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Opening the reconsolidation window using the mind’s eye: Extinction training during reconsolidation disrupts fear memory expression following mental imagery reactivation
Cognition 183 (2019) 277–281
Contents lists available at ScienceDirect
Cognition journal homepage: www.elsevier.com/locate/cognit
Brief article
Opening the reconsolidation window using the mind’s eye: Extinction training during reconsolidation disrupts fear memory expression following mental imagery reactivation
T
Laurent Grégoire, Steven G. Greening CNAPs Lab, Department of Psychology, Louisiana State University, B3 Audubon Hall, Baton Rouge, LA 70803, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Fear conditioning Memory reconsolidation Fear extinction Mental imagery Fear reconsolidation
Can mental imagery rather than external stimulation reactivate an aversive conditioned memory for the purposes of attenuating fear with subsequent extinction training? To answer this question participant underwent a three-day protocol: Day 1 entailed fear acquisition training in which two conditioned stimuli were paired with mild shock (US), while a CS− never was; day 2 included imagery-based reactivation of only one of the two CS+ followed by standard extinction training within the reconsolidation ten minutes later; day 3 included reinstatement by the unsignaled presentation of the US followed by a re-extinction phase. We observed no evidence of fear recovery on the first trial of re-extinction for the reminded, mentally imaged, CS+, whereas fear returned for the non-reminded CS+. Thus, mental imagery was sufficient to reactivate a fear memory thereby opening the reconsolidation window and facilitating fear suppression via extinction training. The clinical implications of this are potentially far-reaching as it allows for in vivo reconsolidation procedures in exposure therapy.
1. Introduction Consolidated memories are not permanently encoded (Lee, Nader, & Schiller, 2017, for a review). Instead, re-exposure to a reminder renders memory susceptible to modification by novel learning, a process known as reconsolidation (Auber, Tedesco, Jones, Monfils, & Chiamulera, 2013; Lee et al., 2017). How can the mechanisms of reconsolidation can be employed to modify learned fear associations, as occurs in PTSD and specific phobia? Recent experimental evidence using fear conditioning, in which a conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US), demonstrates that extinction training (in which the CS+ is repeatedly presented without the US) during reconsolidation produces a disruption of the original fear conditioned association (e.g., Oyarzún et al., 2012; Schiller, Kanen, LeDoux, Monfils, & Phelps, 2013; Schiller et al., 2010). This discovery overcomes previous shortcomings of fear suppression by extinction learning, which is often temporary and susceptible to the return of the conditioned fear response. Mechanistically, the presentation of a reminder cue destabilizes the retrieved memory rendering it transiently labile by instantiating a state of new protein synthesis (Nader, Schafe, & LeDoux, 2000). Subsequent extinction training performed within this reconsolidation window, between 10 min and 1 h after reactivation (Monfils, Cowansage, Klann, &
LeDoux, 2009), allows for the disruption of the initial fear memory and prevents the return of fear (Auber et al., 2013; Lee et al., 2017). Longlasting behavioral effects of fear attenuation have been observed one year (Schiller et al., 2010, Experiment 1) and over 18 months (Björkstrand et al., 2015) after extinction, reflecting the stability of the updated memory. One major limitation of current approaches to fear disruption via reconsolidation is that they rely on the presentation of the physically experienced CS+ as the reminder cue. In practice, for those with PTSD or specific phobias, such an approach is either impractical (e.g., access to trigger stimuli might be impossible) or excessively evocative. An alternative strategy is to employ mental imagery (Pearson, Deeprose, Wallace-Hadrill, Heyes, & Holmes, 2013). Mental imagery is the effortful instantiation of a percept absent external stimulation, reflecting a weak form of perception (Pearson, Naselaris, Holmes, & Kosslyn, 2015). An unexplored possibility is that one could open the reconsolidation window via forming a mental image of the reminded CS+. Supporting this proposition, Lewis, O’Reilly, Khuu, and Pearson (2013) showed that participants can emotionally condition to imagined percept, and such conditioning generalizes to instances of viewing the previously imagined percept. More recently, Agren, Björkstrand, and Fredrikson (2017) showed that fear extinction via mental imagery was comparable to standard visual fear extinction
E-mail addresses: [email protected] (L. Grégoire), [email protected] (S.G. Greening). https://doi.org/10.1016/j.cognition.2018.12.001 Received 19 August 2018; Received in revised form 21 November 2018; Accepted 3 December 2018 0010-0277/ © 2018 Published by Elsevier B.V.
Cognition 183 (2019) 277–281
L. Grégoire, S.G. Greening
previous research (e.g., Dunsmoor, White, & LaBar, 2011; Lim & Pessoa, 2008), SCRs were considered related to stimulus presentation if the trough-to-peak response occurred between 1 and 6 s following stimulus onset, and was greater than 0.02 microsiemens (µS). If these criteria were not met, the SCR was scored as zero. Consistent with prior studies (Greening, Lee, & Mather, 2016), we excluded trials that included shocks as the SCRs on these trials can reflect the unconditioned response and not a conditioned one. SCRs were square-root transformed to attain normality prior to statistical analysis (Levey, 1980). For details regarding our statistical analytic approach refer to the results section below and supplemental materials. Most notably, we calculated a recovery index (Schiller et al., 2013) in order to document a statistical interaction between the reminded CS+ and the non-reminded CS+. The recovery index is the SCR difference between the first trial of reextinction (day 3) and the last trial of extinction (day 2) for the conditioned fear response (CS+ minus CS−). Note that the first CS− trial in the re-extinction phase was disregarded due to the orienting response (Schiller et al., 2010). Calculating the recovery index using the first two trials during the re-extinction phase (Agren et al., 2017) produced similar results (see Supplemental Material).
using a memory retrieval-extinction procedure in which the reminder cues were always viewed. The present study tested the prediction that mental imagery rather than external stimulation is sufficient to open the reconsolidation window by activating a conditioned fear memory trace thereby rendering it susceptible to disruption by extinction training. 2. Method 2.1. Participants Twenty-five undergraduate students completed our three-day protocol, of which 19 participants (14 females, mean age = 19.11 years, SD = 1.74) were included in the current study. To ensure that learning occurred and was expressed, we applied the same exclusion criteria described in previous articles on reconsolidation of fear conditioning (Schiller et al., 2010, 2013; see Supplemental Material), and our sample size was based on prior research. This study was approved by the Institutional Review Board of the Louisiana State University and all participants provided written informed consent. 2.2. Materials
3. Results
The conditioned stimuli consisted of three Gabor patches (diameter: 8°; spatial frequency: 2.1 Hz; contrast ratio: 0.75) generated and presented with Matlab R2016b: one horizontal, one vertical and one oriented 45° from the horizontal (which was referred to as the ‘rightward’ oriented patch). The US consisted of a 4-ms mild electric shock (administered using the STMISOC and STM100C modules of BIOPAC Systems) delivered by means of two electrodes placed on the distal phalanges of the fourth and fifth digits of the left hand.
3.1. Subjective ratings Self-reported ratings of fear following the acquisition phase, day 1, confirmed that subjective fear was similarly acquired for both CS+ s compared to the CS−. We observed a significant main effect of CS type for self-reported fear of shock, F(2, 36) = 22.87, p < .001, ηp2 = 0.560. Self-reported fear of shock was significantly higher for both the reminded CS+ and the non-reminded CS+ compared to the CS− (M = 4.32, SD = 1.86, M = 4.58, SD = 1.95, and M = 1.68, SD = 1.16, respectively), t(18) = 5.50, p < .001, d = 1.26, and t(18) = 5.53, p < .001, d = 1.27, respectively. No significant difference was observed between the two CS+ s, t(18) = 0.64, p = .530. On day 2, as a manipulation check, participants self-reported making a significant effort to form a mental image of the cued CS+ (i.e., the reminded CS+) during the reactivation trial, M = 5.21, SD = 1.36, range: 3–7, when scores were compared to 1, t(18) = 13.52, p < .001, d = 3.10 (the 7-point scale, which aimed to evaluate how hard participants tried to form a mental image, were ranging from “1 = not at all“ to “7 = very hard”), thus confirming that they followed the experimental instructions.
2.3. Procedure The three-day protocol and experimental paradigms are described in Fig. 1 and in detail in the Supplemental Material. Briefly, consistent with previous research into fear reconsolidation, the present experiment spanned three consecutive days with a 24 h interval: day 1, habituation and acquisition; day 2, reactivation and extinction; day 3, reinstatement and re-extinction, in a within-subject design (Oyarzún et al., 2012; Schiller et al., 2010, 2013). The fear conditioning procedure involved a partial reinforcement schedule during acquisition trials and resulted in two CS+ s, one of which was the reminded CS+ during reactivation, while the second CS+ was never reminded (i.e., it was absent from the reactivation phase on day 2). The third CS was never paired with shock (i.e., CS−). During all experimental stages, except for the habituation phase and the breaks, the participants were attached to the SCR and shock electrodes, and the shock stimulator was set to the ‘On’ position.
3.2. Skin conductance responses On day 1, repeated-measures ANOVA of SCRs revealed no significant main effect of time, F(1, 18) = 0.24, p = .630, a significant main effect of CS type, F(2, 36) = 23.10, p < .001, ηp2 = 0.562, and a significant CS type × time interaction, F(2, 36) = 10.45, p < .001, ηp2 = 0.367, reflecting a greater CS type effect in the late phase, F(2,
2.3.1. Self-reported evaluation of subjective fear and imagery effort Following the acquisition phase, participants provided self-reported evaluations of their subjective fear for each conditioned stimulus. Similarly, after the extinction phase on day 2, participants rated how hard they tried to form the mental image during the reactivation trial. Both self-reported evaluations used 7-point Likert scales (see Supplemental Material for more detail).
36) = 76.22, p < .001, ηp2 = 0.809, than in the early phase, F(2, 36) = 0.23, p = .799. During the second half of the acquisition phase, SCRs were significantly higher for the reminded CS+ and the non-reminded CS+ than for the CS−, t(18) = 9.13, p < .001, d = 2.09, and t (18) = 9.97, p < .001, d = 2.29, respectively. No significant difference was observed between the two CS+ s, t(18) = 0.69, p = .501. Therefore, consistent with the self-reported fear of shock, SCRs measured during the second half of the acquisition phase (day 1) indicated that fear conditioning was similarly acquired for the two CS+ s, which is expected given our inclusion criteria. The complete summary of SCR data for the experiment are presented in Fig. 2. On day 2, the SCR data showed that fear was effectively and similarly extinguished for each CS+ at the end of the extinction phase. Repeated-measures ANOVA of SCRs revealed a significant main effect
2.3.2. Skin conductance monitoring Electrodermal activity was recorded with the Biopac MP-150 system and AcqKnowledge software (BIOPAC systems, Goleta, CA, USA), from which we derived SCRs for use as the primary dependent variable. The electrodermal activity was sampled at 2000 Hz. A conductive salinebased gel (Biopac GEL101) was used with Ag/AgCl electrodes that were placed on the distal phalanges of the second and third digits of the left hand. The SCR analysis was carried out in Matlab R2016b. Similar to 278
Cognition 183 (2019) 277–281
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Fig. 1. Three-day experimental design and timeline (A). Sequence of events in the habituation phase and the memory reactivation trial (B–C). Each trial began by an auditory instruction for 2 s followed by a view (B) or imagine (C) trial for 4 s. Then, the ITI varied randomly between 12 and 14 s until the next trial. The memory reactivation phase of day two involved an imagine trial of the reminded CS+ identical to a habituation imagine trial as depicted in (C). All other trial types during acquisition, extinction, and re-extinction involved viewing the conditioned stimuli without antecedent auditory cues.
of time, F(1, 18) = 8.18, p = .010, ηp2 = 0.312, reflecting larger SCRs in the early phase than in the late phase of extinction, no significant main effect of CS type, F(2, 36) = 0.58, p = .567, and no significant CS type × time interaction, F(2, 36) = 1.00, p = .378, indicating no difference between the CSs during either early or late extinction. Additionally, the decrease of SCRs from the second half of acquisition to the last trial of extinction was significant for each CS+: t(18) = 2.26, p = .036, d = 0.52, for the reminded CS+ and t(18) = 2.16, p = .045, d = 0.49, for the non-reminded CS+ (no significant difference for the CS−, t(18) = 1.68, p = .111). In order to test the crucial prediction that imaginal exposure to a CS + was sufficient to open the reconsolidation window and facilitate the attenuation or modulation of conditioned fear, we evaluated the SCR difference between the first re-extinction trial (day 3) and the last extinction trial (day 2) for the reminded CS+ versus the non-reminded CS +. As predicted, and supporting that mental imagery is sufficient to destabilize a fear memory trace, this difference was significant for the non-reminded CS+, t(18) = 2.14, p = .047, d = 0.49, but not for the reminded CS+, t(18) = 0.78, p = .447 (nor for the CS−, t < 1). The magnitude of the recovery index was significantly higher for the nonreminded CS+ than for the reminded CS+, t(18) = 2.54, p = .021, d = 0.58 (Fig. 2B). Thus, skin conductance reactions, indexing fear, did not recover for the reminded (mentally imaged) CS+, whereas it did recover for the non-reminded CS+. This attests that mental imagery facilitated reconsolidation of a conditioned fear association.
using standard extinction training during memory reconsolidation. Over the course of three consecutive days, participants underwent fear acquisition (day 1), an imaginal memory reactivation using mental imagery (i.e., a single trial imagining one of two CS+) followed by standard extinction training ten minutes later including both reactivated and not activated cues, both within the reconsolidation window, on day 2, and during day 3 reinstatement using four unsignaled shocks followed by re-extinction. Importantly, two CSs were fear conditioned during acquisition on day 1 but only one was reminded before extinction (day 2). We observed no evidence of fear recovery on the first trial of re-extinction (day 3) for the reminded CS+, whereas fear returned for the non-reminded CS+. Thus, a fear memory representation can be reactivated by an imaginal reminder and subsequently disrupted by extinction learning. To our knowledge, this study is the first demonstration of fear attenuation using imaginal reactivation. Functional imaging studies indicate that mental imagery is a weak form of the externally stimulated perception (Pearson et al., 2015). The current findings indicate that although imagery is weak form of perception, it is sufficient for opening the reconsolidation window thereby allowing for fear attenuation and possibly erasure via extinction training. This is consistent with observations that imagery can interact with emotional associative learning and generalization (Lewis et al., 2013), and fear extinction (Agren et al., 2017). In addition, while both imagery and externally-generated perception are likely impacting reconsolidation due to their similar activation of perceptual representations, previous research indicates that mental imagery requires additional contributions from memory and visual working-memory processes (Pearson et al., 2015). This suggests that the potentially efficacy of mental imagery reactivation could depend on one’s memory or
4. Discussion The present study demonstrated that an imaginal reactivation trial was sufficient to attenuate the expression of a conditioned fear memory 279
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Fig. 2. (A) Mean SCRs for reminded CS+, non-reminded CS+ and CS− during acquisition (mean of the four last trials), extinction (last trial) and re-extinction (first trial). (B) Recovery index: SCR difference between the first trial of re-extinction (day 3) and the last trial of extinction (day 2) for CS+ minus CS−. (C) Trial-by-trial mean SCRs for reminded CS+, non-reminded CS+ and CS− during acquisition (excluding the CS+ trials paired with the shock), reactivation, extinction and reextinction (excluding the first presentation of CS−). Asterisks indicate significant differences within groups (*p < .05). Error bars represent standard errors.
reconsolidation of conditioned fear associations, though not necessarily all (e.g., Golkar et al., 2012, Experiment 2). Lastly, the present findings widen possible curative applications of cue induced trauma and anxiety disorders by identifying imagery as a potential substitute for physical exposure to triggering stimuli, particularly PTSD (James et al., 2015). Future research is required to determine whether and how imagery affects those factors that appear similar across PTSD and fear condition, such as context-dependent or generalized reconsolidation-enhanced extinction, versus how imagery affects factors apparently unique to PTSD such as intrusions and avoidance (Gray & Bourke, 2015). The current findings might also be useful for the treatment of symptoms associated with specific phobia (e.g., Telch, York, Lancaster, & Monfils, 2017).
working memory ability. Notably, we observed an SCR drop-off following the first trial of reextinction, though a similar pattern was observed by Schiller et al. (2013). Trial-wise SCR measurements can be noisy, hence some previous research averaged across the first two trials of re-extinction in their calculation of the recover index (e.g., Agren et al., 2017). In a supplemental analysis using this criterion we still found significant differences between the non-reminded and reminded CS+ s. The visual properties of the conditioned stimuli could explain why the SCR drop-off during re-extinction occurred abruptly in the current study. While our study used low-level visual stimuli (Gabors) as CSs, which are differentially processed in the primary visual cortex, the colored shapes used by others (e.g., Oyarzún et al., 2012; Schiller et al., 2010) are processed later in the visual stream (e.g., V4 or lateral occipital complex; Grill-Spector, Kourtzi, & Kanwisher, 2001). Related to the importance of conditioned stimulus type, biologically relevant stimuli such as spiders and snakes are resistant to fear extinction generally (Öhman & Mineka, 2001) and appear resistant to reconsolidation (Golkar, Bellander, Olsson, & Öhman, 2012; Kindt & Soeter, 2013). This latter point could explain some of the failures to replicate the
Acknowledgement This research was supported by Louisiana Board of Regents grant to S.G.G.
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Appendix A. Supplementary material
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The data associated with this article can be found at https://osf.io/ dmz2c/. Supplementary data to this article can be found online at https://doi.org/10.1016/j.cognition.2018.12.001. References Agren, T., Björkstrand, J., & Fredrikson, M. (2017). Disruption of human fear reconsolidation using imaginal and in vivo extinction. Behavioural Brain Research, 319, 9–15. https://doi.org/10.1016/j.bbr.2016.11.014. Auber, A., Tedesco, V., Jones, C. E., Monfils, M. H., & Chiamulera, C. (2013). Post-retrieval extinction as reconsolidation interference: Methodological issues or boundary conditions? Psychopharmacology, 226(4), 631–647. https://doi.org/10.1007/s00213013-3004-1. Björkstrand, J., Agren, T., Frick, A., Engman, J., Larsson, E. M., Furmark, T., & Fredrikson, M. (2015). Disruption of memory reconsolidation erases a fear memory trace in the human amygdala: An 18-month follow-up. Plos One, 10(7), e0129393. https://doi. org/10.1371/journal.pone.0129393. Dunsmoor, J. E., White, A. J., & LaBar, K. S. (2011). Conceptual similarity promotes generalization of higher order fear learning. Learning & Memory, 18(3), 156–160. https://doi.org/10.1101/lm.2016411. Golkar, A., Bellander, M., Olsson, A., & Öhman, A. (2012). Are fear memories erasable?reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli. Frontiers in Behavioral Neuroscience, 6, 80. https://doi.org/10.3389/fnbeh.2012.00080. Gray, R. M., & Bourke, F. (2015). Remediation of intrusive symptoms of PTSD in fewer than five sessions: A 30-person pre-pilot study of the RTM Protocol. Journal of Military, Veteran and Family Health, 1(2), 13–20. https://doi.org/10.3138/jmvfh. 2996. Greening, S. G., Lee, T. H., & Mather, M. (2016). Individual differences in anticipatory somatosensory cortex activity for shock is positively related with trait anxiety and multisensory integration. Brain Sciences, 6(1), 2. https://doi.org/10.3390/ brainsci6010002. Grill-Spector, K., Kourtzi, Z., & Kanwisher, N. (2001). The lateral occipital complex and its role in object recognition. Vision Research, 41(10–11), 1409–1422. https://doi. org/10.1016/S0042-6989(01)00073-6. James, E. L., Bonsall, M. B., Hoppitt, L., Tunbridge, E. M., Geddes, J. R., Milton, A. L., & Holmes, E. A. (2015). Computer game play reduces intrusive memories of experimental trauma via reconsolidation-update mechanisms. Psychological Science, 26(8), 1201–1215. https://doi.org/10.1177/0956797615583071. Kindt, M., & Soeter, M. (2013). Reconsolidation in a human fear conditioning study: A test
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Contents lists available at ScienceDirect
Cognition journal homepage: www.elsevier.com/locate/cognit
Brief article
Opening the reconsolidation window using the mind’s eye: Extinction training during reconsolidation disrupts fear memory expression following mental imagery reactivation
T
Laurent Grégoire, Steven G. Greening CNAPs Lab, Department of Psychology, Louisiana State University, B3 Audubon Hall, Baton Rouge, LA 70803, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Fear conditioning Memory reconsolidation Fear extinction Mental imagery Fear reconsolidation
Can mental imagery rather than external stimulation reactivate an aversive conditioned memory for the purposes of attenuating fear with subsequent extinction training? To answer this question participant underwent a three-day protocol: Day 1 entailed fear acquisition training in which two conditioned stimuli were paired with mild shock (US), while a CS− never was; day 2 included imagery-based reactivation of only one of the two CS+ followed by standard extinction training within the reconsolidation ten minutes later; day 3 included reinstatement by the unsignaled presentation of the US followed by a re-extinction phase. We observed no evidence of fear recovery on the first trial of re-extinction for the reminded, mentally imaged, CS+, whereas fear returned for the non-reminded CS+. Thus, mental imagery was sufficient to reactivate a fear memory thereby opening the reconsolidation window and facilitating fear suppression via extinction training. The clinical implications of this are potentially far-reaching as it allows for in vivo reconsolidation procedures in exposure therapy.
1. Introduction Consolidated memories are not permanently encoded (Lee, Nader, & Schiller, 2017, for a review). Instead, re-exposure to a reminder renders memory susceptible to modification by novel learning, a process known as reconsolidation (Auber, Tedesco, Jones, Monfils, & Chiamulera, 2013; Lee et al., 2017). How can the mechanisms of reconsolidation can be employed to modify learned fear associations, as occurs in PTSD and specific phobia? Recent experimental evidence using fear conditioning, in which a conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US), demonstrates that extinction training (in which the CS+ is repeatedly presented without the US) during reconsolidation produces a disruption of the original fear conditioned association (e.g., Oyarzún et al., 2012; Schiller, Kanen, LeDoux, Monfils, & Phelps, 2013; Schiller et al., 2010). This discovery overcomes previous shortcomings of fear suppression by extinction learning, which is often temporary and susceptible to the return of the conditioned fear response. Mechanistically, the presentation of a reminder cue destabilizes the retrieved memory rendering it transiently labile by instantiating a state of new protein synthesis (Nader, Schafe, & LeDoux, 2000). Subsequent extinction training performed within this reconsolidation window, between 10 min and 1 h after reactivation (Monfils, Cowansage, Klann, &
LeDoux, 2009), allows for the disruption of the initial fear memory and prevents the return of fear (Auber et al., 2013; Lee et al., 2017). Longlasting behavioral effects of fear attenuation have been observed one year (Schiller et al., 2010, Experiment 1) and over 18 months (Björkstrand et al., 2015) after extinction, reflecting the stability of the updated memory. One major limitation of current approaches to fear disruption via reconsolidation is that they rely on the presentation of the physically experienced CS+ as the reminder cue. In practice, for those with PTSD or specific phobias, such an approach is either impractical (e.g., access to trigger stimuli might be impossible) or excessively evocative. An alternative strategy is to employ mental imagery (Pearson, Deeprose, Wallace-Hadrill, Heyes, & Holmes, 2013). Mental imagery is the effortful instantiation of a percept absent external stimulation, reflecting a weak form of perception (Pearson, Naselaris, Holmes, & Kosslyn, 2015). An unexplored possibility is that one could open the reconsolidation window via forming a mental image of the reminded CS+. Supporting this proposition, Lewis, O’Reilly, Khuu, and Pearson (2013) showed that participants can emotionally condition to imagined percept, and such conditioning generalizes to instances of viewing the previously imagined percept. More recently, Agren, Björkstrand, and Fredrikson (2017) showed that fear extinction via mental imagery was comparable to standard visual fear extinction
E-mail addresses: [email protected] (L. Grégoire), [email protected] (S.G. Greening). https://doi.org/10.1016/j.cognition.2018.12.001 Received 19 August 2018; Received in revised form 21 November 2018; Accepted 3 December 2018 0010-0277/ © 2018 Published by Elsevier B.V.
Cognition 183 (2019) 277–281
L. Grégoire, S.G. Greening
previous research (e.g., Dunsmoor, White, & LaBar, 2011; Lim & Pessoa, 2008), SCRs were considered related to stimulus presentation if the trough-to-peak response occurred between 1 and 6 s following stimulus onset, and was greater than 0.02 microsiemens (µS). If these criteria were not met, the SCR was scored as zero. Consistent with prior studies (Greening, Lee, & Mather, 2016), we excluded trials that included shocks as the SCRs on these trials can reflect the unconditioned response and not a conditioned one. SCRs were square-root transformed to attain normality prior to statistical analysis (Levey, 1980). For details regarding our statistical analytic approach refer to the results section below and supplemental materials. Most notably, we calculated a recovery index (Schiller et al., 2013) in order to document a statistical interaction between the reminded CS+ and the non-reminded CS+. The recovery index is the SCR difference between the first trial of reextinction (day 3) and the last trial of extinction (day 2) for the conditioned fear response (CS+ minus CS−). Note that the first CS− trial in the re-extinction phase was disregarded due to the orienting response (Schiller et al., 2010). Calculating the recovery index using the first two trials during the re-extinction phase (Agren et al., 2017) produced similar results (see Supplemental Material).
using a memory retrieval-extinction procedure in which the reminder cues were always viewed. The present study tested the prediction that mental imagery rather than external stimulation is sufficient to open the reconsolidation window by activating a conditioned fear memory trace thereby rendering it susceptible to disruption by extinction training. 2. Method 2.1. Participants Twenty-five undergraduate students completed our three-day protocol, of which 19 participants (14 females, mean age = 19.11 years, SD = 1.74) were included in the current study. To ensure that learning occurred and was expressed, we applied the same exclusion criteria described in previous articles on reconsolidation of fear conditioning (Schiller et al., 2010, 2013; see Supplemental Material), and our sample size was based on prior research. This study was approved by the Institutional Review Board of the Louisiana State University and all participants provided written informed consent. 2.2. Materials
3. Results
The conditioned stimuli consisted of three Gabor patches (diameter: 8°; spatial frequency: 2.1 Hz; contrast ratio: 0.75) generated and presented with Matlab R2016b: one horizontal, one vertical and one oriented 45° from the horizontal (which was referred to as the ‘rightward’ oriented patch). The US consisted of a 4-ms mild electric shock (administered using the STMISOC and STM100C modules of BIOPAC Systems) delivered by means of two electrodes placed on the distal phalanges of the fourth and fifth digits of the left hand.
3.1. Subjective ratings Self-reported ratings of fear following the acquisition phase, day 1, confirmed that subjective fear was similarly acquired for both CS+ s compared to the CS−. We observed a significant main effect of CS type for self-reported fear of shock, F(2, 36) = 22.87, p < .001, ηp2 = 0.560. Self-reported fear of shock was significantly higher for both the reminded CS+ and the non-reminded CS+ compared to the CS− (M = 4.32, SD = 1.86, M = 4.58, SD = 1.95, and M = 1.68, SD = 1.16, respectively), t(18) = 5.50, p < .001, d = 1.26, and t(18) = 5.53, p < .001, d = 1.27, respectively. No significant difference was observed between the two CS+ s, t(18) = 0.64, p = .530. On day 2, as a manipulation check, participants self-reported making a significant effort to form a mental image of the cued CS+ (i.e., the reminded CS+) during the reactivation trial, M = 5.21, SD = 1.36, range: 3–7, when scores were compared to 1, t(18) = 13.52, p < .001, d = 3.10 (the 7-point scale, which aimed to evaluate how hard participants tried to form a mental image, were ranging from “1 = not at all“ to “7 = very hard”), thus confirming that they followed the experimental instructions.
2.3. Procedure The three-day protocol and experimental paradigms are described in Fig. 1 and in detail in the Supplemental Material. Briefly, consistent with previous research into fear reconsolidation, the present experiment spanned three consecutive days with a 24 h interval: day 1, habituation and acquisition; day 2, reactivation and extinction; day 3, reinstatement and re-extinction, in a within-subject design (Oyarzún et al., 2012; Schiller et al., 2010, 2013). The fear conditioning procedure involved a partial reinforcement schedule during acquisition trials and resulted in two CS+ s, one of which was the reminded CS+ during reactivation, while the second CS+ was never reminded (i.e., it was absent from the reactivation phase on day 2). The third CS was never paired with shock (i.e., CS−). During all experimental stages, except for the habituation phase and the breaks, the participants were attached to the SCR and shock electrodes, and the shock stimulator was set to the ‘On’ position.
3.2. Skin conductance responses On day 1, repeated-measures ANOVA of SCRs revealed no significant main effect of time, F(1, 18) = 0.24, p = .630, a significant main effect of CS type, F(2, 36) = 23.10, p < .001, ηp2 = 0.562, and a significant CS type × time interaction, F(2, 36) = 10.45, p < .001, ηp2 = 0.367, reflecting a greater CS type effect in the late phase, F(2,
2.3.1. Self-reported evaluation of subjective fear and imagery effort Following the acquisition phase, participants provided self-reported evaluations of their subjective fear for each conditioned stimulus. Similarly, after the extinction phase on day 2, participants rated how hard they tried to form the mental image during the reactivation trial. Both self-reported evaluations used 7-point Likert scales (see Supplemental Material for more detail).
36) = 76.22, p < .001, ηp2 = 0.809, than in the early phase, F(2, 36) = 0.23, p = .799. During the second half of the acquisition phase, SCRs were significantly higher for the reminded CS+ and the non-reminded CS+ than for the CS−, t(18) = 9.13, p < .001, d = 2.09, and t (18) = 9.97, p < .001, d = 2.29, respectively. No significant difference was observed between the two CS+ s, t(18) = 0.69, p = .501. Therefore, consistent with the self-reported fear of shock, SCRs measured during the second half of the acquisition phase (day 1) indicated that fear conditioning was similarly acquired for the two CS+ s, which is expected given our inclusion criteria. The complete summary of SCR data for the experiment are presented in Fig. 2. On day 2, the SCR data showed that fear was effectively and similarly extinguished for each CS+ at the end of the extinction phase. Repeated-measures ANOVA of SCRs revealed a significant main effect
2.3.2. Skin conductance monitoring Electrodermal activity was recorded with the Biopac MP-150 system and AcqKnowledge software (BIOPAC systems, Goleta, CA, USA), from which we derived SCRs for use as the primary dependent variable. The electrodermal activity was sampled at 2000 Hz. A conductive salinebased gel (Biopac GEL101) was used with Ag/AgCl electrodes that were placed on the distal phalanges of the second and third digits of the left hand. The SCR analysis was carried out in Matlab R2016b. Similar to 278
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Fig. 1. Three-day experimental design and timeline (A). Sequence of events in the habituation phase and the memory reactivation trial (B–C). Each trial began by an auditory instruction for 2 s followed by a view (B) or imagine (C) trial for 4 s. Then, the ITI varied randomly between 12 and 14 s until the next trial. The memory reactivation phase of day two involved an imagine trial of the reminded CS+ identical to a habituation imagine trial as depicted in (C). All other trial types during acquisition, extinction, and re-extinction involved viewing the conditioned stimuli without antecedent auditory cues.
of time, F(1, 18) = 8.18, p = .010, ηp2 = 0.312, reflecting larger SCRs in the early phase than in the late phase of extinction, no significant main effect of CS type, F(2, 36) = 0.58, p = .567, and no significant CS type × time interaction, F(2, 36) = 1.00, p = .378, indicating no difference between the CSs during either early or late extinction. Additionally, the decrease of SCRs from the second half of acquisition to the last trial of extinction was significant for each CS+: t(18) = 2.26, p = .036, d = 0.52, for the reminded CS+ and t(18) = 2.16, p = .045, d = 0.49, for the non-reminded CS+ (no significant difference for the CS−, t(18) = 1.68, p = .111). In order to test the crucial prediction that imaginal exposure to a CS + was sufficient to open the reconsolidation window and facilitate the attenuation or modulation of conditioned fear, we evaluated the SCR difference between the first re-extinction trial (day 3) and the last extinction trial (day 2) for the reminded CS+ versus the non-reminded CS +. As predicted, and supporting that mental imagery is sufficient to destabilize a fear memory trace, this difference was significant for the non-reminded CS+, t(18) = 2.14, p = .047, d = 0.49, but not for the reminded CS+, t(18) = 0.78, p = .447 (nor for the CS−, t < 1). The magnitude of the recovery index was significantly higher for the nonreminded CS+ than for the reminded CS+, t(18) = 2.54, p = .021, d = 0.58 (Fig. 2B). Thus, skin conductance reactions, indexing fear, did not recover for the reminded (mentally imaged) CS+, whereas it did recover for the non-reminded CS+. This attests that mental imagery facilitated reconsolidation of a conditioned fear association.
using standard extinction training during memory reconsolidation. Over the course of three consecutive days, participants underwent fear acquisition (day 1), an imaginal memory reactivation using mental imagery (i.e., a single trial imagining one of two CS+) followed by standard extinction training ten minutes later including both reactivated and not activated cues, both within the reconsolidation window, on day 2, and during day 3 reinstatement using four unsignaled shocks followed by re-extinction. Importantly, two CSs were fear conditioned during acquisition on day 1 but only one was reminded before extinction (day 2). We observed no evidence of fear recovery on the first trial of re-extinction (day 3) for the reminded CS+, whereas fear returned for the non-reminded CS+. Thus, a fear memory representation can be reactivated by an imaginal reminder and subsequently disrupted by extinction learning. To our knowledge, this study is the first demonstration of fear attenuation using imaginal reactivation. Functional imaging studies indicate that mental imagery is a weak form of the externally stimulated perception (Pearson et al., 2015). The current findings indicate that although imagery is weak form of perception, it is sufficient for opening the reconsolidation window thereby allowing for fear attenuation and possibly erasure via extinction training. This is consistent with observations that imagery can interact with emotional associative learning and generalization (Lewis et al., 2013), and fear extinction (Agren et al., 2017). In addition, while both imagery and externally-generated perception are likely impacting reconsolidation due to their similar activation of perceptual representations, previous research indicates that mental imagery requires additional contributions from memory and visual working-memory processes (Pearson et al., 2015). This suggests that the potentially efficacy of mental imagery reactivation could depend on one’s memory or
4. Discussion The present study demonstrated that an imaginal reactivation trial was sufficient to attenuate the expression of a conditioned fear memory 279
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Fig. 2. (A) Mean SCRs for reminded CS+, non-reminded CS+ and CS− during acquisition (mean of the four last trials), extinction (last trial) and re-extinction (first trial). (B) Recovery index: SCR difference between the first trial of re-extinction (day 3) and the last trial of extinction (day 2) for CS+ minus CS−. (C) Trial-by-trial mean SCRs for reminded CS+, non-reminded CS+ and CS− during acquisition (excluding the CS+ trials paired with the shock), reactivation, extinction and reextinction (excluding the first presentation of CS−). Asterisks indicate significant differences within groups (*p < .05). Error bars represent standard errors.
reconsolidation of conditioned fear associations, though not necessarily all (e.g., Golkar et al., 2012, Experiment 2). Lastly, the present findings widen possible curative applications of cue induced trauma and anxiety disorders by identifying imagery as a potential substitute for physical exposure to triggering stimuli, particularly PTSD (James et al., 2015). Future research is required to determine whether and how imagery affects those factors that appear similar across PTSD and fear condition, such as context-dependent or generalized reconsolidation-enhanced extinction, versus how imagery affects factors apparently unique to PTSD such as intrusions and avoidance (Gray & Bourke, 2015). The current findings might also be useful for the treatment of symptoms associated with specific phobia (e.g., Telch, York, Lancaster, & Monfils, 2017).
working memory ability. Notably, we observed an SCR drop-off following the first trial of reextinction, though a similar pattern was observed by Schiller et al. (2013). Trial-wise SCR measurements can be noisy, hence some previous research averaged across the first two trials of re-extinction in their calculation of the recover index (e.g., Agren et al., 2017). In a supplemental analysis using this criterion we still found significant differences between the non-reminded and reminded CS+ s. The visual properties of the conditioned stimuli could explain why the SCR drop-off during re-extinction occurred abruptly in the current study. While our study used low-level visual stimuli (Gabors) as CSs, which are differentially processed in the primary visual cortex, the colored shapes used by others (e.g., Oyarzún et al., 2012; Schiller et al., 2010) are processed later in the visual stream (e.g., V4 or lateral occipital complex; Grill-Spector, Kourtzi, & Kanwisher, 2001). Related to the importance of conditioned stimulus type, biologically relevant stimuli such as spiders and snakes are resistant to fear extinction generally (Öhman & Mineka, 2001) and appear resistant to reconsolidation (Golkar, Bellander, Olsson, & Öhman, 2012; Kindt & Soeter, 2013). This latter point could explain some of the failures to replicate the
Acknowledgement This research was supported by Louisiana Board of Regents grant to S.G.G.
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Appendix A. Supplementary material
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