Anesthesia and the Electrophysiology of Auditory Consciousness

Consciousness and Cognition 8, 45–61 (1999) Article ID ccog.1998.0373, available online at http://www.idealibrary.com on

Anesthesia and the Electrophysiology of Auditory Consciousness Susan Pockett Department of Psychiatry and Behavioural Science, University of Auckland, Auckland, New Zealand Empirical work is reviewed which correlates the presence or absence of various parts of the auditory evoked potential with the disappearance and reemergence of auditory sensation during induction of and recovery from anesthesia. As a result, the hypothesis is generated that the electrophysiological correlate of auditory sensation is whatever neural activity generates the middle latency waves of the auditory evoked potential. This activity occurs from 20 to 80 ms poststimulus in the primary and secondary areas of the auditory cortex. Evidence is presented suggesting that earlier or later waves in the auditory evoked potential do not covary with auditory sensation (as opposed to auditory perception) and it is therefore suggested that they are possibly not the electrophysiological correlates of sensation.  1999 Academic Press

INTRODUCTION: DEFINITIONS AND PROBLEMS

The Pocket Oxford Dictionary has no problem defining anesthesia as ‘‘absence of sensation.’’ The definition of sensation gets it into rather more trouble, however; the best it can do being ‘‘consciousness of perceiving or seeming to perceive some condition of one’s body, senses, mind, feelings etc.’’ Taking into account the difficulty of defining the words consciousness, mind, and feeling—and also the problem of drawing a line between sensation, which is taken in some psychological circles to mean basic or ‘‘raw’’ sensory experience and perception, which is used to mean the experience of a raw sensation after it has been compared to preexisting mental templates (so that, for example, a piston engine would be perceived quite differently by a hypothetical aboriginal who had had no contact with western civilization than it would by a qualified mechanical engineer)—the dictionary definition of sensation seems somewhat less than clear. However, since both the dictionary definition of anesthesia and the usage of the word by practising anesthetists agree that anesthesia is the absence of sensation, it would seem to be a good strategy if one wants to discover the neural correlates of sensation to study the periods around the induction of and recovery from anesthesia. In other words, whatever neural events are (1) timelocked to a particular sensory stimulus (2) go away during induction of anesthesia at the same time that the sensation caused by the stimulus goes away and (3) return during recovery from anesthesia at the same time that the sensation caused by the stimulus returns might reasonably be proposed as being the neural correlate of that sensation. A number of practical and theoretical problems soon arise in connection with the performance of experiments designed to establish (2) and (3) above. Perhaps the best E-mail: [email protected] Address correspondence and reprint requests to Dr. S. Pockett, Dept. of Psychiatry and Behavioural Science, University of Auckland, Private Bag 92019, Auckland, New Zealand. Fax: (649)373-7493. 45 1053-8100/99 $30.00 Copyright  1999 by Academic Press All rights of reproduction in any form reserved.

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way to illustrate these problems is to present a very brief subjective report of one subject’s individual experience of general anesthesia (personal observation). The experiences of others will doubtless be different because of differences in the anesthetic cocktail employed or differences in individual physiology and psychology—but this is one anesthetic experience from the subjective viewpoint. SUBJECTIVE REPORT ON AN EXPERIENCE OF GENERAL ANESTHESIA I was not offered any anti-anxiety premedication before the surgical anesthesia. This is probably why my memories of the induction period are unusually clear [the benzodiazepines that are a standard anxiolytic premedication are known to compromise memory formation], but it also meant that when I walked into the operating theatre and lay down on the table I way (though trying to hide the fact with jokes and banter) frankly terrified. Possibly because of the high level of circulating adrenalin associated with this state of being, nothing at all happened to my consciousness for what was apparently an abnormally long time after the induction injection . . . long enough for the anesthetist to start looking puzzled—then (to my eyes anyway) worried—then to ask several times if I felt anything yet. I concentrated hard and tried to oblige him but could really detect no difference whatsoever in the way I felt. Finally I remember saying with some relief ‘‘Ah, here it comes’’, as I experienced a well of blackness rising smoothly from what seemed to be about the level of my heart. Visually, there was a horizontal line, an entirely normal would above it and nothing but a velvety black below it, which took about 2 seconds to rise from shoulder level to nose level—I just had time to wave and say goodbye (I could see above the black line that I had in fact raised my hand to wave, so I must still have had some motor control over the parts of my body that were in the blacked out zone) before the velvet reached my eyes and I was gone. After this I remember nothing at all until my consciousness returned, quite fully and as suddenly as if a light had been switched on, in the recovery room. I could immediately see, hear and feel my body—in fact my vision seemed to be more fine-grained than normal. I had no trouble remembering the situation, or working out where I now was, in what later turned out to be surprisingly accurate detail (using various cues such as the sunlight coming in a window behind me and assorted ambient sounds). So there was nothing much wrong with my brain’s input or cognitive mechanisms. But the output mechanisms were definitely compromised. The thing was, I felt actually rather good in general, but nothing seemed to matter. Even a sharp pain at the injection site in my left hand, while it was recognisable as pain, was only mildly aversive–it certainly didn’t matter enough to do anything about it. Thus when a nurse came to see if I was awake, although I was actually very much awake and feeling quite pleasant and well-disposed towards this solicitous person, it seemed to be just too much trouble to answer the questions. She went away convinced I was still asleep. When she came back quite a bit later I still had to force myself to mumble a few words of reply.

Now, as mentioned earlier, the details of this sort of experience will almost certainly depend largely on the cocktail of anesthetic drugs used and will even then show biological variation. The usefulness of such a case-history account in the present context is that it illustrates some of the possible states of consciousness which may be encountered during the peri-anesthetic period: namely (1) being fully aware and responsive and forming explicit memories (normally awake); (2) being fully aware of some parts of the world and responsive and forming explicit memories (going under a very brief period that might normally pass unnoticed); (3) being unaware and unresponsive and not forming explicit memories (anesthetised); and (4) being fully aware and unresponsive and forming explicit memories (recovering). If you now add to the aware/unaware, responsive/unresponsive and forming/not forming explicit memories axes the possibility of forming or not forming implicit

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memories (which were not tested for in the above situation), there are clearly a large number of different possible states of consciousness that may be encountered during anesthesia. When you further take into account the fact that both sensory awareness itself and the ability to form either implicit or explicit memories of sensation can sometimes be graded, rather than all-or-none phenomena, it can be seen that dissecting the precise condition of sensory awareness of an individual at any particular moment during an anesthetic episode, with the aim of correlating this with some objectively measured neural event, is no easy proposition. In particular, the possible condition of being aware of sensation but unresponsive and not forming either explicit or implicit memories seems to be one that is impossible to detect objectively. All these difficulties notwithstanding, however, there has been a great deal of empirical work published on the correlation of neural events with the onset of and recovery from anesthesia. The rest of this article reviews such work on auditory evoked potentials and as a result makes a proposal about the nature of consciousness in general and the neural correlate of auditory sensation in particular. GENERATION OF AUDITORY EVOKED POTENTIALS

The electroencephalogram (EEG) measured by scalp electrodes is a record of the fluctuations in the electrical activity of large ensembles of neurons in the brain. Specifically, it is a measure of the extracellular current flow associated with the summed activity of many individual neurons—predominantly of cortical pyramidal cells because these are generally oriented parallel to one another with their dendrites perpendicular to the surface of the cortex, while other sorts of neurons and glia are not oriented in any particular relation to each other or to pyramidal cells so that their extracellular field potentials tend to cancel out (Kandel, Schwartz, & Jessell, 1991). Thus electroencephalography is a noninvasive method of measuring brain electrical activity, which offers quite good time resolution but very poor spatial resolution. An extensive treatment of the technical difficulties of interpreting EEGs in terms of the spatial filtering of the head volume conductor is provided by Nunez (1995). Auditory evoked potentials represent the EEG activity that is evoked by an auditory stimulus. When recording evoked potentials it is necessary to average several hundred individual responses to several hundred repetitions of the stimulus in order to pull the tiny signal evoked by the sound stimulus out of the much larger generalized EEG ‘‘noise’’ (which may very well carry biologically important information, but which is random with respect to this particular stimulus). A diagram of the general shape of the auditory evoked response in human subjects is shown in Fig. 1. The auditory evoked response, or evoked potential, consists of a series of positive and negative waves or peaks. Although these are convenient points for measurement, they are not necessarily generated by individual neural events—each peak or trough may represent activity at several different neural sites. Essentially three different methods have been used to determine the sites in the brain of the neural generators of evoked potentials. One is based on simultaneous recording from scalp electrodes and different neural structures exposed during neurosurgery. The recordings made directly from the brain are then correlated with the recordings from the scalp. The second method makes use of pathologies or lesions to neural structures. The third

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FIG. 1. Diagrammatic representation of auditory evoked potential waveforms. Note that the time axis in this diagram is divided into three sections, each with a different linear scale—these sections correspond to the auditory brainstem response (ABR), the auditory middle latency response (AMLR), and the auditory late response (ALR). In practice the early, middle, and late responses would never be observed consecutively like this because different auditory stimuli are optimal for evoking the ABR, the AMLR, and the various components of the ALR. The graph is plotted with positive-going waves, as recorded by a midline scalp electrode connected to the noninverting input of a differential amplifier, shown as upward deflections (contrary to the convention in early evoked potential work that such waves should be shown as downward deflections). Labeling of the peaks is according to the most frequently used convention; however, P1 is sometimes called Pc, N1 is sometimes called N100 and P3 is sometimes called P300.

method, which is probably the most commonly used because it is noninvasive, is also the one that produces results that are the most difficult to interpret. This is to record from a large number of scalp electrodes and try mathematically to solve the notorious ‘‘inverse problem’’ by calculating the location in the brain of various hypothetical dipole sources that could produce the observed pattern of waveform amplitudes on the scalp. The major problem with this method is that there is always more than one mathematical solution which could produce the measured result. However, combining all three methods, it is possible to make some statements about the location of the generators of various components of the auditory evoked potential. Auditory Brainstem Responses The response during the first 10 ms after the stimulus is called the auditory brainstem response (ABR) because it is widely accepted as being generated in the auditory

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nerve and brainstem (for review see Hall, 1990). One common interpretation of the available data is that wave I of the ABR arises from the distal part of the eighth nerve, wave II from the proximal part of the eighth nerve, wave III from the trapezoid body of the cochlear nucleus, wave IV from the superior olivary complex, and wave V from the inferior colliculus in the brainstem. Auditory Middle Latency Responses The waveforms occurring from 10 ms to about 100 ms poststimulus are collectively known as the auditory middle latency response (AMLR). Their neural generators are more complex and more controversial. Wave Na may be generated in the thalamus, though there is little available evidence (Hall, 1990). There is considerable evidence from normal subjects that wave Pa of the AMLR is generated, at least in part, in the supratemporal auditory cortex (Deiber, Ibanez, Fischer, Perrin, & Mauguiere, 1988; Jacobson & Newman, 1990; Lee, Lueders, Dinner, Lesser, Hahn, & Klemm, 1984; Scherg & von Cramon, 1986). Some studies on subjects with brain lesions also show that Pa is reduced in amplitude or undetectable when the primary auditory cortex is damaged, while it is unaffected by lesions in the main auditory portion of the thalamus (the medial geniculate body), in auditory association areas of the cortex, or in the frontal or parietal cortex (Kileny, Paccioretti, & Wilson, 1987; Ho, Kileny, Paccioretti, & McLean, 1987; Kraus, Ozdamar, Hier, & Stein, 1982; Ozdamar & Kraus, 1983; Ozdamar, Kraus, & Curry, 1982; Scherg & von Cramon, 1986). Magnetoencephalographic work (Scherg, Hari, & Hamalainen, 1989) also puts the origin of the peaks arising at 19 and 30 ms poststimulus (equated with Na and Pa of the MLR) in the temporal auditory cortex—with the 19-ms peak arising from a site 5–8 mm deeper than the 30-ms peak. However, Woods, Clayworth, Knight, Simpson, and Naesser (1987) report finding no simple relationship between Na–Pa amplitude and the extent of damage to primary auditory cortex, and record reliable Pa and Na components in patients with bilateral temporal lobe lesions. Parving, Salomon, Eberling, Larsen, and Lassen (1980) also recorded apparently normal MLRs from patients with bilateral temporal lobe infarcts. All in all, however, it seems likely that the early auditory middle latency potentials do arise at least largely from the primary auditory cortex in the temporal region just above the ears. They may have a subcortical component as well. Later middle latency potentials probably arise from the secondary auditory cortex. Liegeois-Chauvel, Musolino, Badier, Marquis, and Chauvel (1994) performed intracerebral recordings on patients undergoing surgery for relief of epilepsy and localized the origins of the various temporal components of near-field potentials evoked by auditory tone-bursts. They found that potentials occurring at 30 and 50 ms after the stimulus originated from adjacent parts of the primary auditary cortex, and potentials at 60–75 ms poststimulus were generated in the lateral part of Herschel’s gyrus, which forms the secondary auditory area. The 40-Hz Auditory Steady State Response The 40-Hz auditory steady state response (ASSR) is an approximately sinusoidal oscillation in the EEG which has a frequency of 40 Hz and occurs when auditory

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stimuli such as clicks or tone-bursts are presented at 40 Hz (Galambos, Makeig, & Talmachoff, 1981; Stapells, Lindon, Suffield, Hamel, and Picton 1984) or when pure tones are amplitude- or frequency-modulated at 40 Hz (Picton, Skinner, Champagne, Kellett, & Maiste, 1987). Two main hypotheses have been advanced as to how this 40-Hz oscillation is generated. The first (Galambos, Makeig, & Talmachoff, 1981) is that the steady state response is simply the linear summation of a series of responses to brief stimuli, i.e., that it is a form of the MLR. The second (Galambos, 1982) is that the auditory network displays an intrinsic rhythm that is driven more or less well depending on the stimulus rate. There is some experimental support for both hypotheses. For the first, if a number of brief auditory stimuli are presented in rapid succession, the algebraic sum of the resultant MLRs does give rise to a stable 40-Hz sinusoid (Galambos, Makeig, & Talmachoff, 1981). The effectiveness of this model for generation of the ASSR has been verified in animals (Ottaviani, Paludetti, Grassi, Draicchio, Santarelli, Serafini, & Pettorossi, 1990) and in humans (Stapells, Galambos, Costello, & Makeig, 1988; Hari, Hamalainen, & Joutsiniemi, 1989; Plourde, Stapells, & Picton, 1991) by both electric and magnetic recordings. Further support for this first hypothesis comes from evidence for a common cortical generator for the MLR and the ASSR (Makela & Hari, 1987; Hari, Hamalainen, & Joutsiniemi, 1989; Pantev, Elbert, Makeig, Hampson, Eulitz, & Hoke, 1993). The second hypothesis, that the auditory network displays an intrinsic rhythm which is more or less well driven depending on the stimulus rate, receives support from the results of Azzena, Conti, Santarelli, Ottaviani, Paludetti, and Maurizi (1995) and Santarelli, Maurizi, Conti, Ottaviani, Paludetti, and Pettorossi (1995). This group of workers have measured auditory steady state potentials at repetition rates of 7, 9, 20, 30, 40, 50, and 60 Hz and compared these with the steady state responses predicted by the superposition of individual auditory evoked potentials shifted by the appropriate time periods. They found that linear addition of the individual traces closely approximated the amplitude and phase of the recorded steady state response only at 40 Hz. At 30 Hz the predicted phase lagged behind the recorded one and at 50 or 60 Hz there was a significant phase lead of the predicted compared to the recorded response. The authors take these results to mean that the ‘‘resonant frequency’’ of the neural system could play a role in the generation of the 40-Hz auditory steady state response. Since both hypotheses about the generation of the ASSR could be considered to be supported by some experimental evidence and neither is ruled out, the most sensible conclusion at this stage may be that the true explanation reflects elements of both hypotheses. However, in this context it should also be pointed out that 40-Hz oscillations are relatively common in the brain. Other sensory systems as well as the auditory system show both spontaneous and event-related activities in the so-called γ band (Galambos & Makeig, 1988; Bressler, 1990) and an activity at around 40 Hz has been shown in direct recordings from several brain sites in response to different sensory stimulations (Basar, Demir, Gondeg, & Ungan, 1979; Basar, Durusan, Gonder, & Ungan, 1979; Basar, 1980; Bressler & Freeman, 1980; Bouyer, Montaran, & Rougeul, 1981). Furthermore, it is thought that intrinsic 40-Hz oscillations (such as those which can be elicited in brain slices, which of course receive no sensory

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input per se) are naturally generated by a combination of interneuron network properties, the characteristics of intrinsic membrane conductances, and long-loop thalamocortical interactions (Whittington, Traub, & Jefferys, 1995). In fact, 40-Hz activity appears to be so important in the brain that it has been postulated as a basic physiological mechanism underlying perceptive processes (Barinaga, 1990; Crick & Kock, 1990; Gray, Konig, Engel, & Singer, 1989; Pantev, Makeig, Hoke, Galambos, Hampson, & Gallen, 1991; Tiitinen, Sinkkonen, Reinikainen, Alho, Lavikainen, & Naatanen, 1993). It must be said that the very ubiquity of these intrinsic 40-Hz oscillations argues against their being the precise neural correlate of any particular sensory or perceptual experience—but the situation at this stage can perhaps best be described as unclear. Long Latency Auditory Evoked Potentials The N1 or N100 wave of the human electric and magnetic response to sound, which peaks at around 85–100 ms poststimulus, has at least six contributing neural generators (Naatanen & Picton, 1978). Three components of the response are controlled by the physical and temporal aspects of the stimulus and by the general state of the subject: (1) a component generated in the supratemporal auditory cortex, (2) a component generated in the association cortex on the lateral aspect of the temporal and parietal cortex, and (3) a component generated in the motor and premotor cortices. Another three components are not necessarily elicited by an auditory stimulus but depend on the conditions in which the stimulus occurs: (4) the mismatch negativity (which occurs only when a stimulus differs from those preceeding it in a homogeneous sequence) and (5 and 6) one temporal and one frontal component of the ‘‘processing negativity’’ (which occur only during the processing of an attended auditory stimulus and not if the stimulus is not being attended to). The mismatch negativity component (4) is also generated in the supratemporal auditory cortex, anterior to component (1) above (Tiitinen, Alho, Huotilainen, Ilmoniemi, Simola, & Naatanen, 1993). Of the late auditory responses, the most prominent is the P3 or P300 (for review see Picton, 1992). This is a very large positive wave that occurs only when an actively engaged subject detects an occasional ‘‘target’’ stimulus in regular train of standard stimuli (the so-called ‘‘oddball’’ paradigm). The typical latency of P3 for a young adult subject making a simple discrimination is about 300 ms, with the latency becoming longer in aging or as cognitive ability decreases with neurological deficits. The P300 wave is not specific to a particular stimulus modality and is detected with visual as well as auditory stimuli. The intracerebral origin of the P300 wave is not known and its role in cognition is not clearly understood, although several hypotheses have been put forward (e.g., Verleger, 1988; Donchin & Coles, 1988). AUDITORY EVOKED POTENTIALS AND ANESTHESIA

Auditory Brainstem Responses The waveform morphology of auditory brainstem responses (ABRs) is grossly unaffected by a wide variety of anesthetics, although the latency of various waves

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may be prolonged slightly. Many references for this general statement are supplied by Hall (1990). Since ABRs remain largely unchanged during complete loss of auditory sensation in clinical anesthesia, these responses must be considered as not very likely to represent the neural correlates of auditory sensation. Auditory Middle Latency Responses Middle latency responses (MLRs), however, are significantly affected by general anesthetics. The latency is increased and the amplitude decreased for waves Pa and Nb in the presence of the volatile anesthetics enflurane (Thornton, Catley, Jordan, Lehane, Royston, & Jones, 1983) and halothane (Thornton, Heneghan, James, & Jones, 1984), with these changes becoming more pronounced as end-tidal concentrations of anesthetic increase until eventually the waveforms are abolished. During recovery from anesthesia in these studies, the amplitudes of Pa and Nb recovered, but no attempts to correlate recovery of the waves with recovery of awareness of the sounds are reported. Later work with enflurane and isoflurane (Thornton, Barrowcliffe, Konierczko, Ventham, Dore, Newton, & Jones, 1989; Newton, Thornton, Konieczko, Jordan, Webster, Luff, Frith, & Dore, 1992) did specifically address the relationship of middle latency auditory evoked responses to awareness, using response to a verbal command to raise a finger or squeeze the experimenter’s hand as a measure of awareness. Despite some false-negatives (subjects’ later reporting hearing the command but failing to respond, for reasons similar to those given earlier in the present paper in the subjective account of anesthetic experience), these studies showed a statistically highly significant relationship between response to command and both latency and amplitude of waves Pa and Nb. The association of auditory middle latency responses with awareness was also found using the anesthetic propofol (Davies, Mantzaridis, Kenny, & Fisher, 1996). Again the measure of awareness was response to a verbal instruction to squeeze the investigator’s hand. Repeated transitions from responsiveness to unresponsiveness and back again for each subject showed statistically significant increases in Na, Pa, and Nb latencies when responsiveness disappeared and decreases when it reappeared again. Qualitatively, the amplitudes of Na, Pa, and Nb were found to decrease with unresponsiveness and increase again with responsiveness, although no numerical measurements are reported. Schwender, Faber-Zullig, Klasing, Poppel, and Peter (1994) found that surgical anesthesia using either propofol or isoflurane was associated with a lack of motor signs of wakefulness (coughing, purposeful movements of the limbs, and eye-opening) and also with abolition of auditory middle latency responses. However, anesthesia (in combination with a regional pain block) with the receptor-specific anesthetics flunitrazepam (which is a benzodiazepine from the same chemical family as Valium) and fentanyl (an opioid) was associated with a significant incidence of motor signs of wakefulness and also with maintenance of MLRs. This fits with their earlier observations that general anesthesia using the benzodiazepines flunitrazepam, diazepam, or midazolam (Schwender, Klasing, Madler, Poppel, & Peter, 1993a) or the opioids fentanyl, alfentanil, or morphine (Schwender, Rimkus, Haessler, Klasing, Poppel, & Peter, 1993) preserved both amplitude and latency of middle latency auditory evoked

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responses, despite the fact that responsiveness to verbal command and explicit memory were abolished. This might be taken to mean the MLRs persist in the absence of auditory sensation—but as we have previously seen, lack of responsiveness to verbal command does not necessarily indicate lack of awareness. Further investigations by the same group (Schwender, Kaiser, Klasing, Peter, & Poppel, 1994) showed a correlation between preservation of middle latency responses under benzodiazepine or opioid anesthesia and formation of implicit (but not explicit) memories for information presented during this anesthesia. The question of whether awareness of the learned stimuli at the time of learning is necessary for the formation of implicit memories is a vexed one (e.g., Andrade, 1996; Bonnebakker, Jelicic, Passchier, & Bonke, 1996; Merikle & Daneman, 1996), but the finding that implicit memories are only formed during anesthesia if auditory middle latency responses are present at the time that the memories are being laid down is at least consistent with the hypothesis that auditory middle latency responses might constitute the neural correlate of awareness of sound. The above evidence can be summarized as follows: (1) it has never been shown that a subject responds to a verbal command in the absence of auditory MLRs and (2) it has never been shown that a subject forms implicit memories in the absence of auditory MLRs. In some circumstances subjects do fail to respond to a command or fail to form memories when auditory MLRs are present—but the reader can easily verify from their own subjective experience that one sometimes fails to respond to a verbal command which one has heard perfectly well and very often fails to remember later something that one has heard quite clearly (and even responded to) at the time. Responsiveness and memory involve many neural steps in addition to basic awareness. Auditory Steady State Responses As pointed out in a previous section, it is not entirely clear whether the 40-Hz auditory steady state response evoked by presentation of auditory stimuli at 40 Hz is simply another form of the auditory middle latency response or whether it also reflects properties of intrinsic 40-Hz oscillations in the brain. Perhaps one piece of evidence for the latter position is that the anesthetic ketamine affects MLRs and ASSRs differently. Ketamine anesthesia does not have any significant effects on AMLRs (Schwender, Klasing, Madler, Poppel, & Peter, 1993b), but it increases the amplitude of the ASSR (Plourde, Baribeau, & Bonhomme, 1997). The latter authors note this apparent discrepancy and resolve it by using the actual data presented by the former authors to compute a predicted effect of ketamine on the ASSR, assuming that the ASSR is purely a summation of overlapping AMLRs. They show that small changes in the ketamine-affected AMLR unremarked by Schwender and colleagues actually result in predicted ketamine-induced changes in the ASSR which parallel the observed changes. However, another interpretation of the fact that ketamine affects AMLRs and the ASSR differently might be that the ASSR does include a component of an intrinsic 40-Hz oscillation. Ketamine is known to block NMDA receptors and NMDA receptors are probably involved in the generation of intrinisic 40-Hz oscillations. In the absence of a detailed knowledge of the anatomy of the neural networks

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generating these particular putative intrinsic 40-Hz oscillations it is impossible to predict how NMDA receptor blockade would affect them, but it could well act to increase their amplitude. We are now left with the finding that ketamine anesthesia has no significant effects on AMLRs—and if we wish to postulate that AMLRs are a substrate of auditory experience, this appears to be a problem. The solution to this problem may lie in the peculiar characteristics of the anesthesia produced by ketamine. Ketamine is known as a ‘‘dissociative’’ anesthetic and the state of consciousness it induces is acknowledged to be different from that induced by other anesthetics. Unpleasant dreams or hallucinations are a common feature of ketamine anesthesia (White, Way, & Trevor, 1982), although inhibition of memory formation (probably due to suppression of synaptic LTP or long-term potentiation by blockade of NMDA receptors) may prevent their being reported. Such dreams or hallucinations may well be due to the fact that auditory sensation continues (or is perhaps even heightened) during ketamine anesthesia, although there is a disconnection between sensation and the ability to perceive the stimulus in the context of the current situation or to respond behaviorally. In this respect ketamine ‘‘anesthesia’’ may have more resemblance to a dream-ridden sleep from which one cannot be aroused than to what is normally thought of as anesthesia [AMLRs are markedly decreased during non-REM sleep, but almost the same in the REM or dreaming stage of sleep as in the awake state (Jones & Baxter, 1988; Deiber, Ibanez, Bastuji, Fischer, & Maugiere, 1989)]. Opioids and benzodiazepines also preserve AMLRs (see above), but with these drugs the affective component of the drug experience seems to be more pleasant than with ketamine. Other anesthetics that have been studied have similar effects on both ASSRs and AMLRs. ASSRs are markedly attentuated during anesthesia with thiopental, fentanyl, and either isoflurane (Plourde & Picton, 1990) or enflurane (Plourde & Villemure, 1996) and reappear suddenly just before, or at the same time as, the ability to respond to a command reappears during emergence. So on current evidence, the presence of relatively high-amplitude auditory middle latency responses or the 40-Hz auditory steady state response seems to be necessary for auditory sensation. Whether this is also a sufficient condition for auditory sensation is unclear. It remains possible, for example, that auditory middle latency responses do not represent the neural correlate of auditory sensation or awareness itself, but are only a necessary step in the neural pathway from the ear to the actual site of the neural correlate of sensation or awareness. Let us then examine the later waves in the auditory evoked potential. Long Latency Auditory Evoked Potentials Both N1 and P3 waves of the auditory evoked potential are abolished by general anesthesia (Plourde & Picton, 1991; deBeer, van Hoof, Brunia, Cluitmans, Korsten, & Beneken, 1996). Furthermore, Plourde and Picton found that before and during induction of anesthesia, when patients were asked to press a button on hearing a certain sound, detected sounds (hits) evoked N1 and P3 waves, while undetected sounds (misses) evoked no recognizable waves. However, during recovery from anesthesia

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there was generally a small N1 and possibly also a small P3 for misses. This effect is obvious to the eye in the records presented and is commented on by the authors, but it does fall short of significance in the statistical test used—and anyway it seems quite likely that the reason for a ‘‘miss’’ during recovery from anesthesia could be lack of motivation to press the button. More seriously, during the period of emergence from anesthesia, correct hits were observed to occur in the absence of either N1 or P3 waves. It is pointed out by the authors of the study that ‘‘it may be possible for a subject to respond to a stimulus automatically, with little if any awareness.’’ However the finding that subjects can respond correctly to a stimulus when N1 and P3 waves are either undetectably small or absent must also be considered as consistent with the idea that N1 and P3 are not the neural correlates of auditory awareness. Further evidence from studies outside the area of anesthesia confirms this observation. First, (remembering that P3 is nonstimulus specific) it has been reported that one ‘‘blindsight’’ patient showed normal P3 waves in the absence of visual awareness (Shefrin, Goodin, & Aminoff, 1988). Secondly, auditory N1 waves quickly habituate in response to frequent stimuli (Naatanen & Picton, 1987) and it is easily verifiable subjectively that the sorts of tones which evoke N1 waves are perfectly audible even when presented at rates which are reported to habituate N1 out of existence. Thus, it seems unlikely that at least the N1 or P3 components of the auditory late response represent the neural correlate of auditory sensation, because (1) awareness can be present when these waves are absent and (2) awareness can be absent when the waves are present. It remains possible that other long latency neural events are both necessary and sufficient for auditory sensation, but this has yet to be demonstrated. THE NEURAL CORRELATE OF AUDITORY SENSATION: A HYPOTHESIS

The evidence presented above is consistent with the hypothesis that the neural correlate of auditory sensation (as distinct from auditory perception, which is taken as including such functions as memory of the sensation and detection of differences between the current sensation and preceding ones) is represented by the middle latency waves of the auditory evoked response. These waves are most probably generated in the supratemporal primary and/or secondary auditory cortex and occur from 20 to 80 ms after the stimulus. Twenty to 80 ms is considerably less than the 500 ms that Benjamin Libet and colleagues have suggested is the objective time lag between stimulus and sensation, but is approximately the same as the 50-ms time lag their experimental subjects experience subjectively (Libet, Alberts, Wright, Delattre, Levin, & Feinstein, 1964; Libet, Alberts, Wright, & Feinstein, 1967, Libet, Wright, Feinstein, & Pearl, 1979). Space precludes detailed discussion of Libet’s work here: suffice it to say that there do exist other interpretations of his experimental findings than Libet’s own (Churchland, 1981; Glynn, 1990; Pockett, 1996; Gomes, 1998). In the visual system, Crick and Koch (1995a) have hypothesized that while activity in the primary visual cortex (area V1 or Brodmann area 17) may be necessary for visual consciousness, it is not sufficient—and that in fact activity in this area does not itself enter visual awareness at all. The reasoning behind this suggestion is that

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the authors consider the evolutionary advantage of visual awareness to be that it is useful in planning actions and they therefore argue that the cortical areas involved in visual awareness must have direct anatomical connections to the cortical areas involved in actions, i.e., to the motor cortex. In monkeys there are direct connections between V4 and V5 and motor cortex, but there are no direct connections between V1 and motor cortex, so it is argued that activity in V1 is unlikely to enter visual awareness directly. This argument seems to place startlingly little importance on cortical association areas, which are widely accepted as subserving cognition and perhaps various aspects of perception (as opposed to sensation) and which might thus be expected to intervene between sensation and action; however, it is the argument used. In answer to criticism of this idea (Pollen 1995), Crick and Koch (1995b) acknowledge that in order to disprove their hypothesis, one would need to show that ‘‘there are at least some neurons in V1 whose firing correlates with some aspects of what is seen and that there are no neurons [sic] in higher cortical areas whose firing correlates exactly with the same aspect of the visual scene.’’ They further say that in order to prove the hypothesis, ‘‘it would be necessary to record from every type of neuron in V1 that expresses properties unique to V1 and show that their firing correlates with aspects of the visual field of which we are unaware.’’ In other words it would be exceedingly difficult to test this hypothesis in any watertight way (as indeed it is difficult to find a definitive test for any hypothesis on the location of a neural correlate of consciousness, the one presented in this article included). Nevertheless there is a considerable body of experimental evidence that supports the hypothesis that visual awareness arises in cortical areas higher than V1. Perhaps the most elegant set of results pointing in this direction is that of Sheinberg and Logothetis (1997). These workers study binocular rivalry, using an experimental paradigm where different information is presented to each eye. In this situation the information that enters consciousness is found to alternate between the information available to one eye and the information available to the other eye. When recordings were made from various areas of the visual cortex in monkeys during this paradigm, it was found that only a small proportion of neurons in V1 and V2 fired exclusively in response to the perceived stimulus, while almost all of the neurons in the infratemporal cortex and the visual areas of the cortex of superior temporal sulcus fired only in response to the perceptually dominant stimulus. While this result does not fulfill Crick and Koch’s criterion for proving the hypothesis that activity in V1 does not enter visual awareness, it certainly suggests that activity in higher areas is more relevant to visual awareness. Anatomically the auditory cortex is much less extensive than the visual cortex. Quite a large region, including Brodmann areas 17, 18, 19, 20, and 21, is involved in various aspects of vision (form vision, color, motion, and depth), while only Brodmann areas 41 and 42, which occupy a relatively small area in Heschl’s gyrus and the superior temporal gyrus, are specialized for hearing. It may prove to be a general rule that primary sensory areas do not contribute to conscious awareness directly, although this can by no means be considered an established fact at this stage. But even if this were so the present hypothesis (that whatever neural activity generates the auditory middle latency response from 20 to 80 ms poststimulus is also the elec-

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trophysiological correlate of auditory sensation) would still stand up to scrutiny, because the specified potentials are generated by activity in both primary and secondary auditory cortex. At present the hypothesis makes no prediction about whether the early or the later waves of the auditory middle latency response (generated in primary or secondary auditory cortex respectively) correlate with auditory sensation. What the present hypothesis does suggest is that the electrophysiological correlate of auditory sensation (as distinct from auditory perception or understanding) is generated in Brodmann areas 41 and/or 42 and not in cortical areas concerned with speech or associative cognition. The hypothesis also suggests that the spatiotemporal pattern of neural activity may be more important in coding sensation than the firing of any single neuron. Thus if one wishes to subscribe to some variety of the Neural Identity Theory of consciousness (as many working neuroscientists do) the version most compatible with the present proposal is probably that consciousness is identical not with the firing of particular neurons per se, but with certain spatiotemporal patterns in the electromagnetic field that are produced by (some but not all) spatio-temporal patterns of neuronal firing.1 According to this idea, the correlation we really should be looking for is a correlational between consciousness and some feature of the spatiotemporal pattern in the electromagnetic field immediately surrounding those neurons whose firing covaries with consciousness. (It should be pointed out that only a very smeared and degraded version of this electromagnetic field configuration or pattern can be measured by EEG electrodes on the scalp: to obtain an unequivocal measure of the field configuration of interest, intracortical field potential recordings from electrodes positioned much closer to the site of generation would be necessary.) Finally, because it is likely that the relevant patterns occupy a smaller area of the cerebral cortex for auditory sensation than for visual sensation (possibly because auditory sensations are in many ways simpler than visual sensations), the auditory system may be a more productive arena than the visual system for investigation of this particular hypothesis. REFERENCES Andrade, J. (1996). Investigations of hypethesia: Using anesthetics to explore relationships between consciousness, learning and memory. Consciousness and Cognition, 5, 562–580. Azenna, G. B., Conti, G., Santarelli, R., Ottaviani, F., Paludetti, G., & Maurizi, M. (1995). Generation of human auditory steady state responses (SSRs). II. Addition of responses to individual stimuli. Hearing Research, 83, 9–18. Barbur, J. L., Watson, J. D. G., Frackowiak, R. S. J., & Zeki, S. (1993). Conscious visual perception without V1. Brain, 116, 1293–1302. Barinaga, M. (1990). The mind revealed? Science, 249, 856–858. Basar, E. (1980). EEG–brain dynamics: Relation between EEG and brain evoked potentials. Amsterdam: Elsevier/North Holland. 1

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