Updating Fearful Memories with Extinction Training during Reconsolidation: A Human Study Using Auditory Aversive Stimuli

Oyarzún, Javiera P.; López-Barroso, Diana; Fuentemilla, Lluís; Cucurell, David; Pedraza, Carmen; Rodrı́guez-Fornells, Antoni; Diego‐Balaguer, Ruth de

doi:10.1371/journal.pone.0038849

Cited by 112 publications

(156 citation statements)

References 64 publications

(111 reference statements)

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“…The failure to "update" and interfere with the reconsolidation process using a nonpharmacological intervention observed in the present study is at odds with the findings of Shiller et al, (2010), and Agren et al, (2012), but consistent with prior negative results from Soeter and Kindt (2011), Kindt and Soeter (2013), Golkar et al (2012) and Oyarzun et al (2012). The explanation for the inconsistent findings across studies is not readily apparent.…”

Section: Discussioncontrasting

confidence: 53%

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Orr¹

2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERMassachusetts General Hospital Boston, Massachusetts 02114 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTAnimal research suggests that reactivation (retrieval) of a consolidated memory can return it to a labile state from which it must be restabilized in order to persist. This stabilization process has been termed "reconsolidation", and various behavioral and pharmacological interventions have been found to modify or block it. The aim of this project was to create an experimental assay in the form of an optimal Pavlovian differential fear-conditioning paradigm, within which the relative strengths of various pharmacological and behavioral, reconsolidation-blocking interventions could be tested. We completed testing for two pharmacological interventions and a behavioral intervention. Study of a third pharmacological intervention was initiated.Results from propranolol and behavioral intervention groups demonstrated differential conditioning learning on Day 1, supporting the validity of our modified fear-conditioning paradigm. Propranolol administration and the behavioral intervention at the time of memory reactivation did not decrease the fear memory, as indexed by skin conductance, when assessing renewal and reinstatement. Mifepristone was tested as a second pharmacological intervention. After adjusting for initial differences in conditioned response strength, results suggest that mifepristone did reduce the fear memory. Results from a third pharmacological intervention, oxytocin, tentatively suggest a generalized reduction of the fear memory. SUBJECT TERMSPost-traumatic stress disorder; reconsolidation; fear conditioning; psychophysiology

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Section: Discussioncontrasting

confidence: 53%

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Orr¹

2015

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“…There is indeed an alternative method where extinction training is presented within the window of reconsolidation 49 . Several studies failed however to replicate these original findings by Schiller et al 29,50-52 but see 53,54 . In addition to these conflicting results, another potential limitation of the extinction within reactivation procedure would be that in clinical practice the fear response is generally not extinguished in a one-session exposure treatment.…”

Section: Discussionmentioning

confidence: 95%

Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic β-Blocker

Kindt

Soeter

Sevenster

2014

JoVE

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The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 -the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 -the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 -the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1-and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.

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“…Recently, it has been shown in mice (10,11), rats (12), and humans (13)(14)(15)(16)) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions).…”

mentioning

confidence: 99%

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

Schiller

Kanen²,

LeDoux

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

252

253

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Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala-PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC-amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.fear | Pavlovian conditioning | defense | learning E fforts to control maladaptive defensive reactions through extinction or exposure therapy are sometimes short-lived because these techniques do not significantly alter the threat memory itself, but rather regulate its expression via the prefrontal cortex's (PFC) inhibition of the amygdala (1, 2). Individual variation in the integrity of this amygdala-prefrontal circuitry has been linked to trait anxiety and posttraumatic stress disorder, suggesting that exposure-based techniques may be least effective in those who suffer from anxiety disorders (3-9).Recently, it has been shown in mice (10, 11), rats (12), and humans (13-16) that precisely timing behavioral extinction to coincide with memory reconsolidation can persistently inhibit the return of defensive reactions (but see refs. 17-19 for a discussion of boundary conditions). Reconsolidation is the state to which memories enter upon retrieval, which makes them prone to interference (20)(21)(22). Behavioral interference of reconsolidation using extinction has been linked to alterations in glutamate receptor function in the amygdala, which plays a critical role in memory plasticity (10,12). These findings are consistent with the suggestion that, in contrast to standar...

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Updating Fearful Memories with Extinction Training during Reconsolidation: A Human Study Using Auditory Aversive Stimuli

Cited by 112 publications

References 64 publications

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic β-Blocker

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

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Updating Fearful Memories with Extinction Training during Reconsolidation: A Human Study Using Auditory Aversive Stimuli

Cited by 112 publications

References 64 publications

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Psychophysiology of Delayed Extinction and Reconsolidation in Humans

Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic &#946;-Blocker

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

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Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic β-Blocker