Auditory Evoked Potentials and 40-Hz Oscillations: An Opportunity To Study Mechanisms of Action of General Anesthetics? 

IN this issue of ANESTHESIOLOGY, 1Dutton et al.  1examine the effects of propofol and desflurane on the 40-Hz activity that is part of the midlatency auditory evoked potential (MLAEP). They show that attenuation of the 40-Hz activity by propofol or desflurane correlates well with the loss of consciousness. Consciousness was defined as responsiveness to simple verbal commands.

Auditory evoked potentials are changes of the electroencephalogram caused by auditory stimuli. Midlatency  designates the potentials that occur 12 to 50 ms after the stimulus (in awake subjects). The MLAEP consists of thee main peaks: Na, Pa, and Nb, with respective usual latencies near 15, 28, and 40 ms in awake subjects. 2These peaks represent variation of electrical potential as a function of time. The first letter indicates the polarity of the wave at the vertex; the second, the order of occurrence. Other peaks (Pb and Nc) can sometimes be identified after Nb. The interval from Pa to Nb approximates a one cycle sinusoid with a period of approximately 25 ms (40 − 15 ms), which corresponds to a frequency near 40 Hz. This is the 40-Hz activity contained in the MLAEP (fig. 1 

).

The article by Dutton et al.  is an important contribution to the abundant literature on the effects of general anesthetics on MLAEP. General anesthetics produce robust concentration-dependent alterations of MLAEP (increased latency and decreased amplitude) that are remarkably similar for most anesthetics. 3Some of these alterations, such as the increase of the latency of wave Nb, allow reliable prediction of the presence or absence of consciousness. 4Madler and Pöppel 5showed that anesthetic-induced changes of MLAEP reflected loss of 40-Hz activity and suggested that this could explain why identification of sensory events is no longer possible during general anesthesia. Substantial 40-Hz MLAEP activity during surgical anesthesia is frequently accompanied by signs of light anesthesia. 6Dutton et al.  1provide a much-needed study: one that examines directly the relationship between 40-Hz MLAEP activity and the level of consciousness.

There are at least two reasons to search for neurophysiologic measures of anesthetic effect on the brain:(1) to help explain mechanisms by which anesthetic drugs exert their effect on consciousness; and (2) to obtain an on-line monitor for clinical use, particularly for the prevention of accidental intraoperative awareness. 7Advanced computerized processing of the electroencephalogram (bispectral analysis and time-domain procedures) combined with statistical modeling has led to the recent development of bispectral index (BIS) technology. 8BIS correlates well with the concentration of general anesthetic and provides excellent prediction of whether a subject is conscious. 9BIS is also easy to use and well suited for on-line monitoring in the operating room. Because BIS is an empirical, statistically derived entity, 8it may be difficult to identify its physiologic basis. Thus, the role that BIS may have in helping to understand how general anesthetics work is unclear.

By contrast, there is ample information about the mechanisms implicated in the generation of MLAEP. 2There is converging evidence that wave Na arises from mesencephalic structures, and that wave Pa originates from the primary auditory cortex with a contribution from subcortical sources. Thalamic cholinergic neurons of the ascending reticular formation are involved in the generation of wave Pb. Therefore, the MLAEP offers a promising method for investigating anesthetic mechanisms. Moreover, the MLAEP also offers the possibility of on-line monitoring. 10 

Changes of MLAEP by general anesthetics are consistent with the hypothesis that alteration of consciousness by these drugs involves thalamic and cortical neuronal assemblies. 11The study by Dutton et al.  suggests that the dysfunction induced by general anesthetics in these systems, leading to unconsciousness, is reflected by the attenuation of the 40-Hz oscillations embedded in the MLAEP.

Another method to study 40-Hz activity evoked by auditory stimulation is the auditory steady-state response, which is produced by stimuli at rates near 40 s⁻¹(instead of rates of ≤ 10 s⁻¹for MLAEP). 12Like the MLAEP, the auditory steady-state response is a sensitive indicator of the effects of general anesthetics. 13 

Dutton et al.  1are to be commended for the methodology of their study. They have studied volunteers, allowing exposure of same subjects to both propofol and desflurane. The recordings were obtained at stable drug concentrations. The actual concentrations were measured in expired air or arterial blood. A sophisticated signal processing technique (joint time–frequency analysis) was used to quantify the 40-Hz MLAEP. Although this technique did not perform better than conventional fast Fourier transform, it revealed the optimal latency for measuring the changes of 40-Hz activity.

Dutton et al.  1summarize the relevant information about the physiologic role of 40-Hz oscillations. The label “40 Hz” is used here to designate rhythmic neuronal activity that occur at a fixed frequency in the 25–80-Hz range (gamma band). There is considerable controversy about the significance of the endogenous, spontaneously occurring 40-Hz rhythms that are associated with states of high vigilance 14and that may be involved in sensory perception, attention, and consciousness. 15The 40-Hz activity of the MLAEP and auditory steady-state response shares certain similarities 16,17with the endogenous 40-Hz oscillations, but there are important differences that must not be overlooked. The 40-Hz component of the MLAEP and auditory steady-state response are stereotyped patterns driven by auditory stimuli. They mainly reflect the ability of the auditory system to sustain fast oscillations. By contrast, endogenous 40-Hz oscillations constitute a background activity that reflect depolarization of thalamic and cortical neurons, a physiologic condition associated with states of high vigilance 18and almost certainly required for the emergence of consciousness. 15The effects of general anesthetics on the endogenous 40-Hz rhythms thus offer fertile opportunities for inquiry.