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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
150
Participants will receive a 3 minutes intermittent Theta Burst Stimulation of the DLPCF of the left hemisphere while not performing any other task
Participants will receive a 3 minutes active intermittent Theta Burst Stimulation of the vmPFC while not performing any other task
Participants will receive a 3 minutes active intermittent Theta Burst Stimulation of the vertex while not performing any other task
Participants will perform the task of the FoodT app for 10 minutes immediately after iTBS (taking advantage of time of maximum brain potentiation, Rossi et al., 2009). This task pairs high-calorie meals with the no-go cue. Images appear on the left, right or center of the smartphone screen and they must touch it or not (depending on the cue) with their index finger as quickly as possible. Participants earn points for correct tap responses and lose points for incorrect tap responses: If the image has a green border around it, you must tap the image and win 1 point. But if the image has a red border around it, you must inhibit the tapping response or you will lose 1 point. Participants must respond as quickly and accurately as possible and improve reaction time. Pictures of healthy and unhealthy foods are always paired with the Go and the No-Go signal, respectively. Non-food images are paired 50% of the time with the Go and the No-Go signal
Mind, Brain and Behavior Research Center at University of Granada (CIMCYC-UGR)
Granada, Spain
RECRUITINGBinge eating symptoms
The Binge Eating Scale (BES) is a self-administered questionnaire composed of 16 items: eight items that describe behavioral manifestations (for example, eating fast or consuming large amounts of food) and eight items on associated feelings and cognitions (for example, fear of not stopping eating). Each item has a response range from 0 to 3 points (0 = no severity of the symptom, 3 = serious problems on the symptom)
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Food craving
The Food Craving Questionnaire Stait-reduced (FCQ-S-r) will be administered to obtain the total score, indicative of the craving state at the time of the evaluation.
Time frame: This will be measured in Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Changes in Food decision making (neuroimaging measures)
The task that will be used, consists of three phases: two rating phases and one decision phase with 50 food images. Participants have to answer on a 5-point Likert scale how healthy they consider the food to be (block 1) and how much they like the taste of the food (block 2). In the third block, the participant decides whether they prefer to eat a neutral reference food (calculated from the previous two blocks) or an alternative food. These forced choices lead to cognitive conflict when the reference food is considered tastier and the alternative food healthier or vice versa. Among trials with cognitive conflict, the choice of the healthier food is defined as a controlled choice, and the choice of the tastier food as an uncontrolled choice. Activation will be compared between the controlled vs. uncontrolled choice conditions. The task will be analysed to assess the brain activity associated with the task, using a psychophysiological interaction analyses (PPI).
Time frame: From baseline (week 2) to the end of the treatment (week 5)
Changes in Brain connectivity at rest (neuroimaging measures)
Participants will be instructed to remain still, with their eyes closed, trying not to think about anything in particular for 9 minutes to obtain images to study the resting connectivity of different brain networks. On the one hand, an independent component analyses (ICA) will be performed, which will allow comparison of the different brain networks, as a whole, between the groups, with special interest in those that have been shown to be altered in the PD population. On the other hand, seed-based connectivity analyses will be performed, in which changes in functional connectivity between the CPFDL and the rest of the brain will be observed.
Time frame: From baseline (week 2) to the end of the treatment (week 5)
Changes in White matter integrity (neuroimaging measures)
Participants will be asked to remain still for 10 minutes to obtain diffusion tensor imaging (DTI) which provides indirect measurements of the architecture and connectivity of white matter fibres. The study of the DTI images will be carried out with the FSL programme, which allows the integrity of the white matter of the different groups to be measured by evaluating the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) maps.
Time frame: From baseline (week 2) to the end of the treatment (week 5)
Changes in Food Go/No-go Paradigm (neuroimaging measures)
Activation during Go and No-go items will be calculated according to the type of images (high calorie and low-calorie foods).
Time frame: From baseline (week 2) to the end of the treatment (week 5)
Changes in eating behavior
Eating behavior: Diet information during the last year (pre-treatment), two last weeks (post-treatment) and tree last months (follow-up) will be collected through a validated food frequency questionnaire (CFA) with 52 items in which participants must record quantities of all the foods and drinks they had consumed during those periods. These data will be transformed into the number of total calories ingested, as well as the number of calories from fats, carbohydrates, and sugars.
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Anxiety and Stress. Mean change from baseline at post-intervention
The Depression Anxiety Stress Scale-21 (DASS-21) will be used, taking into account scores on the stress and anxiety subscales. The scores for both subscales range from 0 to 21, a higher score indicating higher anxiety or stress
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Depression symptoms. Mean change from baseline at post-intervention
Depression symptoms will be measured with the BDI-II.This scale is asses severity of depression. The scores range from 0 to 63 points. The higher the score, the greater the severity of depressive symptoms
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Non homeostatic eating. Mean change from baseline at post-intervention
Dutch Eating Behaviour Questionnaire (DEBQ): it will be administered to assess restrictive eating behaviours related to external cues and emotional states. Higher scores in each subscale reflect higher level of restrained, emotional, and external eating, respectively.The DEBQ uses a 5-point Likert scale, ranging from never (1) to very often (5). The average score is calculated for each subscale by adding scores obtained from individual items and dividing them by the number of items included in a subscale (mean range: 1-5).
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Reward-related eating. Mean change from baseline at post-intervention
Reward-related eating. Reward-Based Eating Scale (RED): it is a 13 items questionnaire that assess worries about foods, losing intake control and absence of satiety. Higher scores reflect higher reward-based eating drive.
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Emotional eating. Mean change from baseline at post-intervention
Emotional eating. Coping subscale of the Palatable Eating Motives Scale (PEMS): it will be used to evaluate the intentionality for eating palatable foods to face negative emotions. The coping subscale includes items that are scored on a 5-point Likert-type scale, the total range being from 5 to 25 points. Low scores indicate that the person rarely resorts to the consumption of pleasant foods as a strategy to cope with negative emotions or stressful situations. High scores suggest that the person frequently uses palatable food as a strategy to cope with stress or negative emotions, which may be related to unhealthy eating habits or emotional eating patterns.
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Emotion Regulation Strategies. Mean change from baseline at post-intervention
Emotion Questionnaire (ERQ): It examines emotional regulation strategies. It10 items to examine cognitive reappraisal and expressive suppression strategies. In cognitive reappraisal the highest score (42) is associated with better emotional outcomes while in expressive suppression the highest score (28) is linked to poorer well-being. Each item is rated on a Likert scale from strongly disagree (1) to strongly agree (7).
Time frame: From baseline (week 2) to the end of the treatment (week 5) and follow-up (week 17)
Motor inhibition. Mean change from baseline at post-intervention
Motor inhibition: FoodT app will register reaction time and commission errors. In the FoodT app reaction time for the high-calorie and low-calorie foods paired with the go and the no-go signal. The average response time for go and no-go items will be calculated according to the type of images (appetizing and healthy foods), and commission errors will be recorded.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Cognitive inhibition. Mean change from baseline at post-intervention
Cognitive inhibition: Food Stroop Task. Using a Stroop task with food, the interference of food-related words on task performance can be measured as an assessment of cognitive inhibition.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Delay of gratification. Mean change from baseline at post-intervention
Delay of gratification: Food Delay Discounting (Food DD). Score on the Food Delay Discounting will be used to measure the sensitivity to immediate rewards vs higher value rewards delayed. Participants' choices are recorded for each trial. Each trial varies in terms of the amount of reward and the amount of time to wait. To model the decisions, a hyperbolic discounting function is generally used.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Inhibition and activation systems. Mean change from baseline at post-intervention
This will be assessed using the Punishment Sensitivity and Reward Sensitivity Questionnaire (PSRSQ) of 48 items. Responses in the scale are in a yes/no format. Higher punishment sensitivity scores are associated with lower number of punishable errors while higher reward sensitivity scores are linked to higher number of passive avoidance errors.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Self-reported impulsivity. Mean change from baseline at post-intervention
Impulsive behaviour scale (UPPS-P). Self-reported impulsivity will be measured with Impulsive behaviour scale (UPPS-P). It consists of 20 items scored on a four point Likert scale, ranging from strongly agree (1) to strongly disagree (4). Higher scores mean worse outcome in impulsivity, while lower scores are related to better self-control and regulation
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Working Memory. Mean change from baseline at post-intervention
Working Memory: N-back Task will be assessed using N-back Task score based on accuracy and reaction times. Higher accuracy scores indicate stronger working memory and attention, while faster reaction times are linked to quicker processing speed and decision-making.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Cognitive flexibility. Mean change from baseline at post-intervention
The Wisconsin Card Sorting Test (WCST) requires sorting response cards with one of four stimulus cards, using feedback based on a rule. Wisconsin Card Sorting Test will be administered to measure shift strategy in response to changing contingencies. There are128 trials where more correct responses, fewer perseverative and non perseverative errors, and more completed categories (max 6) are related to better performance
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
Decision making. Mean change from baseline at post-intervention
Decision making: The Iowa Gambling Task (IGT) assess real-world decision-making in a lab settin using money rewards. Iowa Gambling Task will be used to assess decision-making using money rewards.
Time frame: Pre-treatment assessment (week 2), post-treatment assessment (week 5) and follow-up (week 17)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.