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Anesth Analg 2000;90:213
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Inhaled Nonimmobilizers Do Not Alter the Middle Latency Auditory-Evoked Response of Rats

Robert C. Dutton, MD, Ira J. Rampil, MS, MD, and Edmond I Eger, II, MD

Department of Anesthesia and Perioperative Care, University of California, San Francisco

Address correspondence to Dr. Rampil, C-450, 521 Parnassus, San Francisco, CA 94143-0649. Address e-mail to ira_rampil{at}vaxine .ucsf.edu.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
General anesthetics cause surgical immobility and oblivion (unconsciousness and amnesia). A class of compounds known as "nonimmobilizers" were predicted to be anesthetic, based on their physiochemical properties, but found to cause only amnesia. In humans, cerebrocortical electrical activity after auditory stimulation is depressed by concentrations of anesthetics which impair auditory recall. We sought to use these evoked responses to characterize the effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) and conventional inhaled anesthetics on early sensory processing in rats. Unrestrained rats with chronically implanted epidural silver screw electrodes were put into a chamber. On separate days, the same population of rats were exposed to isoflurane, desflurane, nitrous oxide, or 2N, each at several subminimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus concentrations. After equilibration at each concentration, auditory-evoked responses were obtained. The behavioral state (activity and righting reflex) and electroencephalogram were also examined. 2N did not significantly change the middle latency auditory-evoked response, whereas the anesthetics all slowed conduction and depressed amplitude in a dose-dependent fashion. 2N neither depressed the righting reflex, nor induced epileptiform activity.

Implications: Although the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) suppresses learning, we find that 2N does not depress middle latency auditory-evoked responses. This suggests that 2N may suppress learning by depressing transmission through rostral subcortical structures, such as the amygdala, rather than by acting on the brainstem or neocortical structures.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
General anesthetics must, at a minimum, produce both immobility and unconsciousness with amnesia. Recently a series of volatile compounds, predicted by the Meyer-Overton relationship to be general anesthetics on the basis of their solubility, were evaluated and found to produce amnesia (inhibition of learning) without loss of consciousness or the creation of surgical immobility (1,2). These "non-immobilizing" agents may selectively act at a site involved with learning with little or no activity at other sites involved in the depression of consciousness. Because the identity of these sites and the posited functional division are purely speculative and not immediately accessible to direct test, it is useful to test other possible explanations for the selective actions of the nonimmobilizers. The failure of learning might result from interference by nonimmobilizers with the required perception of external stimuli in the particular learning paradigm (fear-potentiated startle) tested by Kandel et al. (1) and by Sonner et al. (2). Alternatively, nonimmobilizers may interfere in the process of forming an association between the conditioned and unconditioned external stimuli. Finally, they might act as an analgesic to diminish fear of the noxious stimulus. However, Sonner et al. (3) have shown that nonimmobilizers do not have analgesic properties.

We hypothesized that nonimmobilizers do not interfere with auditory perception, but rather with later neural processing involved in forming associations between conditioned and unconditioned stimuli. One additional possibility might be that the nonimmobilizer causes aberrant electrical activity, e.g., epileptiform activity, which might suppress learning.

We tested these hypotheses by examining the effect of the nonimmobilizer 2N (1,2-dichlorohexafluoro- cyclobutane) on auditory-evoked responses. These responses provide a means to evaluate anesthetic-induced depression in sequential loci along the auditory afferent pathway. After an auditory stimulus (usually a "click"), a reproducible series of low amplitude electrical waves may be observed on the cortical surface or the scalp (4). The earliest of these waves (0–10 ms after stimulus in humans, 0–5 ms in rats) derive from the cochlea and several processing points in the brainstem, including, sequentially, the cochlear nuclei, the superior olivary nucleus, and the inferior colliculus. These brainstem-evoked responses (BAER) are resistant to the effects of anesthetics. Waves that occur later in time are known as middle latency (10–50 ms) and late latency (50–300 ms) auditory-evoked responses, or MLAER and LLAER, respectively. Identification of the precise generators of the MLAER waves is controversial, but it is accepted that the waves coincide with the passage of the auditory signal through the thalamus and subsequent processing within several areas of the cerebral cortex, including, but not limited to, the primary auditory cortex and its related association areas. Human MLAER waves have been associated with the perception of auditory stimuli and are depressed at anesthetic concentrations that depress consciousness (5,6). Increasing latency or decreasing amplitude in the evoked response waves generated at specific loci may be inferred to be related to anesthetic-induced suppression of activity at those sites.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With the approval of the institutional committee on animal research, six adult male Sprague-Dawley rats were studied. Rats were first instrumented with chronically implanted epidural electrodes to allow recording in awake and lightly sedated animals. After the induction of anesthesia with ketamine-xylazine (intraperitoneal, 90 mg/kg and 5 mg/kg, respectively), the rats’ scalps were reflected, and 2 mm burr holes were placed paracentrally at the vertex, 5.5 mm anterior to the interaural line, over the frontal sinus 8 mm anterior to the bregma, and a ground electrode over the cerebellum. This electrode array was chosen to maximize acquisition of the "midlatency-" evoked response at the vertex rather than the primary (early) cortical response (7). Silver ball electrodes were introduced epidurally and attached to a quick-connect electrical connector, and the entire assembly was secured to the skull with dental acrylic cement. Rats were allowed to recover after implantation for 5 to 7 days before study.

On the morning of study, the instrumented animals were put into a gas-tight transparent enclosure that was fitted with a high fidelity speaker and lined with sound absorbing foam. After connection to a thin, flexible cable, animals were otherwise unrestrained and allowed to move freely in the chamber. The position of their ears could therefore vary between 8 and 35 cm from the speaker, creating a potential variance of up to 1 ms in the evoked responses because of variable time of flight of the sound in the air of the enclosure. The study chamber had a volume of approximately 6 L and a fresh oxygen flow of 1 L/min. Three anesthetics were administered (on separate days): desflurane, isoflurane, and nitrous oxide, in the concentration steps listed in Table 1. The nonimmobilizer 2N was administered in four concentration steps on a fourth day. The minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus (MAC) equivalent concentration of 2N was based on the oil:gas partition coefficient (8); rat MAC values for the other anesthetics were drawn from recent work in our laboratory (9–11). Chamber gas was analyzed continuously by an infrared analyzer (Capnomac, Datex, Helsinki) for anesthetics and intermittently with gas chromatography for 2N. Thirty minutes for equilibration was allowed after achieving each target concentration in the study chamber. After equilibration, the animals’ behavioral state was qualitatively assessed by visual inspection, and if quiescent, the righting response to a 30° cage tilt was obtained.


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  		Table 1. Anesthetic Exposure Levels (%atm)
 
Cortical electrical activity was amplified using a bioelectric amplifier (P511d, Grass Instruments, Quincy, MA) with analog filter settings of 10 Hz–10 kHz. Further processing was performed by using a virtual software instrument written by the authors (Labview; National Instruments, Austin, TX). The signal was digitized at 20 kHz and digitally filtered to a bandwidth of 0.5 Hz–1 kHz. The electroencephalogram (EEG) was down-sampled to a rate of 256 Hz and a single epoch of 16 s was recorded. The MLAER was elicited by auditory click stimulus consisting of four complete cycles of a 7.5-kHz sine wave played at approximately 80 dB through the speaker mounted in the ceiling of the study chamber. To calculate the MLAER, the auditory stimulus was applied 1024 times at an interstimulus interval of 0.5 Hz. The resulting electrical activity was digitized with 16 bit resolution at a rate of 20 kHz into epochs of 75 ms after each click stimulus. The data were divided into four blocks, each consisting of the mean of 256 individual responses and the four mean wave forms displayed superimposed in order to confirm replicability. The recorded EEG signal was visually assessed to observe possible epileptiform activity. For each subject, values of latency and amplitude of relevant wave form features (latency after stimulus and peak-to-peak amplitude of major waves) were determined manually from the grand mean of the four subblock runs (i.e., all 1024 responses) at each concentration for further analysis.

Quantitative electrophysiologic measurements were compared by using analysis of variance with repeated measures and Student-Newman-Keuls post hoc testing when appropriate (Statview 5.0; SAS, Cary, NC). A P of < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During isoflurane, desflurane, or nitrous oxide inhalation, the animals exhibited progressively somnolent behavior, whereas during 2N exposure, no sedation was obvious by gross visual inspection, the animals’ activity levels did not markedly change, and the right reflex was not depressed (Table 2). No epileptiform activity was observed in the spontaneous EEG recordings.


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  		Table 2. ED50 of Righting Reflex as a Fraction of MAC (mean ± SD)
 
Because of the animals’ mobility during this experiment, the variable air transmission latency made quantitation of the brainstem potentials difficult. The shift in latency of up to 1 ms significantly blurred features in the 2–5 BAER range, but was not a problem in the 18- to 40-ms MLAER feature range.

The pattern of anesthetic depression of the auditory response is demonstrated in Figure 1. Isoflurane, desflurane, and nitrous oxide increased the latency, as illustrated in Figure 2). , and decreased the amplitude of the cortical response (Figure 3 The first MLAER wave was a negative wave at approximately 18 ms and therefore denoted as N18. Volatile anesthetics increased the latency of N18 at all steps at or above 0.25 MAC (P < 0.002 for all anesthetics), producing an average increase in latency of 31% at the 0.75 MAC level. The next prominent feature was a positive wave, which at baseline conditions occurred at 25 ms, hence named P25. The volatile anesthetics produced a more profound impact on this later wave, causing significant differences between all concentrations (P < 0.0001) and producing a mean increase in latency of 79% at 0.75 MAC. The subsequent negative N40 wave was delayed with anesthetics (P < 0.0001), with a mean increase of 83% at 0.75 MAC compared to baseline latency. Amplitude of the MLAER was measured as the difference between the voltage minimum at N18 and the peak at P25. All concentrations of anesthetics significantly depressed the MLAER amplitude, reducing it by approximately 80% of baseline value at 0.75 MAC.



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  		Figure 1. Auditory-evoked response wave forms are depressed by inhaled general anesthetics, but not by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N). Vertical hairlines are drawn at baseline latencies of N18 and N40 for comparison of latencies during the anesthetic administration. The light traces represent individual animals and the heavy trace is the mean of all animals at that condition. Vertical scale is equal for all tracings and is approximately 10 µV full-scale. (MAC here is the measured minimum alveolar concentration of the anesthetics in this strain of rat, and is estimated for 2N, based on oil:gas solubility)

 


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  		Figure 2. Anesthetics prolong the latencies of the middle latency auditory responses (P < 0.0001), and 1,2-dichlorohexafluorocyclobutane (2N) did not. Error bars represent standard deviation. Horizontal offsets between drugs added for clarity.

 


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  		Figure 3. Anesthetics depressed the P25–N18 (peak-to-peak) wave form amplitude, whereas 1,2-dichlorohexafluorocyclobutane (2N) slightly and not significantly (P = 0.17) increased amplitude. Error bars represent standard deviation. Horizontal offsets between drugs added for clarity. Amplitude here is scaled in volts output from bioelectric amplifier.

 
The nonimmobilizer 2N did not significantly alter the evoked potential wave form latencies (Figure 2) or amplitudes (Figure 3), although there was a trend toward increased wave amplitude.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The auditory afferent system is complex and probably involves several separate, concurrent signal pathways following the earliest steps within the brainstem. Simpson and Knight (7,12) proposed two relatively independent generators for the auditory responses observed on the scalps of rats. The set of peaks (P17-N32) most prominent over the primary auditory cortex (Krieg’s area 41) (13) is resistant to barbiturate anesthetics (7). Another response (N18-P25) is maximal over the vertex of the skull, is strongly depressed by anesthetics, and may derive from subcortical structures, such as the hippocampus, the cingulate cortex, or the colliculi (12). Recent unpublished observations suggest a strong cortical influence in these vertex waves (R. C. D., 1999). As noted above, the present study used an electrode configuration designed to preferentially detect this vertex response.

The studies of Kandel et al. (1) and of Sonner et al. (2), which demonstrated inhibition of learning during exposure to nonimmobilizers, relied on a paradigm known as "fear-potentiated startle reflex." This paradigm is based on the observation that a startle reflex (a series of short latency muscle contractions after exposure a sudden loud noise) can be potentiated (i.e., the response exaggerated) by a central state of fear or anxiety. For example, a rat trained to expect an electric shock after a bright conditioning light or a specific warning sound, will jump higher in response to a loud noise when the light is on than when exposed to a startling noise in a dark cage. When light/shock combination training is performed while the animal is inhaling an amnestic anesthetic, the association is not formed and subsequent startle responses (while the animal is breathing air) are not potentiated by the conditioning light (1,2). Of note, the basic startle reflex is a very short latency response and anatomical lesion studies suggest that cerebral hemispheres (including the auditory cortex and medial geniculate nuclei of the thalamus) are not essential components (14,15). The reflex may involve a circuit from the cochlear root to the nucleus reticularis pontine caudalis (PcN) and down to spinal motor neurons (16). The electrical activity generated by this pathway would be embedded within the brainstem latency portion (zero to five milliseconds) of the auditory-evoked response. Davis et al. (17) have proposed that the afferent signal representing conditioned stimuli leading to fear potentiation is relayed from the afferent processing areas in the thalamus to the amygdala, a brain region long associated with fear and anxiety states. The central nucleus of the amygdala projects to PcN, where it modulates the startle response (18). In the present study, training to associate a light with a foot shock was not performed; therefore, no observations of the possible learning-related scalp-derived electrical activity were possible, nor was a direct correlation between evoked response depression and learning. Because we used unrestrained rats in this experiment, we could not demonstrate changes in the BAER. However, previous investigations (19,20) have revealed minimal alteration in wave V of the BAER during exposure to any of the inhaled anesthetics suggesting little change in signal transduction or in transmission through the brainstem substrate common to the major BAER pathway and the circuit underlying the startle response, which includes the acoustic nerve and the ventral cochlear nucleus. Above the ventral cochlear nucleus, the BAER pathway leads to the superior olivary nucleus and the lateral lemniscus, whereas the startle reflex proceeds to the PcN (16).

Consistent with human data, the general anesthetics isoflurane (20), desflurane (19), and nitrous oxide (21,22) all depressed the MLAER at concentrations that would be expected to cause amnesia and depressed consciousness. To our knowledge, there are no previous reports on the dose response of MLAER in rats to desflurane or isoflurane. Studies that examined learning during general anesthesia in humans used paradigms that required far more cognitive function than modulation of the startle reflex. These human studies examined explicit or implicit recall of specific words; a task one must assume required function of the language and association cortex. Anesthetic-induced loss of this cognitive task has been associated with prolonged MLAER latencies by several investigators (6,19,23–25).

The results of our study appear to indicate that the concentrations of general anesthetics, which were sufficient in previous studies to inhibit learning conditioned fear, are sufficient to significantly depress the MLAER, whereas the concentration of 2N, which suppressed this type of learning, did not alter the MLAER. One might therefore conclude that the site at which 2N interferes with learning is not a component generator of the vertex auditory-evoked response. MLAER depression seen with true general anesthetics might indicate suppressive action at an MLAER generator site which is unrelated to learning conditioned fear or to an entirely distinct mechanism and sites of action.


   Footnotes
 
Funded by NIH P01 GM47818 and the Friends of Anesthesia Foundation.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 27, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press