This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Orth, M. Articles by Antognini, J. F. Search for Related Content PubMed PubMed Citation Articles by Orth, M. Articles by Antognini, J. F. Related Collections Mechanisms Pharmacology

---

ANESTHETIC PHARMACOLOGY

The Differential Effects of Halothane and Isoflurane on Electroencephalographic Responses to Electrical Microstimulation of the Reticular Formation

Department of Anesthesiology and Pain Medicine, Section of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, California

Address correspondence and reprint requests to Joseph F. Antognini, MD, Department of Anesthesiology TB-170, University of California, Davis, Davis, CA 95616. Address e-mail to jfantognini{at}ucdavis.edu.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Isoflurane and halothane cause electroencephalographic (EEG) depression and neuronal depression in the reticular formation, a site critical to consciousness. We hypothesized that isoflurane, more than halothane, would depress EEG activation elicited by electrical microstimulation of the reticular formation. Rats were anesthetized with either halothane or isoflurane and stimulating electrodes were positioned in the reticular formation. In a crossover design, anesthetic concentration was adjusted to 0.8 and 1.2 minimum alveolar concentration (MAC) of halothane or isoflurane and electrical microstimulation was performed and the EEG responses were recorded. Microstimulation increased the spectral edge and median edge frequencies 2–2.5 Hz at 0.8 MAC for halothane and isoflurane and 1.2 MAC halothane. At 1.2 MAC isoflurane, burst suppression occurred and microstimulation decreased the period of isoelectricity (24% ± 19% to 8% ± 7%; P < 0.05), whereas the spectral edge and median edge frequencies were unchanged. At anesthetic concentrations required to produce immobility, the cortex remains responsive to electrical microstimulation of the reticular formation, although the EEG response is depressed in the transition from 0.8 to 1.2 MAC. These data indicate that cortical neurons remain responsive to synaptic input during isoflurane and halothane anesthesia.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
General anesthetics, such as isoflurane and halothane, cause electroencephalographic (EEG) depression. Furthermore, these drugs alter EEG responses to a variety of stimuli, including noxious stimulation (1–4). Although the EEG depression likely occurs primarily via a direct action in the brain, part of the EEG depression occurs because of an indirect spinal cord action (2). We have hypothesized that anesthetics act spinally to blunt the ascending transmission of somatosensory signals, thereby decreasing the arousal level in the brain to result in EEG depression, as well as depressing EEG activation elicited by noxious stimulation (2).

As part of our approach, we have used electrical microstimulation of the midbrain reticular formation (MRF), an area critical to cerebral arousal and consciousness (5,6). Moruzzi and Magoun (7) first reported that microstimulation of this area resulted in EEG arousal, and their work laid the groundwork for further studies on the importance of the reticular formation to arousal. Although many of the animals used in that study were anesthetized with chloralose, little work has since been performed to determine how anesthetics alter EEG responses to electrical microstimulation of the MRF and pontine reticular formation. Isoflurane and halothane are two commonly used anesthetics that have disparate EEG effects, with isoflurane generally resulting in more EEG depression than halothane. In the present study, we hypothesized that isoflurane would cause greater depression of the EEG activation elicited by electrical microstimulation of the reticular formation, as compared with halothane.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The local animal care and use committee approved this study. Adult male rats (weight 400–600 g) were anesthetized with either halothane (n = 6) or isoflurane (n = 6) in a chamber. Anesthesia was maintained via mask and a tracheostomy tube (14-gauge) inserted through a neck incision. The rats' lungs were mechanically ventilated. End-tidal CO₂ was maintained at 30–45 mm Hg. Alveolar anesthetic concentration was measured using a calibrated anesthetic agent analyzer (Ohmeda Rascal II, Salt Lake City, UT). A catheter was inserted into a jugular vein for fluid and drug administration and another catheter was inserted into a carotid artery for monitoring mean arterial blood pressure (MAP). Unilateral ligation of a carotid artery does not appreciably alter cerebral blood flow (8). A posterior craniotomy was performed to permit insertion of stimulating electrodes.

Four small stainless steel screws were inserted into the skull for EEG measurement. A ground electrode was placed in the midline over the anterior skull 15 mm anterior to the interaural line and 2 were inserted (on either side) 5 mm lateral to midline and 5–7 mm rostral to the interaural line. The reference electrode was placed over the midline 2–3 mm caudal to the interaural line. Cables were attached to the screws and the EEG signals were downloaded to a Bispectral index (BIS) monitor (A-1050; Aspect Medical, Newton, MA) at 256 samples/s. The filters were set at 2–70 Hz. Impedance was <5000 ohms. The BIS monitor calculated the median edge frequency (MEF) and spectral edge (95%) frequency (SEF) every 5 s and these were downloaded to computer hard drive. The BIS monitor used a "rolling" average of the previous 30-s period. In addition, the raw EEG was recorded onto a computer hard drive using Chart version 5.1 (ADInstruments, Colorado Springs, CO).

The rats were placed into a stereotaxic frame (D. Kopf, Tujunga, CA). Two bipolar stimulating electrodes (FHC, Bowdoinham, ME) were attached to an electrode holder 1 mm apart in the rostral caudal axis and lowered into the brain. We used two electrodes to increase the chance to elicit EEG activation. The areas targeted were the MRF (2 mm lateral to midline, 2 mm rostral to the interaural line, and 6–7 mm below the brain surface) and the pontomesencephalic tegmental area (2 mm lateral to midline, 2 mm rostral to the interaural line, and 7–8 mm below the brain surface). The stimulating sites were confirmed histologically. Pancuronium was administered (0.2–0.3 mg/kg every 1–2 h) to minimize electromyographic artifacts in the EEG recording.

A crossover experimental paradigm was used. The anesthetic concentration was adjusted to either 0.8 or 1.2 minimum alveolar concentration (MAC) (order alternated experiment to experiment) and maintained for at least 15 min. Population MAC values were assumed for halothane (1%) and isoflurane (1.2%) based on previous studies from our laboratory (9,10). Electrical stimuli consisted of 2-s trains of 100-µs square wave pulses delivered at 300 Hz, at current intensities of 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mA. Two to 3 min elapsed between each stimulus train, permitting return to the baseline EEG pattern. The order of the current intensities was randomized. The same paradigm was used to deliver electrical stimuli through the other electrode. In addition, we separately determined EEG responses to supramaximal stimulation of the tail using 2 methods: electrical current (60 mA, 50 Hz for 30 s) via percutaneous platinum needle electrodes placed into the proximal tail and a hemostat clamp applied to the tail for 30 s. The anesthetic concentration was switched and after 15–20 min equilibration the stimulating paradigm was repeated. The anesthetic was then changed (from halothane to isoflurane, or vice versa, counterbalanced across experiments) in 10 animals. After approximately 45 min equilibration, the stimulation paradigm was repeated at 0.8 and 1.2 MAC as described above.

On completion of the study the rats were killed with excess anesthetic and IV potassium chloride. An electrolytic lesion was made by delivering current (6–8 V, 30–60 s) through each of the electrodes, after which the brain was removed. The brains were fixed in 10% buffered formalin and sectioned several days later and counterstained with Neutral Red. Electrolytic lesions were examined under the light microscope and compiled on representative brain sections taken from the atlas of Paxinos and Watson (11).

Data are presented as mean and standard deviation. The EEG parameters were averaged for the 30-s period before microstimulation and the second 30-s period after microstimulation. The EEG responses were nearly identical between the rostrally and caudally placed electrodes so the data from both electrodes were pooled. The EEG data (MEF and SEF) were compared before and after stimulation. The values for each anesthetic were compared using repeated-measures analysis of variance; post hoc testing was performed using the Student-Newman-Keuls test. To compare the 0.8 and 1.2 MAC post-stimulus values for each anesthetic we used an area under the curve analysis whereby the MEF and SEF values for each stimulus current were summed and evaluated using a paired Student's t-test. For the 1.2 MAC isoflurane EEG data, the burst suppression ratio was calculated as the period of isoelectricity divided by the total EEG period evaluated, which was 30 s. The MAP was analyzed using analysis of variance followed by the Student-Newman-Keuls test or with the paired Student's t-test to compare MAP responses at 0.8 and 1.2 MAC. A P < 0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Electrical microstimulation in the reticular formation resulted in EEG activation as demonstrated by a change from a high amplitude, low frequency pattern to a low amplitude, high frequency pattern. The threshold for this change was usually at 0.05–0.1 mA and peaked at 0.2–0.3 mA. At 0.8 MAC for both isoflurane and halothane, SEF and MEF increased significantly at 0.1 mA. An example of the EEG activation in one rat is shown in Figure 1. Note that there was EEG activation at 0.8 MAC for halothane and isoflurane. At 1.2 MAC halothane there was EEG activation after electrical microstimulation of the MRF. At 1.2 MAC isoflurane, however, burst suppression occurred, and electrical microstimulation decreased the period of EEG isoelectricity.

View larger version (28K): [in this window] [in a new window]   Figure 1. Electroencephalographic (EEG) responses during halothane and isoflurane anesthesia. A, This example shows the EEG activation that occurs after electrical microstimulation of the reticular formation in a rat anesthetized with halothane. Electrical microstimulation (2 s, 300 Hz, 0.2 mA) commenced at the dotted lines. Note that at 0.8 minimum alveolar concentration (MAC), there was a change from a low frequency, high amplitude pattern to a high frequency, low amplitude pattern. At 1.2 MAC, a similar EEG activation occurred, although it did not last as long as that occurring at 0.8 MAC. B, This example shows the EEG responses during isoflurane anesthesia. At 0.8 MAC isoflurane, note the EEG activation, which is similar to that occurring at 0.8 MAC halothane. At 1.2 MAC isoflurane, however, burst suppression occurred, and electrical microstimulation markedly decreased the isoelectric period.

Summary data are shown in Figure 2. Electrical microstimulation in the midbrain resulted in EEG activation as demonstrated by the increased SEF and MEF at 0.8 and 1.2 MAC halothane and 0.8 MAC isoflurane. The post-stimulus MEF and SEF for all currents combined were greater at 0.8 MAC as compared with values at 1.2 MAC for both halothane and isoflurane (P < 0.01). The prestimulus SEF at 0.8 MAC was significantly greater compared with the value at 1.2 MAC for halothane (P < 0.05) but not isoflurane. Electrical stimulation of the tail and the tail clamp generally were as effective in causing EEG activation when compared to the electrical microstimulation of the MRF. At 1.2 MAC isoflurane, however, electrical microstimulation did not change SEF and MEF (Fig. 2) but decreased the amount of EEG isoelectricity occurring during burst suppression. At 1.2 MAC isoflurane, the prestimulus burst suppression ratio was 24% ± 19%, whereas the post-stimulus ratio (average of all post-stimuli values) was 8% ± 7%, P < 0.007. The suppression ratios for each stimulus are shown in Figure 3. Burst suppression rarely occurred during 0.8 MAC isoflurane, with the average period of isoelectricity representing only 1% of the EEG activity. Burst suppression was not observed during halothane anesthesia.

View larger version (33K): [in this window] [in a new window]   Figure 2. Electroencephalographic (EEG) responses during halothane and isoflurane anesthesia (MAC, minimum alveolar concentration). Shown are summary data (mean, sd) before and after electrical microstimulation applied to the reticular formation. The spectral edge frequency (SEF) and median edge frequency (MEF) are plotted against stimulus current. In addition, EEG responses to electrical stimulation applied to the tail (ES) and tail clamping (TC) are plotted. Note that at 0.8 and 1.2 MAC halothane and 0.8 MAC isoflurane, the EEG response usually had a threshold at 0.1 mA, and that the response generally peaked at 0.2–0.3 mA. The EEG responses to electrical microstimulation at 0.2 mA or greater were similar to those resulting from noxious stimulation applied to the tail. There were minimal SEF and MEF responses at 1.2 MAC isoflurane. *P < 0.05 compared with prestimulus value. The post-stimulus values (all currents combined) at 0.8 MAC for halothane and isoflurane were significantly greater than the respective values at 1.2 MAC; #P < 0.05.

View larger version (31K): [in this window] [in a new window]   Figure 3. Burst suppression during 1.2 minimum alveolar concentration (MAC) isoflurane. The percent of the 30-s periods (before and after stimulation) containing isoelectric segments are plotted against current intensity (mean, standard deviation). In addition, the EEG responses to tail stimulation (electrical, ES, and tail clamping, TC) are plotted. Note that electrical microstimulation of the reticular formation as well as tail stimulation markedly reduced the amount of EEG isoelectricity. #P < 0.05, combined prestimulus values compared to post-stimulus values.

The MAP increased as a result of electrical microstimulation, with the peak occurring at about 0.5 mA (Fig. 4). The MAP for all currents combined was greater at 0.8 MAC as compared with the values at 1.2 MAC for both isoflurane and halothane (Fig. 4). The stimulus sites were located in the reticular formation, extending from the rostral midbrain to the rostral pons, including the area surrounding the pedunculopontine tegmental nucleus (Fig. 5).

View larger version (43K): [in this window] [in a new window]   Figure 4. Mean arterial blood pressure (MAP) before and after stimulation (mean, sd). Data are plotted against stimulating current, except for the electrical stimulus (ES) to tail and tail clamp (TC). Shown are prestimulus and post-stimulus MAP for (A) isoflurane at 0.8 minimum alveolar concentration (MAC), (B) 1.2 MAC isoflurane, (C) 0.8 MAC halothane, and (D) 1.2 MAC halothane. *P < 0.05 compared to prestimulus value. The post-stimulus values (all currents combined) at 0.8 MAC for halothane and isoflurane were significantly greater than the respective values at 1.2 MAC; #P < 0.05.

View larger version (16K): [in this window] [in a new window]   Figure 5. Stimulating sites. Shown are the microstimulation sites compiled on representative sections of the midbrain 0.7 and 1.7 mm rostral to the interaural line. PPTg = pedunculopontine tegmental nucleus; PAG = periaqueductal gray.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main finding of the present study was that halothane and isoflurane had different effects on the EEG response to electrical microstimulation of the reticular formation. The transition from 0.8 MAC to 1.2 MAC halothane depressed the post-stimulus SEF and MEF, in part because of decreased prestimulus values for halothane only. Isoflurane, however, produced burst suppression at 1.2 MAC, and electrical microstimulation of the reticular formation decreased the period of isoelectricity, but the SEF and MEF were not affected. These findings reflect the differences between the EEG effects of isoflurane and halothane but indicate that the cerebral cortex and subcortical structures remain responsive to the activating effect of electrical microstimulation of the reticular formation, albeit with depression of the EEG response between 0.8 and 1.2 MAC.

When increased from 0.8 to 1.2 MAC, isoflurane ablates EEG activation that follows noxious stimulation (9). Is this effect primarily the result of an action in the brain, or is action in the spinal cord partly responsible? Our prior work suggests that this blunting effect is in large part because of action in the spinal cord (1,2). For example, addition of isoflurane to the torso (and hence spinal cord) ablates EEG activation in animals that have approximately 1 MAC isoflurane administered to the brain (1). With respect to the blunting of EEG activation, how important is isoflurane's and halothane's action in the brain? In the present study we addressed this question by applying a stimulus to the reticular formation that essentially bypasses the spinal cord. Had isoflurane and halothane prevented EEG activation, we could reasonably conclude that their action in the brain was significant. As this was not the case, however, the present study provides further evidence that isoflurane and halothane can depress EEG activity partly via action in subcortical structures such as the spinal cord.

The presence of burst suppression during 1.2 MAC isoflurane anesthesia, and its absence during 1.2 MAC halothane anesthesia, is consistent with other evidence that isoflurane causes more EEG depression than halothane (12–14). In a prior study we (9) reported burst suppression during 1.2 MAC isoflurane anesthesia that was minimally altered by repetitive stimulation that produced EEG activation at 0.8 MAC isoflurane and which normally produces neuronal windup. We did not observe burst suppression during halothane anesthesia. In the present study, electrical microstimulation of the reticular formation, as well as noxious stimulation applied to the tail, significantly decreased the period of isoelectricity during 1.2 MAC isoflurane, indicating that even under deep anesthesia the brain remains responsive to noxious stimulation applied to the periphery and to electrical microstimulation of the reticular formation.

In the present study the burst suppression in isoflurane-anesthetized rats complicated EEG analysis, inasmuch as the SEF and MEF do not accurately reflect the EEG changes (15). That is, although the SEF and MEF were unchanged after electrical microstimulation, the period of EEG isoelectricity decreased from approximately 20% to as little as 1%–2% at the greater electrical currents. Thus, comparing isoflurane and halothane at 1.2 MAC was difficult. Some have argued that SEF and MEF can be linearly corrected for the amount of burst suppression (15). For example, if 50% of the EEG is isoelectric, then the SEF and MEF can be decreased 50%. Although this is a convenient method to handle the data, the choice of linear adjustment is arbitrary. We chose to report the unadjusted SEF and MEF as well as the burst suppression ratio.

The EEG pattern (low amplitude, high frequency) resulting from electrical microstimulation of the reticular formation is normally associated with arousal. In humans in a persistent vegetative state, prolonged microstimulation of deep brain structures, including the reticular formation, can increase arousal (16). Evoked potentials are enhanced after electrical microstimulation of the reticular formation (17). Furthermore, electrical stimulation in the reticular formation causes behavioral arousal in awake animals (18) and is associated with enhanced learning (19). However, depending on the method and site of stimulation, central nervous system depression can also occur. For example, stimulation of the thalamus for 30–60 seconds at 4–8 Hz, instead of faster frequencies, such as the 50–300 Hz described by Moruzzi and Magoun (7), can produce EEG slowing and induce sleep (20). The mechanism is unclear but is possibly related to activation of sleep-promoting areas of the brain, such as the ventrolateral preoptic nucleus and the tuberomammilary nucleus (21).

The reticular formation as a site of anesthetic-induced unconsciousness has received varying attention over the years. Anesthetics such as isoflurane differentially alter neuronal activity, with both excitation and depression occurring (22,23). In addition, neural activity, as indirectly determined using positron emission tomography, is depressed at halothane and isoflurane concentrations associated with unconsciousness (24,25). Infusion of volatile anesthetics into the reticular formation causes unconsciousness (26). In addition, IV anesthetics such as propofol and pentobarbital appear to act, at least in part, on subcortical structures to produce unconsciousness. Devor and Zalkind (27) reported that microinjections of pentobarbital in the mesopontine tegmental area produced anesthesia, while Nelson et al. (21) reported that propofol and pentobarbital act in the tuberomammillary nucleus to produce anesthesia. Collectively, these data suggest that anesthetic action in subcortical structures, including the reticular formation, might be important to anesthetic-induced unconsciousness. Others have argued that anesthetics act in the cerebral cortex to produce unconsciousness (28), in part because cortical neurons, as compared with thalamic (and other subcortical) neurons, appear to be more sensitive to anesthetics. The present data and previously published data (29) indicate, however, that at sub-MAC anesthetic concentrations, the cortex remains responsive to electrical stimulation in the reticular formation as well as to peripheral stimulation.

In summary, we found that electrical microstimulation of the reticular formation resulted in EEG activation that was affected differently by isoflurane and halothane. In the transition from 0.8 MAC to 1.2 MAC, halothane depressed the SEF and MEF response to microstimulation, whereas for isoflurane the amount of burst suppression was decreased. During halothane and isoflurane anesthesia the cortex and subcortical structures remain responsive to electrical stimulation, although the response is depressed.

	Footnotes

 
Accepted for publication January 12, 2006.

Supported, in part, by National Institutes of Health grants GM 57970, GM61283, and P01-GM47818

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Antognini JF, Wang XW, Carstens E. Isoflurane action in the spinal cord blunts electroencephalographic and thalamic-reticular formation responses to noxious stimulation in goats. Anesthesiology 2000;92:559–66.[Web of Science][Medline]
2. Antognini JF, Carstens E, Sudo M, Sudo S. Isoflurane depresses electroencephalographic and medial thalamic responses to noxious stimulation via an indirect spinal action. Anesth Analg 2000;91:1282–8.[Abstract/Free Full Text]
3. Bischoff P, Kochs E, Haferkorn D, Schulte am Esch J. Intraoperative EEG changes in relation to the surgical procedure during isoflurane-nitrous oxide anesthesia: hysterectomy versus mastectomy. J Clin Anesth 1996;8:36–43.[Medline]
4. Kochs E, Bischoff P, Pichlmeier U, Schulte am Esch J. Surgical stimulation induces changes in brain electrical activity during isoflurane/nitrous oxide anesthesia: a topographic electroencephalographic analysis. Anesthesiology 1994;80:1026–34.[Web of Science][Medline]
5. Antognini JF, Jinks SL, Atherley R, et al. Spinal anaesthesia indirectly depresses cortical activity associated with electrical stimulation of the reticular formation. Br J Anaesth 2003;91:233–8.[Abstract/Free Full Text]
6. Antognini JF, Atherley R, Carstens E. Isoflurane action in spinal cord indirectly depresses cortical activity associated with electrical stimulation of the reticular formation. Anesth Analg 2003;96:999–1003.[Abstract/Free Full Text]
7. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455–73.[Medline]
8. Salford LG, Siesjo BK. The influence of arterial hypoxia and unilateral carotid artery occlusion upon regional blood flow and metabolism in the rat brain. Acta Physiol Scand 1974;92:130–41.[Web of Science][Medline]
9. Barter L, Dominguez CL, Carstens E, Antognini JF. The effect of isoflurane and halothane on electroencephalographic activation elicited by repetitive noxious c-fiber stimulation. Neurosci Lett 2005;382:242–7.[Web of Science][Medline]
10. Jinks SL, Carstens E, Antognini JF. Isoflurane differentially modulates medullary ON and OFF neurons while suppressing hind-limb motor withdrawals. Anesthesiology 2004;100:1224–34.[Web of Science][Medline]
11. Paxinos G, Watson C. The rat brain in stereotaxic coordinates, 4th ed. San Diego: Academic Press, 1998:9–78.
12. 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.[Web of Science][Medline]
13. Rampil IJ, Laster MJ. No correlation between quantitative electroencephalographic measurements and movement response to noxious stimuli during isoflurane anesthesia in rats. Anesthesiology 1992;77:920–5.[Web of Science][Medline]
14. Hudetz AG. Effect of volatile anesthetics on interhemispheric EEG cross- approximate entropy in the rat. Brain Res 2002;954:123–31.[Medline]
15. Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998;89:980–1002.[Web of Science][Medline]
16. Yamamoto T, Katayama Y, Oshima H, et al. Deep brain stimulation therapy for a persistent vegetative state. Acta Neurochir Suppl 2002;79:79–82.[Medline]
17. Steriade M, Demetrescu M. Unspecific systems of inhibition and facilitation of potentials evoked by intermittent light. J Neurophysiology 1960; 23:602–17.[Free Full Text]
18. Mallick BN, Thankachan S, Islam F. Differential responses of brain stem neurons during spontaneous and stimulation-induced desynchronization of the cortical eeg in freely moving cats. Sleep Res Online 1998;1:132–46.[Medline]
19. Ammassari-Teule M, Fombon AM, Bloch V. Facilitation of generalization performances in spatial learning problems by posttrial stimulation of the mesencephalic reticular formation. Physiol Behav 1984;32:1027–31.[Medline]
20. Akert K, Koella WP, Hess R, Jr. Sleep produced by electrical stimulation of the thalamus. Am J Physiol 1952;168:260–7.
21. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci 2002;5:979–84.[Web of Science][Medline]
22. Shimoji K, Fujioka H, Fukazawa T, et al. Anesthetics and excitatory/inhibitory responses of midbrain reticular neurons. Anesthesiology 1984;61:151–5.[Web of Science][Medline]
23. Shimoji K, Fujioka H, Ebata T. Anesthetics block excitation with various effects on inhibition in MRF neurons. Brain Res 1984;295:190–3.[Web of Science][Medline]
24. Alkire MT, Pomfrett CJ, Haier RJ, et al. Functional brain imaging during anesthesia in humans: effects of halothane on global and regional cerebral glucose metabolism. Anesthesiology 1999;90:701–9.[Web of Science][Medline]
25. 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.[Web of Science][Medline]
26. Folkman J, Mark VH, Ervin F, et al. Intracerebral gas anesthesia by diffusion through silicone rubber. Anesthesiology 1968;29:419–25.[Medline]
27. Devor M, Zalkind V. Reversible analgesia, atonia, and loss of consciousness on bilateral intracerebral microinjection of pentobarbital. Pain 2001;94:101–12.[Web of Science][Medline]
28. Hentschke H, Schwarz C, Antkowiak B. Neocortex is the major target of sedative concentrations of volatile anaesthetics: strong depression of firing rates and increase of GABAA receptor-mediated inhibition. Eur J Neurosci 2005;21:93–102.[Web of Science][Medline]
29. Antognini JF, Carstens E. Isoflurane blunts electroencephalographic and thalamic-reticular formation responses to noxious stimulation in goats. Anesthesiology 1999;91:1770–9.[Web of Science][Medline]

This article has been cited by other articles:

				J C Murrell, D Waters, and C B Johnson Comparative effects of halothane, isoflurane, sevoflurane and desflurane on the electroencephalogram of the rat Lab Anim, April 1, 2008; 42(2): 161 - 170. [Abstract] [Full Text] [PDF]

				R. Balu, R. T. Pressler, and B. W. Strowbridge Multiple Modes of Synaptic Excitation of Olfactory Bulb Granule Cells J. Neurosci., May 23, 2007; 27(21): 5621 - 5632. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Orth, M. Articles by Antognini, J. F. Search for Related Content PubMed PubMed Citation Articles by Orth, M. Articles by Antognini, J. F. Related Collections Mechanisms Pharmacology