L8 Destructing Fear Memory Flashcards
Learning Objectives
- Explain how modern learning theory explains reduction of fear during exposure (inhibition learning)
- Describe research methods on the return of extinguished fear [paraphrase] and explain how these methods can test the hypothesis of inhibition learning
- Explain how the modern learning theory for fear reduction during exposure (inhibition learning) differs from a habituation explanation.
- Describe the neurobiological processes of extinction (inhibition) learning.
- Explain why, according to the hypothesis of inhibition learning, expectancy violation is crucial for exposure.
- Explain how different strategies can increase extinction (inhibition) learning during exposure and apply these to a clinical case.
- Describe the process of memory reconsolidation and how disrupting of reconsolidation can be used therapeutically.
- Explain why prediction error is considered to be important for reconsolidation.
- Explain the difference in hypothesized mechanisms between exposure and disrupting the process of memory reconsolidation as interventions for anxiety disorders.
In these flashcards…
- Maximizing exposure therapy: An inhibitory learning approach
- Tackling maladaptive memories through reconsolidation: From neural to clinical science
- Lecture
How to read the flashcards in the right order
> flashcards 47-64 (lecture+elsey)
flashcards 19-41 (craske)
flashcards 4-19 (craske)
flashcards 64-… (lecture+elsey)
Maximizing exposure therapy: An inhibitory learning approach
- what does this article talk about?
It provides examples on how to apply Inhibitory Model of Extinction to exposure therapy
- Craske
Exposure therapy
- it has been around for years, for disorders that are anxiety and fear related
- it can differ (e.g. graduated vs intense, brief vs prolongued, imaginative vs in vivo, …)
- it can be based on three different models:
> Inhibitory learning model
> Fear habituation model (emphasis on reducing the fear through exposure)
> Behavioral testing (to explicitly disconfirm threat-laden beliefs and assumptions) - derived from early models of extinction learning
Inhibitory learning model of extinction
- during fear conditioning, the neutral stimulus (CS) is associated to an aversive event (US), leading to a fear response
- during extinction, the CS is repeatedly presented without the US, which reduces the fear response
- however, extinction does not erase the original fear association
→ instead inhibitory learning takes place: individual learns that the CS no longer predicts the US
= after extinction, the CS has:
> original excitatory meaning (CS-US)
> additional inhibitory meaning (CS-no US)
What does inhibitory learning mean?
- process by which an organism learns that a previously feared stimulus (CS) no longer predicts danger (US) after extinction training
- rather than erasing the original CS-US association, extinction creates a new, competing memory that inhibits the fear response
what is the neurological evidence for the inhibitory learning model?
- Fear conditioning→ the amygdala is highly active, creating a strong fear response
- Extinction learning→ the medial prefrontal cortex starts to exert control, inhibiting amygdala activity, reducing fear responses
= this cortical inhibition explains why extinction learning does not erase fear memories, but instead creates a secondary inhibitory memory that can suppress fear expression under the right conditions
Now there are two associations (UC-US & UC-no US)
- what does this imply?
- in what ways?
→ it means that retention of at least part of the original association can be uncovered by various procedures
How?
1. Conditional fear shows spontaneous recovery
2. Surrounding context is changed between extinction and retest
3. Unsignalated (or unpaired) US presentation occurs in between extinction and retest
4. Rapid reaquisition of fear if CS-US pairings are repeated after extinction
- Conditional fear shows spontaneous recovery
- the strength of the CR increases in proportion to the amount of time since the end of extinction
- therefore, since the end of exposure therapy, the fear will come back with time
- Surrounding context is changed between extinction and retest
- fear extinction is specific to context in which it occurs
> e.g. if always occurs with therapist and in clinical setting, if it happens in real life without therapist then fear is likely to return
- Unsignalated (or unpaired) US presentation occurs in between extinction and retest
- this means that fear might come back if an adverse event (US) occurs in an anxiety inducing context, even if not directly following the UC
> e.g. fear of asking questions at work may resurge after being rejected in another social situation, or possibly after other adverse event, such as a car accident
- Rapid reaquisition of fear if CS-US pairings are repeated after extinction
- fears might come back quickly after re-traumatization
> e.g. in combat situations / dangerous environments
Deficits in inhibition and anxiety disorders
- role of deficit in anxiety disorders
- how do they contribute?
- many patients do not really benefit from exposure therapies, or the fear comes back when the therapy ends
- this might be because of deficits in extinction learning & deficits in inhibitory learning and inhibitory neural regulation during extinction
> this is characteristic of individuals with high anxiety
→ this means that they have deficits in mechanisms that are super important for extinction learning
How?
- these deficits in mechanisms might lead to poor response to exposure
- they also contribute to the development of excessive fear and anxiety in the firs place
! Big clinical implication !
Inhibitory learning vs Habituation approach to exposure
- Habituation approach
> fear reduction during exposure is critical focus of therapy - Inhibitory learning approach
> fear reduction is not emphasized
> sometimes use strategies designed to maintain elevated fear throughout exposure trials
> fear experienced at the end of session is not predictive of fear reduction at follow-up extinction
… against habituation approach
- studies show that it is less effective than belief disconfirmation approaches and expectancy violation approaches
- neither fear reduction nor ending fear levels predict long term outcomes from extinction or exposure
- exposure strategies that specifically impede habituation were found to be more effective than strategies that do not
Divergence in response systems
- how can fear show?
- fear can show in two ways:
> an individual may stop showing outward fear responses after extinction training (e.g., they no longer freeze or avoid the stimulus), but the original CS-US association remains intact
> an individual may still show fear behaviors even when they have learned that the CS is no longer dangerous (indicates that their outward response lags behind their internal learning)
what is the fear expressed at follow-up influenced by?
More likely factors:
- passage of time
- context shifts
- adverse events
- relearning
Instead of the originally thought:
- level of fear experience at the end of exposure
Inhibitory learning vs Behavioral testing approach to exposure
Behavioral testing:
- cognitive model
- it emphasizes behavioral testing to disconfirm beliefs and assumptions
Inhibitory learning model:
- not restricted to behavioral testing
- not limited to testing of explicitly stated cognitions
> still, they have many points in common
Therapeutic strategies for enhancing inhibitory learning and retrieval
- Expectancy violation
- Deepened extinction
- Occasional reinforced extinction
- Removal of safety signals
- Variability
- Retrieval cues
- Multiple contexts
- Reconsolidation
- Expectancy violation
- Aim
- Premises
- core point
Aim:
- design exposures that maximally violate expectancies regarding the frequency or intensity of aversive outcomes
Premise:
- mistmatch between expectancy and outcome is crucial for new learning and for the development of inhibitory expectancies (that will compete with excitatory expectancies)
→ The more the expectancy can be violated
by experience, the greater the inhibitory learning
1. Expectancy violation
what is important in Expectancy violation?
1- exposure tasks are designed to accomodate “what you need to learn”, compared to “stay in the situation until fear declines” (like in habituation approach)
> e.g. for persons who irrationally expect to become erratic and hurt themselves due to prolonged anxiety, anxiety is induced for prolonged durations in order to fully violate expectancies regarding their behavior
2- important for client to identify US when predicting expectancy to be violated
> e.g. for clients with social anxiety, predicting that they will “get anxious” during a social interaction would not be sufficient, whereas predicting that they would be ignored or otherwise rejected would be sufficient
1. Expectancy violation
when does the exposure trial end?
+ Mental Rehearsal
- when expectancies are violated, and not just when fear is reduced
After each trial, the learning is consolidated by asking participants to judge
- what they learned regarding the no-US
- discrepancies between what they predicted and what happened
- degree of “surprise” from exposure practice
→ this is called Mental Rehearsal
1. Expectancy violation
what role does distraction play in the awareness of UC-no US association?
- key aspect of expectancy violation is attention to CS-no US association
- distraction→ safety behavior
> it reduces awareness of CS-no US relationship
1. Expectancy violation
what is the influence of cognitive interventions on expectancy violation?
- in expectancy violation, the main point is the extent of the discrepacy between the expectation and what happens
- cognitive interventions might go against this process, if the individuals starts by learning to decrease expectations before exposure
→ therefore, now cognitive interventions are implemented only after exposure
- Deepened extinction
- aim
- process
Aim: strengthening extinction
How:
- extinguish multiple fear CSs separately before combining them
> you first extinguish individually two stimuli that you think will lead to the same adverse outcome
> then, the CSs are presented together during the training (multiple “threatening” stimuli simultaneously)
- pairing a previously extinguished CS with a novel CS
> a CS that has already undergone extinction is presented alongside a new, unextinguished CS
> it promotes generalization of extinction learning
! both stimuli have to predict the same US
2. Deepened extinction
examples
- exposure to one specific type of spider, then a second distinctly different spider, followed by exposure to both spiders at the same time
- exposure to an obsession (such as an obsession of stabbing a loved one), exposure to a cue that triggers obsessions (such as a knife in the presence of a loved one), followed by exposure to both the obsession and the knife in the presence of the loved one
2. Deepened extinction
what is one pro of deepened extinction?
- the procedure could be implemented without specifically asking clients to identify their expectancies beforehand
→ shows that inhibitory learning extends further than behavioral testing regarding belief disconfirmation
- Occasional reinforced extinction
- what is it?
- how does it help?
- occasional CS-US pairings are still included
- it takes advantage of the expectancy violation effect
Benefits:
- weakens fear associations
> pattern is unpredictable, so the patient does not get used to either association
- reduces relapse risks
> learning is more flexible and adaptable, so fear memories are less likely to come back suddenly
- can be implemented without specifically asking clients to identify their expectancies beforehand
> evidence for inhibitory learning approach compared to behavioral testing…
3. Occasional reinforced extinction
short-term vs long-term effects
Short term:
- Sustained fear arousal during extinction
> fear responses remain higher during extinction training compared to standard extinction
Long term:
- Reduced reacquisition of fear
> despite the short-term fear arousal, less fear returned when the CS was later re-paired with the US
> this means that they were less likely to relearn fear quickly
- Removal of safety signals
- what are common safety behaviors?
- safety behaviors & outcome
- presence of another person, therapists, cell phones, medications, or food or drink
- these safety behaviors weaken the learning between UC-no US because they decrease the negative expectations of the US
→ this means that then there is less surprise between the UC and the no-US
→ if there is less surprise, there is less fear to unlearn; if more danger signals are present, there is more fear to unlearn, and extinction learning is stronger
> to ensure treatement attrition, the safety behaviors can be removed gradually
- Variability
- what does it do?
Stimulus variability throughout exposure:
- Enhances the storage capacity of newly learnt information
> experiencing information in different ways creates multiple representations of it in memory, making it more durable
- Pairs the information to-be-learnt with more retrieval cues
> learning the same concept in different settings, formats, or contexts gives the brain more ways to access that information later
- Generates a rule that captures the invariance among tasks
> When exposed to variations of a task, the brain can extract the underlying rule or principle, which helps in transferring knowledge to new situations
Variability = longer memory, more access, transferrable knowledge
5. Variability
The context retrieval model of extinction
- how can context variability help?
- when a learned fear response fades (extinction), the memory of that extinction is still tied to the specific context in which it happened
Context Variability
> if phobic object is encountered in different settings, the learned “fear reduction” is more adaptable
> context renewal effects are prevented, which means that the person is less likely to relapse into fear when they see the stimulus in a new setting
5. Variability
What types of variability are there? (6)
- Context variability
- Timing variability
> variability in length of time between exposure sessions
→ leads to superios outcomes at follow-up - Stimuli variability
> vairability in stimuli used
→ leads to positive outcomes in terms of spontaneous recovery - Hierarchy variability
> usually the phobic objects are presented in a hierarchy from least fearful to most fearful
> we should always start with least fearful object (to avoid treatment refusal)
> but then break the hierarchy and use variability in levels of fear leads to better outcomes - Fear level variability
> more positive outcomes are reached if the patient undergoes different levels of fear throughout treatment
> if fear fluctuates, they get practice in handling fear even when it resurges, making them more resilient - Emotional state variability
- Retrieval cues
- cues/objects that remind the patient of the CS-no US association
- they can be objects (e.g. bracelet) or clear instructions to mentally remember what was learnt during exposure
6. Retrieval cues
- what are the risks?
- when are they best employed?
Risk:
- might become safety signal
> safety signals: directly associated with no US (e.g. benzodiazepines)
> retrieval cues: retrieve the CS-no US relationship (e.g. therapist office)
Best employed as relapse prevention
> if used during the course of the treatment, they might lower the fearful expectations, going against expectation violation
- Multiple contexts
- what is context renewal?
- how does it help?
- Context Renewal: return of fear to phobic stimulus when encountered in a context that differs from the one of therapy
- different studies have different results (unstable evidence)
- we should conduct exposure in different contexts
> e.g. when alone, in unfamiliar places, at varying times of day, varying days a week, …
- Reconsolidation
- Reconsolidation: every time we recall a memory, it temporarily becomes unstable and must be rewritten into long-term memory again
- during this reconsolidation window, the memory is flexible and can potentially be altered or updated before being stored again
1. Memory is retrieved→ becomes active and unstable
2. Reconsolidation begins→ The brain must re-store the memory, using new neurochemical processes
3. Opportunity for change → During this reconsolidation window, if new information is introduced, the memory can be modified before it is saved again
how can change during reconsolidation be applied practically?
- brief reminder of CS given 30 minutes before extinction training
> this dramatically reduced the return of fear (spontaneous recovery, renewal, reinstatement and rapid acquisition)
→ if extinction happens during reconsolidation, the original fear memory itself may be weakened or rewritten, making relapse much less likely - evidence is unclear
Linguistic processing as affect labeling
- ask clients to state their emotional responses during exposure, without trying to change them
- other therapeutic strategy for enhancing inhibitory regulation
- activates right ventrolateral prefrontal cortex
> this reduces the activity in the amygdala
> this attenuates anxious responding - good evidence
Read the 4 case studies
Try to find the 8 therapeutic strategies to enhance inhibitory regulations that were mentioned above, in each case
Tackling maladaptive memories through reconsolidation: From neural to clinical science
- what does the article talk about?
(James Elsey and Merel Kindt)
1- Introduction
2- Memory reconsolidation
3- Reactivation and reconsolidation are not synonymous
4- Prediction error, reconsolidation and extinction
5- Ecological validity of experimental models
6- Mechanisms of change and the demonstration of reconsolidation
7- Continued translation of basic reserach to clinical implications
8- Conclusion
- What will this paper discuss? (Elsey)
- attempts at disrupting reconsolidation of maladaptive memories in anxiety and trauma-related disorders through pharmacological means (particularly propranolol in humans)
> this means that the focus is on the use of meds to stop the reconsolidation of maladaptive memories, in people with anxiety and trauma-disorders
Lecture
- Introduction: Fear memory and anxiety disorders
- Extinction: model for exposure
- Memory reconsolidation & Prediction error
- Reconsolidation intervention - illustration film
History
- when did psychotherapy start to be based on empirical science?
+ examples
- psychotherapy was not based on empirical science until 1960s
- extreme examples: centrifuge therapy, insulin shock, therapy, hydrotherapy, lobotomy (nobel prize for physiology)
The importance of historical awareness
- it can happen in the future as well, to look back at the treatments we have now and criticize them
- scientists should not overestimate the significance of their discoveries
- the process of thinking and arguing, and of critically testing ideas is at least as important as knowing facts
> facts can change
! … science is ongoing process
Irrational fears as common disorders - notes
- anxiety disorders are leading form of mental illness worldwide
- 60 million in Europe (from mild to severe)
- anxiety disorders are conceptualized as irrational and learned fears
- associative fear memory lies at the core of anxiety disorders
> idea that emotional memory is at the core of mental disorders was launched by psychoanalysis (profound impact on our culture and the way we think)
> also at roots of other disorders (e.g. depression and addiction)
how do fears and worries develop?
- fears and worries can develop from traumatic experiences, but also just from modeling other people around you, information transfer, …
- always interaction between predisposition and learning experiences
- people first develop mild fear, and then they have negative experience with object of fear and that experience is perceived as traumatic
the development of psychology
1 Psychoanalysis (Sigmund Freud, 1856-1939)
2 Neuroscience (Eric Kandel, 1929-…)
> Kandel started with psychoanalysis, but went into neuroscience
> he wanted to understand processes of learning and memory principles (which underly CBT)
3 CBT (Aaron Beck, 1921-2021)
> understanding schemas to know what to target in treatment to relieve the symptoms
what is the relation between fear learning and memory?
- in fear conditioning, it only takes a few combinations of CS-US to create a mental associations
- even days later, the rats remember the trigger and present fear response
Animal vs Human experiment
- why controlled stimulus with humans?
- in rats: sound followed by (strong) electric shocks
- in humans: spider image followed by (mild) electric shock
- in humans, there are always also control stimuli (spider photo not followed by shock)
→ this is because dependent variable is physiological response
> therefore, we can measure e.g. heart response at baseline and when presented CS-US
> with rats instead, the fear response can be measured through the rat moving around the cage (not afraid), or freezing (afraid)
why do we always make predictions on what is going to happen?
- animals and humans always make predictions
- we try to find predictors from events that happened in the past
- if we can predict aversive events, we can prevent them
> this makes us more adaptive
why do people that experience trauma blame themselves?
- by blaming themselves, they feel like they could have been in control of the situation
- if it’s your fault, it at least means that you are in control and that in the future you’ll be able to change the situation
Fear conditioning paradigm
- the generalizability of fear memory
- fear memory is strong; it generalizes over time, context and stimuli from the same semantic category
- strong fear memory is functional and helpful in evolution and survival
> e.g. if bit by one dog, every dog is scary
Fear conditioning paradigm
- what if the fear is irrational?
- the same concept applies for irrational fears (e.g. anxiety disorders)
- similar neurobiological processes
- people know that their fear is irrational, but when exposed to imminent threat, they respond with very strong fear response and are no longer convinced that it’s safe
- if they are in safe situation they know that there is no reason to be afraid and that the fear is irrational, but cannot think logically if they are in a situation where they feel in real danger
How can we explain that irrational fears cannot be controlled by rational thinking and that they are so difficult to treat?
Research program:
- understanding how we can change unduly intense fear by targeting processes of fear learning and memory
Idea:
- if fears are learnt responses they have the bases for extinction learning, and therefore exposure tretment
> e.g. fear response gradually declines if present sound to rat without shock
from extinction to return of fear
(see graph)
1. Acquisition
> CS → US
2. Extinction
> CS → no US
3. Retention
> fear memory not observed if tested after short interval from the extinction
The return of fear
- what are all the ways in which fear comes back?
(see graphs)
- Spontaneous Recovery
> after few days (passage of time)
> spontaneous return of fear, even after exposure treatment
- Reinstatement
> imminent return of fear if patient is presented with another (e.g.) shock after extinction (without CS)
- Renawal
> when changing the context
> very relevant in clinical practice, because in real life the context is always different so the fear is often renawed
- Rapid reacquisition
> new learning experience (CS-US)
> it takes (~) 5 trials to install fear memory, but when extinguished, it only takes one trial to get it back
= extinction procedure is effective, but fear memory is not erased and can easily come back!
Re-learning fear
- summary
- only 38% profit long-term from exposure treatment
Spontaneous recovery: passage of time
Renewal: leaving the therapeutic context
Reinstatement: re-exposure to aversive event
Rapid Reacquisition: new learning experience
Acquisition vs Extinction
- Acquisition: context independent
> we learn that stimulus is dangerous across contexts and situations - Extinction: context dependent
> we learn that stimulus is not dangerous anymore only in the context we practiced in
> extinction is “exception to the rule”
> e.g. dogs are dangerou but not in all circumstances
= Generalization of extinction is a challenge!
then, why is it hard to extinguish fear?
+ brain areas
- this is because fear memory is not erased, it is just replaced by other associations in context of exposure
- this replacement memory is called Inhibitory Memory, and it is found in different brain areas
> Hippocampus, vmPFC→ inhibitory memory
> Amygdala→ fear memory (remains intact and can resourface)
Fear: Theory and Therapy
- Habituation (traditional learning theory)
> CS→ no CR
> original theory regarding fear, in the past
> treatment should focus on reducing fear response
> when patient exposed to CS, we should wait until fear response has been completely habituated, before leaving therapeutic session - Learning (Contemporary learning theory)
> CS→ no US
> predict catastrophe if presented with aversive stimulus
> they try to rationalize irrational fear (e.g. “you never know what a spider will do”) - theories are important because they set the ground for what kind of treatment is needed
what is the US in anxiety disorders?
- in anxiety disorders, the US could be e.g. a panic attack for panic disorders,
- the patients start looking for predictors of panick attack (e.g. heart rate, hypervigilance, …)
- to avoid the panick attack, they engage in avoidance behaviors
- by avoiding possible triggers, they don’t get habituated to the symptoms, and the fear doesn’t extinguish
How can exposure treatment be enhanced?
(all the strategies are talked about in the article, flashcard 19-40)
- in general, we should design exposures that violate expectancies
> probability of expected negative outcome (US)
> intensity of anticipated catastrophe
> extent to which the catastrophe is manageable
- focus on learning (mismatch, prediction error), consolidation and retrieval
> one way is to use drugs
How can drugs be used in exposure therapy?
- anxiolitics
- anxiolytic drugs should not be used in exposure therapy
> this is because if we dampen the salience of fear, the prediction error will be very weak, and the learning will not mirror the experience
> also because patients can attribute lower fear to drug, and it can become a safety behavior - antidepressants, psychedelics, …
Disrupting Memory Reconsolidation
- in the past, it was believed that when you learn something it is engrained, and the memory cannot be changed
- now, it is known that a memory can be activated again and it is sensitive to change, before it reconsolidates
→ now, Reconsolidation has been proven across animals and studies, and has become general knowledge
- Memory Reconsolidation
- what is consolidation? (Elsey)
What?
- it is the transition of memories from a short-term and unstable state to more persistent long-term form
How?
- through a protein synthesis that strenghtens the connections between neurons
Protein Synthesis Inhibitors (PSI) (Elsey)
- if used shortly after learning, Protein synthesis inhibitors (PSI) prevent the memory from becoming long-term
! once consolidated, memories are stable and PSIs don’t work anymore
→ this means that if the PSI is not administered early enough, memories consolidate, become long-term and stable
PSI & reconsolidation (Elsey)
- when a memory is recalled (reactivated), it temporarely becomes unstable again (“labile state”)
- memory must go through a second consolidation (“reconso idation”)
- during the reconsolidation window, the memory can be modified or even erased, if intervention is introduced
> e.g. PSIs or new learning
! the window closes after a few hours, making the memory stable again and resistant to change
Reconsolidation process
- New learning (active memory)
— Consolidation - Stored memory (inactive memory)
— Memory reactivation - Labile emory (active memory)
— Reconsolidation - Updated memoy (inactive memory)
(see picture)
Biological processes:
short-term vs long-term memories
- during new learning, there is an action potential that underlies short-term memory
- for long-term memory, learning should be so strong that some other processes are necessary:
> DNA transcription
> RNA translation
> protein synthesis
> neuron has to be “tagged” so that protein synthesis can be active
→ if thes processes are weak there is no long-term memory
→ if these processes are interfered with, the protein synthesis can be disrupted and long-term memory can be prevented
Animal studies
- protein synthesis for long-term memory Consolidation
- do fear conditioning in rats (sound and shock)
- inject rats with drug that block protein synthesis (e.g. Anisomycin), in vasolateral nucleus of amygdala (important brain center for fear learning)
- 3/4h after the injection: you still observe short-term memory (strong freezing response)
- 24h after injection: no long-term memory
> demonstrates that protein synthesis is necessary for consolidation of memory
→ this was already known years ago, but it was not known that it works with memory reconsolidation as well
Animal studies
- protein synthesis for long-term memory Reconsolidation
- fear conditioning
- rats tested after 3/4h and after 24h, and presented both short-term and long-term memory
- then rats where presented with CS (memory was reactivated), and were now injected with anisomycin (protein synthesis blocker)
- tested 3/4h later, and presented short-term memory
- tested again 24h later, no memory
→ this shows that memories can be activated and protein synthesis can be blocked after being already consolidated, changing the long-term memory
When is there no fear reduction even with drug?
- if there is no memory reactivation
- if drug is given 6h after memory reactivation
> limited time window to interfere with neurobiological processes - short-term memory has to be intact 4h after injection
Weakening of memory before reconsolidation vs new inhibitory memory
(see picture)
- by weakening the fear memory before it reconsolidates, we do not need to create another inhibitory memory that replaces the fear memory
- this is useful because we already know that the fear memory is not replaced, is still there and can quickly and easily come back (reinstatement, renawal, …)
Propranolol
- this is the drug that can be used on humans
- Beta-AR blocker
> it blocks the beta-adrenergenic receptors
> this precep os are involved in memory learning, by indirectly triggering protein synthesis - it passes the blood-brain barrier
- when timed with memory reconsolidation, it can help shaping memories associated to feared stimuli
→ this inhibits protein synthesis by stopping noradrenaline-stimulated CREB phosphorylation in the amygdala
(see picture)
what is the optimal time to use propranolol?
- in animals they used anysomicin, which can be injected direcly in amygdala and therefore has an immediate effect
- in humans, this is not possible
- propranolol takes 1/2h to have an effect
> injecting it before memory reactivation→ not optimal
> injecting it 2h after memory reactivation→ too late
> injecting it 1h after memory reactivation→ optimal
= timing is critical!
how was the fear response measured?
- fear response (US)→ startle response
- measured through:
~ skin conductance
~ fear potentiated startle reflex
> electrodes just below the eye
> eye-blink response
> anticipates fearful event - noise alone is necessary to measure the fear potentiated startle response
Startle response - how does it work?
(article)
- it does not reflect simple conscious expectation
> startle can happen even if you are not aware that you are seing a picture of the spider
- startle responses still work even when you are told that there will be no more shocks
- the reflex tracks the emotional valence of the stimuli
> if the stimulus is positive, the response will be smaller; if the stimulus is negative, the startle will be bigger
- “differential fear potentiated startle” (FPS): startle is conditioned to stimulus with shock, and does not come with stimulus without shock
Study
Day 1
- acquisition of memory
- spider image + shock association
- created CS-US associations with differentiated FPS (fear potentiated startle)
Day 2
- reactivation
> pill placebo
> propranolol
> propranolol (with no reactivation)
- single, unreinforced presentation of CS without US (reactivation)
Day 3
- extinction
- participants exposed again to CS+ and CS- (unreinforced)
- test return of fear
> the idea was not only to see if fear response would be less, but also to test if this could be a solution for return of fear after extinction learning
Day 3 or Month 1
- test again
what are the results of the study?
(see graphs)
- all participants still retained declarative memories for conditioning procedure
- participans with placebo+reactivation and participants with propranolol + no reactivation still displayed potentiated startle response
- differential FPS was abolished in the propranolol + memory reactivation group
- negative affective valence of the CS+ was effectively neutralized, while declarative memory for the fear-conditioning episode (as indexed by conscious expectancy of shock) was unaffected
what did other studies show?
(see picture)
- other studies showed that reinstatement, long-term, rapid reacquisition and renawal were much lower in propranolol condition compared to normal extinction
- participants did not re-develop differential FPS any more quickly during re-conditioning than they did during initial learning, suggesting there were no ‘savings’ of the memory trace
Did expectancies change in propranolol condition?
- expectancies did not change, even if startle was completely reduced
- they still expected shock, but they did not respond with startle
- skin conductance is linked to conscious awareness, and it varied depending on the stimulus
→this shows that people’s ability to consciously recognize and expect a fear-inducing event (like a shock) remained intact
= this shows that it is a very different procedure than normal extinction
Drug treatment and Cognitive change
- no general fear dampening effect
- only effective when drug is given in conjunction with memory reactivation
> drug within the first hour from reactivation
> drug has to be propranolol; they tried with other beta blockers but did not find the same effect - an initial cognitive change is not necessary for reconsolidation intervention, to observe a change in fear behavior
> e.g. expectations do not need to be violated in order to see that startle response is already lower
> cognitive changes for long-terms effect are however necessary
Pattern on symptom decline
+ night
- no gradual decline of symptoms, but a single instance of treatment leads to an abrupt decline in fear
> instant reduction, but only observable after sleeping (effect works overnight)
> if tested in same day, still fear expression
> during sleep the brain processes information
what should we pay attention to regarding studies on memory?
- memories are important so that we don’t have to relearn things every time
- we can either update the memory to include new contexts, or create new memories
- there are many studies on memory, but we should be careful not to relate every treatment’s efficiency to memory reconsolidation
! extinction can still be effective, so if a treatment is effective, it is not necessarily because the memory was reconsolidated - show intact memory after intervention
> if immediate effect, then it is not through reconsolidation (it would take more time)
(see graph)
Reactivation ≠ Reconsolidation
- to put a memory back to an unstable state (that then leads to reconsolidation), there should be a reason for the memory to be updated
> it would be not really good evolution-wise if every time we remember something, the memory becomes malleable again
article Elsey
Prediction error
- memories an be destabilized and become more susceptible to disruption if there is a prediction error during memory reactivation
- prediction errors:
> Temporal prediction error→ reinforcement happens, but at a different time than expected
> Contingency prediction error→ reinforcement does not happen at all when it was expected - when these errors occur during memory reactivation, the memory becomes unstable and can be disrupted by PSIs
- if there is no prediction error, then PSIs do not affect the memory even if memory is actively recalled
article Elsey
Is retrieval sufficient for memory reconsolidation?
- memory retrieval is neither necessary nor sufficient to trigger memory reconsolidation
- often in studies, reactivation consists of a signle unreinforced presentation of the CS+
- (!) study: reactivated memory by presenting CS+ without reinforcement, but one group of participants had the wires (for the shock) still attached and the other group had no wires
- the group without wires:
> still presentes memory retrieval (they still startled when presented with CS+)
> propranolol had no effect on their later expression of conditioned responding (memory was not destabilized)
article Elsey
Destabilization of conditioned fear memories: is prediction error or absence of reinforcement necessary ?
Study
- during learning, participants received either 100% (get a shock every time) or 33% reinforcement (they get a shock sometimes)
- at reactivation:
> some participants with 100% reinforcement received a reinforced CS (everything as expected→ no prediction error)
> some participants with 100% reinforcement received a unreinforced CS (they expected the shock but didn’t get it→ negative prediction error)
> participants with 33% reinforcement received a reinforced CS (received a shock even when they weren’t expecting it→ positive prediction error)
- all participants then received propranolol
- startle response was measured
article Elsey
what are the results of the study?
what does this show?
- both the positive and negative prediction error groups showed memory loss for conditioned fear
> shown by loss of differential FPS - no prediction error group did not show any memory loss for conditioned fear
= just removing reinforcement (not giving a shock) is not enough to weaken the memory
→ there has to be a mismatch between expectation and reality (prediction error) for the memory to become unstable
article Elsey
Study - Prediction error and Expectancy
Study results:
- Positive prediction error group (unexpected shock) → expectation of getting shocked increased
- Negative prediction error group (expected shock but didn’t get one) → expectation of getting shocked decreased
- No prediction error group (everything happened as expected) → expectation of getting shocked remained the same
→ the change in shock expectancy suggests that participants’ memories were actively updated (fear memory was altered after experiencing a prediction error)
→ this change in expectation happened independently of their actual fear response, meaning that memory updating (expectation changes) and memory expression (fear response) don’t always line up perfectly
- in PE conditions, by the third day the fear had decreased compared to day 1 and no-PE conditions (see graph)
= only if there is something new to learn about fear condition, propranolol triggers cascade of neurobiological processes
article Elsey
Single or multiple prediction errors?
- with multiple prediction errors, destabilization does not take place and extinction may even occur instead
- therefore, it is important that prediction error is present, but best if it’s not multiple
article Elsey
how can this be applied in clinical practice?
- create a prediction error by investigating the patient’s fear
> e.g. if fear of being overwhelmed when trauma is recalled, then by recalling hard parts of the trauma and seeing that one doesn’t go insane is a good prediction error - learning of additional information
> e.g. through imaginary rescripting (imagining a different version of the trauma)
> new experiences with feared stimuli coudl aslo destabilize the target memory
article Elsey
The importance of the length of memory recall
- longer memory reactivations (keeping memory active for a while)
→ memories are likely to become stable again or fade through extinction
> if too long→ even drugs that usually are able to erase memories stop working - brief memory reactivation (brief recalling of the memory)
→ memory can be changed or erased (reconsolidation)
article Elsey
the Liminal period
- transitional state in which neither reconsolidation nor extinction are the dominant active processes
- interventions during this period cannot neither promote nor disrupt reconsolidation or extinction
Harnessing reconsolidation to tackle naturalistic fears (spider video)
- clinical application
- three conditions
> MR + placebo
> MR + propranolol
> propranolol
→ exposure + propranolol explains the effect
→ long-term effect stays even after one year - these results both in behavioral approach & subjective spider fear questionnaire (SPQ)
(see graphs)
Spider study results
- 1-year effect only in propranolol+MR condition
- able to touch spider, but in questionnaire said that they are still afraid
> here subjective fear follows behavior change
> in exposure, subjective fears alligns with behavior change
! look at difference between post-test in behavioral activation graph and subjective fear graph - first: change in experiencing (you are able to touch spider)
- then: change in remembering (needs practice to touch the spider)
(see graphs)
article Elsey
- Ecological validity of experimental models
- there have been many studies done on animals, and less on humans
- we know that these processes might work on humans for recent and “simple” fears, like phobias
- however, there is not much evidence yet for older or more complicated memories (e.g. anxieties)
article Elsey
Second-order fear conditioning (SOFC)
- study + results
Study:
- tone (CS1) paired with shock (US)
- new stimulus (CS2) paired with tone (CS1)
→ animals learnt to fear CS2, even if it was never paired with shock (US)
- anisomycin administered (animal equivalent of propranolol)
Results:
- if CS1 (tone) was reactivated, anisomycin weakened the fear response to both CS1 and CS2
→ when CS1 is reactivated, both memories become unstable, so anisomycin can disrupt them both
→ both fear memories were disrupted.
- if CS2 (new stimulus) was reactivated, anisomycin only weakened the fear response to CS2
→ when CS2 is reactivated, only that memory becomes unstable, so anisomycin only affects CS2, not CS1
→ original CS1 fear memory remained intact
article Elsey
Why?
- what implications does this have in clinical practice?
- second-order conditioning memories are associated to molecular processes connected to consolidation, not reconsolidation
→ this suggests that second-order conditioning creates a new memory, rather than adding information to a previous one - clinical practice: best to find stimulus that corresponds to primary fear, or results might generalize poorly
article Elsey
The subjective experience of fear conditioning
- reasearch is still missing on the subjective experience associated to fear conditioning/extinction
- propranolol+reactivation conditioned showed less feelings of distress
- negative experience generally lowered, but not nullified
article Elsey
- Mechanisms of change and the demonstration of reconsolidation
- what are the criteria for demonstration of reconsolidation?
Four key criteria for demonstrating that a memory-related experimental manipulation (like giving a drug such as propranolol) affects reconsolidation, rather than just memory in general:
(1) Interaction between memory reactivation and experimental manipulation
> the experimental intervention (e.g., propranolol) should only affect memory if the memory was first reactivated
> if the intervention works even without reactivation, it suggests a general memory effect rather than one specific to reconsolidation
(2) Time-dependent effects
> the manipulation should only work if administered within a specific time window after memory reactivation
> if the same intervention is given outside this window and it doesn’t have the same effect, this suggests that reconsolidation is a time-sensitive process
(3) Memory specificity
> The effect should be specific to the reactivated memory and not just impair all memories indiscriminately
> if the manipulation weakens memory in general, it’s likely affecting something broader (e.g. attention, overall cognition) rather than reconsolidation specifically
(4) Dissociation of immediate and delayed effects
> Right after the intervention, the memory might still seem intact, but over time, the long-term memory is impaired
> this is because short-term memory can persist briefly even if reconsolidation is disrupted, but the long-term trace is weakened
article Elsey
- Continued translation of basic research to clinical implications
- despite the research, many clinicians still apply the habituation model instead of taking into consideration the reconsolidation window
- evolving understanding of memory storage
> recent studies suggest that synaptic potentiation plays a role in memory retrieval, but that the actual storage mechanism might involve a different process - specific neuron networks (engram cells) might help recover memories that seem erased via reconsolidation blockade
> this suggests that reconsolidation disruption does not erase the memory storage site but rather affects the synaptic mechanisms crucial for ordinary recall - Reconsolidation-based interventions appear to suppress maladaptive memory retrieval more effectively than traditional extinction-based approaches
> because memory traces may persist in some form, there is a risk of relapse, meaning that reconsolidation alone may not be enough for long-term symptom improvement
