Reinforcement learning from post-ingestive calories: from body to brain in health and disease

Project Information

CalorieRL

Grant agreement ID: 950357

DOI

10.3030/950357

EC signature date 27 October 2020

Start date 1 November 2020

End date 30 April 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 499 945,00

EU contribution

€ 1 499 945,00

Coordinated by

FUNDACAO D. ANNA DE SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Portugal

Periodic Reporting for period 3 - CalorieRL (Reinforcement learning from post-ingestive calories: from body to brain in health and disease)

Reporting period: 2023-11-01 to 2025-04-30

Summary of the context and overall objectives of the project

Decisions about food are universally relevant, particularly so in understanding determinants of eating disorders, a major global health problem. Alongside taste and other explicit sensory properties of food, nutrient content should contribute towards decision-making about feeding, since nutrition is a fundamental goal of eating. This is indeed the case, and delayed effects of nutrients, i.e. post-ingestive information coming from the digestive system, have direct access to the brain’s reward and decision-making systems. Here we investigate the neural mechanisms through which nutrients exert such influences on human feeding behaviour and how this is relevant for obesity, across several objectives. First, to investigate the effects of nutrients on behaviour, namely implicit effects revealed through subtle differences in behaviour in learning and decision-making tasks, and explicit effects observed through explicit ratings of the intensity and pleasantness of food. Second, to identify the underlying neural circuits, with a focus on brain dopamine responses and neural signalling in associated circuits, as well as the vagus nerve as an information pathway from the digestive system to the brain. Finally, to investigate the involvement of these processes in the context of obesity.

One typical method to study postingestive contributions to feeding is the flavour nutrient conditioning (FNC) paradigm. This involves repeatedly giving participants two flavored foods, one of which paired with a calorie-rich content, and measuring changes in preference for these foods. Existing work in animals indicates that food consumption will increase towards flavours paired with calories. Here we use modified and/or extended versions of FNC where, in addition to changes in preference, we measure more detailed aspects of behaviour in decision-making tasks. Furthermore, since conditioning will be conducted in humans, we will measure explicit assessments of the stimuli used, such as intensity and pleasantness. We will also assess behaviour during brain MRI scans, or using nuclear medicine imaging, to reveal neural and dopaminergic correlates of postingestive learning. Towards understanding contributions of the vagus nerve for nutrient learning, we are recruiting a cohort of patients undergoing partial liver resection, where lesions of the nerve are expected. Finally, we will perform these assessments in patients with obesity, to understand potential contributions in this context.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Last year, we published data describing a reinforcement learning task to assess human choice behaviour, allowing for quantification of model-based and model-free systems of action control, acquired from experience as well as after explicit instruction (Castro-Rodrigues & Akam et al., 2022). We have also completed experiments to optimize conditions where maltodextrin, an insipid carbohydrate, is not detectable by explicit sensory cues when dissolved in flavoured yoghurt, and developed a first FNC protocol using these yoghurt solutions (Ribeiro & Fernandes et al., bioRxiv). Jointly, this work provided appropriate expertise, methods and computational setup to establish learning tasks reinforced by food rewards, leading to development of a custom delivery system accurately controlling amount and timing of delivery of yoghurts, including inside the MRI scanner in order to investigate brain activity associated to postingestive learning. During development of this delivery system, we established an alternate neuroeconomics learning task using visual feedback, rather than online delivery of food. Here we optimized several parameters necessary for adequate control of conditioning with flavoured solutions.

Recently, we published a systematic literature review and meta-analysis, showing that dopamine D2-like receptor (DD2lR) availability, measured using positron emission tomography and single-photon emission computed tomography (SPECT), differed significantly from controls only among patients with severe obesity (Ribeiro et al 2023). We since completed experiments applying our first FNC protocol, as well as [123I] IBZM SPECT to assess DD2lR availability, in a clinical study including patients with obesity, and patients treated with bariatric surgery (Ribeiro & Fernandes et al., bioRxiv). To address explicit assessments of food cues in obesity, we published a systematic review underlining the lack of conclusive evidence on the association between obesity and altered sweet taste perception (Ribeiro et al., 2021). We thus completed a study comparing a large group of patients with severe obese and healthy volunteers, for several measures, including explicit taste ratings. While we did not find any significant effects for pleasantness for any taste quality, including sweet, we did find that patients with obesity reported significantly higher ratings of sweet intensity, while no differences were found for other tastants (Ribeiro et al., 2022).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

By the end of the project we expect to achieve a number of objectives significantly advancing the state of the field. First, we expect to determine whether effects of FNC can be detected in behaviour within learning and decision-making tasks. Such effects can be implicit, i.e manifest without participants being aware of such patterns in their behaviour and we expect to have a more precise understanding of how they relate to explicit effects, such as changes in hedonic assessment and pleasantness .
Second, we expect to have a better understanding of the neural circuitry and activity involved in processing food rewards, with particular focus on the changes in brain activity and dopaminergic signals that take place while humans learn associations between nutrient content and taste, and other explicit properties of food. While uncovering such processes is of fundamental importance for the study of learning in general, specific understanding of these processes when primary rewards (as opposed to monetary rewards) are concerned would be a major contribution to the field.

Third, we expect to uncover the role of the vagus nerve in these processes, as the information pathway linking the digestive tract with the central nervous system. Such knowledge would not only advance fundamental understanding of the mechanisms involved, but also be potentially highly relevant for patients undergoing surgeries that interrupt or otherwise affect this pathway (e.g. patients with hepatic transplantation). Finally, we expect to have a better understanding of the importance of these postingestive mechanisms in obesity. Given the high prevalence of this disease worldwide, obtaining evidence that could further our understanding of its causes or development, and inform prevention and or treatment strategies would be a significant achievement.