Is priming during anesthesia unconscious?

Consciousness and Cognition Consciousness and Cognition 15 (2006) 1–23 www.elsevier.com/locate/concog

Review

Is priming during anesthesia unconscious? Catherine Deeprose, Jackie Andrade * Department of Psychology, University of Sheffield, Sheffield, UK Received 2 September 2004 Available online 25 July 2005

Abstract General anesthesia provides an alternative to typical laboratory paradigms for investigating implicit learning. We assess the evidence that a simple type of learning—priming—can occur without consciousness. Although priming has been shown to be a small but persistent phenomenon in surgical patients (Merikle & Daneman, 1996) there is reason to question whether it occurs implicitly due to problems in detecting awareness using typical clinical signs. This paper reviews the published studies on priming during anesthesia that have included a measure of awareness or of anesthetic depth. We conclude that perceptual priming, but not conceptual priming, takes place in the absence of conscious awareness.  2005 Elsevier Inc. All rights reserved. Keywords: Priming; Anesthesia; Depth; EEG; Auditory evoked potentials; Isolated forearm technique

1. Introduction Anesthesia, is by definition, the loss of sensation and conscious awareness. However, the first attempts by Horace Wells in the mid 1800s to use an inhalational anesthetic during surgery were accompanied by reports of awareness and pain. Modern day anesthetic techniques have advanced considerably, and patients typically receive a combination of agents to provide unconsciousness, analgesia, and muscle relaxation. Nonetheless, the problem of awareness during surgery has not

*

Corresponding author. Fax: +44 114 276 6516. E-mail address: [email protected] (J. Andrade).

1053-8100/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.concog.2005.05.003

2

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

been overcome and remains a rare, but potentially devastating complication. The most recent study of awareness measured by post-operative recall was conducted in the United States, and indicated an occurrence of 0.13%, comparable to the incidence reported in other countries (Sebel et al., 2004). Twenty million anesthetics are given per year in the United States, giving an estimated 26,000 cases of awareness. The incidence is higher in some types of procedure, such as cardiac surgery (Phillips, McLean, Devitt, & Harrington, 1993), trauma surgery (Bogetz & Katz, 1984), and cesarean section (Lyons & MacDonald, 1991). Common reports of awareness during surgery include perceptions of terror, paralysis, pain and helplessness, and psychological sequelae including re-experiencing the traumatic event, avoidance and hyper-arousal, and consistent with chronic post-traumatic stress disorder (Osterman et al., 2001). Despite the relatively low incidence of reported awareness during anesthesia, there has remained suspicion that patients may process information whilst apparently unconscious. In an early study investigating unconscious perception, Levinson (1965) anesthetized 10 dental patients and mid-way through the operation, staged a mock crisis in which he exclaimed, ‘‘Stop the operation. I donÕt like the patientÕs color. His/her lips are much too blue. IÕm going to give a little more oxygen.’’ Following this, the surgery continued as routine and all patients are reported to have made an uneventful recovery. However, under hypnosis one month later, four of the patients repeated verbatim LevinsonÕs statement, and another four had some recall for intra-operative events. Although this study is in many ways methodologically flawed (Levinson conducted both the mock crisis and the hypnosis, for example), it provided a startling demonstration that patients may continue to process information during anesthesia. Recent research has confirmed that auditory information presented to patients during general anesthesia may prime, or temporarily activate, existing representations and thus enhance performance on post-operative implicit memory tasks in the absence of explicit recall (for reviews, see Andrade, 1995; Ghoneim & Block, 1992, 1997). Although there are as many negative as positive findings in the literature, a meta-analysis by Merikle and Daneman (1996) found highly significant memory when patients were tested within 12 h of surgery (12 studies with a total of 708 patients; effect size (r) = .23, p < .001). Thus, priming during anesthesia is a small but significant phenomenon and potentially provides useful insight into unconscious processing in the human brain. However, the extent of the impairment of consciousness during anesthesia—anesthetic depth— has until relatively recently been difficult to ascertain. Anesthetic depth is the balance between the depressing effects of anesthetics and the increased sympathetic activation resulting from surgery, and thus fluctuates during an operation. In many early studies, such as those in Merikle and DanemanÕs meta-analysis, anesthetic depth was not measured beyond observation of typical clinical signs, such as heart rate, respiratory rate, sweating, movement, and tears. This is problematic as the physiological response to surgery may not be related to the state of consciousness (Antognini & Schwartz, 1993; Rampil, Mason, & Singh, 1993). In addition, when neuromuscular blockers are used, these clinical signs are invalid indicators of anesthetic depth due to paralysis. Moerman, Bonke, and Oostings (1993) reported that experienced anesthesiologists were unable to distinguish between cases of anesthetic awareness (with post-operative recall) and control cases (without post-operative recall) based on anesthetic charts reporting standard clinical signs. So awareness during anesthesia is typically very difficult to detect at the time of stimulus presentation, and neither can it be determined retrospectively using post-operative memory tests. Explicit memory on recovery is suggestive of awareness during anesthesia, but can be an

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

3

unreliable indicator because memory tests are not process-pure. Implicit memory may contribute to performance on a putative test of explicit memory, and vice versa. The relative purity of a test of explicit memory is inversely related to its sensitivity. A free recall task (‘‘Can you tell me anything you overheard during your operation?’’) will be fairly resistant to implicit memory contamination but is an insensitive measure of memory. Conversely, a forced-choice recognition task will detect weaker, less easily retrieved explicit memories but is susceptible to implicit memory influences, particularly when participants feel they are guessing. A correct answer to the question ‘‘Did you hear X or Y during surgery?’’ may reflect explicit recognition of X (or Y), and thus explicit processing of the item during surgery, or it may reflect implicit priming of that item in memory. Because memory tests do not provide pure measures of the explicit and implicit memory processes they are intended to measure, it is more accurate to use the term Ôdirect testÕ for a test that explicitly asks participants to retrieve a memory and Ôindirect testÕ for one that assesses memory surreptitiously, for example by asking participants to respond to cues with the first word that comes to mind. However, we have used Ôexplicit memory testÕ and Ôimplicit memory test,Õ respectively, for these tasks, for simplicity of exposition and in keeping with the terminology in the literature we are reviewing, but we have taken care to specify the nature of the tasks used so that readers may assess their relative process purity. In contrast to explicit memory, implicit memory for intra-operative stimuli on recovery tells us nothing about whether those stimuli were processed consciously or unconsciously during surgery. Incidental or even fully unconscious processing may lead to implicit memory formation, but so may conscious processing, as is the case in the many demonstrations of preserved implicit memory in amnesia. Thus, implicit memory for intra-operative stimuli may result from periods of awareness that, owing to the amnestic effects of anesthetics or general forgetting, are not available to conscious recollection on recovery. The difficulty of assessing anesthetic depth and hence the adequacy of anesthesia raises an important question: Is priming during anesthesia occurring in brief moments of undetected awareness, or does it reflect truly unconscious processing? Thus, this field, like the mainstream implicit learning literature, has suffered from problems of detecting awareness. Typical laboratory studies of implicit learning attempt to show learning in the absence of awareness of the stimuli (subliminal presentation, e.g., Marcel, 1983a, 1983b) or of co-variations between stimuli (e.g., artificial grammar learning, Reber, 1967; hidden co-variation detection, Lewicki, Hill, & Sasaki, 1989; and control of dynamic systems, Berry & Broadbent, 1984), in conscious participants. There is continuing debate, mainly focusing on methodological controversies, as to whether participants really are unaware of the information that contributes to enhanced performance at test. As a result, it has been difficult to determine whether unconscious perception actually exists or whether findings are attributable to weak conscious effects (see Shanks & St John, 1994). Problematically, most implicit learning paradigms have to resort to testing awareness retrospectively, typically through verbal report. Because participants are conscious, Ôon-lineÕ awareness testing would increase the risk of them becoming aware of the critical information. Anesthetic paradigms have the potential to avoid this problem by ensuring that patients are unconscious, unaware of all sensory information. There are some reasons to believe unconscious priming may nonetheless be possible. Studies by Mu¨nte and colleagues suggest continued auditory processing during deep anesthesia, shown by the presence of mismatch negativity in the EEG response to ÔoddballÕ auditory stimuli (Gross, Nager, Quandt, Mu¨nte, & Mu¨nte, 2004; Quandt et al.,

4

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

2004). If at least a small amount of auditory processing persists when people are anesthetized, then memory formation for this information may be facilitated by the high levels of catecholamines released in response to surgery and known to act via the amygdala to facilitate memory formation for emotional stimuli (Deeprose, Andrade, Varma, & Edwards, 2004; Stapleton & Andrade, 2000). Advances in anesthetic depth monitoring and cognitive psychology have been combined to provide a more robust methodology than used in early priming during anesthesia research, and may now potentially reveal whether priming or even learning of new information persists in the absence of consciousness. There are now several approaches available to monitor depth of anesthesia, ranging from assessment of response to command to the analysis of EEG activity and auditory evoked potentials. Assessment of response to command reflects a behavioral measure of anesthetic depth, whereas monitors measuring EEG activity, including auditory evoked potentials, are electronic indices of anesthetic depth. Attempts to validate the electronic indices of anesthetic depth have focused on correlations with behavioral indices (e.g., response to command, ObserverÕs Assessment of Alertness and Sedation Scale) and clinical variables. Electronic indices are thus indicators of the probabilistic state of consciousness, rather than indicators of the actual state of consciousness. Recent comparisons of several electronic indices suggest they are fairly comparable in ability to predict consciousness (e.g., Bruhn et al., 2003; Muncaster, Sleigh, & Williams, 2003). However, little research has been directed towards comparing the ability of each monitor to detect or predict subtle cognitive processing, such as priming and memory formation. Theoretical and methodological developments in experimental psychology indicate the need to select appropriate memory tests for priming during anesthesia research. One issue is whether perceptual or conceptual priming is tested. Perceptual priming refers to enhanced processing fluency, e.g., increased accuracy in identifying a word masked in background noise or the generation of a word from a fragment. Conceptual priming refers to activation of related knowledge, for example, presenting the word ‘‘banana’’ during a study phase may increase the tendency to name ‘‘banana’’ when later asked to name types of fruit. Whereas there is some evidence that above chance performance on perceptual implicit memory tests may reflect unconscious priming (e.g., Hutchinson, Neely, & Neil, 2004), there is Ôvirtually no evidence that priming on conceptual tasks reflects unintentional and unconscious memoryÕ (Butler & Berry, 2001, p. 195). Thus, there is little to be gained in using conceptual implicit memory tests (as many early anesthesia studies did) in attempting to detect unconscious priming. In addition to using monitors of anesthetic depth during stimulus presentation, the problem of contamination between explicit and implicit tests may be minimized with the selection of appropriate memory tests. Using comparable implicit and explicit memory tests in conjunction improves the likelihood of accurately detecting the implicit or explicit nature of memory (Reingold & Merikle, 1988). JacobyÕs (1991) process dissociation procedure also offers a promising technique for separating the contributions of conscious and unconscious influences on task performance (e.g., word stem completion or word fragment completion). Rather than comparing performance between implicit and explicit tasks, the procedure aims to measure the within task contributions of conscious and unconscious recollection in responding (Jacoby, 1998). We suggest the combination of measures of awareness (depth and awareness monitors) at the time of stimulus presentation with post-operative behavioral measures (memory tasks) provides a powerful test of whether or not priming during anesthesia is unconscious.

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

5

In an attempt to evaluate whether priming during anesthesia is truly unconscious and thus establish general anesthesia as an arena for investigating implicit learning more broadly, this paper reviews studies of priming during surgical anesthesia that have attempted to detect awareness or used a monitor of anesthetic depth during word presentation, and measured implicit memory for the words on recovery. We take implicit memory for intra-operative stimuli to be evidence for implicit priming when measures of awareness or depth reveal no signs of awareness during word presentation and there is no evidence of explicit memory for the stimuli. Anesthetic techniques vary widely and for simplicity we have kept details of the techniques to a minimum in the text, summarizing them instead in Table 1. We do however note when opioid and benzodiazepine regimes have been used because although such regimes provide analgesia and amnesia for surgery, they do not reliably prevent patients becoming conscious during surgery (Russell, 1993).

2. The isolated forearm technique The isolated forearm technique was originally described by Tunstall (1977). It involves the isolation of one arm from neuromuscular relaxants, using a tourniquet, and then assessing the patientÕs ability to move this arm to command. Recently, this technique has been used and modified by Russell and Wang (1997, 2001) for use in conjunction with a variety of anesthetic techniques and surgical procedures. The assumption in using this technique is that purposeful movements (e.g., movement of the hand on response to a command to Ôsqueeze my fingersÕ) reflect consciousness. It has been described as the Ôgold standardÕ by which to detect awareness and ensure adequacy of anesthetic depth (Jones & Aggarwal, 2001). Evidence for memory priming in the absence of solicited isolated forearm responses would support claims that priming during anesthesia is implicit. Russell and Wang (1997) used the isolated forearm technique with patients played category exemplars (e.g., sour gooseberry, sharp lemon) during surgery. A control group of patients received identical anesthesia but were played radio static during surgery. No patient responded to command during surgery, or had explicit recall when prompted by superficial questioning. However, one patient in the radio static group demonstrated explicit recall when prompted by specific questioning using cue questions which did not pre-suppose a particular response. Under hypnosis, with the same interview, another patient from the radio static group demonstrated recall for the surgical period, along with three patients from the isolated forearm technique group. These incidents occurred when the isolated forearm technique was not in use, providing a strong reminder about the frequency of occurrence of wakefulness in paralyzed patients. However, there was no evidence of implicit memory in the isolated forearm technique group using a using category generation task in which patients named the first five fruits and vegetables they could think of, or a word association test in which patients were presented a word (e.g., sharp) and responded with the first word they could think of, with or without hypnosis. In a second study, Russell and Wang (2001) randomly assigned patients to hear either fruit or vegetable category exemplars, and the isolated forearm technique was used with all patients. Five patients who were played vegetable exemplars and two patients who were played fruit exemplars responded to command at some point during surgery. In these cases, the tape was stopped, the

6

Table 1 Summary of priming during anaesthesia studies Study

Benzodiazepine Premed

Paralyzed

Anesthetic maintenance

N

Times to test

Memory test and outcome

Isolated forearm technique

Russell and Wang (1997)

20 mg temazepam

Yes

0.5% halothane with 66% nitrous oxide in oxygen

Expt. group = 31

1–2 h post-op then again Day 3 post-op

Structured interview

( )

Category generation

( )

Word association Interview under hypnosis Structured interview

( ) ( ) ( )

Category generation Word association Word stem completion

( ) ( ) ( )

Free recall

( )

Forced choice recognition

( )

Structured interview

( )

Forced choice recognition Word stem completion

( ) ( )

Category generation

(+)

Recognition task Structured interview

( ) (+)

Recognition

( )

Word association ·2

(+)

Control group = 34

Russell and Wang (2001)

Lequeux et al. (2003)

20 mg temazepam

None

Yes

No

1

Propofol 9.1 mg ml and alfentanil 45.5 lg ml 1

Propofol up to 1 lg ml to lose of response to command

1

40

Expt. group = 20

Within 2 h post-op

Between 2 and 4 h post-op

Control group = 20 Reference group = 20 Isolated forearm technique and auditory evoked potentials

Auditory evoked potentials

Line missing

Loveman et al. (2001)

10 mg diazepam

Yes

Propofol 2, 6, 4, and then 3 mg kg 1

14

Within 36 h post-op

Villemure et al. (1993)

None

No

Isoflurane 0.4% ET and nitrous oxide 60% ET

10

4 h post-op then 24 h post-op

Ghoneim et al. (2000)

None

Yes

Group 1. 70% nitrous oxide in oxygen, 2.5 lg kg 1 fentanyl bolus when required Group 2. 70% nitrous oxide in oxygen, alfentanil infusion between 1.5 lg kg 1 Group 3. Isoflurane 0.3%, 70% nitrous oxide in oxygen, fentanyl up to 1 lg kg 1 h 1 when required Group 4. As Gp 3 but 0.7% isoflurane

Group 1 = 100

24 h post-op (n = 108);

Group 2 = 40

3–4 days post-op (n = 72)

Group 3 = 16

Group 4 = 23

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Depth/awareness monitor

None

Yes

Fentanyl 1 mg kg 1 + flunitrazepam 1.2 mg kg 1 OR isoflurane 0.6–1.2% OR propofol 4–8 mg h 1

45

3–5 days post-op

Smith et al. (1998)

0.05 mg kg midazolam

No

Group 1. Fentanyl 0.9– 4.0 mcg/kg/h with midazolam 0.6 mcg/kg/min (Experimental) Group 2. Fentanyl 0.9– 4.0 mcg/kg/h with midazolam 0.6 mcg/kg/min (Control) Group 3. Sevoflurane 1.4% ET, midazolam 0.6 mcg/kg/ min (Experimental) Group 4. Sevoflurane 1.4% ET, midazolam 0.6 mcg/kg/ min (Control) Group A. Sevoflurane and air (F1o2 40%) Group B. Sevoflurane and nitrous oxide 60% in oxygen 40% Group C. Isoflurane and air (F1o2 40%) Group D. Isoflurane and nitrous oxide 60% in oxygen 40% Propofol (2 mg/kg initially then up to 8 mg/kg/h) and alfentanil (100 lg/kg initially then up to 4 lg/kg/ min)

Group 1 = 27

Within 24 h of recovery

Aceto et al. (2003)

van Hooff et al. (1995)

Bispectral index and isolated forearm technique

Kerssens et al. (2002)

None

None except for 1 patient

None

Yes

Yes

Yes

BIS guided propofol (with air–oxygen mixture) range 60–70

Structured interview

( )

Word association Word stem completion

(+) (+)

Recall

( )

Free association

( )

Structured interview

( )

Category association Yes/No recognition with AEP recording Structured interview

( ) (+)

Group 2 = 22

Group 3 = 25

Group 4 = 25

Group A = 10

Approx 24 h post-op

Group B = 10

Group C = 10 Group D = 10

12

56

Morning following operation

Within hours post-op.

Word stem completion with PDP

(+)

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Schwender et al. (1994)

(+)

(continued on next page)

7

8

Table 1 (continued) Study

Benzodiazepine Premed

Paralyzed

Anesthetic maintenance

N

Times to test

Memory test and outcome

Bispectral index

Struys et al. (1998)

None

No

Group 1. BIS blinded, mean dose propofol 12.5 mg kg h 1 Group 2. BIS guided to range 40–60, mean dose propofol 12.6 mg;kg h 1 BIS guided propofol to range of 40–60

Group 1 = 30

Not stated

Free association

( )

Expt. group = 41

Mean time to test

Structured interview

( )

Controls = 41

E group = 115 min C group = 110 min Mean time to test 11 h (range 1–28 h)

Recognition Category generation Structured interview

( ) ( ) ( )

Recognition Word stem completion with PDP Interview

( ) ( ) ( )

Word association Structured interview

(+) ( )

Word stem completion with PDP Structured interview

(+)

Kerssens et al. (2001)

Kerssens et al. (2005)

None

None

Yes

Yes

BIS guided nitrous oxide and oxygen with propofol or isoflurane to range of 50–55

Group 2 = 28

96

Smith and Maye (1998)

None

Yes

100% oxygen, 0.3% ET sevoflurane, remifentanyl 0.6–1.0 mc/kg/min

22

Within 24 h of recovery

Iselin-Chaves et al. (in press)

None

No

Nitrous oxide or air–oxygen mixture with isoflurane or propfol

48

Within 36 h of stimuli presentation

Lubke et al. (1999)

Lubke et al. (2000)

None

None

Yes

No

Isoflurane, fentanyl, air–oxygen mixture

Nitrous oxide 70%, 0.2% ET isoflurane and 0.1–0.15 mg/kg morphine

96

24

Mean time to test 42 h (range 6–143 h)

Mean time to test 6.1 h ± 2.4 h

Word stem completion with PDP Structured interview

Word stem completion with PDP

Line missing

(+)

(+) ( )

(+)

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Depth/awareness monitor

Andrade et al. (2001)

Renna et al. (2000)

None

None

Yes— Group 2 and 3

No

No

Group 1. Propofol TCI 2 lg ml 1

Group 1 = 12

Groups 2 and 3. Propofol TCI 5 2 lg ml 1

Group 1. ET sevoflurane 1.2% Group 2. ET sevoflurane 1.5% Group 3. ET sevoflurane 2% Propofol 5–7 mg/kg/ h, nitrous oxide 66%, oxygen 33%

Within 2 h of recovery

Structured interview

( )

Group 2 = 12

Recognition

( )

Group 3 = 12 Controls = 12 Group 1 = 15

Category generation Preference rating Subjective assessment

( ) ( ) ( )

Word identification Structured interview

( ) ( )

Yes/No recognition

( )

Word stem completion Structured interview

(+) ( )

Yes/no recognition Word stem completion

(+) (+)

2–3 h post-op

Group 2 = 16 Group 3 = 16

Word presentation Before surgery = 32 or

Mean time to test 69 min

During surgery = 32 Deeprose et al. (2005)

None

No

Propofol 5–7 mg/kg/ h, nitrous oxide 66%, oxygen 33%

62

Mean time to test 82 min

Spectral edge frequency

Gidron et al. (2002)

None

Yes

Isoflurane, nitrous oxide, oxygen, fentanyl

30

Within 2–4 h post-op

Reaction time word association

(+)

Narcotrend

Mu¨nte et al. (2003)

2–3 mg midazolam

Yes

Propofol, remifentanyl, air–oxygen 30%

Expt. group = 32

4–12 h following word presentation

Structured interview

( )

Free recall

( )

Reading-speed

(+)

Control group = 30

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Deeprose et al. (2004)

None

9

10

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

patient spoken to directly to provide reassurance, and given additional anesthetic. Memory testing again took place within two hours of surgery and included a structured interview, in which no evidence of explicit recall was obtained. Category generation and word association tests did not reveal any implicit memory, regardless of whether the patient had been able to respond to command during surgery or not. Similar results were found by Lequeux, Cantraine, Levarlet, and Barvais (2003) who anesthetized patients to loss of response to verbal command prior to surgery, and then played a word list. There was no evidence for memory using a word stem completion task, forced choice recognition test and free recall test. Loveman, Van Hooff, and Smith (2001) measured the auditory evoked response while using the isolated forearm technique and also found no evidence for memory using the same tests as Lequeux et al. Consistent with Russell & WangÕs studies, no memory was demonstrated even when words were presented when patients were able to respond to command. This study is discussed in further detail in the following section.

3. Auditory evoked potentials The evoked potential reflects specific brain activity in response to a sensory stimulus. In learning during anesthesia research, it is the response to auditory stimulus that is of particular interest as this reflects the processes that may lead to post-operative memory: transmission, detection, and processing of auditory information. Auditory evoked potentials are elicited by auditory stimuli, such as clicks, or tonebursts. The waves produced represent electrical activity from the cochlea to secondary cortices and association areas. The brainstem response has specific anatomical associations denoted I to VI (Jewett, 1970). The early cortical response is labeled No, Po, Na, Pa, and Nb and these waves are referred to as midlatency waves. They arise from the medial geniculate body (thalamus) and primary cortical areas (Kaga, Hink, & Shinoda, 1980). The late cortical response comprises waves P1, N1, P2, and N2. These are associated with the frontal cortex and association areas (Lovrich, Novick, & Vaughan, 1988), but specific origins have not been identified (Thornton & Sharpe, 2001). There are two ways of measuring the auditory evoked response. The first is the transient method, which uses a stimulus rate of around 6–9 Hz and in which mid-latency waves are manually quantified by measuring their peak amplitude (height, i.e., magnitude of the maximum electrical deflection) and peak latency (time from stimulus onset to peak of wave). This represents the early cortical response and that processing is occurring at the primary auditory cortex. However, when the rate of stimulation is around 40 Hz, the peaks of the middle latency portion of the wave become much larger and easier to interpret. This is known as the Ô40 Hz steady state response.Õ Importantly, anesthesia reduces the amplitude and increases the latency of the auditory evoked potential waves (Thornton & Sharpe, 2001). One study briefly discussed earlier, conducted by Loveman et al. (2001), investigated the relationship between responsiveness using the isolated forearm technique, auditory evoked potentials, and post-operative implicit and explicit memory. Patients were played a list of words prior to induction of anesthesia, then anesthetized. When the auditory evoked response was considered stable, the anesthetic was turned off. Patient responsiveness using the isolated forearm technique was checked at 1 min intervals. When the patient responded, the second word list was played.

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

11

Anesthetic infusion was then restarted. When the patient had been unresponsive using the isolated forearm technique for 3 min, a third word list was played. Thereafter, surgery commenced as normal. Patients were tested for memory within 36 h of this procedure. A structured interview and a forced choice recognition test showed no evidence of explicit memory for words presented during the anesthetic infusion. Neither was there evidence of implicit memory using the word stem completion test, precluding any investigation of the relationship between auditory evoked potentials and memory formation. Thus, no memory was demonstrated even when stimuli were presented at times when patients were able to respond to command. This result raises the question of what duration of awareness is necessary for the development of memories for stimuli presented during anesthesia. However, the small sample size (n = 14) may have precluded the detection of priming. Also note that stimuli in this study were presented before surgery, whereas typical studies present them during surgery. We have hypothesized that the surgical stress response facilitates implicit priming during anesthesia (Deeprose et al., 2004; Stapleton & Andrade, 2000). If we are correct, then this study is not a strong test of the hypothesis that priming can occur when surgical patients are unconscious. Studies in which memory was detected allow investigation of the possible relationship between the auditory evoked potential and memory formation. Villemure, Plourde, Lussier, and Normandin (1993) measured mid-latency auditory evoked potentials in patients played lists of nine birds or vegetables. Four hours post-operatively, patients completed a category generation task, which indicated significant implicit memory. No explicit memory, tested using a recognition task, was found. Twenty-four hours post-operatively, another implicit memory test was administered. This revealed significantly greater implicit memory than identified in the previous session. However, a positive correlation between amplitude of the Pa wave and implicit memory at the 24 h post-operative testing session emerged (r = .71). While this suggests that a sufficient number of cells in the primary auditory cortex must be active to facilitate the formation of implicit memory, the lack of correlation between the same variables at the four hour testing session suggests a need for caution when interpreting these results. In a larger study, Ghoneim et al. (2000) compared auditory evoked potentials with explicit and implicit recall in patients assigned to one of four anesthetic regimes. Five minutes following first surgical incision, auditory evoked potential recordings were taken, then the patient was played either a ÔThree Little PigsÕ or ÔWizard of OzÕ story with repeated target words (e.g., Ôpuff,Õ Ôwolf,Õ and ÔemeraldÕ) for a duration of 30 min. Auditory evoked response recordings were taken again. To examine the effects of time of post-operative interview on memory, post-operative interviews were held on either the day following surgery or 3–4 days following surgery (in the hospital or by telephone). In the post-operative interview, patients were asked about recall of anesthesia and surgery using a structured interview. Implicit memory was then tested for the first time by asking patients for associations to target words from both stories (one serving as a target and the other as a control). Patients then responded to filler questions and general questions before being asked a second time about associations to target words from the stories. Then they were told they had heard either a ÔThree Little PigsÕ or ÔWizard of OzÕ story and were asked to choose which one. Six patients had recall of intra-operative events, and these patients all received an opioid regime consisting of high levels of analgesia and less anesthesia than the other groups. Recognition, measured by the identification of the correct story played during anesthesia, did not differ from chance in any group. Interestingly, significant priming was only observed at the second association test,

12

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

and again only in the opioid group. The effects of anesthetics on the auditory evoked responses were significant. The opioid regime had less effect on the latencies of the Na, Pa, Nb, and P1 waves than the other anesthetic regimes. Decreases in the Nb latency were significantly associated with recall among patients receiving the opioid bolus regime. Analysis of priming in the second association test revealed a significant effect of peak latencies Na, Pa, and Nb. This pattern of results suggests that intra-operative priming only occurs when anesthesia is very light, and may not have occurred during unconsciousness. This study essentially replicates the findings of an earlier study by Schwender, Madler, Klasing, Peter, and Poppel (1994), which also found priming using the Robinson Crusoe story with an anesthetic technique that preserved ÔawakeÕ patterns of auditory evoked responding, but not with techniques that provided demonstrably deeper anesthesia. These results are also consistent with those of Smith, Zapala, Thompson, Hoye, and Kelly (1998). Patients in their study were randomly assigned to either a sevoflurane or midazolam anesthetic regime. Patients in an experimental group were played words during surgery while patients in a control group were played white noise. During this time, auditory evoked potentials were measured. Within 24 h of the surgery, patients were tested using a word stem completion task. While there was no evidence for implicit memory in the sevoflurane group, patients in the midazolam experimental group completed 5% more stems than patients in the midazolam control group. Furthermore, there was a significant inverse correlation between the number of correct responses on the word stem completion test and increases in the Pa latency during anesthesia. No such correlation emerged in the sevoflurane group. Interestingly, in the sevoflurane group the change in the Pa latency between the awake and anesthetized state was much larger than in the midazolam group. This suggests that a conventional sevoflurane anesthetic exerts a greater effect on the integrity of the auditory pathways, and therefore priming, than the benzodiazepine midazolam. Aceto, Valente, Gorgoglione, Adducci, and De Cosmo (2003) attempted to maximize priming by presenting material thought to be familiar to patients. Forty Christian patients were randomly assigned to one of four anesthetic regimes. Five minutes following first incision, intra-operative recording of mid-latency auditory evoked potentials (MLAEPs) commenced. One of four Christian biblical stories was then played. At the end of each story, four key words relating to the story were played. Post-operative interviewing took place about 24 hours following surgery. There was no evidence for explicit memory measured using a recall test similar to the structured interview used by Russell and Wang (2001). Implicit memory was tested using a story-related free association test. Only two patients had positive responses and both patients demonstrated only a small increase in Pa latency of the MLAEP, similar to that found in the awake state. Two further patients demonstrated similarly small increases in the Pa latency but did not demonstrate positive responses on the free association test, raising questions about the specificity of the MLAEP in detecting conceptual priming or alternatively, the sensitivity of the test used. van Hooff et al. (1995) adopted a novel approach in testing intra-operative cognitive processing and post-operative memory. Both pre-operatively and intra-operatively, auditory evoked potentials were generated using oddball tasks, which are a typical method of eliciting P300 waves with infrequent, physically deviant stimuli presented among frequent, standard stimuli. In laboratory studies, when subjects are not required to discriminate the deviant stimuli, the detection occurs automatically and is reflected by an early component of the P300, known as the P3a (Squires, Squires, & Hillyard, 1975). When subjects are required to pay attention to the series of stimuli

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

13

and detect deviant events, a later wave called the P3b is elicited. This P3b is believed to reflect controlled stimulus processing and detection, in other words, conscious or explicit awareness of the stimulus (Pritchard, 1981). Patients were required to learn a list of five category exemplars pre-operatively. They were also played two word lists intra-operatively. On recovery, patients were first asked about explicit recall using a structured interview. Then they were tested for implicit memory and asked to name the first three exemplars that came to mind for three target and three control categories. Finally, a recognition task for the intra-operative words was conducted while auditory evoked potentials were measured. van Hooff, Brunia, and Allen (1996) had found that a late positivity in the auditory evoked potential (possibly related to the P3) was reliably elicited by learned words in the absence of overt recognition in awake volunteers. Thus, this psychophysiological measure can provide evidence of covert recognition when used in conjunction with a standard yes/no recognition task. Group results on the category association task and auditory evoked potential yes/no recognition task did not show evidence for post-operative memory. However, individual data on the auditory evoked potential yes/no recognition task demonstrated memory in three out of nine patients. This was evidenced by greater positivity of auditory evoked potentials for intra-operatively presented words in comparison to distracter items. In two of these patients, anesthesia had been light and auditory evoked potentials suggested explicit information processing during stimulus presentation. Thus, auditory evoked potentials cannot only be used as an indicator of depth, shown in the earlier studies, but also as a measure of post-operative memory in the absence of explicit recall. To summarize, studies using auditory evoked responses as a measure of anesthetic depth have shown evidence of intra-operative priming only when words are presented during surgery (rather than before) and only when the anesthetic is light. The lightness of the anesthetic in cases where priming was observed means that we cannot assume priming was truly unconscious.

4. EEG—bispectral index Bispectral index (BIS) has been most heavily investigated with respect to priming during anesthesia. Essentially a method of signal processing, BIS provides a quantitative interpretation of EEG activity in awake and anesthetized states. Electrodes placed on the scalp and forehead measure the electrical activity of a large number of cortical cells which respond to rhythmic discharges from the thalamus which receives incoming sensory input on its way to the primary sensory areas of the cerebral cortex. BIS ranges from 100 (awake) to 0 (minimal brain activity) and has been shown to correlate well with behavioral measures of consciousness (e.g., Observer Assessment of Alertness/Sedation Scale) using both inhalational and intravenous anesthetics (Glass et al., 1997; Iselin-Chaves et al., 1998; Liu, Singh, & White, 1997). The value given is predictive of consciousness, and a BIS score between 40 and 60 is suggested to indicate a high probability of unconsciousness (Kerssens & Sebel, 2001). Three studies have investigated learning during anesthesia maintained within the clinically adequate BIS range of 40–60. Struys et al. (1998) played a Robinson Crusoe story to patients in two groups. In group one, BIS was measured but only typical clinical signs were used to guide infusion of anesthesia. In the second group, BIS was used to guide anesthesia, with a target anesthetic

14

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

depth between BIS 40 and 60. The doses of anesthetic used for induction and maintenance did not differ between the two groups. Neither did the average BIS (means at incision were 56 and 49 for groups 1 and 2, respectively). However, there was greater variation in the depth of anesthesia in group 1, and more movement during surgery in group 1 than group 2. There was a trend towards implicit memory in group 1 (three patients correctly associated Robinson Crusoe with Friday or Desert Island compared to none in group 2). Unfortunately, baseline response for the association test was not reported, and there are no details given regarding an explicit test referred to by the authors. Kerssens, Klein, van der Woerd, and Bonke (2001) similarly titrated the anesthetic in successive steps to achieve a BIS score within the pre-determined range of 40–60. Category exemplars or filler sounds (bird sounds) were presented to patients during surgery. BIS during stimuli presentation in each group was comparable (43.5 and 46.0 in the category exemplar and filler sound study groups, respectively). There was no evidence of conscious recall, recognition or priming. Kerssens, Ouchi, and Sebel (2005) also failed to find evidence of memory using a word stem completion task (with the process dissociation procedure), and word recognition task, in patients played words during a targeted BIS range of 50–55 (with 98% of words actually being played within a BIS range of 40–60). Studies such as these, in which anesthetic depth is tightly controlled, allow a test of whether priming occurs when moments of light anesthesia or awareness are unlikely. The results so far suggest that it does not. Other studies have taken an alternative approach, using greater variation in anesthetic depth to test whether priming is more likely with lighter anesthesia. Smith and Maye (1998) played Trivial Pursuit-style statements to 19 surgical patients receiving a high dose opioid, low dose anesthetic regime. Implicit memory was demonstrated using a word association task, with a mean correct response rate of 21% for experimental word associations and 12% for control word associations. This implicit memory did not correlate significantly with BIS at word presentation (mean BIS = 69). Even presenting stimuli during very light anesthesia, evidenced by BIS of 81 or greater, did not result in a greater likelihood of post-operative implicit memory. Indeed, there was greater implicit memory when stimulus presentation took place at anesthetic depths ranging from 50 to 80 although, with BIS values as high as 80, awareness cannot be ruled out. Iselin-Chaves, Willems, Jermann, Adam, and Linden (in press) played words to patients with a range of anesthetic depths measured using BIS but to which the anesthetist was blinded. There was evidence for memory using a word stem completion task with the process dissociation procedure when words were presented during light anesthesia (BIS = 61–80), and adequate anesthesia (BIS = 41–60) but not during deep anesthesia (BIS = 0–40). The process dissociation procedure revealed that this memory was implicit, and quantitatively equivalent to the implicit memory for words played to non-anesthetized volunteers. Lubke, Kerssens, Phaf, and Sebel (1999) investigated learning in trauma patients, ensuring a wide range in anesthetic depth and type of surgery. BIS scores were noted at the presentation of each word and ranged from 21 to 96, mean 54. Estimates of the probability of explicit and implicit memory in a word stem completion task were obtained using the process dissociation procedure and Buchner, Erdfelder, and Vaterrodt-Plu¨nneckeÕs (1995) multinomial processing model of memory. This analysis indicated that memory for the intra-operative stimuli was implicit. General word stem completion performance was considered in terms of percentage of target hits at categorized BIS levels. This general memory performance increased with increasing BIS values

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

15

(r2 = .12) and was higher than base rate performance at BIS values less than 60.1. At BIS values less than 40.1, general memory performance did not differ significantly from base rate performance. Thus, there was evidence for priming during adequate anesthesia, defined as BIS between 40 and 60, and evidence that priming increased as the anesthetic became lighter. The same researchers found evidence for only explicit memory in two later studies using lighter anesthetic depths. Lubke, Kerssens, Gershon, and Sebel (2000) played words to patients post-delivery following emergency cesarean section during which mean BIS = 76.3. In the next study, word presentation and assessment of response to command took place pre-operatively during which BIS was maintained a level between 60–70 (Kerssens, Lubke, Klein, van der Woerd, & Bonke, 2002). In each study, memory performance tested using the process dissociation procedure was significantly above chance. Estimates of explicit and implicit memory, obtained using Buchner et alÕs model as before, indicated that this memory was explicit, and that patients were apparently able to make correct inclusion/exclusion decisions. Rather than describing this as explicit memory though, the authors speculated that this is evidence for a third type of memory, coined as Ôunconscious-controlledÕ memory, which does not sit easily with current theories of memory. Alternatively, these findings may reflect a problem with the process dissociation procedure as a test for priming during anesthesia. Stapleton and Andrade (2000) also found evidence for explicit memory using the process dissociation procedure in a similar study. Equivalent learning was demonstrated in sedated (very lightly anesthetized) and anesthetized patients, suggesting that depth was unimportant to learning, which is contrary to the expectation that explicit learning should only take place at very light anesthetic depths. They suggested that the apparent explicit memory may be an artefact of patients changing their strategy on the two components of the process dissociation procedure, using a cued recall strategy as instructed in the inclusion condition but in the exclusion condition switching to a generate-recognize strategy, using implicit memory to generate possible responses and then omitting those that they explicitly recognize as previously presented. Such a strategy is contrary to the independence assumption of the process dissociation procedure, as implicit and explicit memory are being used in conjunction. There is some evidence that certain benzodiazepines (lorazepam and flunitrazepam) at equipotent doses may differentially affect response bias on the inclusion and exclusion components of the process dissociation procedure (Pompeia, Bueno, Galduroz, & Tufik, 2003). Although benzodiazepines were not used in either study, Pompeia et alÕs finding suggests a vulnerability of the process dissociation procedure to the sedative and amnestic effects of drugs used in anesthesia, which requires further investigation. Andrade, Englert, Harper, and Edwards (2001) presented stimuli prior to surgical incision to enable greater manipulation of anesthetic depth than would be possible during surgery. Group one underwent light (conscious) sedation in which BIS ranged from 65 to 96.5 during the presentation of category examples and nonsense words. Groups two and three received deeper anesthesia, in which BIS ranged between 29.5 and 73 during stimulus presentation. Nonsense words were presented before tracheal intubation and category examples during intubation in group two, and vice versa in group three. Memory was tested with a category generation task and ratings of preference for the nonsense words, within two hours of recovery. There were slightly more hits on the category generation task when the category examples had been presented during rather than before intubation, but otherwise there was no evidence for priming even in the light sedation group. Renna, Lang, and Lockwood (2000) also played words to patients receiving different doses of anesthetic prior to surgical incision. Eight words were played along with positive or neutral

16

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

statements relating to the progress of the operation, during which BIS ranged from 55 to 85. Surgery commenced following word presentation. Memory was tested two or three hours later using a word identification task. Priming was only demonstrated in the group receiving the lowest dose of anesthetic, suggesting a possible role of depth of anesthesia. However, when the whole patient set was partitioned by BIS score, no relationship between depth of anesthesia and priming emerged. No threshold level of BIS was identified above which patients showed significant priming. As with many of the studies in this field, the very small amount of priming observed makes it difficult to detect any relationships between priming and anesthetic or other variables. To try and combat this problem, we conducted extensive pilot tests to ensure that our combination of stimulus set and memory test provided a sensitive measure of priming (Deeprose et al., 2004). We compared priming in patients played words either before or during surgery, at comparable anesthetic depths (median mean-BIS = 38 before surgery and 42 during). There was no evidence for explicit recall or recognition. Implicit memory, tested using a word stem completion test, was only found in those patients receiving surgery during word presentation (mean score = .08, p < .02; effect size = 0.40). However, their scores were not significantly higher than those of the before-surgery group (mean score = .01). In a second study, we replicated the finding of priming during surgery using the same stimuli and tests as before, and provided stronger evidence that priming occurs in the absence of awareness (Deeprose, Andrade, Harrison, & Edwards, 2005). Each stimulus word was presented 15 times and BIS was recorded at the start and end of each series of repetitions. Anesthesia was relatively deep (median mean BIS = 40) and stable (only 12% of BIS recordings exceeded 60, compared with 20% in the study by Struys et al. (1998) when BIS was used to try and maintain a constant anesthetic depth). No patient revealed spontaneous or prompted recall on the structured interview for intra-operative events. A word stem completion task showed clear evidence of implicit memory for the words presented during surgery (p < .002, effect size 0.39). Significant priming was still evident even when patients with momentary light anesthesia (maximum recorded BIS P 60) and/or any positive responses to targets on the yes/no recognition test were excluded from the analysis. To summarize the studies of priming during BIS monitored anesthesia, there is little (Kerssens et al., 2002; Renna et al., 2000) or no (Andrade et al., 2001; Deeprose et al., 2004) evidence for priming during light anesthesia prior to surgery. Hormonal stress responses may increase the chance of priming during surgery compared with before surgery, but two studies using BIS to control anesthetic depth during surgery found no evidence of priming using the Robinson Crusoe story (Struys et al., 1998) and a category generation task (Kerssens et al., 2001). However, with a word stem completion test, we demonstrated priming during surgery with an anesthetic that was relatively deep on average (Deeprose et al., 2004) and replicated that finding in patients for whom anesthetic depth remained below a BIS value of 60 throughout word presentation (Deeprose et al., 2005). The difference between our results and those of Kerssens et al. (2001) and Struys et al. (1998) may reflect our use of a perceptual rather than conceptual priming task. We will develop this point in Section 7 but note here that the picture is muddied by the results of the very recent studies by Kerssens et al. (2005) and Iselin-Chaves et al. (in press). Both used word stem completion to detect priming, as we did, though they combined it with the process dissociation procedure. Iselin-Chaves et al. replicated our finding of priming with a different anesthetic, whereas Kerssens et al found no priming. Kerssens et al. used BIS monitoring to maintain

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

17

anesthetic depth between BIS 40 and 60, whereas we used it retrospectively to show priming in patients whose BIS values happened to stay below 60 (Deeprose et al., 2005). Although the data are somewhat equivocal, the weight of the evidence from the BIS studies suggests that perceptual priming occurs during adequate anesthesia.

5. EEG—Spectral edge frequency Spectral Edge Frequency (SEF) is derived from the power spectrum of the EEG, having undergone Fourier transformation to separate the component sine waves into different amplitudes. Only one learning during anesthesia study has used SEF as a measure of the adequacy of anesthetic depth. Gidron, Barak, Henik, Gurman, and Stiener (2002) measured SEF during surgery while patients were played one of two lists of 20 word pairs. Each list included 10 neutral word pairs (e.g., boy–girl) and 10 emotional word pairs (e.g., rage–anger). Patients were tested 2–4 h following the operation, and presented one word from each pair. They were asked to provide a word associate as quickly as possible to each word. Response times for studied and unstudied neutral words were comparable, but significantly greater for studied emotional words than unstudied emotional words. However, the significant difference in reaction time to studied and unstudied emotional words may be partly due to an increase in reaction time for unstudied emotional words (2.35 s) compared to unstudied neutral words (2.09 s) rather than a priming effect. Although the data are rather weak, this study does suggest that patients may be particularly susceptible to emotional priming during anesthesia. Priming of emotional words negatively correlated with depth but it is difficult to determine whether this reflects priming in the absence of awareness, especially as patients were paralyzed.

6. EEG–Narcotrend The Narcotrend monitor is another form of processed EEG. Depth of anesthesia is classified based on sleep stages ranging from A (fully awake) to F (no brain activity). Mu¨nte et al. (2003) played patients one of four short stories before surgery during light anesthesia (stages C1–D2) and another story during surgery and deep anesthesia (stages E0–E1). On recovery, no patient had explicit memory for the stories, tested using a structured interview and free recall task. Priming was measured using a reading speed task, commonly used in psycholinguistic research (Just, Carpenter, & Woolley, 1982). Increased reading speed was found only for words presented before surgery during light to moderate anesthesia As in Gidron et alÕs study, it is questionable whether or not this priming took place in the absence of awareness without details of the lightest stage of anesthesia experienced by patients showing priming on recovery.

7. Discussion This review of priming during anesthesia focused on studies using a measure of awareness or anesthetic depth with the aim of determining whether priming during anesthesia can take place in the absence of awareness. The findings are mixed.

18

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Studies using the isolated forearm technique suggest that implicit and explicit memory are abolished at least from the point when the patient is unable to respond to command (Loveman et al., 2001; Russell & Wang, 1997, 2001). Studies measuring auditory evoked potentials provide a similar pattern of data in that priming only appears to take place when the patient displays auditory evoked potentials similar to the awake state (Aceto et al., 2003; Ghoneim et al., 2000; Schwender et al., 1994; Smith et al., 1998). Although this may reflect the degree of integrity of the auditory cortices required for priming to occur rather than awareness, the observation that priming is also associated with low anesthetic and high analgesic regimes suggests it is taking place during moments of awareness. In contrast, some studies using EEG measures suggest that priming does take place in the absence of awareness. Although we see that priming is related to depth, most clearly in Lubke et al.Õs (1999) study of trauma patients, it also takes place when anesthesia is within clinically adequate ranges (Deeprose et al., 2004, 2005; Gidron et al., 2002; Iselin-Chaves et al., in press; Lubke et al., 1999; but see Kerssens et al., 2001, 2005; Smith et al., 1998; Struys et al., 1998). How can we explain these conflicting findings? The isolated forearm technique aims to detect awareness and provides a measure of central nervous system output (e.g., response to command). Criticisms of the technique focusing on the potential ÔunwillingnessÕ of the patient to respond to command are unlikely to apply to those patients undergoing surgery. If a patient is aware during their operation, it seems likely they will be motivated to indicate this to the anesthetist. However, the isolated forearm technique still may not provide a sensitive measure of central nervous system information processing. It requires processing of incoming information, that is, conceptually processing the command to move, and also depends on the central nervous system producing output (i.e., physical movement). It is therefore possible that patients may be unable to respond, but still able to process and remember simple perceptual information. This has not been demonstrated empirically, but Russell and Wang used conceptual implicit memory tests, such as category generation, in their studies, which may not be sensitive enough to tap into priming during anesthesia. Studies in which BIS indicated clinically adequate anesthesia and in which conceptual implicit memory tests were used have also failed to find priming during surgery (Kerssens et al., 2001; Struys et al., 1998). In contrast, most studies using a perceptual implicit memory test, word stem completion, have found evidence for priming during surgery (Deeprose et al., 2004, 2005; Iselin-Chaves et al., in press; Lubke et al., 1999). Only two studies used word stem completion and found no priming during surgery with conventional anesthetic techniques (Kerssens et al., 2005; Smith et al., 1998). As anesthesia leaves low level auditory processing intact, perceptual implicit memory tests which rely upon the same neural networks that subserved initial processing of stimuli (Gabrieli, 1998) are more likely to detect priming during anesthesia than conceptual tests. Conceptual tests, such as category generation and word association tasks, demand higher level, semantic processing of stimuli and priming of links between stimuli, probably in the association areas of the frontal and temporal lobes to which the flow of information is disrupted by anesthesia (Angel, 1993). The role of surgery in facilitating priming is complex. As well as opposing the effects of anesthetics and lightening depth, there is some evidence that surgical stimulation per se may also play role in facilitating priming. Studies in which words were played prior to surgery at a depth comparable to that used during surgery have typically failed to find priming even with perceptual

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

19

priming tests. Although Mu¨nte et al. (2003) found priming in patients presented words prior to surgery, awareness cannot be ruled out. In contrast, for example, Renna et al. (2000) played words prior to surgical incision, with a range of anesthetic depth comparable to that in Lubke et al.Õs (1999) study, but did not demonstrate priming or identify a depth of anesthesia at which priming was likely (see also Andrade et al., 2001). Deeprose et al. (2004) compared priming in patients played words before or during surgery, manipulating presentation time in a single study. Despite comparable depth in each group, only patients played words during surgery showed priming on recovery. It seems that surgery may facilitate priming during anesthesia independently of its effects on depth. Our explanation for this focuses on the fact that the amygdala is implicated in memory formation and may be activated by the stress hormones that are released during surgery (Deeprose et al., 2004; Stapleton & Andrade, 2000). The amygdala plays an important role in fear conditioning (see review by Le Doux, 1995) and this mechanism may also facilitate enhanced perception and encoding of small amounts of verbal implicit memory. The modality specific neocortical regions which form the locus of the perceptual priming (see review by Gabrieli, 1998), also form part of the implicit fear conditioning circuitry. However, whether or not perceptual priming may be enhanced by concurrent arousal in the same way as implicit fear conditioning has yet to be tested. In conclusion, priming is associated with surgical stimulation and light anesthesia, but there is evidence that perceptual priming during anesthesia can occur without conscious awareness. Current measures of consciousness have limitations. Although an effective indicator of awareness and ability to respond to command, the isolated forearm technique may not provide a sensitive measure of information processing during anesthesia. In contrast, auditory evoked potentials and other EEG measures of depth may provide more specific measures of anesthetic depth but are based on probabilistic estimates of consciousness. They do not provide a clear cut-off value between consciousness and unconsciousness for an individual patient and thus awareness may go undetected. In future priming during anesthesia research, studies using probabilistic EEG or AEP measures of depth should also use the isolated forearm technique (as in the case of Kerssens et al., 2002 and Loveman et al., 2001), to determine whether those patients who form implicit memories do so in the absence of awareness. There is also a need to use the most appropriate tests for priming during anesthesia research. Our review suggests that perceptual auditory implicit memory tasks should be used to maximise the probability of detecting any priming which may occur. Now that we have evidence for unconscious, perceptual priming during surgery, future studies should combine modern measures of anesthetic depth with sensitive tests of priming to investigate the extent of implicit memory formation, during surgery and more generally. In addition to priming of word representations, can more general concepts such as stereotypes also be primed during anesthesia? Can new associations be formed implicitly? Finally, in light of the growing evidence that priming can occur despite adequate anesthesia, there is a need to investigate its consequences. Patients who experience intra-operative awareness but who are without explicit recollection upon recovery have been observed to demonstrate Post Traumatic Stress Disorder type symptoms, including anxiety and depression (Wang, 2001). Implicit priming during anesthesia may also have a negative impact on patient recovery, and the implications of this should be addressed in future research.

20

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Acknowledgments This work was supported by a Medical Research Council studentship to Catherine Deeprose [ne´e Hanna], Department of Psychology, University of Sheffield, U.K., and by Wellcome Trust Grant No. 065503. References Aceto, P., Valente, A., Gorgoglione, M., Adducci, E., & De Cosmo, G. (2003). Relationship between awareness and middle latency auditory evoked responses during surgical anaesthesia. British Journal of Anaesthesia, 90(5), 630–635. Andrade, J. (1995). Learning during anaesthesia: A review. British Journal of Psychology, 86(4), 479–506. Andrade, J., Englert, L., Harper, C., & Edwards, N. (2001). Comparing the effects of stimulation and propofol infusion rate on implicit and explicit memory formation. British Journal of Anaesthesia, 86(2), 189–195. Angel, A. (1993). Central neuronal pathways and the process of anesthesia. British Journal of Anaesthesia, 71(1), 148–163. Antognini, J. F., & Schwartz, K. (1993). Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology, 79, 1244–1249. Berry, D. C., & Broadbent, D. E. (1984). On the relationship between task performance and associated verbalisable knowledge. The Quarterly Journal of Psychology, 34A, 209–231. Bogetz, M. S., & Katz, J. A. (1984). Recall of surgery for major trauma. Anesthesiology, 61, 6–9. Bruhn, J., Bouillon, T. W., Radulescu, L., Hoeft, A., Bertaccini, E., & Shafer, S. L. (2003). Correlation of approximate entropy, bispectral index, and spectral edge frequency 95 (SEF95) with clinical signs of ‘‘anesthetic depth’’ during coadministration of propofol and remifentanil. Anesthesiology, 98(3), 621–627. Buchner, A., Erdfelder, E., & Vaterrodt-Plu¨nnecke, B. (1995). Towards unbiased measurement of conscious and unconscious memory processes within the process dissociation framework. Journal of Experimental Psychology: General, 124, 137–160. Butler, L. T., & Berry, D. C. (2001). Implicit memory: Intention and awareness revisited. Trends in Cognitive Sciences, 5, 192–197. Deeprose, C., Andrade, J., Harrison, N., & Edwards, N. (2005). Unconscious auditory priming during surgery with propofol and nitrous oxide anaesthesia: A replication. British Journal of Anaesthesia, 94, 57–62. Deeprose, C., Andrade, J., Varma, S., & Edwards, N. (2004). Unconscious learning during surgery with propofol anaesthesia. British Journal of Anaesthesia, 92, 171–177. Gabrieli, J. D. E. (1998). Cognitive neuroscience of human memory. Annual Review of Psychology, 49, 87–115. Ghoneim, M. M., & Block, R. I. (1992). Learning and consciousness during general-anesthesia. Anesthesiology, 76(2), 279–305. Ghoneim, M. M., & Block, R. I. (1997). Learning and memory during general anesthesia—An update. Anesthesiology, 87(2), 387–410. Ghoneim, M. M., Block, R. I., Dhanaraj, V. J., Todd, M. M., Choi, W. W., & Brown, C. K. (2000). Auditory evoked responses and learning and awareness during general anesthesia. Acta Anaesthesiologica Scandinavica, 44(2), 133–143. Gidron, Y., Barak, T., Henik, A., Gurman, G., & Stiener, O. (2002). Implicit learning of emotional information under anaesthesia. Neuroreport, 13(1), 139–142. Glass, P. S., Bloom, M., Kearse, L., Rosow, C., Sebel, P., & Manberg, P. (1997). Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology, 86(4), 836–847. Gross, M. A. F., Nager, W., Quandt, C., Mu¨nte, T. F., & Mu¨nte, S. (2004). Auditory processing in patients under general anaesthesia. An event related brain potential (ERP) study. British Journal of Anaesthesia, 93, 486. Hutchinson, K. A., Neely, J. H., & Neil, W. T. (2004). Is unconscious identity priming lexcal or sublexical?. Consciousness and Cognition, 13, 512–538.

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

21

Iselin-Chaves, I. A., Flaishon, R., Sebel, P. S., Howell, S., Gan, T. J., Sigl, J., Ginsberg, B., & Glass, P. S. (1998). The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the Bispectral Index. Anesthesia and Analgesia, 87, 949–955. Iselin-Chaves, I. A., Willems, S. J., Jermann, F. C., Adam, S. R. & Linden, M. (in press). Investigation of implicit memory during general anesthesia for elective surgery using the process dissociation procedure. Anesthesiology.. Jacoby, L. L. (1991). A process dissociation framework: Separating automatic from intentional uses of memory. Journal of Memory and Language, 30, 513–541. Jacoby, L. L. (1998). Invariance in automatic influences of memory: Toward a userÕs guide for the process-dissociation procedure. Journal of Experimental Psychology-Learning Memory and Cognition, 24, 3–26. Jewett, D. L. (1970). Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Electroencephalography and Clinical Neurophysiology, 28(6), 609–618. Jones, J. G., & Aggarwal, S. K. (2001). Monitoring depth of anesthesia. In M. M. Ghoneim (Ed.), Awareness during anesthesia (pp. 69–92). Oxford: Butterworth-Heinmann. Just, M. A., Carpenter, P. A., & Woolley, J. D. (1982). Paradigms and processes in reading comprehension. Journal of Experimental Psychology: General, 111, 228–238. Kaga, K., Hink, R. F., & Shinoda, Y. (1980). Evidence for a primary cortical origin of a middle latency auditory evoked potential in cats. Electroencephalography and Clinical Neurophysiology, 50, 254–266. Kerssens, C., Klein, J., van der Woerd, A., & Bonke, B. (2001). Auditory information processing during adequate propofol anesthesia monitored by electroencephalogram bispectral index. Anesthesia and Analgesia, 92(5), 1210–1214. Kerssens, C., & Sebel, P. (2001). BIS and memory during anesthesia. In M. M. Ghoneim (Ed.), Awareness during anesthesia (pp. 103–116). Oxford: Butterworth-Heinmann. Kerssens, C., Lubke, G. H., Klein, J., van der Woerd, A., & Bonke, B. (2002). Predictive value of individual differences. Anesthesiology, 97, 382–389. Kerssens, C., Ouchi, T., & Sebel, P. (2005). No evidence of memory function with propofol or isoflurane with close control of hypnotic state. Anesthesiology, 102, 57–62. Le Doux, J. E. (1995). Emotion: Clues from the brain. Annual Review of Psychology, 46, 209–235. Lequeux, P. Y., Cantraine, M., Levarlet, M., & Barvais, L. (2003). Acta Anaesthesiologica Scandinavica, 47, 833–837. Levinson, B. W. (1965). States of awareness during general anaesthesia. Preliminary communication. British Journal of Anaesthesia, 37, 544–546. Lewicki, P., Hill, T., & Sasaki, I. (1989). Self-perpetuating development of encoding biases. Journal Of Experimental Psychology-General, 118(4), 323–337. Liu, J., Singh, H., & White, P. F. (1997). Electroencephalographic bispectral index correlates with intraoperative recall and depth of propofol-induced sedation. Anesthesia and Analgesia, 84(1), 185–189. Loveman, E., Van Hooff, J. C., & Smith, D. C. (2001). The auditory evoked response as an awareness monitor during anaesthesia. British Journal of Anaesthesia, 86(4), 513–518. Lovrich, D., Novick, B., & Vaughan, H. G. (1988). Topographic analysis of auditory event-related potentials associated with acoustic and semantic processing. Electroencephalography and Clinical Neurophysiology, 71(1), 40–54. Lubke, G. H., Kerssens, C., Phaf, H., & Sebel, P. S. (1999). Dependence of explicit and implicit memory on hypnotic state in trauma patients. Anesthesiology, 90(3), 670–680. Lubke, G. H., Kerssens, C., Gershon, R. Y., & Sebel, P. S. (2000). Memory formation during general anaesthesia for emergency cesarean sections. Anesthesiology, 92(4), 1029–1034. Lyons, G., & MacDonald, R. (1991). Awareness during caesarean section. Anaesthesia, 46, 62–64. Marcel, A. J. (1983a). Conscious and unconscious perception: An approach to the relations between phenomenal experience and perceptual processes. Cognitive Psychology, 15, 238–300. Marcel, A. J. (1983b). Conscious and unconscious perception: Experiments on visual masking and word recognition. Cognitive Psychology, 15, 197–237. Merikle, P. M., & Daneman, M. (1996). Memory for unconsciously perceived events: Evidence from anesthetized patients. Consciousness and Cognition, 5(4), 525–541. Moerman, N., Bonke, B., & Oostings, J. (1993). Awareness and recall during general-anesthesia—Facts and feelings. Anesthesiology, 79(3), 454–464.

22

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

Muncaster, A. R. G., Sleigh, J. W., & Williams, M. (2003). Changes in consciousness, conceptual memory and quantitative electroencephalographical measures during recovery from sevoflurane and remi-fentanyl based anesthesia. Anesthesia and Analgesia, 96, 720–725. Mu¨nte, S., Mu¨nte, T. F., Grotkamp, J., Haeseler, G., Raymondos, K., Piepenbrock, S., & Kraus, G. (2003). Implicit memory varies as a function of hypnotic electroencephalogram stage in surgical patients. Anesthesia and Analgesia, 97(1), 132–138. Osterman, J. E., Hopper, J., Heran, W. J., Keane, T. M., Bessel, A., & van der Kolk, A. (2001). Awareness under anaesthesia and the development of posttraumatic stress disorder. General Hospital Psychiatry, 23, 198–204. Phillips, A. A., McLean, R. F., Devitt, J. H., & Harrington, E. M. (1993). Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass. Canadian Journal Anaesthesia, 40, 922–926. Pritchard, W. S. (1981). Psychophysiology of P300. Psychological Bulletin, 89(3), 506–540. Pompeia, S., Bueno, O. F. A., Galduroz, J. C. F., & Tufik, S. (2003). Stem-completion tasks (indirect, direct inclusion and exclusion) are differently affected by equipotent doses of lorazepam and flunitrazepam. Human Psychopharmacology—Clinical And Experimental, 18(7), 541–549. Quandt, C., Nager, W., Gross, M. AF., Lo¨ffler, N., Piepenbrock, S. A., Mu¨nte, T. F., & Mu¨nte, S. (2004). Auditory perception during general anaesthesia with sevoflurane-event related potentials (ERP) indicate orienting mechanisms. British Journal of Anaesthesia, 93(3), 488. Rampil, I. J., Mason, P., & Singh, H. (1993). Anesthetic potency (Mac) is independent of forebrain structures in the rat. Anesthesiology, 78(4), 707–712. Reber, A. S. (1967). Implicit learning of an artificial grammar. Journal of Verbal Learning and Verbal Behavior, 6, 855–863. Reingold, E. M., & Merikle, P. M. (1988). Using direct and indirect measures to study perception without awareness. Perception and Psychophysics, 44, 563–575. Renna, M., Lang, E. M., & Lockwood, G. G. (2000). The effect of sevoflurane on implicit memory: A double-blind, randomised study. Anaesthesia, 55(7), 634–640. Russell, I. F., & Wang, M. (1997). Absence of memory for intraoperative information during surgery under adequate general anaesthesia. British Journal of Anaesthesia, 78(1), 3–9. Russell, I. F., & Wang, M. (2001). Absence of memory for intra-operative information during surgery with total intravenous anaesthesia. British Journal of Anaesthesia, 86(2), 196–202. Russell, I. F. (1993). Midazolam-alfentanil—an anesthetic—an investigation using the isolated forearm technique. British Journal of Anaesthesia, 70(1), 42–46. Schwender, D., Madler, C., Klasing, S., Peter, K., & Poppel, E. (1994). Anesthetic control of 40-Hz brain activity and implicit memory. Consciousness and Cognition, 3, 129–147. Sebel, P. S., Bowdle, T. A., Ghoneim, M. M., Rampil, I. J., Padilla, R. E., & Gan, T. J. (2004). The incidence of awareness during anesthesia: A multicenter United States study. Anesthesia and Analgesia, 99(3), 833–839. Shanks, D. R., & St John, M. F. (1994). Characteristics of dissociable learning systems. Behavioural and Brain Sciences, 17, 367–447. Smith, T. L. & Maye, J. P. (1998). Evaluation of word associations and the bispectral index monitor as indicators of implicit memory formation during general anaesthesia. In C. Jordan, D.J.A. Vaughan, & D.E.F. Newton (Eds). Memory and awareness in anaesthesia IV (pp. 203–209). London. Smith, T.L., Zapala, D.A., Thompson, C.L., Hoye, W.E., Kelly, W.T. (1998). The role of auditory evoked potentials in evaluating implicit memory formation during the anaesthetised state. In C. Jordan, D.J.A. Vaughan, & D.E.F. Newton (Eds.), Memory and awareness in anaesthesia IV (pp. 210–221). London. Squires, N. K., Squires, K. C., & Hillyard, S. A. (1975). Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroencephalography and Clinical Neurophysiology, 38(4), 387–401. Stapleton, C. L., & Andrade, A. (2000). An investigation of learning during propofol sedation and anesthesia using the process dissociation procedure. Anesthesiology, 93(6), 1418–1425. Struys, M., Versichelen, L., Byttebier, G., Mortier, E., Moerman, A., & Roily, G. (1998). Clinical usefulness of the bispectral in index for titrating propofol target effect-site concentration. Anaesthesia, 53(1), 4–12. Thornton, C., & Sharpe, R. M. (2001). The auditory evoked responses and memory during anesthesia. In M. M. Ghoneim (Ed.), Awareness during anesthesia (pp. 112–117). Oxford: Butterworth-Heinmann.

C. Deeprose, J. Andrade / Consciousness and Cognition 15 (2006) 1–23

23

Tunstall, M. E. (1977). Detecting wakefulness during general anaesthesia for caesarean section. British Medical Journal, 1, 1321. van Hooff, J. C., Brunia, C. H., & Allen, J. J. (1996). Event-related potentials as indirect measures of recognition memory. International Journal of Psychophysiology, 21(1), 15–31. van Hooff, J. C., De Beer, N. A., Brunia, C. H., Cluitmans, P. J., Korsten, H. H., Tavilla, G., & Grouls, R. (1995). Information processing during cardiac surgery: An event related potential study. Electroencephalography and Clinical Neurophysiology, 96(5), 433–452. Villemure, C., Plourde, G., Lussier, I., & Normandin, N. (1993). Auditory processing during isoflurane anesthesia: A study with an implicit memory task and auditory evoked potentials. In P. S. Sebel (Ed.), Memory and awareness in anesthesia (pp. 99–106). Upper Saddle River, NJ, US: Prentice-Hall. Wang, M. (2001). The psychological consequences of explicit and implicit memories of events during surgery. In M. M. Ghoneim (Ed.), Awareness during anaesthesia (pp. 145–154). Oxford: Butterworth-Heinmann.