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Anesthesiology:
Laboratory Investigations

Volatile Anesthetics Enhance Flash-induced γ Oscillations in Rat Visual Cortex

Imas, Olga A. Ph.D.*; Ropella, Kristina M. Ph.D.†; Ward, B Douglas M.S.‡; Wood, James D. R.L.A.T.§; Hudetz, Anthony G. B.M.D., Ph.D.∥

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Abstract

Background: The authors sought to understand neural correlates of anesthetic-induced unconsciousness. Cortical γ oscillations have been associated with neural processes supporting conscious perception, but the effect of general anesthesia on these oscillations is controversial. In this study, the authors examined three volatile anesthetics, halothane, isoflurane, and desflurane, and compared their effects on flash-induced γ oscillations in terms of equivalent concentrations producing the loss of righting reflex (1 minimum alveolar concentration for the loss of righting [MACLR]).
Methods: Light flashes were presented every 5 s for 5 min, and event-related potentials were recorded from primary visual cortex of 15 rats with a chronically implanted bipolar electrode at increasing anesthetic concentrations (0–2.4 MACLR). Early cortical response was obtained by averaging poststimulus (0–100 ms) potentials filtered at 20–60 Hz across 60 trials. Late (100–1,000 ms) γ power was calculated using multitaper power spectral technique. Wavelet decomposition was used to determine spectral and temporal distributions of γ power.
Results: The authors found that (1) halothane, isoflurane, and desflurane enhanced the flash-evoked early cortical response in a concentration-dependent manner; (2) the effective concentration for this enhancement was the lowest for isoflurane, intermediate for halothane, and the highest for desflurane when compared at equal fractions of the concentration that led to a loss of righting; (3) the power of flash-induced late (> 100 ms) γ oscillations was augmented at intermediate concentrations of all three anesthetic agents; and (4) flash-induced γ power was not reduced below waking baseline even in deep anesthesia.
Conclusions: These findings suggest that a reduction in flash-induced γ oscillations in rat visual cortex is not a unitary correlate of anesthetic-induced unconsciousness.
HOW general anesthetic agents produce unconsciousness remains a mystery, despite decades of scientific research into their cellular and molecular actions. Our limited understanding of what phenomenal consciousness really is, how it may arise from neurobiologic events, and how to objectively assess its presence or absence has hampered the elucidation of anesthetic mechanisms.
Cortical γ (20–60 Hz) oscillations in the electroencephalogram, local field potentials, and unit activities have been implicated in cognition,1 attention,2 arousal,3 memory,4 perception,5 and consciousness.6 A reduction in γ oscillations has been suggested as a neural correlate of the anesthetic-induced unconsciousness.7–11 Investigations of the effects of general anesthetics on the resting electroencephalogram,12,13 middle latency auditory evoked potentials,14–17 and auditory steady state responses18–20 have contributed to this contention.
At variance with the above results, several experimental studies in humans and animals have found that the amplitude of cortical and hippocampal high-frequency β or γ oscillations was preserved or even enhanced during sedation with midazolam21 or during urethane, ether, isoflurane, or halothane anesthesia.22–25 A possible reason for this discrepancy is that many of the previous studies did not systematically investigate the concentration-dependent effect of the anesthetic agents. Also, the effects of different agents have not been compared using the same experimental protocol at graded, steady state concentrations.
In this study, we compared the effects of halothane, isoflurane, and desflurane on flash-induced γ oscillations in the rat visual cortex. These anesthetic agents are well known to have important differences in potency and region-specific effects.26–28 Finding a common neurophysiologic effect of different agents has the potential to reveal a unitary component of anesthetic action producing unconsciousness.12
The clinically effective concentrations of halothane, isoflurane, and desflurane are different for different endpoints, such as analgesia, atonia, amnesia, and hypnosis. Because we were interested in neural activities related to the loss of consciousness, we compared the effects of these agents at equivalent concentrations at which they presumably produce unconsciousness. The loss of righting reflex (LORR) has been used widely as a standard behavioral index of unconsciousness in the rat.11,29–33 Therefore, the critical concentration of each agent that produced the LORR was used to define the agent’s equivalent concentration. We demonstrate that the three anesthetics augmented the amplitude of flash-induced γ oscillations at concentrations associated with the LORR. This finding casts doubt on the view of diminished γ power as a neural correlate of unconsciousness.
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Materials and Methods

The experimental procedures and protocols used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee (Medical College of Wisconsin, Milwaukee, Wisconsin). All procedures conformed to the Guiding Principles in the Care and Use of Animals34 and were in accordance with the Guide for the Care and Use of Laboratory Animals.35 Every effort was made to minimize the number of animals used and their suffering.
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Electrode Implantation
Fifteen adult male Sprague-Dawley rats were kept on a reversed light–dark cycle in a dedicated room of the Biomedical Resource Center for 5–10 days before electrode implantation. On the day of the aseptic surgery, the rats (250–300 g) were anesthetized using isoflurane (Abbot Laboratories, Chicago, IL) in an anesthesia box (28.8 × 14.4 × 12.0 mm). The animal’s head was secured in a rat stereotaxic apparatus (model 900; Kopf Instruments, Tujunga, CA), and a gas anesthesia adaptor (Stoelting Co., Wood Dale, IL) was placed over the snout to continue anesthesia at 1.5% isoflurane. The animals were breathing spontaneously. Body temperature was monitored with a rectal probe and maintained at 37°C via a water-circulating heating pad. The dorsal surface of the head was prepared for sterile surgery with iodine spray. Steam-sterilized instruments and drapes were used during surgery. Sterile 1% xylocaine was injected under the skin, and a midline incision was made. The skin was laterally reflected, the exposed cranium was gently scraped of connective tissue, and any bleeding was cauterized.
For recording of intracortical field potentials, a concentric, bipolar semimicro electrode (contacts separation of 0.5 mm; SNEX-100X; Rhodes Medical Instruments, Inc., Woodland Hills, CA) was stereotaxically implanted in the primary visual cortex at coordinates 7 mm posterior, 2–3 mm lateral, and 2–2.3 mm vertical relative to the bregma36 and was secured to the cranium with cold-cure resin. A stainless steel machine screw in the caudal cranium was used as a ground electrode. Two additional skull screws were placed to anchor the skullcap to the cranium, and the assembly was embedded in resin. An antibiotic (10 mg/kg intramuscular enrofloxacin) and pain medication (0.02–0.05 mg/kg subcutaneous Buprenex [Reckitt Benckiser Health Care, Ltd., Hall, United Kingdom]) were administered. Analgesic injections of Buprenex (0.02–0.05 mg/kg subcutaneously twice daily) continued for 3 days, and the antibiotic injections of enrofloxacin (10 mg/kg intramuscular twice daily) were administered for 14 days. The animal was kept in the reversed dark–light cycle room for 7–10 days and observed for any infection or other complications.
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Event-related Potential Experiment
Each rat was assigned to event-related potential (ERP) experiments under each of the three anesthetic agents administered on different days. One week of recovery was allowed before repeating the experiment with a different agent. On the day of the experiment, the animal was placed in a cylindrical plastic restrainer of 6 cm in diameter (Harvard rodent restrainer, model AH-52-0292; Harvard Apparatus, Holliston, MA) stationed inside a rectangular, transparent, plastic anesthesia box. While awake, the animal had limited movement of its head and limbs but was not able to crawl out of the cylinder. The animal’s rectal body temperature was maintained at 37°C with a thermostat-controlled, water-circulated heating pad. The rat was positioned in the apparatus under inhalational anesthesia, vaporized into a mixture of 30% oxygen and 70% nitrogen gas (flow rate of 5.3 l/min), with the same agent that was chosen for that day’s experiment. The animal was breathing spontaneously. When all connections were in place, the anesthetic was turned off, and a 1-h equilibration period was allowed for the animal to regain consciousness. The animal was already fully awake in less than 10 min after the anesthetic administration was terminated, as judged by its attempts to crawl out of the restrainer.
After 1 h of equilibration time, 5 min of spontaneous field potentials were recorded, followed by recording of the ERP to flash stimulation. Subsequently, the anesthetic concentration was increased from 0 to 2.0% in increments of 0.1–0.2% for halothane or isoflurane, or from 0 to 9.0% in increments of 1% for desflurane. The anesthetic concentration was monitored through a sampling line connected to the anesthesia box using a gas analyzer (POET II; Criticare Systems, Inc., Waukesha, WI). Recording of spontaneous field potentials and ERP was repeated at each increased concentration after a 20-min equilibration. Because halothane is known to have a longer equilibration time than either isoflurane or desflurane, the equilibration time of 20 min was chosen to achieve the steady state level of anesthesia that is sufficient for halothane and, as such, also sufficient for the two other agents. Gentle knocking on the side of the anesthesia box was performed to control the animal’s level of arousal before testing.
For flash stimulation, a light guide, connected to a stroboscopic light source (EG & G Electro-Optics, Salem, MA) housed in a soundproof box, was directed at the front of the anesthesia box, 18 cm from the rat’s face and centered to achieve binocular stimulation. The stimulation consisted of 60 discrete flashes repeated every 5 s in a darkened room for a total period of 5 min. The interstimulus interval of 5 s was chosen to ensure that the stimulus-related activity dissipated at least several seconds before the onset of the next stimulus.
The signals were amplified at a gain of 10,000, analog band-pass filtered at 1–250 Hz, analog notch filtered at 60 Hz (second-order filter, rejection at 60 Hz of −40 dB), and digitally sampled at 500 Hz (WINDAQ Data Acquisition Software; DATAQ Instruments, Akron, OH).
A few animals did not survive the ERP experiments with all three agents. From the total of 15 rats, 14 were tested with halothane, 11 of which were also tested with isoflurane, and 8 of which were also tested with desflurane. One animal was tested with isoflurane and desflurane but not halothane.
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Righting Reflex Experiment
One week after the ERP experiment, the animal was tested for LORR as a function of anesthetic concentration. As in the electrophysiologic experiment, the animal was placed in the anesthesia box, but without the restrainer. The same experimental protocol was applied to incrementing the anesthetic concentration as in the ERP experiment. The righting reflex was tested by tilting the anesthesia box sideways by 30° to roll the animal to its side. The righting reflex was marked as present when the animal made a purposeful attempt to right itself. Note that every time the animal made an attempt to right itself, it succeeded. Spontaneous head movement or random limb movement in the absence of righting was not taken as an indication of righting.
In addition to righting, the presence of whisker, corneal, tail, and foot pinch responses was tested in a few animals to obtain a more complete characterization of the rats’ behavioral responses. The response to whisker stimulation was assessed by gently stroking the whiskers on one side of the rat’s face with a cotton-tipped applicator and was marked as present if the animal turned its head toward the stimulus. The corneal response was assessed by gently touching the cornea of one eye with a cotton-tipped applicator, and was marked as present if the rat blinked immediately after the stimulation. Finally, the response to tail or foot pinch was assessed by gently pinching the tail or foot of the rat with a hemostat and was marked as present if the animal withdrew its foot or tail in response to stimulation. Because only a few animals were used in these tests, no quantitative or statistical analyses on whisker, corneal, tail, or foot pinch data were performed. Only the data from the righting reflex experiment were used in the analysis.
As mentioned above, some animals did not survive the ERP experiments with all three agents. A few additional rats died after the ERP experiments were completed but before the righting studies were initiated. For that reason, only 5 rats from the ERP experiments were tested for the loss of righting with halothane and isoflurane, 4 of which were also tested with desflurane. To assemble a statistically appropriate group of animals, additional rats were included in the righting protocol. Thus, 9 additional rats were tested with halothane, 7 of which were also tested with isoflurane. Three additional animals were tested with desflurane only. Hence, the total number of animals tested for the loss of righting was 14 for halothane, 12 for isoflurane, and 7 for desflurane.
The inhaled percent anesthetic concentration at which the righting reflex was abolished was determined by averaging the concentration at which the righting reflex was still preserved and the concentration at which it was lost. We defined this value as one minimum alveolar concentration for the loss of righting (1 MACLR). For all subsequent analyses, the percent inhaled concentrations were expressed as a fraction of 1 MACLR. This definition was introduced in remote analogy of the traditional minimum alveolar concentration (MAC) used to define the critical concentration of inhalational anesthetics associated with an absence of a response to nociceptive stimulation 50% of the time (E50).
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Data Analysis
Single-trial ERPs comprising 1-s poststimulus periods were extracted from the record in each experiment for every anesthetic level using a threshold peak-detection algorithm. These data were normalized to the SD of the concatenated 1-s-long prestimulus activity in the waking state. To examine the effect of anesthetic agents on γ oscillations, single-trial ERP data were band-pass filtered at 20–60 Hz with a bidirectional Butterworth digital filter (n = 2). The use of the bidirectional filter ensures that the original phase information of the ERP is preserved. All consecutive analyses were performed on the γ-filtered data.
The ERP data in each experiment were first examined on a trial-to-trial basis using the visualization tool “ERP image.”37–39 To quantify the temporal and frequency-dependent characteristics of the ERP between 0 and 1,000 ms after stimulus, the single-trial ERP data were wavelet transformed using complex Morlet wavelets.40 The wavelet decomposition was chosen over more traditional short-time fast Fourier transform–based time-frequency methods because it offers variable time and frequency resolutions and allows a reliable detection of rapid transient changes in signal amplitude at higher frequencies. Because the duration of the wavelet is shorter for higher-frequency bands, this method provides a better compromise between temporal and spectral resolutions and has been found to be particularly useful in the analysis of stimulus-induced γ oscillations.40 It also offers improved performance compared with narrow-band filtering because it is designed to minimize side-lobe energy and reduce spectral leakage.
As described in detail elsewhere,40 the wavelet transformation of the single-trial ERP data involved convolving the signal with complex Morlet wavelets with central frequency ranging from 20 to 60 Hz in increments of 1 Hz. Each Morlet wavelet is characterized by a Gaussian envelope in both time and frequency domains around its central frequency. Hence, the SD of the envelope in the time domain determines the temporal resolution of the wavelet, and the SD of the envelope in the frequency domain determines the frequency bandwidth of the wavelet around its central frequency. For the central frequencies of interest, the temporal resolution and spectral bandwidth of the wavelet ranged from 55.7 ms and ±2.8 Hz at 20 Hz to 18.5 ms and ±8.6 Hz at 60 Hz, respectively.
To calculate band power as a function of time for every trial, the wavelet power was averaged within spectral windows of 20–30, 31–40, 41–50, and 51–60 Hz. The averaging is acceptable because it minimizes the time-frequency overlap in 10-Hz-wide spectral windows resulting from continuous wavelet decomposition. The ERP image tool was then used to display the single-trial wavelet power in each spectral window. As is shown in the Results section, these wavelet plots suggested the need to separately examine the early (0–100 ms) and the late (100–1,000 ms) ERP components, termed the early cortical response (ECR) and late γ oscillations, respectively.
The ECR was calculated by averaging the ERP data in each experiment across multiple trials. Because ECR has little phase variability from trial to trial, the averaging was acceptable for this analysis. The amplitude of ECR was determined as the difference from the most positive (maximum) to the most negative (minimum) peak between 0 and 100 ms.
The power of the late (100–1,000 ms) γ oscillations was estimated from the single-trial ERP data using the Thomson multitaper power spectral estimation technique, a short-segment fast Fourier transform analysis that uses orthogonal windows. This technique was chosen because it offers superior performance in the analysis of short temporal data segments with a high degree of nonstationarity.41,42 Due to trial-to-trial phase variation of the late γ oscillations, an averaging of original ERP data were not a desirable approach in this case. Instead, γ-band power was calculated by first averaging the power spectrum within the range of 20–60 Hz in each trial and then averaging across all trials to obtain one datum per anesthetic concentration in each experiment. Thus, these data reflect γ power of both stimulus-locked and nonstimulus locked events. All calculations were done with MATLAB 6.0 (MathWorks Inc., Natick, MA).
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Statistical Analysis
To minimize experiment-to-experiment variance, all ECR amplitude and late γ power data were normalized to their respective means obtained by averaging across all anesthetic concentrations in each experiment. Because it was difficult to obtain exactly the same anesthetic concentration in each experiment, the data were averaged within selected anesthetic ranges of 0.4–0.75, 0.8–1.25, 1.3–1.75, and 1.8–2.40 MACLR in addition to the waking state. This procedure ensured that at least one datum was included in each range and allowed the statistical comparison among different anesthetic levels. To test for a significant effect of anesthetic concentration on ECR and late γ oscillations, the general linear model analysis of variance was used with the anesthetic concentration as a fixed factor and the rat as a random variable. The Bonferroni comparison was used to test for a significant difference in observations at different anesthetic concentrations from waking control. Statistical analyses were conducted using MINITAB (Minitab Inc., State College, PA).
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Results

Righting Reflex
In animals anesthetized with halothane, the LORR occurred between 0.7 and 1.0% (1 MACLR = 0.90 ± 0.1%; n = 14) concentration. In animals anesthetized with isoflurane, the righting reflex was also lost between 0.7 and 1.0% (1 MACLR = 0.84 ± 0.1%; n = 12) concentration. In animals anesthetized with desflurane, the LORR occurred between 3.5 and 5.0% (1 MACLR = 4.26 ± 0.5%; n = 9) concentration. In a few animals tested, the whisker reflex was lost in the same concentration range as the righting reflex for all three anesthetic agents. The responses to corneal stimulation, tail, and foot pinch were preserved past the LORR.
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Anesthetic Effect on Single-trial ERP
Fig. 1
Fig. 1
Image Tools
Figure 1 shows a typical example of the unfiltered and γ-filtered versions of the same ERP to a single flash at four selected values of MACLR for halothane from one animal. At 0.0 MACLR (waking), typical low-frequency (1–4 Hz) afterdischarge with superimposed relatively low-amplitude γ (30–40 Hz) oscillations was present after the flash. The presence of γ oscillations over the 1,000-ms poststimulus period is better revealed by the filtered version of the ERP. Halothane disrupted the afterdischarge at low concentration (0.5 MACLR) and augmented γ oscillations at intermediate concentration (1.0 MACLR). At 2.0 MACLR, γ oscillations between 600 and 1,000 ms were suppressed but were still strongly present between 0 and 500 ms after stimulus.
Fig. 2
Fig. 2
Image Tools
Figure 2 shows typical examples of γ-filtered single-trial ERP data from one animal at four selected values of MACLR for halothane, isoflurane, and desflurane. At 0.0 MACLR, bursts of γ oscillations were present after each flash. The γ bursts repeated at approximately 200-ms intervals with decaying amplitude over the 1,000-ms poststimulus period. Anesthetic agents disrupted the periodicity of γ bursts at low concentration (0.5 MACLR) and transformed the bursts into a more continuous oscillations spanning most of the 100- to 1,000-ms poststimulus period at intermediate concentration (1 MACLR). At 2.0 MACLR, late γ oscillations were diminished, but the early components of the cortical evoked response, confined to 0–100 ms, were still present. These effects were similar with all three agents and suggested that the anesthetics, in general, had distinct effects on the ECR and late γ oscillations.
Fig. 3
Fig. 3
Image Tools
Figures 3 shows further examples of the single-trial ERP in the form of wavelet transforms from seven experiments at different halothane levels selected from four concentration ranges. To minimize the frequency overlap resulting from continuous wavelet decomposition, the wavelet power was averaged within 10-Hz-wide frequency ranges. The figure shows that spectral components of the early response (0–100 ms) were not depressed by halothane even at high concentrations (2.1–2.5 MACLR). The spectral power of the response was the highest in the low γ frequency range (20–30 Hz) at all anesthetic concentrations. In variance with its effect on the early response, halothane augmented late γ oscillations in the 100–1,000 ms window. This effect was the most pronounced in the 30- to 50-Hz range and at medium concentrations (1.0–1.25 MACLR), which included the concentration associated with the LORR. As the figure shows, the augmented activity was variable from trial to trial, and even more from animal to animal, but this did not alter the general trend of γ augmentation within the 1,000-ms poststimulus period. The wavelet transform images obtained for two other anesthetic agents showed patterns similar to those shown here.
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Anesthetic Effect on ECR
Fig. 4
Fig. 4
Image Tools
Figure 4 shows a typical example of the ECR in the waking state and at four selected anesthetic concentrations of the three agents from the same animal. Although individual components of the response varied as a function of anesthetic concentration, all three agents augmented rather than reduced the maximum peak-to-peak amplitude of the ECR. This effect was the most pronounced at highest anesthetic concentrations studied (1.8–2.4 MACLR).
Fig. 5
Fig. 5
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Figure 5 compares the group average effects of the anesthetics on ECR from all experiments. Clearly, each agent enhanced, rather than reduced, the amplitude of ECR in a concentration-dependent manner. There were some differences in the magnitude of their effect at low equivalent concentrations. Thus, isoflurane significantly (P ≤ 0.05) augmented ECR already at 0.4–0.75 MACLR, whereas desflurane produced a significant increase (P ≤ 0.05) only at 1.3–1.75 MACLR. The effect of halothane was intermediate relative to the other two agents. Despite this difference, all three agents significantly (P ≤ 0.05) augmented ECR at high concentrations (1.8–2.4 MACLR). This enhancement relative to waking baseline was 1.7-fold with halothane or isoflurane and 2-fold with desflurane (no significant difference).
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Anesthetic Effect on Late γ Oscillations
Fig. 6
Fig. 6
Image Tools
Figure 6 summarizes the group average effects of the anesthetics on late γ power in the 100- to 1,000-ms window from all animals. All three agents significantly (P ≤ 0.05) augmented late γ power at intermediate anesthetic concentrations (0.8–1.25 MACLR), which included the concentration at which the righting reflex was abolished. This enhancement of late γ power relative to waking baseline was 2.5-fold with halothane, 1.5-fold with isoflurane, and 1.3-fold with desflurane (not significantly different). The augmentation of late γ power was gradually reversed at higher anesthetic concentrations and was not significantly different from the waking baseline in deeply anesthetized states for any of the three agents.
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Discussion

The major findings of this study are (1) halothane, isoflurane, and desflurane enhanced the flash-evoked ECR in a concentration-dependent manner; (2) when the effects of the three agents were compared at equal fractions of MACLR, the effective concentration for an increase in ECR was the lowest for isoflurane, intermediate for halothane, and the highest for desflurane; (3) the power of flash-induced late (> 100 ms) γ oscillations was augmented at intermediate concentrations near MACLR for all three anesthetic agents; and (4) flash-induced γ power was not reduced below waking baseline even in deep anesthesia. These findings suggest that a reduction in flash-induced γ oscillations in rat visual cortex is not a unitary correlate of the anesthetic-induced unconsciousness.
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Methodologic Considerations
In this study, the gross movement of the animals was limited by a body restraint. The potential confounding effect of the restraint is recognized. However, we believe that the restraint did not influence the conclusions of our study for several reasons. First, the rats showed no behavioral signs of discomfort in the waking or lightly anesthetized states in either anesthetic group. During testing, the animals seemed comfortable and calm. They rarely made an attempt to free themselves from the restrainer but seemed to accept their condition, sometimes engaging in chewing, sniffing, and whisking as seen during normal exploratory behavior. Second, when we compared flash-induced cortical responses between waking restrained and freely moving conditions, no difference was found. Therefore, we believe that the restraint did not produce undue arousal and did not influence the result. Although occasional head and orofacial movements were present, it is unlikely that motion artifacts would have contaminated the results because the cortical potentials were recorded differentially, with bipolar electrodes that sample local field activity of small cortical region, and are unaffected by far-field potential sources, such as muscle electrical activity.
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Loss of Righting as a Measure of Unconsciousness
Traditionally, the potencies of inhalational anesthetic agents are compared in terms of the MAC, which designates the threshold at which the response to nociceptive stimulation (surgical cut or tail pinch) is absent 50% of the time. Because in this study we were interested in the agents’ hypnotic effects, instead of MAC we used MACLR. Although there is no objective measure for the loss of consciousness in animals, in addition to our lack of understanding of the nature of animal consciousness, the LORR is thought to be a suitable behavioral index of pharmacologically induced unconsciousness in the rat and has been used extensively as such.11,29–31,33,43,44 This practice is based on the observation that the rat loses its righting reflex at approximately the same MAC fraction at which humans do not respond to verbal commands—the generally accepted index of human unconsciousness.
It is important to emphasize that a comparison of different anesthetic agents’ effective concentrations at equivalent fractions of their MAC and their MACLR can lead to different results. Although MAC is tied to the anesthetic-induced loss of nociceptive response, which is mediated in the major part by spinal mechanisms,45 MACLR reflects the hypnotic effect of anesthetics that depends on a cortical or thalamocortical process.12,46 Also, volatile anesthetics likely exert their antinociceptive effects principally through N-methyl-d-aspartate receptors,47 whereas their hypnotic effects are linked to action at γ-aminobutyric acid type A (GABAA)48 or cholinergic27 receptors. Because of the difference in mechanisms, the potencies of various anesthetic agents may compare differently depending on which particular scale, i.e., MAC or MACLR, is used. For example, in this study, we found that rats lost their righting reflex at the same percent inhaled concentrations of halothane and isoflurane. This observation may be surprising because the percent inhaled concentrations corresponding to 1 MAC of these agents have been reported different.49 However, there are other data that support this finding. For example, isoflurane is known to be more potent than halothane in suppressing the response to verbal and tactile commands when compared at equivalent MAC in human volunteers. Specifically, 1 MAC halothane (1.1%) is necessary to produce unresponsiveness,50 whereas 0.5 MAC isoflurane (0.8%) is sufficient to achieve the same endpoint.51 The percent inhaled concentrations of halothane and isoflurane required for the suppression of these responses were more similar than their MAC values. We also demonstrated previously that halothane and isoflurane are equipotent in affecting the interhemispheric synchronization of frontal electroencephalogram and ablating the righting reflex when measured in percent concentration but not in terms of MAC.52 Thus, agent-specific depression of cortical function is measured more accurately by fractions of MACLR than that of MAC.
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Anesthetic Effect on the Early Cortical Response
Our findings will be compared to those in humans and as well as to those in similar rat experiments. In humans, the average early cortical evoked response is routinely measured using scalp electrodes and is normally referred to as the middle latency evoked potential. Because the rat ECR is measured in the same poststimulus time window (0–100 ms) as the middle latency evoked potential, a limited comparison with the human evoked potential is possible. The middle latency evoked potential shows an oscillatory pattern in the γ frequency band17,20,53 that coincides with the γ band we examined in this study. In general, volatile anesthetic agents are known to decrease the amplitude and increase the latency of middle latency auditory evoked response,15,54–57 a finding that lead to the development of a clinical anesthetic depth monitor.58 Middle latency visual evoked potentials have also been found suppressed by anesthetics,59 although they are more variable60,61 than the auditory evoked response.
In contrast to the findings just described, we showed that the three volatile anesthetics, halothane, isoflurane, and desflurane, all augmented ECR relative to waking. This somewhat surprising finding is not without support from previous experimental studies. For example, Santarelli et al.44 showed that the auditory evoked response was increased in some rats during isoflurane anesthesia. Rabe et al.62 found that halothane at intermediate concentrations (0.25–1.0%) augmented both auditory or visual evoked responses in the rat. We found that volatile anesthetic agents augmented ECR at all concentrations up to 2% of halothane and isoflurane and up to 9% of desflurane.
The difference between rat and human study results is probably not due to a difference in sensory modality because, in humans, both auditory and visual middle latency responses were shown to be depressed by the anesthetic agents. Although there is an obvious difference in species, we find it unlikely that the mechanism of anesthesia would fundamentally differ among the mammalian species. The electroencephalographic effects of anesthetic agents are similar in all these species. Furthermore, because ECR was augmented by at least three volatile anesthetic agents, it is unlikely that agent specificity would provide an explanation.
More plausibly, the difference in the early cortical evoked response between human and some of the animal studies may be due to a difference in the type of electrodes and the neuronal activity they are suited to record. Namely, scalp electroencephalographic electrodes used in human studies record synchronized cortical electrical potentials from an estimated cortical volume of approximately 10 cm3 per electrode. These potentials reflect not only sensory-specific neuronal activity but also activity outside of modality-specific cortex. For example, the traditional middle latency auditory evoked response recorded between the ear and the neocortex of humans may also reflect long-range corticocortical as well as thalamocortical synchronization of sensory evoked activity. In contrast, small bipolar electrodes used in our study to record from the visual cortex sample local field potentials from a tissue volume of approximately 0.01 cm3 that reflect synchronized activity of a relatively small group of neurons. Because the anatomy of local neuronal circuits is different from that of large-scale corticocortical networks, anesthetic agents may exert a different effect on long-range and local synchronization of sensory-stimulus related activity. For example, it is conceivable that anesthetic agents may suppress long-range synchronization while augmenting local synchronization. The anesthetic effect on sensory activity of long-range corticocortical networks would be more apparent in the human scalp recordings, whereas the local circuit effects would be revealed by the local intracortical recordings such as those done in the current study.
Although all three anesthetic agents augmented ECR at high enough concentration, there was some difference in the agents’ potencies at low concentrations: Isoflurane augmented ECR at concentrations at which the other two agents did not, and desflurane augmented ECR at higher concentrations than either halothane or isoflurane. In fact, isoflurane is known to be more effective than halothane in depressing the activity of single neurons,63 the electroencephalogram,57 auditory evoked potentials,57 cerebral metabolism, and blood flow.28 Why desflurane was the least effective of the three agents is less clear. Desflurane is believed to suppress the central nervous system to a degree similar to that produced by isoflurane.64–67
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Anesthesia and the Late γ Oscillations
In addition to the flash-induced early cortical response, which represents a brief stimulus-locked γ oscillatory potential, a delayed increase in the power of γ oscillations was observed and termed late γ oscillations. The phase of late γ oscillations relative to the flash is more dispersed than that of the early cortical response and is therefore not detectable by signal averaging, only by single-trial analysis. To distinguish this activity from the average evoked potential, some authors use the term stimulus-induced as opposed to stimulus-evoked activity.40
As with the ECR, we were surprised to find that volatile anesthetics significantly augmented, rather than reduced, the flash-induced late γ oscillations. In fact, γ power was not reduced below waking baseline even in surgical anesthesia. Unlike their differing effects on ECR, the three agents were similarly effective in augmenting late γ power near 1 MACLR. As discussed in the previous section, the effect of anesthetics on scalp-recorded and intracortically recorded potentials may be different. Therefore, direct extrapolation of the current findings to human electroencephalographic events is not appropriate. However, it may be argued that local field potentials recorded with bipolar intracortical electrodes would give a more accurate representation of the effect of anesthetic agents on stimulus-induced synaptic events than do macropotentials obtained with scalp electrodes. Therefore, our data provide a more accurate insight into the local neuronal mechanism of anesthetic action with respect to visual sensory processes. In this sense, our findings suggest that volatile anesthetics do not suppress the generation of stimulus-induced γ oscillations in visual cortex, as it may have been concluded from human studies. Instead, anesthetics may suppress interregional or long-range synchronization of neuronal activity in the γ frequency range.12
Although the average γ power was significantly augmented by all three anesthetics, the individual response potentials varied from trial to trial, as well as from animal to animal. This variation was clearly shown by the wavelet decomposition revealing both the temporal and spectral distributions of flash-induced γ power. Trial-to-trial variations in the stimulus response may reflect spontaneous variations in the state of arousal and in cortical neuronal excitability.68 To examine this possibility, future experiments involving longer ERP recording times at steady state anesthetic levels may be of interest to perform.
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Neural Correlates of Anesthetic-induced Unconsciousness
The important question that we face is whether the event of loss of consciousness or, in the current experiment, more correctly the LORR, can be related to an anesthetic-induced change in either the early or the late visual evoked cortical γ response. Such a change could be viewed as a neural correlate of unconsciousness.69 For the latter, one would hope to find a relatively abrupt change in the evoked response that would occur consistently at an anesthetic concentration that first produces the behavioral sign of unconsciousness and that would be invariant with respect to the administered anesthetic agent. Because the three volatile agents differed in their effects on ECR near 1 MACLR, ECR does not seem to satisfy the above requirements to be a unitary correlate of unconsciousness. Moreover, the ECR increased, rather than decreased, in anesthesia, making it even less plausible as a correlate of unconsciousness.
The significance of late stimulus-induced γ oscillations in cognitive, sensory-perceptual, and voluntary motor functions has been repeatedly demonstrated.1,3–6,70–78 This implies the hypothesis that anesthetic-induced unconsciousness may be associated with the suppression of stimulus-induced late γ oscillations, rather than that of the early, stimulus-locked response. However, we found that the power of flash-induced late γ oscillations was augmented by the three volatile anesthetic agents at concentrations near MACLR. In fact, γ power was not reduced below waking baseline even in deep anesthesia. Therefore, we conclude that anesthetic-induced unconsciousness cannot be ascribed to a reduction in power of either the early, stimulus-evoked or late, stimulus-induced γ oscillations in rat visual cortex.
As already mentioned, this negative finding does not refute the potential importance of an anesthetic depression of interregional or long-range γ synchronization as an underlying mechanism of unconsciousness. A disruption of both corticocortical and thalamocortical connectivity may be associated with surgical anesthesia.7,46 Furthermore, anesthetic-induced changes in the temporal pattern of γ oscillations, rather than the changes in γ power, may be important. We observed that in waking and shallow anesthetic states, the flash produced bursts of γ oscillations, which were transformed into more-or-less continuous activity at intermediate anesthetic concentrations. This transformation may reflect a change in interregional synchronization of γ oscillations underlying neuronal events potentially associated with unconsciousness. It is also possible that the increased synchronization of local synaptic activity, revealed as an enhancement of local γ power, may disrupt the more subtle spatiotemporal patterns of local γ oscillations associated with information processing and consciousness. Testing of this hypothesis would require multichannel recordings of the neuronal ensemble activity at various anesthetic levels; such experiments are in progress in our laboratory.
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Cellular Mechanism of γ Enhancement by Anesthetic Agents
The cellular mechanism of the anesthetic enhancement of early and late γ oscillations is unknown. Volatile anesthetics are known to potentiate neurotransmission at GABAA receptors by enhancing receptor affinity and prolonging the postsynaptic hyperpolarization current.48 It has been indicated that volatile anesthetics also inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors and, at high concentrations, potentiate kainate receptors.79 Buzsaki et al.80,81 proposed that GABAA synaptic transmission in a network of fast-spiking interneurons in the hippocampus may play a role in the generation of synchronized γ oscillations. Other investigators82–84 extended this hypothesis to cortical networks. This then raises the possibility that halothane, isoflurane, and desflurane may augment γ oscillations through an enhancement of GABAA transmission in the cortical interneuron network.
Why the increase in γ power is reversed at higher anesthetic concentrations is less clear. It is possible that the anesthetic modulation of GABAA receptor activity is nonlinear, such that too much inhibition counteracts the oscillations or that the anesthetic depression of excitatory transmission at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors overcomes the GABAA-mediated enhancement of γ oscillations at higher concentrations. Another explanation may be that the depression of γ power is due to the potentiation of kainate receptors.79 Future experiments using means for selective receptor modulation may help to test some of these hypotheses.
In conclusion, our findings suggest that the anesthetic-induced unconsciousness, referenced by the LORR, is associated with an increase rather than a decrease in flash-induced intracortical potentials in the γ frequency band. Both the stimulus-locked early cortical and phase-dispersed late γ oscillations were enhanced at concentrations producing unconsciousness and were not reduced below the waking baseline even in deep anesthesia. These results suggest that neither of these two parameters is a unitary correlate of the anesthetic-induced unconsciousness.
The authors thank Richard Rys, B.S. (Senior Research Engineer, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin), for the design and construction of electronic equipment and Samhita S. Rhodes, Ph.D. (Postdoctoral Fellow, Department of Anesthesiology, Medical College of Wisconsin), for the implementation of the peak-detection algorithm.
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References

1. Fitzgibbon SP, Pope KJ, Mackenzie L, Clark CR, Willoughby JO: Cognitive tasks augment gamma electroencephalogram power. Clin Neurophysiol 2004; 115:1802–9

2. Muller MM, Keil A: Neuronal synchronization and selective color processing in the human brain. J Cogn Neurosci 2004; 16:503–22

3. Lakatos P, Szilagyi N, Pincze Z, Rajkai C, Ulbert I, Karmos G: Attention and arousal related modulation of spontaneous gamma-activity in the auditory cortex of the cat. Brain Res Cogn Brain Res 2004; 19:1–9

4. Gruber T, Tsivilis D, Montaldi D, Muller MM: Induced gamma band responses: An early marker of memory encoding and retrieval. Neuroreport 2004; 15:1837–41

5. Goffaux V, Mouraux A, Desmet S, Rossion B: Human non-phase-locked gamma oscillations in experience-based perception of visual scenes. Neurosci Lett 2004; 354:14–7

6. Engel AK, Singer W: Temporal binding and the neural correlates of sensory awareness. Trends Cogn Sci 2001; 5:16–25

7. John ER: The neurophysics of consciousness. Brain Res Brain Res Rev 2002; 39:1–28

8. Plourde G, Villemure C: Comparison of the effects of enflurane/N2O on the 40-Hz auditory steady-state response versus the auditory middle-latency response. Anesth Analg 1996; 82:75–83

9. Schwender D, Daunderer M, Mulzer S, Klasing S, Finsterer U, Peter K: Midlatency auditory evoked potentials predict movements during anesthesia with isoflurane or propofol. Anesth Analg 1997; 85:164–73

10. Sleigh JW, Steyn-Ross DA, Steyn-Ross ML, Williams ML, Smith P: Comparison of changes in electroencephalographic measures during induction of general anaesthesia: Influence of the gamma frequency band and electromyogram signal. Br J Anaesth 2001; 86:50–8

11. Ma J, Shen B, Stewart LS, Herrick IA, Leung LS: The septohippocampal system participates in general anesthesia. J Neurosci 2002; 22:RC200

12. John ER, Prichep LS, Kox W, Valdes-Sosa P, Bosch-Bayard J, Aubert E, Tom M, diMichele F, Gugino LD: Invariant reversible QEEG effects of anesthetics. Conscious Cogn 2001; 10:165–83

13. Uchida S, Nakayama H, Maehara T, Hirai N, Arakaki H, Nakamura M, Nakabayashi T, Shimizu H: Suppression of gamma oscillations in the human medial temporal lobe by sevoflurane anesthesia. Neuroreport 2000; 11:39–42

14. Hernandez-Palazon J, Falcon-Arana LF, Domenech-Asensi P, Gimenez-Viudes J, Nuno de la Rosa-Carrillo V, Martinez I: Effects of sevoflurane on mid-latency auditory evoked potentials and the 95% spectral frequency limit [in Spanish]. Rev Esp Anestesiol Reanim 2004; 51:133–6

15. Dutton RC, Smith WD, Rampil IJ, Chortkoff BS, Eger EI II: Forty-hertz midlatency auditory evoked potential activity predicts wakeful response during desflurane and propofol anesthesia in volunteers. Anesthesiology 1999; 91:1209–20

16. Kochs E, Stockmanns G, Thornton C, Nahm W, Kalkman CJ: Wavelet analysis of middle latency auditory evoked responses: Calculation of an index for detection of awareness during propofol administration. Anesthesiology 2001; 95:1141–50

17. Schwender D, Madler C, Klasing S, Peter K, Poppel E: Anesthetic control of 40-Hz brain activity and implicit memory. Conscious Cogn 1994; 3:129–47

18. Bonhomme V, Plourde G, Meuret P, Fiset P, Backman SB: Auditory steady-state response and bispectral index for assessing level of consciousness during propofol sedation and hypnosis. Anesth Analg 2000; 91:1398–403

19. Gilron I, Plourde G, Marcantoni W, Varin F: 40 Hz Auditory steady-state response and electroencephalogram spectral edge frequency during sufentanil anesthesia. Can J Anaesth 1998; 45:115–21

20. Plourde G, Villemure C, Fiset P, Bonhomme V, Backman SB: Effect of isoflurane on the auditory steady state response and on consciousness in human volunteers. Anesthesiology 1998; 89:844–51

21. Veselis RA, Reinsel R, Alagesan R, Heino R, Bedford RF: The electroencephalogram as a monitor of midazolam amnesia: Changes in power and topography as a function of amnesic state. Anesthesiology 1991; 74:866–74

22. Buzsaki G, Leung LW, Vanderwolf CH: Cellular bases of hippocampal electroencephalogram in the behaving rat. Brain Res 1983; 287:139–71

23. Vanderwolf CH: Are neocortical gamma waves related to consciousness? Brain Res 2000; 855:217–24

24. Kral A, Tillein J, Hartmann R, Klinke R: Monitoring of anaesthesia in neurophysiological experiments. Neuroreport 1999; 10:781–7

25. Imas OA, Ropella KM, Wood JD, Hudetz AG: Halothane augments event-related gamma oscillations in rat visual cortex. Neuroscience 2004; 123:269–78

26. Holmstrom A, Rosen I, Akeson J: Desflurane results in higher cerebral blood flow than sevoflurane or isoflurane at hypocapnia in pigs. Acta Anaesthesiol Scand 2004; 48:400–4

27. Nietgen GW, Honemann CW, Chan CK, Kamatchi GL, Durieux ME: Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function. Br J Anaesth 1998; 81:569–77

28. Hansen TD, Warner DS, Todd MM, Vust LJ, Trawick DC: Distribution of cerebral blood flow during halothane versus isoflurane anesthesia in rats. Anesthesiology 1988; 69:332–7

29. Devor M, Zalkind V: Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain 2001; 94:101–12

30. Flood P, Sonner JM, Gong D, Coates KM: Heteromeric nicotinic inhibition by isoflurane does not mediate MAC or loss of righting reflex. Anesthesiology 2002; 97:902–5

31. Gustafsson LL, Ebling WF, Osaki E, Stanski DR: Quantitation of depth of thiopental anesthesia in the rat. Anesthesiology 1996; 84:415–27

32. Kissin I, Stanski DR, Brown PT, Bradley EL Jr: Pentobarbital-morphine anesthetic interactions in terms of intensity of noxious stimulation required for arousal. Anesthesiology 1993; 78:744–9

33. Yang PK, Weinger MB, Negus SS: Elucidation of dose–effect relationships for different opiate effects using alfentanil in the spontaneously ventilating rat. Anesthesiology 1992; 77:153–61

34. Guiding Principles in the Care and Use of Animals. Adapted by the American Physiologic Society in 1909 from principles formulated by Walter B. Canon in 1909. Final accepted revision July 2000

35. Guide for the Care and Use of Laboratory Animals. Institute for Laboratory Animal Research. Commission on Life Sciences. National Research Council. National Academy Press, Washington, D.C., 1996

36. Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates, 4th edition. San Diego, Academic Press, 1998

37. Jung TP, Makeig S, Westerfield M, Townsend J, Courchesne E, Sejnowski TJ: Analyzing and visualizing single-trial event-related potentials. Adv Neural Inf Proc Syst 1999; 11:118–24

38. Jung TP, Makeig S, Humphries C, Lee TW, McKeown MJ, Iragui V, Sejnowski TJ: Removing electroencephalographic artifacts by blind source separation. Psychophysiology 2000; 37:163–78

39. Jung TP, Makeig S, Westerfield M, Townsend J, Courchesne E, Sejnowski TJ: Analysis and visualization of single-trial event-related potentials. Hum Brain Mapp 2001; 14:166–85

40. Tallon-Baudry C, Bertrand O, Delpuech C, Pernier J: Stimulus specificity of phase-locked and non-phase-locked 40 Hz visual responses in human. J Neurosci 1996; 16:4240–9

41. Bronez TP: On the performance advantage of multitaper spectral analysis. IEEE Trans Signal Processing 1992; 40:2941–6

42. Lovett EG, Ropella KM: Time-frequency coherence analysis of atrial fibrillation termination during procainamide administration. Ann Biomed Eng 1997; 25:975–84

43. Kissin I, Morgan PL, Smith LR: Anesthetic potencies of isoflurane, halothane, and diethyl ether for various end points of anesthesia. Anesthesiology 1983; 58:88–92

44. Santarelli R, Carraro L, Conti G, Capello M, Plourde G, Arslan E: Effects of isoflurane on auditory middle latency (MLRs) and steady-state (SSRs) responses recorded from the temporal cortex of the rat. Brain Res 2003; 973:240–51

45. Sonner JM, Antognini JF, Dutton RC, Flood P, Gray AT, Harris RA, Homanics GE, Kendig J, Orser B, Raines DE, Rampil IJ, Trudell J, Vissel B, Eger EI II: Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration. Anesth Analg 2003; 97:718–40

46. White NS, Alkire MT: Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness. Neuroimage 2003; 19:402–11

47. Ueno S, Trudell JR, Eger EI II, Harris RA: Actions of fluorinated alkanols on GABA(A) receptors: Relevance to theories of narcosis. Anesth Analg 1999; 88:877–83

48. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci 1999; 55:1278–303

49. Drummond JC: MAC for halothane, enflurane, and isoflurane in the New Zealand white rabbit: And a test for the validity of MAC determinations. Anesthesiology 1985; 62:336–8

50. Alkire MT, Haier RJ, Shah NK, Anderson CT: Positron emission tomography study of regional cerebral metabolism in humans during isoflurane anesthesia. Anesthesiology 1997; 86:549–57

51. Alkire MT, Haier RJ, Fallon JH: Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn 2000; 9:370–86

52. Hudetz AG: Effect of volatile anesthetics on interhemispheric electroencephalogram cross-approximate entropy in the rat. Brain Res 2002; 954:123–31

53. Galambos R, Makeig S, Talmachoff PJ: A 40-Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci U S A 1981; 78:2643–7

54. Schwender D, Daunderer M, Schnatmann N, Klasing S, Finsterer U, Peter K: Midlatency auditory evoked potentials and motor signs of wakefulness during anaesthesia with midazolam. Br J Anaesth 1997; 79:53–8

55. Plourde G, Boylan JF: The long-latency auditory evoked potential as a measure of the level of consciousness during sufentanil anesthesia. J Cardiothorac Vasc Anesth 1991; 5:577–83

56. Dutton RC, Rampil IJ, Eger EI II: Inhaled nonimmobilizers do not alter the middle latency auditory-evoked response of rats. Anesth Analg 2000; 90:213–7

57. Antunes LM, Golledge HD, Roughan JV, Flecknell PA: Comparison of electroencephalogram activity and auditory evoked responses during isoflurane and halothane anaesthesia in the rat. Vet Anaesth Analg 2003; 30:15–23

58. Struys MM, Jensen EW, Smith W, Smith NT, Rampil I, Dumortier FJ, Mestach C, Mortier EP: Performance of the ARX-derived auditory evoked potential index as an indicator of anesthetic depth: A comparison with bispectral index and hemodynamic measures during propofol administration. Anesthesiology 2002; 96:803–16

59. Kumar A, Bhattacharya A, Makhija N: Evoked potential monitoring in anaesthesia and analgesia. Anaesthesia 2000; 55:225–41

60. Wiedemayer H: Observations on intraoperative monitoring of visual pathways using steady-state visual evoked potentials. Eur J Anaesthesiol 2004; 21:429–33

61. Wiedemayer H, Fauser B, Armbruster W, Gasser T, Stolke D: Visual evoked potentials for intraoperative neurophysiologic monitoring using total intravenous anesthesia. J Neurosurg Anesthesiol 2003; 15:19–24

62. Rabe LS, Moreno L, Rigor BM, Dafny N: Effects of halothane on evoked field potentials recorded from cortical and subcortical nuclei. Neuropharmacology 1980; 19:813–25

63. Villeneuve MY: On the use of isoflurane versus halothane in the study of visual response properties of single cells in the primary visual cortex. J Neurosci Methods 2003; 129:19–31

64. Hoffman WE, Edelman G: Comparison of isoflurane and desflurane anesthetic depth using burst suppression of the electroencephalogram in neurosurgical patients. Anesth Analg 1995; 81:811–6

65. Nishikawa K, Harrison NL: The actions of sevoflurane and desflurane on the gamma-aminobutyric acid receptor type A: Effects of TM2 mutations in the α and β subunits. Anesthesiology 2003; 99:678–84

66. Rehberg B, Bouillon T, Zinserling J, Hoeft A: Comparative pharmacodynamic modeling of the electroencephalography-slowing effect of isoflurane, sevoflurane, and desflurane. Anesthesiology 1999; 91:397–405

67. Lutz LJ, Milde JH, Milde LN: The cerebral functional, metabolic, and hemodynamic effects of desflurane in dogs. Anesthesiology 1990; 73:125–31

68. Cossart R, Aronov D, Yuste R: Attractor dynamics of network UP states in the neocortex. Nature 2003; 423:283–8

69. Crick F, Koch C: A framework for consciousness. Nat Neurosci 2003; 6:119–26

70. Bertrand O, Tallon-Baudry C: Oscillatory gamma oscillations in humans: A possible role for object representation. Int J Psychophysiol 2000; 38:211–23

71. Donoghue JP, Sanes JN, Hatsopoulos NG, Gaal G: Neural discharge and local field potential oscillations in primate motor cortex during voluntary movements. J Neurophysiol 1998; 79:159–73

72. Eckhorn R: Cortical synchronization suggests neural principles of visual feature grouping. Acta Neurobiol Exp 2000; 60:261–9

73. Fries P, Reynolds JH, Rorie AE, Desimone R: Modulation of oscillatory neuronal synchronization by selective visual attention. Science 2001; 291:1560–3

74. Joliot M, Ribary U, Llinas R: Human oscillatory brain activity near 40 Hz coexists with cognitive temporal binding. Proc Natl Acad Sci U S A 1994; 91:11748–51

75. Muller MM, Gruber T, Keil A: Modulation of induced gamma band activity in the human electroencephalogram by attention and visual information processing. Int J Psychophysiol 2000; 38:283–99

76. Tallon-Baudry C, Kreiter A, Bertrand O: Sustained and transient oscillatory responses in the gamma and beta bands in a visual short-term memory task in humans. Vis Neurosci 1999; 16:449–59

77. Tallon-Baudry C, Bertrand O: Oscillatory gamma oscillations in humans and its role in object representation. Trends Cogn Sci 1999; 3:151–62

78. Tiitinen H, Sinkkonen J, Reinikainen K, Alho K, Lavikainen J, Naatanen R: Selective attention enhances the auditory 40-Hz transient response in humans. Nature 1993; 364:59–60

79. Carla V, Moroni F: General anaesthetics inhibit the responses induced by glutamate receptor agonists in the mouse cortex. Neurosci Lett 1992; 146:21–4

80. Buzsaki G: Hippocampal GABAergic interneurons: A physiological perspective. Neurochem Res 2001; 26:899–905

81. Wang XJ, Buzsaki G: Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci 1996; 16:6402–13

82. Jefferys JG, Traub RD, Whittington MA: Neuronal networks for induced “40 Hz” rhythms. Trends Neurosci 1996; 19:202–8

83. Gottschalk A, Haney P: Computational aspects of anesthetic action in simple neural models. Anesthesiology 2003; 98:548–64

84. Galarreta M, Hestrin S: Spike transmission and synchrony detection in networks of GABAergic interneurons. Science 2001; 292:2295–9

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