Understanding maladaptive reward memory in young people who binge eat: Application of novel insights from addiction

Adolescence and young adulthood are periods of heightened vulnerability to a variety of harmful and risky behaviours, as the brain circuits responsible for inhibiting impulsive and risky behaviours are not fully matured. Impulse control problems, and the progression to more serious compulsive-behavioural disorders characterised by harmful overconsumption (e.g. of drugs or food) are a particular concern since they account for the highest levels of preventable morbidity and mortality throughout the world. Binge eating disorder (BED) is an example of these disorders, in which the ability to resist food - or to stop eating once an episode of overeating has begun - is impaired. BED is the most prevalent eating disorder and typically begins in adolescence. However, it is a chronic problem, lasting for many years after onset and contributing to a variety of serious psychiatric and metabolic health problems. While BED has received relatively little attention from neuroscientific researchers, there are striking parallels between BED and substance use disorders (SUDs), which also typically develop in adolescence and have been the subject of extensive basic neuroscientific, clinical and theoretical research. This has shown that abnormally strong reward memories - 'maladaptive reward memories' (MRMs) - formed during drug-use underlie drug craving and the propensity to seek and use drugs when 'trigger cues' are encountered. Coupled with deficits in inhibiting the responses sparked by these cues, MRMs cause continued relapse to drug use. Given the overlap in the behaviours, symptoms, age of onset and comorbidity between SUDs and BED, MRMs also likely play a key role in binge eating in response to food cues. Psychological treatments for BED often rely on the formation of alternative associations between food cues and new, more helpful behaviours. These compete with and temporarily suppress food-related MRMs. However, such treatments do not directly weaken MRMs, and as a result MRMs typically regain dominance over time, resulting in relapse.

In contrast, recent discoveries suggest that it is possible to directly target MRMs using behavioural techniques that could readily be adapted for use in therapy for people with BED. In particular, it is possible to 'reactivate' MRMs, a process which briefly makes these memories pliable, and then to teach new associations that 'rewrite' the MRM into an adaptive form that does not promote bingeing behaviour and prevents relapse. This approach has now been tested in heavy drinkers, smokers and heroin users, and shown to be a very promising strategy for reducing addicts' responses to drug cues. In this project, we will apply this exciting new approach to binge-eaters and determine whether similar effects are found in response to food cues, and on bingeing behaviour. We will test two methods for rewriting food-related MRMs, each targeting a different neural mechanism thought to be important in BED, namely 1) reducing the ability of binge food cues to trigger craving and bingeing and 2) increasing the ability to stop food consumption triggered by these cues.

By testing an 'at-risk ' population of young people, we will be targeting a developmental period when symptoms are beginning to emerge and early intervention might be expected to have an especially powerful effect, as food-related MRM networks are still relatively 'young'. Importantly, at this early stage of testing these new and potentially powerful techniques, it is essential to minimise risk to research participants. As such, our studies will be with young people who show binge eating behaviour but do not have a severe eating- or other psychological disorder. If we demonstrate evidence of rewriting of food-related MRMs, our findings will have important treatment implications. The next step will be to adapt these experimental strategies for use in people seeking help for BED, and possibly related problems like obesity or bulimia.

Recent research has demonstrated technically and clinically tractable methods for behaviourally rewriting maladaptive memories in drug users via reconsolidation. However, no human studies on food memory reconsolidation in binge-eating exist. This is a significant oversight, as the striking theoretical, neurobiological and epidemiological overlap between binge eating disorder (BED) and substance use disorders (SUDs) suggests food-related maladaptive reward memories (MRMs) likely play a central role in aetiology and maintenance of BED. In two studies we will fill this gap in research and explore the role of food-related MRMs by interfering with their reconsolidation in young people who binge eat. Specifically, following a robust, prediction-error driven MRM retrieval (destabilisation) procedure, we will test two forms of adaptive learning (disgust-counterconditioning; CC and cognitive bias modification; CBM) associated with stopping bingeing in response to food cues. In two randomised controlled experiments we will determine whether food-related MRMs are overwritten after memory reactivation using a canonical 3-group design in each study - Grp 1) retrieval + CC or CBM, Grp 2) no retrieval + CC or CBM, Grp 3) retrieval + sham CC or CBM. This will allow us to assess the efficacy-enhancement of CC and CBM training when conducted during food-related MRM reconsolidation, controlling for the effects of simple memory reactivation. We predict larger and enduring reductions in cue-elicited food craving, approach, liking and attentional bias, with associated reductions in bingeing episodes and calorie-intake in Grp 1 of both studies. We will statistically compare the nature and magnitude of these changes following CC vs CBM. Confirmation of these predictions - which are based on solid theoretical and empirical foundations - will suggest a uniquely direct method for interfering with putatively causal MRMs in binge eating, with important implications for treating BED.

1. PEOPLE WITH BINGE EATING DISORDER (BED) AND SUBSYNDROMAL BED: By determining the role of food-related maladaptive reward memories (MRMs) in binge eating using behavioural techniques that weaken their influence (on behaviour) during reconsolidation, our studies directly address limitations in efficacy of current treatments for BED. By testing two distinct experimental learning strategies for rewriting MRMs (counterconditioning; cognitive bias modification), each with a distinct and compelling theoretical and empirical rationale, we increase the likelihood of identifying at least one approach whose efficacy will be enhanced (i.e. have larger, more durable and/or less context bound effects), through rewriting of MRMs during reconsolidation. If both show evidence of enhancement - especially if distinct outcomes are affected - this raises the potential for highly efficacious combination treatments. This impact will be realised in the longer term, and rely on establishing efficacy in clinical trials.

2. PEOPLE WITH RELATED DISORDERS: If efficacy of these learning strategies is enhanced through rewriting of MRM in binge eaters, there is a strong likelihood that people with other conditions associated with overeating (e.g. overweight; obesity) could benefit from these strategies. In addition, since bulimia nervosa (BN), like BED, has phenotypic overlap with addiction, patients with BN may also benefit.

3. CLINICIANS AND NHS SERVICES: Current treatment options for BED are resource-intensive and expensive, yet have limited efficacy. This is a major concern for the NHS as the cost-benefit ratio is high and potentially unsustainable. This is already reflected in long delays (~9 month) between help seeking and eventual treatment. In the ideal, by developing novel approaches to addressing putative causal processes in binge eaters, clinicians will be better equipped to help their patients with treatments that we predicted will be more effective and durable, especially where predictive algorithms and personalised treatments are brought to bear. The greater efficiency this implies would mean shorter waiting times for treatment and larger volumes of treated patients. Again, given the early stage of development of reconsolidation-modulating approaches, this impact will accrue in the long-term via establishment of clinical efficacy.

4. CLINICIANS AND HEALTH SERVICES IN OTHER COUNTRIES: BED is increasingly prevalent in middle income countries, the populations of which are also increasingly consuming a Western-style diet. Controlling the 'epidemic' of obesity and overweight across the globe has been highlighted as a priority by the WHO. Significant improvement in treatment options and efficacy for these conditions through introduction of simple, easily disseminated treatment approaches has the potential to produce global health impact.

5. SOCIETY AT LARGE: Eating disorders impose an enormous financial burden on society (£15 billion in total annually). BED in particular is associated with a variety of health complaints that increase morbidity and early mortality, which have a high cumulative healthcare cost. Reducing the prevalence of these secondary health problems through more effective prevention and treatment strategies, will benefit the health and wealth of the nation in the medium- and long-term.

6. INDUSTRY: Establishing a proof of principle of memory modulation using behavioural probes (counterconditioning and cognitive bias modification) will open up possibilities of achieving this end through pharmacological means. NMDA receptor antagonists in particular have potent effects on reward memory reconsolidation when administered after reactivation. Successful demonstration of efficacy of behavioural strategies would encourage a parallel and entirely novel avenue of drug development/repurposing, an approach we are already pursuing in relation to alcohol use disorder.