In Reply:—
We thank Dr. Veselis for his insightful comments on our article.1His first point is that the lack of specific auditory activation during the light sedation stage was most probably caused by physiologic sleep. The interactions we had with the subjects during the experiment and the informal debriefing between runs make us think this is unlikely: Subjects after the light sedation run seemed more “chatty” than sleepy. In addition, as we point out in the article, normal sleep does not abolish responses to complex sounds. Hence, even if the subjects had fallen asleep, this would not per se explain the lack of auditory responses. Despite these arguments and as indicated in our article, we agree that we have no way to unambiguously demonstrate that subjects were not sleeping during the light sedation recordings. In future experiments, we will have to monitor subjects’ level of arousal more closely, although even asking subjects to perform an active task might not be sufficient. Lack of response would not necessarily indicate sleep; it could also indicate attentional, motivational, motor, or memory alterations due to the anesthesia, for example. The most objective means is probably monitoring of an ongoing electroencephalograph, a complicated task in a magnetic resonance imaging suite.
Irrespective of the sleep issue, we still believe the evidence of increased neural excitability (or disinhibition) after anesthesia with propofol because the level of activation during recovery (propofol plasma concentration: 0.64 μg/ml) significantly exceeded baseline levels. The critical question is, Does the development of this hyperexcitability require previous exposure to a higher concentration of propofol? Veselis believes that the answer is no, based on a study2that revealed a visible increase in statistical activation to auditory stimulation during sedation (not preceded by exposure to higher concentration) with propofol or thiopental. The statistical significance of that effect was not reported. We proposed acute tolerance as the most likely explanation for the increased excitability seen during recovery in our study because we have observed an analogous phenomenon with the 40-Hz auditory steady state response: The amplitude during recovery from propofol anesthesia significantly exceeded baseline amplitude.3This phenomenon was not observed during propofol sedation not preceded by exposure to a higher concentration4or during prolonged recordings in nonanesthetized subjects (unpublished observations, Gilles Plourde, M.D., M.Sc., Professor, Department of Anesthesia, Montreal Neurologic Hospital, Montreal, Quebec, Canada, 2002). We believe that this topic deserves further inquiry.
Dr. Veselis’ second point is that we were not able to demonstrate higher level processing during anesthesia because of insufficient power. We did discuss in the article the factors that could have led to a relative loss of signal during the anesthesia and hence affected our ability to pick up a signal. However, we disagree that the lack of response during anesthesia for higher level processing is explained on the basis of a lack of power:
First, we did have sufficient power to detect speech- and voice-related responses during baseline (and recovery). During anesthesia, we showed, using the same functional magnetic resonance imaging sampling protocol, that these responses were absent with mean signal amplitudes very close to zero and one-sample t tests yielding P > 0.2. Naturally, neither we nor anyone else can prove the null hypothesis of no activation, regardless of how large a sample is studied or how many data points are acquired. However, as we also point out in the article, our conclusion is consistent with electrophysiologic data from higher order visual cortex in monkeys.
Second, and perhaps more important, we successfully demonstrated significant negative activation during anesthesia in the words–versus –scrambled words contrast. This suggests that the protocol had adequate sensitivity, because with the same number of trials, we picked up an atypical response difference between the two stimulus classes. If the lack of normal positive response to words or voice stimuli were simply due to low signal and/or high noise, we would not have detected the unusual negative response either.
Third, the reduced level of significance for the words versus scrambled words and vocal versus nonvocal stimuli was expected because we were comparing activations produced by different classes of stimuli (instead of a stimulus vs. silent baseline). This is therefore not an indication of inadequate signal acquisition.
We look forward to additional research on this topic from Dr. Veselis’ group and others, because much clearly remains to be learned from the study of neural responses during anesthesia.
*McGill University, Montreal, Quebec, Canada. gilles.plourde@staff.mcgill.ca
