Link to recent papers on unconscious mental life.
John F. Kihlstrom
University of California, Berkeley
Randall C. Cork
Louisiana State University Medical Center
Note: An edited version of this article is to appear in S. Schneider & M. Velmans (Eds.), The Blackwell Companion to Consciousness, 2nd Ed. (Chichester.: Wiley, 2016).
In general anesthesia, a “cocktail” of drugs renders a patient unconscious, in what has been called a “controlled coma”. Various measures of patient awareness involve overt behavior, autonomic nervous system activity, processed EEG, and event-related potentials. The incidence of intraoperative awareness is very low, but anecdotal reports suggest that patients might process surgical events unconsciously, leading to unconscious postoperative memories. Careful experimental studies show that priming effects, similar to those observed in implicit memory, can be spared even in the absence of conscious recollection, an outcome which indicates that unconscious perception can occur even in clinically adequate general anesthesia. Deeper planes of amnesia, however, appear to abolish both explicit and implicit perception.
Keywords: anesthesia; conscious sedation; EEG; implicit memory; implicit perception; priming
The purpose of general anesthesia is to render surgical patients unconscious, and thus insensitive to pain and oblivious to events occurring during the procedure, in what is sometimes called a “controlled coma”. For this reason, anesthesia -- like sleep and coma – often enters into philosophical and scientific discussions of consciousness. How do we know that the patient is unconscious? Appearances to the contrary notwithstanding, are there reasons to think that anesthetized patients are actually conscious after all? Assuming that they are actually unconscious, is it possible for them to acquire and retain unconscious memories of pain and surgical events? What can the biological mechanisms of general anesthesia tell us about the neural correlates of consciousness?
Up until the middle of the 19th century, anesthesia was not a feature of surgery. Instead, patients were simply required to withstand the pain of the procedure, perhaps with the aid of alcohol, opiates (such as laudanum), a bite-board, or simply physical restraints. Humphrey Davy (1778-1829), the pioneering electrochemist, discovered the effects of nitrous oxide on headache and dental pain during his research on respiratory physiology; but his report went unnoticed in the medical community and the substance was quickly consigned to use at “laughing gas” parties. In 1845, Horace Wells, an American dentist, attempted to use nitrous oxide for anesthesia during a dental extraction, but the demonstration failed. But on October 16, 1846, William Morton, another dentist, employed ether in the removal of a tumor with no signs or reports of pain in the patient. (An American physician, Crawford W. Long, had employed ether anesthesia in 1842, but he neglected to publicize his success.) That event was memorialized by a painting which hangs in the Countway Library at Harvard Medical School, the “Ether Monument” in the Boston Public Garden, and celebrations of “Ether Day” in hospitals and medical schools throughout the world (Fenster, 2001). Morton died in 1868, and his tombstone in Cambridge’s Mount Auburn Cemetery carries the following epitaph:
Inventor and Revealer of Inhalation Anesthesia:
Before Whom, in All Time, Surgery was Agony;
By Whom, Pain in Surgery was Averted and Annulled;
Since Whom, Science has Control of Pain.
Soon thereafter, chloroform was introduced as an alternative to ether, which had an unpleasant odor and other side effects. Anesthesia was also extended from surgery to obstetrics, although some physicians had qualms about dangers to the neonate, and other authorities objected on the grounds that the pain of childbirth was somehow good for both mother and child. Queen Victoria essentially decided the issue when she received chloroform for the birth of her eighth child, Prince Leopold. Nevertheless, some professionals and others continued to debate a “calculus of suffering” by which some individuals, and some conditions, were deemed more worthy of anesthesia than others (Pernick, 1985).
Debates aside, progress in anesthesia continued. In 1868, nitrous oxide, mixed with oxygen to circumvent drug-induced asphyxia, was finally introduced to medicine. Following the development of the hypodermic needle, morphine was added to the procedure to reduce the amount of inhalant required to produce anesthesia, and to prevent shock, nausea, and other negative sequelae. In 1876, the sequential use of nitrous oxide and oxygen to induce anesthesia, and ether or chloroform to maintain it, was introduced. In the mid-1880s, cocaine and its derivatives, such as novocaine, joined morphine as adjuncts to anesthetic practice.
Throughout the 20th century, the techniques for delivering and maintaining anesthesia were improved (Barash et al., 2013). Beginning in the 1930s, a succession of drugs was introduced for the rapid induction of anesthesia: initially, barbiturates such as thiopental (sodium pentothal); later, benzodiazepines such as diazepam and midazolam began to substitute for barbiturates; and most recently propofol, a synthetic drug which also permits rapid recovery from anesthesia, with fewer lingering aftereffects. Although inhaled anesthetics suppress voluntary responses to what are euphemistically called “surgical stimuli”, curare was introduced in the 1940s to suppress involuntary, reflexive responses as well. It has since been replaced by drugs such as tubocurarine, vecuronium, and succinylcholine. A new generation of inhalational agents including halothane, enflurane, and isoflurane, less volatile than ether and less toxic than chloroform, came into use after World War II. More recently, intravenous opioid anesthetics such as fentanyl and sufentanyl, as well as non-opiods such as propofol, have emerged as alternatives to inhalational agents.
In current practice, the patient typically receives a benzodiazepine sedative immediately before the operation, followed by an infusion of oxygen to displace nitrogen in the lungs. In rapid sequence induction, a short-acting drug such as thiopental or propofol is employed to induce initial unconsciousness before administering neuromuscular blockade to produce muscle relaxation (a euphemism for total paralysis of the skeletal musculature). In an alternative procedure, called inhalation or mask induction, the patient may receive nitrous oxide and oxygen plus a volatile anesthetic such as isoflurane; in this case, anesthesia develops more slowly. Subsequently, inhalants such as isoflurane, desflurane, or sevoflurane may be used to maintain anesthesia induced by other drugs. In intravenous anesthesia, the inhalants are replaced by drugs such as sufentanyl and propofol. In any event, because of the use of muscle relaxants, the patient must be respirated through intubation of the trachea. At the end of the operation, the patient may receive a drug such as neostygmine to reverse the neuromuscular blockade and permit the resumption of normal breathing, as well as morphine to help alleviate postoperative pain. Any residual inhaled anesthetic is removed by the patient’s normal respiration.
The procedure just described, known as balanced anesthesia, achieves the tripartite goals of general anesthesia: sedation, loss of consciousness (sometimes referred to as “narcosis” or “hypnosis”) resulting in amnesia, and muscle relaxation; the analgesic is administered to control post-operative pain. By contrast, various forms of local or regional anesthesia can be achieved by injection of local anesthetics such as lidocaine into the subarachnoid (spinal anesthesia) or epidural (epidural anesthesia) spaces of the spinal cord, or the peripheral nerves supplying some body part (nerve block). In such procedures, adequate anesthesia is defined more narrowly as a loss of tactile sensation, and there is no loss of consciousness. In conscious sedation, local or regional anesthetics are combined with benzodiazepine sedatives or propofol: again, there is no general loss of consciousness, though the use of benzodiazepines will likely render the patient amnesic for the procedure. In hypesthesia, subclinical doses of general anesthetics are administered to nonpatient volunteers for studies of learning and memory (Andrade, 1996).
Anesthetic agents are chemicals that, when introduced into the brain, disrupt consciousness. Therefore, it seems reasonable to suppose that understanding the mechanisms of general anesthesia would shed light on the neural correlates of consciousness (see Chapters 43, 45). Unfortunately, while modern scientific medicine generally disdains “empirical” treatments whose biological mechanisms are not understood, even though they are known to be efficacious, it has made an exception in this case: the mechanisms underlying general anesthesia remain a matter of considerable mystery (Wang, Deeprose, Andrade, & Russell, 2013).
At the systems level of analysis, the question is whether anesthetics suppress activity throughout the cerebral cortex, or only in certain regions. Both sleep and coma result from modulation of activity in, or damage to, the midbrain reticular formation and/or the thalamus. Accordingly, it is possible that anesthetics operate selectively on one or both of these structures, or perhaps on particular thalamic nuclei. Alternatively, anesthetics may disrupt the connections between brain structures, such as thalamocortical circuits (Alkire, Haier, & Fallon, 2000).
At the molecular and cellular level, the question is how anesthetics suppress neural activity, wherever it occurs. As a first pass, it seems plausible that general anesthetics reversibly disrupt neural activity by inhibiting either neural excitability or synaptic activity, but the various classes of anesthetic agents may have different mechanisms of action. For example, many intravenous “hypnotic” drugs interact with GABA, an inhibitory neurotransmitter, to increase the time that chloride ion channels are open, resulting in a hyperpolarization of cell membranes. However, ketamine, another intravenous anesthetic, interacts with NMDA receptors instead. Natural and synthetic opioid anesthetics, of course, act on opioid receptors, inhibiting presynaptic release of neurotransmitters such as Ach and substance P. However, even in high doses these drugs do not, by themselves, induce loss of consciousness. For this purpose, they are often combined with nitrous oxide and oxygen. Nitrous oxide, for its part, has effects on NMDA receptors similar to those of ketamine. One comprehensive theory suggests that the final common pathway uniting all anesthetics is modulation of activity at the NMDA synapse (Flohr, 1995).
Current evidence is broadly consistent with anesthetic action on both synaptic excitation and inhibition, with the contribution of each process varying from agent to agent. Although the general view is that anesthetics act on the postsynaptic side, there are some indications that they inhibit presynaptic neurotransmitter release as well. Furthermore, the practice of balanced anesthesia implies that there are likely to be a number of separate mechanisms working together to produce analgesia, loss of consciousness, immobility, and amnesia. According to one proposal, inhalants such as isoflurane, which induce both immobility and amnesia, achieve these effects by different routes: immobility by acting on GABA receptors in the spinal cord, and amnesia by suppressing activity in the hippocampus.
Some theorists have sought to solve the mystery of anesthesia by invoking another mystery, namely quantum theory. Roger Penrose, a British mathematical physicist, and Stuart Hameroff, an American anesthesiologist, have famously speculated that consciousness is a product of certain processes described by quantum theory (Hameroff & Penrose, 2014). Briefly, quantum coherence (by which individual particles are unified into a wave function) produces a unified conscious self; non-local entanglement (which connects separate particles) is responsible for associative memory; quantum superposition (by which particles simultaneously exist in two or more states) produces alternative unconscious mental representations; and the collapse of the wave function (by which particles attain a definite state) brings one of these alternative mental states into conscious awareness. Within the context of this theory, Hameroff further proposed that these processes take place in microtubules -- proteins found in the walls of neurons that are shaped like hollow tubes. In this view, anesthetics exert their effects on the specific proteins that make up these microtubules, disrupting the “quantum coherence” and thus the conscious awareness that it generates. As opposed to conventional theories of anesthesia, which focus on processes operating in the vicinity of the synapse, the Hameroff-Penrose “Orchestrated-Objective Reduction” (Orch-OR) theory shifts attention to processes operating inside the neuron itself. The Penrose-Hameroff theory of both consciousness and anesthesia has attracted a great deal of interest, but at this stage it remains highly speculative, and has been criticized on both logical and empirical grounds (see, for example, the commentaries on the article cited and Penrose and Hameroff’s responses to them).
Clinically, the success of general anesthesia is marked by the patient’s behavior assessed following induction and intra-operatively, as well as by post-operative memory. One popular assessment tool is the Observer’s Assessment of Alertness/Sedation (OAA/S; Chernik et al., 1990), similar to the Glasgow Coma Scale, which assesses the patient’s behavioral response, speech, facial expressions, and ocular activity to yield a scale from 5 (obviously awake and responsive) to 0 (unresponsive to even noxious stimulation). Evaluated in these terms, general anesthesia is almost always successful. Nevertheless, the use of muscle relaxants in balanced anesthesia makes it possible to perform surgery under lighter doses of anesthetic agents – increasing the risk of intraoperative awareness and postoperative recall at the same time as they decrease the risk of anesthetic morbidity. It was recognized early on that the use of muscle relaxants increased the risks further, by preventing inadequately anesthetized patients from communicating their intraoperative awareness to the surgical team.
In point of fact, the incidence of anesthetic awareness is extremely low (Ghoneim, Block, Haffarnan, & Mathews, 2009). Recent estimates of surgical awareness range from 0.1-0.2% of general surgical cases in the United States and 0.01% in the United Kingdom (Avidan & Mashour, 2013; Pollard, Coyle, Gilbert, & Beck, 2007). A “closed case” analysis of 5,480 malpractice claims against anesthesiologists from 1970 to 1999 found only 22 cases of alleged intraoperative awareness and another 78 cases of postoperative recall (Domino, Posner, & Cheney, 1999). Occasionally, the incident is so serious as to result in post-traumatic stress disorder (Bruchas, Kent, Wilson, & Domino, 2011; Glannon, 2014). But more commonly, the patient is left with only vague – and nondistressing -- memories of intraoperative events. In general surgery, intraoperative awareness, and postoperative recall are usually attributable to light anesthesia, machine malfunction, errors of anesthetic technique, and increased anesthetic requirements – for example, on the part of patients who are obese or abuse alcohol or drugs. The incidence of surgical recall rises somewhat in special circumstances, such as trauma, cardiac, or obstetrical surgery, where cardiovascular circumstances dictate lighter planes of anesthesia; and with obese patients, because some anesthetics dissolve in body fat. Even then, the incidence of surgical recall is remarkably low – in part because even in the absence of complete general anesthesia, the benzodiazepines often used for sedation are themselves amnestic agents (Fisher, Hirshman, Henthorn, Arndt, & Passannante, 2006; Merritt, Hirshman, Hsu, & Berrigan, 2005; Polster, Gray, O'Sullivan, McCarthy, & Park, 1993). In fact, modern anesthetic practice may underestimate the incidence of intraoperative awareness by interfering with postoperative memory. That is to say, an inadequately anesthetized patient may be aware of surgical events at the time they occur, but be unable to remember them later because of sedative-induced anterograde amnesia.
However low, the possibility of surgical awareness means that, in addition to monitoring various aspects of vital function during the operation, the anesthetist must also monitor the patient’s state of consciousness, or anesthetic depth. This task would be made easier if psychology and cognitive science had achieved consensus on the neural or behavioral correlates of consciousness. In the absence of such criteria, anesthesiologists have often been forced to improvise. One set of standards simply relies on measures of anesthetic potency. Research has determined the minimum alveolar concentration (MAC) of inhalant which prevents movement in response to surgical stimulation in 50% of patients. MAC-awake is the concentration required to eliminate response to verbal commands in 50% of patients. As a rule, MAC-awake is roughly one-half of MAC, suggesting that some of the movement in response to surgical stimulation is mediated by subcortical structures, and does not necessarily reflect conscious awareness. Similar standards for adequate anesthesia, based on blood plasma levels, have been worked out for intravenous drugs such as propofol.
It should be noted that the operational definition of MAC-Aware means that 50% of patients will be aware of surgical events despite the presence of anesthetic (“minimum” really means median) -- although a dose amounting to about 1.3 MAC does seem to suffice. Nevertheless, it is important to supplement knowledge of dose-response levels with more direct evaluations of the patient’s conscious awareness. Unfortunately, many obvious clinical signs of consciousness, such as talking or voluntary movement in response to surgical stimulation, are obviated by the use of muscle relaxants. Accordingly, some anesthesiologists rely on presumed autonomic signs of consciousness, such as the PRST score based on the patient’s blood pressure, heart rate, sweating, and secretion of tears. A variant on MAC and MAC--Awake, MAC-BAR, is the minimum concentration of an inhalant anesthetic required to prevent autonomic responses to painful stimulation; it is roughly two times MAC.
In modern practice, most methods for monitoring the depth of anesthesia focus on the central nervous system (Palanca, Mashour, & Avidan, 2009). Analyses of the EEG power spectrum (derived by a fast Fourier transform of the raw EEG signal) show that anesthetized patients typically have a median EEG frequency of 2-3 Hz or less, with “spectral edge frequencies”, at the very high end of the distribution, within or below the range of alpha activity (8-12 Hz). Another derivative of the raw EEG is provided by bispectral analysis, which employs a complicated set of transformations to yield a bispectral index (BIS) that ranges from close to 100 in subjects who are normally awake, to values well under 60 in patients who are adequately anesthetized. Another proprietary device makes use of “processed EEG” to yield “stages” of anesthesia analogous to sleep stages ranging from A (fully awake) to F (absence of brain activity).
Another common monitoring technique employs event-related potentials (ERPs, also known as evoked potentials, or EPs) elicited in the EEG by weak somatosensory, auditory, or even visual stimulation. Adequate anesthesia reduces the amplitude of the various peaks and troughs in the ERP, and increases the latency of various components representing brainstem response and early and late cortical responses. Of course, the late “cognitive” components of the ERP would be expected to disappear entirely during adequate anesthesia. An AEP index of consciousness reflects the degree to which three “midlatency” components of the auditory ERP are delayed with respect to their normal occurrence between 20 and 45 milliseconds after the stimulus.
In 2008, a group of anesthesia researchers at McGill University introduced “McSleepy”, an automated system for delivering anesthetics (Hemmerling, 2009). Given information about a patient’s weight and age, McSleepy calculates the amount of anesthetic to be delivered, and then monitors the patient’s level of consciousness. Depending on measurements of the bispectral index, muscle responsiveness, heart rate, and blood pressure, the device automatically dispenses or withholds additional anesthetic. In 2010, McSleepy was linked to DaVinci, a surgical robot, to perform a prostatectomy. (The McGill group has also developed an intubation robot called Kepler.)
Of course, the simple fact that anesthesia impairs post-operative recall does not mean that anesthetized patients lack on-line awareness of what is going on around them. In principle, at least, they could experience an anterograde amnesia for surgical events similar to that which occurs in conscious sedation. In the absence of a reliable and valid physiological index of conscious awareness – something that is not likely to be available any time soon – what is needed is some kind of direct behavioral measure of awareness, such as the patient’s self-report. In balanced anesthesia, of course, such reports are precluded by the use of muscle relaxants. But a variant on balanced anesthesia, Tunstall’s isolated forearm technique (IFT; Russell & Wang, 1995; Tunstall, 1977)
, actually permits surgical patients to directly report their level of awareness in response to commands and queries. Because muscle relaxants tend to bind relatively quickly to receptors in the skeletal musculature, if the flow of blood is temporarily restricted to one forearm by means of a tourniquet, the muscles in that part of the body will not be paralyzed. And therefore, patients can respond to the anesthetist’s instruction to squeeze their hand or raise their fingers – that is, if they are aware of the command in the first place.
Interestingly, response to the IFT is not highly correlated with ostensible clinical signs of consciousness. Nor does it predict postoperative recollection of intraoperative events. In one study, more than 40% of patients receiving general anesthesia for caesarian section responded positively to commands; yet only about 2% had even fragmentary recollections of the procedure. On the assumption that a patient who responds discriminatively to verbal commands is clearly conscious to some extent, the IFT indicates that intraoperative awareness is somewhat greater than has previously been believed. On the other hand, discriminative behavior also occurs in the absence of perceptual awareness, as in cases of “subliminal” perception, masked priming, and blindsight (see Chapters 38, 39, 40, and 50). Estimates of intraoperative awareness may also be suppressed by anterograde amnesia, which effectively prevents patients from remembering, and thus reporting, any awareness that they experienced during surgery.
By definition, adequate general anesthesia abolishes conscious recollection of surgical events. However, it is possible that unconscious intraoperative perception may lead to unconscious postoperative memory, affecting the patient’s subsequent experience, thought, and action outside of phenomenal awareness (for reviews and references, see Kihlstrom, 1993; Kihlstrom & Schacter, 1990). Clinical lore within anesthesiology includes the “fat lady syndrome”, in which an overweight patient’s postoperative dislike of her surgeon is traced to unkind remarks he made about her body while she was anesthetized; but well-documented cases are hard to find. In the late 1950s and early 1960s, David Cheek, a Los Angeles physician and hypnotherapist, described a number of patients who, when hypnotized, remembered meaningful sounds that occurred in the operating room – particularly negative remarks. Cheek claimed to have corroborated these reports, and attributed unexpectedly poor postoperative outcomes to unconscious memories of untoward surgical events (Cheek, 1959). Unfortunately, the interview method he employed, hypnotic “ideomotor signaling”, is highly susceptible to experimenter bias, and information that would corroborate such memories is not always available. Accordingly, the possibility cannot be excluded that patients’ postoperative “memories”, recovered through this technique, are confabulations.
Cheek’s suggestion was subsequently supported by Bernard Levinson, who as an experiment staged a bogus crisis during surgery (Levinson, 1990; Levinson, 1965). After the anesthesia had been established (with ether), the anesthesiologist, following a script, asked the surgeon to stop because the patient’s lips were turning blue. After announcing that he was going to give oxygen, and making appropriate sounds around the respirator, he informed the surgeon that he could carry on as before. One month later, Levinson hypnotized each of the patients – all of whom had been selected for high hypnotizability and ability to experience hypnotic age regression – and took them back to the time of their operation. Levinson reported that four of the ten patients had verbatim memory for the incident, while another four became agitated and anxious; the remaining two patients seemed reluctant to relive the experience. Levinson’s provocative experiment suggested that surgical events could be perceived by at least some anesthetized patients, and preserved in memory – even if the memories were ordinarily unconscious, and accessible only under hypnosis.
Unconscious perception during general anesthesia remained unexplored territory until the matter was revived by Henry Bennett (Bennett, 1990; Bennett, Davis, & Giannini, 1985). Also inspired by the apparent success of Cheek’s “ideomotor signaling” technique for revealing unconscious memories, Bennett gave anesthetized surgical patients a tape-recorded suggestion that, when interviewed postoperatively, they would perform a specific behavioral response, such as lifting their index finger or pulling on their ears. Although no patient reported any conscious recollection of the suggestion, approximately 80% of the patients responded appropriately to the experimenter’s cue. Bennett, following Cheek, suggested that unconscious memories were more likely to be revealed with nonverbal than with verbal responses.
At about the same time, Evans and Richardson reported that intraoperative suggestions, delivered during general anesthesia, led to improved patient outcome on a number of variables, including a significantly shorter postoperative hospital stay (Evans & Richardson, 1988). Again, the patients had no conscious recollection of receiving these suggestions. Although this study was not concerned with memory per se, the apparent effects of suggestions on post-surgical recovery certainly implied that the suggestions themselves had been processed, if unconsciously, at the time they occurred.
As it happens, subsequent studies have failed to confirm these findings (Andrade & Munglani, 1994; Chortkoff et al., 1995; Dwyer, Bennett, Eger, & Heilbron, 1992; Dwyer, Bennett, Eger, & Peterson, 1992; van der Laan et al., 1996). For example, a double-blind study inspired by Levinson’s report, in which nonpatient volunteers received subanesthetic concentrations of either desflurane or propofol, failed to obtain any evidence of memory for a staged crisis (Chortkoff et al., 1995). Nevertheless, these pioneering studies, combined with an increasing interest in consciousness and unconscious processing within the wider field of psychology and cognitive science, stimulated a revival of interest in questions of awareness, perception, and memory during and after surgical anesthesia.
Of particular importance to this revival was the articulation, in the 1980s, of the distinction between two different expressions of episodic memory -- explicit and implicit (Schacter, 1987; see Chapter 42). Explicit memory is conscious recollection, as exemplified by the individual’s ability to recall or recognize some past event. Implicit memory, by contrast, refers to any change in experience, thought, or action that is attributable to a past event – for example, savings in relearning or priming effects. From the 1960s through the 1980s, a growing body of evidence indicated that explicit and implicit memory were dissociable. For example, amnesic patients show priming effects of items presented for study, even though they cannot remember the items themselves; and they can learn new cognitive and motor skills, even though they do not remember the learning experience (see Chapter 41). Similarly, normal subjects show savings in relearning material that they can neither recall nor recognize as having been learned before. And, again in normals, priming is relatively unaffected by many experimental manipulations that have profound effects on recall and recognition. In a very real sense, implicit memory is unconscious memory, occurring in the absence of, or at least independent of, conscious recollection.
Accordingly, the experimental paradigms developed for studying implicit memory in amnesic patients and normal subjects were soon adapted to the question of unconscious processing of intraoperative events in anesthesia (for reviews of early work, see Andrade, 1995; Andrade, Stapleton, Harper, Englert, & Edwards, 2001; Deeprose & Andrade, 2006; Kihlstrom, 1993; Kihlstrom, Schacter, Cork, & Hurt, 1990; Merikle & Daneman, 1996). In one early study, patients receiving isoflurane anesthesia for elective surgery were played, through earphones, many repetitions of an auditory list of paired associates -- e.g., the cue ocean paired with the response water (Kihlstrom et al., 1990). On a cued-recall test of memory administered in the recovery room, the patients showed no evidence of explicit memory for the wordlist. However, these same patients showed a significant priming effect on a free-association test of implicit memory; the magnitude of the priming effect was on the order of that observed in patients with the amnesic syndrome. This study, the best controlled up to that time, clearly indicated that general anesthesia impaired explicit but could spare implicit memory.
Subsequent studies, employing similar paradigms, produced a mix of positive and negative results (Merikle & Rondi, 1993). For example, we precisely replicated the procedure described above with another group of patients receiving sufentanyl, and found that explicit and implicit memory were equally impaired (Cork, Kihlstrom, & Schacter, 1992). The two studies, taken together, suggested the interesting hypothesis that different anesthetic agents might have different effects on implicit memory (Solt & Forman, 2007; Veselis, 2015). Of course, an equally parsimonious conclusion might have been that the initial isoflurane effects were spurious. Over the next few years, however, the literature began to settle, so that a comprehensive review of 44 studies concluded that adequately anesthetized patients can, indeed, show postoperative implicit memory for unconsciously processed intraoperative events (Merikle & Daneman, 1996; see also A. E. Bonebakker et al., 1996; Bonebakker, Jelicic, Passchier, & Bonke, 1996; R. L. Cork, Couture, & Kihlstrom, 1997).
Explicit and implicit memory are also dissociated in conscious sedation, an anesthetic technique that is increasingly popular in outpatient surgery. In conscious sedation, the patient receives medication for analgesia and sedation, and perhaps regional anesthesia, but remains conscious throughout the procedure. It is well known that high doses of sedative drugs have amnesic effects on their own, such that patients often have poor memory for events that occurred during the procedure. As it happens, sedative amnesia produced by drugs such as diazepam or propofol also dissociates explicit and implicit memory (Cork, Heaton, & Kihlstrom, 1996; Polster, 1993).
Although the more recent literature continues to contain a mix of positive and negative results, there are simply too many positive findings to be ignored, involving a variety of anesthetic agents (Ghoneim, 2001). At the same time, the literature contains enough negative studies, and other anomalous results, to warrant further investigation. For example, Merikle and Daneman concluded that the evidence for unconscious processing during general anesthesia was not limited to “indirect” measures of implicit memory, and extended to “direct” measures of explicit memory as well (Merikle & Daneman, 1996). This is a surprising conclusion, given that adequately anesthetized patients lack conscious recollection by definition. However, these authors included in their survey only the few tests of explicit memory that encouraged guessing, and excluded the many studies that did not – or actively discouraged it. While guessing yields a more exhaustive measure of conscious recollection, it is also true that guessing can be biased by a feeling of familiarity that, itself, has its origins in unconscious priming. Therefore, it is likely that some of the “explicit” memory identified by Merikle and Daneman is, in fact, contaminated by implicit memory.
In support of this idea, a study employing the “process dissociation” procedure (PDP; see Chapter 42) confirmed that postoperative memory was confined to automatic priming effects, and did not involve conscious recollection (Lubke, Kerssens, & Sebel, 1999). Similar results were obtained by others (e.g., Iselin-Chaves et al., 2005; Quan et al., 2013). Other PDP studies seemed to show the influence of conscious recollection, rather than automatic priming, but these outcomes may have been an artifact of excessively conservative response bias on the part of the patients (Kerssens, Lubke, Klein, vanderWoerd, & Bonke, 2002; Lubke, Kerssens, & Sebel, 2000; Stapleton & Andrade, 2000). As with general anesthesia, studies employing the process-dissociation procedure confirm that sedative amnesia impairs conscious recollection, but spares automatic priming effects.
A persisting issue is whether postoperative implicit memory might be an artifact of fluctuations in anesthetic depth which occur naturally during surgery. Lequeux and colleagues, reviewing a number of studies of hypesthesia, found that explicit and implicit memory were frequently dissociated at OAA/S levels of 2 or higher, but not at level 1 (Lequeux, Hecquet, & Bredas, 2014). In the study by Lubke et al., for example, implicit memory varied as a function of the patient’s level of anesthesia. Patients showed more priming for words presented at BIS levels above 60, and no priming for items presented at BIS levels below 40. A subsequent study from the same group, which confined stimulus presentation to BIS levels ranging from 40 to 60, yielded no evidence of implicit memory (Kerssens, Ouchi, & Sebel, 2005); nor did a study which targeted a BIS level of 50 (Lequeux et al., 2014).
These more recent findings should not be misinterpreted. All the patients in these studies were adequately anesthetized, according to the appropriate clinical criteria. There are, then, levels of general anesthesia which abolish explicit memory for intraoperative events (such as presentation of a word list) but spare implicit memory. The use of a monitoring system such as BIS permits physicians to induce deeper levels of anesthesia, and maintain those levels more constantly, and it should surprise no one that even implicit memory is abolished at deeper planes of anesthesia. Moreover, the subjects in most of the later studies were volunteers, not actual surgical patients. One study of surgical patients receiving propofol found spared implicit memory for material presented during surgical stimulation, though not before, even though BIS levels were very low, approximately 40 (Deeprose, Andrade, Varma, & Edwards, 2004). It is well known that emotional arousal enhances memory (McGaugh, 2004), and it may well be that surgical stimulation activates the amygdala, or releases adrenalin, which in turn enhances memory processing by other regions of the brain (Andrade et al., 2001). On the other hand, sevoflurane, an inhaled anesthetic, appears to suppress activity in the amygdala (Alkire et al., 2008). All of which underscores how complicated studying this issue can become.
Most work on implicit memory employs tests of repetition priming, such as stem- or fragment-completion, in which the target item recapitulates, in whole or in part, the prime itself – for example, when the word ashtray primes completion of the stem ash-. Repetition priming can be mediated by a perception-based representation of the prime, which holds information about the physical properties of the item, but not about its meaning. But there are other forms of priming, such as semantic priming, where the relationship between prime and target is based on “deeper” processing of the prime – for example, when the word cigarette primes completion of the stem ash- with -tray as opposed to -can. Semantic priming requires more than physical similarity between prime and target, and must be mediated by a meaning-based representation of the prime. The distinction between repetition and semantic priming is sometimes subtle. For example, in the isoflurane study by Kihlstrom et al. (1990), the paired associates presented as primes were linked by meaning, but because both elements of the pair were presented intraoperatively, the priming effect observed postoperatively could have been mediated by a perception-based representation, rather than a meaning-based one. Implicit memory following surgical anesthesia is fairly well established when it comes to repetition priming, but conclusions about semantic priming are much less secure. Fewer studies have employed semantic priming paradigms, and even fewer of these studies have yielded unambiguously positive results (Ghoneim, 2001). If semantic priming occurs at all following general anesthesia, it is most likely to occur for items presented at relatively light planes. As anesthesia deepens, implicit memory – if it occurs at all – is likely to be limited to repetition priming.
The distinction between perception-based and meaning-based priming may have implications for the use of intraoperative suggestions to improve post-surgical outcome. If implicit memory following anesthesia is limited to repetition priming, implying that the anesthetized patient’s state of consciousness does not permit semantic analysis of the intraoperative message, it is hard to see how such suggestions could have any effects at all. In fact, a comparative study found that intraoperative suggestions had no more effect on postoperative pain than did pre-operative suggestions of the same sort – or, for that matter, the pre- and intraoperative reading of short stories (van der Laan et al., 1996). Intraoperative suggestions will do no harm, and patients may derive some “placebo” benefit from the simple knowledge that they are receiving them during surgery. To the extent that intra-operative suggestions do some good, the limitations on information processing during anesthesia may mean that any positive effects are more likely to be mediated by their prosody, and other physical features, than by their meaning: a soothing voice may be more important that what the voice says. If anesthesiologists want patients to respond to the specific semantic content of therapeutic messages, such messages are probably better delivered while patients are awake, during the pre-operative visit that is already established as the standard of care.
Priming effects are evidence of implicit memory, but they can also serve as evidence of implicit perception – a term coined to refer to the effect of an event on experience, thought, and action, that is attributable to a stimulus event, in the absence of (or independent of) conscious perception of that event (Kihlstrom, Barnhardt, & Tataryn, 1992). The term implicit memory is best applied to events that were consciously perceived at the time, but subsequently forgotten. The concept of implicit perception is more appropriately applied to events that were not consciously perceived, but still create priming and similar effects. Implicit perception is exemplified by “subliminal” perception of degraded stimuli, as well as neurological syndromes such as “blindsight” and neglect (see Chapters 39, 40). In general anesthesia, the patients are presumably unaware of the priming events at the time they occurred. For that reason, evidence of implicit memory following general anesthesia is also evidence of implicit perception. It should be understood, though, that under most circumstances implicit perception is analytically limited, permitting only very simple meaning analyses (Greenwald, 1992). This is true for subliminal perception, and it is almost certainly true for general anesthesia and conscious sedation as well. Explicit and implicit perception can be dissociated in general anesthesia, especially at lighter planes of anesthesia, and especially as measured by repetition priming, which depends only on perception-based representations of stimuli. But deeper levels of anesthesia appear to preclude unconscious semantic processing, and even deeper planes may preclude unconscious perceptual processing as well.
Some anesthesiologists, surgeons, and patients may be concerned that any degree of intraoperative perception, resulting in postoperative repetition priming effects, is undesirable. On the other hand, these priming effects are by definition unconscious, and unlikely to have any influence on the patient’s postoperative everyday life. Implicit perception can occur during adequate general anesthesia, resulting in implicit memory thereafter. That is theoretically interesting, but of unclear practical significance. It is not clear that the abolition of implicit perception and memory is a benefit worth the risks of maintaining very deep levels of anesthesia throughout surgery. Caregivers who wish to avoid the “fat lady syndrome” should simply avoid making unkind remarks about their patients in the first place.
John F. Kihlstrom
Kihlstrom is Professor in the Department of Psychology and Richard and Rhoda Goldman Distinguished Professor in the Division of Undergraduate and Interdisciplinary Studies, University of California, Berkeley. He received his PhD in Personality and Experimental Psychopathology from the University of Pennsylvania in 1975, and has also taught at Harvard, Wisconsin, Arizona, and Yale.
Randall C. Cork
Cork was Professor in the Department of Anesthesiology and Director of the Pain Management Clinic at the Louisiana State University Health Sciences Center. He received his PhD in Electrical Engineering from Arizona State University and his MD from the University of Arizona.
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