated ion channels such as nicotinic acetylcholine and noradrenaline receptors.29 30 Therefore, these modulations of spindle activity are not necessarily regulated by the NMDA-antagonism. Various receptors can contribute to the effect of ketamine on the cortical system, the thalamic system, or both. For instance, we found that ketamine increased the power spectrum in -range. The effects may depend on mechanisms other than the thalamic system.
As shown in Figure 5, in patients under the propofol anesthesia, we found the growth of the bicoherence in the and 
areas in addition to the area, which was in contrast to the significant shift of peaks in the area. Concerning the wave, the high bicoherence value in the area may suggest that the wave is driven by the thalamic circuit, due to TC neurons.5 Because the possible range for calculation of aBIC was limited to frequencies larger than 2 Hz in the present study, a detailed analysis is necessary to verify the results regarding the area (0.5<<4 Hz). Moreover, although ketamine seemed to increase the peaks of bicoherence slightly in the area; the shifts were not obvious compared with the significant shifts of peaks found in the area. Another notable finding is, in contrast to a high bicoherence in the area, that the corresponding power in the area was low. This suggests that the waves making up the rhythm are coupled with each other and synchronized, but the activity is low. However, the physiological interpretation of these findings cannot be explained, because the origin of the wave has not yet been well clarified. Because the power in the wave was low, we think the finding may be less important. Because our present study targeted the spindle waves and did not investigate the and waves, a future study is needed regarding the influence of ketamine on and waves.
Finally, growth of bicoherence in the spindle frequency only indicates that the spindle wave is formed with quadric phase coupling driven by a certain network including the reverberate source. We hypothesized the driving source as the RE–TC system, from the already known information about the origin of spindle waves. Therefore, the pathways and networks have to be directly assessed to determine these points clearly in future. Further, the present study used a fixed concentration of propofol and ketamine. However, the excitatory/inhibitory effects of anesthetics on thalamocortical neurons are dose-dependent. These are the limitations of the present study.
In conclusion, ketamine shifted the -peak induced by propofol from 11 to 14 Hz in both power and bicoherence analyses. This suggests that ketamine changes the frequency of spindle waves by modulating the nonlinear thalamocortical network.
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Acknowledgement |
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This study was supported in part by Grant-in aid for Scientific Research No. 16591555 from the Ministry of Education, Tokyo, Japan.
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References |
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