People with BE are characterized by high impulsivity, high levels of craving for high-calorie foods, deficits in inhibitory control, and maladaptive decision making. These characteristics are related, at brain level, to alterations in the activation of areas such as the dorsolateral prefrontal cortex (DLPFC) and ventromedial prefrontal cortex (vmPFC) among other brain areas and their connectivity. The investigators propose an intervention that seeks to target these issues. Thus, the present study aims to characterize the effects of neuromodulation with intermittent theta burst stimulation (iTBS) of the DLPFC or the vmPFC in combination with inhibitory control training to produce brain, cognitive and behavioral changes, and modify altered biological parameters in people with BE. Participants will be randomly allocated to one of three groups: 1) a group that will receive active iTBS of the DLPFC together with inhibitory control training with a food Go/NoGo paradigm, and 2) a group that will receive active iTBS of the vmPFC together with inhibitory control training with a food Go/NoGo paradigm, and 3) an active control group that will receive sham iTBS together with inhibitory control training with a food Go/NoGo paradigm. The investigators hypothesized that neuromodulation with iTBS applied to DLPFC or vmPFC will modify the dynamics of different brain circuits associated with binge eating. Neuromodulation of the DLPFC or vmPFC in combination with inhibitory control training, will be associated with: (i) decreased appraisal of unhealthy foods, (ii) reduced food craving, (iii) improved eating behavior, (iv) modified brain connectivity and activation both at rest and linked to task performance with food stimuli, (v) a decrease in the frequency and intensity of binge eating, (vi) improved emotional symptoms and emotional eating (depression, anxiety, emotional regulation, emotional eating, reward-related eating, non-homeostatic eating), (vii) improved cognitive abilities (motor and cognitive inhibition, delay of gratification, impulsivity, working memory, cognitive flexibility and decision making), (viii) changes in biological parameters associated to the interventions (plasma and microbiota), and (ix) advantages in cost-effectiveness and cost-utility based on economic evaluation analyses.

1. STARTING HYPOTHESES AND GENERAL OBJECTIVE HYPOTHESIS: Neuromodulation with intermittent theta burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC) or the ventromedial prefrontal cortex (vmPFC) in combination with inhibitory control training with a food Go/NoGo paradigm, will be associated with: (i) decreased appraisal of unhealthy foods, (ii) reduced food craving, (iii) improved eating behavior, (iv) modified brain connectivity and activation both at rest and linked to task performance with food stimuli, (v) a decrease in the frequency and intensity of binge eating, (vi) improved emotional symptoms and emotional eating (depression, anxiety, emotional regulation, emotional eating, reward-related eating, non-homeostatic eating), (vii) improved cognitive abilities (motor and cognitive inhibition, delay of gratification, impulsivity, working memory, cognitive flexibility and decision making), (viii) changes in biological parameters associated to the interventions (blood and microbiota), and (ix) advantages in cost-effectiveness and cost-utility based on economic evaluation analyses.

GENERAL OBJECTIVE: To determine the effects of neuromodulation with iTBS in DLPFC or vmPFC in combination with inhibitory control training to generate brain, behavioural, emotional, cognitive and biological changes in people with binge eating (BE).

1.1. Specific Aims: Objective 1: To study the differential effect of iTBS applied to the left DLPFC compared to vmPFC and sham iTBS (applied to vertex), in combination with inhibitory control training, for the treatment of people with binge eating (improvements in frequency and intensity of binge eating, craving, eating behavior, emotional symptoms and emotional eating, cognitive measures and biological parameters).

Objective 2: To characterize the effects of neuromodulation with iTBS of DLPFC or vmPFC, in combination with inhibitory control training to modify brain connectivity and activation both at rest and linked to task performance with food stimuli with functional magnetic resonance imaging (fMRI).

Objective 3: To determine the relationship of biological parameters obtained in blood, saliva, urine and faeces, as well as candidate genes, with neuropsychological variables (depression, anxiety, stress, emotional regulation, emotional eating, craving, motor and cognitive inhibition, food valuation, delay of gratification, impulsivity, working memory, flexibility and decision making) and brain neuroimaging (activation, grey and white matter volume, connectivity).

Objective 4: To analyze the economic evaluation of the cost-effectiveness and cost-utility of combined training (neuromodulation with iTBS and inhibitory control training) in people with BE, and to analyze the budgetary impact of the program if it was implemented in the public health system.

METHODOLOGY

2.1. Design: Randomized controlled trial of parallel groups.

2.2. Participants: Participants (N=150) will be randomly allocated to three groups: (i) group 1 (active stimulation of the DLPFC with iTBS and inhibitory control training) n=50; (ii) group 2 (active stimulation of the vmPFC with iTBS and inhibitory control training) n=50; group 3 (active control group of sham iTBS and inhibitory control training) n=50.

2.3. Interventions: Pre-treatment interventions (all groups). First, all participants will participate in a group briefing informational session about the study. Also, informative videos and brochures will be provided. In this session no nutritional and exercise recommendations will be given.

Intervention (experimental and active control groups). Duration: 2 weeks of 5 daily sessions of about 10-20 minutes. Sessions have two parts:

Part 1. Neuromodulation with iTBS (DLPFC or vmPFC or vertex) (3 minutes net time) Part 2. Inhibition training with the Food Trainer task (10 minutes net time)

2.4. Outcome measures: binge eating symptoms and food craving-stait will be the main outcome measures. Secondary outcomes will measure changes in neuroimaging measures (brain connectivity at rest, food go/no-go paradigm and food decision making tasks), changes in eating behavior, changes in emotional symptoms and emotional eating (depression, anxiety, stress, emotion regulation, emotional eating, reward-related eating, non homeostatic eating), biomarkers and cognitive measures. Exploratory variables will include sociodemographic information, previous treatments, motivation for change, and biological and clinical variables. Further, assessment will include screening and descriptive variables, and measures to calculate cost-effectiveness, cost-utility and budget impact of the intervention program.

1. PROCEDURE Assessments will be delivered online through LimeSurvey and Milliseconds platforms. Inclusion and exclusion criteria will be checked through the data collected in a questionnaire of sociodemographic and clinical variables. Further, psychopathology exclusion criteria will be tested with three questionnaires to measure depression, anxiety, and stress symptoms as well as severity of binge eating episodes (BDI, DASS-21 and QEWP-5), and a short clinical interview by phone and/or information requested by email in those cases where there are doubts about any of the aspects collected through the online instruments.

All candidates who meet the criteria will attend an information meeting about the project in which participants will receive written and oral information and will be asked for their informed consent. Then, participants will be randomly assigned to groups before the pre-treatment assessment sessions. A simple randomization will be performed by generating five-letter codes with Calculado.net and randomizing the codes into three different groups using Rafflys. The three groups of the study will complete all the three assessments (pr, post and 3-month follow-up). What will differentiate the groups will be, therefore, the stimulation area: active iTBS applied to the left DLPFC with inhibitory control training vs. active iTBS applied to the vmPFC with inhibitory control training vs. sham iTBS (applied to the vertex) with inhibitory control training. At the end of the project, if one treatment is more effective, the other two groups will be offered the complete treatment sessions.

Informative and assessment sessions will be developed in groups of 4-6 people through the platform GoogleMeet. iTBS sessions will be administered individually. If a participant misses a session, it will be rescheduled for the beginning of the next week at a similar time. There will be at least 10 experimental groups of DLPFC stimulation intervention combined with inhibitory control training (50 participants), 10 experimental groups of vmPFC stimulation intervention combined with inhibitory control training (50 participants), and 10 active control groups of sham stimulation (50 participants). The program will comprise 5 weeks including two assessments (pre- and post-treatment), ten intervention sessions (two weeks of 5 daily sessions), and one information session. Also, a follow-up will be conducted 3 months after treatment (see below). Assessment sessions will last about 2 hours while intervention sessions will be approximately 10 to 20 minutes. Sessions will consist of the following:

1. Informative session (session 1; week 1): For the participants to understand the foundation of the intervention, participantes will be informed about the aims, basis of the project and the procedure of the research. Participants will be provided written informed consent as well. At the end of this session, participants will be asked for their informed written consent.

2. Pre-treatment assessment (session 2 and 3; week 2): All participants will complete, in session 1, the following instruments to assess the main and secondary outcomes, and the exploratory and economic measures: WCST, Food Go/NoGo, IGT, Stroop, Food DD, N-Back, CFA, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36, SOCRATES 00, QEWP-5, sociodemographic questionnaire and questions about used health resources. Also, all participants will undergo the fMRI session (session 2) and biological sample collection (blood, saliva, feces and urine)

3. Intervention sessions (sessions 4 to 13; weeks 3 and 4): Intervention will consist of five weekly individual sessions for two weeks, with a 10-20 minutes total duration each. The stimulation parameters are based on the protocols for the application of iTBS in people with food intake problems, and following international safety recommendations.

   The procedure in the three groups consists of:

   i) Localization of the stimulation area by T1 sequence structural neuroimaging images using the Brainsight software for the correct placement of the stimulation coil: in the active stimulation groups it will be the left DLPFC area (x -37, y -34, z 78) corresponding to F3 position on the 10-20 EEG system or the vmPFC area (x -24, y 66, z 12) corresponding to FP1 position on the 10-20 EEG system. In the control group it will be the vertex (x 0, y-34, z 78), an area without cognitive effects after stimulation but matching the sensory effects. After that, neuromodulation with iTBS for 3 minutes with parameters of: frequency 50 Hz, number of pulses 3; number of bursts 10; cycle duration 8 seconds; number of cycles 20; burst frequency 5 Hz; and total number of pulses 600. The stimulation intensity will be maintained at 30% of the stimulator's maximum output.

   ii) Cognitive inhibitory control training (10 minutes): It will be performed with the Food T app, for 10 minutes and will be applied immediately after the iTBS, taking advantage of its time of maximum brain potentiation. In this application, the task consists of touching as quickly as possible the items that appear surrounded with a green circle, and not responding to the items surrounded by a red circle. Some images correspond to food and others are not related to food. Participants can select the categories of the images participants want to train, which should correspond to the foods used for binge eating (candy/gummies, cakes, chocolate, cookies, alcohol, chips, bread, cheese, fast food - burgers, take-out food -, sweet sodas, meat, pizza). Inhibitory control training consists of pairing high-calorie foods 100% of the time with the No-Go signal.

4. Post-treatment assessment (session 14 and 15, week 5): To evaluate the effectiveness of the interventions, BMI and craving (FCQ-T/S-r) will be registered (main outcomes), and the following instruments will be administered to obtain the secondary outcomes; WCST, Food Go/NoGo, IGT, Stroop, Food DD, N-Back, CFA, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36 and questions about used health resources. Also, fMRI and biological samples of the pre-treatment assessment will be repeated.

5. Follow-up (sessions 16; week 15): Follow-up at 3 months after the intervention will include the following measures: WCST, Food Go/NoGo, IGT, Stroop, Food DD, N-Back, CFA, DASS-21, BDI-II, PEMS, RED, DEBQ, PSRSQ, ERQ, UPPS-P, SF-36, and interview about used health resources sociodemographic questionnaire and questions about used health resources and collection of biological samples and anthropometric measures to obtain the main and secondary outcome measures. Every month after the end of the treatment, participants will be contacted by email and mobile message to maintain adherence.

Participants will be instructed to eat two hours before all evaluations (pre- and post-treatment, and the follow-up) and iTBS sessions. All the assessments will be carried out at the same hour.

Inclusion Criteria:

• BMI between 20 and 39.9
• Age between 18 and 60 years
• Two or more binge eating episodes in the past month (assessed with the Binge Eating Scale)
• Proficiency in the Spanish language
• Right lateral dominance to avoid differential effects due to cortical hemispheric specialization

Exclusion Criteria:

• Traumatic, digestive, metabolic or systemic disorders that affect the central nervous system, autonomic or endocrine
• Psychopathological disorders or presence of severe symptoms in the Depression Anxiety and Stress Scale-21 (DASS-21)
• Eeating disorders other than Binge Eating Disorder, or severe or extreme Binge Eating Disorder (8 or more binges per week)
• Contraindication for performing functional magnetic resonance imaging (pregnancy, metal implants, etc.) or iTBS (tinnitus, dizziness, surgical interventions, diseases or drugs that affect the central nervous system, etc.).

All of the individual participant data collected during the trial, after deidentification, will be shared.

Data will be available beginning 3 months and ending 5 years following article publication.

Investigators whose proposed use of the data has been approved by an independent review committee and who provide a methodologically sound proposal. Proposals should be directed to rvilar@ugr.es

The psychologists that conduct the assessments (screening, assessment sessions and follow-ups) will be blinded to the group allocation during the whole project. Further, all participants will be blind to their condition. Also, the people who perform the statistical analyses will be blind to the condition of the groups, through the coding of the interventions. Only the therapist performing the interventions will not be blind to the allocation of the participants.