Presence of 14 Hz spindle oscillations in the human EEG during deep anesthesia

Clinical Neurophysiology 117 (2006) 157–168 www.elsevier.com/locate/clinph

Presence of 14 Hz spindle oscillations in the human EEG during deep anesthesia S. Wolter*, C. Friedel, K. Bo¨hler, U. Hartmann, W.J. Kox, M. Hensel Department of Anesthesiology and Operative Intensive Care Medicine of the Charite´ (CCM)- Universita¨tsmedizin Berlin, Schumannstr. 20/21, 10117 Berlin, Germany Accepted 27 August 2005 Available online 2 December 2005

Abstract Objective: To report on presence of human EEG spindle oscillations on the cortical level within flat periods of the burst–suppression pattern during propofol-induced anesthesia; to search for corresponding oscillations and possible functional connections. Methods: Artefact-free epochs of spindle activation were selected from the electroencephalograms of opiate-dependent patients undergoing rapid opiate detoxification. Power spectral analysis and source localization using low-resolution-brain-electromagnetic-tomography (LORETAKey) were performed. Results: Sinusoidal rhythms with waxing and waning amplitudes appeared after propofol-induced narcosis but no direct correlations could be determined between individual dosage and characteristic spindle attributes. The power maximum stood midline over the cortical areas, especially around Cz. We calculated a peak frequency of 14(G1.2) Hz. Motor fields, particularly in the frontal, parietal, and various cingulate areas, were found to be the primary sources of spindle oscillations in the cortex. Conclusions: The frequent occurrence of these localized spindle sources demonstrates the preference for motor fields. Spindle oscillations observed during propofol-induced narcosis were similar in frequency and shape to those observed in natural sleep. Significance: The results lend support to models that postulate a close link between the motor system and the organization of behavior. In addition, spindle rhythms under propofol bore some resemblance to spindle types which occur during sleep. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Propofol; Narcosis; Burst–suppression; Source localization; Motor fields; Sleep spindles

1. Introduction Rapid opiate detoxification (ROD) is a method used in treating opiate addiction, employing opiate receptor antagonists. In this kind of opiate withdrawal very deep Abbreviations used BA, Brodmann area; BS, burst–suppression; BSR, burst–suppression ratio; CSD, current source density; EEG, electroencephalogram; EMG, electromyogram; EP, evoked potential; GABA, gammaaminobutyric acid; HIV, human immunodeficiency virus; LORETA, lowresolution brain electromagnetic tomography; max, maximum value; mean, average values; MEG, magnetoencephalogram; min, minimum value; ROD, rapid opiate detoxification; SD, standard deviation; SOs, spindle oscillations. * Corresponding author. Tel.: C49 30 450531006; fax: C49 30 450531911. E-mail address: [email protected] (S. Wolter).

anesthesia is required in order to prevent autonomic imbalance with potential accompanying complications (Hensel and Kox, 2000). We performed the anesthesia, with propofol as sole agent, and used electroencephalogram (EEG) online monitoring during the entire detoxification process so as to ensure an unchanging level of anesthesia and to prevent an overdose (Hensel et al., 2000). Immediately following the induction of anesthesia using several repetitive propofol boli, we observed a radical depression of neuronal activity in the EEG. Subsequently, out of the almost flat EEG, a spindle-shaped, rhythmic series of waves emerged, to be later joined by typical burst– suppression (BS) patterns. To a large extent the sequences of w14/s waves with waxing and waning amplitudes appeared simultaneously over several channels.

1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.08.031

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Rhythmic oscillatory activities, whether spontaneous or induced, are commonly recorded in the course of EEG monitoring, and provide the basis for numerous varied behavior patterns and sensory mechanisms. However, there have been few reports on spindling oscillation under deep propofol narcosis (Huotari et al., 2004; Kearse and Fahmy, 1989; Wolter et al., 2003, 2005). For this reason, we investigated this neuroelectric phenomenon and attempted to find correlates, working from our own results as well as the literature available on the subject. Key factors to bear in mind were the unconsciousness state and the influence of propofol, as well as the source localization of motor fields as main spindle oscillation sources. BS patterns induced through anesthetics (Derbyshire et al., 1936) indicate a very deep narcosis, according to the latest research (Akrawi et al., 1996; Lauven et al., 1987; Rampil et al., 1988). Animal experiments have shown that during BS-EEG approximately 95% of cortical cells switch over to alternating sequences of phasic depolarizing events (bursts) and electrical silence (flat periods); while 30–40% of thalamic cells continue to discharge rhythmic spike bursts during flat periods in neocortical neurones. This only occurs, however, when the flat periods are limited to approximately 30 s. A significant proportion of neurones remain active, primarily in the dorsothalamic–reticular thalamic network (Steriade et al., 1994). These structures also play a role in the generation of spindles (Steriade et al., 1993). On the one hand, various anesthetics can trigger spindle patterns (Andersen et al., 1967; Contreras et al., 1997; Lopes da Silva et al., 1973; Steriade and Llina´s, 1988) and these can be an indicator of anesthetic depth (Keifer et al., 1994). On the other hand, however, spontaneous spindles are likewise known to appear in sleep. In the case of animals they emerge periodically as waxing and waning rhythmic waves at 7–14/s every 3–10 s (Steriade and Descheˆnes, 1984), while in humans spindles occur at frequencies of 11– 15 Hz (Anderer et al., 2001; Steriade, 1999). The basic cellular mechanisms underlying the generation and synchronization of spindles have been largely determined through animal experiments (Contreras et al., 1997; Kim et al., 1997; McCromick and Bal, 1997; Steriade and Descheˆnes, 1984; Steriade and Llina´s, 1988; Steriade et al., 1985, 1993) in which the emergence of these spindles were frequently induced with the help of anesthetics. Spindle oscillations (SOs) have been generated within the thalamus even after decortication and high brain-stem transection (Morison and Bassett, 1945; Steriade et al., 1993). Mackenzie et al. support the hypothesis that various spindle rhythms are generated in a similar manner (Mackenzie et al., 2004). In our study, however, we focus not on the genesis, but rather on the possible functional significance of the relevant spindle patterns under narcosis. In doing so, we point to additional spindle-shaped patterns. In general, SOs occur in various behavioral conditions (Steriade et al., 1993). They differ in shape (Contreras et al.,

1997) as well as in their spatio-temporal distribution (Lopes da Silva, 1991) and they can characterize brain-active as well as brain-deafferented states (Steriade, 1997). In sleep, spindles are thought to block the flow of sensory input to the cortex by synaptic inhibition (Steriade, 1997). In the waking state, oscillatory post-movement beta synchronization (Pfurtscheller, 1996) has been interpreted as a sign of ‘idling’ in the motor cortex, its appearance having been found to coincide with periods of decreased cortico-spinal excitability (Chen et al., 1998; Neuper and Pfurtscheller, 2001). Up to now, however, one has only been able to speculate as to why such oscillations only appear to a limited degree in periods when there is no movement (Baker et al., 1999). It was recently reported that, under narcosis, a reduced excitability of spinal motoneurones was detected after the administering of several boli of propofol (Dueck et al., 2003). However, no EEG was taken during the process. We saw spindles in the EEG after administering large doses of propofol. When large doses are used as an anesthetic, the concentration of dopamine in the nucleus accumbens is expected to increase (Pain et al., 2002), and dopamine is implicated in the regulation of movement, motivation, reward, plasticity, and learning. In this context, we are attempting to determine why specific cortex areas were not completely subject to the BS pattern, which normally predominates during deep anesthesia, but instead revealed recurring spindling activity, mostly above the central regions around Cz. If neuronal structures in motor fields give rise to these w14 Hz spindles even during very deep narcosis, then the question arises as to whether this is simply a matter of chance and randomness, and irrational, or whether we are dealing with a necessary consequence with potentially important implications. Do spindles contribute to memory consolidation and short-term plasticity (Destexhe, 2002; Steriade, 1999, 2001; Wang, 1999), as it is assumed they do in sleep, or are synchronous oscillations only a by-product of an oscillating descending command (Baker et al., 1999)? In this article, we shall discuss SOs during propofolinduced BS narcosis in selected EEG-epochs and present the initial analysis results. Possible consequences these results may have for the state of narcosis will also be considered.

2. Methods 2.1. Subjects A total of 43 opiate-dependent patients with a strong motivation to become abstinent were monitored through an EEG during ROD. The primarily sinusoidal rhythms with waxing and waning amplitude appeared shortly after the induction of anesthesia using propofol. Twenty-four patients (11 female and 13 male: age 30(G6.3) years, weight 70.9(G15.8) kg) were chosen whose EEG showed the desired number of 24 epochs with SOs during EEG

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suppression and BS. In 13 other cases, the number of spindle activities occurring during the specified period was too small to allow for analysis of this phenomenon. Two HIVpositive patients and four with neurological diseases were excluded from analysis. All patients gave their written consent, and the local ethics committee gave their approval as well.

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with an amplifier bandpass of 0.5–70 Hz (3 dB points) with 50 Hz notch filtering was used as data acquisition system. The A/C converter sampled 200 Hz per channel with 12-bit resolution. At the same time, the parameters commonly used in the monitoring of intensive-care patients were recorded every 20 s. 2.5. Data analysis

2.2. Rapid opiate detoxification During deep narcosis, patients were treated with competitive opiate receptor antagonists (Hensel and Kox, 2000) such as naltrexone (Legarda and Gossop, 1994) or naloxone (Loimer et al., 1989). Seventeen patients were detoxicated through the use of naltrexone and seven others with naloxone. EEG epochs, including spindle activity, were selected from an earlier period of treatment in order to ensure that the antagonists would not have any effect on EEG spindle analysis. During this procedure, there was no pain stimulation through incision, such as occurs in surgical interventions. 2.3. Anesthetic procedure The patients received 0.1 mg kg K1 midazolam (a benzodiazepine, Hoffmann–La Roche AG) orally on the evening before ROD and an additional 0.1 mg kgK1 midazolam prior to induction. Anesthesia was induced with cumulative 5.4(G1.7) mg kgK1 propofol (an alkylphenol, AstraZeneca GmbH) and delivered by repetitive boli of 0.5–1.0 mg kgK1. Simultaneously, an automatic infusion pump (IVAC770) began administering propofol. Additional boli of cumulative 2.6(G1.6) mg kgK1 propofol were given either when spontaneous movements occurred during induction or in order to facilitate tracheal intubation. No muscle relaxants, opiates, or nitrous oxide were applied. Anesthesia was maintained with 135(G30) mg kgK1 minK1 propofol. The additive clonidine (an alpha2-selective adrenergic agonist, Boehringer Ingelheim Pharma KG) was given in order to alleviate withdrawal symptoms before the use of receptor antagonists was initiated 87(G24) min after induction. The average duration of anesthesia was 563(G73) min in all. 2.4. Data acquisition An EEG continued to be taken throughout the entire detoxification process, with the patients under anesthesia. Monopolar recordings were obtained for 19 electrode positions of the International 10/20-system, referended to linked earlobes. Gold-plated cup electrodes were fixed, using paste and collodion, and the electrode impedances were kept below 5 kU. Additionally, an eye channel (electrooculogram) and an ECG channel (electrocardiogram) were used in order to detect artefacts. The Spectrum32, produced by Cadwell (Kennewick, USA),

First, a visual inspection of EEG traces and spindle patterns was carried out. In the analysis of the spindles, the entire phase from the induction of anesthesia to the application of opiate receptor antagonist was taken into account, since during EEG suppression spindles frequently occurred immediately after boli application of propofol, and other pharmacological agents were not administered until later. EEG suppression during the period defined facilitated the extraction of the single w14 Hz SOs. Twenty-four artefact-free 2.5 s epochs with SOs were extracted from each patient, mainly from prolonged suppression periods (Figs. 1 and 2). The w14 Hz spindle activities that appeared immediately before or after a burst of BS pattern (Fig. 3) were only selected if some epochs were still missing. EEG epochs were excluded if any spontaneous movements occurred. A total of 576 epochs were selectively extracted from the ongoing EEG after an average of from 22(G 19) min to of 48(G35) min after induction (epoch extraction time). In order to quantify the extent of EEG suppression, bursts, and SOs, the ongoing EEG was analyzed during the epoch extraction time, using the burst–suppression ratio (BSR): the percentage of flat periods with amplitudes !G5 mV (Rampil et al., 1988), the number of bursts and the number of spindles per minute, as well as the duration of spindles, flat periods, and bursts (Detsch et al., 2002). With regard to the bursts, we did not distinguish between highamplitude negative waves and negative slow waves (Huotari et al., 2004); the amplitude was OG5 mV with mixed frequencies. Spindles were defined as a rhythmic series of waves with waxing and waning amplitudes (Niedermeyer and Lopes da Silva, 1987). A multiple-channel analysis, part of the Spectrum32 software package, was performed on the selected EEG epochs using Fast-Fourier-Transformation. In the frequency ranges 9.5–20, 9.5–14, and 14–20 Hz, we computed the following for each channel of the monopolar derivations: peak power (pW), peak and mean frequency (Hz) and absolute spectral power (mV2), as well as inter-hemispheric asymmetry and coherence (John et al., 1988). Bearing in mind the spindle epochs in another study (Anderer et al., 2001), 12 EEG epochs per patient were transferred to a BrainVision-Analyzer (Brain Products GmbH, Munich) and filtered (Butterworth filter: 3.5–70 Hz), and current source density (CSD)-transformed. Both the three-dimensional representation of intracerebral current density distribution in the gray matter (2394 voxels with a spatial resolution of 7 mm) as well as source localization were undertaken in

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Fp1-A1A2 Fp2-A1A2 F7-A1A2 F8-A1A2 F3-A1A2 F4-A1A2 Fz-A1A2 T3-A1A2 T4-A1A2 C3-A1A2 C4-A1A2 Cz-A1A2 T5-A1A2 T6-A1A2 P3-A1A2 P4-A1A2 Pz-A1A2 O1-A1A2 O2-A1A2 50 µV 1s

(a)

(b)

(c)

Fig. 1. Spindle oscillations (SOs) which were selectively extracted from the ongoing EEG after induction of anesthesia with propofol (epochs: 3.0 s; filter: 3.5– 70 Hz; reference: linked earlobes A1A2); (a)–(c) were chosen exclusively from prolonged flat periods of BS-EEG. Spindle frequencies were as follows: (a) w14 Hz, (b) w12 Hz, (c) w15 Hz. Note the pronounced SOs, which occur mainly over centrally located regions Cz,C3,C4, as well as the lateral distribution of activity, which varied to some degree from one spindle to the next, especially in (a) C3, C4.

Fp1-A1A2 Fp2-A1A2 F7-A1A2 F8-A1A2 F3-A1A2 F4-A1A2 Fz-A1A2 T3-A1A2 T4-A1A2 C3-A1A2 C4-A1A2 Cz-A1A2 T5-A1A2 T6-A1A2 P3-A1A2 P4-A1A2 Pz-A1A2 O1-A1A2 O2-A1A2 50 µV 1s

(a)

(b)

(c)

Fig. 2. Further spindle oscillations (SOs) which were selectively extracted from the ongoing EEG after induction of anesthesia with propofol (epochs: 3.0 s; filter: 3.5–70 Hz; reference: linked earlobes A1A2); (a)–(c) were chosen exclusively from prolonged flat periods of BS-EEG. Spindle frequencies were as follows: (a) w15 Hz, (b) w14H z, (c) w17 Hz. Note the pronounced SOs, which occur over centrally located regions, especially in (b) Cz,C3,C4, and the contrasting distribution of activity in (c) Fz,F3,F4 confront with Cz,C3,C4 as well as the lateral distribution of activity, especially in (a) C3,C4 and F3,F4 also P3,P4.

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frequency-domain mode using LORETAKey (The KEY Institute for Brain-Mind Research, Zurich) (Pascual-Marqui et al., 1994). This was done initially for all 24 patients, subsequently for each patient individually, as well as for every single epoch of spindles in a frequency range of 9.5– 20 Hz. The three best Brodmann areas (BA) were estimated for each primary maximum. The Talairach co-ordinates (TC) are expressed as follows: {(X, Y, Z) (mm)} with X from left (K) to right (C), Y from anterior (K) to posterior (C), Z from inferior (K) to superior (C) in the Talairach space. 2.6. Statistics Results in the form of mean values (mean) and standard deviation (SD) are consistently expressed in the following way: mean(GSD). The figures for the mean range between minimum (min) and maximum (max) are put in quotation marks: ‘min–max’. In order to describe interdependencies between the characteristic attributes of SOs and other clinically measured values, the bivariate Spearman rank correlation and a stepwise backward multiple linear regression analysis were performed with oscillatory frequency as dependent

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variable. Independent variables were the amount of propofol together with the EEGs epoch extraction time. The correlation coefficients and the multiple square correlation coefficient were calculated.

3. Results Subsequent to the induction of anesthesia using repetitive boli of propofol, the EEGs of all 43 patients’ showed spindle patterns. There were three subjects in whom very few SOs occurred, and in 10 further patients where the number of SO-epochs did not suffice for our analysis. From a total of 24 subjects we were able to analyze the desired number of epochs (nZ576) that included SOs during EEG suppression and BS. It should be kept in mind that during the time the epochs were being extracted, anesthesia was maintained through a continuous infusion of propofol. 3.1. Influence of propofol dosage We observed SOs immediately after the induction of anesthesia through the application of several repetitive

Fig. 3. Spindle oscillations (SOs) which were selectively extracted from the ongoing EEG after induction of anesthesia with propofol (epochs: 4.0 s; filter: 1.5– 70 Hz; reference: linked earlobes A1A2); (a) and (b) were selected from EEG intervals in which SOs occurred together with bursts of the BS patterns. Note the differing fast frequencies before the SO in (a) and during SO in (b). The adherent spectra of the marked 2 s periods using Fast-Fourier-Transformation (DFZ 0.5 Hz) are given for the central electrodes C3, Cz, C4. Spindle frequencies were as follows: in (a) w13 Hz, in (b) w14 Hz; while the other embedded frequencies were faster by a factor of about 2 in (a) w26 Hz, in (b) w28 Hz.

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Table 1 The mean values for peak power (pW), peak and mean frequency (Hz), as well as the absolute spectral power (mV2) and its inter-hemispheric asymmetry and coherence for chosen channels of the monopolar derivations Position

Peak frequency (Hz)

Peak power (pW)

Mean frequency (Hz)

Absolute power (mV2)

Cz C3 C4 Fz F3 F4 Pz P3 P4

14.0G1.2 13.9G1.1 13.9G1.3 14.1G1.4 14.0G1.1 14.0G1.2 14.2G1.4 14.2G1.1 14.0G1.3

425G198 314G140 330G155 300G127 227G98 253G111 269G124 242G100 246G116

14.2G0.8 14.2G0.8 14.3G0.8 14.2G0.6 14.2G0.6 14.2G0.6 14.4G0.7 14.3G0.7 14.3G0.6

145G80 77G42 80G43 57G35 34G21 38G21 59G35 46G28 46G26

Power asymmetry (%)

Coherence (%)

K0.9G12

85G6

K6.6G13

89G5

0.2G11

90G5

These values were computed for a frequency range of 9.5–20 Hz using Fast-Fourier-Transformation. From each of the 24 patients, 24 artefact-free 2.5 s epochs (nZ576) with spindle oscillations (SOs) were selectively extracted from the ongoing EEG after induction of anesthesia. The selected epochs including SOs, mainly from prolonged suppression periods or also from flat periods, which immediately occur before or after a burst of BS pattern.

propofol boli. The spindle activity disappeared completely, however, after administering further boli of propofol. While spindling activity might possibly be related to dosage, no direct correlation between the amount of propofol administered and the characteristic attributes of SOs could not be established for mean and peak frequency, for duration of SOs, for the frequency of their occurrence, or for spectral absolute power. All Spearman correlation coefficients were consistently rather small (r2!0.055). Likewise, no link could be detected using a multiple linear regression analysis (r2!0.04). 3.2. Depth of anesthesia Specific EEG alterations occur during different states of anesthesia (Gibbs et al., 1937; Nuwer et al., 1993; Schultz et al., 2002). A BS pattern induced by anesthetics indicates a very deep narcosis, according to the latest research. The proportion of flat periods in BS-EEG increases with steadily deepening narcosis as does the BSR. Borrowing from Rampil et al. (1988), we calculated the BSR at 0.63(G0.14) for the patients’ period of analysis. Those bursts which occurred did so with an average frequency of 5.4(G 2.4) minK1. The SOs which were recorded with the bursts are presented in Fig. 3. However, the appearance of

the spindling rhythm was not tied to the occurrence of such bursts in the EEG. In most instances flat periods were first interrupted by SOs (Figs. 1 and 2). 3.3. Frequency, shape, and distribution of SOs The average duration of SOs was 1.8(G0.4) or ‘1.4– 3.2’ s, and the average frequency of occurrence was 3.8(G 1.8) for the period of analysis. Specific examples of typically rhythmic waves of ‘11–17’ Hz are depicted in the Figs. 1–3, which show selectively extracted 3 or 4 s EEG intervals of various patients. The oscillatory activity took on its spindle shape through the amplitude, which first waxed and then waned (Figs. 1–3). Maximum amplitudes of about 100–150 mV were often reached. The power and topographic distribution of spindle activity could change somewhat from one epoch to the next. Occasionally parietal or frontal regions (Fig. 2(c)) were more involved, but it was mainly the centrally located regions that showed the more powerful spindles. Spindle sequences usually occurred simultaneously (Figs. 1–3), and in the spindle frequency range a hypercoherence between homologous leads was found (Tables 1 and 2). The hemispherically lateralized distribution (Figs. 1(a) and 2(a)) could shift from epoch to epoch. A tendency toward

Table 2 In the frequency ranges 9.5–14 and 14–20 Hz, the following mean values were calculated using Fast-Fourier-Transformation for selected channels of the monopolar derivations: absolute spectral power (mV2), as well as inter-hemispheric asymmetry and coherence Position

Absolute power 9.5–14 Hz (mV2)

Absolute power 14–20 Hz (mV2)

Cz C3 C4 Fz F3 F4 Pz P3 P4

74G70 39G36 40G36 29G26 18G16 20G16 27G26 20G18 21G20

71G58 38G29 40G33 28G27 16G16 18G17 32G29 26G25 24G21

Power asymmetry 9.5–14 Hz (%)

Power asymmetry 14–20 Hz (%)

Coherence 9.5–14 Hz (%)

Coherence 14–20 Hz (%)

0.15G12

K0.3G15

83G9

83G8

K2.9G14

K4.2G14

88G9

87G7

K0.5G10

0.8G12

88G9

89G5

From each of the 24 patients, 24 artefact-free 2.5 s epochs (nZ576) with spindle oscillations were selectively extracted from the ongoing EEG after induction of anesthesia.

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asymmetry could be observed, insofar as there was more power on the right side in anterior regions and somewhat more on the left side in posterior regions (Table 1). However, the dominance of one hemisphere cannot be deduced from this. Instead the power maximum was located midline, almost always above the central regions at Cz. For this electrode position an average peak power of 425(G198) or ‘176–1079’ pW was calculated (Table 1, first line) as the highest power of the spectrum. The ascent to the peak usually started between 9.5 and 12 Hz and ended at about 15–20 Hz. The average peak frequency at Cz was 14(G1.2) or ‘11–17’ Hz and the mean frequency was 14.2(G0.8) or ‘13–16’ Hz. Table 1 presents an overview, firstly of the average power of all selected epochs (nZ576) at chosen electrode positions, and secondly of the average frequencies. However, the frequency of individual EEG epochs also varied slightly both within the same patient as well as from

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one to another. Sometimes faster frequencies (factor 2–3) intermingled with smaller amplitudes above the 14 Hz oscillations (Fig. 3(b)), or rhythms of different frequencies followed in rapid succession (Fig. 3(a)). This kind of quick shift to faster frequencies was often found to be connected with spindle activities under anesthesia. A dependence between the frequency of individual spindle epochs and the located maximum could not be established (r2!0.002) under narcosis. Such dependences were revealed in investigations of sleep spindles (Anderer et al., 2001), which were grouped according to their topographic distribution. A grouping according to similar topographic aspects was not feasible with our spindle epochs because the maximal amplitude was almost always detected at Cz. For this reason, we subdivided the frequency range once more and calculated the absolute spectral power for 9.5–14 and 14–20 Hz separately. The results (Table 2) in

Fig. 4. Three-dimensional mean LORETAKey images of w14 Hz spindle oscillations (SOs) show the first three local maxima. Top: the primary cortical spindle source {TCZ(K3, K11, 64) (mm)} was pinpointed in the medial frontal, the precentral, and the cingulate gyrus. Middle: the second spindle source {TCZ (K3, K39, 50) (mm)} was found in the paracentral lobule, precuneus, and posterior cingulate areas. Below: a third spindle source {TCZ(K3, 52, 1) (mm)} was detected in medial frontal gyrus and anterior cingulate areas. The color scale (below right) shows the power value range, and the structural anatomy is shown in gray scale. Data were averaged across 12 epochs including SOs of 24 patients each case (nZ288) and using frequency–domain–mode in a range of 9.4–20 Hz.

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the range above 14 Hz showed no essential differences between frontal and parietal power. A positive correlation was found between peak frequency and the frontal absolute power (r2Z0.57, P!0.01) as well as between peak frequency and the parietal absolute power (r2Z0.44, P!0.01) in the range of 14–20 Hz.

lobule could only be ascertained in the case of one patient. A constant second spindle source (Fig. 4, middle), likewise located within pre-/parietal cortex areas (BA5,7,31— superior parietal lobule and cingulate gyrus), was found in 15 patients. Their TC and the BA are given in the second line in the general view in Table 3. The following results were obtained in the analysis of the individual EEG epochs (2.5 s each). From a total of 288 EEG epochs (100%) from all patients, the central spindle oscillation source (comparable to Fig. 4, top) was localized for 186 epochs (65%); for 26 epochs (9%), a more parietal maximum (similar to Fig. 4 middle) was detected; and for another 28 epochs (10%), a more frontal maximum (similar to Fig. 4 below) was found. Various different first local maxima were detected in another 48 epochs (17%). Only in three patients were all 12 selected epochs to be found continuously to the same maximum.

3.4. Source localization of motor fields First, the results regarding the EEG epochs (nZ288) of all 24 subjects will be presented. Three-dimensional mean LORETAKey images (Pascual-Marqui et al., 1994) demonstrate several local maxima (Fig. 4). Primarily modules of the motor system, particularly in the frontal cortex areas and cingulate areas (Devinsky et al., 1995; Fuster, 2000; Gerardin et al., 2000; Roland, 1984; Tanji, 1985), were pinpointed as the first and primary source of SOs {(K3, K11, 64) (mm); BA6,31,4}; (Fig. 4, top). Secondary somatosensory regions and posterior cingulate areas were detected as second spindle source {(K3, K39, 50) (mm); BA5,7,31}; (Fig. 4, middle). A third spindle source {(K3, 52, 1) (mm); BA10,32,42} was found in prefrontal regions and anterior cingulate areas (Fig. 4, below). Table 3 summarizes the TC and the estimated BA of the primary maximum and the immediately following local maxima. With these spindle oscillation sources in mind, we considered each patient separately. In 18 of the 24 subjects, the co-ordinates indicated in the first line (Table 3) were given as the main spindle source (BA6,31,4—superior frontal, cingulate, and precentral gyrus). Two more patients could be added to this group (BA6,31,24—superior frontal and cingulate gyrus) because their co-ordinates deviated only slightly from the first spindle oscillation source (Fig. 4, top). Thus, this spindle source was dominant in more than 83% of the cases. In three other subjects, a main spindle source (BA10,32,42—medial frontal and cingulate gyrus) was detected more in the prefrontal regions. The TC of this spindle oscillation source (Fig. 4, below) and the BA are to be found in the third position in the general evaluation in Table 3. A main spindle source (BA40,7,5—superior parietal lobule and supramarginal gyrus) in the pre-/parietal

4. Discussion When the aforementioned w14 Hz SOs, concentrated at centrally located regions, occurred, the patients had already lost consciousness. Rostral brain regions had been long disconnected functionally from posterior regions; the hemispheres were no longer coupled (John, 2002; John and Prichep, 2005), and the transition to BS-EEG meant a further disconnection of the cortex from its subcortical connections (Wennberg, 2000) and from its sensory inputs. In a situation like this, involving EEG suppression, transmission blocking, and disrupted signal interpretation, one does not normally expect the appearance of non-random oscillatory activities—which repeatedly and almost simultaneously interrupt the flat periods. We observed the spindle activities primarily midline above the central region around Cz, despite a prolonged and almost complete suppression of cortical activity in the EEG. To the best of our knowledge, no previous study of spindles during BS-EEG induced by propofol has investigated their quantitative parameters or has pinpointed the spindle sources in humans. For this reason and also because all spindle types seem to be expressions of a common

Table 3 The first six maxima localized through use of LORETAKey (column 1), their Talairach co-ordinates (column 2), the power value (column 3), the number of subjects for which the respective spindle source on this line was determined (column 4), and the three Brodmann areas which were most often involved (column 5) Local maximum

1 2 3 4 5 6

Talairach co-ordinates (X, Y, Z in mm) X

Y

Z

K3 K3 K3 K59 K59 K45

K11 K39 52 K25 K32 K46

64 50 1 15 15 50

Value (eK02)

Subjects 100%Z24

Brodmann area (1–3 best)

4.6 4.1 3.3 2.9 2.9 2.7

18 (C2)

6, 31, 4/(24) 5, 7, 31 10, 32, 42 42, 40, 41 42, 40, 22 40, 7, 5

3

1

The main oscillation source is in the first line and the immediate following local maxima in the second to sixth lines. Note that the main spindle source on the first line was found to stand at TCZ(K3, K11, 64) (mm) in about 18 (C2) out of 24 subjects.

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phenomenon (Mackenzie et al., 2004) we sometimes refer to similar spindle-shaped patterns in the following. In view of a possible functional role played by the oscillatory phenomenon during deep narcosis, we assessed the following factors in sequence: (1) the influence of propofol dosage, (2) the frequency, shape and distribution of the SOs, (3) the source localization of motor fields, and (4) the depth of anesthesia. (1) The SOs only seem to occur within a specific ‘window of dosage’, incidentally also without nitrous oxide being added (Feshchenko et al., 1997). The propofol infusion reached 230–480 mg kgK1 minK1 in a study involving painful electrical stimulus (Huotari et al., 2004). Kearse and Fahmy (1989) initially administered 2.5 mg kgK1 propofol and then an infusion of 100K200 mg kgK1 minK1 propofol when they noticed ‘fronto-central spindle-like patterns’. We administered similarly large doses in the treatment, but suspect additional factors (Blumenfeld and McCromick, 2000; Huotari et al., 2004) explaining the typical characteristics of midline w14 Hz SOs besides the pharmacological stimulation of the GABAA receptor complex (Nelson et al., 2002; Reinhold et al., 1998) through the sedative-hypnotic propofol. Because the mean frequency of ‘13–16’ Hz sometimes changed briefly from this range to faster frequencies with smaller amplitudes (Fig. 3), it is unlikely that the underlying processes responded only to the amount of propofol. We found no direct correlations between spindle oscillation properties and the individual dosage of propofol. Although admittedly an induction with repeated bolus applications is not very suitable in determining dose dependencies, previous studies confirm that while SOs are produced by anesthetics, this cannot be directly attributed to any of the anesthetic agents because similar patterns are observed during sleep (Steriade et al., 1996). Due to the large doses of propofol which were given to our patients so as to avoid sympathoadrenergic hyperactivity, we assume an increased concentration of dopamine in the nucleus accumbens (Pain et al., 2002) through which a direct influence on cortical– striatal–thalamic–cortical pathways would be possible (Chambers et al., 2003). (2) The peak frequency at the electrode Cz, averaged for all epochs (nZ576), was in the range of ‘11–17’ Hz, and the mean frequency range was ‘13–16’ Hz. These ranges are in keeping with the spindle frequencies of 11–13 Hz (Kearse and Fahmy, 1989) and of 13–15 Hz (Huotari et al., 2004) recorded under propofol. Spindle patterns that appear during human sleep are known to have a frequency of 11–15 Hz (Anderer et al., 2001; Steriade, 1999). Thus, sleep spindles in humans have nearly the same frequency as the SOs we observed when applying propofol. In comparison, similar spindle patterns with similar peak frequencies of 10–14 Hz

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were also found in one and the same animal while under barbiturates and during sleep (Mackenzie et al., 2004). There was only slight deviation from the calculated w14 Hz for other electrode positions (Table 1), but the frequency varied to some degree among the individual epochs (Figs. 1 and 2). We often even observed a switch to faster frequencies closely connected with spindle activities. It is interesting that we were dealing here with frequencies, which were faster by a factor of two (Fig. 3). Such frequency doubling, without any visible alteration in the behavioral state, has already been observed in animal experiments, whereby the role of the ascending activating modulatory systems in producing variable frequencies of fast rhythms within the given state has been emphasized (Steriade, 1997). In this connection, it has been suggested that changes in the power of high frequencies (beta/gamma) associated with spindles probably correlate with the presence of different brain stages (Mackenzie et al., 2004), an assumption which we share. Spindles are defined as a group of rhythmic waves characterized by progressively increasing, then gradually decreasing amplitude (Niedermeyer and Lopes da Silva, 1987). This description almost exactly corresponds to the pattern type we observed. Prolonged and waxing and waning spindles have often been determined during sleep as well, in periods in which there is no slow oscillation (Steriade, 1997). We saw the spindle patterns in almost all patients under deep narcosis, including when bursts were taking place, with occasional simultaneous overlapping. In other studies on propofol similar observations have been made (Huotari et al., 2004). It has even been reported that some features of physiological sleep seem to be better preserved during propofol anesthesia than during anesthesia with other agents (Huotari et al., 2004). It was assumed that principally barbiturate anesthesia faithfully reproduced the spindle pattern observed in natural sleep (Contreras et al., 1997; Mackenzie et al., 2004; Steriade et al., 1993), but this seems to be true for propofol-induced narcoses as well. In a study of intra-hemispheric coherence during slowwave sleep an increase with regard to the 14 Hz component at central, parietal and occipital sites has been detected (Duckrow and Zaveri, 2005). We investigated the coherence of homologous leads (Tables 1 and 2) and suspect that such hypercoherence in spindle frequency between the left and right hemispheres might stem either from strong direct connections—which, as mentioned above, does not apply for BS narcosis—or more likely from common input from the thalamus (Nunez, 2000) in the central, parietal, and also frontal regions. It is also known that these oscillations occur almost simultaneously in the neocortex and in the thalamus (Contreras et al., 1997). Despite EEG suppression and BS patterns, our 14 Hz SOs were rather synchronous, which suggests an intact corticothalamic feedback as in the case of barbiturates as well (Destexhe et al., 1998). The oscillatory modulation might possibly even enhance the mediation of

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activity and increase binding throughout much of the cortex, thalamus, and subcortex (John, 2001). Because our SOs were synchronous and not simply random, they might also function as information (John, 2003). The most powerful spindles were recorded primarily above the centrally located regions. Also in animals the powerful spindles were to be found in neocortical structures which were involved in motor activity and sensory activity (frontal, parietal and hindlimb cortices), or which had modulatory effects on the cortex and thalamus (Mackenzie et al., 2004). (3) Since in the process of source localization, motor system modules (Devinsky et al., 1995; Fuster, 2000; Roland, 1984; Tanji, 1985) have been found to be oscillation sources, we suspect a particular connection between w14 Hz SOs and the specific regions involving movement and the control of movement. We not only found the power maximum of the spindles above precisely such midline cortical areas, but also determined that the LORETAKey images (Fig. 4) revealed the secondary and primary motor areas, as well as some cingulate areas, as the main cortical spindle source (BA6,31,4/24) in 83% of the cases. The frequent occurrence of this localized spindle oscillation source, detected within the frontal lobe, demonstrates the preference for these motor fields. However, no motor acts were carried out. Only occasionally do spontaneous movements accompany the induction of propofol narcoses (Borgeat et al., 1991; Smedile et al., 1996) but we did not analyze these periods. On the basis of a number of studies, it was assumed that behavior is a function of activity in the motor system and that the motor system controls behavior and vital functions (Swanson, 2000). Proceeding from the further assumption that the cingulate cortex projects to the frontal cortex and plays an excitatory role in motivating behavior in general (Lopes da Silva et al., 1990), the SOs within motor fields could be very closely connected with behavioral organization and to activating circuitry (Chambers et al., 2003; Devinsky et al., 1995; Steriade et al., 1994). However, our analysis of single EEG epochs revealed, for 17% of our 2.5 s periods, some additional maxima which deviated from typical main spindle oscillation sources, partly in functionally distinct cortical areas. We were unable to determine a dependency between the located maximum and the frequency for the 24 subjects under narcosis. However, a LORETAKey study with EEG sleep spindles, which were arranged according to their topographic distribution, found the following cortical brain areas relative to spindle frequency: the precuneus (BA7) primarily over 14 Hz and the medial prefrontal gyrus (BA9, 10) below 13 Hz (Anderer et al., 2001). Their main sleep spindle source with TC {(K3, K46, 43) (mm); BA7; precuneus gyrus} could to some degree be closely associated with our second source under propofol with TC {(K3, K39, 50) (mm); BA5,7,31; paracentral lobule, precuneus and cingulate gyrus}. Although in both cases

the somatosensory regions within the parietal lobe were pinpointed, these presumed spindle sources were not completely identical. Only the source {(K45, K46, 50) (mm); BA40,7,5} given in the sixth position in Table 3 was likewise found in the case of sleep spindles (Anderer et al., 2001). But magnetoencephalogram (MEG) sleep spindle dipoles were already detected in all four lobes (Shih et al., 2000) or they were distributed more bilaterally over the centro-parietal regions (Manshanden et al., 2002). It may well be that various sleep spindles (Terrier and Gottesmann, 1978) represent the same phenomenon but in different sleep states (Mackenzie et al., 2004). Anterior spindles should occur after the animals have fallen asleep whereas posterior spindles are unique to slow wave sleep (Terrier and Gottesmann, 1978). Thus, the divergent results obtained in spindle source localization may also be affected by the widely differing behavioral stages, which were reached in sleep and under anesthesia. Nevertheless, a comparable significance cannot be excluded. (4) An almost complete EEG suppression of cortical activity and the presence of typical BS patterns are regarded as features of a very deep anesthesia. During treatment, the BS patterns continued while propofol was being administered (Hensel et al., 2000), and consequently the depth of the narcosis is also presumed to have remained constant, whereas spindling oscillations with varying frequency sometimes appeared and sometimes did not. For this reason, the SOs we observed are probably not a similarly reliable indicator of anesthetic depth, especially of the hypnotic component, in contrast to spindles which appeared in halothane-anesthetized cats, where there were clear correlations between the occurrence of spindles and the dose of anesthetic, administered at least until noxious stimuli were applied (Keifer et al., 1994). It was even reported recently that spindles are a part of a pain-evoked response to a noxious stimulus in non-opiate-dependent patients under deep propofol anesthesia (Huotari et al., 2004). Thus, SOs are not a specific feature of opiate-dependent patients. However, these pain-evoked potentials lend support to the results of recent studies that have shown that, also during spike-burst mode, thalamic neurones are tuned to detect rapid changes in incoming sensory signals and to pass information on to the cortex (Sherman, 2001). Thus, spindles under propofol anesthesia could come to be a sign of transition from brain-deafferented to other conditions. In keeping with this assumption, sleep spindle activities appear primarily during the transition from wakefulness to sleep; while the thalamic nuclei and the cortex are cut-off from sensory inputs from the periphery (Contreras et al., 1997; Lopes da Silva, 1991; Steriade, 1997). However, at the present time we cannot completely determine the functional role of these SOs in narcosis with certainty. In addition to the EEG, evoked potentials (EP), and especially far-field potentials (Kohsaka et al, 2000; Sonoo et al, 2004) should also be employed in order to

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determine the influence of brain-stem regions on the spindle phenomenon. 4.1. Conclusion The w14 Hz SOs appeared during very deep narcosis mostly within the flat periods of BS-EEG. In all probability these patterns are non-random. Motor fields and cingulate areas were particularly important, being repeatedly determined as cortical main spindle sources. Since no movements occurred simultaneously, spindles may play a role in control processes of the behavioral state and of bodily vital functions, which are likewise supported through modules of the motor system (Swanson, 2000). Changes in the features and distribution of oscillations could be related to changing brain stages and to inputs from the periphery. We frequently observed transitions to higher frequencies in close connection with spindle activities. The frequency and shape of the SOs we observed under narcosis were very similar to sleep spindles. Although this was less the case with the localized spindle sources, we suspect there is some correspondence between both spindle patterns, which may share an underlying mechanism (Mackenzie et al, 2004). It remains to be established whether, in the case of propofol-induced narcoses, the same consequences apply as in the state of sleep, with regard to memory storage and retrieval, as well as to short-term plasticity (Steriade, 1999, 2001).

Acknowledgements We wish to thank all staff involved in the rapid opiate detoxification under general anesthesia (FOEN) at the Charite´ hospital. We would also like to thank James Murphy and Kathleen Chapman for editing the English version as well as Ingeborg Ku¨chler for the statistics she supplied.

References Akrawi WP, Drummond JC, Kalkman CJ, Patel PM. A comparison of the electrophysiologic characteristics of EEG burst-suppression as produced by isoflurane, thiopental, etomidate, and propofol. J Neurosurg Anesthesiol 1996;8(1):40–6. Anderer P, Klo¨sch G, Gruber G, Trenker E, Pascual-Marqui RD, Zeitlhofer J, Barbanoj MJ, Rappelsberger P, Saletu B. Low-resolution brain electromagnetic tomography revealed simultaneously active frontal and parietal sleep spindle sources in the human cortex. Neuroscience 2001;103(3):581–92. Andersen P, Andersson SA, Lømo T. Nature of thalamo-cortical relations during spontaneous barbiturate spindle activity. J Physiol (London) 1967;192:283–307. Baker SN, Kilner JM, Pinches EM, Lemon RN. The role of synchrony and oscillations in the motor output. Exp Brain Res 1999;128:109–17.

167

Blumenfeld H, McCormick DA. Corticothalamic inputs control the pattern of activity generated in thalamocortical networks. J Neurosci 2000; 20(13):5153–62. Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M, Schwander D. Propofol and spontaneous movements: an EEG study. Anesthesiology 1991;74:24–7. Chambers RA, Taylor JR, Potenza MN. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 2003;160(6):1041–52. Chen R, Yassen Z, Cohen LG, Hallett M. The time course of coricospinal excitability in reaction time and self-paced movements. Ann Neurol 1998;44:317–25. Contreras D, Destexhe A, Sejnowski TJ, Steriade M. Spatiotemporal patterns of spindle oscillations in cortex and thalamus. J Neurosci 1997; 17(3):1179–96. Derbyshire AJ, Rempel B, Forbes A, Lambert EF. The effects of anesthetics on action potentials in the cerebral cortex of the cat. Am J Physiol 1936; 116:577–96. Destexhe A. Sleep oscillations. In: Arbib MA, editor. The handbook of brain theory and neural networks. 2nd ed. Cambridge, MA: MIT Press; 2002. p. 1049–53. Destexhe A, Contreras D, Steriade M. Mechanisms underlying the synchronizing action of corticothalamic feedback through inhibition of thalamic relay cells. J Neurosci 1998;79:999–1016. Detsch O, Kochs E, Siemers M, Bromm B, Vahle-Hinz C. Increased responsiveness of cortical neurons in contrast to thalamic neurons during isoflurane-induced EEG bursts in rats. Neurosci lett 2002; 317(1):9–12. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118(1):279–306. Duckrow RB, Zaveri HP. Coherence of the electroencephalogram during the first sleep cycle. Clin Neurophysiol 2005;116:1088–95. Dueck MH, Oberthuer A, Wedekind C, Paul M, Boerner U. Propofol impairs the central but not the peripheral part of motor system. Anesth Analg 2003;96:449–55. Feshchenko VA, Veselis RA, Reinsel RA. Comparison of the EEG effects of midazolam, thiopental, and propofol: the role of underlying oscillatory systems. Neuropsychobiology 1997;35:211–20. Fuster JM. Proceedings of the human cerebral cortex: from gene to structure and function. Brain Res 2000;52(5):331–6. Gerardin E, Sirigu A, Lehe´ricy S, Poline JB, Gaymard B, Marsault C, Agid Y, Le Bihan D. Partially overlapping neural networks for real and imagined hand movements. Cereb Cortex 2000;10(11):1093–104. Gibbs FA, Gibbs EL, Lennox WG. Effect on the electro-encephalogram of certain drugs which influence nervous activity. Arch Intern Med 1937; 60:154–66. Hensel M, Kox WJ. Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anesthesia: a prospective study in methadone, heroin, codeine and morphine addicts. Acta Anaesthesiol Scand 2000;44:326–33. Hensel M, Wolter S, Kox WJ. EEG controlled rapid opioid withdrawal under general anaesthesia. Br J Anaesth 2000;84(2):236–8. Huotari AM, Koskinen M, Suominen K, Alahuhta S, Remes R, Haetikainen KM, Jantti V. Evoked EEG patterns during burst suppression with propofol. Br J Anaesth 2004;92(1):18–24. John ER. A field theory of consciousness. Conscious Cogn 2001;10: 184–213. John ER. The neurophysics of consciousness. Brain Res Rev 2002;39:1–28. John ER. A theory of consciousness. Curr Dir Psychol Sci 2003;12(6): 244–50. John ER, Prichep LS. The anesthetic cascade. Anesthesiology 2005;102: 447–71. John ER, Prichep LS, Friedman J, Easton P. Neurometrics: computer assisted differential diagnosis of brain dysfunctions. Science 1988;239: 162–9.

168

S. Wolter et al. / Clinical Neurophysiology 117 (2006) 157–168

Kearse LA, Fahmy NR. The electroencephalographic effects of propofol anesthesia in humans: a comparison with thiopental/enflurane anesthesia. Anesthesiology 1989;71:A121. Keifer JC, Baghdoyam HA, Becke L, Lydic R. Halothane decreases pontine acetylcholine release and increases EEG spindles. NeuroReport 1994;5: 577–80. Kim U, Sanchez-Vives MV, McCormick DA. Functional dynamics of GABAergic inhibition in the thalamus. Science 1997;278:130–4. Kohsaka S, Sakai T, Kohsaka M, Fukuda N, Kobayashi K. Dual control of the brainstem on the spindle oscillation in humans. Brain Res 2000;882: 103–11. Lauven PM, Schwilden H, Stoeckel H. Threshold hypnotic concentration of methohexitone. Eur J Clin Pharmacol 1987;33(3):261–5. Legarda JJ, Gossop M. A 24-h inpatient detoxification treatment for heroin addicts: a preliminary investigation. Drug Alcohol Depend 1994;35: 91–3. Loimer N, Schmid RW, Presslich O, Lenz K. Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addicts during detoxification treatment. J Psychiatr Res 1989;23:81–6. Lopes da Silva FH. Neural mechanisms underlying brain waves: from neural membranes to networks. Electroencephalogr Clin Neurophysiol 1991;79:81–93. Lopes da Silva FH, van Lierop THMT, Schrijer CF, Storm van Leeuwen W. Essential differences between alpha rhythms and barbiturate spindles: spectra and thalamo-cortical coherences. Electroencephalogr Clin Neurophysiol 1973;35:641–5. Lopes da Silva FH, Witter MP, Boeijinga PH, Lohmann AHM. Anatomic organization and physiology of the limbic cortex. Physiol Rev 1990; 70(2):453–511. Mackenzie L, Pope KJ, Willoughby JO. Physiological and pathological spindling phenomena have similar regional EEG power distributions. Brain Res 2004;1008:92–106. Manshanden I, De Munck JC, Simon NR, Lopes da Silva FH. Source localization of MEG sleep spindles and the relation to sources of alpha band rhythms. Clin Neurophysiol 2002;113:1937–47. McCormick DA, Bal T. Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci 1997;20:185–215. Morison RS, Bassett DL. Electrical activity of the thalamus and basal ganglia in decorticated cats. J Neurophysiol 1945;8:309–14. Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway. Nat Neurosci 2002;5(10):979–84. Neuper C, Pfurtscheller G. Evidence for distinct beta resonance frequencies in human EEG related to specific sensorimotor cortical areas. Clin Neurophysiol 2001;112:2084–97. Niedermeyer E, Lopes da Silva FH. Electroencephalography: basic principles, clinical applications, and related fields. 2nd ed. Baltimore, MD: Urban & Schwarzenberg; 1987. Nunez PL. Toward a quantitative description of large-scale neocortical dynamic function and EEG. Behav Brain Sci 2000;23(3):371–437. Nuwer MR, Daube J, Fischer C, Schramm J, Yingling CD. Neuromonitoring during surgery. Electroencephalogr Clin Neurophysiol 1993;87: 263–76. Pain L, Gobaille S, Schleef C, Aunis D, Oberling P. In vivo dopamine measurements in the nucleus accumbens after nonanesthetic and anesthetic doses of propofol in rats. Anesth Analg 2002;95:915–9. Pascual-Marqui RD, Michel CM, Lehmann D. Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain. Int J Psychophysiol 1994;18:49–65. Pfurtscheller G. Post-movement beta synchronization. A correlate of an idling motor area? Electroencephalogr Clin Neurophysiol 1996;98: 281–93.

Rampil IJ, Weiskopf RB, Eger II EI, Brown JG, Donegan JH, Johnson BH, Holmes MA. 1653 and isoflurane produce similar dose-related depression of the electroencephalogram. Anesthesiology 1988;69: 298–302. Reinhold P, Kraus G, Schluter E. Propofol for anesthesia and short-term sedation. The final word on use in children under three years. Anaesthesist 1998;47(3):229–37. Roland PE. Organization of motor control by the normal human brain. Hum Neurobiol 1984;2:205–16. Schultz B, Grouven U, Schultz A. Automatic classification algorithms of the EEG monitor Narcotrend for routinely recorded EEG data from general anaesthesia: a validation study. Biomed Tech 2002;47:9–13. Sherman SM. Tonic and burst firing: dual modes of thalamocortical relay. Trends Neurosci 2001;24:122–6. Shih JJ, Weisend MP, Davis JT, Huang M. Magnetoencephalographic characterization of sleep spindles in humans. J Clin Neurophysiol 2000; 17(2):224–31. Smedile LE, Duke T, Taylor SM. Excitatory movements in a dog following propofol anesthesia. J Am Anim Hosp Assoc 1996;32(4):365–8. Sonoo M, Hatanaka Y, Tsukamoto H, Tsai-Shozawa Y, Shimizu T. N10 component in median nerve somatosensory evoked potentials (SEPs) is not an antidromic motor potential. Clin Neurophysiol 2004;115: 2645–9. Steriade M. Synchronized activities of coupled oscillators in the cerebral cortex and thalamus at different levels of vigilance. Cereb Cortex 1997; 7:583–604. Steriade M. Coherent oscillations and short-term plasticity in corticothalamic networks. Trends Neurosci 1999;22(8):337–45. Steriade M. Active neocortical processes during quiescent sleep. Arch Ital Biol 2001;139(1–2):37–51. Steriade M, Descheˆnes M. The thalamus as a neural oscillator. Brain Res Rev 1984;8:1–63. Steriade M, Llina´s RR. The functional states of the thalamus and the associated neuronal interplay. Physiol Rev 1988;68(3):649–740. Steriade M, Descheˆnes M, Domich L, Mulle C. Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol 1985;54:1473–97. Steriade M, Mc Cromick DA, Sejnanski TJ. Thalamocortical oscillations in the sleeping and aroused brain. Science 1993;262:679–85. Steriade M, Amzica F, Contreras D. Cortical and thalamic cellular correlates of electroencephalographic burst-suppression. Electroencephalogr Clin Neurophysiol 1994;90:1–16. Steriade M, Amzica F, Contreras D. Synchronization of fast (30–40 Hz) spontaneous cortical rhythms during brain activation. J Neurosci 1996; 16:392–417. Swanson LW. Cerebral hemisphere regulation of motivated behavior. Brain Res 2000;886:113–64. Tanji J. Comparison of neuronal activities in the monkey supplementary and precentral motor areas. Behav Brain Res 1985;18(2):137–42. Terrier G, Gottesmann LC. Study of cortical spindles during sleep in rat. Brain Res Bull 1978;3:701–6. Wang XJ. Fast burst firing and short-term synaptic plasticity: a model of neocortical chattering neurons. Neuroscience 1999;89(2):347–62. Wennberg RA. Asynchronous burst suppression. Clin Neurophysiol 2000; 111:327. Wolter S, Hensel M, Friedel C, Boehler K, Hartmann U, Kox WJ. Oscillations in the EEG during anesthesia for rapid opiate detoxification. Brain Topogr 2003;16(2):128. Wolter S, Hartmann U, Kra¨mer C, Graf A, Friedel C, Bo¨hler K, Kox WJ, Hensel M. Spindeloszillationen im EEG wa¨hrend der Ana¨sthesie mit Propofol beim forcierten Opiatentzug (FOEN). Journal fu¨r Ana¨sthesie und Intensivbehandlung 2005;2:197–8.