Reconsolidation and Memory Interference Toolkit (REMIT): Identifying how to destabilise and overwrite maladaptive alcohol memories.

Lead Research Organisation: University College London
Department Name: Clinical Health and Educational Psych

Abstract

Alcohol Use Disorder (AUD) is a global disease challenge which incurs vast health and social costs. Current treatments fail in the long term as they do not address the aberrant memory processes that maintain drinkers' susceptibility to relapse even after years of abstinence. This quiescent susceptibility is due to Maladaptive Motivational Memories (MMMs) that accompany and support alcohol abuse. Associations formed between environmental 'cues' and drinking imbue the cues with motivational properties that cause cravings, alcohol seeking and relapse when similar cues are re-encountered in the environment. Recent evidence shows that memories can be permanently altered by manipulating a process called 'reconsolidation.' This process is initiated under certain circumstances, causing a retrieved memory to become destabilised. During the 'reconsolidation window' - the interval between destabilisation and restabilisation - the memory is rendered malleable. These findings suggest an exciting opportunity for treating alcohol problems by weakening the MMMs at the heart of AUD.
In rodents, MMMs can be destabilised using a reminder of previous learning (e.g. a tone that previously signalled drug availability). Since restabilisation requires activity at certain brain receptors (especially NMDARs), it can be blocked pharmacologically. If this occurs, the animal later behaves as if the memory association had been 'erased' and drug seeking stops. Available NMDA antagonists - like ketamine - could similarly be used to block restabilisation of MMMs in humans. It may also be possible to 'overwrite' MMMs behaviourally, by training adaptive new associations while MMMs are unstable. This type of procedure would also be expected to reduce cue-induced craving and drinking.
While these strategies are promising, there are key issues which must be resolved before MMM-modification can be developed for addiction. These are i) that MMMs only destabilise under certain conditions and ii) we cannot yet measure memory destabilisation directly. The critical first step towards developing MMM-modifying treatments for AUD is therefore to develop methods for reliably destabilising MMMs and metrics for measuring this. The primary factor determining memory destabilisation at retrieval is a mismatch between the outcomes predicted by a memory association (e.g. drinking alcohol) and actual outcome (e.g. the drink is withheld), also called a 'prediction error' (PE).This PE enables memory destabilisation when new information about the availability or effects of alcohol coincides with memory retrieval, allowing the memory to be updated with new information.
This project aims to identify robust procedures for destabilising alcohol-MMMs and measuring this destabilisation. To do this we will examine the effects of i) blocking restabilisation using the NMDAR antagonist, ketamine and ii) overwriting destabilised MMMs so that they no longer promote drinking.
In both studies, we manipulate the mismatch between expected and actual drinking outcomes during retrieval of alcohol-MMMs in harmful drinkers. We predict that unexpected information about alcohol availability or value when recalling alcohol-MMMs will cause their destabilisation. In Study I, we aim to block re-stabilisation with ketamine, weakening the alcohol-MMM's ability to activate alcohol seeking and drinking. In Study II, we will use a behavioural procedure to over-write destabilised alcohol-MMMs by training associations between the alcohol cues and unpleasant outcomes (a very bitter drink and aversive pictures) in the reconsolidation window. This procedure should update the effect of alcohol cues from pro- to anti-consummatory. Both interventions should result in reduced alcohol-seeking and drinking.
If one or both of the procedures are successful, they will have significant potential as clinical treatments for AUD, although wider application to other addictions and psychological disorders is also possible.

Technical Summary

The brief period of memory instability during memory reconsolidation represents the first viable approach for directly weakening or overwriting the enduring Maladaptive Motivational Memories (MMMs) that underlie addiction in humans. Pharmacological approaches (e.g. NMDAR blockade) while memories are unstable may prevent restabilisation, thus weakening or erasing MMMs. Behavioural approaches (e.g. presenting new associations) while memories are unstable may update MMMs with adaptive information. These approaches may overcome the major limitations of current addiction treatments, namely the lack of long-term efficacy.

However, memory destabilisation does not occur upon every retrieval, leading to the identification of boundary conditions that determine the fate of retrieved memories. The presence of a prediction error at retrieval and the structure of the reminder are critical in destabilising memories, but are currently hard to measure naturalistically. Therefore, despite clinical potential of modifying MMMs via reconsolidation, it is essential to begin with proof-of-principle investigations in humans and identify robust procedures for causing and measuring memory destabilisation in alcohol or drug-using populations.

Here, we will examine procedures for destabilising maladaptive alcohol memories in harmful drinkers by manipulating prediction errors during retrieval. We will probe destabilisation with the NMDAR antagonist ketamine, and behaviourally using disgust counter-conditioning during the putative 'reconsolidation window'. Effects of these interventions on harmful drinking will be assessed. Psychophysiological, behavioural and subjective measures during retrieval will be used to derive an independent 'neurobehavioural signature' of destabilisation that can be used in future studies for intervention development.

Planned Impact

1. People with Alcohol Use Disorder (AUD): These will be the primary beneficiaries, although a successful proof-of-principle demonstration through our research with harmful drinkers would suggest that people with a variety of substance use disorders would also be eventual beneficiaries.
How: In the short term, participants in our research, while considered 'sub-clinical,' may benefit throughout the lifetime of this project through reduced harmful drinking. People with AUD (and other substance use disorders) will benefit through involvement in future clinical trials (in the medium term) and as recipients of empirically supported MMM-modifying treatments (long term). Early intervention with young adult drinkers using such treatments in particular, could curtail the longer-term neurocognitive problems associated with chronic alcohol use, improving health, achievement and productivity throughout the lifespan.

2. Wider society: In addition to negative effects on family and other relationships, AUD has far reaching consequences arising from antisocial behaviour, loss of productivity and health spending.
How: Longer-term benefits to the nation's health and economic performance may include improved long-term recovery rates, resulting in reduced NHS spending, as well as improved productivity from lower rates of alcohol-related work absences. In addition, reduced antisocial behaviour means the policing/judiciary/parole systems will be indirect beneficiaries through the redirecting of resources to non-alcohol-related areas of crime.

3. NHS clinicians: Current treatment options for AUD are resource-intensive, yet have limited efficacy.
How: By employing a treatment that targets fundamental addiction processes, clinicians will be more efficient in their treatment and can expect more durable effects using treatments incorporating MMM-modification.

4. Charities: Various charities, such as Alcohol Concern, provide information, education and help to those with alcohol problems.
How: Advisors could educate and advise those with alcohol problems about MMM-modifying treatments. A greater number of people could be encouraged to seek help in the knowledge that a more effective treatment was available.

5. Business: As part of our studies we will develop a smartphone app which identifies craving 'hotspots' and monitors drinking, employing GPS technology.
How: Commercial collaboration with an app development company will ensure an excellent user interface, which will appeal to clinicians and service users as a tool for tracking drinking behaviour. The app may have clinical and commercial potential within the lifetime of the grant.

6. Pharmaceutical industry: There is considerable scope for pharmaceutical development of compounds that can target specific drug memories at reactivation in a temporally specific way. Compounds that either interfere with the restabilisation phase of reconsolidation or improve the likelihood of destabilisation have significant potential as therapeutic agents.
How: Successful identification of a destabilisation procedure will provide a basis for testing novel and existing compounds in humans. In particular, novel (formulations of) NMDAR antagonists with rapid onset and good levels of safety and tolerability may be initial targets for drug development. To increase destabilisation likelihood for robust memory traces, synaptic-plasticity promoting compounds like histone deacetylase inhibitors may also be assessed using our destabilisation metrics.

Publications

10 25 50
 
Description MRC-MRF scheme: Child and young adult mental health - the underpinning aetiology of self-harm and eating disorders
Amount £247,799 (GBP)
Funding ID MR/R004919/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 02/2020
 
Description Pharmacological approaches to Treatment and Prevention of Posttraumatic Stress Disorder
Amount £455,000 (GBP)
Organisation Find a Better Way 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2019 
End 02/2022
 
Description Standard Research grant
Amount £52,619 (GBP)
Organisation Find a Better Way 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2018 
End 01/2019
 
Description UCL Demonstratorship Scheme
Amount £111,080 (GBP)
Organisation University College London 
Department Division of Psychology & Language Sciences
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Reinout Wiers - University of Amsterdam 
Organisation University of Amsterdam
Department Department of Psychology
Country Netherlands 
Sector Academic/University 
PI Contribution We will be developing a novel cognitive bias modification task with RW to appy to a binge eating population in the context of memory reconsolidation.
Collaborator Contribution RW will advise on the various aspects of task design.
Impact Although the primary outcome was the award of a new MRC grant (on binge eating and memory reconsolidation), we have now also applied for an additional European grant (jointly funded by the ESRC, and their equivalent in the Netherlands and Germany). If awarded, this will be directly related to and extend the work of the current (ReMIT) grant.
Start Year 2017
 
Description Ulrike Schmidt - IoPPN 
Organisation University of Sao Paulo
Department Institute of Psychiatry
Country Brazil 
Sector Academic/University 
PI Contribution As an extension to our work on reconsolidation of alcohol memories, we have formed a collaboration with Professor Schmidt, an international eating disorders expert. We liaised extensively with Professor Schmidt to develop a novel reconsolidation based strategy for over-writing binge eating memories. This collaboration was essential to the award of follow-up funding from the MRC to address this this new approach to modifying binge eating symptoms.
Collaborator Contribution US has provided expertise on the development of the therapeutic aspect of the project and advised extensively on diagnostic issues, sample characteristics and study design.
Impact The main outcome was the award of a new MRC grant (commencing 02/02/2018). Further outputs are expected 2019-2021.
Start Year 2017
 
Description Business insider interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This interview was intended to raise awareness of the memory impairing effects of alcohol. Unlike other media engagement activities, this did not involve discussing new treatment approaches for alcohol problems. Nonetheless, it has significant relevance to the ReMIT project in that the focus was on negative consequences of binge drinking. Moreover, it was related to a primary focus of the research, namely, memory.
Year(s) Of Engagement Activity 2018
 
Description Documenrary feature (Vice) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This documetary featured our work on the use of ketamine as a potential memory (reconsolidation) -interfering treatment for alcohol use disorder. It emphasised the experimental nature of our study and the scientific rigour of the approach (rather than immediate clinical application). Given the recent interest from the public, healthcare providers and researchers, this created a significant amount of discussion in the press and among the public (e.g. Youtube video comments). This is extremely important given the ethical and clinical considerations of using a drug with abuse potential to treat alcohol problems.
Year(s) Of Engagement Activity 2017
 
Description Guardian article (print and online) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A Guardian article featured our research. This outlined our novel use of ketamine as a potential reconsolidation-based treatment for alcohol use disorder. This generated numerous other media inquiries and contact from other journals (The Lancet requested that we consider submitting our completed work to them) and journalists (we were contacted by a journalist who has written for Nature and is developing a proposal to write a feature on our work in a upcoming issue. We will also be discussing our work with her as part of her research for a book she is writing on memory modulation as a treatment for psychiatric disorder). We were also contacted by Lion productions, which makes documentaries for the BBC and Channel 4. We will be discussing the possibility of her following an experiment/participant as they complete our study.
Vice magazine have committed to writing an article on our ketamine study.
Importantly, we have been able to fulfil our quota of participants for this study through this and other media involvement, which provided in print and online, details of our study.
Year(s) Of Engagement Activity 2017
URL https://www.theguardian.com/society/2017/jan/24/radical-ketamine-therapy-could-treat-alcohol-addicti...
 
Description Just say know to drugs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This was a general discussion and presentations by Professor Val Curran, Dr Sunjeev Kamboj and Dr Ravi Das on myths related to alcohol and other drugs. This generated considerable interest among practitioners as well as students, who stayed long after to discuss the content.
Year(s) Of Engagement Activity 2015
URL http://uclu.org/whats-on/events-activities/busting-myths-just-say-know-to-drugs
 
Description London Evening Standard (online and print) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This article generated an enormous amount of interest and requests for additional information. This article alone likely helped us fulfil our requirement for participants. It also aimed to dispel some unjustified concerns and myths related to the medical use of ketamine.
Year(s) Of Engagement Activity 2017
URL http://www.standard.co.uk/news/health/heavy-drinkers-offered-party-drug-ketamine-to-curb-alcohol-cra...
 
Description Nature online interview 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Ravi Das was interviewed by Nature. He discussed our studies on counter-conditioning and ketamine in heavy drinkers and their implications for treatment.
Year(s) Of Engagement Activity 2015
URL https://www.youtube.com/watch?v=t7Dsg1ZObFo&feature=youtu.be
 
Description O'Neill award lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was the award lecture associated with the O'Neill Prize for science education awarded to Dr Ravi Das at the 2018 Research Society on Alcoholism conference. There was a large and highly engaged audience and the talk generated a lot of discussion about the clinical application of the presented experimental findings.
Year(s) Of Engagement Activity 2018
 
Description Poster - International Society for Biomedical Research on Alcool (ISBRA) in Berlin 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at ISBRA. Considerable interest in nitrous oxide given that it is, at the subjective and pharmacological level, an analogue of ketamine. Numerous discussions and links made.
Year(s) Of Engagement Activity 2016
 
Description Poster presentation at European College of Neuropsychopharmacology conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation on the reconsolidation-based effects of ketamine. This generated enormous interest, especially given ketamine's 'special' current status as a novel antidepressant. A large number of researchers and practitioners and students attended the poster.
Year(s) Of Engagement Activity 2018
 
Description Retrieval-dependent effects of ketamine on alcohol consumption: moderating effects of family history of alcoholism 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at the San Diego conference of the Research Society on Alcoholism. Numerous researchers and practitioners discussed the findings with me and each other. Made contact with a potential collaborator from the University of Chicago.
Year(s) Of Engagement Activity 2018
 
Description Secrete Garden Party/ Guerila Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Das gave a presentation on drugs and hosted an 'educational immersive event' to educate about synaptic trasnmission and the mechanisms of different drugs
Year(s) Of Engagement Activity 2016
 
Description Soc Neuroscience conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference (poster) presentation of initial findings from the grant, presented in Chicago at the Society for Neuroscience.
Year(s) Of Engagement Activity 2015
 
Description Talk at ISBRA symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given my Dr Ravi Das. This enabled discussion with colleagues with related interests and formation of several collaborations (e.g. Michael Saladin, MUSC, USA; Ron Dorit, UCSF, USA, Segev Barak, Tel Aviv University, Isreal).
Year(s) Of Engagement Activity 2017
 
Description Times article (print edition) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact An article in the Times (Wed 25th Jan 2017) described our work on reconsolidation and ketamine This outlined our novel use of ketamine as a potential reconsolidation-based treatment for alcohol use disorder.

This generated interest from other print and onlline media outlets. Importantly, we have been able to fulfil our quota of participants for this study through this and other media involvement.

This story was picked up by numerous non-media outlets, including health clinics that report on advances in treatment
Year(s) Of Engagement Activity 2017
 
Description Trust me I m a Doctor 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We demonstrated our experiment which involved pairing disgusting tastes and images with alcohol. This was done for Trust me I'm a Doctor, a BBC2 programme on developments in Health, intended for a general audience. Sunjeev Kamboj and Ravi Das explained the experiment and were interviewed by the presenter. This would have reached more than one million viewers.
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/programmes/articles/4QdcFr8RMprXvh8R4dsBrxD/can-erasing-memories-cure-addiction...
 
Description Undark magazine article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact This was an interview given (by Dr Ravi Das) to Undark Magazine on reconsolidation and addiction
Year(s) Of Engagement Activity 2018
URL https://undark.org/article/altering-memory-to-treat-addiction/