The adjustment of maladaptive thoughts and behaviors associated with emotional memories is central to treating psychiatric disorders. Recent research, predominantly with laboratory animals, indicates that memories can become temporarily sensitive to modification following reactivation, before undergoing reconsolidation. A method to selectively impair reconsolidation of specific emotional or traumatic memories in humans could translate to an effective treatment for conditions such as posttraumatic stress disorder. We tested whether deep sedation could impair emotional memory reconsolidation in 50 human participants. Administering the intravenous anesthetic propofol following memory reactivation disrupted memory for the reactivated, but not for a non-reactivated, slideshow story. Propofol impaired memory for the reactivated story after 24 hours, but not immediately after propofol recovery. Critically, memory impairment occurred selectively for the emotionally negative phase of the reactivated story. One dose of propofol following memory reactivation selectively impaired subsequent emotional episodic memory retrieval in a time-dependent manner, consistent with reconsolidation impairment.

All patients, randomly assigned to one of two groups (A or B), underwent three sessions. Session 1 corresponded to day 1 and was the encoding session of the two emotional stories. Session 2 took place 7 days after day 1. All participants performed a memory reactivation task for one of the two emotional stories in the endoscopy unit. Immediately after, they received propofol, followed by the endoscopy procedure. For group B, session 3, the recognition memory test took place after the participants recovered from the procedure and were discharged from the recovery room. For group A, session 3 took place 24 hours after the endoscopy.

Twenty-five patients per group completed the study. One patient in group B was not included in analyses because of outlier-level performance on the DSST before recognition testing. Groups A and B did not differ on any demographical variables (age, gender, years of education, or type of endoscopy procedure) or in terms of dosage of other agents (midazolam or alfentanil) administered. However, there was a significant difference in the amount of propofol administered.

Fifty participants were randomly assigned to one of two groups (A and B) matched for gender ( Table 1 ). During emotional memory encoding, participants viewed slideshows of two distinct negative arousing stories. Both stories comprised three phases: Phases 1 and 3 were emotionally neutral, whereas phase 2 comprised the emotionally negative part of each story. The memory reactivation session took place 1 week after the encoding session ( Fig. 1 ). To reactivate the memory and initiate a memory destabilization process, patients were presented with the first slide of one of the two stories and asked three questions about what had been visible behind a mask placed over a part of the slide. Immediately following memory reactivation, all participants received propofol and underwent endoscopy (gastroscopy, colonoscopy, or both) under deep sedation [depression of consciousness but spontaneous ventilation maintained ( 39 )]. Memory for both stories was tested using a multiple-choice memory test after 24 hours (group A) or immediately after discharge from the recovery room (group B). All participants completed the digit symbol substitution test (DSST), a brief cognitive screening test of digit-symbol pairs, before emotional memory encoding and memory testing.

ECT comprises the application of short-acting general anesthesia, neuromuscular blockade, and cranial electrical stimulation to evoke generalized seizure activity. Although we attributed ECT-induced reconsolidation impairment in patients with depression to cranial electrical stimulation, whether the different components of ECT could individually impair reconsolidation remains an open question. A possibility that the anesthetic was, in part, responsible for ECT-induced reconsolidation impairment is particularly important, as the wide use of this pharmacological class in clinical practice suggests that it could be a relatively safe and accessible method to modify unwanted memories. The mechanism of action of most general anesthetics is the modulation of γ-aminobutyric acid (GABA) receptors, and data from animal models have shown that administration of GABA receptor type A (GABA A ) agonists can disrupt reconsolidation ( 33 – 35 ). If anesthesia alone blocks reconsolidation, then targeted memory disruption in patients with psychiatric disorders could be achieved without the more invasive aspects of ECT. In support of this possibility, human neuroimaging data demonstrate that general anesthetics disrupt activity in the hippocampus and amygdala ( 36 , 37 ), brain areas critically involved in emotional memory ( 38 ). We therefore tested the hypothesis that the intravenous anesthetic propofol impairs reconsolidation of emotional memories reactivated immediately before anesthetic administration in psychiatrically and neurologically healthy individuals who had been referred for endoscopy for clinical indications.

Traumatic memories are more complex than simple associations formed by conditioning. These episodic memories are enriched with what-where-when contextual information ( 27 ), and their retrieval can be triggered by similar experiences ( 2 , 28 ). Therefore, the modulation of reconsolidation of rare traumatic memories may need different manipulations than the ones used in previous studies using simple fear conditioning ( 12 ). Most of the extant studies on episodic memory reconsolidation have used noninvasive behavioral techniques, such as post-reactivation interference learning to update memory ( 29 ) instead of disrupting it. By contrast, we showed recently, in patients with unipolar depression, that ECT can selectively impair reconsolidation of a reactivated emotional episodic memory ( 30 ). This study design met criteria generated from nonhuman animal studies to provide compelling evidence for the reconsolidation phenomena in humans ( 31 ). These criteria include the requirement for (i) reactivation of consolidated memory by a reminder cue and (ii) that the memory effect be observed after sufficient time has elapsed for reconsolidation to take place (typically tested after 24 hours) and not immediately after reactivation ( 11 , 30 , 31 ). A third criterion, which is important for interpreting data as a disruption of reconsolidation ( 32 ), is that the manipulation targeting reconsolidation is delivered after reactivation and not before. This latter criterion was also met.

The development of protocols to selectively reduce unwanted memories via the disruption of reconsolidation could be of potential clinical benefit. However, evidence for reconsolidation in humans remains limited, primarily because the manipulations used to disrupt memory in animals, such as protein synthesis inhibitors, are toxic. Consequently, studies on reconsolidation in humans have largely used behavioral manipulations to target nondeclarative memory ( 12 ), including conditioned fear ( 13 ), which involves repeated pairings of a conditioned stimulus with an aversive unconditioned stimulus such as mild electric shock. Human psychopharmacological approaches using the β-adrenergic antagonist propranolol before or after the reactivation of conditioned fear for simple sensory stimuli show efficacy in blocking reconsolidation ( 14 , 15 ). The rationale for trialing β-adrenergic antagonists in this context is based on previous reports that propranolol blocks emotional memory encoding ( 16 , 17 ) and retrieval ( 18 ). In patient studies targeting reconsolidation to treat PTSD, β-adrenergic antagonists have shown promise ( 19 – 21 ). It should be noted, however, that some studies have failed to replicate these reconsolidation impairing effects in humans using behavioral manipulations ( 22 , 23 ) or propranolol ( 22 – 25 ) to target conditioned fear or using propranolol in patients with PTSD ( 26 ).

Memory for traumatic experience can contribute to anxiety disorders ( 1 – 3 ), such as specific phobias or trauma and stressor-related disorders such as post traumatic stress disorder (PTSD) ( 4 – 6 ). An effective treatment for these disorders should selectively decrease these intrusive, pathological memories. A theoretical obstacle to developing these treatments has been a prevailing view that established memories are relatively fixed. That is, memories are initially labile and sensitive to interference by, e.g., electroconvulsive therapy (ECT) ( 7 ), general anesthesia ( 8 ), or protein synthesis inhibition ( 9 ), but stabilize over time during a period of consolidation, after which memories were considered to be established and no longer sensitive to disruption or modification ( 10 ). However, recent research using nonhuman animals challenges this classical view by showing that reactivating an old memory can temporarily return it to a labile state requiring restabilization processes to persist, referred to as reconsolidation, and rendering the memory restabilization susceptible to manipulation ( 11 ).

Short-acting deep sedation is administered relatively routinely in the hospital setting. Thus, instead of exposing healthy participants to anesthesia that they would otherwise not need, we elected to perform the current study on psychiatrically and neurologically healthy individuals referred for endoscopy. The effects of propofol on memory reconsolidation were therefore studied in the context of an endoscopic procedure. This procedure may stimulate the vagus nerve either at esophageal intubation during gastroscopy or by stretching of the sigmoid mesentery during colonoscopy. Although the memory consequences of vagal stimulation in this context are unknown, continuous electrical stimulation of the vagus nerve in human patients with implanted stimulators has been shown to modulate cerebral blood flow in different brain areas, including the hippocampus and amygdala ( 40 ), raising a possibility that vagal stimulation contributed to the observed memory effects. However, it is reasonable to assume that those individuals undergoing both gastroscopy and colonoscopy would obtain more vagal stimulation than those having just one procedure. That is, whereas the effect of propofol does not depend on the dosage and would appear to reflect sedation level per se, any effect of vagal stimulation on reconsolidation could depend on total stimulation. We therefore tested the reconsolidation effects in group A and found these to be equivalent across the three subgroups undergoing either or both interventions when taking recognition scores for the entire story (F 2,22 = 2.41, P = 0.11, η 2 p = 0.018) or just for the emotional phase 2 (F 2,22 = 0.47, P = 0.63, η 2 p = 0.041). This makes it unlikely that vagal stimulation contributes to the memory effects we observe. In any case, vagal stimulation is thought to up-regulate memory ( 41 ), so if anything, this could have obscured reconsolidation disruption instead of contributing to it.

Propofol was administered entirely for clinical reasons, not for the purposes of the current study. To obtain deep sedation in all patients undergoing endoscopy, prescribed propofol doses are adjusted relative to the weight, age, and clinical condition of the patient. Critically, the degree of sedation was similar for all participants in our study. However, despite randomized group assignment, group A was prescribed, on average, a higher total propofol dose than group B (t 47 = 2.04, P = 0.047, d = 0.59) ( Table 1 ). To mitigate the likelihood that this dose difference contributed to the observed memory impairment in group A and not in group B, we included the dose of propofol as a covariate in the group by reactivation ANOVA described above. Furthermore, we found no linear association between the dose of propofol and phase 2 (emotional) recognition scores in group A (Pearson’s r reactivated = 0.22, P = 0.30; r nonreactivated = −0.007, P = 0.97; r reactivated minus nonreactivated = 0.17, P = 0.40) or in group B (Pearson’s r reactivated = 0.12, P = 0.56; r nonreactivated = −0.005, P = 0.98; r reactivated minus nonreactivated = 0.10, P = 0.63) (fig. S3). Last, we performed a median split on group A based on propofol dose and repeated the comparison of reactivated versus nonreactivated recognition scores for phase 2 (the emotional phase), taking only those 13 participants at, or below, the median propofol dose (2.97 mg/kg). The reactivation-induced reconsolidation impairment observed in group A ( Fig. 2B ) remains statistically significant in this subgroup [t phase2(12) = −2.61, P = 0.023, d = −0.73]. We therefore found no evidence that propofol dose accounts for the specific memory impairment of the emotional part of the reactivated story in group A. This suggests that deep sedation, and not propofol dose per se, is the important factor determining reconsolidation impairment.

Both stories consisted of three phases: Phase 1 (slides 1 to 4) and phase 3 (slides 9 to 11) were of neutral content, whereas the middle part of the stories, phase 2 (slides 5 to 8), had emotionally negative content. Although we did not observe selectivity of reconsolidation disruption for any particular phase of the stories in our previous study involving ECT, recognition accuracy was generally low in those patients with severe depression, and we did not observe the typical enhancement of memory for the emotional phase of the stories ( 16 ). However, on examining recognition scores for reactivated versus nonreactivated stories as a function of phase in group A of the current study ( Fig. 2B ), selective reactivation–induced memory impairment for the emotional part of the story was evident. On post hoc testing, we observed memory differences for phase 2 between the reactivated versus nonreactivated stories [t phase2(24) = −3.05, P = 0.006, P = 0.033 Bonferroni corrected for six tests, d = −0.61] in group A, whereas reactivation did not affect memory for the neutral phases of the stories [t phase1(24) = −0.56, P = 0.58, d = −0.11; t phase3(24) = −1.20, P = 0.91, d = −0.024]. We observed no difference for any of the three phases in group B (P > 0.25 for all phases) ( Fig. 2B ).

( A ) Recognition memory scores for all slides of the reactivated and nonreactivated story (except the first slide) are plotted for each group. Scores (percentage) for each story per group: group A (n = 25 participants) reactivated mean (SEM) = 53.49 (2.29); nonreactivated mean = 59.20 (2.60); group B (n = 24 participants) reactivated mean = 59.52 (1.97); nonreactivated mean = 61.19 (2.11). ( B ) Percent correct recognition memory scores are plotted for the three story phases of the reactivated (R; solid line) and nonreactivated (NR; dashed line) story for each group. There is a significant impairment of memory for the emotional phase of the reactivated story (phase 2) in group A only. Chance recognition performance (25%) is indicated by the dotted horizontal line. *P < 0.05.

Supporting a hypothesis that anesthesia disrupts emotional memory reconsolidation, we observed a group by reactivation interaction (F 1,40 = 4.84, P = 0.034, η 2 p = 0.108) ( Fig. 2A ). There was no main effect of reactivation (F 1,40 = 0.31, P = 0.58, η 2 p = 0.008) or group (F 1,40 = 1.46, P = 0.23, η 2 p = 0.035). Given that reconsolidation is a time-dependent process, we had predicted that reactivation-induced memory impairment should be present only in group A, but not in group B, as in group B, reconsolidation would not yet be complete. Confirming this prediction, planned paired t tests show reduced memory for the reactivated versus nonreactivated story in group A (t 24 = −2.14, P = 0.043, d = 0.44), but no difference in memory for the reactivated versus nonreactivated story in group B (t 23 = −0.87, P = 0.39, d = 0.17). The observed differences in recognition scores between groups A and B are not due to differences in memory reactivation, as there was no between-group difference in memory reactivation scores for the first slide of the reactivated story immediately before propofol administration (t 47 = 0.70, P = 0.49, d = 0.20), i.e., both groups reactivated memory and performed above chance level (fig. S2).

To test our hypothesis that memory would be impaired in group A, but not group B, for the story reactivated before propofol administration, we performed a group (A and B) by reactivation (reactivated story and nonreactivated story) repeated-measures analysis of variance (ANOVA) on recognition memory scores. Variables that could have affected memory function were included as covariates of no interest. These comprised years of education, propofol dose (mg/kg), DSST performance immediately before the recognition test, which of the two stories was reactivated, which endoscopic procedure was performed (gastroscopy, colonoscopy, or both), and diagnostic outcome of the procedure (as this may have influenced levels of anxiety for a given patient). Furthermore, 27 of the 50 participants received adjuvant agents during deep sedation, which included midazolam or phenylpiperidine derivatives ( Table 1 ); thus, adjuvant pharmacological agent administration during the endoscopy was also included as a covariate of no interest.

Groups A and B performed equally in the DSST task (F 1,47 = 2.72, P = 0.11, η 2 p = 0.055) (fig. S1). Both groups improved with repetition of the task. That is, there was a main effect of experiment time point, encoding to recognition (F 1,47 = 5.56, P = 0.023, η 2 p = 0.106), but no experiment time point by group interaction (F 1,47 = 2.39, P = 0.13, η 2 p = 0.048), indicating a comparable cognitive performance across groups at the time of memory testing. Note that one participant from group B was discarded from further analyses because of a worsening of performance between the encoding and memory testing phases (3 SDs below the mean), which could indicate still being under the influence of propofol.

DISCUSSION

We demonstrate that a single dose of the GABA A agonist propofol following memory reactivation impaired reactivated, but not nonreactivated, episodic memory. In keeping with an explanation in terms of reconsolidation impairment, this reduction was only observed if tested 24 hours (group A), but not immediately (group B), after memory reactivation and propofol administration. Post hoc testing indicated that the memory impairment by propofol was selective for the negative phase of the reactivated story.

Evidence for the disruption of reconsolidation by anesthesia derives from animal studies investigating fear-conditioned memories (33–35). To date, the effects of general anesthesia have only been tested on emotional memory encoding in humans (36, 37). The anesthetic gas sevoflurane, a GABA A agonist, was shown to block the episodic memory enhancement associated with emotional arousal at subanesthetic doses, an effect associated with a reduction in connectivity between the amygdala and hippocampus during simultaneous glucose positron emission tomography scanning (36). This result in humans is supported by analogous data from rats showing that propofol (42) and sevoflurane (43) impair emotional learning, but not in animals that had undergone previous lesions to the amygdala. We therefore speculate that human amygdala activity may be highly sensitive to the inhibitory effects of anesthesia and that the emotional memory reconsolidation disruption by propofol observed here is possibly mediated by a down-regulation in amygdala and hippocampal activity and their coupling. A confirmation of this mechanism would be relevant to any application of propofol in the management of PTSD, as a disturbance in this circuit is considered a key pathophysiological feature of PTSD (4, 6).

An alternative potential mechanism underlying the effects of propofol on emotional memory reconsolidation we observe is via influencing the noradrenergic system. In vivo recordings in rodents have shown that propofol inhibits spontaneous firing in locus coeruleus (LC) (44). The noradrenergic antagonist propranolol has been shown to impair reconsolidation of conditioned fear but not episodic memory (14), making it less likely that the episodic memory reconsolidation impairment we observe reflects an effect of propofol on the noradrenergic system. We did not test for an effect of propofol on simple associative (conditioned) fear memory reconsolidation, but it is possible that propofol could impair reconsolidation of fear-conditioned memories via its action on LC. If this is not the case, the administration of both propofol and propranolol with a reminder cue may be required to inhibit conditioned fear and the episodic memory associated with the conditioning event. Reports that propranolol does disrupt reconsolidation of emotional episodic memory (45) would suggest that reconsolidation of both episodic emotional memory and conditioned fear could be disrupted by an effect of propofol on LC. However, in these studies, drug administration typically precedes memory reactivation, raising a possibility that any reduction in memory performance on subsequent testing reflects a sustained retrieval failure at reactivation (18, 26, 46) and not a disruption of reconsolidation, leaving the risk of the return of memory. The current design does not suffer from this limitation in interpreting the results as a disruption of reconsolidation, as administration of propofol is intravenous and therefore acts immediately following successful memory reactivation.

Considering recognition scores for each story in their entirety, our previous study (30) showed an ECT-evoked memory reduction in patients with depression of 8.48% down to chance levels, whereas in the current study, propofol-evoked reduction was 5.71%. Effect sizes for memory for the reactivated versus nonreactivated story in group A (Cohen’s d = 0.44) was lower than following ECT in the analogous group in our previous study (Cohen’s d = 0.90) (30). However, the effect of propofol is qualitatively different from that we reported for ECT, with propofol selectively reducing memory for the emotional phase of the reactivated story by 12.29% and not the neutral phases. Thus, whereas ECT may be a more potent method to disturb emotional episodic memory reconsolidation, propofol is less invasive and may be more selective to the emotional content of memories. Note that in our previous ECT study, the anesthetic administered as part of ECT was etomidate (30). Like propofol, etomidate potentiates the effects of GABA on GABA A receptors (47) and is known to impair learning and memory (48). However, etomidate also produces adrenal cortical inhibition. Given the role of cortisol in emotional memory (49), we eschewed this potential confound by performing this study in participants receiving propofol.

Determining the mechanism by which propofol reduces emotional memory (story phase 2) reconsolidation down to the same level as neutral memory (phases 1 and 3) will address a more fundamental question regarding the effects of emotion on memory. These observations suggest that either there is a degraded episodic memory that retains an emotional enhancement or reconsolidation of the emotional enhancement is impaired by propofol. Analogous effects of a reduction of emotional memory performance to the same level as neutral memory are observed following administration of propranolol (16–18, 50) or sevoflurane (36) at encoding. What is currently unknown is whether emotion simply strengthens the consolidation of an otherwise neutral memory trace or there is a qualitative difference between emotional and neutral memories. If the latter was the case, this would raise the additional question of whether the emotional and neutral components of an emotional memory are independent, but associated, or these two components are necessarily integrated and indivisible. Although the current results cannot discern between these possibilities, we do demonstrate that propofol evokes the same pattern of deficit at reconsolidation as is observed following pharmacological disruption of emotional memory consolidation.

In contrast to the current study, our previous ECT experiment (30) included a third group (group C), for which patients with severe depression underwent the same emotional memory protocol but were not given ECT following memory reactivation. Here, we elected not to include an analogous nontreatment control group for two reasons. First, group C patients in our previous study showed memory enhancement for the reactivated material in the absence of ECT. Although this enhancement was observed in patients with severe depression, it is likely that a similar enhancement would occur in the current study, given cross-species evidence from rodents (51) and healthy human participants (52) that reactivation can strengthen episodic memory via reconsolidation in the absence of post-reactivation treatment designed to impair it. Second, as propofol was administered as part of a clinical intervention, a nontreatment control group (i.e., a group not undergoing deep sedation plus endoscopy following memory reactivation) would have differed on key aspects besides anesthesia that would have likely influenced memory function. These include the absence of anxiety associated with the endoscopic procedure and diagnostic outcome, as well as the anxiety associated with undergoing anesthesia.

We demonstrate propofol-induced reconsolidation impairment at an interval of 24 hours after reactivation and deep sedation. Testing memory after a longer period (e.g., 1 week) would have allowed us to determine whether memory recovers over time. Memory recovery at 1 week would indicate that the reduced recognition memory for the reactivated story observed in group A at 24 hours reflects a temporary retrieval impairment or temporary inhibition of the memory trace and not a reconsolidation blockade. However, the current paradigm is not suited to repeated memory testing (i.e., immediately after recovery from propofol, at 24 hours and at 1 week) within the same individuals. The multiple-choice questionnaires are highly structured, providing substantial information for new learning of the stories that would render performance on a repeat memory test a poor indication of what is remembered from the initial learning experience. This is why we elected to have two groups (immediate testing and at 24-hour delay), as opposed to one group being tested both immediately and at 24 hours, to prevent confounding effects of new learning during recognition.

The aim of this study was to test for a method to reduce aversive episodic memories in a relatively noninvasive way by reactivating these memories before a dose of intravenous anesthetic is administered. The results presented here pertain to impairing the reconsolidation of aversive episodic memories learned in an experimental context by healthy individuals. Thus, these emotional memories remain quite distant from those formed during truly stressful life experiences. While here we provide a proof of concept that a routine anesthetic procedure impairs reconsolidation and could potentially be used to treat psychiatric disorders in which abnormal emotional memory plays a role, clinical trials are required to apply these findings to patients with pathological, traumatic memories. Reactivation of these memories before propofol administration could be achieved by simple script-driven recall through to immersive virtual reality, tailored to the patients’ traumatic event. However, we note that disorders such as PTSD are multifaceted disorders. PTSD involves recurrent, intrusive recollection of the trauma memory and peritraumatic memory disturbances (4, 5, 53), and these different facets may vary in sensitivity to alteration following reactivation. One limiting factor may be the age of the memory; in some animal models, older memories seem to be more resistant to reconsolidation blockade (54). However, there is also evidence that altering parameters of the reactivation session, such as increasing duration (55), can destabilize remote memories (56). The administration of propofol with simultaneous recording of the electroencephalogram may provide useful markers of the depth of sedation and loss of consciousness (57) potentially predictive of efficacy of reconsolidation impairment across patients.